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PHARMACEUTICAL MANUFACTURING ENCYCLOPEDIA Third Edition Volume 1 A through B Volume 2 C through G Volume 3 H through P Volume 4 Q through Z Raw Materials Index Trade Names Index
Copyright © 2007 by William Andrew, Inc. No part of this book may be reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, or by any information storage and retrieval system, without permission in writing from the Publisher, with the exception of the following: Cover by Brent Beckley Library of Congress Cataloging-in-Publication Data Pharmaceutical manufacturing encyclopedia. -- 3rd ed. p. ; cm. Rev. ed. of: Pharmaceutical manufacturing encyclopedia / by Marshall Sittig. c1988. Includes bibliographical references and index. ISBN-13: 978-0-8155-1526-5 (set : alk. paper) ISBN-10: 0-8155-1526-X (set : alk paper) 1. Drugs--Synthesis--Dictionaries. 2. Pharmaceutical chemistry--Dictionaries. I. Sittig, Marshall. Pharmaceutical manufacturing encyclopedia. II. William Andrew Publishing. [DNLM: 1. Pharmaceutical Preparations--Encyclopedias--English. 2. Chemistry, Pharmaceutical--Encyclopedias--English. QV 13 P536 2007] RS402.5.S58 2007 615'.19--dc22 2006023472 Printed in India This book is printed on acid-free paper. 10 9 8 7 6 5 4 3 2 1 Published by: William Andrew Publishing 13 Eaton Avenue Norwich, NY 13815 1-800-932-7045 www.williamandrew.com Exclusively distributed in the Indian Subcontinent by Affiliated East-West Press Pvt. Ltd., G-1/16, Ansari Road, Darya Ganj, New Delhi 110 002 NOTICE To the best of our knowledge the information in this publication is accurate; however the Publisher does not assume any responsibility or liability for the accuracy or completeness of, or consequences arising from, such information. This book is intended for informational purposes only. Mention of trade names or commercial products does not constitute endorsement or recommendation for their use by the Publisher. Final determination of the suitability of any information or product for any use, and the manner of that use, is the sole responsibility of the user. Anyone intending to rely upon any recommendation of materials or procedures mentioned in this publication should be independently satisfied as to such suitability, and must meet all applicable safety and health standards.
Preface The Third Edition of Pharmaceutical Manufacturing Encyclopedia contains descriptions of manufacturing processes, structural formulas, trade names, therapeutic functions, and other information on 2266 pharmaceuticals now being marketed as trade-named products in America and many other countries. Information on 1295 pharmaceuticals has been taken from the Second Edition of the Pharmaceutical Manufacturing Encyclopedia (Marshall Sittig, Noyes Publications, Westwood, New Jersey, USA, 1986). Information on 971 additional pharmaceuticals, including those approved by the U.S. Food and Drug Administration (FDA) since 1986, are included in the Encyclopedia as well. The Encyclopedia comprises 4 volumes: Volume 1: A through B Volume 2: C through G Volume 3: H through P Volume 4: Q through Z, and the Raw Materials and Trade Names Indexes. The pharmaceuticals are listed in alphabetical order. INFORMATION SOURCES USED For the Second Edition, a variety of sources were used to identify the patents associated with particular commercial products and to serve as a source of process information. The sources included the following: Merck Index: followed by a citation of the entry number in the Tenth (1983) Edition.1
vi DFU: The periodical publication, Drugs of the Future,3 published by Prous Science. DOT: The periodical publication, Drugs of Today,4 published by Prous Science. Kleeman & Engel: The encyclopedic German work, Pharmazeutische Werkstoffe,5 second revised edition published in 1982. OCDS: The 3-volume reference series, The Organic Chemistry of Drug Synthesis.7 In addition, sources of pharmacological data and comparative information on trade names used in various countries were obtained from: REM: Remington's Pharmaceutical Sciences.9 Nonproprietary Name Index: The nonproprietary name index published by Paul de Haen.11 I.N.: The biannual Swiss publication, Index Nominum.12 PDR: The guide to commercially available U.S. drugs, the Physicians' Desk Reference.13
For the Third Edition, a number of new and updated sources were used, including the latest edition of The Merck Index.2 Extensive use has been made of the US, British, German, and world patent literature with regard to the process information. In addition, a variety of sources were used to identify the patents associated with particular commercial products and to serve as a source of process information. These include the encyclopedic German work Pharmazeutische Wirkstoffe (4th edition), edited by A. Kleeman and J. Engel,6 and the 6-volume reference series on the Organic Chemistry of Drug Synthesis by Daniel Lednicer8 and references [10] through [14] below.
vii In addition to the patent-derived process information, references to major pharmaceutical reference works where additional information can be obtained on synthesis methods and the pharmacology of the individual products are also cited under each drug entry. Pharmacological data and comparative information on trade names used in various countries were obtained from Organic-Chemical Drugs and Their Synonyms, 8th ed., by M. Negwer and H.-G. Scharnow. 15 July 2006 References 1. Windholz, M., editor, The Merck Index, 10th ed. Rahway, NJ: Merck & Co., Inc. (1983). 2. Smith, Ann, et al., The Merck Index: An Encyclopedia of Chemicals, Drugs, & Biologicals, 13th ed. Rahway, NJ: Merck & Co., Inc. (2001). 3. Prous, J.R., editor, Drugs of the Future, Vol. 30. Barcelona, Spain: Prous Science Publishers (2005) 4. Prous, J.R., editor. Drugs of Today, Vol. 41. Barcelona, Spain: Prous Science Publishers (2005) 5. Kleeman, A. and Engel, J., Pharmazeutische Werkstoffe: Synthesen, Patente, Anwendugen, Stuttgart, Germany: Georg Thieme Verlag, (1982). 6. Kleeman A., Engel J. Pharmazeutische Wirkstoffe. English: Pharmaceutical substances: syntheses, patents, applications, 4th ed. Stuttgart, Germany: Georg Thieme Verlag, (2001). 7. Lednicer, D., and Mitscher, L., The Organic Chemistry of Drug Synthesis, New York: John Wiley and Sons. Vol. 1 (1977); Vol. 2 (1980); Vol. 3 (1984); Vol. 4 (1990). 8. Lednicer, D., The Organic Chemistry of Drug Synthesis, New York: John Wiley and Sons. Vol. 4 (1990); Vol. 5 (1994); Vol. 6 (1998).
viii 9. Philadelphia College of Pharmacy and Science, Remington's Pharmaceutical Sciences, 17th ed. Easton, PA: Mack Publishing Co. (1985). 10. Alfonso R. Gennaro, editor. Remington: The Science and Practice of Pharmacy (Remington's Pharmaceutical Sciences), 20th ed. New York: Lippincott Williams & Wilkins (2000). 11. Paul de Haen International, Inc., Nonproprietary Name Index, 15th ed. Englewood, CO: Paul de Haen International, Inc. (1984). 12. H.P. Jasperson et al., editors. Index Nominum, Zurich, Switzerland: Swiss Pharmaceutical Society (1984). 13. Barnhart, E.R., editor, Physicians' Desk Reference, 40th ed. Oradell, NJ: Medical Economics Co., Inc. (1986). 14. Physicians Desk Reference, 55th ed. Oradell, NJ: Medical Economics Co., Inc. (2001). 15. Negwer, M., and Scharnow, H.-G., Organic-Chemical Drugs and Their Synonyms, 8th ed. New York: John Wiley and Sons (2001).
A
ABACAVIR SULFATE Therapeutic Function: Antiviral Chemical Name: 2-Cyclopentene-1-methanol, 4-(2-amino-6(cyclopropylamino-9H-purin-9-yl), sulfate (salt) (2:1), (1S,4R), sulfate Common Name: Abacavir sulfate Structural Formula:
Chemical Abstracts Registry No.: 188062-50-2; 136470-78-5 (Base) Trade Name Ziagen
Manufacturer GlaxoSmithKline
Country -
Year Introduced -
Ziagen
Glaxo Wellcome
-
-
Ziagenavir
Glaxo Wellcome
-
-
Raw Materials 2,5-Diamino-4,6-dihydroxypyrimidine (Chloromethylene)dimethylammonium chloride (1S,4R)-4-Amino-2-cyclopentene-1-methanol Triethylamine Tartaric acid, dibenzoate, (-)Orthoformate or diethoxymethyl acetate Cyclopropylamine
1
2
Abafungin
Manufacturing Process Treatment of 2,5-diamino-4,6-dihydroxypyrimidine (I) with (chloromethylene)dimethylammonium chloride yielded the dichloropyrimidine with both amino groups derivatized as amidines. Partial hydrolysis with aqueous HCl in hot ethanol gave N-(2-amino-4,6-dichloro-pyrimidin-5-yl)-N,Ndimethylformamidene (II). Subseqent buffered hydrolysis at pH 3.2 yielded the (2-amino-4,6-dichloro-pyrimididin-5-ylamino)acetaldehyde (III). Condensation chloropyrimidine (III) with (1S,4R)-4-amino-2-cyclopentene-1methanol (IV) in the presence of triethylamine and NaOH gave [2-amino-4chloro-6-(4-hydroxymethyl-cyclopent-2-enylamino)pyrimidin-5-ylamino]acetaldehyde (V). The correct enantiomer (IV) of racemic aminocyclopentene was obtained by resolution of diastereomeric salts with D-dibenzoyltartaric acid. Cyclization of (V) to the corresponding purine was accomplished with refluxing triethyl orthoformate or diethoxymethyl acetate to give nucleoside analogue [4-(2-amino-6-chloro-purin-9-yl)-cyclopent-2-enyl]methanol (VI). Displacement of chloride in the purine nucleus with cyclopropyl amine in refluxing butanol afforded abacavir. The structure of obtained compound was confirmed by 1H NMR method and elemental analysis. In practice it is usually used as sulfate salt. References Huff J.R.; Bioorg. Med. Chem., 7, (1999), 2667-2669 Daluga S.M.; European Patent No. 0,434,450; Dec. 12, 1990
ABAFUNGIN Therapeutic Function: Antibacterial, Antifungal Chemical Name: N-{4-[2-(2,4-Dimethylphenoxy)phenyl]thiazol-2-yl}1,4,5,6-tetrahydro-pyrimidinamine Common Name: Abafungin; BAY w 6341 Structural Formula:
Chemical Abstracts Registry No.: 129639-79-8 Trade Name
Manufacturer
Country
Year Introduced
Abafungin
York Pharma
-
-
Abamectin
3
Raw Materials N-(1,4,5,6-Tetrahydropyrimidinyl)thiourea 2-(2,4-Dimethylphenoxy)phenacyl chloride Manufacturing Process 15.8 g (0.12 mole) N-(1,4,5,6-tetrahydropyrimidinyl)thiourea were added to 27.45 g (0.1 mole) 2-(2,4-dimethylphenoxy)phenacyl chloride in 100 ml acetone and heated to reflux for 2 hours. On cooling the falling out product was filtered off, washed with acetone and dried. N-[4-[2-(2,4Dimethylphenoxy)phenyl]-2-thiazolyl]-1,4,5,6-tetrahydro-2-pyrimidinamine hydrochloride was prepared. Yield 91.4%; MP: 160°C. 20.72 g (0.05 mole) above product was stirred with 300 ml 1 N sodium hydroxide for 30 minutes at room temperature. The insoluble product was filtered off, washed and dried. Yield of N-[4-[2-(2,4-dimethylphenoxy)phenyl]2-thiazolyl]-1,4,5,6-tetrahydro-2-pyrimidinamine was 16.2 g (86%). MP: 191°-192°C. References Ippen. Joachim et al.; D.B. Patent No. 3,836,161 A1; Nov. 24, 1988; Bayer AG, 5090 Leverkusen, DE
ABAMECTIN Therapeutic Function: Antiparasitic Chemical Name: Avermectin B1 Common Name: Abamectin; MK-936, Zectin Chemical Abstracts Registry No.: 71751-41-2; 65195-55-3 Trade Name
Manufacturer
Country
Year Introduced
Abamectin
-
-
Kraft TM
Yellow River Enterprise Co. (a.k.a Yelori) Cheminova
-
-
Abamectin 1.8%
LIFES Labo
-
-
Abamectin
Ningbo Sega Chemical Company Institutul Pasteur Romania Merial
-
-
-
-
-
-
Merck Sharp and Dohme Ltd
-
-
Avomec Duotin Enzec
4
Abamectin
Structural Formula:
Raw Materials Streptomyces avermitilis MA-4680 Nutrient medium Manufacturing Process 1. The contents of a lyophilized tube of Streptomyces avermitilis MA-4680 is transferred aseptically to a 250 ml Erlenmeyer flask containing 305 ml of Medium 1: Dextrose 20 g, Peptone 5 g, Meat Extract 5 g, Primary Yeast 3 g, NaCl 5 g, CaCO3 (after pH adjustment) 3 g, Distilled water 1000 ml, pH 7.0. The inoculated flask is incubated for 3 days at 28°C on a rotary shaking machine at a speed of 220 RPM in a 2 inch radius circular orbit. At the end of this time, a 250 ml Erlenmeyer flask containing 50 ml of Medium 2 [Tomato Paste 20 g, Modified Starch (CPC) 20 g, Primary Yeast 10 g, CoCl2·6H2O 0.005 g, Distilled water 1000 ml, pH 7.2-7.4] is inoculated with a 2 ml sample from the first flask. This flask is incubated for 3 days at 28°C on a rotary shaking machine at a speed of 220 RPM in a 2 inch diameter circular orbit. 50 Ml of the resulting fermentation broth containing C-076 is effective against an N.dubius infection in mice.
Abamectin
5
2. A lyophilized tube of Streptomyces avermitilis MA-4680 is opened aseptically and the contents suspended in 50 ml of Medium 1 in a 250 ml Erlenmeyer flask. This flask is shaken for 3 days at 28°C on a rotary shaking machine 220 RPM with a 2 inch diameter circular orbit. A 0.2 ml portion of this seed medium is used to inoculate a Slant of Medium 3: Dextrose 10.0 g , Bacto Asparagine 0.5 g, K2HPO4 40.5 g, Bacto Agar 15.0 g , Distilled water 1000 ml, pH 7.0. The inoculated slant medium is incubated at 28°C for 10 days and stored at 4°C until used to inoculate 4 more slants of Medium 3. These slants are incubated in the dark for 8 days. One of these slants is used to inoculate 3 baffled 250 ml Erlenmeyer flasks containing 50 ml of No. 4 Seed Medium: Soluble Starch 10.0 g, Ardamine 5.0 g, NZ Amine E 5.0 g, Beef Extract 3.0 g, MgSO4·7H2O 0.5 g, Cerelose 1.0 g, Na2HPO4 0.190 g, KH2PO4 182 g, CaCO3 0.5 g, Distilled water 1000 ml, pH 7.0-7.2. The seed flasks are shaken for 2 days at 27-28°C on a rotary shaking machine at 220 RPM with a 2 inch diameter circular orbit. The contents of these flasks are pooled and used to inoculate (5% inoculum) baffled 250 ml Erlenmeyer flasks containing 40 ml of various production media. Flasks containing media 2, 5 and 6 are incubated for 4 days at 28°C on a rotary shaking machine at 220 RPM with a 2 inch diameter circular orbit. The resulting broth containing C-076 is then harvested and tested for anthelmintic activity. In all cases 6.2 ml of whole broth and the solids obtained from centrifuging 25 ml of whole broth are fully active against N.dubius helminth infections in mice. 3. The one of the four slants of Medium 3 prepared as in Example 2 is used to inoculate a baffled 250 ml Erlenmeyer flask containing 50 ml of Seed Medium No. 4. The seed flask is shaken for 1 day at 27- 28°C on a rotary shaking machine at 220 RPM with a 2 inch diameter circular orbit. The seed flask is then stored stationary at 4°C until it is ready to be used. The contents of this flask are then used to inoculate (5% inoculum) 20 unbaffled 250 ml Erlenmeyer flasks containing 40 ml of Medium No. 2. After 4 days incubation at 28°C on a rotary shaking machine at 220 RPM with a 2 inch diameter circular orbit, 19 of the flasks are harvested and pooled. The combined fermentation broths containing C-076 are filtered affording 500 ml of filtrate and 84 g of mycelia. 78 G of mycelia are extracted with 150 ml of acetone for ½ hour with stirring and the mixture filtered. The filter cake is washed with 50 ml of acetone and the filtrate and washings are combined and concentrated to 46.5 ml 30 Ml of the concentrate is adjusted to pH 4 with dilute hydrochloric acid and extracted 3 times with 30 ml portions of chloroform. The extracts are dried by filtering through dry Infusorial Earth (Super-Cel) combined and concentrated to dryness in vacuum. The oily residue of C-076 weighing 91.4 mg is dissolved in chloroform sufficient to make 3 ml of solution which represents 1% of broth volume. The C-076 (Abamectin) obtained in this recovery procedure is fully active against N.dubius infections in mice. In addition, the chloroform extraction achieved a 70 fold purification of C-076 from the whole broth. References Albers-Schonberg G., Wallick H., Ormond R.E., Miller Thomas W., Burg Richard W.; US Patent No. 4,310,519; Jan. 12, 1982; Assigned to Merck and Co., Inc. (Rahway, NJ)
6
Abanoquil mesylate
ABANOQUIL MESYLATE Therapeutic Function: Antiarrhythmic, Coronary vasodilator Chemical Name: 4-Amino, 2-(3,4-dihydro-6,7-dimethoxy-2(1H)-isoquinolyl)6,7dimethoxyquinoline monomethanesulfonate Common Name: Abanoquil mesylate Structural Formula:
Chemical Abstracts Registry No.: 118931-00-3; 90402-40-7 (Base) Trade Name Abanquil
Manufacturer Onbio Inc.
Country -
Year Introduced -
Raw Materials 6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline Acetic anhydride Phosphorus(V) oxychloride 2-Amino-4,5-dimethoxybenzonitrile Sodium hydroxide Zinc chloride Fumaric acid Manufacturing Process Synthesis of 1-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)ethanone: To a stirred solution of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (3.00 g, 15.4 mmol, 1.00 equiv.) in anhydrous pyridine (100 mL) under argon at room temperature was added acetic anhydride (14.5 mL, 154 mmol, 10.0 equiv.) over 15 min. The resulting mixture was stirred at room temperature for 2 h, and then at reflux for 6 h. The volatiles were removed by rotary evaporation at 80°C under high vacuum. The residue was flash chromatographed on silica gel (MeOH-CH2Cl2 8:92) to afford 3.21 g (89%) of 1-(6,7-dimethoxy-3,4dihydro-1H-isoquinolin-2-yl)ethanone as a viscous brown oil. The H-NMR spectrum reflected the presence of two slowly interconverting conformers in a ratio of 1.2:1 at room temperature. Synthesis of 2-[1-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2yl)ethylidineamino]-4,5-dimethoxybenzonitrile:
Abarelix
7
To a stirred solution of 1-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2yl)ethanone (1.00 g, 4.25 mmol, 1.00 equiv.) in CHCl3 at room temperature under argon was added POCl3 (143 µL, 1.53 mmol, 0.36 equiv.). After 10 min, 2-amino-4,5-dimethoxybenzonitrile (763 mg, 4.28 mmol, 1.01 equiv.) was added and the mixture was heated at reflux overnight. The mixture was cooled to room temperature and poured into 1 M aq. NaOH solution (50 mL), and the aqueous phase was extracted with CH2Cl2. The combined organic solutions were dried over MgSO4 and concentrated. The residue was flash chromatographed on silica gel (MeOH-CH2Cl2, 2 5:95) to afford 482 mg (28%) of 2-[1-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)ethylidineamino]-4,5dimethoxybenzonitrile as an yellow solid. Synthesis of 2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-6,7dimethoxyquinolin-4-ylamine hemifumarate hydrate (abanoquil): To a stirred solution of 2-[1-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2yl)ethylidineamino]-4,5-dimethoxybenzonitrile (471 mg, 1.19 mmol, 1.00 equiv.) in refluxing anhydrous N,N-dimethylacetamide (24 mL) under argon was added ZnCl2 (339 mg, 2.49 mmol, 2.10 equiv.) in three portions over 1 h. The solvent was removed by distillation at 70°C under high vacuum. Ether (40 mL) was added to the residue, which was broken up with a stirring rod, and the mixture was stirred at 0°C to precipitate the product. The supernatant was discarded, and the precipitate was washed twice more at 0°C with ether. The solid residue was stirred with 1 M aq. NaOH (25 mL) and CH2Cl2 (25 mL) for 10 min, and the aqueous phase was extracted with CH2Cl2. The combined organic solutions were dried over MgSO4 and concentrated to give 493 mg of brown oil, which was flash chromatographed on silica gel (MeOH-CH2Cl2,12:88 followed by 2-propylamine-CH2Cl2, 5:95) to afford 151 mg (38%) of 2-(6,7dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-6,7-dimethoxyquinolin-4-ylamine as a tan solid. To a solution of 2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-6,7dimethoxyquinolin-4-ylamine (150 mg) in hot CH2Cl2 (4.5 mL) and MeOH (1.5 mL) was added a solution of fumaric acid (22.8 mg, 0.196 mmol, 0.50 equiv.) in hot MeOH (3.0 mL). The resulting mixture was concentrated and the product was recrystallized from MeOH with hot filtration to afford, after filtration, 85 mg of light brown solid: m.p. 239-240°C. In practice it is usually used as mesylate. References Craig D.A., Forrey C.C., Gluchovski Ch., Branchek T.A.; US Patent No. 5,610,174; March 11, 1997; Assigned to Synaptic Pharmaceutical Corporation (Paramus, NJ)
ABARELIX Therapeutic Function: LHRH antagonist
8
Abarelix
Chemical Name: D-Alaninamide, N-acetyl-3-(2-naphthalenyl)-D-alanyl-4chloro-D-phenylalanyl-3-(3-pyridinyl)-D-alanyl-L-seryl-N-methyl-Ltyrosyl-D-asparaginyl-L-leucyl-N6-(1-methylethyl)-L-lysyl-L-prolylCommon Name: Abarelix; PPI-149 Structural Formula:
Chemical Abstracts Registry No.: 183552-38-7 Trade Name
Manufacturer
Country
Year Introduced
Plenaxis
Praecis Pharmaceuticals
-
-
Raw Materials Thioanisole Trifluoroacetic acid 1-Hydroxybenzotriazole Dicyclohexylcarbodiimide 2-Iodopropane
Methylbenzyhydramine resin Diisopropylethylamine Boc-protected amino acids Silver(I) oxide m-Chloroperbenzoic acid Boc-D-Pal (Boc-D- 3-(3'-pyridyl)alanine)
Manufacturing Process Abbreviation Residue or moiety: Nal - 3-(2-naphthyl)alaninyl 4-Cl-Phe - (4'-chlorophenyl)alaninyl Pal - 3-(3'-pyridyl)alaninyl Pal(N-O) - 3-(3'-pyridine-N-oxide)alaninyl Pal(iPr) - 3-N-(2-propyl)-3'-pyridinium)alaninyl BOC - N-t-butyoxycarbonyl
Abarelix
9
DCC - dicyclohexylcarbodiimide Abarelix was synthesized by the solid phase method using an automated synthesizer (e.g. Beckman Model 990). The amino acid residues used can be purchased from commercial sources (e.g. Aldrich Chemical Co., Milwaukee, Wis.), or can be produced from commercially available starting materials according to known methods. Amino acids which are not obtained commercially can be synthesized in a protected form for coupling, or, if appropriate, can be coupled to form a peptide and subsequently modified to the desired form. For example, Boc-D-Pal(iPr) was prepared next way: Boc-D-Pal (4.0 g, 17.7 mmol) and Ag2O (8.0 g, 34.4 mmol) in 22 ml water was stirred at room temperature for 4 hours. The reaction vessel was cooled to 0°C, and 2-iodopropane (20.4 g, 120 mmol) in 40 ml 2-propanol was added. After addition was complete, the mixture was allowed to warm to room temperature and stirred for 4 days. Additional Ag2O (2 g) and 2-iodopropane (2 g) were added after 24 hours and again after 48 hours. The mixture was filtered, and the precipitate was washed with ethanol (2x15 ml). The filtrate was evaporated to yield 4.3 g of a yellow oil. Crystallization from ethanol/ethyl acetate gave light yellow crystals (3.0 g); Yield: 63%; m.p. 182°-185°C. Synthesis of Boc-D-Pal(N-O): Boc-D-Pal (2.0 g, 7.5 mmole) was dissolved in 40 ml acetone and 2.48 g (16.5 mmol) of m-chloroperbenzoic acid (MCPBA) (57-86%; purchased from Aldrich and used as received) in 80 ml acetone was added in one portion. The mixture was stirred at room temperature for 40 hours; a small amount of white precipitate formed as the reaction proceeded. The precipitated was filtered and the mother liquor evaporated to yield a white precipitate. The combined solids were washed with ether (to remove chlorobenzoic acid) and recrystallized from ethyl acetate/hexane. Yield: 1.7 g (80%); m.p. 155°157°C. A typical coupling cycle for peptide synthesis with Boc-amino acids on a peptide synthesizer (Beckman Model 990) was as follows: Methylbenzyhydramine (MBHA) resin (1.18 g, 0.85 meq amino groups/g resin) was weighed into the reaction vessel and washed with two portions of chloroform (26 ml each). The resin was prewashed with 22% thioanisole (5 ml)/66% trifluoroacetic acid (TFA) in 14 ml dichloromethane (DCM) for 5 minutes, and then deprotected for 30 minutes with the same thioanisole/TFA mixture. The resin was washed with three portions of chloroform (20 ml each), two portions of 2-propanol (26 ml each) and two portions of DCM (26 ml each). The resin was neutralized with two portions of 12% diisopropylethylamine (DIPEA) (26 ml each), and then washed with four portions of DCM (26 ml each), followed by two portions of 1:1 DCM:dimethylformamide (DMF) (26 ml each). A solution of a Boc-protected amino acid (2.5 mole equivalents) and 1-hydroxybenzotriazole (HOBt) (2.5 mole equivalents) was introduced as a solution in 10 ml DMF, and DCC was added (256 mg in 6 DMF). Coupling was allowed to proceed for three hours,
10
Abecarnil
or overnight. Hindered residues (e.g. backbone N-methyl amino acids) required longer coupling times. The resin was washed with two 26 ml portions of DMF, followed by two 26 ml portions of 2-propanol and then two 26 ml portions of DCM. Completion of coupling was assessed by Kaiser's test (ninhydrin test). If coupling is not complete, a double coupling was performed (i.e. the resin was neutralized as above and the coupling step repeated). When complete coupling is achieved, the cycle was repeated with the next amino acid. Upon completion of the synthesis, the peptide was cleaved from the resin by treatment with liquid hydrofluoric acid (HF) for 45 minutes at 0°C. The HF was evaporated and the peptide treated with aqueous acetic acid and lyophilized. The crude peptide was then purified by high performance liquid chromatography (HPLC) on a C18 column, eluting with a mixture of acetonitrile and 0.1% TFA in water. Purified fractions (homogeneous by UV and TLC analysis) were combined and lyophilized. Analytical HPLC was used to determine the purity of the final product; peptides synthesized was at least 98% pure. References Folkers K. et al.; 1986; "Increased Potency of Antagonists of the Luteinizing Hormone Releasing Hormone Which Have D-3 Pal in Position 6"; Biochem. Biophys. Res. Comm.; 137(2):709-715 Tian, Z.P. et al.; 1994; "Design and synthesis of highly water soluble LHRH antagonists"; Pept.: Chem., Struct. Biol., Proc. Am. Pept. Symp.; 13th; 562-564 Roeske R. W.; US Patent No. 5,843,901; Dec. 1, 1998; Assigned to Advanced Research and Technology Institute, Bloomington, Ind.
ABECARNIL Therapeutic Function: Anticonvulsant, Anxiolytic Chemical Name: 9H-Pyrido[3,4-b]indole-3-carboxylic acid, 4(methoxymethyl)-6-(phenylmethoxy)-, 1-methylethyl ester Common Name: Abecarnil; SH 524 Structural Formula:
Chemical Abstracts Registry No.: 111841-85-1
Abecarnil Trade Name Abecarnil
Manufacture Schepa
Country -
11
Year Introduced -
Raw Materials Potassium carbonate Anisaldehyde Sodium hydroxide Hydrochloric acid Triethylamine
Hydrochloric acid Glycine isopropyl ester Paraformaldehyde tert-Butyl hypochlorite 5-Benzyloxy-3-(1-isopropylamino-2methoxyethyl)indole
Manufacturing Process Under nitrogen, 6 g (43.5 millimoles) of finely pulverized potassium carbonate is stirred for 10 min at 95°C in 25 ml of absolute dimethylformamide. Then, while the mixture is hot, 10 g (29.6 mmol) of 5-benzyloxy-3-(1isopropylamino-2-methoxyethyl)indole is added and the mixture is stirred approximately 10 min at 95°C until the compound has been dissolved. Thereupon, likewise at 95°C, a solution of 34.5 mmol of glycinimine (prepared from anisaldehyde and glycine isopropyl ester) in 25 ml of dimethylformamide is added dropwise in a time period of 30 min. The solution is agitated until the starting indole can no longer be detected in a thin-layer chromatogram. After cooling, the product is filtered off by suction from potassium carbonate and rinsed with toluene. After adding 100 ml of toluene, 200 ml of 1 N hydrochloric acid is added and the mixture stirred for 3 hours at room temperature. The toluene phase is separated, and the aqueous acidic phase is extracted by shaking with 100 ml of toluene. The organic phase is discarded. The acidic phase is cooled to 5°C, combined with 100 ml of toluene, and adjusted to pH 10-12 with 4 N sodium hydroxide solution. After extraction by shaking, the mixture is again extracted by shaking with 100 ml of toluene, and the combined organic phase is washed with 50 ml of water, dried, filtered, and concentrated, thus obtaining 70% 2-amino-3-(5-benzyloxyindol-3-yl)-4methoxybutyric acid isopropyl ester as an oil. A solution is prepared from 3.8 g of 2-amino-3-(5-benzyloxyindol-3-yl)-4methoxybutyric acid isopropyl ester (10 mmol) in 80 ml of xylene and added dropwise to a suspension of 360 mg of paraformaldehyde in 60 ml of xylene heated for 45 min to 100°C. The mixture is then refluxed for 2 hours on a water trap. After concentration, the residue is chromatographed over silica gel with methylene chloride:acetone=1:1 as the eluent, yielding 2.5 g of 6benzyloxy-4-methoxymethyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid isopropyl ester (65% yield as an oil); or a suspension of 2.56 g of paraformaldehyde in 8 ml of water and 0.8 ml of concentrated hydrochloric acid is refluxed at 80°C for 1 hour. One-tenth of the thus-obtained clear solution is added dropwise, after cooling to room temperature, to a solution of 3.8 g (10 mmol) of 2-amino-3-(5-benzyloxyindol-3-yl)-4-methoxybutyric acid isopropyl ester in 500 ml of water and 10 ml of concentrated hydrochloric acid (pH=3). After ½ hour of agitation, an estimate of the amount of amino compound still remaining is made by thin-layer chromatography, and a corresponding quantity of formaldehyde solution is added. Thereupon, the mixture is stirred for another hour and then extracted twice by shaking with 50 ml of toluene, respectively. The organic phase is discarded. The aqueous phase is adjusted, after adding 100 ml of toluene, to a pH of 5.3 with 27%
12
Abiraterone
strength sodium hydroxide solution. After extraction by shaking, the mixture is additionally extracted by shaking twice with 50 ml of toluene; these 3 organic phases are combined, dried over sodium sulfate, filtered, and concentrated, thus obtaining 3.3 g (85%) of 6-benzyloxy-4-methoxymethyl1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid isopropyl ester as an oil. A solution is prepared from 3.3 g (8.5 mmol) of 6-benzyloxy-4methoxymethyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid isopropyl ester in 150 ml of methylene chloride, combined under argon with 3.9 ml of triethylamine, and cooled to -15°C. At this temperature, a solution of 3.2 ml (25.6 mmol) of t-butyl hypochlorite in 50 ml of methylene chloride is added dropwise without delay to this solution. After the adding step is completed, the mixture is stirred for another 10 min, combined with 2.6 ml of triethylamine, and agitated for 2 hours at room temperature. Subsequently, the mixture is concentrated to one-half thereof and extracted once by shaking with dilute ammonia solution. The organic phase is dried, filtered, and concentrated. The residue is chromatographed over silica gel with methylene chloride:acetone=4:1 as the eluent. Recrystallization from ethyl acetate gives 1.1 g (35% yield) of 6-benzyloxy-4-methoxymethyl-β-carboline-3-carboxylic acid isopropyl ester, m.p. 150-151°C. References Biere H., Huth A., Rahtz D. et al.; US Patent No. 5,414,002; May 9, 1995; Assigned to Schering Aktiengesellschaft, Berlin and Bergkamen, Germany
ABIRATERONE Therapeutic Function: Antiandrogen Chemical Name: Androsta-5,16-dien-3-ol, 17-(3-pyridinyl)-, (3β)Common Name: Abiraterone; CB 7598; Piraterone Structural Formula:
Chemical Abstracts Registry No.: 154229-19-3 Trade Name
Manufacturer
Country
Year Introduced
Abiraterone
Cougar
-
-
Ablukast sodium
13
Raw Materials Diethyl(3-pyridyl)borane 3β-Acetoxyandrosta-5,16-dien-17-yl trifluoromethanesulphonate Bis(triphenylphosphine)palladium(II) chloride Sodium carbonate Sodium hydroxide Hydrochloric acid Manufacturing Proces Diethyl(3-pyridyl)borane (3.38 g, 23 mmol) from Aldrich Chemical Co. Ltd. was added to a stirred solution of 3β-acetoxyandrosta-5,16-dien-17-yl trifluoromethanesulphonate (6.94 g, 15 mmol) in THF (75 ml) containing bis(triphenylphosphine)palladium(II) chloride (0.105 g, 0.15 mmol). An aqueous solution of sodium carbonate (2 M, 30 ml) was then added and the mixture heated, with stirring, by an oil bath at 80°C for 1 h, and allowed to cool. The mixture was partitioned between diethyl ether and water, the ether phase was dried (Na2CO3), filtered through a short plug of silica, and concentrated. Chromatography, on elution with light petroleum-diethyl ether (2:1), afforded the 3β-acetoxy-17-(3-pyridyl)androsta-5,16-diene (4.95 g, 84%) which crystallised from hexane, m.p. 144-145°C. To a solution of 3β-acetoxy-17-(3-pyridyl)androsta-5,16-diene (4.90 g, 12.5 mmol) in methanol (50 ml) was added an aqueous solution of sodium hydroxide (10% w/v, 10 ml) and the mixture heated, with stirring, on an oil bath at 80°C for 5 min, then allowed to cool. The mixture was poured into water, neutralised with hydrochloric acid (1 M), rebasified with saturated sodium bicarbonate solution, and extracted with hot toluene. The toluene extracts were combined, dried (Na2CO3), and concentrated. Chromatography, on elution with toluene-diethyl ether (2:1) afforded the 17-(3pyridyl)androsta-5,16-dien-3β-ol (3.45 g, 79%) which crystallised from toluene, m.p. 228-229°C. References Barrie S.E., Jarman M., Potter G.A., Hardcastle Ian R.; US Patent No. 5,604,213; Feb. 18, 1997; Assigned to British Technology Group Limited (London, GB2)
ABLUKAST SODIUM Therapeutic Function: Antiallergic, Anti-asthmatic Chemical Name: 2H-1-Benzopyran-2-carboxylic acid, 6-acetyl-7-[[5-(4acetyl-3-hydroxy-2-propylphenoxy)pentyl]oxy]-3,4-dihydro-, sodium salt Common Name: Ablukast sodium
14
Ablukast sodium
Structural Formula:
Chemical Abstracts Registry No.: 96565-55-8; 96566-25-5 (Base) Trade Name
Manufacturer
Country
Year Introduced
Ulpax
Roche
-
-
Raw Materials Diethyl oxalate Sodium ethylate Palladium on charcoal 4-Toluenesulfonic acid 5-Bromo-1-pentanyl acetate Acetic acid Methanesulfonyl chloride Sodium hydroxide
2',4'-Dihydroxyacetophenone Hydrochloric acid Hydrogen Boron trifluoride diethyl etherate Tetrabutylammonium hydroxide Triethylamine Tris(3,6-dioxahepyl)amine
Manufacturing Process A solution of 109.8 g (0.75 mol) of diethyl oxalate and 65 g (0.427 mol) of 2',4'-dihydroxyacetophenone in 100 mL of EtOH was added slowly under Ar, with cooling, to a stirred solution of NaOEt (from 40 g of Na and 550 mL of EtOH). The mixture was stirred at 50°C for 3 h, cooled to room temperature, and poured into a separatory funnel containing 500 mL of 2 N HCl. It was extracted with CH2CH2 washed with 500 mL of saturated NaHCO3, dried and evaporated to give a red oil, which was dissolved in 250 mL of EtOH and 10 mL of conc. HCl. The mixture was boiled under reflux for 1 h, cooled to ca. 10°C and the product was collected by filtration. It was washed with some EtOH followed by hexane to give 86.0 g (86% yield) of ethyl 7-hydroxy-4-oxo4H-1-benzopyran-2-carboxylate: m.p. 218-223°C. Crystallization of a portion from hot AcOH gave an analytical sample: m.p. 221-223°C. A solution of 80 g (0.34 mol) of ethyl 7-hydroxy-4-oxo-4H-1-benzopyran-2carboxylate in 60 mL of AcOH and 275 mL of THF was hydrogenated over 4.0 g of 10% Pd on charcoal at 45°C and 65 psi. After hydrogen absorption ceased, the catalyst was removed by filtration and the solvents were evaporated under reduced pressure. Crystallization from CCl4 gave 65 g (85%) of ethyl (R,S)-3,4-dihydro-7-hydroxy-2H-1-benzopyran-2-carboxylate: m.p. 80-82°C. A stirred mixture of 65 g (0.293 mol) of ethyl (R,S)-3,4-dihydro-7-hydroxy2H-1-benzopyran-2-carboxylate in 650 mL of AcOH, 1.5 mL of acetic anhydride, and 65 mL of BF3·OEt2 was heated at reflux for 18 h and evaporated. To the residue was added 700 mL of water, and the mixture was stirred at room temperature for 1.0 h. The product was collected by filtration
Ablukast sodium
15
and washed with hexane. It was then dissolved in 900 mL of MeOH, treated with 6.6 g of p-toluenesulfonic acid, boiled under reflux for 18 h, and cooled to 0°C. The product was collected by filtration to give 52 g (70% yield) of ethyl (R,S)-3,4-dihydro-7-hydroxy-2H-1-benzopyran-2-carboxylate: m.p. 140142°C. A 1 L, 3-necked, round-bottomed flask equipped with a mechanical stirrer and an Ar bubbler was charged with 37.5 g (0.179 moles) of 5-bromo-1-pentanyl acetate, 350 mL of anhyd. DMSO, 40.7 g (0.163 mol) of ethyl (R,S)-3,4dihydro-7-hydroxy-2H-1-benzopyran-2-carboxylate, and 51.0 g (0.369 mol) of powdered potassium carbonate. The mixture was stirred at room temperature for 18 h, poured into 1.0 L of water and extracted into EtOAc (2*1 L). The extract was washed with 1 L of brine, dried and evaporated. The residue was dissolved in 200 mL of ether, cooled to 57°C and, with stirring, diluted with petroleum ether. The product was collected by filtration, washed with a little 1:1 ether-petroleum ether (b.p. 40-60°C) and dried to give 60.0 g (97%) of methyl (R,S)-6-acetyl-3,4-dihydro-7-((5-acetoxypentyl)oxy-2H-1-benzopyran2-carboxylate: m.p.51-53°C. A solution of 72.08 g (0.19 mol) of 5-bromo-1-pentanyl acetate in 1.4 L of MeOH was treated with 38 mL of a 1.0 molar solution of tetrabutylammonium hydroxide and the mixture was stirred at room temperature for 3.0 h, 3.0 mL of AcOH was added and the solution was evaporated at 35°C. The residue was dissolved in 400 mL of EtOAc and the solution was washed with saturated NaHCO3, brine, dried, and evaporated to give 60.45 g (94% yield) of the intermediate hydroxy ester (an analytical sample may be obtained by crystallization from 70% EtOAc in hexane, m.p. 58-61°C. A stirred solution of 60.25 g of the hydroxyester in 700 mL of EtOAc was cooled to 5°C and treated with 75.5 mL (3 equiv.) of triethylamine and 32.6 mL (2.35 equiv.) of methanesulfonyl chloride. The mixture was stirred at 6°C for 2.0 h, transferred to a separatory funnel and washed sequentially with water, 2 N HCl, and brine. Concentration of the EtOAc to ca. 300 mL and dilution cooled to 0°C and treated with 75.5 mL (3 equiv.) of triethylamine and 32.6 mL (2.35 equiv.) of methanesulfonyl chloride. The mixture was stirred at 6°C for 2.0 h transferred to a separatory funnel and washed sequentially with water, 2 N HCl, and brine. Concentration of the EtOAc to ca. 300 mL and dilution with 250 mL of hexane led to crystallization (0°C, 18 h). The product was collected by filtration and washed with some cold hexane - EtOAc (1:1) to give 66 g (84% yield) of methyl (R,S)-6-acetyl-3,4-dihydro-7-[5[(methylsufonyl)oxy]pentyloxy]-2H-1-benzopyran-2-carboxylate: m.p. 7376°C. A mixture of 66.13 g (0.159 mol) of methyl (R,S)-6-acetyl-3,4-dihydro-7-[5[(methylsufonyl)oxy]pentyloxy]-2H-1-benzopyran-2-carboxylate, 30.99 g (0.159 mol) of 1-[2,4-dihydroxy-3-propylphenyl)ethanone, 33.07 g (0.239 mol) of pulverized potassium carbonate, 5.16 g (15.9 mmol) of tris(3,6dioxahepyl)amine in 900 mL of toluene was stirred under Ar at reflux for 6 h and then at room temperature overnight. The mixture was poured into 300 mL of water and the organic phase was separated, washed with brine, dried and evaporated to give 84.3 g of methyl (R,S)-6-acetyl-7-[5-(4-acetyl-3hydroxy-2-propylphenoxy)pentoxy]-3,4-dihydro-2H-1-benzopyran-2carboxilate. Crystallization from MeOH (0°C, 18 h) gave 66 g (81% yield), m.p. 77-80°C.
16
Abunidazole
A stirred solution of 55.82 g (0.109 mol) of methyl (R,S)-6-acetyl-7-[5-(4acetyl-3-hydroxy-2-propylphenoxy)pentoxy]-3,4-dihydro-2H-1-benzopyran-2carboxylate in 725 mL of MeOH was treated with 4.45 g (0.111 mol) of NaOH in 20 mL of water and the mixture was stirred at reflux for 1.25 h. It was cooled, concentrated to a volume of ca 360 mL, diluted with 310 mL of ether and left at 0°C overnight. The product was collected by filtration, dried in to give 45.76 g of (R,S)-6-acetyl-7-[[5-(4-acetyl-3-hydroxy-2propylphenoxy)pentyl]oxy]-3,4-dihydro-2H-H-benzopyran-2-carboxylic acid sodium salt (Ablukast) as the monohydrate. A further 12.27 g of product was obtained from the mother liquor to give a total yield of 99%. References Manchand P.S., Micheli R.A., Saposnik S.J.; Tetrahedron; 1992; 48, 43, 9391
ABUNIDAZOLE Therapeutic Function: Antiprotozoal Chemical Name: α-[5-(1,1-Dimethylethyl)-2-hydroxyphenyl]-1-methyl-5nitro-1H-imidazole-2-methanol Common Name: Abunidazole; PN 4478846 Structural Formula:
Chemical Abstracts Registry No.: 91017-58-2 Trade Name
Manufacturer
Country
Year Introduced
Abunidazole
ZYF Pharm Chemical
-
-
Raw Materials p-tert-Butylphenol Hydrogen chloride
Ethylmagnesium bromide 1-Methyl-5-nitroimidazolyl-2-carboxyaldehyde
Manufacturing Process 150.0 g (1 mol) of p-tert-butylphenol are dissolved in 1200 ml of anhydrous ethyl ether and the thus obtained solution is added to a 10% solution of ethylmagnesium bromide in 1000 ml of anhydrous ether, at room temperature, under stirring. After having evaporated the ether, 1000 ml of anhydrous benzene are added
Acadesine
17
and the mixture is distilled, at normal pressure, until its volume is about 2/3 of the original volume. After cooling at room temperature, 1 mol of 1-methyl5-nitroimidazolyl-2-carboxyaldehyde in 1000 ml of anhydrous benzene is added. The whole is boiled for 1 h, is cooled to about 10°C and is added with 8% HCl to adjust the pH to 7. Benzene layer is dried and concentrated up to 2/3 of the volume. The 2-(1-methyl-5-nitro)imidazolyl-1-(2-hydroxy-5-tertbutylphenylcarbinol is allowed to crystallize, melting point 158°-160°C; yield 0-60%. References Tessitore P.T.; US Patent No. 4,478,846; Oct. 23, 1984
ACADESINE Therapeutic Function: Cardiotonic, Platelet aggregation inhibitor Chemical Name: 1H-Imidazole-4-carboxamide, 5-amino-1β-D-ribofuranosylCommon Name: Acadesine; AICA riboside; Arasine Structural Formula:
Chemical Abstracts Registry No.: 2627-69-2 Trade Name
Manufacturer
Country
Year Introduced
AICA
BIOMOL
-
-
Raw Materials Sodium hydroxide Methyl iodide Formic acid Hydrogen Ammonium hydroxide
Adenosine 3', 5'-cyclic phosphate N'-oxide Sodium bicarbonate Nickel 1,5-Diazabicyclo[5.4.0]undec-5-ene
Manufacturing Process Adenosine 3', 5'-cyclic phosphate N'-oxide (76.0 g, 0.200 mole) as the
18
Acadesine
dihydrate was dissolved in a solution of 400 ml DMSO and 31.0 g (0.204 mole) 1,5-diazabicyclo[5.4.0]undec-5-ene. The solution was cooled to 15°C and 40 ml methyl iodide was added with stirring at room temperature. After 30 min, the mixture had gelled; 1.5 L ethanol was added and the solid was thoroughly homogenized by vigorous stirring. The solid was filtered, and the resulting paste was resuspended in 2 L ethanol and homogenized. The product was again filtered, washed with ethanol and ether, and dried, giving 80.4 g of 1-methoxyadenosine 3',5'-cyclic phosphate suitable for further transformation (recrystallization from aqueous methanol with ether). A solution of 30.0 g 1-methoxyadenosine 3',5'-cyclic phosphate (81.5 mmole), 20.0 g NaHCO3 (238 mmole), and 300 ml H2O was refluxed 45 mm. The pH of the solution was adjusted to 2.5 with Dowex 50x8 (H)+ while warm, and a water pump vacuum was applied to mixture to remove CO2. The pH was readjusted to 9-10 with NaOH, and the resin was removed by filtration. The solution was passed onto a column containing 400 ml Dowex 1x2 (formate, 100-200 mesh), and the column was washed well with water. The column was eluted with a gradient of 4 L water in the mixing chamber and 4 L 4 N formic acid in the reservoir. The first major product, coming after about 2 L eluate, was 5-amino-N-methoxy-1-β-D-ribofuranosylimidazole-4-carboxamidine 3',5'cyclic phosphate, giving 5.4 g (19%) after evaporation of the solvent and trituration of the residue with ethanol (recrystallization from water). A solution of 5.0 g (14.3 mmoles) 5-amino-N-methoxy-1-β-Dribofuranosylimidazole-4-carboxamidine 3',5'-cyclic phosphate in 200 ml H2 preheated to 60°C and containing approximately 5.0 g moist sponge nickel catalyst, was shaken with 2-3 atm. H2 at 60°C for 2 h. The filtered solution was evaporated to dryness to give 3.75 g of 5-amino-1-β-Dribofuranosylimidazole-4-carboxamidine 3',5'-cyclic phosphate (82%), (recrystallization from water). A mixture of 4.0 g (12.5 mmole) 5-amino-1-β-D-ribofuranosylimidazole-4carboxamidine 3',5'-cyclic phosphate and 100 ml conc. NH4OH was heated in a bomb at 100°C for 16 h, then cooled and evaporated in vacuum. The residue was taken up in 100 ml H2O and applied to a 2.5x20 cm column of Dowex 1x2 (formate form, 100-200 mesh). After washing well with H2O the column was eluted with a gradient of 1 L H2O in the mixing chamber and 1 L 3 N formic acid in the reservoir. Fractions containing the product, appearing near the end of the elution, were evaporated. Trituration of the residue with EtOH gave 2.90 g (68%) of 5-amino-1-β-D-ribofuranosylimidazole-4carboxamide 3',5'-cyclic phosphate. The 5-amino-1-β-D-ribofuranosylimidazole-4-carboxamide may be produced by hydrolysis of 5-amino-1-β-D-ribofuranosylimidazole-4-carboxamide 3',5'cyclic phosphate with NaOH. References Meyer R.B., Shuman D.A.; US Patent No. 3,919,192; Nov. 11, 1975; Assigned: ICN Pharmaceuticals, Irvine, Calif.
Acamprosate calcium
19
ACAMPROSATE CALCIUM Therapeutic Function: Psychotropic Chemical Name: 3-(Acetylamino)-1-propanesulfonic, calsium salt (2:1) Common Name: Acamprosate; N-Acetylhomotaurine Structural Formula:
Chemical Abstracts Registry No.: 77337-73-6; 77337-76-9 (Base) Trade Name Campral Campral
Manufacturer Merck Forest Pharm
Country -
Year Introduced -
Raw Materials Sodium hydroxide Aminopropanesulfonic acid
Acetic anhydride Hydrochloric acid
Manufacturing Process In a 4 liter flask provided with stirring means, a bromine funnel and a thermometer, 17.5% sodium hydroxide solution and aminopropanesulfonic acid (homotaurine) are added. After complete dissolution, at a temperature of between 25°-40°C, acetic anhydride are added so as not to exceed a temperature of between 30°-40°C. The mixture is then maintained at this temperature by heating for at least 1 h. The solution is then concentrated in vacuum, the residue is redissolved in 2.5 L of distilled water and the mixture is concentrated again. The residue is then dissolved in 1.6 L of distilled water, filtered, then concentrated almost completely. Drying is terminated in an oven in vacuum. A colorless crystalline powder of 3-acetylaminopropanesulfonate of sodium (sodium Nacetylhomotaurinate) is obtained. The 3-acetylaminopropanesulfonic acid may be produced by treatment of 3acetylaminopropanesulfonate of sodium with hydrochloric acid. In practice it is usually used as calcium salt.
20
Acaprazine
References Durlach J.P.; US Patent No. 4,355,043; Oct. 19, 1982; Assigned: Les Laboratores Meram, France
ACAPRAZINE Therapeutic Function: Adrenergic blocker, Tranquilizer Chemical Name: Acetamide, N-(3-(4-(2,5-dichlorophenyl)-1-piperazinyl) propyl)Common Name: Acaprazine Structural Formula:
Chemical Abstracts Registry No.: 55485-20-6 Trade Name
Manufacturer
Country
Year Introduced
Acaprazine
ZYF Pharm Chemical
-
-
Raw Materials Nickel Raney Sodium hydroxide Sodium carbonate Potassium phthalimide 4-(m-Chloropheny1)-1piperazinopropionitrile Acetic anhydride Triethylamine
N-(3-Chloropropyl)phthalimide 1-(2,5-Dichlorophenyl)piperazine Hydrogen chloride Hydrazine hydrate 1-(3-Chloropropyl)-4-(2,5-dichlorophenyl) piperazine Chlorosuccinimide Hydrogen
Manufacturing Process 2 methods of producing of 1-(3-acetylaminopropyl)-4-(2,5-dichlorophenyl) piperazine: 1. A mixture formed by N-(3-chloropropyl)phthalimide (23.0 g), 1-(2,5dichlorophenyl)piperazine (24.0 g), anhydrous sodium carbonate (14.0 g) and toluene (130 ml) is boiled under stirring for 30 h. The solution is then cooled, filtered, concentrated to dryness, and the residue is treated with water and ether. The ethereal extract is washed, dried and concentrated to dryness. The
Acarbose
21
residue is treated with ethyl acetate and transformed into hydrochloride with ethanolic HCl. N-[3-[4-(2,5-Dichlorophenyl)-1-piperazinyl]propyl]phthalimide hydrochloride (30.0 g) is obtained, melting point 233°C (dec.). N-[3-[4-(2,5-Dichlorophenyl)-1-piperazinyl]propyl]phthalimide (15.0 g) and 99% hydrazinehydrate (2 ml) are heated, under reflux, for 90 min. 5 N HCl (115 ml) is then added and the solution is heated for 30 min under reflux. The solution is cooled, filtered and concentrated to small volume. The residue is diluted with water, made alkaline by means of a solution of NaOH and extracted with CH2Cl2. The organic layer is dried, evaporated and distilled under reduced pressure. 7.0 g of 1-(3-aminopropyl)-4-(2,5-dichlorophenyl) piperazine are obtained. 1-(3-Aminopropyl)-4-(2,5-dichlorophenyl)piperazine (50.0 g) is dissolved in CH2Cl2, and the solution is heated under reflux. Acetic anhydride (25 ml) dissolved in CH2Cl2, (500 ml) is introduced under stirring in about 1 h. The solution is heated for 1 h and is evaporated to dryness in a rotating evaporator. The is treated with H2O, thus obtaining a solid which is separated, washed and dried at 50°C. This solid is then dissolved in ethyl acetate (about 350 ml), treated with charcoal and crystallized. 1-(3-Acetylaminopropyl)-4(2,5-dichlorophenyl)piperazine is obtained in an almost quantitative yield, melting point 114°C. 2. Chlorosuccinimide (5.4 g) is added to a solution of 4-(m-chlorophenyl)-1piperazinopropionitrile (5.0 g) in CH2Cl2 (100 ml). The solution is heated for a few hours and, after removal of the solvent, it is chromatographed on an alumina column. The solution is eluted with a 1:1 mixture of cyclohexane and benzene containing 0.3 % of triethylamine. 4-(2,5-Dichlorophenyl)-1piperazinopropionitrile (2.0 g) is thus obtained. 4-(2,5-Dichlorophenyl)-1-piperazinopropionitrile (20.0 g), acetic anhydride (100 ml), anhydrous sodium sulfate (12.0 g) and a 50% solution of Ni-Raney (6 ml) are hydrogenated at 60.0 pounds per inch at 60°C in a Parr apparatus. After about half an absorption of hydrogen is complete. The reaction mixture is cooled, the is filtered and the solution is concentrated to small volume in a rotating evaporator. The residue is treated with NaOH solution and extracted several times CH2Cl2. The organic layer is washed, dried and evaporated. The residue is crystallized from ethyl acetate. 14.0 g of the 1-(3acetylaminopropyl)-4-(2,5-dichlorophenyl)piperazine are obtained, melting point 114°C. References GB Patent No. 1,443,598; July 21, 1976; Assigned: Aziende Chemiche Riunite Angelini Franceso A.C.R.A.F. S.p.A., Italy
ACARBOSE Therapeutic Function: Antidiabetic
22
Acarbose
Chemical Name: D-Glucose, O-4,6-dideoxy-4-(((1S-(1α,4α,5β,6α))-4,5,6trihydroxy-3-(hydroxymethyl)-2-cyclohexen-1-yl)amino)-α-Dglucopyranosyl-(1-4)-O-α-D-glucopyranosyl-(1-4)Common Name: Acarbose Structural Formula:
Chemical Abstracts Registry No.: 56180-94-0 Trade Name Glicobase Glucobay Glucor Glumida Prandase
Manufacturer Formenti Bayer Limited Laboratoires Bayer Pharma Pensa Yno
Country Italy India France Spain -
Year Introduced -
Precose
Bayer
Germany
-
Precose
Cheshire Drugs
-
-
Precose Precose
Allscripts Physicians TC.
-
-
Raw Materials Microorganisms of family Actinoplanacease (by fermentation) Commercial cation exchanger based on polystyrene with a degree of crosslinking 3-4% Solution of saccharase inhibitor Lewatit Manufacturing Process The title compound was obtained from a cultural broth of fermenting a microorganism of family Actinoplanaceae in particular of strain genus Actinoplanes, according to DT-OS (German Published Specification) No. 2,347,782. 50 g of cation exchange resin (Lewatit S 1040W) in the H+ form and 30 g an anion exchanger (Lewatit M 600) in OH form were added to 300 ml of a culture broth with mycelium content of 25% and an inhibitor content of 50 SIU/ml in solution. The mixture was stirred at room temperature for 50 minutes. The solution, containing a sieving nozzle with 0.1 mm slits. For
Acebutolol
23
testing, a sample of filtered broth was centrifuged and was examined for saccharase inhibitor in the supernatant liquor. The solution contained 2.5 SIU/ml, that is to say 5%, of starting activity. This procedure improved the yield of the aminosugar from 20% in the procedure known from DT-OS (German Published Specification) No. 2,347,782, to 50-60%. It has now found that cation exchangers based on styrene, divinylbenzene and methoxymethylmethacrylamide, oxyethyl(meth)acrylic acid amide (ester), dimethylaminoethyl(meth)acrylic acid amide (ester) or oxypropyl(meth)acrylic acid amide(ester) are preferred in industrial separation procedure of acarbose. This exchanger gave a very sharp separation of the individual homologues and impurities. And it has now found the new biosynthesis of acarbose by using of gen engineering methods. References Rauenbusch E. et al.; US Patent No. 4,174,439, Nov. 13, 1979, Assigned: Bayer Aktiengesellschaft (Leverkusen, DE) Lange P.M. et al.; US Patent No. 4,666,776, May 19, 1987, Assigned: Bayer Aktiengesellschaft (Leverkusen, DE) Deutsches Patent and Markenamt, Offenlegungsschrift DE 100 21 667 A1, 8. 11.2001
ACEBUTOLOL Therapeutic Function: beta-Adrenergic blocker Chemical Name: N-[3-Acetyl-4-[2-hydroxy-3-[(1-methylethyl)-amino] propoxy]phenyl]butanamide Common Name: 5'-Butyramido-2'-(2-hydroxy-3-isopropylaminopropoxy)acetophenone Structural Formula:
Chemical Abstracts Registry No.: 37517-30-9; 34381-68-5 (Hydrochloride salt) Trade Name
Manufacturer
Country
Year Introduced
Sectral
May and Baker
UK
1975
Sectral
Specia
France
1976
Prent
Bayer
W. Germany
1977
24
Acebutolol
Trade Name
Manufacturer
Country
Year Introduced
Neptall
Rhodia Pharma
W. Germany
1977
Sectral
May and Baker
Switz.
1980
Sectral
Roger Bellon
Italy
1980
Sectral
RBJ Pharma
Italy
1980
Acetanol
Kanebo, Ltd.
Japan
1981
Prent Acecor Diasectral Neptal Secradex Sectral
Bayer S.P.A. Rhone Poulenc Rohm Pharma May and Baker Wyeth
Italy Italy UK US
1981 -
Raw Materials Butyramidophenol Aluminum chloride Sodium ethoxide
Acetyl chloride Epichlorohydrin Isopropylamine
Manufacturing Process Crude 5'-butyramido-2'-(2,3-epoxypropoxy)acetophenone (16 g), isopropylamine (20 g) and ethanol (100 ml) were heated together under reflux for 4 hours. The reaction mixture was concentrated under reduced pressure and the residual oil was dissolved in N hydrochloric acid. The acid solution was extracted with ethyl acetate, the ethyl acetate layers being discarded. The acidic solution was brought to pH 11 with 2 N aqueous sodium hydroxide solution and then extracted with chloroform. The dried chloroform extracts were concentrated under reduced pressure to give an oil which was crystallized from a mixture of ethanol and diethyl ether to give 5'-butyramido2'-(2-hydroxy-3-isopropylaminopropoxy)acetophenone (3 g), MP 119-123°C. Crude 5'-butyramido-2'-(2,3-epoxypropoxy)acetophenone used as starting material was prepared as follows: p-butyramidophenol (58 g; prepared according to Fierz-David and Kuster, Helv. Chim. Acta 1939,2282), acetyl chloride (25.4 g) and benzene (500 ml) were heated together under reflux until a solution formed (12 hours). This solution was cooled and treated with water. The benzene layer was separated and the aqueous layer was again extracted with benzene. The combined benzene extracts were dried and evaporated to dryness under reduced pressure to give p-butyramidophenyl acetate (38 g) as an off-white solid, MP 102-103°C. A mixture of p-butyramidophenyl acetate (38 g), aluminum chloride (80 g) and 1,1,2,2-tetrachloroethane (250 ml) was heated at 140°C for 3 hours. The reaction mixture was cooled and treated with iced water. The tetrachloroethane layer was separated and the aqueous layer was extracted with chloroform. The combined organic layers were extracted with 2 N aqueous sodium hydroxide and the alkaline solution was acidified to pH 5 with concentrated hydrochloric acid. The acidified solution was extracted with chloroform and the chloroform extract was dried and concentrated under reduced pressure to give 5'-butyramido-2'-hydroxyacetophenone (15.6 g), MP 114-117°C. A solution of 5'-butyramido-2'-hydroxyacetophenone (15.6 g) in
Acecainide
25
ethanol (100 ml) was added to an ethanolic solution of sodium ethoxide which was prepared from sodium (1.62 g) and ethanol (100 ml). The resulting solution was evaporated to dryness under reduced pressure and dimethylformamide (100 ml) was added to the solid residue. Approximately 10 ml of dimethylformamide was removed by distillation under reduced pressure. Epichlorohydrin (25 ml) was added and the solution was heated at 100°C for 4 hours. The solution was concentrated under reduced pressure to give a residual oil which was treated with water to give a solid. The solid was dissolved in ethanol and the resulting solution was treated with charcoal, filtered and concentrated under reduced pressure to give crude 5'-butyramido2'-(2,3-epoxypropoxy)acetophenone (16 g), MP 110-116°C. The crude compound may be purified by recrystallization from ethyl acetate, after treatment with decolorizing charcoal, to give pure 5'-butyramido-2'-(2,3epoxypropoxy)acetophenone, MP 136-138°C. References Merck Index 13 Kleeman and Engel p. 1 PDR p. 1978 OCDS Vol. 2 p. 109 (1980) DOT 11 (7) p. 264 (1975) I.N. p. 2 Wooldridge, K.R.H. and Basil, B.; US Patent 3,857,952; Dec. 31,1974; Assigned to May and Baker, Ltd.
ACECAINIDE Therapeutic Function: Antiarrhythmic Chemical Name: Benzamide, 4-(acetylamino)-N-(2-(diethylamino)ethyl)Common Name: Acecainide; NAPA Structural Formula:
Chemical Abstracts Registry No.: 32795-44-1
26
Acecarbromal
Trade Name Acecainide
Manufacturer ZYF Pharm Chemical
Country -
Year Introduced -
Raw Materials Acetyl chloride p-Amino-N-(2-diethylaminoethyl)benzamide Sodium hydroxide Manufacturing Process 1.0 g of p-amino-N-(2-diethylaminoethyl)benzamide is dissolved in chloroform. A few ice cubes are added to the solution. Acetyl chloride is added dropwise with stirring until no more white precipitate forms; the latter is separated by filtering under suction. The precipitate is washed with cold acetone and dried overnight in a vacuum oven at room temperature. The product is dissolved in a minimum amount of hot isopropanol and allowed to precipitate in the cold. The p-acetamido-N-(2-diethylaminoethyl)benzamide hydrochloride, is recrystallized a second time from hot isopropanol, melting point 190°-193°C. The free base is obtained from the hydrochloride by dissolving the latter in water, adjusting the pH to greater than 10 with dilute sodium hydroxide, and adding an equal volume of benzene. After shaking in a separatory funnel, the benzene layer is recovered and evaporated to dryness. So the p-acetamido-N(2-diethylaminoethyl)benzamide is obtained. References GB Patent No. 1,319,980; June 13, 1973; Assigned: E.R. Squibb and Sons, Inc., a corporation organized and existing under the laws of the State of Delaware, USA
ACECARBROMAL Therapeutic Function: Sedative, Hypnotic Chemical Name: Butanamide, N-((acetylamino)carbonyl)-2-bromo-2-ethylCommon Name: Acecarbromal; Acetcarbromal; Acetylcarbromal; Sedacetyl Structural Formula:
Chemical Abstracts Registry No.: 77-66-7
Aceclidine Trade Name Acetylcarbromal Afrodor 2000 Afrodor 2000 Paxarel
Manufacturer Pfaltz and Bauer Farco-Pharma Biomenta Circle Pharmaceuticals
Country -
27
Year Introduced -
Raw Materials Urea Bromine Zinc chloride
Diethylacetic acid anhydride Acetic anhydride
Manufacturing Process It was mixed 120 parts of urea and 258 parts of bromodiethylacetylbromide (prepared from diethylacetic acid anhydride and bromine). After 12 hours the mixture was heated for 3 hours at 100°C. The product was mixed with an aqueous solution of sodium bicarbonate and then was filtered. The obtained bromodiethylacetylurea was crystallized from diluted ethanol; melting point 114-118°C. The mixture of 474 parts of bromodiethylacetylurea, 1000 parts of acetic anhydride and 75 parts ZnCl2 was heated at 60°C for 1 hour. The product was stirred with 3000 parts of ice-water and then 1-acetyl-3-(αbromo-α-ethylbutyryl)urea was filtered; melting point 108-109°C. References Merck Index, Monograph number: 18, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. DE Patent 286,760, 1913; Bayer and Co. In Elberfeld DE Patent 327,129, 1917; Bayer and Co., Leverkusen
ACECLIDINE Therapeutic Function: Miotic, Cholinomimetic Chemical Name: 1-Azabicyclo[2.2.2]octan-3-ol acetate Common Name: 3-Quinuclidinol acetate Structural Formula:
Chemical Abstracts Registry No.: 827-61-2; 6109-70-2 (Hydrochloride salt)
28
Aceclidine
Trade Name
Manufacturer
Country
Year Introduced
Glacostat
MSD-Chibret
France
1966
Glaunorm
Farmigea
Italy
1969
Glaudin
Sifi
Italy
-
Raw Materials Methyl isonicotinate Potassium
Ethyl bromoacetate Hydrogen
Manufacturing Process A mixture of 274 g of methyl isonicotinate, 367 g of ethyl bromoacetate and 125 cc of ethyl alcohol was stirred without heating for 4 hours in a flask equipped with a reflux condenser. (The reaction was exothermic and precautions were taken to keep the temperature below 70°C.) The reaction mixture was then left for 15 hours at room temperature. The reaction product (1-carbethoxymethyl-4-carbornethoxy-pyridinium bromide) was obtained in crystalline form. (It formed prisms melting at 166169°C after recrystallization from a mixture of isopropanol and acetone.) It was not necessary to isolate it. For the following reduction step, the reaction mixture was brought into solution by the addition of about 1 liter of warm ethyl alcohol. It was then hydrogenated at about 30 atm pressure in the presence of 2 g of platinum oxide. The temperature rose during this reaction to about 40°C. After the calculated amount of hydrogen had been absorbed, the catalyst was filtered off, the solution was concentrated in vacuum, and the residual syrup was dissolved in ice water. Benzene was added and the mixture was made alkaline with an excess of concentrated ice cold potassium carbonate solution. The temperature was kept low by continuous addition of ice, and the benzene layer was separated and dried with sodium sulfate. The dried benzene solution was concentrated in vacuum and the residual oil was distilled in vacuum. BP 30 mm = 175-182°C, nD25= 1.4613-1.4628. During the reduction, partial alcoholysis occurred, and the product isolated was 1carbethoxymethyl-4-"carbalkoxy"-piperidine, wherein "carbalkoxy" represents a mixture of carbomethoxy and carbethoxy. 100 g of potassium were pulverized in 200 cc of hot toluene in a heated three-neck flask equipped with an efficient condenser, stirrer and dropping funnel. To the refluxing potassium suspension were added in small portions 229 g of the product of the previous step and about 700 cc of toluene. This addition had to be carried out very cautiously; the onset of the exothermic reaction is sometimes delayed. The addition was finished in about 1 hour. To complete the reaction, the refluxing and stirring were continued for about 4 hours. The reaction mixture was then cooled to about +5°C and about 50 cc isopropanol were added to decompose unreacted potassium. Then 2.5 liters of concentrated hydrochloric acid were added and the mixture was refluxed for 15 hours, and then concentrated in vacuum to dryness. To the residue was added with cooling an excess of 50% potassium hydroxide. Ether was then added and the resulting mixture was filtered through a fritted glass funnel, thus removing the precipitated potassium chloride. The ethereal and aqueous layers were separated, and the aqueous layer was extracted repeatedly with 500 cc portions of ether. The organic solutions were combined, dried over
Aceclidine
29
sodium sulfate and concentrated in vacuum. Aqueous hydrochloric acid was added to the residue until the solution became acid. The mixture was then diluted with distilled water to about 300 cc, heated with decolorizing charcoal, filtered and concentrated in vacuum to dryness. The residue was treated with isopropanol, and the precipitated crystalline product was filtered off. The product was recrystallized from a mixture of water and isopropanol and was identified as 1-azabicyclo[2.2.2]-3-octanone hydrochloride; prisms, MP 311313°C, with decomposition. A solution of 50 g of the above ketone-hydrochloride in 30 cc of water was made alkaline by the addition of 30 g of potassium hydroxide. After the alkali was dissolved, 35 g of granular potassium carbonate were added. The free basic ketone was then extracted from the viscous mixture by shaking with 4 portions of hot benzene (300 cc in each portion). The benzene extracts were decanted, filtered over sodium sulfate in order to remove any suspended alkali, and concentrated in vacuum. The residual lszabicyclo[2.2.2]-3-octanone was purified by sublimation (50-70°C/0.5 mm Hg); it can also be purified by recrystallization from petroleum ether. It formed feathery crystals melting at 147-148°C. The product was reduced as follows: A solution of 50 g of 1-azabicyclo[2.2.2]-3-octanone hydrochloride in 200 cc of water was hydrogenated at room temperature and 50 atm pressure with 1 g of platinum oxide as catalyst. After the calculated amount of hydrogen had been absorbed, the mixture was filtered and concentrated in vacuum to dryness. The residual product was recrystallized from a mixture of methanol and acetone and formed prisms melting above 300°C. It was identified as 1azabicyclo[2.2.2]-3-octanol hydrochloride. A solution of 50 g of 1-azabicyclo[2.2.2]-3-octanol hydrochloride in 30 cc water was made alkaline with 30 g of potassium hydroxide. After the alkali was dissolved 35 g of granular potassium carbonate were added. The free basic alcohol was then extracted from the viscous mixture by shaking with four portions of boiling benzene (300 cc in each portion). The benzene extracts were decanted and filtered over anhydrous sodium sulfate, to remove any suspended alkali. The combined benzene solutions were concentrated in vacuum. The residue was recrystallized from benzene and identified as lszabicyclo[2.2.2]-3-octanol, MP 221-223°C. The product can also be purified by recrystallization from acetone, or by sublimation in vacuum (120°C/20 mm Hg). The alcohol was reacted with acetic anhydride to give the product aceclidine. References Kleeman and Engel p. 2 OCDS Vol. 2 p. 295 (1980) I.N. p. 2 Sternbach, L.H.; US.Patent 2,648,667; Aug. 11,1953; Assigned to Hoffman La Roche Inc.
30
Aceclofenac
ACECLOFENAC Therapeutic Function: Analgesic, Antiinflammatory Chemical Name: Benzeneacetic acid, 2-[(2,6-dichlorophenyl)amino]-, carboxymethyl ester Common Name: Aceclofenac; Locomin Structural Formula:
Chemical Abstracts Registry No.: 89796-99-6 Trade Name Reservix Aceclofenac Airtal Kafenac Zurem Beofenac Bristaflam Bristaflam Berlofen Bristaflam Biofenac Biofenac Biofenac Locomin Proflam
Manufacturer Incepta Xian HaiXin pharmaceutical Co., Ltd. Almirall Almirall ABIOGEN PHARMA srl Almirall Egypt Company Co. BMS Co. Elea Bristol UCB BERAGENA EMRA-MED ARZNEIM UCB Eurofarma
Country -
Year Introduced -
-
-
Raw Materials Benzyl bromoacetate Sodium 2-[(2,6-dichlorphenyl)amino]phenylacetate Palladium on carbon Hydrogen Manufacturing Process 50 g of sodium 2-[(2,6-dichlorphenyl)amino]phenylacetate were dissolved in 300 ml of N,N-dimethylformamide under heating to 50°C, and 44.22 g of benzyl bromoacetate were added thereto. Under these condition stirring was
Acediasulfone sodium
31
continued for 9 hours. Upon completion of the reaction, the solvent was removed at reduced pressure, and the sodium salt were precipitated with addition of 400 ml of ether. The solution was then filtered and the ether phase was washed twice time with 100 ml of hexane. The resulting product was crystallized from the hexane/ether and then from acetone/chloroform (1:9) thus obtaining 44.1 g (61%) of benzyl 2-[(2,6dichlorphenyl)amino]phenylacetoxyacetate in the form of white crystals having a melting point of 67-69°C. 45.28 g of benzyl 2-[(2,6-dichlorphenyl)amino]phenylacetoxyacetate were dissolved in 1500 ml of ethyl acetate, and the resulting solution was mixed with 7 g of Pd/C 10% and then hydrogen ted at atmospheric pressure for 14 hours. The solution was filtered, concentrated and crystallized; thereby obtaining 23.51 g (65%) of 2-[(2,6-dichlorphenyl)amino]phenylacetoxyacetic acid; melting point 149-150°C. References Casas A.V.; US Patent No. 4,548,952; Oct. 22, 1985; Assigned to Prodes, S.A., San Justo Desvern, Spain Schickaneder H., Nikolopoulos A., Murphy T.; WO Patent No. 9,955,660; 199911-04; Assigned to Russinsky Ltd (IE), Schickaneder Helmut (IE), Nikolopoulos Aggelos (IE), Murphy Trevor (IE)
ACEDIASULFONE SODIUM Therapeutic Function: Antibacterial Chemical Name: N-p-Sulfanilylphenylglycine sodium Common Name: Acediasulfone sodium; Glycinodiasulfone sodium Structural Formula:
Chemical Abstracts Registry No.: 127-60-6; 80-03-5 (Base) Raw Materials Methyl chloroacetate Lithium hydroxide Sodium hydroxide
4,4'-Diaminodiphenyl sulfone Hydrochloric acid
32
Acedoben
Trade Name
Manufacturer
Country
Year Introduced
Solfone
Bracco
-
-
Manufacturing Process 24.8 g of 4,4'-diaminodiphenyl sulfone, 150 g of methyl chloroacetate and 150 ml of ethanol are refluxed together and refluxed for 24 hours. The alcohol and excess methyl chloroacetate are then distilled off on a steam bath under reduced pressure. The residue consisting of the hydrochloride salt of 4-amino4'-(carbomethoxymethylamino)diphenyl sulfone is mixed with of alcoholic solution containing 2.5 g lithium hydroxide and refluxed for 4 hours on the steam bath. Most of the alcohol is removed by distillation and the residual lithium salt of 4-amino-4'-(carboxymethylamino)diphenyl sulfone taken up water. The solution is filtered and dilute HCl added until no more separation occurs. The 4-amino-4'-(carboxymethylamino)diphenyl sulfone thus obtained is collected and dried. The sodium salt of 4-amino-4'-(carboxymethylamino)diphenyl sulfone is prepared by dissolving the free acid in an aqueous solution containing one equivalent of sodium hydroxide and evaporating the solution to dryness in vacuo. References Merck Index, Monograph number: 21, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. Rawlins A.L.; US Patent No. 2,589,211; Mar. 18, 1952; Assigned to Parke, Devis and Co., Detroit, Michigan Martin H., Habicht E.; US Patent No. 2,751,382; June 19, 1956; Assigned to Cilag Ltd., Schaffhausen, Switzerland
ACEDOBEN Therapeutic Function: Antiviral Chemical Name: Benzoic acid, p-acetamidoCommon Name: Acedoben Structural Formula:
Acefluranol
33
Chemical Abstracts Registry No.: 556-08-1 Trade Name 4-Acetamidobenzoic acid p-Acetamidobenzoic Acid p-Acetamidobenzoic Acid
Manufacturer ARIAC Chembay Chemical Co., LTD Sigma-Aldrich
Country -
Year Introduced -
-
-
Raw Materials Magnesium sulfate N-p-Tolylacetamide Hydrochloric acid
Sodium acetate Potassium permanganate
Manufacturing Process Into a 2 L, 3-necked flask set in a tub and equipped with a stirrer, an air condenser (drying tube), thermometer, was placed 860 ml of water, 43.0 g of MgSO4 and 43.0 g of sodium acetate and heated on water bath. Into heated solution to 70°C stirring 43.0 g of N-p-tolylacetamide were added. Then 136.0 g of KMnO4 by small portions were added at 75°-80°C. The reaction mixture allow to stand for 6 h and stirring was continue till the solution became colorless. Hot solution was filtered and filtrate treated hydrochloric acid to slightly acidic pH. After that 44.0 g (85%) of p-acetoaminobenzoic acid was obtained as white precipitate, melting point 250°C. References Berkengame A.M.; Chemistry and Technology of synthetic drugs; 1935; Moscow
ACEFLURANOL Therapeutic Function: Antiestrogen Chemical Name: (1RS,2SR)-4,4'-(1-Ethyl-2-methyl-1,2-ethanediyl)bis[6fluoro-1,2-benzenediol] tetraacetate Common Name: Acefluranol; BX 591 Structural Formula:
34
Acefluranol
Chemical Abstracts Registry No.: 80595-73-9 Trade Name
Manufacturer
Country
Year Introduced
Acefluranol
ZYF Pharm Chemical
-
-
Raw Materials erythro-3,3'-Difluoro-4,4'-dihydroxy-α-ethyl-α'-methylbibenzyl Pyridine Acetic anhydride Aluminum chloride Sodium hydroxide Hydrogen peroxide Sodium borohydride Hydrochloric acid Manufacturing Process 4.5 g erythro-3,3'-difluoro-4,4'-dihydroxy-α-ethyl-α'-methylbibenzyl in 30 ml pyridine and 10 ml acetic anhydride were left to stand for 24 h at room temperature, thereafter the reaction mixture was worked up to give a crude product, recrystallisation of which from chloroform-diethyl ether (1:4 v/v) gave 5.5 g erythro-3,3'-difluoro-4,4'-diacetoxy-α-ethyl-α'-methylbibenzyl, melting point 118°-120°C. 5.0 g of the erythro-3,3'-difluoro-4,4'-diacetoxy-α-ethyl-α'-methylbibenzyl were ground with 10.0 g aluminum chloride and the mixture was heated at 150°C for 30 min. After cooling, the mass was added portion-wise to ice, stirred and extracted with chloroform. The chloroform solution was washed with water, dried with anhydrous sodium sulfate and concentrated to half its volume. An equal volume of diethyl ether was added thereto and the solution was treated with charcoal and filtered. The filtrate was evaporated and the residue obtained was crystallized from chloroform-diethyl ether (1:1 v/v) to give 2.6 g erythro-3,3'-diacetyl-4,4'-dihydroxy-5,5'-difluoro-α-ethyl-α'methylbibenzyl, melting point 194°-196°C. 0.9 g erythro-3,3'-diacetyl-4,4'-dihydroxy-5,5'-difluoro-α-ethyl-α'methylbibenzyl were suspended in a mixture of 10 ml dioxan and 6 ml 1 N aqueous sodium hydroxide solution. The solution was cooled to 10°C and 0.8 ml 30% hydrogen peroxide added dropwise thereto. The reaction mixture was stirred at 20°C for 1.5 h and then poured into a mixture of dilute hydrochloric acid and ice. The product was extracted with peroxide-free diethyl ether, the extract was evaporated and the residue was crystallized from benzene to give a yellow solid. This was treated in 5 ml ethanol with 2.0 mg sodium borohydride, followed by acidification with hydrochloric acid, rapid extraction with diethyl ether, evaporation of the extract and immediate crystallization from benzene to give 350.0 mg of pure erythro-4,4',5,5'-tetrahydroxy-3,3'difluoro-α-ethyl-α'-methyldibenzyl, melting point 143°-145°C. 1.0 g erythro-3,3'-difluoro-4,4',5,5'-tetrahydroxy-α-ethyl-α'-methyldibenzyl in a mixture of 10 ml pyridine and 5 ml acetic anhydride was left to stand at 20°C for 20 h and at 60°-80°C for 1 h. The reaction mixture was then poured into a mixture of dilute hydrochloric acid and ice, stirred for several h and filtered. The filtrate was evaporated and the residue was taken up in
Aceglutamide aluminum
35
chloroform and the chloroform solution was washed with dilute hydrochloric acid and water, dried over anhydrous sodium sulfate and the solvent removed. The gummy residue was taken up with benzene and the benzene solution filtered through a neutral alumina. The benzene was removed from the filtrate to give 1.0 g pure erythro-3,3'-difluoro-4,4',5,5'-tetraacetoxy-α-ethyl-α'methyldibenzyl; melting point 160°-162°C (crystallised from diethyl ether). References Chan R.P.K.; US Patent No. 4,427,697; Jan. 24, 1984; Assigned: Biorex Laboratories Limited, England
ACEGLUTAMIDE ALUMINUM Therapeutic Function: Antiulcer Chemical Name: Pentakis(N2-acetyl-L-glutaminato)tetrahydroxytrialuminum Common Name: Structural Formula:
Chemical Abstracts Registry No.: 12607-92-0 Trade Name Glumal Glumal
Manufacturer Kyowa Hakko Liade
Raw Materials N-Acetyl-L-glutamine Aluminum isopropoxide
Country Japan Spain
Year Introduced 1978 -
36
Acemetacin
Manufacturing Process A mixture of 37.6 g of N-acetyl-L-glutamine and 1,000 ml of water is heated to 40°C, and 900 ml of an isopropanol solution containing 40.8 g of aluminum isopropoxide is added to the warm mixture with stirring. The stirring is continued for 10 minutes. The reaction mixture is filtered and the filtrate is concentrated under reduced pressure. Isopropanol is added to the aqueous solution and the salt precipitates in the solution. The precipitates are collected by filtration and upon drying, 48.5 g of the crystalline-like aluminum salt of Nacetyl-L-glutamine are obtained. References Merck Index 20 Kleeman and Engel p. 32 DOT 14 (2) p. 54 (1978) I.N. p. 3 Kagawa, T., Fuji, K., Tanaka, M. and Tanaka, H.; US Patent 3,787,466; Jan. 22,1974; Assigned to Kyowa Hakko Kogyo Co., Ltd.
ACEMETACIN Therapeutic Function: Antiinflammatory Chemical Name: 1-(p-Chlorobenzoyl)-5-methoxy-2-methylindole-3acetoxyacetic acid Common Name: Structural Formula:
Chemical Abstracts Registry No.: 53164-05-9 Trade Name Rantudil Rantudil
Manufacturer Bayer Tropon
Country W. Germany W. Germany
Year Introduced 1980 -
Acenocoumarol
37
Raw Materials N-(p-Methoxybenzyl)-p-chlorobenzhydrazide HCl Benzyl levulinoyloxyacetate Hydrogen Manufacturing Process 25.4 g (0.050 mol) of [1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3indoleacetoxy]-benzyl acetate were dissolved in 400 ml of glacial acetic acid and hydrogenated on 2.0 g of palladium carbon at room temperature. After the absorption of hydrogen had finished (1 hour), the catalyst was filtered off, the filtrate was concentrated by evaporation under vacuum and the compound was caused to crystallize by adding petroleum ether. The compound melted at 149.5-150.5°C (determined on the micro-Kofler bench); the yield was 19.4 g which corresponds to 93% of the theoretical yield. The starting material for the above step may be prepared as follows: 5 g (0.016 mol) of N1-(p-methoxyphenyl)-p-chlorobenzhydrazide hydrochloride and 4.75 g (0.018 mol) of benzyl levulinoyloxyacetate were heated in 25 ml of glacial acetic acid for 3 hours at 80°C. The solvent was then evaporated off under vacuum. The residue was taken up in chloroform and the solution was washed neutral by shaking with sodium bicarbonate solution and thereafter with water. After drying the chloroform solution, this was subjected to chromatography on aluminium oxide, the eluate was concentrated by evaporation and the viscous oil remaining as residue was crystallized by adding ether. The compound melted at 94-95°C. The yield was 4.1 g which corresponds to 50.7% of the theoretical yield. References Merck Index 21 DFU 2 (7) p.423 (1977) Kleeman and Engel p. 3 DOT 17 (7) p.279 (1981) I.N. p. 3 Boltze, K.H., Brendler, O., Dell, H.D. and Jacobi, H.; US Patent 3,910,952; October 7,1945; Assigned to Tropenwerke Dinklage and Co. Boltze, K.H., Brendler,O., Dell, H.D. and Jacobi, H.; US Patent 3,966,956; June 29,1976; Assigned to Tropenwerke Dinklage and Co.
ACENOCOUMAROL Therapeutic Function: Anticoagulant, Vitamin Chemical Name: 3-(α-Acetonyl-p-nitrobenzyl)-4-hydroxycoumarin Common Name: Nicoumalone Chemical Abstracts Registry No.: 152-72-7
38
Acenocoumarol
Structural Formula:
Trade Name Sintrom Sintrom Sintrom Sintrom NeoSintrom Ascumar Syncumar Synthrome Sintrom
Manufacturer Geigy Geigy Ciba Geigy Ciba Geigy Geigy Star EGYT Geigy Ciba Geigy
Country US W. Germany Switz. France Finland Hungary UK Japan
Year Introduced 1957 1959 -
Raw Materials 4-Hydroxycoumarin Nitrobenzalacetone Manufacturing Process 16 parts of 4-hydroxycoumarin and 19 parts of 4-nitrobenzalacetoneare thoroughly mixed and heated for 12-14 hours in an oil bath, the temperature of which is between 135°C and 140°C. After cooling, the melt is dissolved in a little acetone. The solution is slowly added to a lye made up from 6 parts of sodium hydroxide in 400 parts of water while stirring and then the mixture is stirred for 30 minutes. A little animal charcoal is then added, the mixture is stirred for a further 15 minutes, 400 parts of water are added and the charcoal and undissolved components are separated by filtration under suction. The clear solution is made acid to Congo red paper with hydrochloric acid and the product which is precipitated is filtered off under suction. 3-[α(4'-Nitrophenyl)-β-acetylethyl]-4-hydroxycoumarin is obtained. MP 196-199°C. It should be noted that the process is akin to that for Warfarin except that 4nitrobenzalacetone replaces benzalacetone as a raw material. References Merck Index 23 Kleeman and Engel p. 4 OCDS Vol. 1 p. 331 (1977) I.N. p.3 Stoll, W. and Litvan, F.; US Patent 2,648,682; August 11, 1953; Assigned to J.R. Geigy A.G., Switzerland.
Aceperone
39
ACEPERONE Therapeutic Function: Vasodilator, Antihypertensive, Neuroleptic Chemical Name: Acetamide, N-((1-(4-(4-fluorophenyl)-4-oxobutyl)-4-phenyl4-piperidinyl)methyl)Common Name: Aceperone; Acetabutone Structural Formula:
Chemical Abstracts Registry No.: 807-31-8 Trade Name Aceperone
Manufacturer ZYF Pharm Chemical
Country Year Introduced -
Aceperone
Vasudha Pharma Chem Limited.
-
-
Raw Materials 1-Benzyl-4-(4-phenyl)-4-(acetaminomethyl)piperidine Sodium bicarbonate 3-(4-Fluorobenzoyl)propyl bromide Thiophenol Sodium hydroxide Manufacturing Process A mixture of 1-benzyl-4-(4-phenyl)-4-(acetaminomethyl)piperidine, 3-(4fluorobenzoyl)propyl bromide, sodium bicarbonate and anhydrous acetone was stirred and heated under reflux. The resulting mixture was filtered while still hot, and the filtrate was concentrated to dryness under reduced pressure. The residue was washed with ether to give 1-benzyl-1-[3-(4-fiuorobenzoyl)propyl](4-phenyl-4-acetaminomethyl)piperidinium bromide. To a stirred mixture of thiophenol and 15% (W/W) aqueous sodium hydroxide was added the 1-benzyl-1-[3-(4-fluorobenzoyl)propyl]-(4-phenyl-4acetaminomethyl)piperidinium bromide and the mixture was heated to 85°90°C for 2 h. After cooling, solid matter precipitated was collected by filtration and washed with water to give 1-[3-(4-fluorobenzoyl)propyl]-4(acetaminomethyl)-4-phenylpiperidine, melting point 111°-112°C.
40
Acepromazine maleate
References Nakao M. et al.; US Patent No. 3,850,935; Nov. 26, 1974; Assigned: Sumitomo Chemical Company, Limited, Osaka, Japan
ACEPROMAZINE MALEATE Therapeutic Function: Neuroleptic, Antiemetic Chemical Name: Ethanone, 1-(10-(3-(dimethylamino)propyl)-10Hphenothiazin-2-yl)-, maleate (1:1) Common Name: Acepromazine maleate; Acetopramazine maleate; Notensil Structural Formula:
Chemical Abstracts Registry No.: 3598-37-6; 61-00-7 (Base) Trade Name Sedaject Anatran Sedalin
Manufacturer Bayer Korea Co. Ayerst Chassot
Country -
Year Introduced -
Raw Materials 3-Acetylphenothiazine Phosgene γ-Dimethylaminopropyl alcohol Manufacturing Process 120 g 3-acetylphenothiazine (0.479 mol) are heated to the boil in 1.2 L xylene and a rapid stream of phosgene then passed in for a period of 12 hours. The solvent is then removed by distillation and the residue taken up in 1 L benzene. The benzene solution is heated to the boil and 112 g of γdimethylaminopropyl alcohol (1.09 mol) are added within a period of 15 min and the reaction mixture boiled for a further 2 hours. After cooling, the precipitated hydrochloride of the γ-dimethylaminopropyl alcohol washed with benzene and the combined benzene solutions rapidly washed with water in order to remove excess basic alcohol. The material is dried over potash and the hydrochloride precipitated by means of ethereal hydrochloric acid. The
Aceprometazine
41
hydrochloride may also be precipitated by passing in gaseous hydrogen chloride. After recrystallisation from isopropanol, 157 g (78% of theory) of γdimethylaminopropyl 3-acetylphenothiazine-10-carboxylate are obtained. The hydrochloride melts at 212°C. In practice it is usually used as maleate salt. References Hoerlein U. et al,; DE Patent No. 1,049,865; Assigned to Farbenfabriken Bayer Aktiengesellschaft, Leverkusen-Bayerwerk GB Patent No. 808,050; Jan. 28,1959; BAYER AG
ACEPROMETAZINE Therapeutic Function: Neuroleptic, Antitussive Chemical Name: Ethanone, 1-(10-(2-(dimethylamino)propyl)-10Hphenothiazin-2-yl)Common Name: Aceprometazine Structural Formula:
Chemical Abstracts Registry No.: 13461-01-3 Trade Name
Manufacturer
Country
Year Introduced
Aceprometazine
ZYF Pharm Chemical
-
-
Raw Materials 2-Acetylphenothiazine 1-Dimethylamino-2-chloropropane Sodium hydride Manufacturing Process In a 1 liter flask, equipped with stirrer, thermometer and nitrogen inlet, 241.0 g of 2-acetylphenothiazine (1 mole) is dissolved in 300 ml of dry dimethylformamide. When the 2-acetylphenothiazine is almost completely soluble, to this solution is added 275 ml of a 4 N solution of 1-dimethylamino2-chloropropane in toluene.
42
Acesulfame potassium
The mixture is heated to 50°C and 26.0 g (1.08 moles) of sodium hydride is added portion-wise, maintaining the temperature at 50°-60°C. The addition should take about 1 h. The reaction is allowed to stir for 3 h at 50°-60°C. Any excess hydride is destroyed by the cautious addition of 10 ml methanol, and the reaction mix is poured into 800 ml of 20% acetic acid. The toluene layer is separated and extracted with 150 ml of 20% acetic acid, and discarded. The acid solutions are combined and washed once with toluene. The toluene is discarded. Fresh toluene (200 ml) is added and caustic solution is added with cooling and stirring until the pH is 9 or above. The toluene layer is separated. The aqueous layer is extracted once more with 75 ml of toluene and discarded. The toluene extracts are combined, given a small water wash, and concentrated. The residue is distilled yielding 10-[2(dimethylamino)propyl]-2-acetylphenothiazine. References Kantor M.L., Tubis S.; US Patent No. 3,100,772; August 13, 1963; Assigned: America Home Products Corporation, New York, N.Y.
ACESULFAME POTASSIUM Therapeutic Function: Pharmaceutic aid Chemical Name: 6-Methyl-1,2,3-oxathiazin-4(3H)-one 2,2-dioxide potassium salt Common Name: Acetylfame K, Acetylfame potassium Structural Formula:
Chemical Abstracts Registry No.: 55589-62-3; 33665-90-6 (Base) Trade Name Acesulfame Potassium Acesulfame K Acesulfame Potassium Acesulfame K Acesulphame K
Manufacturer Hoechst
Country -
Year Introduced -
Wuzhou international Co., Ltd. Zhang Peng International
-
-
-
-
AroKor Holdings Inc.
-
-
Acroyali Holdings Qingdao Co., Ltd.
-
-
Acetaminophen Trade Name
Manufacturer
Acesulfame K
Zhangjiagang Hope Chemicals Co., Ltd. VitaSweet Ace K VitaSweet
43
Country
Year Introduced
-
-
-
-
Raw Materials Dimethylethylamine Sulfamic acid Sulfur trioxide Manufacturing Process 80 g (1.096 mol) of dimethylethylamine were added drop-wise, with cooling, to 80 g (0.825 mol) of sulfamic acid suspended in 500 ml of glacial acetic acid. When dissolution was complete, 80 ml (1.038 mol) of diketene were added, while cooling at 25°-35°C. After 16 hours, the mixture was evaporated and the residue was stirred with acetone, whereupon crystallization of dimethylethylammonium acetoacetamide-N-sulfonate took place. Yield: 110 g (43%), melting point 73°-75°C. 12.7 g (50 mmol) of dimethylethylammonium acetoacetamide-N-sulfonate in 110 ml of methylene chloride were added drop-wise to 8 ml (200 mmol) of liquid SO3 in 100 ml of CH2Cl2 at -30°C, stirring vigorously, within 60 minutes. 30 minutes later, 50 ml of ethyl acetate and 50 g of ice were added to the solution. The organic phase was separated off, and the aqueous phase was extracted twice more with ethyl acetate. The combined organic phases were dried over sodium sulfate, evaporated and the residue was dissolved in methanol. On neutralization of the solution with methanolic KOH, the potassium salt of 6-methyl-3,4-dihydro-1,2,3-oxathiazin-4-one 2,2-dioxide precipitated out. Yield: 7.3 g (73%). The product was detected by thinlayer chromatography; the structure of it was confirmed with IR spectrum. References Clauss K. et al.; US Patent No. 5,103,046; April 7, 1992; Assigned to Hoechst Aktiengesellschaft Frankfurt am Main, DE)
ACETAMINOPHEN Therapeutic Function: Analgesic, Antipyretic Chemical Name: N-(4-Hydroxyphenyl)acetamide Common Name: Paracetamol; Acetyl-p-aminophenol; APAP Chemical Abstracts Registry No.: 103-90-2
44
Acetaminophen
Structural Formula:
Trade Name
Manufacturer
Country
Year Introduced
Trigesic
Squibb
US
1950
Apamide
Ames
US
1952
Nebs
Norwich Eaton
US
1955
Tylenol
McNeil
US
1955
Febrolin
Tilden Yates
US
1957
Tempra
Mead Johnson
US
1957
Fendon
Am. Pharm.
US
1958
Amdil
Breon
US
1958
Lyteca
Westerfield
US
1962
Menalgesia
Clapp
US
1963
Dial-Agesic
Borden
US
1968
Tenlap
Dow
US
1970
SK-APAP
SK and F
US
1971
Valadol Tablets
Squibb
US
1971
Tapar
Parke Davis
US
1974
Cen-Apap
Central
US
1974
Acephen
G and W
US
1978
St. Joseph Aspirin St. Joseph
US
1982
Panadol
Glenbrook
US
1983
Pain and Fever
Lederle
US
-
Accu-Tap
Accu-Med
US
-
Actamin
Buffington
US
-
Am inofen
Dover
US
-
Anuphen
Comatic
US
-
Dapa
Ferndale
US
-
Datril
Bristol-Myers
US
-
Dirox
Winthrop
US
-
Dolanex
Lannett
US
-
Febrogesic
First Texas
US
-
Halenol
Halsey
US
-
Hedex
Winthrop
US
-
Homoolan
Winthrop
US
-
Injectapap
Johnson and Johnson
US
-
Korum
Geneva
US
-
Metalid
Philips Roxane
US
-
Minotal
Carnrick
US
-
Acetaminophen
45
Trade Name
Manufacturer
Country
Year Introduced
Neopap
Webcon
US
-
Neotrend
Bristol-Myers
US
-
Nilprin
AVP
US
-
Panamax
Winthrop
US
-
Panodil
Winthrop
US
-
Parten
Parmed
US
-
Phenaphen
Robins
US
-
Phendex
Mallard
US
-
Phrenilin
Carnrick
US
-
Prompt
Delree
US
-
Proval
Reid-Provident
US
-
Robigesic
Robins
US
-
Valorin
Otis Clapp
US
-
Abrol
Rekah
Israel
-
Abrolet
Rekah
Israel
-
Acamol
Ikapharm
Israel
-
Acetalgin
Streuli
Switz.
-
Aldolor
Novis
Israel
-
Alpiny
SS Pharmaceutical
Japan
-
Alvedon
Draco
Sweden
-
Anaflon
Duphar
UK
-
Anhiba
Hokuriku
Japan
-
APA/Aparacet
Arcana
Austria
-
Apiretal
Ern
Spain
-
Arasol
Horner
Canada
-
Benmyo
Heilmittelwerke Wien Austria
-
Ben-U-Ron
Benechemie
W. Germany
-
Calpol
Calmic
UK
-
Campain
Winthrop
Canada
-
Ceetamol
Protea
Australia
-
Cetadol
Rybar
UK
-
Chemcetaphen
Chemo-Drug
Canada
-
Dipramat Infantil
Byk Gulden
W. Germany
-
Dolamin
Nyal
Australia
-
Doliprane
Bottu
France
-
Dolprone
Siegfried
W. Germany
-
Dymadon
Calmic
UK
-
Efferalgan
UPSA
France
-
Enelfa
Dolorgiet
W. Germany
-
Exdol
Merck-Frosst
Canada
-
Febrilix
Boots
UK
-
46
Acetaminophen
Trade Name
Manufacturer
Country
Year Introduced
Finimal
Mepros
Netherlands
-
Finimal
Pharmaton
Switz.
-
Gelocatil
Gelos
Spain
-
Ildamol
Rekah
Israel
-
Kinder-Finiweh
Cesmopharma
Netherlands
-
Kratofin
Kwizda
Austria
-
Labamol
Vitamed
Israel
-
Langesic
Boots
UK
-
Letamol
Letap
Switz.
-
Momentum
Much
W. Germany
-
Myalgin
Allied Labs
UK
-
Napional
Pharma Import
Austria
-
Nealgyl
Bottu
France
-
Nevral
Lepetit
Italy
-
Pacemo
Alpinapharm
Switz.
-
Pacet
Rekah
Israel
-
Painex
A.L.
Norway
-
Pamol
Marshalls Pharm.
UK
-
Panacete
Prosana
Australia
-
Panadol
Sterwin Espanola
Spain
-
Panadon
Isis
Yugoslavia
-
Panasorb
Winthrop
UK
-
Panasorb
Bayer
W. Germany
-
Panok
B.M. Labs
UK
-
Pantalgin
UCB
Belgium
-
Paracet
Zdravlje
Yugoslavia
-
Paracet
Weifa
Norway
-
Paralgin
ICN
Canada
-
Paramol
Duncan Flockhart
UK
-
Paramolan
Trima
Israel
-
Parasin
Adams
Australia
-
Paraspen
Fisons
UK
-
Para-Suppo
Orion
Finland
-
Parmol
Knoll
Australia
-
Parol
Atabay
Turkey
-
Pasolind
Stada
W. Germany
-
PCM
Napp
UK
-
Pediaphen
Ross
Canada
-
Phenipirin
Aksu
Turkey
-
Pinex
A.L.
Norway
-
Acetaminophen
47
Trade Name
Manufacturer
Country
Year Introduced
Puernol
Formenti
Italy
-
Pyrinazin
Yamanouchi
Japan
-
Pyrital
Medica
Finland
-
Reliv
ACO
Sweden
-
Rivalgyl
Rivopharm
Switz.
-
Rounox
Rougier
Canada
-
Servigesic
Servipharm
Switz.
-
Setamol
Pharmacia
Sweden
-
Setol
Dif-Dogu
Turkey
-
Supramol
Sam-On
Israel
-
Tabalgin
Bayer
W. Germany
-
Tachipirina
Angelini
Italy
-
Temperal
Prodes
Spain
-
Trenodin
Fresenius
W. Germany
-
Tymol
Reckitt and Colman
W. Germany
-
Veralydon
Lelong
France
Raw Materials Nitrobenzene Acetic anhydride Manufacturing Process About 250 ml of a reaction mixture obtained by the electrolytic reduction of nitrobenzene in sulfuric acid solution and containing about 23 grams of paminophenol by assay is neutralized while at a temperature of 60°C to 65°C, to a pH of 4.5 with calcium carbonate. The calcium sulfate precipitate which forms is filtered off, the precipitate washed with hot water at about 65°C and the filtrate and wash water then combined. The solution is then extracted twice with 25 ml portions of benzene and the aqueous phase is treated with 0.5 part by weight, for each part of p-aminophenol present, of activated carbon and the latter filtered off. The activated carbon is regenerated by treatment with hot dilute caustic followed by a hot dilute acid wash, and reused a minimum of three times. To the filtrate obtained, there are then added about 0.2 gram of sodium hydrosulfite or sodium sulfite and 15.0 grams of anhydrous sodium acetate in about 27 grams of acetic anhydride at 40°C. The reaction mixture formed is cooled to 8°C to 10°C with stirring and held at this temperature for 60 minutes. A crystalline precipitate of about 27 grams of N-acetyl-paminophenol is obtained melting at 169-171°C. This is equivalent to a yield of 85%. In lieu of utilizing calcium carbonate as the neutralizing agent, calcium hydroxide, barium hydroxide, barium chloride or other alkaline earth metal salt or hydroxide forming an insoluble sulfate may be employed.
48
Acetaminosalol
References Merck Index 39 Kleeman and Engel p. 684 PDR p. Many References OCDS Vol. 1 p. 111 (1977) DOT 16 (2) p. 59 (1980) I.N. p. 728 REM p. 1111 Wilbert,G. and De Angelis, J.; US Patent 2,998,450; August 29, 1961; Assigned to Warner-Lambert Pharmaceutical Company
ACETAMINOSALOL Therapeutic Function: Analgesic, Antineuralgic, Antirheumatic, Antipyretic Chemical Name: 2-Hydroxybenzoic acid 4-(acetylamino)phenyl ester Common Name: Acetamidosalol; Acetaminosal; Acetylparaminosalol; Acetaminosalol; Phenetsal Structural Formula:
Chemical Abstracts Registry No.: 118-57-0 Trade Name
Manufacturer
Country
Year Introduced
Acetaminosal
ZYF Pharm Chemical
-
-
Raw Materials N-Acetyl-p-aminophenol Acetyl salicylic chloride
Sodium hydroxide Acid chloride
Manufacturing Process 2 Methods of producing of acetyl salicylic acid ester of N-acetyl-paminophenol: 1. 65.0 g of N-acetyl-p-aminophenol were slurried with 400 ml of water and cooled to 10°C. 125 ml of 20% sodium hydroxide were slowly added to the mixture with stirring, the temperature being maintained 10°-15°C. To the solution obtained, 75.0 g of acetyl salicylic chloride were added with vigorous stirring over a period of 0.5 h, the solution being maintained at a temperature
Acetarsol
49
of about 10°C. Towards the end of the reaction the pH was checked and adjusted to greater than 10 by the addition of a small amount of 20% sodium hydroxide. After all the acid chloride had been added, vigorous stirring was continued for 0.5 h during which time the crude product separated out. The acetyl salicylic acid ester of N-acetyl-p-aminophenol was filtered off, washed thoroughly with water and recrystallised from ethanol. 2. 65.0 g of sodium N-acetyl-p-aminophenol were slurried with 500.0 g of dry benzene and 80.0 g of acetyl salicylic chloride added. The mixture was heated under reflux for 4 h and filtered hot. The excess benzene was removed under vacuum and the crude acetyl salicylic acid ester of N-acetyl-p-aminophenol crystallized from ethanol. References Robertson A.; US Patent No. 3,431,293; March 4, 1969; Assigned: Sterling Drug Inc., New York, N.Y.
ACETARSOL Therapeutic Function: Antiprotozoal, Tonic Chemical Name: Arsonic acid, (3-(acetylamino)-4-hydroxyphenyl)Common Name: Acetarsol; Acetarsone; Osarsol(um) Structural Formula:
Chemical Abstracts Registry No.: 97-44-9 Trade Name Acetarsol
Manufacturer Cyklo Pharma Chem Pvt. Ltd.
Country -
Year Introduced -
Acetarsol Fluoryl Gynoplix Laryngarsol Nilacid Orarsan Osarbon
Nizhpharm AFI Theraplix Sanofi-Synthelabo Sanofi-Synthelabo Boots Nizhpharm
-
-
50
Acetazolamide
Trade Name
Manufacturer
Country
Year Introduced
Pallicid
Wander
-
-
Spirocid
Hoechst
-
-
Stovarsol
Abbott
-
-
Raw Materials 4-Chloroaniline Hydrogen chloride Sodium hydroxide Sodium thiosulfate
Sodium nitrite Sodium arsenite Nitric acid/Sulfuric acid Acetic anhydride
Manufacturing Process 1 part of 4-chloroaniline is dissolved with 2 parts of concentrated hydrochloric acid (specific gravity 1.16) and 10 parts of water, and diazotised in the usual manner. 3 parts of sodium arsenite are introduced into the diazo solution thus obtained, the sodium arsenite being dissolved in 5 parts of water and 1 part of 96% ethanol. The solution is heated slowly to 70°C. When evolution of nitrogene ceased, it is filtered from separated oil and the addition of hydrochloric acid precipitates the 4-chlorophenylarsonic acid, which crystallizes out in the form of white needles. By action HNO3/H2SO4 on 4-chlorophenylarsonic acid is obtained 4-chloro-3nitrophenylarsonic acid which is converted at 100°C with 33% aqueous solution of sodium hydroxide to 4-hydroxy-3-nitrophenylarsonic acid. After reduction of NO2 group of 4-hydroxy-3-nitrophenylarsonic acid by the action of Na2S2O3 or Fe/NaOH is obtained 3-amino-4-hydroxyphenylarsonic acid. From 3-amino-4-hydroxyphenylarsonic acid and acetic anhydride is prepared N-acetyl-4-hydroxy-m-arsanilic acid. References Bart H.; GB Patent No. 568; Jan. 9, 1911 GB Patent No. 5595; 06.03.1911; Assigned to Farbwerke vorm. Meister, Lucius, and Bruning, Hoechst, Germany
ACETAZOLAMIDE Therapeutic Function: Carbonic anhydrase inhibitor, Diuretic, Antiglaucoma Chemical Name: N-[5-(Aminosulfonyl)-1,3,4-thiadiazol-2-yl]acetamide Common Name: Chemical Abstracts Registry No.: 59-66-5
Acetazolamide
51
Structural Formula:
Trade Name Diamox Hydrazole Acetamide Acetamox Acetazolam Acetazolamide Chibret Albox Atenezol Defiltran Diazomid Diamox Didoc Diluran Diuramid DirureticumHolzinger
Manufacturer Lederle Softcon Products Nessa Santen ICN Chibret
Country US US Spain Japan Canada France
Year Introduced 1953 1975 -
Kwizda Tsuruhara Jouveinal Dif-Dogu Theraplix Sawai Spofa Polfa Holzinger
Austria Japan France Turkey France Japan Czechoslovakia Poland Austria
-
Diuriwas Donmox Edemox Glauconox Glaupax Glaupax Gleupax Inidrase
Wassermann Hona Wassermann Llorens Erco Baeschlin Dispersa Omikron-Gagliardi
Italy Japan Spain Spain Denmark W. Germany Switz. Italy
-
Nephramid Oedemin Renamid Uramox Zohnox
Chemiek Astra Pliva Taro Konto
E. Germany Sweden Yugoslavia Israel Japan
-
Raw Materials Hydrazine hydrate Ammonium thiocyanate Acetic anhydride Chlorine Ammonia Bromine
52
Acetazolamide
Manufacturing Process According to REM, hydrazine hydrate is reacted with 2 mols of ammonium thiocyanate to produce 1,2-bis(thiocarbamoyl)hydrazine which by loss of ammonia and rearrangement produces 5-amino-2-mercapto-1,3,4-thiadiazole. That compound is acetyled with acetic anhydride. Then, as described in US Patent 2,554,816, the 2-acetylamido-5-mercapto1,3,4-thiadiazole is converted to the sulfonyl chloride by passing chlorine gas into a cooled (5-10°C) solution in 33% acetic acid (66 parts to 4 parts of mercapto compound) used as a reaction medium. Chlorine treatment is continued for two hours. The crude product can be dried and purified by recrystallization from ethylene chloride. The pure compound is a white crystalline solid, MP 194°C, with decomposition, when heated rapidly. The crude damp sulfonyl chloride is converted to the sulfonamide by addition to a large excess of liquid ammonia. The product is purified by recrystallization from water. The pure compound is a white, crystalline solid, MP 259°C, with decomposition. The yield of sulfonamide was 85% of theory based on mercapto compound. An alternative process is described in US Patent 2,980,679 as follows. 15 grams of finely powdered 2-acetylamino-1,3,4-thiadiazole-5-mercaptain are suspended in 200 ml of water containing 4 grams of potassium bromide. From 0.5 to 1 gram of ferric chloride are subsequently added. The mass is energetically stirred and 52 grams of liquid bromide are added by increments for about 45 minutes, while keeping the reaction temperature below 10°C, and, preferably, at 4-8°C by employing a cooling bath. Stirring is continued for a further 10 minutes, then the 2-acetylamino-1,3,4-thiadiazole-5sulfobromide is collected on a funnel equipped with a porous diaphragm, thoroughly washed with cold water and finally subjected to amidation with liquid ammonia. The reaction mixture is allowed to stand for a certain period, then the ammonia is evaporated, after which the residue is taken up with diluted ammonia and, after decolorizing with carbon, the sulfonamide is precipitated with hydrochloric acid. The yield of crude sulfonamide obtained with this process, with respect to the starting mercapto compound is abut 84%. If the amidation is carried out with 33% aqueous ammonia, the yield is slightly lower. References Merck Index 45 Kleeman and Engel p. 6 PDR pp. 830, 1008, 1606 OCDS Vol. 1 p. 249 (1977) I.N. p. 5 REM p.936 Clapp, J.W. and Roblin, R.O., Jr.; US Patent 2,554,816; May 29, 1951; Assigned to Americar Cyanamid Company Gianfranco, P.; US Patent 2,980,679; April 18, 1961; Assigned to OmikronGagliardi Societa di Fatto, Italy
Acetohexamide
53
ACETIROMATE Therapeutic Function: Antihyperlipidemic Chemical Name: Benzoic acid, 4-(4-hydroxy-3-iodophenoxy)-3,5-diiodo-, acetate Common Name: Acetiromate; Adecol Structural Formula:
Chemical Abstracts Registry No.: 2260-08-4 Trade Name
Manufacturer
Country
Year Introduced
Acetiromate
ZYF Pharm Chemical
-
-
Raw Materials 3,5-Diiodo-4-(3-iodo-4-hydroxyphenoxy)benzoic acid Acetic anhydride Manufacturing Process To 3 parts of 3,5-diiodo-4-(3-iodo-4-hydroxyphenoxy)benzoic acid 10 parts of acetic acid anhydride was added and mixture was heated on oil bath for some hours. In the result of this reaction amorphous precipitate was obtained. After recrystallization from glacial acetic acid 2.4 parts of 3,5-diiodo-4-(3-iodo-4acetoxyphenoxy)benzoic acid were obtained. References Fr. Patent No. M1610; Dec. 10, 1962; Assigned: Takeda Chemical Industries, LTD
ACETOHEXAMIDE Therapeutic Function: Hypoglycemic
54
Acetohexamide
Chemical Name: 1-[(p-Acetylphenyl)sulfonyl]-3-cyclohexylurea Common Name: Cyclamide Structural Formula:
Chemical Abstracts Registry No.: 968-81-0 Trade Name
Manufacturer
Country
Year Introduced
Dymelor
Lilly
US
1964
Dimelin
Shionogi
Japan
-
Dimelor
Lilly
UK
-
Gamadiabet
Salvat
Spain
-
Metaglucina
Perga
Spain
-
Ordimel
Lilly
Spain
-
Raw Materials Sodium nitrite Hydrogen chloride Ammonia
p-Aminoacetophenone Sulfur dioxide Cyclohexyl isocyanate
Manufacturing Process Preparation of p-Acetylbenzenesulfonamide: 100 grams of paminoacetophenone were dissolved in a solvent mixture containing 165 ml of 12 N hydrochloric acid and 165 ml of glacial acetic acid. The mixture was cooled with stirring to about 0°C. A solution containing 56.2 grams of sodium nitrite and 175 ml of water was added dropwise with stirring to the acidic solution while maintaining the temperature below 5°C. After the addition had been completed, the acidic solution containing pacetylphenyldiazonium chloride formed in the above reaction was added dropwise with stirring to a mixture of 530 ml of glacial acetic acid and 530 ml of benzene which had been previously cooled, and the cooled solution saturated with sulfur dioxide and to which had been added 34 g of cupric chloride dihydrate. After the addition had been completed, the reaction mixture was stirred at about 40°C for three hours, and was then poured into 3,000 ml of an ice-water mixture. The benzene layer containing p-acetylbenzenesulfonyl chloride formed in the above reaction was separated, and the acidic aqueous phase was extracted twice with 250 ml portions of benzene. The benzene layers were combined, the combined extracts were filtered, and the benzene was evaporated from the resulting filtrate in vacuum.
Acetohydroxamic acid
55
The solid residue comprising p-acetylbenzenesulfonyl chloride was dissolved in 100 ml of dioxane, and the solution was added to 200 ml of 14% aqueous ammonium hydroxide. The resulting solution was stirred overnight at ambient room temperature. The p-acetylbenzenesulfonamide thus prepared was collected by filtration. Recrystallization of the filter cake from aqueous ethanol yielded purified p-acetylbenzenesulfonamide melting at about 176°C to 179°C. Preparation of N-p-Acetylphenylsulfonyl-N'-Cyclohexylurea: A reaction mixture consisting of 32.7 grams of p-acetylbenzenesulfonamide and 64 grams of anhydrous potassium carbonate in 350 ml of anhydrous acetone was stirred at refluxing temperature for about 1% hours, thus forming the potassium salt of p-acetylbenzenesulfonamide. 30.9 grams of cyclohexylisocyanate were added dropwise to the reaction mixture. Refluxing and stirring were continued during the course of the addition and for an additional 16 hours. The acetone was removed by evaporation in vacuum, and about 750 ml of water were added to dissolve the resulting residue. The solution was filtered. The potassium salt of N-p-acetylphenylsulfonyl-N'-cyclohexylurea formed in the above reaction, being water-soluble, passed into the filtrate. Acidification of the filtrate with 6 N aqueous hydrochloric acid caused the precipitation of N-p-acetylphenylsulfonyl-N'-cyclohexylurea which was collected by filtration. Recrystallization of the filter cake from 90% aqueous ethanol yielded purified N-p-acetylphenylsulfonyl-N'-cyclohexylurea melting at about 188-190°C. References Merck Index 53 Kleeman and Engel p. 7 PDR p. 1049 OCDS Vol. 1 p. 138 (1977) I.N. p. 6 REM p.976 Sigal, M.V., Jr. and Van Arendonk, A.M.; US Patent 3,320,312; May 16, 1967; Assigned to Eli Lilly and Company.
ACETOHYDROXAMIC ACID Therapeutic Function: Urease inhibitor Chemical Name: Acetamide, N-hydroxyCommon Name: Acetohydroxamic acid; Uronefrex Structural Formula:
Chemical Abstracts Registry No.: 546-88-3
56
Acetophenazine dimaleate
Trade Name Lithostat Uronefrex
Manufacturer Country Mission Pharmacal Co. Robert -
Year Introduced -
Raw Materials Hydroxylamine Acetamide Nitrohydroxylamine
Ethyl acetic acid ether Acetaldehyde
Manufacturing Process 3 Methods of producing of acetohydroxamic acid: 1. Ethyl acetic acid ether was treated with hydroxylamine and acetohydroxamic acid was obtained. 2. Acetohydroxamic acid was obtained in the result of reaction of acetamide with hydroxylamine. 3. Acetohydroxamic acid was obtained by treatment of acetaldehyde with nitrohydroxylamine. References Karrer P.; Lehrbuch der organischen chemie; Stuttgart; 1959; 1216 s.
ACETOPHENAZINE DIMALEATE Therapeutic Function: Tranquilizer Chemical Name: 10-[3-[4-(2-Hydroxyethyl)-1-piperazinyl]propyl] phenothiazin-2-yl methyl ketone maleate Common Name: Structural Formula:
Acetoxolone aluminum salt
57
Chemical Abstracts Registry No.: 5714-00-1; 2751-68-0 (Base) Trade Name
Manufacturer
Country
Year Introduced
Tindal
Schering
US
1961
Raw Materials 2-Acetylphenothiazine Sodium amide 1-Bromo-3-chloropropane Maleic acid 1-(2-Hydroxyethyl)piperazine Manufacturing Process The requisite intermediate, 10-(3-chloropropyl)-2-acetylphenothiazineis prepared as follows: To a suspension of sodium amide (from 3 grams of sodium) in 300 ml of liquid ammonia is added 30 grams of 2acetylphenothiazine. After stirring for one hour, there is added 19 grams of 1bromo-3-chloropropane. The ammonia is allowed to evaporate and the residue is diluted with 200 ml of water. The mixture is extracted with ether and the ether solution is dried over anhydrous sodium sulfate, filtered and concentrated. The residue consists of crude 10-(3-chloropropy1)-2-acetylphenothiazine as a viscous oil and is used in the next step without further purification. The crude base obtained from the reaction of 10-(3-chloropropyl)-2-acetylphenothiazine with 1-(2-hydroxyethyl)piperazine is purified by conversion to its dimaleate salt, MP 167-168.5°C from ethanol. References Merck Index 64 Kleeman and Engel p. 7 OCDS Vol. 1 p. 383 (1977) I.N. p. 6 REM p. 1086 Sherlock, M.H. and Sperber, N.; US Patent 2,985,654; May 23, 1961; Assigned to Schering Corporation, Bloomfield, N.J.., a corporation of a New Jersey
ACETOXOLONE ALUMINUM SALT Therapeutic Function: Antiulcer Chemical Name: 3-(Acetyloxy)-11-oxoolean-12-en-29-oic acid aluminum salt Common Name: Chemical Abstracts Registry No.: 6277-14-1 (Base)
58
Acetoxolone aluminum salt
Structural Formula:
Trade Name
Manufacturer
Country
Year Introduced
Oriens
Inverni Beffa
Italy
1981
Raw Materials 3-Acetyl-18β-glycyrrhetinic acid Aluminum alcoholate Manufacturing Process The salts of 3-acetyl-18β-glycyrrhetinic acid can be prepared by reaction between 3-acetyl-18β-glycyrrhetinic acid and an aluminum alcoholate. Preferably lower alcoholates are used, i.e., alcoholates in which the alkoxy group or groups have from one to four carbon atoms. The salification reaction may be carried out at room temperature or at an elevated temperature in conventional fashion, preferably in the presence of organic solvents. As organic solvents may be used alcohols, ethers, ketones, chlorinated solvents (methylene chloride, chloroform) ethyl acetate, etc. References Merck Index 70 Bonati, A.; US Patent 3,764,618; October 9,1973; Assigned to Dott. Inverni and Della Befia S.P.A.
Acetrizoate sodium
59
ACETRIZOATE SODIUM Therapeutic Function: Diagnostic aid (radiopaque medium) Chemical Name: 3-(Acetylamino)-2,4,6-triiodobenzoic acid sodium salt Common Name: Structural Formula:
Chemical Abstracts Registry No.: 129-63-5 Trade Name Urokon Sodium Thixokon Cystokon Pyelokon-R Salpix Diaginol Diaginol Vasurix Fortombrin Iodopaque Triurol
Manufacturer Mallinckrodt Inc. Mallinckrodt Inc. Mallinckrodt Inc. Mallinckrodt Inc. Ortho May and Baker Banyu Guerbet Dagra Labaz Lundbeck
Country US US US US US UK Japan France Netherlands Switz. Denmark
Year Introduced 1950 1957 1964 -
Raw Materials 3-Amino-2,4,6-triiodobenzoic acid Acetic anhydride Sodium hydroxide Manufacturing Process 3-Amino-2,4,6-triiodobenzoic acid (51.5 g) was mixed with 125 ml of acetic anhydride containing 2 drops of concentrated sulfuric acid and refluxed for thirty minutes. The mixture was allowed to cool slightly, and then was poured into 600 ml of water at room temperature and stirred until crystallization was complete. The mixed anhydride of 3-acetylamino-2,4,6-triiodobenzoic acid with acetic acid thus prepared was then separated by filtration and washed with water. Without drying, the solid was suspended in 600 ml of water and hydrolyzed with a slight excess of ammonium hydroxide. It was necessary to warm the mixture slightly and stir it for about one-half hour in order to dissolve all the solid. The solution was then treated with activated carbon, filtered and precipitated with an excess of hydrochloric acid, filtered, washed and dried at 70°C. The yield was 51.5 g of 3-acetylamino-2,4,6-triiodobenzoic
60
Acetyl sulfisoxazole
acid which melted at 276.6-278.2°C with decomposition when placed in the melting block at 260°C and heated at the rate of 3°C per minute. Due to decomposition, the melting point varied from about 269-280°C, depending upon the rate of heating and other conditions. 3-Acetylamino-2,4,6-triiodobenzoic acid (28 g) was dissolved in a little over 50 ml of 1 N sodium hydroxide in a round-bottom flask. The pH was adjusted to slightly over 7 and the solution was evaporated on a steam bath under reduced pressure. After the residue became solid, it was further dried overnight in a vacuum desiccator containing calcium chloride. The salt weighed 31.2 g, theory being 29.0 g, indicating that the product contains about 7% water of crystallization when dried under these conditions. The finished salt was scraped from the flask and ground. References Merck Index 73 Kleeman and Engel p. 8 I.N. p.7 Wallingford, V.H.; US Patent 2,611,786; September 23, 1952; Assigned to Mallinckrodt Chemical Works
ACETYL SULFISOXAZOLE Therapeutic Function: Antimicrobial Chemical Name: N-[(4-Aminophenyl)sulfonyl]-N-(3,4-dimethyl-5-isoxazolyl) sulfanilamide Common Name: Acetylsulfafurazol Structural Formula:
Chemical Abstracts Registry No.: 80-74-0 Trade Name Gantrisin Acetyl Lipo-Gantrisin Acetyl Pediazole Raw Materials Sulfisoxazole Acetic anhydride
Manufacturer Roche Roche Ross
Country US US US
Year Introduced 1954 1954 -
Acetylcysteine
61
Manufacturing Process 267 grams (1 mol) of sulfisoxazole were suspended in 400 ml of acetone and 79 grams (1 mol) of dry pyridine at 20-25°C in a round-bottom flask equipped with a stirrer and thermometer. 132 grams (1 mol) of acetic anhydride were added within 3 minutes with stirring. The sulfisoxazole dissolved in the mixture and a clear solution resulted. The temperature rose to 39-40°C. After stirring for several minutes, the product started to crystallize as a white crystalline mush. The temperature rose to 42-43°C maintained itself at this temperature for 15-30 minutes, and then started to drop. Stirring was continued for 5 hours and the mixture was then allowed to stand for 10 hours. One liter of 2.5-3.0% ice-cold aqueous ammonia and some fresh ice were then added while stirring and the crystals were filtered without delay. The crystals were washed on the filter with 1 liter of ice-cold 1% ammonia and then with 1 liter of water. The material on the filter was well pressed off, washed with 200-300 ml of alcohol and dried at 70°C to constant weight. The N-monoacetyl sulfisoxazole melted at 193-194°C and showed a positive Bratton-Marshall reaction and a positive Hucknall-Turfat reaction. The product is in the form of colorless crystals which are somewhat water repellent. It is insoluble in alkali but is saponified upon standing in alkaline suspension (3% ammonia). It is soluble in strong acids (20-36% HCl or 10 N H2SO4) and is rapidly saponified upon standing. References Merck Index 104 Kleeman and Engel p. 13 PDR pp. 1487, 1558 I.N. p. 10 Hoffer, Max; US Patent 2,721,200; October 18, 1955; Assigned to HoffmannLa Roche Inc.
ACETYLCYSTEINE Therapeutic Function: Expectorant Chemical Name: N-Acetyl-L-cysteine Common Name: Structural Formula:
Chemical Abstracts Registry No.: 616-91-1
62
Acetylcysteine
Trade Name Mucomyst Acetein Airbron Broncholysin Brunac Fabrol Fluimucetin Fluimucetin Fluimucil Inspir Mucolyticum Mucosolvin NAC Parvolex Mucomist Mucisol Rinofluimucil A.R.B. Mucofilin
Manufacturer Mead Johnson Senju BDH Spofa Bruschettini Ciba Zambon Inpharzam Zambon Vitrum Lappe VEB Berlin Chemie Mead Johnson Duncan Flockhart Bristol Deca Inpharzam Tokyo Tanabe Eisai
Country US Japan UK Czechoslovakia Italy Italy Belgium Italy Sweden W. Germany E. Germany UK Italy Italy W. Germany Japan Japan
Year Introduced -
Raw Materials L-Cysteine HCl Acetic anhydride Manufacturing Process To a suspension of 35.2 grams (0.2 mol) of L-cysteine hydrochloride monohydrate stirred in a reaction vessel containing 87 ml of 91% aqueous tetrahydrofuran under a nitrogen atmosphere there is added 54.4 grams (0.4 mol) of sodium acetate trihydrate. The mixture is stirred for 20 minutes at room temperature to insure neutralization of the hydrochloride salt resulting in the formation of a suspension of equimolar amounts of cysteine and sodium acetate. The mixture is then chilled to 3-6°C by external cooling and 20 ml (20.8 grams, 0.21 mol) of acetic anhydride is added thereto in dropwise fashion with cooling in the above range. The resulting mobile suspension is stirred for 6 hours at room temperature, allowed to stand overnight, and finally heated at reflux (72°C) for 4 hours. The resulting suspension of sodium N-acetyl-Lcysteinate is then neutralized by treatment at 5-10°C with 8 grams of hydrogen chloride. Resulting sodium chloride is removed by filtration and the product is isolated by distilling the solvent from the filtrate in vacuum and crystallizing the residue from 35 ml of water, yield 26.3 grams (80.6%) of Nacetylcysteine as a white solid, MP 109-110°C. References Merck Index 82 Kleeman and Engel p. 8
Acetyldigitoxin
63
PDR p. 1126 DOT 16 (2) p. 42 (1980) I.N. p. 8 REM p. 867 Martin, T.A. and Waller, C.W.; US Patent 3,184,505; May 18, 1965; Assigned to Mead Johnson and Company.
ACETYLDIGITOXIN Therapeutic Function: Cardiotonic Chemical Name: Card-20(22)-enolide, 3-((O-2,6-dideoxy-β-D-ribohexopyranosyl-(1.4)-O-2,6-dideoxy-beta-D-ribo-hexopyranosyl-(1.4)-2,6dideoxy-β-D-ribo-hexopyranosyl)oxy)-14-hydroxy-, monoacetate, (3β,5β)Common Name: Digitoxin monoacetate Structural Formula:
Chemical Abstracts Registry No.: 1111-39-3 Trade Name Acylanid Acygoxine Acylanide Acylanid Sandolanid
Manufacturer Sandoz Sandoz Sandoz Sandoz Sandoz
Country US France France Italy W. Germany
Year Introduced 1954 1972 1954 1966 1968
Raw Materials Digitalis Ferruginea Leaves Manufacturing Process Acetyldigitoxin-α can be obtained from acetyldigitoxin-β by heating it in an
64
β-Acetyldigitoxin
anhydrous or aqueous organic solvent at neutral, weakly acid or weakly alkaline pH, i.e., at a pH range from about 3.5 to about 8. The acetylidigitoxin-β used for this purpose is a cardiac glycoside which can be obtained either by splitting off the glucose residue from lanatoside A, or by extraction of the leaves of Digitalis ferrugines. It is composed of the aglycone digitoxigenin and 3 molecules of digitoxose, to one of which an acetyl group is attached. Acetyldigitoxin-α, obtained from acetyldigitoxin-β by rearrangement, differs from the latter in the position of the acetyl group. The process may be carried out, for example, in the following manner: A solution of acetyldigitoxin-β in a suitable solvent, such as methanol, is boiled under reflux and then diluted with water. The unchanged acetyldigitoxin-β, which crystallizes out first, is filtered off and can again be submitted to the same process. On concentrating the filtrate, acetyldigitoxin-α separates out in crystalline form and after filtering off and recrystallizing is obtained in a pure state. The acetyldigitoxin-α crystallizes from aqueous methanol in platelets melting at 217-221°C. References Merck Index 83 Kleeman and Engel p. 9 I.N. p.8 Stoll, A. and Kreis, W.; US Patent 2,776,963; January 8, 1957; Assigned to Sandoz, AG, Switzerland.
β-ACETYLDIGOXIN Therapeutic Function: Cardiotonic Chemical Name: Card-20(22)-enolide, 3-((O-4-O-acetyl-2,6-dideoxy-beta-dribo-hexopyranosyl-(1.4)-O-2,6-dideoxy-beta-d-ribo-hexopyranosyl-(1.4)2,6-dideoxy-beta-d-ribo-hexopyranosyl)oxy)-12,14-dihydroxy-, (3β,5β,12β)Common Name: beta-Acetyldigoxin; Betagoxinum Chemical Abstracts Registry No.: 5355-48-6 Trade Name
Manufacturer
Country
Year Introduced
Novodigal
Asta Medica Arzneimittel
-
-
Novodigal
Lilly
-
-
Digoxin
Didier
-
-
Digoxin
Elkins-Sinn
-
-
Digoxin
Roxane
-
-
Digoxin
Wyeth-Ayerst
-
-
β-Acetyldigitoxin
65
Trade Name
Manufacturer
Country
Year Introduced
Lanoxin
GlaxoSmithKline
-
-
Digitek
Bertek
-
-
Digoxin
Novartis
-
-
Corotal
Rosch and Handel
-
-
Structural Formula:
Raw Materials Crude partial acetylated digoxin Dicyclohexylcarbodiimide
Digoxin Acetic acid
Manufacturing Process Dried crude product of the partial acetylation of digoxin (42 g) prepared from digitalis - is dissolved under reflux in acetone (480 ml) and n-hexane (2400 ml) is added to the solution with stirring. Fine crystals, which begin to separate immediately, are left at room temperature for 5 hours, then they are filtered with suction, washed with n-hexane and dried in vacuum at 40°C, yielding 32 g of crude β-acetyldigoxin (product 1). Product 1 (31 g) is dissolved under reflux in chloroform (500 ml) and toluene (2500 ml) is added thereto with stirring. The crystals, which separate after standing for 6 hours at room temperature, are filtered, washed with toluene and ether and dried in vacuum yielding 29 g of β-acetyldigoxin (product 2). MP: 249°-251°C. The filtrate, which results from the separation of product 1, is evaparated to dryness in vacuum. The residue, which mainly contains unreacted digoxin, is purified by recrystallization from pyridine/ether/water (3.5:5:40) and repeatedly acetylated. It can then be recycled to produce more βacetyldigoxin. The filtrate resulting from the separation of product 2 is evaporated to dryness. The resulting residue contains the di- and polyacetyl derivatives of digoxin, which are deacetylated to digoxin in a known manner
66
Acetylmethadol
and later is returned to a further acetylation process and can then be recycled to produce more β-acetyldigoxin. Beta-Acetyldigoxin may be prepared from digoxin, acetic acid and dicyclohexylcarbodiimide using the last one as a condensing agent. References Pelan B. et al.; G.B. Patent No. 2,000,145 A; June 22, 1977 Haberland G., Arzneim.Forsh. 15, 481 (1965)
ACETYLMETHADOL Therapeutic Function: Narcotic analgesic Chemical Name: Benzeneethanol, β-(2-(dimethylamino)propyl)-α-ethyl-βphenyl-, acetate (ester) Common Name: Acemethadone; Acetyldimepheptanol; Acetylmethadol; Amidolacetat; Dimepheptanolacetat; Methadyl acetate; RaceAcetylmethadol Structural Formula:
Chemical Abstracts Registry No.: 509-74-0 Trade Name
Manufacturer
Country
Year Introduced
Acetylmethadol
National Inst. for Drug Abuse
-
-
ORLAAM
Roxane Laboratories, Inc.
-
Raw Materials Vinyl propionate Novozym 435 Sodium hydroxide Dibenzo-18-crown-6 Sodium borohydride
1-Dimethylamino-2-propanol Thionyl chloride Diphenylacetonitrile Hydrogen chloride Ethyl magnesium bromide
Acetylmethadol
67
Acetyl chloride Cerium (III) chloride heptahydrate Manufacturing Process Racemic 1-dimethylamino-2-propanol (100.0 g, 0.97 mol) was stirred with vinyl propionate (63.6 ml, 0.58 mol) at 40°C and Novozym 435 (5.0 g) was added. The reaction was stirred slowly for 75 h and after this time TLC (10% methanol/dichloromethane-visualize KMnO4 solution) indicated that the reaction had gone to at least 50% conversion. The enzyme was removed by filtration and the filtrate was distilled at reduced pressure. S-(+)-1Dimethylamino-2-propanol was obtained as a colourless oil (31.6 g, 64%), boil point 35°C. A solution of thionyl chloride (37 ml, 0.48 mol) in chloroform (20 ml) was added slowly, with stirring, to a cooled (ice/water) solution of S-(+)-1dimethylamino-2-propanol (30.6 g, 0.32 mol) in chloroform (85 ml). When the addition was complete a precipitate formed. The mixture was allowed to warm to room temperature over 30 min and then heated to reflux for a further 30 min. The precipitate redissolved on heating but then the product crystallized out from the boiling solvent as it formed. More chloroform (20 ml) was needed to maintain the stirring. The cooled mixture was diluted with ether and filtered. The 45.0 g (96%) of crude product was isolated. This was recrystallised from 2-propanol as in the other series to give 30.9 g (65%) of R-(-)-1-dimethylamino-2-chloropropane, melting point 192°-193°C. A 50% w/v solution of sodium hydroxide in water (12.5 ml, 0.32 mol) was added to a mechanically stirred suspension of diphenylacetonitrile (15.0 g,0.08 mol) and dibenzo-18-crown-6 (0.5 g, cat.) in dimethylsulphoxide (12.5 ml). The color rapidly deepened to an orange/brown. R-(-)-1-Dimethylamino2-chloropropane (30.0 g, 0.095 mol) was added in portions over 30 min, this caused the temperature to rise to 30°C. After the addition was complete the mixture was warmed to 45°-50°C (water bath) and stirred for a further hour. The reaction mixture was then allowed to cool to room temperature and was poured into ice/water (250 ml) and extracted with ethyl acetate (3 times 150 ml). The combined extracts were dried (MgSO4) and filtered and evaporated down to -100 ml. The product was extracted into 1N HCl (100 ml+50 ml) and this was back washed with ethyl acetate. The aqueous was basified with 2 M sodium hydroxide and extracted into ethyl acetate (3 times 100 ml). The extracts were washed with brine (70 ml), dried (MgSO4), and evaporated down to a yellow oil. This was chilled and triturated with cold hexane (50 ml) to give a white solid which was collected by filtration and washed thoroughly with a further portion of cold hexane (100 ml). 14.65 g (33%) of S-(+)-2,2diphenyl-4-dimethylaminopentanenitrile were obtained, melting point 100°101°C (recrystallised from hexane). All apparatus was dried and the reaction was carried out under an inert atmosphere of argon. A solution of S-(+)-2,2-diphenyl-4dimethylaminopentanenitrile (10.0 g, 0.018 mol) in toluene (15 ml) was added to a stirred solution of 3 M ethyl magnesium bromide in ether (10.7 ml, 0.03 mol). The ether was removed under reduced pressure and the remaining solution heated at reflux (135°-140°C) for 3 h. The solution went slightly cloudy but there was no significant precipitation. After cooling to room temperature 2 N HCl (30 ml) was added with care and then stirring was
68
Acexamic acid
continued at 135°-140°C for a further 30 min. The two phases were allowed to separate and cool to room temperature. After scratching the sides of the flask a solid started to crystallise from the aqueous phase. The flask was cooled to complete crystallisation and the white solid was collected by filtration. This solid was recrystallised from water to yield 6.6 g (53%) of S(+)-methadone hydrochloride (6-dimethylamino-4,4-diphenyl-3-heptanone hydrochloride) were obtained, melting point 240°-241°C. S-(+)-Methadone hydrochloride (600.0 mg,1.74 mmol) was dissolved in ethanol (10 ml) and the solution was stirred whilst sodium borohydride (3.47 mmol) was added portion-wise over a period of 5 min. When the addition was complete a spatula end of cerium (III) chloride heptahydrate was added. The resultant solution was allowed to stir at room temperature for 30 min then the ethanol was removed under reduced pressure. The residue was portioned between diethyl ether (40 ml) and water (40 ml). The aqueous layer was extracted with more diethyl ether (2 times 20 ml) and then the combined organics were washed with brine (40 ml) and dried (MgSO4). The ether was removed under reduced pressure to leave 435.0 mg, (80%) of 6dimethylamino-4,4-diphenyl-3-heptanol. 6-Dimethylamino-4,4-diphenyl-3-heptanol (435.0 mg, 1.40 mmol) dissolved in ethyl acetate (10 ml) was treated with acetyl chloride (183.0 mg, 2.33 mmol). The mixture was refluxed for 2 h. After allowing the solution to cool to room temperature the solvent was removed under reduced pressure to leave a white foam, this crystallised from ethyl acetate to give 6-dimethylamino-4,4diphenyl-3-acetoxyheptane hydrochloride (levo-α-acetyl methadol hydrochloride) (420.0 mg, 79%). The 6-dimethylamino-4,4-diphenyl-3-acetoxyheptane may be produced by treatment of the 6-dimethylamino-4,4-diphenyl-3-acetoxyheptane hydrochloride with sodium hydroxide. References Scheinmann F. et al.; US Patent No. 6,143,933; Nov. 7, 2000; Assigned: Salford Ultrafine Chemicals and Research Ltd., United Kingdom
ACEXAMIC ACID Therapeutic Function: Antifibrinolytic Chemical Name: Hexanoic acid, 6-(acetylamino)Common Name: Acexamic acid; Plastesol Structural Formula:
Acexamic acid
69
Chemical Abstracts Registry No.: 57-08-9 Trade Name Acexamic acid Acide Acexamicum Plastenan
Manufacturer Flamma ZYF Pharm Chemical Sanofi Winthrop
Country -
Year Introduced -
Raw Materials Calcium hydroxide Acetylcaprolactame Hydrogen chloride Manufacturing Process 400 L of demineralized water, 5.0 kg of calcium hydroxide, and 155.0 kg (1000 moles) of acetyl-caprolactame are introduced under stirring and at a temperature of about 25°C into a 1000 L stainless double walled reactor. The temperature is raised to 30°C. 75.0 kg of calcium hydroxide are introduced stepwise in the form of successive amounts of 2.0 kg each in the medium, under stirring and at a temperature adjusted and maintained 25°30°C through external cooling, in a manner such that the time required to introduce into the reactor the whole amount of calcium hydroxide approximates 1.5 h. When the stirring is stopped, the pH is about 7.5-7.8. The obtained mixture is stirred continuously at a temperature of 30°C during 14 h. At the end of this operation the pH is again adjusted at a value 7.5-7.8. The hydrolysate is filtered on a 60 x 60 pressfilter comprising 6 compartments and equipped with fabrics of the polyester known under the designation TERGAL which have been previously coated with a suspension of a cellulose commercialized under the trademark SOLKA FLOX BW20. The duration of filtration is of 1.5 h. 580 L of the filtrate are recovered and subjected to a concentration under reduced pressure in an evaporator the volume of which is of 750 L, at a distillation temperature ranging from 45°-50°C under a reduced pressure of 10-15 Torr. The operation is ran until concentration of the solution to 280 L, the concentrated solution being then left standing. The crystallisation is already considerable 2 h after the end of the operation of concentration. Crystallisation is ended after 16-24 h. The crystals are centrifuged at a speed of 700 revolutions/minute. The centrifuged crystals of calcium acexamate are washed twice on the centrifuge with 20 l of acetone. 107.0 kg of crystals are obtained, which are dried under vacuum at 40°C. The 96.0 kg of dry calcium acexamate obtained are ground and sifted. Acexamic acid may be produced by treatment of the calcium acexamate with HCl.
70
Acipimox
References Goulay J.; US Patent No. 3,974,215; Aug. 10, 1976; Assigned: Choay S.A., Paris, France
ACIPIMOX Therapeutic Function: Antihyperlipidemic Chemical Name: 2-Pyrazinecarboxylic acid, 5-methyl-, 4-oxide Common Name: Acipimox; Zopinox Structural Formula:
Chemical Abstracts Registry No.: 51037-30-0 Trade Name
Manufacturer
Country
Year Introduced
Olbetam
Pfizer
-
-
Nedios
Byk Pharmaceuticals
-
-
Olbemox
Pharmacia
-
-
Olbemox
Pfizer
-
-
Raw Materials Ethyl chloroformate Ammonia Hydrogen peroxide Hydrochloric acid
2-Carboxy-5-methylpyazine Acetic acid Sodium hydroxide
Manufacturing Process 2-Carboxy-5-methylpyazine (9.7 g) in dry dioxan (114 ml) and tributylamine (17.7 ml) was treated with ethyl chloroformate (7.5 ml), keeping the temperature at 0-5°C. After 10 min, dioxan (190 ml) saturated with ammonia was added. The mixture was stirred for 3 h at room temperature, then dioxin was distilled off, and the residue was taken up tin saturated aqueous sodium bicarbonate (20 ml). The mixture was filtered and the product washed with water to give 2-carbamoyl-5-methylpyrazine (9.2 g), melting point 204°206°C.
Acitazanolast
71
This 2-carbamoyl-5-methylpyrazine (7.0 g) in glacial acetic acid (30 ml) and 35% (w/v) hydrogen peroxide (20 ml) was heated with stirring at 70°C for 7 h. The reaction mixture was cooled, the product which separated was filtered and washed with water to give 2-carbamoyl-5-methylpyrazine-4-oxide (5.5 g), melting point 206°-208°C. 2-Carbamoyl-5-methylpyrazine 4-oxide (5.0 g) was added to 10% by weight sodium hydroxide (50 ml) and then refluxed for 30 min. The reaction mixture was acidified with dilute hydrochloric acid and extracted in a continuous extractor with ethyl acetate. The ethyl acetate extract was concentrated to small volume and gave, after filtration 2-carboxy-5-methylpyrazine 4-oxide (3.2 g), melting point 178°-180°C. References GB Patent No. 1,361,967; July 31, 1974; Assigned: CARLO ERBA SPA an Italian body corporate of Via Carlo Imbonati 24, 20159 Milan, Italy
ACITAZANOLAST Therapeutic Function: Anti-asthmatic, Antiallergic, Bronchodilator Chemical Name: Acetic acid, oxo-((3-(1H-tetrazol-5-yl)phenyl)amino)Common Name: Acitazanolast; Azitanolast; Zepenolast Structural Formula:
Chemical Abstracts Registry No.: 114607-46-4 Trade Name
Manufacturer
Country
Year Introduced
Zepelin
Kowa
-
-
Zepelin
Wakamoto
-
-
Raw Materials 3-(1H-Tetrazol-5-yl)aniline Oxalyl chloride Hydrochloric acid
Triethylamine Sodium hydroxide
72
Acitemate
Manufacturing Process 2 Methods of preparation of 3-(1H-tetrazol-5-yl)oxanilic acid: 1. 5.0 g of 3-(1H-tetrazol-5-yl)aniline was dissolved in 25 ml of N,Ndimethylformamide, followed by adding 5.68 g of triethylamine. Then, 5.64 g of ether oxalyl chloride was dropwise added to the solution while cooling in ice water. After completion of the dropwise addition, the reaction temperature was slowly raised up to room temperature and the reaction was continued for 15 h. After the reaction was completed, the reaction mixture was poured into 100 ml of ice water and crystals separated out from the solution was filtered off to obtain 8.3 g of ethyl 3-(1H-tetrazol-5-yl)oxanilate (yield 94.1%), melting point 192°-l93°C (recrystallized from acetone/n-hexane). The ethyl 3-(1H-tetrazol-5-yl)oxanilate (5.0 g), was dissolved in 35 ml of ethanol and 100 ml of 0.5 N sodium hydroxide was dropwise added thereto under water cooling. After the dropwise addition, the reaction temperature was slowly raised up to room temperature and under such condition, the reaction was carried out for 3 h. This solution was dropwise added to 70 ml of 4 N hydrochloric acid at room temperature. Thereafter, the solution was stirred for 1 h and crystals separated out from the solution was filtered off. The resultant crystals were washed with water and 3.9 g of 3-(1H-tetrazol-5yl)oxanilic acid was recovered (yield 87.4%), melting point 241°-243°C (dec. recrystallized from isopropyl). 2. Oxalyl chloride (12.0 g) was dissolved in 50 ml of anhydrous dimethoxyethane. To this solution a solution of 3-(1H-tetrazol-5-yl)aniline (5.0 g) in 250 ml of anhydrous dimethoxyethane was dropwise added over 3 h at room temperature while stirring. Insolubles were removed by filtering the solution, then 50 ml of water was gradually added to the reaction mixture under ice cooling and stirring was continued for 1 h at room temperature. Then, 500 ml of ethyl acetate was added thereto to carry out extraction, the extract was washed with water, dried over anhydrous sodium sulfate and then the solvent was distilled off to obtain 5.4 g of the 3-(1H-tetrazol-5- yl)oxanilic acid (yield 74.8%), melting point 241°-243°C (dec. recrystallized from isopropyl). References Sawaki S. et al.; US Patent No. 4,795,754; Jan. 3, 1989Assigned: Wakamoto Pharmaceutical Co., Ltd., Tokyo, Japan
ACITEMATE Therapeutic Function: Platelet aggregation inhibitor, Antihyperlipidemic Chemical Name: 3-(Ethoxycarbonyl)-6,7,8,9-tetrahydro-6-methyl-4-oxo-4Hpyrido[1,2-a]pyrimidine-9-acetic acid Common Name: Acitemate; Vapedrine
Acitemate
73
Structural Formula:
Chemical Abstracts Registry No.: 64405-40-9 Trade Name Acitemate
Manufacturer Onbio Inc.
Country -
Year Introduced -
Raw Materials 3-Ethoxycarbonyl-7-methyl-4-oxo-6,7,8,9-tetrahydro-4Hpyrido[1,2a]pyrimidine Palladium on carbon Glyoxylic acid monohydrate Hydrogen Manufacturing Process 23.6 g of 3-ethoxycarbonyl-7-methyl-4-oxo-6,7,8,9-tetrahydro-4Hpyrido[1,2a]pyrimidine and 10.0 g of glyoxylic acid monohydrate are reacted and the obtained 3-ethoxycarbonyl-7-methyl-9-carboxy(hydroxymethyl)-4oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2a]pyrimidine is heated in 150 ml ethanol under stirring for 3 h. After cooling the crystals are filtered off and recrystallized from ethanol. Thus 3-ethoxycarbonyl-7-methyl-9(carboxymethylene)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2a]pyrimidine melting point 110°-112°C, is obtained (yield: 51%). 55.6 g of 3-ethoxycarbonyl-9-(carboxymethylene)-4-oxo-6,7,8,9-tetrahydro4H-pyrido[1,2a]pyrimidine are hydrogenated in 500 ml of ethanol in the presence of 20.0 g of 9% by weight Pd/C catalyst containing metal. When 1 mole of hydrogen has been used up, the catalyst is removed from the reaction mixture by filtration and the solution is evaporated under reduced pressure. The 3-ethoxycarbonyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-9acetic acid is obtained (yield: 57%), melting point 156°-157°C (recrystallized from ethanol). References Hermecz I. et al.; US Patent No. 4,123,533; Oct. 31, 1978; Assigned: Chinoin Gyogyazer es Vegyeszeti Termekek Gyara R.T., Budapest, Hungary
74
Acitretin
ACITRETIN Therapeutic Function: Antipsoriatic Chemical Name: 2,4,6,8-Nonatetraenoic acid, 3,7-dimethyl-9-(4-methoxy2,3,6-trimethyl-phenyl)-, (all-E) Common Name: Acitretin; Etretin Structural Formula:
Chemical Abstracts Registry No.: 56079-83-9 Trade Name Acitretin Neotigason Neotigason Soriatane
Manufacturer Roche Roche Pty Limited Roche Roche Pharmaceuticals
Country Australia -
Year Introduced -
Raw Materials 5-(4-Methoxy-2,3,6-trimethylphenyl)-3-methylpenta-2,4-diene-1triphenylphosphonium bromide 3-Formylcrotonic acid butyl ester Sodium hydride Manufacturing Process 228 g of 5-(4-methoxy-2,3,6-trimethyl-phenyl)-3-methyl-penta-2,4-diene-1triphenylphosphonium bromide was added under nitrogen to 910 ml of dimethylformamide and treated at 5-10°C within 20 min. with 17.5 g of a suspension of sodium hydride (about 50% by weight) in mineral oil. The mixture was stirred for 1 hour at about 10°C, then 61.8 g of 3-formylcrotonic acid butyl ester was added dropwise at 5-8°C, a mixture was heated for 2 hours at 65°C, subsequently introduced into 8 L of ice-water, then was added 300 g of sodium chloride, and the mixture thoroughly extracted with a total 18 L of hexane. The extract was washed 5 times with 1 L of methanol/water (6:4 parts by volume) each time and 2 times with 1.5 L water each time, dried over sodium sulphate and evaporated under reduced pressure to leave 9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid butyl ester, m.p. 80-81°C. 125.8 g of this ester was introduced into 2 L of abs. ethanol and treated with a solution of 125.6 g of hydroxide in 195 ml of water. The mixture was heated
Acivicin
75
to boiling under nitrogen gassing for 30 minutes, then cooled, introduced into 10 L of ice-water and, after the addition of about 240 ml of conc. hydrochloric acid (pH 2-4), thoroughly extracted with total 9 L methylene chloride. Extract is washed with about 6 L water to neutrality, dried over calcium chloride and evaporated under reduced pressure. The residue is taken up in 700 ml of hexane. The precipitated 9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethylnona-2,4,6,8-tetraen-1-oic acid melts at 228-230°C. References W. Bollang, R. Ruegg, G. Ryser, US Patent No. 4,105,681, Aug. 8, 1978
ACIVICIN Therapeutic Function: Antineoplastic Chemical Name: 5-Isoxazoleacetic acid, α-amino-3-chloro-4,5-dihydro-, (S(R*,R*))Common Name: Acivicin; NSC-163501 Structural Formula:
Chemical Abstracts Registry No.: 42228-92-2 Trade Name
Manufacturer
Country
Year Introduced
Acivicin
ZYF Pharm Chemical
-
-
LKT-A0934-M010
LKT Laboratories, Inc.
-
-
Raw Materials cis-2-Buten-1,4-dio Trichloroacetonitrile Dibromoformaldoxime
Monotrichloroacetimidate tert-Butyl benzene Bromonitrile oxide
Manufacturing Process Starting from commercial, cis-2-buten-1,4-diol, the monotrichloroacetimidate was obtained as a colorless liquid (60%, b.p. 88°-102°C/0.2 mm Hg) by treatment with trichloroacetonitrile (1 equivalent) in tetrahydrofuran at -23°C in the presence of catalytic amount of sodium. Monotrichloroacetimidate upon refluxing in tert-butyl benzene for about 1 hour underwent, smoothly,
76
Aclarubicin
rearrangement to afford the vinylglycine synton (84%, MP: 30°C). The treatment of the last compound with bromonitrile oxide (3 equiv.) generated in situ from dibromoformaldoxime in ethyl acetate containing excess of KHCO3 and trace amounts of water afforded 3:2 mixture of cycloadducts threo- and erythro-N-[1-(3-bromo-4,5-dihydroisoxazol-5-yl)-2-hydroxyethyl]-2,2,2trichloroacetamide. The undesired threo- isomer (MP: 164°-165°C) was quantitatively removed from the mixture by fractional crystallization from chloroform. The erythro-isomer (oil) was refluxed with methanolic-HCl for 1 hour to give the chloro-alchohol (50%, syrup), which upon Jones oxidation (with H2Cr2O7/acetone) followed by deprotection of trichloroacetyl group (Ba(OH)2/H2O, H3+O) afforded racemic acivicin (66 %). The synthetic, racemic antibiotic was spectrally (UV, 1H NMR) indistinguishable from natural product, prepared from fermentation broth of Stretomyces sviceus. References Vyas D.M., Chiang Y. and Doyle T.W.; Tetrahedron Letters, vol. 25, No 5, p.p. 487-490; 1984 Mrtin D.G., Duchamp D.J. and Chidester C.G.; Tetrahedron Letters, No 27, p.p. 2549-2552, 1973
ACLARUBICIN Therapeutic Function: Antitumor, Antibiotic Chemical Name: Aclacinomycin A Common Name: Aclacinomycin A Structural Formula:
Chemical Abstracts Registry No.: 57576-44-0 Trade Name Aclacinon Aclacinomycine
Manufacturer Yamanouchi Roger Bellon
Country Japan France
Year Introduced 1981 1981
Aclarubicin
77
Raw Materials Carbohydrates Manufacturing Process An aqueous medium having the following composition was prepared: Percent Potato starch Glucose Prorich KH2PO4
1 1 1.5 0.1
K2HPO4 MgSO4·7H2O NaCl Minerals* Silicone (KM75) pH
Percent 0.1 0.1 0.3 0.125 0.05 7.0
*2.8 g CuSO4·5H2O, 0.4 g FeSO4·7H2O, 3.2 g MnCl2·4H2O, 0.8 g ZnSO4·7H2O in 500 ml water 100 ml of this medium was sterilized at 120°C for 15 min in a 500 ml Sakaguchi-shaking flask which was inoculated from an agar slant culture of Streptomyces galilaeus MA144-M1 by platinum loop. Incubation proceeded for 48 hr at 28°C on a reciprocal shaker. 10 L of the previously sterilized medium in a 20 L stainless steel jar fermenter were aseptically inoculated with 200 ml of the above seed cultures. Fermentation was carried out at 28°C for 32 hours with agitation (240 rpm) and aeration (5 L/min). The cultured broth obtained was adjusted to pH 4.5, mixed with an adsorbent siliceous earth material and filtered from the mycelium. The filtrate and cake obtained thereby were extracted separately. The cake was suspended in acetone (3 L/kg wet cake), stirred for 2 hr and filtered, and the cake was further extracted with acetone once again. The extracts thus obtained were evaporated to one-tenth volume in vacuum. The culture filtrate was adjusted to pH 6.8 and extracted twice with one-third volume of ethyl acetate, and the ethyl acetate extracts were concentrated to one-tenth volume in vacuum. Twenty grams of the resulting oily substances were mixed with 20 grams of silicic acid (Mallinckrodt Chemical Co.), applied to a column 40 cm in length and 4.5 cm in diameter filled with silicic acid, and eluted with a benzeneacetone-methanol mixture. The initial eluate which eluted with a 1:1:0 mixture was discarded and the active fractions eluted with 1:3:0 and 1:3:0.3 mixtures were collected and concentrated to dryness in vacuum. 11.5 g of this crude substance was then dissolved in a small amount of ethyl acetate and applied to the same silicic acid column as above. After discarding the initial eluates by the 1:1 and 2:1 benzene-acetone mixtures, aclacinomycin B fractions were first eluted with the above mixtures of 1:3 and 1:5 ratio, and aclacinomycin A fractions were then eluted with the 1:5:0.5 and 1:5:1
78
Aclatonium napadisylate
benzene-acetone-methanol mixtures. The eluates were dried over anhydrous sodium sulfate and concentrated to dryness in vacuum. 4.8 g of crude aclacinomycin A and 3.5 g of aclacinomycin B were obtained as yellow powder. 2.0 g of crude aclacinomycin A obtained as above were dissolved in a small amount of chloroform, applied to a column 20 cm in length and 20 cm in diameter filled with 30 g of silicic acid. After eluting off the pigments containing aglycone and aclacinomycin B and other impurities with chloroform and 1.5% methanol-containing chloroform, aclacinomycin A fractions were eluted with 2% methanol-containing chloroform, and concentrated to dryness in vacuum. 53 mg of yellow powder of aclacinomycin A was obtained. Its melting point was 129°C to 135°C. References DFU2 (3) 171 (1978) (as Aclacinomycin A) DOT 18 (10) 517 (1982) I.N. p.42 (1984) Umezawa, H., Takeuchi, T., Hamada, M., Takamatsu, A. and Oki, T.; US Patent 3,988,315; October 26, 1976; Assigned to Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai
ACLATONIUM NAPADISYLATE Therapeutic Function: Cholinergic Chemical Name: 2-[2-(Acetyloxy)-1-oxopropoxy]-N,N,N-trimethylethanaminium 1,5-naphthalenedisulfonate (2:1) Common Name: Bis[acetoxy-methyl acetic acid trimethylammoniumethyl ester]-naphthalene-1,5-disulfonate Structural Formula:
Chemical Abstracts Registry No.: 55077-30-0 Trade Name
Manufacturer
Country
Year Introduced
Abovis
Toyama
Japan
1981
Acodazole hydrochloride
79
Raw Materials Bis(choline)-naphthalene-1,5-disulfonate Lactic acid anhydride diacetate Manufacturing Process 5.2 g of bis(choline)-naphthalene-1,5-disulfonate was suspended in 30 ml of acetonitrile, and 10 g of lactic acid anhydride diacetate was added thereto. This mixture was refluxed for 3 hours. The resulting reaction mixture was allowed to stand at room temperature while cooling to precipitate the desired product crystals, which were collected by filtration. 5.5 g (76% yield) of the desired product having a melting point of 189°C to 191°C were obtained. References Merck Index 110 DFU 7 (4) 227 (1982) DOT 19 (1) 8 (1983) I.N.p.42 Miura, K., Takagawa, N., Suzuki, Y. and Matsumoto, Y.; US Patent 3,903,137; September 2, 1975; Assigned to Toyama Chemical Co., Ltd.
ACODAZOLE HYDROCHLORIDE Therapeutic Function: Antineoplastic Chemical Name: Acetamide, N-methyl-N-(4-((7-methyl-1H-imidazo[4,5f]quinolin-9-yl)amino)phenyl)-, hydrochloride Common Name: Acodazole hydrochloride; NSC-305884 Structural Formula:
Chemical Abstracts Registry No.: 55435-65-9; 79152-85-5 (Base) Trade Name
Manufacturer
Country
Year Introduced
Acodazole Hydrochloride
ZYF Pharm Chemical
-
-
80
Acodazole hydrochloride
Raw Materials Acetic anhydride Hydrogen 5-Nitrobenzimidazole Ethyl acetoacetate Acetic acid Sodium hydroxide
N-Methyl-p-nitroaniline Nickel Raney Palladium on carbon Calcium sulfate POCl3 Dowtherm®
Manufacturing Process An 82.0 g (0.5 mole) of 5-nitrobenzimidazole in 900 ml of ethanol was reduced over 4.0 g of 5% Pd/C catalyst containing 50% H2O. After filtration of the catalyst, 65.0 g (0.5 mole) of ethyl acetoacetate, 20.0 g of anhydrous calcium sulfate, and 0.5 ml of HOAc was added. After filtration, the solution was concentrated in vacuo till a solid remained. The product was filtered and washed with fresh ethanol and air-dried. The yield of ethyl 3-(5benzimidazolylamino)crotonate was 84.0 g (69%), melting point 160°-162°C. 40.0 g of ethyl 3-(5-benzimidazolylamino)crotonate was added to 80 ml of boiling Dowtherm® and the boiling was continued for 5 min. The product separated upon cooling. The product was filtered, washed with Dowtherm® and then acetone and air-dried. The yield of 7-methyl-9-imidazo[4,5f]quinolinol was 29.0 g (91%), melting point 345°-347°C. Into a 22 L, 4-necked flask set in a tub and equipped with a stirrer, an air condenser (drying tube), thermometer, and dropping funnel was placed POCl3 (4590 ml). The 7-methyl-9-imidazo[4,5-f]quinolinol (1062.0 g, 5.33 moles) was added with no heating effect noted. Dimethylformamide (4690 ml) was added dropwise over a 2.5 h period at a rate to control the temperature below 85°C. The resulting viscous solution was allowed to stand overnight at room temperature and then added cautiously to ice to a total volume of ca. 50 L. The resulting solution was then adjusted to a pH of 7 to 8 by the addition of NaOH pellets (9771.0 g). More ice was added as needed to keep the temperature below 45°C. The resulting precipitate was collected by filtration, washed well by stirring in water (3x20 L) and dried at 60°C to yield 1107.0 g (95.5%) of 9-chloro-7-methylimidazo[4,5-f]quinolone. To 500 ml of acetic anhydride was added portionwise, 100.0 g (0.658) of Nmethyl-p-nitroaniline. Following the addition, the solution was heated on a steam bath for 2 h, then stirred overnight at room temperature. The white precipitate of the N-methyl-4-nitroacetanilide was collected by filtration, washed with ether and air-dried to give 53.0 g, melting point 153°-156°C. The filtrate was concentrated in vacuum to give another 61.0 g, melting point 150°-154°C. A mixture of 114.0 g (0.587 m) of N-methyl-4-nitroacetanilide and 800 ml of ethanol was shaken with hydrogen over one teaspoon of Raney active nickel catalyst in water. A pressure drop of 127 psi was recorded (calc. 118 psi). The catalyst was removed by filtration and the ethanol filtrate refluxed overnight with 127.0 g (0.587 m) of the 9-chloro-7-methylimidazo[4,5-f]quinolone. The mixture was chilled, filtered, washed with ether and air-dried to give 75.5 g of 9-[p-(N-methylacetamido)anilino]-7-methyl-1-H-imidazo[4,5-f]quinoline
Acoxatrine
81
hydrochloride sesquihydrate, melting point 315°-318°C (recrystallized from 4,000 ml of MeOH). By treatment of 9-p-(N-methylacetamido)anilino-7-methyl-1H-imidazo[4,5f]quinolone hydrochloride sesquihydrate with NaOH may be produced the 9-p(N-methylacetamido)anilino-7-methyl-1H-imidazo[4,5-f]quinolone. References Spencer C.F., Snyder H.R.; US Patent No. 3,878,206; April 15, 1975; Assigned: Morton-Norwich Products, Inc., Norwich, N.Y.
ACOXATRINE Therapeutic Function: Vasodilator, Antihypertensive Chemical Name: Acetamide, N-((1-(1,4-benzodioxan-2-ylmethyl)-4-phenyl4-piperidyl)methyl)Common Name: Acetoxatrine; Acoxatrine Structural Formula:
Chemical Abstracts Registry No.: 748-44-7 Trade Name
Manufacturer
Country
Year Introduced
Acoxatrine
ZYF Pharm Chemical
-
-
Raw Materials Lithium aluminum hydride Acetyl chloride
DL-1-Cyano-4-phenyl-piperidine Sodium hydroxide
Manufacturing Process To a solution of 11.5 parts lithium aluminum hydride in 100 parts tetrahydrofurane is added dropwise a solution of 94 parts DL-1-cyano-4phenyl-piperidine in 240 parts tetrahydrofurane, at a temperature of about 45°C. After the addition is complete, the reaction mixture is stirred first at the same temperature for 3 h and 30 min and then refluxed for 1 h. The whole is decomposed by successive addition of 12 parts water, 9 parts sodium
82
Acriflavine hydrochloride
hydroxide 20% and 50 parts water. The mixture is filtered from inorganic matter. The filter-cake is washed with tetrahydrofurane and the combined filtrates are evaporated. The oily residue is dissolved in 240 parts 2-propanol and to this solution are added about 60 parts concentrated hydrochloric acid. After keeping at room temperature, the precipitated salt is filtered off, washed with 2-propanol and dried, yielding DL-4-(amino-methyl)-1-[1,4benzodioxanyl)methyl]-4-phenylpiperidine dihydrochloride; melting point 272°-278°C as a white amorphous powder. From 4.1 parts DL-4-(aminomethyl)-1-[2-(1,4-benzodioxanyl)methyl]-4phenylpiperidine dihydrochloride, the free base is liberated in the usual manner and extracted with chloroform. The organic layer is separated, dried and evaporated. The DL-4-(aminomethyl)-1-[2-(1,4-benzodioxanyl)methyl]-4phenylpiperidine obtained is dissolved in 128 parts anhydrous chloroform. This solution is cooled to 5°C and there is added dropwise a solution of 1.6 parts acetylchloride in 7 parts anhydrous chloroform (exothermic reaction). The reaction mixture is stirred over night at room temperature and then alkalized with about 25 parts sodium hydroxide 20% at a temperature of 20°C. The aqueous layer is separated and extracted twice with chloroform. The combined organic layers are washed with water, dried over magnesium sulfate, filtered and evaporated. The oily residue is dissolved in a mixture of 40 parts acetone and 20 parts diisopropyl ether and evaporated again. The solid residue is triturated in diisopropylether, yielding DL-4-(N-acetylaminomethyl)-1-[2-(1,4benzodioxanyl)-methyl]-4-phenylpiperidine; melting point 140°-141.1°C, as a white microcrystalline powder. References Janssen P.A.J.; US Patent No. 3,166,561; January 19, 1965; Assigned: Research Laboratorium Dr. C. Janssen N.V., a corporation of Belgium
ACRIFLAVINE HYDROCHLORIDE Therapeutic Function: Antiseptic, Topical antibacterial Chemical Name: Acridinium, 3,6-diamino-10-methyl-, chloride, monohydrochloride, mixture with 3,6-acridinediamine hydrochloride Common Name: Acid acriflavine; Acriflavin; Acriflavinium chloride; Euflavin; Flavacridinum; Xanthacridinum Structural Formula:
Acriflavine hydrochloride
83
Chemical Abstracts Registry No.: 6034-59-9; 837-73-0 (Base) Trade Name
Manufacturer
Country
Year Introduced
Acriflavine hydrochloride Acriflavine hydrochloride
ABCR GmbH and Co. KG
-
-
Advance Scientific and Chemical, Inc.
-
-
Acriflavine hydrochloride
Spectrum Chemicals and Laboratory Products, Inc.
-
Acriflavine hydrochloride Acriflavine hydrochloride
Ruger Chemical Co., Inc. -
-
AppliChem
-
-
Acriflavine hydrochloride
Amend Drug and Chemical Company
-
-
Acriflavine hydrochloride
CCA (Changzhou) Biochemical Co., Ltd.
-
-
Acridina
Fatro
-
-
Acriflavin
Koi
-
-
Acriflavin
Vipor Chemicals Pvt.Ltd.
-
-
Acriflavin
Advance Scientific and Chemical, Inc.
-
-
Acriflavin
C. Krieger + Co. Nachf. GmbH + Co.
-
-
Acriflavin
Exim-Pharm International -
-
Acriflavin
Hasco-Lek
-
-
Acriflavin
Dr Zdrowie SA
-
-
Acriflavin
Rasfer Internacional, S.A. -
-
Acriflavin
Trannspharma, Sas
-
-
Acriflavin
Mediplus International
-
-
Acriflavin
Unical (Ceylon) Limited
-
-
Acriflavin
Olita Scientific Works
-
-
Acriflavin
Hygea SA; Polska Grupa Aptekarska
-
-
Acriflavin
Internatio NV
-
-
Acrinol
Pasteur
-
-
Burnol
Boots Company PLC
-
-
Diacrid
Sidroga AG
-
-
Euflavin
Macsen Laboratories
-
-
Gonacrine
May and Baker
-
-
Panflavin
Chinosolfabrik
-
-
Trypaflavin
Zoolek
-
-
84
Acrisorcin
Raw Materials 4,4-Diaminodiphenylmethane Nitric acid Hydrochloric acid Tin Ferric chloride Acetanhydride 4-Toluolsulfomethyl ether Manufacturing Process 4,4-Diaminodiphenylmethane reacted with HNO3 and as a result of this reaction 4,4-diamino-2,2-dinitro-diphenylmethane was obtained. By reducing of 4,4-diamino-2,2-dinitro-diphenylmethane with HCl and Sn, 2,2,4,4-tetraaminodiphenylmethane was produced, which at heating to 150°C gave 3,6-diamino-9,10-dihydroacridine. The 3,6-diamino-9,10-dihydroacridine by oxidation with FeCl3 was converted to 3,6-diaminoacridine. 3,6-Diaminoacridine was reacted with acetanhydride and 3,6-bis(acetylamino)-acridine was produced. 3,6-Bis-(acetylamino)-acridine was methylated by p-toluolsulfomethyl ether and 3,6-bis-(acetylamino)-10-methylacridinumtosylate was produced. Then the 3,6-bis-(acetylamino)-10-methylacridinumtosylate was converted to 3,6-diamino-10-methylacridinum chloride (acriflavinum chloride) by reaction with hydrochloric acid. References Kleemann A., Engel J.; Pharmazeutische Wirkstoffe, GeorgThieme Verlag Stuttgart, New York, 1982
ACRISORCIN Therapeutic Function: Antifungal, Anthelmintic Chemical Name: 1,3-Benzenediol, 4-hexyl-, compd. with 9acridinamine (1:1) Common Name: Acrisorcin; Akrinol; Aminacrine hexylresorcinate Chemical Abstracts Registry No.: 7527-91-5
Acrivastine
85
Structural Formula:
Trade Name
Manufacturer
Country
Year Introduced
Aminacrine hexylresorcinate
ZYF Pharm Chemical
-
-
Raw Materials 4-Hexylresorcinol Hydrochloric acid
Potassium hydroxide 9-Aminoacridine
Manufacturing Process 4-Hexylresorcinol 194.0 g is added to a solution composed of 56.1 g potassium hydroxide in 1.5 L of water with stirring, and the mixture heated to about 40°C to effect complete solution. The pH of this solution is 12. A second solution of 9-aminoacridine hydrochloride is prepared as follows: 2 L of water containing 83 ml of concentrated hydrochloric acid are heated with stirring to about 80°C. Slowly 194.0 g of 9-aminoacridine are added. Heating is continued until a clear solution is obtained. About 2 ml of additional concentrated hydrochloric acid are added in small increments until the solution is slightly acid (pH of about 6). The 4-hexyl resorcinol solution is now slowly added under rapid agitation to the 9-aminoacridine hydrochloride solution. A copious precipitate is formed which, upon :stirring and continued addition of the 4-hexylresorcinol solution, becomes a creamy yellow slurry. At the end of the addition, the pH is 7-8 (indicator paper). The slurry is stirred while heated for an additional 15 min and then rapidly filtered on a 15 cm Buchner funnel. The product thus obtained is washed thoroughly, using about 1 L of cold water, to give a very pale yellow color in the last wash. The compound is then pressed dry and then oven-dried for 2-3 h at 50°C. The resultant product, 9aminoacridine 4-hexyl resorcinolate, has a melting point of 189°-190°C. References Seneca H.; US Patent No. 3,122,553; Feb. 25, 1964; Assigned: Bansen, Inc., New York, N.Y., a corporation of New York
ACRIVASTINE Therapeutic Function: Antihistaminic
86
Acrivastine
Chemical Name: 2-Propenoic acid, 3-(6-(1-(4-methylphenyl)-3-(1pyrrolidinyl)-1-propenyl)-2-pyridinyl)-, (E,E)Common Name: Acrivastine; Semprex Structural Formula:
Chemical Abstracts Registry No.: 87848-99-5 Trade Name Acrivastine Semprex Cap. Benadryl Benadryl
Manufacturer ZYF Pharm Chemical Glaxo Wellcom-Misr Co. Warner-Lambert Pfizer
Country -
Year Introduced -
Raw Materials Sulfuric acid Butyl lithium 4-Tolunitrile Sodium carbonate Ammonia Sodium hydroxide
Triphenyl-2-pyrrolidinoethylphosphonium bromide 2,6-Dibromopyridine Hydrochloric acid 4-Toluenesulfonic acid Sodium hydride Triethyl phosphonoacetate
Manufacturing Process Butyl lithium (50 ml, 1.65 mol in hexane) was added under nitrogen to a stirred suspension of 2,6-dibromopyridine (19.5 g) in dry ether (200 ml) at 50°C. After 0.75 h a solution of 4-tolunitrile (10.0 g) in ether (50 ml) was added; stirring was continued at -50°C for 3 h. The mixture was allowed to warm to -30°C and treated with hydrochloric acid (200 ml, 2 mol). The precipitated solid was collected, washed with water to give the 2-bromo-6-(4toluoyl)pyridine as colourless needles (12.2 g), melting point 97°-98°C (recrystallized from aqueous ethanol). A mixture of 2-bromo-6-(4-toluoyl)pyridine (200.0 g), ethylene glycol (85 ml), p-toluenesulphonic acid (32.0 g) and benzene (11 ml) was boiled under a Dean/Stark trap until water collection had become very slow (about 20 ml collected in 16 h). The cooled solution was poured into ice/water containing sodium carbonate (100.0 g) with stirring. The benzene layer was separated, washed with water, dried with sodium sulfate and evaporated to about 500 ml. Cooling gave a
Acrivastine
87
first crop of 2-(6-bromo-2-pyridyl)-2-(4-tolyl)-1,3-dioxolan, melting point 113°-114°C (170.0 g). Dilution with petroleum ether gave a second crop, melting point 109°-112°C (34.0 g). The residue after evaporation (31.0 g) was recycled. A solution of 2-(6-bromo-2-pyridyl)-2-(4-tolyl)-1,3-dioxolan, vide supra, (70.0 g) in dry toluene (800 ml) was added dropwise during 5 h to a stirred solution of butyl lithium (1.6 mol in hexane, 200 ml) and toluene (200 ml) at -65° to 72°C under nitrogen. After a further 30 min at -70°C, dry dimethylformamide (40 ml) was added during 35 min. Stirring continued overnight at -70° to 60°C. Hydrochloric acid (2 N, 400 ml) was added, allowing the temperature to rise to about -10°C. After 30 min, 2 N ammonia (ca. 90 ml) was added to pH 7-8. The toluene layer was separated and the aqueous phase was extracted with ether. The combined organic liquids were washed with ice/water, dried (MgSO4) and evaporated in vacuum below 50°C. The aldehyde, 2-(6-formyl-2pyridyl)-2-(4-tolyl)-1,3-dioxolan, (63.9 g) crystallized on keeping at 3°C, melting point 52-63°C. The 2-(6-formyl-2-pyridyl)-2-(4-tolyl)-1,3-dioxolan (2.5 g) was dissolved in 1,2-dimethoxyethane (10 ml) and added to a solution of the phosphonate carbanion produced from triethyl phosphonoacetate (2.0 g) and sodium hydride (0.22 g) in the same solvent. The mixture was stirred for 2 h, diluted with ether (25 ml) and treated with hydrochloric acid (5 ml, 2 mol). The organic phase was separated, washed with water, dried, and evaporated. The resulting oil was dissolved in ethanol (20 ml) containing concentrated hydrochloric acid (3 ml) and water (3 ml). After heating on the steam bath for 10 min, the solution was diluted with ice water, rendered alkaline with sodium bicarbonate solution, and extracted with ether. Evaporation gave 1.0 g ((E)-3(6-(4-toluoyl)-2-pyridyl)acrylate as colourless platelets, melting point 108°111°C (crystallized from cyclohexane). Butyl lithium (10 ml, 1.64 mol in hexane) was added under nitrogen to a stirred suspension of triphenyl-2-pyrrolidinoethylphosphonium bromide (7.2 g) in dry toluene (75 ml). After 0.5 h, ((E)-3-(6-(4-toluoyl)-2-pyridyl)acrylate, vide supra, (4.8 g) in toluene (50 ml) was added. The suspension, initially orange, became deep purple, then slowly faded to yellow during 2 h heating at 75°C. The cooled solution was diluted with ether (150 ml) and treated with hydrochloric acid (50 ml, 2 mol). The aqueous phase was separated, washed with ether, and basified with potassium carbonate (ice) and extracted with ether. The mixture of isomeric esters obtained by evaporation was dissolved in ethanol (100 ml) containing sodium hydroxide solution (20 ml, 1 mol) and partially evaporated on the steam bath under reduced pressure for 5 min. The residual aqueous solution was neutralized with sulfuric acid (20 ml, 0.5 mol) and evaporated to dryness. The solid residue was extracted with hot isopropanol (3x50 ml) and the extracts were concentrated until crystallization commenced. The (E)-3-(6-(3-pyrrolidino-1-(4-tolyl)prop-1-(E)-enyl)-2pyridyl)acrylic acid, melting point 222°C (dec. recrystallization from isopropanol) was obtained. References Coker G.G., Findlay J.W.A.; EU Patent No. 0,085,959; Feb. 3, 1983; Assigned: The Wellcome Foundation Limited 183-193 Euston Road, London NW1 2BP(GB)
88
Acrocinonide
ACROCINONIDE Therapeutic Function: Antiinflammatory, Antiallergic Chemical Name: (11β,16α)-9-Fluoro-11,21-dihydroxy-16,17-[2propenylidenebis(oxy)]pregna-1,4-diene-3,20-dione Common Name: Acrocinonide Structural Formula:
Chemical Abstracts Registry No.: 28971-58-6 Trade Name
Manufacturer
Country
Year Introduced
Acrocinonide
Onbio Inc.
-
-
Raw Materials 9-Fluoro-11β,16α,17,21-tetra-hydroxy-pregna-1,4-diene-3,20-dione Perchloric acid Sodium bicarbonate Acrolein Manufacturing Process A suspension of 1.0 g of 9-fluoro-11β,16α,17,21-tetra-hydroxy-pregna-1,4diene-3,20-dione in a mixture of 35 ml of dioxan, 15 ml of acrolein and 0.1 ml of perchloric acid was stirred for 3 h at room temperature. The clear solution thus obtained was poured into an aqueous saturated solution of sodium bicarbonate. The mixture was extracted twice with benzene, and the benzenic extract was concentrated to a small volume. The resulting crystals were collected and the 9-fluoro-11β,21-dihydroxy-16α,17-(2-propenylidenedioxy)pregna-1,4-diene-3,20-dione was obtained as white crystals, melting point 200°-205°C. References GB Patent No. 1,292,269; Oct. 11, 1972; Assigned: ROUSSEL-UCLAF SOCIETE ANONYME, a body corporate organized under the laws of France, of 35 Boulevard des Invalides, Paris 7e, France
Acronine
89
ACRONINE Therapeutic Function: Antineoplastic Chemical Name: 7H-Pyrano[2,3-c]acridin-7-one, 3,12-dihydro-6-methoxy3,3,12-trimethylCommon Name: Acronine; Acronycine; NSC-403169 Structural Formula:
Chemical Abstracts Registry No.: 7008-42-6 Trade Name
Manufacturer
Country
Year Introduced
Acronine
ZYF Pharm Chemical
-
-
Raw Materials 2-Nitrobenzoyl chloride 3-Chloro-3-methylbutyne Sodium hydride
3,5-Dimethoxyphenol Zinc Methyl iodide
Manufacturing Process The acridone alkaloids constitute a small group of natural products found exclusively in the Rutaceae family of higher plants. A sustained interest in this field has been due to the reported activity of acronycine a constituent of Acronnychia baueri and Vepris amphody as an anti-tumor agent. There are different methods of the synthetic preparation of acronycine (W. M. Bandaranayake et al., J. Chem. Soc. Perkin 1, 998 (1968); J. Hlubucek et al.; Aust. J. Chem. 23, 1881 (1970). One of them is described below. FriedelCrafts condensation between 2-nitrobenzoyl chloride and 3,5dimethoxyphenol. 2-Nitrobenzoyl chloride (12 g) and AlCl3, (anhyd., 13 g) were dissolved in dry ether (50 ml) and this mixture added to a solution of 3.5-dimethoxyphenol (5 g) in dry ether 150 ml) at 0°C and the final mixture stirred at 0°C for 3 hours, brought to 20°C and stirred for a further 3 h. Diluted HCl and ice were added and the product extracted with EtOAc (3x50 ml), this extract was washed with aq. NaHCO3, water, dried (MgSO4), filtered and evaporated under reduced pressure to yield a dark red oil. This oil was treated with 2 M aq. NaOH. (100 ml) for 1 h., acidified with diluted HCl and re-extracted with
90
Acronine
EtOAc which gave, after a similar work up, a paled red oil (5.0 g). Thin layer chromatography (TLC) showed three components one of which was the starting phenol. Column chromatography (150 g silica gel) and elution with benzene:petrol ether 40°-60°C (1:1) followed by increasing polarity of solvents (benzene through chloroform to chloroform:ether (4:1) gave 59 fractions. Fractions 1-12 were combined to gave a solid, which crystallized from benzene to give 4,6-dimethoxy-2-hydroxy-2-nitrobenzophenone, MP: 198°-199°C. Fractions 13-21 were discarded. Fractions 22-42 were combined (0.3 g), crystallized from benzene and the product added to that obtained from fractions 43-59 which crystallized from benzene to give 2,6-dimethoxy7-hydroxy-2-nitrobenzophenone (0.5 g) MP: 175°-177°C. Condensation of 3-chloro-3-methylbutyne with 2,6-dimethoxy-7-hydroxy-2nitrobenzophenone: A solution of the above benzophenone (2 g) and excess 3-chloro-3methylbutyne (4.5 g) in dry DMF (60 ml) containing anhydrous K2CO3 (4 g) and dry KI (2 g) was stirred and heated at 65°C for 14 hours (under N2). The mixture was cooled, diluted with water, acidified, extracted with chloroform (3x50 ml) and the extract was worked up in the usual way (including a NaOH wash) to give an oil, which was redissolved in DMF (20 ml) and heated at 130°C, under N2, for 7 h whence most of the starting material had disappeared. The solvent was removed under reduced pressure to give a product (0.62 g) which was purified by preparative layer chromatography on silica gel to give 6-(2-nitrobehzoyl)-5,7-dimethoxy-2,2-dimethylchromene (0.22 g) which crystallized from EtOH, MP: 92°-93°C. 6-(2-Aminobenzoyl)-5,7-dimethoxy-2,2-dimethylchromene (0.2 g) was dissolved in EtOH (30 ml) containing water (5 ml) and ammonium chloride (1 g) and Zn mossy (1.5 g) was added in portions and the mixture stirred at room temperature for 5 days. The solution was filtered, evaporated to dryness under reduced pressure and the residue dissolved in EtOAc (25 ml) and worked up in the usual way to give a solid (0.19 g). It crystallised from EtOH with MP: 123°-126°C. Cyclization of aminodimethylchromenylbenzophenone: 6-(2-aminobenzoyl)5,7-dimethoxy-2,2-dimethylchromene (0.12 g) was dissolved in DMSO (8 ml) and NaH (0.06 g) added, the mixture was stirred for 6 days at room temperature. A further addition of NaH (0.06 g) was made and the solution heated to 50°C for 0.5 h whence it was poured into water, extracted with EtOAc and worked up in the usual way to give a crude mixture (0.11 g; components). Separation of this mixture on plate (silica gel:benzene:EtOAc, 10:4) gave band 1 (Rf 0.45: 38 mg) identified as starting material. Band 2 (Rf 0.32: 42 mg; 43%) which crystallized from ethylacetate as des-Nmethylisoacronycine, MP: 293°-295°C. Band 3 (Rf 0.10; 29 mg, 29%) crystallized from ethyl acetate as des-N-methylacronycine. MP: 237°-240°C. Des-N-methylacronycine (14 mg) was dissolved in dry acetone (10 ml), anhydrous K2CO3 (1 g), and MeI (2 ml) added and the mixture refluxed for 11 hours. The solution was filtered and the solvents evaporated to give a solid (12 mg) which after purification on TLC, gave acronycine which crystallized from aqueous MeOH, MP: 171°-173°C. This product showed identical U.V. and Rf characterization when compared with acronycine and had an accurate mass
Actaplanin
91
measurement of 321.1368. C20H19NO3, required: 321.1364. UV and 1H NMR spectrum confirmed the structures of all described compounds. References Adams Joyce H. et al.; Tetrahedro,n v.37, pp 209-217, 1981 Coker G.G., Findlay J.W.A.; EU Patent No. 0,085,959; Feb. 3, 1983; Assigned: The Wellcome Foundation Limited 183-193 Euston Road, London NW1 2BP(GB)
ACTAPLANIN Therapeutic Function: Growth stimulant Chemical Name: See structure Common Name: Structural Formula: Complex of glycopeptide antibiotics produced by Actinoplanes missourinesis Chemical Abstracts Registry No.: 37305-75-2 Trade Name
Manufacturer
Country
Year Introduced
Actaplanin
Onbio Inc.
-
-
Raw Materials Potassium chloride Ferric sulfate Agar Hydrochloric acid Dextrin Yeast extract Dextrose Peptone Corn steep liquor Sulfuric acid Actinoplanes sp
Magnesium sulfate heptahydrate Yeast Pre-cooked oatmeal Glucose Soybean meal Calcium carbonate Dextrin Molasses, beet sugar Betaine Potassium phosphate dibasic
Manufacturing Process The microorganism used for the production of antibiotic Actaplanin (A-4696) has been identified as a strain of a species of Actinoplanes of the family Actinoplanaceae. The Actinoplanaceae are a new family of microorganisms of the order Actinomycetales, having been first described by Dr. John N. Couch, Jour. Elisha Mitchell Sci. Soc., 65, 315-318 (1949). The Actinoplanes sp. useful for the production of A-4696 was isolated from a sample of soil obtained from the Cascade mountain area in the state of
92
Actaplanin
Washington. Mycelial fragments of Actinoplanes sp., strain ATCC 23342 were inoculated on a nutrient agar slant having the following composition (g): pre-cooked oatmeal 60.0; yeast 2.5; K2HPO4 1.0; dried distiller's solubles 5.0; Czapek's mineral stock 5.0 ml; agar 25.0; water, deionized 1 L; Czapek's mineral stock has the following composition (g): KCl 100.0; MgSO4·7H2O 100.0; FeSO4·7H2O 2.0; (dissolve in 2 ml conc. HCl); deionized water 1 L. The slant was inoculated with ATCC 23342 and incubated for 6 days at 30°C. The culture does not normally sporulate on this medium, and it is necessary to macerate the mycelial mat with a flattened, sharpened, inoculating needle in order to increase the number of potential growth centers. The macerated mature culture was covered with sterile distilled water and scraped carefully with a sterile rod to obtain a mycelial suspension. The suspension thus obtained was used to inoculate 100 ml of a sterile vegetative medium having the following composition (g): glucose 5.0; dextrin 20.0; soybean meal 5.0; yeast extract 2.5; calcium carbonate 1.0; tap water 1 L. The inoculated vegetative medium was grown for 48 h at 30° on a rotary shaker operating at 250 rpm. 10 ml of the incubated vegetative medium was inoculated into 100 ml of a sterile "bump" medium of the same composition as given next above. The thus inoculated "bump" medium was incubated for 24 h at 30°C with constant shaking on a rotary shaker operating at 250 rpm. 0.4 ml of the incubated "bump" medium was inoculated into 100 ml portions of a production medium of the composition shown below contained in 500 ml. Erlenmeyer flasks, and sterilized at 120°C for 30 min (g): dextrose 1.0; dextrin 3.0; peptone 1.5; soybean meal 0.5; MgSO4·7H2O 0.2; molasses, beet sugar 1.5; corn steep liquor 0.5; betaine 0.1; K2HPO4 0.05; deionized water q.s. 25 L. The pH of the medium was adjusted to 7.5 with 5 N sodium hydroxide solution before sterilization. After sterilization the pH was approximately 6.9. The production fermentation was shaken for about 96 h at a temperature of 30°C on a rotary shaker operating at 250 rpm. The pH at the end of the fermentation cycle was about 7.2. The preparation of the inoculum proceeded through the incubation of the "bump" medium detailed above 25 L of a production medium as outlined above, with 0.02% Dow Corning antifoam added, was sterilized by autoclaving at 120°C for 30 min and charged into a 40 L fermentation tank. 100 ml of incubated "bump" medium was inoculated into the sterile production medium. The inoculated production medium contained in the 40 L tank was allowed to ferment for 4 days at 30°C. The fermentation was aerated with sterile air in an amount of about 0.5 volume of air per volume of culture medium per minute. The fermenting production medium was agitated with a mixer utilizing an impeller of a proper size and turning at an appropriate rpm to insure adequate mixing of air with the medium. The pH of the culture medium gradually increased from an initial level of about 6.9-7.2 as the fermentation proceeded.
Actisomide
93
The whole broth obtained from an A-4696 fermentation, was filtered with the aid of a commercial filter aid. The filtrate was set aside. The mycelial cake was washed with 32 L of water and the wash water set aside. The mycelial cake was then suspended in an additional 32 L of water and the pH of the mixture adjusted to pH 10.5 with 5 N sodium hydroxide solution. The mycelial cake water suspension was stirred for 45 min and the mixture was filtered. This filtrate and the water wash were combined with the original filtrate from the fermentation broth and the pH of combined filtrates was adjusted to pH 4.0 with H2SO4. The acidified combined filtrates was passed through a carbon column utilizing 1.0 kg of activated carbon, (Pittsburgh, 12x40). The activated carbon column was washed until the effluent was colorless. The A-4696 activity was adsorbed on the carbon column. The A-4696 activity was eluted from the carbon column utilizing a 1% H2SO4 solution in acetone: H2O (1:1). 2 L of the acidified acetone-water solution was sufficient to elute the A-4696 activity from the carbon column. The eluate containing the A-4696 activity as treated with a saturated barium hydroxide solution, in order to form a precipitate of barium sulfate, thus removing the sulfate ions from the solution. The mixture was filtered and the barium sulfate precipitate was discarded. The filtrate containing the A-4696 activity was concentrated under vacuum to dryness. The resulting residue comprising the A-4696 activity amounted to approximately 80.0 g. References Hamill R.L. et al.; US Patent No. 3,952,092; April 20, 1976; Assigned: Eli Lilly and Company, Indianapolis, Ind.
ACTISOMIDE Therapeutic Function: Cardiac depressant Chemical Name: 3H-Pyrido[1,2-c]pyrimidin-3-one, 4-(2-(bis(1-methylethyl) amino)ethyl)-4,4a,5,6,7,8-hexahydro-1-methyl-4-phenyl-, cis-(+-)Common Name: Actisomide; Dizactamide Structural Formula:
Chemical Abstracts Registry No.: 96914-39-5
94
Acyclovir
Trade Name Dizactamide
Manufacturer ZYF Pharm Chemical
Country -
Year Introduced -
Raw Materials Platinum oxide N,N-Dimethylacetamide dimethylacetal 4-Diisopropylamino-2-phenyl-2-pyridin-2-yl-butyramide Lithium aluminum hydride Manufacturing Process Hydrogenation of 4-diisopropylamino-2-phenyl-2-pyridin-2-yl-butyramide over platinum oxide catalyst reduced the pyridine ring to a piperidine to give 4diisopropylamino-2-phenyl-2-piperidin-2-yl-butyramide as a white solid, MP: 107°-108°C. Structure was confirmed by proton, carbon-13-NMR spectra and by elemental analysis. 2-(1-Acetylpiperidin-2-yl)-4-diisopropylamino-2-phenylbutyramide was prepared by acetylation of above product with N,N-dimethylacetamide dimethylacetal by heating at 80°C for about 14 hours. The acetamide melted at 191°-192°C. The treatment of that intermediate with lithium aluminum hydride led the newly introduced acetyl group to condense with the adjacent amide nitrogen. There was thus obtained 4-(2-diisopropylaminoethyl)-1methyl-4-phenyl-4,4a,5,6,7,8-hexahydropyrido[1,2-c]pyrimidin-3-one, the new anti-arrhythmic agent actisomide, MP: 70°-75°C. Its structure was confirmed by proton NMR and infrared spectra and by elemental analysis. References Adelstein G.W., Chorvat R.J.; EP Patent No. 0,104,647; Sept. 27, 1983 Lednicer D., The Organic Chemistry of Drug Synthesis; v. 5; pp. 149-150; 1995; Wiley and Sons Inc.
ACYCLOVIR Therapeutic Function: Antiviral Chemical Name: 2-Amino-1,9-dihydro-9-[(2-hydroxyethoxy)methyl]-6Hpurin-6-one Common Name: Acycloguanosine; 9-(2-Hydroxyethoxymethyl)guanine Structural Formula:
Acyclovir
95
Chemical Abstracts Registry No.: 59277-89-3 Trade Name Zovirax Zovirax Zovirax Zovirax Zovirax Zovirax
Manufacturer Burroughs-Wellcome Burroughs-Wellcome Burroughs-Wellcome Burroughs-Wellcome Burroughs-Wellcome Burroughs-Wellcome
Country UK US Switz. W. Germany Sweden France
Year Introduced 1981 1982 1982 1983 1983 1983
Raw Materials Sodium nitrite 2-Chloro-9-(2-hydroxyethoxymethyl)adenine Ammonia Manufacturing Process Solid sodium nitrite (0.97 g) was added at room temperature with stirring over a period of one hour to a solution of 2-chloro-9-(2hydroxyethoxymethyl)adenine (0.5 g) in glacial acetic acid (10 ml). The reaction mixture was stirred for an additional 4½ hours. The white solid was removed by filtration, washed with cold acetic acid and then well triturated with cold water to remove the sodium acetate present. The solid product was retained. The combined acetic acid filtrate and wash was evaporated at reduced pressure and 40°C bath temperature and the residual oil triturated with cold water. The resulting solid material was combined with the previously isolated solid and the combined solids dried and recrystallized from ethanol to give 2-chloro-9-(2-hydroxyethoxymethyl)-hypoxanthine (0.25 g), MP>310°C. Elemental analysis and NMR spectrum were consistent with this structure. A mixture of 2-chloro-9-(2-hydroxyethoxymethyl)-hypoxanthine (0.375 g) and methanol (80 ml) saturated with anhydrous ammonia was heated in a bomb at 125°C for 5 hours. The bomb was cooled in an ice bath and the reaction mixture removed. Solvent and excess ammonia were removed under reduced pressure at 50°C. After the residue was triturated with cold water to remove the ammonium chloride formed, the remaining solid was dried and then recrystallized from methanol to give pure 9-(2-hydroxyethoxymethyl) guanine (0.24 g), MP 256.5-257°C. References Merck Index 140 DFU 4 (11) 842 (1979) Kleeman and Engel p. 14 PDR p. 773 OCDS Vol. 3 p. 229 DOT 18 (2) 52 (1982) REM p. 1231 Schaeffer, H.J.; US Patent 4,199,574; April 22, 1980; Assigned to BurroughsWellcome Co.
96
Adafenoxate
ADAFENOXATE Therapeutic Function: Nootropic, Psychostimulant Chemical Name: 2-(1-Adamantylamino)ethyl (p-chlorophenoxy)acetate Common Name: Adafenoxate Structural Formula:
Chemical Abstracts Registry No.: 82168-26-1 Trade Name
Manufacturer
Country
Year Introduced
Adafenoxate
Laboratorios Wassermann
-
-
Raw Materials 1-Aminoadamantine-2-ethanol p-Chlorophenoxyacetyl chloride p-Chlorophenoxyacetic acid Manufacturing Process Preparation of the p-chlorophenoxyacetate of 1-aminoadamantine-2-ethanol, starting from a p-chlorophenoxyacetic acid halide: 22 g (0.11 mol) of 1-aminoadamantine-2-ethanol dissolved in 250 ml of benzene are poured into a 500 ml flask fitted with a mechanical stirrer, using a decanting funnel. 23 g (0.11 m) of p-chlorophenoxyacetyl chloride are added in drops while stirring, the mixture then being stirred for 30 minutes. 120 ml of a 10% solution of sodium carbonate is then added, and the resulting mixture is stirred for 10 minutes. The organic phase is decanted, and the benzene is then removed by distillation. The residue is crystallized with petroleum ether. This yields 37 g (93%) of a white solid. Preparation of the p-chlorophenoxyacetate of 1-aminoadamantine-2-ethanol, starting from p-chlorophenoxyacetic acid: In a 1 liter flask, provided with a Dean-Stark separator tube and reflux refrigerant, a mixture of 20.5 g (0.011 m) of p-chlorophenoxyacetic acid, 22 g (0.11 m) of 1-aminoadamantine-2-ethanol, 98 g of conc. sulfuric acid and 700 ml of toluene is heated to boiling point over a period of 24 hours. At the end
Adamexine
97
of this period, the mixture is treated with an aqueous solution of 5% sodium carbonate to an alkali pH, and is then washed with water. The mixture is then dried on anhydrous sodium sulphate, and the toluene is removed by distillation at reduced pressure. The crude product so obtained is crystallized with petroleum ether. The yield is 35.2 g (88%) of a white solid. Preparation of the chlorhydrate of p-chlorophenoxyacetate of 1aminoadamantine-2-ethanol: A solution of 60 g (0.16 m) of p-chlorophenoxyacetate of 1-aminoadamantine2-ethanol in 300 ml of ether is subjected to the passage of HCl gas until the precipitation of a solid product is completed. It is left to cool in a refrigerator over a period of 6 hours and it is then filtered. The resulting solid is recrystallized with a mixture of ether and methanol. 61 g (92%) of the product are obtained. References Andreoli R.R. et al; US Patent No. 4,476,319; Oct. 9, 1984; Assigned to Sociedad Espanola de Espacialides Formaco-Terapeuticas S.A., Barselona, Spain
ADAMEXINE Therapeutic Function: Mucolytic Chemical Name: Acetamide, N-(2,4-dibromo-6-((methyltricyclo [3.3.1.13,7]dec-1-ylamino)methyl)phenyl)Common Name: Adamexine; Broncostyl Structural Formula:
Chemical Abstracts Registry No.: 54785-02-3 Trade Name
Manufacturer
Country
Year Introduced
Adamexine
ZYF Pharm Chemical
-
-
Broncostyl
Robert
-
-
98
Adapalene
Raw Materials 2-Bromomemtyl-4,6-dibromo-N,N,diacetylaniline N-Methyladamantyl Manufacturing Process 4.3 g 2-brommemtyl-4,6-dibromo-N,N-diacetylaniline and 1.65 g Nmethyladamantyl amine in 100 ml of absolute ethanol were heated to reflux for 8 hours. The ethanol was removed and a residue was washed with some times with ether. The resulting hard mass was refluxed with 150 ml 2 N HCl for 2 hours. The obtained product was cooled and stood for 10-12 hours at 4°C in a refrigerator. The crystalline 2-(N-(1-adamantyl)-Nmethylaminomethyl-4',6'-dibromacetanilid hydrochloride (adamexine) was filtered off and thoroughly washed with distilled water. It was recrystallized from a mixture glacial acetic acid/water 2:1 (v/v) to give a white crystalline powder, melting at 250°-254°C. The hydrochloride is better for a pharmaceutical composition because of solubility in water. The free base may be prepared by adding of an equivalent of any basic compound (NaOH, NaHCO3 and so on). References B.D. Patent No. 2,436,909; July 31, 1974; Ferrer Internacional, S. A. Barcelona (Spain)
ADAPALENE Therapeutic Function: Antiacne Chemical Name: 2-Naphthalenecarboxylic acid, 6-(4-methoxy-3-tricyclo (3.3.1.13,7))dec-1-ylphenyl)Common Name: Adapalene Structural Formula:
Chemical Abstracts Registry No.: 106685-40-9
Adapalene
99
Trade Name
Manufacturer
Country
Year Introduced
Adaferin
Laboratoires Galderma
France
-
Adapalene
Laboratoires Galderma
France
-
Differin
Laboratoires Galderma
France
-
Raw Materials 4-Bromophenol 1-Adamantanol Sodium hydride Methyl iodide Dibromoethane Zinc chloride Nickel chloride/1,2-(diphenylphosphino)ethane-complex Manufacturing Process Preparation of 6-(3-(1-adamantyl)-4-methoxyphenyl)-2-naphthoic acid consist of 4 steps. 1. 2-(1-Adamantyl)-4-bromophenol. 34.6 g (200 mmol) of p-bromophenol and 30.4 g (200 mmol) of 1adamantanol are dissolved in 100 ml of dichloromethane. To the resulting solution there are slowly added 10 ml of concentrated sulfuric acid. The mixture is stirred for 8 hours at ambient temperature, poured into water, neutralized with sodium bicarbonate, extracted with methylehe chloride, dried and evaporated. After recrystallization in isooctane 52.8 g of the expected product are obtained. Yield - 86%. MP: 140°-141°C. 2. 2-(1-Adamantyl)-4-bromoanisole. To suspension of sodium hydride (80% in oil, 4.32 g, 144 mmol) in 50 ml of THF, there are slowly added while maintaining the temperature at 20°C, 36.8 g (120 mmol) of 2-(1-adamantyl)-4-bromophenol. The mixture is stirred for 1 hour at ambient temperature at which point 9 ml of methyl iodide are added. The mixture is then stirred for 2 hours at 20°C, poured into water, extracted with ether, dried and evaporated. The product is purified by passage through a silica column (10x30), eluting with a mixture of hexane (90%) and dichloromethane (10%). On evaporation, 26.2 g of a white solid are obtained. Yield - 68%. MP: 138°-139°C. 3. Methyl ester of 6-(3-(1-adamantyl)-4-methoxyphenyl)-2-naphthoic acid. To a suspension of magnesium (1.64 g, 67.5 mmol in 30 ml of THF, there is added a solution of 1.4 g (4.5 mmol) of 2-(1-adamantyl)-4-bromoanisole and 0.39 ml of dibromoethane in 10 ml of THF. The mixture is stirred until the reaction is initiated and then there is slowly added a solution of (40.8 mmol) of 2-(1-adamantyl)-4-bromoanisole in 90 ml of THF. The mixture is refluxed for 2 hours, and then cooled to 20°C. After that 6.2 g (45 mmol) of anhydrous ZnCl2 are added. The mixture is stirred for 1 hour at 20°C at which point 7.95 g (30 mmol) of methyl 6-bromo-2-naphthoate are added followed by addition of 300 g of NiCl2/1,2-(diphenylphosphino)ethane-complex as the catalyst. The mixture is stirred again for 2 hours at 20°C, poured into water, extracted with CH2Cl2 dried and evaporated. The product is isolated by column
100
Adatanserin hydrochloride
chromatography, eluting with a mixture of heptane (70%) and dichloromethane (30%) and then recrystallized in ethyl acetate. 12.2 g of the expected product are obtained. Yield - 78%. MP: 222°-223°C. 4. 6-(3-(1-Adamantyl)-4-methoxyphenyl)-2-naphthoic acid. 10.5 g of the ester obtained above (step 3) are treated with a solution of soda in methanol (200 ml, 4.2 N). The mixture is heated at reflux for 48 hours. The solvents are evaporated and the resulting residue is taken up in water and acidified with concentrated HCl. The solid is filtered and dried under vacuum over phosphoric anhydride. The resulting white solid is recrystallized in a mixture of THF and ethyl acetate. 8.2 g of expected product are obtained. Yield - 81%. MP: 325°-327°C. References Shroot B. et al.; US Patent No. 4,940,696; July 10, 1990; Assigned to Centre International de Recherches Dermatologioues (CIRD), Valbonne, France
ADATANSERIN HYDROCHLORIDE Therapeutic Function: Anxiolyticá Antidepressant Chemical Name: Tricyclo[3.3.1.13,7]decane-1-carboxamide, N-(2-(4-(2pyrimidinyl)-1-piperazinyl)ethyl)-, hydrochloride Common Name: Adatanserin hydrochloride Structural Formula:
Chemical Abstracts Registry No.: 144966-96-1; 127266-56-2 (Base) Trade Name
Manufacturer
Country
Year Introduced
WY-50324
Centre de Recherche Pierre Fabre
-
-
Adatanserin hydrochloride
ESTEVE QUIMICA SA
-
-
Raw Materials [4-(2-Pyrimidinyl)piperazino]ethylamine Triethylamine Adamantane-1-carboxylic acid chloride
Ademetionine
101
Manufacturing Process To a stirred solution of [4-(2-pyrimidinyl)piperazino]ethylamine (2.0 g, 0.01 mol) in 50 ml of methylene chloride, adamantane-1-carboxylic acid chloride (3.6 g, 0.018 mol) and triethylamine (2.9 g, 0.015 mol) were added. Stirring was continued at room temperature overnight. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The remaining residue was subjected to preparative HPLC. The residue was dissolved in ethyl acetate (10 ml) and subjected to flash chromatography using a 9 inch column of silica gel and ethyl acetate as the eluent. The N-[2-[4-(2-pyrimidinyl)-1piperazinyl]ethyl]tricyclo[3.3.1.1(3,7)] decane-1-carboxamide was separated. In practice it is usually used as hydrochloride. References Abou Gharbia M. A.-M. et al.; GB Patent No. 2,218,988A; Oct. 29, 1989
ADEMETIONINE Therapeutic Function: Metabolic, Antiinflammatory Chemical Name: S-Adenosyl-DL-methionine Common Name: Ademethionium; Ademetionine; Adenosylmethionine Structural Formula:
Chemical Abstracts Registry No.: 29908-03-0 Trade Name
Manufacturer
Country
Year Introduced
Donamet
Ravizza
-
-
Geptral
Knoll
-
-
Gumbaral
AWD.Pharma
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-
Gumbaral
Asta Pharma AWD -
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Legend
Fidia
-
-
102
Ademetionine
Trade Name
Country
Year Introduced
S-Amet parenteral Europharma
Manufacturer
-
-
Transmetil
Knoll
-
-
Twin
San Carlo
-
-
FO-1501
Sampl-Gibipharma -
-
Samyr
Knoll
-
-
Raw Materials Glucose Polypeptone Yeast extract Sucrose Urea Methionine, LBoric acid Potassium iodide Acetic acid Sulfuric acid
Potassium phosphate monobasic Magnesium sulfate heptahydrate Calcium chloride dihydrate Zinc sulfate heptahydrate Ferric sulfate heptahydrate Copper sulfate pentahydrate Cobalt(II) chloride hexahydrate Perchloric acid Potassium hydrocarbonate
Manufacturing Process S-Adenosyl methionine (SAM) is produced is prepared by cultivating of Saccharomyces cerevisiae. One loopful of each of the microorganism strains (IFO 2342, IFO 2343, IFO 2345, IFO 2346, IFO 2347) was inoculated in 10 ml of a heat-sterilized culture medium adjusted to pH 6.0 and composed of 5.0 g/dl of glucose, 0.5 g/dl of polypeptone, 0.4 g/dl of KH2PO4, 0.4 g/dl of K2HPO4, 0.02 g/dl of MgSO4·7H2O and 0.2 g/dl of yeast extract, and cultivated with shaking at 28°C for 24 h. 1 L of a culture medium adjusted to pH 6.0 and composed of 10.0 g/dl of sucrose, 1.0 g/dl of yeast extract, 0.4 g/dl of K2HPO4, 0.01 g/dl of MgSO4·7H2O, 1.5 g/dl of urea (separately sterilized), 0.75 g/dl of Lmethionine, 0.02 g/dl of CaCl2·2H2O, 0.25 mg/dl of ZnSO4·7H2O, 0.25 mg/dl of FeSO4·7H2O, 125.0 mg/dl of MnSO4·6H2O, 2.0 µg/dl of CuSO4·5H2O, 2.0 µg/dl of H3BO3, 0.2 µg/dl of CoCl2·6H2O and 1.0 µg/dl of KI was put in a 2liter fermentor and sterilized. Then, 5 ml of the seed culture broth prepared as above was inoculated in the culture medium and cultivated at 28°C for 72 h with aeration and agitation. After the cultivation, the microbial cells were collected by centrifugal separation, washed once with physiological saline, suspended in 100 ml of 1.5 N perchloric acid, and shaken at room temperature for 1 h. The suspension was then centrifuged to remove the microbial cells, and the resulting liquid was adjusted to pH 4.5 by adding potassium hydrogen carbonate. The resulting precipitate of potassium perchlorate was removed by centrifugal separation to give an extract containing SAM. The amount of SAM in the extract was determined, and the amount of SAM based on the dry cells.
Adenosine triphosphate
103
The extract in an amount of 0.2 g as SAM was passed through a column filled with 50 ml of Amberlite IRC-50 (H+ form), a weakly acidic cation exchange resin, to cause adsorption of SAM. 0.005 N acetic acid was passed through the column to wash it until the absorbance at 260 nm of the eluate becames less than 0.1. Thus, impurities were removed. Then, 0.1 N sulfuric acid was passed through the column, and SAM was eluted until the absorbance at 260 nm of the eluate becames less than 0.05. The eluate was treated with Amberlite IRA 900 resin (OH- form) to adjust its pH to 3.0, and then lyophilized to obtain SAM sulfate. The SAM based may be produced from SAM sulfate by treatment with potassium hydrogen carbonate. The purity of SAM was measured by cellulose thin-layer chromatography, paper chromatography and high-performance liquid chromatography. The yield of SAM based on the dry cells: IFO 2343-12.1%; IFO 2346-18.8%; IFO 2347-16.7%. References Shiozaki S. et al.; US Patent No. 4,562,149; Dec. 31, 1985; Assigned: Nippon Zeon Co., Ltd., Tokyo, Japan
ADENOSINE TRIPHOSPHATE Therapeutic Function: Coenzyme, Vasodilator Chemical Name: Adenosine 5'-(tetrahydrogen triphosphate) Common Name: ATP; Triphosadenine Structural Formula:
Chemical Abstracts Registry No.: 56-65-5 Trade Name
Manufacturer
Country
Year Introduced
Atepodin
Medix
Spain
-
Atriphos
Biochimica
Switz.
-
Estriadin
Boizot
Spain
-
Striadyne
Auclair
France
-
Triphosphodine
I.C.I.
UK
-
104
Adimolol hydrochloride
Raw Materials 1,3-Dicyclohexylguanidinium adenosine 5'-phosphoramidate Bis-Triethylammonium pyrophosphate Manufacturing Process With a solution of 0.29 part by weight of well dried 1,3dicyclohexylguanidinium adenosine 5'-phosphoramidate in 5 parts by volume of ortho-chlorophenol is admixed a solution of 0.95 part by weight of bistriethylammonium pyrophosphate in a mixed solvent composed of 1 part by volume of ortho-chlorophenol and 2 parts by volume of acetonitrile. The mixture is left standing at 20°C for 2 days. Then 30 parts by volume of water is added to the mixture. After washing with three 15 parts by weight volumeportions of diethyl ether, the aqueous layer is separated, and the remaining diethyl ether in the aqueous layer is removed under reduced pressure. Five parts by weight of activated charcoal is added to the aqueous layer and the mixture is stirred for 30 minutes. The activated charcoal is filtered and further 1 part by weight of activated charcoal is added to the filtrate. After 20 minutes agitation, the activated charcoal is taken out by filtration. The combined activated charcoal is washed with a little water, and eluted twice with respective 300 and 200 parts by volume-portions of 50% (volume) ethanol containing 2% (volume) of concentrated aqueous ammonia. The eluate is concentrated to 40 parts by volume, then is passed through a column packed with 20 parts by volume of a strongly basic anion exchange resin in bead form (chloric type) (polystyrene trimethylbenzyl ammonium type resin sold under the name of Dowex-1 from Dow Chemical Company, Mich. USA). Then, the column is washed with 750 parts by volume of an acid aqueous saline solution containing 0.01 normal hydrochloric acid and 0.02 normal sodium chloride and then eluted with 600 parts by volume of an acid aqueous saline solution composed of 0.01 normal hydrochloric acid and 0.2 normal sodium chloride. After neutralizing with a diluted sodium hydroxide solution, the eluate is treated with activated charcoal to adsorb ATP as its sodium salt. The separated activated charcoal is washed with water and eluted with 60% (volume) ethanol containing 2% (volume) of concentrated aqueous ammonia. The eluate is concentrated to 0.5 part by volume, then 5 parts by volume of ethanol is added. The precipitate thus deposited is centrifuged and dried at low temperature to obtain 0.155 part by weight of tetra-sodium salt of ATP containing 4 mols of water of crystallization as a colorless crystalline powder. The yield is 47% relative to the theoretical. References Merck Index 146 I.N.p. 983 Tanaka, K.and Honjo, M.; US Patent 3,079,379; February 26, 1963; Assigned to Takeda Pharmaceutical Industries, Ltd.
ADIMOLOL HYDROCHLORIDE Therapeutic Function: Alpa- and Beta-adrenergic blocker
Adiphenine hydrochloride
105
Chemical Name: ()-1-(3-((2-Hydroxy-3-(1-naphthyloxy)propyl)amino)-3methylbutyl)-2-benzimidazolinone hydrochloride Common Name: Adimolol hydrochloride; Imidolol hydrochloride Structural Formula:
Chemical Abstracts Registry No.: 75708-29-1; 78459-19-5 (Base) Trade Name
Manufacturer
Country
Year Introduced
Adimolol hydrochloride
ZYF Pharm Chemical
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-
Raw Materials 1-(3-Amino-3,3-dimethyl-n-propyl)benzimidazolidinone-2 1-[Naphthyl-1-oxyl]propylene-(2,3)-epoxide Manufacturing Process A mixture consisting of 3 g of 1-(3-amino-3,3-dimethyl-n-propyl) benzimidazolidinone-2, 3.3 g of 1-[naphthyl-(1)-oxyl]propylene-(2,3)-epoxide and 12 ml of 98% ethanol were refluxed for three hours. Thereafter, the ethanol was distilled off, the residue was taken up in some methanol, and the solution was acidified with 1 N hydrochloric acid and then extracted with ethyl acetate. The ethyl acetate was distilled out of the extract solution, and ether and some water were added to the residue, whereupon a crystalline substance separated out. The product was recrystallized from ethanol, yielding 60% of theory of ()-1-(3-((2-hydroxy-3-(1-naphthyloxy)propyl)amino)-3methylbutyl)-2-benzimidazolinone, which had a melting point of 161°C. In practice it is usually used as hydrochloride. References Koppe H. et al.; US Patent No. 4,255,430; March 10, 1981; Assigned to Boehringer Ingelheim GmbH, Ingelheim am Rhein, Fed. Rep. of Germany
ADIPHENINE HYDROCHLORIDE Therapeutic Function: Anticholinergic, Spasmolytic, Smooth muscle relaxant
106
Aditeren
Chemical Name: Benzeneacetic acid, α-phenyl-, 2-(diethylamino)ethyl ester, hydrochloride Common Name: Adiphenine hydrochloride Structural Formula:
Chemical Abstracts Registry No.: 50-42-0; 64-95-9 (Base) Trade Name Adiphenine hydrochloride
Manufacturer Country Spectrum Chemicals and Laboratory Products, Inc.
Year Introduced -
Neuro-Trasentin Paxil Paxil Paxil Trasentine
Aleve Frosst SKB GlaxoSmithKline Ciba
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-
Raw Materials α,α-Diphenylacetic acid Thionyl chloride Diethylaminoethanol Manufacturing Process 10.6 parts of α,α-diphenylacetic acid are treated with thionyl chloride and the diphenylacetylchloride thus produced is caused to react with 5.9 parts of diethylaminoethanol at 120°C. The α,α-diphenylacetic acid, 2(diethylamino)ethanol ester hydrochloride thus produced is crystallized from ethyl acetate; it melts at 113-114°C. References Merck Index, Monograph number: 160, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. Miescher K., Hoffmann K., US Patent No. 2,079,962; May 11, 1937; Assigned to Society of Chemical Industry, Basel, Switzerland
ADITEREN Therapeutic Function: Diuretic
Aditeren
107
Chemical Name: 2,4-Diamino-5-(4-amino-3,5-dimethoxybenzyl)pyrimidine Common Name: Aditeren Structural Formula:
Chemical Abstracts Registry No.: 56066-19-4 Trade Name
Manufacturer
Country
Year Introduced
Aditeren
Onbio Inc.
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-
Raw Materials Aniline p-Anilinepropionitrtile Sodium nitrite Guanidine carbonate Aluminum oxide 4-Toluenesulfonic acid Acetamide Bromosuccinimide Bromine Palladium on carbon Dimethylsulfone Sodium hydride Sodium methylate Sodium borohydride 3-Hydroxy-5-keto-3-cyclohexenecarboxylic acid Manufacturing Process A solution of 6.9 g of sodium in 1 liter of absolute ethanol were treated with 54 g of guanidine carbonate and 31.0 g of 4-amino-α-(anilinemethylene)-3,5dimethoxyhyrocinnamic acid nitrile and boiled under reflux for 20 hours. 500 ml of water were added and the alcohol was removed in vacuum. After standing at room temperature for 2 hours, the crystallized 2,4-diamino-5-(4amino-3,5-dimethoxybenxyl)pyrimidine was filtered off under suction, washed with water and recrystallised from methanol; melting point 215°-216°C. The starting material was prepared as follows: 13.8 g of sodium were dissolved in 900 ml of methanol. To this solution were added 46.8 g of 3-hydroxy-5-keto-3-cyclohexenecarboxylic acid. This mixture was stirred, held between -4° and -8°C by means of a cooling bath and treated during 30 minutes with a phenyl-diazonium chloride solution [prepared from 27.9 g of aniline, 450 ml of water, 72 ml of concentrated hydrochloric acid and 21.0 g of sodium nitrite in 90 ml of water]. The resulting mixture was stirred for a further 1 hour at -5°C to -10°C. The deposited, red reaction product was filtered off under vacuum and washed with ca 1000 ml of water. There was obtained 3-hydroxy-5-keto-4-phenyl-azo-3-cyclohexenecarboxylic acid of melting point 218°C.
108
Aditeren
60 g of 3-hydroxy-5-keto-4-phenyl-azo-3-cyclohexenecarboxylic acid, 200 ml of methanol, 1200 ml of benzene and 5 g of p-toluenesulphonic acid were boiled together under reflux on a water separator for 18 hours. After cooling, the solution was washed with 500 ml of a 5% sodium bicarbonate solution, then washed with water, dried and evaporated. The residue was dissolved in ethyl acetate and purified on an aluminum oxide column [500 g; activity stage I]. After evaporation of the ethyl acetate and recrystallisation of the residue from benzene/petroleum ether, there was obtained 3-hydroxIy-5-keto-4phenyl-azo-3-cyclohexenecarboxylic acid methyl ester as a solid of melting point 144°C. 54.8 g of 3-hydroxy-5-keto-4-phenyl-axe-3-cyclohexenecarboxylic acid methyl ester, 12.0 g of acetamide and 2.0 g of bromosuccinimide were stirred in 600 ml of chloroform and treated dropwise with 32.0 g of bromine in 400 ml of chloroform [the reaction temperature being held below 35°C]. The separation of acetamide hydrobromide soon began. The mixture was stirred for a further 30 minutes at room temperature, the acetamide hydrobromide filtered off and the filtrate evaporated to dryness. The residue was taken up in a small amount of ethanol, filtered off under vacuum and washed with ethanol. There was obtained 3,5-dihydroxy-4-phenylazobenzoic acid methyl ester of melting point 216°-218°C. A mixture of 27.2 g of 3,5-dihydroxy-4-phenylazobenzoic acid methyl ester, 150 ml of methanol and 64 g of dimethyl sulfate was treated during 45 minutes with a solution of 23 g of sodium hydroxide in 50 ml of water while stirring. Care was taken that the temperature did not exceed 55°C by means of a cooling bath. The mixture was stirred at room temperature for a further 1 hour, cooled with ice water, filtered off under vacuum and recrystallized from 400 ml of ethanol. Red crystals of 3,5-dimethoxy-4-phenylazobenzoic acid methyl ester were obtained; melting point 130°-132°C. 12 g of 3,5-dimethoxy-4-phenylazobenzoic acid methyl ester were dissolved in 400 ml of ethanol and, after the addition of 0.80 g of palladium on carbon, hydrogenated under atmospheric pressure and at room temperature. With slight warming, 2 moles of hydrogen were taken up during 1.5 hours. The catalyst was filtered off and the filtrate concentrated in vacuum. The resulting aniline was distilled off with steam. After cooling, the 4-amino-3,5dimethoxybenzoic acid methyl ester which remained as an aqueous suspension, was filtered off under vacuum, dried and recrystallised from cyclohexane; melting point 115°-116°C. A suspension of 214 g of dimethylsulphone and 78.2 g of sodium hydride (50% dispersion in oil) in 400 ml of absolute dimethyl sulfoxide was stirred at 50°C under nitrogen and with exclusion of moisture for 3 hours. The mixture was cooled to 30°C, whereupon 137 g of 4-amino-3,5-dimethoxybenzoic acid methyl ester were added, the temperature rising to 50°C. After stirring under nitrogen and at room temperature for ca 1 hour, the resulting mixture was left to stand for 3 hours and then dissolved in 2 liters of water under addition of ice. The solution was adjusted to pH 6-7 with glacial acetic acid. After stirring under ice-cooling for 1 hour, the crystallized 4'-amino-3',5'-dimethoxy-2methylsulfonyl-acetophenone was filtered off under suction, washed with water, dried and recrystallised from ethyl acetate; MP: 166°-167°C. A suspension of 123 g of 4'-ammo-3',5'-dimethoxy-2-methylsulphonyl-
Adosopine
109
acetophenone and 68 g of sodium borohydride in 1.5 liters of alcohol was stirred at room temperature for 20 hours. The suspension was diluted with 1.5 liters of water. The alcohol was evaporated in vacuum and the resulting 4amino-3,5-dimethoxy-α-(methylsulfonylmethyl)benzyl alcohol was filtered off under suction, washed with water and dried; melting point 178°-179°C. A mixture of 8.64 g of sodium methylate, 14.6 g of p-anilinepropionitrtile and 22.0 g of 4-amino-3,5-dimethoxy-α-(methylsulfonylmethyl)benzyl alcohol in 50 ml of absolute dimethyl sulfoxide was stirred at 50°C for 1 hour under nitrogen and with the exclusion of moisture. The solution was poured into 500 ml of ice-water and the resulting emulsion was extracted with two 500 ml portions of ethyl acetate. The ethyl acetate extracts were washed with two 250 ml portions of water, dried over magnesium sulfate and evaporated in vacuum. The residue was dissolved in 60 ml ethyl acetate. After standing at room temperature for 20 hours, the crystallized 4-amino-α(anilinemethylene)-3,5-dimethoxyhydrocinnamic acid nitrile was filtered off under suction, washed with a small amount of ethyl acetate and dried; MP: 150°-151°C. References G.B. Patent No. 1,484,481; Sept. 11, 1974; F. Hoffmann-La Roche and CO., Aktiengesellschaft, Swiss Company, 124-184 Grenzacherstrasse Basle, Switzerland
ADOSOPINE Therapeutic Function: Urinary incontinence agent Chemical Name: N-(6,11-Dihydro-5-methyl-6,11-dioxo-5H-dibenz[b,e] azepin-10-yl)acetamide Common Name: Adosopine Structural Formula:
Chemical Abstracts Registry No.: 88124-26-9 Trade Name
Manufacturer
Country
Year Introduced
Adosopine
Menarini Group
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-
110
Adrafinil
Raw Materials Acetic anhydride Sodium methylate
1-Aminoanthraquinone Methyl iodide
Manufacturing Process 2 ml of acetic anhydride are added to 2.5 g of 10-amino-5,6-dihydro-11Hdibenzo[b,e]azepine-6,11-dione (prepared from 1-aminoanthraquinone in accordance with Caronna and Palazzo-Gaz. Chim. It. 83, 533, 1953) in 50 ml of dioxane. After maintaining for 2 h under reflux, the mixture is evaporated almost to dryness under reduced pressure, the residue is then poured into water, filtered and dried to give 2.0 g of crude product. The 2.0 g of previously obtained crude product is suspended in 20 ml of N,Ndimethylformamide, and 710.0 mg of sodium methylate in 10 ml of methanol are added. After maintaining for 30 min at room temperature, 2.5 ml of methyl iodide are added, and mixture is allowed to stand for 24 h after which the mixture is poured into water, the product filtered off, dried and crystallized from ethanol, to give 5-methyl-10-acetamino-5,6-dihydro-11H-dibenzo[b,e] azepine-6,11-dione, melting point 199°-201°C. References Pestellini V. et al.; US Patent No. 4,551,451; Nov. 5, 1985; Assigned: A.Menarini S.a.S., Italy
ADRAFINIL Therapeutic Function: Psychostimulant Chemical Name: Acetamide, 2-((diphenylmethyl)sulfinyl)-N-hydroxyCommon Name: Adrafinil; Olmifon Structural Formula:
Chemical Abstracts Registry No.: 63547-13-7 Trade Name
Manufacturer
Country
Year Introduced
Olmifon
Cephalon
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-
Adrafinil
111
Raw Materials 3-Chloroacetic acid Sulfuric acid Sodium methylate Hydrogen peroxide Chlorodiphenylmethane
Sodium carbonate Hydroxylamine hydrochloride Hydrogen chloride Thiourea Sodium hydroxide
Manufacturing Process 7.6 g (0.1 mol) of thiourea and 100 ml of dematerialized water are introduced into a 500 ml three-neck flask equipped with a magnetic stirrer, a dropping funnel and a condenser; the mixture is heated to 50°C and 20.25 g (18 ml; 0.1 mol) of chlorodiphenylmethane are then added all at once. The solution is left refluxing until it has become limpid, and is then cooled to 20°C, and 200 ml of 2.5 N NaOH are added dropwise. So the sodium benzhydrylthiolate is obtained. A solution of sodium 3-chloroacetate is added to the solution of sodium benzhydrylthiolate at about 60°C. Thereafter the temperature is raised to the boil, the mixture is left under reflux for about 0.5 h and is then cooled, filtered over charcoal and acidified with concentrated HCl, and 3(benzhydrylthio)acetic acid are thus precipitated. To the solution of 3-(benzhydrylthio)acetic acid in 1,2-dichloroethane, methanol and concentrated H2SO4 have been added. The whole is heated to the reflux temperature for about 5 h, cooled, and decanted, the aqueous phase is discarded and the organic phase is washed with a saturated sodium bicarbonate solution and then with water until the wash waters have a neutral pH. After drying over MgSO4 and evaporating the solvent, the 3(benzhydrylthio)acetic acid methyl ester is obtained. The 3-(benzhydrylthio)acetic acid methyl ester dissolved in methanol, is added to a solution of hydroxylamine base [prepared by neutralising 0.15 mol (10.4 g) of hydroxylamine hydrochloride with 0.15 mol of sodium methylate]. The whole is left at ordinary temperature (15°-25°C) for 48 h, the sodium chloride is filtered off, the methanol is evaporated, the residue is taken up with aqueous alkali, the solution is filtered over charcoal, the filtrate is acidified with concentrated HCl, and the 3-(benzhydrylthio)acethylhydroxamic acid (recrystallised from benzene) is thus obtained. The 3-(benzhydrylthio)acethylhydroxamic acid, dissolved in anhydrous CH3COOH, is reacted with H2O2. The mixture is left at 40°-45°C for about 1.5 h, the acetic acid is evaporated and the residue is taken up in 50 ml of ethyl acetate; the 2-[(diphenylmethyl)sulfinyl]-N-hydroxyacetamide (CRL 40028) crystallises (recrystallised from isopropanol). References Lafon L.; US Patent No. 4,066,686; Jan. 3, 1978; Assigned: Laboratoire L. Lafon, Maisons Alfort, France
112
Afalanine
ADRENALONE Therapeutic Function: Hemostatic, Sympathomimetic, Vasoconstrictor Chemical Name: Ethanone, 1-(3,4-dihydroxyphenyl)-2-(methylamino)Common Name: Adrenalone; Adrenone Structural Formula:
Chemical Abstracts Registry No.: 99-45-6 Trade Name
Manufacturer
Adrenalone
Yick-Vic Chemicals and Pharmaceuticals (HK) Ltd.
Country
Year Introduced -
Raw Materials ω-Chloro-3,4-dihydroxyacetophenone Methylamine Manufacturing Process To a suspension of 1 part ω-chloro-3,4-dihydroxyacetophenone (prerared from chloroacetyl chloride and benzcatechole, see J. Russ. Phys. Chem. Ges., 25, 154) was added dropwise 1 part 60% solution of methylamine. Immediately was formed a residue of the salt of methylamine and ω-chloro-3,4dihydroxyacetophenone. The dissolution of the salt was carried out by heating of the mixture. Then the salt was converted in crude 3,4-dihydroxy-αmethylaminoacetophenone. The product was dissolved in dilute hydrochloric acid. To this solution was added dropwise aqueous ammonium solution to prepare light yellow crystal of 3,4-dihydroxy-α-methylaminoacetophenone. The base and the hydrochloride of 3,4-dihydroxy-α-methylaminoacetophenone decomposed at temperature near 230°C and 240°C respectively. References Merck Index, Monograph number: 170, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. DE Patent No. 152,814; 1903.08.15; Assigned to Farbwerke vorm. Meister and Bruening in Hoechst a. M.
AFALANINE Therapeutic Function: Antidepressant
Afloqualone
113
Chemical Name: DL-Phenylalanine, N-acetylCommon Name: Afalanine Structural Formula:
Chemical Abstracts Registry No.: 2901-75-9 Trade Name
Manufacturer
Country
Year Introduced
Afalanine
Sankyo
-
-
Raw Materials Phenylalanine Sodium hydroxide Acetylbromide Manufacturing Process The phenylalanine was dispersed in water. A 1 N aqueous solution of sodium hydroxide was slowly added to this dispersion, and the pH of the solution reached a value of 7-8. Then acetylbromide was dissolved in this solution, to give a Nacetylphenylalanine. References Shiogari T. et al.; EU Patent No. 0,178,911; April 23, 1986; Assigned: Sankyo company limited. N 1-6, 3-chome Nihonbashi Honcho Chuo-ku Tokyo (JP)
AFLOQUALONE Therapeutic Function: Muscle relaxant Chemical Name: 6-Amino-2-(fluoromethyl)-3-(o-tolyl)-4(3H)-quinazolinone Common Name: Chemical Abstracts Registry No.: 56287-74-2; 56287-75-3 (Hydrochloride salt)
114
Afloqualone
Structural Formula:
Trade Name
Manufacturer
Country
Year Introduced
Arofuto
TANABE SEIYAKU
Japan
1983
Raw Materials Fluoroacetyl chloride Acetic anhydride
N-(2-Amino-5-nitrobenzyl)-o-toluidine Hydrogen
Manufacturing Process 14.4 g (0.053 mol) of N-(2-amino-5-nitrobenzoyl)-o-toluidine and 6.3 g (0.08 mol) of pyridine are dissolved in 300 ml of tetrahydrofuran. 12.2 g (0.126 mol) of fluoroacetyl chloride are added to the solution for 10 minutes under ice-cooling. The solution is stirred at the same temperature for 30 minutes and then at room temperature for 2.5 hours. The reaction solution is allowed to stand at room temperature overnight. The crystalline precipitate is collected by filtration, washed with water and then dried. 16.4 g of N-(2fluoroacetamido-5-nitrobenzoyl)-o-toluidine are obtained. Yield: 93.7%; MP 238-239°C. 16.5 g (0.05 mol) of N-(2-fluoroacetamido-5-nitrobenzoyl)-o-toluidine and 25.5 g (0.25 mol) of acetic acid anhydride are dissolved in 250 ml of glacial acetic acid. The solution is refluxed for 2 hours under heating. Then, the reaction solution is evaporated to remove solvent. The residue thus obtained is poured into ice-water, and the aqueous mixture is adjusted to pH 9 with potassium carbonate. The crystalline precipitate is collected by filtration. 15.5 g of 2-fluoromethyl-3-(o-tolyl)-6-nitro-4(3H)-quinazolinone are obtained. Yield: 98.7%; MP 155-158°C (recrystallized from ethanol). A mixture of 2.0 g (0.064 mol) of 2-fluoromethyl-3-(o-tolyl)-6-nitro-4(3H)quinazolinone, 0.2 g of 5% palladium-carbon and 100 ml of acetic acid is shaken for 30 minutes in hydrogen gas. The initial pressure of hydrogen gas is adjusted to 46 lb and the mixture is heated with an infrared lamp during the reaction. After 30 minutes of this reaction, the pressure of hydrogen gas decreases to 6 lb. After the mixture is cooled, the mixture is filtered to remove the catalyst. The filtrate is evaporated to remove acetic acid, and the residue is dissolved in chloroform. The chloroform solution is washed with 5% aqueous sodium hydroxide and water, successively. Then, the solution is dried and evaporated to remove solvent. The oily residue thus obtained is dissolved in 2 ml of chloroform, and the chloroform solution is passed through a column of 200 g of silica gel. The silica gel column is eluted with ethyl acetatebenzene (1:1). Then, the eluate is evaporated to remove solvent. The crude crystal obtained is washed with isopropyl ether and recrystallized from
Afurolol
115
isopropanol. 0.95 g of 2-fluoromethyl-3-(o-tolyl)-6-amino-4(3H)-quinazolinone is obtained. Yield: 52.5%; MP 195-196°C. References DFU 7 (8) 539 (1982) DOT 19 (1) 581 (1983) Inoue, L., Oine, T., Yamado, Y., Tani, J., Ishida, R. and Ochiai, T.; US Patent 3,966,731; June 29, 1976; Assigned to Tanabe Seiyaku Co., Ltd.
AFUROLOL Therapeutic Function: Beta-adrenergic blocker Chemical Name: 7-[3-[(1,1-Dimethylethyl)amino]-2-hydroxypropoxy]-1(3H)isobenzofuranone Common Name: Afurolol Structural Formula:
Chemical Abstracts Registry No.: 65776-67-2 Trade Name
Manufacturer
Afurolol
ZYF Pharm Chemical -
Country
Year Introduced -
Raw Materials 7-Hydroxyphthalide 1-Chloro-2,3-epoxypropane t-Butylamine Manufacturing Process A mixture of 18.0 g (0.12 mole) 7-hydroxyphthalide, 180.0 g of 1-chloro-2,3epoxypropane (2 moles) and 0.5 ml of piperidine is heated at 100°C for about 5 h and then the unreacted 1-chloro-2,3-epoxypropane is distilled off in vacuum to yield 12.0 g (48%) of 7-(2,3-epoxypropoxy)phthalide, melting point 88°-90°C, (crystallized successively from methanol and ethyl acetate). The 7-(2,3-epoxypropoxy)phthalide is dissolved in methanol and t-butylamine are added to the solution at about 20°C. The solution is allowed to stand
116
Aganodine
overnight and, the mixture is evaporated in vacuum and the residue is dried to give 7-(2-hydroxy-3-t-butylamino-propoxy)phthalide. References Bellasio E.; US Patent No. 3,935,236; Jan. 27, 1976; Assigned: Gruppo Lepetit, S.p.A., Milan, Italy
AGANODINE Therapeutic Function: Antihypertensive Chemical Name: Guanidine, (4,7-dichloro-2-isoindolinyl)Common Name: Aganodine Structural Formula:
Chemical Abstracts Registry No.: 86696-87-9 Trade Name
Manufacturer
Country
Year Introduced
Aganodine
ZYF Pharm Chemical
-
-
Raw Materials 3,6-Dichlorophthalic anhydride Lithium aluminum hydride Cyanamide
Carbazic acid, tert-butyl ester Hydrochloric acid Sodium bicarbonate
Manufacturing Process The solution of 3,6-dichlorophthalic anhydride in 300 ml of N,Ndimethylformamide are heated to the boiling point over 15 min with tbutylcarbazate. Subsequent to evaporation of the solvent, N-(tbutyloxycarbonylamino)-3,6-dichlorophthalimide is obtained from ethanol. The solution of N-(t-butyloxycarbonylamino)-3,6-dichlorophthalimide in 400 ml of absolute tetrahydrofuran are slowly dripped into a suspension of aluminum lithium hydride in absolute tetrahydrofuran. The mixture is heated to the boiling point. Conventional processing yields N-(t-butyloxycarbonylamino)-4,7dichloroisoindoline.
Ajmaline
117
N-(t-Butyloxycarbonylamino)-4,7-dichloroisoindoline are introduced into concentrated hydrochloric acid and stirred at room temperature. The hydrochloride of 2-amino-4,7-dichloroisoindoline precipitates in the form of crystals is obtained, melting point 230°-232°C. 2-Amino-4,7-dichloroisoindoline hydrochloride and cyanamide are heated over 2 h to the boiling point in n-amyl alcohol. The solvent is evaporated off and the residue recrystallized from isopropyl alcohol and ethyl ether, yielding the (4,7-dichloroisoindolin-2-yl)guanidine in the form of hydrochloride, melting point 235°-237°C. To obtained the base (4,7-dichloroisoindolin-2-yl)guanidine the salt (4,7dichloroisoindolin-2-yl)guanidine hydrochloride is treated with sodium bicarbonicum. References Cohnen E, Armah B.; US Patent No. 4,526,897; July 2, 1985; Assigned: Beiersdorf Aktiengesellschaft, Hamburg, Fed.Rep. of Germany
AJMALINE Therapeutic Function: Antiarrhythmic Chemical Name: Ajmalan-17,21-diol, (17R,21α)Common Name: Ajmaline; Rauwolfine Structural Formula:
Chemical Abstracts Registry No.: 4360-12-7 Trade Name
Manufacturer
Country
Year Introduced
Ajmaline
Solvay Pharma
-
-
Aritmina
Farmacie Petrone
-
-
Aritmina
Solvay
-
-
Neo-Aritmina
Giulini Pharma
-
-
Gilurytmal
Solvay
-
-
Gilurytmal
Solvay Arzneimittel
-
-
118
Alacepril
Trade Name
Manufacturer
Country
Year Introduced
Gilurytmal
Solvay Pharmaceuticals (Spolka z o.o.)
-
-
Gilurytmal
Solvay Pharmaceuticals
-
-
Gilurytmal
Solvay Pharma, Klosterneuburg
-
-
Neo-Gilurytmal
Solvay Pharmaceuticals
-
-
Rauwolfine
Extrasynthese
-
-
Ritmos
Inverni
-
-
Serenol
Laboratoires Plantes et Medecines
-
-
Tachmalin
Arzneimittelwerk Dresden
-
-
Raw Materials Rauwolfia canescens L. roots Acetic acid Ammonia Manufacturing Process Ajmaline isolated from Rauwolfia sp. roots: Rauwolfia serpentine Benth., Rauwolfia vomitoria Afr., Rauwolfia canescens L. Threshed roots of Rauwolfia canescens L. extracted with 5% solution of acetic acid at room temperature for 24 h. Then extract was decanted to flask. This extract was alkalified with ammonia (alkaloid salts were converted to alkaloid bases). The obtained thus method solution was extracted with chloroform 3 or more times. Then chloroform extract was chromatographed on column through Al2O3 sorbent. After chromatography ajmalin was obtained, which had melting point at 205°C (recyrstallization from methanol). References Belikov A.S.; Alkaloids of Rauwolfia canescens L.//Chemistry of natural compounds 1969, 3. P.64
ALACEPRIL Therapeutic Function: Antihypertensive Chemical Name: L-Phenylalanine, N-(1-(3-(acetylthio)-2-methyl-1oxopropyl)-L-prolyl)-, (S)-
Alacepril
119
Common Name: Alacepril; Cetapril Structural Formula:
Chemical Abstracts Registry No.: 74258-86-9 Trade Name
Manufacturer
Country
Year Introduced
Alacepril
Sumika Fine Chemicals Co., Ltd.
-
-
Alacepril
ZYF Pharm Chemical
-
-
Cetapril
Dainippon Pharmaceutical Co., Ltd.
-
-
Raw Materials N-Methylmorpholine 1-(D-3-Acetylthio-2-methylpropanoyl)-L-proline Phenyl chloroformate L-Phenylalanine t-butyl ester hydrochloride Sodium bicarbonate Hydrochloric acid Anisole Trifluoroacetic acid Manufacturing Process N-Methylmorpholine (1.03 g) was added to a solution of 1-(D-3-acetylthio-2methylpropanoyl)-L-proline (2.65 g) in dry tetrahydrofuran (50 ml). The resulting solution was stirred and cooled at -20° to -15°C. Phenyl chloroformate (1.61 g) was added, and after 5 min, a solution of Lphenylalanine t-butyl ester hydrochloride (2.4 g) and N-methylmorpholine (1.03 g) in dry tetrahydrofuran (30 ml) was added. The mixture was stirred at -20° to -15°C for 1 h and then at room temperature overnight. After removal of insoluble materials by filtration, the filtrate was concentrated under reduced pressure and the residue was dissolved in chloroform. The chloroform solution was washed successively with 1 N sodium hydroxide, water, 10% citric acid, and water, dried and concentrated under reduced pressure. The residue was chromatographed on silica gel with chloroformmethanol (99:1) to give 4.2 g the 1-(D-3-acetylthio-2-methylpropanoyl)-Lprolyl-L-phenylalanine tert-butyl ester. 1-(D-3-Acetylthio-2-methylpropanoyl)-L-prolyl-L-phenylalanine tert-butyl ester
120
Alafosfalin
(2.5 g) was dissolved in a mixture of anisole (18 ml) and trifluoroacetic acid (37 ml). The solution was allowed to stand at room temperature for 1 h and then concentrated to dryness under reduced pressure. The residue was crystallized from diethyl ether. The 1-(D-3-acetylthio-2-methylpropanoyl)-Lprolyl-L-phenylalanine was obtained (1.8 g), melting point 155°-156°C (recrystallization from ethanol/n-hexane). References Sawayama T. et al.; US Patent No. 4,248,883; Feb. 3, 1981; Assigned: Dianippon Pharmaceutical Co., Ltd., Osaka, Japan
ALAFOSFALIN Therapeutic Function: Antibacterial Chemical Name: Phosphonic acid, ((1R)-1-(((2S)-2-amino-1-oxopropyl) amino)ethyl)Common Name: Alafosfalin; Alaphosfalin Structural Formula:
Chemical Abstracts Registry No.: 60668-24-8 Trade Name
Manufacturer
Country
Year Introduced
Alafosfalin
Roche Product Limited
-
-
Raw Materials N-Hydroxysuccinimide ester of N-benzyloxycarbonyl-L-alanine (1R,S)-1-Aminoethylphosphonic acid Benzylamine Palladium on carbon 1R-(L-Alanylamino)ethanephosphonous acid Mercuric chloride Propylene oxide Manufacturing Process 14.1 g (0.168 mol) of solid sodium bicarbonate were added to a solution of 7 g (0.056 mol) of (1R,S)-1-aminoethylphosphonic acid in 280 ml of water and 140 ml of ethanol while stirring at 0°C. While stirring this mixture at 0°C, a solution of 17.9 g (0.056 mol) of the N-hydroxysuccinimide ester of N-
Alafosfalin
121
benzyloxycarbonyl-L-alanine in 140 ml of warm ethanol was added dropwise over ca 15 minutes. The latter solution was washed in with 70 ml of ethanol. The heterogeneous mixture was stirred for 1 hour at 0°C and then for a further 16 hours at room temperature, the mixture becoming homogeneous. The mixture was evaporated and re-evaporated with 200 ml of water to give a gum, which was dissolved in 500 ml of water. The solution was extracted firstly with 500 ml of chloroform and then with 250 ml portions of chloroform, acidified to pH 2 with ca 80 ml of 2 N hydrochloric acid and again extracted with 500 ml of chloroform followed by two 250 ml portions of chloroform. The aqueous layer was concentrated and passed down a column of cation exchange resin (B.D.H., Zerolit 225, SRC 13, RSO3H; 750 g; freshly regenerated in the acid cycle). The column was eluted with water and there were collected six 250 ml fractions. The first four fractions were combined, evaporated and re-evaporated with water to remove hydrogen chloride. There was obtained a final residue of (1R,S)-1-[(N-benzyloxycarbonyl-L-alanyl)amino]ethylphosphonic acid which was separated as follows: The latter residue was dissolved in 400 ml of water and titrated with 1 M benzylamine to pH 4.5. The resulting solution was concentrated and crystallized from water to give 5.3 g of the benzylamine salt of (1S)-1-[(Nbenzyloxycarbonyl-L-alanyl)amino]ethylphosphonic acid of melting point 210215°C. Concentration of the mother liquors followed by further recrystallization from water gave the benzylamine salt of (1R)-1-[(Nbenzyloxycarbonyl-L-alanyl)amino]ethylphosphonic acid in a first crop of 0.59 g [melting point 226-228°C (decomposition); [α]D20 = -32.3° (c = 1% in acetic acid)] and a second crop of 0.825 g] melting point 225-227°C (decomposition); [α]D20 = -33.0° (c = 1% in acetic acid)]. Recrystallization of the first crop from water gave 0.333 g of pure benzylamine salt of the Rstereoisomer; melting point 226-228°C (decomposition); [α]D20 = -33.1° (c=1% in acetic acid). 1.1 g (2.5 mmol) of the benzylamine salt of (1R)-1-[(N-benzyloxycarbonyl-Lalanyl)amino]-ethylphosphonic acid were dissolved in 4 ml of 2 N ammonium hydroxide, passed down a column of cation exchange resin (B.D.H., Zerolit 225, SRC 13, RSO3H; 120 g; freshly regenerated in the acid cycle) and eluted with water. There were collected 200 ml of acid eluate, which was concentrated to 100 ml. To this were added 100 ml of methanol, 0.3 g of 5% palladium-on-charcoal catalyst and 3 drops of glacial acetic acid. The mixture was hydrogenated at room temperature and atmospheric pressure. The catalyst was filtered off and the solvent evaporated. The residual gum was reevaporated with three 50 ml portions of n-propanol to give 0.6 g of a gummy solid of melting point ca 275-280°C (decomposition). After further recrystallization from water and ethanol, there was obtained 0.2 g of (1R)-1(L-alanylamino)-ethylphosphonic acid of melting point 295-296°C (decomposition); [α]D20 = -44.0° (c=1% in water). The different ways of synthesis of alafosfalin were described: 1). 1R-1-(L-alanylamino)-ethanephosphonous acid (0.034 M), mercuric chloride (0.068 M) and water (175 ml) were mixed and heated to reflux for 1 hour The white insoluble mercuric chloride which formed was removed by filtration and the aqueous filtrate was evaporated to dryness. The oily residue was dissolved in ethanol (20 ml) and propylene oxide was added until
122
Alanosine
precipitation was complete. Filtration gave 1R-1-(L-alanylamino)ethylphosphonic acid, which was recrystallised from ethanol/water. MP: 293295°C, [α]D20 =-49.3° (1%, H2O). Yield was 100% of theory. 2). Papain (50 mg; 2.2 U/mg) was added to the solution of 0.5 mmol Z-L-Ala, 1.15 mmol racemic diisopropyl ester of 1-aminoethylphosphonic acid and 50 ml 2-mercaptoethanol in the mixture of 2.3 ml acetonitrile and 0.2 ml water The suspension was shaken for about 2 days until all the Z-ala was consumed (TLC-control). The enzyme was filtered off and washed with 10% KHSO4, water, saturated NaHCO3, dried with anhydrous Na2SO4 and evaporated under reduced pressure. The resulting phosphonopeptide was dissolved in 2 ml of 40% HBr in glacial acetic acid and left overnight. Anhydrous ether (10 ml) was added and the mixture was stirred for 10 min and upper phase decanted. The residue was evaporated, the remaining gum was dissolved in 2 ml of methanol and treated with excess of propylene oxide. The precipitated material was filtered off and crystallized from water water-ethanol to give pure alafosfalin, yield 60%, MP: 273-276°C (decomposition); [α]D20 =-45° (0.2% in water). Only L-aminophosthonate is involved in the peptide bond formation because of papain presence. References Atherton F.R. et al.; US Patent No. 4,016,146; April 5, 1977; Assigned to Hoffmann-La Roche Inc., Nutely, N.Y. Baylis E.; US Patent No. 4,331,591; May 25, 1982; Assigned to Ciba-Geigy Corporation, Ardsley, N.Y. Solodenko V., Kukar V.; Tetrahedron Letters, v. 30, No. 49, pp 6917-6918, 1989
ALANOSINE Therapeutic Function: Antineoplastic Chemical Name: 3-(Hydroxynitrosoamino)-L-alanine Common Name: Alanosine Structural Formula:
Chemical Abstracts Registry No.: 5854-93-3 Trade Name
Manufacturer
Country
Year Introduced
Alanosine
Triangle Pharmaceuticals
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-
Alanosine
123
Raw Materials Streptomyces alanosinicus n. sp. ATCC 15710 Peptone-agar-glucose-yeast extract medium Glucose Dried whale meat (Pascor) 6% of Darco G-60 charcoal Sodium methoxide Manufacturing Process Alanosine is an antibiotic isolated from the fermentation broth of Streptomyces alanosinicus n. sp. Oat meal agar slants seeded with Streptomyces alanosinicus n. sp. ATCC 15710 were incubated at 20°C for 7 to 10 days and then used to inoculate 100 ml of a peptone-agar-glucose-yeast extract medium contained in 500 ml Erlenmeyer flask. The composition of this fermination medium is: Meat extract Peptone Yeast extract Enzymatic casein hydrolysate Cerelose NaCl
5.0 5.0 5.0 3.0 2.0 1.5
g./liter g./liter g./liter g./liter g./liter g./liter
The medium is adjusted to pH 7.2 prior to sterilization for 20 minutes at 121°C and 15 Ibs steam pressure. The germination flasks are incubated at 28°C for 48 hours on rotary shaker having a 2 inch throw and making 240 rpm. A 3% transfer is made from the germination flask to 500 ml Erlenmeyer fermentation flaks containing 100 ml of medium TVF/5 having the following composition: Glucose Dried whale meat (Pascor) CaCO4 (NH4)2SO4 MgSO4·7H2O CuSO4 sol. 0.5% FeSO4 sol. 0.1% ZnSO4 sol. 0.2% MnSO4 sol. 0.8%
50.0 g/L 10.0 g/L 5.0 g/L 1.0 g/L 1.0 g/L 1 ml 1 ml 1 ml 1 ml
The medium is adjusted to pH 7.0 prior to sterilization for 20 minutes at 121°C. The fermentation flasks are incubated and agitated under similar conditions as the germination flasks. After 72 hours the mycelium was separated by centrifugation and the untreated broth assayed by the streak dilution method. 30 liters of broth are centrifuged and 6% of Darco G-60 charcoal is added to the clear solution, which is stirred for 30 minutes; then the charcoal is filtered off to give an almost colorless solution which is concentrated in vacuum at 45-50°C to 1.5 liters. The concentrated solution is poured under stirring into 5 liters of methanol, the formed precipitate is
124
Alatrofloxacin mesylate
filtered, washed with much acetone and dried in vacuum. Yield 230 g of crude product assaying about 10%. Purification: The above crude product is suspended in 400 ml of water and to the suspension, cooled to 4°C and kept stirred, sulfuric acid is added to pH 2.02.5; the undissolved residue is filtered off, the solution is further diluted with 400 ml of water and 1.6 liters of methanol are added to precipitate the antibiotic. The mixture is kept at 4°C for some hours to complete precipitation, then it is filtered, washed with acetone and dried in vacuum over P2O5. Yield 62 g of a product assaying 27%. The dried product is suspended in anhydrous methanol and the mixture is kept stirred; perchloric acid (75%) is added at about 4°C to reach a pH of 3.0, the undissolved portion is filtered off and the antibiotic is precipitated by adjusting the pH 5.5 with sodium methoxide. The suspension is allowed to decant for some hours at 4°C, then it is filtered and the precipitate is washed with diethyl ether. Yield 30 g (titer 43%). An amount of 3.2 g of the obtained antibiotic is dissolved in 60 ml of H2O and the pH is adjusted to 8; the undissolved portion is filtered off and by the addition of glacial acetic acid, the pH is adjusted to 4-4.5. On cooling at 4°C, 1.2 g of antibiotic in crystalline form (assaying 75%) are obtained. An amount of 2.9 g of said crystalline antibiotic is dissolved in 900 ml of water heating the solution to 70-80°C, then it is filtered, concentrated to 200 ml and allowed to stand 8-10 hours at 4°C; then it is filtered and washed with cold water. Yield 1.45 g (97%). By further concentrating the solution to 100 ml a further amount of antibiotic is obtained: 1 g (80%). Alanosine melts at 190°C, [α]D25= -37.8° (c=0.5, water). Antibiotic was also prepared by syntheses from anhydrous hydroxylamine and methyl-2-acetamido-3-chloropropionate followed by reaction with NaNO2 in dilute acetic acid. The prepared racemic product was separated on individual isomers. References Thiemann J. et al.; US Patent No. 3,676,490; July 11, 1972; Assigned to Lepetit S.P.A., Milan, Italy Lancini G.C.A, Diena and E. Lassari; Tetrahedron Letters No. 16, pp. 17691772, 1966
ALATROFLOXACIN MESYLATE Therapeutic Function: Antibacterial Chemical Name: L-Alaninamide, L-alanyl-N-(3-(6-carboxy-8-(2,4difluorophenyl)-3-fluoro-5,8-dihydro-5-oxo-1,8-naphthyridin-2-yl)-3azabicyclo[3.1.0]hex-6-yl)-, (1α,5α,6α)-, monomethanesulfonate Common Name: Alatrofloxacin mesilate
Alatrofloxacin mesylate
125
Structural Formula:
Chemical Abstracts Registry No.: 146961-77-5; 146961-76-4 (Base) Trade Name
Manufacturer
Country
Year Introduced
Alatrofloxacin mesylate Alatrofloxacin mesylate
Pfizer
-
-
Fairview Pharm
-
-
Alatrofloxacin mesilate
Cipla
-
-
Trovan Preservative Free
Pfizer
-
-
Trovan iv
Pfizer
-
-
Turvel iv
Roerig Farmaceutici Italiana S.p.A. Pfizer
-
-
-
-
Turvel iv Raw Materials
Diphenylphosphinous azide Dihydropyrrole Ethyldiazoacetate Palladium Alanylalanine 1-(2,4-Difluoro-phenyl)-6,7-difluoro-4-oxo-1,4-dihydro[1,8] naphthylridine-3-carboxylic acid ethyl ester Manufacturing Process The dipolar cycloaddition of ethyldiazoacetate to the protected dihydropyrrole (with carbobenzyloxy (CBZ) protecting group) gives the fused pyrrazolidine(CBZ-3-ethylperoxy-1,3a,4,5,6,6a-hexahydro-pyrrolo{3,4-c}pyrazole). Pyrolysis results in loss of nitrogen and formation of the cyclopyrrolidine ring. The ester is then saponified to the corresponding carboxylic acid (CBZ-6-azabicyclo[3.1.0]hexene-3-carboxylic acid).This acid undergoes a version of the
126
Albendazole
Curtius rearrangement when treated with diphenylphosphinous azide to afford transient isocyanate. That reactive function adds tert-butanol from the reaction medium to afford the product as its butoxycarbonyl (BOC) derivative. CBZ-protecting group is removed by catalytic hydrogenation on Pd to afford the BOC-protected secondary amine - BOC-6-aza-bicyclo[3.1.0]hex-3-ylamine. In a standard quinolone reaction, this amine is then used to displace the more reactive fluorine at 7-position in the quinolone - 1-(2,4 difluoro-phenyl)-6,7difluoro-4-oxo-1,4-dihydro[1,8]naphthylridine-3-carboxylic acid ethyl ester. Treatment of the displacement product with hydrogen chloride cleaves the BOC protecting group to afford the antibiotic trovafloxacin. The peptide-like alanylalanylamide derivative, alatrofloxacin can in principle be prepared by reaction of the ester precursor of trovafloxacin with alanylalanine followed by saponification and treatment by methane sulphonic acid (mesylate). References Lednicer D., The organic Chemistry of Drug Synthesis, vol. 5, Wiley, NY, p.123 (1985) Brighty K.E.; US Patent No. 5,164,402; Nov. 17, 1992, Assigned to Pfizer Inc., New York, N.Y. Lednicer D., The organic Chemistry of Drug Synthesis, vol.6, Wiley, NY, p.154 (1999)
ALBENDAZOLE Therapeutic Function: Anthelmintic Chemical Name: [5-(Propylthio)-1H-benzimidazol-2-yl]carbamic acid methyl ester Common Name: Structural Formula:
Chemical Abstracts Registry No.: 54965-21-8 Trade Name
Manufacturer
Country
Year Introduced
Zentel
SK and F
France
1981
Raw Materials 3-Chloro-6-nitroacetanilide Hydrogen Methyl chloroformate
Propyl Mercaptan Cyanamide
Albifylline
127
Manufacturing Process A mixture of 6.65 g of 3-chloro-6-nitroacetanilide, 3.2 ml of propylmercaptan, 5.6 g of 50% sodium hydroxide and 100 ml of water is heated at reflux overnight. The cooled mixture is filtered to give the desired 2-nitro-5propylthioaniline, MP 69.5-71.5°C after recrystallization from ethanol then hexane-ether. NMR (CDCl3) 40%. The aniline (2.5 g) is hydrogenated with 1.9 ml of concentrated hydrochloric acid, 100 ml ethanol and 5% palladium-on-charcoal to give 4-propylthio-ophenylene-diamine hydrochloride. A mixture of 2.5 ml of 50% sodium hydroxide in 5 ml of water is added to a mixture of 1.9 g of cyanamide, 2.2 g of methylchloroformate, 3.5 ml of water and 3 ml of acetone over 45 minutes below 10°C, pH raised to 6.5. A molar equivalent solution of the diamine in 100 ml of ethanol is added. The mixture is heated until the easily volatile solvents are expelled, to about 85°C, then maintained at this temperature with some water added for one-half hour. The product, methyl 5-propylthio-2-benzimidazolecarbamate, is separated, washed to give a colorless crystalline solid, MP 208-210°C. References Merck Index 197 DFU 2 (2) 81 (1977) OCDS Vol.2 p. 353 (1980) DOT 15 (3) 89 (1979) I.N. p. 50 Gyurik, R.J. and Theodorides, V.J.; US Patent 3,915,986; October 28, 1975; Assigned to Smith Kline Corp.
ALBIFYLLINE Therapeutic Function: Vasodilator Chemical Name: 3,7-Dihydro-1-(5-hydroxy-5-methylhexyl)-3-methyl-1Hpurine-2,6-dione Common Name: Albifylline Structural Formula:
Chemical Abstracts Registry No.: 107767-55-5
128
Albifylline
Trade Name
Manufacturer
Country
Year Introduced
HWA-138
Hoechst-Roussel
-
-
Raw Materials 1-Chloro-5-hexanone 3-Methylxanthine Palladium on carbon
Methyl magnesium chloride Benzyl bromide
Manufacturing Process 1-(5-Hydroxy-5-methylhexyl)-3-methylxanthine may be prepared next way: 1). 1-Chloro-5-hydroxy-5-methylhexane: A solution of 67.3 g (0.5 mol) of 1-chloro-5-hexanone in 50 ml of anhydrous ether is added dropwise to 44.9 g (0.6 mol) of methyl magnesium chloride in the form of a 20% strength solution in tetrahydrofuran and 200 ml of dry ether at 0° to 5°C, while stirring. The mixture is then subsequently stirred initially at room temperature for one hour and then while boiling under reflux for a further hour, the tertiary alkanolate formed is decomposed by addition of 50% strength aqueous ammonium chloride solution, the ether phase is separated off and the aqueous phase is extracted by shaking with ether. The combined ethereal extracts are washed in succession with aqueous sodium bisulfite solution and sodium bicarbonate solution as well as a little water, dried over sodium sulfate, filtered and concentrated in vacuo and the liquid residue is subjected to fractional distillation under reduced pressure. Yield: 64.1 g (85.1% of theory), boiling point (20 mbar) 95-97°C, refractive index nD25 =1.4489. 2). 7-Benzyl-3-methylxanthine: 20 g (0.5 mol) of sodium hydroxide dissolved in 200 ml of water are added to a suspension of 83 g (0.5 mol) of 3-methylxanthine in 500 ml of methanol, the mixture is stirred at 70°C for one hour, 85.5 g (0.5 mol) of benzyl bromide are then added dropwise at the same temperature and the reaction mixture is kept between 70°C and 80°C for 5 hours. It is then cooled and filtered cold with suction, the product on the suction filter is washed with water and dissolved in 1000 ml of 1 N sodium hydroxide solution under the influence of heat, the solution is filtered and the pH is brought slowly to 9.5 with 4 N hydrochloric acid, while stirring. The crystals are filtered off from the still warm solution, washed with water until free from chloride and dried in vacuum. Yield: 81.7 g (63.8% of theory), melting point: 262-264°C. 3). 7-Benzyl-1-(5-hydroxy-5-methylhexyl)-3-methylxanthine: A mixture of 20.5 g (0.08 mol) of 7-benzyl-3-methylxanthine, 12.4 g (0.09 mol) of potassium carbonate and 13.61 g (0.09 mol) of above 1-chloro-5hydroxy-5-methylhexane in 300 ml of dimethylformamide is heated at 110° to 120°C for 8 hours, while stirring, and is then filtered hot and the filtrate is evaporated under reduced pressure. The residue is taken up in chloroform, the mixture is washed first with 1 N sodium hydroxide solution and then with
Albuterol
129
water until neutral and dried, the solvent is distilled off in vacuum and the solid residue is recrystallized from ethyl acetate, with the addition of petroleum ether Yield: 23.8 g (80.3% of theory), melting point: 109-111°C. 4). 1-(5-Hydroxy-5-methylhexyl)-3-methylxanthine: 14.8 g (0.04 mol) of the above mentioned 7-benzylxanthine are hydrogenated in 200 ml of glacial acetic acid over 1.5 g of palladium (5%) on active charcoal at 60°C under 3.5 bar in the course of 24 hours, while shaking. After cooling, the mixture is blanketed with nitrogen, the catalyst is filtered off, the filtrate is concentrated under reduced pressure and the solid residue is recrystallized from ethyl acetate. Yield of albifylline: 9.6 g (85.6% of theory), MP: 192-193°C. References Gebert U. et al.; US Patent No. 4,833,146; May 23, 1989; Assigned to Hoechst Aktiengeselschaft, Frankfurt am Main, Fed. Rep. of Germany
ALBUTEROL Therapeutic Function: Bronchodilator Chemical Name: α1-[[(1,1-Dimethylethyl)amino]methyl]-4-hydroxy-1,3benzenedimethanol Common Name: Salbutamol, α'-tert-Butylaminomethyl-4-hydroxy-m-xyleneα1,α3-diol Structural Formula:
Chemical Abstracts Registry No.: 18559-94-9; 51022-70-9 (Sulfate) Trade Name Ventolin Sultanol Ventoline Ventolin Ventolin Ventolin Ventolin Broncollenas Buto-Asma Proventil
Manufacturer Allen and Hanburys Glaxo Glaxo Glaxo Sankyo Glaxo Glaxo Llenas Aldo Union Schering
Country UK W. Germany France Italy Japan Switz. US Spain Spain US
Year Introduced 1969 1971 1971 1973 1973 1981 1981 -
130
Albuterol
Trade Name Rotacaps Salbumol Salbutol Salbuvent Salbuvent
Manufacturer Schering Medica Iltas Leiras Nyegaard
Country Finland Turkey Finland Norway
Year Introduced -
Raw Materials 5-(N-Benzyl-N-tert-butylglycyl)salicylic acid methyl ester hydrochloride Lithium aluminum hydride Hydrogen Manufacturing Process (a) α1-Benzyl-tert-butylaminomethyl-4-hydroxym-xylene-α1,α3-diol: 3.0 g of 5-(N-benzyl-N-tert-butylglycyl)-salicylic acid methyl ester hydrochloride in 40 ml of water was basified with sodium bicarbonate solution and extracted into ether. The ethereal solution was dried over MgSO4 and evaporated and the basic residue in 20 ml of dry tetrahydrofuran was added with stirring to 1.0 g of lithium aluminum hydride in 100 ml of dry tetrahydrofuran, over a period of 5 minutes. The light gelatinous precipitate that formed was stirred and refluxed for 8 hours after which time 7 ml of water was carefully added and the solvents were removed under reduced pressure. The residue was acidified with dilute hydrochloric acid and brought to pH 8 with sodium hydroxide and sodium bicarbonate. The mixture was filtered and the filtrate and orange solid were separately extracted with chloroform. The combined, dried, chloroform solutions were evaporated to give 22 g of the crude basic triol as an orange solid, when triturated with ether. A portion of the material was recrystallized from ether/light petroleum (BP 40-60°C) to give a white solid, MP 109-111°C. In an alternative process, sodium borohydride was used as the reducing agent, as follows: 36 g of 2-(benzyl-tert-butylamino)-4'-hydroxy-3'-hydroxymethyl acetophenone, hydrochloride was shaken with 100 ml of 10% sodium carbonate solution and 100 ml of ethyl acetate. The ethyl acetate layer was separated, washed with water, dried over anhydrous sodium sulfate and evaporated in vacuum. The residual gum was dissolved in 360 ml of ethanol and cooled to 15°C in an ice/water bath, 8 g of sodium borohydride was then added in portions over 30 minutes while maintaining the temperature at 15-20°C. After a further 30 minutes at 20°C the solution was stirred at room temperature for 2 hours. The solution was again cooled in ice and 250 ml of 2 N sulfuric acid were slowly added, then the solution was evaporated in vacuum until the ethanol had been removed. The clear aqueous solution was then treated with 250 ml of 10% sodium carbonate solution and the oil which precipitated was extracted into ethyl acetate. The ethyl acetate layer was washed with sodium carbonate solution, then with water, and was dried over anhydrous sodium
Alclofenac
131
sulfate and evaporated in vacuum, to a small volume. Petroleum ether (BP 40-60°C) was added, and after standing overnight a white solid was obtained. This was filtered off to give 23 g of the product, MP 110-114°C. (b) α1-tert-Butylaminomethyl-4-hydroxy-m-xylene-α1,α3-diol: 0.8 g of α1benzyl-tert-butyl-aminomethyl-4-hydroxy-m-xylene-α1,α3-diol in 20 ml of ethanol and 2 ml of water was shaken with hydrogen in presence of 0.50 g of pre-reduced 10% palladium on charcoal catalyst. When uptake of hydrogen was complete, the solution was filtered and evaporated under reduced pressure to give 0,4 g of the base as a colorless oil which yielded a white solid, MP 144-145°C when triturated with ether/cyclohexane. Recrystallization from ethyl acetate-cyclohexane gave a white solid, MP 147-149°C. References Merck Index 206 DFU 4 (9) 629 (1979) Kleeman and Engel p. 813 PDR 40 pp. 916, 1649 OCDS Vol. 2 p. 43 (1980) DOT 16 (8) 269 (1980) I.N. p. 860 REM p. 881 Lunts, L.H.C. and Toon, P.; US Patent 3,644,353; February 22, 1972; Assigned to Allen and Hanburys Ltd.
ALCLOFENAC Therapeutic Function: Antiinflammatory Chemical Name: 3-Chloro-4-(2-propenyloxy)benzene-acetic acid Common Name: (4-(Allyloxy)-3-chlorophenyl]acetic acid Structural Formula:
Chemical Abstracts Registry No.: 22131-79-9 Trade Name Mervan Prinalgin Neoston
Manufacturer Cooper Berk Beiersdorf
Country Switz. UK W. Germany
Year Introduced 1971 1972
132
Alclometasone dipropionate
Trade Name
Manufacturer
Country
Year Introduced
Allopydin
Chugai
Japan
1976
Zumaril
Abbott
Italy
1976
Epinal
Kyorin
Japan
1976
Darkeyfenac
Cuatrecasas-Darkey
Spain
-
Desinflam
Sintyal
Argentina
-
Medifenac
Medici
Italy
-
Mervan, Mirvan
Continental Pharma
Belgium
-
Vanadian
Federico Bonet
Spain
-
ZumariI
Sidus
Italy
-
Rentenac
Tosi
Italy
-
Raw Materials 3-Chloro-4-allyloxyphenyl acetonitrile Potassium hydroxide Manufacturing Process 103.7 grams of 3-chloro-4-allyloxyphenylacetonitrile in 500 cc of ethanol, 100 grams of potassium hydroxide and 100 cc of water are refluxed for 4 hours. Maximum of alcohol is evaporated, the residue is diluted with water and ice, and acidified with 20% HCl. The solid is filtered and washed with petroleum ether. 91.5 grams of acid are obtained (Yield: 81%) which is recrystallized from aqueous methanol; MP 92-93°C. References Merck Index 209 Kleeman and Engel p. 19 OCDS Vol. 2 p. 68 (1980) DOT 8 No. 9, 329 (1972) I.N. p. 50 British Patent 1,174,535; December 17, 1969; Assigned to Madan AG, Switzerland
ALCLOMETASONE DIPROPIONATE Therapeutic Function: Antiinflammatory, Antiallergic Chemical Name: Pregna-1,4-diene-3,20-dione, 7-chloro-11-hydroxy-16methyl-17,21-bis(1-oxopropoxy)-, (7α,11β,16α)Common Name: Alclometasone dipropionate; Perderm; Modrasone Chemical Abstracts Registry No.: 66734-13-2
Alclometasone dipropionate
133
Structural Formula:
Trade Name
Manufacturer
Country
Year Introduced
Alclovate
GlaxoSmithKline
-
-
Afloderm
Belupo
-
-
Miloderme
Schering-Plough
-
-
Raw Materials 16α-Methyl-1,4,6-pregnatriene-11β,17α,21-triol-3,20-dione 17,21dipropionate Hydrogen chloride Sodium borohydride Manufacturing Process A). Add 16α-methyl-1,4,6-pregnatriene-11β,17α,21-triol-3,20-dione 17,21dipropionate (2.0 g) to dioxane (24 ml) which has been saturated with dry hydrogen chloride gas. Stir at room temperature for 16 hours, pour into ice water (600 ml), separate the resultant precipitate by filtration, wash the precipitate with water and dry in air. Separate the components in the foregoing precipitate on silica gel via thin layer chromatography utilizing as developing solvent ether:hexane (2:1), and elute with ethyl acetate the band containing 7α-chloro-16α-methyl-1,4-pregnadiene-11β,17α,21-triol-3,20-dione 17,21-dipropionate as shown by ultraviolet light. Evaporate the combined ethyl acetate eluates and triturate the resultant residue with acetone:ether, then filter and dry the triturated precipitate to obtain 7α-chloro-16α-methyl1,4-pregnadiene-11β,17α,21-triol-3,20-dione 17,21-dipropionate. Alternatively, the 7α-chloro-16α-methyl-1,4-pregnadiene-17α,21-diol-3,11,20trione 17,21-dipropionate is prepared according to following procedures B and C. B). Saturate dry tetrahydrofuran (137 ml) at 0°C with dry hydrogen chloride gas. Add 16α-methyl-1,4,6-pregnatriene-17α,21-diol-3,11,20-trione 17,21dipropionate (6.85 g) and stir the reaction mixture at 0°C for 1 hour. Pour into ice water (1 liter) and stir for ½ hour. Separate the resultant precipitate by filtration, wash with water, and air dry to give 7v-chloro-16α-methyl-1,4pregnadiene-17α,21-diol-3,11,20-trione 17,21-dipropionate. Purify from methanol:acetone containing a trace of propylene oxide; [α]D26 +76.2°
134
Alcuronium chloride
(dimethylformamide). C). To a solution of 7v-chloro-16α-methyl-1,4-pregnadiene-17α,21-diol3,11,20-trione 17,21-dipropionate (3.2 g) in tetrahydrofuran (24 ml) and methanol (8 ml) at 0°C under an atmosphere of nitrogen add sodium borohydride (0.697 g) and stir the reaction mixture for 15 min at 0°C. Pour into ice water (1.8 liters) and 250 ml of 1 N hydrochloric acid. Separate the resultant precipitate by filtration and air dry to give 7α-chloro-16α-methyl11β,17α,21-triol-3,20-dione 17,21-dipropionate. Purify by crystallizing twice from acetone:methanol:isopropyl ether; m.p. 212°-216°C; [α]D26 +42.6° (dimethylformamide). λmax 242 nm (methanol, ε 15,600). By saponification of 7α-chloro-16α-methyl-1,4-pregnadiene-17α,21-diol3,11,20-trione 17,21-dipropionate is prepared (7α,11β,16α)-7-chloro11,17,21-trihydroxy-16-methylpregna-1,4-diene-3,20-dione. References Green M., Shue Ho-Jane; US Patent No. 4,124,707; Nov. 7, 1978; Schering Corporation (Kenilworth, NJ)
ALCURONIUM CHLORIDE Therapeutic Function: Muscle relaxant Chemical Name: N,N'-Diallylnortoxiferinium dichloride Common Name: Structural Formula:
Aldosterone
135
Chemical Abstracts Registry No.: 15180-03-7 Trade Name
Manufacturer
Country
Year Introduced
Alloferin
Roche
UK
1966
Alloferin
Roche
W. Germany
1968
Alloferine
Roche
France
1968
Dialferin
Nippon Roche
Japan
1969
Toxiferin
Roche
-
-
Raw Materials Diallyl Nortoxiferine Diiodide Chloride Ion Exchange Resin Manufacturing Process 31 g of diallylnortoxiferine diiodide are suspended in 1 liter of water and shaken with 1,100 ml of Amberlite IRA-400 [chloride ion form, described Merck Index, 7th edition, Merck and Co., Inc., Rahway, New Jersey (1960), page 1584], for 2 hours. The diiodide thereby goes into solution. The ion exchanger is filtered off and then washed in 3 portions with a total of 1 liter of water. The combined filtrates are then allowed to run through a column of 300 ml of Amberlite IRA-400 (chloride ion form), rinsed with 300 ml of water and the eluate evaporated to dryness in a vacuum while excluding air. The residue gives on recrystallization from methanol/ethanol crystalline pure colorless diallylnortoxiferine dichloride in a yield of 18.6 g. The compound contains 5 mols of water of crystallization after equilibration in air. References Merck Index 215 Kleeman and Engel p. 19 I.N. p.51 Boller, A., Els, H. and Furst, A.; US Patent 3,080,373; March 5, 1963; Assigned to Hoffman La Roche, Inc.
ALDOSTERONE Therapeutic Function: Mineralocorticoid Chemical Name: Pregn-4-en-18-al, 11,21-dihydroxy-3,20-dioxo-, (11β)Common Name: Aldosterone; Elektrocortin; Oxocorticosterone; Reichstein's substance X Chemical Abstracts Registry No.: 52-39-1
136
Aldosterone
Structural Formula:
Trade Name Aldosterone Aldosterone Aldocorten
Manufacturer Sigma Chemical Company Andard-Mount Company Limited Ciba
Country -
Year Introduced -
-
-
-
-
Raw Materials 3α,11β-Dihydroxy-D-homo-18noretiocholan-17α-one Sodium hydride Potassium hydroxide Acrylonitrile 4-Toluenesulfonic acid monohydrate Acetic acid Sodium borohydride Ozone Sodium metaperiodate Sodium arsenite Sodium bicarbonate Potassium iodide Piperidine Pyridine Acetic anhydride Zinc Diazomethane Lithium Bromobenzene Thyonyl chloride Palladium Chromic oxide Dinitrophenylhydrazine Furfural Hydrogen chloride Manufacturing Process In 1.0 L of methanol (purified by distillation from potassium hydroxide) was dissolved 27.02 g of 3α,11β-dihydroxy-D-homo-18-noretiocholan-17α-one (melting point 169°-173°C Patent No. 2,847,457; May 26, 1955). The solution was cooled to 5°C, and 54 ml of freshly distilled furfural was added. The air in the flask was replaced by nitrogen, 400 ml of 15% aqueous potassium hydroxide was added and the flask was sealed tightly. The solution was allowed to stand at room temperature overnight. The precipitate was collected on a filter, washed generously with water, and was dried to constant weight in vacuo, yielding 28.45 g of 3α,11β-dihydroxy-D-homo-18-noretiocholan-17furfurylidene-17α-one as colorless lustrous plates, melting point 193°-194°C (after repeated recrystallization from methanol and acetone-petroleum ether). A solution of 48 mg of sodium hydride in 6 ml of anhydrous methanol was cooled to 5°C, and to it was added slowly 1.20 ml of acrylonitrile (b.p. 75°78°C). The solution was allowed to stand at room temperature for an 1 h and then cooled again to 5°C. The 3α,11β-dihydroxy-D-homo-18-noretiocholan-17-
Aldosterone
137
furfurylidene-17α-one was added and the solution was stirred at room temperature for 2 h and then heated at reflux for 2 h. After a total of 8 h of heating at reflux the mixture was cooled to 5°C, and acetic acid was added until the solution was acidic. It was then diluted with water and extracted with ethyl acetate. The extract was washed with aqueous sodium bicarbonate and water, dried over magnesium sulfate, and distilled to dryness under reduced pressure. The product was crystallized from a small volume of acetone, and the crystals were washed with hot petroleum ether and then ether. This gave 750 mg of 3α,11β-dihydroxy-13α-(2-cyanoethyl)-D-homo-18-noretiocholan17-furfurylidene-17α-one as colorless plates, melting point 193°-194°C (after repeated recrystallization from methanol). A solution of 1.02 g of 3α,11β-dihydroxy-13α-(2-cyanoethyl)-D-homo-18noretiocholan-17-furfurylidene-17α-one in 60 ml of methanol and 5 ml of pyridine was cooled to -70°C, and a stream of oxygen containing ozone was passed through until the solution turned a faint blue color (25 min). The solution was quickly put under reduced pressure to remove any dissolved ozone, and after 3 min a solution of 1.0 g of sodium borohydride in 10 ml of water was added slowly, allowing the solution to warm to 0°C. Within two min after the borohydride was added (an acidified portion of the solution gave no starch-iodide test, indicating absence of ozonide). An additional 3.0 g of borohdride was added in 1 g portions at 1 h intervals, and the solution was allowed to stand for a total of 35 h. Acetic acid was added slowly and stirring until the solution yield pH 5. The methanol was distilled, under reduced pressure, the last portions being co-distilled with ethyl acetate and water. The aqueous solution was then extracted three times with ethyl acetate. The extracts were washed in turn with 5% aqueous hydrochloric acid (cold), water, aqueous sodium bicarbonate, and water. The combined ethyl acetate solutions were dried over sodium sulfate and concentrated to dryness under reduced pressure. The crude product (71%) of 3α,11β,17,17a-tetrahydroxy-13α-(2cyanoethyl)-D-homo-18-noretiocholan was obtained as colorless rods, melting point 137°-140°C (several recrystallization from aqueous methanol). To a solution of 280 mg of 3α,11β,17,17a-tetrahydroxy-13α-(2-cyanoethyl)-Dhomo-18-noretiocholan in 17 ml of methanol at room temperature contained in a 25 ml volumetric flask there was added 162 mg of sodium metaperiodate in 8 ml of water. A small amount of water was added to bring the volume to 25 ml. After 15 min an aliquot was withdrawn and added to a measured amount of sodium arsenite solution containing sodium bicarbonate and potassium iodide. After 10 min, the solution was titrated with standard iodine solution. The solution was diluted with water and extracted twice with ethyl acetate, each extract being washed in turn with sodium combined, dried over magnesium sulfate and concentrated to dryness under reduced pressure, yielding 265 mg of a colorless, amorphous product of 4b-methyl-1β-(2formylethyl)-2β-formyl-2-(2-cyanoethyl)-4β,7αdihydroxyperhydrophenanthrene. A solution of 240 mg of 4b-methyl-1β-(2-formylethyl)-2β-formyl-2-(2cyanoethyl)-4β,7α-dihydroxyperhydrophenanthrene dissolved in 30 ml of anhydrous methanol containing 20 mg of p-toluenesulfonic acid monohydrate was allowed to stand at room temperature for 36 h. Aqueous sodium bicarbonate was added and the methanol was evaporated under reduced pressure. An ether extraction of the aqueous layer afforded 260 mg of a benzene soluble oil, which was chromatographed on 12 g of florisil. The 4b-
138
Aldosterone
methyl-1β-(2-formylethyl)-2β-formyl-2-(2-cyanoethyl)-4β,7αdihydroxyperhydrophenanthrene 1β-methyl acetal 2β,4β-lactol methyl ether was eluted between 20% benzene in ether and ether. A solution of 560 mg of the 4b-methyl-1β-(2-formylethyl)-2β-formyl-2-(2cyanoethyl)-4β,7α-dihydroxyperhydrophenanthrene 1β-methyl acetal 2β,4βlactol methyl ether in 10 ml of pyridine and 5 ml of acetic anhydride was heated at 100°C for 10 min. The solution was cooled and poured on iced aqueous sodium bicarbonate. The mixture was extracted with ether, the extract being washed with water, dried over magnesium sulfate and concentrated to dryness at aspirator pressure. The pyridine was removed at 2 mm with as little heating as possible. From a small volume of methanol, the colorless oil remaining gave a heavy precipitate of crystals which was washed with petroleum ether (b.p. 32°-35°C). The pure 4b-methyl-1β-(2-formylethyl)2β-formyl-2-(2-cyanoethyl)-4β,7α-dihydroxyperhydrophenanthrene 1β-methyl acetal 2β,4β-lactol methyl ether 7α-acetate was obtained as colorless prisms, melting point 126°-127°C, by several recrystallizations from methanol. The 4b-methyl-1β-(2-formylethyl)-2β-formyl-2-(2-cyanoethyl)-4β,7αdihydroxyperhydrophenanthrene 1β-methyl acetal 2β,4β-lactol methyl ether 7α-acetate (360 mg) was stirred in 3 ml of ether. Upon the addition of 9 ml of 70% aqueous acetic acid the crystals dissolved immediately. The solution was allowed to stand at room temperature for 16 h and was then extracted with ether. The extract was washed thoroughly with water and aqueous sodium bicarbonate, dried over magnesium sulfate and concentrated to dryness under reduced pressure, yielding 337 mg of oil. On trituration with ether there was obtained 305 mg of crystals of 4b-methyl-1β-(2-formylethyl)-2β-formyl-2-(2cyanoethyl)-4β,7α-dihydroxyperhydrophenanthrene 2β,4β-lactol methyl ether 7α-acetate as platelets, melting point 85°-105°C after recrystallizations from benzene-petroleum ether. After standing at room temperature for 10 min, a solution of 710 mg of the 4b-methyl-1β-(2-formylethyl)-2β-formyl-2-(2-cyanoethyl)-4β,7αdihydroxyperhydrophenanthrene 2β,4β-lactol methyl ether 7α-acetate in 5 ml of piperidine and 10 ml of benzene was heated at brisk reflux in a nitrogen atmosphere. After 3 h the solvents were removed under reduced pressure, leaving 820 mg of 4b-methyl-1β-[3-(1-piperidyl)-2-propenyl]-2β-formyl-2-(2cyanoethyl)-4β,7α-dihydroxyperhydrophenanthrene 2β,4β-lactol methyl ether 7α-acetate as colorless oil. Through a solution of 810 mg of crude 4b-methyl-1β-[3-(1-piperidyl)-2propenyl]-2β-formyl-2-(2-cyanoethyl)-4β,7α-dihydroxyperhydrophenanthrene 2β,4v-lactol methyl ether 7α-acetate in 60 ml of methylene chloride and 1.5 ml of pyridine at -70°C was passed a stream of oxygen containing ozone until the solution turned blue (17 min). 3 g of zinc dust and 6 ml of glacial acetic acid were added immediately. The stirred solution was allowed to warm to 0°C and to remain at that temperature for 30 min. The solution was filtered and washed with aqueous sodium bicarbonate. The organic solvent was dried over magnesium sulfate and was distilled below room temperature, affording 750 mg of a benzene soluble, pale yellow oil. The product was chromatographed and eluted 310 mg (45%) of 4b-methyl-1β-(2-formylmethyl)-2β-formyl-2-(2cyanoethyl)-4β,7α-dihydroxyperhydrophenanthrene 2β,4β-lactol methyl ether 7α-acetate.
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139
A solution of 310 mg of the chromatographed noncrystalline 4b-methyl-1β-(2formylmethyl)-2β-formyl-2-(2-cyanoethyl)-4β,7αdihydroxyperhydrophenanthrene 2β,4β-lactol methyl ether 7α-acetate in 60 ml of anhydrous methanol containing 40 mg of p-toluenesulfonic acid monohydrate was allowed to stand at room temperature for 9 h. Aqueous sodium bicarbonate was added, and methanol was evaporated under reduced pressure. The remaining mixture was extracted with ether and extract was dried over magnesium sulfate and concentrated to dryness in vacuo, affording 325 mg of oil. This was chromatographed on 12 g of florisil. Ether eluted 285 mg of oil which crystallized from petroleum ether, giving 230 mg of 4bmethyl-1β-(2-formylmethyl)-2β-formyl-2-(2-cyanoethyl)-4β,7αdihydroxyperhydrophenanthrene 1β-methyl acetal 2β,4β-lactol methyl ether 7α-acetate as irregular prisms, melting point 149°-152°C. A solution of 220 mg of the 4b-methyl-1β-(2-formylmethyl)-2β-formyl-2-(2cyanoethyl)-4β,7α-dihydroxyperhydrophenanthrene 1β-methyl acetal 2β,4βlactol methyl ether 7α-acetate in 5 ml of methanol and 10 ml of 10% aqueous potassium hydroxide was heated at reflux 17 h. The methanol was distilled off and the remainder was extracted with chloroform. The aqueous solution was cooled to 5°C and was acidified to pH 4 with cold 3 N hydrochloric acid. The solution was rapidly extracted twice with cold ethyl acetate, each extract being washed in turn 3 times with water. To the combined extracts (300 ml) was added 10 ml of methanol followed by solution excess diazomethane in 50 ml of ether. After 10 min the diazomethane was blown off, and the solvent was evaporated under reduced pressure, affording 235 mg of an oil. Chromatography of this material on 6 g of florisil and elution gave 220 mg of 4b-methyl-1β-(2-formylmethyl)-2β-formyl-2-(2-methylcarboxyethyl)-4β,7αdihydroxyperhydrophenanthrene 1β-methyl acetal 2β,4β-lactol methyl ether. Excess phenyllithium (prepared from 0.210 g of lithium wire and 2.4 g of bromobenzene following the directions given by J.C.W. Evans and C.F.H. Allen, Org. Syntheses, vol. 2, p. 22 (1943)) in 20 ml of ether was added to 215 mg of the 4b-methyl-1β-(2-formylmethyl)-2β-formyl-2-(2-methylcarboxyethyl)4β,7α-dihydroxyperhydrophenanthrene 1β-methyl acetal 2β,4β-lactol methyl ether in 20 ml of anhydrous ether under an atmosphere of nitrogen. After the solution was stirred at room temperature for 2 h, the excess reagent was decomposed by the drop wise addition of ethanol. Water was added, and the mixture was extracted with ether. The extract was washed with water, dried over magnesium sulfate and concentrated to dryness under reduced pressure, yielding 310 mg of an oil which was chromatographed ed on 6 g of florisil; ether eluted 267 mg of an oil which giving 252 mg of 4b-methyl-1β-(2formylmethyl)-2β-formyl-2-(3,3,3-hydroxydiphenylpropyl)-4β,7αdihydroxyperhydrophenanthrene 1β-methyl acetal 2β,4β-lactol methyl ether as needles, melting point 116°-119°C (from ether). A solution of 250 mg of the 4b-methyl-1β-(2-formylmethyl)-2β-formyl-2(3,3,3-hydroxydiphenylpropyl)-4β,7α-dihydroxyperhydrophenanthrene 1βmethyl acetal 2β,4β-lactol methyl ether, in 10 ml of pyridine and 5 ml of acetic anhydride was heated at 100°C for 10 min. The solution was cooled and poured onto iced aqueous sodium bicarbonate. The mixture was extracted with ether, dried over magnesium sulfate and concentrated to dryness under reduced pressure, affording 255 mg (95.2%) of the colorless 4b-methyl-1β(2-formylmethyl)-2β-formyl-2-(3,3,3-hydroxydiphenylpropyl)-4β,7αdihydroxyperhydrophenanthrene 1β-methyl acetal 2β,4β-lactol methyl ether
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Aldosterone
7α-acetate. To a solution of 250 mg of the 4b-methyl-1β-(2-formylmethyl)-2β-formyl-2(3,3,3-hydroxydiphenylpropyl)-4β,7α-dihydroxyperhydrophenanthrene 1βmethyl acetal 2β,4β-lactol methyl ether 7α-acetate in 10 ml of benzene and 1.0 ml of pyridine at 0°C was added 0.5 ml of thyonyl chloride. After standing at 0°C for 15 min, the solution was poured onto iced sodium bicarbonate, and resulting mixture was extracted with ether. The extract was dried over magnesium sulfate, and the ether was removed under reduced pressure. Pyridine (20 ml) was added and solution was heated at 100°C for 20 min. The solution was then concentrated to dryness under reduced pressure and the residue was dissolved in a small volume of benzene. The benzene solution was poured on 6 g of florisil; elution with ether provided 230 mg of colorless 4bmethyl-1β-(2-formylmethyl)-2β-formyl-2-(3,3-diphenyl-2-propenyl)-4β,7αdihydroxyperhydrophenanthrene 1β-methyl acetal 2β,4β-lactol methyl ether 7α-acetate. Through a solution of 225 mg of the 4b-methyl-1β-(2-formylmethyl)-2βformyl-2-(3,3-diphenyl-2-propenyl)-4β,7α-dihydroxyperhydrophenanthrene 1βmethyl acetal 2β,4β-lactol methyl ether 7α-acetate in 30 ml of methylene dichloride and 0.15 ml of pyridine at -70°C was passed a stream of oxygen containing ozone. When the solution turned a faint blue color, 3 g of zinc dust and 6 ml of glacial acetic were added immediately. The solution was stirred at 0°C until it gave a negative starch iodide test (10 min); the mixture was filtered, washing the zinc with additional methylene dichloride. The organic solution was washed with aqueous sodium bicarbonate, dried over magnesium sulfate and concentrated to dryness in vacuo, giving 230 mg of oil. This was chromatographed on 5 g of florisil; elution with ether gave 110 mg of 4bmethyl-1β,2α-bis-(2-formylmethyl)-2β-formyl-4β,7αdihydroxyperhydrophenanthrene 1β-methyl acetal 2β,4β-lactol methyl ether 7α-acetate. In 1 ml of ether was dissolved 20 mg of the crude 4b-methyl-1β,2α-bis-(2formylmethyl)-2β-formyl-4β,7α-dihydroxyperhydrophenanthrene 1β-methyl acetal 2β,4β-lactol methyl ether 7α-acetate. To this was added 3 ml of 70% aqueous acetic acid, and the homogeneous solution was allowed to stand at room temperature to 10 h. The material was extracted with ether, and extract was washed with aqueous sodium bicarbonate, dried over magnesium sulfate and concentrated to dryness under reduced pressure, yielding 15 mg of 4bmethyl-1β,2α-bis-(2-formylmethyl)-2β-formyl-4β,7αdihydroxyperhydrophenanthrene 2β,4β-lactol 7α-acetate. A benzene solution (5 ml) of 15 mg of the 4b-methyl-1β,2α-bis-(2formylmethyl)-2β-formyl-4β,7α-dihydroxyperhydrophenanthrene 2β,4β-lactol 7α-acetate containing 3.4 mg of piperidine and 6.2 mg of acetic acid was heated at 60°C in slow stream of nitrogen with an azeotropic separator. After 1 h, half the solution was withdrawn, diluted with benzene, and washed with diluted aqueous hydrochloric acid and with aqueous sodium bicarbonate. The benzene extract dried over magnesium sulfate and concentrated to dryness under reduced pressure, giving 3α-acetoxy-17-formyl-16-etiocholen-11β-ol18-one 11β,18-lactol as colorless oil. The 3α-acetoxy-17-formyl-16-etiocholen-11β-ol-18-one 11β,18-lactol can be converted to aldosterone by conventional methods as follows.
Alendronate sodium trihydrate
141
The unsaturated 3α-acetoxy-17-formyl-16-etiocholen-11β-ol-18-one 11β,18lactol is hydrogenated in the presence of palladium catalyst to saturate the 16,17-double bond, and then saturated aldehyde are oxidized by treatment with chromic oxide in pyridine to give 3α-acetoxy-11β-ol-18-one-pregnane 11β,18-lactone 17-carboxylic acid. Then as a result of reaction of 3α-acetoxy-11β-ol-18-one-pregnane 11β,18lactone 17-carboxylic acid and HCl the 3α-acetoxy-11β-ol-18-one-pregnane 11β,18-lactone 17-carboxylic acid chloride was obtained. The 3α-acetoxy-11βol-18-one-pregnane 11β,18-lactone 17-carboxylic acid chloride was treated with diazomethane to give 3α-acetoxy-11β-ol-18-one-pregnane 11β,18-lactone 17-diazoketone. The saponification of acetoxy group and reacting of 3α-acetoxy-11β-ol-18one-pregnane 11β,18-lactone 17-diazoketone with acetic acid were carried out to afford acetic acid 3α,11β-dihydroxy-18,20-dione-pregnane 11β,18-lactone 17-oxoethyl ether. The 3-keto-δ4 system is introduced by conventional methods, that is, by oxidation of the 3-hydroxy group to a 3-keto group with chromic oxide. Bromination at the 4-position, and finally dehydrobromination with dinitrophenylhydrazine or with lithium chloride in dimethylformamide were carried out to give acetic acid 11β-hydroxy-3,18,20-trione-pregn-4-ene 11β,18-lactone 17-oxoethyl ether. 2 Methods of producing of aldosterone: 1. Further, acetic acid 11β-hydroxy-3,18,20-trione-pregn-4-ene 11β,18-lactone 17-oxoethyl ether has been converted to 11β,21-dihydroxy-3,18,20-trionepregn-4-ene by methods of reduction of the lactone group and deacetylation of 17-oxoethyl group, described by Schmidlin, Anner, Biller and Wettstein (Experimentia, XI, 365 (1955). 2. Further, acetic acid 11β-hydroxy-3,18,20-trione-pregn-4-ene 11β,18-lactone 17-oxoethyl ether has been converted to 11β-hydroxy-18-one-pregn-4-ene 11β,18-lactone-3,20-bis-ethylenketal 17-oxoethyl ether, which was reduced with lithium-aluminum hydride to 3,20-bis-ethylenketal aldosterone. Then by hydrolisation of 3,20-bis-ethylenketal aldosterone with HClO4 aldosterone can be obtained. References Johnson W.S., Johns W.F.; US Patent No. 3,049,539; August 14, 1962; Assigned: Wisconsin Alumini Research Foundation, Madison,Wis., a corporation of Wisconsin Chaletsky A.M.; Pharmaceutical Chemistry, 'Medicina', L., 1966. 761p.
ALENDRONATE SODIUM TRIHYDRATE Therapeutic Function: Antiosteoporotic
142
Alendronate sodium trihydrate
Chemical Name: (4-Amino-1-hydroxybutylidene)diphosphonic acid monosodium salt trihydrate Common Name: Alendronate sodium Structural Formula:
Chemical Abstracts Registry No.: 129318-43-0; 66376-36-1 (Base) Trade Name
Manufacturer
Country
Year Introduced
Adronat
Neopharmed
Italy
-
Adronat
Tecnifar
Portugal
-
Alendronate sodium
BARR
-
-
Arendal
Syncro
Argentina
-
Alendros
Abiogen
Italy
-
Brek
TRB
Argentina
-
Dronal
Sigma Tau
Italy
-
Elandur
Sidus
Argentina
-
Endronax
Sintofarma
Brazil
-
Fosalan
Merck Pharmaceutical Corporation
-
-
Fosamax
Merck Sharp and Dohme
Netherlands
-
Holadren
Laboratorio Chile S.A.
-
-
Lafedam
Elvetium
Argentina
-
Marvil
Elisium
Argentina
-
Onclast
Teijin Pharma Ltd.
Japan
-
Osteoral
Ache
-
-
Phostarac
Rontag
Argentina
-
Regenesis
Elea
Argentina
-
Teiroc
Teijin Pharma Ltd.
Japan
-
Raw Materials Phosphorous acid Phosphorus trichloride 4-Aminobutyric acid
Alentamol
143
Manufacturing Process 4-Amino-1-hydroxybutylidene-1,1-diphosphonic acid (ABDT). Orthosphophorous acid (102.7 g; 1.25 moles) is introduced into a 2 liter-flask with condenser, stirrer and dropping funnel, placed on a thermostatized bath; the air is then removed with a nitrogen stream which is continued during all the reaction. The acid is melted by heating the bath to 95°C. When melting is complete, 4-aminobutyric acid (103.3; 1 mole) is added under stirring which is continued till obtaining a doughy fluid. Phosphorous trihalide (176 ml; 2 moles) is added dropwise causing the mixture to boil and evolution of gaseous hydrochloric acid which is damped by means of a suitable trap. The addition rate is adjusted so as to keep a constant reflux for about 60 minutes. When the addition is nearly over, the mixture swells, slowly hardening. Stirring is continued as long as possible, whereafter the mixture is heated for further 3 hours. Without cooling, but removing the bath, water (300 ml) is added, first slowly and then quickly. Heating and stirring are started again. Decolorizing charcoal is added and the mixture is boiled for about 5 minutes, then hotfiltered on paper and the filtrate is refluxed for 6 hours. After cooling is slowly poured in stirred methanol (1500 ml) causing thereby the separation of a white solid which collected and dried (161 g; 64.6%). The structure of ABDT is confirmed by IR spectrum, proton magnetic and nuclear magnetic resonance spectrum and elemental analysis. The sodium salt of this acid may be prepared by adding of equivalent of sodium hydroxide. References G. Staibano; US Patent No. 4,705,651; Nov. 10, 1987; Assigned to Instituto Gentili S.p.A., Pisa, Italy
ALENTAMOL Therapeutic Function: Antipsychotic, Dopamine agonist Chemical Name: 1H-Phenalen-5-ol, 2-(dipropylamino)-2,3-dihydro-, hydrobromide, (+/-) Common Name: Alentamol Structural Formula:
144
Alentamol
Chemical Abstracts Registry No.: 121514-27-0 Trade Name
Manufacturer
Country
Year Introduced
U 68553B
Upjohn Company
-
-
Raw Materials Triethylamine Hydrogen chloride Trifluoroacetic acid Sodium hydroxide n-Propyl bromide
5-Methoxy-2,2-dicarboxy-2,3-dihydro-1H-phenalene Diphenyl phosphoryl azide t-Butyl carbamate Hydrogen bromide Potassium carbonate
Manufacturing Process The solid 5-methoxy-2,2-dicarboxy-2,3-dihydro-1H-phenalene, was decarboxylated (one carboxyl group removed) by heating in an oil bath at 190°-210°C for 50 min. The resulting liquid was cooled, and the solid was ground to a fine powder to obtain 37.1 g (98% yield) of the subtitled 2carboxyl-5-methoxy-2,3-dihydro-1H-phenalene, melting point 194°-196°C. A mixture of the 5-methoxy-2,3-dihydro-1H-phenalen-2-yl-carboxylic acid, (37.1 g; 0.153 mole), 42.1 g (0.153 mole) of diphenyl phosphoryl azide, 17.0 g (0.168 mole) of triethylamine and 1950 ml of dry tert-butyl alcohol was refluxed for 21 h. The initially formed solution became a suspension. The solvent was evaporated in vacuo and the residue was taken up in a chloroform/water mixture. The resulting suspension was filtered. The filtrate was separated, the aqueous phase was extracted with chloroform, and the combined organic liquid phases was washed with 5% w/v sodium hydroxide aqueous solution (3x100 ml), with water and with saturated sodium chloride salt solution and then dried over magnesium sulfate and evaporated.The resulting residual yellow solid, 35.9 g, was extracted with boiling SKELLYSOLVE B brand of hexanes (5x200 ml), the resulting solution was concentrated to about 300 ml, clarified with diethyl ether and allowed to crystallize at 0°C to obtain 28.6 g of the 5-methoxy-2-(tertbutoxycarbonylamino)-2,3-dihydro-1H-phenalene, melting point 113°-115°C. Trifluoroacetic acid, 85 ml, was added to 30.5 g (0.0958 mole) of the 5methoxy-2-(tert-butoxycarbonylamino)-2,3-dihydro-1H-phenalene. The resulting solution was stirred for 20 min. Ice was then added, and the resulting mixture was made pH basic with 20% w/w sodium hydroxide in water solution and stirred for 1 h at room temperature. The mixture was extracted well with chloroform, the chloroform extract was separated and washed with water, with saturated sodium chloride solution; dried with magnesium sulfate, and evaporated to give 18.8 g (92% yield) of the 2amino-5-methoxy-2,3-dihydro-1H-phenalene as a brown oil. This 2-amino-5-methoxy-2,3-dihydro-1H-phenalene was converted to its hydrochloride salt in methanol with 1.5 N hydrogen chloride in diethyl ether solution to give 18.11 g of the 2-amino-5-methoxy-2,3-dihydro-1H-phenalene hydrochloride as colorless needle crystals, melting point 252°C (dec.). A mixture of 2-amino-5-methoxy-2,3-dihydro-1H-phenalene, 2.6 g (0.0122 mole), released from its hydrochloride, 6.46 g (0.0525 mole) of n-propyl
Alexidine
145
bromide, 7.25 g (0.0525 mole) of potassium carbonate and 50 ml of acetonitrile was refluxed for 20 h. Another 3.3 g of n-propyl bromide, 3.6 g of potassium carbonate and 25 ml of acetonitrile were added to the reaction mixture. The mixture was refluxed for 26 h. GC analysis of a sample of the reaction mixture indicated complete reaction. The mixture was evaporated, and the residue was taken up in a diethyl ether/water mixture. The organic liquid layer was washed with saturated sodium chloride (salt) solution and dried with magnesium sulfate, and evaporated. The residue was dissolved in petroleum ether (boiling point 30°-60°C), and filtered from some insoluble brown material, and the filtrate was evaporated to leave the 2-(di-npropylamino)-5-methoxy-2,3-dihydro-1H-phenalene. The 2-(di-n-propylamino)-5-methoxy-2,3-dihydro-1H-phenalene was dissolved in diethyl ether, treated with ethereal hydrogen chloride which resulted in the formation of the crude gummy solid hydrogen chloride salt. 2.67 g (66% yield) of the 2-(di-n-propylamino)-5-methoxy-2,3-dihydro-1H-phenalene hydrochloride, melting point 196°-197°C (crystallized from a methanol/diethyl ether). A mixture of 2-(di-n-propylamino)-5-methoxy-2,3-dihydro-1H-phenalene, (1.65 g; 5.55 mmol), released from the hydrochloride salt, and 20 ml of 48% aqueous hydrogen bromide solution was heated for 15 min in an oil bath at 125°-130°C. The reaction mixture was evaporated, the residue was dissolved in a minimum amount of methanol, diethyl ether was added until the mixture became cloudy, and the mixture was filtered through a filter aid (CELITE) to remove some oily impurity. The filtrate was diluted with diethyl ether and seeded. There was obtained 1.28 g (63% yield) of the 2-(di-n-propylamino)2,3-dihydro-lH-phenalen-5-ol hydrobromide, melting point 233°-234°C (dec.). References Szmuszkovicz J. et al.; Patent Coop. Treaty (WIPO), 1987, 87/04153; July 16, 1987; Assigned: The UPJOHN COMPANY [US/US]; 301 Henrietta Street, Kalamazoo, MI 49001 (US)
ALEXIDINE Therapeutic Function: Antiseptic Chemical Name: 2,4,11,13-Tetraazatetradecanediimidamide, N,N''-bis(2ethylhexyl)-3,12-diiminoCommon Name: Alexidine Chemical Abstracts Registry No.: 22573-93-9 Trade Name
Manufacturer
Country
Year Introduced
Alexidine
Science Lab.
-
-
Alexidine
Chemos GmbH
-
-
146
Alfacalcidol
Structural Formula:
Raw Materials 1,1'-Hexamethylene-bis(3-cyanoguanidine) Ethylhexylamine hydrochloride Manufacturing Process A mixture of 16 g (0.09 mole) 1,1'-hexamethylene-bis(3-cyanoguanidine) and 20 d (0.12 mole) 2-ethylhexylamine hydrochloride is heated at 150-155°C for 3 hours. The mixture is cooled and the product is dissolved in 75 ml of hot water. The solution is treated with activated charcoal. 1,1'-Hexamethylene-bis(5-(ethylhexyl)biguanide) is recrystalluized from methanol-ether, melting point 220.6-223.4°C. References Fr. Patent No. 1,463,818; Apr. 8, 1965; Assigned to Sterling Drug Inc. Residant in USA
ALFACALCIDOL Therapeutic Function: Calcium regulator, Vitamin Chemical Name: 9,10-Secocholesta-5,7,10(19)-triene-1,3-diol Common Name: 1α-Hydroxycholecalciferol; 1α-Hydroxyvitamin D3 Structural Formula:
Alfacalcidol
147
Chemical Abstracts Registry No.: 41294-56-8 Trade Name One-Alpha Eins-Alpha Alfarol One-Alpha Delakmin Etalpha Un-Alfa
Manufacturer Leo Thomae Chugai Teljin Roussel Leo Leo
Country UK W. Germany Japan Japan France Denmark -
Year Introduced 1978 1980 1981 1981 -
Raw Materials Cholesta-1,5,7-trien-3β-ol m-Chloroperbenzoic acid
4-Phenyl-1,2,4-triazoline-3,5-dione Lithium aluminum hydride
Manufacturing Process 1. Preparation of 1,4-cyclized adduct of cholesta-1,5,7-trien-β-ol and 4phenyl-1,2,4-triazoline-3,5-dione: a solution of 400 mg of cholesta-1,5-7trien-3β-ol in 30 ml of tetrahydrofuran is cooled with ice, and 190 mg of 4phenyl-1,2,4-triazoline-3,5-dione is added little by little to the solution under agitation. The mixture is agitated at room temperature for 1 hour and the solvent is distilled under reduced pressure. The residue is purified by chromatography using a column packed with silica gel. Fractions eluted with ether-hexane (7:3 v/v) are collected and recrystallization from ether gives 550 mg of a 1,4-cyclized adduct of cholesta-1,5,7-trien-3β-ol and 4-phenyl1,2,4-triazoline-3,5-dione having a melting point of 178°C to 182°C. 2. Preparation of 1,4-cyclized adduct of cholesta-5,7-dien-3β-ol-1α-epoxide and 4-phenyl-1,2,4-triazoline-3,5-dione: 1.25 g of the 1,4-cyclized adduct of cholesta-1,5,7-trien-3β-ol and 4-phenyl-1,2,4-triazoline-3,5-dione is dissolved in 50 ml of chloroform, and 560 mg of m-chloroperbenzoic acid is added to the solution. The mixture is agitated for 20 hours at room temperature, and 200 mg of m-chloroperbenzoic acid is further added and the mixture is agitated again for 20 hours. The reaction mixture liquid is diluted with chloroform, washed with a 10% aqueous solution of potassium carbonate and dried with magnesium sulfate. Then, the solvent is distilled under reduced pressure. The residue is purified by silica gel chromatography, and first effluent fractions eluted with ether are collected, and recrystallization from methanol gives 680 g of a crystal melting at 172°C to 173°C. The second ether effluent fractions are collected, and recrystallization from methanol gives 400 mg of a 1,4-cyclized adduct of cholesta-5,7-dien-3β-ol-1α,2α-epoxide and 4-phenyl-1,2,4-triazoline-3,5-dione having a melting point of 152°C to 154°C. 3. Preparation of cholesta-5,7-diene-1α,3β-diol: a solution of 500 mg of the 1,4-cyclized adduct of cholesta-5,7-dien-3β-ol-1α,2α-epoxide and 4-phenyl1,2,4-triazoline-3,5-dione in 40 ml of tetrahydrofuran is added dropwise under agitation to a solution of 600 mg of lithium aluminum hydride in 30 ml of THF. Then, the reaction mixture liquid is gently refluxed and boiled for 1 hour and cooled, and a saturated aqueous solution of sodium sulfate is added to the reaction mixture to decompose excessive lithium aluminum hydride. The organic solvent layer is separated and dried, and the solvent is distilled. The
148
Alfadolone
residue is purified by chromatography using a column packed with silica gel. Fractions eluted with ether-hexane (7:3 v/v) are collected, and recrystallization from the methanol gives 400 mg of cholesta-5,7-diene-1α,3βdiol. 4. Preparation of 1α,3β-dihydroxyprovitamin D3: a solution of 25 mg of cholesta-5,7-diene-1α,3β-diol in 650 ml of ether is subjected to radiation of ultraviolet rays for 14 minutes in an argon gas atmosphere by passing it through a Vycor filter using a 200-W high pressure mercury lamp (Model 654A-36 manufactured by Hanobia). The solvent is distilled at room temperature under reduced pressure. This operation is repeated twice, and 50 mg of the so obtained crude product is fractionated by chromatography using a column packed with 20 g of Sephadex LH-20. The first effluent fractions eluted with chloroform-hexane (65:35 v/v) give 13.5 mg of oily 1α,3βdihydroxyprovitamin D3. The composition exhibits a maximum ultraviolet absorption at 260 nm in an ether solution. 5. Preparation of 1α-hydroxycholecalciferol: a solution of 13.5 mg of 1α,3βdihydroxyprovitamin D3 in 200 mi of ether is allowed to stand still in the dark at room temperature in an argon gas atmosphere for 2 weeks. During this period, the position of the maximum ultraviolet absorption is shifted from 260 nm to 264 nm, and the absorption intensity becomes 1.6 times as high as the original intensity. The solvent is distilled at room temperature under reduced pressure, and the residue is purified by chromatography using a column packed with 10 g of Sephadex LH-20. The fractions eluted with chloroformhexane (65:35 v/v) give 6.5 mg of oily 1α-hydroxycholecalciferol. References Merck Index 4730 Kleeman and Engel p. 21 DOT 6 (3) 104 (1970); 14 (10) 441 (1978) I.N. p. 52 Ishikawa, M., Kaneko, C., Suda, T., Yamada, S., Eguchi, Y., Sugimoto, A. and Sasaki, S.; US Patent 3,929,770; December 30, 1975; Assigned to Wisconsin Alumni Research Foundation
ALFADOLONE Therapeutic Function: Anesthetic Chemical Name: 5α-Pregnane-11,20-dione, 3α,21-dihydroxyCommon Name: Alfadolone; Alphadolone Chemical Abstracts Registry No.: 14107-37-0 Trade Name
Manufacturer
Country
Year Introduced
Alphadolone
RiboTargets Ltd.
-
-
Alfadolone
149
Structural Formula:
Raw Materials Acetic acid Potassium hydroxide Potassium acetate Hydrogen Lead tetraacetate
3β-Acetoxy-5α-pregn-16-ene-11,20-dione 4-Toluenesulfonyl chloride Palladium on carbon Boron trifluoride etherate Sodium bicarbonate
Manufacturing Process A solution of 3β-acetoxy-5α-pregn-16-ene-11,20-dione (Chamberlin et al., J.Amer. Chem Soc., 1951, 73, 2396) (25.7 g) in dioxan (Analar, 500 ml) was treated with potassium hydroxide (10 g) and water 250 ml and the mixture allowed to stand at room temperature for 1 h. After a further 1 h at 40°C the mixture was diluted with water and the product filtered off. The crude material was dissolved in chloroform and filtered through a column of grade III neutral alumina (100 g). The material obtained was crystallized from acetonepetroleum to give pure 3β-hydroxy-5α-pregn-16-ene-11,20-dione (17.65 g, 77.5%) as small plates, melting point 217.5°C. A solution of 3β-hydroxy-5α-pregn-16-ene-11,20-dione (39.6 g) in dry pyridine (165 ml) was treated with toluene-p-sulfonyl chloride (43.9 g) to give the toluene sulfonate (56.7 g), melting point 147-151°C. A portion (10.7 g) of this material was crystallized from ethyl acetate-petroleum to give the pure 3β-toluene-p-sulfonyloxy-5α-pregn-16-ene-11,20-dione (9.2 g) as plates, melting point 154°-155°C. 2 Methods of producing of 3α-hydroxy-5α-pregn-16-ene-11,20-dione from 3βtoluene-p-sulfonyloxy-5α-pregn-16-ene-11,20-dione: 1. A solution of 3β-toluene-p-sulfonyloxy-5α-pregn-16-ene-11,20-dione (19.1 g) in N,N-dimethylformamide (160 ml) and water (16.0 ml) was treated with potassium acetate (29.2 g) and the mixture heated at 115°C for 2.5 h. The solvents were removed in vacuo and residue partitioned between chloroform and water. The chloroform extract was washed with water, dried and evaporated. The residue was taken up in methanol (500 ml) and solution flushed with nitrogen. Potassium hydroxide (17 g) in water (70 ml) was added and the solution refluxed for 1 h. Glacial acetic acid was added to bring the pH to about 6 and most of the methanol evaporated in vacuo. Dilution with water gave a gummy precipitate which was extracted into chloroform to give the crude product. This material was extracted with ether and the residue boiled with benzene. The insoluble material was crystallized from chloroformpetroleum to give 3α-hydroxy-5α-pregn-16-ene-11,20-dione (3.28 g) as large
150
Alfadolone
prisms, melting point 243°-244°C. 2. A mixture of the 3β-toluene-p-sulfonyloxy-5α-pregn-16-ene-11,20-dione (60 g; 0.124 mole) in N,N-dimethylformamide (350 ml) and potassium acetate (92 g, 0.94 mole) in water (935 ml) was stirred at 115°C for 4 h. The brown solution was cooled and most of the N,N-dimethylformamide removed by evaporation at 50°C and 4 mm to give a brown solid mass. Another run with to sylate (58 g, 0.12 mole), potassium acetate (90 g, 0.91 mole), N,Ndimethylformamide (350 ml) and water (35 ml) was carried out as described above. The combined aqueous fractions were extracted with chloroform (3 x 100 ml) and dried over magnesium sulfate. The chloroform was removed in vacuo and residual N,N-dimethylformamide was evaporated at 50°C and 4 mm to give the crude 3α-acetate-5α-pregn-16-ene-11,20-dione (92 g) as a brown solid. A solution of 3α-acetate-5α-pregn-16-ene-11,20-dione (92 g) in dioxin (1000 ml) was mixed with a solution of potassium hydroxide (45 g, 0.8 mole) in water (500 ml) to give a two-phase system. A homogeneous solution was obtained by the addition of dioxin (440 ml) and water (625 ml). Nitrogen was bubbled through the solution which was heated at 50°C for 2 h. The port colored solution was treated with glacial acetic acid (40 ml) to bring the pH about 7 and two thirds of the solvent was removed by distillation in vacuo (water pump). Water (3 L) was added to the resultant mixture (which had already begun to crystallize) and the precipitated solid was filtered off, washed with water and dried over phosphorus pentoxide to give the crude 3αhydroxy-5α-pregn-16-ene-11,20-dione (73.9 g). Producing of 3α,21-dihydroxy-5α-pregnane-11,20-dione from 3α-hydroxy-5αpregn-16-ene-11,20-dione: A solution of 3α-hydroxy-5α-pregn-16-ene-11,20-dione (200 mg) in freshly distilled tetrahydrofuran (8 ml) with 5% palladium on carbon (100 mg) was hydrogenated till hydrogen uptake ceased. The mixture was filtered through a pad of kieselguhr and the tetrahydrofuran removed in vacuo to give 3αhydroxy-5α-pregnane-11,20-dione (196 mg), melting point 171°-172°C. Boron trifluoride etherate (37.9 ml) was added to a stirred solution of 3αhydroxy-5α-pregnane-11,20-dione (6.64 g, 20 mmol) and lead tetraacetate (10.1 g, 22 mmol) in dry benzene (280 ml) and methanol (15.1 ml) at room temperature. After 2 h the mixture was poured into water (2 L) and extracted with ether (1 L). The combined ether extracts were washed successively with sodium bicarbonate solution and water, dried over magnesium sulfate, and concentrated in vacuo to give a white crystalline mass. Four recrystallizations from acetone-petroleum (b.p. 40°-60°C) gave 21-acetoxy-3α-hydroxy-5αpregnane-11,20-dione as fine needles (4.22 g, 54%), melting point 172°173°C. The 3α,21-dihydroxy-5α-pregnane-11,20-dione is conveniently prepared by the deacylation of 21-acetoxy-3α-hydroxy-5α-pregnane-11,20-dione under basic conditions, for example, in the presence of potassium or sodium hydrogen carbonate, conveniently in the presence of a solvent e.g. methanol, ethanol or tetrahydrofuran, reesterifying the resultant product.
Alfaxalone
151
References Davis B. et al.; US Patent No. 3,781,435; December 25, 1973
ALFAXALONE Therapeutic Function: Anesthetic component Chemical Name: 3-Hydroxypregnane-11,20-dione Common Name: Alphaxolone Structural Formula:
Chemical Abstracts Registry No.: 23930-19-0 Trade Name
Manufacturer
Country
Year Introduced
Althesin
Glaxo
UK
1972
Alfadion
Nippon Glaxo
Japan
1978
Alfathesin
Glaxo
France
-
Aurantex
Glaxo
W. Germany
-
Raw Materials 3α-Hydroxy-5α-pregn-16-ene-11,20-dione Hydrogen Manufacturing Process A solution of 3α-hydroxy-5α-pregn-16-ene-11,20-dione (200 mg) in freshly distilled tetrahydrofuran (8 ml) with 5% palladium on carbon (100 ml) was hydrogenated until hydrogen uptake ceased. The mixture was filtered through a pad of kieselguhr and the tetrahydrofuran removed in vacuum to give 196 mg, MP 171°C to 172°C. References Merck Index 225 Kleeman and Engel p. 23 DOT 8 (11) 407 (1972)
152
Alfentanil hydrochloride
I.N. p. 53 Davis, B., Pearce, D.R. and Phillips, G.H., British Patent 1,317,184; May 16, 1973; Assigned to Glaxo Laboratories, Ltd. Davis, B. and Phillips, G.H.; US Patent 3,714,352; January 30, 1973; Assigned to Glaxo Laboratories, Ltd.
ALFENTANIL HYDROCHLORIDE Therapeutic Function: Narcotic analgesic Chemical Name: N-[1-[2-(4-Ethyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)ethyl]4-(methoxy-methyl)-4-piperidinyl]-N-phenylpropaneamide hydrochloride Common Name: Structural Formula:
Chemical Abstracts Registry No.: 69049-06-5 Trade Name
Manufacturer
Country
Year Introduced
Rapifen
Janssen
Belgium
1983
Rapifen
Janssen
Netherlands
1983
Rapifen
Janssen
W. Germany
1983
Rapifen
Janssen
UK
1983
Rapifen
Janssen
Switz.
1983
Raw Materials 1-Ethyl-1,4-dihydro-5H-tetrazol-5-one 1-Bromo-2-chloroethane N-[4-(Methoxymethyl)-4-piperidinyl]-N-phenylpropanamide Manufacturing Process A mixture of 22 parts of 1-ethyl-1,4-dihydro-5H-tetrazol-5-one, 45 parts of 1bromo-2-chloroethane, 26 parts of sodium carbonate, 0.3 part of potassium iodide and 240 parts of 4-methyl-2-pentanone is stirred and refluxed overnight with water-separator. The reaction mixture is cooled, water is added and the layers are separated. The aqueous phase is extracted three times with
Algestone acetophenide
153
dichloromethane. The combined organic phases are dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using trichloromethane as eluent. The pure fractions are collected and the eluent is evaporated, yielding 28.4 parts (80%) of 1-(2-chloroethyl)-4-ethyl1,4-dihydro-5H-tetrazol-5-one as a residue. A mixture of 1.8 parts of 1-(2-chloroethyl)-4-ethyl-1,4-dihydro-5H-tetrazol-5one, 3.45 parts of N-[4-(methoxymethyl)-4-piperidinyl]-Nphenylpropanamide, 5 parts of sodium carbonate, 0.2 part of potassium iodide and 240 parts of 4-methyl-2-pentanone is stirred and refluxed overnight with water-separator. The reaction mixture is poured onto water and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is purified by column-chromatography over silicagel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is converted into the hydrochloride salt in 2-propanone. The salt is filtered off and crystallized from 2-propanone, yielding 1.5 parts (33.3%) of N-[1-[2-(4-ethyl4,5-dihydro-5-oxo-1H-tetrazol-1-yl]-4-(methoxymethyl)-4-piperidinyl]-Nphenylpropanamide monohydrochloride monohydrate; melting point 140.8°C. References DFU 6 (6)335 (1981) OCDS Vol. 3 p. 118 (1984) DOT 19 (12) 683 (1983) I.N. p. 53 Janssens, F.; US Patent 4,167,574; September 11, 1979; Assigned to Janssen Pharmaceutica NV.
ALGESTONE ACETOPHENIDE Therapeutic Function: Progestin, Contraceptive Chemical Name: 16,17-[(1-Phenylethylidene)bis(oxy)]pregn-4-ene-3,20dione Common Name: 16α,17α-Dihydroxyprogesterone acetophenide; Alphasone acetophenide Structural Formula:
Chemical Abstracts Registry No.: 24356-94-3
154
Alibendol
Trade Name Neolutin Depo Neolutin Depositum Droxone Decadroxone Decadroxate
Manufacturer Medici Orma Squibb Squibb Sauibb
Country Italy Italy US -
Year Introduced 1982 -
Raw Materials 16α,17α-Dihydroxyprogesterone Acetophenone Manufacturing Process To a suspension of 500 mg of 16α,17α-dihydroxyprogesterone in 25 ml of freshly redistilled acetophenone is added 0.125 ml of 72% perchloric acid and the mixture is agitated at room temperature for one hour. The clear solution is washed with dilute sodium bicarbonate to remove excess acid and the acetophenone layer, after addition of chloroform is separated from the aqueous phase. The organic layer is dried over sodium sulfate and after removal of the chloroform and acetophenone in high vacuum the residue is crystallized from 95% alcohol. The pure acetophenone derivative has a melting point of about 142°C to 144°C. References Merck Index 227 Kleeman and Engel p. 24 OCDS Vol. 2 p. 171 (1980) DOT 19 (2) 110 (1983) I.N. p. 54 Fried, J.; US Patent 2,941,997; June 21, 1960; Assigned to Olin Mathieson Chemical Corp. Fried, J. and Diassi, P.A.; US Patent 3,008,958; November 14, 1961; Assigned to Olin Mathieson Chemical Corp.
ALIBENDOL Therapeutic Function: Choleretic, Spasmolytic Chemical Name: 2-Hydroxy-N-(2-hydroxyethyl)-3-methoxy-5-(2-propenyl) benzamide Common Name: Chemical Abstracts Registry No.: 26750-81-2 Trade Name
Manufacturer
Country
Year Introduced
Cebera
Bouchara
France
1981
Alifedrine hydrochloride
155
Structural Formula:
Raw Materials 2-Hydroxy-3-methoxy-5-allylbenzoic acid Ethanol Ethanolamine Manufacturing Process 36 g of ethyl ester of 2-hydroxy-3-methoxy-5-allyl-benzoic acid [obtained by the process described by Pearl, et al., J. Amer. Chem. Soc., Vol. 71, 10671068 (1949)] and 61 g of ethanolamine were admixed and left to stand for 1 hour at ambient temperature after which it was heated for 1 hour at 120°C. The mixture was extracted with chloroform and the organic phases were washed with half diluted hydrochloric acid, then with water, and the chloroform evaporated off. The residue, after recrystallization from benzene, was a 78% yield of 2-hydroxy-3-methoxy-5-allyl-N-(β-hydroxyethyl)benzamide having a melting point of 95°C. The product appeared in the form of colorless crystals which were insoluble in water and soluble in dilute sodium hydroxide. References Merck Index 230 DOT 18 (10) 525 (1982) Clemence, F. and Le Martret, O.; US Patent 3,668,238; June 6, 1972; Assigned to Roussel Uclaf.
ALIFEDRINE HYDROCHLORIDE Therapeutic Function: Sympathomimetic; Cardiotonic Chemical Name: 1-Propanone, 1-cyclohexyl-3-((2-hydroxy-1-methyl-2phenylethyl)amino)-, (R-(R*,S*))-, hydrochloride Common Name: Alifedrine Chemical Abstracts Registry No.: 72913-80-5
156
Alifedrine hydrochloride
Structural Formula:
Trade Name
Manufacturer
Country
Year Introduced
Alifedrine hydrochloride
Chemiewerk Homberg
-
-
Raw Materials 1-Acetyl-1-cyclohexene 1-Norephedrine Palladium on carbon Aluminum chloride
Dimethylamine hydrochloride Cyclohexanecarboxylic acid chloride Cyclohexyl-β-chloroethyl ketone
Manufacturing Process There are some means to produce aliflurane: 1). 2.2 g (0.01 mol) of (2-dimethylaminoethyl)cyclohexylketone hydrochloride (produced by Mannich reaction from 1-acetyl-1-cyclohexene with formaldehyde and dimethylamine hydrochloride and subsequent hydrogenation with Pd/C as catalyst) and 1.5 g (0.01 mol) of 1-norephedrine were dissolved in 20 ml of warm isopropanol. The product crystallizing out in the cooling was filtered off with suction and recrystallized from ethanol. Yield of desired 1-propanone, 1-cyclohexyl-3-((2-hydroxy-1-methyl-2phenylethyl)amino)-, (R-(R*,S*) hydrochloride 24%, M.P: 219-221°C. 2). 13.8 g (0.1 mol) of cyclohexylvinyl ketone (obtainable by the splitting off of HCl during the distillation of cyclohexyl-β-chloroethyl ketone) and 15.1 g (0.1 mol) of 1-norephedrine were dissolved in 50 ml of isopropanol. The desired compound crystallized out as the free base in the standing overnight. The hydrochloride was made with isopropanolic hydrochloric acid. M.P. of the hydrochloride: 219-221°C. 3). The oily cyclohexyl-β-chloroethyl ketone obtained from a solution of 200 g (1.36 mol) of cyclohexanecarboxylic acid chloride in 500 ml of dried 1,2dichloroethane by portion-wise addition of 182 g (1.3 mol) of AlCl3 at -5°C, then leading ethylene through, subsequent hydrolysis with 500 ml of water at room temperature and concentration of the organic phase dried with Na2SO4 in a vacuum (analogous to U.S. Pat. No. 2,792,406) was added to a solution of 164 g (1.09 mol) of 1-norephedrine in 1000 ml of dioxane. The desired product crystallized out overnight, was filtered off with suction and recrystallized from ethanol/water 1:1 (by volume). Yield: 67% (based on the cyclohexane carboxylic acid chloride). M.P. of the hydrochloride: 219-221°C.
Alimadol
157
References Engel J. et al.; US Patent No. 4,542,159; September 17, 1985; Assigned to Degussa Aktiengeselschaft, Frankfurt, Fed. Rep. of Germany
ALIMADOL Therapeutic Function: Analgesic Chemical Name: N-(3-Methoxy-3,3-diphenylpropyl)allylamine Common Name: Alimadol Structural Formula:
Chemical Abstracts Registry No.: 52742-40-2 Trade Name
Manufacturer
Country
Year Introduced
Alimadol
ZYF Pharm Chemical
-
-
Raw Materials Trifluoroacetic anhydride Allyl bromide
3,3-Diphenyl-3-methoxypropylamine Hexamethyl phosphoric acid amide
Manufacturing Process 12 g 3,3-diphenyl-3-methoxypropylamine, 13.5 g trifluoroacetic acid anhydride, 6.0 g pyridine and 100 ml benzene was heated by stirring for 1 hour at 40°C. Then in was cooled to 0°C and poured in water. The organic layer was separated, washed with diluted HCl and water, and evaporated to dryness. The residue N-(3,3-diphenyl-3-methoxypropyl)trifluoroacetamide melted at 108°-110°C. Yield: 98%. 8 g above amide was in 80 ml hexamethyl phosphoric acid amide dissolved mixed with 1.7 g sodium hydride and stirred for 3 hours. Then 5.7 g allyl bromide was added dropwise and the mixture was stirred for 30 minutes. It was diluted with water and extracted with benzene. Benzene layer was separated, evaporated to dryness. The residue was mixed with 100 ml of 75% ethanol and 1 g sodium hydroxide and heated for 1 hour. Ethanol was distilled off and reaction product was extracted with ether. Yield of N-(3-methoxy-3,3diphenylpropyl)allylamin (or 1,1-diphenyl-1-methoxy-3-allylaminopropane) was 6.5 g (97%). MP: 40°-50°C. Hydrochloride melted at 137°-138°C.
158
Alinastine
References Hollinger R. et al.; DE Patent No. 2,339,528; Sept. 11, 1972; Lenia GmdH, Chem. u. pharm. Erzeugnisse-Indusriebedarf, 8000 Munchen
ALINASTINE Therapeutic Function: Antihistaminic, Antiallergic Chemical Name: Benzimidazole, 2-(1-(p-tert-butylphenethyl)-4-piperidyl)-1(2-ethoxyethyl)Common Name: Alinastine Structural Formula:
Chemical Abstracts Registry No.: 154541-72-7 Trade Name Alinastine
Manufacturer Fabrica Espanola de Productos Quimicos y Farmaceuticos
Country -
Year Introduced -
Raw Materials Sodium hydride 2-(2-Ethoxyethyl)tosylate 2-[1-(2-(4-(1,1-Dimethylethyl)phenyl)ethyl)piperidin-4-yl]-1Hbenzimidazole Manufacturing Process 1.5 g of a sodium hydride suspension in oil are added to another suspension of 10.83 g of 2-[1-(2-(4-(1,1-dimethylethyl)phenyl)ethyl)piperidin-4-yl]-1Hbenzimidazole in 150 ml of dimethylformamide and the mixture is stirred for 1 h at room temperature, then a solution of 2-(2-ethoxyethyl)tosylate in dimethylformamide are slowly added. The mixture is heated at 60°C for 16 h, poured onto water and extracted with ether. The extracts are washed with water, dried over anhydrous sodium sulfate and concentrated. The obtained oil is purified by column chromatography yielding 6.0 g of 1-(2-ethoxyethyl)-2[1-(2-(4-(1,1-dimethylethyl)phenyl)ethyl)piperidine-4-yl]-1H-benzimidazole, melting point 138°-140°C.
Alinidine hydrobromide
159
References Orjales-Venero A., Rubio-Royo V.; US Patent No. 5,322,850; June 21, 1994; Assigned: Fabrica Espanola de Productos Quimicos y Farmaceuticos, S.A., Leiva-Lamiaco, Spain
ALINIDINE HYDROBROMIDE Therapeutic Function: Antiarrhythmic, Bradycardic, Analgesic Chemical Name: N-(2,6-Dichlorophenyl)-4,5-dihydro-N-2-propenyl-1Himidazol-2-amine monohydrobromide Common Name: Alinidine hydrobromide Structural Formula:
Chemical Abstracts Registry No.: 71306-36-0 Trade Name
Manufacturer
Country
Year Introduced
Alinidine hydrobromide
Boehringer Ingelheim Laboratories
-
-
Raw Materials 2-(2',6'-Dichlorophenylamino)-2-imidazoline Allyl bromide Manufacturing Process 2-(N-Allyl-N-(2,6-dichlorophenyl)amino)-2-imidazoline: A mixture consisting of 2.0 g of 2-(2',6'-dichlorophenylamino)-2-imidazoline, 3 ml of allyl bromide, 1 ml of pyridine and 10 ml of absolute methanol was heated for about 15 hours at 100°C in a closed tube. Thereafter, the reaction mixture was evaporated to dryness in vacuum, the residue was dissolved in a small amount of dilute hydrochloric acid, the resulting solution was purified by extraction with ether, and the ether extracts were discarded. The acidic aqueous solution was made alkaline with 5 N sodium hydroxide where upon an oily substance separated out which crystallized through upon standing for some time on an ice bath. The crystalline product was collected by vacuum filtration, washed with distilled water and dried. 1.5 gm (83% of theory) of the compound having a melting point of 130-131°C was obtained.
160
Alizapride
References Stahle H. et al.; US Patent No. 3,708,485; January 2, 1973; Assigned to Bohehringer Ingelheim am Rein, Germany
ALIZAPRIDE Therapeutic Function: Neuroleptic, Antiemetic Chemical Name: 6-Methoxy-N-[[1-(2-propenyl)-2-pyrrolidinyl]methyl]-Hbenzotriazole-5-carboxamide Common Name: Structural Formula:
Chemical Abstracts Registry No.: 59338-93-1 Trade Name Plitican Vergentan
Manufacturer Delagrange Delagrange
Country France W. Germany
Year Introduced 1981 1981
Raw Materials 2-Methoxy-4,5-azimidobenzoic acid 1-Allyl-2-aminomethylpyrrolidine Phosphoric anhydride Manufacturing Process 38.6 g (0.2 mol) of 2-methoxy-4,5-azimidobenzoic acid were dissolved in anhydrous toluene and 56 g (0.4 mol) of 1-allyl-2-amino-methylpyrrolidine were added. The mixture was heated to 50°C and then 42 g (0.3 mol) of phosphoric anhydride were added. The mixture was warmed at reflux temperature for 3 hours and then cooled to 80°C. After adding water, the aqueous layer was alkalized. The crystals were filtered, washed with water and then dissolved in 450 ml of acetone. After crystallization, the product was
Alkofanone
161
filtered, washed and dried. 40.4 g (yield 65%) of N-(1'-allyl-2'-pyrrolidylmethyl)-2-methoxy-4,5azimidobenzamide having a melting point of 139°C were obtained. References Merck Index 231 DFU 6 (1) 11 (1981) DOT 18 (4) 162 (1982) I.N. p.55 Bulteau, G., Acher, J., Collignon, C. and Monier, J.C.; US Patent 4,039,672; August 2, 1977; Assigned to Societe D'Etudes Scientifiques et Industrielles de I'lle-de-France
ALKOFANONE Therapeutic Function: Antidiarrheal Chemical Name: 3-[(4-Aminophenyl)sulfonyl]-1,3-diphenyl-1-propanone Common Name: Structural Formula:
Chemical Abstracts Registry No.: 7527-94-8 Trade Name
Manufacturer
Country
Year Introduced
Clafanone
Roche
US
1956
Raw Materials Benzal acetophenone p-Aminobenzene sulfinic acid Manufacturing Process 38 g benzal-acetophenone and 25 g p-aminobenzene-sulfinic acid are refluxed
162
Allantoin
for 5 hours in 700 cc of 85% ethyl alcohol. Fine crystals soon begin to appear and fill the reaction vessel. While still hot, the mixture is suction-filtered. The reaction product is washed first with 750 cc warm absolute alcohol, then with 500 cc water, and finally again with 300 cc alcohol, and then dried in vacuum. Yield 32 g. MP 210-212°C with decomposition. References Merck Index 240 Goldberg, M.W.; US Patent 2,421,836; June 10, 1947; Assigned to HoffmannLa Roche, Inc.
ALLANTOIN Therapeutic Function: Vulnerary, Antiulcer (topical), Antipsoriatic Chemical Name: Urea, (2,5-dioxo-4-imidazolidinyl)Common Name: Allantoin Structural Formula:
Chemical Abstracts Registry No.: 97-59-6 Trade Name
Manufacturer
Country
Year Introduced
Allantoin
Arocor Holdings Inc.
-
-
Allantoin
Hunan Xinyu
-
-
Allantoin
Akema Fine Chemicals
-
-
Allantoin
Allan Chemical Corporation
-
-
Allantoin
Hangzhou Greenda Chemical Co., Ltd.
-
-
Allantoin
Kunshan Hua Xin Daily Chemicals Co., Ltd.
-
-
Allantoin
Omikron
-
-
Allantoin
-
-
Cutemol
Xiamen Linyo Technology Co., Ltd. Summers Laboratories Inc.
-
-
Egopsoryl
Ego Pharmaceuticals
-
-
Egopsoryl
SMP Vet
-
-
Herker
Herker Industries
-
-
Soothex
Jamieson Laboratories Ltd.
-
-
Allobarbital
163
Raw Materials Urea Sulfuric acid Sodium nitrite Ammonium sulfate
Glyoxal Cobalt(II) nitrate hexahydrate Hydrogen chloride
Manufacturing Process To a mixture of 13.14 kg 40% solution of glyoxal in water and a solution of 0.5 L of concentrated HCl in 3 L of water was added 1.8 g Co(NO3)2·6H2O. The mixture was heated at 50-60°C, to the solution was added 20 g of sodium nitrite and then at 40-60°C was added dropwise the mixture of 6 L of concentrated HNO3, 4.2 L of water and 30 g of sodium nitrite. The product obtained was mixed with 2.4 kg ammonium sulfate and filtrated. The filtrate was heated with 14.5 kg urea at 70°C for 10 hours. Allantoin was filtrated and recrystallized from the water; M.P. 233-235°C. References Merck Index, Monograph number: 255, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. DE Patent No. 1,939,924, 18 Feb., 1971 Christmann et al.; US Patent No. 2,802,011; Aug. 6, 1957; Assigned to Carbogen Corporation, New York DE Patent No. 2,714,938; 11.05.1978
ALLOBARBITAL Therapeutic Function: Sedative, Hypnotic Chemical Name: Barbituric acid, 5,5-diallylCommon Name: Diallylbarbituric acid, Allobarbital, Diallymal Structural Formula:
Chemical Abstracts Registry No.: 52-43-7 Trade Name
Manufacturer
Country
Year Introduced
Allobarbital
Fluorochem Ltd.
-
-
Dorm
Funke
-
-
164
Alloclamide hydrochloride
Raw Materials Allyl bromide Barbituric acid Sodium hydroxide Manufacturing Process To a mixture of 43 parts barbituric acid, 200 parts of water and 5 parts of cuprous sulfate in 10 parts of water is added 82 parts of allylbromide. Then at room temperature is added 27 parts of sodium hydroxide (10% aqueous solution). 5,5-Diallylbarbituric acid is isolated by filtration. After recrystallization from water 5,5-diallylbarbituric acid has melting polint 169170°C. References Patent DE 268158; 30.June 1911; Assigned to Geselschaft fur Chemische Industrie in Basel Patent DE 526854; 22. Feb. 1930; Assigned to F.Hoffmann-La Roche and Co. Act.-Ges. in Basel
ALLOCLAMIDE HYDROCHLORIDE Therapeutic Function: Antitussive Chemical Name: Benzamide, 4-chloro-N-(2-(diethylamino)ethyl)-2-(2propenyloxy)-, monohydrochloride Common Name: Alloclamide hydrochloride; Depryn; Pectex Structural Formula:
Chemical Abstracts Registry No.: 5107-01-7; 5486-77-1 (Base) Trade Name
Manufacturer
Country
Year Introduced
Alloclamide hydrochloride
ZYF Pharm Chemical
-
-
Alloclamide hydrochloride
165
Raw Materials 2-Hydroxy-4-chlorobenzoic aci β-Diethylaminoethylamine
Allyl bromide Thionyl chloride
Manufacturing Process (a) 200 g of 2-hydroxy-4-chlorobenzoic acid and 1 liter of methanol are brought to reflux. Dry hydrogen chloride gas is bubbled through the mixture during a time period of 8 hours. The excess of methanol is evaporated, the residue is poured into cold water, neutralized and extracted with ether. After evaporation of the solvent the product is distilled under vacuum. The boiling point of the compound at 15 mm Hg is 127°C, and the yield is 85% of the theoretical. (b) The production of 2-allyloxy-4-chloromethyl benzoate: 4-Chloro-2-hydroxymethyl benzoate 186 g (1 mole), 152 g anhydrous potassium carbonate, 133 g redistilled allyl bromide in 350 ml acetone are heated of refluxing under agitation. At the end of 6 hours the reaction is completed. The reaction mixture is filtered for removal of the mineral salts. The acetone is evaporated. There is thus obtained an oily residue, which rapidly crystallizes. After recrystallization from methanol the obtained product is a white crystal solid, which melts at 56°C. The yield is 84%. (c) The production of 2-allyl-oxy-4-chlorobenzoyl chloride: The 2-allyloxy-4-chloromethyl benzoate obtained under (b) above is saponified under the usual conditions on for obtaining the corresponding acid, and the corresponding acid is obtained in a yield of 91%, the acid melting at 87°C. The chloride of the acid is prepared by treating 1 mol of the acid with 1.5 moles of thionyl chloride (freshly rectified on linseed oil) in the presence of benzene. There is thus obtained a pale yellow viscous liquid, which can be further used without preliminary distillation. (d) Preparation of the amide and of the hydrochloride: 115.5 g (0.5 mol) of the benzoyl chloride produced under (c) above is dissolved in 500 ml of anhydrous chloroform. There is added to this solution drop by drop while agitating and under cooling in an ice bath 116 g of βdiethylaminoethylamine. After the addition is completed the agitation is continued for 1 hour at ambient temperature. The reaction mass is then washed with water, the chloroform is evaporated, the residue is taken up the minimum of absolute alcohol, and there is then added a slight excess of absolute alcohol saturated with hydrogen chloride. The hydrochloride crystallizes by the addition of anhydrous ether. After recrystallization in absolute alcohol plus ether there is obtained white crystals, which are soluble in water and in alcohol. The 2-allyloxy-4-chloro-N-(βdiethylaminoethyl)benzamide hydrochloride melts at 125°-127°C.
166
Allomethadione
References Mauvernay R-Y.; US Patent No. 3,160,557; Dec. 8, 1964; Assigned to Centre European de Recherches Mauvernay, Chateau de Bardon, Riom, Puy-deDome, France
ALLOMETHADIONE Therapeutic Function: Anticonvulsant, Antiepileptic Chemical Name: 2,4-Oxazolidinedione, 5-methyl-3-(2-propenyl)Common Name: Allomethadione, Aloxidone Structural Formula:
Chemical Abstracts Registry No.: 526-35-2 Trade Name
Manufacturer
Country
Year Introduced
Aloxidone
ZYF Pharm Chemical
-
-
Raw Materials Allyl bromide Urea
5-Methyloxazolidine-2,4-dione Ethyl lactate
Manufacturing Process A mixture of 11.4 parts of 5-methyloxazolidine-2,4-dione and 15 parts anhydrous potassium carbonate in 150 parts of dry acetone is stirred for 0.5 hour. 15 parts of allyl bromide are then added and the mixture boiled under reflux with stirring for 4 hours. After cooling and filtering, the solvent and any unchanged allyl bromide are removed by distillation. The residue is extracted with ether end the extract washed with saturated aqueous sodium bicarbonate until the subsequent water-washings are either neutral or just alkaline to litmus paper. The solvent is then distilled and the residue fractionated when 3allyl-5-methyloxazolidine-2,4-dione is obtained in 65% yield as a colorless oil, BP: 88°-90°C/1.8 mm, nd20 = 1.4710. The dry sodium salt of 5-methyloxazolidine-2,4-dione, obtained from 4.6 parts of sodium, 100 parts of ethanol, 12 parts of urea and 23.6 parts of ethyl lactate, is suspended in 100 parts of dry benzene and 30.25 parts of allyl bromide are added. The mixture is boiled under reflux for 20 hours and the benzene decanted or filtered from any solid. The solution is washed with
Allopurinol
167
saturated aqueous sodium bicarbonate until the subsequent water-washings are neutral or just alkaline to litmus paper. The dried benzene solution is then distilled to remove solvent and the residue fractionated, when 3-allyl-5methylosazolidine-2,4-dione is obtained in 27% yield as a colorless oil, BP: 89°-90°C/1 mm, nd20 = 1.4712. The dry sodium salt of 5-methyloxazolidine-2,4-dione obtained as above is mixed with 100 parts of dry dioxane and 31.25 parts of allyl bromide are added. After boiling under reflex for 24 hours, decanting the solution and distilling off the dioxane under reduced pressure, the residue is dissolved in ether and the ethereal extract mashed with aqueous sodium bicarbonate as above. Fractionation of the residue after removing the olvent furnishes 3-allyl5-methyloxazolidine-2,4-dione in 48.5% yield as a colorless oil; BP: 94°95°C/11.75 mm; nd20 = 1.4710. References Davis J.S.H. and Hook W.H.; GB Patent No. 632,423; June 28, 1948; British Schering Research Laboratories, Great Britain
ALLOPURINOL Therapeutic Function: Xanthine oxidase inhibitor, Gout therapy Chemical Name: 1H-Pyrazolo[3,4-d]pyrimidin-4-ol Common Name: Structural Formula:
Chemical Abstracts Registry No.: 315-30-0 Trade Name
Manufacturer
Country
Year Introduced
Zyloprim
Burroughs-Wellcome
US
1966
Zyloric
Wellcome
Switz.
-
Zyloric
Burroughs-Wellcome
UK
1966
Zyloric
Wellcome
W. Germany
1967
Zyloric
Wellcome
Italy
1968
Zyloric
Wellcome
Japan
1969
Zyloric
Wellcome
France
1969
Lopurin
Boots
UK
1980
Adenock
Tanabe
Japan
-
Adenock
Shiraimatsu
Japan
-
Allopin
Yeni
Turkey
-
168
Allopurinol
Trade Name Allomaron Alloprim Alloprin Allopur Allopur Allopurinol Allopurinol Allopurinol Allopurinol Allopurinol Allopurinol Allorin Allozym Allural Allural Allurit Aloc Alositol Anoprocin Antigot Anzief Aprinol Apurin Apurin Apurol Bleminol Caplenal Capurate Cellidrin Cosuric Dabroson Embarin Epidropal Flogorex Foligan Geapur Gichtex Ketawrift Ketobun A Lopurin Lysuron Masaton Melianin Mephanol Milurit
Manufacturer Nattermann Iltas ZCN Gea Nyegaard Sigfried Efeka Woelm Pharma Lederle Kowa Showa Towa Sawai Nativelle Pan Quimica Schoum Toho Iyaku Tanabe Nippon Shoji Yurtoglu Nippon Chemiphar Daisan Gea Madica Siegfried Desitin Berk Fawns and McAllan Henning DDSA Hoyer Diabetylin Fresenius Lancet Henning Gea Gerot Ohta Isei Generics Corp. Boehringer Mannheim Zensei Kohjin Mepha EGYT
Country W. Germany Turkey Canada Denmark Norway W. Germany W. Germany W. Germany Japan Japan Japan Japan Japan Italy Spain Italy Japan Japan Japan Turkey Japan Japan Denmark Finland Switz. W. Germany UK Australia W. Germany UK W. Germany W. Germany W. Germany Italy W. Germany Denmark Austria Japan Japan US W. Germany Japan Japan Switz. Hungary
Year Introduced -
Allopurinol
169
Trade Name
Manufacturer
Country
Year Introduced
Monarch
SS Pharmaceutical
Japan
-
Nektronan
W. Germany
-
Neufan
ICN Pharmaceuticals Inc. Teikoku
Japan
-
Neufan
Teisan
Japan
-
Novopurol
Novopharm
Canada
-
Progout
Protea
Australia
-
Puricos
Lennon
S. Africa
-
Purinol
Horner
Canada
-
Riball
Mitsui
Japan
-
Roucol
Rougier
Canada
-
Serviprinol
Servipharm
Switz.
-
Suspendol
Merckle
W. Germany
-
Takanarumin
Takata
Japan
-
Urbol
Heilit
W. Germany
-
Urbol
Gea
Denmark
-
Uredimin
Chassot
Switz.
-
Uricemil
Farnex
Italy
-
Uricemil
Fardeco
Italy
-
Uriconorm
Streuli
Switz.
-
Uridocid
Reig Jofre
Spain
-
Uriscel
Armour Med.
Italy
-
Urobenyl
Endopharm
W. Germany
-
Urolit
Magis
Italy
-
Urosin
Boehringer Mannheim
W. Germany
-
Urozyl-SR
Restan
S. Africa
-
Urtias
Sabona
W. Germany
-
Vedatan
Corvi
Italy
-
Xanturat
Gruenenthal
W. Germany
-
Zylol
Teva
Israel
-
Raw Materials Cyanoacetamide Morpholine
Triethylorthoformate Hydrazine hydrate
Manufacturing Process 3-Morpholino-2-cyanoacrylamide: A stirred mixture of cyanoacetamide (63 g), triethylorthoformate (134 g), morpholine (82.5 g) and acetonitrile (37.5 ml) was heated under reflux for 4 hours. The initial reflux temperature was 117°C and the final reflux temperature was 82°C. At the end of the reflux period the mixture was cooled to 30°C and the heavy
170
Allylestrenol
crystalline precipitate was collected and washed with 2 x 75 ml of ethanol. The product was dried in vacuum at 30°C. Wt = 111 g. Yield = 82%, MP 173175°C. 3-Aminopyrazole-4-carbxamide hemisulfate: To water (253 ml) at 60°C was added 3-morpholino-2-cyanoacrylamide (63.4 g) and 85% technical hydrazine hydrate (22.7 g). The mixture was rapidly heated to 95°C and the temperature was maintained at >90°C for 20 minutes. The mixture was then cooled to 60°C and the pH carefully adjusted to 1.5 by the addition of a mixture of sulfuric acid (45.7 g) and ice. The acidified reaction was cooled to 5°C and the crystalline product collected and washed with cold water (2 x 100 ml) and acetone (2 x 50 ml). The product was dried in vacuum at 80°C. Wt =5.8 g. Yield =95%, MP 237-239°C. 4-Hydroxypyrazolo[3,4-d]pyrimidine: A suspension of 3-aminopyrazole-4carboxamide hemisulfate (113 g) in formamide (325 g) was stirred and heated to 145°C. The reaction was held at 145°C for 5 hours. The reaction was then cooled to 30°C and the product collected and washed with formamide (2 x 50 ml), water (2 x 150 ml) and acetone (2 x 100 ml). Wt of crude product = 79 g. The crude product was recrystallized by dissolution in a solution made from sodium hydroxide (25 g) in water (1,200 ml) with treatment at 25°C with charcoal (8 g), followed by reprecipitation by the addition of concentrated hydrochloric acid to pH 5. The product was collected and washed with cold water (2 x 300 ml), acetone (2 x 200 ml) and dried in vacuum at 60°C. Wt = 70 g. Yield = 80%. References Merck Index 273 Kleeman and Engel p. 27 PDR pp. 685,774,830,993,1606 OCDS Vol. 1 pp. 152, 269 (1977) I.N. p. 57 REM p. 1111 Druey, J. and Schmidt, P.; US Patent 2,868,803; January 13, 1959; Assigned to Ciba Pharmaceutical Products Inc. Hitchings, G.H. and Falco, E.A.; US Patent 3,474,098; October 21, 1969; Assigned to Burroughs Wellcome and Co. Cresswell, R.M. and Mentha, J.W.; US Patent 4,146,713; March 27, 1979; Assigned to Burroughs Wellcome and Co.
ALLYLESTRENOL Therapeutic Function: Progestin; Antiandrogen Chemical Name: 17α-Allylestr-4-en-17β-ol Common Name: Alilestrenol; Allylestrenol; Allyloestrenol Chemical Abstracts Registry No.: 432-60-0
Allylestrenol
171
Structural Formula:
Trade Name Alilestrenol Alilestrenol PA Allyloestrenol Allyloestrenol Anin Astanol Gestanin Gestanin Gestanon Tab. Gestin Gestormone Gravidin Gynonys Fetugard Fulterm Maintane Tab. Nidagest Orageston Pregular Profar Premaston Profar Turinal Turinal Turinal Turinal Turinal Tab.
Manufacturer Terapia AAA Principio Activo Belco Pharma Huei-Ho Industries Ind-Swift Ltd. Rekvina Pharma Organon Donmed Organon Walter Bushnell Zorka Alidac Sankyo Biddle Sawyer Micro Nova Jagsonpal Systopic Akzo Helios Infar Kalbe Infar Richter Co. Gedeon Richter Medimpex Mekim October Pharma Co.
Country -
Year Introduced -
Raw Materials Methylamine Chromium trioxide Acetic acid Allyl bromide
Lithium Oestradiol-3-methylether Magnesium
Manufacturing Process To 145 ml of dry methylamine which is cooled to -20°C 1.5 g of lithium cut to
172
Almagate
small pieces are added. To the solution which is blue in color after 10-20 min, a solution of 3.0 g of oestradiol-3-methylether in 145 ml of absolute ether is added drop wise. Subsequently the reaction mixture is stirred at -10°C for 40 h, after which 50 ml of absolute ethanol are added. Then the methylamine is distilled off at law pressure. To the remaining solution 50 ml of ether and 50 ml of water are added. The water layer is separated and extracted with ether. The ethereal layer is washed with a 2 N hydrochloric acid solution, subsequently with a saturated sodium bicarbonate solution, and then with water. The ethereal solution is dried and evaporated to dryness. The resulting crude reaction product is dissolved in a mixture of benzene and petroleum ether (1:3) and chromatographed over aluminium oxide. The δ4-17β-hydroxy-oestrene obtained after chromatographic purification has a melting point of 80°-90°C and 95°-100°C after repeated crystallization from petroleum ether. A solution of 13.2 g of chromium trioxide in a mixture of 120 ml of water and 20 ml of acetic acid is added, with stirring, to a solution of 20 g of δ4-17βhydroxy-oestrene in 400 ml of benzene. Subsequently the reaction mixture is vigorously stirred at room temperature for 16 h, after which the benzene layer is separated. The remaining aqueous layer is extracted a few times with benzene and the benzene extracts collected are then added to the separated benzene layer. The benzene extracts are successively washed with dilute sulfuric acid and water and then evaporated to dryness. The residue is crystallized from acetone, and the δ4-17β-oxo-oestrene, melting point 114°-116°C is obtained. To a mixture of 22.4 ml of absolute ether and 1.84 g of magnesium, a mixture of 2.72 ml of allyl bromide and 2.72 ml of absolute ether is added in nitrogen atmosphere. Subsequently a solution of 2 g of δ4-17β-oxo-oestrene in 30 ml of absolute ether is added to this reaction mixture, after which the whole is stirred for 4 h. Then the reaction mixture is poured into acidified ice water. The aqueous mixture is extracted with ether; the ether layer is separated, washed with water, dried over sodium sulfate and evaporated to dryness. The residue is recrystallized from a mixture of ether and petroleum ether, giving δ4-17β-hydroxy-17α-allyl-oestrene, melting point 79.5°-80°C. References GB Patent No. 841,411; April 2, 1958; Assigned: Organon Laboratories Limited, a British Company of Brettenham House, Lancaster Place, London
ALMAGATE Therapeutic Function: Antacid Chemical Name: Magnesium, (carbonato(2-))heptahydroxy(aluminum)tri-, dihydrate
Almasilate
173
Common Name: Almagate Structural Formula: AlMg3(CO3)(OH)7 Trade Name Almagate
Manufacturer AGARWAL PHARCHEM (I) PVT. LTD.
Country -
Year Introduced -
Chemical Abstracts Registry No.: 66827-12-1 Raw Materials Aluminum hydroxide Triethylamine Water
Magnesium hydroxide Ammonium hydroxide
Manufacturing Process 2 Methods of producing of basic aluminium magnesium carbonate: 1. A suspension of aluminum hydroxide (9.57 g, corresponding to 5.09 g of Al2O3 0.05 mol), magnesium hydroxide of 92.09% purity (18.87 g; 0.3 mol), concentrated ammonium hydroxide (4.89 ml; 0.33 mol) and water (500 ml) was boiled under reflux for 6 h while a stream of carbon dioxide was passed through the mixture. Then the reaction mixture was cooled, and the insoluble compound was filtered off, washed several times with water and dried in vacuum at a temperature of 60°C. Basic aluminum magnesium carbonate (31.1 g) was obtained. 2. A suspension of aluminium hydroxide (9.57 g, corresponding to 5.09 g of Al2O3 0.05 mol) magnesium hydroxide of 92.09% purity (18.87 g; 0.3 mol), triethylamine (33.4 g; 0.33 mol) and water (500 ml) was boiled under reflux for 8 h while a stream of carbon dioxide was passed through the mixture. After cooling, the insoluble compound was filtered off, washed several times with water and dried at 60°C under reduced pressure. Basic aluminum magnesium carbonate (30.8 g) was obtained. References Spickett R.G.W. et al.; US Patent No. 4,447,417; May 8, 1984; Assigned: Anphar S.A., Madrid, Spain
ALMASILATE Therapeutic Function: Antacid Chemical Name: Magnesium aluminosilicate (MgAl2Si2O8) hydrate Common Name: Simagel; Almasilate
174
Almasilate
Structural Formula: MgAl2Si2O8·H2O Trade Name
Manufacturer
Megalac Almasilat
Krewel Meuselbach -
Country
-
Simagel
Philopharm
-
-
Year Introduced
Chemical Abstracts Registry No.: 71205-22-6 Raw Materials Magnesium chloride Caustic soda Aluminum sulfate Sodium silicate (Na2O, 9%, SiO2, 29%) Manufacturing Process 203 g of crystalline magnesium chloride such as is used as a food additive, containing 46% MgCl2, is dissolved in 600 ml of water, to which 96 g of caustic soda dissolved in 250 ml of water is added with stirring and a solution comprising 50 ml of water with 207 g of sodium silicate (Na2O, 9%, SiO2, 29%) is further added and is then vigorously stirred to produce basic sodium magnesium silicate (which is designated as Slurry A). Secondly 593 g of aluminum sulfate containing 17.2% Al2O3, dissolved in 1,700 ml of water is gently added with stirring to 216 g of caustic soda dissolved in 600 ml of water, to which 50 ml of water added to 207 g of sodium silicate (Na2O 9%, SiO2, 29%) is slowly added and is then vigorously stirred to produce tetrabasic dialuminum silicate (which is designated as Slurry B). Slurry A and Slurry B are mixed up vigorously with stirring for 3 hours at room temperature. The thus obtained white gel-like precipitate is washed by decantation to remove free alkali, sodium sulfate, sodium chloride, etc. produced as reaction by-products. The residue is filtered and dried at 105°-110°C and 340 g of white powder of fine particle size is obtained as the final product. The molar ratio of MgO to Al2O3, to SiO2, in this product is approximately 1: 1: 2. 203 g of crystalline magnesium chloride such as is used as a food additive, containing 46% MgCl2, and 593 g of aluminum sulfate containing 17.2% Al2O3, are dissolved in 2,300 ml of water, to which a solution comprising 272 g of caustic soda with 800 ml of water, is slowly added with stirring. Thereafter, a solution comprising 414 g of sodium silicate (Na2O, 9%, SiO2, 29%) with 100 ml of water is added, the mixture is heated and is stirred for five hours, while keeping the temperature at 60°C. When the reaction mixture becomes neutral it is allowed to cool and to stand, the supernatant fluid is withdrawn and the white gel-like precipitate is washed by decantation to remove the impurities and dried at 105°-110°C and 350 g of white powder of fine particle size is obtained as the final product (almasilate). References Hidetaka Uoda et al.; GB Patent No. 1,153,513; Feb. 17, 1967; Fuji Kagaku Kogyo Kaushiki Kaisha, a Japanese Company, of 55 Yokohooji, Kamiichimachi, Naka-Niikawa-gun, Toyama-ken, Japan
Alminoprofen
175
ALMINOPROFEN Therapeutic Function: Analgesic, Antiinflammatory Chemical Name: Benzeneacetic acid, α-methyl-4-((2-methyl-2-propenyl) amino)Common Name: Alminoprofen; Minalfene Structural Formula:
Chemical Abstracts Registry No.: 39718-89-3 Trade Name Alminoprofen
Manufacturer ZYF Pharm Chemical
Country -
Year Introduced -
Minalfene
Bouchara-Recordati
-
-
Raw Materials Methyl 2-(p-nitrophenyl)acrylate Methallyl chloride
Palladium on charcoal Pyridine
Manufacturing Process Methyl 2-(p-aminophenyl)propionate: Methyl 2-(p-nitrophenyl)acrylate (52 g) is hydrogenated in ethanol (500 ml) in the presence of 5% palladium-over-charcoal, while maintaining the temperature at +5°C. The theoretical amount of hydrogen is taken up within one hour. After separation of the catalyst and concentration to dryness, the resulting material gives methyl 2-(p-aminophenyl)proprionate which crystallizes: MP: = 40°-43°C. Methyl 2-(p-methallylaminophenyl)propionate hydrochloride: A mixture of methyl 2-(p-aminophenyl)propionate (44.75 g), methallyl chloride (34 g) and pyridine (30 ml) in isopropanol (400 ml) is boiled during 30 hours. The solvent is removed in vacuo and the residue is taken up into water and ether. After separation, the organic phase is washed repeatedly with water, after which it is dried and concentrated in vacuo. The resulting oil is fractionally distilled in vacuo (0.1 mm Hg; 5 g of oil essentially consisting of methyl 2-(p-aminophenyl)propionate are collected at 115°-120°C; 30 g of oil consisting of a mixture of mono- (80%) and disubstituted (20%) amines is collected at 128°-130°C. This oil is used to prepare the hydrochloride, which is recrystallized from ethyl acetate, to give white crystals (22.7 g) melting at
176
Almitrine
115°C. Saponification in the cold methanolic hydroxide gives the desired 2-(4(methallylamino)phenyl)propionic acid (alminoprofen). MP: 120°C. References Bouchara E.; US Patent No. 3,957,850; May 18, 1976
ALMITRINE Therapeutic Function: Respiratory stimulant Chemical Name: 1,3,5-Triazine-2,4-diamine, 6-(4-(bis(4-fluorophenyl) methyl)-1-piperazinyl)-N,N'-di-2-propenylCommon Name: Almitrine Structural Formula:
Chemical Abstracts Registry No.: 27469-53-0 Trade Name Armanor Duxaril Duxil Vectarion
Manufacturer Les Laboratoires Servier Les Laboratoires Servier Servier-Egypt Co. Les Laboratoires Servier
Country -
Year Introduced -
Raw Materials 4,6-Bis(allylamino)-2-chloro-s-triazine 1-p,p'-Difluorobenzhydryl piperazine dihydrochloride Sodium hydroxide Manufacturing Process A solution of 4,6-bis(allylamino)-2-chloro-s-triazine, melting point 204°C
Almotriptan malate
177
(Kofler) and dihydrochloride of 1-p,p'-difluorobenzhydryl piperazine, melting point 178°-180°C (capillary) in anhydrous dimethylformamide are heated under reflux. On completion of this operation the solvent is removed under vacuum and the residue taken up in a mixture of chloroform and of water (1:1). The organic phase is separated, and repeatedly extracted with aqueous N-methanesulphonic acid and the aqueous acidic layers separated. The aforementioned acidic solutions are then combined and rendered alkaline (pH 10) with dilute aqueous sodium hydroxide, the base extracted with ether, the extract dried over anhydrous potassium carbonate, and filtered. The etheral filtrate, upon evaporation yields the 2,4-bis(allylamino)-6-(4-(bis(pfluorophenyl)methyl)-1-piperazinyl)-s-triazine, melting point 175°-180°C. References Regnier G. et al.; US Patent No. 3,647,794; March 7, 1972; Assignee: Societe en nom collectiff "Science Union et Cie", Societe Francaise de Recherche Medicale
ALMOTRIPTAN MALATE Therapeutic Function: Migraine therapy Chemical Name: Pyrrolidine, 1-[[[3-[2-(dimethylamino)ethyl]-1H-indol-5yl]methyl]sulfonyl]-, hydroxybutanedioate salt (1:1) Common Name: Almotriptan malate Structural Formula:
Chemical Abstracts Registry No.: 181183-52-8; 154323-57-6 (Base) Trade Name Almogran Axert Axert Axert
Manufacturer Lundbeck Aetna Inc. Jannsen-Ortho Pharmacia Corporation
Country -
Year Introduced -
Raw Materials 1-[[2-Carboxy-3-(2-dimethylaminoethyl)-5-indolyl]methanesulphonyl]pyrrolidine Quinoline Copper oxide
178
Alniditan dihydrochloride
Manufacturing Process To a solution of previously dried 1-[[2-carboxy-3-(2-dimethylaminoethyl)-5indolyl]methanesulphonyl]-pyrrolidine (1.6 g; 0.0442 moles) in anhydrous quinoline (75 ml) and under atmosphere of nitrogen, cuprous oxide (160 mg; 0.0011 moles) was added. The reaction mixture was heated to 190°C for 15 minutes, stirred to room temperature, poured into a mixture of 1 N hydrochloric acid (150 ml) and ethyl acetate (50 ml), shaken and decanted. The aqueous solution was washed several times with ethyl acetate, then solid sodium bicarbonate was added until pH = 7.8, and washed with n-hexane to eliminate the quinoline. The aqueous solution was made alkaline with solid potassium carbonate and extracted with ethyl acetate. The organic solution was dried (Na2SO4), the solvent removed under reduced pressure when a dark oil was obtained (1.3 g; yield 92%). This product was purified by column chromatography with silica gel and methylene chloride:ethanol:ammonium hydroxide (60:8:1) as eluent and a white foam (0.8 g) of 1-[[3-(2dimethylaminoethyl)-5-indolyl]methanesulphonyl]-pyrrolidine was obtained. To a solution of the above product (0.8 g) in acetone (30 ml), a few drops of hydrogen chloride saturated dioxan solution, were added. The precipitated solid was collected by filtration, washed with acetone and dried to give 1-[(3(2-(dimethylamino)ethyl)-5-indolyl)methanesulphonyl]-pyrrolidine hydrochloride (0.75 g). Melting point 218°-220°C. In practice it is usually used as malate salt. References F. Former et al.; WO 94/02460; 28.07.92 D. Lednicer; The organic chemistry of drug synthesis; p. 124, 1999; Wiley and Sons
ALNIDITAN DIHYDROCHLORIDE Therapeutic Function: Migraine therapy Chemical Name: 1,3-Propanediamine, N-((3,4-dihydro-2H-1-benzopyran-2yl)methyl)-N'-(1,4,5,6-tetrahydro-2-pyrimidinyl)-, dihydrochloride, (2R)Common Name: Alniditan dihydrochloride; Pasmigren Structural Formula:
Chemical Abstracts Registry No.: 155428-00-5; 152317-89-0 (Base)
Alniditan dihydrochloride Trade Name Pasmigren
Manufacturer Janssen-Cilag
Country -
179
Year Introduced -
Raw Materials Methylbenzene 2-Chloropyrimidine Thionyl chloride Thiophene Hydrogen Potassium acetate Sodium hydroxide Nickel Raney
3,4-Dihydro-2H-1-benzopyran-2carboxylic acid, (+)2,2'-Oxybispropane Acetamide, N,N-dimethylPalladium on charcoal Benzenemethanamine 2-Propenenitrile Sodium carbonate
Manufacturing Process To a stirred and heated +80°C mixture of 3,4-dihydro-2H-1-benzopyran-2carboxylic acid and methylbenzene were added dropwise thionyl chloride during a period of 85 min. Upon complete addition, stirring was continued for 2 h at 80°C. After cooling to room temperature, the reaction mixture was evaporated. The residue was taken up in methylbenzene and the solvent was evaporated again, yielding (R)-3,4-dihydro-2H-1-benzopyran-2-carbonyl chloride. A mixture of (R)-3,4-dihydro-2H-1-benzopyran-2-carbonyl chloride in N,Ndimethylacetamide and 2,2'-oxybispropane was hydrogenated in the presence of palladium-on-charcoal catalyst (10%) and a solution of thiophene in methanol (4%). After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was added to a mixture of benzenemethanamine, potassium acetate and methanol. This mixture was hydrogenated again in the presence of palladium-on-charcoal catalyst (10%) and a solution of thiophene in methanol (4%). After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was poured into water and the whole was basified with NaOH (50%). The product was extracted with dichloromethane and the extract was dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2/CH3OH 95:5). The eluent of the desired fraction was evaporated and the residue was converted into the hydrochloride salt in 2-propanone by adding 2-propanol saturated with HCl. The salt was filtered off and dried, yielding (R)-3,4-dihydro-N-(phenylmethyl)-2H-1benzopyran-2-methanamine. A mixture of 28.0 g of (R)-3,4-dihydro-N-(phenylmethyl)-2H-1-benzopyran-2methanamine and 300 ml of methanol was hydrogenated in the presence of 2.0 g of palladium-on-charcoal catalyst (10%). After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 18.2 g (100%) of (-)-(R)-3,4-dihydro-2H-1-benzopyran2-methanamine as crude residue. A mixture of 18.0 g of (-)-(R)-3,4-dihydro-2H-1-benzopyran-2-methanamine, 60.0 g of 2-propenenitrile and 400 ml of ethanol was stirred for 4 h at reflux temperature. The reaction mixture was evaporated and the residue was dried, yielding 20.0 g (84%) of (-)-(R)-3-[[(3,4-dihydro-2H-1-benzopyran-2yl)methyl]amino]propanenitrile.
180
Alonacic
A mixture of 20.0 g (-)-(R)-3-[[(3,4-dihydro-2H-1-benzopyran-2yl)methyl]amino]propanenitrile and 300 ml of methanol was hydrogenated in the presence of 5.0 g of Raney Nickel. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 21.0 g (100%) of (-)-(R)-N-[(3,4-dihydro-2H-1benzopyran-2-yl)methyl]-1,3-propanediamine as crude residue. A mixture of (-)-(R)-N-[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]-1,3propanediamine, 2-chloropyrimidine, sodium carbonate and ethanol was stirred for 4 h at reflux temperature. The reaction mixture was evaporated. The residue was purified by column chromatography (silica gel; CHCl3/CH3OH 90:10). The eluent of the desired fraction was evaporated and the residue was converted into the hydrochloride salt in 2-propanol. The salt was filtered off and dried in vacuum, yielding (-)-(R)-N-[(3,4-dihydro-2H-1-benzopyran-2yl)methyl]-N'-(2-pyrimidinyl)-1,3-propanediamine dihydrochloride hemihydrate. A mixture of 3.6 g of (-)-(R)-N-[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]N'-(2-pyrimidinyl)-1,3-propanediamine dihydrochloride hemihydrate in 150 ml of methanol and 20 ml of 2-propanol saturated with HCl was hydrogenated in the presence of 1.5 g of palladium-on-charcoal catalyst (2%). After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The product was crystallized from acetonitrile, filtered off and dried, yielding 2.7 g (74.0%) of (-)-(R)-N-[(3,4-dihydro-2H-1benzopyran-2-yl)methyl]-N'-(1,4,5,6-tetrahydro-2-pyrimidinyl)-1,3propanediamine dihydrochloride hemihydrate; melting point 200.2°C. The base (-)-(R)-N-[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]-N'-(1,4,5,6tetrahydro-2-pyrimidinyl)-1,3-propanediamine may be obtained by treatment of (-)-(R)-N-[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]-N'-(1,4,5,6tetrahydro-2-pyrimidinyl)-1,3-propanediamine dihydrochloride hemihydrate with NaOH. References Van Lommen G.R.E. et al.; US Patent No. 5,541,180; July 30, 1996; Assigned: Janssen Pharmaceutica N.V., Beerse, Belgium
ALONACIC Therapeutic Function: Mucolytic Chemical Name: N-(((2RS,4R)-2-Methyl-4-thiazolidinyl)carbonyl)-β-alanine, methyl ester Common Name: Alonacic Chemical Abstracts Registry No.: 105292-70-4
Alonacic
181
Structural Formula:
Trade Name Alonacic
Manufacturer Onbio Inc.
Country -
Year Introduced -
Raw Materials β-Alanine methyl ester hydrochloride N-Methylmorpholine Dicyclohexylcarbodiimide N-Hydroxybenzotriazole N-t-Butoxycarbonyl-2-methylthiazolidine-4-carboxylic acid Manufacturing Process Preparation of (2-methylthiazolidin-4-carbonyl)-β-alanine methyl ester: To a solution of β-alanine methyl ester hydrochloride (5.08 g, 36.4 mmol) in dimethylformamide (35 ml) kept under stirring at -5°C, N-methylmorpholine (4.01 ml, 36.4 mmol) and then a solution of N-t-butoxycarbonyl-2methylthiazolidine-4-carboxylic acid (9 g, 36.4 mmol) in dimethylformamide (15 ml) were added. To the resulting solution kept under stirring at -5°C, dicyclohexylcarbodiimide (9 g, 43.68 mmol) and N-hydroxybenzotriazole (5.89 g, 43.68 mmol) were added. After 24 hours under stirring at +4°C, the precipitate (dicyclohexylurea) was filtered and the filtrate was evaporated to dryness. An oil was obtained which was dissolved in ethyl acetate and the solution was washed with an aqueous solution of citric acid at 10%, with an aqueous sodium bicarbonate solution at 10% and with water. The organic solution, dried on sodium sulphate was evaporated to dryness under vacuum at 40°C. (N-t-Butoxycarbonyl-2-methylthiazolidine-4-carbonyl)-β-alanine methyl ester (10.7 g) was thus obtained as oil. The obtained product (7.9 g) was treated at room temperature under nitrogen, with ethyl acetate (90 ml) containing 13% (w/v) of hydrogen chloride. After 1 hour the solution was evaporated to dryness under vacuum at 35°C. The residue, after crystallization from isopropyl alcohol diethyl ether, afforded (2-methylthiazolidine-4-carbonyl)-β-alanine methyl ester hydrochloride (5.4 g). [α]D20=-85° (c=1, CH3OH); MP:=124°-125°C. The base form may be prepared by adding of equivalent of any basic product (NaHCO3, Et3N and so on). References Pilotto A. et al.; US Patent No. 4,761,399; Aug. 2, 1988; Assigned to Zambon S.P.A., Vicenza, Italy
182
Alonimid
ALONIMID Therapeutic Function: Sedative, Hypnotic Chemical Name: Spiro[naphthalene-1(4H),3'-piperidine]-2',4,6'-trione, 2,3dihydroCommon Name: Alonimid Structural Formula:
Chemical Abstracts Registry No.: 2897-83-8 Trade Name Alonimide Alomid
Manufacturer ZYF Pharm Chemical Merrel
Country -
Year Introduced -
-
-
Raw Materials Phenylacetonitrile Ethyl acrylate Polyphosphoric acid Manufacturing Process To a stirred mixture of 58.6 g (0.5 M) of phenyl-acetonitrile and 150 g (1.5 M) of ethyl acrylate was carefully added sodium methoxide in small increments (about 0.1 g). The exothermic reaction was controlled by ice bath cooling to keep the reaction mixture at 50°C. When further additions of sodium methoxide were no longer exothermic, the reaction mixture was stirred for one half hour more and the excess ethyl acrylate removed under reduced pressure on a steam bath. The resulting oil was added to 1.500 g of polyphosphoric acid and stirred on a steam bath for three hours. After cooling to about 50°C, 0.5 liter of chloroform was added followed by additions of crushed ice until the aqueous phase was free flowing. The chloroform layer was separated and combined with three 150 ml chloroform extracts of the aqueous layer. The organic phase was then dried over anhydrous magnesium sulfate, filtered and concentrated to a semi-solid residue. Recrystallization from acetone gave 2,3-dihydrospiro[naphthalene-1(4H),3'piperidine]-2',4,6'-trione, melting point 197°-199°C.
Alosetron hydrochloride
183
References Carr et al.; US Patent No. 3,647,797; March, 7, 1972; Assigned to Richardson-Merrell Inc., New York, N.Y.
ALOSETRON HYDROCHLORIDE Therapeutic Function: Antidiarrheal Chemical Name: 1H-Pyrido[4,3-b]indol-1-one, 2,3,4,5-tetrahydro-5-methyl2-[(5-methyl-1H-imidazol-4-yl)methyl]-, monohydrochloride Common Name: Alosetron hydrochloride Structural Formula:
Chemical Abstracts Registry No.: 122852-69-1; 122852-42-0 (Base) Trade Name Alosetron hydrochloride Lotronex
Manufacturer GlaxoSmithKline
Country -
Year Introduced -
GlaxoSmithKline
USA
-
Raw Materials Thionyl chloride Maleic acid Sodium hydride Polyphosphoric acid
1-(Triphenylmethyl)-1H-imidazole-4-methanol Hydroxylamine hydrochloride 3,4-Dihydro-4-methylcyclopent[b]indol-1-(2H)-one
Manufacturing Process 4-(Chloromethyl)-1-(triphenylmethyl)-1H-imidazole. Thionyl chloride (0.829 g) was added over 1 min to a stirred suspension of 1(triphenylmethyl)-1H-imidazole-4-methanol (1.3 g) in a mixture of dichloromethane (50 ml) and DMF (1.0 ml) at 23°C. The solution so obtained was stirred for 15 min. and extracted with 8% sodium bicarbonate solution (80 ml). The organic phase was washed with water (50 ml), dried and evaporated to give an oil which solidified. The solid was slurried in hexane and filtered to give the title compound (1.28 g), m.p. 139-141°C. 3,4-Dihydro-4-methylcyclopent[b]indol-1(2H)-one oxime.
184
Alosetron hydrochloride
3,4-Dihydro-4-methylcyclopent[b]indol-1(2H)-one (1.7 g) and hydroxylamine hydrochloride (1.925 g) in pyridine were heated at 60°C for 18 h and cooled. The reaction mixture was evaporated in vacuo to a residue to which was added 8% sodium bicarbonate (150 ml). Extraction with ethyl acetate (300 ml) produced a suspension in the organic layer; this layer and associated solid was separated from the aqueous layer. The aqueous layer was re-extracted with ethyl acetate (250 ml). The combined organic extracts (and suspended solid) were evaporated to a residue, boiled with a mixture of ethanol (150 ml) and methanol (150 ml) and cooled to 50°C. The residue was adsorbed from this solution on to FCC silica and applied to an FCC column. Elution with ethyl acetate/3-10% methanol provided the title compound (1.69 g), m.p. 219224°C (decomp.). 2,3,4,5-Tetrahydro-5-methyl-1H-pyrido[4,3-b]indol-1-one. 3,4-Dihydro-4-methylcyclopent[b]indol-1(2H)-one oxime (1.53 g), polyphosphoric acid (409 g) and dioxan (15 ml) were heated at 110-120°C for 2.2 h under nitrogen. The reaction mixture was cooled, and treated with 2 N sodium carbonate solution (1 L). The suspension was extracted with ethyl acetate (4x400 ml) and the combined extracts were dried. Evaporation gave a solid (1.43 g) which was recrystallised from ethyl acetate/cyclohexane. This solid was purified by FCC, eluting with dichloromethane:ethanol:ammonia solution (200:10:1) to give a solid (1.26 g) which was recrystallised from ethanol to provide the title compound (960 mg), m.p. 234-238°C. 2,3,4,5-Tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1Hpyrido[4,3-b]indol-1-one maleate. A mixture of 2,3,4,5-tetrahydro-5-methyl-1H-pyrido[4,3-b]indol-1-one (0.6 g) and 78% sodium hydride dispersion in mineral oil (0.109 g) in dry DMF (15 ml) was stirred under nitrogen at 50°C until hydrogen evolution ceased (ca. 1.5 h). The mixture was cooled to 40°C and a solution of 4-(chloromethyl)-5methyl-1-(triphenylmethyl)-1H-imidazole (1.12 g) in dry THF (15 ml) was added. The reaction was then stirred at 40°C for 3 h, at 20°C for 16 h and a further portion of 4-(chloromethyl)-5-methyl-1-(triphenylmethyl)-1H-imidazole (1.12 g) in dry THF (15 ml) was added. The resulting mixture was heated at 40°C for 3 h, quenched with water (20 ml) and acetic acid (20 ml), and heated at 100°C for 2 h. The mixture was then concentrated in vacuo to ca. 60 ml, diluted with 1 M hydrochloric acid (40 ml) and washed with ethyl acetate (3x50 ml). The organic phase was discarded and the acidic aqueous phase was basified (pH=9) with potassium carbonate and extracted with ethyl acetate:ethanol (20:1; 3x100 ml). The extracts were combined, dried and evaporated to give a brown gum (ca. 1 g). This gum was adsorbed onto silica and purified by FCC eluting with dichloromethane:ethanol:ammonia solition (100:8:1) to give a pale brown solid (0.8 g); m.p. 238-240°C (decomp.). This solid was dissolved in a mixture of (hot ethanol and methanol (1:1; 100 ml) and treated with an ethanolic solution of maleic acid (3.18 g). The resulting solution was concentrated to ca. 20 ml and diluted with dry diethyl ether (ca. 8 ml) to precipitate the title compound (0.75 g) as an off-white solid melting point 160-162°C. Hydrochloride may be prepared by treating the above solid with an equivalent of an ethanolic solution of HCl.
Alpertine
185
References Harold I.H. et al.; European Patent Office No 0 306 323 A2; 02.09.88
ALPERTINE Therapeutic Function: Antipsychotic; Neuroleptic Chemical Name: 1H-Indole-2-carboxylic acid, 5,6-dimethoxy-3-(2-(4-phenyl1-piperazinyl)ethyl)-, ethyl ester Common Name: Alpertine Structural Formula:
Chemical Abstracts Registry No.: 27076-46-6 Trade Name Alpertine Win 31665
Manufacturer ZYF Pharm Chemical Sterling-Winthrop
Country -
Year Introduced -
Raw Materials γ-Butyrolactone Ethyl oxalate 3,4-Dimethoxyphenylhydrazine hydrochloride Manufacturing Process 1-[2-(2-Carbethoxy-5,6-dimethoxy-3-indolyl)ethyl]-4-phenylpiperazine: To a suspension of 23 g (1.0 mole) of sodium pellets in 800 ml of absolute ether was added 80 ml of a mixture of 86 g (1.0 mole) of γ-butyrolactone and 146 g (1.0 mole) of ethyl oxalate. The reaction mixture began to boil gently and was allowed to reflux spontaneously for two hours, after which time the remainder of the γ-butyrolactone and ethyl oxalate mixture was added
186
Alphaprodine hydrochloride
cautiously. When addition was complete, the mixture was refluxed for one hour, allowed to stand overnight, and the ether removed in vacuo. The residue was mixed with ice, acidified with cold, dilute sulfuric acid, extracted with ether, and the ether extracts dried over sodium sulfate and taken to dryness. Distillation of the residue in vacuo at 0.05 mm afforded 98 g of α-ethoxalyl-γbutyrolactone, collected between 110-126°C. Forty grams (0.215 mole) of the latter were heated under reflux in 100 ml of 2 N sulfuric acid until the evolution of carbon dioxide ceased, giving a solution of α-keto-δ-valerolactone. 3,4-Dimethoxyphenylhydrazine hydrochloride (44 g, 0.22 mole) was dissolved in 300 ml of water, treated with a solution of 12.3 g (0.22 mole) of potassium hydroxide in 50 ml of water, and cooled. To this mixture was added the above described solution of α-keto-δ-valerolactone, and the pH of the mixture was adjusted to about 2 with 10% sodium hydroxide. The mixture was warmed on a hot plate for five minutes, allowed to cool, extracted with chloroform, and the extracts dried over magnesium sulfate and concentrated to dryness giving 66 g of crude hydrazone. The latter was dissolved in 100 ml of absolute ethanol, the mixture acidified with 400 ml of saturated ethanolic hydrogen chloride, and a stream of hydrogen chloride gas was passed through the mixture causing the temperature to rise to 80°C. The solid which separated from the reaction mixture was collected after standing overnight, and washed with cold absolute ethanol to give 38 g of crude 2-carboxy-5,6 -dimethoxy-3-(2hydroxyethyl)indole. The latter was suspended in 300 ml of absolute ethanol and the solution saturated with anhydrous hydrogen chloride for one hour. The mixture was allowed to stand for two hours, and the solid which separated was collected and dried to give 24 g of 2-carbethoxy-5,6-dimethoxy-3-(2-chloroethyl)indole, M.P. 179-181°C. The latter was added to 15 ml of 1-phenylpiperazine and the mixture heated at 140-160°C for one hour and twenty minutes. The cooled mixture was triturated with 100 ml of ether, filtered, and the ether filtrate concentrated to dryness. The residue was mixed with water and acetic acid, the pH adjusted to about 5.0, and the insoluble material was collected by filtration giving 5 g of crude product which was recrystallized from methanol to give 2.2 g of 1-[2(2-carbethoxy-5,6-dimethoxy-3-indolyl)ethyl]-4-phenylpiperazine, M.P. 142.5144.0°C. References Archer S.; US Patent No. 3,562,278; Feb. 9, 1971; Assigned to Sterling Drug Inc., New York, N.Y., a corporation of Delawere
ALPHAPRODINE HYDROCHLORIDE Therapeutic Function: Narcotic analgesic
Alphaprodine hydrochloride
187
Chemical Name: cis-1,3-Dimethyl-4-phenyl-4-piperidinolpropanoate hydrochloride Common Name: Structural Formula:
Chemical Abstracts Registry No.: 77-20-3 (Base); 49638-24-6 (Hydrochloride salt) Trade Name
Manufacturer
Country
Year Introduced
Nisentil
Roche
US
1949
Raw Materials Lithium Bromobenzene Hydrogen chloride
1,3-Dimethyl-4-piperidone Propionic anhydride
Manufacturing Process In a round-bottom flask provided with stirrer, dropping funnel, condenser and a gas outlet for keeping the system under nitrogen, 200 cc of dry ether is placed and 4.6 grams of lithium cut into thin strips is added. 52 grams of bromobenzene in 50 cc of dry ether are added dropwise and after addition, the mixture is refluxed for 2 hours. This procedure results in the formation of phenyl-lithium. Other aryl-lithium compounds can be prepared in a similar manner by reacting lithium metal or a lithium compound capable of transferring lithium and a compound having an exchangeable halogen group as, for example, bromonaphthalene. The solution of phenyl-lithium is cooled to -20°C and to this a solution of 12.7 grams of 1,3-dimethyl-4-piperidone, prepared according to the method of Howton, J. Org. Chem. 10, 277 (1945), in ether is added dropwise with stirring. After the addition, the stirring is continued for a further 2 hours at 20°C. The lithium complex, 1,3-dimethyl-4-phenyl-4-oxylithium piperidine, which forms is soluble in the ether and can be recovered there from. To prepare the piperidinol, the lithium complex, while in the reaction mixture is decomposed by the addition of an ice and hydrochloric acid mixture. The acidified layer is separated, basified and extracted with ether. After drying the ether solution and removing the solvent, the residue on distillation in vacuum distills chiefly at 155°C/10 mm, yielding the product, 1,3-dimethyl-4-phenyl4-hydroxypiperidine, which, on crystallization from n-hexane melts at 102°C. On treatment with propionic anhydride catalyzed with a trace of sulfuric acid,
188
Alpidem
1,3-dimethyl-4-propionoxy-4-phenylpiperidine is attained. The latter compound can be converted into the hydrochloride salt by reaction with hydrogen chloride. This salt after crystallization from acetone has a melting point of 209°C. References Merck Index 302 Kleeman and Engel p. 29 PDR p. 1494 OCDS Vol. 1 pp. 304 and 2328 (1977) I.N. p.60 REM p. 1107 Lee, J. and Ziering, A.; US Patent 2,498,433; February 21, 1950; Assigned to Hoffmann-La Roche Inc.
ALPIDEM Therapeutic Function: Anxiolytic Chemical Name: Imidazo[1,2-a]pyridine-3-acetamide, 6-chloro-2-(4chlorophenyl)-N,N-dipropylCommon Name: Ananxil Structural Formula:
Chemical Abstracts Registry No.: 82626-01-5 Trade Name
Manufacturer
Country
Year Introduced
Ananxil
Synthelabo
-
-
Raw Materials Formic acid 6-Chloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridine-3-acetonitrile Hydrogen chloride Ammonia Potassium hydroxide Acetic acid
Alprazolam
189
Manufacturing Process Two methods of synthesis of 6-chloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridine-3-N,N-dimethylacetamide: 1. 22 g (0.0788 mol) of 6-chloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridine-3acetonitrile are added to 85 ml of 99% formic acid and the solution is treated with a stream of dry hydrogen chloride for 3 to 4 hours. When all the nitrile has been converted, the solution is heated slightly to degas it, and the cooled solution is then poured into 1 liter of water; the mixture is stirred for 10 min and then rendered alkaline with 200 ml of concentrated ammonia solution. The solid is filtered off, washed copiously with water and dried under a waterpump vacuum. The 6-chloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridine-3acetamide is recrystallised from ethanol. Melting point = 285-287°C. 2. 19.2 g of 6-chloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridine-3-acetamide and 19 g of KOH are added successively to 550 ml of 75% ethanol. The suspension is heated at the reflux temperature for 10-16 hours. When the reaction has ended, the solution is concentrated in vacuo and the residue is dissolved in ½ liter of water. The small amount of insoluble material is filtered off and the filtrate is treated with 50 ml of acetic acid. The expected acid precipitates and it is filtered off and roughly dried. The crude product is taken up in 500 ml of acetone and the 6-chloro-2-(4-chlorophenyl)imidazo[1,2a]pyridine-3-acetic acid is filtered off hot. Melting point=258-260°C. References Kaplan J.-P., George Pascal; US Patent No. 4,460,592; July 17, 1984; Assigned to Synthelabo
ALPRAZOLAM Therapeutic Function: Tranquilizer Chemical Name: 8-Chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4] benzodiazepine Common Name: Structural Formula:
190
Alprazolam
Chemical Abstracts Registry No.: 28981-97-7 Trade Name Xanax Xanax Xanax Xanax
Manufacturer Upjohn Upjohn Upjohn Upjohn
Country US Switz. UK Australia
Year Introduced 1981 1982 1983 1983
Raw Materials 2,6-Dichloro-4-phenylquinoline Hydrazine hydrate Triethyl orthoacetate Sodium periodate Paraformaldehyde Phosphorus tribromide Ammonia Manufacturing Process 6-Chloro-2-hydrazino-4-phenylquinoline: A stirred mixture of 2,6-dichloro-4phenylquinoline (2.7 g, 0.01 mol) and hydrazine hydrate (6.8 g) was refluxed under nitrogen for 1 hour and concentrated in vacuum. The residue was suspended in warm water, and the solid was collected by filtration, dried and recrystallized from ethyl acetate-Skelly B hexanes to give 1.81 g (67% yield) of 6-chloro-2-hydrazino-4-phenylquinoline of melting point 156.5-157°C. 7-Chloro-1-methyl-5-phenyl-s-trizolo[4,3-a]quinoline: A stirred mixture of 6chloro-2-hydrazino-4-phenylquinoline (1.4 g, 0.0052 mol), triethylorthoacetate (0.925 g, 0.0057 mol) and xylene (100 ml) was refluxed, under nitrogen, for 2 hours 40 minutes. During this period the ethanol formed in the reaction was removed by distillation through a short, glass helix-packed column. The mixture was concentrated to dryness in vacuum and the residue was crystallized from methanol-ethyl acetate to give: 1.28 g of 7-chloro-1methyl-5-phenyl-s-triazolo[4,3-a]quinoline (83.9% yield). The analytical sample was crystallized from methylene chloride:methanol and had a melting point 252.5-253.5°C. 5-Chloro-2-(3-methyl-4H-1,2,4-triazol-4-yl)benzophenone (Oxidation of 7chloro-1-methyl-5-phenyl-s-trizolo[4,3-a]quinoline): A stirred suspension of 7chloro-1-methyl-5-phenyl-s-triazolo[4,3-a] quinoline (2,94 g, 0.01 mol) in acetone (110 ml) was cooled in an ice-bath and treated slowly with a solution prepared by adding sodium periodate (2 g) to a stirred suspension of ruthenium dioxide (200 mg) in water (35 ml). The mixture became dark. Additional sodium periodate (8 g) was added during the next 15 minutes. The ice-bath was removed and the mixture was stirred for 45 minutes. Additional sodium periodate (4 g) was added and the mixture was stirred at ambient temperature for 18 hours and filtered. The solid was washed with acetone and the combined filtrate was concentrated in vacuum. The residue was suspended in water and extracted with methylene chloride. The extract was dried over anhydrous potassium carbonate and concentrated. The residue was chromatographed on silica gel (100 g) with 10% methanol and 90% ethyl acetate; 50 ml fractions were collected. The product was eluted in fractions 10-20 and was crystallized from ethyl acetate to give: 0.405 g of melting
Alprazolam
191
point 168-169.5°C and 0.291 g of melting point 167.5-169°C (23.4% yield) of 5-chloro-2-(3-methyl-4H-1,2,4-triazol-4-yl)benzophenone. The analytical sample had a melting point of 168°C. 5-Chloro-2-[3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone: A stirred mixture of 5-chloro-2-(3-methyl-4H-1,2,4-triazolo-4yl)benzophenone, (2.98 g, 0.01 mol) paraformaldehyde (3 g) and xylene (100 ml) was warmed under nitrogen, in a bath maintained at 125°C for 7 hours. The mixture was then concentrated in vacuum. The residue was chromatographed on silica gel (150 g) with 3% methanol-97% chloroform. Fifty ml fractions were collected. The product was eluted in fractions 20-44. The fractions were concentrated and the residue was crystallized from ethanol-ethyl acetate to give: 1.64 g of melting point 138-142°C; 0.316 g of melting point 138.5-141°C; 0.431 g of melting point 139-141°C (72.8% yield) of 5-chloro-2-[3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazol-4yl]benzophenone. The analytical sample had a melting point of 138-139°C. 5-Chloro-2-[3-(bromomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]-benzophenone: A solution of 5-chloro-2-[3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone (328 mg, 0.001 mol) in dry, hydrocarbon-stabilized chloroform (5 ml) was cooled in an ice-bath and treated with phosphorus tribromide (0.1 ml). The colorless solution was kept in the ice-bath for 55 minutes, at ambient temperature (22-24°C), for 5 hours. The resulting yellow solution was poured into a mixture of ice and dilute sodium bicarbonate. This mixture was extracted with chloroform. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was crystallized from methylene chloride-ethyl acetate to give: 0.285 g of melting point 200240°C (decomposition) and 0.030 g of melting point 200-220°C (decomposition) of 5-chloro-2-[3-(bromomethyl)-5-methyl-4H-1,2,4-triazol-4yl]benzophenone. The analytical sample had a melting point of 200-240°C. 8-Chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine: A stirred suspension of 5-chloro-2-[3-(bromomethyl)-5-methyl-4H-1,2,4-triazol4-yl]-benzophenone (391 mg, 0.001 mol) in tetrahydrofuran (15 ml) was cooled in an ice-bath and treated with a saturated solution of ammonia in methanol (12.5 ml). The resulting solution was allowed to warm to ambient temperature and stand for 24 hours. It was then concentrated in vacuum. The residue was suspended in water, treated with a little sodium bicarbonate and extracted with methylene chloride. The extract was washed with brine, dried with anhydrous potassium carbonate and concentrated. The residue was crystallized from methylene chloride-ethyl acetate to give 0.220 g of crude product of melting point 227-228.5°C. Recrystallization of this material from ethyl acetate gave 0.142 g of melting point 228-229.5°C of 8-chloro-1methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine. References Merck Index 303 DFU 1 (12) 551 (1976) Kleeman and Engel p. 30 PDR p. 1865 OCDS Vol. 3 p. 197 (1984) DOT 11 (5) 179 (1975) I.N. p. 60
192
Alprenolol hydrochloride
Hester, J.B., Upjohn Hester, J.B., Upjohn Hester, J.B., Upjohn
Jr.; US Patent 3,681,343; August 1, 1972; Assigned to The Company Jr.; US Patent 3,781,289; December 25, 1973; Assigned to The Company Jr.; US Patent 3,709,898; January 9, 1973; Assigned to The Company
ALPRENOLOL HYDROCHLORIDE Therapeutic Function: Beta-adrenergic blocker Chemical Name: 1-[(1-Methylethyl)amino]-3-[2-(2-propenyl)phenoxy]-2propanol hydrochloride Common Name: Structural Formula:
Chemical Abstracts Registry No.: 13655-52-2 (Base); 13707-88-5 (Hydrochloride salt) Trade Name
Manufacturer
Country
Year Introduced
Aptol
Globopharm
Switz.
-
Aptin
Astra France
W. Germany
1967
Aptine
Lematte/Boinot
France
1971
Aprobal
Fujisawa
Japan
1971
Aptin
Byk Gulden
Italy
1972
Apllobal
Hassle
Sweden
-
Aptina
Made
Spain
-
Aptol-Duriles
Astra
-
-
Betacard
Beecham
UK
-
Elperl
Sawai
Japan
-
Gubernal
Geigy
France
-
Regletin
Teikoku
Japan
-
Sinalol
Kaken
Japan
-
Yobir
Maruko
Japan
-
Alprostadil
193
Raw Materials Ammonia Hydrogen chloride Acetone
o-Allyl epoxy propoxy benzene Sodium borohydride
Manufacturing Process A solution of 24.6 g of o-allyl-epoxypropoxybenzene dissolved in 250 ml of absolute ethanol saturated with ammonia was placed in an autoclave and heated on a steam-bath for 2 hours. The alcohol was then removed by distillation and the residue was redissolved in a mixture of methanol and ethylacetate. Hydrogen chloride gas was introduced into the solution. The hydrochloride salt was then precipitated by the addition of ether to yield 11.4 g of product. Five grams of the amine-hydrochloride thus formed were dissolved in 50 ml of methanol and 9 ml of acetone. The resulting solution was cooled to about 0°C. At this temperature 5 g of sodium borohydride were added over a period of 1 hour. Another 2.2 ml of acetone and 0.8 g of sodium borohydride were added and the solution was kept at room temperature for 1 hour, after which 150 ml of water were added to the solution. The solution was then extracted with three 100-ml portions of ether which were combined, dried over potassium carbonate, and evaporated. The free base was then recrystallized from petrol ether (boiling range 40-60°C) to yield 2.7 g of material having a melting point of 57°C. The corresponding hydrochloride was prepared by dissolving 2 g of the product, prepared above, in 20 ml of acetone, and adding to the resulting solution acetone saturated with hydrogen chloride until the pH was reduced to about 3. The precipitated hydrochloride salt was then recrystallized from acetone. References Merck Index 304 Kleeman and Engel p. 31 OCDS Vol. 1 p. 177 (1977) DOT 9 (6) 245 (1973) I.N. p. 60 Brandstrom, A.E., Corrodi, H.R. and Alblad, H.R.G.; US Patent 3,466,376; September 9, 1969; Assigned to Aktiebolaget Hassie
ALPROSTADIL Therapeutic Function: Vasodilator, Abortifacient, Antihypertensive, Bronchodilator Chemical Name: Prost-13-en-1-oic acid, 11,15-dihydroxy-9-oxo-, (11α,13E,15S)Common Name: Alprostadil; Prostaglandin E1
194
Alprostadil
Structural Formula:
Chemical Abstracts Registry No.: 745-65-3 Trade Name Alprostadil Alprostapint Alprostan Alpostin Alprox-TD Befar Bondil Caverject Muse Prostin VR Topiglan Vazaprostan
Manufacturer Schwarz Pharmacia BAG Leciva Samarth Pharma Pvt. Ltd. NexMed, Inc. Nexmed Pharmaceutical Meda Pharmacia and Upjohn Meda Pharmacia India (P) Ltd. MacroChem Copr. Schwarz Pharma
Country Germany Czech Republic India
Year Introduced -
USA Belgium UK India Germany
-
Raw Materials 3α,6,7,7α-Tetrahydro-4-methyl-2-oxo-1β-indaheptanoic acid methyl ester 4-Toluenesulfonic acid monohydrate Ethylene glycol Sodium hydride Sodium periodate Trifluoroperacetic acid Etheral diazomethane Sodium methoxide Osmium tetroxide Potassium t-butoxide Manufacturing Process Manufacturing process for prostaglandin E1 includes 15 steps. 1. A mixture of 11.8 g of (+/-)-3α,6,7,7α-tetrahydro-4-methyl-2-oxo-1βindaheptanoic acid methyl ester, 27 ml of ethylene glycol and 300 mg of ptoluene sulfonic acid mono-hydrate in 600 ml of benzene was refluxed with stirring for 18 hours using a Dean-Stark trap to separate the water formed in the reaction. The reaction mixture was cooled and added to 300 ml of cold 5% potassium bicarbonate. The aqueous layer extracted twice with 2:1 benzene-hexene. The combined organic fractions were washed 3 times with saturated aqueous NaCl, dried over sodium sulfate and evaporated to dryness
Alprostadil
195
affording 12.6 g of (+/-)-3α,6,7,7α-tetrahydro-4-methyl-2-oxo-1βindaheptanoic acid methyl ester, 2-cyclic ethylene acetal. 2. To 5.69 g of this acetal in 410 ml of t-butanol and 11 ml of water was added a mixture of 5.80 g of potassium carbonate, 22,8 g of sodium periodate, and 270 mg of potassium permanganate in 1230 ml of water. The reaction mixture was stirred at 20-25°C for 20 hours and concentrated in vacuo to remove t-butanol. Ethylene glycole (0.5 ml) was added and reaction mixture extracted with 1:1 ether-benzene to remove neutral material. The aqueous layer acidified with solid sodium dihydrogen phosphate and extracted 4 times with 1:1 ethyl acetate-benzene. The organic layer was dried over sodium sulfate and evaporated to dryness in vacuo affording (+/-)-3-acetyl2α-(2-carboxyethyl)-5-oxo-1β-cyclopentaneheptanoic acid methyl ester, 5cyclic ethylene acetal as a mixture of the 3α and 3β isomers. 3. (+/-)-3β-Acetyl-2α-(2-methoxycarbonylethyl)-5-oxo-1βcyclopentaneheptanoic acid methyl ester, 5-cyclic ethylene acetal, NMR (CDCl3) δ 2.13 [3H - CH3CO], was prepared from above (+/-)-3-acetyl-2α-(2carboxyethyl)-5oxo-1β-cyclopentaneheptanoic acid methyl ester, 5-cyclic ethylene acetal with etheral diazomethane and subsequent stirring with sodium methoxide in methanol for 18 hours at room temperature. 4. (+/-)-3β-Acetoxy-2α-(2-methoxycarbonylethyl)-5-oxo-1βcyclopentaneheptanoic acid methyl ester, 5-cyclic ethylene acetal was produced by stirring the solution of 4.5 g of (+/-)-3β-acetyl-2α-(2methoxycarbonylethyl)-5-oxo-1β-cyclopentaneheptanoic acid methyl ester, 5cyclic ethylene acetal in 25 ml methylene chloride, containing 60 g of solid disodium monohydrogen phosphate, with 85 ml freshly prepared 0.3 M trifluoroperacetic acid in methylene chloride for 42 hours at room temperature. The reaction mixture was filtered, the precipitate washed with methylene chloride and the organic extract was washed with cold aqueous potassium iodide and cold thiosulfate. Organic layer was washed with potassium bicarbonate, dried over sodium sulfate and evaporated in vacuo. 5. The reaction 4.25 g of (+/-)-3β-acetoxy-2α-(2-methoxycarbonylethyl)-5oxo-1β-cyclopentaneheptanoic acid methyl ester, 5-cyclic ethylene acetal in 25 ml of methanol with 6 ml of 1.00 N sodium methoxide under nitrogen at room temperature for 2 hours produced pure (+/-)-2α-(2-methoxycarbonylethyl)3β-hydroxy-5-oxo-1β-cyclopentaneheptanoic acid methyl ester, 5-cyclic ethylene acetal after chromatographical purification with silica gel (eluent 25% acetone in chloroform). 6. (+/-)-2α-(2-Carboxyethyl)-3β-hydroxy-5-oxo-1β-cyclopentaneheptanoic acid methyl ester δ-lactone, 5-cyclic ethylene acetal was prepared as follows: 1.66 g of (+/-)-2α-(2-methoxycarbonylethyl)-3β-hydroxy-5-oxo-1βcyclopentaneheptanoic acid methyl ester, 5-cyclic ethylene acetal in 350 ml of benzene was refluxed with 0.25 ml of 0.66 M potassium t-butoxide in butanol and 140 ml of benzene in a nitrogen atmosphere for 4 hours. Above lacton was produced after washing of organic fraction with of saturated aqueous solutions of sodium dihydrogen phosphate and NaCl and evaporating in vacuo to dryness. 7. 210 mg of 50% sodium hydride was added to a stirred solution above δlactone under nitrogen at 0°C. The mixture was stirred for 1 hour at 0°C and
196
Alprostadil
4 hours at 20°C. The solvent was removed in vacuo and residue washed with ether and filtered. The residue was recrystallized from ether-hexane affording (+/-)-2α-(2-carboxy-2-formylethyl)-3β-hydroxy-5-oxo-1βcyclopentaneheptanoic acid methyl ester δ-lactone, 5-cyclic ethylene acetal, m.p. 88-90°C. 8. A solution of 460 mg of (+/-)-2α-(2-carboxy-2-formylethyl)-3β-hydroxy-5oxo-1β-cyclopentaneheptanoic acid methyl ester δ-lactone, 5-cyclic ethylene acetal in 6 ml of methylene chloride and 4.4 ml of pyridine was treated with a 5% ozone-oxygen mixture at - 70°C until the mixture had persistent pale blue color. The excess of ozone was evaporated by bubbling nitrogen into reaction and the solvents were removed in vacuo. The residue was tirturaed with ether affording crystalline (+/-)-2α-(2-carboxy-2-oxoethyl)-3β-hydroxy-5-oxo-1βcyclopentaneheptanoic acid methyl ester δ-lactone, 5-cyclic ethylene acetal, m.p. 114-116°C. 9. The product of ozonolysis was acetylated in 6 ml of pyridine and 3 ml acetic anhydride at room temperature for 17 hours, 6 ml xylene was added and the reaction mixture evaporated in vacuo. The residue was triturated with etherhexane affording crystalline (+/-)-2α-(2-acetoxy-2-carboxyvinyl)-3β-hydroxy5-oxo-1β-cyclopentaneheptanoic acid methyl ester δ-lactone, 5-cyclic ethylene acetal, m.p. 82-84°C. 10. 14 mg of osmium tetroxide in 1.4 ml methanol was added to a stirred solution of δ-lactone (step 9) in 16 ml of methanol. The reaction mixture darkened in 10-15 minutes and 440 mg of sodium periodate was added portionwise over 3 hours. The mixture was stirred 1 additional hours and filtered, filtrate evaporated to dryness in vacuo. The residue was dissolved in 2.5 ml of 1:1 ethyl acetate - benzene and the solution washed in usual way, dried over sodium sulfate and evaporated according (+/-)-2α-formyl-3β[(methoxyalyl)oxy]-5-oxo-1β-cyclopentaneheptanoic acid methyl ester δlactone, 5-cyclic ethylene acetal as an oil. 11. 230 mg of dimethyl-2-oxoheptyl phosphonate in 4 ml of tetrahydofuran was stirred with 50 mg of 50% sodium hydride in 10 ml tetrahydrofuran under a nitrogen at 0°C for 30 minutes. A solution of 420 mg of (+/-)-2α-formyl-3β[(methoxyalyl)oxy]-5-oxo-1β-cyclopentaneheptanoic acid methyl ester δlactone, 5-cyclic ethylene acetal in 4 ml of tetrahydrofuran was added dropwise over 5 min. After 10 min the mixture was allowed to warm to room temperature and stirred 2 hours. The reaction mixture was added to saturated aqueous dihydrogen phosphate at 10°C and extracted with ethyl acetate. After usual washing and drying procedure, extract was evaporated to dryness affording (+/-)-3β-[(methoxyalyl)oxy]-2α-(3-oxo-1-octenyl)-5-oxo-1βcyclopentaneheptanoic acid methyl ester, 5-cyclic ethylene acetal. 12. The above product was dissolved in 7.5 ml of methanol and 60 mg of ethylenediamine in 5 ml of methanol was added dropwise at 0°C and the mixture stirred for 45 min at 20°C. And the solvent evaporated in vacuo. The residue was chromatographed on 35 g silica gel eluting with 30% acetone and chloroform taking 40 fractions of 4 ml each. Fraction 5-14 was evaporated to dryness in vacuo affording 250 mg (+/-)-3β-hydroxy-2α-(3-oxo-1-octenyl)-5oxo-1β-cyclopentaneheptanoic acid methyl ester, 5-cyclic ethylene acetal, λmax (methanol, 232 nm, E 12500).
Alrestatin sodium
197
13. Prostaglandin E1, methyl ester, cyclic ethylene acetal was prepared from 245 mg of (+/-)-3β-hydroxy-2α-(3-oxo-1-octenyl)-5-oxo-1βcyclopentaneheptanoic acid methyl ester, 5-cyclic ethylene acetal, in 6 ml of methanol by stirring with 23 mg of sodium borohydride in 2 ml of methanol at -10°C for 40 min. After usual washing and evaporating to dryness the residue was chromatographed on 20 g of silica gel eluting with 50% acetonechloroform. (+/-)-3β-hydroxy-2α-(3β[R]-hydroxy-1-octenyl)-5-oxo-1βcyclopentaneheptanoic acid methyl ester, 5-cyclic ethylene acetal and (+/-)3β-hydroxy-2α-(3β[S]-hydroxy-1-octenyl)-5-oxo-1β-cyclopentaneheptanoic acid methyl ester, 5-cyclic ethylene acetal, m.p. 54-56°C were afforded. 14. 40 mg of (+/-)-3β-hydroxy-2α-(3β[S]-hydroxy-1-octenyl)-5-oxo-1βcyclopentaneheptanoic acid methyl ester, 5-cyclic ethylene acetal in 1 ml was saponificated with a solution of 45 mg of KOH in 2.5 ml of water at 0°C in nitrogen atmosphere. The mixture was allowed to warm to room temperature and stirred for 3 hours. After usual procedures of evaporating, extracting, washing, drying and evaporating, (+/-)-prostaglandin E1, (+/-)-3β-hydroxy2α-(3β[S]-hydroxy-1-octenyl)-5-oxo-1β-oxocyclopentaneheptanoic acid, 5cyclic ethylene acetal, m.p. 82-84°C, was afforded. 15. A mixture of 37 mg of (+/-)-prostaglandin E1 and 3 ml 1:1 acetic acidwater was stirred at 25°C for 3 hours. Saturated aqueous Na2HPO4 solution was added and the mixture extracted with 1:1 ethyl acetate-benzene. The organic layer was washed, evaporated to dryness affording the crystalline residue (+/-)-prostaglandin E1, m.p. 111-113°C (recrystallized from ethyl acetate-benzene). References Wendler N.L. et al.; US Patent No. 3,870,747; Mar. 11, 1975; Assigned: Merck and Co., Inc., Rahway, N.J. Nelson N.A.; US Patent No. 3,933,897; Jan. 20, 1976; Assigned: The Upjohn Company (Kalamazoo, MI)
ALRESTATIN SODIUM Therapeutic Function: Aldose reductase inhibitor Chemical Name: 1H-Benz[de]isoquinoline-2(3H)-acetic acid, 1,3-dioxo-, sodium salt Common Name: Alrestatin sodium Structural Formula:
198
Alsactide
Chemical Abstracts Registry No.: 51876-97-2; 51411-04-2 (Base) Trade Name
Manufacturer
Country
Year Introduced
Alrestatin
BIOMOL
-
-
Raw Materials 1,8-Naphthalic acid anhydride Glycine Manufacturing Process 1,3-Dioxo-1H-benz[de]isoquinoline-2(3H)-acetic acid: 1,8-Naphthalic acid anhydride (110 g, 0.556 mole), glycine (48 g, 0.64 mole) and dimethylformamide (750 ml) are heated and stirred at reflux for 2 hr. The homogeneous dark solution is cooled to about 100°C and 750 ml of hot water is added slowly to the stirred solution. The reaction mixture is cooled and allowed to stand in a refrigerator for 16 hr. The precipitate is collected and recrystallized from ethanol, using decolorizing charcoal, to give the title compound, MP: 271°-272°C. In practice it is usually used as sodium salt. References Sestanj K. et al.; US Patent No. 3,821,383; June 28, 1974; Assigned to A. Mc and Harrison Limited, Larent, Quebec, Canada
ALSACTIDE Therapeutic Function: Adrenocorticotropin Chemical Name: α1-17-Corticotropin, 1-β-alanine-17-(N-(4-aminobutyl)-Llysinamide)Common Name: Alisactide ;Alsactide Chemical Abstracts Registry No.: 34765-96-3 Trade Name
Manufacturer
Country
Year Introduced
Alsactide
ZYF Pharm Chemical
-
-
Raw Materials Z-Lys(Boc) OTCP Triethylamine Palladium N-Ethylmorpholine
Z-Lys(Boc)-NH-(CH2)4-NH-Boc 4-Toluenesulfonic acid Z-Lys(Boc)-Pro-Val-Gly-Lys(Boc)-OH 1-Hydroxybenzotriazole
Alsactide
199
Trifluoroacetic acid Dicyclohexylcarbodiimide Thioglycolic acid Boc-β-Ala-Tyr-Ser-Met-Glu-(OBut)-His-Phe-Arg-Trp-Gly-OH·4H2O Structural Formula:
Manufacturing Process Abbreviations: Boc - tert-butoxycarbonyl; TCP - 2,4,5-trichlorophenyl; Z - carbobenzyloxy. (a) β-Ala-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-Gly-Lys-Lys-LysNH-(CH2)4-NH2-acetate, aq. Z-Lys(Boc)-NH-(CH2)4-NH-Boc: 7.0 g (31 mmols) of Boc-NH-(CH2)4-NH2-HCl and 4.2 ml (30 mmols) of triethylamine in 100 ml of dimethylformamide are stirred for 20 hours together with 16.8 g (30 mmols) of Z-Lys(Boc) OTCP. The product is filtered off the triethylammonium chloride and the filtrate is evaporated to dryness in vacuo. The residue is dissolved in ethyl acetate, thoroughly shaken at 0°C with 2 N citric acid, 1 N bicarbonate and H2O and dried over sodium sulfate. After distilling off the solvents, the residue is recrystallized two times from isopropanol/ether. Yield: 14.1 g (83%), M.P. 83°-85°C. (b) H-Lys(Boc)-NH-(CH2)4-NH-Boc-tosylate: 11.4 g of the Z-compound prepared according to (a) are hydrogenated in the presence of Pd in 80 ml of methanol with, while adding methanolic toluene-sulfonic acid at pH 5. After the reaction is complete, the product is filtered to remove the catalyst, the methanol is distilled off in vacuo and the residue is triturated with ether. For purification purposes it is dissolved in warm isopropanol and precipitated with ether. Yield: 10.3 g (88%).
200
Alteconazole
(c) Z-Lys(Boc)-Pro-Val-Gly-Lys(Boc)-Lys(Boc)-Lys(Boc)-NH-(CH2)4-NH-Boc: 10.9 g (10 mmols) of Z-Lys(Boc)-Pro-Val-Gly-Lys(Boc)-OH and 5.89 g (10 mmols) of Boc-NH-(CH2)4-NH2-tosylate in 100 ml of dimethylformamide are combined with 12.8 ml (10 mmols) of N-ethylmorpholine and 2.7 g (20 mmols) of 1-hydroxybenzotriazole. 2.2 g of dicyclohexylcarbodiimide (11 mmols) are added at -10°C. The whole is then allowed to come to room temperature. The stirring is continued for 3 hours, the solvent is distilled off in vacuo. The residue is digested with 1 N bicarbonate and water and, after drying, recrystallized from acetonitrile. Yield: 10.6 g (74.2%). M.P. 150°155°C (while foaming). [α]D20: -24.0° (c=1 in dimethylformamide). (d) H-Lys(Boc)-Pro-Val-Gly-Lys(Boc)-Lys(Boc)-Lys(Boc)-NH-(CH2)4-NH-Boctosylate-dihydrate: 15.1 g (10 mmols) of the Z-compound prepared according to (c) are catalytically hydrogenated in the presence of Pd in 300 ml of methanol, a pH of 5 being maintained by simultaneously adding methanolic toluene-sulfonic acid. After complete reaction, the methanol is distilled off and the residue is reprecipitated from pyridine/ ether and methanol/water. The oil, which first precipitates becomes solid after a short time. Yield: 12.1 g (77.5%). (e) 1.65 g (1.1 mmols) of Boc-β-Ala-Tyr-Ser-Met-Glu-(OBut)-His-Phe-Arg-TrpGly-OH·4H2O and 1.56 g (1 mmol) of H-Lys(Boc)-Pro-Val-Gly-Lys(Boc)-Lys(Boc)-Lys(Boc)-NH-(CH2)4-NH-Boc-tosylate-dihydrate are dissolved together with 540 mg (4 mmols) of 1-hydroxybenzotriazole in 30 ml of dimethylformamide. A solution of 1.25 g (6 mmols) of dicyclohexylcarbodiimide in 4 ml of dimethylformamide is prepared and 1/3 of this solution is added to the above solution. The whole is stirred for 1 hour, then another third is added and, after a further hour, the last third is fed in. After a further 2 to 3 hours of stirring, the reaction product is precipitated with ether. Yield: 3.1 g. Without further purification, the compound is freed from the protective groups by standing for 1 hour in 80-90% trifluoroacetic acid containing some thioglycolic acid, and is subsequently precipitated by adding 150 ml of ether. Yield: 3.06 g of crude peptide-trifluoroacetate. After purification on carboxymethyl cellulose, 1.45 g of the chromatographically pure peptide are obtained in the form of acetate. [α]D20:-68.6°-2° (c=0.5 in 1% acetic acid). Amino acid analysis: Ser0.86Glu0.99Pro0.97Gly2.00Val1.03Met0.98Tyr0.02Phe1.00βAla1.01Lys4.00His1.02Arg0.94. References Geiger R. et al.; US Patent No. 3,749,709; July 31, 1973; Assigned to Farbwerke Hoechst Aktiengesellschaft vormals Meister Lucius and Bruning, Frankfurt am, Main, Germany
ALTECONAZOLE Therapeutic Function: Antifungal
Alteconazole
201
Chemical Name: (cis)-1-[[2-(4-Chlorophenyl)-3-(2,4-dichlorophenyl)oxiranyl] methyl]-1H-1,2,4-triazole Common Name: Alteconazole Structural Formula:
Chemical Abstracts Registry No.: 93479-96-0 Trade Name
Manufacturer
Country
Year Introduced
Alteconazole
Onbio Inc.
-
-
Raw Materials Potassium t-butylate 4-Chloroacetophenone 2,2'-Azoisobutyrodinitrile 1,2,4-Triazole
2,4-Dichlorobenzyltriphenylphosphonium chloride N-Bromosuccinimide 3-Choroperoxybenzoic acid Sodium hydride
Manufacturing Process 63.6 g of potassium t-butylate in 300 ml of dry methanol were introduced into a solution of 229 g of 2,4-dichlorobenzyltriphenylphosphonium chloride in 800 ml of dry methanol at 10°C, and 77.2 g of 4-chloroacetophenone were added after half an hour. The reaction solution was refluxed for 3 hours, the precipitated salt was filtered off at room temperature, the filtrate was evaporated down under reduced pressure, the residue was digested with petroleum ether at from 50°C to 70°C to free it from triphenylphosphine oxide, and the solution was evaporated down under reduced pressure. The residue was taken up in 1 liter of carbon tetrachloride, and the solution was refluxed with 81.7 g of N-bromosuccinimide and 4 g of 2,2'azoisobutyrodinitrile. After the reaction was complete, the succinimide was filtered off, the filtrate was evaporated down under reduced pressure and the residue was recrystallized from methanol. 73.4 g (38.8%) of Z-1-(2,4dichlorophenyl)-2-(4-chlorophenyl)-3-bromoprop-1-ene of melting point 128°C was obtained. 58.9 g of Z-1-(2,4-dichlorophenyl)-2-(4-chlorophenyl)-3-bromoprop-1-ene were refluxed with 52.3 g of 3-choroperoxybenzoic acid in 590 ml of chloroform. After the reaction was complete, the chloroform phase was
202
Althiazide
washed acid-free with aqueous sodium bicarbonate solution and water, dried over sodium sulfate and evaporated down under reduced pressure, and the residue was recrystallized from methanol to give two crystalline fractions: 41.3 g (70.2%) of 2-bromomethyl-2-(4-chlorophenyl)-3-(2,4-dichlorophenyl) oxirane (isomer A) of melting point 98-99°C, and, 12 g (20.4%) of 2bromomethyl-2-(4-chlorophenyl)-3-(2,4-dichlorophenyl)oxirane (isomer B) of melting point 93-95°C. 20.9 g of 1,2,4-triazole and 4.4 g of sodium hydride (50% strength dispersion in mineral oil) were dispersed in 150 mL of N,N-dimethylformamide, and a solution of 39.2 g of 2-bromomethyl-2-(4-chlorophenyl)-3-(2,4dichlorophenyl)oxirane (isomer A) and 16.6 g of potassium iodide in 150 ml of N,N-dimethylformamide was added at room temperature. After 8 hours, the reaction solution was worked up, and the product was recrystallized from diisopropyl ether. 31 g (81.9%) of 2-(1,2,4-triazol-1-ylmethyl)-2-(4chlorophenyl)-3-(2,4-dichlorophenyl)oxirane (isomer A) - alteconazole was obtained. MP: 119°C. References Janssenet B. al.; US Patent No. 4,464,381; August 7, 1984; Assigned to BASF Aktiengesellschaft, Fed. Rep. of Germany
ALTHIAZIDE Therapeutic Function: Diuretic, Antihypertensive Chemical Name: 2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4dihydro-3-((2-propenylthio)methyl)-, 1,1-dioxide Common Name: Althiazide; Altizide Structural Formula:
Chemical Abstracts Registry No.: 5588-16-9 Trade Name
Manufacturer
Country
Year Introduced
Althiazide
Solchem
-
-
Altizide
Bayer
-
-
Altretamine
203
Raw Materials 4-Amino-2-chloro-5-(methylsulfamyl)benzenesulfonamide Dimethyl allylmercaptoacetal Manufacturing Process To 6.75 g (0.0225 mole) of 4-amino-2-chloro-5-(methylsulfamyl) benzenesulfonamide in 45 ml of dimethylformamide is added 4.86 g (0.03 mole) of dimethyl allylmercaptoacetal followed by 1.5 ml ethyl acetate saturated with hydrogen chloride gas. The solution is refluxed for 1.5 hours, cooled and added dropwise with stirring to ice/water. The resulting precipitate is filtered, dried and recrystallized from isopropanol. The recrystallization gave 4.0 g of 2-methyl-3-allylthiomethyl-6-chloro-7-sulfamyl-3,4-dihydro-1,2,4benzothiadiazine-1,1-dioxide; M.P. 168.5-170°C. References Merck Index, Monograph number: 326, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. GB Patent No. 902,658; Aug. 9, 1962 McManus J.M. et al.; US Patent No. 3,102,882; Sept. 3, 1963; Assigned to Chas. Pfizer and Co., Inc., New York
ALTRETAMINE Therapeutic Function: Antitumor Chemical Name: 2,4,6-Tris(dimethylamino)-1,3,5-triazine Common Name: Hexamethylmelamine Structural Formula:
Chemical Abstracts Registry No.: 645-05-6 Trade Name
Manufacturer
Country
Year Introduced
Hexastat
Roger Bellon
France
1979
Hexastat
Rhone Poulenc
Switz.
1981
Altretamine
Rhone Poulenc
W. Germany
1982
204
Aluminum nicotinate
Raw Materials Hexamethylolmelamine-Hexamethyl Ether Hydrogen Manufacturing Process 50 g of hexamethylolmelamine-hexamethyl ether in 950 cc methanol are hydrogenated, at 90°C to 100°C, in the presence of 2 g Raney nickel with 100 atmospheres excess pressure of hydrogen in a steel autoclave holding 2 L until the absorption of hydrogen is terminated. After the catalyst has been filtered off with suction, the methanol is distilled off. As a result, 23.1 g (86% of the theoretical) of crude hexamethylmelamine are formed having a melting point of 158°C to 162°C. After recrystallization from methanol, the pure product is obtained having a melting point of 168°C. References Merck Index 310 DFU 5 (10) 492, 635 (1980) DOT 18 (4) 165 (1982) I.N. p. 61 von Brachel, H. and Kindler, H.; US Patent 3,424,752; January 28, 1969; Assigned to Casella Farbwerke Mainkur AG
ALUMINUM NICOTINATE Therapeutic Function: Vasodilator Chemical Name: 3-Pyridinecarboxylic acid aluminum salt Common Name: Tris(nicotinato)aluminum Structural Formula:
Chemical Abstracts Registry No.: 1976-28-9 Trade Name Nicalex Alunitine
Manufacturer Merrell Dow Continental Pharma
Country Belgium US
Year Introduced 1960 -
Alverine citrate
205
Raw Materials Nicotinic acid Aluminum hydroxide Manufacturing Process Aluminum nicotinate is prepared by dissolving nicotinic acid in hot water and adding a slurry of aluminum hydroxide to it. A slight excess of aluminum hydroxide is used in order that the final product would be free of nicotinic acid. The precipitate is collected on a filter and dried. The final product contains a mixture of aluminum nicotinate and a small but acceptable amount of aluminum hydroxide. References Merck index 346 Kleeman and Engel p. 33 I.N.p.62 Miale, J.P.; US Patent 2,970,082; January 31, 196l; Assigned to Walker Laboratories, Inc.
ALVERINE CITRATE Therapeutic Function: Anticholinergic, Spasmolytic Chemical Name: Benzenepropanamine, N-ethyl-N-(3-phenylpropyl)-, citrate Common Name: Alverine citrate Structural Formula:
Chemical Abstracts Registry No.: 5560-59-8; 150-59-4 (Base) Trade Name
Manufacturer
Country
Year Introduced
Alverine citrate
Kemikos
-
-
Alverine citrate
Norgine
-
-
Alverine citrate
Bristhar Laboratorios -
-
Alvercol
Norgine
-
-
206
Amadinone
Trade Name
Manufacturer
Country
Year Introduced
Antispasmin
Balkanpharma Dupnitza Co.
-
-
Spasmaverine
Bellon
-
-
Spasmonal
Norgine
-
-
Spasmonal
Ying-Yuan Chemical Pharmaceutical Co., Ltd.
-
Raw Materials Ethylamine Hydrogen Platinum
3-Phenylpropylchloride Potassium hydroxide Barium sulfate
Manufacturing Process 2 Methods of producing of alverine: 1. 3-Phenylpropylchloride reacted with ethylamine in the presence potassium hydroxide and N-ethyl-3,3'-diphenyldipropylamine (alverine) was obtained. 2. 3-Phenylpropenal reacted with ethylamine in the presence hydrogen and Pt as catalyst and BaSO4 and N-ethyl-3,3'-diphenyldipropylamine (alverine) was obtained. In practice it is usually used as citrate. References Kleemann A., Engel J.; Pharmazeutische Wirkstoffe, GeorgThieme Verlag Stuttgart. New York, 1982
AMADINONE Therapeutic Function: Progestin Chemical Name: 19-Norpregna-4,6-diene-3,20-dione, 6-chloro-17-hydroxyCommon Name: Amadinone, 19-Norchlormadinone Chemical Abstracts Registry No.: 30781-27-2 Trade Name
Manufacturer
Country
Year Introduced
Amadinone
ZYF Pharm Chemical
-
-
Amadinone
207
Structural Formula:
Raw Materials δ(4)-3,20-Dioxo-6α,7α-oxido-17α-acetoxy-19-norpregnene Hydrochloric acid Methanesulfonyl chloride Sodium acetate Manufacturing Process A solution of 250.0 mg of δ4-3,20-dioxo-6α,7α-oxido-17α-acetoxy-19norpregnene in 15 ml of 1 N hydrochloric acid in dioxan is kept for 1 h at 25°C, then poured into water and neutralized with sodium bicarbonate solution. The precipitated crude product is dissolved in a 5:1 mixture of ether and methylene chloride, washed with water until the washings run neutral, and the solution is dried and evaporated under vacuum to give the δ4-3,20dioxo-6-chloro-7α-hydroxy-17α-acetoxy-19-nor-pregnene. The crude δ4-3,20-dioxo-6-chloro-7α-hydroxy-17α-acetoxy-19-nor-pregnene is dissolved in 3 ml of pyridine, mixed at 5°-0°C with 0.3 ml of methanesulphonyl chloride while being stirred, and the mixture is kept for 2 days at 10°C. The reaction product is then poured into dilute sodium bicarbonate solution, dissolved in ether, and the ethereal solution is washed until the washings run neutral, dried and evaporated under vacuum and the δ4-3,20-dioxo-6-chloro-7α-mesyloxy-17α-acetoxy-19-norpregnene is obtained. The δ4-3,20-dioxo-6-chloro-7α-mesyloxy-17α-acetoxy-19-norpregnene is dissolved in 25 ml of dimethyl formamide, mixed with 4.5 g of anhydrous sodium acetate, and the whole is heated for 75 min at 85°C under nitrogen while being stirred. The cooled reaction mixture is diluted with water, extracted with a 5:1-mixture of ether and methylene chloride, and the organic layer is washed with 100 ml of water, dried and evaporated. The resulting crude product is dissolved in benzene and chromatographed on 15 times its own weight of alumina (activity II). The afore-mentioned solvent elates 105.0 mg of pure δ4,6-3,20-dioxo-6-chloro-17α-acetoxy-19-norpregnadiene, melting point 159°-161°C (recrystallized from methylene chloride:hexane). The δ4,6-3,20-dioxo-6-chloro-17-hydroxy-19-norpregnadien, melting point 159°-161°C, may be produced by hydrolysis of δ4,6-3,20-dioxo-6-chloro-17αacetoxy-19-norpregnadiene.
208
Amafolone hydrochloride
References GB Patent No. 1,007,758; Dec. 29, 1961; Assigned: Ciba Limited, a body corporate organized according to the laws of Switzerland, of Basle, Switzerland
AMAFOLONE HYDROCHLORIDE Therapeutic Function: Antiarrhythmic Chemical Name: (2β,3α,5α)-3-Amino-2-hydroxyandrostan-17-one hydrochloride Common Name: Amafolone hydrochloride Structural Formula:
Chemical Abstracts Registry No.: 51740-76-2; 50588-47-1 (Base) Trade Name
Manufacturer
Country
Year Introduced
Amafolone hydrochloride
ZYF Pharm Chemical
-
-
Raw Materials Perchloric acid Acetic acid Ammonia
N-Bromoacetamide 5α-Androst-2-en-17-one Potassium hydroxide
Manufacturing Process A solution of 70% perchloric acid (60 ml) in water (280 ml) was added to a stirred solution of 5α-androst-2-en-17-one (200.0 g) in ether (1.15 l) at 15°C followed by portionwise addition of N-bromacetamide (112.0 g) over 10 min. After stirring for 1 h the precipitated white crystalline solid was filtered off, washed neutral with ether and water and crystallised to give 2β-hydroxy-3αbromo-5α-androstan-17-one (172.0 g). The ether layer of the filtrate was washed neutral, dried (Na2SO4) and concentrated to give a second crop (28.0 g). The two crops (200.0 g) were suspended in methanol (1 L), 10 N aqueous potassium hydroxide solution (100 ml) added and the mixture slowly distilled over 45 min. Addition of water precipitated the product as a white solid which
Amanozine hydrochloride
209
was filtered off, washed with water, dried and 88.0 g of 2β,3β-epoxy-5αandrostan-17-one were obtained (crystallisation from ether:light petrol). A solution of the 2β,3β-epoxy-5α-androstan-17-one (30.0 g) in ethanol (130 ml), water (15 ml) and liquid ammonia was heated in an autoclave at 150°C for 6 h and the resultant crystalline suspension evaporated to dryness. Water (35 ml) and acetic acid (36 ml) were added and the solution kept at 90°C for 1 h, cooled and excess water added. The precipitated material was filtered off and the filtrate made alkaline with aqueous 10 N potassium hydroxide solution to precipitate a white solid which was filtered off, washed neutral with water, dissolved in methylene chloride, the solution dried (Na2SO4) concentrated and ether added to give 2β-hydroxy-3α-amino-5α-androstan-17-one (14.3 g), melting point l92°-195°C. In practice it is usually used as hydrochloride. References Hewett C.L., Savage D.S.; US Patent No. 3,862,196; Jan. 21, 1975; Assigned: Akzona Incorporated, Asheville, N.C.
AMANOZINE HYDROCHLORIDE Therapeutic Function: Diuretic Chemical Name: N-Phenyl-1,3,5-triazine-2,4-diamine monohydrochloride Common Name: Amanozine, Amenozine Structural Formula:
Chemical Abstracts Registry No.: 6011-10-5; 537-17-7 (Base) Trade Name
Manufacturer
Country
Year Introduced
Amanozine
Onbio Inc.
-
-
Raw Materials 1-Phenylbiguanide hydrochloride Sodium carbonate
210
Amantanium bromide
Manufacturing Process 21.3 g (0.1 mole) of 1-phenylbiguanide hydrochloride were dissolved in hot water and the solution was added to 5.3 g (0.05 mole) sodium carbonate by stirring. On cooling 15 g of the needle crystals have fallen. They were heated to reflux with 80 ml of dry formic acid. Then 40-50 ml formic acid was distilled off. The residue was with water diluted, cooled with ice and the conc. alkali was added. The precipitate fallen. It was filtered off and recrystallized from 40-50% ethanol. The pure product 4-amino-2-anilino-1,3,5-triazine had MP: 232°-233°C. Monochlorohydrate of it crystallized as long colorless needles melted at 258°260°C. References Clauder O. et al.; Austrian Patent No. 168,063; April 10, 1959; Richter Gedeon Vegyeszeti R.T. in Budapest Kleemann A., Engel J.; Pharmazeutische Wirkstoffe, GeorgThieme Verlag Stuttgart. New York, 1982
AMANTANIUM BROMIDE Therapeutic Function: Antiseptic Chemical Name: (2-(1-Tricyclo[3.3.1.13,7]decylcarbonyloxy)ethyl) decyldimethyl-ammonium bromide Common Name: Amantanium bromide Structural Formula:
Chemical Abstracts Registry No.: 58158-77-3 Trade Name
Manufacturer
Country
Year Introduced
Amantanium bromide
Onbio Inc.
-
-
Amantidine hydrochloride
211
Raw Materials 2-Dimethylaminoethanol 1-Bromodecan
1-Adamantanecarboxylic acid chloride Sodium hydroxide
Manufacturing Process A solution of 21.7 g (0.11 mole) 1-adamantanecarboxylic acid chloride in 100 ml ether was added to a solution of 19.4 g (0.22 mole) 2dimethylaminoethanol in 200 ml ether. The reaction mixture was stirred overnight at room temperature. Then additional 15.0 g (0.17 mole) 2dimethylaminoethanol was added and the reaction mixture again stirred overnight. The reaction mixture was poured into 300 ml water and treated with 20 ml of 10% NaOH solution. From the ether layer was recovered 23.0 g of 2-dimethylaminoethyl 1-adamantanecarboxylate as oil. The 2-dimethylaminoethyl 1-adamantanecarboxylate was mixed with 1bromodecan and allowed to stand for about 6 weeks. The resultant crystalline mass was washed with ether and dried to gave 2-(1’adamantanecarbonyloxy)ethyldimethyldecylammonium bromide as white crystals, melting point 183°-184.5°C (two recrystallizations from ethyl acetate). References Bauman R.A.; US Patent No. 3,928,411; Dec. 23, 1975; Assigned: ColgatePalmoliv Company, New York, N.Y.
AMANTIDINE HYDROCHLORIDE Therapeutic Function: Antiviral, Antiparkinsonian Chemical Name: 1-Adamantanamine hydrochloride Common Name: 1-Aminoadamantane hydrochloride Structural Formula:
Chemical Abstracts Registry No.: 665-66-7 Raw Materials Adamantane Sodium hydroxide
Hydrocyanic acid Hydrogen chloride
212
Amantidine hydrochloride
Trade Name Symmetrel Symmetrel Symmetrel Mantadan Mantadix Symmetrel Amantadin Amantan Amazolon Antadine Atarin Contenton Influenol Paramantin Paritrel PK-Mertz Protexin Solu-Contenton Trivaline Viregyt Virofral Virofral Virosol
Manufacturer DuPont (Endo) Geigy Geigy De Angeli Theraplix Fujisawa Ratiopharm Byk Gulden Sawai DuPont Medica SK Dauelsberg Santos Orion Trima Mertz Landerlan SK and F Farmex EGYT Duphar Ferrosan Phoenix
Country US W. Germany UK Italy France Japan W. Germany Japan Australia Finland W. Germany Spain Finland Israel W. Germany Spain W. Germany France Hungary Belgium Denmark Argentina
Year Introduced 1966 1966 1971 1971 1973 1975 -
Manufacturing Process 360 ml of 96% sulfuric acid and a solution of 13.6 grams (0.1 mol) of adamantane in 100 ml of n-hexane were emulsified in the apparatus described and provided with an inclined centrifugal stirrer. Then a mixture of 46 grams (1.7 mols) of liquid hydrocyanic acid and 29.6 grams (0.4 mol) of tertiary butanol was added dropwise within 1.5 hours at about 25°C. After 30 minutes of postreaction, the product was poured on ice. The granular mass which precipitated [N-(adamantyl-1)formamide] was sucked off and washed with water. The raw product (37 grams) was then refluxed for 10 hours with a solution of 60 grams of NaOH in 600 ml of diethylene glycol. After cooling, the solution was diluted with 1.5 liters of water and subjected to three extractions with ether. The amine was extracted from the ethereal solution with 2 N HCl and liberated therefrom by the addition of solid NaOH (while cooling). The alkaline solution was extracted with ether and the ethereal solution was dried with solid NaOH. Distillation resulted in 10.6 grams (70% of the theory) of 1-aminoadamantane which, after sublimation, melted at 180°C to 192°C (seal capillary). It is converted to the hydrochloride. References Merck Index 373 Kleeman and Engel p. 33
Amantocillin
213
PDR p. 862 OCDS Vol. 2 p. 18 (1980) DOT 3 (1) 6 (1967) and 7 (2) 44 (1971) I.N. p. 63 REM p. 927 Haaf, W.; US Patent 3,152,180; October 6, 1964; Assigned to Studiengesellschaft Kohle GmbH, Germany
AMANTOCILLIN Therapeutic Function: Antibiotic Chemical Name: 4-Thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid, 6(((3-aminotricyclo[3.3.1.13,7]dec-1-yl)carbonyl)amino)-3,3-dimethyl-7oxo-, (2S-(2α,5α,5β))Common Name: Amantocillin Structural Formula:
Chemical Abstracts Registry No.: 10004-67-8 Trade Name
Manufacturer
Country
Year Introduced
Amantocillin
Onbio Inc.
-
-
Raw Materials Sulfuric acid Sodium hydroxide Thionyl chloride Triethylamine
3-Bromoadamantane-1-carboxylic acid Acetic acid 6-Aminopenicillanic acid
Manufacturing Process A mixture of 3-bromoadamantane-1-carboxylic acid (5.8 g), acetonitrile (45 ml) and concentrated sulphuric acid (9 ml) was refluxed for 20 h. After cooling, the mixture was poured into water (250 ml), and the resulting suspension concentrated in vacuo to remove most of the acetonitrile. Aqueous sodium hydroxide (33%) was added until the pH was 4.0 (about 24 ml). The precipitate was filtered off, washed with water, and dried to yield 4.4 g of the 3-acetaminoadamantane-1-carboxylic acid, melting point 254°-258°C (two recrystallizations from methanol-aceto nitrile).
214
Ambazone
A solution of 3-acetamino-adamantane-1-carboxylic acid (3.0 g) in 4 N sodium hydroxide (40 ml) was refluxed for 5 h. After cooling, the pH of the solution was adjusted to 7 with acetic acid. The crystalline precipitate was filtered off, washed with ethanol and dried to yield 2.20 g of the desired compound, melting point over 330°C. In order to purify the compound, 2.0 g of it was suspended in water (10 ml), 4 N NaOH (2 ml) was added, and the resulting solution filtered through a filter aid known under the registered trademark 'Dicalite'. The filtrate was adjusted to a pH of 6.5 with acetic acid. The resulting crystalline precipitate was filtered off, washed with a little water followed by alcohol, and dried to yield 1.55 g of pure 3-amino-adamantane-1carboxylic acid. 3-Aminoadamantane-1-carboxylic acid (1.0 g) was refluxed with thionyl chloride (4.6 ml) for 1 h. Excess of thionyl chloride was removed in vacuo. The residue was dissolved in benzene (3 ml), and the resulting solution evaporated under reduced pressure to remove traces of thionyl chloride. This process was repeated to leave 1.3 g of a 3-thionyliminoadamantane-1carboxylic acid chloride, almost colourless. 500.0 mg of 3-thionyliminoadamantane-1-carboxylic acid chloride were dissolved in dry acetone (8 ml), and the resulting solution was added during 20 min at room temperature with stirring, to a suspension of 6aminopenicillanic acid (520.0 mg) in 50% aqueous acetone (20 ml), previously adjusted to a pH of 7.0 with triethylamine. During the process, a pH value of 7.0 was maintained by the addition of a 1 N solution of triethylamine in 50% aqueous acetone from an automatic titrator. At the end of the reaction, a clear solution was obtained. Acetone was removed in vacuo, and 70% of the theoretical amount of 3-amino-adamantyl-1-penicillin was formed. The aqueous solution was concentrated in vacuo to a volume of 4 ml. Addition of acetone (40 ml) gave an oily precipitate which after decanting and addition of fresh acetone gave 900.0 mg of a semicrystalline solid which contained 50% of the theoretical amount of 3-aminoadamantyl-1-penicillin. References Godtfredsen W.O.; US Patent No. 3,564,049; Feb. 16, 1971; Assigned: Lovens Kemiske Fabrik Produktionsaktieselskab, Ballerup, Denmark, a firm
AMBAZONE Therapeutic Function: Antiseptic Chemical Name: Guanidine, ((4-oxo-2,5-cyclohexadien-1-ylidene)amino)-, thiosemicarbazone monohydrate Common Name: Ambazone; Guanothiazone Chemical Abstracts Registry No.: 6011-12-7; 539-21-9 (Base)
Ambenonium chloride
215
Structural Formula:
Trade Name
Manufacturer
Country
Year Introduced
Ambazone
Generic
-
-
Ambazone
Terapia
-
-
Ambazone
East-Asia Pharmaceutical Chemical Co., Ltd.
-
Faringosept
Terapia
-
-
Faringosept
Interprindera
-
-
Iversal
Bayer
-
-
Primal
Bayer
-
-
Raw Materials Quinone monoguanylhydrazone nitrate Thiosemicarbazide Nitric acid Manufacturing Process To a solution of 22.7 g of quinone monoguanylhydrazone nitrate in 250 ml water is added dropwise hot aqueous solution of 9.1 g thiosemicarbazide, then is added slowly a solution of 5 ml concentrated nitric acid in 10 ml of water. The mixture is stirred at 60°C for 1 hour. The product is dissolved in 1-1.2 L of water at 100°C. The solution is filtered and added to an aqueous ammonium solution. Blue residue of p-benzoquinone amidinohydrazone thiosemicarbazone is filtered and dried, melting point 188°C (decomp.). References Merck Index, Monograph number: 395, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. Petersen S., Domagk G.; DE Patent No. 965,723; 1957-06-19; Assigned to Bayer AG
AMBENONIUM CHLORIDE Therapeutic Function: Cholinesterase inhibitor Chemical Name: N,N'-[(1,2-Dioxo-1,2-ethanediyl)bis(imino-2,1-ethanediyl)] bis[2-chloro-N,N-diethylbenzenemethanaminium] dichloride
216
Ambenonium chloride
Common Name: Structural Formula:
Chemical Abstracts Registry No.: 115-79-7 Trade Name Mytelase CL Mytelase Mytelase Mytelase Mytelase Mysuran
Manufacturer Winthrop Winthrop Winthrop Winthrop Nippon Shoji Winthrop
Country US W. Germany France UK Japan -
Year Introduced 1956 1950 1970 -
Raw Materials 2-Diethylaminoethylamine Ethyl oxalate 2-Chlorobenzyl chloride Manufacturing Process N,N'-Bis(2-Diethylaminoethyl)Oxamide: A solution of 150 grams (1.32 mol) of 2-diethylaminoethylamine in 250 ml of xylene was gradually added to a solution of 73.0 grams (0.5 mol) of ethyl oxalate in 250 ml of xylene, with external cooling. The mixture was then refluxed for eight hours, cooled and diluted with ether. The ether-xylene solution was extracted with 10% hydrochloric acid, and the hydrochloric acid extracts were in turn extracted with ether and then made alkaline with 35% sodium hydroxide solution. The organic material which separated was extracted with ether, and the ether solution was dried over anhydrous sodium sulfate and concentrated, giving 106.5 grams of N,N'-bis(2-diethylaminoethyl)oxamide, MP 40-42°C. N,N'-Bis(2-Diethylaminoethyl)Oxamide Bis(2-Chlorobenzochloride): A solution of 7 grams (0.025 mol) of N,N'-bis(2-diethylaminoethyl)oxamide and 16.1 grams (0.1 mol) of 2-chlorobenzyl chloride in 100 ml of acetonitrile was refluxed for eleven hours. The solid which separated upon cooling was collected by filtration and recrystallized by dissolving it in ethanol and adding ether to cause the product to separate. After drying at about 60°C (1-3 mm) there was obtained 4.1 grams of N,N'-bis(2-diethylaminoethyl)oxamide bis(2chlorobenzochloride), MP 196-199°C.
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References Merck Index 378 Kleeman and Engel p. 34 I.N. p. 64 REM p. 898 Kirchner, F.K.; US Patent 3,096,373; July 2, 1963; Assigned to Sterling Drug Inc. Behr, L.C. and Schreiber, R.S.; US Patent 2,438,200; March 23, 1948; Assigned to E.I. du Pont de Nemours and Co.
AMBENOXAN Therapeutic Function: Muscle relaxant Chemical Name: 2,3-Dihydro-N-[2-(2-methoxyethoxy)ethyl]-1,4benzodioxine-2-methanamine Common Name: Structural Formula:
Chemical Abstracts Registry No.: 2455-84-7 Trade Name
Manufacturer
Country
Year Introduced
Ambenoxan
ZYF Pharm Chemical
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Raw Materials 2-Aminomethyl-1,4-benzodioxane β-Methoxyethoxy ethyl chloride Potassium carbonate Manufacturing Process 2-Aminomethyl-1,4-benzodioxane (17 g) and β-methoxyethoxy ethyl chloride (7 g) were heated at 160°C for 2 hours. The reaction mixture was cooled and chloroform (30 ml) and a solution of potassium carbonate (7 g) in water (20 ml) added thereto.The chloroform layer was removed and the aqueous layer extracted twice with chloroform (10 ml each time). The chloroform extracts were combined and dehydrated over anhydrous sodium sulfate. Filtration, followed by distillation gave 2-(β-methoxyethoxyethyl)amino-methyl-1,4benzodioxane (yield 7.7 g) as a pale yellow oil boiling at 180-186°C/11.5 mm. The base was converted to a white hydrochloride having a melting point of
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104-106°C by the addition of alcoholic hydrogen chloride to an ether solution of the base and isolation of the salt which separated. References Shapero M., Green P.N.; US Patent No. 3,308,136; Mar. 7, 1967; Assigned to Ward Blenkinsop and Company Limited, Middlesex, England, a British company
AMBICROMIL Therapeutic Function: Antiallergic, Histamine H1 antagonist Chemical Name: 4H,6H-Benzo[1,2-b:5,4-b']dipyran-2,8-dicarboxylic acid, 4,6-dioxo-10-propylCommon Name: Probicromil; Ambicromil Structural Formula:
Chemical Abstracts Registry No.: 58805-38-2 Trade Name
Manufacturer
Country
Year Introduced
Probicromil
ZYF Pharm Chemical
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Raw Materials Benzyltrimethylammonium hydroxide Dimethyl acetylenedicboxylate Chlorosulfonic acid Manufacturing Process 4,6-Dioxo-10-propyl-4H,6H-benzo[1,2-b:5,4-b']dipyran-2,8-carboxylic acid: 2 ml of benzyltrimethylammonium hydroxide was added to a solution of 18.3 g 2-propylresorcine and dimethyl acetylenedicboxylate in 500 ml of ethanol and the mixture obtained was heated for 20 hours at reflux. The solution was cooled, 30 g sodium hydroxide in 150 ml of water was added and all mass was heated for 2 hours at reflux. On cooling the reaction mixture was poured into 2 L of water and washed with ethyl acetate. The water layer was acidified with conc. hydrochloric acid and a precipitate fallen was collected, washed
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with water, and dried in vacuum at 80°C to give 21 g cream-colored solid product. 21 g above product was in portion added to 200 ml of chlorosulfonic acid by ice cooling. The temperature of reaction was not higher 10°C. Then the reaction mixture was heated for 2.5 hours at 50°C. On cooling it was poured into 3 L of ice/water, the fallen precipitate was filtered off, washed with water and dried in vacuum. The solid product was heated with 100 ml of ethanol, an insoluble part was collected and boiled with 100 ml of ethyl acetate. Insoluble product was centrifuged and dried in vacuum at 60°C. Yield of title product hydrate 10.5 g. 4,6-Dioxo-10-propyl-4H,6H-benzo[1,2-b:5,4-b']dipyran-2,8carboxylic acid melted at 310°-311°C (deg). References Cairns H. et al.; D.E. Patent No. 2,851,440; Nov. 11, 1978
AMBROXOL Therapeutic Function: Expectorant Chemical Name: 4-[[(2-Amino-3,5-dibromophenyl)methyl]amino] cyclohexanol Common Name: Structural Formula:
Chemical Abstracts Registry No.: 18683-91-5 Trade Name Mucosolvan Mucosolvan Mucosolvon
Manufacturer Thomae De Angeli Boehringer Ingelheim
Country W. Germany Italy Switz.
Year Introduced 1980 1981 1982
Fluixol Fluibron Muciclar
Ripari-Gero Chiesi Piam
Italy Italy Italy
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Raw Materials N-(trans-p-Hydroxycyclohexyl)-(2-aminobenzyl)-amine Bromine
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Manufacturing Process 6.5 g of N-(trans-p-hydroxycyclohexyl)-(2-aminobenzyl)-amine were dissolved in a mixture of 80 cc of glacial acetic acid and 20 cc of water, and then 9.6 g of bromine were added dropwise at room temperature while stirring the solution. After all of the bromine had been added, the reaction mixture was stirred for two hours more and was then concentrated in a water aspirator vacuum. The residue was taken up in 2 N ammonia, the solution was extracted several times with chloroform, and the organic extract solutions were combined and evaporated. The residue, raw N-(trans-phydroxycyclohexyl)-(2-amino-3,5-dibromobenzyl)-amine, was purified with chloroform and ethyl acetate over silica gel in a chromatographic column, the purified product was dissolved in a mixture of ethanol and ether, and the solution was acidified with concentrated hydrochloric acid. The precipitate formed thereby was collected and recrystallized from ethanol and ether, yielding N-(trans-p-hydroxycyclohexyl)-(2-amino-3,5-dibromobenzyl)-amine hydrochloride, MP 233-234.5°C (decomposition). References Merck Index 383 DFU 1 (3) 95 (1976) Kleeman and Engel p. 35 I.N. p. 64 Kack, J., Koss, F.W., Schraven, E. and Beisenherz, G.; US Patent 3,536,713; October 27, 1970; Assigned to Boehringer Ingelheim G.m.b.H.
AMBRUTICIN Therapeutic Function: Antifungal Chemical Name: 2H-Pyran-2-acetic acid, 6-(2-(2-(5-(6-ethyl-3,6-dihydro-5methyl-2H-pyran-2-yl)-3-methyl-1,4-hexadienyl)-3-methylcyclopropyl) ethenyl)tetrahydro-4,5-dihydroxyCommon Name: Ambruticin; SMP-78 Structural Formula:
Chemical Abstracts Registry No.: 58857-02-6
Ambruticin Trade Name Ambruticin
Manufacturer Universitet Karlsruhe (TH)
Country -
Ambruticin
Kosan Biosciences Inc.
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Raw Materials Methyltriphenylphosphonium Methyl 2,3-di-O-benzyl-α-Dbromide glucopyranoside Tributyltin hydride t-Butyldiphenylsilyl chloride DMAP Tetrabutylammonium fluoride (-)-Dimenthyl succinate 2,2,6,6-Tetramethylpiperidine 1,1-Bromochloroethane Potassium hydroxide Diborane-THF complex Periodinane Triphenylphosphine Diisobutylaluminum hydride Triphenylmethyl chloride 1,1'-Thiocarbonyldiimidazole Diazomethane Sodium methoxide Sulfuric acid Acetic anhydride Glycosyl fluoride 4-Toluenesulfonic acid Triethylamine Diethylaminosulfur trifluoride Doss-Martin's periodinane PDC Sodium hydride Aldehyde Hydroquinone Imidazole Glyoxylic acid Potassium fluoride 2,4'-Dibromoacetophenone Oxalyl chloride (+)-α-Methylbenzylamine Methyl magnesium bromide trans-Propenyltrimethyltin Acetic anhydride N,N-Diisopropylamine Sodium hydrogen carbonate Butyl lithium Hydrogen hydrochloride 4-Toluenesulfonyl fluoride Lithium hydroxide Lithium Tetrabromomethane Sodium Tetramethylammonium acetate Ammonium chloride Benzylchlorobis(triphenylphosphine)palladium (II) Manufacturing Process Preparation of methyl 2,3-di-O-benzyl-1,4-dideoxy-1α/1β-fluoro-Dglucoheptopyranuronate: To a stirred solution of the methyl 2,3-di-O-benzyl-α-D-glucopyranoside (1.01 g, 2.70 mmol) in DMF (10 ml) was added imidazole (0.37 g, 5.40 mmol) followed by a solution of t-butyldiphenylsilyl chloride (0.89 g, 3.24 mmol) in DMF (3.5 ml) at 0°C. The resulting solution was stirred at room temperature for 2 h, cooled to 0°C, H2O (1 ml) was added, and the mixture was stirred for 10 min. The resulting solution was poured into H2O (100 ml) and extracted with Et2O (3x100 ml). The organic layers were combined, washed with brine, dried over sodium sulfate and filtered. The solvent was removed in vacuum to give a colorless oil, which was purified by column chromatography over silica gel (hexane-Et2O, 7:3) to afford 1.64 g (99%) of methyl 2,3-di-O-benzyl-6-Ot-butyldiphenylsilyl-α-D-glucopyranoside as a colorless viscous oil.
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To a stirred solution of methyl 2,3-di-O-benzyl-6-O-t-butyldiphenylsilyl-α-Dglucopyranoside (0.617 g, 1.01 mmol) in toluene (5 ml) was added 1,1'thiocarbonyldiimidazole (0.359 g, 2.01 mmol) at room temperature. The solution was heated at reflux. The reaction mixture was poured into 0.5 N HCl (50 ml) and extracted with CH2Cl2 (3x50 ml). The organic layers were combined, washed with sat. sodium bicarbonate solution followed by brine, dried over sodium sulfate and filtered. The solvent was removed in vacuum to give a crude yellow oil, which was purified by column chromatography over silica gel (hexane-EtOAc, 7:3) to afford 0.676 g (93%) of methyl 2,3-di-Obenzyl-6-O-t-butyldiphenylsilyl-4-O-imidazolyl-thiocarbonyl-α-Dglucopyranoside as a colorless viscous oil. To a stirred solution of nBu3SnH (0.24 g, 0.83 mmol) in toluene (4.2 ml) was added a solution of methyl 2,3-di-O-benzyl-6-O-t-butyldiphenylsilyl-4-Oimidazolyl-thiocarbonyl-α-D-glucopyranoside (0.30 g, 0.42 mmol) in toluene (2 ml) over 2 min at 100°C. The resulting solution was heated at reflux for 12 h. The solvent was removed in vacuum and the resulting crude oil was purified by column chromatography over silica gel (hexane-Et2O, 9:1) to afford 0.20 g (83%) of the methyl 2,3-di-O-benzyl-6-O-t-butyldiphenylsilyl-4deoxy-α-D-glucopyranoside as a colorless viscous oil. To a stirred solution of the methyl 2,3-di-O-benzyl-6-O-t-butyldiphenylsilyl-4deoxy-α-D-glucopyranoside (25.9 g, 43.4 mmol) in THF (400 ml) was added dropwise a 1 M solution of nBu4NF 65.1 ml in THF over 30 min at room temperature. The resulting solution was stirred at room temperature for 18 h and then poured into H2O (500 ml). The mixture was extracted with Et2O (3x500 ml). The organic extracts were combined, washed with brine, dried over sodium sulfate and filtered. The solvent was removed in vacuum to give a colorless oil, which was purified by column chromatography over silica gel (hexane-EtOAc, 1:1) to afford 14.81 g (95%) of methyl 2,3-di-O-benzyl-4deoxy-α-D-glucopyranoside as a colorless viscous oil. To a stirred solution of methyl 2,3-di-O-benzyl-4-deoxy-α-D-glucopyranoside (6.12 g, 17.1 mmol) in DMF ( 69 ml) was added 21.81 g (58 mmol) of PDC at room temperature. The resulting red-brown viscous solution was stirred at room temperature for 20 h. The reaction mixture was diluted with Et2O (100 ml) and stirred for 10 min. The clear yellow liquid was collected by decantation. The gummy brown residue was extracted with Et2O (3x100 ml). The extracts were combined, and concentrated in vacuum to give a yellow viscous oil, which was purified by column chromatography over silica gel (CH2Cl2 -MeOH, 10:1) to give 5.60 g (88%) of methyl 2,3-di-O-benzyl-4deoxy-α-D-glucopyranosiduronic acid as an amorphous powder. To a stirred solution of the methyl 2,3-di-O-benzyl-4-deoxy-α-Dglucopyranosiduronic acid (1.73 g, 4.65 mmol) in CH2Cl2 (30 ml) was added oxalyl chloride (0.943 g, 0.65 ml, 7.43 mmol) followed by DMF (0.23 mmol) at room temperature. The resulting clear solution was stirred at room temperature for 2 h, and then concentrated in vacuo. To a solution of the crude acyl chloride derivative in Et2O (50 ml) was added a solution of diazomethane in Et2O (30 ml) at 0°C over 20 min. The resulting clear yellow solution was stirred at room temperature for 30 min and then
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evaporated in vacuo at under 20°C to give a crude yellow oil, which was purified by column chromatography over silica gel (hexane-Et2O, 1:1) to afford 1.44 g (78%) of the corresponding diazoketone as a yellow viscous oil. A solution of the diazoketone prepared above (1.39 g, 3.52 mmol) in MeOH (60 ml) was placed in a 100 ml pyrex test tube, and irradiated by a Hanovia 30620 type medium pressure UV arc under constant cooling by running H2O for 48 h. The reaction mixture was concentrated in vacuo to give a yellow oil, which was purified by column chromatography over silica gel (hexane-Et2O, 3:2) to afford 0.96 g (68%) of methyl (methyl 2,3-di-O-benzyl-4-deoxy-α-Dglucoheptopyranosiduronate as a colorless viscous oil. To a stirred solution of the methyl (methyl 2,3-di-O-benzyl-4-deoxy-α-Dglucoheptopyranosiduronate (0.705 g, 1.76 mmol) in acetic anhydride (7 ml) was added 1 ml of a 10% solution of H2SO4 in acetic anhydride at -30°C. The resulting solution was stirred at -20°C for 10 min. The reaction mixture was poured into a sat. sodium bicarbonate solution (100 ml) and stirred well for 30 min at room temperature to destroy the excess of acetic anhydride. The resulting mixture was extracted with Et2O (3x100 ml). The organic extracts were combined, washed with brine, dried over sodium sulfate and filtered. The solvent was removed in vacuum to give a colorless oil, which was purified by column chromatography over silica gel (hexane-Et2O, 3:2) to afford 0.664 g (88%) of 82:18 mixture of methyl (acetyl 2,3-di-O-benzyl-4-deoxy-α/β-Dglucoheptopyranosiduronate). To a freshly prepared solution of sodium methoxide (1.931 mmol) in MeOH (15 ml) was added a solution of methyl (acetyl 2,3-di-O-benzyl-4-deoxy-α/βD-glucoheptopyranosiduronate) (413.0 mg, 0.966 mmol) in MeOH (5 ml) at 0°C. The resulting solution was stirred at 0°C for 10 min and then poured into H2O (50 ml). The mixture was extracted with Et2O (3x50 ml). The organic extracts were combined, washed with brine, dried over sodium sulfate and filtered. The solvent was removed in vacuum to give a residue, which was purified by column chromatography over silica gel (hexane-EtOAc, 3:2) to afford 360.0 mg (97%) of the mixture of methyl 2,3-di-O-benzyl-4-deoxy-α/βD-glucoheptopyranuronate. To a stirred solution of methyl 2,3-di-O-benzyl-4-deoxy-α/β-Dglucoheptopyranuronate (472.0 mg, 1.22 mmol) in CH2Cl2 (12 ml) was added diethylaminosulfur trifluoride (DAST) (590.0 mg, 3.66 mmol) at -30°C. The resulting colorless solution was stirred at 0°C for 20 min and then cooled again to -30°C. MeOH (1 ml) was added to the reaction mixture to destroy the excess of DAST. After stirring at 0°C for 10 min, the solution was poured into a sat. sodium bicarbonate solution (50 ml) and extracted with Et2O (3x50 ml). The organic extracts were combined, washed with brine, dried over sodium sulfate and filtered. The solvent was removed in vacuum to give a colorless oil, which was purified by column chromatography over silica gel (hexane-Et2O, 3:2) to afford 454.0 mg (96%) of 27:73 mixture of methyl 2,3di-O-benzyl-1,4-dideoxy-1α/1β-fluoro-D-glucoheptopyranuronate. Preparation of methyl (8E,10S,11S,12S)-2,3-di-O-benzyl-1,4-dideoxy-1β-[11methyl-12-formylcyclopropylethenyl]-D-glucoheptopyranuronate.
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A dry, 1.0 L, three-necked, round-bottomed flask containing a magnetic stirring bar, and a thermometer was charged with freshly distilled 2,2,6,6tetramethylpiperidine (29.7 ml, 176 mmol) and dry THF (240 ml). The solution was cooled to 0°C and nBuLi 2.5 M in hexane, 70.4 ml, 176 mmol) was added dropwise over 45 min. Following the addition, the mixture was stirred for 20 min at 0°C, then cooled to -78°C. A solution of (-)-dimenthyl succinate (31.56 g, 80 mmol) in THF (80 ml) was added dropwise over 1 h. The resulting yellow solution of succinate dianion was stirred for 1 h. To the reaction mixture was added a solution of 1,1-bromochloroethane (10.1 g, 70.4 mmol) in THF (15 ml) over a 5 h-period. After the reaction mixture was stirred for 2.5 h, it was poured into ice-cooled 0.5 N HCl (320 ml) and the product extracted with Et2O (3x300 ml). The combined organic phases were washed with brine (1x400 ml), dried over sodium sulfate, filtered, and concentrated in vacuum. The residue was chromatographed over silica gel (hexane-Et2O 20:1) to give 13.23 g (45 %) of dimenthyl (1S,2S)-3methylcyclopropane-1,2-dicarboxylate as colorless crystals, melting point 98°99°C. To a solution of the dimenthyl (1S,2S)-3-methylcyclopropane-1,2dicarboxylate (2.5 g, 5.94 mmol) in THF (10 ml) was added a 10% KOH solution in 9:1( EtOH-H2O (3.94 ml, 7.02 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3.5 days, then the solvent was evaporated, diluted with H2O, and extracted with Et2O. The aqueous layer was acidified with a 10% HCl solution to pH ~ 3 and extracted several times with Et2O. The combined organic layers were washed successively with H2O, brine, and dried over sodium sulfate. Evaporation of the solvent in vacuum afforded 1.4 g (83%) of the menthyl (1S,2S,3S)-2carboxy-3-methylcyclopropane-1-carboxylate as a clear oil. To a solution of the menthyl (1S,2S,3S)-2-carboxy-3-methylcyclopropane-1carboxylate (1.32 g, 4.68 mmol) in dry THF (40 ml) cooled to 0°C was added dropwise a 1.0 M solution of B2H6-THF complex (5.62 ml, 5.62 mmol) over a 20 min-period. The reaction mixture was allowed to warm to room temperature and stirred for 8 h, followed by the addition of a second equivalent of B2H6-THF complex (5.617 ml, 5.617 mmol). When all the starting material had disappeared, the reaction mixture was carefully quenched at room temperature by a dropwise addition of 1:1, H2O-AcOH (1 ml) with stirring until no more gas evolution occurred. The reaction mixture was concentrated at room temperature, and the slurry was diluted with EtOAc (80 ml) and washed with H2O (30 ml). The aqueous phase was extracted with EtOAc (3x80 ml). The combined organic layers were washed with a sat. sodium bicarbonate solution, brine, and then dried over sodium sulfate. Solvent removal and purification of the residue by chromatography (hexaneEtOAc, 8:2) gave 1.25 g (100%) of menthyl (1S,2S,3S)-2-hydroxymethyl-3methylcyclopropane-1-carboxylate as a white solid, melting point 85°-86°C. A solution of the menthyl (1S,2S,3S)-2-hydroxymethyl-3-methylcyclopropane1-carboxylate (0.536 g, 2 mmol) in CH2Cl2 (10 ml) was added to a suspension of periodinane (1.017 g, 2.4 mmol) in CH2Cl2 (10 ml) with stirring. The reaction mixture was stirred at room temperature for 1.5 h, followed by the addition of a second equivalent of the periodinane reagent. When all the starting material had disappeared, the reaction mixture was filtered through
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Celite, and the filter cake was washed with CH2Cl2. The solvent was evaporated in vacuum, and the residue was chromatographed over silica gel (hexane-EtOAc, 95:5) to give 0.51 g (96%) of menthyl (1S,2S,3S)-2-formyl3-methylcyclopropane-1-carboxylate as a white crystalline solid, melting point 66°-67°C. A solution of triphenylphosphine (1.42 g, 5.41 mmol) in CH2Cl2 (15 ml) was cooled to 0°C and treated with CBr4 (0.896 g, 2.70 mmol). A solution of menthyl (1S,2S,3S)-2-formyl-3-methylcyclopropane-1-carboxylate (0.360 g, 1.35 mmol) in CH2Cl2 (10 ml) was then added dropwise. The yellow solution was stirred at 0°C for 30 min. The solvent was evaporated in vacuum, and the residue was chromatographed over silica gel (hexane-EtOAc, 96:4) to give 0.56 g (98%) of menthyl (1S,2S,3S)-2-(2,2-dibromovinyl)-3methylcyclopropane-1-carboxylate as a white solid, melting point 75°-76°C. To a stirred solution of the menthyl (1S,2S,3S)-2-(2,2-dibromovinyl)-3methylcyclopropane-1-carboxylate (3.96 g, 9.37 mmol) in toluene (50 ml) was added a 1 M solution of diisobutylaluminum hydride (DIBALH) (28.1 ml, 28.1 mmol) in hexane at -78°C. The resulting solution was stirred at -78°C for 10 min and then at 0°C for 30 min. The reaction mixture was poured into 0.2 N HCl (200 ml) and extracted with Et2O (3x200 ml). The organic extracts were combined, washed with brine, dried over sodium sulfate and filtered. The solvent was removed in vacuum to give a colorless crude oil, which was purified by column chromatography over silica gel (hexane-Et2O, 1:1) to afford 2.29 g (90%) of the corresponding cyclopropylcarbinol as a colorless oil. To a stirred solution of the cyclopropylcarbinol obtained above (2.33 g, 8.64 mmol) in DMF (35 ml) was added triphenylmethyl chloride (9.64 g, 34.6 mmol) followed by Et3N (9.63 ml, 69.1 mmol) and DMAP (0.21 g, 1.73 mmol) at room temperature. The resulting mixture was stirred at room temperature for 72 h, poured into an aqueous ammonium chloride solution (100 ml), and then extracted with Et2O (3x200 ml). The organic layer was combined, washed with brine, dried over sodium sulfate and filtered. The solvent was removed in vacuum to give a colorless oil, which was purified by column chromatography over silica gel (hexane-CH2Cl2, 8:1) to afford 3.98 g (90%) of the (1S,2S,3S)-2-(2,2-dibromovinyl)-3-methyl-1triphenylmethoxymethylcyclopropane as a colorless viscous oil. To a stirred solution of the (1S,2S,3S)-2-(2,2-dibromovinyl)-3-methyl-1triphenylmethoxymethyl-cyclopropane (128.6 mg, 0.251 mmol) in THF (5 ml) was added dropwise a 1.42 M solution of nBuLi (0.35 ml, 0.50 mmol) in hexane at -78°C. After stirring at -78°C for 10 min, the solution was poured into H2O (30 ml) and extracted with Et2O (3x30 ml). The organic extracts were combined, washed with brine, dried over sodium sulfate and filtered. The solvent was removed in vacuum to give a colorless residue, which was purified by column chromatography over silica gel (hexane-Et2O, 20:1) to afford 81.4 mg (92%) of (1S,2S,3S)-3-ethynyl-2-methylcyclopropylmethyl triphenylmethyl ether as a colorless viscous oil. To a stirred solution of the (1S,2S,3S)-3-ethynyl-2-methylcyclopropylmethyl triphenylmethyl ether (333.0 mg, 0.945 mmol) in hexane (3 ml) was added a
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1.0 M solution of DIBALH (0.95 ml, 0.95 mmol) in hexane at 40°C. The resulting solution was stirred at 50°C for 2 h. After cooling to room temperature, the reaction mixture was diluted with toluene (4 ml). To this in situ-generated vinylalane solution was added a solution of methyl 2,3-di-Obenzyl-1,4-dideoxy-1α/1β-fluoro-D-glucoheptopyranuronate (anomeric mixture, α:β=27:73, 282.0 mg, 0.727 mmol) in toluene (1 ml) at -20°C. The resulting colorless solution was stirred at -20°C for 10 min then at room temperature for 30 min. The reaction mixture was poured into 0.2 N HCl (20 ml) and extracted with Et2O (3x30 ml). The organic extracts were combined, washed with brine, dried over sodium sulfate and filtered. The solvent was removed in vacuum to give a colorless crude residue, which was purified by column chromatography over silica gel (hexane-CH2Cl2-EtOAc, 20:20:1) to afford 0.256 g (49%) of methyl (8E,10S,11S,12S)-2,3-di-O-benzyl-1,4dideoxy-1β-[11-methyl-12-triphenylmethoxymethylcyciopropylethenyl]-Dglucoheptopyranuronate and 0.150 g (28%) of methyl (8E,10S,11S,12S)-2,3di-O-(benzyl-1,4-dideoxy-1α-[11-methyl-12triphenylmethoxymethylcyclopropylethenyl]-D-glucoheptopyranuronate as colorless oils. To a stirred solution of methyl (8E,10S,11S,12S)-2,3-di-O-benzyl-1,4-dideoxy1β-[11-methyl-12-triphenylmethoxymethylcyclopropylethenyl]-Dglucoheptopyranuronate (173.0 mg, 0.24 mmol) in CH2Cl2 (2 ml) was added a solution of p-toluenesulfonic acid (9.0 mg, 0.048 mmol) in MeOH (2 ml) at room temperature. The resulting solution was stirred at room temperature for 2 h and then poured into a sat. sodium bicarbonate solution (20 ml). This mixture was extracted with Et2O (3 x 30 ml). The organic extracts were combined, washed with brine, dried over sodium sulfate and filtered. The solvent was removed in vacuum to give a colorless residue, which was purified by preparative thin layer chromatography (hexane-EtOAc, 1:1) to afford 106.0 mg (92%) of the methyl (8E,10S,11S,12S)-2,3-di-O-benzyl-1,4-dideoxy-1β[11-methyl-12-hydroxymethylcyclopropylethenyl]-D-glucoheptopyranuronate as a colorless oil. To a stirred solution of the methyl (8E,10S,11S,12S)-2,3-di-O-benzyl-1,4dideoxy-1β-[11-methyl-12-hydroxymethylcyclopropylethenyl]-Dglucoheptopyranuronate (96.2 mg, 0.20 mmol) in CH2Cl2 (5 ml) was added Doss-Martin's periodinane (127.0 mg, 0.30 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 30 min and then diluted with Et2O (20 ml). This mixture was poured into a sat. sodium bicarbonate solution (10 ml) containing sodium thiosulfate (0.5 g). The organic layer was separated and the aqueous layer was washed with Et2O (2x20 ml). The organic extracts were combined, washed with brine, dried over sodium sulfate and filtered. The solvent was removed in vacuum to give a crude residue, which was purified by preparative thin layer chromatography (hexane-EtOAc, 3:1) to afford 86.5 mg (90%) of methyl (8E,10S,11S,12S)2,3-di-O-benzyl-1,4-dideoxy-1β-[11-methyl-12-formylcyclopropylethenyl]-Dglucoheptopyranuronate as a colorless oil. Preparation of (+)-6-ethyl-5-methyl-2-(4-sulfotolyl-1,3-dimethyl-but-1-ene)yl-3,6-dihydro-2H-pyran: Sodium hydride (16.0 g, 0.4 mol, as a 60% dispersion in mineral oil) in a 1.0 L three-necked flask was washed with hexane (3x50 ml) to remove the
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mineral oil. The flask was then equipped with rubber stoppers, a reflux condenser, and a mechanical stirrer. The system was alternatively evacuated and filled with nitrogen; DMSO (140 ml) was introduced rapidly, and the mixture was heated at 75°-80°C for 60 min, or until the evolution of hydrogen ceased. The resulting black-greenish solution of methylsulfinyl carbanion was cooled in an ice-H2O bath, and methyltriphenylphosphonium bromide (142.8 g, 0.4 mol) in warm DMSO (320 ml) was added at 15°-20°C. The resulting solution was allowed to warm to it and stirred for 10 min, then at 30°-32°C for 10 min or until a red-brownish color developed. The reaction mixture was cooled to 15°C and the aldehyde (43.34 g, 0.44 mol) was added dropwise (through a cannula), keeping the temperature between 15°-20°C. The reaction mixture was stirred at room temperature for 25 min, then at 30°32°C for 20 min. The reaction was immediately distilled in the presence of a cat. amount of hydroquinone under reduced pressure to give 32.0 g (75%) of 3-methyl-1,3-hexadiene collected in a solid carbon dioxide trap, boiling point 35°-37°C/59 mm Hg. Freshly distilled 3-methyl-1,3-hexadiene (15.6 g, 0.162 mol) was placed into a Carius tube containing a cat. amount of hydroquinone, glyoxylic acid monohydrate (22.45 g, 0.244 mol), and CHCl3 (80 ml). The tube was sealed and heated at 115°-120°C for 12 h. The reaction mixture was cooled to 0°C and diluted with H2O (30 ml), the organic phase was separated and the aqueous phase was extracted with CH2Cl2 (3x60 ml). The combined organic extracts were washed with H2O (1x100 ml), brine (1x100 ml), and dried over sodium sulfate. Complete removal of solvent afforded 22.5 g (81%) of a 4:1 mixture of (cis:trans) 6-ethyl-5-methyl-3,6-dihydro-2H-pyran-2-carboxylic acid as a reddish viscous oil, which was used directly in the next step without further purification. A mixture of potassium fluoride (33.83 g, 0.582 mol), 2,4'dibromoacetophenone (80.93 g, 0.291 mol), and DMF (350 ml) was stirred at room temperature for 5 min. A solution of 4:1 mixture of (cis:trans) acids (45.0 g, 0.265 mol) in DMF (50 ml) was then added to the reaction mixture and the whole stirred at room temperature for 3 h, then at 100°C for 30 min. The reaction mixture was cooled to room temperature and diluted with H2O (200 ml). The aqueous solution was extracted with Et2O (4x400 ml). The combined ethereal extracts were washed with H2O (3x400 ml) and dried over sodium sulfate. After the solvent was partially removed in vacuo, a precipitate was formed. The slurry was the filtered to give 51.0 g (53%) of pbromophenacyl ester of 6-ethyl-5-methyl-3,6-dihydro-2H-pyran-2-carboxylic acids as a white solid material, melting point 137°-138°C. To a solution of the p-bromophenacyl ester of 6-ethyl-5-methyl-3,6-dihydro2H-pyran-2-carboxylic acids (46.0 g, 0.125 mol) in glacial AcOH (650 ml) was slowly added zinc (dust, 49.31 g, 0.754 mol) in a 60 min-period at room temperature. The reaction mixture was stirred at room temperature for 8 h, then filtered on Celite, and the zinc residue washed with AcOH (200 ml), then THF (200 ml). Most of the solvent was evaporated and the crude reaction mixture diluted with Et2O and washed with H2O (2x150 ml). The organic layer was treated with a diluted NaOH solution to pH ~ 10. The aqueous phase was washed with Et2O several times, then acidified with a 1.0 N HCl solution to pH ~ 4, and extracted with Et2O. The combined organic extracts were
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successively washed with H2O, brine, and dried over sodium sulfate. After evaporation of the solvent, 19.23 g (90%) of pure (+)-6-ethyl-5-methyl-3,6dihydro-2H-pyran-2-carboxylic acid was obtained as a yellowish solid, melting point 61°-63°C. This acid was used in the next step without further purification. To a solution of (+)-6-ethyl-5-methyl-3,6-dihydro-2H-pyran-2-carboxylic acid (21.0 g, 0.123 mol) in MeOH (125 ml) was added (+)-α-methylbenzylamine (14.97 g, 0.123 mol) with stirring. The solvent was partially evaporated in vacuo and Et2O (100 ml) was added. The solvents were partially evaporated and more Et2O was added. The process was repeated until crystallization occurred. The reaction mixture was cooled to 0°C and filtered to give 19.0 g of the salt. The recrystallization process was repeated four more times or until the optical rotation of the corresponding acid was constant. After five recrystallizations, 6.0 g of the corresponding salt were obtained. This salt was then acidified with a 1.0 N HCl solution to pH ~ 4 and extracted with Et2O several times. The organic phase was successively treated with H2O, brine, and then dried over sodium sulfate. Evaporation of the solvent in vacuo gave 3.4 g (32%, from the racemic acid) of the optically pure acid (+)-6-ethyl-5methyl-3,6-dihydro-2H-pyran-2-carboxylic acid as a clear viscous oil. To a stirred solution of the (+)-6-ethyl-5-methyl-3,6-dihydro-2H-pyran-2carboxylic acid (3.0 g, 17.65 mmol) in CH2Cl2 (60 ml), and DMF (0.12 ml) at 0°C was added oxalyl chloride (1.82 ml, 21.18 mmol) over a 30 min-period. The reaction mixture was stirred at 0°C for 1 h, then at room temperature for 2 h. The solvent was evaporated in vacuum, and the residue was used directly in the next reaction without further purification. In a 50 ml, two-necked, round-bottomed flask equipped with a Teflon-covered magnetic stirring bar, a drierite filled trap, and a thermometer was placed the crude acid chloride in HMPA (16 ml). Freshly prepared trans-propenyltrimethyltin (4.34 g, 21.18 mmol) was then added followed by the addition of benzylchlorobis(triphenylphosphine)palladium (II) (13.6 mg, 0.02 mmol). The yellow solution was heated at 65°-70°C with stirring under an air atmosphere for 3 h. The reaction mixture was cooled to room temperature and H2O (15 ml) was added. The mixture was extracted with Et2O (3x60 ml). The ethereal solutions were combined and washed with H2O, brine, dried over sodium sulfate, and the solvent removed in vacuum. The residue was purified by chromotography over silica gel (hexane-EtOAc, 98:2) to give 3.1 g (90%) of (+)-6-ethyl-5-methyl-2-(but-2-ene-1-one)-yl-3,6-dihydro-2H-pyran as a colorless volatile oil. A solution of the α,β-(+)-6-ethyl-5-methyl-2-(but-2-ene-1-one)-yl-3,6dihydro-2H-pyran (3.02 g, 15.44 mmol) in THF (80 ml) was cooled to 0°C and MeMgBr (3.1 M solution in Et2O, 6.5 ml, 20.1 mmol) was added dropwise over a 30 min-period. After the addition, the reaction mixture was stirred at 0°C for 2 h under argon. The reaction mixture was quenched at 0°C by addition of a sat. ammonium chloride solution (14 ml), then H2O (14 ml). The mixture was extracted with Et2O (3x70 ml). The ethereal solutions were combined and washed with brine (1x50 ml), dried over sodium sulfate and the solvent removed by evaporation. The residue was purified by chromatography over silica gel (hexane-EtOAc, 98:2) to give 3.0 g (92 %) of the (+)-6-ethyl-5methyl-2-(1-methyl-1-hydroxy-2-buten)-yl-3,6-dihydro-2H-pyran-as a clear
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volatile liquid. Acetic anhydride (3.02 ml, 31.96 mmol) was added to a stirred solution of (+)-6-ethyl-5-methyl-2-(1-methyl-1-hydroxy-2-buten)-yl-3,6-dihydro-2Hpyran (3.36 g, 15.98 mmol), Et3N (4.46 ml), and DMAP (0.39 g, 3.2 mmol) in CH2Cl2 (15 ml) at room temperature. The solution was stirred at room temperature for 3 days in a sealed tube. Excess of anhydride was quenched by the addition of MeOH. Evaporation of the solvents gave a reddish-oily residue, which was suspended in Et2O and successively treated with 1.0 N HCl, aqueous sodium hydrogen carbonate, and sodium chloride sat. solution. The organic layer was dried over sodium sulfate and evaporated in vacuum. Purification of the residue by chromatography over silica gel (hexane-EtOAc, 98:2) gave 2.9 g (72%) of the acetic acid (+)-6-ethyl-5-methyl-2-(1-methyl1-hydroxy-2-buten)-yl-3,6-dihydro-2H-pyran ester as a colorless oil. To a stirred solution of dry N,N-diisopropylamine (1.1 ml, 7.85 mmol) in THF (10 ml) cooled to 0°C was added nBuLi (2.5 M in hexanes, 3.14 ml, 7.85 mmol) over several min. After the solution was stirred for 10 min following the addition, the reaction mixture was cooled to -78°C, and an additional 1 ml of THF was added. The acetic acid (+)-6-ethyl-5-methyl-2-(1-methyl-1hydroxy-2-buten)-yl-3,6-dihydro-2H-pyran ester (1.65 g, 6.54 mmol) in THF (7 ml) was slowly added over a 40 min-period at -78°- (-70)°C. After the reaction was stirred for 5 min, TBSCl (1.18 g) in THF-HMPA (1:1,6 ml) was added in one portion. The cooling bath was then removed, and the reaction mixture was allowed to warm to 0°C and stirred for 1 h, then at room temperature for an additional 1 h, and finally 1.5 h at 65°C. The yellow solution was cooled to room temperature and diluted with THF (60 ml), then treated with a 10% HCl aqueous solution (16 ml). The reaction mixture was stirred at room temperature for 3 h The solvent was evaporated and the residue diluted with Et2O and treated with a 1.0 N KOH aqueous solution; the organic phase was discarded, and the aqueous solution was washed with Et2O. The basic solution was acidified with 10% HCl and the product isolated by ether extraction. This afforded 1.0 g (61%) of a 12:1 mixture of (+)-6-ethyl5-methyl-2-(3-methyl-hex-4-enoic acid)-3,6-dihydro-2H-pyran as a colorless oil. This mixture was carried through the next reaction without further purification. A solution of (+)-6-ethyl-5-methyl-2-(3-methyl-hex-4-enoic acid)-3,6-dihydro2H-pyran (1.0 g, 3% mmol) in Et2O (20 ml) was treated with an excess of diazomethane. The solvent was then evaporated, and the two isomers were cleanly separated by chromatography over silica gel (hexane-EtOAc, 98:2) to give 0.97 g (92%) of the methyl (+)-6-ethyl-5-methyl-2-(3-methyl-hex-4enoic acid)-3,6-dihydro-2H-pyran ester as a clear liquid. A solution of N,N-diisopropylamine (0.24 ml, 1.7 mmol) in THF (3 ml) was treated with nBuLi (2.5 M in hexane, 0.68 ml, 1.7 mmol) at 0°C, under a nitrogen atmosphere. After 20 min at 0°C, the solution was cooled to -78°C, and a solution of the methyl (+)-6-ethyl-5-methyl-2-(3-methyl-hex-4-enoic acid)-3,6-dihydro-2H-pyran ester (266.0 mg, 1 mmol) in THF (3 ml) was slowly added. After 1 h at -78°C, p-toluenesulfonyl fluoride (348.0 mg, 2.0 mmol) in THF (2 ml) was added all at once. The reaction mixture was allowed to warm to room temperature and stirred for 24 h, then cooled to 0°C, quenched by careful addition of a sat. ammonium chloride solution, and
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Ambruticin
extracted with EtOAc several times. The combined organic extracts were washed with H2O and brine, dried over sodium sulfate, and concentrated in vacuum. The residue was chromatographed over silica gel (hexane-EtOAc, 9:1) to give 180.0 mg (43% isolated yield) of methyl (+)-6-ethyl-5-methyl-2(2-sulfonyl-benzene-3-methyl-hex-4-enoic acid)-3,6-dihydro-2H-pyran ester, melting point 129°-131°C as a mixture of diastereomers. This diastereomeric mixture was used directly in the next step without further purification. To a stirred solution of methyl (+)-6-ethyl-5-methyl-2-(2-sulfonyl-benzene-3methyl-hex-4-enoic acid)-3,6-dihydro-2H-pyran ester (130.0 mg, 0.31 mmol) in HMPA (2 ml) was added (Me)4N+ -OAc (370.0 mg, 2.78 mmol) and the mixture was heated at 96°-100°C for 17 h. The reaction mixture was cooled and diluted with EtOAc, washed with H2O several times, brine, dried over magnesium sulfate, and the solvent removed in vacuum. The residue was purified by chromatography over silica gel (hexane-EtOAc 9:1) to give 0.08 g (71%) of (+)-6-ethyl-5-methyl-2-(4-sulfotolyl-1,3-dimethyl-but-1-ene)-yl-3,6dihydro-2H-pyran as a clear liquid. Preparation of (+)-Ambruticin: To a stirred solution of (+)-6-ethyl-5-methyl-2-(4-sulfotolyl-1,3-dimethyl-but1-ene)-yl-3,6-dihydro-2H-pyran (54.4 mg, 0.15( mmol) in dry Et2O (1 ml) cooled to 0°C was added dropwise a solution of nBuLi (1.5 M in hexane, 0.18 mmol). The yellow solution was stirred at 0°C for 10 min, then at -42°C for 15 min. Dry hexane (0.5 ml) was added, and a solution of the methyl (8E,10S,11S,12S)-2,3-di-O-benzyl-1,4-dideoxy-1β-[11-methyl-12formylcyclopropylethenyl]-D-glucoheptopyranuronate (60.0 mg, 0.125 mmol) in Et2O (0.5 ml) was added dropwise. The reaction mixture was stirred at 42°C for 2 h, then quenched with ammonium chloride, and extracted with EtOAc several times. The combined organic extracts were washed with brine, dried over sodium sulfate, and the solvent removed in vacuum. The residue was chromatographed over silica gel (hexane-EtOAc, 8:2) to give 53.7 mg (51%) of a mixture of diastereomers. The mixture was used in the next reaction without further purification. To a stirred solution of this mixture (10.0 mg, 0.012 mmol) in a mixture of MeOH-THF 1:1 (0.8 ml) cooled to -35°C was added an excess of Na(Hg) 6% (300.0 mg) in one portion. The reaction mixture was stirred at -35°C for 3.5 h, then diluted with Et2O and filtered through Celite; the cake was washed several times with Et2O. To the ether solution was added a sat. solution of ammonium chloride and then 1.0 N HCl solution until pH - 4. The aqueous phase was extracted several times with EtOAc, and the combined organic phase was washed with H2O, brine, dried over sodium sulfate, and concentrated in vacuum. The residue was chromatographed over silica gel (hexane-EtOAc, 9:1) to give 13(E)-tetraene (methyl 5α,6βdibenzyloxypolyangioate) as the main product, in 63% overall yield, as a clear colorless liquid. Careful chromatography of this E/Z mixture eluted with CH2Cl2/hexane/Et2O (10:10:1) produced pure 13(E) product. To a stirred solution of 13(E) methyl 5α,6β-dibenzyloxypolyangioate (7.0 mg, 0.0105 mmol) in THF (1.5 ml) was added a solution of LiOH (1.3 mg, 0.0525 mmol) in H2O (0.5 ml) at room temperature. The resulting solution was
Ambucaine
231
stirred at room temperature for 18 h and then poured into 0.2 N HCl (10 ml). This mixture was extracted with Et2O (3x20 ml). The organic extracts were combined, washed with brine, dried over sodium sulfate and filtered. The solvent was removed in vacuum to give 7.0 mg of crude 5α,6βdibenzyloxypolyangioic acid as a colorless oil. This crude acid was used in next debenzylation step without further purification. To a stirred solution of the crude 5α,6β-dibenzyloxypolyangioic acid (7.0 mg, 0.0105 mmol) in liquid ammonia (10 ml, distilled from sodium) and EtOH (2 ml) at -78°C was added 0.7 mg (0.105 mmol) of lithium wire. The resulting mixture was stirred at -78°C for 30 min. Ammonium chloride (20.0 mg) was added to this mixture to quench the excess lithium and stirred for 30 min at 78°C. To the resulting mixture was added CH2Cl2 (10 ml), stirred for 1 h at room temperature, then poured into 0.2 N HCl (10 ml), and extracted with CHCl3 (3x20 ml). The organic extracts were combined, washed with brine, dried over sodium sulfate and filtered. The solvent was removed in vacuum to give a colorless oil, which was purified by preparative thin layer chromatography (EtOAc-i-PrOH-H2O, 85:10:5) to afford 3.2 mg (63% from 5 L) of ambruticin as an amorphous powder. References Kende A.S. et al.; Total synthesis of natural (+)-ambruticin; Tetrahedron Vol. 49, N 36, pp. 8015-8038, 1993
AMBUCAINE Therapeutic Function: Local anesthetic Chemical Name: Benzoic acid, 4-amino-2-butoxy-, 2-(diethylamino)ethyl ester Common Name: Ambucaine; Ambutoxate; 2-Butoxyprocaine Structural Formula:
Chemical Abstracts Registry No.: 119-29-9 Trade Name Ambucaine Ambucaine
Manufacturer ZYF Pharm Chemical Onbio Inc.
Country -
Year Introduced -
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Ambucaine
Raw Materials Potassium carbonate Sodium carbonate Hydrochloric acid Hydrogen Ammonia
4-Nitro-2-hydroxybenzoic acid n-Butylbenzenesulfonate Nickel Raney Diethylaminoethyl chloride
Manufacturing Process A stired mixture of 4-nitro-2-hydroxybenzoic acid, anhydrous potassium carbonate and n-butyl benzenesulfonate in xylene was refluxed under a continuous water separator for about 19 h. The insoluble potassium salts were filtered off and washed with hot dry toluene. The combined filtrate and washings were distilled under reduced pressure to remove the solvents, thereby leaving a residual oil which solidified on cooling. The solid yields of greater than 95% of n-butyl 4-nitro-2-n-butoxybenzoate (recrystallized from methanol). The n-butyl 4-nitro-2-n-butoxybenzoate obtained was dissolved in 50% aqueous ethanol. To this solution was added 2 - 3 molecular equivalents of sodium carbonate, and the resulting mixture, was stirred under reflux for about 16 h. After the ethanol has been distilled off under reduced pressure, the remaining aqueous solution was diluted with water and made acidic with concentrated hydrochloric acid. The precipitated yellow solid was filtered, washed with water, dried in a vacuum oven at 90°C and recrystallized from ethyl acetate. There was thus obtained a 4-nitro-2-n-butoxy-benzoic acid (95.5% yield), melting point 120.9°-122.8°C (corr.). A mixture of 4-nitro-2-n-butoxybenzoic acid, anhydrous potassium carbonate and 400 ml of dry toluene was refluxed and stirred under a continuous water separator. When the evolution of water had ceased (3 h), the water separator was removed and there was added diethylaminoethyl chloride. The mixture was then refluxed with stirring for about 20 h, filtered while hot, and the solvent was removed from the filtrate by distilling in vacuo. The residual oil was dissolved in dilute hydrochloric acid, the solution was decolorized with activated carbon and the base was liberated by the addition of excess ammonia. The base was extracted with ethyl acetate, the solution was dried, and the ethyl acetate was removed by distilling in vacuo, yielding 2diethylaminoethyl 4-nitro-2-n-butoxybenzoate as a pale yellow oil. The 2-diethylaminoethyl 4-nitro-2-n-butoxybenzoate in ethanol is hydrogenated using 50 lbs. pressure of hydrogen at 25°C in the presence of Raney nickel (alternatively platinum oxide monohydrate). After the rapid exothermic reaction, the catalyst is filtered off and the filtrate evaporated to dryness to give the 2-diethylaminoethyl 4-amino-2-n-butoxybenzoate. References Clinton R.O., Laskowski S.C.; US Patent No. 2,689,248; Sept. 14, 1954; Assigned: Sterling Drug Inc., New York, N.Y., a corporation of Delaware
Ambuphylline
233
AMBUPHYLLINE Therapeutic Function: Diuretic, Smooth muscle relaxant Chemical Name: 3,7-Dihydro-1,3-dimethyl-1H-purine-2,6-dione compound with 2-amino-2-methyl-1-propanol (1:1) Common Name: Theophylline aminoisobutanol; Bufylline Structural Formula:
Chemical Abstracts Registry No.: 5634-34-4 Trade Name
Manufacturer
Country
Year Introduced
Butaphyllamine
Merrell Dow
US
1944
Buthoid
Merrell Dow
US
-
Raw Materials Theophylline 2-Amino-2-methyl-1-propanol Manufacturing Process Equimolecular proportions of theophylline and 2-amino-2-methyl-1-propanol are dissolved in water and the water is evaporated until crystallization is almost complete. The crystals are filtered off and dried. The product has a melting point of 254-256°C, softening at 245°C. It has a water solubility of about 55%. It may be compounded in the form of tablets, for oral administration, or may be prepared in solution for distribution in ampoules. For the manufacture of solutions for packaging in ampoules, it is more convenient to simply dissolve the theophylline and the butanolamine in water, without going through the intermediate step of separating the crystalline salt. References Merck Index 385 I.N. p. 64 Shelton, R.S.; US Patent 2,404,319; July 16, 1946; Assigned to The Wm. S. Merrell Co.
234
Ambuside
AMBUSIDE Therapeutic Function: Diuretic, Antihypertensive Chemical Name: N'-Allyl-4-chloro-6-[(3-hydroxy-2-butenylidene)amino]-mbenzenedisulfonamide Common Name: Structural Formula:
Chemical Abstracts Registry No.: 3754-19-6 Trade Name
Manufacturer
Country
Year Introduced
Hydrion
Robert and Carriere
France
1970
Raw Materials 2-Allylsulfamyl-5-chloro-4-sulfamylaniline Acetaldehyde dimethylacetal Manufacturing Process Preparation of 2-Allylsulfamyl-4-Sulfamyl-5-Chloro-N-(3-Hydroxy-2Butenylidene)Aniline or Ambuside: 2-allylsulfamyl-5-chloro-4sulfamylanilinemonohydrate (6.9 grams, 0.020 mol) was dissolved in 14 ml acetylacetaldehyde dimethylacetal at room temperature and the viscous solution was filtered. Addition of 6 drops of 10:1 H2O/concentrated HCl, and stirring for 20 hours gave a heavy suspension. Dilution with 150 ml of ethanol, collection of the solid, washing twice with 40 ml portions of ethanol, and drying gave 6.2 grams (78%) of product, MP 204-206°C. References Merck Index 386 Kleeman and Engel p. 35 OCDS Vol.2 p. 116 (1980) I.N. p. 64 Robertson, J.E.; US Patent 3,188,329; June 8, 1955; Assigned to ColgatePalmolive Co.
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235
AMCINAFIDE Therapeutic Function: Antiinflammatory, Antiallergic Chemical Name: 9-Fluoro-11,21-dihydroxy-16,17-[(1-phenylethylidene) bis(oxy)]pregna-1,4-diene-3,20-dione Common Name: Amcinafide Structural Formula:
Chemical Abstracts Registry No.: 7332-27-6 Trade Name
Manufacturer
Country
Year Introduced
Amcinafide
Onbio Inc.
-
-
Raw Materials Triamcinolone Perchloric acid Acetophenone Manufacturing Process 1 ml 72% perchloric acid was added to a suspension of 4 g triamcinolone in 100 ml of fresh distilled acetophenone and the mixture was stirred at a room temperature before all triamcinolone solved (for about 2 hours). The solution was neutralized with help of 8 ml of 1.1 N sodium hydroxide and sufficient quantity of sodium bicarbonate. Then chloroform and water were added. Organic layer was separated and concentrated in vacuum. The residue was recrystallized from acetone-hexane and thoroughly washed from acetophenone with hexane. Triamcinolone acetophenide (amicinafide) was prepared. It had MP: 281°-283°C (decomp.);αD23 = +23°. (c = 0.98 in CHCl3). References Fried J.; D. E. Patent No. 1,099,529; August 6, 1958; Olin Mathieson Chemical Corporation New York, N.Y. (USA)
236
Amcinonide
AMCINONIDE Therapeutic Function: Topical corticosteroid, Antiinflammatory Chemical Name: 16α,17α-Cyclopentylidenedioxy-9α-fluoro-11β,21-dihydroxy1,4-pregnadiene-3,20-dione-21-acetate Common Name: Amcinopol Structural Formula:
Chemical Abstracts Registry No.: 51022-69-6 Trade Name
Manufacturer
Country
Year Introduced
Cyclocort
Lederle
US
1979
Amcinonid
Cyanamid
W. Germany
1981
Visderm
Lederle
Japan
1982
Penticort
Lederle
France
-
Mycoderm
Lederle
-
-
Raw Materials 16α,17α-Cyclopentylidenedioxy-9α-fluoro-11β,21-dihydroxy-1,4pregnadiene-3,20-dione Acetic anhydride Manufacturing Process An 11.1 g (24.1 mmol) portion of the compound 16α,17αcyclopentylidenedioxy-9α-fluoro-11β,21-dihydroxy-1,4-pregnadiene-3,20-dione is placed in a 250 ml round-bottom flask. A 100 ml portion of pyridine is added and the mixture is stirred to a complete solution. A 5.5 ml (54.6 mmol) portion of acetic anhydride is added dropwise and the mixture is stirred for 2% hours. An 11 ml portion of methanol is added and the mixture is stirred an additional hour. This mixture is concentrated under reduced pressure to about 10 to 15 ml and then poured slowly into a mixture of ice, water and dilute hydrochloric acid. This mixture is stirred and the solid which forms is collected by filtration, washed with water to a neutral pH and air dried yielding 11.5 g. This solid is taken up in hot acetone, treated with activated charcoal and filtered while hot through diatomaceous earth. The filtrate is concentrated on a steam bath while adding n-hexane to the point of incipient crystallization. This mixture is allowed to cool to room temperature. The solid which forms is
Amebucort
237
collected by filtration, washed with acetone-n-hexane (1:14) and air dried yielding 7.0 g of the desired product. References Merck Index 389 DFU 3 (5) 337 (1978) Kleeman and Engel p. 36 PDR p. 1007 DOT 16 (10) 322 (1980) I.N. p. 65 REM p.972 Schultz, W., Sieger, G.M. and Krieger, C.; British Patent 1,442,925; July 14, 1976; Assigned to American Cyanamid Company.
AMEBUCORT Therapeutic Function: Antiinflammatory, Antiallergic Chemical Name: 21-Acetoxy-17-butyryloxy-11β-hydroxy-6α-methyl-4pregnene-3,20-dione Common Name: Amebucort Structural Formula:
Chemical Abstracts Registry No.: 83625-35-8 Trade Name Amebucort
Manufacturer ZYF Pharm Chemical
Country -
Raw Materials 17,21-Dihydroxy-6α-methyl-4-pregnene-3,20-dione Pyridinium tosylate Trimethyl orthoformate
Year Introduced -
238
Amebucort Sweetwort slant with Curvularia lunata (NRRL 2380) Glucose Germination culture Butyric anhydride Sulfuric acid
Manufacturing Process (a) 100 g of 17,21-dihydroxy-6α-methyl-4-pregnene-3,20-dione and 10 g of pyridinium tosylate are dissolved in 700 ml of dimethylformamide at room temperature and under agitation, and the clear solution is diluted with 3.5 L of toluene. The solution is then warmed up in a glycerin bath and, at a temperature of 120°C, 1.2 L of toluene is distilled off to remove traces of water. Under agitation, 240 ml of trimethyl orthoformate is gradually poured into the hot reaction solution; the latter is reacted for 30 min and thereafter additional toluene and other readily volatile reaction components are removed by 1 hour of distillation. The mixture is combined with 120 ml of pyridine, cooled to 60°C, and concentrated under vacuum at a bath temperature of 70°C. The mixture is then diluted with 400 ml of dimethylformamide, and the solution is poured under agitation into 10 L of water, thus obtaining the product in the form of a yellowish-white, crystalline precipitate. The mixture is stirred for another 2 hours, vacuum-filtered, washed with water, and dried for 24 hours at 40°C in a vacuum over phosphorus pentoxide, thus obtaining 111.6 g of 17,21-(1-methoxyethylidenedioxy)-6α-methyl-4-pregnene-3,20dione, melting point 85-87°C. (b) A 7-14 day old sweetwort slant with Curvularia lunata (NRRL 2380) is freed of the supernatant with 3 ml of physiological sodium chloride solution, and this supernatant is used to inoculate a 2-liter Erlenmeyer flask containing 500 ml of a nutrient solution of 2% glucose and 2% cornsteep, sterilized for 30 min at 120°C in an autoclave and adjusted to pH 6.5. After 60 hours of shaking on a rotary shaker at 30°C, 250 ml of this germination culture is used to inoculate the preliminary fermentor. A 20-liter prefermentor charged with 15 L of a nutrient medium of the same composition as the germination medium and sterilized at 121°C and 1 bar gauge pressure is inoculated with 250 ml of germination culture. With the addition of silicone SH as the defrother, germination is now conducted up to 29°C and 0.6 bar pressure under aeration (15 L/min) and agitation (220 rpm) for 24 hours. The main fermentor is inoculated with 1.5 L of this prefermentor culture. A 20-liter main fermentor, filled with 13.5 L of a sterilized nutrient medium made up of 3% cornsteep liquor and 0.7% glucose, adjusted to pH 5.5, is inoculated with 1.5 L of prefermentor culture. After an incubation phase of 12 hours under prefermentation conditions, a sterile-filtered solution of 12.18 g of 17,21-(1methoxyethylidenedioxy)-6α-methyl-4-pregnene-3,20-dione in 130 ml of dimethylformamide is added thereto and the mixture is further agitated and aerated. 4 hours after addition of the substrate, the pH value of the culture broth is set at pH 4.5 and held at this value. The pH 0.2 by automatic control with 16% sodium hydroxide solution and 20% sulfuric acid until the end of the fermentation. After a contact period of 51 hours, the microbiological conversion is complete. The content of the fermentor is then treated in a continuous centrifuge, and the culture filtrate as well as the centrifuged fungal mycelium are extracted separately with methyl isobutyl ketone. The extracts are combined and first concentrated in a forced-circulation evaporator to 1 liter at 40°C under vacuum, and then entirely evaporated to dryness in a 2-
Amesergide
239
liter round flask on a rotary evaporator under vacuum at a bath temperature of 40°C. The remaining oily residue is combined with 400 ml of hexane and decanted after vigorous shaking. Subsequently, the residue is once again combined with 400 ml of hexane and agitated at room temperature for 2 hours. The now completely crystallized residue is vacuum-filtered, washed with 100 ml of hexane, and dried for 4 hours at 60°C in a vacuum. Yield: 9.9 g of 17-acetoxy-11β,21-dihydroxy-6α-methyl-4-pregnene-3,20-dione which, after recrystallization from acetone-diisopropyl ether, melts at 192-194°C. A solution of 1.0 g of 17-acetoxy-11β,21-dihydroxy-6α-methyl-4-pregnene3,20-dione in 20 ml of pyridine is combined with 3 ml of butyric anhydride and stirred at room temperature for 2 hours. The reaction solution is then allowed to flow into 150 ml of cooled 8% sulfuric acid and agitated for another 5 hours; the product, initially precipitated in oily form, becomes completely crystallized. The product is vacuum-filtered, washed with water, and dried for 6 hours at 80°C in a vacuum. For purifying purposes, the crude product is recrystallized from acetone-diisopropyl ether, thus obtaining 940 mg of 17acetoxy-21-butyryloxy-11β-hydroxy-6α-methyl-4-pregnene-3,20-dione, melting point 98-120°C. References Annen K., Petzoldt K., Laurent H., Wiechert R., Hofmeister H.; US Patent No. 4,912,098; March 27, 1990; Assigned to Schering Aktiengesellschaft (Berlin and Bergkamen, DE)
AMESERGIDE Therapeutic Function: Serotonin antagonist Chemical Name: Ergoline-8-carboxamide, N-cyclohexyl-6-methyl-1-(1methylethyl)-, (8β)Common Name: Amesergide Structural Formula:
Chemical Abstracts Registry No.: 121588-75-8 Trade Name
Manufacturer
Country
Year Introduced
Amesergide
Onbio Inc.
-
-
LY 237733
Lilly
-
-
240
Amezepine
Raw Materials (8β)-1-Isopropyl-6-methylergoline-8-carboxylie acid Potassium carbonate Isobutyl chloroformate Cyclohexylamine Ammonium hydroxide Manufacturing Process To a 250 ml three-neck round bottom flask was added 10.0 g (32.01 mmol) of (8β)-1-isopropyl-6-methylergoline-8-carboxylie acid, 4.43 g (32.1 mmol) of potassium carbonate and 200 ml of N,N-dimethylformamide. The mixture was refluxed and 25 ml of a distillate was collected. The remaining solution was cooled in an ice bath, and then with an acetonitrile/carbon dioxide bath which lowered the temperature of the reaction mixture to about -45°C this mixture was added 4.59 g (33.62 mmol) of isobutyl chloroformate dropwise. The resulting mixture was stirred for approximately 5 min and 3.49 g (35.21 mmol) of cyclohexylamine was added. The reaction mixture was allowed to warm to room temperature and stirred for approximately 19 h. To the mixture was added 500 ml of ice water containing 25 ml of concentrated ammonium hydroxide. The mixture was cooled and the precipitated solid was collected by vacuum filtration. The resulting solid was washed with water and dried in vacuo to provide 10.13 g (yield 76.8%) of the (8β)-N-cyclohexyl-1-isopropyl6-methylergoline-8-carboxamide having a purity of 92.3%. The resulting solid was combined with three other lots of the desired compound previously synthesized to provide a total weight of 33.6 g. This material was dissolved in 1200 ml of hot methanol and the resulting solution was filtered. The filtrate was allowed to cool to room temperature and 600 ml of water was added dropwise. The mixture was cooled in the freezer and the precipitated crystals were collected by vacuum filtration. The crystals were washed with methanol and dried in vacuo to provide 26.95 g of the desired compound having a purity of 96.5% as determined by HPLC. The dried solid was dissolved in 1100 ml of hot methanol, and the resulting solution was filtered hot and allowed to cool. To this mixture was added 600 ml of water and again the precipitated solid was collected by vacuum filtration. The solid was washed with water and dried in vacuo to provide 25.82 g of the (8β)-Ncyclohexyl-1-isopropyl-6-methylergoline-8-carboxamide, melting point 250°C. The assayed material indicated 98.7% purity. References Foreman M.M. et al.; European Patent Application 0,296,748; June 6, 1988; Hudson, Christopher Mark et al Erl Wood Manor Windlesham Surrey GU20 6PH (GB)
AMEZEPINE Therapeutic Function: Antidepressant
Amezepine
241
Chemical Name: 5H-Dibenz[b,f]azepine, 5-methyl-10-(2-methylamino) ethyl)Common Name: Amezepine Structural Formula:
Chemical Abstracts Registry No.: 60575-32-8 Trade Name Amezepine Amezepine
Manufacturer ZYF Pharm Chemical Onbio Inc.
Country -
Year Introduced -
Raw Materials Potassium Sodium hydroxide Fumaric acid Hydrochloric acid Caustic potash
9-Methoxycarbony-10-methylacridinium methosulphate Potassium borohydride Lithium aluminum hydride Phosphorus pentoxide 1-Dimethylamino-2-chloroethane hydrochloride
Manufacturing Process 78.0 g 9-methoxycarbony-10-methylacridinium methosulphate salt (obtained according to a process analogous to that described by Rauhut et al. [J. Org. Chem.,(30, 3587 (1965)], 800 ml ethanol and 40 ml distilled water are mixed; then 80.0 g potassium borohydride are added over the course of 45 min, at room temperature. The mixture is agitated for 30 min, poure into a water-ice mixture, agitated for 2 h, and extracted with ether; the extract is dried by vacuum distillation. 51.0 g 9-methoxycarbonyl-10-methylacridan, melting point 106°C (recrystallized from isopropyl ether) are obtained. 250.0 g 1-dimethylamino-2-chloroethane hydrochloride and 250 ml water are mixed and cooled; 250 ml sodium hydroxide solution are added at a temperature below 10°C; the mixture is agitated for 15 min at 5°C and extracted with ether. The ethereal phases are washed with water and dried over magnesium sulfate; the ether is distilled off and the residue is redistilled. 130.0 g 1-dimethylamino-2-chloroethane, boiling point 106°-108°C, are obtained. 36.5 g 9-methoxycarbonyl-10-methylacridan and 1 L of toluene are mixed; 50 ml toluene are distilled off and the mixture is cooled. 5.56 g potassium are
242
Amezepine
added at a temperature below +10°C; the mixture is agitated for 2 h at room temperature, refluxed for 30 min, and cooled. A solution of 52.5 ml 1-dimethylamino-2-chloroethane in 200 ml toluene is added at a temperature below 20°C; the mixture is refluxed for 20 h and cooled, and 100 ml t-butanol are added. The mixture is agitated for 1 h at room temperature, 35 ml ethanol are added, and the mixture is again agitated for 30 min at room temperature. It is then extracted with 2 N hydrochloric acid; the acidic phases are washed with ether, made alkaline by the addition of sodium hydroxide solution, and extracted with ether; the ethereal phases are washed with water, dried over magnesium sulphate and then distilled to dryness under a vacuum. The residue is dissolved in 100 ml methanol; 300 ml of a saturated solution of fumaric acid in methanol are added; the methanol is distilled off and replaced by ethyl acetate. Crystallization is allowed to commence and the mixture is cooled with ice for 30 min and suction-filtered; the precipitate is washed with water and dried. 37.0 g 9-(2-dimethylaminoethyl)-9-methoxycarbonyl-10-methylacridan fumarate are obtained, melting point 176°C (recrystallized from methanolethyl acetate). 50.0 g of the 9-(2-dimethylaminoethyl)-9-methoxycarbonyl-10-methylacridan fumarate are suspended in 500 ml water; the suspension is cooled and 30 ml sodium hydroxide solution are added. The mixture is extracted with dichloromethane and the organic phases are washed with water, dried over magnesium sulphate and then distilled to dryness under a vacuum 36.0 g 9(2-dimethylaminoethyl)-9-methoxycarbonyl-10-methylacridan are obtained. 400 ml tetrahydrofuran are cooled and 20.0 g lithium aluminum hydride are added over the course of 15 min, followed by a solution of 36.0 g 9-(2dimethylaminoethyl)-9-methoxycarbonyl-10-methylacridan in 400 ml tetrahydrofuran added over the course of 30 min. The mixture is refluxed for 2 h and cooled, and 200 ml tetrahydrofuran containing 20% water are added at a temperature below 0°C. The mixture is filtered, washed with dichloromethane, and distilled to dryness under a vacuum; the residue is dissolved in dichloromethane and the organic phases are washed with water, dried over magnesium sulfate, and concentrated, ethyl acetate being added to replace the dichloromethane. Crystallization is allowed to commence and the mixture is cooled with ice for 1 h, suction-filtered, washed with water, and dried. 24.5 g 9-(2-dimethylaminoethyl)-9-hydroxymethyl-10-methylacridan, melting point 150°C (recrystallized from dichloromethane - ethyl acetate) are obtained. On concentration of the mother liquors, a second yield of 1.6 g of product is obtained (total yield: 79%). A mixture of 24.5 g 9-(2-dimethylaminoethyl)-9-hydroxymethyl-10(methylacridan) 1 L of m-xylene and 125.0 g phosphorus pentoxide are refluxed for 3 h; the reacture mixture is cooled, poured on to ice, agitated for 15 min, alkaline by the addition of sodium hydroxide solution, and extracted with ethyl acetate; the organic phases are washed with water, dried over magnesium sulfate, and dried by vacuum distillation. The residue is dissolved in ether, filtered, and concentrated to a small volume; pentane is added with distillation to remove the ether. The mixture is filtered and concentrated to about 100 ml; crystallization is allowed to commence and the mixture is
Amezinium methyt sulfate
243
cooled with ice for 1 h and suction-filtered; the precipitate is washed with water and dried in vacua. After chromatographing on magnesium silicate, eluting with ether 16.0 g 5-methyl-10-(2-dimethylaminoethyl)-5Hdibenz[b,f]azepine, melting point 78°C (recrystallized from pentane) are obtained (yield: 70%). 32.5 ml benzene and 5 ml ethyl chloroformate are mixed; a solution of 6.5 g 5-methyl-10-(2-dimethylaminoethyl)-5H-dibenz[b,f] azepine in 32.5 ml benzene are added; the mixture is refluxed for 5 h and cooled; ethyl acetate is added and the mixture is agitated in the presence of N-hydrochloric acid; the organic phase is decanted off, washed with water, dried over magnesium sulfate, and distilled to dryness under a vacuum; 5.0 g 5-methyl-10-[2-(Nethoxycarbonyl-N-methylamino)ethyl]-5H-dibenz[b,f]azepine are obtained. (Yield: 64%). 5.0 g caustic potash in 50 ml n-butanol is added to 5.0 g 5-methyl-10-[2-(Nethoxycarbonyl-N-methylamino)ethyl]-5H-dibenz[b,f]azepine; the mixture is agitated and refluxed for 20 h, and the butanol is distilled off in vacua; the residue is taken up with water, the mixture is extracted with ethyl acetate, and the organic phases are washed with water and dried over magnesium sulfate, and then distilled to dryness under vacuum; the residue is dissolved in 10 ml ether and the solution is chromatographed on magnesium silicate, eluting with ether, and distilled to dryness under a vacuum; 3.5 g crude 5methyl-10-(2-methylamino-ethyl)-5H-dibenz[b,f] azepine are obtained. References GB Patent No. 1,316,361; May 9, 1973; Assigned: ROUSSEL UCLAF, a French Body Corporate of 35 Boulevard des Invalidies, Paris 7e, France
AMEZINIUM METHYL SULFATE Therapeutic Function: Antihypotensive Chemical Name: 4-Amino-6-methoxy-1-phenylpyridazinium methyl sulfate Common Name: Structural Formula:
Chemical Abstracts Registry No.: 30578-37-1 Trade Name Regulton Regulton
Manufacturer Nordmark Knoll
Country W. Germany Switz.
Year Introduced 1981 1983
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Amfecloral
Raw Materials 1-Phenyl-4-aminopyridazone Dimethyl sulfate Manufacturing Process 18.7 parts of 1-phenyl-4-aminopyridazone-(6) and 19 parts of dimethyl sulfate in 400 parts of xylene are kept at 120°C for one hour while mixing well. The reaction mixture is suction filtered, 28 parts (89.5% of the theory) of 1-phenyl-4-amino-6-methoxypyridazinium methosulfate is obtained having a melting point of 173°C to 174°C after recrystallization from acetonitrile. The perchlorate has a melting point of 179°C to 182°C. References Merck Index 395 DFU 5 (4) 207 (1980) DOT 18 (7) 317 (1982) I.N. p. 66 Reicheneder. F. and Kropp, R.; US Patent 3,631,038; December 28, 1971; Assigned to Badische Anilin und Soda-Fabrik A.G.
AMFECLORAL Therapeutic Function: Anorexic Chemical Name: 1-Phenyl-N-(2,2,2-trichlorethylidene)-2-propylamine Common Name: Amfecloral; Amphecloral Structural Formula:
Chemical Abstracts Registry No.: 5581-35-1 Trade Name
Manufacturer
Country
Year Introduced
Amphecloral
ZYF Pharm Chemical
-
-
Raw Materials d-Amphetamine Chloral hydrate Manufacturing Process Molar equivalents of d-amphetamine base and chloral hydrate were dissolved
Amfenac sodium
245
in benzene and the solution was heated to distill off benzene and water, azeotropically. Two molar equivalents of water were separated in this manner. The remainder of the benzene was distilled off, leaving a liquid residue which was then fractionally distilled to yield the clear, colorless liquid condensation product, N-[2-(1-phenylpropyl)]-2,2,2-trichloroethylidenimine, which boiled at 95°C/0.5 mm and had an index of refraction, nD20 of 1.530 and a specific optical rotation of +49.9(+/-)0.3° [in dioxane]. Following the above procedure but using dl-amphetamine, the DL-form of N[2-(1-phenyl-propyl)]-2,2,2-trichloroethylidemmine was also prepared. It had the same boiling point and index of refraction as the (-)-form above but its specific optical rotation was zero. References Ch. J. Cavallito; US Patent No. 2,923,661; Feb. 2, 1960; Assigned to Irwin, Neigler and Co., Decatur, III.; a corporation of Illinoi
AMFENAC SODIUM Therapeutic Function: Antiinflammatory Chemical Name: 2-Amino-3-benzoylbenzeneacetic acid sodium salt Common Name: Amfenac sodium, Fenamate Structural Formula:
Chemical Abstracts Registry No.: 61618-27-7; 51579-82-9 (Base) Trade Name Amfenac sodium Fenazox
Manufacturer Country Yungjin Pharmacetical Co. Ltd. Chemos GmbH -
Year Introduced -
Raw Materials Hydrochloric acid Acetic acid Sodium hydroxide
Ethyl 2-acetamido-3-benzoylphenylacetate 2-Acetamido-3-benzoylphenylacetic acid
246
Amflutizole
Manufacturing Process 7-Benzoylindolin-2-one: Method A. A mixture of 2.5 g (0.0077 mole) of ethyl 2-acetamido-3benzoylphenylacetate in 50 ml of 3 N hydrochloric acid was refluxed for one hour. The reaction mixture was filtered and the filtrate was poured into a mixture of ice and water. The precipitate was collected and recrystallized from acetone; yield of 7-benzoylindolin-2-one 1 g (55%); melting point 154°C. Method B. A solution of 1.3 g (0.0044 mole) of 2-acetamido-3benzoylphenylacetic acid in 15 ml of 3 N hydrochloric acid and 15 ml of acetic acid was refluxed for three hours. The cooled solution was poured into ice water and the 7-benzoylindolin-2-one which precipitated was collected and dried. 2-Amino-3-benzoylphenylacetic acid: A mixture of 1.0 g (0.004 mole) of 7-benzoylindolin-2-one was added to 30 ml of 3 N sodium hydroxide and the basic solution was refluxed for 45 min under nitrogen. The mixture was filtered and the filtrate was neutralized with glacial acetic acid. The precipitate was filtered off, washed with water and dried. The 2-amino-3-benzoylbenzeneacetic acid melted at 122°C (dec.). The yield was 0.8 g (72%). References Welstead, Jr., William J., Moran H. W.; US Patent No. 4,045,576; August 30, 1977; Assigned to A. H. Robins Company, Incorporated (Richmond, VA)
AMFLUTIZOLE Therapeutic Function: Uricosuric Chemical Name: 5-Isothiazolecarboxylic acid, 4-amino-3-(3-(trifluoromethyl) phenyl)Common Name: Amflutizole Structural Formula:
Amicarbalide isethionate
247
Chemical Abstracts Registry No.: 82114-19-0 Trade Name LY 141894 Amflutizole
Manufacturer Eli Lilly Onbio Inc.
Country -
Year Introduced -
Raw Materials 3-Trifluoromethyl-α-(p-toluenesulfonyloxyimino)benzylcyanide Methyl thioglycolate Triethylamine Potassium hydroxide Manufacturing Process To a stirred solution of 3-trifluoromethyl-α-(p-toluenesulfonyloxyimino) benzylcyanide in methanol containing methyl thioglycolate was added dropwise over a 30 min period triethylamine. The reaction mixture was stirred at room temperature for 4 h following complete addition, and then was cooled to 0°C and filtered. The precipitate which was collected was recrystallized from hexane and ethyl acetate to provide methyl 3-(3-trifluoromethylphenyl)4-amino-5-isothiazolecarboxylate, melting point 94°-95°C. A solution of methyl 3-(3-trifluoromethylphenyl)-4-amino-5isothiazolecarboxylate and potassium hydroxide in methanol was heated at reflux for 6 h. The reaction mixture was then poured into ice containing 12 N aqueous hydrochloric acid. The free acid precipitated from the acidic solution, and after all of the ice had melted, the aqueous acidic mixture was filtered. The precipitate was crystallized from ethanol and water to provide 3-(3trifluoromethylphenyl)-4-amino-5-isothiazolecarboxylic acid, melting point 179°-180°C. Yield 80%. References Beck J.R. et al.; US Patent No. 4,346,094; August 24, 1982; Assigned: Eli Lilly and Company, Indianapolis, Ind.
AMICARBALIDE ISETHIONATE Therapeutic Function: Antiprotozoal Chemical Name: 3,3'-(Carbonyldiimino)bis[benzenecarboximidamide] isethionate (1:2) Common Name: Amicarbalide isethionate; Diampron Chemical Abstracts Registry No.: 3671-72-5; 3459-96-9 (Base)
248
Amicarbalide isethionate
Structural Formula:
Trade Name
Manufacturer
Country
Year Introduced
Diampron
May and Baker
-
-
Amicarbalide isethionate
Onbio Inc.
-
-
Raw Materials Phosgene Hydrogen chloride
Saturated anhydrous ethanolic ammonia m-Aminobenzonitrile
Manufacturing Process m-Aminobenzonitrile (50 g) in anhydrous pyridine (200 ml) was treated with a solution of phosgene (15 ml) in anhydrous toluene (100 ml) over 10 min with mechanical stirring. The red solution was heated for 0.5 hour on the steam bath, cooled, and added to water (2 litres). The pale grey precipitate was filtered off, washed with ether, and crystallised from methanol (250 ml). N,N1Di(m-cyanophenyl)urea separated as grey prisms, melting point 205-206°C. A suspension of N,N1-di(m-cyanophenyl)urea (42 g) in anhydrous chloroform (420 ml), containing anhydrous ethanol (70 ml), was saturated with anhydrous hydrogen chloride at 0-5°C. After setting aside for 2 hours, a clear solution was obtained, which began to crystallise. After a week, the crystals were filtered off, washed well with anhydrous ether, and dried over calcium chloride. The iminoether hydrochloride so obtained (72 g) was added to saturated anhydrous ethanolic ammonia (720 ml), and the suspension heated at 55-60°C for 6 hours. After cooling to 20°C the crystals were filtered off, and recrystallized from 2 N hydrochloric add (300 ml). 3,31Diamidinodiphenylurea dihydrochloride monohydrate separated as white prisms, melting point 286°C (decomp.). In practice it is usually used as isethonate salt. References GB Patent No. 888,965; Feb. 7, 1962; Assigned to May and Baker Limited, a British Copmpany, of Dagenham, Essex
Amidephrine mesylate
249
AMIDEPHRINE MESYLATE Therapeutic Function: Vasoconstrictorá Nasal decongestant Chemical Name: N-(3-(1-Hydroxy-2-(methylamino)ethyl)phenyl) methanesulfonamide monomethanesulfonate Common Name: Amidefrine mesilateæ Amidephrine mesylate Structural Formula:
Chemical Abstracts Registry No.: 1421-68-7; 3354-67-4 (Base) Trade Name
Manufacturer
Country
Year Introduced
Amidefrine mesylate
Pharm. Chemical Shanghai Lansheng Corporation
-
-
Raw Materials N-Benzylmethylamine Methanesulfonic acid Hydrogen
3-(2-Bromoacetyl)methanesulfonanilide Palladium on carbon Sodium hydroxide
Manufacturing Process A solution of N-benzylmethylamine 7.27 g (0.06 mole) in 25 ml of acetonitrile is added dropwise during 10 min to a solution of 8.76 g (0.03 mole) of 3-(2bromoacetyl)methanesulfonanilide (M.P. 118-121°C) in 100 ml of acetonitrile. External cooling is employed to maintain a reaction temperature of 10°C during the addition. The cooling bath is then removed and the solution stirred for an additional 20 min. Concentration of the reaction mixture yields a yellow oil which is dissolved in 300 ml of ether and washed with water to remove byproduct N-benzylmethylamine hydrobromide. The ethereal solution is dried over magnesium sulfate and the solvent distilled leaving a viscous oil. The oil is purified by dissolving in ether (250 ml), and filtering the ether solution through diatomaceous earth to remove insoluble colored impurities. The treated ether solution is diluted with 100 ml of acetonitrile. Treatment of the ether-acetonitrile solution with an ether solution of methanesulfonic acid yields 3-(2-benzylmethylaminoacetyl)methanesulfonanilide methanesulfonate as a white precipitate which is collected and washed with 100 ml of 1:1 acetonitrile-ether and dried. It weighs 9.0 g (70%), and exhibits M.P. 197.5201°C. It is recrystallized from 96% ethanol, yielding 8.0 g (62.3%) of the 3(2-benzylmethylaminoacetyl)methanesulfonanilide methanesulfonate as a crystalline product, M.P. 206-209°C.
250
Amifloverine
A solution of 31.8 g (0.74 mole) of 3-(2-benzylmethylaminoacetyl) methanesulfonanilide methanesulfonate in 700 ml of absolute ethanol is reduced in an atmospheric hydrogenation unit (2 to 5 p.s.i. g positive pressure) during 24 hours with a 10% palladium catalyst prepared from 320 mg of palladium chloride and 2.0 g of pulverized charcoal. After absorption of the calculated amount of hydrogen, the catalyst is filtered, the filtrate concentrated to about 100 ml, mixed with about 500 ml of ether, resulting in precipitation of a white solid weighing 24.3 g (96%), M.P. 201-203.5°C. Two recrystallizations from ethanol (35 ml/g of solid) yield the analytically pure 3(2-methylamino-1-hydroxyethyl)methanesulfonanilide methanesulfonate, 19.6 g (75%), M.P. 207-209°C. 3-(2-Methylamino-1-hydroxyethyl)methanesulfonanilide methanesulfonate, 17.0 g (0.05 mole) is dissolved in 50 ml of 1 N sodium hydroxide, yielding a yellow solution having pH 8. The water is removed from the solution by evaporation in vacuo and the residue is treated with several portions of ethanol which are evaporated to remove last traces of moisture. The bulk of the sodium methanesulfonate byproduct is then removed from the residue by dissolving the product in 350 ml of hot absolute ethanol and clarifying by filtration through a diatomaceous earth filter aid. The ethanolic filtrate is evaporated to dryness. Last traces of sodium methanesulfonate are then removed by washing the residue with 15 ml of cold water and then with two 15 ml portions of 1:1 cold water-isopropanol, and finally with ether, yielding 7.7 g of 3-(2-methylamino-1-hydroxyethyl)methanesulfonanilide as a white solid, M.P. 159-161°C. In practice it is usually used as monomethanesulfonate salt. References Merck Index, Monograph number: 418, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. Larsen A.A., Uloth R.H.; US Patent No. 3,341,584; Sept. 12, 1967; Assigned to Mead Johnson and Co., Evansville, Ind., Indiana
AMIFLOVERINE Therapeutic Function: Spasmolytic Chemical Name: 2-(3,5-Diethoxyphenoxy)-N,N-diethylethanamine Common Name: Amifloverine Structural Formula:
Amifostine
251
Chemical Abstracts Registry No.: 54063-24-0 Trade Name
Manufacturer
Country
Amifloverine
ZYF Pharm Chemical -
-
Amifloverine
Onbio Inc.
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-
Year Introduced
Raw Materials Sodium 1-Chloro-2-diethylaminoethane hydrochloride 3,5-Dimethoxyphenol Manufacturing Process 4.6 g of sodium was reacted with 125 ml of ethanol and, when the sodium had disappeared, 15.4 g of 3,5-dimethoxyphenol in 50 ml of absolute ethanol was added, followed by 17.2 g of 1-chloro-2-diethylaminoethane hydrochloride in suspension in 25 ml of ethanol. The mixture was refluxed for 6 hours. Then the precipitated sodium chloride was separated and the alcoholic solution was concentrated. The residue was taken up in 50 ml of ether and etheral hydrogen chloride was slowly added under reduced pressure. The mixture was filtered after cooling in ice and was dried under reduce pressure over potassium carbonate. For purification, the product (2-(3,5-diethoxyphenoxy)N,N-diethylethanamine) was recrystallized from 200 ml of boiling isopropanol using vegetable carbon black. 16.4 g (yield 56.7%) of white crystals melting at 127°C was obtained. References Lafon L.; US Patent No. 3,740,397; June 19, 1973; Assigned to Societe Orsymonde, Paris, France
AMIFOSTINE Therapeutic Function: Radioprotective, Chemoprotectant, Mucolytic Chemical Name: 2-[(3-Aminopropyl)amino]ethanethiol dihydrogen phosphate (ester) Common Name: Amifostine; Ethiofos; Fosteamine Structural Formula:
Chemical Abstracts Registry No.: 20537-88-6
252
Amifostine
Trade Name
Manufacturer
Country
Year Introduced
Ethyol
MedImmune, Inc.
-
-
Amifostine
Haorui PharmaChem Inc.
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-
Ethyol
Schering-Plough
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-
Raw Materials 2-(3-Aminopropylamino)ethanol Hydrobromic acid Trisodium phosphorothioate Manufacturing Process A solution of 2-(3-aminopropylamino)ethanol (25.0 g, 0.212 mole) in 48 % hydrobromic acid (200 ml) was distilled until 35 ml of distillate had been collected. The solution was refluxed and, periodically, more distillate was collected. The total volume of distillate removed in 7 distillation periods was 160 ml, or 80 % of the original volume of 48% hydrobromic acid, and the time of continuous boiling was approximately 48 hours. The residual solution was then evaporated to dryness under reduced pressure with the aid of several added portions of methanol. The crystalline residue was thoroughly triturated with acetone, collected, and washed on the funnel with acetone. After the product had been pressed as dry as possible on the funnel, it was dissolved in a slight excess of boiling methanol and the solution was filtered. Addition of acetone to the filtrate precipitated pure N-(2-bromoethyl)-1,3propanediamine dihydrobromide as colorless crystals, which were dried in vacuum over phosphorus pentoxide: yield 58.0 g (80%), melting point 205206°C. Trisodium phosphorothioate (6.93 g, 38.5 mmoles) was gradually added in small portions with vigorous stirring to water (38 ml) cooled externally by means of a water bath (15°-20°C). To the resulting suspension was added N-(2-bromoethyl)-1,3-propanediamine dihydrobromide (13.3 g, 38.8 mmoles). After a few minutes, complete solution occurred, and N,Ndimethylformamide (19 ml) was added with continued external cooling at 15°20°C. After the solution had been stirred at about 20°C for 90 min, it was poured into methanol (250 ml), and the mixture was refrigerated at 4°C overnight. The white precipitate that formed was collected and pressed as dry as possible on the funnel. The solid was dissolved in water (40 ml), and the solution was filtered. Addition of methanol (250 ml) reprecipitated the product. After the mixture had been refrigerated about 1 hour, the product was collected and washed on the funnel, first with methanol and finally with ether. The white solid was dried in vacuo at room temperature, then exposed to ambient conditions of the laboratory for 5 hours, and bottled under nitrogen and stored in a freezer. The yield of S-2-(3-aminopropylamino)ethyl dihydrogen phosphorothioate monohydrate, melting point (from methanol) 160-161°C, dec., was 8.15 g (91%). References Piper J.R., Johnston Th. P.; US Patent No. 3,892,824, July 1, 1975; Assigned to Southern Research Institute, Birmingem, Ala.
Amikacin
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AMIKACIN Therapeutic Function: Antibacterial Chemical Name: (S)-O-3-Amino-3-deoxy-α-D-glucopyranosyl-(1-6)-O-[6amino-6-deoxy-α-D-glucopyranosyl-(1-4)]-N1-(4-amino-2-hydroxy-1oxobutyl)-2-deoxy-D-streptamine Common Name: 1-N-[L(-)-4-Amino-2-hydroxybutyryl]kanamycin A Structural Formula:
Chemical Abstracts Registry No.: 37517-28-5; 39831-55-5 (Sulfate) Trade Name Amikin Amiklin Biklin Amikin Biklin BB-K8 Amiglyde-V Amisin Biklin Briclin Kaminax Likacin Novamin Amikacin
Manufacturer Bristol Bristol Gruenenthal Bristol Bristol Banyu Bristol Bristol Faro Frika Mead Johnson Ausonia Lisapharma Bristol Banyu
Country US France W. Germany UK Japan Italy Turkey Austria Italy Italy Japan
Year Introduced 1976 1976 1976 1976 1977 1978 -
Raw Materials N-Hydroxysuccinimide Sulfuric acid
L-(-)-γ-Amino-α-hydroxybutyric acid 6'-Monobenzyloxy-carbonyl-kanamycin A
254
Amikacin Sodium hydroxide Hydrogen
Carbobenzoxy chloride Palladium on carbon
Manufacturing Process Preparation of L-(-)-γ-benzyloxycarbonylamino-α-hydroxybutyric acid: L-(-)-γamino-α-hydroxybutyric acid (7.4 g, 0.062 mol) was added to a solution of 5.2 grams (0.13 mol) of sodium hydroxide in 50 ml of water. To the stirred solution was added dropwise at 0-5°C over a period of 0.5 hour, 11.7 grams (0.068 mol) of carbobenzoxy chloride and the mixture was stirred for another hour at the same temperature. The reaction mixture was washed with 50 ml of ether, adjusted to pH 2 with dilute hydrochloric acid and extracted with four 80 ml portions of ether. The ethereal extracts were combined, washed with a small amount of saturated sodium chloride solution, dried with anhydrous sodium sulfate and filtered. The filtrate was evaporated in vacuum and the resulting residue was crystallized from benzene to give 11.6 grams (74%) of colorless plates; MP 78.5°C to 79.5°C. Preparation of N-Hydroxysuccinimide Ester of L-(-)-γ-Benzyloxycarbonylaminoα-hydroxybutyric acid: A solution of 10.6 grams (0.042 mol) of L-(-)-γbenzyloxycarbonylamino-α-hydroxybutyric acid and 4.8 grams (0.042 mol) of N-hydroxysuccinimide in 200 ml of ethyl acetate was cooled to 0°C and then 8.6 grams (0.042 mol) of dicyclohexylcarbodiimide was added. The mixture was kept overnight in a refrigerator. The dicyclohexylurea which separated was filtered off and the filtrate was concentrated to about 50 ml under reduced pressure to give colorless crystals of L-(-)-γ-benzyloxycarbonylaminoα-hydroxybutyric acid which were collected by filtration; 6.4 grams, MP 121122.5°C. The filtrate was evaporated to dryness in vacuum and the crystalline residue was washed with 20 ml of a benzene-n-hexane mixture to give an additional amount of L-(-)-γ-benzyloxycarbonylamino-α-hydroxybutyric acid. The total yield was 13.4 grams (92%). Preparation of 1-[L-(-)-γ-Benzyloxycarbonylamino-α-Hydroxybutyryl]-6'Carbobenzoxykanamycin A: A solution of 1.6 grams (4.6 mmol) of L-(-)-γbenzyloxycarbonylamino-α-hydroxybutyric acid in 40 ml of ethylene glycol dimethyl ether (DME) was added dropwise to a stirred solution of 2.6 grams (4.2 mmol) of 6'-monobenzyloxycarbonylkanamycin A in 40 ml of 50% aqueous ethylene glycol dimethyl ether and the mixture was stirred overnight. The reaction mixture was evaporated under reduced pressure to give a brown residue 1-[L-(-)-γ-benzyloxycarbonylarnino-α-hydroxybutyryl]-6'carbobenzoxykanamycin A which was used for the next reaction without further purification. Preparation of 1-[L-(-)-γ-Amino-α-Hydroxybutyryl] Kanamycin A: The crude product 1-[L-(-)-γ-benzyloxycarbonylamino-α-hydroxybutyryl]-6'carbobenzoxykanamycin A was dissolved in 40 ml of 50% aqueous dioxane and a small amount of insoluble material was removed by filtration. To the filtrate was added 0.8 ml of glacial acetic acid and 1 gram of 10% palladiumon-charcoal and the mixture was hydrogenated at room temperature for 24 hours in a Parr hydrogenation apparatus. The reaction mixture was filtered to remove the palladium catalyst and the filtrate was evaporated to dryness in vacuum. The residue was dissolved in 30 ml of water and chromatographed on a
Amiloride hydrochloride
255
column of CG-50 ion exchange resin (NH4+ type, 50 cm x 1.8 cm). The column was washed with 200 ml of water and then eluted with 800 ml of 0.1 N NH4OH, 500 ml of 0.2 N NH4OH and finally 500 ml of 0.5 N NH4OH. Ten milliliter fractions were collected and fractions 146 to 154 contained 552 mg (22%. based on carbobenzoxykanamycin A, 6'monobenzyloxycarbonylkanamycin A) of the product which was designated BB-K8 lot 2. MP 187°C (dec). Relative potency against B. subtilis (agar plate) = 560 mcg/mg (standard: kanamycin A free base). A solution of 250 mg of BB-K8 lot 2 in 10 ml of water was subjected to chromatography on a column of CG-50 (NH4+ type, 30 cm x 0.9 cm). The column was washed with 50 ml of water and then eluted with 0.2 N NH4OH. Ten milliliter fractions were collected. Fractions 50 to 63 were combined and evaporated to dryness under reduced pressure to give 98 mg of the pure product base. Preparation of the Monosulfate Salt of 1-[L-(-)-γ-Amino-α-Hydroxybutyryl] Kanamycin A: One mol of 1-[L-(-)-γ-amino-α-hydroxybutyryl] kanamycin A is dissolved in 1 to 3 liters of water. The solution is filtered to remove any undissolved solids. To the chilled and stirred solution is added one mol of sulfuric acid dissolved in 500 ml of water. The mixture is allowed to stir for 30 minutes, following which cold ethanol is added to the mixture till precipitation occurs. The solids are collected by filtration and are determined to be the desired monosulfate salt. References Merck Index 405 Kleeman and Engel p. 38 PDR p. 692 DOT 12 (5) 202 (1976) I.N. p. 68 REM p. 1180 Kawaguchi, H., Naito, T. and Nakagawa, S.; US Patent 3,781,268; December 25, 1973; Assigned to Bristol-Myers Company Schreiber, R.H. and Kell, J.G.,; US Patent 3,974,137; August 10, 1976; Assigned to Bristol-Myers Company
AMILORIDE HYDROCHLORIDE Therapeutic Function: Diuretic Chemical Name: 3,5-Diamino-N-(aminoiminomethyl)-6-chloropyrazine carboxamide hydrochloride Common Name: Guanamprazine; Amipramidin; Amipramizide Chemical Abstracts Registry No.: 2016-88-8; 2609-46-3 (Base)
256
Amiloride hydrochloride
Structural Formula:
Trade Name Midamor Modamide Arumil Midamor Colectril Moducren Moduretic Nilurid Pandiuren Puritrid
Manufacturer Merck Merck Sharp and Dohme Merck Merck DohmeGhibret Merck Merck Sintyal Leiras
Country UK France W. Germany US US France Argentina Finland
Year Introduced 1971 1973 1975 1981 -
Raw Materials Sulfuryl chloride Ammonia Guanidine
Methyl-3-aminopyrazinoate Sodium Hydrogen chloride
Manufacturing Process Step A: Preparation of methyl 3-amino-5,6-dichloropyrazinoare: Methyl 3aminopyrazinoate (765 g, 5 mols) is suspended in 5 liters of dry benzene. While stirring under anhydrous conditions sulfuryl chloride (1.99 liters, 3.318 g, 24.58 mols) is added over a period of 30 minutes and stirring is continued for 1 hour. During this period, the temperature rises to about 50°C and then begins to drop. The mixture is heated cautiously to reflux (60°C), refluxed for 5 hours and then stirred overnight at room temperature. The excess sulfuryl chloride is distilled off at atmospheric pressure (distillation is stopped when vapor temperature reaches 78%). The dark red mixture is chilled to 6°C. The crystals are filtered off, washed by displacement with two 100 ml portions of cold (8°C) benzene, then washed with 300 ml petroleum ether and dried in vacuum at room temperature, yielding 888 g (80%) of methyl 3-amino-5,6dichloropyrazinoate in the form of red crystals, MP 228-230°C. The crude product is dissolved in 56 liters of boiling acetonitrile and passed through a heated (70-80°C) column of decolorizing charcoal (444 g). The column is washed with 25 liters of hot acetonitrile, the combined eluate concentrated in vacuum to about 6 liters and chilled to 5°C. The crystals that form are filtered, washed three times with cold acetonitrile, and air dried to constant weight, yielding 724 g (82% recovery, 66% overall) of methyl 3-amino-5,6dichloropyrazinoate in the form of yellow crystals, MP 230-234°C. After additional recrystallizations from acetonitrile the product melts at 233-234°C. Step B: Preparation of methyl-3,5diamino-6-chloropyrazinoete: In a 2-liter, 3-
Amineptine hydrochloride
257
necked flask fitted with a a mechanical stirrer, thermometer and gas inlet tube is placed dry dimethyl sulfoxide (1 liter). Methyl 3-amino-5,6dichloropyrazinoate (100 g, 0.45 mol) is added and the mixture stirred and heated at 65°C on a steam bath until solution is effected. A stream of dry ammonia gas is admitted to the solution with continuous stirring, over a period of 45 minutes while the temperature is maintained at 65-70°C. The solution is cooled to about 10°C with continuous stirring and ammonia gas is admitted for an additional 1 1/4 hours. The yellow reaction mixture is poured, with stirring, into cold water (2 liters) and the light yellow solid that separates is removed by filtration, thoroughly washed with water, and dried in a vacuum desiccator to give 82.5 g (91%) of methyl 3,5-diamino-6-chloropyrazinoate, MP 210-212°C. Recrystallization from acetonitrile gives material melting at 212-213°C. Step C: Preparation of the base: A 300 ml one-necked, round-bottomed flask, equipped with a water-cooled condenser, calcium chloride tube and magnetic stirrer is charged with anhydrous methanol (150 ml) and sodium metal (5.75 g, 0.25 g atom). When the reaction is complete, the solution is treated with dry guanidine hydrochloride (26.3 g, 0.275 mol) and stirred for 10 minutes. The sodium chloride that forms is removed by filtration. The solution is concentrated in vacuum to a volume of 30 ml and the residue treated with the product of Step B, heated one minute on a steam bath and kept at 25°C for 1 hour. The product is filtered, washed well with water, dissolved in dilute hydrochloric acid and the free base precipitated by addition of sodium hydroxide to give the amiloride product base, a solid which melts at 240.5241.5°C. To produce the hydrochloride, the base is suspended in water (70 ml) and treated with sufficient 6 N hydrochloric acid to dissolve the free base. The solution is filtered and treated with concentrated hydrochloric acid (5 ml). The hydrochloride salt (22 g, 97%) separates and is recrystallized from water (50 ml) containing concentrated hydrochloric acid (3 ml). References Merck Index 406 Kleeman and Engel p.40 PDR p. 1199 OCDS Vol. 1 p. 278 (1977) DOT 19 (3) 172 (1983) I.N. p. 69 REM p. 941 Cragoe, E.J., Jr.; US Patent 3,313,813; April 11,1967; Assigned to Merck and Co., Inc.
AMINEPTINE HYDROCHLORIDE Therapeutic Function: Central stimulant Chemical Name: 7-[10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylamino]heptanoic acid hydrochloride
258
Amineptine hydrochloride
Common Name: Structural Formula:
Chemical Abstracts Registry No.: 57574-09-1 (Base); 30272-08-3 (Hydrochloride salt) Trade Name
Manufacturer
Country
Year Introduced
Survector
Eutherapie
France
1978
Survector
Servier
Italy
1982
Maneon
Poli
Italy
1982
Raw Materials 5-Chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene Ethyl 7-aminoheptanoate Manufacturing Process 6.5 g of 5-chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene in 60 ml of nitromethane and 10.8 g of ethyl 7-aminoheptanoate in 12ml of nitromethane were mixed at ambient temperature. The reaction was slightly exothermic. The reaction mixture was left to stand overnight and the solvent was evaporated in vacuum. The residue was taken up in normal hydrochloric acid and the resulting precipitate was filtered off. 10.5 g of crude ethyl 7-[dibenzo(a,d)cycloheptadiene-5-yl]aminoheptanoate hydrochloride were obtained, of which a sample recrystallized from benzene gave a pure product melting instantaneously at 166°C to 168°C. The hydrochloride of the crude ester obtained above was added to 25 ml of 2 N hydrochloric acid. The whole was kept under reflux for 2 hours. The material dissolved and a new hydrochloride then reprecipitated. After cooling, the hydrochloride of the crude acid was filtered off, washed with iced water and then recrystallized from distilled water. 5.7 g of 7[dibenzo(a,d)cycloheptadienb-yl] aminoheptanoic acid hydrochloride were obtained, melting instantaneously at 226°C to 230°C. References Merck Index 409 Kleeman and Engel p. 40 DOT 19 (10) 547 (1983)
Aminobenzoic acid
259
I.N. p. 69 Melen, C., Danree, B. and Poignant, J.C.; US Patent 3,758,528; September 11, 1973; Assigned to Societe en nom Collectif Science Union et Cie; Societe Francaise de Recherche Medicale Melen, C., Danree, B. and Poignant, J.C.; US Patent 3,821,249; June 28, 1974; Assigned to Societe en nom Collectif Science Union et Cie; Societe Francaise de Recherche Medicale
AMINOBENZOIC ACID Therapeutic Function: Sunscreen agent, Antirickettsial Chemical Name: p-Aminobenzoic acid Common Name: Vitamin H; Vitamin Bx; PABA Structural Formula:
Chemical Abstracts Registry No.: 150-13-0 Trade Name
Manufacturer
Country
Year Introduced
Pabalate
Robins
US
1949
Hachemina
Medea
Spain
-
Pabafilm
Owen
US
-
Pabagel
Owen
US
-
Pabanol
Elder
US
-
Potaba
Westwood
US
-
Pre-Sun
Westwood
US
-
Sunbrella
Dorsey
US
-
Raw Materials Xylene Ammonium sulfate Sodium hypochlorite Manufacturing Process The following example illustrates in detail the preparation of amino benzoic acids from the hot reaction product obtained by the oxidation of a xylene and containing a mixture of salt, amide salt and diamide of a phthalic acid. 800 cc of hot aqueous oxidation product, obtained from the oxidation of pxylene with ammonium sulfate, hydrogen sulfide and water are boiled and
260
Aminobenzoic acid
agitated for 4 hours to remove carbon dioxide, hydrogen sulfide and ammonia, sufficient water being added to maintain a constant volume. The mixture is filtered to remove a precipitate containing elemental sulfur. 12 grams of activated charcoal are added to the filtrate and the mixture held at a temperature of 180°F for 20 minutes. Filtration through diatomaceous earth removes color bodies formed during the oxidation process and yields a pale yellow filtrate. The filtrate is acidified with sulfuric acid to a pH of 3 or less to precipitate approximately 49 grams of white solid, comprising a mixture of terephthalic acid and amides of terephthalic acid, which are removed by filtration. This solid is then washed with water at 200°F and redissolved in 200 cc of water containing 28.6 grams of sodium hydroxide. A mixture of sodium hypochlorite and sodium hydroxide is prepared by adding 27.5 grams of chlorine to a vessel equipped with cooling means and containing a solution of 50 grams of sodium hydroxide in 375 cc of water, thereafter adding sufficient water to produce 500 cc of solution. 190 cc of this cold solution are slowly added to the acid-amide solution previously prepared so as to keep the temperature of the mixture below 55°F. The mixture is stirred for 15 minutes and then heated rapidly to 200°F and maintained at that temperature for one hour. 2 grams of sodium thiosulfate are added to consume excess sodium hypochlorite. The solution is acidified to a pH of 3 or less and filtered hot. The filter cake, comprising about 26.9 grams of terephthalic acid, is then suspended in 300 cc of dilute sulfuric acid of pH about 2, heated to 200°F and filtered hot. The filtrates are combined, cooled, and extracted with three successive 200 cc portions of ether. The pH of the filtrate is then raised to 3.5 with sodium hydroxide and the filtrate extracted with six successive 200 cc portions of ether to yield the balance of the product. The crude p-aminobenzoic acid product is recovered by evaporation of ether and is suspended in hot benzene, cooled and filtered to remove benzoic and toluic acids together with small amounts of impurities soluble in the filtrate. Recrystallization of the product from 200 cc of water yields 14.5 grams of light tan needles of p-aminobenzoic acid having an acid number of 411 (theoretical value 409). Aminobenzoic acid can be then purified and decolorized by a process described in US Patent 2,735,865. References Merck Index 423 PDR pp.926, 1894 I.N. p.1012 REM p.787 Toland, W.G. and Heaton, C.D.; US Patent 2,878,281; March 17, 1959; Assigned to California Research Corporation Spiegler, L.; US Patent 2,947,781; August 2, 1960; Assigned to E.I. Du Pont de Nemours and Company Lyding, A.R.; US Patent 2,735,865; February 21, 1956; Assigned to Heyden Chemical Corporation
Aminocaproic acid
261
AMINOCAPROIC ACID Therapeutic Function: Antifibrinolytic Chemical Name: 6-Aminohexanoic acid Common Name: Epsilcapramin Structural Formula:
Chemical Abstracts Registry No.: 60-32-2 Trade Name Epsilon Epsilon-Aminoca Capramol Amicar Epsikapron Acikaprin Amicar Capracid Capracid Capralense Capramol Caprolisin EACA Ekaprol Epsilon Hemocaprol Capusumine Hemotin Ipsilon Resplamin
Manufacturer Roche Roche Choay Lederle Kabi Vitrum Polfa Lederle Kabi Vitrum Bonomelli-Hommel Choay Intalfarmaco Malexi Kasi Vitrum Difrex Star Delagrange Nichiiko Hokuriku Daiichi Kyorin
Country W. Germany W. Germany France US UK Poland US Sweden Italy France Italy Italy Sweden Australia Finland France Japan Japan Japan Japan
Year Introduced 1962 1962 1963 1964 1967 -
Raw Materials Caprolactam Water Manufacturing Process 5 kg of caprolactam were heated with 40 liters of water in a pressure vessel
262
Aminoglutethimide
at 250°C for a period of four hours. These quantities of reactants correspond to a water:lactam molecular ratio of 50:1. After cooling, the small quantity of the nonsoluble substance that is formed is filtered off, and the filtrate is evaporated as far as possible. The resulting concentrate is mixed with three times its volume of strong alcohol, thereby causing the desired product, epsilon-aminocaproic acid (6-aminohexanoic acid), to crystallize out. After separating the crystalline product thus obtained, a further quantity of epsilonaminocaproic acid can be obtained from the mother liquid if desired. References Merck Index 433 Kleeman and Engel p. 41 PDR pp. 872, 997 I.N. p. 13 REM p. 831 Koch, T.; US Patent 2,453,234; November 9, 1948; Assigned to American Enka Corporation
AMINOGLUTETHIMIDE Therapeutic Function: Cytostatic Chemical Name: 3-(4-Aminophenyl)-3-ethyl-2,6-piperidinedione Common Name: α-(p-Aminophenyl)-α-ethylglutarimide Structural Formula:
Chemical Abstracts Registry No.: 124-84-8 Trade Name
Manufacturer
Country
Year Introduced
Ellipten
Ciba
US
1960
Cytadren
Ciba Geigy
US
1980
Orimeten
Ciba Geigy
Switz.
1981
Orimeten
Ciba Geigy
UK
1982
Raw Materials α-Phenyl-α-ethyl glutarimide Nitric acid Hydrogen
Aminolevulinic acid hydrochloride
263
Manufacturing Process The α-(p-nitrophenyl)-α-ethyl-glutarimide starting material can be prepared as follows: 217 g of α-phenyl-α-ethyl-glutarimide are dissolved in 800 g of concentrated sulfuric acid with subsequent cooling to about -10°C and nitration is carried out at -10°C to +10°C by slow addition of a mixed acid consisting of 110 g of concentrated sulfuric acid and 110 g of 63% nitric acid. The nitration solution is stirred into ice, the separated nitro compound taken up in methylene or ethylene chloride, the solution washed with water and sodium carbonate solution until neutral and the solvent evaporated under vacuum. The residue is crystallized from methanol or ethyl acetate, whereby a yellowish crystal powder of MP 128-136°C is obtained in a yield of about 85% which consists for the most part of α-(p-nitrophenyl)-α-ethyl-glutarimide. By recrystallization from methanol the pure p-nitrophenyl compound is obtained of MP 137-139°C. From the residues of the mother liquors a small quantity of the isomeric α-(o-nitrophenyl)-α-ethyl-glutarimide of MP 170-172°C can be obtained. 26.2 g of α-(p-nitrophenyl)-α-ethyl-glutarimide of MP 137-139°C dissolved in ethyl acetate, are reduced in the presence of nickel with hydrogen in a shaking flask at 50-70°C until the absorption of hydrogen falls off. The catalyst is then filtered off with suction and the solution concentrated and cooled, as a result of which colorless crystals of MP 146-149°C are obtained. Recrystallization from methanol gives pure α-(p-aminophenyl)-α-ethylglutarimide of MP 149-150°C (yield 97%). Instead of ethyl acetate another solvent can be used in the above reduction, such as methanol or ethanol. The hydrochloride of MP 223-225°C is obtained by dissolving the base with alcohol and the corresponding quantity of hydrochloric acid gas in the hot with subsequent cooling of the solution. Colorless crystals are formed of MP 223225°C, which are easily soluble in water. References Merck Index 443 PDR p. 794 OCDS Vol. 1 p.257 (1977) I.N. p. 71 REM p. 1143 Hoffmann, K. and Urech, E.; US Patent 2,848,455; August 19, 1958; Assigned to Ciba Pharmaceutical Products, Inc.
AMINOLEVULINIC ACID HYDROCHLORIDE Therapeutic Function: Photosensitizer Chemical Name: Pentanoic acid, 5-amino-4-oxo-, hydrochloride
264
Aminolevulinic acid hydrochloride
Common Name: Aminolevulinic acid hydrochloride Structural Formula:
Chemical Abstracts Registry No.: 5451-09-2; 106-60-5 (Base) Trade Name
Manufacturer
Country
Year Introduced
Levulan Kerastick
DUSA Pharmaceuticals Inc.
-
-
Raw Materials N-Furfurylphthalimide Rose Bengal Palladium on carbon Manufacturing Process 1) Oxidation Step 2.27 g (10.0 mmol) of N-furfurylphthalimide was charged into a three-necked glass flask equipped with an oxygen feed tube, a thermometer, and a reflux condenser, and dissolved in 100 ml of anhydrous pyridine. After the addition of 7.0 mg of Rose Bengal, oxygen gas was fed at a rate of 20 ml/min at 10°20°C under irradiation by light. A 27 W white fluorescent lamp was used as a light source and the radiation was performed from the outside of the flask. After 7 hours, the irradiation was terminated and the pyridine was evaporated under reduced pressure to obtain 2.47 g of a light brown, semi-crystalline product. 2) Reduction Step (Hydrogenation) 2.00 g of the semi-crystalline solid obtained in (1) was dissolved in 40 ml of methanol and stirred at 50°C in a hydrogen atmosphere under atmospheric pressure in the presence of 200 mg of 5% palladium-on-carbon catalyst. After five hours, the reaction was terminated and the mixture was allowed to cool to room temperature. The catalyst was removed by filtration and methanol was evaporated to obtain 2.11 g of white crystals. The crystals were identified to be 5-phthalimidolevulinic acid by NMR analysis. The yield was 97%. 3) Hydrolysis Step 100 ml of 6 N hydrochloric acid was added to 2.11 g of the white crystals (2), and the mixture was heated under reflux for 5 hours.
Aminometradine
265
After evaporating the hydrochloric acid under reduced pressure, a brown solid product was obtained and dissolved in ethanol. Acetone was added to the solution and the crystals produced were collected by filtration to obtain 0.689 g of 5-aminolevulinic acid hydrochloride. The yield based on Nfurfurylphthalimide was 51%. NMR spectrum data conformed to 5-aminolevulinic acid hydrochloride References Takeya H. et al.; US Patent No. 5,380,935; Jan. 10, 1995; Assigned Cosmo Research Institute; Cosmo Oil Co., Ltd., both of Tokyo, Japan
AMINOMETRADINE Therapeutic Function: Diuretic Chemical Name: 6-Amino-3-ethyl-1-(2-propenyl)-2,4(1H,3H)pyrimidinedione Common Name: Aminometramide Structural Formula:
Chemical Abstracts Registry No.: 642-44-4 Trade Name
Manufacturer
Country
Year Introduced
Mincard
Searle
US
1954
Mictine
Searle
-
-
Raw Materials Monoallyl urea Sodium hydroxide
Cyanoacetic acid Diethyl sulfate
Manufacturing Process 85 parts of monoallylurea are dissolved in 105 parts of acetic anhydride, and 85 parts of cyanoacetic acid are added gradually and the mixture is maintained at 65°C for 2.5 hours. The mixture is distilled at 20 mm until a syrup remains. 50 parts of water are added to this syrup and distillation is resumed. The resulting syrup is dissolved in 96% ethanol at 60°C, stirred with charcoal and filtered. One to one and one-half volumes of ether are added to the filtrate at 40°C. Upon cooling the N-cyanoacetyl-N'-allylurea precipitates.
266
Aminopentamide
It is collected on a filter and washed with ether. The white crystals melt at about 142-143°C. The N-cyanoacetyl-N'-allylurea is dissolved by warming with 10% sodium hydroxide. Sufficient 70% sodium hydroxide is added to raise the pH to 10. The solution is maintained at 60°C for five minutes. After cooling the crystals are collected on a filter and recrystallized from water. 1-Allyl-6amino-1,2,3,4-tetrahydro-2,4-pyrimidinedione is obtained in the form of white crystals melting at 270-272°C. 334 parts of 1-allyl-6-amino-1,2,3,4-tetrahydro-2,4-pyrirnidinedione are dissolved in a solution of 88 parts of sodium hydroxide in 1,100 parts of water. While this mixture is stirred rapidly at 50°C, 430 parts of diethyl sulfate are added in the course of 30 minutes. Stirring is continued at 50-55°C for one hour longer, and an alkaline reaction is maintained by occasional additions of small portions of 20% aqueous sodium hydroxide solution, about 300 parts in all being required. On cooling, the 1-allyl-3-ethyl-6-amino-1,2,3,4tetrahydro-2,4-pyrimidinedione separates as the monohydrate; it is filtered off, washed with cold water, and recrystallized from water containing a small amount of sodium hydroxide to hold in solution any unreacted 1-allyl-6amino-1,2,3,4-tetrahydro-2,4-pyrimidinedione. The air dried product thus obtained contains 1 mol of crystal water and melts over a wide range with dehydration at 75-115°C. After dehydration by treatment with anhydrous ether, the anhydrous 1-allyl-3-ethyl-6-amino-1,2,3,4-tetrahydro-2,4pyrimidinedione melts sharply at about 143-144°C. References Merck Index 455 OCDS Vol. 1 p. 265 (1977) I.N. p. 72 Papesch, V. and Schroeder, E.F.; US Patent 2,650,922; September 1, 1953; Assigned to G.D. Searle and Co.
AMINOPENTAMIDE Therapeutic Function: Anticholinergic Chemical Name: 4-(Dimethylamino)-2,2-diphenylvaleramide Common Name: Dimevamide Structural Formula:
Aminophylline
267
Chemical Abstracts Registry No.: 60-46-8 Trade Name
Manufacturer
Country
Year Introduced
Centrine
Bristol
US
1953
Raw Materials α,α-Diphenyl-γ-dimethylaminovaleronitrile Hydroxylamine hydrochloride Manufacturing Process A mixture of 14 g (0.05 mol) of α,α-diphenyl-γ-dimethylaminovaleronitrile, 16 g (0.2 mol) of sodium acetate, 14 g (0.2 mol) of hydroxylamine hydrochloride and 75 ml of ethyl alcohol was refluxed 18 hours. The mixture was cooled, poured into water and neutralized with ammonium hydroxide. The heavy white precipitate solidified on standing. The material was filtered and recrystallized from isopropanol. After three recrystallizations the aminopentamide product melted at 177° to 179°C. The product is often used as the acid sulfate which is produced as follows: 252.0 g (0.85 mol) of α,α-diphenyl-γ-dimethylaminovaleronitrile was dissolved in one liter of isopropanol, and 70 ml of concentrated sulfuric acid was added as rapidly as possible. The mixture was heated until clear, then filtered and diluted with 1,500 ml of anhydrous ethyl acetate. The solution was cooled and filtered, and the white crystalline product was dried in vacuum over P2O5. References Merck Index 463 I.N. p. 342 Specter, M.E.; US Patent 2,647,926; August 4, 1953; Assigned to Bristol Laboratories, Inc.
AMINOPHYLLINE Therapeutic Function: Diuretic, Cardiac stimulant, Smooth muscle relaxant, Vasodilator Chemical Name: 1H-Purine-2,6-dione, 3,7-dihydro-1,3-dimethyl-, compd. with 1,2-ethanediamine (2:1) Common Name: Aminophelline; Teofyllamin; Theophyllin-Athylendiamin; Theophylline; Theophyl(l)amin; Ethylenediamine Chemical Abstracts Registry No.: 317-34-0
268
Aminophylline
Structural Formula:
Trade Name
Manufacturer
Country
Year Introduced
Memcophylline
Memphis Co.
-
-
Memcophylline IV
Memphis Co.
-
-
Aminophyl
Neon Laboratories Ltd.
-
-
Aminophylline
Wellcome
-
-
Aminophylline
AroKor Holdings Inc.
-
-
Aminophylline
West-ward Pharmaceutical Corp.
-
-
Aminophylline, Anhydrous
Spectrum Chemicals and Laboratory Products, Inc.
-
-
Afonilum
Knoll
-
-
Aminodur
Berlex
-
-
Cardophylin
Rhone Poulenc
-
-
Euphyllina
Byk Gulden
-
-
Pecram
Novartis
-
-
Phyllocontin
Purdue Frederick
-
-
Phyllotemp
Mundipharma
-
-
Planphylline
Asta
-
-
Pulmovet
Solvay
-
-
Tefamin
Recordati
-
-
Ventax
Yamanouchi Europe
-
-
Diffumal 24
Malesci Instituto Pharmabiologico
-
-
Durofilin
Zdravle
-
-
Retafyl
Orion Pharma International
-
-
Slow-Bid
Rhone-Poulenc Rorer
-
-
Spophyllin Retard
Slovakofarma
-
-
Theo
Amoun
-
-
Theostat
Pierre Fabre Medicament
-
-
Teotard
Krka
-
-
Uni-Dur
Schering-Plough
-
-
Aminocardol
Wander
-
-
Aminofilin
Srbolek
-
-
Aminopromazine fumarate
269
Trade Name
Manufacturer
Country
Year Introduced
Aminofilina
Ariston
-
-
Aminofilina
Biochimico
-
-
Aminofilina
IMA
-
-
Aminofilina
Sandoz
-
-
Aminofilina
Uniao Quimica Farm.
-
-
Aminofilina
Vital Brazil
-
-
Aminofilina
Azevedos
-
-
Aminofilina
C.P. Higiene
-
-
Aminofilina
Apteka im.T.Kosciusz
-
-
Theophyllaminum
Leiras
-
-
Theodrox
Suomen Astra
-
-
Theodrox
3 M Riker
-
-
Raw Materials Theophylline Ethylenediamine hydrate Manufacturing Process A mixture of 198 g (1 mol) theophylline and 60-78 g (0.75-1 mol) ethylenediamine hydrate in 300 g of water was stirred at 50°C and then the mixture was concentrated in vacuo. The product (aminophylline) was separeted by suction filtration. Aminophylline was used as an aqueous solution. References Byk H., DE Patent No. 223,695, June 30, 1910; Assigned to Chemische Werke
AMINOPROMAZINE FUMARATE Therapeutic Function: Spasmolytic Chemical Name: 10-(2,3-Bis(dimethylamino)propyl)phenothiazine fumarate (2:1) Common Name: Aminopromazine fumarate; Proquamezine fumarate; Tetrameprozine Chemical Abstracts Registry No.: 3688-62-8;58-37-7 (Base)
270
Aminopromazine fumarate
Structural Formula:
Trade Name Jenotone Jenotone Lispamol Lorusil Myspamol Sedofarmolo
Manufacturer Coopers Schering-Plough Specia Biochemie May and Baker Centralvet
Country -
Year Introduced -
Raw Materials Phenothiazine Sodium amide 1,3-Bis(dimethylamino)-2-chloropropane Manufacturing Process Phenothiazine (20 g) is heated under reflux for 1 hour with sodium amide (5 g) in xylene (80 ml). A solution of 1,3-bis(dimethylamino)-2-chloropropane (27 g) (prepared by a method analogous to that described in Ingold and Rothstein J.C.S. 1931, 1676) in xylene (30 ml) is then added over 2 hours. Heating is continued for a further 1 hour and then the mixture is taken up in water (270 ml) and hydrochloric acid (d=1.19; 20 ml). The decanted acid layer is treated with caustic soda (d 1.33; 25 ml) and the base is extracted with ether (2 x 50 ml) which is then dried over potassium carbonate. On distillation there is obtained at 218-220°C/0.6 mm Hg a mixture (20 g) containing a major proportion of 10-[2,3-bis(dimethylamino)-1propyl]phenothiazine and a minor proportion of 10-[1,3-bis(dimethylamino)-1propyl]phenothiazine. A mixture of bases (11 g) obtained is dissolved in isopropanol (25 ml). Ether (25 ml) containing dry hydrogen chloride (2 g) is added, the mixture is left to crystallise overnight in a refrigerator and the product is filtered off, washed and dried. There is thus obtained a salt (2.5 g), M.P. 244°C, which is 10-[1,3bis(dimethylamino)-1-propyl]phenothiazine hydrochloride. On evaporation of the mother liquors from the above hydrochloride a residue is obtained from which is isolated its isomer, 10-[2,3-bis(dimethylamino)-1propyl]phenothiazine, the base crystallising from ethanol and melting at 58°C. The structure of these two isomers has been confirmed by comparison of their infra-red adsorption spectra with those of related products of known structure. In practice it is usually used as fumarate.
Aminopterin hydrate
271
References Merck Index, Monograph number: 487, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. GB Patent No. 800,635; Nov.4,1955; Assigned to Socciete des Usines Chimiques Rhone-Poulenc, a French body corporate
AMINOPTERIN HYDRATE Therapeutic Function: Antineoplastic Chemical Name: L-Glutamic acid, N-(4-(((2,4-diamino-6-pteridinyl)methyl) amino)benzoyl)-, hydrate Common Name: 4-Amino-4-deoxyfolic acid; 4-Aminofolsäure; 4-Amino-PGA; Aminopterin; 4-Aminopteroylglutamic acid; 4-Aminopteroylglutaminsäure; Antifolic acid; Antifolsäure Structural Formula:
Chemical Abstracts Registry No.: 54-62-6 (Base) Trade Name
Manufacturer
Country
Year Introduced
Aminopterin
Sigma Chemical Company
-
-
Raw Materials 1,3-Dihydroxyacetone Bromine Cysteine hydrochloride hydrate Triphenylphosphine
Barium chloride dihydrate N-(4-Aminobenzoyl)-L-glutamic acid 2,4,5,6-Tetraaminopyrimidine sulfate hydrate
Manufacturing Process 2,4,5,6-Tetraaminopyrimidine·H2SO4·H2O (75.0 g, 0.293 mole) was added to a stirred solution of BaCl2·2H2O (71.5 g, 0.293 mole) in H2O (1.45 L) at 8590°C. The mixture was stirred rapidly at about 90°C for 15 min, cooled to 40°C, and filtered from BaSO4, which was washed thoroughly on a funnel with
272
Aminopterin hydrate
H2O. The clear, yellow filtrate was then diluted further with H2O to give a volume of 4.35 L. This solution of the tetraaminopyrimidine·2HCl was then added to a solution of NaOAc (4.35 L of 4 N) in which 1,3-dihydroxyacetone (79.3 g, 0.88 mole) and cysteine·HCl·H2O (51.5 g, 0.293 mole) had just been dissolved. The resulting solution was stirred mechanically at room temperature while a slow stream of air was continuously passed through it for 26 hours. (Yellow-orange solid began separating after 2 hours). The mixture was then kept in a refrigerator for 16 hours before the solid was collected, washed successively with cold H2O, EtOH, and Et2O before it was dried to constant weight in vacuo over P2O5 at 25°C. [The crude product mixture (47 g) was weighed in order to obtain an estimate of the volume of 48% HBr required to form hydrobromide salts]. A mechanically stirred mixture of the dried solid and EtOH (6.05 L) was heated to 70°C, and a solution of 48% HBr (28 ml) in EtOH (490 ml) was added in a thin stream while the mixture was maintained at 70-75°C. The mixture was then refluxed for about 5 min with rapid stirring while nearly all of the solid dissolved. The hot solution was treated with Norit and filtered through a Celite mat. The clear yellow filtrate was kept in a refrigerator overnight while a first crop of orange colored solid separated. The collected solid was washed with EtOH, then dried in vacuo (56°C over P2O5) to give 17.2 g of product. The filtrate was concentrated by evaporation (rotary evaporator) to about 2 L and then refrigerated to give a second crop of 10.2 g, which was dried as before; total yield of crude 2,4diamino-6-pteridinemethanol hydrobromide 27.4 g (34%). The PMR spectrum of this material in CF3CO2D showed it to contain a barely detectable amount of methyl-substituted 2,4-diaminopteridine·HBr. Bromine (59.6 g, 0.373 mole) was added dropwise over a 30 min to a stirred solution of triphenylphosphine (97.7 g, 0.373 mole) in anhydrous dimethylacetamide (486 ml) kept at 10°C (ice bath) and protected from atmospheric moisture. (Bromine remaining in the funnel was rinsed with 10 ml of dimethylacetamide). A smooth suspension containing finely divided, crystalline triphenylphosphine dibromide resulted. The 2,4-diamino-6pteridinemethanol·HBr (25.4 g, 0.093 mole) described above was added in one portion through a powder funnel (with the aid of 10 ml dimethylacetamide). The ice bath was removed, and the stirred mixture was allowed to warm to 20-25°C. After about 1 hour, complete solution had occurred. The solution, which gradually developed a dark red color, was kept at 20-25°C for 1 hour longer and was then chilled (ice bath) before it was treated with EtOH (72 ml). After overnight refrigeration, the solvents were removed by evaporation in vacuo. The dark, semisolid residue was stirred with two 300 ml of C6H6 (to remove triphenylphosphine oxide), and each portion was removed from the C6H6 insoluble product by decantation. The solid that remained was dissolved with stirring in glacial AcOH (660 ml) which had been preheated to 80°C. The mixture was kept in a bath at 80°C until solution was complete. Tan crystalline solid separated as the dark solution was allowed to cool. Overnight refrigeration caused the AcOH to partially freeze. When it had thawed, the solid was collected, washed with chilled AcOH followed by Et2O, and dried in vacuo (over P2O5 and NaOH pellets) at successive temperatures of 25°C, 56°C, and 110°C. (The higher temperature was necessary for complete removal of AcOH). The yield was 15.3 g (49%). (Some runs afforded 60% yield). This sample was further purified by reprecipitation from MeOH solution (Norit) by addition of Et2O followed by drying in vacuo (25°C, P2O5), yield 13.0 g (42%) of 2,4-diamino-6-(bromomethyl)pteridine hydrobromide as
Aminosalicylic acid
273
a pale yellow solid. A mixture of 2,4-diamino-6-(bromomethyl)pteridine hydrobromide (168 mg, 0.500 mmole) and N-(4-aminobenzoyl)-L-glutamic acid (400 mg, 1.50 mmoles) in dimethylacetamide (2 ml) was stirred at 25°C under N2 in a stoppered flask protected from light. Solution occurred after 2 hours. After 18 hours, the orange solution was mixed with H2O (15 ml) with stirring to give a finely divided, yellow precipitate. The mixture was centrifuged, and the supernatant removed by decantation. The yellow solid was stirred with four 15 ml portions of H2O, each of which was removed by decantation after centrifugation. The solid was then suspended in EtOH (15-20 ml), collected by filtration, washed with Et2O, and dried in vacuo (25°C, P2O5) to give hydrated N-[4-[[(2,4-diamino-6-pteridinyl)methyl]amino]benzoyl]-L-glutamic acid (Aminopterin) hydrate (4:7) in 68% yield (160 mg). Examination by TLC revealed one UV-absorbing spot and no fluorescence at any point. References Merck Index, Monograph number: 493, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. James R.P., Montgomery J.A.; US Patent No. 4,079,056; Mar. 14; Assigned to The Unites States of America, Departament of Health, Education and Welfare, Washington
AMINOSALICYLIC ACID Therapeutic Function: Antitubercular Chemical Name: 4-Amino-2-hydroxybenzoic acid Common Name: Structural Formula:
Chemical Abstracts Registry No.: 65-49-6 Trade Name
Manufacturer
Country
Year Introduced
Pamisyl
Parke Davis
US
1948
Parasal
Panray
US
1950
Rexipas
Squibb
US
1954
Aminacyl
Wander
UK
-
B-Pas
Salvoxyl-Wander
France
-
Enseals
Lilly
US
-
Nemasol
I.C.N.
Canada
-
274
Aminosalicylic acid
Trade Name
Manufacturer
Country
Year Introduced
Neopasalate
Mallinckrodt Inc.
US
-
Panacyl
-
Paramisan
Pharma W. Germany Rheinpreussen Smith and Nephew UK
Para-Pas
Gold Leaf
US
-
Pas
Sumitomo
Japan
-
Pasido
Ferrosan
Sweden
-
Propasa
-
-
Rezipas
Merck Sharp and Dohme Squibb
US
-
Sanpas
Sanyo
Japan
-
Sta-Pas
Debat
France
-
Tebacin Acid
Consol. Midland
US
-
-
Raw Materials Sodium-p-aminosalicylate m-Aminophenol Ammonium carbonate Manufacturing Process As described in US Patent 427,564, aminosalicylic acid may be prepared from m-aminophenol by heating with ammonium carbonate in solution under pressure. Alternatively, aminosalicylic acid may be made from sodium p-aminosalicylate as described in US Patent 2,844,625 as follows: 196 grams of commercial sodium para-aminosalicylate (18.5% H2O) was dissolved in 196 ml of water and 150 ml of isopropanol. 6 grams of sodium bisulfite was dissolved in the solution and the solution filtered. While stirring and keeping the temperature between 25-31°C, seven grams of 85% formic acid and 27.5 grams of 95% sulfuric acid in 150 ml of water was added during 1 ½ hours. The mixture was stripped 1 hour longer, cooled to 23°C and filtered. The filter cake was washed with 100 cubic centimeters of water, further washed with 100 cc of 25% isopropanol and 100 cc of water, and vacuum dried to constant weight at 4550°C. Weight of p-aminosalicylic acid was 76.5 grams (92.7% yield) exhibiting a bulk density of 47 cc/oz. References Merck Index 485 Kleeman and Engel p. 43 I.N. p. 74 REM p. 1213 Gnehm, R.and Schmid, J.; US Patent 427,564; May 13, 1890 Centolella, A.P.; US Patent 2,844,625; July 22, 1958; Assigned to Miles Laboratories, Inc. Doub, L.; US Patent 2,540,104; February 6, 1951; Assigned to Parke Davis and Co.
Amiodarone hydrochloride
275
AMIODARONE HYDROCHLORIDE Therapeutic Function: Coronary vasodilator Chemical Name: (2-Butyl-3-benzofuranyl)[4-(2-diethylamino)ethoxyl-3,5diiodophenyl]methanone hydrochloride Common Name: Structural Formula:
Chemical Abstracts Registry No.: 1951-25-3 (Base) Trade Name Cordarone Cordarone Cordarone X Cordarone Cordarexne Amiodacore Atlansil Miodarone Procor Ritmocardyl Trangorex Uro-Septra
Manufacturer Labaz Sigma Tau Labaz Labaz Labaz C.T.S. Roemmers Biosintetica Unipharm Bago Labaz Biosintetica
Country France Italy UK Switz. W. Germany Israel Argentina Brazil Israel Argentina Brazil
Year Introduced 1971 1980 1981 1982 -
Raw Materials 2-n-Butyl-3-(3,5-diiodo-4-hydroxybenzoyl)benzofuran Sodium methoxide β-Diethylaminoethyl chloride Manufacturing Process 135 grams of 2-n-butyl-3-(3,5-diiodo-4-hydroxybenzoyl)benzofuran dissolved in 600 cc of ethyl carbonate were treated with 5.7 grams of sodium in the form of sodium methoxide in methanol. Then, β-diethylaminoethyl chloride which had been obtained from 51.6 grams of the hydrochloride in ethyl
276
Amiphenazole
carbonate was introduced into a suspension of the sodium salt. The mixture was heated to a temperature of approximately 90°C which was maintained for approximately 2 hours. The mixture was cooled and allowed to stand overnight during which time the sodium chloride settled down. The toluene solution containing diethylaminoethyl ether was extracted with increasingly diluted aqueous hydrochloric acid solutions while stirring. Extraction was continued until the alkalized solution produced no further precipitate. The combined aqueous solutions were washed with ether and then made strongly alkaline with aqueous sodium hydroxide. Extraction with ether was carried out three times. The organic layers were washed with water and then dried over anhydrous potassium carbonate. In order to produce the hydrochloride, the carbonate was filtered off and then the hydrochloride was precipitated from the ether solution with an ethereal hydrochloric acid solution. After the solution had been allowed to stand for a few hours, decantation was carried out and the syrupy hydrochloride residue was taken up in 500 cc of boiling acetone. The salt crystallized out by cooling. The substance was allowed to stand overnight at 0°C, and centrifuged, washed with ethyl acetate and then with ether and dried. 130 grams of 2-n-butyl-3(3,5-diiodo-4-β-N-diethylaminoethoxybenzoyl)benzofuran hydrochloride in the form of a crystalline powder which melts at 156°C were obtained. References Merck Index 491 Kleeman and Engel p. 43 DOT 5 (4) 123 (1969) I.N. p. 75 Tondeur, R. and Binon, F.; US Patent 3,248,401; April 26, 1966; Assigned to Societe Beige de I'Azote et des Produits Chimiques du Marly, SA, Belgium
AMIPHENAZOLE Therapeutic Function: Respiratory stimulant, Barbiturate antagonist, Morphine antagonist Chemical Name: Thiazole, 2,4-diamino-5-phenylCommon Name: Amifenazole; Amiphenazole Structural Formula:
Chemical Abstracts Registry No.: 490-55-1
Amisometradine
277
Trade Name
Manufacturer
Country
Year Introduced
Aamphisol
RJR
-
-
Raw Materials Thiourea α-Bromophenylacetonitrile Manufacturing Process Thiourea reacted with α-bromophenylacetonitrile and as a result of this reaction 2-(cyanophenylmethyl)isothiourea was obtained. By cyclisation of the 2-(cyanophenylmethyl)isothiourea 2,4-diamino-5phenylthiazole (amiphenazol) was produced. References Kleemann A., Engel J.; Pharmazeutische Wirkstoffe, GeorgThieme Verlag Stuttgart. New York, 1982
AMISOMETRADINE Therapeutic Function: Diuretic Chemical Name: 6-Amino-3-methyl-1-(2-methyl-2-propenyl)-2,4(1H,3H)pyrimidinedione Common Name: Structural Formula:
Chemical Abstracts Registry No.: 550-28-7 Trade Name
Manufacturer
Country
Year Introduced
Rolicton
Searle
US
1956
Raw Materials Methallylamine Cyanoacetic acid
Methyl isocyanate Sodium hydroxide
278
Amisulpride
Manufacturing Process Preparation of the ethyl analog is as follows (methyl isocyanate is used in amisometradine manufacture). To a cooled and stirred solution of 142 parts of methallylamine in 900 parts of benzene, 156 parts of ethyl isocyanate are added dropwise. Upon concentration in vacuum N-ethyl-N'-methallylurea is obtained. 260 parts of this urea derivative are dissolved in 500 parts of acetic anhydride and treated with 157 parts of cyanoacetic acid at 60°C and heated at that temperature for 2 hours. The solution is then concentrated in vacuum to a syrup. 100 parts of water are added and the vacuum distillation is repeated. The remaining syrup contains a mixture of N-cyanoacetyl-N-ethyl-N'methallylurea and a small quantity of N-cyanoacetyl-N-methallyl-N'-ethylurea. This syrup is treated with sufficient 20% sodium hydroxide solution to raise the pH to 10. A violent reaction occurs. The reaction mixture is diluted with 50 parts of water, stirred, cooled and filtered. The material collected on the filter is recrystallized from 10% ethanol to yield a mixture of 1-methallyl-3-ethyl-6amino-1,2,3,4-tetrahydro-2,4-pyrimidinedione and 1-ethyl-3-methallyl-6amino-1,2,3,4-tetrahydro-2,4-pyrimidinedione melting at about 157-159°C. References Merck Index 493 OCDS Vol. 1 p. 266 I.N. p. 76 Papesch, V. and Schroeder, E.F.; US Patent 2,729,669; January 3, 1956; Assigned to G.D. Searle and Co.
AMISULPRIDE Therapeutic Function: Antipsychotic Chemical Name: Benzamide, 4-amino-N-((1-ethyl-2-pyrrolidinyl)methyl)-5(ethylsulfonyl)-2-methoxyCommon Name: Aminosultopride; Amisulpride Structural Formula:
Amisulpride
279
Chemical Abstracts Registry No.: 71675-85-9 Trade Name Solian Amitrex Socian
Manufacturer Lorex-Synthelabo Synthelabo Sanofi-Synthelabo GmbH
Country -
Year Introduced -
Raw Materials 2-Methoxy-4-amino-5-mercaptobenzoic acid Caustic soda Ethyl sulfate Manufacturing Process 2-Methoxy-4-amino-5-ethylthiobenzoic acid: 159 g of 2-methoxy-4-amino-5-mercaptobenzoic acid, 355 ml of water and 160 ml of caustic soda solution are placed in a flask fitted with a condenser. The mixture is heated until the solid dissolves, then 123 g of ethyl sulfate is added. The mixture is heated to reflux, treated with 10 ml of 30% caustic soda solution, then heated to reflux for 1 hour. After cooling, 800 ml of water is added and the solution is filtered. The precipitate obtained by adding 100 ml of concentrated hydrochloric acid in the presence of ether is drained, washed with water and dried. 162 g of 2-methoxy-4-amino-5-ethylthiobenzoic acid is obtained (yield=88%). 2-Methoxy-4-amino-5-ethylsulfonylbenzoic acid: 123 g of 2-methoxy-4-amino-5-ethylthiobenzoic acid is dissolved hot in 542 ml of acetic acid. The solution obtained is cooled to 35°C, then 185 ml of hydrogen peroxide is added in small quantities while the temperature is raised to 80°C. The temperature is lowered to 40°C and the mixture is kept at that temperature for some hours and then cooled to 10°C. The precipitate formed is drained, washed with acetic acid and dried, then dissolved in 600 ml of water and 100 ml of 20% ammonia. The precipitate formed by adding 70 ml of concentrated hydrochloric acid is cooled, drained, washed with water and dried. 61.5 g of 2-methoxy-4-amino-5-ethylsulfonylbenzoic acid is obtained (yield 42%, M.P. 95-100°C). 4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2methoxybenzamide: 81 g of 2-methoxy-4-amino-5-ethylsulphonylbenzoic acid and 297 ml of acetone are placed in a flask fitted with an agitator, a thermometer and a dropping funnel, followed by 33 g of triethylamine. The solution is cooled to 0°C, then 30 g of ethyl chloroformate is added drop by drop between 0° and 5°C. When the mixture has been agitated 51 g of 1-ethyl-2aminomethylpyrrolidine is added drop by drop between 5° and 10°C. The mixture is agitated at 10°C then at ambient temperature. The triethylamine hydrochloride which precipitates is drained, then the acetone is distilled. The residue is dissolved in 600 ml of water in the presence of caustic soda
280
Amitraz
solution. The base crystallizes after seeding and is drained, washed with water and dried. When the crystals have been purified by passing them through hydrochloride and recrystallising them in acetone, 66 g of 4-amino-N-[(1ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamideis obtained (yield 61%, M.P. 126-127°C). References Thominet M., Acher J., Monier J.; US Patent No. 4,401,822; Aug. 30, 1983; Assigned to Societe de'Etudes Scientifiques et Industrielles de l'Ile-de France (Paris, FR)
AMITRAZ Therapeutic Function: Acaricide, Scabicide, Tickicide, Appetite stimulant Chemical Name: Methanimidamide, N'-(2,4-dimethylphenyl)-N-(((2,4dimethylphenyl)imino)methyl)-N-methylCommon Name: Amitraz; Ectodex; Topline Structural Formula:
Chemical Abstracts Registry No.: 33089-61-1 Trade Name Aludex Ectodex
Manufacturer Hoechst Roussel Vet Ltd. Intevet
Country -
Year Introduced -
-
-
Raw Materials Sodium hydroxide N-Methylformamide
2,4-Dimethylaniline hydrochloride 4-Toluenesulfonyl chloride
Manufacturing Process A mixture of 55.1 g 2,4-dimethylaniline hydrochloride, 83.7 g ptoluenesulphonyl chloride and 150 ml N-methylformamide was stirred with occasional cooling to maintain the temperature at 20°-35°C. When the exothermic reaction had subsided, the mixture was stirred at room temperature for 4 h, poured into a mixture of ice and water, and basified with 10 N sodium hydroxide solution, keeping the temperature of the mixture
Amitriptyline hydrochloride
281
below 10°C. The precipitated solid was filtered, washed with water until free from alkali, dried at room temperature, to give N-2,4-dimethylphenyl-N'methylformamidine, melting point 75°-76°C (recrystallized from cyclohexane). A solution of 19.4 g N-2,4-dimethylphenyl-N'-methylformamidine and 0.3 g ptoluenesulphonic acid in 195 ml dry xylene was refluxed under anhydrous conditions for 48 h, causing the evolution of methylamine. The xylene was distilled off under reduced pressure to give 1,5-di-(2,4-dimethylphenyl)-3methyl-1,3,5-triaza-penta-1,4-diene, melting point 88°-89°C (crystallized twice from isopropyl). References Harrison I. R. et al.; US Patent No. 3,781,355; Dec. 25, 1973; Assigned: Boots Pure Drug Company Limited, Nottingham, England
AMITRIPTYLINE HYDROCHLORIDE Therapeutic Function: Antidepressant Chemical Name: 3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)N,N-dimethyl-1-propaneamine hydrochloride Common Name: Structural Formula:
Chemical Abstracts Registry No.: 549-18-8; 50-48-6 (Base) Trade Name Elavil HCl Elavil Triptizol Laroxyl Endep Amitril Amitid Arnavil
Manufacturer Merck Sharp and Dohme DDSA Merck Sharp and Dohme
Country US
Year Introduced 1961
UK Italy
1962 1962
Roche Roche WL/PD Squibb Mallard
Italy US US US US
1962 1975 1978 1979 1980
282
Amitriptyline hydrochloride
Trade Name
Manufacturer
Country
Year Introduced
Enovil
Hauck
US
1982
Adepril
Lepetit
Italy
-
Adepress
Essex-Shionogi
Japan
-
Ami-Aneiun
Lorente
Spain
-
Amilent
Warner Lambert
US
-
Amiprin
Kobayashi
Japan
-
Amiptanol
Kanto
Japan
-
Amitrip
Glebe
Australia
-
Amitriptol
Bracco
Italy
-
Annolytin
Kodama
Japan
-
Annolytin
Nippon Shoji
Japan
-
Deprestat
Script Intal
S. Africa
-
Domical
Berk
UK
-
Elatrol
ICN
Canada
-
Elatrol
Teva
Israel
-
Elatrolet
Teva
Israel
-
Lantron
Yamanouchi
Japan
-
Lentizol
Warner Lambert
US
-
Levate
ICN
Canada
-
Limbitrol
Roche
France
-
Limbitrol
Roche
US
-
Mareline
Elliott-Marion
Canada
-
Meravil
Medic
Canada
-
Miketorin
Mitsui
Japan
-
Mitaptyline
Toyo Pharm.
Japan
-
Mutanxion
Cetrane
France
-
Mutaspline
Cetrane
France
-
Normaln
Sawai
Japan
-
Novotriptyn
Novopharm
Canada
-
Redomex
Labaz
-
-
Saroten
Lundbeck
W. Germany
-
Saroten
Tropon
W. Germany
-
Saroten
Warner
UK
-
Sarotex
Lundbeck
W. Germany
-
Schuvel
Tokyo Hosei
Japan
-
Sensival
Pfizer Taito
Japan
-
Teperin
EGYT
Hungary
-
Trepiline
Lennon
S. Africa
-
Triavil
Merck Sharp and Dohme Kimya Evi
US
-
Turkey
-
Triptilin
Amitriptyline hydrochloride
283
Trade Name
Manufacturer
Country
Year Introduced
Triptyl
Farmos
Finland
-
Tryptal
Unipharm
Israel
-
Tryptanol
Merck-Banyu
Japan
-
Tryptizol
Sharp and Dohme W. Germany
-
Tryptizol
Sharp and Dohme UK
-
Raw Materials Phthalic anhydride Hydrochloric acid Phenylacetic acid
3-(Dimethylamino)propyl chloride Hydrogen
Manufacturing Process Phthalic anhydride is reacted with phenylacetic acid to form 3benzylidenephthalide which is then hydrogenated to 2-phenethylbenzoic acid. Conversion to the acid chloride followed by intramolecular dehydrochlorination yields the ketone, 5H-dibenzo[a,d]cyclohepten-5-one. The ketone undergoes a Grignard reaction with 3-(dimethylamino)propyl chloride to give 5-(γdimethylaminopropylidene)-5H-dibenzo[a,d]cycloheptene. Then, as described in US Patent 3,205,264, a solution of 5-(γdimethylaminopropylidene)-5H-dibenzo[a,d]cycloheptene (42 grams; 0.153 mol) in 105 ml of ethanol is hydrogenated over Raney nickel (1.5 grams) at 65°C under an initial hydrogen pressure of 450 lb. After 1 mol of hydrogen is absorbed (3.5 hours), the reaction mixture is filtered to remove the catalyst and is acidified with 80 ml of 2.5 N hydrochloric acid (0.2 mol). The acidic solution is concentrated to dryness under vacuum and is flushed three times with 100 ml of benzene to remove residual water. The solid residue then is dried under vacuum at 40°C to yield 44.9 grams (94% of theory) of the product, MP 187-189.5°C, equivalent weight 307, ultraviolet absorption A% 2380432. Recrystallization from isopropyl alcohol and ether affords the product in high purity. In practice it is usually used as hydrochloride. References Merck Index 496 Kleeman and Engel p. 44 PDR pp. 673, 993, 1174, 1217, 1314, 1509, 1513, 1569, 1606, 1617 OCDS Vol. 1 pp. 151, 404 DOT 9 (6) 219 (1973) I.N. p. 76 REM p. 1093 Tristram, E.W. and Tull, R.J.; US Patent 3,205,264; September 7, 1965; Assigned to Merck and Co., Inc.
284
Amitriptyline oxide
AMITRIPTYLINE OXIDE Therapeutic Function: Antidepressant Chemical Name: 3-(3'-Dimethylaminopropylidene)dibenzo[a,d]cyclohepta1,4-diene N-oxide Common Name: Structural Formula:
Chemical Abstracts Registry No.: 4317-14-0 Trade Name
Manufacturer
Country
Year Introduced
Equilibrin
Nattermann
W. Germany
1980
Ambivalon
Nattermann
W. Germany
-
Raw Materials Dibenzo[a,d]cyclohepta-1,4-diene-5-one 3-Dimethylaminopropanol magnesium chloride Hydrogen peroxide Manufacturing Process 31.3 g (0.1 mol) of 3-(3'-dimethylaminopropylidene)dibenzo[a,d]cyclohepta1,4-diene hydrochloride are dissolved in water, and the free base is liberated by means of a 28% aqueous solution of sodium hydroxide. The free base is sucked off, washed with water, and dissolved in 100 ml of methanol. To the solution are added 31 ml of 30% hydrogen peroxide. After 7 days, the reaction mixture is diluted with 200 ml of water, and the major part of the methanol is evaporated in vacuum. The precipitated N-oxide crystals are filtered off, washed with water, and dried, yielding 27 g of the dihydrate of 3(3'-dimethylaminopropylidene)dibenzo[a,d]cyclohepta-1,4-diene N-oxide with melting point of 102° to 103°C. In dehydrated state the melting point is 228°C to 230°C. By dissolving the N-oxide in acetone, and bubbling dry hydrogen chlorine gas through the solution until slightly acid reaction, the hydrochloride of the Noxide is precipitated as a white crystalline substance with melting point of 172°C to 173.6°C.
Amixetrine hydrochloride
285
The starting material can be prepared in known manner from dibenzo[a,d]cyclohepta-1,4-diene-5-one by a Grignard reaction with 3dimethylaminopropyl magnesium chloride, hydrolysis and dehydration of the resulting carbinol. References Merck Index 497 DFU 5 (7) 329 (1980) Kleeman and Engel p. 45 DOT 18 (3) 110 (1982) I.N. p. 77 Pedersen, J.B.; British Patent 991,651; May 12, 1965; Assigned to A/S Dumex (Dumex, Ltd.) Merck and Co., Inc.; British Patent 1,095,786; December 20, 1967 Pedersen, J.B.; US Patent 3,299,139; January 17, 1967; Assigned to A/S Dumex (Dumex, Ltd.)
AMIXETRINE HYDROCHLORIDE Therapeutic Function: Antiinflammatory, Anticholinergic, Antidepressant Chemical Name: N-(2-Phenyl-2-isoamyloxy)ethylpyrrolidine hydrochloride Common Name: Structural Formula:
Chemical Abstracts Registry No.: 24622-52-4; 24622-72-8 (Base) Trade Name
Manufacturer
Country
Year Introduced
Somagest
Riom
France
1972
Raw Materials Styrene Hydrogen chloride Pyrrolidine
Isoamyl alcohol t-Butyl hypobromite
Manufacturing Process There is heated under reflux with stirring for 10 hours: 117 g of (2-phenyl-2-
286
Amlexanox
isoamyloxy)ethyl bromide, 61.5g of pyrrolidine and 250 ml of toluene. After filtration of the pyrrolidine hydrobromide, the toluene is removed under reduced pressure. The residue is then taken up with 4 N HCl. The aqueous solution is washed with ether. It is made alkaline by a solution of 50% NaOH. It is extracted with ether. The ethereal phase is dried over anhydrous sodium sulfate, and rectified under reduced pressure after removing the solvent. There is thus obtained 90 g of a colorless oil with an amine odor. The hydrochloride is prepared in the usual manner by dissolving the amine in anhydrous ether and adding to it the requisite amount of dry gaseous hydrochloric acid, dissolved in absolute alcohol. There is obtained a white crystalline powder melting at 150°C, very soluble in water and alcohol, very slightly soluble in ether and ethyl acetate. The starting material above is prepared by reacting styrene with isoamyl alcohol and then reacting that product with t-butyl hypobromite. References Merck Index 499 Kleeman and Engel p. 46 DOT 8 (9) 334 (1972) I.N. p. 77 Centre Europeen de Recherches Mauvernay, RIOM; British Patent 1,253,818; November 17, 1971
AMLEXANOX Therapeutic Function: Antiulcer (topical) Chemical Name: 5H-[1]Benzopyrano[2,3-b]pyridine-3-carboxylic acid, 2amino-7-(1-methylethyl)-5-oxoCommon Name: Amlexanox, Amoxanox Structural Formula:
Chemical Abstracts Registry No.: 68302-57-8 Trade Name
Manufacturer
Country
Year Introduced
Aphthasol
Block Drug Company
-
-
Apthasol
Access Pharmaceuticals
-
-
Amlodipine besylate
287
Trade Name Apthera OraDisc
Manufacturer Paladin Labs Access Pharmaceuticals
Country -
Year Introduced -
OraRinse
Paladin Labs
-
-
Raw Materials Morpholine Piperidine
6-Isopropyl-4-oxo-4H-1-benzopyran-3-carbonitrile Ethyl cyanoacetate
Manufacturing Process A mixture of 2 ml of morpholine, 3 ml of dimethylformamide and 10 ml of water was heated to 60°C and under stirring the equal molecular quantity of 6-isopropyl-4-oxo-4H-1-benzopyran-3-carbonitrile was added for 5 minutes. The mixture was heated at that temperature for one hour and the resultant precipitate was filtered, rained with water recrystallized from acetic acid and washed with chloroform. By the above procedure was obtained 2-amino-6isopropyl-4-oxo-4H-1-benzopyran-3-carboxaldehyde melting at 206°-208°C. A mixture of 4 ml ethyl cyanoacetate, 50 ml of ethanol, 5 ml of piperidine and the equal molecular quantity of 2-amino-6-isopropyl-4-oxo-4H-1-benzopyran3-carboxaldehyde was refluxed for 30 minutes and, after cooling, the crystalline precipitate was filtered and washed with chloroform. By above procedure was obtained ethyl-2-amino-7-isopropyl-1-azaxanthone-3carboxylate, melting after recrystallization from ethanol at 243°-244°C. A mixture of 10 ml of acetic acid and 10 ml of 55% sulfuric acid the equal molecular quantity and 2-ethyl-amino-7-isopropyl-1-azaxanthone-3carboxylate was stirred at 130°C for 4 hours and, after water was added, the precipitate was collected by filtration and recrystalllized from dimethylformamide to give the 2-amino-7-(1-methylethyl)-5-oxo-5H[1]benzopyrano[2,3-b]pyridine-3-carboxylic acid, melting point 300°C. References Nohara Akira et al.; US Patent No. 4,143,042; March, 6, 1979; Assigned Takeda Chemical Industries, Ltd., Osaka, Japan
AMLODIPINE BESYLATE Therapeutic Function: Antianginal, Antihypertensive Chemical Name: 2-[(2-Aminoethoxy)methyl]-4-(2-chlorophenyl)-3ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine monobenzenesulfonate Common Name: Amlodipine besylate Chemical Abstracts Registry No.: 111470-99-6; 881150-42-9 (Base)
288
Amlodipine besylate
Structural Formula:
Trade Name
Manufacturer
Country
Year Introduced
Amlodin
-
-
Amlodipine besilate
Sumitomo Pharmaceuticals Co., Ltd. Ultra-tech Spc. Pvt. Ltd.
India
-
Amlogard
Pfizer
-
-
Amlovas
India
-
India
-
Normodipine
Unique Pharmaceutical Laboratories Macleods Pharmaceuticals Pvt. Ltd. Gedeon Richter
Hungary
-
Norvasc
Lincoln
-
-
Stamlo
Dr. Reddy's Laboratories Ltd. PT Pfizer
India
-
Indonesia
-
Amlovas
Tensivask Raw Materials
Hydrazine hydrate Phthalimide Ethylacetoacetate
2-Chlorobenzaldehyde Methyl-3-aminocrotonate
Manufacturing Process 2-[(2-Aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5methoxycarbonyl-6-methyl-1,4-dihydropyridine (amlodipine) was prepared from 2-(phthalimidoaminoethoxy)acetoacetate, 2-chlorobenzaldehyde and methyl-3-aminocrotonate under refluxing in ethanol for 24 hours. The ketoester was prepared by the method of Troostwijk and Kellog (JCS Chem. Comm., 1977, p.932). Methyl-3-aminocrotonate can be prepared by known method. Phthalimido-amino-protecting group was removed using hydrazine hydrate in ethanol at the reflux temperature. Although amlodipine is effective as the free base, in practice it is best administered form of a salt of a pharmaceutically acceptable acid.
Amobarbital
289
Benzensulphonic salt of amlodipine was prepared as follows: Amlodipine base (65.6 g, 0.161 mols) was slurried in industrial methylated spirit (denatured alcohol, 326.4 ml) and cooled to 5°C. Benzensulphonic acid (26.2 g, 0.168 mols) was dissolved in industrial methylated spirit (65.6 ml) at 5°C and added to base. The resulting slurry was then granulated, filtered and washed with 2 volumes the same solvent (65.6 ml). The damp solid was slurred at 5°C for 1 hr in 327.6 ml industrial methylated spirit, filtered, washed with 2 volumes of the same solvent (65.6 ml) and dried under vacuum at 55°C for 24 hr. A yield of besylate salt of amlodipine 65 g. References Campbell S.F. et al.; US Patent No. 4,572,909, Feb. 25, 1986; Assigned: Pfizer Inc. (New York, NY) (Preparation 2a) Davison E. et al.; US Patent No. 4,879,303, Nov. 7, 1989; Assigned: Pfizer Inc. (New York, NY)
AMOBARBITAL Therapeutic Function: Hypnotic, Antiepileptic Chemical Name: Barbituric acid, 5-ethyl-5-isopentylCommon Name: 5-Ethyl-5-isopentylbarbituric acid; Amobarbitone; Amylbarbitone; Pentymal Structural Formula:
Chemical Abstracts Registry No.: 57-43-2 Trade Name Hypnotal Isonal Sednotic Transital
Manufacturer Pharmacal Leiras Dista Miquel
Country -
Year Introduced -
Raw Materials Malonic acid diethyl ester Ethyl bromide
Sodium ethylate Isopentyl bromide
Manufacturing Process By interaction of malonic acid diethyl ester with sodium ethylate (molar ratio 1:1) and then with ethyl bromide (molar ratio 1:1) was prepared ethylmalonic
290
Amocarzine
acid diethyl ester. From ethylmalonic acid diethyl ester and sodium ethylate (molar ratio 1:1) and then with isopentylbromide was synthesized α-ethyl-αisopentylmalonic acid diethyl ester. By condensation of α-ethyl-αisopentylmalonic acid diethyl ester with urea in the presence of sodium ethylate was obtained ethyl-isopentylbarbituric acid. References Layraud E.; GB Patent No. 191,008; Oct. 25, 1923 Shonle H.A.; US Patent No. 1,856,792; May 3, 1932; Assigned to Eli Lilly and Company, of Indianapolis, Indiana, a Corporation of Indiana
AMOCARZINE Therapeutic Function: Anthelmintic Chemical Name: 1-Piperazinecarbothioamide, 4-methyl-N-(4-((4-nitrophenyl) amino)phenyl)Common Name: Amocarzine; Phenthiourezine Structural Formula:
Chemical Abstracts Registry No.: 36590-19-9 Trade Name
Manufacturer
CGP 6140
CIBA-GEIGY Corp. -
Country
Year Introduced -
Raw Materials 4-Nitro-4'-isothiocyanodiphenylamine N-Methylpiperazine Manufacturing Process A solution of 4-nitro-4'-isothiocyanodiphenylamine in toluene was treated at 50°C with stirring with a solution N-methylpiperazine in toluene. After 3 hours the solution was filtered from the precipitate obtained. By recrystallization the crude product from methanol the 4-methyl-N-[4-[(4nitrophenyl)amino]phenyl]-1-piperazinecarbothioamide was obtained; melting point 191-196°C.
Amodiaquin
291
References Ruediger Spaun et al.; US Patent No. 3,781,290; Dec. 25, 1973; Assigned to Ciba-Geigy Corporation, Ardsley, N.Y.
AMODIAQUIN Therapeutic Function: Antimalarial Chemical Name: 4-[(7-Chloro-4-quinolinyl)amino]-2-[(diethylamino)methyl] phenol Common Name: 4-(3'-Diethylaminomethyl-4'-hydroxyanilino)-7chloroquinoline Structural Formula:
Chemical Abstracts Registry No.: 86-42-0 (Base); 69-44-3 (Dihydrochloride salt) Trade Name Camoquin HCl Flavoquine Corbutyl Camoquin
Manufacturer Parke Davis Roussel I.S.H. Parke Davis
Country US France France UK
Year Introduced 1950 1979 -
Raw Materials 4,7-Dichloroquinoline Diethylamine
p-Aminophenol hydrochloride Paraformaldehyde
Manufacturing Process 72.8 g (0.5 mol) of p-aminophenol hydrochloride is dissolved in 500 cc of water and added to 99 g (0.5 mol) of 4,7-dichloroquinoline. After a few minutes of warming in a steam bath, 4-(4'-hydroxyanilino)-7-chloroquinoline hydrochloride, of sufficient purity for use in further experiments, precipitates as a yellow crystalline solid. Recrystallized from methanol, the MP is over 300°C. A mixture consisting of 13.5 g of 4-(4'-hydroxyanilino)-7-chloroquinoline hydrochloride dissolved in absolute ethanol is treated with a solution of 4.38 g
292
Amoproxan hydrochloride
of diethylamine and 1.8 g of paraformaldehyde in 20 cc of absolute ethanol. The reaction mixture is heated under reflux for 16 hours, evaporated to onehalf volume and the warm solution treated with an excess of hydrogen chloride dissolved in absolute ethanol. Acetone is added to the warm solution until it becomes turbid and then the solution is cooled. The crude dihydrochloride which separates is collected and purified by recrystallization from methanol; MP 240-242°C. By using an equivalent amount of 4-(4'-hydroxyanilino)-7-bromoquinoline in the above procedure, 4-(3'-diethylaminomethyl-4'-hydroxyanilino)-7bromoquinoline dihydrochloride is obtained; MP (base) 206-208°C dec. References Merck Index 593 Kleeman and Engel p. 47 I.N. p.78 REM p. 1217 Burckhalter, J.H., Jones, E.M., Rawlins, A.L., Tendick, F.H, and Holcomb, W.F.; US Patent 2,474,821; July 5, 1949; Assigned to Parke, Davis and Co.
AMOPROXAN HYDROCHLORIDE Therapeutic Function: Antiarrhythmic, Antianginal Chemical Name: 3,4,5-Trimethoxybenzoic acid 1-[(3-methylbutoxy)methyl]2-(4-morpholinyl)ethyl ester hydrochloride Common Name: Amoproxan hydrochloride, Aproxim Structural Formula:
Chemical Abstracts Registry No.: 22661-96-7 Trade Name
Manufacturer
Country
Year Introduced
Bisolaryn
Boehringer Ingelheim
-
-
Ambrobeta
Betapharm
-
-
Exabrol
Pharmacos
-
-
Amoproxan hydrochloride
293
Raw Materials Isoamyl alcohol Boron trifluoride Epichlorohydrin Morpholine Hydrogen chloride (3,4,5-Trimethoxy)benzoyl chloride Manufacturing Process To a mixture of 176 g (2 M) of isoamyl alcohol and 4 ml of a 10% solution of BF3 in anhydrous ether, were added, with stirring, 278 g (3 M) of epichlorohydrin while maintaining the temperature at approximately 45°C. After the addition, the reaction was maintained for an additional hour at 60°C. It was then cooled and a solution of 160 g of NaOH in pellets in 200 ml H2O was added while maintaining the temperature at approximately 15°C. Stirring was continued for an additional 2 hours, the NaCl formed was filtered and the organic phase decanted. Vacuum fractionation gave 142 g of 3-isoamyloxy1,2-epoxypropane. Boiling point 67-68°C. To a solution of 115.2 g (0.8 M) of 3-isoamyloxy-1,2-epoxypropane in 200 ml of absolute ethanol were added 76 g of morpholine. The temperature rose to approximately 40°C. Heating under reflux was continued for one additional hour, the solvent was distilled and the reaction mixture vacuum fractionated to obtain 166 g of 4-[3-isoamyloxy-2-hydroxy]propyltetrahydro-1,4-oxazine. Boiling point 163°C, nD21 = 1.4620, yield=90%. In a 2 liter three-neck flask, provided with a tight-fitting stirrer and a reflux condenser, were charged: 115.5 g (0.5 M) of 4-[3-isoamyloxy-2hydroxy]propyl tetrahydro-1,4-oxazine in 750 ml of anhydrous benzene, 50.5 g of triethylamine and 115.25 g of (3,4,5-trimethoxy)benzoyl chloride. The mixture was slowly brought to reflux, which was maintained for 4 hours. After cooling, it was filtered, the solvent was stripped off under vacuum, the residue taken up in 4 N HCl (in the cold) and the aqueous solution washed with ether. The aqueous solution was then treated with sodium carbonate and the oil formed extracted with the ether. It was dried over anhydrous sodium sulfate and the solvent tripped off to obtain a highly viscous oily residue, which was taken up in 600 ml of ethyl acetate; the required quantity of absolute ethanol, with 30% HCl gas, was then added, affording the hydrochloride. After standing for several hours in the ice-box, it was filtered, and after recrystallization from anhydrous isopropyl alcohol and drying under vacuum at 60°C to constant weight, 155 g of (3,4,5-trimethoxy)benzoyl chloride were obtained. Yield=67%, melting point 145°C. References Mauvernay R. Y., Busch N., Simond J., Moleyre J.; US Patent No. 3,790,569; Feb. 1, 1974; Assigned to Centre Europeen de Recherches Mauvernay, Riom, France
294
Amosulalol hydrochloride
AMOSULALOL HYDROCHLORIDE Therapeutic Function: Alpha-adrenergic blocker, Beta-adrenergic blocker, Antihypertensive Chemical Name: (+/-)-5-(1-Hydroxy-2-((2-(o-methoxyphenoxy)ethyl)amino) ethyl)-o-toluenesulfonamide monohydrochloride Common Name: Amosulalol hydrochloride; Lowgan Structural Formula:
Chemical Abstracts Registry No.: 70958-86-0; 85320-68-9 (Base) Trade Name
Manufacturer
Country
Year Introduced
Amosulalol hydrochloride
Yamanouchi
-
-
Raw Materials Methyl ethyl ketone Sodium borohydride Hydrogen chloride Hydrogen
N-Benzyl-2-(2-methoxyphenoxy)ethylamine 5-Bromoacetyl-2-methylbenzenesulfonamide Palladium on charcoal
Manufacturing Process A mixture of N-benzyl-2-(2-methoxyphenoxy)ethylamine, methyl ethyl ketone, and 5-bromoacetyl-2-methylbenzenesulfonamide was refluxed with stirring. After cooling the reaction mixture, ethyl ketone was distilled off under reduced pressure and the residue formed was dissolved in benzene. Then, ether was added to the solution and after removing the hydrobromide of N-benzyl-2-(2methoxyphenoxy)ethylamine precipitated, the solvent was distilled off under reduced pressure to provide a viscous oily product. The viscous oily product was dissolved in ethanol and after adding to the solution an excess amount of sodium borohydride, the mixture was stirred at room temperature followed by distilling off ethanol under reduced pressure. The residue was dissolved in ethyl acetate and the ethyl acetate layer recovered was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to provide a viscous oily product. The product was subjected to a silica gel column chromatography and eluted using benzene and then a mixture of benzene and ethyl acetate of 10:1 by volume ratio to provide 5-{1-hydroxy-2-[N-benzyl-2-(2methoxyphenoxy)ethylamino]ethyl}-2-methyl-benzenesulfonamide as a viscous oily product.
Amoxapine
295
In 200 ml of methanol was dissolved 20.0 g of 5-{1-hydroxy-2-[N-benzyl-2(2-methoxyphenoxy)ethylamino]ethyl}-2-methyl-benzenesulfonamide. After adding thereto 20 ml of ethanol containing about 10% hydrogen chloride and 1.0 g of 10% palladium charcoal, the mixture was shaken in hydrogen gas stream. When the absorption of hydrogen stopped, the catalyst was filtered away and the filtrate was distilled off under reduced pressure. The residue was dissolved in 100 ml of ethanol while it was hot and the solution was allowed to stand overnight in ice chamber, whereby 12.8 g of the α-type crystals of 5-{1-hydroxy-2-[2-(2-methoxyphenoxy)ethylamino]ethyl}-2methylbenzenesulfonamide were obtained as the colorless crystals, melting point 169°-171°C. In practice it is usually used as monohydrochloride References Imai K. et al.; US Patent No. 4,217,305; August 12, 1980; Assigned: Yamanouchi Pharmaceutical Co., Ltd., Tokyo, Japan
AMOXAPINE Therapeutic Function: Antidepressant Chemical Name: 2-Chloro-11-(1-piperazinyl)dibenz[b,f][1,4]oxazepine Common Name: Structural Formula:
Chemical Abstracts Registry No.: 14028-44-5 Trade Name
Manufacturer
Country
Year Introduced
Asendin
Lederle
US
1980
Moxadil
Lederle
France
1980
Amoxan
Lederle
Japan
1981
Omnipress
Cyanamid
W. Germany
1983
Demolox
Lederle
-
-
296
Amoxapine
Raw Materials N-Carbethoxypiperazine o-(p-Chlorophenoxy)aniline hydrochloride Ethyl chlorocarbonate Phosphorus pentoxide Manufacturing Process A mixture of 125 g of o-(p-chlorophenoxy)aniline hydrochloride and 100 ml of dry pyridine is treated cautiously with a solution of 90 ml of ethyl chlorocarbonate in 150 ml of ether. The mixture is kept at room temperature for 3 days, diluted with about 500 ml of water and extracted with 300 ml of ether, The ethereal extract is washed with 300 ml of water, dried over calcium chloride, filtered and concentrated. The resulting ethyl o-(pchlorophenoxy)carbanilate is obtained in a viscous oil suitable for use in the next step without further purification. A solution of 70 g of ethyl o-(p-chlorophenoxy)carbanilate and 120 g of Ncarbethoxypiperazine in 100 ml of benzene containing a little sodium methoxide is heated on a steam bath for about 5 days. The solvent is removed by distillation and the residue is triturated with water. The resulting solid is dissolved in ether and dried over sodium sulfate. Filtration and concentration then yields ethyl 4-[[o-(p-chlorophenoxy)phenyl]carbamoyl]-1piperazinecarboxylate, melting at 89°C to 91°C, and suitable for cyclization. A mixture of 10 g of the above piperazine carboxylate ester, 8 g of phosphorus pentoxide and 20 ml of phosphorus oxychloride is heated under reflux for about 1 day, diluted with 100 ml each of chloroform and benzene and quenched with 200 g of ice. The mixture is made basic with 10% sodium hydroxide. The organic layer is isolated and extracted with 150 ml of dilute hydrochloric acid. The product is precipitated from the aqueous layer by addition of 10% sodium hydroxide, extracted with benzene and dried over potassium carbonate. Recrystallization from benzene-petroleum ether gives 2chloro-11-(1-piperazinyl)dibenz[b,f][1,4]oxazepine which melts at 175°C to 176°C. References Merck Index 598 PDR p. 1005 DOT 8 (2) 78 (1972) and 15 (3) 73 (1979) REM p. 1094 DFU 1 (11) 511 (1976) OCDS Vol. 2 p. 478 (1980) I.N. p. 79 Howell, C.F., Hardy, R.A., Jr. and Quinones, N.Q.; US Patent 3,663,696; May 16, 1972; Assigned to American Cyanamid Company Howell, C.F., Hardy, R.A., Jr. and Quinones, N.Q.; US Patent 3,681,357; August 1, 1972; Assigned to American Cyanamid Company
Amoxicillin
297
AMOXICILLIN Therapeutic Function: Antibacterial Chemical Name: 6-([Amino-(4-hydroxyphenyl)acetyl]amino)-3,3-dimethyl-7oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Common Name: p-Hydroxyampicillin Structural Formula:
Chemical Abstracts Registry No.: 26787-78-0; 61336-70-7 (Trihydrate) Trade Name
Manufacturer
Country
Year Introduced
Arnoxil
Bencard
UK
1972
Clamoxyl
Beecham
W. Germany
1973
Clamoxyl
Beecham
France
1974
Larotid
Roche
US
1974
Amoxil
Beecham
US
1974
Polymox
Bristol
US
1975
Sawacillin
Fujisawa
Japan
1975
Pasetocin
Kyowa Hakko
Japan
1975
Velamox
Zambeletti
Italy
1975
Wymox
Wyeth
US
1978
Utimox
WL/PD
US
1979
Agerpen
Cepa
Spain
-
A-Gram
Inava
France
-
Alfamox
Alfa
Italy
-
Alfida
Esteve
Spain
-
Alfoxil
Fako
Turkey
-
Am-73
Medici
Italy
-
Amocilline
Inpharzam
Belgium
-
Amoclen
Spofa
Czechoslovakia
-
Amodex
Robert and Carriere
France
-
Amo-Flamisan
Mazuelos
Spain
-
Amoksilin
Nobel
Turkey
-
Amoksina
Mustafa Nevzat
Turkey
-
298
Amoxicillin
Trade Name
Manufacturer
Country
Year Introduced
Arnolin
Takeda
Japan
-
Amorion
Orion
Finland
-
Amosin
Sanli
Turkey
-
Amox
Lusofarmaco
Spain
-
Amox
Prodes
Spain
-
Amoxamil
Lafi
Brazil
-
Amoxaren
Areu
Spain
-
Arnoxi-Basileos
Basileos
Spain
-
Amoxibiotic
Aristochimica
Italy
-
Amoxicil
Dincel
Turkey
-
Amoxicillin
Toho
Japan
-
Amoxidal
Roemmers
Argentina
-
Amoxidin
Normon
Switz.
-
Amoxi-Gobens
Lagap
Spain
-
Amoxillin
Esseti
Italy
-
Amoximedical
Medical
Spain
-
Amoxipen
Gibipharma
Italy
-
Amoxipenil
Montpellier
Argentina
-
Amoxiroger
Roger
Spain
-
Amoxi-Tabs
Beecham
-
-
Amoxypen
Gruenenthal
W. Germany
-
Amplimox
Ausonia
Italy
-
Amplimox
Iton
Italy
-
Ampy-Penyl
Proto
Switz.
-
Apitart
Isei
Japan
-
Ardine
Antibioticos
Spain
-
Aspenil
Chemil
Italy
-
Augmentin
Beecham
US
-
Ax-1000
Durachemie
W. Germany
-
Axbiot
Galepharma Iberica
Spain
-
Becabil
Alfar
Spain
-
Benzoral
Biosintetica
Brazil
-
Bioxidona
Faes
Spain
-
Bristamox
Bristol
-
-
Cabermox
Caber
Italy
-
Chitacillin
Banyu
Japan
-
Cidanamox
Cidan
Spain
-
Clamox
Roussel-Diamant
Morocco
-
Clamoxyl
Wulfing
W. Germany
-
Amoxicillin
299
Trade Name
Manufacturer
Country
Year Introduced
Clarnoxyl
Beecham-Sevigne
France
-
Dacala
Guadalupe
Spain
-
Damoxicil
Elmu
Spain
-
Daxipen
Recofarma
Brazil
-
Delacillin
Sankyo
Japan
-
Demoksil
Deva
Turkey
-
Doksilin
Iltas
Turkey
-
Draximox
Novo
-
-
Efpenix
Toyo Jozo
Japan
-
Eupen
Uriach
Spain
-
Flemoxin
Gist Brocades
-
-
Fullcilina
Sintyal
Argentina
-
Grinsil
Argentia
Argentina
-
Hiconcil
Allard
France
-
Himinomax
Kaken
Japan
-
Hosboral
Hosbon
Spain
-
Ibiamox
IBI
Italy
-
Imacillin
Astra
-
-
Infectomycin
Heyden
W. Germany
-
Isimoxin
ISI
Italy
-
Kapoxi
Kappa
Spain
-
Largopen
Bilim
Turkey
-
Majorpen
Cyanamid
US
-
Megacillin
Mulda
Turkey
-
Metifarma
Novofarma
Spain
-
Morgenxil
Morgens
Spain
-
Moxacin
C.S.L.
Australia
-
Moxal
Roger Bellon
Italy
-
Moxalin
Mead Johnson
US
-
Moxilean
Organon
-
-
Moxipin
Gamir
Spain
-
Moxypen
Teva
Israel
-
Novamoxin
Novopharm
Canada
-
Nuvosyl
Mepha
Switz.
-
Optium
Disprovent
Argentina
-
Ospanox
Biochemie
Austria
-
Pamocil
Lancet
Italy
-
Paradroxil
Bristol
-
-
Pasetocin
Kyowa
Japan
-
300
Amoxicillin
Trade Name
Manufacturer
Country
Year Introduced
Penamox
Beecham
-
-
Penimox
Ibsa
Switz.
-
Piramox
Pharmax
Italy
-
Precopen
Fides
Spain
-
Primasin
Eczacibasi
Turkey
-
Raudopen
Alter
Spain
-
Raylina
Robert
Spain
-
Reloxyl
Biologia Marina
Spain
-
Remoxil
Kimya Evi
Turkey
-
RivoxicilIin
Rivopharm
Switz.
-
Robamox
Robins
US
-
Sancixomal
Santos
Spain
-
Sawamezin
Sawai
Japan
-
Sigamopen
Siegfried
Switz.
-
Simplamox
ISF
Italy
-
Sinacilin
Galenika
Yugoslavia
-
Sint edix
Castillon
Spain
-
Sintoplus
Aesculapius
Italy
-
Sumox
Reid-Provident
US
-
Superpeni
Efeyn
Spain
-
Tolodina
Estedi
Spain
-
Triamoxil
Squibb
US
-
Trifamox
Bago
Argentina
-
Trimoksilin
Abdi Ibrahim
Turkey
-
Trimox
Squibb
US
-
Unicillin
Tobishi
Japan
-
Uro-Clamoxyl
Beecham
-
-
Utimox
Parke Davis
-
-
Wassermox
Wassermann
Spain
-
Widecillin
Meiji
Japan
-
Zamocillin
Zambon
Italy
-
Zimox
Farmitalia
Italy
-
Raw Materials 6-Aminopenicillanic acid Sodium bicarbonate Ethyl chlorocarbonate Hydrogen O,N-Dibenzyloxycarbonyl-p-oxy-di-α-aminophenylacetic acid Manufacturing Process Ethyl chlorocarbonate (2.2 ml) was added to an ice cold solution of O,N-
Amperozide
301
dibenzyloxycarbonyl-p-oxy-dl-α-aminophenylacetic acid (10 grams) and triethylamine (3.85 ml) in dry acetone (193 ml). The mixture was stirred at 0°C for 5 minutes during which triethylamine hydrochloride precipitated. The suspension was cooled to -30°C and stirred vigorously while adding as rapidly as possible an ice cold solution of 6-aminopenicillanic acid (5.85 grams) in 3% aqueous sodium bicarbonate (193 ml), the temperature of the mixture never being allowed to rise above 0°C. The resulting clear solution was stirred for 30 minutes at 0°C, and then for a further 30 minutes, without external cooling, and finally extracted with diethyl ether (3 x 200 ml) only the aqueous phase being retained. This aqueous solution was brought to pH 2 by the addition of hydrochloric acid and the 6-(O,N-dibenzyloxycarbonyl-p-oxy-dl-αaminophenylacetamido)penicillanic acid so liberated was extracted into diethyl ether (50 ml and 2 portions of 30 ml). The ether phase was washed with water (3 x 5 ml) and the water washings were discarded. Finally, the penicillin was converted to the sodium salt by shaking the ether solution with sufficient 3% sodium bicarbonate to give a neutral aqueous phase, separating the latter and evaporating it at low pressure and temperature below 20°C. The product was finally dried over phosphorus pentoxide in vacuo to give sodium 6-(O,N-dibenzyloxycarbonyl-p-oxy-dl-αaminophenylacetamido)-penicillanate (9.2 grams). A suspension of palladium on calcium carbonate (36 grams of 5%) in water (150 ml) was shaken in an atmosphere of hydrogen at room temperature and atmospheric pressure for 1 hour. A neutral solution of sodium 6-(O,Ndibenzyloxycarbonyl-p-oxy-dl-α-aminophenylacetamido)penicillanate (9 grams) in water (100 ml) was then added and shaking in hydrogen was resumed for one hour. The suspension was then filtered and the collected catalyst was washed well with water without being allowed to suck dry between washings. The combined filtrate and washings were then brought to pH 6.5 with dilute hydrochloric acid and evaporated to dryness at reduced pressure and temperatures below 20°C. The product was finally dried over phosphorus pentoxide in vacuo to give a solid (5.4 grams) containing 6-(phydroxy-dl-α-aminophenylacetamido)penicillanic acid. References Merck Index 600 Kleeman and Engel p. 48 PDR pp.658, 673, 705, 993, 1315, 1606, 1769, 1997 OCDS Vol. 1 p. 414 DOT 19 (3) 169 (1983) I.N. p. 79 REM p. 1193 Nayler, J.H.C. and Smith, H.; US Patent 3,192,198; June 29, 1965
AMPEROZIDE Therapeutic Function: Anti-aggressive, Antiarrhythmic
302
Amperozide
Chemical Name: 4-[4,4-Bis(4-fluorophenyl)butyl]-N-ethyl-1piperazinecarboxamide Common Name: Amperozide; Hogpax Structural Formula:
Chemical Abstracts Registry No.: 75558-90-6 Trade Name
Manufacturer
Country
Year Introduced
Amperozide
Ferrosan
-
-
FG 5606
Kabi Pharmacia
-
-
Raw Materials Sodium bicarbonate Hydrogen chloride Potassium carbonate Phenyl N-ethylcarbamate
N'-Ethyl-1-piperazinecarboxamide 4-Chloro-1,1-(di-p-fluorophenyl)butane 1-[4,4-(Di-p-fluorophenyl)butyl]piperazine
Manufacturing Process (1). A stirred mixture of 4.7 g (0.03 mole) of N'-ethyl-1piperazinecarboxamide, 10.1 g (0.036 mole) of 4-chloro-1,1-(di-pfluorophenyl)butane, 5.0 g of sodium bicarbonate and 10 ml of ethanol was heated at reflux for 60 hours. 50 ml of water was added. The mixture was extracted twice with ether. The combined extracts were dried over sodium sulfate and concentrated. The residue was dissolved in ethanol-ether and the hydrochloride was precipitated with hydrogen chloride in ethanol. The solid was collected by filtration and recrystallised from 2-butanone-isopropanol 4:1 to give 6.4 g of N'-ethyl-4-[4,4-(di-p-fluorophenyl)butyl]-1piperazinecarboxamide hydrochloride. Melting point 177-178°C. (2). A stirred mixture of 9.9 g (0.03 mole) of 1-[4,4-(di-pfluorophenyl)butyl]piperazine, 5,0 g (0,03 mole) of phenyl N-ethylcarbamate, 6,6 g of potassium carbonate and 100 ml of toluene was heated at reflux for 45 minutes. The mixture was filtered and the solvent was removed. The residual oil was dissolved in ethanol-ether and the hydrochloride was precipitated with hydrogen chloride in ethanol. The solid was collected by filtration and recrystallized from 2-butanone-isopropanol 4:1 to give 6.8 g of N'-ethyl-4-[4,4-(di-p-fluorophenyl)butyl]-1-piperazinecarboxamide hydrochloride. Melting point 177-178°C.
Amphetamine phosphate
303
References Bjork Anders K. K., Olsson Knut G., Abramo Aina L., Christensson Erik G.; US Patent No. 4,308,387; December 29, 1981; Assigned to AB Ferrosan (Malmo, SE)
AMPHETAMINE PHOSPHATE Therapeutic Function: Central stimulant Chemical Name: 1-Phenyl-2-aminopropane monophosphate Common Name: Structural Formula:
Chemical Abstracts Registry No.: 139-10-6 Trade Name Raphetamlne Amphate Leptamine Monophos Profetamine
Manufacturer Strasenburgh Storck Bowman Durst Clark and Clark
Country US US US US US
Year Introduced 1950 -
Raw Materials Phenyl nitropropylene Phosphoric acid Manufacturing Process 1 mol of phenyl-nitropropylene, C6H5CH=C(CH3)NO2, is dissolved with a solvent prepared by mixing one liter of ethanol with one-half liter of acetic acid and one-half liter of 12 N sulfuric acid. The resultant solution is placed in the cathode compartment of a divided electrolytic cell containing a metallic cathode of mercury, copper, or other metal of similar nature. Current is passed, using a current density of ~0.2 amp/cm2 of cathode surface. The temperature is kept at about 40°C during the electrolysis which is continued until at least eight Faradays of electricity have been passed. When the reduction is completed, the 1-phenyl-2-aminopropane may be separated from the solution. A convenient way of doing this is by removing
304
Amphomycin calcium
the ethanol and ethyl acetate present by evaporation and then making the residual solution strongly alkaline by addition of caustic alkali. The basic layer thus formed is separated from the aqueous solution and contains the desired 1-phenyl-2-aminopropane. 135 g (1 mol) of amphetamine (1-phenyl-2-aminopropane) were stirred into 300 cc of acetone in a stainless-steel vessel. To the resultant solution there were slowly added under constant agitation 115.3 g of 85% phosphoric acid (containing 1 mol of H3PO4), care being taken to avoid any sudden rise in temperature or local overheating due to the considerable amount of heat that is evolved. During the addition of the phosphoric acid a fine, white, flocculent precipitate appears which becomes more and more dense and abundant, as the quantity of added acid increases. When the entire quantity of the phosphoric acid has thus been added, agitation of the mixture is continued for about a half-hour or more to insure complete conversion. The precipitate is then allowed to settle, the supernatant liquid is drawn off, and the residue is filtered. The precipitate thus separated may, if desired, be washed with acetone and is then dried by evaporation to constant weight. It forms a fine, white, impalpable powder consisting of pure monobasic amphetamine phosphate. References Merck Index 607 I.N. p. 80 Alles, G.A.; US Patent 1,879,003; September 27, 1932 (amphetamine base mfg.) Goggin, T.C.; US Patent 2,507,468; May 9, 1950; Assigned to Clark and Clark Co. (amphetamine conversion to phosphate)
AMPHOMYCIN CALCIUM Therapeutic Function: Antibiotic Chemical Name: Amphomycin calcium Common Name: Glumamicin Chemical Abstracts Registry No.: 1402-82-0 (Base) Trade Name
Manufacturer
Country
Year Introduced
Amphocortrin CR
Warner Lambert
US
1963
Raw Materials Amphomycin Calcium hydroxide
Amphomycin calcium
305
Structural Formula:
Manufacturing Process The process for producing amphomycin comprises cultivating a strain of Streptomyces canus in an aqueous, nutrient-containing carbohydrate solution under submerged aerobic conditions until substantial antibacterial activity is imparted to the solution and then recovering the so-produced amphomycin from the fermentation broth. The process of decolorizing solutions of amphomycin then involves treatment with activated charcoal, followed by the steps of (1) extracting the antibiotic into a water-immiscible organic solvent under strongly acid conditions or precipitating the amphomycin from aqueous solution by adjusting the pH to a point within the range of pH 3.0 to 4.0, (2) removing impurities from strongly acid, aqueous solution of amphomycin by extraction of the impurities with methyl isobutyl ketone and amyl acetate, (3) extracting the amphomycin from a strongly acid solution in butanol by the use of water having a pH higher than 4, (4) extracting the amphomycin from solution in water-immiscible organic solvent into water whose pH is greater than 6.0, (5) precipitating amphomycin from solution by formation of insoluble derivatives of the basic function, and (6) precipitating amphomycin from solution by formation of insoluble derivates of the acidic function.
306
Amphotalide
The amphomycin is then converted to the calcium salt with calcium hydroxide. References Merck Index 609 Heinemann, B., Cooper, I.R. and Kaplan, M.A.; US Patent 3,126,317; March 24, 1964; Assigned to Bristol-Myers Co.
AMPHOTALIDE Therapeutic Function: Antischistosomal Chemical Name: 1H-Isoindole-1,3(2H)-dione, 2-(5-(4-aminophenoxy) pentyl)Common Name: Amphotalide; Schistomide Structural Formula:
Chemical Abstracts Registry No.: 1673-06-9 Trade Name Amphotalide
Manufacturer ZYF Pharm Chemical
Country -
Year Introduced -
Amphotalide
May and Baker Ltd.
-
-
Raw Materials 5-Phthalimidopentyl bromide Hydrogen
Potassium p-nitrophenoxide Platinum oxide
Manufacturing Process A mixture of 5-phthalimidopentyl bromide (Drake and Garman, J.Amer. Chem. Sec, 1949, 71, 2426) (296.0 g) and potassium p-nitrophenoxide (177.0 g) in ethanol (1.5 L) was stirred mechanically, boiled under reflux for 20 h, concentrated to half its volume, cooled and filtered. The product was washed with water, dried and crystallised from acetone, giving 1-p-nitrophenoxy-5phthalimidopentane, melting point 123°-124°C. The foregoing 1-p-nitrophenoxy-5-phthalimidopentane (100.0 g) in ethanol (1 L) was reduced by hydrogen over 2% of platinum oxide at 74°C/73 lb. per sq. in. The filtered solution on cooling gave L-p-aminophenoxy-5-
Amphotericin B
307
phthalimidopentane, melting point 111°-112° C (recrystallisation from ethanol). References Barber H.J. et al.; GB Patent No. 769,706; April 20, 1955; Assigned: May and Baker Limited, British Company, of Dagenham, Essex
AMPHOTERICIN B Therapeutic Function: Antifungal Chemical Name: Amphotericin B Common Name: Structural Formula:
Chemical Abstracts Registry No.: 1397-89-3 Trade Name
Manufacturer
Country
Year Introduced
Fungizone
Squibb
US
1958
Ampho-Moronal
Heyden
W. Germany
-
Fungizone
Squibb
France
1969
Amphocycline
Squibb
France
-
Amphozone
Squibb
-
-
Fungilin
Squibb
UK
-
Fungilin
Squibb
Italy
-
Fungizone
Squibb-Sankyo
Japan
-
Mysteclin
Heyden
W. Germany
-
Raw Materials Carbohydrates Streptomyces nodosus
308
Ampicillin
Manufacturing Process The process for producing amphotericin comprises cultivating a strain of Streptomyces nodosus in an aqueous nutrient medium comprising an assimilable, fermentable carbohydrate and an assimilable organic nitrogen source, under submerged aerobic conditions, until substantial antifungal activity is imparted to the medium and recovering amphotericin from the medium. References Merck Index 611 Kleeman and Engel p. 50 PDR pp. 1743, 1752 DOT 7 (5) 192 (1971) I.N. p. 81 REM p. 1226 Dutcher, J.D., Gold, W., Pagano, J.F. and Vandeputte, J.; US Patent 2,908.611; October 13, 1959; Assigned to Olin Mathieson Chemical Corporation
AMPICILLIN Therapeutic Function: Antibacterial Chemical Name: 6-[D-Amino-(2-phenylacetamido)]-3,3-dimethyl-7-oxo-4thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Common Name: Di-α-aminobenzylpenicillin Structural Formula:
Chemical Abstracts Registry No.: 69-53-4 Trade Name
Manufacturer
Country
Year Introduced
Binotal
Bayer
W. Germany
1962
Penicline
Delagrange
France
1963
Penbritin
Ayerst
US
1963
Penbritin
Beecham
UK
1963
Omnipen
Wyeth
US
1966
Ampisint
Proter
Italy
1969
Acucillin
Fuji
Japan
-
Ampicillin
309
Trade Name
Manufacturer
Country
Year Introduced
Adobacillin
Tobishi
Japan
-
Albipen
Gist Brocades
-
-
Alfasilin
Fako
Turkey
-
Almopen
Gist Brocades
-
-
Alpen
Lederle
US
-
Amblosen
Hoechst
W. Germany
-
Amcill
Parke Davis
US
-
Amfipen
Gist Brocades
UK
-
Amfipen
Schering
W. Germany
-
Amipenix
Toyo Jozo
Japan
-
Ampen
Medosan
Italy
-
Ampen
ICN
Canada
-
Ampensaar
Chephasaar
W. Germany
-
Ampibeta
Violani-Farmavigor Italy
-
Ampibiotic
Ottolenghi
Italy
-
Ampicil
Ausonia
Italy
-
Ampicillina Pharmax
Pharmax
Italy
-
Ampicillina Pierrel
Pierrel
Italy
-
Ampicina
Sigma Tau
Italy
-
Ampicyn
Protea
Australia
-
Ampifen
Intersint
Italy
-
Ampikel
Dreikehl
Spain
-
Ampilan
Ibern
Italy
-
Ampiland
Landerlan
Spain
-
Ampilisa
Lisapharma
Italy
-
Ampilux
Tubi Lux Pharma
Italy
-
Ampimed
Aristochimica
Italy
-
Ampinebiot
Bertran Hathor
Spain
-
Ampinova
Spain
-
Ampinoxi
Cheminova Espanola Therapia
Spain
-
Ampiopen
Ibern
Italy
-
Ampi-Plena Simple Pradel
Spain
-
Ampisil
Dif-Dogu
Turkey
-
Ampisina
Mustafa Nevzat
Turkey
-
Ampi-Tablinen
Sanorania
W. Germany
-
Ampitex
Neopharmed
Italy
-
Ampivax
Ripari-Gero
Italy
-
Ampixyl
Pharma-Plus
Switz.
-
Amplenil
Orma
Italy
-
310
Ampicillin
Trade Name
Manufacturer
Country
Year Introduced
Amplibios
Panther-Osfa
Italy
-
Amplicid
Cifa
Italy
-
Amplipen
Labif
Italy
-
Amplipenyl
ISF
Italy
-
Ampliscocil
I.C.I.
Italy
-
Amplisom
Isom
Italy
-
Amplital
Farmitalia
Italy
-
Amplizer
O.F.F.
Italy
-
Anhypen
Gist Brocades
-
-
Anidropen
Wyeth
Italy
-
Anticyl
San Carlo
Italy
-
A-Pen
Orion
Finland
-
Argocillina
Beta
Italy
-
Austrapen
CSI
Australia
-
Benusel
ICN
-
-
Bio-Ampi
Donatello
Italy
-
Biocellina
Magis
Italy
-
Bionacillin
Takata
Japan
-
Bonapicillin
Taiyo
Japan
-
Britapen Oral
Federico Bonet
Spain
-
Britcin
DDSA
UK
-
Bropicilina
Byk Gulden
-
-
Cilleral
Bristol Banyu
Japan
-
Citicil
C.T.
Italy
-
Combipenix
Toyo Jozo
Japan
-
Copharcilin
Cophar
Switz.
-
Deripen
Schering
W. Germany
-
Doktacillin
Astra
-
-
Domicillin
Dainippon
Japan
-
Drisilin
Drifen
Turkey
-
Espectrosira
Clariana
Spain
-
Eurocillin
Borromeo
Italy
-
Farmampil
Gazzini
Italy
-
Fidesbiotic
Fides
Spain
-
Fortapen
Continental Pharma
Belgium
-
Geycillina
Geymonat
Italy
-
Gramcillina
Caber
Italy
-
Grampenil
Argentia
Argentina
-
Guicitrina
Perga
Spain
-
Hostes Pedriatico
Lando
Argentina
-
Ampicillin
311
Trade Name Ikapen Isocillin Iwacillin Lampocillina Orale Lifeampil Marisilan Makrosilin Maxicilina Napacil NC-Cillin Negopen Nuvapen Orocilin Overcillina Overcillina Pen Ampil
Manufacturer Ikapharm Kanto Iwaki Sidus Lifepharma Wakamoto Atabay Antibioticos Montefarmaco Nippon Chemiphar Deva Cepa Isa Lepetit Archifar Nuovo. Const. Sanit. Naz.
Country Israel Japan Japan Italy Spain Japan Turkey Spain Italy Japan Turkey Spain Brazil Italy Italy Italy
Year Introduced -
Penbrock Penibrin Penimic Peninovel Penisint B.G. Penoral Penorsin Pentrex Pentrexyl Pharcillin Platocillina Plumericin Policilin Polycillin Principen Quimetam Radiocillina Recenacillin Resan Rivocillin Saicil Sentapent Sernabiotic Sesquicillina Sintopenyl SK-Ampicillin Togram
Beecham Teva SS Pharmaceutical Larma Boniscontro Nobel Wassermann Banyu Galenika Toyo Pharm. Crosara Torlan Bristol Bristol Squibb Ouimicos Unidos Radiumpharma Maruko Alacan Rivopharm Libra Kimya Evi Libra Ita Aesculapius SK and F Morgens
Israel Japan Spain Italy Turkey Spain Japan Yugoslavia Japan Italy Spain US US Spain Italy Japan Spain Switz. Italy Turkey Italy Italy Italy US Spain
-
312
Ampicillin
Trade Name
Manufacturer
Country
Year Introduced
Tokiocillin
Isei
Japan
-
Totacillin
Beecham
Japan
-
Totaclox
Beecham
Japan
-
Totalciclina
Benvegna
Italy
-
Totapen
Bristol
France
-
Trafarbiot
Novopharm
Spain
-
Ultrabion
Lifasa
Spain
-
Vastacyn
Ankerfarm
Italy
-
Vexampil
Ifi
Italy
-
Vicclilin
Meiji
Japan
-
Raw Materials α-Aminophenylacetic acid 6-Aminopenicillanic acid Hydrogen
Ethyl chlorocarbonate Benzyl chlorocarbonate
Manufacturing Process α-Carbobenzyloxyaminophenylacetic acid (0.1 mol), which is obtained by the reaction of equivalent quantities of α-aminophenylacetic acid and benzyl chlorocarbonate in aqueous sodium hydroxide, dissolved in dry acetone is stirred and cooled to approximately -5°C. To this there is added dropwise with continued cooling and stirring a solution of ethyl chlorocarbonate (0.1 mol). After approximately 10 minutes, the acylating mixture is cooled to about -5°C and then is slowly added to a stirred ice-cold mixture of 6-aminopenicillanic acid (0.1 mol), 3% sodium bicarbonate solution (0.1 mol) and acetone. This reaction mixture is allowed to attain room temperature, stirred for an additional thirty minutes at this temperature and then is extracted with ether. The extracted aqueous solution is covered with butanol and the pH adjusted to 2 by the addition of HCl. The acidified aqueous phase is extracted with butanol, the pH of the aqueous phase being adjusted to pH 2 each time. The combined butanol solutions which contain the free acid, αcarbobenzyloxyaminobenzylpenicillin, are washed with water, and are then shaken with water to which sufficient 3% sodium bicarbonate has been added to bring the aqueous phase to pH 7. The process of washing and shaking is repeated with fresh water and bicarbonate solution. The combined aqueous solutions are washed with ether and then are evaporated under reduced pressure and low temperature. The product, the sodium salt of αcarbobenzyloxyaminobenzylpenicillin, is obtained as a yellow solid in a yield of 65%. A suspension of palladium on barium carbonate (3.7 grams of 30%) in water (20 ml) is shaken in an atmosphere of hydrogen at room temperature. The catalyst is then filtered and washed well with water, care being taken that it does not become dry. A solution of the sodium salt of αcarbobenzyloxyaminobenzylpenicillin (4 grams) in water (20 ml) is added to the pretreated catalyst and the suspension is shaken in an atmosphere of hydrogen at room temperature and pressure for one hour. The catalyst is then
Ampicillin trihydrate
313
filtered off, washed well with water, and the combined filtrate and washings adjusted to pH 7 with hydrochloric acid. The resulting solution is evaporated in vacuum at a temperature below 20°C to give α-aminobenzylpenicillin (2.4 grams, 74% yield), which is assayed at approximately 48% pure by the manometric method. References Merck Index 612 Kleeman and Engel p. 50 PDR pp.673, 703, 1314, 1722, 1964 OCDS Vol. 1 p. 413; Vol. 2 p. 437 I.N. p. 81 REM p. 1194 Doyle, F.P., Nayler, J.H.C., and Smith, H.; US Patent 2,985,648; May 23, 1961 Kaufmann, W. and Bauer, K.; US Patent 3,079,307; Feb. 26, 1963; Assigned to Farben-fabriken Bayer AG, Germany Johnson, D.A. and Wolfe, S.; US Patent 3,140,282; July 7, 1964; Assigned to Bristol-Myers Company Grant, N.H. and Alburn, H.E.; US Patent 3,144,445; August 11, 1964; Assigned to American Home Products Corporation
AMPICILLIN TRIHYDRATE Therapeutic Function: Antibacterial Chemical Name: 6-[D-Amino-(2-phenylacetamido)]-3,3-dimethyl-7-oxo-4thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid trihydrate Common Name: Structural Formula:
Chemical Abstracts Registry No.: 7177-48-2 Trade Name
Manufacturer
Country
Year Introduced
Polycillin
Bristol
US
1963
Principen
Squibb
US
1967
314
Ampicillin trihydrate
Trade Name
Manufacturer
Country
Year Introduced
Amcill
Parke Davis
US
1968
Alpen
Lederle
US
1969
Totacillin
Beecham
US
1970
Pensyn
Upjohn
US
1972
Ro-Ampen
Rowell
US
1972
Pen A
Pfizer
US
1972
Trimox
Squibb
US
1978
AB-PC
Tojo Jozo
Japan
-
Acillin
ICN
-
-
Amblosin
Hoechst
-
-
Amcap
Circle
US
-
Amperil
Geneva
US
-
Ampexin
Therapex
Canada
-
Ampicsl
Uva
France
-
Ampichelle
Rachelle
US
-
Ampicil
Jeba
Spain
-
Ampiciman
Liberman
Spain
-
Ampi-Co
Coastal
US
-
Ampifar
Benedetti
Italy
-
Ampikel
Dreikehl
Spain
-
Ampilag
Lagap
Switz.
-
Ampileta
Lagap
Switz.
-
Ampi-Oral
Biologia Marina
Spain
-
Ampiorus
Horus
Spain
-
Ampiscel
Rachelle
US
-
Ampixyl
Pharma-Plus
Switz.
-
Ampi-Zoja
Zoja
Italy
-
Amplin
Winston
US
-
Arcocillin
ICN
-
-
Benusel
ICN
-
-
Binotal
Bayer
-
-
Cetampin
CTA Pharma
Switz.
-
Cetampin
Scarium
Switz.
-
Cimexillin
Cimex
Switz.
-
Cymbl
Dolorgiet
W. Germany
-
Citicil
C.T.
Italy
-
D-Amp
Dunhall
US
-
D-Cillin
Dunhall
US
-
Delcillin
Marlop
US
-
Divercillin
Ascher
US
-
Dumopen
Dumex
Denmark
-
Dur Ampicillin
Durachemie
W. Germany
-
Ampicillin trihydrate
315
Trade Name
Manufacturer
Country
Year Introduced
Espimin-Cilin
Spyfarma
Spain
-
Fuerpen
Hermes
Spain
-
Gobemicina Simple Normon
Spain
-
Helvecillin
Helvepharm
Switz.
-
Lifeampil
Lifepharma
Spain
-
Morepen
Morejon
Spain
-
Novoexpectro
Aldon
Spain
-
Penbristol
Bristol-Myers
Austria
-
Penimaster
Liade
Spain
-
Peninovel
Larma
Spain
-
Pentraxyl
Bristol
-
-
Pentrexyl Oral
Antibioticos
Spain
-
Pentricine
Ibsa
Switz.
-
Poenbiotico
Poen
Argentina
-
Prestacilina
Pental
Spain
-
Q I Damp
Mallinckrodt Inc.
US
-
Rosampline
Rosa-Phytopharma France
-
Servicillin
Servipharm
Switz.
-
Standacillin
Biochemie
Austria
-
Sumipanto Oral
Asla
Spain
-
Texcillin
First Texas
US
-
Trafarbior
Novopharm
Spain
-
Trafacilina
Bago
Argentina
-
Vampen
Vangard
US
-
Vidopen
Berk
UK
-
Raw Materials Ampicillin beta-naphthalene sulfonate Secondary amines Manufacturing Process The known methods for the preparation of D-(-)-α-aminobenzylpenicillin by the acylation of 6-aminopenicillanic acid result in the preparation of aqueous mixtures which contain, in addition to the desired penicillin, unreacted 6aminopenicillanic acid, hydrolyzed acylating agent, and products of side reactions such as the products of the acylating agent reacted with itself and/or with the desired penicillin, as well as other impurities. The D-(-)-α-aminobenzylpenicitlin may then be recovered from the aqueous reaction mixture by concentration to small volume and recovering the product by filtration. However, due to the fact that anhydrous D-(-)-αaminobenzylpenicillinis soluble in water to the extent of about 20-25 mg/ml at 20°-25°C, it is very difficult to recover the product in high yields.
316
Ampiroxicam
Furthermore, the recovered D-(-)-α-aminobenzylpenicillin may be obtained in the form of a monohydrate. The monohydrates (as well as the dihydrates) of D-(-)-α-aminobenzylpenicillin possess poor biological stability. The trihydrate which is obtained in high yields, is relatively insoluble in water, possesses high biological stability and can be obtained by contacting, at a temperature not above 60°C, an acid addition salt of D-(-)-αaminobenzylpenicillin with an amine in a water immiscible solvent containing at least 3 mols of water per mol of such penicillin. The following is an example of the conduct of such a process. To a vigorously agitated mixture of 100 ml of methyl isobutyl ketone there are added at 25° to 30°C 15 ml of water and 10 ml of a mixture of secondary amines. To this mixture there is then added slowly over a period of 30 minutes 10 grams of D-(-)-α-aminobenzylpenicillin α-naphthalenesulfonate. The mixture is agitated for 3 hours at 25-30°C. The product, D-(-)-α-aminobenzylpenicillin trihydrate precipitates and is collected by filtration. The filter cake of the product is washed several times with methyl isobutyl ketone and is dried at 40°C. The product is obtained in about a 90% yield and has a potency of 865 mcg/mg. It is determined by Karl Fischer analysis to have a moisture content of 13.4% by weight. References Merck Index 612 Kleeman and Engel p. 81 PDR pp. 993, 1606, 1758 I.N. p. 50 Johnson, D.A. and Hardcastle, G.A., Jr.; US Patent 3,157,640; November 17, 1964; Assigned to Bristol-Myers Company
AMPIROXICAM Therapeutic Function: Antiinflammatory Chemical Name: Carbonic acid ethyl 1-[[2-methyl-3-[(2-pyridinyl) aminocarbonyl]-2H-1,2-benzothiazin-4-yl]oxy]ethyl ester, S,S-dioxide Common Name: Ampiroxicam Structural Formula:
Amprenavir
317
Chemical Abstracts Registry No.: 99464-64-9 Trade Name Ampiroxicam
Manufacturer Country NANJING PHARMA -
Year Introduced -
Raw Materials Piroxicam Potassium carbonate
α-Chloroethyl ethyl carbonate Sodium iodide
Manufacturing Process To a round bottomed flask equipped with a reflux condenser and stirring bar were added 2-methyl-N-(2-pyridyl)-4-hydroxy-2H-1,2-benzodiazine-3carboxamide 1,1-dioxide (piroxicam, 10.0 g, 30.2 mmol), potassium carbonate (8.35 g, 60.4 mmol), α-chloroethyl ethyl carbonate (12.35 mL, 13.81 g, 90.6 mmol) and acetone (350 mL). The heterogenous reaction mixture was heated to reflux under a nitrogen atmosphere. After 19 hours, anhydrous sodium iodide (22.6 g, 150.7 mmol) was added and reflux continued for an additional 5 hours. The acetone was removed in vacuum leaving a brown residue which was treated with water (250 mL) and methylene chloride (250 mL). The organic layer was separated and the aqueous layer extracted with additional methylene chloride (250 mL). The combined organic extracts were washed with water (250 mL), brine (250 mL), dried (Na2SO4) and concentrated in vacuum to a brown oil. Column chromatography on silica gel (1:9 ethyl acetate:methylene chloride) afforded a pale yellow foam (10.67 g, 79.0%). The 4-[1-(ethoxycarbonyloxy)ethoxy]2-methyl-N-(2-pyridyl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide was recrystallized from toluene to give 9.50 g of pure white crystals; melting point 159-161°C. References European Patent No.147,177 Marfat A.; US Patent No. 4,551,452; Nov. 5, 1985; Assigned to Pfizer Inc. (New York, NY)
AMPRENAVIR Therapeutic Function: Antiviral Chemical Name: Carbamic acid, ((1S,2R)-3-(((4-aminophenyl)sulfonyl)(2methylpropyl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-, (3S)tetrahydro-3-furanyl ester Common Name: Amprenavir Chemical Abstracts Registry No.: 161814-49-9
318
Amprenavir
Structural Formula:
Trade Name
Manufacturer
Country
Year Introduced
Agenerase
GlaxoSmithKline
UK
-
Amprenavir
Vertex Pharmaceuticals Inc
-
Amprenavir
GlaxoSmithKline
UK
-
KVX-478
Glaxo Wellcome
-
-
Prozei
Kissei Pharmaceutical Co., Ltd.
-
-
VX-478
Glaxo Wellcome
-
-
141W94
Glaxo Wellcome
-
-
Raw Materials Isobutylamine (1-Oxiranyl-2-phenylethyl)-carbamic acid t-butyl ester Benzyl chloroformate Diisopropylethylamine (S)-(+)-3-Hydroxytetrahydrofuran Phosgene p-Nitrobenzenesulfonyl chloride Manufacturing Process (1-Oxiranyl-2-phenylethyl)-carbamic acid t-butyl ester may be synthesized from available starting materials (see B. E. Evans et al., J. Org. Chem., 50, p.4615 (1985)). The amprenavir may be preparated with the next steps. 1. (1-Benzyl-3-isobutylaminopropyl)-carbamic acid t-butylester. A solution of 4.1 g of epoxide (1-oxiranyl-2-phenylethyl)-carbamic acid t-butyl ester in 30 ml of ethanol was treated with 22.4 ml of isobutylamine and heated under reflux for 1 h. The mixture was concentrated to yield the title compound as a white solid which was used without subsequent purification. 2. To a solution of the above compound (2.5 g, 7.43 mmol) in CH2Cl2 (50 ml) was added triethylamine (2.1 ml, 14.9 mmol) followed by addition of benzyl chloroformate (1.2 ml, 8.1 mmol). The mixture was allowed to stir at ambient temperature for 6 h. The solution was diluted with 1 L of CH2Cl2 and washed with water. The organics were dried over anhydrous MgSO4, concentrated
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319
under reduced pressure, then purified via silica gel chromatography. Gradient solvent system: CH2Cl2 followed by 3:97 methanol/CH2Cl2. (3-tButoxycabonylamino-4-phenylbutyl)-isobutylcarbamic acid benzyl ester (2.97 g) was obtained as a colorless oil. TLC: Rf= 0.14, 3:97 methanol/CH2Cl2. 3. BOC - protecting group was removed as followed: to a solution of 1.5 g (3.187 mmol) of the above compound of in ethyl acetate (25 ml) at - 20°C was bubbled anhydrous HCl gas for 10 min. The ice bath was removed and after an additional 15 min the reaction mixture was sparged with nitrogen, then concentrated in vacuo to provide 1.29 g of deprotected product as a white solid which was used directly for the next reaction TLC: Rf= 0.14, 10% methanol/CH2Cl2. 4. Isobutyl[4-phenyl-(S)-3-tetrahydrofuran-3-yl-oxycarbonylamino)-butyl]carbamic acid benzyl ester. To a solution of 1.077 g of the above resultant crude compound (2.647 mmol) in acetonitrile (10 ml) was added sequentially at ambient temperature under an atmosphere of nitrogen, 1.61 ml (9.263 mmol) of diisopropylethylamine and 910 mg (3.97 mmol) of the Nsuccinimidyl-(S)-3-tetrahydrocfuryl carbonate. The last one was prepared from phosgene and (S)-(+)-3-hydroxytetrahydrofuran by usual procedure. After stirring for 3 h, an additional 223 mg (0.973 mmol) of the N-succinimidyl-(S)3-tetrahydrocfuryl carbonate was added. The mixture was stirred for 16 h and then concentrated in vacuo. The residue was taken up in ethyl acetate and washed with water, 0.5 N HCl, saturated sodium bicarbonate, saturated brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by low pressure silica gel column chromatography using a gradient 10% to 25% ethyl acetate in CH2Cl2 eluent to yield 1.025 g of the title product as a white solid. TLC: Rf= 0.10, 10% ethyl acetate/CH2Cl2. 5. A solution of 872 mg (1.799 mmol) isobutyl[4-phenyl-(S)-3tetrahydrofuran-3-yl-oxycarbonylamino)-butyl]-carbamic acid benzyl ester in (10 ml) of ethyl alcohol was added, at ambient temperature under a nitrogen atmosphere, to a slurry of 87 mg (10% by weight) of 10% palladium on carbon in (5 ml) ethyl alcohol and hydrogenated for 16 h under a slight positive pressure of hydrogen. The mixture was filtered and concentrated in vacuo to yield 553.2 mg of the carbamic acid as a colorless glass which was used directly for ensuing reaction. TLC: Rf = 0.46, 10% methanol/CH2Cl2. 6. A solution of 102 mg of the resultant compound of a step 5 in 4:1 CH2Cl2/saturated aqueous NaHCO3 was treated sequentially, at ambient temperature under an atmosphere of nitrogen, with 65 mg of pnitrobenzenesulfonyl chloride and 51 mg of sodium bicarbonate. The mixture was stirred for 14 h, diluted with CH2Cl2, washed with saturated NaCl, then dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by low pressure silica gel chromatography using 20% diethyl ether/CH2Cl2 as eluent to provide 124 mg of the 1-benzyl-3-[isobutyl-(4nitrobenzenesylfonyl)-amino]-propylcarbamic acid tetrahydrofuran-3(S)-yl] ester as a white solid. TLC: Rf = 0.36, 20% diethyl ether/CH2Cl2, HPLC: Rt = 15.15 min. (1H)-NMR (CDCl3) consist with structure. 7. A solution of 124 mg of the resultant compound of the step 6 in ethyl acetate was treated, at ambient temperature, with 13 mg of 10% palladium
320
Amprolium chloride
on carbon. The mixture was stirred for 14 h under an atmosphere of hydrogen, filtered through a pad of celite filter agent, and concentrated in vacuo. The residue was subjected to preparative HPLC to yield 82 mg of the ((1S,2R)-3-(((4-aminophenyl)sulfonyl)(2-methylpropyl)amino)-2-hydroxy-1(phenylmethyl)propyl)-, (3S)-tetrahydro-3-furanyl carbamic ester a white solid. TLC: Rf= 0.10, 20% ether/CH2Cl2, HPLC: Rt= 13.16 min. (1H)-NMR (CDCl3) consistent with structure. References Tung et al.; US Patent No. 5,691,372; Nov. 25, 1997; Assigned Vertex Pharmaceuticals Incorporated Tung et al.; WO 94/05639, March 1994
AMPROLIUM CHLORIDE Therapeutic Function: Coccidiostatic Chemical Name: Pyridinium, 1-((4-amino-2-propyl-5-pyrimidinyl)methyl)-2methyl-, chloride Common Name: Amprocidum; Amprolium chloride; Mepyrium Structural Formula:
Chemical Abstracts Registry No.: 121-25-5 Trade Name
Manufacturer
Country
Year Introduced
Neoprol
SIMB
-
-
Raw Materials 4-Toluenesulfonyl chloride 2-n-Propyl-4-amino-5-hydroxy-methyl pyrimidine 2-Methylpyridine Hydrochloric acid Manufacturing Process 1.9 grams of p-toluene sulfonyl chloride was added gradually with shaking to a cooled (0-5°C) solution of 1.67 grams of 2-n-propyl-4-amino-5-hydroxymethyl pyrimidine in 10 ml of 2-methylpyridine. The reaction mixture, after
Amrinone
321
standing three hours in an ice bath, and 15 hours at room temperature, was evaporated to dryness in vacuo. The residue was dissolved in 20 ml of water, acidified with hydrochloric acid and poured over a column of Amberlite IRA400 ion exchange resin on the chloride cycle. The eluate was evaporated to dryness to give a residue of 1-(2-n-propyl-4-amino-5-pyrimidylmethyl)-2methyl pyridinium chloride hydrochloride. On recrystallization from a methanol-ethanol mixture, the quaternary had melting point 246°C (dec.). References Rogers E.F., Sarett L.H.; US Patent No. 3,020,277; Feb. 6, 1962; Assigned to Merck and Co, Inc., Rahway, N.J.., a corporation of New Jersey
AMRINONE Therapeutic Function: Cardiotonic Chemical Name: 3-Amino-5-(4-pyridinyl)-2(1H)-pyridinone Common Name: Structural Formula:
Chemical Abstracts Registry No.: 60719-84-8 Trade Name Inocor Inocor
Manufacturer Sterling Winthrop Sterling Winthrop
Country Philippines Mexico
Year Introduced 1982 1983
Raw Materials 3-Nitro-5-(4-pyridinyl)-2(1H)-pyridinone Hydrogen Manufacturing Process A mixture containing 10g of 3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone, 200 ml of dimethylformamide and 1.5 g of 10% palladium-on-charcoal was hydrogenated under pressure (50 psi) at room temperature until the uptake of hydrogen ceased (about 30 minutes). The reaction mixture was filtered through infusorial earth and the filtrate was heated in vacuum to remove the solvent. The residual material was crystallized from dimethylformamide, washed successively with ethanol and ether, and dried in a vacuum oven at 80°C for 8 hours to yield 6 g of 3-amino-5-(4-pyridinyl)-2(1H)-pyridinone, melting point 294° to 297°C with decomposition.
322
Anagestone acetate
References Merck Index 616 DFU 4 (4) 245 (1979) PDR p. 1909 OCDS Vol. 3 p. 147 DOT 18 (10) 547 (1982) and 19 (10) 581 (1983) I.N. p.85 Lesher, G.Y. and Opalka, C.J.; US Patent 4,004,012; January 18, 1977; Assigned to Sterling Drug Inc. Lesher, G.Y. and Opalka, C.J.; US Patent 4,107,315; August 15, 1978; Assigned to Sterling Drug Inc.
ANAGESTONE ACETATE Therapeutic Function: Progestin Chemical Name: Pregn-4-en-20-one, 17-hydroxy-6α-methyl-, acetate Common Name: Anagestone acetate; Anapregnone Structural Formula:
Chemical Abstracts Registry No.: 3137-73-3 Trade Name ORF 1658 Anagestone acetate
Manufacturer ZYF Pharm Chemical Ortho Pharm
Country -
Year Introduced -
Raw Materials Ethanedithiol Nickel Acetic acid Acetic anhydride
6α-Methyl-4-pregnen-17α-ol-3,20-dione Pyridine chlorhydrate 4-Toluenesulfonic acid
Manufacturing Process To solution of 6α-methyl-4-pregnen-17α-ol-3,20-dione (1.0 g) in ethane-
Anagrelide hydrochloride
323
dithiol (1 ml) and methylene chloride (2 ml) pyridine chlorhydrate (1 g) was added and mixed 3 min at room temperature. Then to reaction mixture methanol (30 ml) was added and cooled in ice bath during of 2 min. Precipitate was filtered and washed with cool methanol. 6α-Methyl-4-pregnen17α-ol-20-one-3-thioacetal was obtained (0.9 g), melting point 186°-188°C (recrystalisation from methanol-dichlormethane). To the solution of 6α-methyl-4-pregnen-17α-ol-20-one-3-thioacetal (2 g) in 95% ethanol (200 ml) Ni (Renney) (50 g) was added and mixed at heating. Then reaction mixture was cooled to room temperature. The mixture was filtered, and filtrate was evaporated, obtaining residue was crystallisated from methanol with dichloromethane and in the result 6α-methyl-4-pregnen-17αol-20-one (0.95 g) was produced, melting point 190°-193°C. To the solution of 6α-methyl-4-pregnen-17α-ol-20-one (1.5 g) in acetic acid (75 ml) and acetic anhydride (15 ml) p-toluenesulfonic acid was added and the reaction mixture allayed to stand at room temperature any time. Then crystals were recrystallised from methanol with dichlormethane. Acetate 6αmethyl-4-pregnen-17α-ol-20-one (1.3 g) was obtained, melting point 173°175°C. References BE Patent No. 624,370; Oct. 31, 1962; Assigned: Ortho Pharmaceutical Corporation
ANAGRELIDE HYDROCHLORIDE Therapeutic Function: Platelet aggregation inhibitor Chemical Name: 6,7-Dichloro-1,5-dihydroimidazo[2,1-b]quinazolin-2(3H)one hydrochloride Common Name: Anagrelide hydrochloride Structural Formula:
Chemical Abstracts Registry No.: 58579-51-4; 68475-42-3 (Base) Trade Name Agrylin
Manufacturer Shire Pharmaceuticals
Country -
Year Introduced -
Agrelin Anagrelide Hydrochloride
Pharma Internacional Cipla Limited
India
-
324
Anastrazole
Raw Materials 6-Chloro-2-nitrobenzylchloride Cyanogen bromide Ethylglycine hydrochloride Ferric chloride anhydrous Chlorine Bromine Manufacturing Process 6,7-Dicloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-one was produced from 6-chloro-7-bromo-1,2,3,5-tetrahydroimidazo[2,1-b]quinozolin-2-one by substitution the bromine an equimolar quantity chlorine. 6-Chloro-7-bromo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-one was produced next way: to a solution of 1.30 g (8 mmole) of anhydrous ferric chloride in 30 ml of nitromethane was added 1.30 g (5 mmole) of solid 6chloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-one and 0.80 g (5 mmole) of bromine. The system was stoppered, warmed to 50°C in an oil bath overnight, cooled to room temperature and the solvent removed in vacuo. The resulting solid was suspended in water (50 ml), the mixture was made basic (pH=10) with sodium bicarbonate and stirred at home temperature for 20 min. The solid was filtered under suction, washed with water, then isopropyl alcohol and dried yielding 1.19 g of 6-chloro-7-bromo1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-one (78% yield). Purification was effected by formation of the hydrochloride salt (mp 275°C) from acetonitrile. 6-Chloro-1,2,3,5,-tetrahydroimidazo[2,1-b]quinazolin-2-one was produced from 6-chloro-2-nitrobenzylchloride, ethylglycine hydrochloride and cyanogen bromide in 3 steps. References Beveriung Jr. et al.; US Patent No. 3,932,407; Jan. 13, 1976; Assigned: Bristol-Myers Company (New York, NY)
ANASTRAZOLE Therapeutic Function: Antitumor Chemical Name: 1,3-Benzenediacetonitrile, α,α,α',α'-tetramethyl-5-(1H1,2,4-triazol-1-ylmethyl)Common Name: Anastrozole Chemical Abstracts Registry No.: 120511-73-1
Anastrazole
325
Structural Formula:
Trade Name
Manufacturer
Altraz
Alkem Laboratories Ltd. India
Country
Year Introduced -
Anastrozole
AstraZeneca
UK
-
Arimidex
AstraZeneca
UK
-
Raw Materials N-Bromosuccinimide 1,2,4-Triazole sodium salt Tetrabutylammonium bromide Iodomethane
Benzoyl peroxide 3,5-Bis(bromomethyl)toluene Potassium cyanide Sodium hydride
Manufacturing Process A mixture of 2,2-(5-methyl-1,3-phenylene)di(2-methylpropionitrile) (2.26 g), N-bromosuccinimide (1.78 g), benzoylperoxide (0.05 g) and carbon tetrachloride (50 ml) was refluxed for 2 hours, cooled and filtered, and the filtrate was evaporated to dryness under reduced pressure. The residue was dissolved in dimethylformamide (20 ml), sodium triazole (1.8 g) was added, and the mixture was stirred at room temperature for 18 h. Water (100 ml) was added, and the mixture was extracted twice with ethyl acetate, dried and evaporated to dryness and the residue was purified by flash column chromatography, eluting with ethyl acetate to give 2,2-[5-(1H-1,2,4-triazol-1ylmethyl)-1,3-phenylene]di(2-methylpropionitrile), mp 81-82°C after crystallization from ethyl acetate/cyclohexane. The 5-methyl-1,3-phenylene compound used as starting material in above process may be prepared as follows. The mixture of 3,5bis(bromomethyl)toluene (30 g), tetrabutyl-ammonium bromide (1 g), KCN (17.6 g), dichloromethane (100 ml) and water (30 ml) was stirred vigorously and refluxed for 3 h. The mixture was cooled, diluted with water (100 ml) and extracted three times with ethyl acetate, dried and evaporated to dryness, the residue was purified by flash chromatography, eluting with petroleum ether/ethyl acetate (3:1) to give 2,2-(5-methyl-1,3-phenylene)diacetonitrile, mp 73-74°C after crystallization from carbon tetrachloride. A mixture of this diacetonitrile (11.5 g), iodomethane (42 g) and dimethylformamide (150 ml) was cooled in an ice and stirred while sodium hydride (50% dispersion in mineral oil, 15 g) was added slowly, over 1 hour, then the mixture was allowed to warm to room temperature, stirred for 2 h, 500 ml of water was added, and the mixture was extracted twice with ethyl acetate, the extracts were dried and evaporated to dryness and the residue was crystallized from carbon tetrachloride to give the required 5-methyl-1,3-phenylene starting
326
Anaxirone
material, mp 126-127°C. References Edwards P.N. et al.; US Patent No. RE36,617 Mar. 14, 2000; Assigned: Zeneca Limited (London, GB) Thomson and Siiteri, J. Biol. Chem., 249, 5364 (1974)
ANAXIRONE Therapeutic Function: Antineoplastic Chemical Name: 1,2,4-Triazolidine-3,5-dione, 1,2,4-tris(oxiranylmethyl)Common Name: Anaxirone; Triglycidylurazol Structural Formula:
Chemical Abstracts Registry No.: 77658-97-0 Trade Name
Manufacturer
Country
Year Introduced
Anaxirone
Onbio Inc.
-
-
Raw Materials Triazolidine-3,5-dione Epichlorohydrin Triethylamine Manufacturing Process In a 4-liter three-necked flask equipped with a stirrer, thermometer and reflux condenser, 101 g (1 mole) of triazolidine-3,5-dione, 2775 g (30 moles) of epichlorohydrin and 2 ml of triethylamine are heated to 80°C by means of an oil bath. The mixture reacts exothermically so that the oil bath may be removed. After the exothermic reaction has abated, the reaction mixture is stirred at 80°C. The total reaction time is 10 hours. 250 g of 50% sodium hydroxide solution are added dropwise to the solution obtained over a period of 4 hours at from 30 to 40°C in such a way that the water added and the water formed during the reaction is continuously removed by azeotropic
Ancarolol
327
distillation at from 30 to 60 Torr using a water separator. To complete the reaction, the reaction mixture is stirred for another hour and the sodium chloride formed is separated by filtration. The sodium chloride is washed twice with 200 g of epichlorohydrin and the combined epichlorohydrin solutions are washed with 200 ml of water. After the organic phase has been dried over sodium sulfate, the solvent is removed by concentration in a rotary evaporator and the residue is dried, ultimately at 80°C/0.2 mbar, to constant weight. 240 g of a light brown viscous oil are obtained. It was found to have an epoxide value of 0.93 and has a chlorine content of 2.75%. The viscous oil crystallizes after standing for from a few hours to days. The practically pure 1,2,4triglycidyl triazolidine-3,5-dione melting at from 98° to 103°C crystallizes by dissolution in methanol and cooling to 5°C. IR- and NMR-spectra in conjunction with elemental analysis and epoxide determination confirm the assumed structure. Melting point 94-96°C. References Rottmaier Ludwig, Merten Rudolf; US Patent No. 4,283,546; Aug. 11, 1981; Assigned to Bayer Aktiengesellschaft (DE)
ANCAROLOL Therapeutic Function: Beta-adrenergic blocker Chemical Name: N-[2-[3-[(1,1-Dimethylethyl)amino]-2-hydroxypropoxy] phenyl]-2-furancarboxamide (+/-) Common Name: Ancarolol Structural Formula:
Chemical Abstracts Registry No.: 75748-50-4 Trade Name
Manufacturer
Country
Year Introduced
Ancarolol
ZYF Pharm Chemical
-
-
Ancarolol
Onbio Inc.
-
-
Raw Materials 2'-(2,3-Epoxypropoxy)-furan-2-carboxylic acid anilide t-Butylamine
328
Ancitabine hydrochloride
Manufacturing Process A mixture of 23 g of 2'-(2,3-epoxypropoxy)-furan-2-carboxylic acid anilide, 7.3 g of t-butylamine and 50 ml of isopropanol is boiled under reflux for 10 hours. On cooling, 2'-(2-hydroxy-3-t-butylaminopropoxy)-furan-2-carboxylic acid anilide (ancarolol) crystallizes out from the solution. The chromatographically pure base is obtained in the form of a white solid of melting point 112°-113°C by recrystallization from ethyl acetate. The yield is 12 g. The colorless, crystalline base is dissolved in alcohol, alcoholic HCl is added and the hydrochloride is induced to crystallize by adding ether dropwise. After isolation, the salt is recrystallized again from ethanol. This gives 10 g of the hydrochloride, melting point 189°-191°C. References Ulendorf J. et al.; US Patent No. 4,269,855; May 26, 1981; Assigned to A. Nattermann and Cie, GmbH, Cologne, Fd.Rep. of Germany
ANCITABINE HYDROCHLORIDE Therapeutic Function: Antineoplastic Chemical Name: 2,3,3a,9a-Tetrahydro-3-hydroxy-6-imino-6Hfuro[2',3';4,5]oxazolo[3,2-a]pyrimidine-2-methanol hydrochloride Common Name: Structural Formula:
Chemical Abstracts Registry No.: 10212-25-6; 31698-14-3 (Base) Trade Name
Manufacturer
Country
Year Introduced
Cyclo-C
Kohjin
Japan
1975
Raw Materials Uridine Imidazole Hydrogen sulfide Acetic anhydride Ammonia Hydrogen chloride
Trityl chloride Thiophosgene Acetic acid Phosphorus pentasulfide Bromine
Ancrod
329
Manufacturing Process A series of reaction steps may be employed in which: (1) Uridine is reacted with trityl chloride to give 5'-o-trityluridine; (2) Imidazole is reacted with thiophosgene and that product reacted with the 5'-o-trityluridine to give 2,2'anhydro-1-(5'-o-trityl-β-D-arabinofuranosyl)uracil; (3) The preceding uracil product is converted to the thiouracil using hydrogen sulfide; (4) The trityl group is removed by treatment with 80% acetic acid; (5) A triacetylated product is obtained using acetic anhydride; (6) A dithiouracil is prepared from the uracil intermediate using phosphate pentasulfide. Preparation of 1-(β-D-arabinofuranosyl)-2-thiocytosine: A solution of 2.0 g of 1-(2',3',5'-O-triacetyl-β-D-arabinofuranosyl)-2,4-dithiouracilin 100 ml of methanol is saturated with anhydrous ammonia at 0°C. The mixture, in a glass liner, is heated in a pressure bomb at 100°C for three hours. The reaction mixture is concentrated to a gum in vacuum, and most of the byproduct acetamide is removed by sublimation at 60°C/0.1 mm. The residue is chromatographed on 100 g of silica gel. Elution of the column with methylene chloride-methanol mixtures with methanol concentrations of 2-25% gives fractions containing acetamide and a series of brown gums. The desired product is eluted with 30% methanol-methylene chloride to give a total yield of 0.386 g (30%), MP 175-180°C (dec.). Recrystallization from methanolisopropanol furnishes an analytical sample, MP 180-182°C (dec.). To a solution of 80 mg of 1-(β-D-arabinofuranosyl)-2-thiocytosine in 12 ml of water is added dropwise 3 ml of a 1 M bromine solution in carbon tetrachloride. At this point the color of the bromine persists for about 2-3 minutes after each addition. The unreacted bromine is blown off with a stream of nitrogen, and the reaction mixture is concentrated to a syrup in vacuum using a bath temperature less than 50°C. The residue is evaporated three times with 10 ml portions of ethanol, whereupon it crystallizes. The product is triturated with cold ethanol and with ether to obtain 17 mg of 2,2'-anhydro-1(β-D-arabinofuranosyl)cytosine hydrobromide, MP 240°C (dec.). Treatment of the hydrobromide with a slight excess of ethanolic ammonia yields the base which may then be converted to the hydrochloride. References Merck Index 654 Kleeman and Engel p. 53 DOT 12 (8) 304 (1976) I.N. p.87 Shen, T.Y. and Ruyle, W.V.; US Patent 3,463,850; August 26, 1969; Assigned to Merck and Co., Inc.
ANCROD Therapeutic Function: Anticoagulant Chemical Name: Agkistrodon serine proteinase
330
Ancrod
Common Name: Ancrod; Venacil Chemical Abstracts Registry No.: 9046-56-4 Trade Name Viprinex Arvin
Manufacturer Country Knoll Pharmaceuticals Knoll AG/BASF Pharma -
Year Introduced -
Raw Materials Venom of the Malayan pit-viper Agkistrodon rhodostoma Triethylaminoethyl cellulose powder (Serva) tris(Hydroxymethyl)aminomethane Manufacturing Process Triethylaminoethyl cellulose powder (Serva) of capacity 0.71 m.equiv./gm is suspended in 2 M sodium chloride buffered with 0.1 M tris/phosphate pH 6.0 and the slurry is packed into a glass column 3.6 cm in diameter until the height of the packed material reaches 20 cm. The column is washed with a further 2 L of the solvent used for preparing the slurry and is then equilibrated with 0.01 M tris/phosphate buffer pH 8.5. Tris is an abbreviation for tris(hydroxymethyl)aminomethane. 330-360 mg of crude A. rhodostoma venom is dissolved in 20 ml of 0.01 M tris/phosphate buffer pH 8.5, centrifuged to remove insoluble material, and the clear supernatant is applied to the column. The fractionation is carried out at room temperature at a flow rate of 90-100 ml (35 ml/hour). The protein concentration in the eluate is estimated from the extinction of the solution at 280 m/t in 1 cm cells. The chromatogram is developed with the following buffers. In all cases the molarity of the buffers are with respect 40 to tris. 0.01 M tris/phosphate pH 8.5 (to wash venom onto the column) (fractions 1, 2, 3). 0.01 M tris/phosphate pH 7.0 (fraction 4), 0.02 M tris/phosphate pH 6.0, 0.04 M tris/phosphate pH 6.0 (fraction 5), 0.10 M tris/phosphate pH 6.0 (fraction 6), 0.10 M tris/phosphate + 0.10 M NaCl pH 6.0 (fraction 7). The changes in eluting buffer are made after the column has equilibrated with the buffer. The protein fractions obtained in this way are assayed for coagulant activity. Less than 1% of the applied coagulant activity is recovered in fraction Nos. 1, 2, 3, 4. Fraction 1 however possesses proteolytic activtity which in concentrated solutions would dissolve fibrin clots. The thrombin-like activity is eluted from these columns in significant amounts at a buffer strength of 0.04 M or greater. The eluate is freeze dried to give a light powdery product. Yield: 18-20 mg per 350 mg dry venom. Calculation of molecular weight of the protein based on the amino acid composition gives a value of 30.000 which is in a very good agreement with that obtained by physical methods.
Anetholtrithion
331
References Reid H.A. et al.; US Patent No. 3,657,416; April 18, 1972; Assigned to Natinal Research Development Corporation, London, England
ANETHOLTRITHION Therapeutic Function: Salivation stimulant, Choleretic, Neuroprotective Chemical Name: 3H-1,2-Dithiole-3-thione, 5-(4-methoxyphenyl)Common Name: Anethole dithiolthione; Trithioparamethoxyphenylpropene; Anethole trithione Structural Formula:
Chemical Abstracts Registry No.: 532-11-6 Trade Name
Manufacturer
Country
Year Introduced
Sialor
Paladin Labs
-
-
Anetholtrithion
Shanghai Jinsai Medicine Chemical Industry Co. Ltd.
-
Anetholtrithion
-
-
Anetholtrithion
Tianjin Mid-Chem Co., Ltd. Shanghai Lansheng Corporation
-
-
Secrebil
Wassermann
-
-
Secrebil
Vicente Scavone y CIA. C.I.S.A.
-
Bilitherap
Kaigen
-
-
Felviten
Nippon Shinyaku
-
-
Halpen
Toho Kagaku
-
-
Mucinol
-
Sialor
Sanofi-Synthelabo OTC, D-Berlin Solvay-Kingswood -
Sonicur
Kalifarma
-
-
Sufralen
Solvay
-
-
Sulfarlem
Solvay
-
-
-
332
Angiotensin amide
Trade Name
Manufacturer
Sulfarlem
Solvay-Kingswood -
Country
Year Introduced -
Sulfarlem
UCM
-
-
Sulfarlem
Tobishi
-
-
Sulfarlem
Ouiheng
-
-
Sulfarlem
Frik
-
-
Sulfarlem
Ethimed
-
-
Raw Materials Anethol (1-Methoxy-4-propenyl-benzene) Sulfur Manufacturing Process 1 mol anethol (1-methoxy-4-propenyl-benzene) and 3 mol sulfur were heated in an open vessel to temperature 190°-200°C. H2S was removed at this temperature. On cooling the reaction mixture was getting solid. The solid product was recrystallizated from acetone or ethanol to give the orange-red needles of 5-(4-methoxyphenyl)-3H-1,2-dithiole-3-thione; MP 108.5°C. References Boettcher B.; D.B. Patent No. 869,799; May 8, 1940
ANGIOTENSIN AMIDE Therapeutic Function: Vasoconstrictor Chemical Name: L-Asparaginyl-L-arginyl-L-valyl-L-tyrosyl-L-valyl-L-histidyl-Lprotyl-L-phenylalanine Common Name: Chemical Abstracts Registry No.: 53-73-6 Trade Name
Manufacturer
Country
Year Introduced
Hypertensin
Ciba
W. Germany
1961
Hypertensin
Ciba
US
1962
Raw Materials L-Asparaginyl-L-arginyl-L-valyl-L-tyrosyl-L-valyl-L-histidyl-L-prolyl-Lphenylalanine methyl ester trihydrochloride Sodium hydroxide
Anilamate
333
Structural Formula:
Manufacturing Process 48 mg (0.042 mmol) of L-asparaginyl-L-arginyl-L-valyl-L-tyrosyl-L-valyl-Lhistidyl-L-prolyl-L-phenylalanine methyl ester trihydrochloride are suspended in 0.5 ml of methanol, and treated gradually in the course of one hour with 0.3 ml of N-caustic soda solution (about 7 equivalents) so that the pH value of the solution is maintained between 10.5 and 11.5. After a further 30 minutes the solution is freed from methanol under vacuum at room temperature, adjusted with 1 N acetic acid to pH 7.4 and lyophilized. The residual mixture of free peptide and inorganic salts (79 mg) is fractionated by countercurrent distribution in the system butanol/0.1 N ammonium hydroxide. The pure octapeptide is obtained as a colorless powder which is soluble in water and methanol, more sparingly soluble in ethanol, and insoluble in acetone. References Merck Index 674 Kleeman and Engel p. 55 I.N. p. 89 Schwyzer, R., Iselin, B., Kappeler, H., Ritter, W. and Riuiker, B.; US Patent 2,978,444; April 4, 1961; Assigned to Ciba Pharmaceutical Products, Inc.
ANILAMATE Therapeutic Function: Antiinflammatory Chemical Name: 2-[[(Methylamino)carbonyl]oxy]-N-phenylbenzamide Common Name: Anilamate
334
Anileridine dihydrochloride
Structural Formula:
Chemical Abstracts Registry No.: 5591-49-1 Trade Name
Manufacturer
Country
Year Introduced
Anilamate
Onbio Inc.
-
-
Raw Materials Salicylanilide Triethylamine Methyl isocyanate Manufacturing Process 32 g of salicylanilide was dissolved in 1000 ml of diethyl ether, 2 ml of triethylamine and 25 ml of a 50% solution of methyl isocyanate in toluene were added to the solution and the reaction mixture was allowed to stand overnight at about 25°C. The resulting crystals of salicylanilide methylcarbamate were removed by filtration, washed with 100 ml of diethyl ether, and dried in vacuo to provide 37.5 g (92% yield) of salicylanilide methylcarbamate having melting point of 160-161°C. References Strube R.E.; US Patent No. 3,091,633; May 28, 1963; Assigned to The Upjon Company, Kalamazoo, Mich., a corporation of Delawere
ANILERIDINE DIHYDROCHLORIDE Therapeutic Function: Narcotic analgesic Chemical Name: 1-[2-(4-Aminophenyl)ethyl]-4-phenyl-4-piperidinecarboxylic acid ethyl ester dihydrochloride Common Name: Chemical Abstracts Registry No.: 126-12-5; 144-14-9 (Base)
Anileridine dihydrochloride
335
Structural Formula:
Trade Name
Manufacturer
Country
Year Introduced
Leritine HCl
US
1958
Apodol Tabs
Merck Sharp and Dohme Squibb
US
1965
Leritine
Merck-Frosst
Canada
-
Raw Materials Sodium carbonate Hydrogen chloride
β-(p-Aminophenyl)ethyl chloride 4-Phenyl-4-carbethoxypiperidine carbonate
Manufacturing Process A mixture of 7.8 grams (0.05 mol) of β-(p-aminophenyl)ethyl chloride hydrochloride, 12.5 grams (0.025 mol) of 4-phenyl-4-carboethoxypiperidine carbonate, 10.5 grams (0.125 mol) sodium bicarbonate, and 100 cc of anhydrous ethanol are mixed, stirred and heated under reflux for a period of approximately 40 hours and then concentrated in vacuum to dryness. The residual material is triturated with 50 cc of water, decanted, washed by decantation with an additional 50 cc of water, and then dried in vacuum to give N-[β-(p-aminophenyl)ethyl]-4-phenyl-4-carboethoxypiperidine. The N-[β-(p-aminophenyl)ethyl]-4-phenyl-4-carboethoxypiperidine is dissolved in 50 cc of hot anhydrous ethanol, an excess (about 20 cc) of 20% alcoholic hydrochloric acid solution is added; upon scratching the side of the container crystals form. One hundred cubic centimeters of ether are then added to the mixture, the ethereal mixture is cooled, and the crystalline material which precipitates is recovered by filtration, washed with ether, and dried to give 12.7 grams of N-[β-(p-aminophenyl)ethyl]-4-phenyl-4-carboethoxypiperidine dihydrochloride which can be further purified by recrystallization from ethanol or methanal to give substantially pure material; MP 275-277°C. References Merck Index 680 Kleeman and Engel p. 56 OCDS Vol. 1 p. 300 (1977) I.N. p. 90 Weijlard, J. and Pfister, K., III; US Patent 2,966,490; December 27, 1960; Assigned to Merck and Co., Inc.
336
Anipamil
ANIPAMIL Therapeutic Function: Coronary vasodilator, Antihypertensive Chemical Name: 2-[3-[(m-Methoxyphenethyl)methylamino]propyl]-2-(mmethoxyphenyl)tetradecanenitrile Common Name: Anipamil; LU 42668 Structural Formula:
Chemical Abstracts Registry No.: 83200-10-6 Trade Name
Manufacturer
Country
Year Introduced
Anipamil
Onbio Inc.
-
-
Anipamil
ZYF Pharm Chemical
-
-
Raw Materials 3-Methoxyphenylacetonitrile 1-Bromododecane 1-Bromo-3-chloropropane
1-Cyano-1-(3-methoxyphenyl)tridecane N-Methyl-β-(3-methoxyphenyl)ethylamine Sodium amide
Manufacturing Process 1,7-Bis-(3-ethoxyphenyl)-3-methylaza-7-cyano-nonadecane: 0.06 mole of 1-cyano-1-(3-methoxyphenyl)tridecane (prepared by phase transfer-catalyzed alkylation of 3-methoxyphenylacetonitrile with 1bromododecane) and 0.06 mole of 1-chloro-4-methylaza-6-(3methoxyphenyl)hexane [prepared from N-methyl-β-(3methoxyphenyl)ethylamine and 1-bromo-3-chloropropane by a method similar to that described in Arzneim.-Forsch. 28 (II) (1978), 2048] were dissolved in 100 ml of dry toluene in a three-necked flask provided with a stirrer, dropping funnel, reflux condenser and thermometer. 9.3 g (0.07 mole) of a 30% strength suspension of sodium amide in toluene were then added dropwise at from 100° to 110°C, with stirring, and stirring was continued under reflux for a further 90 minutes.
Aniracetam
337
The resulting reaction solution was poured into 200 ml of ice water, and the toluene phase was separated off and washed twice with water. The required amount of hydrochloric acid was added to the toluene solution, the toluene was distilled off under reduced pressure and the residue, which remained was recrystallized from acetone to give 1,7-bis-(2-methoxyphenyl)-3-methylaza-7cyanononadecane hydrochloride or α-dodecyl-3-methoxy-α-[3-[[2-(3methoxyphenyl)ethyl]methylamino]propyl]benzene-acetonitrile (anipamil); MP: 60°-69.5°C. References Ehrmann O. et al.; US Patent No. 4,438,131; March 20, 1984; Assigned to BASF Aktiengesellshaft, Fed. Rep. of Germany
ANIRACETAM Therapeutic Function: Nootropic Chemical Name: 2-Pyrrolidinone, 1-(4-methoxybenzoyl)Common Name: Aniracetam; Memodrin Structural Formula:
Chemical Abstracts Registry No.: 72432-10-1 Trade Name Pergamid AM Ro13-5057
Manufacturer Rontag ABATRA Technology Co., Ltd.
Country -
Year Introduced -
Memodrin
Lavipharm Group
-
-
Raw Materials 2-Pyrrolidinone Triethylamine Sodium hydride
p-Methoxybenzoyl chloride p-Methoxybenzoic acid pentachlorophenyl ester 1-Trimethylsilyl-2-pyrrolidinone
Manufacturing Process There are a few versions of synthesis of title compound.
338
Aniracetam
Preparation of 1-(p-methoxybenzoyl)-2-pyrrolidinone: 1. 40.0 g of p-methoxybenzoyl chloride, 25.0 g of 2-pyrrolidinone and 110 ml of absolute diethyl ether are treated at between 0°C and 10°C while stirring with 52.5 ml of triethylamine. The mixture is stirred at room temperature for a further 30 minutes and at reflux for 3 hours, then cooled down and treated at 2°C with cold water. The insoluble constituents are filtered off under suction and washed with water and diethyl ether. The thus obtained solid substance is recrystallized from alcohol after drying over phosphorus pentoxide. There is obtained 1-(p-methoxybenzoyl)-2-pyrrolidinone which melts at 121°-122°C. 2. 20.2 g of the sodium salt of 2-pyrrolidinone (prepared using sodium hydride) suspended in 270 ml of dimethylformamide are added in four portions at -10°C to a solution of 37.0 g of p-methoxybenzoyl chloride in 50 ml of dimethylformamide. Subsequently, the mixture is stirred at room temperature for 1 hour and then at 40°C for 4 hours. The solvent is evaporated and the residue is treated with diethyl ether and with cold sodium bicarbonate solution. The insoluble crystalline constituents are filtered off, washed with water and diethyl ether and dried in vacuum over phosphorus pentoxide. There is obtained 1-(p-methoxybenzoyl)-2-pyrrolidinone having a melting point of 120°-121°C. 3. 20 g of p-methoxybenzoyl chloride and 20 g of 2-pyrrolidinone are boiled at reflux in 20 ml of diethyl ether for 16 hours and then diethyl ether, ice and 2 N aqueous ammonia are added to the mixture. The insoluble constituents are filtered off and washed ion-free with diethyl ether and water. The filter cake is dried and there is obtained 1-(p-methoxybenzoyl)-2-pyrrolidinone having a melting point of 119.5°-120.5°C. 4. 20 g of p-methoxybenzoyl chloride and 20 g of 2-pyrrolidinone are boiled at reflux in 20 ml of diethyl ether for 16 hours and then diethyl ether, ice and 2 N aqueous ammonia are added to the mixture. The insoluble constituents are filtered off and washed ion-free with diethyl ether and water. The filter cake is dried and there is obtained 1-(p-methoxybenzoyl)-2-pyrrolidinone having a melting point of 119.5°-120.5°C. The procedure described in item is followed, but the starting materials are heated in 20 ml of toluene instead of diethyl ether. The resulting 1-(p-methoxybenzoyl)-2-pyrrolidinone melts at 117°118°C. 5. 10 g of 2-pyrrolidinone and 10 g of p-methoxybenzoyl chloride are heated at 80°-90°C (internal temperature) in the absence of a solvent for 1 hour. The mixture is then left to cool down and is worked-up as described in item 3. After recrystallization from alcohol, there is obtained 1-(p-methoxybenzoyl)-2pyrrolidinone having a melting point of 120°-121°C. 6. 24.4 g of p-methoxybenzoyl chloride and 22.5 g of 1-trimethylsilyl-2pyrrolidinone are mixed and the mixture is stirred at room temperature for 10 minutes. Then, the resulting trimethylchlorosilane is distilled off under reduced pressure in an oil bath at 80°C. The residue is triturated with 100 ml of diethyl ether. The mixture is filtered and the filter cake is recrystallized from ethanol. There is obtained 1-(p-methoxybenzoyl)-2-pyrrolidinone having a melting point of 120°-121°C. 7. 7.0 g of the sodium salt of 2-pyrrolidinone (prepared using sodium hydride)
Anirolac
339
suspended in 120 ml of dimethylformamide are added at -10°C to a solution of 20.0 g of p-methoxybenzoic acid pentachlorophenyl ester in 100 ml of dimethylformamide. Subsequently, the mixture is stirred at room temperature for 1 hour and at 55°C for 8 hours. The solvent is evaporated, the residue is treated with cold aqueous acetic acid solution and the mixture is extracted with ethyl acetate. The organic phase is washed with cold sodium bicarbonate solution and water, dried over sodium sulfate, filtered and evaporated. The residue is taken up in ethanol and stirred in an ice bath. The separated crystals are filtered off and there is obtained 1-(p-methoxybenzoyl)-2pyrrolidinone having a melting point of 119°-120°C. References Kyburz E. et al.; US Patent No. 4,369,139; Jan. 18, 1983; Assigned to Hoffmann-La Roche Inc., Nutaey, N.J.
ANIROLAC Therapeutic Function: Antiinflammatory, Analgesic Chemical Name: 1H-Pyrrolizine-1-carboxylic acid, 2,3-dihydro-5-(4methoxybenzoyl)-, (+-)Common Name: Anirolac Structural Formula:
Chemical Abstracts Registry No.: 66635-85-6 Trade Name Anirolac Anirolac
Manufacturer Syntex Inc. Onbio Inc.
Country -
Year Introduced -
Raw Materials N,N-Dimethyl-p-methoxybenzamide Phosphorous oxychloride Isopropyl 1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate Manufacturing Process A solution of 1.1 equivalent of N,N-dimethyl-p-methoxybenzamide and 1
340
Anisacril
equivalent of phosphorous oxychloride in 2 ml of 1,2-dichloroethane is refluxed for 30 minutes. To this solution is added a solution of 1 equivalent of isopropyl 1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate in 2 ml of 1,2dichloroethane. The reaction mixture is refluxed under an argon atmosphere for 8 hours, treated with equivalent of sodium acetate and refluxed for a further 5 hours. The resultant mixture is then evaporated to dryness and the residue is chromatographed on 12 g of silica gel, eluting with hexane: ethyl acetate (3:1), monitoring the course of the reaction by TLC. Isopropyl 5-pmethoxybenzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate was obtained as an oil. UV, IR, NMR spectrum confirmed the structure of obtained compound. A solution of 1 equivalent of isopropyl 5-p-methoxybenzoyl-1,2-dihydro-3Hpyrrolo[1,2-a]pyrrole-1-carboxylate in 10 ml of methanol is treated with a solution of 1 equivalent of potassium carbonate in 5 ml of water. The reaction mixture is refluxed under nitrogen atmosphere for 30 minutes, cooled, and evaporated to dryness. The residue is taken up in 10 ml of 10% aqueous hydrochloric acid and 50 ml of water and the resultant mixture extracted with ethyl acetate (2x50 ml). The combined extracts are dried over magnesium sulfate and evaporated to dryness under reduced pressure. Crystallization of the residue from ethyl acetate-hexane affords 5-p-methoxybenzoyl-1,2dihydro-3H-pyrrolo[1, 2-a]pyrrole-1-carboxylic acid (anirolac); MP: 187°187.5°C. References Syntex (USA) Inc.; G.B. Patent No. 1,554,075; Oct. 17, 1979
ANISACRIL Therapeutic Function: Anorexic, Antihyperlipidemic Chemical Name: Acrylic acid, 2-(o-methoxyphenyl)-3,3-diphenylCommon Name: Anisacril Structural Formula:
Chemical Abstracts Registry No.: 5129-14-6 Trade Name
Manufacturer
Country
Year Introduced
SCF 16046
Smith Kline
-
-
Anisindione
341
Raw Materials o-Bromoanisole Hydrochloric acid Sodium hydroxide
Magnesium Diphenyl pyruvic acid
Manufacturing Process A solution of Grignard reactive (prepared from 247 g of o-bromoanisole and 31.6 g of magnesium in 1500 ml of ether) is added dropwise to a solution of 91 g of diphenyl pyruvic acid in ether. The mixture is refluxed for 2 hours. After cooling to the reaction mixture is added 5% hydrochloric acid and the product is extracted with 5% solution of sodium hydroxide. α-(o-Anisyl)-β,βdiphenyl lactic acid is precipitated by addition of concentrated hydrochloric acid; yield 62 g, melting point 194-195°C. 4 g of α-(o-anisyl)-β,β-diphenyl lactic acid is heated at 210-215°C for 10-15 min. The α-(o-anisyl)-β,β-diphenyl acrylic acid is recrystallized from benzene, yield 2.85 g (74%), melting point 195-196°C. References FR Patent No. 1,442,295; Oct. 8, 1964; Assigned to Smith Kline and French Laboratories residant aux Etats-Unis d'Amerique
ANISINDIONE Therapeutic Function: Anticoagulant Chemical Name: 2-(4-Methoxyphenyl)-1H-indene-1,3(2H)-dione Common Name: Anisindandione Structural Formula:
Chemical Abstracts Registry No.: 117-37-3 Trade Name Miradon Unidone Unidone
Manufacturer Schering Unilabo Centrane
Country US France France
Year Introduced 1960 1964 -
342
Anisopirol
Raw Materials p-Methoxybenzaldehyde Sodium ethoxide Phthalide Manufacturing Process To a hot solution of 20.6 g of sodium in 400 ml of absolute ethanol, there is added a solution of 110 g of phthalide and 110 g of p-methoxybenzaldehyde. A vigorous reaction ensues and one-half of the alcohol is distilled off over a two hour period. Ice and water are added to the red solution and the diluted solution is acidified with hydrochloric acid. The resulting gum solidifies and the aqueous phase is removed by decantation. The crude solid is recrystallized twice from two liters of ethanol yielding 2-(p-methoxyphenyl)-1,3-indandione as pale yellow crystals, MP 155-156°C. References Merck Index 690 Kleeman and Engel P.57 OCDS Vol. 1 p. 147 (1977) I.N. p.90 REM p.828 Sperber, N.; US Patent 2,899,358; August 11, 1959; Assigned to Schering Corporation
ANISOPIROL Therapeutic Function: Neuroleptic Chemical Name: (+/-)-α-(4-Fluorophenyl)-4-(2-methoxyphenyl)-1piperazinebutanol Common Name: Anisopirol Structural Formula:
Chemical Abstracts Registry No.: 442-03-5 Trade Name
Manufacturer
Country
Year Introduced
Anisopirol
ZYF Pharm Chemical
-
-
Anisotropine metylbromide
343
Raw Materials γ-Chloro-4-fluorobutyrophenone 1-(2-Methoxyphenyl)piperazine Sodium borohydride Manufacturing Process A mixture of 6.6 parts of γ-chloro-4-fluorobutyrophenone and 12.5 parts of 1(2-methoxyphenyl)piperazine, heated for 10 hours at a temperature of 110°C. The reaction mixture is treated with 800 parts of ether and fiItered. The ether layer is washed with water, dried over anhydrous potassium carbonate and filtered, whereupon hydrogen chloride gas is introduced into the solution. The precipitate is collected on a filter and dissolved in a mixture of 240 parts of 2propanol and 80 parts of acetone to yield 1-[γ-(4-fluorobenzoyl)propyl]-4-(2methoxyphenyl)piperazine hydrochloride. This monohydrochloride is collected on a filter and dissolved in 240 parts of 2-propanol. Anhydrous, gaseous hydrogen chloride is passed through the solution. On cooling, the 1-[γ-(4fluorobenzoyl)propyl]-4-(2-methoxyphenyl)piperazine hydrochloride precipitates. A second crop of product is obtained by passing hydrogen chloride gas through the solution of mother liquors. The pale-brown, amorphous powder is collected on a filter and found to melt at about 205°-205.5°C. This salt is dissolved in water and treated with sodium hydroxide. The precipitated base is recovered by filtration and recrystallized from diisopropylether. The white crystals melt about 67.5°-68.5°C. By dissolving 4 parts of 1-[γ-(4-fluorobenzoyl)propyl]-4-(2-methoxyphenyl) piperazine dihydrochloride in 800 parts of water, rendering alkaline, extracting with 400 parts of ether, drying over calcium chloride, filtering, and evaporating the resulting solution, the free base of 1-[γ-(4-fluorobenzoyl) propyl]-4-(2-methoxyphenyl)piperazine is obtained. This product is dissolved in 120 parts of absolute ethanol and 0.03 part of sodium borohydride is added portionwise at 35°C. After decomposition with 150 parts of 1 N hydrochloric acid, the mixture is diluted with 500 parts of water, made alkaline with 4 N sodium hydroxide, and further diluted to a volume of 1,000 parts. Upon cooling for 4 hours at 0°C the precipitate formed is filtered, dried, and recrystallized from diisopropyl ether to yield 1-(4-fluorophenyl)-4-[4-(2methoxyphenyl)piperazine]-1-butanol (anisopirol). The white granular powder of this compound has a melting point of about 105°-106°C. References Jansen P. A.J.; US Patent No. 2,997,474; August 22, 1961
ANISOTROPINE METHYLBROMIDE Therapeutic Function: Anticholinergic
344
Anisotropine metylbromide
Chemical Name: endo-8,8-Dimethyl-3-[(1-oxo-2-propylpentyl)oxy]-8azoniabicyclo[3.2.1]octane bromide Common Name: Octatropine methyl bromide Structural Formula:
Chemical Abstracts Registry No.: 80-50-2 Trade Name
Manufacturer
Country
Year Introduced
Valpin
Endo (Du Pont)
US
1963
Valpinax
Crinos
Italy
1966
Valpin
Lacer
Spain
-
Valpin
Sankyo
Japan
-
Raw Materials Tropine Di-n-propyl acetyl chloride Methyl bromide Manufacturing Process Preparation of Di-n-propyl acetyl tropine hydrochloride: Tropine (11.12 grams) was dissolved in 100 ml of anhydrous pyridine and to this solution was added 15.64 grams of di-n-propyl acetyl chloride. The mixture was refluxed for 6 hours. This solution was then cooled and the pyridine removed in vacuum. The residue was dissolved in chloroform. The chloroform solution was washed with 10% hydrochloric acid to remove the residual trace of pyridine. The hydrochloride of the product ester is soluble in chloroform and is not extracted from chloroform by hydrochloric acid. This is an unexpected property. The chloroform solution of the hydrochloride was dried over anhydrous calcium sulfate, and evaporated to dryness, leaving a semisolid residue of product ester hydrochloride. This was recrystallized from chloroform-hexane mixture, MP 186°C. Preparation of the Anisotropine Methyl Bromide: To the acetone solution of the free base was added an acetone solution, containing an excess of methyl bromide. Within a few minutes the methobromide started to crystallize. The mixture was allowed to stand for several hours. The crystallized solid was filtered, and additional product was obtained by evaporation of the filtrate. The yield was nearly quantitative. After recrystallization from acetone, the product melted at 329°C.
Anistreplase
345
References Merck Index 693 Kleernan and Engel p. 655 PDR p. 865 I.N. p. 699 REM p.913 Weiner, N. and Gordon, S.M.; US Patent 2,962,499; November 29, 1960; Assigned to Endo Laboratories, Inc.
ANISTREPLASE Therapeutic Function: Thrombolytic Chemical Name: Anisoylated plasminogen streptokinase activator complex Common Name: Eminase; Fibrit; Iminase; Multilase; Anisoylated plasminogen streptokinase activator complex Structural Formula: Binary complex of streptokinase and human plasminogen Chemical Abstracts Registry No.: 81669-57-0 Trade Name
Manufacturer
Country
Year Introduced
Anistreplase
Beecham
-
-
Raw Materials Streptokinase (250,000 units, Kabi, Stockholm, Sweden) 0.1 M p-amidinophenyl p'-anisate in dimethylsulphoxide Human lys-plasminogen [Kabi, Stockholm] L-Lysine-sepharose 4B 0.1 M ε-aminocaproic acid Manufacturing Process Preparation of freeze dried p-anisoyl streptokinase/plasminogen complex without internal peptide bond cleavages: Streptokinase (250,000 units, Kabi, Stockholm, Sweden) was dissolved in 0.1 M trishydroxymethylmethane hydrochloride pH 7.4 (2.5 ml) and a solution of 0.1 M p-amidinophenyl p'-anisate in dimethylsulphoxide (0.25 ml) added. A slight cloudiness resulted. To this mixture was added 0.5 ml of a solution of human lys-plasminogen (8.99 mg/ml in the above buffer) [Kabi, Stockholm] and the solution was thoroughly and rapidly mixed. After standing on ice for 15 minutes, the solution was stored on ice until use. After approximaely 2 hours 0.4 ml (40,000 units) of the material was diluted with 3.0 ml of a slurry of L-lysine-sepharose 4B (a 33% wet wt/volume suspension in the above buffer) and stood at 0°C for 1 hour. The gel was filtered on a glass sinter
346
Anitrazafen
funnel at 4°C under suction and washed with the buffer (100 ml). The gel was eluted under gentle suction with the same buffer containing 0.1 M εaminocaproic acid (3 lots of 5 ml). The combined filtrates were dialysed for 2 hours at 4°C against ammonium bicarbonate buffer (50 mM pH 7.0) containing 2.5% w/v mannitol. The product was then freeze dried to 0.799 g of a white solid. Approximately 195 mg of this material was analysed by slab gel polyacrylamide gel electrophoresis using 10% w/v gels in the presence of sodium dodecyl sulphate. Two main polypeptide bands were observed corresponding to lys-plasminogen (m.w. 84,000) and streptokinase (m.w. 47,000). There was also a trace of contaminating human serum albumin derived from the commercial streptokinase preparation. References Smith R.A.G. et al.; US Patent No. 4,808,405; Feb. 28, 1989; Assigned Beecham Group P.L.C., England
ANITRAZAFEN Therapeutic Function: Antiinflammatory Chemical Name: 1,2,4-Triazine, 5,6-bis(4-methoxyphenyl)-3-methylCommon Name: Anitrazafen Structural Formula:
Chemical Abstracts Registry No.: 63119-27-7 Trade Name
Manufacturer
Country
Year Introduced
Lilly 122512
Eli Lilly
-
-
Raw Materials 3-Hydroxy-5,6-bis(4-methoxyphenyl)-1,2,4-triazine Anisil (4,4'-dimethoxybenzil) Semicarbazide hydrochloride Phosphorous oxychloride Methyltriphenylphosphonium bromide Butyl lithium
Anpirtoline hydrochloride
347
Manufacturing Process Preparation of 5,6-bis(4-methoxyphenyl)-3-methyl-1,2,4-triazine: (A) 3-Hydroxy-5,6-bis(4-methoxyphenyl)-1,2,4-triazine 2 moles, 540 g of anisil (4,4'-dimethoxybenzil), 222 g (2 moles) of semicarbazide hydrochloride, 180 g (2.2 moles) of sodium acetate, and 2.5 liters of acetic acid were heated at reflux overnight. The cooled reaction mixture was poured into 5 liters of water. The crude solid product was collected by filtration, washed with water, and recrystallized from acetic acid, giving 434 g of 3-hydroxy-5,6-bis(4methoxyphenyl)-1,2,4-triazine; MP: about 272°-274°C. (B) 3-Chloro-5,6-bis(4-methoxyphenyl)-1,2,4-triazine: 10 grams of 3-hydroxy-5,6-bis(4-methoxyphenyl)-1,2,4-triazine and 50 ml of phosphorous oxychloride were heated at reflux for 1.5 hours. The cooled mixture was poured onto crushed ice and the resultant mixture was extracted with diethyl ether. The extract was washed successively with 2% sodium hydroxide and water until the washings were neutral. The ether extract was dried over anhydrous sodium sulfate and evaporated. The residue was taken up in ether, filtered, and the filtrate was evaporated to yield 9.0 g of 3-chloro5,6-bis(4-methoxyphenyl)-1,2,4-triazine; MP: about 130°-132°C. (C) 5,6-Bis(4-methoxyphenyl)-3-methyl-1,2,4-triazine: To a slurry of 11.7 g (0.33 mole) of methyltriphenylphosphonium bromide in 150 ml of dry tetrahydrofuran at -35°C was added, over a 15-minute period, 20 ml (0.033 mole) of n-butyl lithium. The reaction mixture was stirred for one hour. To the reaction mixture at -35° to -40°C was added over a 10minute period a solution of 5.7 g (0.0165 mole) of 3-chloro-5,6-bis(4methoxyphenyl)-1,2,4-triazine in 50 ml of tetrahydrofuran. The reaction mixture was allowed to warm to ambient temperature and was stirred overnight. A solution of 1.05 g (0.0165 mole) of sodium carbonate in 50 ml of water was added dropwise to the reaction mixture which then was heated at reflux for three hours. The reaction mixture was cooled, poured over ice, and extracted with diethyl ether. The diethyl ether extract was washed with water, dried over anhydrous sodium sulfate, and concentrated. The concentrate was chromatographed over silica gel, with three fractions being collected. After evaporation of solvent, the third fraction solidified; MP: about 109°-113°C. The solid was identified as 5,6-bis(4-methoxyphenyl)-3-methyl-1,2,4-triazine by nuclear magnetic resonance analysis, mass spectrographic analysis, and elemental microanalysis. References Lacefield W.B.; US Patent No. 4,190,725; Feb. 26, 1980; Assigned to Eli Lilly and Company, Indianapolis, Ind.
ANPIRTOLINE HYDROCHLORIDE Therapeutic Function: Analgesic, Antidepressant
348
Anpirtoline hydrochloride
Chemical Name: 2-Chloro-6-(4-piperidinylthio)pyridine monohydrochloride Common Name: Anpirtoline hydrochloride Structural Formula:
Chemical Abstracts Registry No.: 99201-87-3; 98330-05-3 (Base) Trade Name
Manufacturer
Country
Year Introduced
Anpirtoline Hydrochloride
YQBio (Shanghai) Co. Ltd.
-
-
Anpirtoline Hydrochloride
Biomol Research Lab.
-
-
Raw Materials Sodium hydride Silica gel
4-Mercaptopiperidine hydrochloride 2,6-Dichloropyridine
Manufacturing Process 2-Chloro-6-(4-piperidinylthio)pyridine: The reaction is carried out under an argon atmosphere. 0.27 g of 80% sodium hydride (0.009 mol) are suspended in 10 ml of dimethylacetamide; the mixture is cooled with ice and then 0.615 g (0.004 mol) of solid 4mercaptopiperidine hydrochloride are added and stirred for 10 minutes. A solution of 0.588 g (0.004 mol) of 2,6-dichloropyridine in 5 ml of dimethylacetamide are then added dropwise to this mixture and the reaction mixture is stirred for 2.5 hours at room temperature. Working up of the reaction mixture: 25 ml of water are added dropwise with cooling, 20 ml of methylene chloride are then added, the organic phase is separated off, the aqueous phase is then extracted twice with 15 ml of methylene chloride each time, the combined organic phase is washed twice, in each case with 10 ml of water, dried with sodium sulfate, the solution is concentrated on a rotary evaporator, the residue is mixed with 10 ml of absolute ethanol and then reconcentrated. The product which is obtained on removal of the eluant is diluted with 10 ml of ether, an equivalent quantity of HCl in isopropanol is added dropwise and the mixture is placed for several hours in a deep freezer after addition of seed crystals. The hydrochloride of the 2-chloro-6-(4-piperidinylthio)pyridine which crystallizes out is filtered off with suction, washed with ether and dried under oil pump vacuum at 50°C. Melting point of the hydrochloride 132°-133°C.
Ansoxetine
349
References Engel J. et el.; US Patent No. 4,643, 995; Feb. 17, 1987; Assigned to Deguss Akkktiengesellschaft, Frankfurt am Main, Fed. Rep. of Germany
ANSOXETINE Therapeutic Function: Antidepressant Chemical Name: 6-[3-(Dimethylamino)-1-phenylpropoxy]-2-phenyl-4H-1benzopyran-4-one Common Name: Ansoxetine Structural Formula:
Chemical Abstracts Registry No.: 79130-64-6 Trade Name
Manufacturer
Country
Year Introduced
Ansoxetine
ZYF Pharm Chemical
-
-
Raw Materials 1-Chloro-1-phenyl-3-dimethylaminopropane Manufacturing Process A solution of 1 gram-equivalent of 6-hydroxyflavanone in equivalent of 0.5 N ethanolic NaOH is evaporated, the residue is dissolved in 200 ml of DMF and the solution is heated to 150°C; a solution of g-eguivalent of 1-chloro-1phenyl-3-dimethylaminopropane in 50 ml of DMF is added, while stirring. The mixture is stirred for 1.5 hours at 150°C and 6-(1-phenyl-3dimethylaminopropoxy)flavonone is precipitated by adding water. References Hausberg H.-H. et al.; US Patent No. 4,780,478; October 25, 1988; Assigned to Merck Patent Gesellschaft mit Berschrankter Heftung, Darmstadt, Fed.Rep. of Germany
350
Antazoline hydrochloride
ANTAZOLINE HYDROCHLORIDE Therapeutic Function: Antihistaminic Chemical Name: 4,5-Dihydro-N-phenyl-N-(phenylmethyl)-1H-imidazole-2methanamine hydrochloride Common Name: Imidamine Structural Formula:
Chemical Abstracts Registry No.: 2508-72-7; 91-75-8 (Base) Trade Name Antistine HCl Antistine Antistine Antasten Arithmin Azalone Histotab Phenazoline
Manufacturer Ciba Ciba Geigy Ciba Ciba Lannett Smith, Miller and Patch Boots Polfa
Country US France W. Germany US US
Year Introduced 1948 -
UK Poland
-
Raw Materials 2-Chloromethylimidazoline hydrochloride N-Benzylaniline Hydrogen chloride Manufacturing Process 15.4 parts of 2-chloromethylimidazoline hydrochloride, 45.8 parts of Nbenzylaniline and 150 parts of alcohol are heated in an oil bath at 100° to 110°C. After distilling off the alcohol, the reaction mass is maintained at this temperature for a further 3 hours and then triturated with water and 10 parts of sodium bicarbonate. The unconsumed benzylaniline is extracted with ether and the aqueous solution neutralized with dilute hydrochloric acid. By evaporating this solution and extracting the residue with alcohol there is obtained 2-(N-phenyl-N-benzylaminomethyl)imidazoline hydrochloride in the
Antienite
351
form of colorless crystals of melting point 227° to 229°C. References Merck Index 701 Kleeman and Engel p. 57 OCDS Vol. 1 p. 242 (1977) I .N. p. 91 Miescher, K. and Klarer, W.; US Patent 2,449,241; September 14, 1948; Assigned to Ciba Pharmaceutical Products, Inc.
ANTIENITE Therapeutic Function: Anthelmintic Chemical Name: Imidazo[2,1-b]thiazole, 5,6-dihydro-6-(2-thienyl)-, (+/-)Common Name: Antienite; Thiazothielite Structural Formula:
Chemical Abstracts Registry No.: 5029-05-0 Trade Name Antienite Antienite
Manufacturer Onbio Inc. ZYF Pharm Chemical
Country -
Year Introduced -
Raw Materials 2-Iminothiazoline Acetic anhydride Thionyl chloride Oxalic acid dihydrate
Bromomethyl-2-thienylketone Sodium borohydride Phosphoroxy chloride
Manufacturing Process A mixture of 4 parts of 2-iminothiazoline, 8.3 parts of bromomethyl-2thienylketone and 40 parts of absolute ethanol is stirred and refluxed for 2 hours in a water-bath. After cooling, the precipitated hydrobromide is filtered off. From this salt the free base is liberated on treating with ammonium hydroxide solution and it is extracted with chloroform. The organic extract is separated, treated with activated charcoal, filtered and the filtrate is first dried over magnesium sulfate and then evaporated. The solid residue is recrystallized from 24 parts 2-propanol, to yield 2-imino-3-[(2thienylearbonyl)-methyl]-thiazoline; MP: 117.5°-118.5°C.
352
Antienite
A mixture of 4 parts of 2-imino-3-[(2-thienylcarbonyl)methyl]thiazoline, 50 parts of acetic anhydride and 1.15 parts of sodium acetate is stirred and refluxed for 15 minutes. The formed sodium bromide is filtered off. From the filtrate, the excess of acetic anhydride is distilled and the residual solid is recrystallized from 2-propanol. The solid is filtered off and dried in vacuum, yielding 2-(acetylimino)-3-[(2-thienylcarbonyl)methyl]thiazoline; MP: 146°147.5°C. To a stirred mixture of 13 parts of 2-(acetylimino)-3-(2thienylcarbonyl)methyl]thiazoline hydrobromide and 64 parts of ethanol are added portion wise 3 parts of sodium borohydride (exothermic reaction). After the addition is complete, the whole is stirred and refluxed for one hour. The solvent is evaporated. The solid residue is dissolved in hydrochloric acid 4 N. After keeping at room temperature, it crystallizes again. The solid is filtered off and dissolved in water. The aqueous solution is rendered alkaline with ammonium hydroxide and extracted with chloroform. The chloroform extract is dried over magnesium sulfate and evaporated. The solid residue is recrystallized twice: first from 4-methyl-2-pentanone and once more from 400 parts of water. After drying in vacuum, DLl-2-(acetylimino)-3-[2-hydroxy-2-(2thienyl)ethyl]thiazoline is obtained; MP: 132.5°-133°C. A solution of 2 parts of DL-2-(acetylimino)-3-[2-hydroxy-2-(2thienyl)ethyl]thiazoline in 16 parts of thionylchloride and 45 parts chloroform is stirred and refluxed for one hour. After cooling the whole is extracted with water. The acid aqueous solution is separated, washed with toluene, alkalized with ammonium hydroxide solution and extracted with chloroform. The extract is dried over magnesium sulfate and evaporated. The oily residue is dissolved in 40 parts boiling 2-propanol. To this warm solution is added a warm solution of an equivalent quantity of oxalic acid dihydrate in 2-propanoL After cooling to room temperature, the precipitated oxalate is filtered off and dried in vacuum, yielding DL-5,6-dihydro-6-(2-thienyl)imidazo[2,1-b]thiazole oxalate; MP: 192°-193°C. A mixture of 6 parts DL-2-(acetylimno)-3-[2-hydroxy-2-(2thienyl)ethyl]thiazoline and 80 parts phosphoroxy-chloride is heated in a water-bath for 2 hours at a temperature of 100°C. On cooling, the reaction mixture is poured into water. The whole is alkalized with ammonium hydroxide solution and extracted with toluene. The extract is dried over magnesium sulfate and evaporated in vacuum. The oily residue is dissolved in 40 parts boiling 2-propanol. To this warm solution is added a warm solution of an equivalent quantity of oxalic acid dihydrate in 2-propanol. After cooling to room temperature, the precipitated salt is filtered off and dried in vacuum, yielding DL-5,6-dihydro-6-(2-thienyl)imidazo[2,1-b]thiazole oxalate; MP: 193°-194°C. An aqueous solution of this salt is alkalized with ammonium hydroxide and extracted with toluene. The extract is dried over magnesium sulfate and evaporated. The oily residue is crystallized from 12 parts xylene. The solid is filtered off and dried in vacuum, yielding DLl-5,6-dihydro-6-(2thienyl)imidazo[2,1-b]thiazole; MP: 58°-62°C. To a solution of 1.2 parts of DL-5,6-dihydro-6-(2-thienyl)imidazo[2,1b]thiazole in 24 parts acetone is added a slight excess of a solution of hydrogen chloride in 2-propanol. The oily precipitate solidifies on seeding with
Antrafenine
353
the solid hydrochloride salt and scratching. The salt is filtered off and dried, to yield DL-5,6-dihydro-6-(2-thienyl)imidazo[2,1-b]thiazole hydrochloride; M.P. 159°-160.5°C. References Raenmaekers A. et al.; US Patent No. 3,274,209; Sept. 20, 1966; Assigned to Janssen Pharmaceutica N.V., a corporation of Belgium
ANTRAFENINE Therapeutic Function: Analgesic Chemical Name: 2-(4'-m-Trifluoromethylphenylpiperazino)ethyl 2-(7'trifluoromethyl-4'-quinolylamino)benzoate Common Name: Structural Formula:
Chemical Abstracts Registry No.: 55300-29-3 Trade Name Stakane
Manufacturer Dausse
Country France
Year Introduced 1977
Raw Materials Allyl 2-(7'-trifluoromethyl-4'-quinolinylamino)benzoate 2-(4'-m-Trifluoromethylphenylpiperazino)ethanol Sodium Manufacturing Process A mixture of 18.65 g (0.05 mol) of allyl 2-(7'-trifluoromethy-4'quinolylamino)benzoate, 16.2 g (0.059 mol) of 2-(4'-mtrifluoromethylphenylpiperazino)ethanol, 150 ml of anhydrous toluene and 0.03 g of sodium is heated under reflux for 2 ½ hours, while the allyl alcohol formed during the reaction is slowly removed by distillation. A slight amount of insoluble matter is filtered off and the toluene is evaporated from the filtrate. The residue is dissolved in a mixture of methylene chloride and acetone (8:2) and this solution is passed through a silica column. Elution is carried out with the same mixture of solvents and the eluate is collected in 50
354
Antramycin
ml fractions. These fractions are examined by thin layer chromatography. Those which contain the desired almost pure ester are combined and the solvent is driven off from them. The residual product is triturated in a mixture of ether and petroleum ether, filtered off and dried. 16.8 g (yield 57%) of 2(4'-m-trifluoromethylphenylpiperazino)ethyl 2-(7'-trifluoromethyl-4'quinolylamino)benzoate, melting point 88° to 90°C, are thus isolated. References Merck Index 746 DFU 2 (12) 786 (1977) Kleeman and Engel p. 57 DOT 14 (2) 55 (1978) I.N. p. 94 Giudicelli, D.P.R.L., Najer, H., Manory, P.M.J. and Dumas, A.P.F.; US Patent 3,935,229; January 27, 1976; Assigned to Synthelabo
ANTRAMYCIN Therapeutic Function: Antineoplastic Chemical Name: 2-Propenamide, 3-(5,10,11,11a-tetrahydro-9,11-dihydroxy8-methyl-5-oxo-1H-pyrrolo[2,1-c][1,4]benzodiazepin-2-yl)-, (11R[2(E),11α11aβ])Common Name: Anthramycin; Antramycin; Refuin Structural Formula:
Chemical Abstracts Registry No.: 4803-27-4 Trade Name Anthramycin Antramycin
Manufacturer ZYF Pharm Chemical Onbio Inc.
Country -
Year Introduced -
-
-
Raw Materials Streptomyces sp. NRRL 1143 Bacto yeast extract Enzyme hydrolyzed casein
Bacto tryptone Bacto soytone Enzyme hydrolyzed soy protein
Antramycin
355
Manufacturing Process Several loopfuls of spores of Streptomyces sp. NRRL 1143 are transferred from a mature (2-3 day old) 45° stock agar slant to 100 ml of germination medium composed as follows in g/liter: Bacto tryptone Bacto yeast extract Bacto soytone Soluble starch Mannitol Magnesium sulfate·7H2O Ferrous ammonium sulfate·6H2O Zinc chloride Manganous chloride·4H2O Copper sulfate·5H2O Cobalt nitrate·6H2O Boric acid
5g 2g 2g 10 g 5g 200 mg 10 mg 2.1 mg 1.8 mg 0.3 mg 0.5 mg 0.6 mg
The medium is contained in a 1000 ml Pyrex Blake mottle. After inoculation the medium is incubated at 45°C with constant vigorous agitation, on a rotary shaker for 16 hours. During this period a vigorous growth of the organism ensues. The contents of two such incubated Blake bottles are pooled into a 500 ml Pyrex inoculum transfer bottle fitted with a tubulature at the bottom and containing 150 ml of sterile water. The entire contents of the inoculum transfer bottle are transferred to a 100gallon stainless steel fermentor, which is prepared for it as follows: To 25 gallons of clean tap water contained in a stainless steel fermentor fitted for controlled agitation, aeration, and temperature control are added the following inegredients: Potato starch Bacto yeast extract Enzyme hydrolyzed casein Enzyme hydrolyzed soy protein Aqueous extract of yeast Mannitol Magnesium sulfate·7H2O Ferrous ammonium sulfate·6H2O Zinc chloride Manganous chloride·4H2O Copper sulfate·5H2O Cobalt nitrate·6H2O Boric acid Dow Coming Silicone A emulsion
1500 g 2g 750 g 300 g 300 g 750 g 30 g 1.5 g 315 mg 270 mg 45 mg 75 mg 90 mg 2.5 g
When all the ingredients are dissolved the volume is brought to 40 gallons (150 liters) with tap water and the pH adjusted to 7.2 with about 60 ml of 5 N potassium hydroxide. The fermentor is then closed and the contents sterilized by being brought to a temperature of 120°C and maintained at that
356
Antramycin
temperature from 30-40 minutes. The batch is then cooled to 48°C and inoculated as described above. After inoculation the batch is aerated with 3 cubic feet per minute of sterile air and agitated at a shaft speed of 400 r.p.m., the while maintaining a temperature of 48°C. Foam is controlled by the addition, as needed, of a sterile 2.5% suspension of Dow Silieone Emulsion AF. About 3000 ml of defoamer suspension is used during the batch. Hourly samples are taken aseptically from the 12th hour on and assayed for in vitro potency. This batch reaches its maximum potency in 18-20 hours. The above process is repeated ten times, the broths obtained are combined, the pH is adjusted to 6, the combined broths are filtered, and the resulting filtrate is extracted countercurrently at the rate of 128 gallons per hour with about the same rate of butanol, in a 12" diameter by 11 ft. high Karr extraction column. A water backwash of 0.2 times the butanol rate is employed at the top of the extraction column to minimize the carry-over of water soluble components. The butanol extract is concentrated to approximately a 5% solution which comprises the feed to the center of a 3" diameter by 20 ft. high Karr fractional liquid extraction column. This column is operated at a water to butanol ratio of about 10 to 1, and the butanol extract contains the product. The butanol extract is concentrated by evaporation to a solution or paste containing about 5 to about 20% ent solids; then about 25 to about 50 volumes of n-hexane are added, and the resulting slurry filtered. The precipitated product is then vacuum-dried to give a solid compound. 7 g of the product prepared by the above process is dissolved in 350 ml of chloroform-isopropanol (1:1) which was previously equilibrated with water. This solution is introduced into the center of a one-inch diameter by twentyfoot high Karr extraction column at the rate of 0.5 ml/min. Simultaneously 60 ml/min of equilibrated aqueous phase is introduced at the bottom of the column and 14.6 ml/min of equilibrated solvent phase is introduced at the top of the column. Most of the product is extracted into the aqueous phase leaving the top of the column. The aqueous phase is re-extracted countercurrently in a one-inch diameter by ten-foot high extraction column employing a 1:1 isopropanol-chloroform solvent at a solvent to water ratio of 1:1. The product passes into the isopropanol-chloroform solvent, which leaves at the bottom of the extraction column. This solution is concentrated to 58 ml, filtered, and then treated with 2.9 liters of technical hexane to precipitate the product. The product is filtered and dried. The dried product, which is 90% pure is crystallized from acetone to yield a highly active purified material. 20 g of the product above was distributed between 120 ml each of upper and lower phases of a solvent system consisting of isopropanol;chloroform: water (1:1:2). The phases were then introduced into the first three tubes of a 200tube Craig countercurrent distribution apparatus and run at room temperature for 197 transfers. The upper and lower phases of tubes 45 to 75 were combined, the organic phase evaporated at a temperature below 35°C in vacuum and the residue added to the corresponding aqueous phase, and the aqueous phase lyophylized. The lyophylized residue was crystallized from acetone to yield a purified antibiotic antramycin. Yellow prisms decomposed at 188°-194°C; [α]
25 D
= +930° (DMF).
Apalcillin sodium
357
References Berger J. et al.; US Patent No. 3,361,742; January 2, 1966; Assigned to Hoffmann-La Roche Inc.,Nutley, N.J.,a corporation of New Jersey
APALCILLIN SODIUM Therapeutic Function: Antibacterial Chemical Name: 6-[[[[(4-Hydroxy-1,5-naphthyridin-3-yl)carbonyl] amino]phenylacetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0]heptane-2-carboxylic acid sodium salt Common Name: D-α-(4-Hydroxy-1,5-naphthyridine-3-carbonamido) benzylpenicillin sodium Structural Formula:
Chemical Abstracts Registry No.: 58795-03-2; 63469-19-2 (Base) Trade Name Lumota
Manufacturer Thomae
Country W. Germany
Year Introduced 1982
Raw Materials Phenacyl-6-aminopenicillate hydrochloride D-Phenylglycyl chloride hydrochloride 4-Hydroxy-1,5-naphthyridine-3-carboxylic acid N-succinimide ester Sodium bicarbonate Sodium thiophenoxide Triethylamine Manufacturing Process (a) Preparation of 6-D-α-aminobenzylpenicillin phenacyl ester: To a suspension of phenacyl 6-aminopenicillanate hydrochloride (1.85 g) and Dphenylglycyl chloride hydrochloride (1.29 g) in dichloromethane (20 ml), sodium bicarbonate (1.05 g) was added, and the resultant mixture was stirred
358
Apaxifylline
while cooling with ice for 6 hours. The reaction mixture was filtered to eliminate the by-produced sodium chloride. The filtrate was admixed with isopropanol and concentrated under reduced pressure by the aid of a rotary evaporator. After the evaporation of dichloromethane, the precipitate was collected by filtration to give the objective compound in the form of the hydrochloride (2.19 g) MP 142° to 148°C (decomposition). (b) Preparation of D-α-(4-hydroxy-1,5-naphthyridine-3carbonamido)benzylpenicillin: To a solution of 6-D-α-aminobenzylpenicillin phenacyl ester (hydrochloride) (2.01 g) and triethylamine (0.808 g) in dimethylformamide (20 ml), 4-hydroxy-1,5-naphthyridine-3-carboxylic acid Nsuccinimide ester [MP 310° to 311°C (decomposition)] (1.15 g) was added while cooling with ice, and the resultant mixture was stirred for 1 hour. Stirring was further continued at room temperature for 2 hours. After cooling with ice, 1% sodium bicarbonate solution (100 ml) was added thereto. The precipitated crystals were collected by filtration, washed with water and dried over phosphorus pentoxide to give D-(α-4-hydroxy-1,5-naphthyridine-3carboxamido)benzylpenicillin phenacyl ester (2.17 g). The above product was dissolved in dimethylformamide (65 ml), sodium thiophenoxide (0.89 g) was added thereto, and the resultant mixture was stirred at room temperature for 1 hour. To the resultant mixture, acetone (650 ml) was added, and the separated crystals were collected by filtration and washed with acetone and ether in order to give the objective compound in the form of the sodium salt (1.3 g). In the above procedure, the use of 4-hydroxy-1,5-naphthyridine-3-carbonyl chloride in place of 4-hydroxy-1,5-naphthyridine-3-carboxylic acid Nsuccinimide ester can also afford the same objective compound as above. The use of sodium thio-n-propoxide in place of sodium thiophenoxide can also give the objective compound in the form of the sodium salt. References Merck Index 748 DFU 4 (3) 225 (1979) DOT 19 (2) 110 (1983) I.N. p. 94 Yamada, H., Tobiki, H., Nakatsuka, I., Tanno, N., Shimago, K. and Nakagome, T.; US Patent 4,005,075; January 25, 1977; Assigned to Sumitomo Chemical Co., Ltd.
APAXIFYLLINE Therapeutic Function: Adenosine A1-antagonist, Nootropic Chemical Name: (S)-3,7-Dihydro-8-(3-oxocyclopentyl)-1,3-dipropyl-1Hpurine-2,6-dione Common Name: Apaxifylline
Apaxifylline
359
Structural Formula:
Chemical Abstracts Registry No.: 151581-23-6 Trade Name Apaxifylline
Manufacturer Boehringer Ingelheim/Upjohn
Country -
Year Introduced -
Raw Materials 3-Oxocyclopentancarboxylic acid methyl ester Carbonyldiimidazole 1,6-Diamino-1,3-di-n-propyluracil Manufacturing Process 1,3-Dipropyl-8-(3-oxocyclopentyl)xanthyne: 1). 100 g 3-oxocyclopentancarboxylic acid methyl ester (0.7 moles) was heated with 1000 ml of 2 M hydrochloric acid to reflux for 10 hours. On cooling the solution was evaporated in vacuum. Residual water was removed by azeotropic dehydratation. The residue was distilled in high vacuum to give 3-oxocyclopentancarboxylic acid as colorless oil, b.p.: 116°-121°C/0.002 mm; yield 74.0 g (82 %). 2). 11.6 g carbonyl diimidasole was added to 8.8 g 3oxocyclopentancarboxylic acid (0.072 moles) in 240 ml methylene chloride at 20°-25°C and stirred for 2 hours at room temperature. Then 16.0 g 1,6diamino-1,3-di-n-propyluracil (0.072) at 20°-25°C was added and was stirred 3 hours at room temperature. The mixture was evaporated in vacuum to dryness. The residue oil was diluted with 3200 ml water, 35 g of calcium hydroxide was added and all taken was heated at 80°C for 0.5 hour by stirring. The mixture was cooled to 5°C, acidified with pH 1-2 with hydrochloric acid and extracted with CH2Cl2 (3x100 ml). The organic phase was washed with 1x100 ml water and dried over magnesium sulfate. The solution was purified with of 350 g silica gel S 160. CH2Cl2 : CH3OH (99:1) was used as eluent. Refined residue was evaporated and treated with 100 ml ether. 11.5 g 1,3-dipropyl-8-(3-oxocyclopentyl)xanthyne (apaxifylline) obtained (50.2 %). MP: 164-168°C. References Kufter-Muuhl U. et al.; Europe Patent No. 0,374,808; Dec. 18, 1989; Boehringer Ingelheim International G.M.B.H.
360
Apazone
APAZONE Therapeutic Function: Antiarthritic Chemical Name: 5-(Dimethylamino)-9-methyl-2-propyl-1H-pyrazolo[1,2a][1,2,4]benzotriazine-1,3(2H)-dione Common Name: Azapropazone Structural Formula:
Chemical Abstracts Registry No.: 113539-598 Trade Name Prolixan Prolixan Cinnamin Rheumox Prolixan Prolixan Prolixan Prodisan Prodisan Prolix Prolixano Rheumox Xani
Manufacturer Siegfried Siegfried Nippon Chemiphar Robins Logeais Malesci Embil Embil Roche Roche Leo Robins Farmakos
Country W. Germany Switz. Japan UK France Italy Turkey Turkey US Yugoslavia
Year Introduced 1970 1970 1971 1976 1976 1977 -
Raw Materials 3-Dimethylamino-(1,2-dihydro1,2,4-benzotriazine) Diethyl propyl malonate Sodium Triethylamine
3-Dimethylamino-1,2,4benzotriazine oxide Propyl malonyl chloride Hydrogen
Manufacturing Process The following describes two alternatives for the synthesis of the closely related butyl analog.
Apicycline
361
Alternative (a): In a three-neck flask with descending condenser to 3.8 grams of 3-dimethylamino-(1,2-dihydro-1,2,4-benzotriazine) are added 0.52 gram metallic sodium, dissolved in a small volume of absolute alcohol, 4.5 g of diethylbutylmalonate (diethylpropylmalonate for Apazone) and 15 ml of xylene, in a nitrogen atmosphere. The mixture is heated for 2 hours to 70°C, then for 3 hours to 110-130°C and for one more hour to 150°C, slowly distilling off the alcohol and most of the xylene. To the resulting light brown colored mass are added 200 ml of water. The resulting solution is extracted twice with ether or benzene and afterwards acidified with HCl. Yield 3.6 g of 1,2-butylmalonyl-3-dimethylamino-(1,2-dihydro-1,2,4-benzotriazine). After crystallization from alcohol the melting point is 189-190°C. Alternative (b): 3-Dimethylamino-1,2,4-benzotriazine oxide is shaken in the presence of Raney nickel in 15 volume parts of an alcohol-acetic acid (9:1) mixture in a hydrogen atmosphere. The mixture absorbs 2 mols hydrogen per 1 mol starting material. Hydrogenation can also be effected using a palladium catalyst with a suitable solvent. After reduction it is filtered on a Buchnerfunnel through a Hyflow-layer and the solvent is evaporated in vacuum under nitrogen. The residue is dissolved in 20 parts of water-free dioxane and treated at 60°C with the calculated amount of butylmalonyl chloride (propyl malonyl chloride for Apazone) (1 mol/mol) and triethylamine (2 mol/mol). The separated triethylamine hydrochloride is filtered, the dioxane-solution is evaporated under vacuum to dryness, and the residue is dissolved in 7 volume parts of boiling acetic acid. After cooling, the product separates in lightly yellowish crystals. They are dissolved in the calculated amount of 0.25 N NaOH, treated with a small amount of carbon and precipitated with HCl. Melting point of the purified product is 187°C. Yield: approximately 60% of the theoretical amount. References Merck Index 750 Kleeman and Engel p. 66 OCDS Vol. 2 p. 475 (1980) I.N. p. 110 Molnar, I., Wagner-Jauregg, T., Jahn, U. and Mixich, G.; US Patent 3,349,088; October 24, 1967; Assigned to Siegfried AG, Switzerland Molnar, I., Wagner-Jauregg, T., Jahn, U. and Mixich, G.; US Patent 3,482,024; December 2, 1969; Assigned to Siegfried AG.
APICYCLINE Therapeutic Function: Antibiotic Chemical Name: α-(4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro3,6,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2naphthacenecarboxamido)-4-(2-hydroxyethyl)-1-piperazineacetic acid Common Name: Apicycline; Traserit Chemical Abstracts Registry No.: 15599-51-6
362
Apicycline
Structural Formula:
Trade Name Travert Travert
Manufacturer Country Baxter Pharmacia Upjohn -
Year Introduced -
Raw Materials Glyoxylic acid monohydrate N-(2-Hydroxyethyl)piperazine| Tetracycline base trihydrate Manufacturing Process Glyoxylic acid monohydrate (1.96 g, 20 mrnoles) is dissolved in 200 ml of methanol, and a solution of 2.60 g (20 mmoles) of N-(2-hydroxyethyl) piperazine in 50 ml of methanol is slowly added thereto with stirring. Stirring is maintained for 15 minutes and the medium is cooled to 5°C. There is then added 10.2 g (20 mmoles) of tetracycline base trihydrate and the reaction medium is maintained for 20 hours at 5°C under stirring. After that reaction time, the solution is concentrated up to 50 ml and 0.25 liter of acetone is added for precipitating a yellowish product which is filtered and dried to yield N-[(carboxy)(4-β-hydroxyethylpiperazino)methyl] tetracycline (apicycline). When tested for antibiotic potency against Bacillus cereus var. mycoides ATCC 9634 (diffusion method), the product is shown to present an antibiotic potency equivalent to 97% of the tetracycline present therein. Anhydrous tetracycline base (0.90 g, 2 mmoles) is dissolved in 30 ml of nbutanol at about 40°C. There is then added thereto under stirring a solution of 0.26 g (2 mmoles) of N-(2-hydroxyethyl)piperazine in 10 ml of butanol and 0.191 g (2 mmoles) of glyoxylic acid monohydrate. A precipitate appears after a few minutes and the suspension is maintained for six hours under stirring and at room temperature. After that reaction time, precipitation is completed by addition of 120 ml of ether. The yellowish precipitate is filtered and dried to yield N-[(carboxy)(4-βhydroxyethylpiperazino)methyl]tetracycline (apicycline). Yellow, amorphous powder with slight amine odor, MP: 144.5°C (dec). Freely solves in water. [α]D =-123° (c = 0.5 in methanol); [α]D =-133° (c = 0.5 in water).
Apomorphine hydrochloride
363
The pH value of a 2% aqueous solution of this product is 6.2. When tested for antibiotic potency against Bacillus cercus var. mycoides ATCC 9634 (diffusion method), the product is shown to present an antibiotic potency equivalent to 95% of the tetracycline present therein. References Rondelet J.; US Patent No. 3,456,007; July 15, 1969; Assigned to Recherche et Industrie Therapeutiques R.I.T., Genval, Belgium, a corporation of Belgium
APOMORPHINE HYDROCHLORIDE Therapeutic Function: Emetic, Expectorant, Hypnotic, Antiparkinsonian, Dopamine agonist Chemical Name: 4H-Dibenzo(de,g)quinoline-10,11-diol, 5,6,6a,7-tetrahydro6-methyl-, (R)-, hydrochloride Common Name: Apafinum; Apomorfin; Apomorphine Structural Formula:
Chemical Abstracts Registry No.: 314-19-2; 58-00-4 (Base) Trade Name Apomorphine hydrochloride Apofin Apofin Apokyn Apokyn Apokinon Apomine Britaject Ixense Uprima
Manufacturer Nastech Pharmaceuticals Company, Inc. Chiesi Farmaceutici Amro Trust Company (Suisse) SA Mylan Bertek Pharmaceuticals Bertek Pharmaceuticals Aguettant Faulding Britannia Takeda Abbott Laboratories
Country -
Year Introduced -
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364
Apovincamine
Raw Materials Morphine Phosphoric acid Hydrogen hydrochloride Manufacturing Process 2 Methods of producing of apomorphine 1. The apomorphine was obtained by dehydratation of morphine at heating to 120°C in the presence phosphoric acid and rendering of HCl gas over reaction mixture. 2. The morphine was converted to β-chloromorphine and then to dichlorodihydrodesoxymorphine at heating to 140°-150°C in the presence hydrochloric acid. Then apomorphine is obtained by dehydratation of dichlorodihydrodesoxymorphine. References Chaletsky A.M.; Pharmaceutical chemistry, Medicina, L., 1966, 761p. Belikov V.G.; Pharmaceutical chemistry, Pyatigorsk, 2003, 713p. Fiser L., Fiser M.; The chemistry of natural compounds of phenantren line. 1953, 656 p.
APOVINCAMINE Therapeutic Function: Vasodilator Chemical Name: Eburnamenine-14-carboxylic acid methyl ester, (3α,16α)Common Name: Apovincamine Structural Formula:
Chemical Abstracts Registry No.: 4880-92-6 Trade Name Apovincamine
Manufacturer GC Promochem
Country -
Year Introduced -
Apraclonidine hydrochloride
365
Raw Materials Vincamine Tartaric acid, dibenzoate, (-)Manufacturing Process Apovincamine is semisynthethetic derivative of (+)-vincamine. Vincamine is alkaloid of Vinca minor. Alcoloid of Tabernaemontana rigida (Apocynaceae) also is used as raw material for preparing of apovincamine. (+)- Vincamine was transformed into oxime ester by reaction with NaNO2 in acetic acid at 0°C -(+/-)-methyl-3-((12bR)-1-ethyl-1,2,3,4,6,7,12,12b-octahydroindolo[2,3a]quinolizin-1-yl)-2-(hydroxyimino)propanoate, which was resolved on the isomers with dibenzoyl D-tartratic acid. (-)-Methyl 3-((12bR)-1-ethyl1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizin-1-yl)-2(hydroxyimino)propanoate was re-crystallized from methanol to afford (-)methyloxime ester, MP: 195°C. 2 g of above oxime methyl ester was heated in mixture of methanol (37.5 ml) and conc. H2SO4 (13.5 ml) on water bath for 1 hour. The solution was poured into ice-water (80 ml), basified with conc. NH4OH to pH 9, and extracted with CH2Cl2 (3x20 ml). The combined extracts were dried (MgSO4), filtered, evaporated in vacuum and the residue was re-crystallized from MeOH (5 ml) to yield 1.32 g (72.5%) of (+)-apovincamine, MP: 160°-162°C. References Szabo L. et al., Tetrahedron; V. 39, No 22, pp 3737-3737; 1983
APRACLONIDINE HYDROCHLORIDE Therapeutic Function: Antiglaucoma Chemical Name: 1,4-Benzenediamine, 2,6-dichloro-N1-(4,5-dihydro-1Himidazol-2-yl)-, hydrochloride Common Name: p-Aminoclonidine hydrochloride; Apraclonidine hydrochloride; Aplonidine hydrochloride Structural Formula:
Chemical Abstracts Registry No.: 73218-79-8; 66711-21-5 (Base)
366
Apraclonidine hydrochloride
Trade Name Alfadrops Iopidine
Manufacturer Cipla Limited Alcon
Country India -
Year Introduced -
Raw Materials 2,6-Dichloro-4-nitroaniline t-Butyl methyl ether Methanol Ethylenediamine Hexane
Nickel Raney Thiophosgene 2-Propanol Toluene
Manufacturing Process The preparation of p-aminoclonidine (apraclonidine) consists of 6 steps. In the first step 2,6-dichloro-4-nitroaniline was converted to 2,6-dicloro-4nitrophenylisothiocyanate by addition of thiophosgene in toluene according to the method described in Great Britain Patent No.: 1,131,780 (Beck et al.). The second step involved the conversation of 2,6-dichloro-4-nitrophenylisothiocyanate to 1-(2-aminoethyl)-3-(2,6-dichloro-4-nitrophenyl)-thiourea ethylenediamine solvate. The solution of 2,6-dicloro-4-nitrophenylisothiocyanate (432 g, 1.73 mol) in 2 L of toluene was added dropwise to the cooled (0°C) solution ethylenediamine (244 ml, 3.66 mol, 2.1 eq.) in toluene (4 L) under a nitrogen atmosphere. 2-Propanol (1 L) was added and after 5 minutes, the solid was collected by filtration, washed with 20% 2propanol/toluene, and dried to a constant weight of 602 g (94%). This product is hygroscopic, mp 120°C (dec.). The third step was the conversation of 1-(2-aminoethyl)-3-(2,6-dichloro-4nitrophenyl)-thiourea ethylenediamine solvate to 2-[(2,6-dicloro-4nitrophenyl)imino]imidazoline ethylenediamine solvate. (500 g, 1.35 mol) of above prepared thiourea solvate was suspended with toluene (4 L) and was heated at reflux for 15 hours. The mixture was cooled to 23°C and 1 M aqueous hydrochloric acid (4 L) was added. After stirring for 10 min the biphasic mixture was filtered to remove a sticky insoluble material. The aqueous phase was neutralized to pH=7.0 using 50% NaOH. After stirring for 1 hour the yellow solid was collected by filtration, washed with water (4 L) and t-butyl methyl ether (2 L) and dried in air to constant weight of 195 g (52%), m.p. 289-292°C. The fourth step was the conversation of 2-[2,6-dichloro-4-nitrophenyl) imino]imidazoline (150 g, 0.55 mol) in methanol (1,5 L) to 2-[(2,6-dichloro-4aminophenyl)imino]imidazoline by hydrogen with 30 g Raney nickel catalyst at 23°C for 22 hours. After removing the catalyst hydrogen chloride gas was bubbled into solution until pH of the reaction mixture was 1.0. The solvent was rotary removed in vacuum and the residual solid was slurried with 2propanol (1 L). The solvent was again removed by rotary evaporation, the cream solid was triturated with 2-propanol (600 ml). After aging for 1 hour, the solid was collected by filtration, washed with 2-propanol and t-butyl methyl ether, and dried for 15 hours at 6°C and t-butyl methyl ether, and dried for 15 hours at 60°C and 20 mm Hg. Yield of dihydrochloride 167 g
Aprindine hydrochloride
367
(96%), mp 260°C (dec.). The dihydrochloride was converted to the monochloride (step 5) by adding 5 M aqueous sodium hydroxide dropwise to pH=6.5 at 5°C for 2 hours. Yield of hydrochloride 87%. The last step was recrystallization of product from water. The recrystallized material had m.p. 300°C. Calculated for: C9H10Cl2N4HCl: C, 38.39; H, 3.94; N, 19.90; Cl, 37.78. Found: C, 38.36; H, 3.91; N, 19.83; Cl, 37.77. References Councel, J. Med Chem., v 30, p.1214 (1987) Pierce D.R., Dean W.D., Deason M.E.; Patent WO9521818; 17.08.1995; Assigned to Alcon Laboratories Inc.
APRINDINE HYDROCHLORIDE Therapeutic Function: Antiarrhythmic Chemical Name: N-[3-(Diethylamino)propyl]-N-phenyl-2-indanamine hydrochloride Common Name: Structural Formula:
Chemical Abstracts Registry No.: 33237-74-0; 37640-71-4 (Base) Trade Name Amidonal Fiboran Fibocil Fiboran Ritmusin
Manufacturer Madaus Sedaph Lilly Christiaens Gebro
Country W. Germany France US Belgium Austria
Year Introduced 1976 1977 -
Raw Materials N-Phenyl-2-aminoindane Sodium hydroxide Hydrogen chloride
γ-Chloropropyl diethylamine Sodium amide
368
Aprobarbital
Manufacturing Process 104.6 g (0.5 mol) N-phenyl-2-aminoindane and 2.5 liters benzene are introduced into a reaction vessel of 5 liters, under an atmosphere of nitrogen. 37 g (0.95 mol) sodium amide are added and the mixture is stirred during 3 hours at room temperature. 119.7 g (0.8 mol) of γ-chloropropyl diethylamine are then quickly added. After agitation during 1 hour at room temperature, the reaction mixture is refluxed and stirred under nitrogen during 21 hours. The mixture is then allowed to cool and poured onto ice. The obtained aqueous phase is extracted by means of 500 cm3 of benzene. The benzene extract is washed two times with 200 cm3 of water and the benzene is then evaporated. The residue is treated with 500 cm3 of hydrochloric acid (2 N). The obtained solution is evaporated to dryness and the oily residue is recrystallized from ethanol. 176.9 g (yield 89.4%) of dihydrochloride of N-phenyl-Ndiethylaminopropyl-2-aminoindane are obtained, MP 208° to 210°C. The dihydrochloride is converted into monohydrochloride by dissolving 26.36 g (0.066 mol) of dihydrochloride into 158 cm3 of water, adding drop by drop a suitable amount (0.066 mol) of caustic soda (1 N), evaporating the aqueous solution to dryness, drying by means of benzene, filtering the formed sodium chloride (3.8 g) and crystallizing the cooled obtained benzene solution. 22.6 g (95%) of monohydrochloride are obtained, MP 120° to 121°C. References Merck Index 776 Kleeman and Engel p. 58 OCDS Vol. 2 p. 208 DOT 10 (4) 120 (1974) REM p. 860 Vanhoof, P. and Clarebout, P.; British Patent 1,321,424; June 27, 1973; Assigned to Manufacture de Produits Pharmaceutiques A. Christiaens, SA
APROBARBITAL Therapeutic Function: Sedative, Hypnotic Chemical Name: 5-Allyl-5-isopropylbarbituric acid Common Name: Allopropylbarbital; Allylcarbamidum; Allypropymal; Aprobarbital; Aprobarbitone Chemical Abstracts Registry No.: 77-02-1 Raw Materials Isopropylbarbituric acid
Aprofene
369
Sodium hydroxide Allyl bromide Structural Formula:
Trade Name Alurate Aprobarbital Isonal
Manufacturer Roche Arocor Holdings Inc. Leo
Country -
Year Introduced -
Manufacturing Process 170 parts of isopropylbarbituric acid are mixed with 500 parts of water and dissolved by adding 135 parts of a 30 percent of the solution of sodium hydroxide. To this solution are added 130 parts of 130 parts of allylbromide. An emulsion obtained is stirred at an inner temperature of about 25°C. The reaction is at first accompanied by a slight development of heat. After 12 hours the reaction is brought to a close. When cooled down the isopropylallylbarbituric acid is drawn off. The yield is more than 80 percent of the theoretically calculated quantity. By crystallization from diluted alcohol the pure isopropylallylbarbituric acid is obtained in colorless crystals of the melting point 137-138°C. References Merck Index, Monograph number: 794, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. Kurz F. and Kappeler V.W.; US Patent No. 1,444,802; Feb. 13, 1923; Assigned to Ernst Preiswerk
APROFENE Therapeutic Function: Spasmolytic Chemical Name: Benzeneacetic acid, α-methyl-α-phenyl-, 2-(diethylamino) ethyl ester Common Name: Aprofene; Aprophene Chemical Abstracts Registry No.: 3563-01-7
370
Aprotinin
Structural Formula:
Trade Name Aprofene Aprofene
Manufacturer ZYF Pharm Chemical ICN Pharmaceuticals
Country -
Year Introduced -
Raw Materials Diphenylpropionic acid Thionyl chloride Diethylaminoethanol Diphen (CIS prep.) Manufacturing Process 32 parts of α,α-diphenylpropionic acid chloride (made from diphenylpropionic acid and thionyl chloride, B.P./12 mm 170°C) are mixed with 50 parts of diethylaminoethanol. The mixture is heated for two hours to 150°-160°C. It is then suspended in dilute hydrochloric acid. The solution is treated with ether. After separation of the aqueous solution, the base is precipitated with sodium hydroxide solution and suspended in ether. After removal of the ether by distillation, the residue is distilled in a vacuum. α,α-Diphenylpropionic acid β-diethylaminoethyl ester is obtained as a thick oil by distilling under 2 mm pressure at 180°-185°C. It is readily soluble in diluted acids. References Wander A.; G.B. Patent No. 641,573; Dec. 19, 1947; Switzerland
APROTININ Therapeutic Function: Proteinase inhibitor Chemical Name: Trypsin inhibitor, pancreatic basic Common Name: Aprotinin; Frey inhibitor; Kallikrein-trypsin inhibitor Chemical Abstracts Registry No.: 9087-70-1
Aprotinin
371
Structural Formula:
Trade Name Trasylol Antagosan Antilysin Spofa Apronin Aprotimbin Contrykal Gordox Iniprol Inibil Kallikrein-trypsin inhibitor Kontrikal Trasylol
Manufacturer Bayer Hoechst Marion R. d.o.o Spofa Chandra Bhagat Pharma Pvt. Ltd. Biochemie GmbH AWD GmbH and Co.KG Gedeon Richter Sanofi-Winthrop Sclavo Bayer
Country -
Year Introduced -
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Pliva d. d. Bayer
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Raw Materials Parotid of cattle Acetic acid
Acetone Ammonia
372
Aptazapine maleate
Manufacturing Process 1 kg of parotid of cattle, which were freed of fat and flesh are comminuted in a meat chopper and twice extracted with 5 L of acetone. The acetone was removed as far as possible by sucking off and the moist material is digested for 2.5 hours in 1.2 L of 1 N acetic acid and 2.8 L of 96% ethanol at 50°C. The filtrate containts about 230.000 inactivator units. The alcoholic solution is concentrated to 1.2 L by evaporating in vacuo and shaken with an equal amount of ether. Dark coloring matters and residues of fat are thus dissolved. The aqueous phase is now mixed with acetone until a precipitate occurs and the dissolved in dilute acetic acid. The solution is brought to a weakly alkaline pH by addition of ammonia. It is then centrifuged and the inactivator is precipitated with five times the amount of ethanol. The yield amounts to about 180.000 kallikrein inactivator units in 0.4-0.5 g of substance. References Kraut H., Koerbel R.; US Patent No. 2,890,986; June 16, 1959; Assigned to Farbenfabriken Bayer Aktiengesellschaft, Leverkusen, Germany, a corporation of Germany
APTAZAPINE MALEATE Therapeutic Function: Antidepressant Chemical Name: 2H,10H-Parazino[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine, 1,3,4,14b-tetrahydro-2-methyl-, maleate (1:1) Common Name: Aptazapine maleate Structural Formula:
Chemical Abstracts Registry No.: 71576-40-4 (Base); 71576-41-5 Trade Name
Manufacturer
Country
Year Introduced
Aptazapine maleate
ZYF Pharm Chemical
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Aptazapine maleate
373
Raw Materials Diborane N-Potassium phthalimide Hydrazine hydrate Chloroacetonitrile Platinum oxide Palladium on charcoal
Maleic acid o-Nitrobenzyl chloride 2,5-Dimethoxytetrahydrofuran N-Methylbenzylamine Diethyl oxalate
Manufacturing Process To the suspension of 12.8 g of 2-methyl-3,4-dioxo-1,3,4,14b-tetrahydro-10Hpyrazino[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine in 460 ml of tetrahydrofuran, 200 ml of 1-molar diborane in tetrahydrofuran are added while stirring and cooling with ice. The mixture is refluxed for one hour, again cooled and combined with 25 ml of acetic acid. It is evaporated, the residue taken up in 50 ml of 30% aqueous sodium hydroxide and the mixture extracted with methylene chloride. The extract is dried, evaporated, the residue dissolved in diethyl ether, the solution filtered and the filtrate evaporated, to yield the crude 2-methyl-1,3,4,14b-tetrahydro-10Hpyrazino[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine. It is triturated with ethyl acetate-diethyl ether, chromatographed on 70 g of silica gel and eluted with methanol-chloroform (1:9). The eluate is evaporated and the residue salified. 9.7 g thereof are dissolved in the minimum amount of isopropanol and the solution acidified with a concentrated solution of 4.45 g of maleic acid is isopropanol. The precipitate formed is collected and recrystallized from methanol-diethyl ether, to yield the corresponding mono-maleate melting at 180°-182°C. The starting material is prepared as follows: the mixture of 54.0 g of Npotassium phthalimide, 50.0 g of o-nitrobenzyl chloride and 120 ml of dimethylformamide is refluxed for 3 hours and poured into 900 ml of icewater while stirring. After 30 minutes, it is filtered, and the residue washed with water, to yield the N-o-nitrobenzyl-phthalimide melting at 190°-209°C. The mixture of 70.0 g thereof, 14.6 g of hydrazine hydrate and 600 ml of ethanol is refluxed for 4 hours and combined with 50 ml of concentrated hydrochloric acid. After 30 minutes, it is cooled to room temperature, filtered and the residue washed with water. The filtrate is concentrated, the aqueous concentrate filtered and the filtrate basified with 3 N aqueous sodium hydroxide. It is extracted with diethyl ether, the extract dried and evaporated, to yield the o-nitrobenzylamine. To the solution of 7.6 g thereof in 25 ml of glacial acetic acid, 6.6 g of 2,5dimethoxytetrahydrofuran are added and the mixture is refluxed for one hour. It is evaporated, the residue poured into ice water and the mixture extracted with ethyl acetate. The extract is washed with saturated aqueous sodium bicarbonate, dried and evaporated. The residue is taken up in diethyl ether, the solution decolorized with charcoal, filtered and evaporated, to yield the 1(o-nitrobenzyl)pyrrole. Through the mixture of 13.42 g thereof, 140 ml of diethyl ether and 6.85 ml of chloroacetonitrile, hydrogen chloride is bubbled while stirring and cooling in
374
Aptiganel hydrochloride
an ice-salt bath. The saturated mixture is stirred at room temperature overnight, filtered and the residue suspended in 100 ml of water. It is extracted 3 times with 100 ml of ethyl acetate, warmed on the steam bath while stirring until all is dissolved, and the solution evaporated, to yield the 1o-nitrobenzyl-2-chloroacetylpyrrole. To the solution of 16.2 g thereof in 450 ml of ethanol, 14.10 g of N-methylbenzylamine are added and the mixture is refluxed for 3 hours. It is evaporated, the residue taken up in methylene chloride, the solution washed with saturated aqueous sodium carbonate dried, filtered and evaporated. The residue is triturated with diethyl ether, to yield the 1-(o-nitrobenzyl)-2-(Nmethyl-N-benzylaminoacetyl)pyrrole. The solution of 3.0 g thereof in 30 ml of glacial acetic acid is hydrogenated over 100 mg of platinum oxide at 2.7 atm and room temperature until the theoretical amount of hydrogen has been absorbed. It is filtered, the filtrate evaporated, the residue taken up in methylene chloride-diethyl ether and the solution washed with saturated aqueous sodium bicarbonate. It is dried, evaporated, the residue chromatographed on 30 g of silica gel and eluted with methanol-chloroform (1:9), to yield the 11-(N-methyl-N-benzylaminomethyl)10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine melting at 147°-149°C. The solution of 500 mg thereof in 35 ml of ethanol and 5 ml of glacial acetic acid is hydrogenated over 250 mg of 5% palladium on charcoal at 2.7 atm and 40°C for 7 hours. The mixture is filtered, the filtrate evaporated and the residue taken up in methylene chloride. The solution is washed with saturated aqueous sodium carbonate, the aqueous phase extracted with methylene chloride and the combined organic solutions dried and evaporated, to yield the 11-(N-methylaminomethyl)-10,11-dihydro-5H-pyrrolo[2,1c][1,4]benzodiazepine. The mixture of 300 mg thereof and 232 mg of diethyl oxalate is slowly heated to 140°C during 45 minutes and to 180°C during 15 minutes, at which temperature it is maintained for 30 minutes. It is cooled, diluted with benzene, chromatographed on silica gel and eluted with methanol-chloroform (1:9), to yield the 2-methyl-3,4-dioxo-1,3,4,14b-tetrahydro-10H-pyrazino[1,2a]pyrrolo[2,1-c][1,4]benzodiazepine melting at 178°-179°C. In practice it is usually used as maleate salt. References Wasley J.W.F., Chatham; US Patent No. 4,316,900; February 23, 1982; Assigned to Ciba-Geigy Corporation, Ardsley, N.Y.
APTIGANEL HYDROCHLORIDE Therapeutic Function: NMDA antagonist
Aptiganel hydrochloride
375
Chemical Name: N-(3-Ethylphenyl)-N-methyl- N'-1-naphthalenylguanidine monohydrochloride Common Name: Cerestat; Aptiganel hydrochloride Structural Formula:
Chemical Abstracts Registry No.: 137160-11-3 Trade Name Aptiganel Cerestat
Manufacturer Oregon State University Cambridge NeuroScience
Country -
Year Introduced -
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Raw Materials m-Ethylphenylcyanamide Methyl iodide Sodium hydroxide
Sodium hydride 1-Aminonaphthalene Hydrochloric acid
Manufacturing Process A solution of m-ethylphenylcyanamide (1.46 g, 10 mmol) and sodium hydride (480 mg, 20 mmol, prewashed with hexane) in anhydrous THF (10 ml) was heated at 80-85°C for 2.5 hours. After it was allowed to cool to room temperature, methyl iodide (3.5 g, 25 mmol) was added and stirring continued at room temperature for 2 hours. Methanol (10 ml) followed by water (20 ml) was added and the reaction mixture was extracted with dichloromethane (3x25 ml). Concentration of the organic layer followed by flash chromatography on SiO2 afforded N-(m-ethylphenyl)-N-methylcyanamide (960 mg, 60%) as a colorless liquid: IR (film): 2220, 3400cm-1. A mixture of m-ethylphenyl-N-methylcyanamide (520 mg, 3.25 mmol) and 1aminonaphthalene hydrochloride (508 mg, 3.25 mmol) was placed in a preheated oil bath at 160°C for 3 hours and then allowed to cool to room temperature. The resulting solid was taken into dichloromethane and washed with 10% sodium hydroxide solution. The organic layer was concentrated and the resulting residue was dissolved in absolute ethanol (2 ml) and treated with dilute hydrochloric acid. It was concentrated and the solid was twice
376
Aranidipine
recrystallized from absolute ethanol-ether to give N-(1-naphthyl)-N'-(methylphenyl)-N'-methylguanidine hydrochloride (403 mg, 37%) as off-white needles, melting point 223-225°C. References Weber Eckard, Keana John F. W.; US Patent No. 5,262,568; November 16, 1993; Assigned to State of Oregon (Portland, OR)
ARANIDIPINE Therapeutic Function: Antihypertensive Chemical Name: 3,5-Pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-4(2-nitrophenyl)-, methyl 2-oxopropyl ester Common Name: Aranidipine; Asanidipine Structural Formula:
Chemical Abstracts Registry No.: 86780-90-7 Trade Name Aranidipine
Manufacturer Shiono Chemical Co., Ltd.
Country -
Year Introduced -
Aranidipine
INTERCHEMICAL(chongqing) CO. LTD Verychem Co. Taiho Pharmaceutical Co., Ltd.
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Aranidipine Sapresta
Raw Materials Sodium hydride Diketene Ammonia
2,2-Ethylenedioxypropanol Methyl 2'-nitrobenzylidene acetoacetate Hydrochloric acid
Araprofen
377
Manufacturing Process 100.0 mg of 50% sodium hydride was added to a mixture of 20.0 g of 2,2ethylenedioxypropanol and 100 ml of benzene, and 20.0 g of diketene was added dropwise to the mixture while refluxing the mixture. After refluxing the mixture for 2 h, the solvent was distilled off and the resulting residue was distilled under reduced pressure to obtain 21.5 g (70% yield) of 2,2ethylenedioxypropyl acetoacetate as a colorless oil, boiling point of 90°C (6 mm Hg). Ammonia gas was passed through a mixture of 19.0 g of 2,2ethylenedioxypropyl acetoacetate and 100 ml of methanol for 2.5 h under icecooling while stirring. The solvent was then distilled off and the residue was distilled under reduced pressure to obtain 16.0 g (84% yield) of 2,2ethylenedioxypropyl 3-aminocrotonate as a pale yellow oil, boiling point of 120°C (5 mm Hg). A mixture of methyl 2'-nitrobenzylidene acetoacetate, 2,2-ethylenedioxypropyl 3-aminocrotonate and ethanol was refluxed for 10 h. The resulting reaction solution was allowed to stand overnight, and the precipitated crystals were collected by filtration and recrystallized from ethanol to obtain methyl 2,2ethylenedioxypropyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5dicarboxylate. Methyl 2,2-ethylenedioxypropyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4dihydropyridine-3,5-dicarboxylate was refluxed in an ethanol solution containing 10% hydrochloric acid for 6 h. The solvent was then distilled off and the residue was crystallized from diethyl ether to give methyl 2-oxopropyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate as yellow prisms, melting point 155°C (recrystallized from a mixture of ethyl acetate and hexane). References Ohno S. et al.; US Patent No. 4,446,325; May 1, 1984; Assigned: Maruko Seiyaku Co., Ltd., Nagoya, Japan
ARAPROFEN Therapeutic Function: Antiinflammatory, Analgesic Chemical Name: (+/-)-4-[(2-Carboxyphenyl)amino]-α-methylbenzeneacetic acid Common Name: Araprofen; Camprofen Chemical Abstracts Registry No.: 15250-13-2 Trade Name
Manufacturer
Country
Year Introduced
Araprofen
Onbio Inc.
-
-
378
Arbaprostil
Structural Formula:
Raw Materials Potassium carbonate Copper Sulfuric acid
2-(4-Aminophenyl)propionic acid Potassium o-chlorobenzoate
Manufacturing Process A mixture of 2-(4-aminophenyl)propionic acid (52.2 g), potassium ochlorobenzoate (61.5 g), potassium carbonate (43.6 g) and copper powder (0.3 g) in amyl alcohol (620 ml) is heating under reflux for 16 h. The major proportion of the solvent is then removed by steam distillation. The residual aqueous solution is treated with decolorising charcoal (20.0 g) and acidified with 4 N sulfuric acid (220 ml). The cream product which crystallises is dissolved in diethyl ether (500 ml). The aqueous mother liquors are extracted with methylene chloride (900 ml). The organic phases are combined, washed with water (800 ml) and dried over anhydrous sodium sulfate. After filtration, the filtrate is concentrated to dryness under a pressure of 20 mm Hg to give a semicrystalline paste (65.0 g) which is recrystallised from acetonitrile (550 ml). The crystals are filtered off, and the product recovered (32.0 g) is recrystallised from acetonitrile (600 ml). There is thus obtained 2-[4-(2-carboxyphenyl)aminophenyl]propionic acid (18.4 g) melting point 191°-192°C. References GB Patent No. 1,053,269; Dec. 30, 1966; Assigned: Rhone-Poulenc S.A., a French Body Corporate, 22, Avenue Montaigne, Paris, France
ARBAPROSTIL Therapeutic Function: Gastric antisecretory; Antiulcer Chemical Name: Prosta-5,13-dien-1-oic acid, 11,15-dihydroxy-15-methyl-9oxo-, (5Z,11α,13E,15R)Common Name: Arbaprostil
Arbaprostil
379
Structural Formula:
Chemical Abstracts Registry No.: 55028-70-1 Trade Name Arbaprostil
Manufacturer ZYF Pharm Chemical
Country -
Year Introduced -
Raw Materials Prostaglandin E2 Hexamethyldisilazane Ammonium chloride Potassium hydroxide Diazomethane
2,3-Dichloro-5,6-dicyano-1,4-benzoquinone Trimethylchlorosilane Methyl magnesium bromide Hydrochloric acid
Manufacturing Process 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone is added to a solution of PGF2a [(5Z,11α,13E)-11,15-dihydroxy-9-oxoprosta-5,13-dien-1-oic acid or Prostaglandin E2] in dioxane. The mixture is stirred 24 h at 50°C under nitrogen, and then is cooled to 20°C and filtered. The filtered solids are washed with dichloromethane. Evaporation of the combined filtrate and washings at reduced pressure gives a residue which is chromatographed on silica gel (Silicar CC-4; Malincrodt), eluting with 50% ethyl acetate in Skellysolve B (a mixture of isomeric hexanes). Evaporation of the eluates gives 15-oxo-PGF2a. A mixture of hexamethyldisilazane and tri-methylchlorosilane is added to a solution of 15-oxo-PGF2a in tetrahydrofuran. This mixture is stirred 16 h at 25°C under nitrogen, and is then filtered. The filtrate is evaporated under reduced pressure. Xylene is added to the residue and the mixture is evaporated at 60°C under reduced pressure. This addition of xylene and evaporation is repeated twice. The resulting residue is the tris-(trimethylsilyl) derivative of 15-oxo-PGF2a. A 3 M diethyl ether solution of methylmagnesium bromide is added dropwise to a stirred solution of the tris-(trimethylsilyl) derivative of 15-oxo-PGF2a in diethyl ether at 25°C.
380
Arbekacin
The mixture is stirred 30 min at 25°C, after which an additional the methylmagnesium bromide solution is added and stirring is continued an additional 30 min. The resulting reaction mixture is poured into saturated aqueous ammonium chloride solution at 0°C. After stirring several minutes, the mixture is extracted repeatedly with diethyl ether. The combined diethyl ether extracts are washed with saturated aqueous sodium chloride solution and then dried with anhydrous sodium sulfate. Evaporation of the diethyl ether gives a yellow oil which is dissolved in ethanol. That solution is diluted with water, and the mixture is stirred 4 h at 25°C. The ethanol in the resulting solution is evaporated at reduced pressure, and the aqueous residue is saturated with sodium chloride and then extracted with ethyl acetate. Solution, dried with anhydrous sodium sulfate, and evaporated under reduced pressure to give a mixture of 15-methyl-PGF2a and 15-methyl-15(R)-PGF2a. The 520.0 mg mixture of 15-methyl-PGF2a and 15-methyl-15(R)-PGF2a is dissolved in diethyl ether and cooled to 0°C. Excess diazomethane dissolved in diethyl ether is then added, and the mixture is maintained 5 min at 0°C and then 5 min at 25°C. The solution is evaporated in a stream of nitrogen, and the residue is chromatographed on 500.0 g of neutral silica (Merck), eluting successively with 20%, 40%, and of 50% ethyl acetate in Skellysolve B. The corresponding eluates emerging from the column are discarded. Elution is continued successively with gradients of 4 L of 50% and 4 L of 60% ethyl acetate in Skellysolve B, and 5 L of 60% and 5 L of 75% ethyl acetate in Skellysolve B, and then with 4 L of 75% ethyl acetate in Skellysolve B, collecting the corresponding eluates in 500 ml fractions. Elution is further continued successively with 5 L of 75% ethyl acetate in Skellysolve B and with 6 L of 100% ethyl acetate, collecting the corresponding eluates in 200 ml fractions. Eluate fractions 29-35 are combined and evaporated to give 109.0 mg of 15-methyl-15(R)-PGF2a methyl ester. Aqueous potassium hydroxide solution is added to a solution of 15-methyl15(R)-PGF2a methyl ester in a mixture of methanol and of water under nitrogen. The resulting solution is stirred 2 h at 25°C, and is then poured into several volumes of water. The aqueous mixture is extracted with ethyl acetate, acidified with 3 N hydrochloric acid, saturated with sodium chloride, and then extracted repeatedly with ethyl acetate. The latter ethyl acetate extracts are combined, washed successively with water and saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate, and evaporated under reduced pressure. The crystalline residue is recrystallized from a mixture of ethyl acetate and Skellysolve B to give 15-methyl-15(R)-PGF2a. References Bundy G.L.; US Patent No. 3,804,889; April 16, 1974; Assigned: Upjohn Company, Kalamazoo, Mich.
ARBEKACIN Therapeutic Function: Antibiotic
Arbekacin
381
Chemical Name: L-Streptamine, O-3-amino-3-deoxy-α-D-glucopyranosyl-(16)-O-(2,6-diamino-2,3,4,6-tetradeoxy-α-D-erythro-hexopyranosyl-(1-4))N1-(4-amino-2-hydroxy-1-oxobutyl)-2-deoxy-, (S)Common Name: Arbekacin; Habekacin Structural Formula:
Chemical Abstracts Registry No.: 51025-85-5 Trade Name Habekacin Habekacin
Manufacturer Meiji-Seika Co. Ltd. Choong Wae Pharma. Co
Country -
Year Introduced -
Arbeka
Reyon Pharmaceutical Co. Ltd.
-
-
Raw Materials 3',4'-Dideoxykanamycin Benzyloxycarbonyl chloride Ammonia Acetic acid Hydrogen Palladium on carbon N-Hydroxysuccinimide ester of (S)-4-benzyloxycarbonylamino-2hydroxybutyric acid Manufacturing Process 13.53 g (30 mmole) of 3',4'-dideoxykanamycin (abbreviated as DKB) in the form of the free base was dissolved in 135 ml of water, and to this solution was added dropwise 5.61 g (33 mmole) of benzyloxycarbonyl chloride over 1 h under stirring and under ice-cooling (0°-5°C). After the addition, the mixture was further stirred for 1 h at room temperature and filtered to remove the precipitate. The filtrate was washed with 135 ml of ethyl ether. The aqueous phase was neutralized by addition of aqueous ammonia and then concentrated under reduced pressure. The concentrated solution was passed through a column of 480 ml of a cation-exchange resin essentially consisting of a copolymer of methacrylic acid and divinylbenzene (available under a trade name "Amberlite
382
Arbekacin
CG 50", a product of Rohm and Haas Co., U.S.A. the ammonium form) to effect the adsorption of the benzyloxycarbonylated DKB by the resin. The resin column was washed with water (1920 ml) and then eluted with 0.1 N aqueous ammonia. 960 ml of the first running of the eluate was discarded, and the subsequently running fraction of the eluate amounting to 780 ml was collected, concentrated and freeze-dried to give 5.43 g (yield 31%) of 6'-Nbenzyloxycarbonyl DKB as a colorless powder, melting point 113°-115°C (dec.). 4.04 g (6.9 mmole) of the 6'-N-benzyloxycarbonyl DKB was dissolved in 26 ml of water, and to this solution was added a solution of 2.94 g (8 mmole) of Nhydroxysuccinimide ester of (S)-4-benzyloxycarbonylamino-2-hydroxybutyric acid in 45 ml of dimethoxyethane. The admixture was stirred at room temperature for 90 min and then the reaction mixture was concentrated to dryness. The residue was taken up in a volume of water and the aqueous solution was poured into a column of 560.0 g of silica gel. The elution was conducted using methanol-chloroform-17% aqueous ammonia (4:2:1), and such eluate fractions containing the unreacted materials were discarded. The fractions containing the mixed acylated products were collected and concentrated to give 5.63 g of the mixed acylated products. The mixed acylated products were dissolved in a mixture of 67 ml of glacial acetic acid, 63 ml of methanol and 17 ml of water, and the solution so obtained was admixed with 1.6 g of 5% palladium-carbon and hydrogenated with hydrogen at atmospheric pressure for 4 h to remove the benzyloxycarbonyl groups of the acylated products. The reaction mixture was filtered to remove the catalyst, and the filtrate was concentrated to under reduced pressure to give 5.20 g of a powder of the acetate of the acylated products comprising 1-N[(S)-4-amino-2-hydroxybutyryl] DKB acetate. The aqueous solution of 1-N-[(S)-4-amino-2-hydroxybutyryl] DKB acetate was poured into a column of 250 ml of a cation-exchange resin made of a copolymer of methacrylic acid and divinylbenzene (commerically available as "Amberlite CG 50" ammonium form). The resin column was washed with water and eluted successively with aqueous ammonia (0.1 N 850 ml, 0.3 N 830 ml, 0.63 N 830 ml and 1 N 830 ml). The eluate was collected in 17 ml fractions. 320 ml of the fractions which were eluted by using 1 N aqueous ammonia and which showed high antibacterial activity to Bacillus subtilis PC 1219 and Escherichia coli JR 66/W 677 were combined together and concentrated to dryness to give 301.0 mg of a powder. This powder was rechromatographed again into a column of 11 ml of a cation-exchange resin made of a copolymer of methacrylic acid with divinylbenzene (commercially available as "Amberlite CG 50", ammonium form). Thus, the resin column was at first washed with 40 ml of water and then with 90 ml of 0.5 N aqueous ammonia, and subsequently the elution was made using 0.75 N aqueous ammonia. Such fractions of the eluate were combined together to a total volume of 26 ml and concentrated to dryness to give 61.0 mg (yield 1.6%) of 1-N-[(S)-4-amino-2-hydroxybutyryl]DKB as a colorless crystalline powder, melting point 178°C (dec.). References Umezawa H. et al.; US Patent No. 4,107,424; August 15, 1978; Assigned: Zaidan Hojin Biseibutsu Kagaku Kenkyu Kal, Tokyo, Japan
Arbutamin hydrochloride
383
ARBUTAMIN HYDROCHLORIDE Therapeutic Function: Cardiotonic Chemical Name: 1,2-Benzenediol, 4-((1R)-1-hydroxy-2-((4-(4hydroxyphenyl)butyl)amino)ethyl)-, hydrochloride Common Name: Arbutamine hydrochloride Structural Formula:
Chemical Abstracts Registry No.: 125251-66-3; 128470-16-6 (Base) Trade Name
Manufacturer
Country
Year Introduced
Genesa
Genesia Automedics
UK
-
Raw Materials 3,4-Dihydroxybenzaldehyde t-Butyldimethylsilyl chloride Nitromethane (S)-6,6'-Bis(triethylsilylethynyl)-1,1'-dihydroxy-2,2-binaphthalene Butyl lithium 4-(4-Methoxymethoxyphenyl)butanoic acid Diethylphosphorylcyanide Triethylamine Lithium aluminum hydride Manufacturing Process (R)-Arbutamin was produced as follows: 89.3 mg of (-)-1-di(tbutyldimethylsiloxy)phenyl)-2-aminoethanol, 50.0 mg of 4-(4methoxymethoxyphenyl)butanoic acid, diethylphosphorylcyanide, and triethylamine were dissolved in N,N-dimethylformamide at 0°C, reacted at room temperature, so as to obtain 108.6 mg (in a yield of 82%) of amide compound. The amide compound obtained was reduced lithium aluminium hydride in an ether solvent at reflux temperature, so as to quantitative obtain amine. And 55.6 mg of (R)-arbutamin which is intended compound was obtained by deprotecting the hydroxyl-protecting group of amine in a methanol-THF solvent at room temperature using hydrochloric acid. [α]D25 = -17 (c 1.15, EtOH). (-)-1-(Dibutyldimethylsiloxy)phenyl)-2-aminoethanol was obtained by a hydrogenization of (R)-1-(3,4-di(t-butyldimethylsiloxyphenyl)-2-nitroethanol
384
Arclofenin
on 10% Pd/C. The last compound was prepared as follows: the hydroxyl groups of 3,4dihydroxy-benzaldehyde was protected using t-butyldimethylsilylchloride (1). 100 mg (0.26 mmol) of 3,4-di(t-butyl-methylsiloxy)benzaldehyde was dissolved in 1 ml tetrahydrofurane under atmosphere of argon at -40°C, and 0.30 ml of metal complex from (S)-6,6'-bis(triethylsilylethynyl)-1,1-dihydroxy2,2'-binaphtalene (2) mixed with a solution of n-butyllitium in hexane.After stirring for 30 minutes, 79.4 mg (1.3 mmol) of nitromethane was added dropwise to the mixture. After 67 hour reaction time, 2 ml of 1 N aqueous solution of hydrochloric acid added to stop the reaction. Product was extracted with 50 ml ethyl acetate, dehydrated with anhydrous sodium sulfate and concentrated within evaporator followed by silica gel chromatography (nhexane/acetone = 10/1), after which (R)-1-(3,4-di(t-butyldimethylsiloxy) phenyl)-2-nitroethanol with an optical purity of 92% e.e. was obtained in a yield of 93%. References Aldrich, Catalogue Handbook of Fine Chemicals, 2000, p.312 Shibasaki et al.; US Patent No. 6,632,955B1; Oct. 14, 2003 Monte W.T. et al.; US Patent No. 5,874,601; Feb. 23, 1999; Assigned: Abbott Laboratories (Abbott Park, IL)
ARCLOFENIN Therapeutic Function: Diagnostic aid Chemical Name: Glycine, N-(2-((2-benzoyl-4-chlorophenyl)amino)-2oxoethyl)-N-(carboxymethyl) Common Name: Arclofenin Structural Formula:
Chemical Abstracts Registry No.: 87071-16-7
Arfendazam
385
Trade Name
Manufacturer
Country
Year Introduced
Arclofenin
ZYF Pharm Chemical
-
-
Raw Materials Acetic anhydride Pyridine Nitrilotriacetic acid Sodium hydroxide 2-Amino-5-chlorobenzophenone Manufacturing Process A round bottom flask is charged with dimethylformamide 72.0 g, acetic anhydride 25.0 g, pyridine 2.0 g, and nitrilotriacetic acid (NTA) 38.2 g and the suspension is nitrogen purged for several minutes. The flask is stoppered and the mixture is stirred at room temperature for 3 days. A small amount of unreacted NTA is filtered out. The bulk of the solvent 79 ml is removed in vacuo at a bath temperature of 60°-70°C. The resulting viscous solution is twice roto-vacued after two successive additions of 40 ml dimethylformamide. So the 2,6-diketo-N-carboxymethyl morpholine (NTA anhydride) is prepiared. To the viscous solution of NTA anhydride is added 300 ml toluene. The mixture is stirred at room temperature until uniform. Then 46.3 g of 2-amino5-chlorobenzophenone dissolved in 300 ml toluene is added to the stirred solution of NTA anhydride and heated at 90°-100°C for 1 h. After cooling, the reaction mixture is flashed to dryness. The residue is taken up in 400 ml of 1N sodium hydroxide and filtered. The filtrate is extracted with chloroform, ether and charcoaled. The charcoal is removed by filtration. The product is precipitated from the filtrate by the careful addition of 6 N HCl. The precipitate is removed by filtration to give the N-[N'-(2-benzoyl-4chlorophenyl)carbamoylmethyl]iminodiacetic acid, melting point 180°-186°C (dec., recrystallized from hot methanol/water). References Roleston R.E.; US Patent No. 4,454,107; June 12, 1984; Assigned: Merck and Co., Inc., Rahway, N.J.
ARFENDAZAM Therapeutic Function: Tranquilizer Chemical Name: 1H-1,5-Benzodiazepine-1-carboxylic acid, 7-chloro-2,3,4,5tetrahydro-4-oxo-5-phenyl-, ethyl ester Common Name: Arfendazam Chemical Abstracts Registry No.: 37669-57-1
386
Argatroban hydrate
Structural Formula:
Trade Name Arfendazam
Manufacturer ZYF Pharm Chemical
Country -
Year Introduced -
Raw Materials Phosgene Ethanol 8-Chloro-1-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-2-one Manufacturing Process A phosgene was mixed with ethanol, then cooling by ice-water the solution of 8-chloro-1-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-2-one in chloroform was added dropwise, mixed and allowed to stand. Then the reaction mixture was concentrated, and crystals was filtered off. So the 7chloro-2,3,4,5-tetrahydro-4-oxo-5-phenyl-1H-1,5-benzodiazepine-1-carboxylic acid ethyl ester was obtained, melting point 172°-173°C (dec.). References Bub O. et al.; SU 474,986; Oct. 25, 1975; Assigned: Knol AG, FRG. Karrer, Lehrbuch der organischen chemie, 1959
ARGATROBAN HYDRATE Therapeutic Function: Anticoagulant Chemical Name: (2R,4R)-4-methyl-1-[N2-3-methyl-1,2,3,4-tetrahydro-8quinolinsulfonyl-L-arginyl]-2-piperidinecarboxylicacid hydrate Common Name: Argatroban; Argipidine Chemical Abstracts Registry No.: 141396-28-3; 74863-84-6 (Base) Raw Materials Triethylamine N(G)-Nitro-N(2)-(tert-butoxycarbonyl)-L-arginine Isobutyl chloroformate
Argatroban hydrate
387
Ethyl 4-methyl-2-piperidinecarboxylate Palladium 3-Methyl-8-quinolinesulfonyl chloride Structural Formula:
Trade Name Acova Argatroban
Manufacturer SmithKline Beecham Texas Biotechnology Corporation
Country -
Year Introduced -
Novastan
Mitsubishi Chemical Corp.
Japan
-
Slonnon
Mitsubishi Chemical Corp.
Japan
-
Manufacturing Process To a stirred solution of 28.3 g of NG-nitro-N2-(tert-butoxycarbonyl)-L-arginine in 450 ml of dry tetrahydrofuran were added in turn 9.0 g of triethylamine and 12.2 g of isobutyl chloroformate while keeping the temperature at -20°C. After 10 minutes, to this was added 15.2 g of ethyl 4-methyl-2piperidinecarboxylate and the mixture was stirred for 10 minutes at -20°C. At the end of this period, the reaction mixture was warmed to room temperature. The solvent was evaporated and the residue taken up in 400 ml of ethyl acetate, and washed successively with 200 ml of water, 100 ml of 5% sodium bicarbonate solution, 100 ml of 10% citric acid solution and 200 ml of water. The ethyl acetate solution was dried over anhydrous sodium sulfate. The solution was evaporated to give 31.5 g (75 %) of ethyl 1-[NG-nitro-N2(tert-butoxycarbonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylate in the form of a syrup. To a stirred solution of 30 g of ethyl 1-[NG-nitro-N2-(tert-butoxycarbonyl)-Larginyl]-4-methyl-2-piperidinecarboxylate in 50 ml of ethyl acetate was added 80 ml of 10% dry HCl-ethyl acetate at 0°C. After 3 hours, to this solution was added 200 ml of dry ethyl ether to precipitate a viscous oily product. This was filtered and washed with dry ethyl ether to give ethyl 1-[NG-nitro-L-arginyl]-4methyl-2-piperidinecarboxylate hydrochloride as an amorphous solid.
388
Arginine aspartate
To a stirred solution of ethyl 1-(NG-nitro-L-arginyl)-4-methyl-2piperidinecarboxylate hydrochloride in 200 ml of chloroform were added in turn 18.5 g of triethylamine, and 14.7 g of 3-methyl-8-quinolinesulfonyl chloride at 5°C, and stirring was continued for 3 hours at room temperature. At the end of this period, the solution was washed twice with 50 ml of water. The chloroform solution was dried over anhydrous sodium sulfate. Upon evaporation of the solvent, the residue was chromatographed on 50 g of silica gel packed in chloroform, washed with chloroform and eluted with 3% methanol-chloroform. The fraction eluted from 3% methanol-chloroform was evaporated to give 32.1 g (91%) of ethyl 1-[NG-nitro-N2-(3-methyl-8quinolinesulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylate in the form of an amorphous solid. A solution of 30 g the above product in 100 ml of ethanol and 100 ml of 1 N sodium hydroxide solution was stirred for 24 hrs at room temperature. At the end of this period, the solution was neutralized with 1 N hydrochloric acid and then concentrated to 70 ml. The solution was adjusted to pH=11 with 1 N sodium hydroxide solution, washed three times with 100 ml of ethyl acetate, acidified with 1 N hydrochloric acid and then extracted three times with 100 ml of chloroform. The combined chloroform solution was dried over anhydrous sodium sulfate and evaporated to give 28.0 g (97%) of 1-[NG-nitro-N2-(3methyl-8-quinolinesulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylic acid as an amorphous solid. IR (KBr): 3,300, 1,720, 1,630 cm-1. To a solution of 3.00 g of 1-[NG-nitro-N2-(3-methyl-8-quinolinesulfonyl)-Larginyl]-4-methyl-2-piperidinecarboxylic acid in 50 ml of ethanol was added 0.5 g of palladium black and then the mixture was shaken under 10 kg/cm2 H2 pressure at 100°C for 8 hrs. At the end of this period, the ethanol solution was filtered to remove the catalyst and evaporated to give 2.50 g (90%) of 1[N2-(3-methyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl)-L-arginyl]-4-methyl-2piperidinecarboxylic acid as an amorphous solid. IR (KBr): 3,400, 1,620, 1,460, 1,380 cm-1. References Okamoto S. et al.; US Patent No. 4,201,863; May 6, 1980; Assigned: Mitsubishi Chemical Industries, Limited (Tokyo, JP) Mano T. et al.; US Patent No. 5,506,241; Apr. 9, 1996; Assigned: Mitsubishi Chemical Corporation (Tokyo, JP)
ARGININE ASPARTATE Therapeutic Function: Tonic, Stimulant, Hepatoprotectant Chemical Name: L-Aspartic acid, compound with L-arginine (1:1) Common Name: Arginine aspartate; Aspargininum Chemical Abstracts Registry No.: 7675-83-4
Arginine aspartate
389
Structural Formula:
Trade Name Arginine aspartate
Manufacturer Microbase Biotech Co., Ltd. Flamma S.P.A. Euro-Labor' Grunenthal
Country -
Year Introduced -
-
-
Bio-Energol Bio-Energol Desfatigan Dynamisan Dynamisan
Medicum Yamanouchi IMA Mipharm S.p.A Novartis Santé Familiale SAS
-
-
Dynamisan Eubiol Lacorene Pargine Pargine Potenciator Sangenor Sargenor Sorbenor Targifor Targifor
Famar, S.A. Chephasaar Spedrog Caillon Viatris Asta Medica Valderrama Roche Viatris S.p.A Casen Fleet, SA. Aventis Pharma Silva Araujo Roussel S.A.
-
-
Taurargin
Laboratorios Baldacci S.A.
-
-
Arginine aspartate Asparten
Raw Materials Calcium aspartate Arginine dihydrochloride Manufacturing Process 1000 ml of polystyrene-trimethylbenzylammonium ion exchange resin were converted into the chloride form by passing aqueous hydrochloride acid over the resin. The resin was washed with distilled water to remove all traces of
390
Arginine glutamate
hydrochloric acid and a 1 N aqueous solution of calcium aspartate was then passed over the resin. A 10% excess of the calcium aspartate solution over the theoretical ion-exchange capacity of the resin was used and the resin was then washed with water until the wash water was free of chloride ions. At the end of this treatment, the resin was in the aspartic acid form. An aqueous solution containing 168.56 g of calcium aspartate and 49.44 g of arginine dihydrochloride per litre was prepared, and this solution was passed slowly over the aspartic acid form resin. The effluent liquid was collected in fractions of 200 ml, then of 100 ml, and towards the end, in fractions of 50 ml. After about 1000 ml of eluate had been collected, the succeeding fractions were examined very carefully for the presence of chloride ion. All the eluate fractions prior to the first one containing traces of chloride, i.e. all the chloride-free eluate fractions, were combined; the combined chloride eluates amounted to about 1300 ml. The arginine present was determined by Sakaguchis method and the total nitrogen in the combined eluates was also determined. These determinations showed that the eluates contained from 270 to 300 g of arginine aspartare per litre. The combined eluates were evaporated to a volume of about 500 ml and allowed to crystallize at a low temperature (0°-4°C). After seeding with a crystal of arginine aspartate, colourless crystals were obtained; they were filtered off, washed with aqueous ethanol, and then dried. About 210 g, i.e. 70% of the theoretical yield, of crystals having a decomposition point of 220°C was obtained. The mother liquor from the first crystallization was evaporated down to a volume of about 150 ml. Ethanol was added to the solution until cloudiness which persisted was obtained, the solution was cooled to 0°C and a second crop of crystals was obtained. The size of this second crop was increased by adding further ethanol after the major portion of the second crop had crystallized and allowing the mixture to stand for 48 hours at 0°C. After separation, the second fraction consisted of 75 g of a crystalline mass which had the same physico-chemical and chemical properties as the main fraction. References GB Patent No. 1,045,060; Sept. 15, 1965; Assigned to Mundipharma S.A.
ARGININE GLUTAMATE Therapeutic Function: Ammonia detoxicant (hepatic failure) Chemical Name: Glutamic acid compound with L-arginine Common Name: Chemical Abstracts Registry No.: 4320-30-3 Raw Materials L-Arginine L-Glutamic acid
Aripiprazole
391
Structural Formula:
Trade Name Modamate Eucol
Manufacturer Abbott Lefranco
Country US France
Year Introduced 1960 1970
Manufacturing Process This salt may be prepared by mixing L-arginine with L-glutamic acid in water and crystallizing the resulting salt from the water by the addition of a polar water miscible organic solvent to the water. For instance, when 17.2 g of Larginine and 14.5 g of L-glutamic acid were dissolved in 155 g of water, a clear homogeneous solution resulted which had a pH of 5.3. This solution was filtered and the filtrate was evaporated at 50°C under reduced pressure to a solution having a solids content of about 45%. Absolute methanol (220 g) was added to the concentrated solution of the salt and this mixture cooled to 5°C for one hour. The resulting solid salt was removed from the mixture by filtration and washed with absolute methanol. After being dried preliminarily in the air, the salt was further dried in a vacuum oven at 60°C for 3 hours. The resulting salt, L-arginine-L-glutamate, weighed 30 g (94.6% of the theoretically possible yield based on the amount of L-arginine and L-glutamic acid employed) and melted at 193-194.5°C with decomposition. References Merck Index 798 DFU 3 (1) 10 (1978) DOT 17 (3) 87 (1981) I.N. p.98 Barker, N.G. and Chang, R.W.H., US Patent 2,851,482; September 9, 1958; Assigned to General Mills, Inc.
ARIPIPRAZOLE Therapeutic Function: Antipsychotic Chemical Name: 2(1H)-Quinolinone, 7-(4-(4-(2,3-dichlorophenyl)-1piperazinyl)butoxy)-3,4-dihydro-
392
Aripiprazole
Common Name: Aripiprazole Structural Formula:
Chemical Abstracts Registry No.: 129722-12-9 Trade Name
Manufacturer
Country
Year Introduced
Abilify
Bristol-Myers Squibb
USA
-
Abilify
Otsuka America Pharmaceutical, Inc.
USA
-
Abilitat
Bristol-Myers Squibb
USA
-
Aripiprazole
Bristol-Myers Squibb
USA
-
Aripiprazole
Otsuka Pharmaceutical Japan Company, Ltd.
-
Raw Materials 2,3-Chloroaniline 7-Hydroxy-3,4-dihydrocarbostyril 1,4-Dibromobutane Di(2-bromethyl)amine Triethylamine Manufacturing Process To a solution of 4.06 g of K2CO3 with 400 ml of water was added 40 g of 7hydroxy-3,4-dihydrocarbostyril [1] and 158 g of 1,4-dibrombutane. The mixture was refluxed for 3 hours. Then it was extracted with dichloremethane, dried with anhydrous MgSO4, the solvent was removed by evaporation. The residue was purified by means of silica gel chromatography (eluent: dichloromethane) and recrystallized from n-hexane-ethanol to yield 50 g of 7(4-bromobutoxy)-3,4-dihydrocarbostyril, mp 110.5°-110.0°C. 47 g of 7-(4-bromobutoxy)-3,4-dihydrocarbostyril, 35 g of NaJ in 600 ml of acetonitrile was refluxed for 30 minutes. To this suspension was added 40 g of 1-(2,3-dichlorophenyl)piperazine (it was prepareted from 2,3-chloroaniline and di(2-bromoethyl)amine [1]) and 33 ml of triethylamine. The mixture was refluxed for 3 hours. After removing of the solvent, the residue was dissolved in chloroform, washed with water and dried with anhydrous MgSO4. The solvent was removed by evaporation, and residue was recrystallized from ethanol twice to yield 57.1 g of 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydrocarbostyril. Melting point: 139.0°-139.5°C.
Arnolol
393
References J. Pharmacol. Exp. Ther., 277, 137-143 (1996) Banno K. et al.; US Patent No. 4,734,416; March 29, 1988; Assigned: Otsuka Pharmaceutical Co., Ltd. (JP) Oshiro Y. et al.;. US Patent No. 5,006,528; April 9, 1991; Assigned: Otsuka Pharmaceutical Co., Ltd. (Tokyo, JP)
ARNOLOL Therapeutic Function: Beta-adrenergic blocker (ophthalmic) Chemical Name: 2-Butanol, 3-amino-1-(4-(2-methoxyethyl)phenoxy)-3methylCommon Name: Arnolol Structural Formula:
Chemical Abstracts Registry No.: 87129-71-3 Trade Name Arnolol
Manufacturer ZYF Pharm Chemical
Country -
Year Introduced -
Raw Materials Palladium on charcoal 1-[4-(2-Methoxyethyl)phenoxy]-3-nitro-3-methylbutan-2-ol Acetic acid Sodium hydroxide Zinc Hydrochloric acid Manufacturing Process 2 methods of producing of 1-[4-(2-methoxyethyl)-phenoxy]-3-amino-3methyl-butan-2-ol: 1). 19.0 g of 1-[4-(2-methoxyethyl)phenoxy]-3-nitro-3-methylbutan-2-ol are hydrogenated at 60°C and under a pressure of 6 bar in a mixture of 250 ml of ethanol and 50 ml of glacial acetic acid in the presence of 4.0 g of palladiumon-charcoal (10% Pd). After the mixture has been filtered and the solvent has been evaporated off, the residue is rendered alkaline with 2 N NaOH and the
394
Arotinolol hydrochloride
mixture is extracted with CH2Cl2. The organic phase is washed with water and dried with Na2SO4 to give, after evaporation, 15.0 g of the 1-[4-(2methoxyethyl)phenoxy]-3-amino-3-methylbutan-2-ol, melting point 120°122°C (dec.). 2). 18.3 g of zinc dust are gradually added to 20.0 g of 1-[4-(2-methoxyethyl) phenoxy]-3-nitro-3-methylbutan-2-ol in 400 ml of ethanol and 60 ml of concentrated hydrochloric acid at 50°-60°C. The mixture is stirred at this temperature for 1 h and filtered and the solvent is evaporated off. After 200 ml of 40% strength NaOH have been added, the product is extracted with methylene chloride. Solvent is distilled and the 1-[4-(2-methoxyethyl) phenoxy]-3-amino-3-methylbutan-2-ol is produced, melting point 120°-122°C (dec.). References Cohnen E., Heilwigstrasse, Fed. Rep. of Germany
AROTINOLOL HYDROCHLORIDE Therapeutic Function: Beta-adrenergic blocker Chemical Name: 2-Thiophenecarboxamide, 5-(2-((3-((1,1-dimethylethyl) amino)-2-hydroxypropyl)thio)-4-thiazolyl)-, monohydrochloride Common Name: Arotinolol hydrochloride; Tarotiolol hydrochloride Structural Formula:
Chemical Abstracts Registry No.: 68377-92-4 (Base); 68377-91-3 Trade Name
Manufacturer
Country
Year Introduced
Arotinolol hydrochloride
ZYF Pharm Chemical
-
-
Raw Materials 2-Mercapto-4-(5'-carbamoyl-2'-thiophenyl)thiazole Sodium hydroxide 1-Chloro-3-t-butylaminopropanol
Arprinocid
395
Manufacturing Process To a solution of 2-mercapto-4-(5'-carbamoyl-2'-thiophenyl)thiazole, 3.2 g in 20 ml of 0.3 % aqueous sodium hydroxide solution, 1-chloro-3-tbutylaminopropanol, 12.64 g in 20 ml of methanol was added, while the temperature was maintained at 20°C. The reaction solution was stirred at room temperature for 4 h, and then condensed to a half volume in vacuo. The residual solution, added with 100 ml of water, was extracted with chloroform. The chloroform extract was washed with water, dried over anhydrous magnesium sulfate and evaporated in vacuo to give 4.8 g of 2-(3'-t-butylamino-2'-hydroxypropylthio)-4-(5'-carbamoyl-2'thiophenyl)thiazole, as crystals, melting point 234°-235.5°C (dec., recrystallized from methanol/water). In practice it is usually used as hydrochloride. References Hibino T. et al.; US Patent No. 3,932,400; January 13, 1976; Assigned: Sumitomo Chemical Company, Limited, Japan
ARPRINOCID Therapeutic Function: Coccidiostatic Chemical Name: 9H-Purin-6-amine, 9-((2-chloro-6-fluorophenyl)methyl)Common Name: Arprinocid Structural Formula:
Chemical Abstracts Registry No.: 55779-18-5 Trade Name Arprinocid
Manufacturer Country NANJING PHARMA CHEMICAL PLANT
Year Introduced -
Arprinocid
Hallochem Pharma Co., Ltd.
-
Arprinocid
Shanghai abochem chemical co., Ltd.
-
396
Arpromidine
Raw Materials Adenine 2-Chloro-6-fluorobenzyl chloride Potassium t-butoxide Manufacturing Process To a solution of potassium t-butoxide in absolute ethanol slowly adding dry adenine. This mixture was stirred for about 2 h, and then 2-chloro-6fluorobenzyl chloride was added over a period of about 4 h. The resulting mixture was heated to reflux with stirring and allowed to react for about 42 h, after which it was cooled to about 10°C. The crude product thus formed was isolated by filtration and then washed with ice cold ethanol and ice cold water to yield a 6-amino-9-(2-chloro-6-fluorobenzyl)purine. References Lira E.P. et al.; US Patent No. 3,846,426; Nov. 5, 1974; Assigned: International Minerals and Chemical Corporation, Libertyville, III. G.B. Patent No. 1,123,457; 11 August 11, 1966; Warner Lambert Pharmaceutical Company, a Corporation of Delaware, USA
ARPROMIDINE Therapeutic Function: Histamine H2-receptor agonist Chemical Name: Guanidine, N-(3-(4-fluorophenyl)-3-(2-pyridinyl)propyl)-N'(3-(1H-imidazol-4-yl)propyl)Common Name: Arpromidine Structural Formula:
Chemical Abstracts Registry No.: 106669-71-0 Trade Name
Manufacturer
Country
Year Introduced
Arpromidine
Onbio Inc.
-
-
Arpromidine
397
Raw Materials Sodium hydride Sodium hydroxide Sulfuric acid Ammonia Hydrochloric acid
(4-Fluorophenyl)-pyrid-2-yl acetonitrile N-(2-Bromoethyl)phthalimide 3-(Imidazol-4-yl)-propylamine N-Benzoyldiphenylimidocarbonate
Manufacturing Process 42.4 g (0.2 mol) of (4-fluorophenyl)-pyrid-2-yl-acetonitrile are dissolved in 50 ml of dimethylformamide and introduced dropwise into a suspension, cooled with ice, of 5.0 g of sodium hydride (put into the process as a dispersion in mineral oil) in 150 ml of dimethylformamide. The reaction mixture is then stirred at room temperature for 15 min and thereafter heated under reflux for 5 h after the addition of 53.4 g (0.21 mol) of N-(2-bromoethyl)phthalimide. When the resulting reaction mixture has cooled down, it is diluted with 500 ml of ether and the organic phase is washed with water until neutral, dehydrated over sodium sulfate and then concentrated by evaporation under vacuum. The N-[3-(cyano-3-(4-fluorophenyl)-3-(pyrid-2-yl)propyl]phthalimide, oily residue, melting point 154°C (crystallizing from methanol), yield: 48.5 g (63%). 46.25 g (0.12 mol) of N-[3-cyano-3-(4-fluorophenyl)-3-(pyrid-2yl)propyl]phthalimide in 100 ml of 75% sulfuric acid are heated to 150°C for 5 h. When the reaction mixture is cold, it is poured out on ice, filtered through a glass filter, alkalized with sodium hydroxide solution and extracted with ether. The combined extracts are washed with water, dehydrated over sodium sulfate and concentrated by evaporation under vacuum, and the product obtained is isolated by distillation at 150°-155°C/0.8 mm Hg. 19.1 g (yield: 69%) of the 3-(4-fluorophenyl)-3-(pyrid-2-yl) propylamine are obtained. 1.15 g (5 mmol) of 3-(4-fluorophenyl)-3-(pyrid-2-yl)-propylamine and 1.59 g (5 mmol) of N-benzoyl-diphenylimidocarbonate are stirred together in 20 ml of methylene chloride for 15 min at room temperature. The solvent is distilled off under vacuum and the residue is taken up with 30 ml of pyridine and then heated under reflux for 60 min after the addition of 0.69 g (5.5 mmol) of 3(imidazol-4-yl)-propylamine. The reaction mixture is concentrated by evaporation under vacuum and the residue is dissolved in dilute acid and extracted with ether to remove the phenol formed in the reaction. Alkalization of the aqueous phase with ammonia is followed by extraction with methylene chloride, and the organic phase is washed with water, dehydrated over sodium sulfate and concentrated by evaporation under vacuum. The crude product is purified by preparative layer chromatography (silica gel 60 PF254, containing gypsum; solvent: chloroform/methanol 99+1, ammoniacal atmosphere). 1.4 g (yield 58%) of N-benzoyl-N'-[3-(4-fluorophenyl)-3-(pyrid-2-yl)propyl]-N"-[3(imidazol-4-yl)propyl]-guanidine a non-crystalline solid (foam) are obtained (crystallisation from ethyl acetate). 0.97 g (2 mmol) of N-benzoyl-N'-[3-(4-fluorophenyl)-3-(pyrid-2-yl)propyl]-N"[3-(imidazol-4-yl)propyl]-guanidine are heated under reflux in 45 ml of 18% hydrochloric acid for 6 h. When the reaction mixture has cooled down, the benzoic acid formed is removed by extraction with ether, the aqueous phase is evaporated to dryness under vacuum and the residue is dehydrated in a high vacuum: 0.9 g (yield 92%) of a hygroscopic, non-crystalline N-[3-(4-
398
Arsanilic acid
fluorophenyl)-3-(pyrid-2-yl)propyl]-N'-[3-(imidazol-4-yl)propyl]-guanidine is obtained. References Buschauer A. et al.; US Patent No. 5,021,431; June 4, 1991; Assigned: Heumann Pharma GmbH and Co., Nuremberg, Fed. Rep. of Germany
ARSANILIC ACID Therapeutic Function: Antibacterial Chemical Name: Arsonic acid, (4-aminophenyl)Common Name: Acidum arsanilicum; Arsanilic acid Structural Formula:
Chemical Abstracts Registry No.: 98-50-0 Trade Name Arsanilic acid Arsanilic acid Arsanilic acid Acidum arsanilicum
Manufacturer Fleming Laboratories, Inc. AroKor Holdings Inc. Idea'l Nutrition Science And Development Co., LTD ZYF Pharm Chemical
Country -
Year Introduced -
-
-
Raw Materials Arsenic acid Aniline Hydrochloric acid Sodium hydroxide Manufacturing Process 342.0 g (2 mol) of 83% arsenic acid were added during 75 min to a rapidly stirred mixture of 372.5 g (4 mol) aniline and 111.0 g chlorobenzene while the temperature of the mixture was kept at 147°-150°C. After the addition of arsenic acid was complete the mixture was stirred for an additional 8 h while being maintained at 149°-153°C. Water was continuously removed by distillation, and the organic phase of the distillate was continuously recycled
Arsthinol
399
back into the reaction mixture. At the end of that time a total of 121.0 g of water, containing the condensation of aniline and arsenic acid has been removed. The mixture was then allowed to cool to 110°C. 562.0 g (2.81 mol) of 20% sodium hydroxide were added over a 2 h period while water, chlorobenzene and excess aniline were distilled off at a temperature of from 102°-113°C. The distillation was continued for an additional 2 h while the volume of the mixture was kept at about 700 ml by the addition of water. The mixture was then diluted with water to a volume of 1400 ml and allowed to cool to 23°C. At this point, 52.0 g of by-product material, which was predominantly tri-(p-aminophenyl)-arsineoxide, were filtered out. The pH of the filtrate was then brought from 8.7 to 5.1 by the addition of 1.8 mol of hydrochloric acid while the volume of the mixture was increased to 2,200 ml by the addition of water. The mixture was stirred for 5 h at room temperature and again filtered. 108.0 g of by-product material comprising predominantly di-(p-aminophenyl)-arsinic acid was filtered off at this point. The pH of the filtrate was lowered to 4.5 by the addition of 0.2 mole of hydrochloric acid, and an additional 5.0 g of by-products, the composition of which was not determined, was filtered off. The filtrate was then brought to a pH of 3.2 by addition of 0.6 mole of hydrochloric acid, and 128.0 g (29.5% based upon arsenic acid) of arsanilic acid were recovered as a precipitate. The arsanilic acid filtrate was combined with the by-products filtered off during each of the three filtration steps. 2.8 mol of hydrochloric acid were added to the combined arsanilic acid filtrate and the mixture was heated at 80°C for 5 days. Arsanilic acid was then precipitated from the remaining hydrolyzed mixture in the manner described for the primary reaction product, and an additional 120.0 g (27.5% based on arsenic acid) were recovered. The filtrate contained 14.0 g (3.2%) of arsanilic acid which could be recovered at least partially in subsequent processing. Thus it can be seen from this example that an arsanilic acid yield of 59% was obtained. References Hoffmannn H., Green H.E.; US Patent No. 3,763,201; October 2, 1973
ARSTHINOL Therapeutic Function: Antiprotozoal Chemical Name: 3-Hydroxypropylene ester of 3-acetamido-4hydroxydithiobenzene-arsonous acid Common Name: Arsthinenol; Arsthinol; Mercaptoarsenical; Mercaptoarsenol Chemical Abstracts Registry No.: 119-96-0
400
Arteflene
Structural Formula:
Trade Name Arsthinol
Manufacturer ZYF Pharm Chemical
Country -
Year Introduced -
Raw Materials 4-Hydroxy-3-acetylaminophenyl-arsenoxide 2,3-Dimercaptopropanol Manufacturing Process 0.1 mol of 4-hydroxy-3-acetylaminophenyl-arsenoxide is suspended in 50 times its weight of water, and to the suspension 3 mols of sodium carbonate and 11 ml (110 mmols) of 2,3-dimercaptopropanol are added with rapid stirringfor 60 min. The resulting precipitate is filtered off, washed with water and dried in vacuo. So the N-[2-hydroxy-5-[4-(hydroxymethyl)-1,3,2-dithiarsolan-2-yl]phenyl] acetamide, melting point 163°-166°C is obtained. References Friedheim E.A.H.; US Patent No. 2,772,303; November 27, 1956
ARTEFLENE Therapeutic Function: Antimalarial Chemical Name: 2,3-Dioxabicyclo[3.3.1]nonan-7-one, 4-(2-(2,4-bis (trifluoromethyl)phenyl)ethenyl)-4,8-dimethyl- (1S-(1α,4β(Z),5α,8α))Common Name: Arteflene Structural Formula:
Arteflene
401
Chemical Abstracts Registry No.: 123407-36-3 Trade Name Arteflene
Manufacturer Roche
Country -
Year Introduced -
Raw Materials Carvone, (-) Sulfuric acid Sodium sulfite Butyl lithium Zinc chloride Hydrogen bromide Sodium methanolate Silver trifluoroacetate
3-Chloroperbenzoic acid Sodium hydroxide Sodium metaperiodate Sodium bicarbonate n-Butyltriphenylphosphonium bromide Hydrogen peroxide Sodiumbis(trimethylsilyl)amide 2,4-Bis(trifluoromethyl)benzyltriphenylphosphonium bromide
Manufacturing Process A solution of 3-chloroperbenzoic acid (55%) in methylene chloride is cooled in an ice bath. (5R)-(-)-Carvone are added dropwise thereto so that the temperature does not rise above 20°C. The reaction mixture is stirred at room temperature for 3.5 h, whereby a precipitate of 3-chlorobenzoic acid forms. This suspension is stirred for 30 min and cooled with ice in order to complete the precipitation. The precipitate is filtered off and washed with hexane/methylene chloride (9:1). The filtrate is evaporated carefully. The thus-obtained oil (epoxide) is suspended in ice-water and treated with 3 N sulfuric acid while cooling in an ice bath so that the temperature does not rise above 20°C. The mixture is stirred at room temperature for 15 h. The pH is adjusted to 6.5 by adding 3 N sodium hydroxide solution. A small amount of 3-chlorobenzoic acid is filtered off. The aqueous phase is cooled to 0°C, whereupon sodium (meta)periodate are added in portions over 30 min so that the temperature does not rise above 20°C. After stirring at room temperature for 2 h sodium sulfite and sodium bicarbonate are added in succession. The suspension is filtered and the filtrate is extracted three times with methylene chloride each time. The combined organic phases are dried over sodium sulfate and evaporated. There is obtained (5R)-5-acetyl-2-methyl-2cyclohexen-1-one (crystallized from hexane/ethyl acetate at 0°C). n-Butyltriphenylphosphonium bromide are suspended in dry tetrahydrofuran under argon and cooled to -50°C. 1.33 N n-butyl lithium in hexane are added thereto. The orange coloured suspension is warmed to room temperature and then again cooled to -50°C. (5R)-5-Acetyl-2-methyl-2-cyclohexen-1-one dissolved in dry tetrahydrofuran are added dropwise thereto over a period of 20 min. The cooling bath is then removed and the suspension is left to warm to room temperature. After stirring for 2 h the reaction mixture is filtered through siliceous earth. The filtrate is evaporated, the dark residue is dissolved in ethyl acetate and washed twice with water each time. The organic phase is dried over sodium sulfate and evaporated. The thus-obtained oil is purified by column chromatography on silica gel with hexane/ethyl acetate (95:5) as the elution agent. There is obtained (5R)-2-methyl-5-[(Z)-1-methyl1-pentenyl]-2-cyclohexen-1-one. (5R)-2-Methyl-5-[(Z)-1-methyl-1-pentenyl]-2-cyclohexen-1-one are dissolved
402
Artilide fumarate
in methylene chloride and cooled to 0°C. After adding a catalytic amount zinc chloride the solution is saturated with hydrogen bromide gas. After 30 min the solution is filtered through silica gel and evaporated carefully. The resulting oily residue is dissolved in dry ether, cooled to 0°C and treated with 100% hydrogen peroxide. Silver trifluoroacetate dissolved in dry ether are added dropwise over a period of 30 min. The excess of silver ions is precipitated by adding 1 N hydrochloric acid and the suspension obtained is filtered through silica gel. In order to remove the excess hydrogen peroxide, the filtrate is washed 5 times with water each time. The ether phase is then evaporated carefully and the residue is taken up methanol. A catalytic amount of sodium methanolate is added to this solution, whereupon the mixture is left to stand at room temperature for 15 h. The methanol is distilled off and the residue is purified and separated into the two diastereomers (1:1) by chromatography on silica gel while eluting with hexane/ethyl acetate (7:3). There are obtained (1S,4R,5R,8S)-4-butyl-4,8-dimethyl-2,3-dioxabicyclo[3.3.1]nonan-7-one. (1S,4R,5R,8S)-4-Butyl-4,8-dimethyl-2,3-dioxabicyclo[3.3.1]nonan-7-one is dissolved in methylene chloride. 2,4-Bis(trifluoromethyl) benzyltriphenylphosphonium bromide and sodium bis(trimethylsilyl)amide are added thereto and the solution is left to stand at room temperature for 24 h. The methylene chloride is distilled off and the (1S,4R,5R,8S)-4-[(Z)-2,4bis(trifluoromethyl)styryl-4,8-dimethyl-2,3-dioxabicyclo[3.3.1]nonan-7-one, melting point 124°C is obtained. References Hofneinz W. et al.; US Patent No. 4,977,184; December 11, 1990; Assigned: Hoffmann-La Roche Inc., Nutley, N.J.
ARTILIDE FUMARATE Therapeutic Function: Antiarrhythmic Chemical Name: Methanesulfonamide, N-(4-(4-(dibutylamino)-1hydroxybutyl)phenyl)-, (R)-, fumarate (2:1) (salt) Common Name: Artilide fumarate Chemical Abstracts Registry No.: 133267-19-3 (Base); 133267-20-6 Raw Materials Aniline Aluminum chloride Sodium bicarbonate 1-Hydroxybenzotriazole Lithium aluminum hydride 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride
Methanesulfonyl chloride Succinic anhydride Hydrogen hydrochloride Dibutylamine Sodium potassium tartrate
Artilide fumarate
403
Structural Formula:
Trade Name Artilide fumarate
Manufacturer Upjohn (Pharmacia)
Country -
Year Introduced -
Manufacturing Process A mechanically stirred solution of aniline (139.7 g, 1.5 mol) in pyridine (2 L), under N2 is cooled in an icebath. Methanesulfonyl chloride (171.8 g, 1.5 mol) is added dropwise to this solution while the temperature is maintained at 15°20°C, which results in a red-orange color change in the reaction mixture. After the addition is complete the ice bath is removed and the reaction is allowed to continue at room temperature for 2.5 h. The reaction mixture is concentrated in vacuo and the residue is combined with 700 ml of water which results in crystallization of a dark red material. This material is filtered and washed several times with water. The filtered material is dissolved in CH2Cl2, washed with brine, dried (Na2SO4), and concentrated in vacuo to give four crops (157.37 g, 19.27 g, 26.55 g, 5.07 g) of methanesulfonanilide, melting point 93°C (decolorizing with Darco carbon and crystallization from ethyl acetate). A mechanically stirred suspension of aluminum chloride (88.0 g, 0.66 mol) and 150 ml of carbon disulfide under N2 is cooled in an ice bath. Methanesulfonanilide (30.0 g, 0.175 mol) and succinic anhydride (17.5 g, 0.175 mol) are combined and added rapidly to the cooled reaction mixture. The ice bath is removed and the mixture is stirred at room temperature for 6 h. The reaction mixture is then heated to 55°C and allowed to continue for 18 h. The reaction mixture is separated into two layers the bottom of which solidifies. The upper layer is decanted and the remaining solid layer is decomposed with ice. The resulting suspension is filtered and the solid is washed several times with methylene chloride and dissolved in a mixture of saturated sodium bicarbonate (500 ml) and water (500 ml). This solution is
404
Ascorbic acid
acidified (pH 2) with HCl and the resulting precipitate is collected by filtration, redissolved in NaHCO3 and reprecipitated with HCl. The solid is collected by filtration and dried to give 4-[(methylsulfonyl)amino]-γ-oxobenzenebutanoic acid, melting point 198°-200°C. A mixture of 4'-[(methylsulfonyl)amino]-γ-oxobenzenebutanoic acid and 1hydroxybenzotriazole in dimethylformamide (DMF) under nitrogen, is treated with dibutylamine in DMF. The mixture is cooled in an ice bath and 1-ethyl-3(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC) added in portions over 5 min. The mixture is stirred in the cold 1 h and overnight at room temperature. The solvent is removed in vacuo (bath temperature 35°C). The residue is treated with ice and ethyl acetate and the organic layer washed sequentially with 0.5 N monopotassium sulfate, cold 4% NaHCO3, cold water and finally brine. The organic solution is dried (Na2SO4) and concentrated in vacuo. The N,N-dibutyl-γ-oxo-4-[(methylsulfonyl)amino]benzenebutan-amide (crystallized from ethyl acetate-hexane) is obtained. Lithium aluminum hydride is suspended in dry tetrahydrofuran (THF), under nitrogen and the mixture cooled in an ice bath. To this mixture is added N,Ndibutyl-γ-oxo-4-[(methylsulfonyl)amino]benzenebutanamide, (partly as a suspension in THF added over 10 min and partly as a solid added in portions over 30 min). The mixture is stirred for 2.5 h in the cold. The cold reaction mixture is then treated cautiously with a saturated solution of sodium potassium tartrate in water and stirred for 10 min in the cold. This mixture is extracted with EtOAc. The pooled ethyl acetate extracts are washed with brine, dried (Na2SO4) and concentrated in vacuo to give a solid. The aqueous residue from the above extractions is diluted with 10 ml of water and extracted with ethyl acetate. The pooled extract is washed with brine, dried (Na2SO4) and concentrated to give solid. The two solids are recrystallized separately from EtOAc to give N-4[4-(dibutylamino)-1-hydroxybutyl]phenyl]methanesulfonamide (recrystallized from EtOAc-hexane). By recrystallyzation of stereo-isomers of N-4-[4-(dibutylamino)-1hydroxybutyl]phenyl]methanesulfonamide may be obtained the (R)-N-4-[4(dibutylamino)-1-hydroxybutyl]phenyl]methanesulfonamide, melting point 179°-180°C. References Boling H.J.; EU Patent No. 0,164,865; May 1, 1985; Assigned: Perry, Robert Edward et al., GILL JENNINGS and EVERY 53-64 Chancery Lane London WC2A 1HN (GB)
ASCORBIC ACID Therapeutic Function: Vitamin Chemical Name: 3-Keto-L-gulofuranolactone
Ascorbic acid
405
Common Name: Acide ascorbique; Acido ascorbico; Acidium ascorbicum; Acidum ascorbinicum; Ascorbic acid; Ascorbinsaure; Askorbinsyra; Cevitamic acid; C-Vitamin; Hexuronic acid; Hexuronsaure; Vitamin C; Witamina C Structural Formula:
Chemical Abstracts Registry No.: 50-81-7 Trade Name Ascorbic acid Cebion Celin Chewable Plivit C
Manufacturer Natur Product Merck KGaA Glaxo Pliva
Country France Germany India Croatia
Year Introduced -
Styptovit
Dr. Reddy's Laboratories Ltd.
India
-
Upsavit Vitamin C Vitamin C
UPSA Hemofarm
Vitamin CInjektopas Vitamin C Nycomed Vitrum Plus Vitamin C
Pascoe Naturmedizin
France Serbia and Montenegro Germany -
Nycomed Pharma A/S
Norway
-
Unipharm
USA
-
Raw Materials Glucose Nickel Raney Acetone Sodium hypochlorite Manufacturing Process D-Glucose was reduced to the D-sorbitol with a hydrogen over Ni Raney, then it was turned into the L-sorbose with the acetobacter suboxydans and the hydroxyl groups of L-sorbose were protected with acetone treatment yielded the diaceton-L-sorbose. Subsequent treatment with NaOCl/Raney Ni produced di-O-isopropylidene-2-oxo-L-gulonic acid. Partial hydrolysis with aqueous HCl gave deprotected 2-oxo-L-gulonic acid, which yielded ascorbinic acid by heating with HCl.
406
Asobamast
References Reichstein T., Grusser A.; Helv. Chim. Acta, 17, 311 (1934) Kirk-Othmer, Encyclopedia of Chemical Technology, 2 Aufl. Vol. 2, s.747 ff
ASOBAMAST Therapeutic Function: Antiallergic, Anti-asthmatic Chemical Name: 2-Ethoxyethyl (4-(3-methyl-5-isoxazolyl)-2-thiazolyl) oxamate Common Name: Asobamast; Sobamast Structural Formula:
Chemical Abstracts Registry No.: 104777-03-9 Trade Name Asobamast
Manufacturer Onbio Inc.
Country -
Year Introduced -
Raw Materials Bromine 3-Methyl-5-acetylisoxazole Thiourea 2-Ethoxyethyloxalyl chloride Manufacturing Process 1). 179 mmol of bromine in 20 ml of chloroform were added dropwise in 10 minutes to a solution of 172 mmol of 3-methyl-5-acetylisoxazole, (Gass. Chim. Ital. 72, 242, 194) containing 4.9 ml of glacial acetic acid while the reaction mixture was maintained under stirring at 48°-50°C. After 5 minutes the mixture was poured into 300 g of water and crushed ice. The organic layer was separated, washed with water, dried and evaporated to residual 3methyl-5-bromoacetylisoxazole. Yield 87%; white crystalline compound, MP: 44°-46°C (isopropyl ether).
Asocainol hydrochloride
407
2). A mixture of 50 mmol of 3-methyl-5-bromoacetylisoxazole and 100 mmol of thiourea in 164 ml of ethyl alcohol was refluxed for 90 minutes and then cooled for 1 hour with an ice bath. The precipitate was collected by filtration and added to a mixture of 25 ml of a 10% aqueous solution of sodium hydroxide and 100 ml of ethyl acetate under vigorous stirring. The organic layer was separated, washed, dried and evaporated to dryness after recrystallization from acetonitrile the 2-amino-4-(3-methyl-5isoxazolyl)thiazole melts at 208°-210°C. Yield, 57%. 3). To a mixture of 20.5 mmol of 2-amino-4-(3-methyl-5-isoxazolyl)thiazole in 37.4 ml of pyridine maintained under stirring at 5°C were added dropwise 23.6 mmol of 2-ethoxyethyloxalyl chloride. The reaction mixture was maintained under stirring overnight, then poured into 100 g of crushed ice, made acid with concentrate hydrochloric acid and extracted with chloroform. The chloroform extracts were washed with water, dried and evaporated to dryness. The residual 2-ethoxyethyl-4-(3-methyl-5-isoxazolyl)thiazole-2oxamate was re-crystallized from 65 ml of acetonitrile. Yield, 91%; MP: 155°156°C. References Carenzi A. et al.; US Patent No. 4,766,137; August 23, 1988; Assigned: Zambon S.p.A., Vicenza, Italy
ASOCAINOL HYDROCHLORIDE Therapeutic Function: Antiarrhythmic Chemical Name: (+/-)-6,7,8,9-Tetrahydro-2,12-dimethoxy-7-methyl-6-(2phenylethyl)-5H-dibenz[d,f]azonin-1-ol hydrochloride Common Name: Asocainol hydrochloride Structural Formula:
Chemical Abstracts Registry No.: 77400-65-8 (Base); 91574-89-9 Trade Name
Manufacturer
Country
Year Introduced
Asocainol hydrochloride
ZYF Pharm Chemical
-
-
408
Asparaginase
Raw Materials Phenethyl bromide Activated magnesium turnings Thebaine Ammonium chloride Manufacturing Process A solution of a Grignard reagent is prepared from 5.5 g (0.23 mol) activated magnesium turnings and 41.5 g (0.24 mol) phenethyl bromide in 200 ml anhydrous diethyl ether. To this is added dropwise, at 35-40°C, a solution of 31.5 g (0.1 mol) thebaine in 0.4 liters dry benzene. After heating under reflux for 2 hours, the reaction mixture is decomposed with a solution of 48 g ammonium chloride in 200 ml water. The usual working up, after conversion of the base into the hydrochloride by means of hydrogen chloride in ethyl acetate, gives 7.3 g (21% of theory) (+/-)-2,12-dimethoxy-1-hydroxy-7methyl-6-phenethyl-5,6,8,9-tetrahydro-7H-dibenz[d,f]azonine hydrochloride; melting point 227.6°C, after recrystallization from propan-2-ol. References Satzinger Gerhard, Herrmann Manfred, Fritschi Edgar, Bahrmann Heinrich, Ganser Volker, Wagner Bernd, Steinbrecher Wolfgang; US Patent No. 4,689,339; Nov. 15, 1983; Assigned to Godecke Aktiengesellschaft (Freiburg, DE)
ASPARAGINASE Therapeutic Function: Antineoplastic (acute leukemia) Chemical Name: See Structural Formula Common Name: Colapase; L-Asnase Structural Formula: L-Asparagine amidohydrolase (an enzyme of MW 133,000 ± 5,000 believed to consist of 4 equivalent subunits) Trade Name Crasnitin Crasnitin Leunase Kidrolase Crasnitin Elspar
Manufacturer Bayer Bayer Kyowa Hakko Specia Bayer Merck Sharp and Dohme
Country W. Germany Italy Japan France UK US
Year Introduced 1969 1971 1971 1971 1971 1978
Kidrolase Leucogen
Rhone Poulenc Bayer
Canada -
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Aspartame
409
Chemical Abstracts Registry No.: 9015-68-3 Raw Materials Erwinia bacteria Nutrient medium Manufacturing Process Therapeutically active L-asparaginase is isolated from bacteria from the genus Erwinia, a known genus pathogenic towards plants. L-asparaginase is conveniently isolated from this genus by growing the bacteria upon a suitable nutrient medium until a desired quantity is obtained and then extracting the L-asparaginase either by conventional cell disruption methods, or preferably, by processes more fully described in US Patent 3,660,238. References Merck Index 849 Kleernan and Engel p. 62 PDR p. 1176 I.N. p. 102 REM p. 1143 Wade, H.E.; US Patent 3,660,238; May 2, 1972 Herbert, D. and Wade, H.E.; US Patent 3,686,072; August 22, 1972
ASPARTAME Therapeutic Function: Sugar supplement Chemical Name: N-L-α-Aspartyl-L-phenylalanine 1-methyl ester Common Name: Structural Formula:
Chemical Abstracts Registry No.: 22839-47-0
410
Aspartame
Trade Name Canderel Canderel Equal Canderel Canderel Nutrasweet
Manufacturer Searle Searle Searle Wander Muro Searle
Country France Switz. US W. Germany US US
Year Introduced 1979 1981 1982 1983 -
Raw Materials L-Phenylalanine methyl ester hydrochloride N-Benzyloxycarbonyl-L-aspartic acid α-p-nitrophenyl, β-benzyl diester Hydrogen Manufacturing Process A solution of 88.5 parts of L-phenylalanine methyl ester hydrochloride in 100 parts of water is neutralized by the addition of dilute aqueous potassium bicarbonate, then is extracted with approximately 900 parts of ethyl acetate. The resulting organic solution is washed with water and dried over anhydrous magnesium sulfate. To that solution is then added 200 parts of Nbenzyloxycarbonyl-L-aspartic acid α-p-nitrophenyl, β-benzyl diester, and that reaction mixture is kept at room temperature for about 24 hours, then at approximately 65°C for about 24 hours. The reaction mixture is cooled to room temperature, diluted with approximately 390 parts of cyclohexane, then cooled to approximately -18°C in order to complete crystallization. The resulting crystalline product is isolated by filtration and dried to afford βbenzyl N-benzyloxycarbonyl-L-aspartyl-L-phenylalanine methyl ester, melting at about 118.5-119.5°C. To a solution of 180 parts of β-benzyl N-benzyloxycarbonyl-L-aspartyl-Lphenylalanine methyl ester in 3,000 parts by volume of 75% acetic acid is added 18 parts of palladium black metal catalyst, and the resulting mixture is shaken with hydrogen at atmospheric pressure and room temperature for about 12 hours. The catalyst is removed by filtration, and the solvent is distilled under reduced pressure to afford a solid residue, which is purified by recrystallization from aqueous ethanol to yield L-aspartyl-L-phenylalanine methyl ester. It displays a double melting point at about 190°C and 245247°C. References Merck Index 852 DOT 16 (2) 65 (1980) I.N. p. 102 Schlatter, J.M.; US Patent 3,492,131; January 27, 1970; Assigned to G.D. Searle and Co.
Aspirin
411
ASPIRIN Therapeutic Function: Analgesic, Antipyretic, Antiinflammatory Chemical Name: 2-(Acetyloxy)benzoic acid Common Name: Acetylsalicylic acid Structural Formula:
Chemical Abstracts Registry No.: 50-78-2 Trade Name Entab Easprin Ecotrin Zorprin Verin AAS Acesal Acetard Acetisal Acetisal Acetisal Acetical Acetophen Acetylin Acetylo Acetylosal Acetyl-Sal Acetysal Acetysal Acetysal Acimetten Acisal Adiro Alaspine Albyl Algo Alka-Seltzer
Manufacturer Mayrand WL/PD Menley and James Boots Verex Sterwin Espanola Oranienbourg Benzon Alkaloid Farmakos Galenika Rekah Merck-Frosst Heyden Chemedica Maria Heil Hartz Jugoremedija Krka Zdravlje Kwizda Pliva Bayer Liba AFI Lokman Miles
Country US US US US US Spain E. Germany Denmark Yugoslavia Yugoslavia Yugoslavia Israel Canada W. Germany Switz. Austria Canada Yugoslavia Yugoslavia Yugoslavia Austria Yugoslavia Turkey Norway Turkey Italy
Year Introduced 1982 1982 1983 1983 1983 -
412
Aspirin
Trade Name Ancasal Antidol Apernyl Apyron
Manufacturer Anca Gebro Bayer Lingner and Fischer
Country Canada Austria Japan W. Germany
Year Introduced -
Asart Asatard Asdol Aspalgin Aspec
SK and F De Angeli Srbolek Krka Kempthorne Prosser Egic Otis Clapp Buffington Bayer Dover Miles Bayer Nicholas Pan Quimica Rivopharm Medic Atabay Pfizer Deva Boots Izal Teva Buffington Dover Yer Sinclair Liade Theraplix Cederroths Bayer Nicholas Nicholas Nicholas Fass Bayer Spitzner
US Italy Yugoslavia Yugoslavia New Zealand
-
France US US W. Germany US US W. Germany Italy Spain Switz. Canada Turkey US Turkey UK UK Israel US US Spain UK Spain France Sweden Italy UK France Spain W. Germany W. Germany
-
Rougier Maggioni Medici Domus Andromaco
Canada Italy Italy Argentina
-
Aspegic Aspercin Aspermin Aspirin Aspirtab Aspirvess Aspisol Aspro Aspro Asrivo Astrin Ata spin Babypyrin Bebaspin Bi-Prin Breoprin Bufacyl Buffaprin Buf fasal Calmo Yer Caprin Casprium Catalgine Cedrox Cemerit Claradin Claragine Clariprin Codalgina Colfarit ContrheumaRetard Coryphen Diaforil Domupirina Ecasil
Aspirin Trade Name Ecoprin Ecotrin Empirin Endospirin Endyol Entericin Enterosarine Entrophen Eskotrin Extren Flectadol Genasprin Godamed Globentyl Globoid Glucetyl Hagedabletten Halgon Idotyl Juveprine Kilios Levius Levius Licyl Longasa Magnecyl Magnyl Measurin Medisyl Mejoral Infantil Micristin Neopirine Neutracetyl Nibol Nova-Phase Novasen Pharmacin Premaspin Pyronoval Rectosalyl Reunyl Rhodine Rhonal Rhonal
Manufacturer Sam-On SK and F BurroughsWellcome Enila-Lotecia Guidotti Bristol-Myers Sarein Merck-Frosst SK and F Vicks Maggioni Fisons Pfleger Nyegaard Nyegaard Technicopharm Hageda Togal Ferrosan Sarget Farmitalia Pharmitalia Montedison A.L. Squibb ACO DAK Breon Medica Sterwin Espanola Gyogyert Casgrain and Charbonneau Promedica Bosnalijek Nova Novopharm Optrex Laake Hoechst Bouty Hassle Specia Specia Rhodia Iberica
413
Country Israel US US
Year Introduced -
Brazil Italy US France Canada US US Italy UK W. Germany Norway Norway Switz. W. Germany W. Germany Denmark France Italy UK W. Germany Norway US Sweden Denmark US Finland Spain Hungary Canada
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France Yugoslavia Canada Canada UK Finland W. Germany Italy Sweden France France Spain
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414
Aspirin
Trade Name Rhusal Riphen Rodina Sal Adult Sal Infant Sargepirine Saspryl Seclopyrine Servisprin Solprin Solpyron Solucetyl Solusal St. Joseph Supasa Tasprin Temagin Triaphen Trineral Winsprin
Manufacturer G.P. Riva Farmitalia Beecham Beecham Sarget Teva Seclo Servipharm Reckitt Beecham Sarbach Hamilton Plough Nordic Ticen Beiersdorf Trianon Beiersdorf Winthrop
Country Australia Canada Italy UK UK France Israel France Switz. UK UK France Australia US Canada UK W. Germany Canada W. Germany US
Year Introduced -
Raw Materials Salicylic acid Acetic anhydride Ketene Manufacturing Process As described in US Patent 2,731,492, a glass-lined reactor of 1,500 gallons capacity, fitted with a water-cooled reflux condenser, thermometers with automatic temperature registers and an efficient agitator, is employed. To start the process, a mother liquor is made by dissolving 1,532 kg of acetic anhydride (15 mols) in 1,200 kg of toluene. To this mother liquor, add 1,382 kg of salicylic acid (10 mols), heat the reaction mixture under an efficient reflux condenser, to 88-92°C and maintain within this temperature range for 20 hours. The reaction mixture is now transferred to aluminum cooling tanks, and is allowed to cool slowly, over a period of 3 to 4 days, to a terminal temperature of 15-25°C (room temperature). The acetylsalicylic acid precipitates as large, regular crystals. The mother liquor is now filtered or centrifuged from the precipitated acetylsalicylic acid and the filter cake is pressed or centrifuged as free of mother liquor as possible. The crystals are washed with distilled water until completely free of acetic acid, pressed or centrifuged as dry as possible and the filter cake is then dried in a current of warm air at a temperature of 60-70°C.
Aspoxicillin
415
The filtrate from this first batch will comprise a solution of 180 to 270 kg of unprecipitated acetylsalicylic acid (1.0 to 1.5 mols), 510 kg of acetic anhydride (5.0 mols), 600 kg of acetic acid (10.0 mols) (obtained as a byproduct in the acetylation step) and 1,200 kg of the diluent toluene. Into this filtrate, at a temperature of 15° to 25°C, ketene gas is now passed through a sparger tube or diffuser plate, with good agitation, until a weight increase of 420.5 kg of ketene (10 mols) occurs. The reaction mixture will now contain 180-270 kg of unprecipitated acetylsalicylic acid (1.0-1.5 mols) and 1,532 kg of acetic anhydride (15 mols) in 1,200 kg of toluene. This mother liquor is recycled to the first step of the process for reaction with another batch of 1,382 kg of salicylic acid. On recirculating the mother liquor, the yield of pure acetylsalicylic acid is 1,780 to 1,795 kg per batch. References Merck Index 863 Kleeman and Engel p. 12 PDR (Many References) DOT 16 (10) 359 (1980) REM p. 1112 Kamlet, J.; US Patent 2,731,492; January 17, 1956 Hamer, W.E. and Phillips, G.V.; US Patent 2,890,240; June 9, 1959; Assigned to Monsanto Chemicals, Limited, England Edmunds, R.T.; US Patent 3,235,583; February 15, 1966; Assigned to The Norwich Pharmacal Company
ASPOXICILLIN Therapeutic Function: Antibiotic Chemical Name: Glycinamide, N-methyl-D-asparaginyl-N-(2-carboxy-3,3dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-6-yl)-D-2-(4hydroxyphenyl)-,(2S-(2-α,5-α,6-β))Common Name: Apaxicillin; Aspoxicillin; Doyle Structural Formula:
Chemical Abstracts Registry No.: 63358-49-6
416
Aspoxicillin
Trade Name Aspoxicillin Aspoxicillin Aspoxicillin
Manufacturer Shiono Chemical Co., Ltd. ZYF Pharm Chemical INTERCHEMICAL(chongqing) CO. LTD
Country -
Year Introduced -
-
-
Raw Materials D-2-Amino-3-N-methylcarbamoyl-propionic acid hydrochloride (D-N'methylasparagine HCl) Benzyloxycarbonyl chloride Dicyclohexylcarbodiimide N-Hydroxysuccinimide p-Hydroxy-D-phenylglycine Citric acid 6-Aminopenicillanic acid Triethylamine Palladium on barium carbonate Manufacturing Process 1). 3 g (23.6 millimoles) of D-2-amino-3-N-methylcarbamoyl-propionic acid hydrochloride (D-N'-methylasparagine HCl), 4.5 g of benzyloxycarbonyl chloride, 30 g of water, 30 ml of tetrahydrofuran and 12 g of potassium carbonate are mixed at 5° to 10°C. Then, the mixture is stirred at the same temperature for 2 hours. During the reaction, the mixture is kept at a slightly alkaline pH (pH 8) with potassium carbonate. 10 ml of water are added to the reaction mixture, and insoluble materials are filtered off. The filtrate is washed twice with ethyl acetate, acidified with citric acid and then extracted three times with 50 ml of ethyl acetate. The ethyl acetate extracts are washed with water, dried and evaporated to remove solvent. 5.1 g of D-2benzyloxycarbonylamino-3-N-methylcarbamoyl-propionic acid are obtained. MP: 142°-143°C. 2). 2.8 g (10 millimoles) of D-2-benzyloxycarbonylamino-3-Nmethylcarbamoyl-propionic acid, 2.27 g of dicyclohexylcarbodiimide, 1.27 g of N-hydroxysuccinimide and 120 ml of tetrahydrofuran are mixed at 0° to 5°C, and the mixture is stirred at the same temperature for 16 hours. Insoluble materials are filtered off. Then, the filtrate is evaporated at 20°C under reduced pressure to remove the solvent, and the crystalline precipitates thus obtained are washed with a mixture of benzene-ether. 2.6 g of N-(D-2benzyloxycarbonylamino-3-N-methylcarbamoyl-propionyloxy)succinimide are obtained. MP: 132°-134°C. 3). 3.75 g of N-(D-2-benzyloxycarbonylamino-3-Nmethylcarbamoylpropionyloxy)succinimide are dissolved in 50 ml of tetrahydrofuran. 12.5 ml of an aqueous 1 N-sodium hydroxide solution containing 2.3 g of p-hydroxy-D-phenylglycine are added to the solution. The mixture is stirred at room temperature for 24 hours. 20 ml of ethyl acetate and 20 ml of water are added to the reaction mixture, and said mixture is shaken. Then, the aqueous layer is separated, adjusted to pH 3 with citric acid
Astemizole
417
and extracted with a mixture of 20 ml of tetrahydrofuran and 10 ml of ethyl acetate. The extract is washed with water, dried and evaporated to remove solvent. The residue thus obtained is washed with ether. 3.0 g of D-2-(D-2benzyloxycarbonylamino-3-N-methylcarbamoylpropionamido)- 2-phydroxyphenylacetic acid are obtained as colorless crystalline powder. MP: 154°-156°C(decomp.). 4). 429 mg of D-2-(D-2-benzyloxycarbonylamino-3-Nmethylcarbamoylpropionamido)-2-p-hydroxyphenylacetic acid and 382 mg of 6-aminopenicillanic acid triethylamine salt are dissolved in 10 ml of dimethylformamide. 303 mg of diphenylphosphoric azide [N3PO(OC6H5)2] and 110 mg of triethylamine are added to the solution at -5°C, and the mixture is stirred at -5°C for 15 hours. After the reaction, the mixture is adjusted to pH 3 with an aqueous 5% citric acid solution and extracted with a mixture of 15 ml of tetrahydrofuran and 10 ml of ethyl acetate. The extract is washed with water, dried and then evaporated at below 40°C to remove the solvent. Ether is added to the residue obtained, and precipitates are collected by filtration. 509 mg of 6-[D-2-(D-2-benzyloxycarbonylamino-3-Nmethylcarbamoylpropionamido)-2-p-hydroxyphenylacetamido]penicillanic acid are obtained as a colorless powder. 5). 627 mg of 6-[D-2-(D-2-benzyloxycarbonylamino-3-N-methylcarbamoylpropionamido)-2-p-hydroxyphenylacetamido]penicillanic acid and 400 mg of 30% palladium-BaCO3 are suspended in 10 ml of methanol. The suspension is shaken at room temperature for 30 minutes. Said shaking step is carried out in a hydrogen gas atmosphere under atmospheric pressure. After the reaction is completed, the catalysts are removed by filtration. The filtrate is evaporated at below 40°C to remove the solvent, and ether is added to the residue. Then, a colorless crystalline powder is collected by filtration and washed with tetrahydrofuran. 443 mg of 6-[D-2-(D-2-amino-3-N-methylcarbamoylpropionamido)-2-p-hydroxyphenylacetamido]penicillanic acid are obtained. MP: 198°-201°C(decomp.). References Kawazu M. et al.; US Patent No. 4,053,609; October 11, 1977; Assigned to Tanabe Seiyaku Co., Ltd., Osaka, Japan
ASTEMIZOLE Therapeutic Function: Antiallergic, Antihistaminic Chemical Name: 1-[(4-Fluorophenyl)methyl]-N-[1-[2-(4-methoxyphenyl) ethyl]-4-piperidinyl]-1H-benzimidazol-2-amine Common Name: Chemical Abstracts Registry No.: 68844-77-9
418
Astemizole
Structural Formula:
Trade Name Hismanal
Manufacturer Janssen
Country UK
Year Introduced 1983
Raw Materials 2-(4-Methoxyphenyl)ethyl methane sulfonate 1-[(4-Fluorophenyl)methyl]-N-(4-piperidinyl)-1H-benzimidazol-2-amine dihydrobromide Sodium carbonate Manufacturing Process A mixture of 2.3 parts of 2-(4-methoxyphenyl)ethyl methanesulfonate, 4.9 parts of 1-[(4-fluorophenyl)methyl]-N-(4-piperidinyl)-1H-benzimidazol-2amine dihydrobromide, 3.2 parts of sodium carbonate, 0.1 part of potassium iodide and 90 parts of N,N-dimethylformamide is stirred overnight at 70°C. The reaction mixture is poured onto water. The product is extracted with methylbenzene. The extract is washed with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 2,2'-oxybispropane, yielding 2.2 parts (48%) of 1(4-fluorophenylmethyl)-N-[1-[2-(4-methoxyphenyl)ethyl]-4-piperidinyl]-1Hbenzimidazol-2-amine; MP 149.1°C. References Merck Index A-1 DFU 7 (1) 10 (1982) OCDS Vol. 3 p. 177 DOT 19 (7) 412 (1983) I.N.p. 102 Janssens, F., Stokbroekx, R., Torremans, J. and Luyckx, M; US Patent 4,219,559; August 26, 1980; Assigned to Janssen Pharmaceutica N.V.
Astromicin sulfate
419
ASTROMICIN SULFATE Therapeutic Function: Antibiotic Chemical Name: L-chiro-Inositol, 4-amino-1-((aminoacetyl)methylamino)1,4-dideoxy-3-O-(2,6-diamino-2,3,4,6,7-pentadeoxy-β-L-lyxoheptopyranosyl)-6-O-methyl-, sulfate (1:2) Common Name: Astromicin sulfate; Fortimicin A Structural Formula:
Chemical Abstracts Registry No.: 55779-06-1 (Base); 72275-67-3 Trade Name Fortimicin sulfate Astromicin sulfate
Manufacturer Youngjin Pharma AroKor Holdings Inc.
Country -
Year Introduced -
Astromicin sulfate
ZYF Pharm Chemical Abbott Kyowa Hakko Kogyo Co., Ltd.
-
-
-
-
Abbott-44747 Fortimicin A Raw Materials
Micromonospora olivoasterospora MK-70 (ATCC 21819) Yeast extract Starch Corn steep liquor Magnesium sulfate heptahydrate Calcium carbonate Amberlite
Glucose Peptone Calcium carbonate Soybean meal Potassium phosphate, dibasic Potassium chloride Radiolite No. 600 Dowex
Manufacturing Process Aminoglycoside antibiotic complex produced by Micromonospora
420
Astromicin sulfate
olivoasterospora. Micromonospora olivoasterospora MK-70 (ATCC 21819) (FERM-P No. 1560) is used as a seed strain. One loopful of the seed strain is inoculated into 10 ml of a seed medium containing 2% glucose, 0.5% peptone, 0.5% yeast extract and 0.1% calcium carbonate (pH 7.5 before sterilization) in a 50 ml large test tube. Culturing is carried out at 30°C for 5 days. 10 ml of the seed culture broth is then inoculated into 30 ml of a second seed medium in a 250 ml Erlenmeyer flask. The composition of the second seed medium is the same as that of the first seed medium. The second seed culturing is carried out at 30°C for 2 days with shaking. Then 30 ml of the second seed culture broth is inoculated into 300 ml of a third seed medium in a 2 L Erlenmeyer flask provided with baffles. The composition of the third seed medium is the same as that of the first seed medium. The third seed culturing is carried out at 30°C for 2 days with shaking and 1.5 L of the third seed culture broth (corresponding to the content of five flasks) is inoculated into 15 L of a fourth seed medium in a 30 L glass jar fermenter. The composition of the fourth seed medium is the same as that of the first seed medium. Culturing in the jar fermenter is carried out at 37°C for 2 days with aeration and stirring (revolution: 350 r.p.m.; aeration: 15 L/min). Thereafter, 15 L of the fourth seed culture broth is inoculated into 150 L of a main fermentation medium in a 300 L fermenter. The main fermentation medium comprises 4% soluble starch, 2% soybean meal, 1% corn steep liquor, 0.05% K2HPO4, 0.05% MgSO4·7H2O, 0.03% KCl and 0.1% CaCO3 (pH 7.5 before sterilization). Culturing in the fermenter is carried out at 37°C for 4 days with aeration and stirring (revolution: 150 r.p.m.; aeration: 80 L/min). After the completion of culturing, the resulting fermentation broth is adjusted to a pH of 2.5 with concentrated sulfuric acid, and stirred for 30 minutes. Then, about 7 kg of a filter aid, Radiolite No. 600 (product of Showa Kagaku Kogyo Co., Ltd., Japan) is added thereto and the microbial cells are removed by filtration. The filtrate is adjusted to a pH of 7.5 with 6 N sodium hydroxide and passed through a column packed with about 20 L of a cation exchange resin, Amberlite IRC-50 (ammonium form), and the effluent is discarded. Active substances are adsorbed on the resin. After washing the resin with water, the adsorbed active substances are eluted out with 1 N aqueous ammonia. Activity of the eluate is determined by a paper disc method, using an agar plate of Bacillus subtilis No. 10707. The active fractions are collected and the mixture is concentrated to about 1 L under reduced pressure. The concentrate is passed through a column packed with 500 ml of an anion exchange resin, Dowex 1x2 (OH- form). Then, about 2 L of water is passed through the column, whereby impurities are removed and active substances are eluted out. The thus obtained active fractions are collected, and concentrated to about 100 ml under reduced pressure, and the resulting concentrate is passed through a column packed with about 50 ml of active carbon powder. The active substances are adsorbed onto the carbon powders. Then, the column is washed with water and the effluent and the washing water are discarded. Then, the adsorbed active substances are eluted out with 0.2 N sulfuric acid. Activity of the eluate is determined by the paper disc method using Bacillus subtilis, and the active fractions are collected. The thus obtained fractions are passed through a column of Dowex 44 (OH- form), and active substances are eluted out with water. The active fractions are again collected and concentrated to about 50 ml. The thus obtained concentrate is lyophilized, whereby about 32 g of a crude powder containing Fortimicin A is
Atamestane
421
obtained. The crude powder exhibits an activity of 575 unit/mg (the activity of 1 mg of a pure product corresponds to 1000 units). Then 10 g of the crude powder is placed as a thin and uniform layer on 500 ml of silica gel packed in a glass column. The glass column is prepared by suspending the silica gel in a solvent of the lower layer of a mixture comprising chloroform, isopropanol and 17% aqueous ammonia (2:1:1 by volume), and then packing the suspension tightly in the column as a uniform layer, and thereafter washing with the same solvent. After placing the crude powder at the head of the column, elution is carried out with the abovedescribed solvent by gradually pouring into the column from its top, and thereafter elution is carried out at a flow rate of about 50 ml/hour. The eluate is obtained as fractions of 20 ml each, and the activity of each fraction is determined by a paper disc method. Fortimicin B is eluted out at first. Thereafter, fractions containing Fortimicin A are obtained. The active fractions are subjected to paper chromatography, and the fractions containing Fortimicin A are collected and concentrated under reduced pressure to completely remove the solvent. The concentrate is then dissolved in a small amount of water. After freeze-drying the solution, about 1.8 g of purified preparate of the free base of Fortimicin A is obtained. The activity of the preparate is about 970 unit/mg. White amorphous powder, MP: >200° (dec.). [α] D25 +87.5° (c = 0.1 in water); solves in water and lower alcohols, insoluble in organic solvents. References Nara T. et al.; US Patent No. 3,946,768; August 24, 1976; Assigned to Abbott Laboratories, North Chicago Ill.
ATAMESTANE Therapeutic Function: Aromatase inhibitor Chemical Name: Androsta-1,4-diene-3,17-dione, 1-methylCommon Name: Atamestane Structural Formula:
Chemical Abstracts Registry No.: 96301-34-7
422
Atenolol
Trade Name Atamestane
Manufacturer Schering AG
Country -
Year Introduced -
Raw Materials 17β-Hydroxy-1-methylandrosta-1,4-dien-3-one Chromic acid Manufacturing Process 6.01 g of 17β-hydroxy-1-methylandrosta-1,4-dien-3-one is dissolved in 100 ml of acetone. At room temperature, 22 ml of a chromic acid solution (prepared from 6.67 g of CrO3, 6 ml of concentrated sulfuric acid, replenished with water to 100 ml) is added dropwise to this solution. The mixture is stirred for one hour and then precipitated into ice water; the product is suctioned off and dried, thus obtaining after recrystallization from acetone/hexane 5.25 g of 1-methylandrosta-1,4-diene-3,17-dione, melting point 165-166°C. References Kerb Ulrich, Sauer Gerhard, Wiechert Rudolf, Henderson David, Nishino Yukishige, Beier Sybille; US Patent No. 4,591,585; May 27, 1986; Assigned to Schering Aktiengesellschaft (Berlin and Bergkamen, DE)
ATENOLOL Therapeutic Function: Beta-adrenergic blocker Chemical Name: 4-[2-Hydroxy-3-[(1-methylethyl)amino]propoxy] benzeneacetamide Common Name: Structural Formula:
Chemical Abstracts Registry No.: 29122-68-7 Trade Name Tenormin Tenormin
Manufacturer Stuart I.C.I.
Country UK W. Germany
Year Introduced 1976 1976
Atenolol
Trade Name Tenormin Tenormin Tenormin Tenormin Atenol Blokium Ibinolo Myocord Normiten Seles Beta Tenoretic Vericordin
Manufacturer I.C.I. I.C.I. I.C.I. Stuart C.T. Prodes I.B.I. Szabo-Kessler Abic Farmitalia Stuart Lazar
Country Switz. Italy France US Italy Spain Italy Argentina Israel Italy US Argentina
423
Year Introduced 1978 1979 1979 1981 -
Raw Materials p-Hydroxyphenylacetamide Epichlorohydrin Isopropylamine Manufacturing Process 1 gram of 1-p-carbamoylmethylphenoxy-2,3-epoxypropane and 10 ml of isopropylamine in 25 ml of methanol is heated in a sealed tube at 110°C for 12 hours. The mixture is evaporated to dryness and the residue is partitioned between 50 ml of chloroform and 50 ml of aqueous 2 N hydrochloric acid. The aqueous acidic layer is separated, made alkaline with sodium carbonate and extracted twice with 50 ml of chloroform each time. The combined extracts are dried and evaporated to dryness and the residue is crystallized from ethyl acetate. There is thus obtained 1-p-carbamoylmethyiphenoxy-3isopropylamino-2-propanol, MP 146-148°C. The 1-p-carbamoylmethylphenoxy-2,3-epoxypropane used as starting material may be obtained as follows: a mixture of 3.2 grams of phydroxyphenylacetamide, 25 ml of epichlorohydrin and 6 drops of piperidine is heated at 95-100°C for 6 hours. The mixture is cooled and filtered and the solid product is crystallized from methanol. There is thus obtained 1-pcarbamoylmethylphencxy-2,3-epoxypropane, MP 158-160°C. References Merck Index 868 DFU 1 (1) 7 (1976) Kleeman and Engel p. 62 PDR pp. 1786, 1788 OCDS Vol. 2 p. 109 (1980) DOT 13 (2) 49 (1977) and 16 (1) 30 (1980) I.N. p. 103 REM p. 904 Barrett, A.M., Carter, J., Hull, R., Le Count, D.J. and Squire, C.J.; US Patent 3,663,607; May 16, 1972; Assigned to Imperial Chemical Industries Limited, England
424
Atevirdine mesylate
Barrett, A.M., Carter, J., Hull, R., Le Count, D.J. and Squire, C.J.; US Patent 3,836,671; September 17, 1974; Assigned to Imperial Chemical Industries Limited, England
ATEVIRDINE MESYLATE Therapeutic Function: Antiviral Chemical Name: Piperazine, 1-(3-(ethylamino)-2-pyridinyl)-4-((5-methoxy1H-indol-2-yl)carbonyl)-, monomethanesulfonate Common Name: Atevirdine mesylate Structural Formula:
Chemical Abstracts Registry No.: 136816-75-6 (Base); 138540-32-6 Trade Name Atevirdine mesylate
Manufacturer Upjohn
Country -
Year Introduced -
Raw Materials 1,1'-Carbonyldiimidazole Chlorotrimethylsilane Methanesulfonic acid
5-Methoxyindole-2-carboxylic acid 1-(3-N-Ethylamino-2-pyridinyl)piperazine
Manufacturing Process 1-[5-Methoxyindolyl-2-carbonyl]-4-[3-(ethylamino)-2-pyridinyl]piperazine: 1,1'-Carbonyldiimidazole (0.55 g) is added to a 20°-25°C solution of 5methoxyindole-2-carboxylic acid (0.59 g) in tetrahydrofuran (7.0 ml). After stirring 1 hour, the reaction is transferred via cannnula into a solution of 1-(3N-ethylamino-2-pyridinyl)piperazine (0.70 g) in tetrahydrofuran (7 ml) at 12°C (ice/acetone bath). The reaction is stirred at -10°C for 30 minutes, then slowly warmed to 20°-25°C and stirred a further 18 hours. After diluting with
Atibeprone
425
ether (60 ml), the mixture is washed with saturated aqueous sodium bicarbonate (70 ml), saline (70 ml) and dried over anhydrous sodium sulfate. The mixture is concentrated under reduced pressure to a residue which is purified by flash chromatography (2 cm x 20 cm) eluting with methanol/chloroform (2/98) to give the title compound, mp 153°-154°C. 1-[5-Methoxyindolyl-2-carbonyl]-4-[3-(ethylamino)-2-pyridinyl]piperazine hydrochloride: 1-(Ethyl)-3-(dimethylaminopropyl)carbodiimide (1.25 g) is added to a solution of 1-(3-ethyl-2-pyridinyl)piperazine (1.12 g) in THF (15 ml). The reaction is stirred at 20°-25°C for 3 hr; then it is dissolved in chloroform (50 ml) and extracted with saturated aqueous sodium bicarbonate, saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by flash column chromatography (200 g silica) eluting with ethyl acetate/hexane (50/50), the appropriate fractions are pooled and concentrated to give the title compound, The product is dissolved in methanol (150 ml) with heating, cooled to 20°-25°C and chlorotrimethylsilane (4.70 mmol) is added. The mixture is concentrated to half-volume, ether is added until cloudy and the flask is stored at 0°C overnight. Filtration gives the hydrochloride salt, MP: 194°-195°C. The mesylate salt is formed by dissolving the free base in methanol and by adding methanesulfonic acid (1 eq). The solution is diluted with diethyl ether until the salt crystallizes out of solution. The crystals are collected and dried to afford the mesyl salt of the title compound, MP: 215°-216°C. References Allen M.M. et al.; WO Patent No. 91/09849; 1991/07/11; Pharmacia and Upjohn Company, U.S.
ATIBEPRONE Therapeutic Function: Antidepressant Chemical Name: 7-((5-Isopropyl-1,3,4 thiadiazol-2-yl)methoxy)-3,4dimethylcoumarin Common Name: Atibeprone Structural Formula:
426
Atipamezole
Chemical Abstracts Registry No.: 153420-96-3 Trade Name Atibeprone
Manufacturer BASF
Country -
Year Introduced -
Raw Materials 7-Methoxy-3,4-dimethylcoumarin Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4diphosphetane 2,4-disulfide) Manufacturing Process 10 mmol of 7-methoxy-3,4-dimethylcoumarin were stirred with 10 mmol (4.04 g) of Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4diphosphetane 2,4-disulfide) in 20 ml of toluene at 90°C for 1-2.5 h. After cooling, the solvent was distilled off, the residue was taken up in DMF, and water was added. The precipitate was filtered off with suction and the crude 3,4-dimethyl-7-(2-isopropyl-1,3,4-thiadiazol-5-ylmethoxy)-2-thiocoumarin was purified by recrystallization from methanol or by column chromatography (silica gel, methylene chloride). Yield: 98%, melting point: 134-135°C. References Rendenbach-Mueller Beatrice, Karl Ulrich, Weifenbach Harald; US Patent No. 5,414,006; May 9, 1995; Assigned to BASF Aktiengesellschaft (Ludwigshafen, DE)
ATIPAMEZOLE Therapeutic Function: Antihypertensive Chemical Name: 4-(2-Ethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole Common Name: Structural Formula:
Chemical Abstracts Registry No.: 104054-27-5 Trade Name Antisedan MPV 1248
Manufacturer Novartis Orion Farmos Group Ltd.
Country -
Year Introduced -
Atolide
427
Raw Materials 2-Acetyl-1-indanone Sodium carbonate Bromine Palladium on carbon
Ethyl bromide Sodium borohydride Hydrochloric acid
Manufacturing Process (a). 2-Acetyl-1-indanone (Liebigs Ann. Chem. 1906, 347, 112) is alkylated with ethylbromide in acetone in the presence of sodium carbonate to 2-acetyl2-ethyl-1-indanone. The acetyl group is brominated with bromine in methanol and to imidazole by heating in formamide as before. The melting point of the 4(5)-(2,3-dihydro-2-ethyl-1-oxo-1H-inden-2-yl)imidazole is 126-127°C (from ethyl acetate). (b). The carbonyl group of 4(5)-(2,3-dihydro-2-ethyl-1-oxo-1H-inden-2yl)imidazole is reduced to the alcohol group with sodium borohydride in ethanol. The product is the mixture of cis-trans stereoisomers, the purification of which is accomplished by liquid chromatography: cis-isomer as hydrochloride (melting point 184-185°C); 1H NMR (80 MHz, MeOH-d4): 0.73 (3H, t), 1.86 (2H, m), 3.36 (2H, m), 3.61 (3H, s), 5.15 (1H, s), 7.06 (1H, d), 7.2-7.4 (4H, m), 8.69 (1H, d), and trans-isomer as hydrochloride; 1H NMR (80 MHz, MeOH-d4): 0.80 (3H, t), 1.84 (2H, m), 3.15 (2H, m), 3.24 (3H, s), 5.15 (1H, s), 6.87 (1H, d), 7.2-7.4 (4H, m), 8.54 (1H, d). The oxo derivative prepared in step (a) or the hydroxy derivative prepared in step (b) is hydrogenated in 2 N hydrochloric acid in the presence of 10% palladium on carbon at 70°C. When the uptake of hydrogen ceases, the reaction mixture is filtered and made alkaline. The product is extracted with methylene chloride which is washed with water, dried and evaporated to dryness. From the residue, which is the product as base, is made the hydrochloride of 4(5)-(2,3-dihydro-2-ethyl-1H-inden-2-yl)imidazole using dry hydrogen chloride in ethyl acetate. It has melting point 211-215°C. References Karjalainen Arto J., Virtanen Raimo E., Karjalainen Arja L., Kurkela Kauko O.A.; US Patent No. 4,689,339; August 25, 1987; Farmos Yhtyma oy (Turku, FI)
ATOLIDE Therapeutic Function: Anticonvulsant Chemical Name: 2-Amino-N-[4-(diethylamino)-2-methylphenyl]benzamide Common Name: Atolide Chemical Abstracts Registry No.: 16231-75-7
428
Atorvastatin calcium
Structural Formula:
Trade Name Atolide
Manufacturer ZYF Pharm Chemical
Country -
Year Introduced -
Raw Materials 2-Amino-5-diethylaminotoluene Isatoic acid anhydride Manufacturing Process 0.8 kg (4.5 moles) of freshly distilled 2-amino-5-diethylaminotoluene is mixed thoroughly with 0.75 kg (4.5 moles) of isatoic acid anhydride and the mixture heated to 100°C with stirring for three hours. The product formed is taken up before cooling in 2.5 liters of boiling ethyl acetate and the solution filtered. On cooling the filtrate 1.1 kg (83% of theory) of 2-amino-4'-(diethylamino)-2'methylbenzanilide precipitates out. After re-crystallzation from n-propanol the colorless crystalline product obtained melts at 152°C. References G.B. Patent No. 1,123,457; 11 August 11, 1966; Warner Lambert Pharmaceutical Company, a Corporation of Delaware, USA
ATORVASTATIN CALCIUM Therapeutic Function: Anticholesteremic Chemical Name: (βR,δR)-2-(4-Fluorophenyl)-β,δ-dihydroxy-5-[(1methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt (2:1) Common Name: Atorvastatin calcium Chemical Abstracts Registry No.: 134523-03-08; 134523-00-5 (Base) Raw Materials n-Butyl diisopropyl amine t-Butylcarboxylic acid
Sodium borohydride Butyl lithium
Atorvastatin calcium
429
Triethylborane Bromine Magnesium S-(+)-2-Acetoxy-1,1,2-triphenylethanol 5-(4-Fluorophenyl)-2-(1-methylethyl)-1-(3-oxopropyl)-N,4-diphenyl-1Hpyrrole-3-carboxamide Structural Formula:
Trade Name Cardyl Citalor
Manufacturer Pfizer Pfizer Pharmaceuticals
Country Spain Ireland
Year Introduced -
Lipibec Lipibec Lipitor Lipitor Xarator
IVAX Arg. Syncro Parke Davis Pfizer Pfizer Italy S.p.A.
Argentina Italy
-
Manufacturing Process 285 ml 2.2 M n-butyl lithium in hexane was added dropwise to 92 ml diisopropylamine at -50-60°C under nitrogen. The well stirred solutions warmed to about -20°C, then it was cannulated into a suspension of 99 g of S(+)-2-acetoxy-1,1,2-triphenylethanol in 500 ml absolute tetrahydrophuran (THF) at -70°C and the reaction mixture was allowed to warm to -10°C for 2 hours. A suspension of MgBr2 was made from 564 ml (0.63 mol) of bromine and 15.3 g of magnesium (0.63 mol) in 500 ml THF cooled to -78°C. The enolate solution was cannulated into this suspension within 30 min and was stirred for 60 min at -78°C. 150 g 5-(4-fluorophenyl)-2-(1-methylethyl)-1-(3oxopropyl)-N,4-diphenyl-1H-pyrrole-3-carboxamide in 800 ml absolute THF was added dropwise over 30 min; stirred 90 min at -78°C, then was added 200 ml acetic acid, this is removed to a cool bath, 500 ml of H2O was added and the mixture concentrate in vacuo at 40-50°C. After adding of 500 ml of 1:1 EtOAc/heptane the mixture was filtered. The filtrate was washed extensively with 0.5 N HCl, then several times with H2O and finally
430
Atosiban
EtOAc/heptane (3:1) and cooled with dry ice to -20°C. The light brown crystalline product was dried in vacuum oven at 40°C. The yield was 194 g. 112 g of the same product was produced by evaporation of mother liquor after recrystallization and chromatographic purification on a silicagel. 162 g of this substance was suspended in methanol/THF (5:3) and was stirred with 11.7 g of sodium methoxide until everything was dissolved and kept in the freezer overnight. Later it was quenched with AcOH concentrated in vacuo, was added to 500 ml H2O and extracted twice with EtOAc (300 ml). The combined extracts was washed with saturated NaHCO3 brine and dried over anhydrous MgSO4, purified on silica-gel and gave 86.1 g of white crystals m.p. 125-126°C, αD20=4.23° (1.17 M, CH3OH). 81 g of the last product in 500 ml absolute THF was added as quickly as possible to the mixture of 77 ml THF at diisopropylamine, 200 ml 2.2 M of nbutyl lithium and 62 ml of t-butylacetate in 200 ml THF -40-42°C under nitrogen. Stirring was continued for 4 hours at -70°C. The reaction mixture was concentrated in vacuo, the residue was taken up in EtOAc, washed with water, then saturated NH4Cl, NaHCO3 (saturated), dried over anhydrous MgSO4, filtred and the solvent evaporated. The organic phase was dried and concentrated in vacuo to yield 73 g crude product, that was dissolved in 500 ml absolute THF, 120 ml triehtylborane and 0.7 g t-butylcarboxylic acid, 70 ml methanol and 4.5 g sodium borohydride was added. The mixture was stirred at -78°C under a dry atmosphere for 6 hours, poured slowly into 4:1:1 mixture of ice/30%H2O2/H2O and stirred overnight. CHCl3 (400 ml) was added and organic layer washed extensively with H2O until no peroxide could be found, was dried over MgSO4, filtered and was treated by chromatography on silica gel to yield 51 g. The product was dissolved in THF/methanol and saponificated with NaOH and, concentrated to remove organic solvents at room temperature, added 100 ml H2O, and extracted with Et2O twice. Organic layer was thoroughly dried and it was left at room temperature for the next 10 days, then concentrated. Chromatography on silica gel yielded 13.2 g racemate of lactone - trans-(+/)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-di-diphenyl-1-[2-(tetrahydro-4hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide. This racemate was divided by chiral synthesis which was made analogously the method in US Pat. No. 4,581,893. Then each isomer was saponificated with NaOH and purificated by HPLC. The calcium salt corresponding acid was prepared by reaction with 1 eq. of CaCl2·2H2O in water. References Roth B.D.; US Patent No. 5,273,995; Dec. 28, 1993; Assigned: WarnerLambert Company (Morris Plains, NJ)
ATOSIBAN Therapeutic Function: Oxytocin antagonist
Atosiban
431
Chemical Name: Oxytocin, 1-(3-mercaptopropanoic acid)-2-(O-ethyl-Dtyrosine)-4-L-threonine-8-L-ornithineCommon Name: Atosiban; Tractotile Structural Formula:
Chemical Abstracts Registry No.: 90779-69-4 Trade Name Tractocile Antocin Antocin Tractotile Atosiban
Manufacturer Ferring srl Ortho Ferring Ferring ASI Bio-tech's products
Country -
Year Introduced -
Raw Materials BocGly resin O-Ethyl-D-tyrosine Boc-L-ornithine Ammonia sodium BOC-L-Asparagine Diisopropylethylamine Dicyclohexylcarbodiimide
3-Mercaptopropanoic acid Boc-L-threonine 4-Ethoxyphenyl-D-alanine Boc-L-cysteine Boc-isoleucyne Hydroxybenzotriazole
Manufacturing Process BocGly resin (3.0 g, 3 meq) was placed in the reaction vessel of a Vega Model 50 semiautomatic peptide synthesizer. The peptide was built up by increments on the resin in accordance with Tables 1 and 2. TABLE 1 Solid phase synthesis
432
Atosiban
Step Solvent/Reagent 1 Dichloromethane 2 50% trifluoroacetic acid/dichloromethane
Vol. [ml] 70 70
Time [min] 3 15
Number of cycles 2 2
3 4 5
Isopropanol Dichloromethane 10% diisopropylethylamine in dichloromathane
70 70 70
3 3 3
2 2 2
6 7 8 9
Dichloromethane Activated amino acid Isopropanol Dichloromethane
70 70 70 70
3 120* 3 3
2 1 2 2
*30 for BocAsn and BocGln TABLE 2 Termination procedure Step Solvent/Reagent 1
2
1 M Imidazole: dichloromethane + acetic acid anhydride Isopropanol
3
Dichloromethane
Vol. [ml] Time [min]
Number of cycles
70 + 7
30
1
70
3
2
70
3
4
Activation of the amino acid was carried out by dissolving 10 meq of a suitably protected amino acid, 15 meq of hydroxy benzotriazole and 10 meq of dicyclohexylcarbodiimide in DMF (70 ml), whereupon the mixture was left at room temperature for 1 h (asparagine and glutamine were activated at 0°C for 15 min), whereupon the precipitate was filtered off, and the filtrate was treated the activated amino acid in Table 1 (step 7). The completion of the coupling step was checked by the method of Kaiser (Anal. Biochem. 34, 595 (1970)) after the cycle had been completed (step 9). If the test was positive (coupling yield below 99%), the cycle was repeated starting from step 7. If the test was negative, the termination procedure was performed according to Table 2. When the whole sequence had been coupled, the resin was placed on a filter and washed repeatedly with methanol. The dried product was placed in a glass vessel and cooled in an ethanol-dry ice bath and suspended in methanol (about 100 ml). The mixture was then saturated with sodium-dried ammonia to achieve approximately 50% concentration. Then the vessel was placed in a steel cylinder and left at room temperature for two days. After the pressure had been relieved, the product was filtered, and the residue was extracted with hot (about 100°C) DMF (2x100 ml). The filtrate and the extract were combined and evaporated. The residue was dissolved in a small amount of hot DMF, and methanol was added to the coupling point. The precipitate was collected by filtration and washed on the filter with methanol. After drying in vacuum, the purity was checked by thin-layer chromatography. Yield about 2.8 g. 100 mg of the above described protected peptide were placed in a 100 ml
Atovaquone
433
round-bottom flask, and dry nitrogen was flushed through for about 15 min. 50 ml of sodium-dried ammonia were distilled in, and the protective group was removed from the product by adding sodium until blue color remained in the solution for 15 sec. The excess of sodium was destroyed by adding of ammonium chloride. Ammonia was removed in a nitrogen stream, and the residue was dissolved in 1 liter of methanol. The pH of the solution was adjusted to about 4 with concentrated acetic acid, and the solution was then titrated with 0.1 mM of iodine in methanol to brownish color. The mixture was stirred with 3 g of Dowex 50x2 ion exchanger in chloride form for 10 min at room temperature. The ion exchanger was removed by filtration, and the filtrate was evaporated to dryness. The residue was dissolved in 3 ml of 20% acetic acid and purified by chromatography on Sephadex G-25 with 20% acetic acid as eluent. The final purification was achieved by reverse phase HPLC. The purity of the product was determined on a HPCL column µBondapak C-18 in 45% ethanol and 55% 5 mM trifluoroacetic acid in water. The column was supplied by Water Associates, Inc., Millford, Mass., U.S.A. The purity of the product was also shown by amino acid analysis. References Per O.R. Melin et al.; US Patent No. 4,504,469; March 12, 1985; Assigned to Ferring AB, Malmo, Sweden
ATOVAQUONE Therapeutic Function: Antiprotozoal Chemical Name: 2-(trans-4-(p-Chlorophenyl)cyclohexyl)-3-hydroxy-1,4naphthoquinone Common Name: Atovaquone Structural Formula:
Chemical Abstracts Registry No.: 95233-18-4 Trade Name
Manufacturer
Country
Year Introduced
Atovaquone
GlaxoSmithKline
-
-
Mepron
GlaxoSmithKline
USA
-
434
Atovaquone
Trade Name
Manufacturer
Country
Year Introduced
Tropine
India
-
Wellvone
Neon Laboratories Ltd. GlaxoSmithKline
USA
-
Wellvone Suspension
GlaxoSmithKline Australia Pty Ltd.
Australia
-
Raw Materials 2-Chloro-1,4-napthohinone Acetyl chloride Carbon disulfide Aluminum chloride Silver nitrate Cyclohexene Ammonium persulfate Bromine Sodium metabisulphite Manufacturing Process Preparation of intermediate 4-(4-chlorophenyl)cyclohexane-1-carboxylic acid was needed at first. It was made as follows: acetyl chloride (30 g), aluminium chloride (60 g) in carbon disulfide (120 ml) were stirred at -50°C. Cyclohexen (30 g) previously cooled to -50°C was added dropwise during 10 minutes and the mixture was stirred for 60 minutes at -50°C. The solvent was decanted and 300 ml chlorobenzene was added, the so-obtained solution heated at 40°C for 3 hours with stirring, poured onto a mixture of ice and concentrated hydrochloric acid and the organic layer washed with 2 M HCl, 2 M NaOH and water, dried over anhydrous Na2SO4. The product was distilled in vacuo, the fraction boiling at 140°-154°C (0.1 mm Hg) collected, diluted with an equal volume of petroleum ether, cooled to -6°C and a stream of nitrogen gas bubbled through. 3.1 g above obtained hexahydroacetophenone was dissolved in dioxan (15 ml) and the fresh preparated hypobromite (8 ml) in a solution of NaOH (6.2 g) in water (42 ml) at 0°C was added at below 20°C. The mixture was stirred at ambient temperature for 6 hours then allowed to stand overnight. Excess hypobromite was destroyed with sodium metabisulphite, cooled and then acidified to give a colourless solid. It was filtered off, washed with water, dried and recrystallysed from ethanol to give 4-(4-chlorophenyl)cyclohexane-1carboxylic acid, m.p. 254°-256°C. A mixture of this acid, 2-chloro-1,4naphthoquinone and silver nitrate was added to ammonium persulfate to give the corresponding naphthoquinone which was saponificated with KOH and was yielded 2-trans-4-(p-chlorophenyl)cyclohexyl)-3-hydroxy-1,4 naphthoquinone, m.p. 216°-219°C, shown by NMR to be the pure trans isomer. References Hudson A.T. et al.; US Patent No. 5,053,432; Oct. 1, 1991; Assigned: Burroughs Wellcome Co. (Research Triangle Park, NC)
Atracurium besylate
435
ATRACURIUM BESYLATE Therapeutic Function: Neuromuscular blocker Chemical Name: N,N'-4,10-Dioxa-3,11-dioxotridecylene-1,13-bistetrahydropapaverine dibenzenesulfonate Common Name: Structural Formula:
Chemical Abstracts Registry No.: 64228-81-5 Trade Name
Manufacturer
Country
Year Introduced
Tracrium
Burroughs-Wellcome
US
1983
Tracrium
Burroughs-Wellcome
UK
1983
Tracrium
Burroughs-Wellcome
Switz.
1983
Raw Materials Acryloyl chloride Tetrahydropapaverine
Pentane-1,5-diol Methyl benzene sulfonate
Manufacturing Process Acryloyl chloride (0.2 mol) in dry benzene (60 ml) was added over 0.5 hour with mechanical stirring to pentane-1,5-diol (0.1 mol), triethylamine (0.2 mol) and pyrogallol (0.1 g) in dry benzene (100 ml). Further dry benzene (ca 100 ml) was added followed by triethylamine (10 ml), and the mixture stirred at 50°C for 0.5 hour. The triethylamine hydrochloride was filtered off and the solvent removed in vacuum to leave a yellow oil which was distilled in the presence of a trace of p-methoxyphenol, excluding light, to give 1,5pentamethylenediacrylate (12.9 g; 61%; BP 90° to 95°C/0.01 mm Hg). A solution of tetrahydropapaverine (4.43 g) and 1,5-pentamethylene diacrylate (1.30 g) in dry benzene (15 ml) was stirred under reflux for 48 hours excluding light. The solvent was removed in vacuum and the residual pale red oil dissolved in chloroform (10 ml). Addition of ether (ca 400 ml), followed by saturated ethereal oxalic acid solution (ca 500 ml) gave a flocculent white precipitate, which was filtered off, washed with ether and
436
Atreleuton
dried. Crystallization (twice) from ethanol gave N,N'-4,10-dioxa-3,11dioxotridecylene-1,13-bis-tetrahydropapaverine dioxalate as a white powder (3.5 g; 51%; MP 117° to 121°C). The free base, N,N'-14,10-dioxa-3,11-dioxotridecylene-1,13-bistetrahydropapaverine, was obtained by basifying an aqueous solution of the dioxalate with sodium bicarbonate solution, followed by extraction with toluene and evaporation of the solvent, to give a colorless viscous oil. Scrupulously dried base (0.5 g) in spectroscopically pure acetonitrile (8 ml) was treated with methyl benzene sulfonate at room temperature for 22 hours. The filtered reaction mixture was added dropwise to mechanically stirred, filtered, dry ether (ca 450 ml). The flocculent white precipitate was filtered off, washed with dry ether, and dried in vacuum over P2O5 at 50°C to yield the product, an off-white powder melting at 85° to 90°C. In practice it is usually used as dibenzenesulfonate. References Merck Index A-2 DFU 5 (11) 541 (1980) PDR p.766 DOT 19 (2) 111 (1983) I.N. p.104 REM p.925 Stenlake, J.B., Waigh, R.D., Dewar, G.H., Urwin, J. and Dhar, N.C.; US Patent 4,179,507 December 18,1979; Assigned to Burroughs Wellcome Company
ATRELEUTON Therapeutic Function: Antiallergic, Anti-asthmatic Chemical Name: 1-((R)-3-(5-(p-Fluorobenzyl)-2-thienyl)-1-methyl-2propynyl)-1-hydroxyurea Common Name: Atreleuton; ABT 761 Structural Formula:
Chemical Abstracts Registry No.: 154355-76-7
Atreleuton Trade Name Abbott-85761
Manufacturer Abbott
Country -
437
Year Introduced -
Raw Materials Thiophene Butyl lithium N-Iodosuccinimide Sodium thiosulfate Triethylamine Hydroxylamine Sodium hydroxide Triphenylphosphine Copper (I) iodide
tetrakis(Triphenylphosphine)palladium(O) Bis(acetonitrile)palladium(II) chloride 4-Fluorobenzylbromide p-Toluenesulfonyl chloride (S)-3-Butyn-2-ol Hydrogen chloride Potassium cyanate (R)-N-Hydroxy-N-(3-butyn-2-yl)urea Diethylamine
Manufacturing Process A solution of thiophene (12.6 g, 0.15 mol) in a mixture of anhydrous ether (230 ml) and anhydrous THF (70 ml) was treated dropwise at 0°C with a 2.5 M solution of n-butyl lithium in hexane (54.0 ml, 0.134 mol). The mixture was stirred at 0°C for 1.5 h and then transferred by cannula into a -78°C solution of 4-fluorobenzylbromide (23.6 g, 0.125 mol) containing tetrakis(triphenylphosphine)palladium(O) (1.25 g) in anhydrous THF (200 ml). The reaction mixture was stirred for 17 h at room temperature and then quenched with saturated aqueous NH4Cl solution (100 ml) and partitioned between ether and additional NH4Cl solution. The ether layer was dried over MgSO4, concentrated in vacuum and the residue subjected to vacuum distillation to give 19.4 g (81%) of 2-(4-fluorophenylmethyl)thiophene, boiling point 74°-83°C at 0.6-0.7 mm of Hg. A mixture of 2-(4-fluorophenylmethyl)thiophene (3.85 g, 20.0 mmol) and Niodosuccinimide (4.50 g, 20.0 mmol) in 1:1 chloroform-acetic acid (40 ml) was stirred at room temperature for 1 h and then diluted with an equal volume of water. The organic layer was washed with saturated aqueous NaHCO3 solution (2 times 50 ml), 10% aqueous sodium thiosulfate solution (2 times 50 ml) and once with brine. After drying over MgSO4, the organic layer was concentrated in vacuum to give 6.07 g (95%) of 2-iodo-5-(4fluorophenylmethyl)thiophene as a gold colored oil. To a solution of (S)-O-p-toluenesulfonyl-3-butyn-2-ol (11.2 g, 50.0 mmol), prepared by addition of p-toluenesulfonyl chloride and triethylamine to (S)-3butyn-2-ol, in methanol (100 ml), was added 55% aqueous hydroxylamine (30 ml, 0.50 mol) and the reaction mixture was stirred at room temperature for 40 h. The reaction mixture was cooled to 10°C and concentrated HCl (50 ml) was added dropwise. The reaction mixture was concentrated in vacuum and the residue was partitioned between H2O (50 ml) and ethyl acetate (200 ml). The 2-phase mixture was cooled to 10°C and taken to pH 8 with 50% aqueous NaOH solution (60 ml). After stirring for 15 min the layers were separated and the aqueous phase was extracted twice with 200 ml of ethyl acetate. The combined ethyl acetate extracts were cooled to 10°C and a solution of KOCN (8.1 g, 0.10 mmol) in H2O (30 ml) was added, followed by dropwise addition of 11 ml of concentrated HCl, and the reaction mixture was
438
Atrimustine
stirred for 30 min. The ethyl acetate layer was separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuum to give 5.9 g (92% yield) of (R)-N-hydroxy-N-(3-butyn-2-yl)urea, melting point 129°C. To a solution of 2-iodo-5-(4-fluorophenylmethyl)thiophene (5.30 g, 16.6 mmol), in anhydrous DMF (5.0 ml) was added (R)-N-hydroxy-N-(3-butyn-2yl)urea (2.12 g, 16.6 mmol), triphenylphosphine (84.0 mg, 0.32 mmol), bis(acetonitrile)palladium(II) chloride (40.0 mg, 0.16 mmol), copper(I) iodide (16.0 mg, 0.08 mmol), and diethylamine (5.6 ml). The mixture was stirred under nitrogen at room temperature for 22 h and concentrated in vacuum at 32°C. The residue was subjected to chromatography on silica eluting with 27% MeOH in CH2Cl2, crystallization from ethyl acetate-hexane and trituration in CH2Cl2 to afford (R)-N-{3-[5-(4-fluorophenylmethyl)thien-2-yl]-1-methyl-2propynyl}-N-hydroxyurea as a cream-colored solid 0.94 g (18%), melting point 135°-136°C, (dec). References Brooks D.W. et al.; US Patent No. 5,506,261; April 9, 1996; Assigned: Abbott Laboratories, Abbott Park, Ill.
ATRIMUSTINE Therapeutic Function: Antineoplastic Chemical Name: Estra-1,3,5(10)-triene-3,17-diol, (17β)-, 3-benzoate, 17((4-(4-(bis(2-chloroethyl)amino)phenyl)-1-oxobutoxy)acetate) Common Name: Atrimustine; Busramustine Structural Formula:
Chemical Abstracts Registry No.: 75219-46-4
Atrimustine
Trade Name Atrimustine
Manufacturer Onbio Inc.
Country -
439
Year Introduced -
Raw Materials 1,3,5(10)-Estratriene-3,17β-diol Monobromoacetyl bromide Dimethyl sulfoxide Manufacturing Process Preparation of 3-hydroxy-1,3,5(10)-estratriene-17β-[4-{p-[bis(2chloroethyl)amino]phenyl}butyryloxy]acetate: Preparation of 3-hydroxy-1,3,5(10)-estratriene-17β-monobromoacetate. 10 g of 1,3,5(10)-estratriene-3,17β-diol was dissolved in 400 ml of anhydrous tetrahydrofuran (THF), and then, 8.8 g of pyridine was added. A solution of 22.5 g of monobromoacetyl bromide in 74 g of carbon tetrachloride was added dropwise to the resulting solution at about -5°C to -7°C. The mixture was kept for one night. After the reaction, the resulting precipitate was separated by a filtration. The solvent was distilled off from the filtrate. The residue was dissolved in ether and recrystallized from ether to obtain 1,3,5(10)-estratriene-3,17β-bis(monobromoacetate). 2 g of the product was dissolved in 900 ml of methanol and the solution was cooled to -5°C. A solution of 0.24 g of K2CO3 in 20 ml of water was added dropwise to the resulting solution. After the reaction for 30 minutes, 1000 ml of water was added and the resulting precipitate was separated and dried. It was confirmed that the product was 3-hydroxy-1,3,5(10)-estradiene-17β-monobromoacetate by the elementary analysis and the IR spectrum. Preparation of 3-hydroxy-1,3,5(10)-estratriene-17β-[4{p-[bis(2chloroethyl)amino]phenyl}butyryloxy]acetate: 200 mg of silver [4-{p-[bis(2-chloroethyl)amino]phenyl}butyrate (silver salt of Chlorambucil) was added in 10 ml of DMSO to form a white colloidal solution. Then, 190.8 mg of 3-hydroxy-1,3,5(10)-estratriene-17βmonobromoacetate was added and the mixture was stirred at room temperature for 64 hours in the dark. The precipitate was changed to yellowish green color. A small amount of acetone was added and the precipitate was separated by a filtration through G-4 filter. The precipitate was changed from yellowish green color to blackish green color by the irradiation of light. The filtrate was colorless and transparent. DMSO was distilled off under a reduced pressure on a water bath at 80°C and 100 ml of water was added to precipitate white crystals. The crystals were kept for 1 hour to remove DMSO and the crystals were separated through G-4 filter and thoroughly washed with distilled water and dried under a reduced pressure in a desiccator. A crude yield was 330.5 mg. Purification of the product 330.5 mg of crude crystals were dissolved in a mixed solvent of 50 vol. parts of cyclohexane and 10 vol. parts of ethyl acetate. The solution was slowly passed through a column filling 40 g of silica gel and the product was gradually separated to obtain 188.2 mg (yield: 62.86%) of pure product. It was confirmed that the product was 3-hydroxy-
440
Atrinositol sodium
1,3,5(10)-estratriene-17β-[4{p-[bis(2-chloroethyl)amino]phenyl} butyryloxy]acetate by the elementary analysis and the IR spectrum. References Asano K. et al.; US Patent No. 4,332,797; June 1, 1982; Assigned to Kureha Kagaku Kogyo Kabushiki Kaisha, Tokyo, Japan
ATRINOSITOL SODIUM Therapeutic Function: Neuropeptide antagonist, Antiinflammatory Chemical Name: D-myo-Inositol 1,2,6-tris(dihydrogen phosphate) pentasodium salt Common Name: Atrinositol sodium; Minosifate sodium; α-Trinositol sodium Structural Formula:
Chemical Abstracts Registry No.: 136033-48-2 Trade Name
Manufacturer
Country
Atrinositol sodium Perstorp (Sweden) -
Year Introduced -
Raw Materials Borane-methyl sulphide complex 4-Toluenesulfonyl chloride cis-3,5-Cyclohexadiene-1,2-diol 1'-Dynamax 83,123-6 column Silver oxide Sodium hydride Palladium on charcoal Tetrabenzylpyrophosphate
Mandelic acid, (S)-,(+)Lithium aluminum hydride m-Chloroperbenzoic acid Benzyl bromide Cyclohexene N,N,N',N'-Tetramethylenediamine Diisopropylamine Butyl lithium
Atrinositol sodium
441
Manufacturing Process Pseudomonas putida oxidation of benzene affords cis-3,5-cyclohexadiene-1,2diol which is used as a novel precursor for the synthesis of D- and L-myoinositol trisphosphates, which was prepared in 11 steps: 1). (R)-(+)-sec-Phenethyl alcohol: Borane-methyl sulfide complex (68 ml, 0.71 mol) was added dropwise to a solution of (S)-(+)-mandelic acid (98.5 g, 0.65 mol) in THF (900 ml) at room temperature (RT) under a flow of argon over 3 h. The reaction was stirred for 6 h. Then methanol was added dropwise and stirring continued for a further 13 h. The volatiles were then removed in vacuum, the residue stirred in methanol, and the process repeated 3 times. Column chromatography (MeOHethyl acetate-petrol, gradient elution) of the residue afforded the diol (57.3 g, 64%). p-Toluenesulphonyl chloride (80 g, 98% 0.41 mol) was then added portionwise to a solution of the diol in pyridine (700 ml) at 0°C over 8 h. The reaction was stirred at RT for 13 h, then the volatiles removed in vacuum. The residue was washed with water, dried (MgSO4), and the residual pyridine removed in vacuum to afford the tosylate as an orange oil. A solution of the tosylate in ether/THF (500 ml) was added dropwise to a stirred suspension of lithium aluminium hydride (15.6 g, 0.41 mol) in ether (500 ml) at RT under argon. The reaction was stirred for 16 h, then water (15.6 ml), aqueous sodium hydroxide solution (15.6 ml), and water (46.8 ml) were successively added dropwise. After 4 h, sodium sulfate was added and stirring continued. The mixture was filtered through a pad of celite, washed with dichloromethane, and the solvents evaporated in vacuum. Column chromatography (0-100% ether-petrol, gradient elution) followed by distillation (b.p. 96°C/20mmHg) afforded the title alcohol (24.1 g, 48%) as a colourless liquid, [α]D27+41.48°. 2). (3aα,6α,7α,7aα)-6,7-Epoxy-3a,6,7,7a-tetrahydrobenzo[d]-1,3-dioxol-2-one and (3aα,6β,7β,7aα)-6,7-Epoxy-3a,6,7,7a-tetrahydrobenro[d]-1,3-dioxol-2one: Freshly prepared sodium methoxide (0.1 ml of a 1 M solution in methanol, 10 mmol) was added dropwise to a solution of cis-3,5-cyclohexadiene-1,2-diol (112 mg, 1 mmol) in dimethyl carbonate (1.7 ml) and methanol (0.2 ml) at RT under argon, and stirred for 20 min. A small aliquot was removed, solvent evaporated in vacuum (bath T 22°C) and the resulting solid was washed with a small volume of chilled (-20°C) ether and chilled (-20°C) petrol (b.p. 30°40°C) to afford the 3a,7a-dihydrobenzo[1,3]dioxol-2-one (cyclic carbonate) as a beige-coloured solid, mp 90°C (dec.). The remaining solution was diluted with DCM (2 ml), and m-chloroperbenzoic acid (mCPBA) (0.30 g, 2.0 mmol) was added portionwise. After stirring at RT for 40 h, the mixture was extracted with DCM and washed successively with aqueous sodium sulfite solution, aqueous sodium bicarbonate solution and water, dried (MgSO4) and evaporated in vacuum. Column chromatography (45-70% ether-petrol, gradient elution) of the residue afforded the title epoxides (3aα,6α,7α,7aα)-6,7-epoxy-3a,6,7,7a-tetrahydrobenzo[d]-1,3-dioxol2-one (73 mg, 47%) mp 87°-89°C and (3aα,6β,7β,7aα)-6,7-epoxy-3a,6,7,7a-
442
Atrinositol sodium
tetrahydrobenro[d]-1,3-dioxol-2-one, (16 mg 10%) mp 107.5°-108.5°C. 3). [3aR-[3aα,4α,5β(R),7aα]-3a,4,5,7a-Tetrahydro-4-hydroxy-5-(1phenylethoxy)benzo[d]-1,3-dioxol-2-one and [3aS-[3aα,4α,5β(R),7aα]3a,4,5,7a-tetrahydro-4-hydroxy-5-(1-phenylethoxy)benzo[d]-1,3-dioxol-2one: Tetrafluoroboric acid-diethyl ether complex (catalytic amount) was added to a stirred solution of epoxide (+/-)-(3aα,6α,7α,7aα)-6,7-epoxy-3a,6,7,7atetrahydrobenzo[d]-1,3-dioxol-2-one (32 mg, 0.2 mmol) and (R)-(+)-secphenethyl alcohol (0.048 ml, 0.4 mmol) in DCM at RT under argon. After 30 min, water was added and the mixture extracted with DCM (3 times). The combined organic phase was dried (MgSO4) and evaporated in vacuum. Column chromatography (30-75% ether-petrol, gradient elution) of the residue afforded the alcohols [3aR-[3aα,4α,5β(R),7aα]-3a,4,5,7a-tetrahydro4-hydroxy-5-(1-phenylethoxy)benzo[d]-1,3-dioxol-2-one and [3aS[3aα,4α,5β(R),7aα]-3a,4,5,7a-tetrahydro-4-hydroxy-5-(1phenylethoxy)benzo[d]-1,3-dioxol-2-one. (37 mg, 67%) as a thick oil and a 1:1 mixture of diastereomers. Subsequent HIPLC (1'-Dynamax 83,123-6 column; 6% isopropanol-petrol, 15 ml/min) effected separation of the diastereomers. Less polar [3aR-[3aα,4α,5β(R),7aα]-3a,4,5,7a-tetrahydro-4hydroxy-5-(1-phenylethoxy)benzo[d]-1,3-dioxol-2-one had retention time 16.3 min; [α]D20 +90.1° (c 1.1, CHCl3). 4. [3aS-[3aα,6β(R),7α,7aα]-7-Benzyloxy-3a,6,7,7a-tetrahydro-6-(1phenylethoxy)benzo[d]-1,3-dioxol-2-one): Freshly prepared silver oxide (88 mg, 0.38 mmol) was added to a stirred solution of the alcohol [3aR-[3aα,4α,5β(R),7aα]-3a,4,5,7a-tetrahydro-4hydroxy-5-(1-phenylethoxy)benzo[d]-1,3-dioxol-2-one (53 mg, 0.19 mmol) and benzyl bromide (0.080 ml, 0.67 mmol) in DMF (2 ml) at RT under argon and the mixture stirred vigorously in the dark for 64 h. The mixture was diluted with ether, filtered through a pad of silica which was then washed copiously with ether and DCM, and the filtrate evaporated in vacuum. The residue was dissolved in ether, washed with water and brine, dried (MgSO4) and evaporated in vacuum. Column chromatography (30-100% ether-petrol, gradient elution) of the residue afforded the title benzyl erher. (70 mg, 100%) as needles, m.p. 97°-99°C; [α]D20 +102.9° (c 1.0, CHCl3). 5). [1S-[1α,2α,5α(R),6β]-6-Benzyloxy-5-(1-phenylethoxy)-3-cyclohexene-1,2diol: The carbonate (0.459 g, 1.25 mmol) was stirred in 1:5:1 triethylamine/methanol/water (12 ml) at RT. After 72 h, the volatiles were removed in vacuum and the residue freeze-dried. The crude product was purified by column chromatography (50-100% ethyl acetate-petrol, gradient elution) to afford the title diol (0.421 g, 99%) as a white solid, mp 46°-47°C; [α]D20 +82.4° (c 2.5, CHCl3). 6. [1R-[1α,2α,3β,4α(R),5α,6α)-3-Benzyloxy-5,6-epoxy-4-(1-phenylethoxy) cyclohexane-1,2-diol: mCPBA (2.68 g, 80% 12.4 mmol) was added to a stirred solution of olefin
Atrinositol sodium
443
(2.111 g, 6.2 mmol) in DCM (30 ml) at RT under argon. After stirring for 48 h, cyclohexene was added dropwise (excess) and the mixture stirred for 90 min. The solvents were removed in vacuum to afford the title epoxydiol (1.93 g, 92%) as a foam and a 17:1 mixture of epoxide stereoisomers. Column chromatography (10-50% ethyl acetate-petrol, gradient elution) yielded the major epoxide (1.928 g, 87%) as a foam, [α]D20 +98.9° (c 0.92, CHCl3). 7). [3aR-[3aα,4α,5β(R),6β,7β,7aα)-4-Benzyloxy-6,7-epoxy-5-(1-phenylethoxy) hexahydro-2,2-dimethylbenzo[d]-1,3-dioxole: Camphorsulphonic acid monohydrate (catalytic amount) was added to a stirred solution of [1R-[1α,2α,3β,4α(R),5α,6α)-3-benzyloxy-5,6-epoxy-4-(1phenylethoxy)cyclohexane-1,2-diol (0.321 g, 0.9 mmol) in 2,2dimethoxypropane (10 ml) at RT under argon. After 16 h, the mixture was poured into DCM and washed with aqueous sodium bicarbonate solution and water. The aqueous layers were reextracted with DCM and the combined organic extracts dried (MgSO4) and evaporated in vacuum column chromatography (50% ether-petrol) of the residue afforded the title epoxy acetonide (0.317 g, 89%) as needles, m.p. 114°-115°C (recrystallized from ether-petrol); [α]D20+134.1° (c 1.00, CHCl3). 8). [2(R)]-L-3-O-Benzyl-4,5-O-isopropylidene-6-O-[2-(5,5-dimethyl-1,3dioxan-2-yl)ethyl]-2-O-(1-phenylethyl)-muco-inositol and [S(R)]-D-4-OBenzyl-2,3-O-isopropylidene-6-O-[2-(5,5-dimethyl-1,3-dioxan-2-yl)ethyl]-5-O(1-phenylethyl)-myo-inositol: The 1,3-dioxane-2-ethanol (2 ml) was added dropwise to sodium hydride (396 mg of 60% dispersion, 10 mmol) at RT under argon. When the effervescence had ceased, N,N,N',N'-tetramethylenediamine (TMEDA) (1 ml) was added, the mixture stirred for a further 4 h and then a solution of the epoxide (396 mg, 1.0 mmol) in TMEDA (1.0 ml) was added dropwise. The mixture was stirred at 100-110°C for 3 days and then allowed to cool to RT. Water was added and, after 5 min the mixture extracted with ether. The extract was washed with water and the aqueous phase reextracted with ether. The combined organic extracts were dried (MgSO4) and evaporated in vacuum column chromatography (4% MeOH-10% ether-86% petrol) of the residue afforded [2(R)]-L-3-O-Benzyl-4,5-O-isopropylidene-6-O-[2-(5,5-dimethyl-1,3-dioxan-2yl)ethyl]-2-O-(1-phenylethyl)-muco-inositol (176 mg, 31%), [α]D20 +63.4° (c 1.4, CHCl3); and [S(R)]-D-4-O-Benzyl-2,3-O-isopropylidene-6-O-[2-(5,5dimethyl-1,3-dioxan-2-yl)ethyl]-5-O-(phenylethyl)-myo-inositol (273 mg, 48%), mp 108°-110°C, [α]D20+29.3° (c 0.76, CHCl3) as a thick oil and a white solid respectively, and starting epoxide (65 mg, 16%). 9). D-6-O-[2-(5,5-Dimethyl-1,3-dioxan-2-yl)ethyl]-2,3-O-isopropylidene-myoinositol: 10% Palladium on activated charcoal (Fluka) (catalytic amount) was added to a solution of [S(R)]-D-4-O-benzyl-2,3-O-isopropylidene-6-O-[2-(5,5-dimethyl1,3-dioxan-2-yl)ethyl]-5-O-(phenylethyl)-myo-inositol (105 mg, 0.18 mmol) in ethanol (10 ml) at RT under argon. The flask was flushed through with hydrogen and the mixture stirred vigorously under a hydrogen atmosphere. After 16 h, the flask was refluxed with argon and the mixture filtered through a pad of celite, which was washed copiously with ether and then DCM.
444
Atropine
Evaporation of the solvents in vacuum afforded. D-6-O-[2-(5,5-Dimethyl-1,3dioxan-2-yl)ethyl]-2,3-O-isopropylidene-myo-inositol (65 mg, 100%) as a white solid, mp 96.5°-97.5°C; [α]D20 +24.7° (c 0.45, CHCl3). 10). D-6-O-[2-(5,5-Dimethyl-1,3-dioxan-2-yl)ethyl]-2,3-O-isopropylidenemyo-inositol 1,4,5-tris(dibenqylphosphate): n-Butyl lithium (0.172 ml of a 2.5 M solution in hexanes, 0.43 mmol) was added dropwise to a solution of the above compound (45 mg, 0.12 mmol) in THF (4 ml) at -30°C under argon. Diisopropylamine (0.073 ml, 0.52 mmol) was then added and the mixture stirred at -30°-(-25)°C for 20 min. Tetrabenzylpyrophosphate (242 mg, 0.45 mmol) was added in one portion and the reaction allowed to warm gradually to +2°C over 4 h. The precipitated lithium dibenzylphosphate was filtered off, the cake washed with THF and the solvent evaporated in vacuum. Column chromatography (30-100% ethyl acetate-petrol, gradient elution) of the residue afforded the triphosphate (95 mg, 67% ) as a thick oil, [α]D20 -4.5° (c 1.13, CHCl3). 11). D-(-)-myo-lnositol 1,4,5-trisphosphate: 10% Palladium on activated charcoal (Fluka) (catalytic amount) was added to a solution of the protected trisphosphate (243 mg, 0.21 mmol) in ethanol (10 ml) at RT under argon. The flask was flushed through with hydrogen and the mixture stirred vigorously under a hydrogen atmosphere. After 48 h, the flask was refluxed with argon, the mixture filtered and washed with ethanol. The volatiles were removed in vucuo and the residue freeze-dried to afford fully debenzylated material. This was stirred in 80% aqueous trifluoroacetic acid (cu. 6 ml) at RT for 4 h. After removing the volatiles in vacuum, the residue was again freeze-dried. Purification of the crude product by HPLC (Spherisorb S5SAX column, 202 mm x 250 mm; 0.2 M ammonium formate buffer at pH 4, 12 ml/min) afforded atrinositol (64 mg, 88%), retention time 42 min, [α]D20 22°-24° (c 0.15, H2O, pH 6.9). UR, 1H-NMR, 31P-NMR spectra confirmed the structure of described compounds. References Ley S.V. et al.; Tetrahedron; vol. 46, No 13/14, pp. 4995-5026; 1990
ATROPINE Therapeutic Function: Anticholinergic Chemical Name: 1-α-H,5-α-H-Tropan-3-α-ol (+/-)-tropate (ester) Common Name: Atropine; DL-Hyoscyamine Chemical Abstracts Registry No.: 51-55-8
Atropine methonitrate
445
Structural Formula:
Trade Name Atromed Atropen Atropinol
Manufacturer Promed Exports Meridian Wenzer
Country India USA Denmark
Year Introduced -
Raw Materials Plants from botanic family Slanaceae: Atropa belladonna, Atropa acminata, Atropa boetica, Hyocyamus niger Chloroform Manufacturing Process Atropin was obtained from belladonna roots and by racemisation of Lhyoscyamine with dilute alkali or by heating in chloroform solution. The alkaloid was crystallised from alcohol on addition of water, or from chloroform on addition of light petroleum, or from acetone in long prisms, m.p. 118°C, sublimed unchanged when heated rapidly. It is soluble in alcohol or chloroform, less soluble in ether or hot water, sparingly so in cold water (in 450 L at 25°C) and almost insoluble in light petroleum. Atropine is optically inactive. References Ann., 1833, 5, 43 6, 44, 7 269. Arch. Pharm., 1850 74, 245, Pesci, Gazzetta, 1882 12, 59, Will and Bredig, Ber., 1888 21, 1717, 2797, Schmidt, ibid. 1829 Gadamer, Arch. Pharm., 1901, 239, 294 Chemnitius, J. pr. Chem., 1927 [ii], 116, 276 Dilius, Chem. Zeit., 1930, 54, 182
ATROPINE METHONITRATE Therapeutic Function: Anticholinergic, Mydriatic, Spasmolytic Chemical Name: 8-Azoniabicyclo[3.2.1]octane, 3-(3-hydroxy-1-oxo-2phenylpropoxy)-8,8-dimethyl-, (3-endo)-, nitrate (salt)
446
Atropine methonitrate
Common Name: Methylatropine nitrate; Atropine methonitrate Structural Formula:
Chemical Abstracts Registry No.: 52-88-0 Trade Name Methylatropine nitrate
Manufacturer Paganfarma
Country -
Methylatropine nitrate
Yick-Vic Chemicals and Pharmaceuticals (HK) Ltd.
-
Atropine methyl nitrate
Sigma
-
-
Year Introduced -
Raw Materials Atropine Atropine sulfate
Methyl nitrate Barium nitrate
Manufacturing Process There are 2 methods of synthesis of methyl atropine nitrate: 1) To a solution of 28.9 g atropine of in 100 g of methanol was added at 110°C for 2 hours 7.7 g methyl nitrate. Methanol was evaporated and methyl atropine nitrate was crystallysed, M.P. 163°C. 2) To a solution of 70.4 g methyl atropine sulfate (prepared from methyl atropine chloride and silver nitrate) in water was added aqueous solution of 26.1 g barium nitrate. Barium sulfate was deleted by filtration. Filtrate was concentrated and the methyl atropine nitrate was obtained. References DE Patent No. 138,443; Nov. 28, 1901; Assigned to Farbenfabriken vorm. Friedr. Bayer and Company in Elberfeld DE Patent No. 137,622; Nov.28, 1902; Assigned to Farbenfabriken vorm. Friedr. Bayer and Company in Elberfeld
Auranofin
447
AURANOFIN Therapeutic Function: Antiarthritic Chemical Name: S-Triethylphosphine gold 2,3,4,6-tetra-O-acetyl-1-thio-β-Dglucopyranoside Common Name: Structural Formula:
Chemical Abstracts Registry No.: 34031-32-8 Trade Name Ridaura Ridaura
Manufacturer SK and F SK and F
Country W. Germany Switz.
Year Introduced 1982 1983
Raw Materials Thiodiglycol Triethylphosphine S-(2,3,4,6-Tetra-O-acetylglucopyranosyl)thiopseudourea hydrobromide Gold acid chloride trihydrate Potassium carbonate Manufacturing Process (A) Triethylphosphine gold chloride: A solution of 10.0 g (0.08 mol) of thiodiglycol in 25 ml of ethanol is mixed with a solution of 15.76 g (0.04 mol) of gold acid chloride trihydrate in 75 ml of distilled water. When the bright orange-yellow solution is almost colorless, it is cooled to -5°C and an equally cold solution of 5.0 g (0.0425 mol) of triethylphosphine in 25 ml of ethanol is added dropwise to the stirred solution. After the addition is complete, the cooled mixture is stirred for ½ hour. Solid that separates is removed and the filtrate is concentrated to about 30 ml to yield a second crop. The combined solid is washed with aqueous-ethanol (2:1) and recrystallized from ethanol by adding water to the cloud point. The product is obtained as white needles, MP 85° to 86°C. (B) Auranofin: A cold solution of 1.66 g (0.012 mol) of potassium carbonate in
448
Aurothioglycanide
20 ml of distilled water is added to a solution of 5.3 g (0.011 mol) of S(2,3,4,6-tetra-O-acetylglucopyranosyl)-thiopseudourea hydrobromide [Methods in Carbohydrate Chemistry, vol 2, page 435 (1963)] in 30 ml of water at -10°C. A cold solution of 3.86 g (0.011 mol) of triethylphosphine gold chloride in 30 ml of ethanol containing a few drops of methylene chloride is added to the above mixture before hydrolysis of the thiouronium salt is complete. After the addition is complete, the mixture is stirred in the cold for ½ hour. The solid that separates is removed, washed first with aqueous ethanol then water and dried in vacuum. There is obtained colorless crystals, MP 110° to 111°C, of S-triethylphosphine gold 2,3,4,6-tetra-O-acetyl-1-thio-βD-glucopyranoside. References Merck Index 882 DFU 1 (10) 451 (1976) PDR p. 1721 DOT 18 (9) 463 (1982) I.N. p. 106 REM p. 1122 McGusty, E.R. and Sutton, B.M.; US Patent 3,708,579; January 2, 1973; Assigned to Smith Kline and French Laboratories Nemeth, P.E. and Sutton, B.M.; US Patent 3,635,945; January 18, 1972; Assigned to Smith Kline and French Laboratories
AUROTHIOGLYCANIDE Therapeutic Function: Antiarthritic Chemical Name: [[(Phenylcarbamoyl)methyl]thio]gold Common Name: Aurothioglycollic acid anilide Structural Formula:
Chemical Abstracts Registry No.: 16925-51-2 Trade Name Lauron
Manufacturer Endo
Raw Materials Potassium bromoaurate Sulfur dioxide Thioglycolic acid anilide
Country US
Year Introduced 1945
Avilamycin
449
Manufacturing Process The product is made preferably by reacting thioglycolic acid anilide with an aurous bromide (AuBr). Prior art methods for making the starting material, HSCH2CONHC6H5 are disclosed in an article by Beckurts et al. in Journ. Praktische Chemie (2) 66 p. 174, and in the literature referred to in the mentioned article. Ten grams of the potassium salt of bromoauric acid are dissolved in 100 cc of 96% ethyl alcohol. This salt is also designated as potassium auribromide. Sulfur dioxide (SO2) is then led through this solution, through a fine capillary tube, for several minutes. This reaction produces aurous bromide (AuBr). The solution of the aurous bromide is then allowed to stand for 2 to 3 hours until it is colorless. A precipitate of KBr is thus formed. This precipitate is separated from the solution of the aurous bromide which is added to a solution of three grams of the thioglycolic acid anilide in 50 cc of ethyl alcohol. This is done at about 20°C. Then 300 cc of water are added to this mixture, at 20°C. The water is then removed by decantation or any suitable method, and the mixture is repeatedly thus treated with water, in order to remove all impurities which can thus be removed. The product is then centrifuged twice with 96% ethyl alcohol. It is then centrifuged three times with 100% or absolute ethyl alcohol, and then centrifuged three times with water-free ligroin (petroleum ether), i.e., the 40-60°C fraction which is distilled from petroleum. After each centrifuging, the product is separated from the liquid which has been used during the centrifuging. The product is then dried in a high vacuum with the use of phosphorus pentoxide (P2O5). References Merck Index 889 I.N. p. 106 Lewenstein, M.J.; US Patent 2,451,841; October 19, 1948
AVILAMYCIN Therapeutic Function: Antibiotic Chemical Name: Avilamycin A, mixture of small quantities of avilamycin B, C, D1, D2 and E Common Name: Avilamycin; Maxus Chemical Abstracts Registry No.: 11051-71-1
450
Avilamycin
Structural Formula:
Trade Name Maxus Avilamicina
Manufacturer Eli Lilly Eli Lilly
Country -
Year Introduced -
Raw Materials Meat meal Peptone Glucose Meat extract
Salt extract Calcium carbonate Streptomyces viridochromogenes NRRL 2860 Sodium chloride
Manufacturing Process Avilamycin is produced from Streptomyces viridochromogenes NRRL 2860: A nutrient solution is prepared which contains 20.0 g of meat meal, 20.0 g of salt extract, 10.0 g of calcium carbonate and 1 L of tap water and adjusted to pH=7. This solution, or a multiple thereof, is charged into conical flasks of 500 ml capacity (100 ml of nutrient solution each) or into fermenters of 500 L capacity (300 L of nutrient solution each) and sterilized for 20-30 min under a pressure of 1 atm. The contents of the flasks are then inoculated with up to 10% of a partially sporulating vegetative culture of Streptomyces viridochromogenes NRRL 2860 and incubated at 27°C with thorough shaking or stirring, and in the fermenters with aerating with about 1 volume of sterile air per volume of nutrient solution per minute. The cultures are allowed to grow for 24-48 h, mixed with about 1.5% of a filtration assistant and then filtered depending on the volume, through a suction filter or a filter press or a rotary filter to free the antibiotically active aqueous solution from the mycelium and other solid constituents. The medium described above is replaced the nutrient media: 10.0 g of crude glucose, 5.0 g of peptone, 3.0 g of meat extract (Oxo Lab- Lemco), 5.0 g of sodium chloride, 10.0 g of calcium carbonate and 1 L of tap water; pH - prior
Avizafone hydrochloride
451
to sterilization: 7.5, analogous sterilization, inoculation with Streptomnyces viridochromogenes NRRL 2860, incubation at 27°C and filtration likewise yield aqueous antibiotically active solutions. 90 L of culture filtrate are extracted with 20 L of ethyl acetate, and the extract is concentrated to 400 ml. When the concentrate is kept for 20 h at 2°C, avilamycin precipitates in the form of a dense floccular substance which is filtered off. After having been dried in an exsiccator, the practically colorless crystal cake consisting of strongly felted small needles weighs 3.07 g. The mother liquors are concentrated to about 200 ml and mixed with twice the amount of ether. When the concentrate is kept for 4 days at 0°C, a further 3.28 g of avilamycin crystallize out. 3.0 g of the crystallizate are dissolved in 50 ml of acetone, and a small amount of insoluble sludge is filtered off. The clear filtrate is mixed with ether and concentrated. On cooling, 2.0 g of colorless fine needles crystallize out. Concentration of the mother liquors to about one quarter their volume produces a further 0.48 g of crystals. For analysis a test portion of these crystals is recrystallized 4 times from acetone+ether and dried for 20 h in a high vacuum at 70°C. The analytically pure antibiotic avilamycin have a melting point 188°-189.5°C. Optical rotation [α]D20=+0.8° (c=1.165 in absolute ethanol). References Gaeumann E., Prelog V.; US Patent No. 3,131,126; April 28, 1964; Assigned: Ciba Corporation, a corporation of Delaware
AVIZAFONE HYDROCHLORIDE Therapeutic Function: Anxiolytic, Anticonvulsant Chemical Name: 2'-Benzoyl-4'-chloro-2-((S)-2,6-diaminohexanamido)-Nmethylacetanilide dihydrochloride Common Name: Avizafone hydrochloride Structural Formula:
Chemical Abstracts Registry No.: 65617-86-9 (Base); 60067-16-5
452
Avizafone hydrochloride
Trade Name Avizafone hydrochloride Avizafone hydrochloride
Manufacturer Onbio Inc.
Country -
Year Introduced -
Roche Product Ltd.
-
-
Raw Materials N-Benzyloxycarbonylglycine Isobutylchloroformate N-Methylmorpholine 5-Chloro-2-methylaminobenzophenone Hydrogen bromide N(α),N(ε)-Bisbenzyloxycarbonyl-L-lysyl N-hydroxysuccinimide ester Amberlite Manufacturing Process (a) 20.9 g of N-benzyloxycarbonylglycine were suspended in 1500 ml of dry 1,2-dimethoxyethane and the suspension was cooled to -20°C. 10.1 g of Nmethylmorpholine and 13.7 g of isobutylchloroformate were added, the resulting solution was stirred at -20°C for 1 hour and then filtered. The filtrate was added portion-wise over a period of several hours to a refluxing solution of 24.55 g of 5-chloro-2-methylaminobenzophenone in 200 ml of 1,2dimethoxyethane, the resulting mixture was boiled overnight and then evaporated to dryness in vacuum. The yellow residue was dissolved in ethyl acetate, washed with two portions of water and one portion of saturated sodium chloride solution, dried over anhydrous magnesium sulfate and then evaporated. Column chromatography of the residue on Florisil (Trade Mark) using mixtures of benzene and chloroform yielded 35 g (80%) of pure 2-(Nbenzyloxycarbonylamino)-N-(2-benzoyl-4-chlorophenyl)-N-methylacetamide as a pale yellow gum. 43.7 g of 2-(N-benzyloxycarbonylamino)-N-(2-benzoyl-4-chlorophenyl)-Nmethylacetamide were dissolved in 200 ml of a 30% solution of hydrogen bromide in glacial acetic acid and the resulting solution was stirred overnight at room temperature. The mixture was added slowly to a large excess (2000 ml) of dry diethyl ether with vigorous stirring. The product, which separated was allowed to settle and the supernatant liquors were decanted off. The residue was triturated with 150 ml of acetone and the product filtered off, washed consecutively with the minimum amount of acetone and dry diethyl ether and dried in vacuum to give 29.5 g (77%) of 2-amino-N-(2-benzoyl-4chlorophenyl)-N'-methylacetamide hydrobromide as a white hygroscopic powder of melting point 194°-195°C (decomposition). (b) 84 g of N-benzyloxycarbonylglycine were suspended in 500 ml of alcoholfree chloroform and the suspension was cooled to -200°C. The stirred suspension was treated portion-wise over a period of 15 minutes with 90 g of phosphorus pentachloride and the stirring was continued until a clear solution was obtained. At this point, the cold mixture was added dropwise over a period of 30 minutes to a cold (-5°C) vigorously stirred emulsion consisting of 82 g of 5-chloro-2-methylaminobenzophenone, 347 g of potassium bicarbonate, 700 ml of chloroform and 1400 ml of water. The resulting
Avizafone hydrochloride
453
mixture was stirred for a further 1 hour at -5°C and then overnight at room temperature. The stirring was then discontinued and the liquid phases allowed to separate. The chloroform layer was washed three times with 500 ml of water each time and evaporated in VW to give 150.7 g of a viscous yellow gum which was shown by physical methods to be almost pure (above 95%) 2(N-benzyloxycarbonylamino)-N-(2-benzoyl-4-chlorophenyl)-Nmethylacetamide. The product above obtained was dissolved in 650 ml of a 30% solution of hydrogen bromide in glacial acetic acid and treated in an identical manner to that described in part (a) to give 2-amino-N-(2-benzoyl4chlorophenyl)-N-methylacetamide hydrobromide in a 77% overall yield from 5-chloro-2-methylaminobenzophenone. (c) 1 mole of Nα,Nε-bisbenzyloxycarbonyl-L-lysyl N-hydroxysuccinimide ester was dissolved in 50 ml of dry dimethylformamide. The resulting solution was cooled to -20°C and there were added 1 mole of 2-amino-N-(2-benzoyl-4chlorophenyl)-N-methylacetamide hydrobromide followed by the dropwise addition of 1 mole of N-ethylmorpholine. The resulting mixture was vigorously stirred for 1 hour at -20°C and then overnight at room temperature. The solvent was evaporated in vacuum and the residue dissolved in a mixture of dichloromethane and water. The organic and aqueous layers were separated and the aqueous phase extracted with further portions of dichloromethane. The combined organic phases (250 ml) were washed three times with 50 ml of water each time, dried over anhydrous magnesium sulfate and evaporated in vacuum to give a yellow oily residue, which was shown by physical methods to consist of Nα,Nε-bisbenzyloxycarbonyl-L-lysyl-N-(2-benzoyl-4-chlorophenyl)N-methylglycinamide as an almost colorless light-sensitive gum; [α]D20= -9.3° (c=1 in ethanol). Nα,Nε-Bisbenzyloxycarbonyl-L-lysyl-N-(2-benzoyl-4-chlorophenyl)-Nmethylglycinamide was converted using a 30% solution of hydrogen bromide in glacial acetic acid into L-lysyl-N-(2-benzoyl-4-chlorophenyl)-Nmethylglycinamide dihydrobromide which was obtained as a hygroscopic powder of melting point 145°C (decomposition); [α]D20= + 15.6° (c=1 in water). Treatment of the foregoing dihydrobromide in aqueous solution by passage over an excess of an anion-exchange resin such as 'Amberlite' IRA-401 in the chloride form followed by lyophilisation of the eluate gave, in quantitative yield, L-lysyl-N-(2-benzoyl-4-chlorophenyl)-N-methylglycinamide dihydrochloride (avizafone) as a hygroscopic white light-sensitive powder of melting point 125°-145°C (slow decomposition); [α]D20= +19.3° (c= 1 in water). References Hassall G.H. et Limited; a Hassall G.H. et Limited; a
al.; GB Patent No. 1,517,165; May 21, 1975; Roche Product British Company al.; GB Patent No. 1,517,166; August 11, 1975; Roche Product British Company
454
Avobenzone
AVOBENZONE Therapeutic Function: Sunscreen agent Chemical Name: 1,3-Propanedione, 1-(4-(1,1-dimethylethyl)phenyl)-3-(4methoxyphenyl)Common Name: Avobenzone; Episol Structural Formula:
Chemical Abstracts Registry No.: 70356-09-1 Trade Name Avobenzone Avobenzone Clarins Episol
Manufacturer AroKor Holdings Inc. Vivimed Labs Ltd Clarins Schering-Plough
Country -
Year Introduced -
-
-
Raw Materials p-t-Butylbenzoic acid Sodium carbonate Acetylanisole Methanol
Sulfuric acid Sodium amide Hydrochloric acid
Manufacturing Process 356.0 g (2 mol) of p-t-butylbenzoic acid, 243.0 g (7.6 mol) of methyl alcohol and 35.0 g of sulfuric acid (96%) are added to a four-necked round flask which is provided with a stirrer and a condenser. The mixture is held for 8 h at reflux temperature with slight stirring. The condenser is then replaced by a distillation column and the excess methyl alcohol is distilled off, towards the end under a slight vacuum but without the temperature exceeding 100°C. The mixture is cooled and poured on to ice. The phases are left to separate, the organic phase is washed with ice-water, with a saturated sodium carbonate solution in the presence of ice and finally with ice until neutral. The organic phase is dried over sodium sulfate and there is thus obtained a precipitate. By distillation on a Widmer column (120 mm) there are obtained 345.0 g (90% yield) of the p-t-butylbenzoic acid methyl ester, boiling point 76°C/0.02 mmHg. 2 methods of producing of 4-(1,1-dimethylethyl)-4'-methoxydibenzoylmethane
Avorelin
455
from p-t-butylbenzoic acid methyl ester: 1). To a round flask which has been well dried and flushed with nitrogen are added 85.0 g (1.1 mol) of sodium amide (50% suspension in toluene) and 180.0 g of isopropyl ether and there are now added dropwise thereto at a temperature of 50°-60°C 150.2 g (1 mol) of acetylanisole in 180.0 g of isopropyl ether. Reaction sets in immediately and a white paste-like mass forms. After completion of the addition, the mixture is stirred for a further 0.5 h and then 192.3 g of p-t-butylbenzoic acid methyl ester are added rapidly at 25°-30°C. The mixture is stirred for 0.5 h at room temperature, then for 3 h at 60°-70°C and left to stand for 12 h. 200.0 g of ice are then added and the mixture is acidified with 128.0 g (1.1 mol) of technical hydrochloric acid and 200 ml of ice-water. The mixture is stirred until the sodium salt of the product has dissolved. The phases are separated and the organic phase is washed with ice-water until neutral. The organic phase is concentrated on a rotary evaporator and there are thus recovered 290.0 g of isopropyl ether. The yield of 4-(1,1-dimethylethyl)-4'-methoxydibenzoylmethane, melting point 83.5°C is 199.8 g (64.5%) (recrystallisation from methanol). 2). 36.0 g (1.2 mol) of 80% sodium amide and 300.0 g of dry toluene are added to a round flask which was flushed with nitrogen. The mixture is heated to 50°C and 150.2 g (1 mol) of acetylanisole in 309.0 g of toluene are added within 1.5 h. After completion of the addition, the mixture is held at 50°C for 15 min and there are then added thereto at this temperature within 1 h 50 min 192.3 g (1 mol) of p-t-butylbenzoic acid methyl ester. The mixture is stirred for a further 1 h at 50°C and then heated at 100°C for 1 h, after which time the product has separated out in the form of a solid precipitate. The mixture is left to stand for 12 h and there are then added thereto 300 ml of ice-water followed by a mixture of 100 ml of pure hydrochloric acid and 250 ml of ice-water. The phases are separated and the organic phase is washed twice with water. The organic phase is dried over sodium sulfate and treated simultaneously with 20.0 g of active carbon. After filtration, the filtrate is concentrated until crystallisation begins. 50 ml of hexane are added, the mixture is cooled and then filtered over a Buchner funnel. There is obtained a total yield of 220.91 g (71.2%) of the desired 4-(1,1-dimethylethyl)-4'methoxydibenzoylmethane, of melting point 83.5°C (recrystallisation from 600 ml of methanol). References De Polo K.-F.; US Patent No. 4,387,089; June 7, 1983; Assigned: Givaudan Corporation, Clifton, N.J.
AVORELIN Therapeutic Function: LHRH agonist Chemical Name: 10-deglycinamideluteinizing hormone-releasing factor (pig), 6-(2-methyl-D-tryptophan)-9-(N-ethyl-L-prolinamide)Common Name: Avorelin
456
Avorelin
Structural Formula:
Chemical Abstracts Registry No.: 140703-49-7 Trade Name
Manufacturer
Country
Year Introduced
Avolerin
Mediolanum
-
-
Raw Materials Benzhydrylamine resin Diisopropylcarbodiimide Aminoacids: 5-oxoproline, histidine, typthophan, serine, tyrosine, leucyne, arginine,N-ethyl proline amide Trifluoroacetic acid Hydrogen fluoride Sephadex G-50 F column Manufacturing Process It is well known that the incorporation or substitution of a D-tryptophan residue into a biologically active peptide chain enhances the activity of that chain. Furthermore, such incorporation or substitution will prolong the biological activity. The prolonged and enhanced effectiveness of such peptides probably relates the increased resistance to degradation by peptidases. [D-2-Methyl-Trp6] LHRH and [Des-Gly10-D-2-methyl-Trp6-Pro-ethylamide9]
Avridine
457
LHRH. 2-Methyl-tryptophan is known (cf. H.N. Rydon, J. Chem. Soc. 1948, 705) and the homologous alkylated derivatives are conveniently prepared from the corresponding 2-alkyl indoles by well known methods (cf. J.P. Li et al., Synthesis (1), 73, 1988). The resolution of the racemic tryptophan derivatives to give the D-enantiomers can also be achieved by a variety of methods (cf. Amino Acids, Peptides and Proteins, Vol. 16, pages 18-20, The Royal Society of Chemistry, London, 1985). The both solution phase or the solid phase method of peptide synthesis can be used to make 5-oxo-L-prolyl-L-histidyl-Ltryptophyl-L-seryl-L-tyrosyl-2-methyl-D-tryptophyl-L-leucyl-L-arginyl-N-ethylL-prolinamide (cf. R. Geiger et al., "The Peptides", Academic Press, New York 1981). If the solid phase method is used, peptide synthesizers such as the Applied Biosystem 430A, Bioresearch Sam 9500 or the Beckman Model 990 are preferably used. According to this methodology, the first amino acid is linked to the benzhydrylamine resin and the remaining protected amino acids are then coupled in a stepwise manner using the standard procedures recommended by the manufacturers of the synthesizers. For instance, amino acid couplings are performed by using symmetrical anhydrides in the Applied Biosystems Synthesizer and diisopropylcarbodiimide in the Bioresearch or Beckman machines. The amino acid derivatives are protected by the tertiary butoxy-carbonyl groups on the α-amino function during the synthesis. The functional groups present in the amino-acid in the side chain are previously protected. For instance, the functional groups of histidine are protected by benzyloxymethyl (His(Bom)), tosyl (His(Tos)), the functional groups of tryptophan by formyl (Trp(For)), those of serine by benzyl (Ser(Bzl)), those of tyrosine by 2-Br-benzyloxycarbonyl (Tyr(2-Br-Z)), those of arginine by tosyl (Arg(Tos)); those of proline by O-benzyl HCl (Pro(OBzl HCl)). The Boc protective groups on the α-aminic function are removed at each stage by treatment with 60% trifluoroacetic acid ("TFA") in dichloromethane. The crude peptides after HF cleavage are purified on a Sephadex G-50 F column in 50% acetic acid or by preparative reverse phase HPLC using gradients of acetonitrile and water containing 0.1% trifluoroacetic acid. References DEGHENGHI, Romano [It/CH]; Chesaux Dessus B1, CH-1264 S.-Cergue (CH); W.O. 91/18016
AVRIDINE Therapeutic Function: Antiviral Chemical Name: Ethanol, 2,2'-((3-(dioctadecylamino)propyl)imino)bisCommon Name: Avridine Chemical Abstracts Registry No.: 35607-20-6
458
Avridine
Structural Formula:
Trade Name Avridine
Manufacturer Chemical Formulations, LLC
Country -
Year Introduced -
Raw Materials Dioctadecylamine Acrylonitrile N-Propionyl chloride Manufacturing Process N,N-Dioctadecyl-1,3-propanediamine: A). A two-gallon autoclave is charged with 3-(dioctadecylamino)propionitrile (100 g), ethanol (3750 ml) containing anhydrous ammonia (100 g) and Raney nickel (20 g dry basis) and purged with nitrogen, then with hydrogen. It is then sealed and the hydrogen pressure raised to 250 psi. The autoclave is agitated, the temperature raised to 70°C and the mixture held at this temperature for 1.5 hours at which time hydrogen absorption has ceased. The autoclave is cooled to 20°C, vented, and the contents removed. The catalyst is filtered off, washed with ethanol, and the combined washings and reaction mixture concentrated in vacuum to a viscous green-yellow oil (82 g) which solidified upon standing; MP: 39°-41°C. 3-(Dioctadecylamino)propionitrile is prepared by refluxing a mixture of dioctadecylamine (200 g) and acrylonitrile (1903.8 ml) for eighteen hours. The mixture is then concentrated to a waxy semi-solid which is slurried in acetone, filtered, and air dried overnight. B). The monoacyl derivatives of N,N-dioctadecyl-1,3-propanediamine are prepared as follows: To a solution of methylene chloride (500 ml per 0.1 mole of reactants) containing equimolar amounts of N,N-dioctadecyl-1,3-propanediamine and triethylamine and cooled in an ice-bath is added an equimolar amount of the appropriate acyl chloride in methylene chloride (25 ml per 0.1 mole of acyl chloride) over a period of 15 minutes. The mixture is stirred for ten minutes then brought to room temperature and stirred for one hour. The methylene chloride phase is separated and extracted with water (3x25 ml). The water is
Azabon
459
in turn extracted with methylene chloride (2x25 ml) and the combined methylene chloride phases dried (Na2SO4) then evaporated under reduced pressure. The residue is taken up in benzene and the solution passed through a silica gel column. The column is eluted with benzene, then with benzene containing increasing amounts of ethyl acetate; e.g., 5, 10, 25, and 50 %. The eluate is subjected to thin layer chromatography (ethyl acetate) and those fractions, which show only one spot, combined and evaporated to give N,N-dioctadecyl-N',N'-bis(2-hydroxyethyl)propanediamine M.P. 48.5°-49°C. References GB Patent No. 1,369,247; August 7, 1970; Pfizer Inc. St Delaware, USA
AZABON Therapeutic Function: Central stimulant Chemical Name: 3-[(4-Aminophenyl)sulfonyl]-3-azabicyclo[3.2.2]nonane Common Name: Azabon Structural Formula:
Chemical Abstracts Registry No.: 1150-20-5 Trade Name Azabon
Manufacturer ZYF Pharm Chemical
Country -
Year Introduced -
Raw Materials Sodium hydroxide 1,4-Cyclohexane-bis(methylamine) Nickel Raney 4-Nitrobenzenesulfonyl chloride Hydrogen Manufacturing Process The 1,4-cyclohexane-bis(methylamine) feed line was connected to the top of the preheater in a pyrolysis tube. The pyrolysis section was heated by external electric heaters. For a typical run, the pyrolysis temperature was
460
Azacitidine
maintained at 385°-395°C; the feed rate was 8.4 g per minute of 1,4cyclohexanebis(methylamine) and 1.47 g per minute of nitrogen this is a ratio of 0.885 mole of nitrogen per mole of 1,4-cyclohexanebis(methylamine) per h. The crude reaction product was collected in a chilled flask and the nitrogen and reaction gases were vented to a hood. These conditions were maintained for 15.5 h, during which time 7,849 g (55 moles) of 1,4cyclohexanebis(methylamine) was fed to the unit. Tile total crude product obtained weighed 7,269 g. Distillation of the crude product at atmospheric pressure to a base temperature of 260°-270°C yielded 1,480 g of 3azabicyclo[3.2.2]nonane (recrystallized from an equal weight of acetone). Gas chromatography of the filtrates of this first fraction through a 6-foot column packed with 15% Carbowax 20M on white Chromosorb indicated 1,854 g of 1,4-cyclohexanebis(metnylamine) and 721.0 g of 3-azabicyclo[3.2.2]nonane present. The remainder of the crude product was distilled at 1-5 mm to a base temperature of 200°-225°C. Thus, a total of 2,201 g (17.6 moles, 62.1% yield) of 3-azabicycla[3.2.2]nonane was produced. To a 3 L, three-neck flask equipped with a stirrer, thremometer, and condenser was charge 30.0 g (0.24 mole) of 3-azabicyclo[3.2.2]nonane, 44.3 g (0.2 mole) of p-nitrobenzenesulfonyl chloride and 2 L of water. The pH of the reaction mixture was adjusted to 14 with a 10% solution of sodium hydroxide; the reaction mixture was then slowly heated to 75°C and heating stopped. The reaction mixture was cooled to 20°C and 44.0 g (71% of theory) of crude 3-(p-nitrobenzenesulfonyl)-3-azabicyclo[3.2.2]nonane was collected by filtration. The crude 3-(p-nitrobenzenesulfonyl)-3-azabicyclo[3.2.2]nonane (44.0 g, 0.14 mole), 5.0 g alcohol wet Raney nickel, and 400 ml methyl alcohol were charged to an autoclave and reduced at 70°C at 1000 p.s.i. hydrogen pressure until absorption of hydrogen had stopped. The crude reduced product was filtered hot to remove the Raney nickel catalyst. The filtrate was cooled to 20°C and the solid 3-(p-ammobenzenesulfonyl)-3-azabicyclo[3.2.2]nonane was collected by filtration (38.9 g 98% theory), melting point 149°-151°C. References Pircio A.W. et al.; US Patent No. 3,351,528; Nov. 7, 1967; Assigned: BristolMyers Company, New York, N.Y.
AZACITIDINE Therapeutic Function: Antineoplastic Chemical Name: 1,3,5-Triazin-2(1H)-one, 4-amino-1β-D-ribofuranosylCommon Name: Azacitidine; 5-Azacytidine; Ladakamycin Chemical Abstracts Registry No.: 320-67-2
Azacitidine
461
Structural Formula:
Trade Name
Manufacturer
Country
Year Introduced
5-Azacytidine
AroKor Holdings Inc.
-
-
5-Azacytidine
Xinxiang Tuoxin BiochemicTechnology and Science Co., Ltd.
-
-
Mylosar
Upjohn
-
-
Raw Materials 1-(2,3,5-tri-O-Benzoyl-β-D-ribofuranosyl)-4-methylthio-1,2-dihydro1,3,5-triazin-2-one Ammonia Potassium hydroxide Sodium methoxide Manufacturing Process A mixture of 1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-4-methylthio-1,2dihydro-1,3,5-triazin-2-one (0.5875 g), absolute methanol (5 ml) and a normal methanolic sodium methoxide solution (1.2 ml) is stirred at room temperature with the exclusion of atmospheric moisture (a guard tube filled with potassium hydroxide pellets is fitted to the reaction vessel). The starting compound passes into solution in the course of 5 min. The resulting solution is allowed to stand at room temperature for 45 min and then the cations are removed by passage of the solution through a column packed with 10 ml of a weakly acidic cation exchange resin in the H+ form prewashed with water and methanol. The methanolic effluent (60 ml) is evaporated under reduced pressure at 30°C, the residue is dissolved in methanol (20 ml) and the solution once again is evaporated and the 1-β-D-ribofuranosyl-4-methoxy-1,2dihydro-1,3,5-triazin-2-one was obtained. The residual crude crystalline 1β-D-ribofuranosyl-4-methoxy-1,2-dihydro1,3,5-triazin-2-one is dissolved in a 10% solution of dry ammonia in absolute methanol (4 ml) and the whole reaction mixture is allowed to stand in a stoppered flask for 30 min at room temperature (the product begins to deposit in the course of 5 min) and for 12 h in a refrigerator at -10°C. The resulting 5-azacytidine is collected with suction, washed with methanol and dried under reduced pressure. A yield of 0.216 g (88.6%) of 5-azacytidine, that is [1-β-D-ribofuranosyl-4-amino-1,3,5-triazin-2(1H)-one], melting point 232°-234°C (dec.), is obtained.
462
Azaconazole
References GB Patent No. 1,227,691; April 7, 1971; Assigned: Ceskoslovenska akademie ved, a Corporation organized and existing under the law of Czechoslovakia of N 3 Narodni, Prague 1, Czechoslovakia
AZACONAZOLE Therapeutic Function: Antifungal Chemical Name: 1H-1,2,4-Triazole, 1-((2-(2,4-dichlorophenyl)-1,3-dioxolan2-yl)methyl)Common Name: Azaconazolel; Azoconazole Structural Formula:
Chemical Abstracts Registry No.: 60207-31-0 Trade Name Azaconazole
Manufacturer Chemical Formulations, LLC
Country -
Year Introduced -
Raw Materials Hydrochloric acid Acetic acid Sodium hydroxide 1H-1,2,4-Triazole Sodium
1-(2,4-Diaminopheny1)-1-ethanone Sodium nitrite Bromine 4-Methylbenzenesulfonic acid
Manufacturing Process A stirred and cooled (0°C) solution of 1-(2,4-diaminophenyl)-1-ethanone in a concentrated hydrochloric acid solution, water and acetic acid was diazotated with a solution of sodium nitrite in water. After stirring at 0°C, the whole was poured onto a solution of copper (I) chloride in a concentrated hydrochloric acid solution while stirring. The mixture was heated at 60°C. After cooling to room temperature, the product was extracted twice with 2,2'-oxybispropane. The combined extracts were washed successively with water, a diluted sodium hydroxide solution and again twice with water, dried, filtered and evaporated, yielding 1-(2,4-dichlorophenyl)-1-ethanone.
Azacosterol hydrochloride
463
1-(2,4-Dichlorophenyl)-1-ethanon were dissolved in 1,2-ethanediol at heating. While stirring bromine were added dropwise, without external heating. After stirring at room temperature, 4-methylbenzenesulfonic acid and benzene were added. The whole was stirred and refluxed overnight with water-separator. The reaction mixture was evaporated and the residue was taken up in 2,2'oxybispropane. The resulting solution was washed successively once with a dilute sodium hydroxide solution and 3 times with water, dried, filtered and evaporated. The residue was distilled, yielding 2-(bromomethyl)-2-(2,4dichlorophenyl)-1,3-dioxolane. 6.9 parts of 1H-1,2,4-triazole in 150 parts of dimethylformamide were added to a stirred solution of 2.3 parts of sodium in 120 parts of methanol. The methanol was removed at normal pressure until the internal temperature of 130°C was reached. Then, 25 parts of 2-(bromomethyl)-2-(2,4dichlorophenyl)-1,3-dioxolane were added. The reaction-mixture was stirred and refluxed for 3 h. It was allowed to cool to room temperature and poured onto water. The precipitated product was filtered off, yielding 12 parts of 1-[2(2,4-dichlorophenyl)-1,3-dioxolan-2-yl-methyl]-1H-1,2,4-triazole; melting point 109.9°C (crystallized from diisopropylether; activated charcoal). References GB Patent No. 1,522,657; August 23, 1978; Assigned: Janssen Pharmaceutica N.V., a Belgian Body Corporate, of Turnhoutsebaan 30, Beerse, Belgium
AZACOSTEROL HYDROCHLORIDE Therapeutic Function: Hypocholesteremic Chemical Name: Androst-5-en-3β-ol, 17β-((3-(dimethylamino)propyl) methylamino)-, dihydrochloride Common Name: Azacosterol hydrochloride; Diazacholesterol dihydrochloride; Diazasterol hydrochloride Structural Formula:
Chemical Abstracts Registry No.: 1249-84-9; 313-05-3 (Base) Trade Name
Manufacturer
Country
Ornitrol
Avitrol Corporation -
Year Introduced -
464
Azacosterol hydrochloride
Raw Materials 3β-Hydroxyandrost-5-en-17-one 3-Dimethylaminopropylamine Lithium aluminum hydride Manufacturing Process A solution of 15 parts of 3β-hydroxyandrost-5-en-17-one and 30 parts of 3dimethylaminopropylamine in 36.6 parts of formic acid is heated in an oil bath at about 170-180°C for about 24 hours. The cooled mixture is diluted with about 500 parts of water, and the resulting aqueous mixture is extracted with chloroform, containing a small amount of methanol. The organic layer is separated, washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The viscous residue is dissolved in a mixture of 80 parts of isopropyl alcohol and 420 parts of ether, and this solution is treated with isopropanolic hydrogen chloride. The resulting precipitate is collected by filtration and washed with acetone to afford 17β-[N(3-dimethylaminopropyl)formamido-1-androst-5-en-3β-ol hydrochloride. A solution of this hydrochloride in aqueous methanol is made alkaline by the addition of dilute aqueous sodium hydroxide, and the resulting colloidal precipitate is extracted with chloroform. The chloroform extracts washed with water, dried over anhydrous sodium sulfate and concentrated to dryness to afford a residue, which is crystallized from acetone, resulting in 17β-[N-(3dimethylaminopropyl)formamido]androst-5-en-3β-ol, which displays a double melting point at about 116-118°C and 143-148°C; [α]D= -67.5° (chloroform). To a slurry of 4 parts of LiAlH4 in 150 parts of dioxane is added dropwise with stirring, at the reflux temperature a solution of 10 parts of 17β-[N-(3dimethylaminopropyl) formamido]androst-5-en-3β-ol in 150 parts of dioxane. This reaction mixture is heated at reflux for about 18 hours longer, and then treated dropwise successively, at the reflux temperature, with a solution of 4 parts of water in 25 parts of dioxane, 3 parts of 20% aqueous sodium hydroxide, and 14 parts of water. The resulting mixture is clarified by filtration, and the residue on the filter is washed with fresh dioxane. The filtrates are combined, evaporated to dryness under reduced pressure, and the resulting residue is recrystallized from acetone-methanol to produce 17β-[N-methyl-N-(3dimethylaminopropyl)amino]androst-5-en-3β-ol, M.P. about 146-148°C; [α]D= -54.5° (chloroform). A solution of this amine in ether-isopropyl alcohol is treated with isopropanolic hydrogen chloride to afford the corresponding dihydrochloride; [α]D= -32° (methanol). References Merck Index, Monograph number: 924, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. Counsell R.E. et al.; US Patent No. 3,084,156; Apr. 2, 1963; Assigned to G.D. Searle and Co., Chicago, Ill., a corporation of Delawere
Azacyclonol
465
AZACYCLONOL Therapeutic Function: Tranquilizer Chemical Name: α,α-Diphenyl-4-piperidinemethanol Common Name: γ-Pipradol Structural Formula:
Chemical Abstracts Registry No.: 115-46-8; 1798-50-1 (Hydrochloride salt) Trade Name
Manufacturer
Country
Year Introduced
Frenquel
Merrell
US
1955
Frenoton
Draco
Sweden
-
Frenquel
Inibsa
Spain
-
Frenquel
Merrell-Tourade
France
-
Frenquel
Shionogi
Japan
-
Raw Materials α-(4-Pyridyl)-benzhydrol Hydrogen Manufacturing Process A mixture of 26 g (0.1 mol) of α-(4-pyridyl)-benzhydrol, 1.5 g of platinum oxide, and 250 ml of glacial acetic acid is shaken at 50-60°C under hydrogen at a pressure of 40-50 lb/in2. The hydrogenation is complete in 2 to 3 hours. The solution is filtered and the filtrate evaprated under reduced pressure. The residue is dissolved in a mixture of equal parts of methanol and butanone and 0.1 mol of concentrated hydrochloric acid is added. The mixture is cooled and filtered to give about 30 g of α-(4-piperidyl)benzhydrol hydrochloride, MP 283285°C, as a white, crystalline substance. The free base is readily obtained from the hydrochloride salt by treatment with ammonia and when so obtained has a melting point of 160-161°C. References Merck Index 898 Kleeman and Engei p. 65 OCDS Vol. 1 p. 47
466
Azalanstat hydrochloride
I.N.p. 109 Schumann, E.L., Van Campen, M.G., Jr. and Pogge, R.C.; US Patent 2,804,422; August 27, 1957; Assigned to The Wm. S. Merrell Co.
AZALANSTAT HYDROCHLORIDE Therapeutic Function: Antihyperlipidemic Chemical Name: Benzenamine, 4-(((2-(2-(4-chlorophenyl)ethyl)-2-(1Himidazol-1-ylmethyl)-1,3-dioxolan-4-yl)methyl)thio)-, (2S,4S)-, hydrochloride Common Name: Azalanstat hydrochloride Structural Formula:
Chemical Abstracts Registry No.: 143393-27-5 (Base); 143484-82-6 Trade Name Azalanstat hydrochloride
Manufacturer Syntex
Country -
Year Introduced -
Raw Materials 4-Chlorophenethyl alcohol N-Bromosuccinimide Peracetic acid Potassium carbonate Imidazole Triethylamine Sodium hydroxide Methanesulfonyl chloride
Triphenylphosphine Vinyl bromide Sodium acetate Sodium hydride Oxalyl chloride Glycerol 4-Toluenesulfonic acid monohydrate 4-Aminothiophenol
Manufacturing Process A stirred solution of 4-chlorophenethyl alcohol (131.0 g) and triphenylphosphine (241.3 g) in dry THF (500 ml) at 0°C was treated portionwise over 30 min with N-bromosuccinimide (163.75 g). The resulting black solution was stirred overnight at room temperature, whereupon the THF was evaporated and the residue stirred with ether. The solution was filtered and the filtrate evaporated and treated with hexane. The stirred mixture was filtered, evaporated, and the residue distilled under reduced pressure to give 100.0 g of 4-chlorophenethyl bromide as a colorless liquid, boiling point 85°C
Azalanstat hydrochloride
467
(3 mm Hg). To a flame-dried flask containing magnesium turnings under ether was added 4-chlorophenethyl bromide in anhydrous ether at such a rate as to maintain a gentle reflux. When the addition was complete, the mixture was heated under reflux for an additional hour and then treated dropwise over 1 h with vinyl bromide in ether maintaining a gentle reflux. The resulting mixture was stirred overnight at room temperature and then poured onto ice-cold dilute sulfuric acid. The product was extracted with ethyl acetate and the combined extracts were washed with dilute aqueous potassium carbonate, dried MgSO4 and evaporated. The resulting brown oil was distilled under reduced pressure to give 4-(4-chlorophenyl)but-1-ene. To a solution of 4-(4-chlorophenyl)but-1-ene in dichloromethane was added dropwise with stirring a mixture of 40% peracetic acid and sodium acetate. The resulting mixture was heated under reflux, cooled, and stirred with water. The dichloromethane layer was separated, washed with dilute aqueous potassium carbonate until neutral, water, and dried (MgSO4) and evaporated to give 4-(4-chlorophenyl)-1,2-epoxybutane as a colorless oil. To a suspension of sodium hydride (50% dispersion in mineral oil) in dry DMF under nitrogen was added imidazole in dry DMF with stirring at such a rate as to keep the temperature below 65°C (ice bath). When the evolution of gas had ceased, 4-(4-chlorophenyl)-1,2-epoxybutane was added dropwise and the mixture stirred overnight at room temperature. The resulting brown solution was added water, extracted with ethyl acetate and the combined extracts were washed with water 3 times, dried (MgSO4) and evaporated to give an oil which crystallized. Washing the solid with ether and filtration give 1-(4-(4chlorophenyl)-2-hydroxybutyl)imidazole. A solution of oxalyl chloride (74.8 g) in dry dichloromethane (1350 ml) at below -70°C under a nitrogen atmosphere was treated with dry dimethylsulfoxide (91.5 ml) in methylene chloride (270 ml) dropwise over 1520 min while maintaining the temperature of the reaction mixture below 50°C. After an additional 5 min a solution of (+/)-1-(4-(4-chlorophenyl)-2hydroxybutyl)imidazole (128.3 g) in a mixture of dimethylsulfoxide (50 ml) and methylene chloride (200 ml) was added over a period of 20 min keeping the reaction mixture at temperatures below -65°C. After a further 15 min dry triethylamine (300 ml) was added rapidly and after 15 min the reaction mixture was allowed to warm to 0°C. Water (20 ml) was then added to the reaction mixture, the methylene chloride then removed by evaporation and the resulting slurry was then treated with water and filtered. The filter cake was washed well with ice water, cold ethyl acetate and then dried in air to yield 118.0 g of 4-(4-chlorophenyl)-1-(imidazol-1-yl)butan-2-one. A mixture of 4-(4-chlorophenyl)-1-(imidazol-1-yl)butan-2-one (50.0 g), ptoluenesulfonic acid monohydrate (42.07 g) and glycerol (37.0 g) in toluene (200 ml) was heated under reflux, with stirring, through a Dean-Stark trap for 6 h. The two layers were allowed to separate and the hot toluene (upper layer) decanted and discarded. The lower layer was poured into 2 N sodium hydroxide (500 ml), the transfer completed by washing the flask with 1 N sodium hydroxide and methylene chloride, and the product extracted with methylene chloride (4x200 ml). The extracts were dried (MgSO4) evaporated
468
Azaloxan fumarate
and the residue recrystallized from toluene to give 61.4 g of (cis/trans)-2-(2(4-chlorophenyl)ethyl)-2-(imidazol-1-yl)methyl-4-hydroxymethyl-1,3dioxolane, melting point 96°-110°C. (cis/trans)-2-[2-(4-Chlorophenyl)ethyl]-2-(imidazol-1-yl)methyl-4hydroxymethyl-1,3-dioxolane (39.7 g) in pyridine (150 ml) at 0°C was treated drop-wise with stirring with methanesulfonyl chloride (10.6 ml) and the mixture stirred overnight. The resulting solid mass was stirred with ether (500 ml) to break up the solid, filtered and washed well with ether to give (cis/trans)-2-[2-(4-chlorophenyl)ethyl]-2-(imidazol-1-yl)methyl-4(methylsulfonyloxy)methyl-1,3-dioxolane hydrochloride, melting point 107°110°C (recrystallized from dichloromethane/isopropanol). The (cis/trans)-2-[2-(4-chlorophenyl)ethyl]-2-(imidazol-1-yl)methyl-4(methylsulfonyloxy)methyl-1,3-dioxolane hydrochloride was basified with aqueous potassium carbonate solution, extracted with ethyl acetate (2x400 ml) and the extracts washed, dried (MgSO4) and evaporated. The resulting semicrystalline mass was chromatographed on silica gel (900.0 g) eluting with dichloromethane, aqueous ethyl acetate (2.2% water) to give 25.4 g of (+/-)cis-2-(2-(4-chlorophenyl)ethyl)-2-(imidazol-1-yl)methyl-4(methylsulfonyloxy)methyl-1,3-dioxolane, as a snow white solid, melting point 93.5°-96°C. Further elution gave, after a small mixed fraction, pure (+/-)trans-2-[2-(4-chlorophenyl)ethyl]-2-(imidazol-1-yl)methyl-4(methylsulfonyloxy)methyl-1,3-dioxolane, as a white solid, melting point 93°95°C. A mixture of (+/-)-cis-2-[2-(4-chlorophenyl)ethyl]-2-(imidazol-1-yl)methyl-4(methylsulfonyloxy)methyl-1,3-dioxolane (31.0 g), 4-aminothiophenol (12.6 g) and anhydrous potassium carbonate (23.1 g) in acetone (250 ml) was stirred overnight under reflux under nitrogen. The reaction mixture was then evaporated to dryness, and the resulting residue was extracted with methylene chloride (300 ml) and filtered. The solid filter cake was then washed with methylene chloride (200 ml). The methylene chloride extracts were then combined and concentrated and flash chromatographed on a silica gel eluting with methylene chloride followed by 30% acetone in methylene chloride. The pure product was dissolved in a minimum amount of hot ethyl acetate (125 ml), the solution diluted with an equal volume of hot hexane and seeded to give 30.0 g of (+/-)-cis-2-[2-(4-chlorophenyl)ethyl]-2-(imidazol-1yl)methyl-4-(4-amino-phenylthio)methyl-1,3-dioxolane, melting point 121°122.5°C. In practice it is usually used as hydrochloride. References Walker K.A. et al.; US Patent No. 5,158,949; Oct. 27, 1992; Assigned: Syntex (U.S.A.) Inc., Palo Alto, Calif.
AZALOXAN FUMARATE Therapeutic Function: Antidepressant
Azaloxan fumarate
469
Chemical Name: (S)-1-[1-[2-(1,4-Benzodioxan-2-yl)-ethyl]-4-piperidyl]-2imidazolidinone fumarate Common Name: Azaloxan fumarate Structural Formula:
Chemical Abstracts Registry No.: 72822-56-1 (Base); 86116-60-1 Trade Name
Manufacturer
Country
Year Introduced
Idulian
Unicet
-
-
CGS7135A
Ciba-Geigy
-
-
Azaloxan Fumarate
ZYF Pharm Chemical
-
-
Raw Materials Bromine Catechol Allyl cyanide Sulfuric acid 4-Aminopyridine Hydrogen Furmaric acid
Acetic acid 4-Toluenesulfonyl chloride Sodium bis(2-methoxyethoxy)aluminum hydride Potassium carbonate Sodium methanolate 2-Chloroethylisocyanate Ruthenium on carbon
Manufacturing Process The producing of starting materials 1 and 2: 1). The solution of 16.0 g of bromine in 10 ml of petroleum ether is slowly added to the solution of 6.7 g of allyl cyanide in 30 ml of the same solvent, while stirring and keeping the temperature at about -15°C. After removal of the solvent the oily 3,4-dibromo-butyronitrile is obtained [J.A. C.S. 67, 400 (1945)]. 227.0 g of 3,4-dibromobutyronitrile are added dropwise in 5 equal parts to the stirred mixture of 85.0 g of catechol and 50. g of anhydrous potassium carbonate in 100 ml of refluxing acetone each. Another 50.0 g of potassium carbonate are added, followed by a slow addition of another part of nitrile. After 3 more cycles, using 40.0 g of potassium carbonate, 1 part nitrile each and sufficient acetone to allow stirring, the mixture is refluxed for 20 h. It is
470
Azaloxan fumarate
filtered, the filtrate evaporated, the residue distilled and the fraction boiling at 105°C/0.15 mm Hg collected, to yield the 1,4-benzodioxan-2-yl-acetonitrile [Belgium Pat. No. 643,853-Aug. 14, 1964]. The mixture of 111.0 g of 1,4-benzodioxan-2-yl-acetonitrile, 63.5 ml of sulfuric acid, 160 ml of acetic acid and 160 ml of water is refluxed for 48 h. It is poured on ice, the resulting solid collected to yield the 1,4-benzodioxan-2yl-acetic acid, melting point 100°C, (recrystallized from benzene-petroleum ether) [Belgium Pat. No. 613,211-July 30, 1962]. The solution of 5.8 g of 1,4-benzodioxan-2-yl-acetic acid in 100 ml of benzene is added dropwise to 16.5 ml of a refluxing, 70% benzene solution of sodium bis(2-methoxyethoxy)aluminum hydride under nitrogen. When addition is complete, the mixture is refluxed for 4 h, cooled and poured slowly into 20 ml of 25% sulfuric acid. After filtration and removal of the solvent, the residue is taken up in methylene chloride, the solution washed several times with saturated aqueous sodium bicarbonate, dried and evaporated, to yield the oily 2-(2-hydroxyethyl)-1,4-benzodioxan. The mixture of 3.6 g of 2-(2-hydroxyethyl)-1,4-benzodioxan, 5.7 g of ptoluenesulfonyl chloride and 20 ml of dry pyridine is stirred and cooled in an ice bath for 2 h. Ice is then added to the mixture, the resulting solid is filtered off to yield the 2-(2-tosyloxyethyl)-1,4-benzodioxan, melting point 82°-83°C (recrystallized from ethyl acetate-petroleum ether). 2). To the solution of 1.6 g of 4-aminopyridine in 7 ml of dimethylformamide 2.0 g of 2-chloroethylisocyanate are added while stirring and keeping the temperature below 40°C. After 2 h 28 ml of water are added and stirring is continued for 2 h at room temperature. The precipitate formed is filtered off, washed with water, dried to yield the 1-(4-pyridyl)-3-(2-chloroethyl)urea, melting point 120°-122°C, (recrystallized from aqueous ethanol). To the suspension of 2.66 g of 1-(4-pyridyl)-3-(2-chloroethyl)urea in 4 ml of boiling methanol, 2.68 g of 30.8% methanolic sodium methanolate are added while stirring and the mixture is refluxed for 1 h. It is filtered hot, washed with hot methanol, the filtrate evaporated, to yield the 1-(4-pyridyl)-2imidazolidinone, melting point 204°-207°C, (recrystallized from 90% aqeuous ethanol). The solution of 5.0 g of 1-(4-pyridyl)-2-imidazolidinone in 45 ml of water is hydrogenated over 0.8 g of 10% ruthenium on carbon at 120°C and 120 atm until the hydrogen absorption ceases. It is filtered, the filtrate evaporated, the residue taken up in chloroform, the solution dried, evaporated to yield the 1(4-piperidyl)-2-imidazolidinone, melting point 155°-157°C (recrystallized from methylene chloride-petroleum ether). The producing of (cis)-(S)-1-[1-[2-(1,4-benzodioxan-2-yl)ethyl]-4-piperidyl]2-imidazolidinone fumarate: The mixture of 4.9 g of 2-(2-tosyloxyethyl)-1,4-benzodioxan, 2.54 g of 1-(4piperidyl)-2-imidazolidinone, 5.0 g of anhydrous sodium carbonate and 100 ml of 4-methyl-2-pentanone is stirred and refluxed for 3 days. It is filtered, evaporated, to yield the 1-[1-[2-(1,4-benzodioxan-2-yl)-ethyl]-4-piperidyl]-2imidazolidinone, melting point 125°C, (recrystallized from isopropanol).
Azanidazole
471
To the solution of 2.0 g of 1-[1-[2-(1,4-benzodioxan-2-yl)-ethyl]-4-piperidyl]2-imidazolidinone in the mini-mum amount of ethanol, the saturated solution of 0.78 g of furmaric acid in boiling ethanol is added. The mixture is cooled to 0°C and the precipitate collected, to yield the 1-[1-[2-(1,4-benzodioxan-2-yl)ethyl]-4-piperidyl]-2-imidazolidinone fumarate, melting point 190°C. The (cis)-(S)-form may be produced by chromatographic division of isomers of 1-[1-[2-(1,4-benzodioxan-2-yl)ethyl]-4-piperidyl]-2-imidazolidinone fumarate. References Huebner Ch. F.; US Patent No. 4,329,348; May 11, 1982; Assigned: CibaGeigy Corporation, Ardsley, N.Y.
AZANIDAZOLE Therapeutic Function: Antiprotozoal, Antibacterial Chemical Name: 2-Amino-4-[2-(1-methyl-5-nitroimidazol-2-yl)vinyl] pyrimidine Common Name: Nitromidine Structural Formula:
Chemical Abstracts Registry No.: 62973-76-6 Trade Name
Manufacturer
Country
Year Introduced
Triclose
Ist. Chemioter.
Italy
1977
Triclose
I.C.I.
Italy
-
Raw Materials 2-Amino-4-methylpyrimidine 2-Formyl-1-methyl-5-nitroimidazole Sulfuric acid Manufacturing Process Into a mixture of 1.6 g of 2-amino-4-methylpyrimidine with 10 ml of glacial acetic acid is slowly added 2.13 g of concentrated sulfuric acid. A mixture of 2.4 g of 2-formyl-1-methyl-5-nitroimidazole in 20 ml of glacial acetic acid is slowly added to the mixture of the pyrimidine under stirring. The reaction
472
Azaperone
mixture is maintained at a temperature of about 55°C for 4 hours. The resultant mixture is then diluted with 200 ml of distilled water and neutralized with a saturated aqueous solution of sodium bicarbonate. A brownish-yellow precipitate (MP 232° to 235°C) is formed and recovered. The product is analyzed by infrared spectroscopy and is found to conform to 2-amino-4-[2(1-methyl-5-nitro-2-imidazolyl)vinyl]pyrimidine. References Merck Index 902 DOT 14 (6) 234 (1978) I.N. p. 109 Garzia, A.; US Patent 3,882,105; May 6, 1975; Assigned to Istituto Chemioterapico Italiano SpA Garzia, A.; US Patent 3,969,520; July 13, 1976; Assigned to Istituto Chemioterapico Italiano SpA
AZAPERONE Therapeutic Function: Neuroleptic, Hypnotic Chemical Name: 1-Butanone, 1-(4-fluorophenyl)-4-(4-(2-pyridinyl)-1piperazinyl)Common Name: Azaperone; Sedaperone Structural Formula:
Chemical Abstracts Registry No.: 1649-18-9 Trade Name
Manufacturer
Azaperone
Dayang Chemicals Co. Ltd.
-
Azaperolo
C.E.R. Laboratoire D'Hormonologie
-
Azaperone
C.E.R. Laboratoire D'Hormonologie
-
Raw Materials γ-Chloro-4-fluorobutyrophenone 1-(2'-Pyridyl)piperazine
Country
Year Introduced
Azapetine phosphate
473
Manufacturing Process A mixture of γ-chloro-4'-fluorobutyrophenone and 1-(2'-pyridyl)piperazine is heated on an oil bath. The mixture is then boiled in diisopropyl ether and the precipitates is collected and boiled with water and benzene. The benzene layer is treated with activated charcoal, added to the ethereal filtrate, and evaporated to give a residue which is taken up in diisopropyl ether. After cooling an oil is precipitated, which after decantation and drying yields 1-[γ(4'-fluorobenzoyl)propyl]-4-(2'-pyridyl)piperazine. References Janssen P.A.J.; US Patent No. 2,958,694; Nov. 1, 1960
AZAPETINE PHOSPHATE Therapeutic Function: Adrenergic blocker Chemical Name: 6,7-Dihydro-6-(2-propenyl)-5H-dibenz[c,e]azepine phosphate Common Name: Structural Formula:
Chemical Abstracts Registry No.: 130-83-6; 146-36-1 (Base) Trade Name
Manufacturer
Country
Year Introduced
Ilidar
Roche
US
1954
Ilidar
Roche
W. Germany
-
Raw Materials Diphenic acid Lithium aluminum hydride Allyl bromide
Ammonia Acetic anhydride Phosphoric acid
474
Azapetine phosphate
Manufacturing Process 29 grams of diphenic acid were stirred in 900 cc of acetic anhydride at 120°C for one hour, The cooled mixture was filtered and washed with acetic acid to give diphenic anhydride, colorless crystals, MP about 222-226°C. 24.11 grams of diphenic anhydride were mixed with 50 cc of concentrated ammonia. The mixture warmed up and cooling was applied, after which the mixture was stirred until a clear solution formed and for 1½ hours afterward. The mixture was acidified and allowed to stand overnight. Water was added, initiating precipitation. The mixture was chilled and filtered to yield diphenamic acid, a colorless solid, MP about 191-193°C. 23.5 grams of diphenamic acid were heated at 200°C in an oil bath, first for about 20 hours at atmospheric pressure and then for about 10 hours at about 20 mm. Melting points were taken at intervals in order to gain an idea of the extent of reaction. The final residue was boiled with alcohol but since the solid exhibited insufficient solubility in the hot solvent, the mixture was filtered. The residue consisted of tan crystals, MP about 220-221°C, and the filtrate on cooling gave an additional crop of tan crystals, MP about 219-221°C. The two materials were identical and consisted of diphenimide. 5.58 g of diphenimide were placed in a Soxhlet thimble and extracted for about 3 days with a boiling mixture of 9.0 g of lithium aluminum hydride in 600 cc of sodium-dried ether. Excess lithium aluminum hydride was then decomposed cautiously with water and the mixture was filtered through a filter aid by suction. The filtrate consisted of two layers. The ether layer was separated and dried with anhydrous potassium carbonate and acidified with alcoholic hydrochloric acid to give 6,7-dihydro-5H-dibenz[c,e]azephine hydrochloride, MP about 287-289°C. One gram of 6,7-dihydro-5H-dibenz[c,e]azepine hydrochloride was dissolved in water, made alkaline with concentrated ammonia, and the resultant base extracted twice with benzene, The benzene layers were combined, dried with anhydrous potassium carbonate, and mixed with 0.261 g of allyl bromide at 25-30°C. The reaction solution became turbid within a few minutes and showed a considerable crystalline deposit after standing 3½ days. The mixture was warmed 1 3/4 hours on the steam bath in a loosely-stoppered flask, then cooled and filtered. The filtrate was washed twice with water and the benzene layer evaporated at diminished pressure. The liquid residue was dissolved in alcohol, shaken with charcoal and filtered. Addition to the filtrate of 0.3 gram of 85% phosphoric acid in alcohol gave a clear solution which, when seeded and rubbed, yielded 6-allyl-6,7-dihydro-5H-dibenz[c,e]azepine phosphate, MP about 211-215°C with decomposition. References Merck Index 904 Kleeman and Engel p. 65 I.N. p. 109 Schmidt, R.A. and Wenner, W.; US Patent 2,693,465; November 2, 1954; Assigned to Hoffmann-La Roche, Inc.
Azaquinzole
475
AZAQUINZOLE Therapeutic Function: CNS depressant Chemical Name: 1,3,4,6,7,11b-Hexahydro-2H-pyrazino[2,1-a]isoquinoline Common Name: Azaquinzole Structural Formula:
Chemical Abstracts Registry No.: 5234-86-6 Trade Name
Manufacturer
Country
Year Introduced
Azaquinzole
Onbio Inc.
-
-
Raw Materials Diethyl ester of oxalic acid Lithium aluminum hydride 1-Aminomethyl-1,2,3,4-tetrahydroisoquinoline Ethylene dibromide Potassium carbonate Sodium hydroxide Manufacturing Process 2 Methods of producing of 1,2,3,6,7,11b-hexahydro-4H-pyrazino-[2,1a]isoquinoline: 1). 214.0 g diethyl ester of oxalic acid are mixed with a solution of 238.0 g 1aminomethyl-1,2,3,4-tetrahydroisoquinoline in 200 ml alcohol are boiled for 7 h. After cooling, the obtained crystals of 1,2,3,6,7,11b-hexahydro-4Hpyrazino[2,1-a]isoquinoline-3,4-dione are vacuum-filtered and washed with acetone and dried, melting point 220°C. Yield: 240.0 g. 55.0 g lithium aluminum hydride are dissolved in 650 ml absolute tetrahydrofuran and mixed dropwise with a suspension of 120.0 g 1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline-3,4-dione in 300 ml absolute tetrahydrofuran. After 7 h of boiling, the residual hydride is decomposed by the addition of water, and the reaction solution is worked up. The obtained 1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline is distilled in vacuum, boiling point 98°-100°C/0.01 mm. Yield: 86.0 g. 2). 16.2 g 1-aminomethyl-1,2,3,4-tetrahydroisoquinoline and 18.7 g ethylene dibromide are boiled for 4 h in n-butanol, with the addition of 13.8 g potassium carbonate. After the solvent is evaporated, the residue is treated
476
Azaserine
with water, mixed with sodium hydroxide solution, and shaken out with chloroform. The chloroform solution is dried, concentrated by evaporation, and the resulting 1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline is distilled at 98°-100°C/0.01 mm. The yield amounts to 7.5 g. References Thesing J. et al.; US Patent No. 3,393,195; July 16, 1968; Assigned: E. Merch Aktiengeselischaft, Darmstadt, Germany
AZASERINE Therapeutic Function: Antineoplastic, Antifungal Chemical Name: L-Serine diazoacetate (ester) Common Name: Azaserine Structural Formula:
Chemical Abstracts Registry No.: 115-02-6 Trade Name
Manufacturer
Country
Year Introduced
Azaserine
TG International Chemical Co. Sigma
-
-
-
-
Azaserine
CalbiochemNovabiochem Corp.
-
-
Azaserine
ICN Biomedicals Inc.
-
-
Azaserine
Raw Materials Streptomyces fragilis Soybean expeller oil meal Yeast Sodium hydroxide Ammonium nitrate Mineral oils
Glucose Acid hydrolyzed casein Sodium chloride Calcium carbonate Castile soap
Manufacturing Process The azaserine is produced by microbiological synthesis using culture of Streptoniyces fragili:
Azaserine
477
10 gallons of a nutrient medium having the following composition (%):glucose 1.0; soybean expeller oil meal 1.0; acid hydrolyzed casein 0.5; debittered yeast 0.5; sodium chloride 0.5; water sufficient to make 100.0% is placed in a 30 gallon stainless steel fermenter, the pH adjusted to 7.5 with 6 N sodium hydroxide solution and 0.1% calcium carbonate added. The medium is sterilized by heating at 121°C for 30 min after which the pH of the medium is 6.85. The medium is cooled and inoculated with the spares from two fourteen day old Moyer's sporulation agar slant cultures of Streptoniyces fragilis suspended in 20 ml of sterile 0.01% castile soap solution. The culture mixture is incubated at 27°C for 24 h during which time aeration is supplied through a sparger at the rate of one volume of air per volume of medium per minute. The incubated culture thus obtained is used to inoculate the main culture as described below. 150 gallons of a medium having the following composition (%): glucose 1.0; soybean expeller oil meal 1.0; acid hydrolyzed casein 0.5; debittered yeast 0.5; sodium chloride 0.5; ammonium nitrate 0.25; water sufficient to make 100.0 percent. 6 N sodium hydroxide solution-sufficient to bring the pH to 7.5;calcium carbonate - (added after pH adjustment) is placed in a 200-gallon stainless steel fermenter and sterilized by heating at 121°C for 30 min. The medium is cooled, inoculated with the 10-gallon culture of Streptomyces fragilis prepared as described above, and incubated at 26°C for 44 h. During the incubation period air is supplied through a sparger at the rate of 1.5-volumes of air per volume of medium per min and the mixture stirred at the rate of 150 r.p.m. for the first 12 h and at 300 r.p.m. for the final 32 h, 1.5 gallons of a sterilized mixture of crude lard and mineral oils containing mono- and diglycerides being added as needed to control foaming. The solid material present in the incubated fermentation mixture is removed by filtration and the filter cake washed with water. The washings are combined with the main filtrate and 110 gallons of this solution stirred with 2079.0 g of activated carbon for about 1 h. The carbon is removed by filtration and the filter cake washed with deionized water. The combined filtrate and washes (136 gallons) are concentrated in vacuum to a volume of about 20 gallons. Three volumes of acetone are added to the concentrate with stirring, and the precipitate which forms removed by filtration and the filter cake washed with 75% aqueous acetone. The combined aqueous acetone filtrate and washings is concentrated in vacuum to a volume of about 19.5 gallons, the concentrate so obtained frozen and dried from the frozen state under high vacuum. 1.0 kg of dry powder is extracted with one 10-liter portion of 90% (by volume) ethanol followed by extraction with one 2-liter portion of the same solvent. The combined extracts (about 12 L) are diluted with sufficient water to reduce the ethanol concentration to 75% by volume, and this alcoholic solution passed through an adsorption column prepared as described below. 3.0 kg of alumina are stirred with dilute hydrochloric acid so that the pH remains constant at 7.7. The alumina is removed, washed with water and activated by heating at 200°C for 4 h. The alumina is stirred with 75% aqueous ethanol and packed into an adsorption column having a diameter of 4 inches. The total packed volume is approximately 3500 ml. The alcoholic solution prepared above is added to the adsorption column at the rate of 6 L/h and the percolate discorded. The column is washed with 35 L of 75% ethanol (by volume), the washing discarded and the column finally washed with 21 L of 50% ethanol. Some O-diazoacetyl-L-serine may be
478
Azasetron hydrochloride
detected in the last wash solution. After the washing has been completed the adsorbed O-diazoacetyl-L-serine is eluted from the adsorption column by passing 17.5 L of distilled water through the column. The aqueous eluate is concentrated and frozen and the concentrate dried from the frozen state under high vacuum. The powder thus obtained, a O-diazoacetyl-L-serine content of 5.8%. 500.0 g of the material assaying 5.8% O-diazoacetyl-L-serine is dissolved in 1,320 ml of water. A column of activated charcoal is prepared. A mixture of 2.0 kg of activated charcoal (Darco (1-60) and 2.0 kg of diatomaceous earth is packed as a thick slurry in a 6 inch column. The pH of the water is 5.2-5.5. With this bed, a head of 4 feet of solvent is necessary to achieve a suitable flow rate. After packing, the column is washed with water for several hours to settle and remove solubles. The solution is applied to the column with positive pressure equivalent to a head of four foot of water. One retention volume of 9 L of water is then applied to the column. This is followed by a 5% acetone solution. The total solvent flow is 36 L. The colorless eluate is discarded. The elution front which is easily detected is a light yellowish-green solution. This solution is retained. The solution is concentrated by vacuum distillation until a concentration of 20-25 mg/ml is reached. This solution is applied to a column prepared in an identical manner as described herein and treated by the same procedure as the primary adsorption. The percolate is concentrated by vacuum distillation until a concentration of 60-75 mg/ml is reached. The quantity of solution is now approximately 300 ml. Absolute alcohol (450 ml) is added. The solution is gently warmed to complete solution and then stored at 5°C for several hours. The O-diazoacetyl-L-serine which separates in crystalline form is collected and purified by recrystallization from 60-70% ethanol; is an aqueous buffer of pH 7. References Ehrlich J. et al.; US Patent No. 2,996,435; Aug. 15, 1961; Assigned: Parke, Davis and Company, Detroit, Moch., a corporation of Michigan
AZASETRON HYDROCHLORIDE Therapeutic Function: Antiemetic Chemical Name: (+/-)-N-1-Azabicyclo[2.2.2]oct-3-yl-6-chloro-3,4-dihydro-4methyl-3-oxo-2H-1,4-benzoxazine-8-carboxamide monohydrochloride Common Name: Azasetron hydrochloride; Nazasetron hydrochloride Chemical Abstracts Registry No.: 123040-69-7 (Base); 141922-90-9 Raw Materials 2-(2-Carboxy-4-chlorophenoxy)acetic acid Nitric acid Ferric sulfate heptahydrate Potassium t-butoxide
Sulfuric acid Ammonia Hydrochloric acid Methyl iodide
Azasetron hydrochloride 3-Amino-8-azabicyclo[3.2.1]octane Ethyl chlorocarbonate Sodium hydrogen carbonate
479
Triethylamine Potassium hydroxide
Structural Formula:
Trade Name
Manufacturer
Country
Year Introduced
Azasetron hydrochloride Azasetron hydrochloride
Pharm Chemical
-
-
HangZhou Ohua Pharmaceutical Technology Co., Ltd. Yoshimoti
-
-
-
-
Serotone
Manufacturing Process To a solution of 2-(2-carboxy-4-chlorophenoxy)acetic acid in concentrated sulfuric acid is added dropwise a mixed liquid of fuming nitric acid and concentrated sulfuric acid under stirring with keeping at a temperature below 10°C. After the addition, the reaction mixture is stirred and poured into 10 L of ice-cold water. The precipitated crystals are collected by filtration, washed with 2 L of water four times and them dried to give 2-(2-carboxy-4-chloro-6nitrophenoxy)acetic acid. To a solution of ferrous sulfate heptahydrate in of hot water is added a solution of 2-(2-carboxy-4-chloro-6-nitrophenoxy)acetic acid and aqueous concentrated ammonia solution in water under stirring. After stirring, to the reaction mixture is twice added aqueous concentrated ammonia solution. While the reaction mixture becomes exothermic, stirring is continued. The resultant mixture is filtered through a celite layer under reduced pressure and washed with hot water twice. The filtrate is cooled and made acid with concentrated hydrochloric acid. The precipitated crystals are washed with water and dried to give 6-chloro-3,4-dihydro-3-oxo-2H-1,4-benzoxazine-8carboxylic acid. A mixture of 6-chloro-3,4-dihydro-3-oxo-2H-1,4-benzoxazine-8-carboxylic acid, methanol and concentrated sulfuric acid is refluxed under heating with stirring, and then cooled. The precipitated crystals are collected by filtration, washed with methanol and dried to give methyl 6-chloro-3,4-dihydro-3-oxo2H-1,4-benzoxazine-8-carboxylate, melting point 239°-241°C. To a solution of methyl 6-chloro-3,4-dihydro-3-oxo-2H-1,4-benzoxazine-8-
480
Azastene
carboxylate in dimethylformamide is added potassium t-butoxide and solution stirred at room temperature. To the resultant solution is added dropwise a solution of methyl iodide in dimethylformainide under stirring. After the reaction solution is stirred, water is added thereto. The insoluble substance is collected by filtration, washed with water and dried to give methyl 6-chloro3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazine-8-carboxylate. A mixture of methyl 6-chloro-3,4-dihydro-4-methyl-3-oxo-2H-1,4benzoxazine-8-carboxylate, ethanol and 4% aqueous potassium hydroxide solution is refluxed with heating. The resultant solution is cooled and water is added thereto followed by filtration. The filtrate is made acid with concentrated hydrochloric acid. The precipitated crystals are collected by filtration, washed with water and dried, and then recrystallized from ethanol to give 6-chloro-3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazine-8-carboxylic acid, melting point 241°-243°C. A solution of 6-chloro-3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazine-8carboxylic acid in tetrahydrofuran and dimethylformamide is cooled to below 0°C and triethylamine is added under stirring thereto. Further, ethyl chlorocarbonate is added and the mixture is stirred at room temperature. To the resultant mixture is added 3-amino-8-azabicyclo[3.2.1]octane and the mixture stirred. After completion of the reaction, aqueous sodium hydrogen carbonate and ethyl acetate are added. The organic layer is separated, washed with water and dried over magnesium sulfate. The solvent is distilled off to give 6-chloro-3,4-dihydro-4-methyl-N-(8-azabicyclo[3.2.1]oct-3-yl)-3oxo-2H-1,4-benzoxazine-8-carboxamide. In practice it is usually used as hydrochloride. References Tahara T. et al.; US Patent No. 4,892,872; Jan. 9, 1990; Assigned: Yoshitomi Pharmaceutical Industries, Ltd., Osaka, Japan
AZASTENE Therapeutic Function: Contraceptive Chemical Name: Androsta-2,5-dieno[2,3-d]isoxazol-17-ol, 4,4,17-trimethyl-, (17β)Common Name: Azastene Structural Formula:
Azastene
481
Chemical Abstracts Registry No.: 13074-00-5 Trade Name
Manufacturer
Country
Year Introduced
Azastene
ZYF Pharm Chemical
-
-
Raw Materials 4,4,17α-Trimethyl-2,5-androstdien-17β-ol-3-one Sodium Methanol Ethyl formate Hydrochloric acid Sodium acetate Hydroxylamine hydrochloride Acetic acid Manufacturing Process A solution of 4,4,17α-trimethyl-androsta-2,5-dien-17β-ol-3-one in benzene was added to sodium methoxide (from sodium and of absolute methanol, concentrating the solution and drying the residue for 1 h at 150°-160°C and 15 mm). Ethyl formate was then added with stirring in a nitrogen atmosphere. The reaction mixture was stirred for 4 h at room temperature, allowed to stand for about 15 h, stirred for 2 h and then poured into water. The reaction mixture was extracted with benzene, the aqueous layer warmed until clear, filtered and cooled below room temperature. Concentrated hydrochloric acid and ice were added to the filtrate until the mixture was acid to Congo red, and the product was extracted with chloroform. The chloroform extracts were washed with water, dried over anhydrous sodium sulfate, filtered and concentrated vacuum, whereupon there separated 2-hydroxymethylene4,4,17α-trimethyl-androsta-2,5-dien-17β-ol-3-one. To a solution of sodium acetate in acetic acid was added hydroxylamine hydrochloride, and methanol was added until solution resulted. This solution was added to a solution of 2-hydroxymethylene-4,4,17α-trimethyl-androsta2,5-dien-17β-ol-3-one in absolute methanol, and the combined solution was refluxed for 40 min on a steam bath. The reaction mixture was concentrated, the residue extracted with ethyl acetate, and the ethyl acetate extracts were washed with ethyl acetate, and the ethyl acetate extracts were washed with 5% hydrochloric acid, dried over anhydrous sodium sulfate and concentrated whereupon there separated solid material. The mother liquors were concentrated to dryness and the residue recrystallized from ether to give solid product. The latter was chromatographed on a column of silica gel in benzene solution, recrystallized from ethyl acetate and dried at 75°C for 20 h to give 17β-hydroxy-4,4,17αtrimethyl-androsta-2,5-dien[2,3-d]isoxazole. The crude product was chromatographed on silica gel in benzene solution, eluted with benzene containing 5% of ether and recrystallized from ethanol to give 17β-hydroxy-4,4,17α-trimethyl-androsta-2,5-dien[2,3-d]isoxazole.
482
Azatadine maleate
References Clinton R.O., Manson A.J.; US Patent No. 3,135,743; June 2, 1964; Assigned: Sterling Drug Inc., New York, N.Y., a corporation of Delaware
AZATADINE MALEATE Therapeutic Function: Antihistaminic Chemical Name: 6,11-Dihydro-11-(1-methyl-4-piperidinylidene)-5Hbenzo[5,6]cyclohepta[1,2-b]pyridine maleate Common Name: Structural Formula:
Chemical Abstracts Registry No.: 3978-86-7 Trade Name
Manufacturer
Country
Year Introduced
Idulian
Unilabo
France
1968
Optimine
Schering
US
1977
Optimine
Warrick
UK
1978
Optimine
Warrick
Italy
1983
Optimine
Byk-Essex
W. Germany
1983
Trinalin
Schering
US
-
Verben
Schering
-
-
Zadine
Schering
-
-
Raw Materials N-Methyl-4-chloropiperidine Polyphosphoric acid 4-Aza-10,11-dihydro-5-H-dibenzo-[a,d]cycloheptene-5-one Ethyl bromide
Azatepa
483
Magnesium Maleic acid Manufacturing Process Preparation of 4-aza-5-(N-methyl-4-piperidyl)-10,11-dihydro-5Hdibenzo[a,d]cycloheptene-5-ol: Add 17.4 g of N-methyl-4-chloropiperidine to a stirred mixture containing 3.2 g of magnesium, 20 ml of anhydrous tetrahydrofuran, 1 ml of ethyl bromide and a crystal of iodine. Reflux for two hours, cool to 30-35°C and add a solution of 13 g of 4-aza-10,11-dihydro-5Hdibenzo[a,d]cycloheptene-5-one in 25 ml of tetrahydrofuran. Stir for five hours, remove the solvent by distillation in vacuum and add 250 ml of ether. Add 100 ml of 10% ammonium chloride solution and extract the mixture with chloroform. Concentrate the chloroform solution to a residue and recrystallize from isopropyl ether obtaining 20 g of the carbinol, MP 173-174°C. Preparation of 4-aza-5-(N-methyl-4-piperidylidene)-10,11-dihydro-5Hdibenzo[a,d]cycloheptene: Heat 5.4 g of the carbinol and 270 g of polyphosphoric acid for 12 hours at 140-170°C. Pour into ice water and make alkaline with sodium hydroxide. Extract with ether. Dry ether solution and concentrate to a residue. Crystallize from isopropyl ether, MP 124-126°C. Preparation of 4-aza-5-(N-methyl-4-piperidylidene)-10,11-dihydro-5Hdibenzo[a,d]cycloheptene dimaleate: To a solution containing 4.3 g of 4-aza(N-methyl-4-piperidylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene in 55 ml of ethyl acetate, add a solution of 3.45 g of maleic acid dissolved in ethyl acetate. Filter the resulting precipitate and recrystallize the desired product from an ethyl acetate-methanol mixture to yield 4-aza-5-(N-methyl-4piperidylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene dimaleate, MP 152-154°C. References Merck Index 906 PDR pp. 1643, 1657 OCDS Vol. 2 p. 424 DOT 5 (2) 47 (1969) I.N. p. 110 REM p. 1131 Villani, F.J.; US Patents 3,326,924; January 20, 1967; 3,357,986; December 12, 1967; and 3,419,565; December 31, 1968; all Assigned to Schering Corp.
AZATEPA Therapeutic Function: Antineoplastic Chemical Name: Phosphinic amide, P,P-bis(1-aziridinyl)-N-ethyl-N-1,3,4thiadiazol-2-ylCommon Name: Azatepa; Azetepa; Thiatriamide
484
Azathioprine
Structural Formula:
Chemical Abstracts Registry No.: 125-45-1 Trade Name
Manufacturer
Country
Year Introduced
Azatepa
ZYF Pharm Chemical
-
-
Raw Materials 2-Ethylamino-1,3,4-thiadiazole hydrochloride Phosphorus oxychloride Ethylenimine Triethylamine Manufacturing Process N-Ethyl-N-(1,3,4-thiadiazol-2-yl)amidophosphoryl chloride is prepared by refluxing 16.4 parts of 2-ethylamino-1,3,4-thiadiazole hydrochloride with 84 parts of phosphorus oxychloride for 6 h and then removing the excess phosphorus oxychloride by distillation under reduced pressure. The residual oil is washed with cold petroleum ether, dried and dissolved in 310 parts of dry benzene. The solution of N-ethyl-N-(1,3,4-thiadiazol-2-yl)amidophosphoryl chloride is added slowly at 10°C to a mixture of 9.5 parts of ethylenimine, 30.3 parts of triethylamine, and 44 parts of warm dry benzene. Agitation is continued for 2 h without cooling after which the triethylamine hydrochloride is filtered off. The benzene is distilled from the filtrate under reduced pressure, and the N,N'-diethylene-N''-ethyl-(N'-(1,3,4-thiadiazo-2-yl)phosphoramide is recrystallized from hexane, melting point 95°-96°C. References GB Patent No. 885,370; Dec. 28, 1961; Assigned: American Cyanamid Company, State of Maine, USA
AZATHIOPRINE Therapeutic Function: Immunosuppressive Chemical Name: 6-[(1-Methyl-4-nitroimidazol-5-yl)thio]purine Common Name: Azothioprine
Azathioprine
485
Structural Formula:
Chemical Abstracts Registry No.: 446-86-6 Trade Name
Manufacturer
Country
Year Introduced
Imuran
Wellcome
UK
1964
Imurel
Wellcome
France
1967
Imurek
Wellcome
W. Germany
1967
Imuran
Wellcome
US
1968
Imuran
Wellcome
Italy
1968
Imuran
Tanabe
Japan
1969
Azamun
Medica
Finland
-
Azanin
Tanabe
Japan
-
Azapress
Lennon
S. Africa
-
Raw Materials N,N'-Dimethyloxaldiamide Nitric acid
Phosphorus pentachloride 6-Mercaptopurine
Manufacturing Process N,N'-Dimethyloxaldiamide is reacted with PCl5, to give 4-chloro-1-methyl imidazole. This is nitrated with HNO3 to give 5-nitro-1-methyl-4chloroimidazole. Then, a mixture of 4.6 grams of anhydrous 6mercaptopurine, 5 grams of 1-methyl-4-chloro-5-nitroimidazole and 2.5 grams of anhydrous sodium acetate in 100 ml of dry dimethyl sulfoxide was heated at 100°C for 7 hours. After standing overnight at room temperature, the mixture was poured into 200 ml of cold water and the yellow precipitate of 6-(1'-methyl-4'-nitro-5'imidazolyl)mercaptopurine (7.0 grams) collected. After recrystallization from 50% aqueous acetone, the product melted at 243-244°C, dec., and had an UV spectrum with λ maximum = 280 nm at pH 1 and λ max. = 285 nm at pH 11. References Merck Index 907 Kleeman and Engel p. 67 PDR p. 744 OCDS Vol. 2 p. 464 DOT 16 (10) 360 (1980) I.N.p. 110
486
Azelaic acid
REM p. 1143 Hitchings, G.H. and Elion, G.B.; US Patent 3,056,785; October 2, 1962: Assigned to Burroughs Wellcome and Co.
AZELAIC ACID Therapeutic Function: Antiacne, Depigmentor Chemical Name: 1,7-Heptanedicarboxylic acid Common Name: Acide azelaique; Acidum azelaicum; Anchoic acid; Azelaic acid; Azelainsaure; Lepargylic acid Structural Formula:
Chemical Abstracts Registry No.: 123-99-9 Trade Name
Manufacturer
Country
Year Introduced
Azelaic acid
Schering Health Care
-
-
Azelan
Schering-Plough
-
-
Azelex
Schering-Plough
-
-
Aziderm
Micro Labs
India
-
Skinoran
Schering
-
-
Skinoren
Schering
-
-
Raw Materials Oleic acid Hydrogen peroxide Nitric acid
Linoleic acid Formic acid Sodium metavanadate
Manufacturing Process Two step oxidation of tall oil fatty acid using peroxyformic acid and nitric acid/sodium metavanadate were used to produce azelaic acid. Step 1 (derivatization of the double bond): A hydroxy acyloxy derivative of tall oil fatty acid (TOFA) was prepared by mixing 200 g of TOFA (63% oleic acid, 31% linoleic acid) with 500 mL of
Azelaic acid
487
formic acid. The resulting mixture was vigorously stirred by magnetic action. Hydrogen peroxide solution, 180 mL of 35% by weight, was added in aliquots to the mixture throughout the course of the reaction. A third of the total amount of peroxide solution was added at once to initiate the reaction. The peroxyformic acid in this case was prepared in situ. The start of the reaction was signalled by heat evolution and a dramatic color change, from pale yellow to deep rust red. The exothermicity of the reaction required external cooling to control the temperature. The reaction was maintained at 40°C to minimize oxygen loss through the decomposition of the peroxide. As required, the temperature of the reaction was maintained with an external heating source. A total reaction time of 5 to 6 hours was necessary for complete reaction. The end of the reaction was indicated by a color change; the reaction mixture changed from rust red back to yellow. One last aliquot of peroxide solution was added at the end of the reaction period to provide a peroxide atmosphere during the reaction work-up. TOFA as a substrate produced a mixture of mono- and dihydroxy formoxystearic acid from the oleic and linoleic acid components, respectively. The final product was obtained in essentially 100% yield by removing the unreacted formic acid and hydrogen peroxide as well as water. It was obtained as a viscous, syrupy yellow oil that upon gas chromatographic analysis of the methyl esters of the reaction mixture gave no evidence of unreacted substrate. Step 2 (oxidation of derivative obtained from step 1): A 2 L three neck flask fitted with an air condenser attached to a gas scrubbing apparatus was filled with 500 mL of concentrated nitric acid (70% by weight). The acid was stirred by magnetic action and 1 g of sodium metavanadate was added to it. The resulting mixture was heated slowly to 40°-50°C. At this point a small amount of product as obtained from Step 1 was added to the acid-catalyst mixture. Heating was continued until a sharp temperature increase accompanied by evolution of NOx gases was observed. The reaction temperature was self-sustained with the addition of aliquots of the hydroxy formoxy ester mixture obtained from Step 1. (External cooling may be required throughout the substrate addition period to keep the temperature within 65°-70°C). At the end of the addition period the reaction temperature was maintained for an additional 1.5 to 2 hours, for a total reaction time of 3 hours. The final products were obtained by quenching the reaction by adding excess water and extracting the organic layer with purified diethyl ether. The ether extract was dried over anhydrous sodium sulfate overnight before its removal with a roto-vap apparatus. Addition of petroleum ether (boiling range 35°60°C) to the product mixture caused precipitation of the diacid component. Vacuum filtration was used to remove the solid diacids from the liquid monoacid mixture. The latter was obtained by removing the excess petroleum ether from the resulting filtrate. Quantitative analysis by gas chromatography of the methyl esters showed that the products to be 96% yield of diacid (66% azelaic, 30% suberic). References Malek A. et al.; US Patent No. 5,380,928; Jan. 10, 1995; Assigned: Synergistic Industries, Inc., Canada
488
Azepindole
AZEPINDOLE Therapeutic Function: Antidepressant Chemical Name: 1H-[1,4]Diazepino[1,2-a]indole, 2,3,4,5-tetrahydroCommon Name: Azependole Structural Formula:
Chemical Abstracts Registry No.: 26304-61-0 Trade Name
Manufacturer
Country
Year Introduced
Azependole
ZYF Pharm Chemical
-
-
McN-2453
McNeil Laboratories, Inc.
-
-
Raw Materials Ethyl indole-2-carboxylate Acetic acid Acetic anhydride Hydrogen Lithium aluminum hydride
Acrylonitrile Tenzyltrimethylammonium hydroxide Nickel Raney Sodium hydride
Manufacturing Process Ethyl indole-2-carboxylate (9.84 g, 0.052 mole) is dissolved in 150 ml dioxane. Acrylonitrile (3.11 g, 0.0588 mole) and benzyltrimethylammonium hydroxide (Triton B) (2 ml) are added and the mixture is warmed, with stirring, at 50°-55°C for 45 min. The solution is cooled to room temperature and stirred overnight. The reaction mixture is added to 500 ml water containing 3 ml glacial acetic acid. The mixture is extracted with methylene chloride, the organic layer washed with 2x25 ml water and dried over magnesium sulfate. The solvent is removed under reduced pressure. The remaining oil is dissolved in ether and filtered through alumina with ether as eluant. Evaporation of the ether gives a solid. The product obtained is ethyl N(β-cyanoethyl)indole-2-carboxylate, melting point 84°-86°C. A 2.42 g (0.01 mole) of ethyl N-(β-cyanoethyl)indole-2-carboxylate is suspended in acetic anhydride (20 ml). The suspended compound is hydrogenated on a Parr shaker in the presence of Raney nickel. The uptake of hydrogen is complete after 1.5 h. The product recovered is recrystallized from benzene-hexane. The product obtained is ethyl 1-(3-acetamidopropyl)indole2-carboxylate, melting point 83.5°-84.5°C.
Azetirelin
489
Ethyl 1-(3-acetamidopropyl)indole-2-carboxylate (1.44 g, 0.005 mole) is cyclized in the presence of sodium hydride (0.30 g, 0.00625 molar in hydride) in xylene under reflux. A few drops of absolute ethanol are added after 1 h reflux. Total reflux time is 2 h. The product recovered is crystallized from benzenehexane. The product obtained is 2,3,4,5-tetrahydro-1H-1,4diazepino[1,2-a]indol-1-one, melting point 181°-183°C. 2,3,4,5-Tetrahydro-1H-1,4-diazepino[1,2-a]indol-1-one (6.0 g, 0.03 mole) in 200 ml of monoglyme is added dropwise to a stirred suspension of lithium aluminum hydride (2.8 g, 0.08 mole) in 200 ml of monoglyme, and the mixture heated under reflux overnight. Water is added to the cooled mixture, and the mixture filtered. The filtrate is dried with anhydrous magnesium sulfate and concentrated in vacuum, giving an oil which solidifies on standing to give about 85% theoretical yield of the free amine, 2,3,4,5-tetrahydro-1H1,4-diazepino[1,2a]indol, melting point 75°-77°C. References Reynolds B.E., Carson J.R.; US Patent No. 3,867,374; February 18, 1975; Assigned: McNeil Laboratories, Incorporated, Ft. Washington, Pa.
AZETIRELIN Therapeutic Function: TRH analogue Chemical Name: L-Prolinamide, N-((4-oxo-2-azetidinyl)carbonyl)-L-histidyl-, (S)Common Name: Azetirelin Structural Formula:
Chemical Abstracts Registry No.: 95729-65-0 Trade Name
Manufacturer
Country
Year Introduced
Azetirelin
ZYF Pharm Chemical
-
-
Azetirelin
Yamanouchi
-
-
490
Azidamfenicol
Raw Materials L-Histidyl-L-prolinamide 2-hydrobromide Triethylamine (S)-2-Azetidinone-4-carboxylic acid Hydroxybenzotriazole Dicyclohexylcarbodiimide Manufacturing Process In 13 ml of DMF was dissolved 826.0 mg of L-histidyl-L-prolinamide 2hydrobromide and then 2 ml of a DMF solution of 405.0 mg of triethylamine was added to the solution under ice-cooling. After maintaining 30 min under ice-cooling, the precipitates thus formed were filtered off to provide L-histidylL-prolinamide. In 10 ml of DMF was dissolved 230.0 mg of (S)-2-azetidinone-4-carboxylic acid and then 351.0 mg of N-hydroxy-1,2,3-benzotriazole and 453.0 mg of dicyclohexylcarbodiimide were added to the solution under ice-cooling. Then, after stirring the mixture for 15 min, the reaction was maintained for 15 min at room temperature. The reaction mixture was ice-cooled again and 15 ml of a DMF solution of foregoing L-histidyl-L-prolinamide was added to the reaction mixture followed by reaction overnight at 0°C. The precipitates thus formed were filtered off, the filtrate was concentrated to dryness, the residue was dissolved in 10 ml of chloroform-methanol (4:1) and subjected to silica gel column chromatography. The eluates by chloroform-methanol (7:3) were collected and concentrated to dryness to provide 509.0 mg of crude product. When the product was subjected to silica gel column chromatography again and eluted by a mixture of chloroform, methanol, and aqueous ammonia (40:10:1) to provide 394.0 mg of pure Nepsilon-[(S)-2-azetidinone-4-carbonyl]L-histidyl-L-prolinamide, melting point 183°-185°C (crystallization from a small amount of methanol). References Tamura T. et al.; US Patent No. 4,636,567; January 13,1987; Assigned: Yamanouchi Pharmaceutical Co., Ltd., Tokyo, Japan
AZIDAMFENICOL Therapeutic Function: Antibiotic Chemical Name: Acetamide, 2-azido-N-((1R,2R)-2-hydroxy-1(hydroxymethyl)-2-(4-nitrophenyl)ethyl)Common Name: Azidamfenicol; Azidoamphenicol Chemical Abstracts Registry No.: 13838-08-9
Azidocillin
491
Structural Formula:
Trade Name
Manufacturer
Country
Year Introduced
BerlicetinAugentropfen
Chauvin
-
-
Berlicetin
Chauvin Ankerpharm
-
-
Leucomycin-N
Bayer
-
-
Posifenicol
Ursapharm
-
-
Thilocanfol
Alcon
-
-
Raw Materials D-(-)-Threo-1-p-nitrophenyl-2-aminopropane-1,3-diol Azidoacetonitrile Hydrochloric acid Manufacturing Process 21.2 g of D-(-)-threo-1-p-nitrophenyl-2-aminopropane-1,3-diol are stirred with 10 g of azidoacetonitrile (B.P. 68°C/25 mm) in a mixture of 125 ml of methanol and 125 ml of water at 30-40°C for a few days. The mixture is filtered off from a little undissolved base and the solvent is distilled in vacuo. The residue is treated with a little normal hydrochloric acid until acid to Congo red and extracted with ethylacetate. By evaporating the solvent and recrystallizing the residue from ethylene chloride is obtained D-(-)-threo-1-pnitrophenyl-2-azidoacetylamino-propane-1,3-diol; M.P. 107°C. References Merck Index, Monograph number: 941, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. Meisser W. et al.; US Patent No. 2,882,275; Apr. 14, 1959; Assigned to Farbenfabriken Bayer Aktiengesellschaft, Germany
AZIDOCILLIN Therapeutic Function: Antibacterial Chemical Name: 6-(D-2-Azido-2-phenylacetamido)-3,3-dimethyl-7-oxo-4thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid
492
Azidocillin
Common Name: α-Azidobenzylpenicillin Structural Formula:
Chemical Abstracts Registry No.: 17243-38-8 Trade Name
Manufacturer
Country
Year Introduced
Nalpen
Beecham
W. Germany
1972
Longatren
Bayer
Italy
1981
Longatren
Bayer
Japan
-
Astracilina
Astra
Sweden
-
Finacillin
Sedequil
Portugal
-
Syncillin
Tropon
W. Germany
-
Raw Materials α-Azidophenylacetic acid 6-Aminopenicillanic acid Thionyl chloride
Ethyl chloroformate Triethylamine
Manufacturing Process Example 1: α-Azidobenzylpenicillin via the Mixed Anhydride - A solution of αazidophenylacetic acid (8.9 grams, 0.05 mol) of triethylamine (5.1 grams, 0.05 mol) in 50 ml of dry dimethylformamide was stirred and chilled below 5°C. At this temperature ethyl chloroformate (4.7 ml) was added in portions so that the temperature was never above -5°C. After the mixture had been stirred for 20 minutes, dry acetone (100 ml), chilled to -5°C, was added in one portion, immediately followed by an ice-cold solution of 6aminopenicillanic acid (10.8 grams, 0.05 mol) and triethylamine (5.1 grams, 0.05 mol) in 100 ml of water, and the stirring was continued for 1½ hours at 0°C. The pH of the mixture was adjusted to 7.5 by adding a saturated sodium bicarbonate solution. After being washed twice with diethyl ether, the reaction solution was acidified to pH 2 with dilute hydrochloric acid and extracted with ether. The ether solution containing the free penicillin was washed twice with water and then extracted with 50 ml of N potassium bicarbonate solution. After freeze drying of the obtained neutral solution, the potassium salt of αazidobenzylpenicillin was obtained as a slightly colored powder (11.2 grams, 54% yield) with a purity of 55% as determined by the hydroxylamine method (the potassium salt of penicillin G being used as a standard).
Azimilide hydrochloride
493
The infrared spectrum of this substance showed the presence of an azido group and a beta-lactam system. The substance inhibited the growth of Staph. aureus Oxford at a concentration of 0.25 mcg/ml. Example 2: α-Azidobenzylpenicillin via the Acid Chloride - 6-aminopenicillanic acid (18.5 grams, 0.085 mol) and sodium bicarbonate (21 grams, 0.025 mol) were dissolved in 200 ml of water and 100 ml of acetone. To this solution, chilled in ice, was added α-azidophenylacetyl chloride (16.6 grams, 0.085 mol), diluted with 10 ml of dry acetone. The temperature is held at 0° to 5°C and the reaction mixture was stirred for 2½ hours. The resulting solution was treated as described in Example 1 to give the potassium salt of α-azidobenzylpenicillin as a white powder (29.4 grams, 84% yield) with a purity of 83% as determined by the hydroxylamine method (the potassium salt of penicillin G being used as a standard). The product showed the same properties as the product obtained in Example 1;. it inhibits the growth of Staph. aureus Oxford at a concentration of 0.13 mcg/ml. The α-azidophenylacetyl chloride was prepared by treating α-azidophenylacetic acid with thionylchloride in portions at room temperature and then heating the solution under reflux for one hour. The α-azidophenylacetyl chloride distils at 115°C under a pressure of 10 mm Hg. References Merck Index 913 Kleeman and Engel p. 68 DOT 7 (5) 186 (1971) and 8 (7) 248 (1972) I.N.p. 111 Sjoberg, B.O.H. and Ekstrom, B.A.; US Patent 3,293,242; December 20, 1966; Assigned to Beecham Group Limited, England
AZIMILIDE HYDROCHLORIDE Therapeutic Function: Antiarrhythmic Chemical Name: 1-{[5-(4-Chlorophenyl)furan-2-ylmethylene]amino}-3-[4(4-methylpiperazin-1-yl)butyl]imidazolidine-2,4-dione dihydrochloride Common Name: Azimilide hydrochloride; Stedicor Chemical Abstracts Registry No.: 149908-53-2 (Base); 149888-94-8 Trade Name
Manufacturer
Country
Year Introduced
Stedicor
Procter and Gamble
-
-
494
Azimilide hydrochloride
Structural Formula:
Raw Materials 1-Bromo-4-chlorobutane Sodium hydride 1-Methylpiperazine Hydrogen chloride Hydrogen Sodium iodide
1-(Benzylideneamino)hydantoin Sodium iodide Sodium bicarbonate Palladium on carbon 5-(4-Chlorophenyl)-2-furancarboxaldehyde
Manufacturing Process 1-Phenylmethylenamino-3-(4-chlorobutyl)-2,4-imidazolidinedione dihydrochloride is prepared by adding 60% sodium hydride in mineral oil (7.8 g, 0.1944 mole) over 1 h to a stirred solution o f 1(benzy1ideneamino)hydantoin [prepared as described by J. Gut, A Novacet, and P. Fiedler, Coll. Czech. Chern. Comrnun., Vol. 33, pp. 2087-2096; No. 71, 1968] (39.5 g , 0.1944 mole) in dimethyl formamide (1000 ml). After complete addition, the solution is heated at steam bath temperature (approximately 100°C) for 1.5 h. The resulting mixture is allowed to cool to room temperature (30°C). While stirring at room temperature, 1-bromo-4-chlorobutane (100 g ,0.5832 mole, 3 eq.) is added in one portion. The mixture becomes exothermic reaching around 35°C in approximately 30 min. The near-solution is heated a t approximately 80°C by steam bath for 4 h, cooled and stirred for approximately 8 h at room temperature (30°C). The cloudy mixture is filtered, removing a small amount of insoluble solid. The filtrate is concentrated under reduced pressure to a semi-solid residue. This residue is triturated with H2O (400 ml), collected, recrystallized from acetonitrile, and then air-dried to give 43.1 g (0.1467 mole) of 1-phenylmethyleneamino-3-(4-chlorobutyl)-2,4imidazolidinedione. A mixture of 1-phenylmethyleneamino-3-(4-chlorobutyl)-2,4imidazolidinedione (43.1 g, 0.1467 mole), acetone (1200 ml) and sodium iodide (48.4 9, 0.3227 mole) is heated to reflux. Reflux is maintained for 5 h. The mixture is filtered, collecting the insoluble. The filtrate is recharged with sodium iodide (10.0 g) and reflux is resumed and is maintained for 15 h. After cooling to room temperature, the mixture is filtered, removing the insoluble NaCl (total recovery, 9.5 g, 110%). The filtrate is poured into H2O (2000 ml) while stirring. After stirring for 30 min, the solid is collected and air-dried to yield 51.5 g (0.1337 mole) of 1-phenylmethyleneamino-3-(4-iodobutyl)-2,4imidazolidinedione.
Azimilide hydrochloride
495
A solution of 1-phenylmethyleneamino-3-(4-iodobutyl)-2,4-imidazolidinedione (10.0 g, 0.0260 mole), dimethylformamide (150.0 mg) and 1methylpiperazine (11.5 ml, 10.4 9, 0.1040 mole) is heated to reflux. Reflux is maintained for 3 h. After cooling to approximately 40°C, the solution is concentrated under reduced pressure by rotary evaporator to an oily-solid residue. This residue is dissolved in H2O (200 ml) then made basic with saturated NaHCO3 (200 ml). The resulting mixture is stirred for 2 h. The solid is collected and air-dried, and is next dissolved in absolute ethanol (150 ml), next filtered, then made acidic to wet litmus with EtOH/HCl. After cooling several hours, the solid is collected and air-dried to give 8.04 g (0.0187 mole) of 1-phenylmethyleneamino-3-[4-(4-methyl-1-piperazinyl)butyl]-2,4imidazolidinedione dihydrochloride. A mixture of 1-phenylmethyleneamino-3-[4-(4-methyl-1-piperazinyl)butyl]2,4-imidazolidinedione dihydrochloride (8.04 g, 0.0187 mole), 2 N HCl (125 ml) and 5% Pd/C: 50% H2O (1.5 g) is subjected to hydrogen on a Parr apparatus at 40 psi at room temperature. After 2 h, the catalyst is removed by filtration. The filtrate is divided into two equal portions. Each is concentrated under reduced pressure on a rotary 10 evaporator to an oily residue of 1-amino-3-[4-(4-methyl-1-piperazinyl)butyl]-2,4-imidazolidinedione hydrochloride. A solution of 1-amino-3-[4-(4-methyl-1-piperazinyl)butyl]-2,4imidazolidinedione hydrochloride (0.0094 mole), dimethylformamide (75 ml) and 5-(4-chlorophenyl)-2-furancarboxaldehyde [prepared as described in U.S. Patent No. 20 4,882,354, to Huang et al., assigned to Norwich Eaton Pharmaceuticals, Inc., issued November 21, 1984; see Cols. 7 and 8] (1.94 g , 0.0094 mole) is stirred at room temperature for 72 h. The mixture is filtered, collecting the solid. Recrystallization from absolute ethanol/H2O and air-drying gives 2.63 g (0.0050 mole) of 1-[[[5-(4-chlorophenyl)-2furanyl]methylene]amino]3-[4-(4-methyl-1-piperazinyl)butyl]-2,4imidazolidinedion hydrochloride. 1-[[[5-(4-Chlorophenyl)-2-furanyl]methylene]amino]-3-[4-(4-methyl-1piperazinyl)butyl]-2,4-imidazolidinedione hydrochloride, (6.56 g, 0.0124 mole) is dissolved in H2O (300 ml) and washed with (1x100 ml). The aqueous phase is made basic with saturated NaHCO3 solution. The resulting mixture is extracted with CH2Cl2 (4x100 ml). The extract is washed with saturated NaCl (2x50 ml), dried over MgSO4 (activated charcoal), filtered and concentrated under reduced pressure to a solid residue. This solid is triturated in anhydrous ether, collected and air-dried. Recrystallization once from absolute EtOH and then from toluene (activated charcoal), next washing with anhydrous ether and air drying gives 2.05 g (0.0045 mole) of 1-[[[5-(4-chlorophenyl)-2furanyl]methylene]amino]-3-[4-(4-methyl-1-piperazinyl)butyl]-2,4imidazolidinedione. References Pelosi S.S., Calcagno M.A.; WO Patent No. 93/04061; March 4, 1993; Assigned: Procter and Gamble Pharmaceuticals [US/US]; NY (US)
496
Azintamide
AZINTAMIDE Therapeutic Function: Choleretic Chemical Name: (6-Chlorpyridazin-3-ylthio)diethylacetamide Common Name: Azintamide; Azinthiamide Structural Formula:
Chemical Abstracts Registry No.: 1830-32-6 Trade Name
Manufacturer
Country
Year Introduced
Azintamide
Bristhar Laboratorios
-
-
Azintamide
Nycomed Austria GmbH Pharm Chemical Shanghai Lansheng Corporation
-
-
-
-
Biluen
Byk Argentina
-
-
Colerin
Laboratorios LAB, LDA
-
-
Ora-Gallin purum
Nycomed
-
-
Oragallin
Austerreichcshe Shtkttofwerke
-
-
Soragallin
Misr Co.
-
-
Soragallin
Linz Co.
-
-
Azintamide
Raw Materials 3-Chloro-6-mercaptopyridazine Chloroacetic acid diethyl amide Caustic soda Manufacturing Process 7.3 parts of 3-chloro-6-mercaptopyridazine are neutralised with 20 parts of 10% caustic soda solution, diluted with 60 parts of 50% ethanol, and heated to 60°C. 7.5 parts of chloroacetic acid diethyl amide dissolved in 20 parts of ethanol are added to this solution over a period of 10 min and the resulting mixture is heated to 60°C for 30 min. The reaction solution is then cooled, the
Azithromycin
497
resulting crystallisate is removed by suction, and the filtrate is extracted with ethyl acetate. The solvent is removed by evaporation and the concentration residue is combined with the crystallisate. After two recrystallisations from benzene, 11 parts of 3-chloro-pyridazine-6-mercaptoacetic acid diethyl amide, having a melting point of from 139° to 140°C are yielded. References Merck Index, Monograph number: 945, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. Stormann, Arzneim.-Forsch., 1964, 14, 266
AZITHROMYCIN Therapeutic Function: Antibiotic Chemical Name: Azithromycin Common Name: Azithromycin Structural Formula:
Chemical Abstracts Registry No.: 83905-01-5 Trade Name
Manufacturer
Country
Year Introduced
ATM
Indoco Remedies Ltd.
India
-
AZ-1
Kopran Limited
India
-
Azee Rediuse
Protech Biosystems
-
-
Azicare
Olcare Laboratories
India
-
Azifast
Innova (IPCA)
India
-
Azilide
Micro Nova Pharmaceuticals Ltd.
India
-
498
Azithromycin
Trade Name
Manufacturer
Country
Year Introduced
Azithral
Alembic Ltd.
India
-
Azithro-250
Ind-Swift Ltd.
India
-
Azithromycin
Alembi
India
-
Azitop
Talent Laboratories
India
-
Aziwok
Wockhardt Ltd.
India
-
Hemomycin
Hemofarm
Serbia and Montenegro
-
Licathrom
Replica Remedies
India
-
Sumamed
Pliva
Croatia
-
Vicon
Pfizer
-
-
Zady
Mankind Pharma Pvt. Ltd.
India
-
Zathrin
FDC Ltd.
India
-
Zithromax
Teuto/Neo Quimica
-
-
Zithromax
Pfizer
-
-
Zycin
IRM Pharma
India
-
Raw Materials 11-Aza-10-deoxo-10-dihydroerythromycin A Formic acid Formaldehyde Manufacturing Process To a solution of 0.54 g (0.000722 mole) of 11 aza-10-deoxo-10dihydroerythromycin A in 20 ml CHCl3 were added 0.0589 ml (0.000741 mole) of formaldehyde (approx. 35% w./w.) and 0.00283 g (0.000735 mole) of formic acid (approx. 98 to 100% w./w.). The reaction mixture was stirred for 8 hours while heating under reflux, then cooled to ambient temperature, whereupon were added 15 ml of water (pH 5.8). The pH of the reaction mixture was adjusted to 5.0 by means of 2 N HCl, whereupon the CHCl3 layer was separated. To the aqueous part was added 15 ml of CHCl3, the pH of the reaction suspension was adjusted to 7.5 by means of 20% NaOH, the layers were separated and subsequently the aqueous layer was extracted three times with 15 ml of CHCl3. The combined chloroform extracts having pH 7.5 were dried over K2CO3 and evaporated under reduced pressure, yielding 0.45 g (82.4%) of N-methyl-11-aza-10-deoxo-10-dihydro erythromycin A (azithromycin), m.p. 113°-115°C. [α]D20= - 37.0 (1% in CHCl3). References Murphu H.W. et al.; US Patent No. 3,417,077; Dec. 17, 1968 Kobrehel G. et al.; US Patent No. 4,328,334; May 4, 1982; Assigned: PLIVA Pharmaceutical and Chemical Works (Zagreb, YU) Bright G.M.; US Patent No. 4,474,768; Oct. 2, 1984; Assigned: Pfizer Inc. (New York, NY)
Azlocillin
499
AZLOCILLIN Therapeutic Function: Antibacterial Chemical Name: D-α-(Imidazolidin-2-on-1-yl-carbonylamino)benzylpenicillin, sodium salt Common Name: Structural Formula:
Chemical Abstracts Registry No.: 37091-66-0; 37091-65-9 (Sodium Salt) Trade Name
Manufacturer
Country
Year Introduced
Securopen
Bayer
W. Germany
1977
Securopen
Bayer
Switz.
1980
Securopen
Bayer
UK
1980
Azlin
Miles
US
1982
Securopen
Bayer
France
1983
Raw Materials D-(-)-α-[(Imidazolidin-2-on-1-yl)carbonylamino]phenyl acetic acid 6-Aminopenicillanic acid Manufacturing Process 3.8 parts by weight of D-(-)-α-[(imidazolidin-2-on-1-yl)carbonylamino]phenylacetic acid were dissolved in 65 parts by volume of dichloromethane. 2.7 parts by weight of 1-methyl-2-chloro-δ1-pyrrolinium chloride were added, and after cooling to -10°C 2.0 parts by volume of triethylamine were added gradually. This reaction mixture was then stirred for one hour at -5°C (mixture A). 4.0 parts by weight of 6-aminopenicillanic acid in 80 parts by volume of dichloromethane were treated with 4.4 parts by volume of triethylamine and 4.0 parts by weight of anhydrous sodium sulfate and then stirred for two hours at room temperature. After filtration, the solution was cooled to -20°C and combined with the mixture A. The reaction mixture was left to reach 0°C of its own accord, and was then stirred for a further hour at 0°C. The solvent was removed in a rotary evaporator, the residue was dissolved in water, and the solution was covered with a layer of ethyl acetate
500
Azolimine
and acidified with dilute hydrochloric acid at 0° to 5°C, while stirring, until pH 1.5 was reached. The organic phase was then separated off, washed with water, dried over magnesium sulfate while cooling, and filtered, and after dilution with an equal amount of ether the sodium salt of the penicillin was precipitated from the filtrate by adding a solution of sodium 2-ethylcaproate dissolved in ether containing methanol. Yield: 1.3 parts by weight. References Merck Index 916 Kleeman and Engel p. 69 PDR p. 1247 OCDS Vol. 3 p. 206 (1984) DOT 13 (10) 409 (1977) I.N.p. 111 REM p. 1200 Konig, H.B., Schrock, W., Disselknotter, H. and Metzger, K.G.; US Patents 3,933,795; January 20, 1976; 3,936,442; February 3, 1976; 3,939,149; February 17, 1976; 3,974,140; August 10, 1976; 3,978,223; August 31, 1976 and 3,980,792; September 14, 1976; all
AZOLIMINE Therapeutic Function: Diuretic Chemical Name: 4-Imidazolidinone, 2-imino-3-methyl-1-phenylCommon Name: Azolimine Structural Formula:
Chemical Abstracts Registry No.: 40828-45-3 Trade Name
Manufacturer
Country
Year Introduced
Azolimine
ZYF Pharm Chemical
-
-
Raw Materials Sodium hydroxide Phenylcyanamide N-Methylchloroacetamide Sodium methoxide Phenylcyanamide hemihydrate
Azosemide
501
Manufacturing Process 2 methods of producing of 1-phenyl-2-imino-3-methyl-4-oxoimidazolidine: 1). In 29 ml of water containing 1.0 g of sodium hydroxide was dissolved 3.55 g of phenylcyanamide. To the clear solution was added 2.7 g of Nmethylchloroacetamide. The reaction mixture was left to stir for 120 h at room temperature. The solvent was therefore stripped off on a rotary evaporator under vacuum. The solid residue was slurried in dilute alkali and filtered to yield 1.0 g (21%) of 1-phenyl-2-imino-3-methyl-4-oxoimidazolidine, melting point 163°-165°C. 2). 133.0 g of phenylcyanamide hemihydrate was dissolved in 1500 ml of absolute alcohol. To this solution was added 55.0 g of sodium methoxide. This mixture was stirred for 30 min and 113.0 g of N-methylchloroacetamide then added. This mixture was heated to reflux for 4 h and allowed to stand overnight. The white precipitate was filtered and washed with ethanol. This ethanol filtrate was concentrated on the rotating evaporator and cooled giving additional product. Both crops of product were combined, washed with water and dried to give 87.0 g (47%) of 1-phenyl-2-imino-3-methyl-4oxoimidazolidine, melting point 169°-170°C. References Hanifin J.W. et al.; US Patent No. 4,044,021; August 23, 1977; Assigned: American Cyanamid Company, Stamford, Conn.
AZOSEMIDE Therapeutic Function: Diuretic Chemical Name: 5-(4'-Chloro-2'-thenylamino-5'-sulfamoylphenyl)tetrazole Common Name: Structural Formula:
Chemical Abstracts Registry No.: 27589-33-9
502
Azotomycin
Trade Name
Manufacturer
Country
Year Introduced
Diurapid
Boehringer Mannheim
W. Germany
1981
Raw Materials 4-Chloro-2-fluoro-5-sulfamoyl benzonitrile Thenylamine Sodium azide Manufacturing Process The 4-chloro-5-sulfamoyl-2-thenylaminobenzonitrile used as starting material is obtained by the reaction of 4-chloro-2-fluoro-5-sutfamoyl-benzonitrile with thenylamine in anhydrous tetrahydrofuran. Then the 5-(4'-chloro-5'-sulfamoyl-2'-thenylamino)phenyltetrazole (MP 218° to 221°C; yield 37% of theory) is obtained by the reaction of 4-chloro-5sulfamoyl-2-thenylaminobenzonitrite (MP 170° to 174°C) with sodium azide and ammonium chloride, References Merck Index 922 DFU 4 (6)393 (1979) OCDS Vol. 3 p. 27 (1984) Popelek, A., Lerch, A., Stach, K., Roesch, E. and Hardebeck, K.; US Patent 3,665,002; May 23, 1972; Assigned to Boehringer Mannheim GmbH
AZOTOMYCIN Therapeutic Function: Antineoplastic Chemical Name: L-Norleucine, 6-diazo-N-(6-diazo-N-L-γ-glutamyl-5-oxo-Lnorleucyl)-5-oxoCommon Name: Azotomycin; Duazomycin B Structural Formula:
Azotomycin
503
Chemical Abstracts Registry No.: 7644-67-9 Trade Name
Manufacturer
Country
Year Introduced
Azotomycin
ZYF Pharm Chemical
-
-
Raw Materials γ-OBzl-N-Boc-L-Glu Trifluoroacetic acid N-Methylmorpholine Oxalyl chloride Sephadex LH-20
Diazomethane Isobutyl chloroformate Palladium on carbon Triethylamine
Manufacturing Process Azotomycin is anticancer antibiotic produced by Streptomyces ambofaciens. Total sythesis of it from γ-benzyl-N-tert-butyloxycarbonyl-L-glutamic acid (γOBzl-N-Boc-L-Glu) has been accomplished in nine steps. The mixed carbonic anhydride method was chosen for peptide bond formation. Commerically available γ-OBzl-N-Boc-L-Glu was esterified with ethereal diazomethane, deprotected with trifluoroacetic acid-methylene chloride (1:1), and converted to hydrochloride γ-benzyl-L-glutamic acid α-methyl ester (γ-OBzl-L-Glu-α-OMe HCl) by treatment with dry hydrogen chloride in ethyl ether, MP: 129°-135°C (dec.); [α]D25= + 13.3° (CHCl3). Reaction of γ-OBzl-N-Boc-L-Glu with isobutyl chloroformate and Nmethylmorpholine followed by addition of γ-OBzl-L-Glu-α-OMe HCl afforded dipeptide γ-OBzl-N-Boc-L-Glu-γ-OBzl-L-Glu-α-OMe; yield 93%, MP: 58.5°60°C; [α]D25= + 7.10° (CHCl3). After cleaving (trifluoroacetic acid-methylene chloride) the Boc group of above dipeptide, N-Tfa-L-Glu-OMe (Tfatrifluoroacetyl) was condensed with the product to afford tripeptide N-(γ-NTfa-L-Glu-α-OMe)-v-OBzl-N-Boc-L-Glu-γ-OBzl-L-Glu-α-OMe as colorless crystals, MP: 120°-122°C, [α]D25= + 7.7° (CHCl3). Following hydrogenolysis of benzyl esters using palladium-on-carbon (10%), diacid N-(γ-N-Tfa-L-Glu-αOMe)-L-Glu-L-GluOMe was obtained in yield 94% as colorless crystals, MP: 181°-184°C; [α]D25= - 37.6° (CH3OH). Selectively protected above diacid was converted to (γ-N-Tfa-L-Glu-α-OMe)-LGlu-L-Glu-tetra-OMe next way. To a solution of N-(γ-N-Tfa-L-Glu-α-OMe)-L-GluL-Glu-α-OMe (0.18 g) in dry acetone (20 ml cooled to 0°C was added with magnetic stirring ethereal diazomethane (0.8 mole) until yellow color persisted. After evaporation of solvent, the colorless solid was recrystallized from methylene chloride-hexanes to afford 0.17 g (92%) of colorless crystals of (γ-N-Tfa-L-Glu-α-OMe)-L-Glu-L-Glu-tetra-OMe; MP: 150°-152°C; [α]D25= 8.5° (CHCl3). A 1.00 g (1.9 mmoles) of (γ-N-Tfa-L-Glu-α-OMe)-L-Glu-L-Glu-tetra-OMe was dissolved under argon in dry dimethoxyethane (30 ml) with warming and magnetic stirring, and triethylamine (0.55 ml, 3.97 mmoles) was added. The reaction mixture was cooled to -30°C (dry ice isopropyl alcohol), and oxalyl chloride (0.35 ml, 3.97 mmoles) was added followed by dimethylformamide (2
504
Aztreonam
drops). The reaction mixture was warmed to 0°C by addition of hot isopropyl alcohol to the dry ice bath, stirred for 40 min, and then cooled to -78°C. The cold acid chloride solution was slowly (30 min) added through the sintered-glass filter into ethereal solution of diazomethane (0.5 moles, 30 ml) cooled to -23°C (dry ice-carbon tetrachloride). After the mixture was stirred 30 min at -23°C and 30 min at 0°C, solvent was evaporated by steam argon, and the residue was chromatographed in 19:1 ethyl acetate-methanol on column of silica gel (70 g). The fraction (24:1 ethyl acetate-methanol) with TLC Rf 0.16 were collected and solvent evaporated to 0.30 g (38 %) of light yellow crystals of N-Tfa(-)-azotomycin-di-OMe, which upon recrystallization from chloroform-ethyl ether, melted at 134°-136°C; [α]D25= - 22.9°. To a mixture of N-Tfa(-)-azotomycin-di-OMe (106 mg, 0.18 mmoles) and methanol (0.12 ml) was added 1.0 N sodium hydroxide (0.83 ml, 8.3 mmoles) at room temperature and stirred for 30 min. Then the solution was acidified to pH 6.9 with 0.1 N hydrochloric acid and extracted with chloroform (2x25 ml). The aqueous phase was dissolved in methanol and passed through a column of Sephadex LH-20 (250 g), and fractions containing the magor product (TLC Rf 0.31, methanol, tailing) were collected. Solvent was evaporated and the residue was freeze-dried to yield 54.3 mg (65%) of (-)-azotomycin as a light yellow solid, which slowly decomposed at ambient temperature; [α]D25= 4.3°; IR, UV, 1H NMR, 13C NMR spectrum confirmed the structures of all described compounds. References Pettit G.R., Nelson P.S.; J Org.Chem.; v.51, No 8, pp 1282-1286; 1986
AZTREONAM Therapeutic Function: Antibiotic Chemical Name: Propanoic acid, 2-(((Z)-(1-(2-amino-4-thiazolyl)-2(((2S,3S)-2-methyl-4-oxo-1-sulfo-3-azetidinyl)amino)-2-oxoethylidene) amino)oxy)-2-methylCommon Name: Azthreonam; Aztreonam Chemical Abstracts Registry No.: 78110-38-0 Trade Name
Manufacturer
Country
Year Introduced
Azactam
Bristol-Myers Squibb
USA
-
Azenam
Aristo Pharmaceutical Ltd. Bristol-Myers Squibb
India
-
-
-
Aztreonam
Aztreonam
505
Structural Formula:
Raw Materials Arrobacterium radiobacter A.T.C.C. No. 31700 Carbohydrates Dimethybenzylammonium chloride Sodium tiocyanate Glucose Manufacturing Process The solutions for fermentation having the following composition was preparated: Yeast extract Glucose Oatmeal Tomato paste
2% 10% 2% 2%
This mixture was sterilized for 15 minutes at 121°C at 15 lbs/inch2 steam pressure prior to use. The fermentation flasks were incubated at 25°C for 40 to 45 hours on a of rotary shaker. A 250 liter batch of Agrobacterium radiobacter A.T.C.C. No. 31700 is fermented in a 100 gallon steel vessel with a media and operating conditions described below. Culture of Agrobacterium radiobacter grown out on agar slants, pH 7.3 consisted of yeast extract (1 g), beef extract (1 g), NZ amine A (2 g), glucose (10 g), agar (15 g) in 1000 ml distilled water. Loopful of surface growth from agar slant was used as the source of incolumn. Medium of oatmeal (20 g), tomato paste (20 g) tapped water to 1000 ml, pH 7, was sterilized for 15 min at 121°C at 15 lbs/inch2 steam pressure prior to use. 100 ml of the medium, containing incolumn is incubated at 25°C for about 24 hours on a rotary shaker. It was added to a mixture of yeast extract (5 g), glucose (10 g) in 1 L distilled water and incubated for about 42 hours at 25°C in 100 gallon stainless steel fermentation vessel. During incubation, the broth is agitated at 155 r.p.m. and aerated at rate of 10.0 cubic feet per minute. An antifoam agent (Ucon LB625, Union Carbide) was added as needed. The fermentation beer was adjusted to pH 4 with aqueous HCl and calls separated by centrifugation. The supernatante (200 L)
506
Azumolene sodium
was extracted with 40 L of 0.05 m cetyldimethylbenzyl ammonium chloride in dichloromethane and extract concentrated in vacuo to 5.5 L. The concentrate was then extracted with solution of 177 g of sodium thiocyanate in 2 L of water, adjusting the mixture of pH 4.35 with phosphoric acid. The aqueous extract was concentrated in vacuo to 465 ml and added to 1840 ml of methanol. Solids are filtrated yielded 194 g of crude solid product. It was dissolved and chromatographed on a 5x106.5 cm column of Sephadex G-10 three times and after concentrating in vacuo gave 3.5 g of crude antibiotic M53 (azetreonam) which was chromatographed at first on QAE Sephadex A25 (liner gradient, prepared from 2.5 L of water and 2.5 L of 0.25 M sodium nitrate). Then the residue (fractions 26-75) gave M53 (natrium salt) after evaporation. It was triturated with methanol and the souble fraction, 0.40 g was chromatographed on a 2.5x20 cm column of Diaion HP20AG, eluting at 2 ml per minute with water and collecting 20 ml fractions. Fractions 26-75 gave 51.9 mg of antibiotic M53 (sodium salt). In practice it is usually used as free base. References Sykes R.B. et al.; US Patent No. 4,321,326; Mar. 23, 1982; Assigned: E. R. Squibb and Sons, Inc. (Princeton, NJ)
AZUMOLENE SODIUM Therapeutic Function: Muscle relaxant Chemical Name: 2,4-Imidazolidinedione, 1-(((5-(4-bromophenyl)-2-oxazolyl) methylene)amino)-, sodium salt Common Name: Azumolene sodium Structural Formula:
Chemical Abstracts Registry No.: 64748-79-4 (Base) Trade Name
Manufacturer
Country
Year Introduced
Azumolene sodium
ZYF Pharm Chemical
-
-
Azumolene sodium
Procter and Gamble
-
-
Azumolene sodium
507
Raw Materials 2-Bromo-4'-bromoacetophenone Hexamethylenetetramine [[(2,4-Dioxo-1-imidazolidinyl)imino]methyl]formyl chloride Hydrogen chloride Amine hydrochloride Phosphorus oxychloride Manufacturing Process To a stirred solution of 2-bromo-4'-bromoacetophenone (100.0 g, 0.36 mole) in chloroform (500 ml) was added hexamethylenetetramine (50.0 g, 0.36 mole). The mixture was stirred for 2.5 h and 143.0 g of the product was collected by filtration (100%). The product above was combined with a solution of methanol (300 ml) and conc. HCl (410 ml), and the mixture was stirred for 52 h. The solid was collected by filtration and was washed with isopropanol. The product was recrystallized from methanol (Darco) to give 55.0 g (61%, in three crops), melting point 284°-287°C. To a stirred mixture of the above amine hydrochloride (55.0 g, 0.22 mole) and [[(2,4-dioxo-1-imidazolidinyl)imino]methyl]formyl chloride (42.0 g, 0.22 mole) was added a solution of 440 ml of dimethylformamide and 44 ml of pyridine. The mixture was stirred for 20 h and poured into 2 L of water. The solid was collected by filtration and washed with ethanol and ether to give 36.0 g (28%) of N-[2-(4-bromophenyl)-2-oxoethyl]-[[(2,4-dioxo-1-imidazolidinyl)imino]methyl]formamide, melting point 267°-269°C (recrystallization from 2200 ml acetic acid). The of N-[2-(4-bromophenyl)-2-oxoethyl]-[[(2,4-dioxo-1-imidazolidinyl) imino]methyl]formamide (22.0 g, 0.061 mole) was combined with phosphorus oxychloride (310 ml) and the mixture was stirred and refluxed for 7 h. The solid was filtered off and stirred into an ice and water mixture (1 L). The 15.0 g (70%) of 1-[[[5-(4-bromophenyl)-2-oxazolyl]methylene]amino]-2,4imidazolidinedione was collected by filtration, melting point 290°-292°C (recrystallization from 700 ml acetic acid). In practice it is usually used as sodium salt. References White R.L.; US Patent No. 4,049,650; September 20, 1977; Assigned: Morton-Norwich Products, Inc., Norwich, N. Y.
B
BACAMPICILLIN Therapeutic Function: Antibacterial Chemical Name: 6-[(Aminophenylacetyl)amino]-3,3-dimethyl-7-oxo-4-thia1-azabicyclo-[3.2.0]heptane-2-carboxylic acid 1-[(ethoxycarbonyl)oxy]ethyl ester Common Name: 1'-Ethoxycarbonyloxyethyl 6-(D-α-aminophenylacetamido) penicillinate Structural Formula:
Chemical Abstracts Registry No.: 50972-17-3; 37661-08-8 (Hydrochloride salt) Trade Name Penglobe Bacacil Penglobe Bacacil Ambaxin Spectrobid Bacacil Penglobe Bamaxin Ambacamp Bacampicin Velbacil
Manufacturer Astra Pfizer Lematte/Boinot Pfizer Upjohn Pfizer Pfizer Taito Yoshitomi Upjohn Upjohn Upjohn Pfizer
Country W. Germany Switz. France Italy UK US Japan Japan Canada W. Germany -
508
Year Introduced 1977 1978 1978 1980 1981 1981 1981 1981 1982 -
Bacitracin
509
Raw Materials Sodium 6-(D-α-azidophenylacetamido)penicillinate α-Chlorodiethyl carbonate Sodium bicarbonate Hydrogen Palladium on carbon Manufacturing Process 1'-Ethoxycarbonyloxyethyl 6-(D-α-azidophenylacetamido)penicillinate (98 g) was prepared from sodium 6-(D-α-azidophenylacetamido)penicillinate (397 g, 1 mol), α-chlorodiethylcarbonate (458 g, 3 mols) and sodium bicarbonate (504 g, 6 mols). The product showed strong IR absorption at 2090 cm-1 and 1780-1750 cm-1 showing the presence of azido group and β-lactam and ester carbonyls. It was dissolved in ethyl acetate (700 ml) and hydrogenated at ambient conditions over a palladium (5%)on carbon catalyst (18 g). The catalyst was removed by filtration and washed with ethyl acetate. The combined filtrates were extracted with water at pH 2.5 by addition of dilute hydrochloric acid. Lyophilization of the aqueous phase gave the hydrochloride of 1'ethoxycarbonyloxyethyl 6-(D-α-aminophenylacetarnido)penicillinate (94 g), MP 171°-176°C. References Merck Index 933 Kleeman and Engel p. 69 PDR p. 1531 OCDS Vol. 3 p. 204 (1984) DOT 11 (11) 428 (1975) and 13 (10) 415 (1977) I.N.p.113 REM p. 1200 Ekstrom, B.A. and Sjoberg, B.O.H.; US Patents 3,873,521; March 25, 1975;and 3,939,270; February 17, 1976; both assigned to Astra Lakemedal A.B.
BACITRACIN Therapeutic Function: Antibacterial Chemical Name: Complex polypeptide mixture containing predominantly bacitracin A Common Name: Chemical Abstracts Registry No.: 1405-87-4; 21373-17-1 (Bacitracin A)
510
Bacitracin
Structural Formula:
Trade Name Baciguent Topitracin Bacitracine Bacitracine Bacitracin Bacitracin Batrax Cicatrin Cicatrex Enterostop Fortracin Hydroderm
Manufacturer Upjohn Comm. Solvents Novopharm Djamant Kayaku Upjohn Gewo Calmic Wellcome Schiapparelli A.L. Merck Sharp and Dohme
Country US US Switz. France Japan US W. Germany UK W. Germany Italy US UK
Year Introduced 1948 1948 1953 -
Medicrucin Nebacetin Neobacrin Neo-Caf Neo-Polycin Neosporin
Medice Byk Gulden Glaxo Francia Dow BurroughsWellcome
W. Germany W. Germany UK Italy US US
-
Orobicin Polybactrin Polybactrin Polycin Polyfax Polysporin
Fulton Calmic Wellcome Dow Wellcome BurroughsWellcome
Italy UK W. Germany US UK US
-
Rikospray Topitracin
Riker Reed Carnrick
UK US
-
Bacitracin
511
Raw Materials Bacillus subtilis Nutrient medium Manufacturing Process The early patent, US Patent 2,498,165 first disclosed bacitracin and described a process for preparing bacitracin, comprising cultivating Bacillus subtilis Tracy I in a nutritive medium, at substantially pH 7 and 37°C, for more than three days, extracting the antibiotic from the resulting medium with a low molecular weight alcohol, concentrating the resulting alcoholic solution in vacuo, acidifying the resulting concentrate, extracting the antibiotic from the resulting solution, and precipitating the antibiotic from the resulting solution, with a precipitating agent for the antibiotic, selected from the group consisting of Reinecke's salt, phosphotungstic acid, phosphomolybdic acid, molybdic acid, picric acid, ammonium rhodanilate, and azobenzene-p-sulfonicacid. A subsequent patent, US Patent 2,828,246 described a commercial process for bacitracin production. A 1,230 gallon portion of a medium containing 10% soybean oil meal, 2.50% starch and 0.50% calcium carbonate having a pH of 7.0 was inoculated with a culture of bacitracin-producing bacteria of the Bacillus subtilis group and the inoculated medium incubated for a period of 24 hours with aeration such that the superficial air velocity was 12.1. An assay of the nutrient medium following the fermentation revealed a yield of bacitracin amounting to 323 units/ml. This was more than twice the yields previously obtained. Then, a patent, US Patent 2,834,711 described the purification of bacitracin. In this process for purifying bacitracin, the steps comprise adding a watersoluble zinc salt to a partially purified aqueous solution of bacitracin, adjusting the pH to from 5 to 9, recovering the precipitate which forms, dissolving the precipitate in water at a pH not substantially in excess of 4, and removing the zinc ion by passing the aqueous solution through a cation exchange resin and drying the resulting solution to obtain dry solid bacitracin. Another patent, US Patent 2,915,432describes a process of recovering and concentrating bacitracin from aqueous filtered fermentation broth containing on the order of 3% protein-aceous solids which comprises intimately contacting the broth with a synthetic organic cation exchange resin having as its functional groups nuclear sulfonic acids and having a crosslinkage of the order of 1 to 2%, with the resin being in the hydrogen form, and eluting the adsorbed bacitracin from the resin with a weak base. Bacitracin recovery is described in US Patents 3,795,663 and 4,101,539. References Merck Index 937 Kleeman and Engel p.70 PDR p.888 I.N. p.113 REM p.1201
512
Baclofen
Chaiet, L. and Cochrane, T.J., Jr.; US Patent 2,915,432; December 1, 1959; assigned to Merck and Co., Inc. Johnson,R.A. and Meleney, F.L.; US Patent 2,498,165; February 21, 1950; assigned to US Secretary of War Freaney, T.E. and Allen, L.P.; US Patent 2,828,246; March 25, 1958; assigned to Commercial Solvents Corporation Zinn, E. and Chornock, F.W.; US Patent 2,834,711; May 13, 1958; assigned to Commercial Solvents Corporation Miescher, G.M.; US Patent 3,795,663; March 5, 1974; assigned to Commercial Solvents Corp. Kindraka,J.A. and Gallagher, J.B.; US Patent 4,101,539; July 18, 1978; assigned to IMC Chemical Group, Inc.
BACLOFEN Therapeutic Function: Muscle relaxant Chemical Name: γ-Amino-β-(p-chlorophenyl)butyric acid Common Name: Structural Formula:
Chemical Abstracts Registry No.: 1134-47-0 Trade Name Lioresal Lioresal Lioresal Lioresal Lioresal Lioresal Lioresal Gabalon Baclon Spastin
Manufacturer Ciba Geigy Ciba Geigy Ciba Geigy Ciba Geigy Ciba Geigy Ciba Geigy Ciba Geigy Daiichi Medica Yurtoglu
Country Switz. W. Germany UK France US Japan Japan Japan Finland Turkey
Raw Materials β-(p-Chlorophenyl)glutaric Acid Imide Sodium hydroxide Bromine
Year Introduced 1971 1972 1974 1974 1977 1979 1979 -
Bacmecillinam
513
Manufacturing Process 42.45 g of β-(p-chlorophenyl)glutaric acid imide are stirred into a solution of 8.32 g of sodium hydroxide in 200 ml of water. The mixture is heated for 10 minutes at 50°C, and the solution thus formed is cooled to 10° to 15°C. At this temperature there are then added dropwise a solution of 40.9 g of sodium hydroxide in 200 ml of water and then, in the course of 20 minutes, 38.8 g of bromine. When all has been dropped in, the batch is stirred for 8 hours at 20° to 25°C. The reaction solution is then cautiously adjusted with concentrated hydrochloric acid to pH 7, whereupon finely crystalline γ-aminoβ-(p-chlorophenyl)butyric acid settles out. To purify it, it is recrystallized from water. Melting point is 206°to 208°C. References Merck Index 939 Kleeman and Engel p.71 PDR p.894 OCDS Vol.2 p.121 (1980) DOT 8 (2) 49 (1972) I.N. p.114 REM p.925 Keberle, H., Faigle, J.W. and 1969; assigned to Ciba Keberle, H., Faigle, J.W. and 1972; assigned to Ciba
Wilhelm, M.; US Patent 3,471,548; October 7, Corporation Wilhelm, M.; US Patent 3,634,428; January 11, Corporation
BACMECILLINAM Therapeutic Function: Antibiotic Chemical Name: 4-Thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid, 6(((hexahydro-1H-azepin-1-yl)methylene)amino)-3,3-dimethyl-7-oxo-, 1((ethoxycarbonyl)oxy)ethyl ester, (2S-(2α,5α,6β))Common Name: Bacmecillinam; KW-1100 Structural Formula:
514
Balazipone
Chemical Abstracts Registry No.: 50846-45-2 Trade Name
Manufacturer
Country
Year Introduced
Bacmecillinam
ZYF Pharm Chemical
-
-
Bacmecillinam
LHA CHEMPHARMA CO. LTD.
-
-
Raw Materials 1-Hexamethyleneiminocarboxaldehyde dimethylacetate Triethylamine 1’-Ethoxycarbonyloxyethyl 6-aminopenicillanate Manufacturing Process 1-Hexamethyleneiminocarboxaldehyde dimethylacetate (3.1 g) in chloroform (50 ml) was added dropwise at -30°C to a solution of 1’ethoxycarbonyloxyethyl 6-aminopenicillanate (5.0 g) and triethylamine (1.9 ml) in chloroform (150 ml) during 15 min. Then, the temperature is allowed to rise to 0°C during 30 min, and the mixture is stirred at 0°C for another 60 min. Water (120 ml) is added, and stirring is continued for 10 min. The water phase is separated and the organic layer is washed with water and stripped. There was obtained 5.0 g of the 1’-ethoxycarbonyloxy-ethyl 6-(hexahydro-1Hazepin-l-yl) methyleneaminopenicillanate. References Bamberg P. et al.; US Patent No. 4,089,963; May 16, 1978; Assigned: Astra Pharmaceutical Products, Inc., Framingham, Mass.
BALAZIPONE Therapeutic Function: Immunomodulator Chemical Name: 3-(2-Acetyl-3-oxo-1-butenyl)benzonitrile Common Name: Balazipone; OR-1364 Structural Formula:
Chemical Abstracts Registry No.: 137109-71-8 Trade Name Balazipone
Manufacturer Orion
Country -
Year Introduced -
Balofloxacin
515
Raw Materials 3-Cyanbenzaldehyde Acetic acid
2,4-Pentanedione Piperidine
Manufacturing Process A mixture containing 3-cyanbenzaldehyde, 2,4-pentanedione, piperidine and acetic acid in toluene was refluxed for some hours. After standing over night at room temperature the crystals were filtered and washed with toluene and dried. There was obtained the 3-[(2-cyanophenyl)methylene]-2,4pentanedione. References Backstrom R.J.; EU Patent No. 0,440,324 A2; August 7, 1991
BALOFLOXACIN Therapeutic Function: Antibacterial Chemical Name: 3-Quinolinecarboxylic acid, 1-cyclopropyl-6-fluoro-1,4dihydro-8-methoxy-7-(3-(methylamino)-1-piperidinyl)-4-oxoCommon Name: Balfloxacin; Balofloxacin Structural Formula:
Chemical Abstracts Registry No.: 127294-70-6 Trade Name Balofloxacin Balofloxacin
Manufacturer Country Hangzhou Greenda Chemical Co., Ltd. Shanghai Acychem Trade Co, Ltd.
Year Introduced -
Raw Materials Ethyl 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3carboxylate 3-Acetamidopiperidine
516
Balofloxacin Dimethyl sulfoxide Sodium methoxide Triethylamine
Manufacturing Process (1) A mixture of ethyl 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4oxoquinoline-3-carboxylate (933 mg), 3-acetamidopiperidine (710 mg), triethylamine (400 mg) and dimethylsulfoxide (10 ml) was heated at 100°C for 2 hours with stirring. Thereafter the mixture was cooled down and ice water was added thereto. The resulting mixture was extracted with chloroform and the chloroform layer was washed with water three times before being dried over anhydrous sodium sulfate. Removal of the solvent in vacuum followed by purification by silica gel column chromatography (chloroformethanol) gave ethyl 7-(3-acetamidopiperidin-1-yl)-1-cyclopropyl-6,8-difluoro1,4-dihydro-4-oxo quinoline-3-carboxylate (930 mg). Re-crystallization from ethanol-ether afforded a colorless crystalline substance (MP: 217°-218°C). (2) Ethyl 7-(3-acetamidopiperidin-1-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro4-oxo-quinoline-3-carboxylate obtained from the foregoing step: (a) (433 mg) of above product was dissolved in 6 N hydrochloric acid (5 ml) and heated at 100°C. for 2.5 hours with stirring. After the removal of the solvent in vacuum, methanol was added to the residue and the insoluble materials were filtered off. Removal of the solvent followed by purification by silica gel column chromatography (chloroform-methanol) gave hydrochloride of 7-(3-aminopiperidin-1-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4oxoquinoline-3-carboxylic acid (colorless, crystalline-powder). MP: color change at about 272°C; decomposition at about 280°C. (b) A mixture of 7-(3-acetamidopiperidin-1-yl)-1-cyclopropyl-6,8-difluoro-1,4dihydro-4-oxoquinoline-3-carboxylic acid (4.05 g), sodium methoxide (2.16 g) and N,N-dimethylformamide (120 ml) was stirred for 2 hours at 100°-140°C. The reaction mixture was concentrated in vacuum and water was added to the residue. The mixture was neutralized with 1 N hydrochloric acid and the neutralized mixture was then concentrated in vacuum. Purification of the concentrated mixture by silica gel column chromatography (chloroformmethanol) gave 7-(3-acetamidopiperidin-1-yl)-1-cyclopropyl-6-fluoro-1,4dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid. MP: 248°-250°C. (c) 7-(3-Acetamidopiperidin-1-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8methoxy-4-oxoquinoline-3-carboxylic acid (1.25 g) above obtained was suspended in 6 N hydrochloric acid (30 ml) and ethanol (5 ml) and heated at 100°C for 3 hours. Then the reaction mixture was concentrated in vacuum and the residue was purified by silica gel column chromatography (chloroform:methanol:ammonium hydroxide=100:30:5) to afford 7-(3aminopiperidin-1-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4oxoquinoline-3-carboxylic acid. MP: 176°-177°C. References Nagano, Hiroyuki (Saitama, JP); Yokota, Takeshi (Chiba, JP); Katoh, Yasuyuki; US Patent No. 5,051,509; September 24, 1991; Assigned to Chugai Seiyaku Kabushiki Kaisha (Tokyo, JP)
Balsalazide disodium salt
517
BALSALAZIDE DISODIUM SALT Therapeutic Function: Antiinflammatory Chemical Name: Benzoic acid, 5-((4-(((2-carboxyethyl)amino)carbonyl) phenyl)azo)-2-hydroxy-, (E)-, disodium salt Common Name: Balsalazide sodium; Balsalazine disodium Structural Formula:
Chemical Abstracts Registry No.: 213594-60-6; 80573-04-2 (Base) Trade Name Colazal Colazide
Manufacturer Salix Pharmaceuticals, Inc. Shire Pharmaceuticals
Country USA
Year Introduced -
-
-
Raw Materials 4-Nitrobenzoyl chloride Palladium on charcoal Salicylic acid
Alanine, βSodium nitrite
Manufacturing Process 125 g finely powdered 4-nitrobenzoyl chloride were added portionwise, while stirring, to a solution of 70 g β-alanine in 500 ml water containing 65 g sodium hydroxide and cooled to 5°C. The reaction mixture was stirred for 3 hours and then added to a mixture of ice and hydrochloric acid. The precipitate obtained was filtered off, washed with water and dried by suction. After crystallisation of the dried product from hot acetone, there were obtained 130 g 4-nitrobenzoyl-β-alanine; M.P. 164°-166°C. A suspension of 15 g finely powdered 4-nitrobenzoyl-β-alanine in 200 ml ethanol was stirred in an atmosphere of hydrogen in the presence of 1 g of palladium-charcoal (5%), while cooling gently. When the absorption of hydrogen had ceased, the reaction mixture was filtered and the filtrate concentrated to a small volume. Upon adding diethyl ether and cooling 4aminobenzoyl-β-alanine was obtained. The yield was 11.5 g; M.P. 156°-158°C.
518
Bamaluzole
8.8 g 4-aminobenzoyl-β-alanine were triturated with 12 ml hydrochloric acid and the paste obtained was dissolved in 100 ml water. The solution was cooled to -5°C and a solution of 3 g sodium nitrite in 20 ml water, cooled to 0°C, was added dropwise, while stirring. The diazotised solution was left for 1 hour at 0°C and was then added dropwise at -5°C to a solution of 6 g salicylic acid in 70 ml water containing 3.6 g sodium hydroxide and 7 g sodium carbonate. The final reaction mixture was adjusted to a pH of about 8, stirred for 2 to 3 hours and added to a mixture of dilute hydrochloric acid and ice. The precipitate obtained was filtered off, washed with water and suction dried. Crystallisation from hot ethanol gave 11.9 g 5-[(2-carboxy-ethylcarbamoyl)phenylazo]-2-hydroxy-benzoic acid; M.P. 254°-255°C. 10.7 g of the free acid were dissolved in 300 ml warm ethanol and treated with a solution of 2.4 g sodium hydroxide in 25 ml ethanol. The precipitate obtained was filtered off, washed with ethanol and diethyl ether and dried in a vacuum at 50°C to give 11.5 g of the disodium salt of 5-[(2-carboxyethylcarbamoyl)-phenylazo]-2-hydroxy-benzoic acid; M.P. >350°C. References Chan R.P.K.; US Patent No. 4,412,992; Nov. 1, 1983; Assigned to Biorex Laboratories Limited, England Lednicer D., The organic chemistry of drug synthesis, V. 6, p.49, 1999, John Wiley and Sons, Inc.
BAMALUZOLE Therapeutic Function: Anticonvulsant Chemical Name: 4-[(2-Chlorophenyl)methoxy]-1-methyl-1H-imidazo[4,5c]pyridine Common Name: Bamaluzole Structural Formula:
Chemical Abstracts Registry No.: 87034-87-5 Trade Name
Manufacturer
Country
Year Introduced
Bamaluzole
Onbio Inc.
-
-
Bambuterol
519
Raw Materials 1-Chlorophenyl-2-methanol 4-Methylamino-3-nitropyridine Formic acid Acetic anhydride
Sodium hydride Hydrogen chloride Tin(II) chloride
Manufacturing Process 1-Chlorophenyl-2-methanol is dissolved in dimethylformamide; NaH is added and the mixture is stirred at 20°C for 1 h. After a solution of 4-chloro-1methyl-1H-imidazo[4,5-c]pyridine [melting point 132°-134°C; obtainable by reaction of 4-methylamino-3-nitropyridine with HCl/SnCl2 to give 3-amino-2chloro-4-methylaminopyridine (melting point 170°-173°C) and reaction with HCOOH/acetic anhydride] in dimethylformamide has been added, the mixture is stirred at 90°-95°C for 15 h. The mixture is evaporated and the residue is worked up in the customary manner to give 4-o-chlorobenzyloxy-1-methyl1H-imidazo[4,5-c]pyridine, melting point 132°-135°C (crystallize from ethyl acetate-tetrahydofuran). References Irmscher K. et al.; US Patent No. 4,654,350; March 31, 1987; Assigned: Merck Patent Gesellschaft Mit Beschrankter Haftung, Darmstadt, Fed. Rep. of Germany
BAMBUTEROL Therapeutic Function: Anti-asthmatic Chemical Name: 5-(2-(tert-Butylamino)-1-hydroxyethyl)-m-phenylene bis(dimethylcarbamate) Common Name: Bambuterol; Terbutaline bis(dimethylcarbamate) Structural Formula:
Chemical Abstracts Registry No.: 81732-65-2
520
Bambuterol
Trade Name Bambuterol Bambec Oxeol Oxeol Bambuterol
Manufacturer Paranova AstraZeneca Orifarm AstraZeneca King Sun Chemical and Pharmaceutical Co., Ltd.
Country -
Year Introduced -
Raw Materials Palladium on carbon Bromine N-Benzyl-t-butylamine
3,5-Dihydroxyacetophenone N,N-Dimethylcarbamoyl chloride Benzyl chloride
Manufacturing Process Preparation of 1-[bis-(3',5'-N,N-dimethylcarbamoyloxy)phenyl]-2-N-tbutylaminoethanol hydrochloride: A solution of 78 g of bis-3',5'-(N,N-dimethylcarbamoyloxy)-2-(N-benzyl-tbutyl)aminoacetophenone in 300 ml of ethanol was hydrogenated in a Parr equipment in the presence of 25 ml of benzyl chloride and 3.5 g of 10% Pd/C. The hydrogenation time was 24 hrs at a pressure of 345 KPa (50 psig) and a temperature of 50°C. The catalyst was filtered off, and the filtrate was evaporated to dryness. The residue was dissolved in isopropanol, filtered, and to the filtrate was added diethylether to precipitate the title compound. The identity of the title product obtained was confirmed with NMR. Yield: 46.5 g. The bis-3',5'-(N,N-dimethylcarbamoyloxy)-2-(N-benzyl-tbutyl)aminoacetophenone which was used as starting material was prepared as follows: (1a). Bis-3,5-(N-N-dimethylcarbamoyloxy)acetophenone: To a solution of 152 g of 3,5-dihydroxyacetophenone in 700 ml dry pyridine was added 280 ml of N,N-dimethylcarbamoyl chloride. The mixture was stirred for 18 hrs at 60°-70°C. After evaporation in vacuum the residue was treated with a mixture of diethylether and water. The water phase was extracted with diethylether, whereafter the combined diethylether phases were washed with water, and dried over MgSO4. After evaporation, the residue was recrystallized from isopropylalcohol-petroleum ether b.p. 40°-60°C. The identity of the product was confirmed with NMR. Yield: 180.4 g. (1b). Bis-3',5'-(N,N-dimethylcarbamoyloxy)-2-bromoacetophenone: To a solution of 180 g of bis-3,5-(N,N-dimethylcarbamoyloxy)acetophenone obtained in step 1a in 700 ml of dioxane was added dropwise a solution of 31 ml of bromine in 200 ml of dioxane. The mixture was stirred at 35°C for 1 hr. The residue obtained after evaporation in vacuum was recrystallized from isopropylalcohol-petroleum ether b.p. 40°-60°C. The identity of the product was confirmed with NMR. Yield: 174 g.
Bamifylline hydrochloride
521
(1c). Bis-3',5'-(N,N-dimethylcarbamoyloxy)-2-(N-benzyl-tbutyl)aminoacetophenone: To a solution of 5.6 g of the bromoacetophenone obtained in step 1b in 75 ml of acetone was added a solution of 4.9 g of N-benzyl-t-butylamine in 30 ml of acetone. The mixture was refluxed under stirring for 18 hrs, filtered, and evaporated in vacuum. The residue was dissolved in diethyl ether, petroleum ether b.p. 61°-70°C was added, and the yellow precipitate formed filtered off. After washing with water followed by a 1:1 mixture of isopropylalcoholpetroleum ether white crystals were obtained. The identity of the product was confirmed with NMR. Yield: 4.6 g. References Torsten Olsson O. A.; US Patent No. 4,419,364; December 6, 1983; Assigned to aktiebolaget Draco, Lund Sweden
BAMIFYLLINE HYDROCHLORIDE Therapeutic Function: Bronchodilator, Coronary vasodilator Chemical Name: 7-[2-[Ethyl(2-hydroxyethyl)amino]ethyl]-3,7-dihydro-1,3dimethyl-8-(phenylmethyl)-1H-purine-2,6-dione monohydrochloride Common Name: Bamifylline hydrochloride; Benzetamophylline; Bamiphylline hydrochloride Structural Formula:
Chemical Abstracts Registry No.: 2016-63-9 (Base); 20684-06-4 Trade Name Bamifylline hydrochloride
Manufacturer ZYF Pharm Chemical
Bamifix Trentadil
Farmalab Laboratoires Evans Medical
Country -
Year Introduced -
522
Bamipine
Trade Name Airest Bamifix
Manufacturer Caber Chiesi Farmaceutici spa
Bamifix BB
Chiesi Farmaceutici spa TEOFARMA Laboratoires Evans Medical
Briofil Bamifylline hydrochloride
Country -
Year Introduced -
-
-
-
-
Raw Materials 8-Benzyltheophilline Sodium carbonate
N-Ethylethanolamine Hydrochloric acid
Manufacturing Process A mixture of 100 kg of 8-benzyltheophilline, 36 L of N-ethylethanolamine, 300 L of 1,2-dichlorethane and 71 kg of sodium carbonate was refluxed for 24 hours. Then 36 L of N-ethylethanolamine was added and the reaction mixture was refluxed. After cooling to the mixture was added the water and hydrochloric acid. The organic phase was extracted with hydrochloric acid. The acidic phase was neutralized with sodium carbonate and the 7-(N-ethyl-N-βhydroxyethylaminoethyl)-8-benzyltheophilline was extracted with dichloromethane. The solvent was evaporated and the free base of 7-(N-ethylN-β-hydroxyethylaminoethyl)-8-benzyltheophilline was dissolved in methanol. Hydrochloride of 7-(N-ethyl-N-β-hydroxyethylaminoethyl)-8-benzyltheophilline was obtained by addition to the solution the hydrochloric acid; yield 81%, melting point 185-186°C. References Ridder R.R.; DE Patent No. 3,120,909; 1982-04-08; Applicant CYRISNIAENS SAA (BE)
BAMIPINE Therapeutic Function: Antihistaminic, Antiallergic Chemical Name: 1-Methyl-N-phenyl-N-(phenylmethyl)-4-piperidinamine Common Name: Bamipine; Piperamine Chemical Abstracts Registry No.: 4945-47-5 Raw Materials Aniline Acetic acid
1-Methyl-piperidone-4 Activated borings of aluminum
Bamipine
523
Structural Formula:
Trade Name Bamipine
Manufacturer Pharm Chemical Shanghai Lansheng Corporation
Country -
Year Introduced -
Soventol Soventol Soventol Comp. Soventol Comp.
Knoll Rentschler Adco Co. Knoll
-
-
Manufacturing Process 80 g of 1-methyl-piperidone-4 and 70 g of aniline are boiled, using a water separator in 350 ml of toluene to which several drops of glacial acetic acid have been added, until the theoretical quantity of water (12.7 ml) has separated out. The toluene is then distilled off and the remains are fractionated at reduced pressure. At a boiling point of 156°C/13 mm of Hg pressure, 118 g of a weakly yellow colored oil of the anil of 1-methyl-1piperidone-4 are obtained. 100 g of the above described anil of 1-methyl-1-piperidone-4 are boiled for 8 hours, using a reflux condenser, with 30 g of activated borings of aluminum in 300 ml of methanol diluted with 60 ml of water. The liquid phase is then separated from the solid phase, the solvent is evaporated and the residuum is fractionated at reduced pressure, 95 g of a colorless oil being obtained boiling at 163-165°C at 15 mm of Hg pressure. The oil solidifies at once to a mass of crystals of 4-N-phenylaimno-1-methylpiperidine. After having been recrystallized from dibutyl ether the base melts at 87°C, its dihydrochloride has the melting point of 246°C. 95 g of 4-N-phenylamino-1-methylpiperidine are boiled together with 22 g of pulverized sodium amide in 300 ml of benzene, using a reflux condenser, while nitrogen is passed through the reaction mixture, until the evolution of ammonia has ceased. 64 g of benzyl chloride are then gradually added drop by drop to the boiling reaction product and boiling is continued for several hours. After having been cooled the solution is shaken with water and subsequently dried with potassium carbonate. The solvent having been evaporated the remaining base of 4-(N-phenyl-N-benzyl)-amino-1methylpiperidine solidifies with the formation of crystals, the yield amounting to 123 g. The base is recrystallized from dibutyl ether and has a melting point of 115°C; its dihydrochloride melts at 189°C.
524
Barbexaclone
References Merck Index, Monograph number: 983, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. Kallischnigg R., US Patent No. 2,683,714; July 13, 1954; Knoll A.G., Ludwigschaffen (Rhine), Germany
BARBEXACLONE Therapeutic Function: Antiepileptic Chemical Name: (-)-N-α-Dimethylcyclohexaneethylamine compound with 5ethyl-5-phenyl-5-phenylbarbituric acid Common Name: Structural Formula:
Chemical Abstracts Registry No.: 4388-82-3 Trade Name
Manufacturer
Country
Year Introduced
Maliasin
Knoll
Italy
1983
Raw Materials Phenyl ethyl barbituric acid 1-Cyclohexyl-2-methylamino propane hydrochloride Manufacturing Process 25.4 g of sodium salt of phenyl ethyl barbituric acid and 19.1 g of 1cyclohexyl-2-methylamino propane hydrochloride are boiled under reflux in a mixture of 125 cc of acetic acid ethyl ester and 125 cc of ethanol. After boiling for half an hour, the solution is filtered, while still hot, to separate the precipitated sodium chloride. The filtrate is concentrated by evaporation to about half its volume. After cooling 42.5 g of the salt of 1-cyclohexyl-2methylamino propane and of phenyl ethyl barbituric acid are obtained in crystalline form. Its melting point is 130°-133°C.
Barmastine
525
References Kleeman and Engel p. 73 I.N. p. 115 Suranyi, L.; US Patent 3,210,247; October 5, 1965; assigned to Knoll A.G.
BARMASTINE Therapeutic Function: Antihistaminic Chemical Name: 4H-Pyrido[1,2-a]pyrimidin-4-one, 3-(2-(4-((3-(2furanylmethyl)-3H-imidazo[4,5-b]pyridin-2-yl)amino)-1-piperidinyl)ethyl)2-methylCommon Name: Barmastine; Ramastine Structural Formula:
Chemical Abstracts Registry No.: 99156-66-8 Trade Name Barmastine
Manufacturer ZYF Pharm Chemical
Country -
Year Introduced -
Raw Materials Thiophene Ammonia Hydrogen Sulfur Acetic acid Hydrobromic acid
N-(3-Nitro-2-pyridinyl)-2-furanylmethanamine Platinum on charcoal Mercury (II) oxide Ethyl 4-isothiocyanato-1-piperidinecarboxylate Potassium hydroxide Sodium carbonate 3-(2-Hydroxyethyl)-2-methyl-pyrido[2,1b]pyrimidin-4-one
Manufacturing Process A mixture of N-(3-nitro-2-pyridinyl)-2-furanylmethanamine, of a solution of thiophene in ethanone 4% and of methanol saturated with ammonia was hydrogenated at normal pressure and at room temperature with platinum-on-
526
Barmastine
charcoal catalyst 5%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was crystallized from acetonitrile, yielding the N2-(2-furanylmethyl)-2,3pyridinediamine. A mixture of 54 parts of ethyl 4-isothiocyanato-1-piperidinecarboxylate, 48 parts of N2-(2-furanylmethyl)-2,3-pyridinediamine and 450 parts of tetrahydrofuran was stirred and refluxed overnight. The reaction mixture was evaporated and the residue was crystallized from a mixture of 2-propanone and 2,2'-oxybispropane. The product was filtered off and dried, yielding 76 parts (75%) of ethyl 4-[[[2-[(2-furanylmethyl)amino]-3pyridinyl]aminothioxomethyl]amino]-1-piperidinecarboxylate; melting point 132.7°C. A mixture of 74 parts of ethyl 4-[[[2-[(2-furanylmethyl)amino]-3pyridinyl]aminothioxomethyl]amino]-1-piperidinecarboxylate, 96 parts of mercury (II) oxide, 0.1 parts of sulfur and 800 parts of ethanol was stirred and refluxed for 3 h. The reaction mixture was filtered over Hyflo and the filtrate was evaporated to give 52.5 parts (79%) of ethyl 4-[[3-(2furanylmethyl)-3H-imidazo[4,5-b]pyridin-2-yl]amino]-1-piperidinecarboxylate; melting point 149.2°C (crystallized from acetonitrile). A mixture of ethyl 4-[[3-(2-furanylmethyl)-3H-imidazo[4,5-b]pyridin-2yl]amino]-1-piperidinecarboxylate and of a hydrobromic acid solution 48% in water was stirred and heated for 3 h at about 80°C. The reaction mixture was evaporated and the residue was dried, yielding the 3-(2-furanylmethyl)-N-(4piperidinyl)-3H-imidazo[4,5-b]pyridin-2-amine dihydrobromide (crystallized from methanol). A mixture of 3-(2-hydroxyethyl)-2-methyl-pyrido[2,1-b]pyrimidin-4-one, of acetic acid and of a hydrobromic acid solution 67% in acetic acid was stirred and heated to reflux. Stirring was continued overnight at reflux temperature. The reaction mixture was evaporated and the solid residue was triturated in 2propanone. The product was filtered off and dried, yielding 3-(2-bromoethyl)2-methyl-pyrido[1,2-a]pyrimidin-4-one monohydrobromide. A mixture of 3-(2-bromoethyl)-2-methyl-pyrido[1,2-a]pyrimidin-4-one monohydrobromide, 3-furan-2-yl-methyl-(3H-imidazo[4,5-b]pyridine-2yl)-4piperidinyl)-amine dihydrobromide, of sodium carbonate and of N,Ndimethylformamide was stirred and heated overnight at about 70°C. The reaction mixture was poured onto water. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (94:6 by volume), saturated with ammonia, as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 3-(2-(4-((3-(2furanylmethyl)-3H-imidazo[4,5-b]pyridin-2-yl)amino)-1-piperidinyl)ethyl)-2methyl-4H-pyrido[1,2-a]pyrimidin-4-one; melting point 202°C. References Janssens F.E. et al.; US Patent No. 5,025,014; June18, 1991; Assigned: Janssen Pharmaceutica N.V., Beerse, Belgium
Barnidipine hydrochloride
527
BARNIDIPINE HYDROCHLORIDE Therapeutic Function: Coronary vasodilator Chemical Name: (+)-(3'S,4S)-1-Benzyl-3-pyrrolidinyl methyl 1,4-dihydro2,6-dimethyl-4-(m-nitrophenyl)-3,5-pyridinedicarboxylate monohydrochloride Common Name: Barnidipine hydrochloride; Mepirodipine hydrochloride Structural Formula:
Chemical Abstracts Registry No.: 104713-75-9 (Base); 104757-53-1 Trade Name
Manufacturer
Country
Year Introduced
Barnidipine hydrochloride
Yamanouchi
-
-
Cyress
Yamanouchi
-
-
Libradin
Sigma-Tau Industrie Farmaceutiche Riunite spa
-
Libradin
Andromaco
-
-
Vasexten
Yamanouchi
-
-
Vasexten
Fournier
-
-
Raw Materials 3-Nitrobenzaldehyde 1-Benzyl-3-acetoacetyloxypyrrolidine β-Aminocrotonic acid Manufacturing Process In 5 ml of isopropyl alcohol were dissolved 1.5 g (0.01 mole) of 3nitrobenzaldehyde, 2.6 g (0.01 mole) of 1-benzyl-3-acetoacetyloxypyrrolidine, and 1.3 g (0.01 mole) of β-aminocrotonic acid methyl ester and then the solution was refluxed for 8 hours. The solvent was distilled off under reduced pressure, the residue obtained was dissolved in a small amount of chloroform, and the solution was applied to silica gel column chromatography (column diameter 1.5 cm, height 20 cm, and about 200 ml of chloroform was used as the eluent). The eluates were collected and concentrated to give 3.4 g of oily
528
Batebulast hydrochloride
2,6-dimethyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3(1-benzylpyrrolidin-3-yl)ester-5-methyl ester: [α]D20=+64.8° (c = 1 in methanol). In practice it is usually used as monohydrochloride. References Kojima Tadao, Takenaka Toichi; US Patent No. 4,220,649; September 2, 1980; Assigned to Yamanouchi Pharmaceutical Co., Ltd. (Tokyo, JP)
BATEBULAST HYDROCHLORIDE Therapeutic Function: Antiallergic, Anti-asthmatic Chemical Name: p-tert-Butylphenyl trans-4-(guanidinomethyl) cyclohexanecarboxylate monohydrochloride Common Name: Batebulast hydrochloride; Telbulast hydrochloride Structural Formula:
Chemical Abstracts Registry No.: 81907-78-0 (Base); 83373-31-3 Trade Name Batebulast hydrochloride
Manufacturer Onbio Inc.
Country -
Batebulast hydrochloride
Nippon Chemiphar -
Raw Materials trans-4-Guanidinomethylcyclohexanecarboxylic acid p-t-Butylphenol Dicyclohexylcarbodiimide
Year Introduced -
Batimastat
529
Manufacturing Process A mixture of 9.4 g of trans-4-guanidinomethylcyclohexanecarboxylic acid, 7.2 g of p-t-butylphenol and 10.0 g of dicyclohexylcarbodiimide was suspended in a solution of 61 ml of dry pyridine and ml of dry dimethylformamide, and the suspension was stirred at room temperature for 24 h.The solvent was removed under reduced pressure.The residue was washed and dried.There was obtained the 4’-t-butylphenyl trans-4-guanidinomethylcyclohexanecarboxylate. In practice it is usually used as hydrochloride. References Muramatsu M. et al.; US Patent No. 4,465,851; August 14, 1984; Assigned: Nippon Chemiphar Co., Ltd., Tokyo, Japan
BATIMASTAT Therapeutic Function: Antineoplastic Chemical Name: Butanediamide, N4-hydroxy-N1-(2-(methylamino)-2-oxo-1(phenylmethyl)ethyl)-2-(2-methylpropyl)-3-((2-thienylthio)methyl)-, (2R(1(S*),2R*,3S*))Common Name: Barinatrix; Batimastat Structural Formula:
Chemical Abstracts Registry No.: 130370-60-4 Trade Name Batimastat
Manufacturer British Biotech
Country -
Raw Materials Leucine, DSulfuric acid Sodium bicarbonate Potassium t-butoxide
Potassium bromide Sodium nitrite Dibenzyl malonate Hydroxy benztriazole
Year Introduced -
530
Batimastat N-Methylmorpholine Palladium on charcoal Piperidine Thiophenethyol N-(Dimethylaminoethyl)-N’ethylcarbodiimide
Ammonium formate Phenylalanine-N-methylamide Formaldehyde Dicyclohexylcarbodiimide
Manufacturing Process D-Leucine (100.0 g, 0.76 mol) and potassium bromide (317.5 g, 2.67 mol) were dissolved in aqueous acid (150 ml concentrated sulfuric acid in 500 ml of water). The solution was cooled to -2°C and sodium nitrite (69.6 g, 0.95 mol in water) was added over 1 h taking care to maintain the temperature between -1°C and -2°C. After addition was complete the mixture was kept at 0°for a further hour, then DCM was added and the mixture stirred for a few minutes. The layers were separated and the aqeous phase was washed with further portions of DCM (5 x 250 ml). The combined organic layers were dried over magnesium sulfate then the solvent removed to give the 2R-bromo-5methylpentanoic acid as a pale yellow oil (123.1 g, 0.63 mol, 83%). 2R-Bromo-5-methylpentanoic acid (123.0 g, 0.63 mol) was dissolved in DCM (400 ml) and the solution cooled to -40°C while isobutene was condensed in to roughly double the volume. Maintaining the temperature at -40°C concentrated sulfuric acid (4 ml) was added dropwise. When the addition was complete the reaction was allowed to warm to room temperature overnight. The resultant solution was concentrated to half the volume by removing the solvent at reduced pressure, then the DCM was washed twice with an equal volume of 10% sodium bicarbonate solution. The organic layer was dried over magnesium sulfate and the solvent removed under reduced pressure to leave the t-butyl 2R-bromo-5-methylpentanoate as a yellow oil (148.1 g, 0.59 mol, 94%). Dibenzyl malonate (124.5 g, 0.44 mol) was taken up in dry DMF and potassium t-butoxide (49.2 g, 0.44 mol) was added portionwise with stirring and cooling. When a homogeneous solution had formed it was cooled to 0°C, then t-butyl-2R-bromo-5-methylpentanoate (110.1 g, 0.44 mol) in DMF (200 ml) was added dropwise over 1 h. When addition was complete the reaction was transfered to a cold room at 5°C and left for 4 days. The reaction mixture was partitioned between ethyl acetate and saturated ammonium chloride then the aqueous layer extracted with further ethyl acetate (4 x 500 ml), drying and solvent removal left an oil (228.0 g) heavily contaminated with DMF. This oil was taken into ether (1 L) and washed with brine (2 x 11) then the organic layer dried (magnesium sulfate), solvent removed under reduced pressure to leave the benzyl (2-benzyloxycarbonyl-3R-(t-butoxycarbonyl)-5methylhexanoate (179.0 g) contaminated with a small amount of dibenzyl malonate. Benzyl (2-benzyloxycarbonyl-5-methyl-3R-t-butoxycarbonyl)hexanoate (281.4 g, 0.56 mol) was taken up in 5% water in TFA (410 ml) and allowed to stand at 5°C overnight. After this time the TFA was evaporated under reduced pressure then the residue partitioned between DCM (1 L) and brine (200 ml). Solvent removal left an oil which crystallised on standing (230.0 g). The crude acid from this reaction was dissolved in DMF (1 L), then hydroxy benztriazole (95.3 g, 0.64 mol), N-methylmorpholine (64.0 g, 0.64 mol) and
Batimastat
531
phenylalanine-N-methylamide (113.1 g, 0.64 mol) were added at room temperature. The mixture was cooled to 0°C before dropwise addition of dicyclohexylcarbodiimide (131.0 g, 0.64 mol) in THF (1 L). This solution was stirred to room temperature over the weekend. The precipitated dicyclohexylurea was removed by filtration then the solvents were removed from the filtrate under reduced pressure to leave an oil. This oily residue was dissolved methyl acetate then washed with 10% citric acid, 10% sodium bicarbonate and saturated brine. The organic layer was dried (magnesium sulfate), filtered then the solvent removed under reduced pressure to give the title compound as an oil (400.0 g). This material was columned on silica using gradient elution (0-50% ethyl acetate in hexane) to remove impurities and separate a small amount of the minor diastereoisomer. The material from the column (195.0 g) was recrystallised from diisopropyl ether to give the [4benzyloxy-3-benzyloxycarbonyl-2R-isobutylsuccinyl]-L-phenylalanine-Nmethylamide as a white crystalline solid (140.2 g, 0.25 mol, 47%), melting point 98°-99°C. The 4-benzyloxy-3-benzyloxycarbonyl-2R-isobutylsuccinyl]-L-phenylalanine-Nmethylamide (29.6 g, 53 mmol) was taken up in ethanol, ammonium formate (16.7 g, 265 mmol) added followed by 10% palladium on charcoal (6.0 g) as a slurry in isopropyl alcohol. After 30 min at room temperature the catalyst was removed by filtration, then washed with ethanol to give a solution of the crude diacid. To this was added piperidine (5.0 g) and the mixture stirred at room temperature for 15 min before addition of aqueous formaldehyde (40% solution, 25 ml). After 18 h at room temperature the mixture was refluxed for 1 h. Solvents were removed under reduced pressure and the residue partitioned between ethyl acetate and citric acid. The acid layer was extracted with further portions of ethyl acetate (2 x 250 ml), the combined organic layers were extracted with potassium carbonate (3 x 200 ml). These base extracts were acidified to pH 4 and reextracted with DCM then the organic layer dried over magnesium sulfate. Solvent removal under reduced pressure gave the [4-hydroxy-2R-isobutyl-3-ethenylsuccinyl]-L-phenylalanine-Nmethylamide as a white solid (9.35 g, 27.0 mmol, 51%), melting point 149°151°C. The [4-hydroxy-2R-isobutyl-3-ethenylsuccinyl]-L-phenylalanine-N-methylamide (400.0 mg, 1.16 mmol) was dissolved in thiophenethyol and the mixture stirred in the dark under nitrogen at 60°C for 2 days. Ether was added to the cooled reaction mixture and the precipitated product collected by filtration. The solid was washed with large volumes of ether and dried under vacuum to give the [4-N-hydroxy-2R-isobutyl-3S-(thienylthiomethyl)succinyl]-Lphenylalanine-N-methylamide (320.0 mg, 0.73 mmol, 63%), melting point 184°-186°C. The [4-N-hydroxy-2R-isobutyl-3S-(thienylthiomethyl)succinyl]-Lphenylalanine-N-methylamide and hydroxy benztriazole were dissolved in DCM/DMF (4:1) and the mixture cooled to 0°C before adding N(dimethylaminoethyl)-N’-ethylcarbodiimide and N-methylmorpholine. The mixture was stirred at 0°C or 1 h to ensure complete formation of the activated ester. Hydroxylamine hydrochloride and NMM were dissolved in DMF then this mixture added dropwise to the cooled solution of the activated ester. After 1 h the reaction was poured into ether/water (1:1) whereupon the desired product precipitated as white crystals. These were collected by filtration, further washed with ether and water then dried under vacuum at
532
Batoprazine hydrochloride
50°C. So the [4-(N-hydroxyamino)-2R-isobutyl-3S-(thienylthiomethyl) succinyl]-L-phenylalanine-N-methylamide was obtained, melting point 236°238°C (recrystallised from methanol/ water 1:1). References Campion C. et al.; US Patent No. 5,240,958; August 31,1993; Assigned: British Bio-Technology Limited, Oxford, England
BATOPRAZINE HYDROCHLORIDE Therapeutic Function: Psychotropic Chemical Name: 8-(1-Piperazinyl)-2H-1-benzopyran-2-one monohydrochloride Common Name: Batoprazine hydrochloride Structural Formula:
Chemical Abstracts Registry No.: 105684-52-4 Trade Name Batoprazine hydrochloride
Manufacturer Duphar
Country -
Year Introduced -
Raw Materials 5-Amino-1-benzopyran-2-one Sodium hydroxide Bis-(2-chloroethyl)amine hydrochloride Manufacturing Process 5-Amino-1-benzopyran-2-one and bis-(2-chloroethyl)amine hydrochloride were suspended in chlorobenzene. The mixture was heated at 130°C for about 66 h while stirring.
Batroxobin
533
The reaction mixture was cooled to 90°C and diluted with ethyl acetate. The solid was filtered off, washed with ethyl acetate and dried. So the 1-[5-(1benzopyran-2-one)]piperazine hydrochloride was obtained, melting point 250°C (dec.; recrystallized from ethanol). To obtained the base, 1-[5-(1-benzopyran-2-one)]piperazine, the 1-[5-(1benzopyran-2-one)]piperazine hydrochloride was treated by solution of sodium hydroxide. References Hartog J. et al.; EU Patent No. 0,189,612; August 6, 1986
BATROXOBIN Therapeutic Function: Hemostatic Chemical Name: See under structural formula; no defined name Common Name: Structural Formula: It is a complex enzyme of molecularweight no greater than 40,000 in monomeric form. Chemical Abstracts Registry No.: 9039-61-6 Trade Name
Manufacturer
Country
Year Introduced
Defibrase
Serono
W. Germany
1982
Botrophase
Ravizza
Italy
-
Ophidiase
Labaz
Switz.
-
Reptilase
Disperga
Austria
-
Reptilase
Knoll
W. Germany
-
Raw Materials Venom of Bothrops Atrox (A Pit Viper) Phenol Manufacturing Process The process for preparing the enzyme composition comprises treating an aqueous solution of the snake venom at a pH of about 4 to 6 with phenol or a phenol derivative in order to precipitate an insoluble complex containing the active venom fraction and decomposing the complex in order to release the thrombinlike enzyme composition. References Merck Index 1010
534
Baxitozine
DOT 18 (4) 169 (1982) I.N.p. 117 Percs, E.E., Stocker, K.F., Blomback, B., Blomback, M.and Hessel, B.;US Patent 3,849,252; November 19, 1974; assigned to Pentapharm A.G.
BAXITOZINE Therapeutic Function: Gastric cytoprotective; Antiulcer Chemical Name: 2-Butenoic acid, 4-oxo-4-(3,4,5-trimethoxyphenyl)-, (E)Common Name: Baxitozine; RU 38086 Structural Formula:
Chemical Abstracts Registry No.: 84386-11-8 Trade Name Baxitozine
Manufacturer ZYF Pharm Chemical
Country -
Year Introduced -
Raw Materials Glyoxylic acid Acetic acid Sodium carbonate
Hydrochloric acid 3,4,5-Trimethoxy acetophenone
Manufacturing Process 29.6 g of glyoxylic acid of 50% by weight are heated in water under reduced pressure until elimination of 80% of the water present, whereupon, after cooling, 84.1 g of 3,4,5-trimethoxy acetophenone are introduced into the reaction mixture. Heating is effected for 2 h at 95°-100°C under reduced pressure (about 50 mm/Hg), at the same time distilling off the residual water present. After cooling of the medium, 120 ml of water containing 11.6 g of sodium carbonate and ether are introduced, the aqueous phase is decanted and washed with : ether, whereupon the aqueous phase is acidified to a pH of 1 with 50% hydrochloric acid. The desired product is extracted with ethyl acetate. After elimination of the extraction solvent 31.5 g of the 4-(3,4,5trimethoxyphenyl)-4-oxo-2-hydroxy butanoic acid, melting point 119°-120°
Bazinaprine
535
are obtained (recrystallization from 1,2-dichloroethane). 15.8 g of 4-(3,4,5-trimethoxyphenyl)-4-oxo-2-hydroxy butanoic acid, 20 ml of acetic acid and 20 ml of concentrated hydrochloric acid (d-1.18) are heated for 2.5 h under reflux. The reaction medium is cooled and precipitated by water. The precipitate formed is filtered off. 10.5 g of the (E)-4-(3,4,5trimethoxyphenyl)-4-oxo-2-butenoic acid, melting point 140°C are obtained (recrystallization from ethanol-water 1:1). References Christidis Y, Fournex R.; US Patent No. 4,450,292; May 22, 1984; Assigned: Roussel Uclaf, Paris, France
BAZINAPRINE Therapeutic Function: Antidepressant Chemical Name: 4-Pyridazinecarbonitrile, 3-((2-(4-morpholinyl)ethyl)amino)6-phenylCommon Name: Bazinaprine; SR 95191 Structural Formula:
Chemical Abstracts Registry No.: 94011-82-2 Trade Name SR 95.191
Manufacturer Clin Midy/Sanofi Winthrop
Country -
Year Introduced -
Raw Materials Ethyl malonate Potassium iodide Hydrazine hydrate Ammonia Sulfuric acid Sodium hydroxide
Potassium carbonate Phenacyl chloride Acetic acid Phosphorus oxychloride N-(2-Aminoethyl)morpholine Bromine
536
Bazinaprine
Manufacturing Process 240.25 g of ethyl malonate, 138.0 g of potassium carbonate, 5.0 g of potassium iodide and 154.0 g of phenacylchloride in 2 L of anhydrous acetone are heated under reflux overnight. After the inorganic salts have been filtered off, the filtrate is evaporated to dryness and the excess ethyl malonate is then distilled off under reduced pressure (pressure: 0.5 mbar; temperature: about 60°C). The distillation residue is chromatographed on a silica column using a cyclohexane/ethyl acetate mixture (9:1) as the eluent. The ethyl phenacylmalonate is obtained in the form of a red oil. Yield: 80.3%. 40.5 g of the ethyl phenacylmalonate are dissolved in 70 ml of absolute ethanol, and 7.25 g of hydrazine hydrate are added dropwise to the reaction medium at 0°C, with stirring. When the reaction medium has returned to room temperature, it is stirred for 24 h and the beige precipitate obtained, which corresponds to the expected pyridazinone, is then filtered off. The filtrate is treated with 3.62 g of hydrazine hydrate. After stirring for 24 h, an additional quantity of pyridazinone can be filtered off. The same operation is repeated once more on the filtrate. After purification by passage through a silica column using a cyclohexane/ethyl acetate mixture (1:1) as the eluent, the 4-ethoxycarbonyl-6-phenyl-4,5-dihydro-2H-pyridazin-3-one is obtained. Yield: 37%. 9.0 g of the 4-ethoxycarbonyl-6-phenyl-4,5-dihydro-2H-pyridazin-3-one are dissolved in 200 ml of acetic acid, and 11.18 g of bromine are then added to the solution, with stirring. Decolouration of the medium occurs after 5 min. After 2 h at room temperature, and with stirring, the medium is poured into 200 ml of water, the mixture is then extracted with methylene chloride and the organic phase is evaporated to dryness. The residue is taken up 3 times with cyclohexane. The beige powder obtained is chromatographed on a silica column using a cyclohexane/ethyl acetate mixture (1:1) as the eluent. The 4ethoxycarbonyl-6-phenyl-2H-pyridazin-3-one, melting point 150°C is obtained. Yield: 51%. 2.0 g of the 4-ethoxycarbonyl-6-phenyl-2H-pyridazin-3-one are added to 40 ml of concentrated ammonia solution and the mixture is stirred overnight at room temperature. The solid is filtered off and dried to give the 6-phenyl-3oxo-2H-pyridazine-4-carboxamide, melting point >300°C. Yield: 86%. 1.5 g of the 6-phenyl-3-oxo-2H-pyridazine-4-carboxamide are dissolved in 20 ml of phosphorus oxychloride and the solution is then heated at 80°C for 5 h. The mixture is poured into 50 ml of water. A precipitate appears, which is filtered off and dried. There are obtained 58.3% of 3-chloro-4-cyano-6phenylpyridazine, melting point 206°C. 7.3 g of the 3-chloro-4-cyano-6-phenylpyridazine are dissolved in 60 ml of nbutanol, and 8.0 g of N-(2-aminoethyl)-morpholine are added. The mixture is heated under reflux for 3 h and then poured into 1000 ml of water. The organic phase is extracted with ether and the ether solution is then extracted with a 1 N solution of sulfuric acid. The aqueous phase is separated off, rendered alkaline with sodium hydroxide and extracted with ether. The ether phase is dried over magnesium sulfate and the solvent is then evaporated off to dryness in vacuo to give the 3-(2-morpholinoethylamino)-4- cyano-6phenylpyridazine, as yellow solid, melting point 138°C. Yield: 81.3%.
Beclamide
537
References Kan J.-P. et al.; US Patent No. 4,631,280; December 23, 1986; Assigned: Sanofi, Paris, France
BECLAMIDE Therapeutic Function: Anticonvulsant Chemical Name: 3-Chloro-N-(phenylmethyl)propanamide Common Name: Benzchloropropamide; Benzylchloropropionamide; Chloroethylphenamide Structural Formula:
Chemical Abstracts Registry No.: 501-68-8 Trade Name Posedrine Posedrine Beclamid Neuracen Nydrane Nydrane Posedrine Posedrine Posedrine Seclar
Manufacturer Biosa Aron Aron Promonta Lipha Aron Lasa Byk Gulden Spemsa Andromaco
Country Switz. France W. Germany W. Germany UK France Spain Italy Argentina
Year Introduced 1970 1975 -
Raw Materials Benzylamine p-Chloropropionyl chloride Sodium hydroxide Manufacturing Process A 100 gallon lined jacketed kettle provided with cooling is charged with 100 lb of benzylamine and 150 liters of water. The mixture is cooled to 5°C and with stirring 119 lb of β-chloropropionyl chloride and a solution of 45 lb of sodium hydroxide pellets in 40 liters of water are added simultaneously at such a rate that the temperature does not exceed 10°C. During this period the pH of the
538
Beclobrate
mixture should be on the alkaline side but below pH 9.5. When the addition is complete the pH should be about 8. The mixture is stirred overnight in the cold, and the solid product is filtered. The filter cake is reslurred with about 80 gallons of water, filtered, and air-dried. Yield, 128 pounds. The crude material is recrystallized by dissolving it in the minimal quantity of hot methanol (about 50 gallons), adding Norite, and filtering hot. Upon cooling slowly (finally to about 5°C) large crystals separate: they are filtered and air-dried. Yield, 109 pounds. Melting point 92° to 93°C. References Merck Index 1017 Kleeman and Engel p. 74 I.N. p. 118 Cassell, R.T. and Kushner, S.; US Patent 2,569,288; September 25, 1951: assigned to American Cyanamid Company
BECLOBRATE Therapeutic Function: Antihyperlipidemic Chemical Name: Butanoic acid, 2-(4-((4-chlorophenyl)methyl)phenoxy)-2methyl-, ethyl ester, (+/-)Common Name: Beclobrate; Turec Structural Formula:
Chemical Abstracts Registry No.: 55937-99-0 Trade Name Beclobrate Beclipur
Manufacturer ZYF Pharm Chemical SIEGFRIED HOLDING AG
Country -
Raw Materials 4-Chloro-4'-hydroxydiphenylmethane Potassium carbonate 2-Bromo-2-ethyl-2-methylacetic acid ethyl ester
Year Introduced -
Beclomethasone dipropionate
539
Manufacturing Process 87.0 g (0.4 mol) of 4-chloro-4'-hydroxydiphenylmethane are heated together with 27.0 g (0.2 mol) of anhydrous potassium carbonate in 350 ml of anhydrous xylene for 30 min to reflux temperature, whereafter a solution of 83.5 g (0.4 mol) of 2-bromo-2-ethyl-2-methyl acetic acid ethyl ester in 50 ml of anhydrous xylene is added. The mixture is kept for 24 hours and with vigorous stirring at reflux temperature. After filtering off the precipitated potassium bromide and evaporating the solvent in a Buchi rotary evaporator, the residue is taken up in ether and extracted with normal sodium hydroxide solution. The ether extracts are washed with water, dried over MgSO4 and concentrated by evaporation. The brown oil (82.0 g) thereby obtained is dissolved in n-hexane and filtered through a column of 200 g of basic Al2O3. After evaporating the solvent and distillation at reduced pressure, 34.7 g of pure ethyl (+/-)-2-((α-(p-chlorophenyl)-p-tolyl)oxy)-2-methylbutyrate are obtained with the boiling point 200-204°C/0.01-0.1 mm Hg. References Thiele K., Quazi A., Adrian R., Jahn U.; US Patent No. 4,483,999; November 20, 1984; Assigned to Siegfried Aktiengesellschaft (Zofingen, CH)
BECLOMETHASONE DIPROPIONATE Therapeutic Function: Topical antiinflammatory, Glucocorticoid Chemical Name: 9-Chloro-11β,17,21-trihydroxy-16β-methylpregna-1,4diene-3,20-dione dipropionate Common Name: Structural Formula:
Chemical Abstracts Registry No.: 5534-09-8; 4419-39-0 (Base)
540
Beclomethasone dipropionate
Trade Name Propaderm Eecotide
Manufacturer Kyowa Hakko Allen and Hanburys
Country Japan UK
Year Introduced 1972 1972
Cleniderm Sanasthmyl Becotide Beconase Vanceril Beclotide Nasal Becotide Aldesin Beclovent Becotide Becloforte
Chiesi Glaxo Glaxo Glaxo Schering Glaxo Glaxo Shionogi Glaxo Glaxo Allen and Hanburys
Italy W. Germany France W. Germany US Italy Japan Japan US Switz. UK
1974 1975 1976 1976 1976 1977 1978 1978 1979 1981 1982
Aldecin Anceron Beclacin Beclacin Beclamet Beclo-Asma Beclomet Beclosona Beclovent Becotide Betozon Betozon Bronco-Turbinal Clenil Dermisone Beclo Entyderma Gnadion Hibisterin Inalone Korbutone Proctisone Propaderm Propavent Rino-Clenil Turbinal Vaderm Viarex Viarex Viarox Zonase Zonide
Schering Essex Kaigai Morishita Orion Aldo Union Orion Spyfarma Meyer Pliva Ohta Ono Valeas Chiesi Frumtost Taiyo Pliva Nippon Zoki Lampugnani Nippon Glaxo Chiesi Duncan Glaxo Chiesi Valeas Schering Essex Schering Byk-Essex Script Intal Script Intal
Argentina Japan Japan Finland Spain Finland Spain US Yugoslavia Japan Japan Italy Italy Spain Japan Yugoslavia Japan Italy Japan Italy Italy UK Italy Italy Italy US W. Germany S. Africa S. Africa
-
Beclomethasone dipropionate
541
Raw Materials 16β-Methyl-1,4-pregnadiene-11β,17α,21-triol-3,2-dione-21-acetate Methanesulfonyl chloride Sodium methoxide N-Chlorosuccinimide Perchloric acid Manufacturing Process 6 grams of 6β-methyl-1,4-pregnadiene-11β,17α,21-triol-3,20-dione-21-acetate is dissolved in a mixture of 35 ml of dimethylformamide and 6 ml of pyridine. To the resulting solution is added 2.5 ml of methanesulfonyl chloride and the reaction mixture maintained at 80°-85°C for about 1 hour. The resulting red solution is cooled in an ice bath and treated successively with 55 ml of methanol, 240 ml of 5% aqueous sodium bicarbonate and finally with 360 ml of water. The resulting reaction mixture is then allowed to stand at room temperature overnight after which the precipitated product is removed by filtration, washed repeatedly with water and dried to a constant weight in air at about 50°C to produce 6β-methyl-1,4,9(11)-pregnadiene-11α,21-diol-3,20dione-21-acetate. Hydrolysis of the acetate ester with alkali, e.g., sodium methoxide in methanol, affords the free alcohol, 16β-methyl-1,4,9(11)-pregnadiene-17α,21diol-3,20-dione. To a suspension of 3 grams of 6β-methyl-1,4,9(11)pregnadiene-17α,21-diol-3,20-dione-21-acetate 40 ml of acetone is added at 0°C with stirring 2 grams of N-chlorosuccinimide and then 7 ml of a perchloric acid solution prepared by dissolving 0.548 ml of 70% perchloric acid in 33 ml of water. The resulting reaction mixture is stirred at 0° for about 4 hours 45 minutes. The excess of N-chlorosuccinimide is destroyed by the addition of about 15 drops of allyl alcohol and 180 ml of water is then added with stirring. This mixture is held at 0°C for about one hour. The precipitated 16β-methyl-1,4pregnadiene-9α-chloro-11β,17α,21-triol-3,20-dione-21-acetate is recovered filtration. A solution of 250 mg of the chlorohydrin in 5 ml of 0.25N perchloric acid in methanol is stirred for about 18 hours at room temperature to produce 16β-methyl-9α-chloro-11β,17α,21-trihydroxy-1,4-pregnadiene-3,20-dione which is recovered by adding water to the reaction mixture and allowing the product to crystallize. Propionic anhydride is then used to convert this material to the dipropionate. References Merck Index 1018 Kleeman and Engel p.74 PDR pp.906, 1659 DOT 9 (8) 335 (1973) I.N. p.118 REM p. 962 Merck and Co., Inc. British Patent 912,378; December 5, 1962 Taub, D., Wendler, N.L. and Slates, H.L.; US Patent 3,345,387; October 3, 1967; assigned to Merck and Co., Inc.
542
Befunolol
BEFUNOLOL Therapeutic Function: Beta-adrenergic blocker Chemical Name: 2-Acetyl-7-(2-hydroxy-3-isopropylaminopropoxy)benzofuran Common Name: Structural Formula:
Chemical Abstracts Registry No.: 39552-01-7 Trade Name Bentos
Manufacturer Kakenyaku Kako
Country Japan
Year Introduced 1983
Raw Materials 2-Acetyl-7-hydroxybenzofuran Epichlorohydrin Isopropylamine Manufacturing Process To 8.8 g of 2-acetyl-7-hydroxybenzofuran were added 80 ml of epichlorohydrin and 0.2 g of piperidine hydrochloride and the mixture was heated at 105°C for 3 hours. After the reaction, the excess of epichlorohydrin was evaporated and the resultant was distilled under reduced pressure to give 9.3 g of 2-acetyl-7-(2,3-epoxypropoxy)benzofuranhaving a boiling point of 175° to 176°C/0.7 mm Hg. 6 g of the product was dissolved in 30 ml of ethanol and to the solution was added 10 ml of isopropylamine. After refluxing the mixture for 40 minutes, the solvent was evaporated from the reaction mixture. The resulting residue was recrystallized from cyclohexane-acetone to give 6 g of 2-acetyl-7-(2-hydroxy-3-isopropylaminopropoxy)benzofuran having a melting point of 115°C. References Merck Index 1022 DFU 6 (10) 601 (1981) Ito, K., Mashiko, I., Kimura, K. and Nakanishi, T.; US Patent 3,853,923; December 10, 1974; assigned to Kakenyaku Kakko Co., Ltd.
Bekanamycin sulfate
543
BEKANAMYCIN SULFATE Therapeutic Function: Antibacterial Chemical Name: D-Streptamine, O-3-amino-3-deoxy-α-D-glucopyranosyl-(16)-O-[2,6-diamino-2,6-dideoxy-α-D-glucopyranosyl-(1-4)]-2-deoxy sulfate (1:1) Common Name: Aminodeoxykanamycin Structural Formula:
Chemical Abstracts Registry No.: 29701-07-3; 4696-76-8 (Base) Trade Name Kanendomycin Stereocidin Coltericin Kanendomicina Kanendos Visumetazone Antibiotica Visumicina
Manufacturer Meiji Seika Crinos Argentia Lefa Crinos ISF
Country Japan Italy Argentina Spain Italy Italy
Year Introduced 1969 1980 -
ISF
Italy
-
Raw Materials Bacterium S. Kanamyceticus Nutrient broth Manufacturing Process 200 liters of the medium containing 2.0% starch, 1.0% soybean meal, 0.05% KCl, 0.05% MgSO4·7H2O, 0.3% NaCl, 0.2% NaNO3 was placed in the 400 liter fermenter, the pH was adjusted to 7.5, and the medium was then sterilized (pH after the sterilization was 7.0) for 30 minutes at 120°C, inoculated with 1,000 ml of 40 hour shake-cultured broth of S. kanamyceticus (a selected subculture of K2-J strain) and tank-cultured at 27°-29°C. As antifoam,
544
Bemesetron
soybean oil (0.04%)and silicone (0.04%) were added. The broth after 48 hours was found to contain 250 mcg/ml of kanamycin. A portion (950 ml) of the rich eluate was adjusted to pH 6.0 by the addition of sulfuric acid. Ultrawet K (7.0 g) in 70 ml water was added slowly to the neutralized eluate to precipitate kanamycin B dodecylbenzenesulfonate which was collected by filtration after adding filter aid (Dicalite). The cake was washed with water and extracted with 100 ml methanol. After filtering and washing with methanol, sulfuric acid was added to the filtrate until no more kanamycin B sulfate precipitated. After addition of an equal volume of acetone to provide more complete precipitation, the kanamycin B sulfate was collected by filtration, washed with methanol and dried in vacuo at 50°C. References Merck Index 5118 Kleeman and Engel p. 75 I.N. p. 120 REM p. 1181 Umezawa, H., Maeda, K. and Ueda, M.; US Patent 2,931,798; April 5, 1960. Johnson, D.A. and Hardcastle, G.A.; US Patent 2,967,177; January 3,1961; assigned to Bristol-Myers Co. Rothrock, J.W. and Potter, I.; US Patent 3,032,547; May 1, 1962; assigned to Merck and Co., Inc.
BEMESETRON Therapeutic Function: Serotonin antagonist Chemical Name: Benzoic acid, 3,5-dichloro-, (endo)-8-methyl-8-azabicyclo [3.2.1]oct-3-yl ester Common Name: Bemesetron Structural Formula:
Chemical Abstracts Registry No.: 40796-97-2 Trade Name Bemesetron
Manufacturer Merrel Dow
Country -
Year Introduced -
Benactyzine hydrochloride
545
Raw Materials Tropine 3,5-Dichlorobenzoylchloride Manufacturing Process Tropine (34.24 g) is treated with anhydrous diethyl ether and ethereal hydrogen chloride and the precipitated hydrochloride is isolated by evaporation of the solvent. 3,5-Dichlorobenzoylchloride (51.7 g) is added and the mixture stirred at 140°C for 15 minutes during which time the mixture liquifies, evolves hydrogen chloride gas and resolidifies. After heating for a further 15 minutes the cooled solid is dissolved in water, an excess of an aqueous solution of potassium carbonate is added, and the base is extracted with ethyl acetate. Evaporation of the dried ethyl acetate solution yields a solid, which is recrystallized from aqueous methanol to yield 3,5dichlorobenzoic acid 8-methyl-8-aza-bicyclo[3.2.1]oct-1-yl ester (endo). MP: 95°C (51.8 g). References Fozard J. R. et al.; US Patent No. 4,563,465; January 7, 1986; Assigned to Merrell Dow Pharmazeuticals Inc., Cincinnati, Ohio
BENACTYZINE HYDROCHLORIDE Therapeutic Function: Tranquilizer; Anticholinergic Chemical Name: α-Hydroxy-α-phenylbenzene acetic acid-2-(diethylamino) ethyl ester hydrochloride Common Name: β-Diethylaminoethylbenzilate hydrochloride Structural Formula:
Chemical Abstracts Registry No.: 57-37-4; 302-40-9 (Base) Trade Name Suavitil Phebex
Manufacturer Merck Sharp and Dohme Hoechst
Country US
Year Introduced 1957
US
1958
546
Benactyzine hydrochloride
Trade Name Cedad Cevanol Deprol Lucidil Morcain Nutinal Parasan Parpon Phobex Phobex
Manufacturer Recordati I.C.I. Wallace Smith and Nephew Tatsumi Boots Medix Santen Lloyd Dabnev and Westerfield
Country Italy UK US UK Japan UK Spain Japan -
Year Introduced -
Raw Materials Ethyl benzilate β-Diethylaminoethanol
Sodium Hydrogen chloride
Manufacturing Process 114 parts of ethyl benzilate, 175 parts of β-diethylaminoethanol and 0.2 part of metallic sodium were placed in a flask attached to a total-reflux variable take-off fractionating column. The pressure was reduced to 100 mm and heat was applied by an oil bath the temperature of which was slowly raised to 90°C. During three hours of heating 17 parts of ethanol distilled (35.5°C). When the distillation of the ethanol became slow, the bath temperature was raised to 120°C. When the vapor temperature indicated distillation of the amino alcohol the take off valve was closed and the mixture was refluxed for one hour. At the end of this period the vapor temperature had dropped and two more parts of ethanol were distilled, The remaining aminoalcohol was slowly distilled for three hours. The pressure was then reduced to 20 mm and the remainder of the aminoalcohol distilled at 66°C. During the reaction the color of the solution changed from yellow to deep red. The residue was dissolved in 500 parts of ether, washed once with dilute brine, and three times with water, dried over sodium sulfate and finally dried over calcium sulfate. 500 parts of a saturated solution of HCl in absolute ether was added and the resulting precipitate filtered. Dry HCl gas was passed into the filtrate to a slight excess and the precipitate again filtered. The combined precipitates were washed with cold acetone. The 106 parts of product was purified by recrystallization from acetone as fine white crystals which melt at 177°178°C. References Merck Index 1028 Kleeman and Engel p.76 PDR p.1874 OCDS Vol.1 p.93 (1977) DOT 9 (6) 241 (1973) I.N. p.120 Hill, A.J. and Holmes, R.B.; US Patent 2,394,770; February 12, 1946; assigned to American Cyanamid
Benapryzine hydrochloride
547
BENAPRYZINE HYDROCHLORIDE Therapeutic Function: Anticholinergic, Antiparkinsonian Chemical Name: α-Hydroxy-α-phenylbenzeneacetic acid 2(ethylpropylamino)ethyl ester hydrochloride Common Name: 2-Ethylpropylaminoethyl diphenylglycollate hydrochloride Structural Formula:
Chemical Abstracts Registry No.: 3202-55-9; 22487-42-9 (Base) Trade Name Brizin
Manufacturer Beecham
Country UK
Year Introduced 1973
Raw Materials Sodium methoxide Hydrogen chloride
2-Ethylpropylaminomethanol Methyl α,α-diphenyl glycollate
Manufacturing Process A methanolic solution of sodium methoxide [from sodium (0.2 gram) and dry methanol (3 ml)] was added dropwise during 20 minutes to a boiling solution of methyl α,α-diphenylglycollate (11 grams) and 2-ethylpropylaminoethanol (6 grams) in light petroleum (150 ml, BP 80°-100°C) and the methanol that separated was removed by using a Dean and Starke apparatus. At the end of 5 hours no further separation of methanol occurred and the reaction mixture after being washed with water (3 x 20 ml) was extracted with 1N hydrochloric acid (3 x 30 ml). The acid extracts (after washing with 50 ml ether) were made alkaline with aqueous 5 N sodium hydroxide solution, the liberated base was extracted into ether (4 x 50 ml) and the ether extracts were dried (MgSO4). Treatment of the extracts with hydrogen chloride gave the hydrochloride (11 grams, 70%), which was obtained as rectangular plates, MP 164° to 166°C, after several crystallizations from butanone. References Merck Index 1030 Kleeman and Engel p. 77
548
Benazepril hydrochloride
OCDS Vol.2 p.74 (1980) DOT 9 (6) 241 (1973) I.N. p.121 Mehta, M.D. and Graham, J.; US Patent 3,746,743; July 17, 1973; assigned to Beecham Group Limited
BENAZEPRIL HYDROCHLORIDE Therapeutic Function: Antihypertensive Chemical Name: 1H-1-Benzazepine-1-acetic acid, 2,3,4,5-tetrahydro-3-((1(ethoxycarbonyl)-3-phenylpropyl)amino)-2-oxo-, monohydrochloride,(S(R*,R*))-, monohydrochloride Common Name: Benazepril hydrochloride; Labopal Structural Formula:
Chemical Abstracts Registry No.: 86541-74-4; 86541-75-5 (Base) Trade Name
Manufacturer
Country
Year Introduced
Lotensin
Novartis
-
-
Benazepril hydrochloride
DSM Catalytica Pharmaceuticals, Inc.
-
-
Cibace
Ciba-Geigy
-
-
Cibacen
Novartis
-
-
Labopal
Morrith
-
-
Labopal
Beecham
-
-
Normacen
Normal
-
-
Tensanil
CRINOS Industria Farmacobiologica S.p.A
-
Zinadril
ERREKAPPA EUROTERAPICI
-
-
Bendacort
549
Raw Materials Sodium azide 1,2,4,5-Tetrahydrobenzo[b]azepin-2-one Sodium cyanoborohydride 2-Oxo-4-phenylbutyric acid ethyl ester Manufacturing Process The synthesis of benzazepril based on a benzazepinone. It started by chlorination of lactam - 1,2,4,5-tetrahydrobenzo[b]azepin-2-one to the dichloro derivative 3,3-dichloro-1,2,4,5-tetrahydrobenzo[b]azepin-2-one. Catalytic reduction removed one of the gem chloro substituents to give 3chloro-1,2,4,5-tetrahydrobenzo[b]azepin-2-one; the halogen was then displaced with sodium azide to give 3-azido-1,3,4,5tetrahydrobenzo[b]azepin-2-one. Alkylation of the amide with ethyl bromoacetate in the presence of base yielded the ester (3-azido-2-oxo2,3,4,5-tetrahydrobenzo[b]azepin-1-yl)acetic acid ethyl ester. Hydrogenation then converted the azide to an amino group to give 3-amino-2-oxo-2,3,4,5tetrahydrobenzo[b]azepin-1-yl)acetic acid ethyl ester. It was then resolved by classical salt formation and crystallization. Saponification of the S enantiomer - S-(3-amino-2-oxo-2,3,4,5-tetrahydrobenzo[b]azepin-1-yl)acetic acid ethyl ester with sodium hydroxide afforded (3-amino-2-oxo-2,3,4,5tetrahydrobenzo[b]azepin-1-yl)acetic acid. Reductive alkylation of it with 2oxo-4-phenylbutyric acid ethyl ester and sodium cyanoborohydride gave the desired product as 70:30 mixture of diastereoisomers. The isolation of the predominant isomer gave benazepril. The epimerization occurred thermally and therefore required a sufficiently high temperature. The high temperature condition can be achieved by either using a high boiling-point solvent such as xylene or by heating the reaction mixture under pressure to increase its boiling-point temperature. Good results can be achieved in both polar and non-polar solvent systems. For example, both p-xylene and ethylene glycolwater systems are found suitable to conduct this process. The crude product acid 3-[(1-ethoxycarbonyl)-3-phenyl-(1S)-propylamino]-2,3,4,5-tetrahydro-2oxo-1H-1-benzazepine-1-acetic acid was heated to reflux temperature for 30 hours in p-xylene. The mixture was cooled down to room temperature. Solvent removal resulted in a solid, which was then dried at reduced pressure to give a 98:2 diasteriomeric mixture as determined by HPLC, MP: 287°290°C. IR and 1H-NMR spectrum analysis. was confirmed the structure of product. References Lednicer D., The Organic Chemistry of Drug Synthesis; v. 5; pp. 135-136; 1995; Wiley and Sons Inc. W-Hong Tseng et al.; US Patent No. 6,548,665B2; April 15, 2003; Assigned to Scinopharm, Taiwan, Ltd., Tainan (CN)
BENDACORT Therapeutic Function: Glucocorticoid
550
Bendazac
Chemical Name: 21-Ester of [(1-benzyl-1H-indazol-3-yl-oxy]-acetic acid with 11β,17α-dihydroxy-pregn-4-ene 3,20-dione Common Name: Ester of Bendazac with hydrocortisone Structural Formula:
Chemical Abstracts Registry No.: 53716-43-1 Trade Name Versacort
Manufacturer Angelini
Country Italy
Year Introduced 1978
Raw Materials Hydrocortisone Bendazac chloride ([(1-benzyl-1H-indazol-3-yl)oxy]acetic acid chloride) Manufacturing Process Hydrocortisone (25 g) and bendazac chloride (21 g) are suspended in anhydrous dioxane (250 ml). Pyridine (6 ml) is added and the solution is kept under stirring for 2 hours at room temperature. Pyridine hydrochloride which separates is filtered and the clear dioxane solution is added, under strong stirring, to a solution of sodium bicarbonate (20 g) in distilled water (2,500 ml). The colorless precipitate which is formed is filtered, washed with water and dried on a porous plate. The substance crystallizes from ethanol. Needles. MP 174°-176°C. Yield: 75%. References Merck Index 4689 Baiocchi, L.; US Patent 4,001,219; January 4, 1977
BENDAZAC Therapeutic Function: Antiinflammatory
Bendazac
551
Chemical Name: [(1-Benzyl-1H-indazol-3-yl)oxy]acetic acid Common Name: Bendazolic acid Structural Formula:
Chemical Abstracts Registry No.: 20187-55-7 Trade Name Versus Zildasac Hubersil Versus
Manufacturer Angelini Chugai Hubber Werfft Chemie
Country Italy Japan Spain Austria
Year Introduced 1970 1979 -
Raw Materials 1-Benzyl-3-oxy-indazole Chloroacetonitrile Hydrogen chloride Manufacturing Process 11 grams of the sodium salt of 1-benzyl-3-oxy-indazole are dissolved in 70 ml of absolute ethanol by heating the resulting solution to boiling and stirring. 3.5 grams of chloroacetonitrile dissolved in 5 ml of absolute ethanol are then added within 2-3 minutes and after 10 minutes a further portion of 1.7 grams of chloroacetonitrile are added. The reaction is finally brought to completion with an additional 45 minutes of boiling. The reaction mixture is allowed to cool at room temperature and is then filtered. The alcohol solution is evaporated to dryness under reduced pressure; the resulting residue is taken up again with ether and the ether solution is washed in sequence with dilute HCl, water, NaOH and water. The solution is dried on Na2SO4 and then the solvent is removed. The residue consists of (1-benzyl-indazole3)oxyacetonitrile which is crystallized from methanol. It has a melting point of 93°C. 1 gram of the (1-benzyl-indazole-3)oxyacetonitrile is pulverized and is added with stirring to 5 ml concentrated HCl. By heating on a boiling water bath for 2-3 minutes, the nitrile product melts and soon thereafter solidifies. The precipitate is cooled, then filtered and washed well in a mortar with water. After dissolution in 10% Na2CO3 it is precipitated again with dilute HCl. After
552
Bendroflumethiazide
crystallization from ethanol, 1-benzyl-indazole-3-oxyacetic acid is obtained. It has a melting point of 160°C. References Merck Index 1033 Kleeman and Engel p.79 OCDS Vol.2 p.351 (1980) I.N. p.121 Palazzo, G.; US Patent 3,470,194; September 30, 1969; assigned to Aziende Chimiche Riunite Angelini, Francesco ACRAF SPA, Italy
BENDROFLUMETHIAZIDE Therapeutic Function: Diuretic, Antihypertensive Chemical Name: 3,4-Dihydro-3-(phenylmethyl)-6-(trifluoromethyl)-2H-1,2,4benzothiadiazine-7-sulfonamide 1,1-dioxide Common Name: Benzydroflumethiazide; Benzylhydroflumethiazide; Bendrofluazide Structural Formula:
Chemical Abstracts Registry No.: 73-48-3 Trade Name Naturetin Sinesalin Naturine Leo Benuron Aprinox Benzide Berkozide Bristuric Bristuron Centyl Centyl Corzide Neo-Naclex Neo-Rontyl
Manufacturer Squibb I.C.I. Leo Bristol Boots Protea Berk Bristol Bristol Leo Leo-Sankyo Squibb Glaxo Leo
Country US W. Germany France US UK Australia UK US Denmark Japan US UK Denmark
Year Introduced 1959 1961 1965 -
Bendroflumethiazide Trade Name Notens Pluryl Polidiuril Poliuron Rauzide Salural Salures Seda-Repicin Sinesalin Sodiuretic Tensionorm Urizid
Manufacturer Farge Leo Bios Lepetit Squibb ICE Ferrosan Boehringer Ingelheim Arcana Squibb Leo Rekah
553
Country Italy Denmark Italy Italy US Italy Denmark W. Germany
Year Introduced -
Austria Italy France Israel
-
Raw Materials α,α,α-Trifluoro-m-toluidine ω-Ethoxystyrene Phenylacetaldehyde
Ammonia Chlorosulfonic acid
Manufacturing Process The process is described in US Patent 3,392,168 as follows: (A) Preparation of 5-Trifluoromethylaniline-2,4-Disulfonylchloride - 113 ml of chlorosulfonic acid is cooled in an ice bath, and to the acid is added dropwise while stirring 26.6 grams of α,α,α-trifluoro-m-toluidine. 105 grams of sodium chloride is added during 1-2 hours, where after the temperature of the reaction mixture is raised slowly to 150° - 160°C which temperature is maintained for three hours. After cooling the mixture, ice-cooled water is added, whereby 5-trifluoromethylaniline-2,4-disulfonyl chloride separates out from the mixture. (B) Preparation of 5-Trifluoromethyl-2,4-Disulfamylaniline - The 5trifluoromethylaniline-2,4-disulfonyl chloride obtained in step (A) is taken up in ether and the ether solution dried with magnesium sulfate. The ether is removed from the solution by distillation, the residue is cooled to 0°, and 60 ml of ice-cooled, concentrated ammonia water is added while stirring. The solution is then heated for one hour on a steam bath and evaporated in vacuo to crystallization. The crystallized product is 5-trifluoromethyl-2,4disulfamylaniline, which is filtered off, washed with water and dried in a vacuum-desiccator over phosphorus pentoxide. After recrystallization from a mixture of 30% ethanol and 70% water, the compound has a MP of 247°248°C. (C) Preparation of 3-Benzyl-6-Trifluoromethyl-7-Sulfarnyl-3,4-Dihydro-1,2,4Benzothiadiazine-1,1-Dioxide - 6.4 grams of 5-trifluoromethyl-2,4disulfamylaniline is dissolved in 12 ml of dioxane, 2.7 ml of phenylacetaldehyde and a catalytic amount of p-toluenesulfonic acid are added. After boiling for a short time under reflux, the reaction mixture crystallizes, and, after filtration and recrystallization from dioxane, the desired
554
Benfluorex hydrochloride
product is obtained with a MP of 224.5°-225.5°C. (D) Alternative to (C) - 9.6 grams of 5-trifluoromethyl-2,4-disulfarnylaniline and 4.9 grams of ω-ethoxystyrene are dissolved in 35 ml of n-butanol. 0.5 grams of p-toluenesulfonic acid is added, and the mixture is heated on a steam bath while stirring. When the solution is clear, 55 ml of hexane is added, whereafter the mixture is heated further for one and a half hours. After cooling, the substance identical to that of Example (C) is filtered off and has a MP of 222°-223°C. Sterile compositions containing Bendroflumethiazide for parenteral administration may be prepared as described in US Patent 3,265,573. References Merck Index 1036 Kleeman and Engel p.79 PDR pp.1741, 1753, 1767 OCDS Vol.1 p.358 (1977) DOT 16(3) 94 (1980) I.N. p.122 REM p.938 Goldberg, M.; US Patent 3,265,573; August 9, 1966; assigned to E.R. Squibb and Sons, Inc. Lund, F., Lyngby, K. and Godtfredsen, W.O.; US Patent 3,392,168; July 9, 1968; assigned to Lovens Kemiske Fabrik ved A. Kongsted, Denmark
BENFLUOREX HYDROCHLORIDE Therapeutic Function: Antihyperlipidemic, Cardiovascular Chemical Name: 1-(m-Trifluoromethylphenyl)-2-(β-benzoyloxyethyl) aminopropane hydrochloride Common Name: Structural Formula:
Chemical Abstracts Registry No.: 23642-66-2; 23602-78-0 (Base)
Benfotiamine Trade Name Mediator Mediaxal Mediaxal Minolip
Manufacturer Servier Stroder Servier Chiesi
Country France Italy Switz. Italy
555
Year Introduced 1976 1981 1982 -
Raw Materials 1-(m-Trifluoromethylphenyl)-2-(β-hydroxyethyl)amino propane Benzoyl chloride Manufacturing Process To a solution of 24.7 parts of 1-(m-trifluoromethylphenyl)-2-(βhydroxyethyl)amino propane in 140 parts of anhydrous benzene, there were added successively 15 parts of 4.7N hydrochloric ether and a solution of 14 parts of benzoyl chloride in 24 parts of anhydrous benzene. The addition required 10 minutes, the reaction mixture was then refluxed for 8 hours. The solid product was collected by filtration and after recrystallization from 230 parts of ethyl acetate, there were obtained 15 parts of 1-(mtrifluoromethylphenyl)-2-(β-benzoyloxyethyl)amino propane hydrochloride melting at 161°C. 10 parts hydrochloride are put in suspension in 100 parts of water, 80 parts ether are added, then 10 parts of a concentrated solution of ammonium hydroxide. The mixture is stirred a few minutes until the salt is dissolved, then the ethered solution is poured off and dried. After the ether is eliminated, 9 parts of 1-(m-trifluoromethylphenyl)-2-(βbenzoyloxyethyl)amino propane are obtained; the base is a colorless oil. References Merck Index 1037 DFU 2 (8) 557 (1976) Kleeman and Engel p.80 DOT 13 (1) 12 (1977) I.N. p.122 Beregi, L. Hugon, P. and Le Douarec, J.C.; US Patent 3,607,909; September 21, 1971; assigned to Science Union et Cie Societe Francaise de Recherche Medicale
BENFOTIAMINE Therapeutic Function: Analgesic Chemical Name: Benzoic acid, thio-, S-ester with N-((4-amino-2-methyl-5pyrimidinyl)methyl)-N-(4-hydroxy-2-mercapto-1-methyl-1-butenyl) formamide dihydrogen phosphate (ester)
556
Benfotiamine
Common Name: Benfotiamine; Benphothiamin; Benzoylthiamine monophosphate Structural Formula:
Chemical Abstracts Registry No.: 22457-89-2 Trade Name Biotamin
Manufacturer Sankyo
Country -
Year Introduced -
Vitanevril
Sanofi Winthrop
-
-
Milgamma
Worwag Pharma GmbH and Co
-
-
Benfogamma
Worwag Pharma GmbH and Co
-
-
Bio-Towa
Towa Pharmaceutical Co., Ltd.
-
-
Benfothiamin
Shanghai BR Chemical Co., Ltd.
-
Benfotiamin
Shanghai Lansheng Corporation
-
-
Raw Materials Phosphoric acid Thiamine hydrochloride Benzoyl chloride Manufacturing Process 28.6 g 84% phosphoric acid was heated to temperature about 270°C. After cooling to 100°C 4 g thiamine hydrochloride (vitamin B1 hydrochloride) was added and left at temperature 100°C before an isolation of HCl was ended. After adding of an ice water and acetone, phosphate ester of vitamin B1 was fallen. The precipitate was dissolved in 17 ml 1 N HCl and stood at ambient temperature 7 days for a hydrolysis. Then a solution was with acetone diluted and the mixture was cooled, whereupon vitamin B1 monophosphate hydrochloride was isolated.
Benfurodil hemisuccinate
557
The solution of 4.3 parts vitamin B1 monophosphate hydrochloride in 16 parts of water was diluted with 11 parts 15% NaOH, 2.1 parts benzoyl chloride was dropwise added with stirring and cooling. The obtained mixture was neutralized, evaporated in vacuum, acidified with concentrated HCl to pH 3.54, whereupon a crude S-derivative of vitamin B1 monophosphate ester was precipitated. The product was suspended in water, was bringing with NaOH to pH 7 and was acidified to pH 4. 3.4 g refined S-benzoylthiamine Omonophosphate was prepared; MP: 165°C (with decomposition). References Sankyo Kabushiki Kaisha, Tokyo; D.B. Patent No. 1,130,811; April 14, 1960
BENFURODIL HEMISUCCINATE Therapeutic Function: Coronary vasodilator; Cardiotonic Chemical Name: Succinic acid monoester with 4-[2-(1-hydroxyethyl)-3methyl-5-benzofuranyl]-2(5H)-furanone Common Name: Structural Formula:
Chemical Abstracts Registry No.: 3447-95-8 Trade Name Eucilat Clinodilat Eucilat Eucilat
Manufacturer Clin Midy Mack-Midy Midy Clin-Comar-Byla
Country France W. Germany Italy France
Raw Materials Aluminum chloride Succinic anhydride Acetyl chloride 4-(4-Methoxyphenyl)-2oxo-2,5-dihydrofuran
Chloroacetone Hydrogen chloride Sodium borohydride
Year Introduced 1970 1981 1981 -
558
Benfurodil hemisuccinate
Manufacturing Process (A) Preparation of 4-(3-Acetyl-4-Hydroxyphenyl)-2-Oxo-2,5-Dihydrofuran (1567 CB): A solution of 57 grams of 4-(4-methoxyphenyl)-2-oxo-2,5dihydrofuran (0.3 mol) in 300 ml of methylene chloride is added slowly to 200 grams of anhydrous powdered aluminum chloride, while stirring and cooling in a bath of iced water. When this is completed, one removes the bath and leaves the reagents in contact for 10 minutes, and then introduces 72 grams of acetyl chloride at a speed sufficient to maintain refluxing of the solvent. One subsequently heats under reflux for 3 hours 30 minutes, decomposes by pouring on to crushed ice, filters off the crystalline product and washes it with water. 56 g, MP = 200°C. Yield: 80%. The product is recrystallized from acetic acid and then melts at 201°-202°C. (B) Preparation of 4-[3-Acetyl-4-(2-Oxopropyloxy)Phenyl]-2-Oxo-2,5Dihydrofuran: 5.45 grams (0.025 mol) of compound 1567 CB prepared according to (A) dissolved in 50 ml of dimethyl formamide is stirred at room temperature for 15 minutes with 5 grams of potassium carbonate and 1 gram of sodium iodide, and 5 grams of chloracetone are then added drop by drop. The temperature spontaneously rises a few degrees. The disappearance of the phenolic compound is checked by testing with an alcoholic solution of ferric chloride; this test should be negative at the end of the reaction (approximately 2 hours). One then dilutes with 10 volumes of water, filters the product which crystallizes out under these conditions and recrystallizes it from acetic acid. It has the form of yellow needles (4 grams yield: 63%). MP, = 155°-157°C. (C) Preparation of 2-Acetyl-3-Methyl-5-(2-Oxo-2,5-Dihydro-4Furyl)Benro[b]Furan (3556 CB): (1) A suspension of 2 grams of the compound prepared according to (B) in 20 ml of concentrated hydrochloric acid, is heated to about 50°C, just until it dissolves. There after it is heated for 2 minutes to 70°C, just until precipitation commences. The mixture is allowed to cool, diluted with water, filtered, the residue washed, dried, and sublimed at 200°C and 0.1 mm pressure. 1.4 grams of product (Yield: 70%) is obtained. MPc=218°-221°C. A second sublimation produces a chemically pure product. MPc= 221°-222°C. (2) Compound 1567 CB and chloracetone are caused to react as in (B), the mineral salts subsequently filtered, 12 ml of concentrated hydrochloric acid are added to the solution in dimethyl formamide without dilution with water, and the mixture heated for 40 minutes on a water bath. The product crystallizes in the warm mixture, the mixture is cooled to room temperature, filtered, the residue washed with water and crystallized from acetic acid. MPc= 222°C. Yield: 60% based on compound 1567 CB. (D) Preparation of 2-(1-Hydroxyethyl)-3-Methyl-5-(2-Oxo-2,5-Dihydro-4Furyl)Benzo[b]-Furan (3574 CB): 13.2 grams of compound 3556 CB of which the preparation is described in (C) are treated successively with 66 ml of methylene chloride, 27 ml of methanol and, with stirring, 1.6 grams of sodium borohydride added in stages. The reaction takes 1 hour. The mixture is poured into water acidified with a sufficient amount of acetic acid, the solvents are stripped under vacuum, the crystalline product removed, washed with water, and recrystallized from ethyl acetate. Yield: 90%. MPk= 158°C. (E) Preparation of 2-(1-Succinyloxyethyl)-3-Methyl-5-(2-Oxo--2,5-Dihydro-4-
Benmoxin
559
Furyl)Benzo[b]-Furan (4091, CB): 8.65 grams of compound 3574 CB in 43 ml of pyridine are warmed for 30 minutes, on a water bath, with succinic anhydride. At the end of this, the pyridine is stripped off in vacuo. The mixture is treated with dilute sulfuric acid and with ether, the crystalline product filtered off, washed with water and with ether, and recrystallized from ethyl acetate (9.35 grams). MPc=144°C (measured after drying at 90°C and 0.1 mm). Yield: 77%. The product yields an equimolecular compound with morpholine. MPc=136°C (from ethyl acetate). References Kleeman and Engel p.81 OCDS Vol.2 p.355 (1980) DOT 6 (6) 203 (1970) I.N. p. 123 Schmitt, J.; US Patent 3,355,463; November 28, 1967; assigned to Etablissements Clin-Byla, France
BENMOXIN Therapeutic Function: Antidepressant Chemical Name: 1-Benzoyl-2-(alpha-methylbenzyl)hydrazine Common Name: Benmoxin; Mebamoxine Structural Formula:
Chemical Abstracts Registry No.: 7654-03-7 Trade Name Neuralex
Manufacturer Millot
Country -
Year Introduced -
Raw Materials Acetylhydrazine Hydrogen
Acetophenone Palladium on carbon
Manufacturing Process A mixture of 29.6 parts of acetylhydrazine, 48 parts of acetophenone and 140 parts of ethanol is heated under reflux for 18 hours and is then cooled to 20-
560
Benorylate
25°C and filtered. The solid residue, M.P. 135-136°C, is washed with diethyl ether and dried at 40°C. 28.5 parts of this dried product in 180 parts of methanol is shaken in an atmosphere of hydrogen under a pressure of 100 atmospheres and at a temperature of 25°C in the presence of 3 parts of a 5% palladium on carbon catalyst until the theoretical amount of hydrogen is absorbed. The mixture is filtered and the filtrate is evaporated. The residue is fractionally distilled under reduced pressure and there is thus obtained 1-(αmethylbenzyl)-2-acetylhydrazine, B.P. 182-186°C/15 mm, M.P. 72-74°C. References Merck Index, Monograph number: 1072, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. Crowther A.F. et al.; US Patent No. 3,297,530; Jan. 10, 1967; Assigned to Imperial Chemical Industrie Limited, London, England Brevet DInvention FR Patent No. 1,314,362; Dec. 22, 1962; Assigned to Imperial Chemical Industries Limited residant en Gdande-Bretagne
BENORYLATE Therapeutic Function: Analgesic, Antiinflammatory, Antipyretic Chemical Name: 2-(Acetyloxy)benzoic acid 4-(acetylamino)phenyl ester Common Name: Fenasprate; p-N-Acetamidophenyl acetylsalicylate Structural Formula:
Chemical Abstracts Registry No.: 5003-48-5 Trade Name
Manufacturer
Country
Year Introduced
Benortan
Winthrop
Switz.
-
Benoral
Winthrop
UK
1972
Benortan
Winthrop
W. Germany
1975
Benortan
Winthrop
France
1976
Benorile
Rubio
Spain
-
Benortan
Pharmacal
Finland
-
Bentum
Inpharzam
Belgium
-
Salipran
Bottu
France
-
Benoxaprofen
561
Trade Name
Manufacturer
Country
Year Introduced
Sinalgin
Robin
Italy
-
Triadol
Sterling Heath
UK
-
Winorylate
Sterwin Espanola
Spain
-
Raw Materials N-Acetyl-p-aminophenol Acetyl salicoyl chloride Manufacturing Process Example 1: 65 grams of N-acetyl-p-aminophenol were slurried with 400 ml of water and cooled to 10°C. 125 ml of 20% sodium hydroxide were slowly added to the mixture with stirring, the temperature being maintained between 10°and 15°C. To the solution obtained, 75 grams of acetyl salicoyl chloride were added with vigorous stirring over a period of 1/2 hr, the solution being maintained at a temperature of about 10°C. Towards the end of the reaction the pH was checked and adjusted to greater than 10 by the addition of a small amount of 20% sodium hydroxide. After all the acid chloride had been added, vigorous stirring was continued for half an hour during which time the crude product separated out. This product was filtered off, washed thoroughly with water and recrystallized from ethanol. Example 2: 65 grams of sodium N-acetyl-p-aminophenol were slurried with 500 grams of dry benzene and 80 grams of acetyl salicoyl chloride added. The mixture was heated under reflux for four hours and filtered hot. The excess benzene was removed under vacuum and the crude acetyl salicyclic acid ester of N-acetyl-p-aminophenol crystallized from ethanol. References Merck Index 1043 Kleeman and Engel p.82 DOT 8 (6) 208 (1972) I.N. p.123 Robertson, A.; US Patent 3,431,293; March 4, 1969; assigned to Sterling Drug, Inc.
BENOXAPROFEN Therapeutic Function: Antiinflammatory, Analgesic Chemical Name: 2-(2-p-Chlorophenyl-5-benzoxazolyl)propionic acid Common Name: Chemical Abstracts Registry No.: 51234-28-7
562
Benoxaprofen
Structural Formula:
Trade Name
Manufacturer
Country
Year Introduced
Opren
Dista Lilly
UK
1980
Coxigon
Lilly
W. Germany
1981
Inflamid
Lilly
France
1981
Coxigon
Lilly
Switz.
1982
Coxigon
Schweiz. Serum I
Switz.
1982
Oraflex
Lilly
US
1982
Bexopron
Lilly
-
-
Raw Materials Ethyl-2-(3-hydroxy-4-amlnophenyl)propionate p-Chlorobenzoyl chloride Manufacturing Process The 6-benzoxazolyl analog of the 5-benzoxazolyl product is prepared as follows: (a) Ethyl 2-(2-p-chlorophenyl-6-benzoxazolyl)propionate: A solution of ethyl 2-(3-hydroxy-4-aminophenyl)propionate (2.5 g) in pyridine (15 ml) was treated with p-chlorobenzoyl chloride (1.65 ml) at 5°C. After stirring for 2 hours at room temperature the solution was evaporated to dryness. The residue was heated at 220°C until no more water was evolved, then was allowed to cool. This yielded ethyl 2-(2-p-Chlorophenyl-6benzoxazolyl)propionate. (b) 2-(2-p-Chlorophenyl-6-benzoxazolyl)propionic acid: A solution of ethyl 2(2-chlorophenyl-6-benzoxazolyl)propionate (4 g) in aqueous sodium hydroxide (30 ml) was heated on a steam bath for one-half hour. On cooling the black solution was washed with chloroform. On acidification of the black solution with hydrochloric acid the mixture was extracted with chloroform. This solution on evaporation yielded 2-(2-p-chlorophenyl-6-benzoxazolyl)propionic acid, MP 196°C. References Merck Index 1044 DFU 2 (9)565 (1977) Kleeman and Engel p. 82 OCDS Vol. 2 p. 356 (1980) DOT 16 (9) 283 (1980)
Benoxinate hydrochloride
563
I.N.p. 123 Evans, D., Dunwell, D.W. and Hicks, A.; US Patent 3,912,748; October 14, 1975; assigned to Lillv Industries Ltd. Evans, D., Dunwell, D.W. and Hicks, T.A.; US Patent 3,962,441; June 8, 1976; assigned to Lilly Industries, Ltd. Evans, D., Dunwell, D.W. and Hicks, T.A.; US Patent 3,962,452; June 8, 1976; assigned to Lilly Industries, Ltd.
BENOXINATE HYDROCHLORIDE Therapeutic Function: Local anesthetic Chemical Name: 4-Amino-3-butoxybenzoic acid 2-(diethylamino)ethyl ester hydrochloride Common Name: Oxybuprocaine Structural Formula:
Chemical Abstracts Registry No.: 5987-82-6; 99-43-4 (Base) Trade Name
Manufacturer
Country
Year Introduced
Dorsacaine HCl
Dorsey
US
1953
Novesine
Marck-Chibret
France
1960
Anemixin
Zeria
Japan
-
Benoxil
Santen
Japan
-
Benoxinate
Barnes Hind
US
-
Cebesine
Chauvin-Blache
France
-
Colirio Anestesico
Collado
Spain
-
Collu-Blache
Chauvin-Blache
France
-
Conjuncain
Mann
W. Germany
-
Lacrimin
Santen
Japan
-
Minims Benoxinate
Smith and Nephew
UK
-
Novesin
Wander
Switz.
-
Novesin
Dispersa
Switz.
-
Prescaina
Llorens
Spain
-
Scarlene
Chauvin-Blache
France
-
564
Benoxinate hydrochloride
Raw Materials 3-Oxy-4-nitrobenzoic acid Potassium hydroxide Thionyl chloride Hydrogen Ethanol Butanol Diethylaminoethanol Hydrogen chloride Manufacturing Process 25 grams of 3-oxy-4-nitrobenzoic acid are esterified (ethyl ester) and 26 grams of the ester are dissolved in 200 cc of absolute ether and treated with 7 grams of caustic potash in 20 cc of absolute methanol. The red potassium phenolate with 7 grams of pure butyl bromide and 7 grams of absolute alcohol are heated for 5 hours in the oven to 150°C. When cool, the alcohol is evaporated in vacuo and the butoxy-nitrobenzoic acid ethyl ester is precipitated with water. The substance is sucked off and saponified for 15 minutes with a solution of 2.5 grams of caustic potash in 30 cc of alcohol on a water bath. The alcohol is evaporated in vacuo and the 3-butoxy-4nitrobenzoic acid is precipitated with hydrochloric acid. It forms needles which melt at 174°C. 7.9 grams of dry acid are boiled for 45 minutes under a reflux condenser with 25 cc of thionyl chloride. The excess of thionyl chloride is then removed in vacuo, and the oil is distilled. The acid chloride has a yellow color and solidifies. 7.3 grams of the acid chloride are treated with 6.6 grams of diethyl-aminoethanol in 20 cc of absolute benzene. The mixture is then warmed for 1 hour on a water bath. When cold, it is treated with a solution of soda and washed with ether. After drying over potash, the ether and benzene are removed by distillation and 3-butoxy-4-nitrobenzoic acid diethylamino-ethyl ester is obtained, having a BP 215°C/2.5 mm. 5.0 grams of this product are hydrogenated in absolute alcohol solution with fresh Raney nickel. When the absorption of hydrogen ceases (5 hours), the solution is filtered and the alcohol evaporated in vacuo. The 3-butoxy-4aminobenzoic acid diethyl-amino-ethyl ester boils at 215°-218°C at 2 mm pressure; it is an almost colorless oil. By precipitation of a solution of the ester in absolute ether with hydrogen chloride gas, the dihydrochloride is obtained; upon recrystallization from alcohol/ether, it forms crystals which melt at 196°-197°C. References Merck Index 1045 Kleeman and Engel p. 671 I.N. p.716 REM p. 1057 Dr. A. Wander, AG, Switzerland; British Patent 654,484; June 20,1951
Benperidol
565
BENPERIDOL Therapeutic Function: Tranquilizer Chemical Name: 1-[1-[4-(4-Fluorophenyl)-4-oxobutyl]-4-piperidinyl]-1,3dihydro-2H-benzimidazol-2-one Common Name: Benzperidol Structural Formula:
Chemical Abstracts Registry No.: 2062-84-2 Trade Name Frenactil Gliahimon Anquil
Manufacturer Clin-Comar-Byla Tropon Janssen
Country France W. Germany UK
Year Introduced 1965 1966 1973
Raw Materials γ-Chloro-4-fluorobutyrophenone 1-(4-Piperidyl)-2-benzimidazoline HCl Manufacturing Process A mixture of 3.4 parts of γ-chloro-4-fluorobutyrophenone, 4 parts of 1-(4piperidyl)-2-benzimidazolinone hydrochloride, 6 parts of sodium carbonate and 0.1 part of potassium iodide in 176 parts of 4-methyl-2-pentanone is stirred and refluxed for 48 hours. The reaction mixture is cooled and 120 parts of water is added. The separated organic layer is dried over magnesium sulfate and the solvent is evaporated to leave an oily residue which is dissolved in dilute hydrochloric acid and boiled. The acidic solution is filtered and cooled at room temperature whereupon there crystallizes from solution 1-(1-[γ-(4fluorobenzoyl)propyl] -4-piperidyl)-2-benzimidazolinone hydrochloride hydrate melting at about 134°-142°C. References Merck Index 1046 Kleeman and Engel p. 83
566
Benproperine
OCDS Vol. 2 p. 290 (1980) I.N.p. 124 British Patent 989,755; April 22, 1965; assigned to N.V. Research Laboratorium Dr. C. Janssen Janssen, P.A.J.: US Patent 3,161,645; December 15, 1964; assigned to Research Laboratorium Dr. C. Janssen N.V.
BENPROPERINE Therapeutic Function: Antitussive Chemical Name: 1-[1-Methyl-2-[2-(phenylmethyl)phenoxy]ethyl]piperidine Common Name: Structural Formula:
Chemical Abstracts Registry No.: 2156-27-6 Trade Name Tussafug Blascorid Flaveric Tussafugsaft Pirexyl Blascorid Pectipront
Manufacturer Medipharm Guidotti Pfizer Taito Robugen Pharmacia Pharmacia Mack
Country Switz. Italy Japan W. Germany Sweden Sweden W. Germany
Year Introduced 1968 1970 1976 -
Raw Materials o-Benzylphenoxy-β-chloropropane Piperidine Manufacturing Process A mixture of 26.1 g of o-benzylphenoxy-β-chloropropane and 17 g of piperidine is refluxed over a period of 32 hours until the temperature is about 124°C and a nearly solid mixture is formed due to the precipitation of a salt. The mixture is then refluxed over a period of 48 hours at about 160°C and the reaction product obtained is cooled and dissolved in methanol. The solution is concentrated under reduced pressure to yield an oil which is added
Benserazide
567
to 200 ml 3N hydrochloric acid whereupon the mixture is shaken with ether, 3 x 100 ml, until the aqueous phase is clear. The ether solution is washed with water, 3 x 50 ml, and the water present in the combined aqueous phase and water used for washing is evaporated under reduced pressure methanol being added three times when the residue appears to be dry. The impure hydrochloride of o-benzylphenoxy-β-N-piperidinopropane, 41 g, obtained is dissolved in 100 ml water and 100 ml 30% aqueous sodium hydroxide solution are added, whereupon precipitated oil is extracted with ether, 1 x 100 and 2 x 50 ml. The ether solution is washed with water, 4 x 50 ml, dried with magnesium sulfate and the ether is removed under reduced pressure. The residue, 25.2 g, is distilled under reduced pressure and the main fraction, 23.2 g, BP 159°-161°C/0.2 mm. References Merck Index 1047 Kleeman and Engel p. 83 OCDS Vol. 2 p. 100 (1980) DOT 13 (6) 223 (1977) I.N. p. 124 Rubinstein, K.; US Patent 3,117,059; January 7, 1964; assigned to A.B. Pharmacia
BENSERAZIDE Therapeutic Function: Antiparkinsonian Chemical Name: DL-Serine 2-[(2,3,4-trihydroxyphenyl)methyl]hydrazide Common Name: Structural Formula:
Chemical Abstracts Registry No.: 322-35-0 Trade Name
Manufacturer
Country
Year Introduced
Madopar
Roche
Italy
1974
Madopar
Roche
UK
1975
Modopar
Roche
France
1975
Madopar
Roche
W. Germany
1975
Neodopasol
Daiichi
Japan
1980
568
Bentazepam
Trade Name Madopar EC-Doparyl Madopark Prolopa
Manufacturer Nippon Roche Kyowa Hakko Roche Roche
Country Japan Japan -
Year Introduced 1980 1980 -
Raw Materials DL-Seryl hydrazide HCl Pyrogallolaldehyde Hydrogen Manufacturing Process 35.5 grams of DL-seryl-hydrazide hydrochloride was dissolved in 350 ml of water and 35 grams of pyrogallolaldehyde (2,3,4-trihydroxy-benzaldehyde) added thereto at one time. In about 5-10 minutes a clear solution resulted, whereupon slow crystallization occurred and the temperature rose to about 6°-7°C. The crystallization was permitted to continue overnight at 5°C, and the very fine precipitate was then isolated by centrifugation and in the centrifuge washed with water, ethanol, and ether, yielding the dihydrate of DLseryl-(2,3,4-trihydroxy-benzylidene) hydrazide hydrochloride, which melted at 134°-136°C and was poorly soluble in cold water, but very readily dissolved in hot water. The condensation was also effected in absolute ethanol yielding the anhydrous form of the hydrazone, which melted at 225°-228°C. 33.5 grams of the hydrazone-dihydrate was suspended in 330 ml of methanol and hydrogenated with 2.5 grams of palladium-carbon. After the absorption of 2.8 liters of hydrogen, the catalyst was filtered off and the solution evaporated in vacuo to a weight of about 52-55 grams. It was then immediately mixed with 160 ml of absolute ethanol and permitted to crystallize for 24 hours at room temperature and then for a further 24 hours at 0°C. The product was then filtered off with suction and washed with absolute ethanol and absolute ether. The so-obtained DL-seryl-(2,3,4-trihydroxy-benzyl)-hydrazide hydrochloride formed a white crystalline powder which was readily soluble in water and which melted at 146°-148°C. References Merck Index 1048 Kleernan and Engel p. 84 DOT 10 (9) 322 (1974) I.N.p. 124 Hegedus, B.and Zeller, P.; US Patent 3,178,476; April 13, 1965; assigned to Hoffmann-La Roche Inc.
BENTAZEPAM Therapeutic Function: Anticonvulsant, Tranquilizer
Bentiromide
569
Chemical Name: 2H-[1]Benzothieno[2,3-e]-1,4-diazepin-2-one, 1,3,6,7,8,9hexahydro-5-phenylCommon Name: Bentazepam; Liberan Structural Formula:
Chemical Abstracts Registry No.: 29462-18-8 Trade Name Bentazepam Tiadipona Bentazepam
Manufacturer Laboratorios Made S. A. Knoll ZYF Pharm Chemical
Country -
Year Introduced -
Raw Materials N-Phthalimidoacetic acid 2-Amino-3-benzoyl-4,5-tetramethylene thiophene Manufacturing Process To a solution of 3.4 kg N-phthalimidoacetic acid in 20 L of methylene chloride was added a solution of 2.8 kg of 1,1-carbonyl diimidazol in 20 L of methylene chloride. The mixture was refluxed for 1 hour. After cooling to the obtained solution was added a solution of 4.3 kg of 2-amino-3-benzoyl-4,5tetramethylene thiophene in 30 L of methylene chloride and the reaction mixture was refluxed for 16 hours. After cooling the mixture was washed with 30 L of water, dried with sodium sulfate and filtered. After removing the solvent was obtained the 2-(N-phthalimidoacetylamino)-3-benzoyl-4,5tetramethylene thiophene, yield 70%, melting point 230°C. References ES Patent No. 8,602,009; 1986-03-01; Assigned to MADE LABOR SA [ES]
BENTIROMIDE Therapeutic Function: Diagnostic aid (pancreatic function)
570
Bentiromide
Chemical Name: 4-[[2-(Benzoylamino)-3-(4-hydroxyphenyl)-1-oxopropyl] amino]benzoic acid Common Name: N-Benzoyl-L-tyrosyl-p-aminobenzoic acid Structural Formula:
Chemical Abstracts Registry No.: 37106-97-1 Trade Name
Manufacturer
Country
Year Introduced
PFD Oral Sol
Eisai
Japan
1980
PFT Roche
Roche
Switz.
1982
Chymex
Adria
US
-
Raw Materials L-Tyrosine N-Methylmorpholine
Benzoyl chloride p-Aminobenzoic acid
Manufacturing Process A mixture was made of L-tyrosine (18.1 g, 0.1 mol) benzoyl chloride (7.0 g, 0.05 mol) and 200 ml anhydrous THF. After stirring at reflux for 2 hours, the mixture was cooled to room temperature, and the precipitate of tyrosine hydrochloride filtered off (11 g, 46 meq. Cl-). The THF was evaporated and the residue extracted with CCl4 (3 X 100 ml at reflux, discarded) and then dissolved in ethyl acetate (200 ml) filtering off insolubles. The ethyl acetate solution was evaporated to yield 132 g solid product, MP 159°-162°C (93%). The tyrosine was recovered (8 g) by neutralization with aqueous alkali, from the hydrochloride. A solution was made of N-benzyl-L-tyrosine (5.7 g, 20 mmols) and Nmethylmorpholine (2.04 g, 20 mmols) in 60 ml of THF, at -15°C, and to it was added ethyl chloroformate (2.08 g, 20 mmols). After 12 minutes, paminobenzoic acid (2.74 g, 20 mmols) dissolved in 25 ml of THF and 0.38 g of p-toluenesulfonic acid (2 mmols) were added, and the temperature allowed to rise to 5°C. After 2 hours and forty minutes, the mixture was poured into l liter of 0.1 N cold HCl, stirred one-half hour, filtered and dried, to give 8,7 g, MP 192°-223°C. The product was recrystallized from 90 ml methanol and 40 ml water, to give 6 g (74%) of product, N-benzoyl-L-tyrosyl-p-aminobenzoic
Benzarone
571
acid, MP 240°-242°C. References Merck Index 1050 OCDS Vol. 3 p. 60 (1984) DOT 16 (10) 354 (1980) I.N. p. 125 De Benneville, P.L. and Greenberger, N.J.; US Patent 3,745,212; July 10,1973; assigned to Rohm and Haas Co.
BENZARONE Therapeutic Function: Antihemorrhagic Chemical Name: Methanone, (2-ethyl-3-benzofuranyl)(4-hydroxyphenyl)Common Name: Benzarone; Venagil Structural Formula:
Chemical Abstracts Registry No.: 1477-19-6 Trade Name Fragivix Fragivix Fragivix Fragivix Vasoc Benzarone Venagil
Manufacturer Labaz Sigma-Tau Schwarz Pharma AG C.P. Higiene Lindopharm Tohira Pharma Ltd. Erbamont Italia
Country -
Year Introduced -
Raw Materials Salicylic aldehyde Hydrazine hydrate Tin tetrachloride
Coloroacetone 2-Metoxybenzoyl chloride Pyridine hydrochloride
Manufacturing Process The process of preparation of the 2-ethyl-3-(4'-hydroxybenzoyl)benzofurane
572
Benzbromarone
includes the next steps: 1. To 1 mol of potassium hydroxide in absolute ethanol is added 1 mole of salicylic aldehyde. The mixture is brought to boiling point in water bath until the potassium salt formed is dissolved. One mole of coloroacetone is gradually added and the solution boiled in a reflux condenser for 2 hours. On cooling the potassium chloride precipitate is separated off by filtration. The residue is distilled to give 2-acetyl-1-benzofurane, BP: 135°C/15 mm Hg. 2. It was reduced by hydrazine hydrate in an alkaline medium (by process of Hyuang-Minlon, J.A.C.S., 1946, 68, 2487) to give 2-ethyl-1-benzofurane BP: 211°-212°C. 3. 2-Ethyl-1-benzofurane is condensed with 2-metoxybenzoyl chloride in the presence of tin tetrachloride (according to the process described by Bisagni, J.C.S., 1955, 3694). Thus 2-ethyl-3-(4-methoxybenzoyl)-1-benzofyrane is obtained. BP: 226°C/15 mm Hg. 4. 1 part of 2-ethyl-3-(4-methoxybenzoyl)-1-benzofyrane is mixed with 2 parts of pyridine hydrochloride and heated at an oil bath at 210°C in N2 current for 1 hour. On cooling 10 parts of 0.5 N HCl are added. A water layer is mixed with 20 parts of 1% NaOH. The alkaline layer is separated, acidified with diluted HCl. The dropped precipitate (2-ethyl-3-(4'-hydroxybenzoyl) benzofurane) is recrystallized from acetic acid. MP: 124.3°C. References G.B. Patent No. 836,272; Dec. 12, 1957; Societe des Labaz, a Belgiam Body Corporate, of 168 Louise, Brusseles, Belgium Shalk W. et al.; D.B. Patent No. 1,076,702; March 20, 1960; Societe des Laboratories Labaz, Bruessel Hoi N.P.B., Beaudet C.; US Patent No. 3,012,042; Dec. 5, 1961; Assigned to Societe Belge l'Azote et Produits Chimiques du Marly, Liege, Belgium
BENZBROMARONE Therapeutic Function: Uricosuric, Antiarthritic Chemical Name: (3,5-Dibromo-4-hydroxyphenyl)-(2-ethyl-3-benzofuranyl) methanone Common Name: Structural Formula:
Benzbromarone
573
Chemical Abstracts Registry No.: 3562-84-4 Trade Name
Manufacturer
Country
Year Introduced
Desuric
Labaz
Switz.
-
Uricovac
Labaz
W. Germany
1971
Desuric
Labaz
France
1976
Desuric
Sigma Tau
Italy
1977
Urinorm
Torii
Japan
1979
Azubromaron
Azupharma
W. Germany
-
Allomaron
Nattermann
W. Germany
-
Exurate
Mead Johnson
US
-
Hipuric
Labaz
-
-
Max-Uric
Labinca
Argentina
-
Minuric
Labaz
-
-
Narcaricin
Heumann
W. Germany
-
Normurat
Gruenenthal
W. Germany
-
Obaron
Mepha
Switz.
-
Raw Materials Chloroacetone Bromine Anisoyl chloride
Hydrazine hydrate Salicylic aldehyde
Manufacturing Process The propyl analog of the benzbromarone intermediate containing an ethyl group is prepared as follows: to a solution of potassium hydroxide (56 g = 1 mol) in absolute ethyl alcohol (750 cc) is added one mol of salicylic aldehyde (122 grams). The mixture is brought to boiling point in a water-bath until the potassium salt formed is dissolved. One mol of ethyl chloromethyl ketone (106.5 grams) (methyl chloromethyl ketone or chloracetone in the case of benzbromarone) is gradually added and the solution boiled in a reflux condenser for two hours. After cooling, the potassium chloride precipitate is separated off by filtration, and the greater part of the solvent removed by distillation. The residue is then puritied by distillation. In this way, 140 grams of 2-propionyl coumarone are obtained, boiling at 135°C under 15 mm Hg. A mixture is then prepared as follows: 215 grams of 2-propionyl coumarone, 550 cc of diethylene glycol and 200 grams of hydrazine hydrate at 85% and maintained at boiling point in a reflux condenser for 10 minutes. After cooling, 180 grams of potassium hydroxide are added and the mixture brought up to 120°-130°C. This temperature is maintained until no more nitrogen is liberated (about 1 hour). The mixture is then distilled by means of super-heated steam (150°-160°C). The distillate is neutralized by means of concentrated HCl, decanted, and the aqueous layer extracted by means of ether. The oily layer and the ethereal extract are mixed, washed with diluted HCl, then with water, and finally dried over sodium sulfate. The solvent is removed and the residue rectified under
574
Benzethonium chloride
reduced pressure. In this way, 130 grams of 2-propyl coumarone are obtained, boiling at 112°C under 17 mm of mercury. The following substances are then placed in a 250 cc flask fitted with a stirrer and a separatory funnel: 12.96 grams of 2-propyl coumarone, 55 cc of carbon sulfide and 14 grams of anisoyl chloride. The mixture is cooled by means of iced water and 21.5 grams of stannic chloride introduced dropwise, while the mixture is stirred. Stirring is continued for three hours at 0°C, after which the mixture is allowed to stand overnight. 50 cc of carbon sulfide is added and the mixture is treated, while being stirred, with the following: 20 cc of HCl and 100 cc of iced water. The organic layer is decanted and washed with water, dried over silica gel and rectified. 16.16 grams of 2-propyl-3-anisoyl coumarone are obtained (Yield: 72%), boiling at 189°C under 0.5 mm Hg. The methoxylated coumarone so obtained is mixed as follows: 1 part of 2-propyl-3-anisoylcoumarone and 2 parts of pyridine hydrochloride and the mixture maintained for one hour under a stream of dry nitrogen in an oil bath at 210°C (under a vertical condenser). After cooling, the mixture is triturated with 0.5 N hydrochloric acid (10 parts). The aqueous layer is separated and the residue extracted with ether. The ethereal extract is treated with 20 parts of 1% caustic soda. The alkaline layer is separated by decanting and acidified by means of diluted HCl. The precipitate is purified by recrystallization in aqueous acetic acid. 0.8 part of 2-propyl-3p-hydroxybenzoyl coumarone is obtained, melting at 123°C. Then the dibromo counterpart of benzbromarone may be prepared as follows: 8.05 g of 3-ethyl-2-p-hydroxybenzoyl coumarone, prepared as described above, are dissolved in very silght excess of 3% caustic soda. To this solution is gradually added a slight excess of bromine dissolved in a 25% aqueous solution of potassium bromide. The resultant solution is acidified with a 20% solution of sodium bisulfite, centrifuged, washed with water and then dried under vacuum. The product is then recrystallized in acetic acid and 13.6 g of 2-(4'-hydroxy-3',5'-dibromo-benzoyl)-3-ethyl coumarone obtained. MP 151°C. References Merck Index 1062 Kleeman and Engel p. 87 OCDS Vol. 2 p. 354 (1980) I.N. p. 127 Hoi, N.P.B. and Beaudet, C.; US Patent 3,012,042; December 5, 1961; assigned to Societe Belge de I'Azote et des Produits Chirniques du Marly, Belgium
BENZETHONIUM CHLORIDE Therapeutic Function: Topical antiinfective Chemical Name: N,N-Dimethyl-N-[2-[2-[4-(1,1,3,3-tetrarmethylbutyl) phenoxy]ethyl]benzenemethanaminium chloride
Benzethonium chloride
575
Common Name: Structural Formula:
Chemical Abstracts Registry No.: 121-54-0 Trade Name Phemerol Premithyn Benzalcan Dalidyne Desamon Hyarom Sterilette Uni Wash
Manufacturer Parke Davis Flint Siegfried Dalin Streuli Teva Farmitalia United
Country US US Switz. US Switz. Israel Italy US
Year Introduced 1942 1959 -
Raw Materials p-Diisobutylphenol Benzyl chloride Dichlorodiethyl ether Dimethylamine Manufacturing Process A mixture of 32 g of p-(α,α,γ,γ-tetramethylbutyl)phenoxyethoxyethyldimethylamine and 12.7 parts of benzyl chloride was warmed in 50 g of benzene for 2 hours. The benzene was then evaporated. The residual viscous mass gave a foamy, soapy solution in water. The original starting materials are p-diisobutylphenol, dichlorodiethyl ether and dimethylamine. References Merck Index 1072 PDR pp. 829, 1826 I.N.p. 127 REM p. 1166 Bruson, H.A.; US Patents 2,115,250; April 26, 1938; 2,170,111; August 22, 1939; and 2,229,024; January 21, 1941; all assigned to Rohm and Haas Co.
576
Benzilonium bromide
BENZILONIUM BROMIDE Therapeutic Function: Anticholinergic Chemical Name: Pyrrolidinium, 1,1-diethyl-3-((hydroxydiphenylacetyl)oxy)-, bromide Common Name: Benzilonium bromide; Ulcoban Structural Formula:
Chemical Abstracts Registry No.: 1050-48-2; 16175-92-1 (Base) Trade Name Benzilonium bromide
Manufacturer Pharm Chemical Shanghai Lansheng Corporation
Country -
Year Introduced -
Ulcoban
Parke-Davis
-
-
Raw Materials 1-Ethyl-3-hydroxypyrrolidine Diphenylchloroacetyl chloride
Ethylbenzilate Ethyl bromide
Manufacturing Process A mixture containing of 23 g of 1-ethyl-3-hydroxypyrrolidine, 51.2 g of ethylbenzilate and 1.50 ml of benzene is subjected to azeotropic distillation to remove traces of water and then 250 mg of metallic sodium added to the residual solution. The mixture heated under reflux for about 8 hours while slowly drawing off the benzene-alcohol azeotrope formed. The reaction mixture is cooled, treated with 1 ml of acetic acid and washed with water. The benzene is removed by distillation and the residue distilled in vacuo to obtain the desired 1-ethyl-3-pyrrolidinyl benzilate as a viscous oil; yield 44 g, 68.1%; b.p. 164-170°C at 0.2 mm. If desired, this same product can be prepared by adding 8 g of 1-ethyl-3hydroxypyrrolidine in about 40 ml of dry methylene dichloride to 18.4 g of diphenylchloroacetyl chloride in about 40 ml of boiling methylene dichloride and refluxing the mixture for 1 hour. The solvent is evaporated and the residue heated on a steam bath with 200 ml of water for 5 min and then
Benziodarone
577
allowed to stand at room temperature for 2 days. The mixture is treated with potassium carbonate, extracted with benzene and the benzene distilled from the extract to obtain crude l-ethyl-3-pyrrolidinyl benzilate. Distillation in vacuo yields the pure l-ethyl-3-pyrrolidinyl benzilate; yield 8 g (31%); b.p. 197°C at 2 mm. 22 g of 1-ethyl-3-pyrrolidinyl benzilate prepared by either of the above methods is mixed with 32 g of ethyl bromide in 100 ml of isopropanol and refluxed for 1 hour to give 23 g of 1,1-diethyl-3-pyrrolidinium bromide benzilate, m.p.196-197°C. References Merck Index, Monograph number: 1110, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. Nguen Phac Bao Hoi, GB Patent No. 821,436; Dec. 5, 1961; Assigned to Societe Belge de l'Azote et des Produits Chimiques du Marly, Liege, Belqium DE Patent No. 1,136,338; Fev. 12, 1957; Assigned to Parke, Davis and Co., Detroit, Michigan
BENZIODARONE Therapeutic Function: Coronary vasodilator, Uricosuric Chemical Name: Methanone, (2-ethyl-3-benzofuranyl)(4-hydroxy-3,5diiodophenyl)Common Name: Benziodarone; Ethofuridione Structural Formula:
Chemical Abstracts Registry No.: 68-90-6 Trade Name Amplivix Amplivix Amplivix Amplivix Dilafurane Plexocardio
Manufacturer Sigma-Tau Sanofi Pharma AG Sumitomo C.P. Higiene Sanofi-Winthrop Benvegna
Country -
Year Introduced -
578
Benzoctamine hydrochloride
Raw Materials Salicylic aldehyde Tin tetrachloride Potassium iodide
Chloroacetone 4-Methoxy-benzoylchloride Iodine
Manufacturing Process The starting product 2-ethyl-3-benzofuranyl p-hydroxyphenyl ketone (benzaron) was prepared in 4 steps: 1. First step was a reaction of salicylic aldehyde with chloroacetone to produce 2-acetyl-1-benzofuran. 2. It was reduced by hydrazine hydrate in an alkaline medium by process of Hyuang-Minlon, J.A.C.S., 1946, 68, 2487 to give 2-ethyl-1-benzofurane. 3. 2-Ethyl-3-(4-methoxybenzoyl)-1-benzofuran was obtained from 2-ethyl-1benzofuran and 4-methoxy-benzoylchloride in a presence of tin tetrachloride. 4. It was heated with pyridine hydrochloride at 200°-220°C to give 2-ethyl-3benzofuranyl p-hydroxyphenyl ketone (benzaron) as described in N.P.B.Hoi, C.Beaudet; US Patent No. 3,012,042; Dec. 5, 1961. Benzaron (1 part) was dissolved in a very slight excess of 3% caustic soda. To this solution is gradually added a slight excess of iodine dissolved in a 25% aqueous solution of potassium iodide. The resultant solution is acidified with a 20% solution of sodium bisulphite, centrifuged, washed with water and then recrystallized in acetic acid to give of 2-ethyl-3-benzofuranyl 4-hydroxy-3,5diiodophenyl ketone. MP: 167°C. References GB Patent No. 836,272; Dec. 17, 1957; Societe des Labaz, a Belgiam Body Corporate, of 168 Louise, Brusseles, Belgium
BENZOCTAMINE HYDROCHLORIDE Therapeutic Function: Sedative, Muscle relaxant Chemical Name: N-Methyl-9,10-ethanoanthracene-9(10H)-methanamine hydrochloride Common Name: Chemical Abstracts Registry No.: 10085-81-1; 17243-39-9 (Base)
Benzonatate
579
Structural Formula:
Trade Name
Manufacturer
Country
Year Introduced
Tacitin
Ciba Geigy
Switz.
-
Tacitine
Ciba Geigy
France
1970
Tacitin
Ciba Geigy
UK
1971
Tacitin
Ciba Geigy
Italy
1971
Tacitin
Ciba Geigy
W. Germany
1972
Raw Materials Anthracene Methylamine
Acrolein Hydrogen
Manufacturing Process A solution of 10 g of 9:10-dihydro-9:10-ethano-(1:2)-anthracene-(9)aldehyde (made from anthracene and acrolein) and 10 g of monomethylamine in 100 cc of ethanol is heated at 80°C for 4 hours in an autoclave. The reaction mixture is then evaporated to dryness under reduced pressure to leave a crystalline residue which is dissolved in 150 cc of ethanol and, after the addition of 2 g of Raney nickel, hydrogenated at 40°C under atmospheric pressure. When the absorption of hydrogen has subsided, the catalyst is filtered off and the filtrate evaporated under reduced pressure. An oil remains which is covered with 100cc of 2N hydrochloric acid, The 9-methylamino-methyl-9:10-dihydro-9:10ethano-(9:10)-anthracene hydrochloride crystallizes immediately; after crystallization from methanol it melts at 320°-322°C. References Merck Index 1087 Kleeman and Engel p. 88 DOT 6 (4) 123 (1970) I.N. p. 129 Schmidt, P., Wilhelm, M. and Eichenberger, K.; US Patent 3,399,201; August 27, 1968; assigned to Ciba Corp.
BENZONATATE Therapeutic Function: Antitussive
580
Benzonatate
Chemical Name: 4-(Butylamino)benzoic acid 3,6,9,12,15,18,21,24,27nonaoxaoctacos-1-yl ester Common Name: Benzononatine Structural Formula:
Chemical Abstracts Registry No.: 104-31-4 Trade Name
Manufacturer
Country
Year Introduced
Tessalon
Endo (Du Pont)
US
1958
Ventusasin
Warren Teed
US
1964
Tessalon
Ciba Geigy
Switz.
-
Raw Materials p-Butylaminobenzoic acid ethyl ester Nonaethylene glycol monomethyl ether Manufacturing Process 4.42 parts of para-butylamino-benzoic acid ethyl ester are put with 16.0 parts of a mixture of polyethylene glycol monomethyl ethers, boiling at 180°-220°C at a pressure of 0.01 mm of mercury, in a closed reaction vessel which is fitted with an adjustable inlet tube for solvents and a connection for distilling off in vacuo. In order to dry the mixture completely, it is heated for an hour at 100°-105°C and absolute xylene is introduced under the surface of the mixture in vacuo at a pressure of 12 mm of mercury. There is thus a constant stream of xylene steam passing through the whole apparatus, which removes the last traces of moisture and any other volatile impurities. The xylene is condensed in a cooler. The whole is cooled to 20°-30°C and 0.06 part of sodium methylate dissolved in 0.6 part of methanol is added.
Benzphetamine hydrochloride
581
Thereupon xylene is introduced again in vacuo at a temperature of 100°105°C whereby all the methanol and the ethanol formed during reesterification evaporates. The re-esterification is continued under these conditions until a specimen of the reaction mass is clearly soluble in cold water, which occurs after about 2-3 hours. There is now obtained in almost quantitative yield the ester of the formula wherein n stands for approximately 7 to 9, which still contains an excess of polyethylene glycol monomethyl ether. The ester is purified by dissolving in benzene and being washed several times with a sodium carbonate solution of 5% strength. It is advantageous to agitate all the washing solutions with fresh benzene. In this distribution between benzene and sodium carbonate solution the new ester remains in the benzene, the excess polyethylene glycol monomethyl ether and a small amount of brown impurities are taken up by the dilute soda solution. By evaporating the dried and filtered benzene solution there is obtained the new ester in the form of a colorless to very faintly yellow oil which is easily soluble in most organic solvents with the exception of aliphatic hydrocarbons. The new ester is precipitated from aqueous solutions when heated to about 42°C. but it dissolves again readily on cooling. References Merck Index 1099 Kleeman and Engel p.89 PDR p. 862 I.N.p. 130 REM p. 870 Matter, M.; US Patent 2,714,608; August 2, 1955; assigned to Ciba Pharmaceutical Products, Inc.
BENZPHETAMINE HYDROCHLORIDE Therapeutic Function: Antiobesity Chemical Name: N-α-Dimethyl-N-(phenylmethyl)benzeneethanamine hydrochloride Common Name: Structural Formula:
Chemical Abstracts Registry No.: 5411-22-3; 156-08-1 (Base) Trade Name Didrex Inapetyl Didrex
Manufacturer Upjohn Upjohn Upjohn
Country US France UK
Year Introduced 1960 1969 -
582
Benzpyrinium bromide
Raw Materials Benzyl chloride Sodium hydroxide
d-Desoxyephedrine hydrochloride Hydrogen chloride
Manufacturing Process Fifty grams of d-desoxyephedrine hydrochloride was dissolved in a small amount of water and a molar excess of sodium hydroxide was .added thereto. The resulting forty grams of precipitated oily d-desoxyephedrine was collected in ether and the whole was thereafter dried with anhydrous potassium carbonate. The ether was then removed, the resulting oily residue having an nD22 of 1.5045 was stirred in a flask with 40 grams of anhydrous sodium carbonate at 120°C, and 34.6 grams of benzyl chloride was added dropwise thereto over a period of thirty minutes. Stirring was continued for 2 hours, whereafter the reaction mixture was extracted with benzene. The benzene was distilled from the extract and the residue of d-N-methyl-Nbenzyl-β-phenylisopropylamine was distilled at reduced pressure. The thus obtained free base, distilling at 127°C at a pressure of 0.2 mm of mercury and having an nD19 of 1.5515, was dissolved in ethyl acetate and a molar equivalent of ethanolic hydrogen chloride was added thereto. Anhydrous ether was added to the mixture and d-N-methyl-N-benzyl-β-phenylisopropylamine hydrochloride precipitated from the reaction mixture as an oil which was crystallized from ethyl acetate to give crystals melting at 129° to 130°C. References Merck Index 1122 Kleeman and Engel p.89 PDR p.1841 OCDS Vol. 1 p.70 (1977) I.N. p.131 REM p.891 Heinzelman, R.V. and Aspergren, B.D.; US Patent 2,789,138; April 16, 1957; assigned to The Upjohn Company
BENZPYRINIUM BROMIDE Therapeutic Function: Cholinergic Chemical Name: 3-[[(Dimethylamino)carbonyl]oxy]-1-(phenylmethyl) pyridinium bromide Common Name: Chemical Abstracts Registry No.: 587-46-2
Benzpyrinium bromide
583
Structural Formula:
Trade Name
Manufacturer
Country
Year Introduced
Stigmonene
Warner Lambert
US
1949
Raw Materials Dimethylcarbamyl chloride 3-Pyridol Benzyl bromide Manufacturing Process 56 grams of dimethylcarbamyl chloride were gradually added over a period of 50 minutes to a solution of 45 grams of 3-pyridol in a mixture of 300 cc of benzene and 69 grams of triethylamine. The reaction mass was then agitated at 80°C for 3 hours and permitted to cool. The triethylamine hydrochloride was removed by filtration and solvents distilled from the filtrate under vacuum in a nitrogen atmosphere. The residual oil was then fractionated under vacuum whereby, after removal of unchanged dimethylcarbamyl chloride, a product distilling at 90°C at 0.3 mm was obtained; this product was the dimethylcarbamyl ester of 3-pyridol. 60 grams of the ester prepared as above described were dissolved in 225 cc of benzene and 92.5 grams of benzyl bromide were added thereto. The solution was stirred at room temperature for 24 hours and refluxed for 3 additional hours. At the end of this time the crude product which formed was separated, washed with benzene and dissolved in water. The aqueous solution was extracted with ether, filtered through charcoal and then evaporated to dryness in a nitrogen atmosphere; traces of water were removed by redissolving the oily residue in absolute alcohol, adding benzene and then evaporating the mixture to dryness under vacuum. The yellow oil thus obtained was then dissolved in a mixture of 300 cc of benzene and 55 cc of absolute alcohol under reflux, the solution cooled, and 340 cc of absolute ether added. The solution was then seeded and maintained at 5°C for two days. The crystalline product obtained was filtered and dried, a product melting between 115°C and 116°C being obtained. This product was the desired 1 benzyl-3-(dimethylcarbamyloxy)-pyridinium bromide. References Merck Index 1124 I.N. p. 131 Wuest, H.M.; US Patent 2,489,247; November 22, 1949; assigned to William R. Warner and Co., Inc.
584
Benzquinamide
BENZQUINAMIDE Therapeutic Function: Tranquilizer, Antinauseant Chemical Name: 2-(Acetyloxy)-N,N-diethyl-1,3,4,6,7,11b-hexahydro-9,10dimethoxy-2H-benzo[a]quinolizine-3-carboxamide Common Name: Structural Formula:
Chemical Abstracts Registry No.: 63-12-7; 30046-34-5 (Hydrochloride salt) Trade Name
Manufacturer
Country
Year Introduced
Emete-Con
Roerig
US
1974
Promecon
Endopharm
W. Germany
1983
Quantril
Pfizer
US
-
Raw Materials 2-Oxo-3-carboxy-9,10-dimethoxy-1,2,3,4,6,7-hexahydro-11b-Hbenzopyridocoline Diethylamine Hydrogen Hydrogen chloride Manufacturing Process According to US Patent 3,055,894, a solution consisting of 3.4 grams (0.01mol) of 2-oxo-3-carboethoxy-9,10-dimethoxy-1,2,3,4,6,7-hexahydro11b-H-benzopyridocoline and 0.8 grams (0.011 mol) of freshly distilled diethylamine dissolved in 50 ml of xylene was refluxed under a nitrogen atmosphere for 24 hours. After cooling to room temperature, the reaction mixture was successively extracted with four 100 ml portions of water. The aqueous phase was then discarded and the xylene layer was passed through a paper filter containing a bed of sodium sulfate and activated charcoal. The resulting filtrate was then heated under reduced pressure (65 mm Hg) via a water bath at 50°C in order to remove the xylene solvent, and the residual oil so obtained was cooled to approximately 5°C and held at that point until a semisolid formed (required approximately 16 hours). Recrystallization of the
Benzquinamide
585
semisolid from aqueous ethanol in the presence of activated charcoal afforded light yellow crystals of 2-oxo-3-(N,N-diethylcarboxamido)-9,10-dimethoxy1,2,3,4,6,7-hexahydro-11b-H-benzopyridocoline, MP 150°-152°C. Then, as described in US Patent 3,053,845, one hundred grams (0.278 mol) of 2-oxo-3-(N,N-diethylcarboxamido)-9,10-dimethoxy-1,2,3,4,6,7-hexahydro11b-H-benzopyridocoline was dissolved in 1,500 ml of hot methanol and the resulting solution was allowed to cool to room temperature. After removal of all the dissolved oxygen therein by saturation of the solution with dry nitrogen, 5.0 grams of Adams' platinum oxide catalyst was introduced into the system in one portion while still maintaining same under a nitrogen atmosphere. The reaction flask and its contents were then shaken at room temperature under slightly greater than one atmosphere of hydrogen pressure until the total hydrogen uptake was completed. Dissolved hydrogen gas was then removed from the reaction solution by saturation of same with respect to dry nitrogen, while the platinum black was removed by means of gravity filtration. Concentration of the resulting filtrate under reduced pressure on a steam bath then afforded a nearly quantitative yield of 2-hydroxy-3-(N,Ndiethyicarboxamido)-9,10-dimethoxy-1,2,3,4,6,7-hexahydro-11b-Hbenzopyridocoline as a yellow crystalline solid (mixture of the axial and equatorial forms). A mixture consisting of 2 grams of 2-hydroxy-3-(N,N-diethylcarboxamido)9,10-dimethoxy-1,2,3,4,6,7-hexahydro-11 b-H-benzopyridocoline (OH-axial) hydrochloride (prepared by treating the base with hydrogen chloride gas in absolute ether) dissolved in 7 ml of acetic anhydride containing 3 ml of pyridine was heated at 100°C for 2 hours under a nitrogen atmosphere. At the end of this period, a crystalline precipitate had formed and the resultant mixture was subsequently diluted with an equal volume of diethyl ether and filtered. The crystalline hydrochloride salt so obtained, i.e., the solid material collected on the filter funnel, was then converted to the corresponding free base by distribution in 10 ml of a benzene-aqueous 5% sodium carbonate system. The product recovered from the benzene extracts was then recrystallized from diisopropyl ether to afford 1.46 grams of 2-acetoxy-3-(N,Ndiethylcarboxamido)-9,10-dimethoxy-1,2,3,4,6,7-hexahydro-11b-Hbenzopyridocoline (CH3COO-axial), MP 130°-131.5°C. References Merck Index 1125 Kleeman and Engel p.90 PDR p.1523 OCDS Vol.1 p.350 (1977) DOT 11 (1) 11 (1975); 9 (6) 233 (1973) I.N. p. 131 REM p.807 Tretter, J.R.; US Patent 3,053,845; September 11, 1962; assigned to Chas. Pfizer and Co., Inc. Lombardino, J.G. and McLamore, W.M.; US Patent 3,055,894; September 25, 1962; assigned to Chas. Pfizer and Co., Inc.
586
Benzthiazide
BENZTHIAZIDE Therapeutic Function: Diuretic, Antihypertensive Chemical Name: 6-Chloro-3-([(phenylmethyl)thio]methyl)-2H-1,2,4benzothiadiazine-7-sulfonamide 1,1-dioxide Common Name: Structural Formula:
Chemical Abstracts Registry No.: 91-33-8 Trade Name Exna Dytide Diteriam Aquatag Edemex Lemazide Aquapres Aquastat Aquatag Decaserpyl Dihydrex Exosalt Fovane Hydrex Hy-Drine Proaqua Regulon Tensimic Urese
Manufacturer Robins SK and F Roussel Tutag Savage Lemmon Coastal Lemmon Reid-Provident Roussel Astra Bayer Taito Pfizer Trimen Zemmer Reid-Provident Yamanouchi Roussel Pfizer
Country US UK France US US US US US US France Sweden W. Germany Japan US US US Japan France US
Raw Materials 2,4-Disulfamyl-5-chloroaniline Chloroacetaldehyde Benzyl mercaptan Manufacturing Process The preparation of the dihydro analog is as follows:
Year Introduced 1960 1960 1962 1965 1970 1970 -
Benztropine mesylate
587
(A) Preparation of 3-Chloromethyl-6-Chloro-7-Sulfamyl-3,4-DihydroBenzothiadizine-1,1-Dioxide - To 8 ml of 40-50% chloroacetaldehyde aqueous solution and 7 ml of dimethylformamide are added 10 grams of 2,4disulfamyl-5-chloroaniline. The mixture is heated on a steam bath for 2 hours after which it is concentrated at reduced pressure. The residue is triturated with water. The solid material is recrystallized from methanol-ether after treatment with activated carbon to give 7.2 grams of product, MP 229°230°C. (B) Preparation of Benzylthiomethyl-6-Chloro-7-Sulfamyl-3,4Dihydrobenzothiadiazine-1,1-Dioxide - A mixture of 3-(chloromethyl)-6-chloro7-sulfamyl-3,4-dihydrobenzothiadiazine-1,1-dioxide (0.02 mol) and benzylmercaptan (0.024 mol) in 20 ml of 10% sodium hydroxide and 20 ml of dimethylformamide is stirred at room temperature for 6 hours. After heating for 10 minutes on a steam bath, the mixture is cooled and acidified with 6 N HCl. The product, after recrystallization from acetone, melts at 210°-211°C. References Merck Index 1126 Kleeman and Engel p. 90 PDR pp. 1458, 1807 I.N.p. 132 REM p.938 McLamore, W.M. and Laubach, G.D.; US Patent 3,111,517; November 19, 1963; assigned to Chas. Pfizer and Co., Inc.
BENZTROPINE MESYLATE Therapeutic Function: Antiparkinsonian Chemical Name: 3-(Diphenylmethoxy)-8-methyl-8-azabicyclo[3.2.1]octane methanesulfonate Common Name: Tropine benzohydryl ether methanesulfonate; Benzatropine Mesylate; Benztropine methanesulfonate Structural Formula:
Chemical Abstracts Registry No.: 132-17-2
588
Benztropine mesylate
Trade Name Cogentin
Manufacturer Merck Sharp and Dohme
Country US
Year Introduced 1954
Cogentinol Cogentine Cogentin Akitan Bensylate
Astra Merrell Merck-Banyu Farmos ICN
W. Germany France Japan Finland Canada
1966 -
Raw Materials Diphenyldiazomethan Hydrogen bromide Methanesulfonic acid
Tropine Sodium hydroxide
Manufacturing Process Diphenyldiazomethane was prepared by shaking 7.9 grams of benzophenone hydrazone and 8.8 grams of yellow mercuric oxide in petroleum ether, filtering and evaporating off the petroleum ether from the filtrate under reduced pressure. To the residual diphenyldiazomethane 2.83 grams of tropine and 4.5 ml of benzene were added. The mixture was warmed in a pan of hot water at about 85°C under reflux for 24 hours after which time the original purple color had been largely discharged. The reaction mixture was dissolved by adding benzene and water containing hydrochloric acid in excess of the quantity theoretically required to form a salt. A rather large amount of water was required since the tropine benzohydryl ether hydrochloride was not very soluble and tended to separate as a third phase. The aqueous layer was separated, washed with benzene and with ether and made alkaline with an excess of sodium hydroxide. The resulting insoluble oil was extracted with benzene. The benzene extracts were dried over potassium carbonate and evaporated under reduced pressure, leaving a residue of 4.1 grams. The residue (tropine benzohydryl ether) was dissolved in ether and treated with hydrogen bromide gas until an acidic reaction was obtained. The precipitate soon became crystalline and was collected on a filter and dried. The tropine benzohydryl ether hydrobromide weighed 4.1 grams. Recrystallization from absolute ethanol gave 3.3 grams of first crop melting at 247°-248°C (dec.). Twelve grains of tropine benzohydryl ether hydrobromide was converted to the free base by warming with dilute aqueous sodium hydroxide. The oily base was extracted with toluene. The toluene extract was washed with water and then extracted with about 100 ml of water containing 28.1 ml of 1.10 N methanesulfonic acid, (an equimolecular quantity). The toluene solution was extracted twice more with fresh portions of water. The combined water extracts were evaporated under reduced pressure. Residual water was removed by dissolving the residue in absolute ethanol and evaporating under reduced pressure several times. Residual alcohol was then removed by dissolving the residue in acetone and evaporating under reduced pressure several times. The resulting residue was recrystallized by dissolving in acetone and adding ether. The crystalline precipitate was collected on a filter, washed
Benzydamine hydrochloride
589
with ether and dried at 56°C in vacuo. The tropine benzohydryl ether methanesulfonate weighed 10.2 grams, MP 138°-140°C. References Merck Index 1127 Kleeman and Engel p.86 PDR pp.1149, 1606 DOT 18 (2) 91 (1982) I.N.p.127 REM p.928 Phillips, R.F.; US Patent 2,595,405; May 6, 1952; assigned to Merck and Co., Inc.
BENZYDAMINE HYDROCHLORIDE Therapeutic Function: Analgesic, Antiinflammatory, Antipyretic Chemical Name: 1-Propanamine, N,N-dimethyl-3-((1-(phenylmethyl)-1Hindazol-3-yl)oxy)-, monohydrochloride Common Name: Benzidammina; Benzydamine hydrochloride Structural Formula:
Chemical Abstracts Registry No.: 132-69-4; 642-72-8 (Base) Trade Name
Manufacturer
Country
Year Introduced
Tantum
-
-
Afloben
Angelini Pharmaceuticals Esseti
-
-
Afloben
Benedetti SpA
-
-
Andolex
3M Pharma
-
-
Benalgin
Polfa-Pabianice
-
-
Benzyrin
Yoshitomi
-
-
Benzydamine Hydrochloride
Shanghai Lansheng Corporation
-
-
590
Bephenium hydroxynaphthoate
Trade Name Difflam Enzamin Salyzoron Saniflor Saniflor Verax Lonol Lonol
Manufacturer Carnegie Kowa Hishiyama Esseti Benedetti Tosi Promero Boehringer Ingelheim Promeco
Country -
Year Introduced -
Multum
Lampugnani
-
-
Raw Materials Hydrochloric acid Sodium nitrite
Anthranilic acid methyl ester Sodium hydroxide
Manufacturing Process To a solution of 175 g of anthranilic acid methyl ester in 2 L of water and 120 ml of concentrated hydrochloric acid at 25°C was added concentrated solution of 80 g sodium nitrite. The product was dissolved in solution of 500 g NaOH in 1.5 L of water. To this solution under nitrogen was added 400 g of sodium bisulfite. The mixture was stirred for 6 hours at 75°C under nitrogen. The obtained solid product was dissolved in water and then to the solution was added 750 ml glacial acetic acid. The yield of 1-benzyl-3-(3-(dimethylamino) propoxy)-1H-indazole 70%, M.P. 154-156°C. In practice it is usually used as monohydrochloride salt. References Merck Index, Monograph number: 1157, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. Fr. Patent No. 1,382,855; 21.02.1964; Assigned to Aziende Chimiche Riunite Angeloni Francesco, residant en Italie
BEPHENIUM HYDROXYNAPHTHOATE Therapeutic Function: Anthelmintic Chemical Name: N,N-Dimethyl-N-(2-phenoxyethyl)benzenemethanaminium hydroxynaphthoate Common Name: Chemical Abstracts Registry No.: 7181-73-9
Bephenium hydroxynaphthoate
591
Structural Formula:
Trade Name
Manufacturer
Country
Year Introduced
Alcopar
Wellcome
UK
1960
Alcopar
Wellcome
France
1965
Alcopara
Burroughs-Wellcome
US
1967
Alcopar
Wellcome-Tanabe
Japan
-
Raw Materials Chloro-2-phenoxyethane Dimethyl amine
Benzyl chloride 2-Hydroxy-3-naphthoic acid
Manufacturing Process First, dimethylamino-2-phenoxyethanewas made by reacting chloro-2phenoxyethane with dimethylamine. Benzyl chloride (10 grams) was then added to a solution of 1-dimethylamino-2-phenoxyethane (12.3 grams) in acetone (35 ml). The mixture warmed spontaneously and N-benzyl-N,Ndimethyl-N-2-phenoxyethylammonium chloride slowly crystallized. After 24 hours, this solid was filtered off, washed with fresh acetone and dried immediately in vacuo, MP 135°-136°C. 2-Hydroxy-3-naphthoic acid (1.88 grams) was dissolved in hot aqueous sodium hydroxide (0.5N; 20 ml) and the resulting solution was slowly added to a solution of N-benzyl-N,N-dimethyl-N-2-phenoxyethylammonium chloride (2.9 grams) in water (5 ml). A gum separated at first but it solidified on scratching. After the addition was complete, the mixture was allowed to stand at room temperature for 2 hours and then filtered. The residue was washed with water and dried in vacuo to give N-benzyl-N,N-dimethyl-N-2phenoxyethylammonium 2-hydroxy-3-naphthoate, MP 170°-171°C. References Merck Index 1159 Kleeman and Engel p.93 DOT 4 (3) 114 (1968) I.N. p. 134 Copp, F.C.; US Patent 2,918,401; December 22, 1959; assigned to BurroughsWellcome and Co.. Inc.
592
Bepotastine besilate
BEPOTASTINE BESILATE Therapeutic Function: Antiallergic Chemical Name: 1-Piperidinebutanoic acid, 4-((S)-(4-chlorophenyl)-2pyridinylmethoxy)-, monobenzenesulfonate Common Name: Bepotastine besilate; Betotastine besilate Structural Formula:
Chemical Abstracts Registry No.: 190786-44-8; 190786-43-7 (Base) Trade Name
Manufacturer
Country
Year Introduced
Bepotastine besilate Talion
Ube
-
-
TANABE SEIYAKU
-
-
Raw Materials Trioxane Palladium on carbon 4-Toluenesulfonic acid monohydrate Lithium aluminum hydride Magnesium beta-Propiolactone t-Butyldimethylsilyl chloride Pyridine Cerium (III) chloride heptahydrate Dimethyl 3-methyl-2-oxo-hept5-yne-phosphonate
Dicyclohexylcarbodiimide Hydrogen Sodium hydrogen carbonate Thionyl chloride Copper iodide Diazomethane Imidazole Trifluoroacetic acid Sodium methoxide 7-Bromo-3a,8b-cis-3a,8b-dihydro3H-5-cyclopenta[b] benzofurancarboxylic acid
Manufacturing Process Methyl 2-endo-hydroxy-1-exo-hydroxymethyl-3a,8b-cis-2,3,3a,8b-tetrahydro1H-5-cyclopenta[b]benzofurancarboxylate: To a suspension of 4 g of trioxane in 28 ml of acetic acid was added 1.2 ml of concentrated sulfuric acid, and the mixture was heated to 80°C with stirring.
Bepotastine besilate
593
To the solution was added in small portions 2 g of 7-bromo-3a,8b-cis-3a,8bdihydro-3H-5-cyclopenta[b]benzofurancarboxylic acid. After being stirred at 80°C for 14 hours, the reaction mixture was cooled, and the acetic acid was removed under reduced pressure. The residue was subjected to azeotropic operation with toluene two times, and ether was added to the residue. The precipitate derived from trioxane was removed by filtration and washed with ether, and the combined ethereal solutions were concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed with water and aqueous saturated solution of sodium chloride, was dried, and was concentrated to give 4 g of an oily material. The oily material was dissolved in 20 ml of methanol and to the solution was added 20 ml of aqueous 1 N solution of sodium hydroxide, and the mixture was stirred for 14 hours at room temperature. After removal of methanol under reduced pressure, water was added to the mixture, and this solution was acidified to pH 3 with aqueous 2 N hydrochloric acid. The mixture was extracted five times with ethyl acetate, and the ethyl acetate extract was dried and concentrated to give 3.5 g of crude crystals. After addition of ethanol to the crude crystals, the crude crystals were filtered. The filtrate was concentrated, and to the residue was added ethanol and ethyl acetate, and precipitate was collected by filtration. The combined amount of the crude crystals was 1.6 g. After the combined crude crystals were methylated with diazomethane, the reaction product was dissolved in 20 ml of ethyl acetate. To this solution was added 1.5 g of sodium acetate and 300 mg of 10% palladium-carbon, and the mixture was stirred for 2 hours under hydrogen. Then, the reaction product was filtered, and after addition of aqueous saturated solution of sodium hydrogen carbonate to the filtrate, the mixture was extracted two times with ethyl acetate. The extract was washed with an aqueous saturated solution of sodium chloride, dried, and concentrated to give 1.3 g of crude crystals. The crude crystals were recrystallized from ethyl acetate to yield 765 mg of the title compound (melting point 134-135°C, yield 43%). Methyl 3-methyl-trans-4a-cisoid-4a,5a-cis-5a-1,4a,5,5a,10b,10c-hexahydro-7dioxin o[5,4-a]cyclopenta[b]benzofurancarboxylate: To a stirred suspension of 3 g of methyl 2-endo-hydroxy-1-exohydroxymethyl-3a,8b-cis-2,3,3a,8b-tetrahydro-1H-5-cyclopenta[b]benzofurancarboxylate in 30 ml of anhydrous tetrahydrofuran was added 1.5 ml of a solution which is obtained by dissolving 10 ml of 1,1-diethoxyethane and 200 mg of p-toluenesulfonic acid monohydrate into 10 ml of tetrahydrofuran followed by drying over molecular sieves, and the mixture was stirred for 14 hours at 60°C and then cooled. To the reaction mixture was added 100 mg of sodium hydrogen carbonate, and the mixture was stirred for 10 min at room temperature. Then, water was added to the reaction mixture and the mixture was extracted three times with ethyl acetate. The combined organic layers were washed with water and aqueous saturated solution of sodium chloride, was dried, and was concentrated to give 3.5 g of the crude crystals. The crude crystals were recrystallized from benzene-hexane to yield 2 g of the title compound (m.p. 162-163°C). The filtrate was concentrated and the residue was dissolved again in 10 ml of anhydrous tetrahydrofuran. To this solution were added 2.5 ml of 1,1diethoxyethane and 1 ml of the above-mentioned solution of p-toluenesulfonic
594
Bepotastine besilate
acid monohydrate in tetrahydrofuran and the mixture was stirred for 14 hours at 60°C and then cooled. To the reaction mixture was added 100 mg of sodium hydrogen carbonate, and the mixture was stirred for 10 min at a room temperature. After addition of water, the mixture was extracted three times with ethyl acetate. The combined organic layers were washed with water and aqueous saturated solution of sodium chloride, dried, and concentrated to give 1.5 g of crude crystals of methyl 3-methyl-trans-4a-cisoid-4a,5a-cis-5a1,4a,5,5a,10b,10c-hexahydro-7-dioxino[5,4-a]cyclopenta[b]benzofurancarboxylate. The crude crystals were recrystallized from benzene-hexane to yield 740 mg of the title compound (m.p. 154-156°C, yield 83%). 3-Methyl-trans-4a-cosoid-4a,5a-cis-5a-1,4a,5,5a,10b,10c-hexahydro-7dioxino[5,4-a]cyclopenta[b]benzofuranylmethanol: To a suspension of 1 g of lithium aluminum hydride in 10 ml of anhydrous tetrahydrofuran cooled in an ice bath was added dropwise a solution of 1.94 g of methyl 3-methyl-trans-4a-cisoid-4a,5a-cis-5a-1,4a,5,5a,10b,10chexahydro-7-dioxino[5,4-a]cyclopenta[b]benzofurancarboxylate in 40 ml of anhydrous tetrahydrofuran. After being stirred for 30 min at room temperature, the reaction mixture was cooled in an ice bath. The excess of lithium aluminum hydride was decomposed by the addition of ethyl acetate, and aqueous saturated solution of potassium sodium tartarate was added to the reaction mixture. After filtration of the mixture, the filtrate was concentrated and the residue was dissolved in 10 ml of methanol. After addition of 2 g of potassium carbonate to the solution, the mixture was stirred for 3 hours at room temperature and was concentrated. After water was added to the residue, the aqueous mixture was extracted 3 times with ethyl acetate. The combined organic layers were washed with water and saturated aqueous solution of sodium chloride, dried, and concentrated to give 2 g of crude crystals. The crude crystals were recrystallized from ethyl acetatehexane to yield 1.49 g of the pure crystals of the titled compound (m.p. 124125°C, yield; 85%). 7-Chloromethyl-3-methyl-trans-4a-cisoid-4a,5a-cis-5a-1,4a,5,5a,10b,10chexahydrodioxino[5,4-a]cyclopenta[b]benzofuran: To a solution of 1.14 g of 3-methyl-trans-4a-cisoid-4a,5a-cis-5a1,4a,5,5a,10b,10c-hexahydro-7-dioxino[5,4-a]cyclopenta[b]benzofuranylmethanol in 10 ml of dimethoxyethane cooled in an ice bath was added 0.43 ml of anhydrous pyridine and 0.38 ml of thionyl chloride, and the mixture was stirred for 3 hours at room temperature. After addition of ether to the reaction mixture, the precipitate was filtered, and water was added to the filtrate and the mixture was extracted three times with ether. The extract was washed with aqueous saturated solution of copper sulfate, water, aqueous saturated solution of sodium hydrogen carbonate and aqueous saturated solution of sodium chloride, dried, and concentrated to give 1.2 g of crude crystals. The crude crystals were recrystallized from ethyl acetate-hexane to yield 1 g of the pure titled chloride (m.p. 94-95°C, yield; 83%). 4-[3-Methyl-trans-4a-cisoid-4a,5a-cis-5a-1,4a,5,5a,10b,10c-hexahydro-7dioxino[5,4-a]cyclopenta[b]benzofuranyl]butyric acid: A solution of 482 mg of 7-chloromethyl-3-methyl-trans-4a-cisoid-4a,5a-cis5a-1,4a,5,5a,10b,10c-hexahydrodioxino[5,4-a]cyclopenta[b]benzofuran in 5
Bepotastine besilate
595
ml of anhydrous tetrahydrofuran was added dropwise to 84 mg of turnings of metallic magnesium with stirring to prepare a Grignard reagent. To the thus prepared Grignard reagent cooled in an ice bath were added 30 mg of cuprous iodide and 0.1 ml of beta-propiolactone, and the mixture was stirred for one hour. Aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was acidified with 1 N hydrochloric acid to PH 3-4 to decompose the excess of magnesium. The resulting solution was extracted 5 times with ether, and the combined ethereal layers were washed with water and aqueous saturated solution of sodium chloride, dried and concentrated to give 500 mg of crude crystals. The crude crystals were recrystallized from ethyl acetate-hexane to yield 279 mg of the pure crystals of the carboxylic acid (melting point 148-149°C, yield; 54%). Methyl 4-[2-endo-hydroxy-1-exo-hydroxymethyl-3a,8b-cis-2,3,3a,8btetrahydro-1H-5- cyclopenta[b]benzofuranyl]butyrate: To a solution of 390 mg of 4-[3-methyl-trans-4a-cisoid-4a,5a-cis-5a1,4a,5,5a,10b,10c-hexahydro-7-dioxino[5,4-a]cyclopenta[b]benzofuranyl] butyric acid in 5 ml of ethyl acetate cooled in an ice bath was added an excess of an ethereal solution of diazomethane, and after being stirred for 5 min the mixture was concentrated. The resulting oily material was dissolved in 3 ml of methanol, and to the solution was added 1 ml of 1 N hydrochloric acid and the mixture was stirred for 3 hours at room temperature. After concentration of the reaction mixture and addition of 1 ml of water, the mixture was extracted 3 times with each 5 ml of ethyl acetate. The combined layers of ethyl acetate were washed with 3 ml of water and 3 ml of aqueous saturated solution of sodium chloride, dried and concentrated to give 380 mg of crude crystals. The crude crystals were recrystallized from ethyl acetatehexane to yield 200 mg of the pure captioned product (m.p. 56-57°C, yield; 53%). Methyl 4-[2-endo-acetoxy-1-exo-hydroxymethyl-3a,8b-cis-2,3,3a,8btetrahydro-1H-5-cyclopenta[b]benzofuranyl]butyrate: To a solution of 350 mg of methyl 4-[2-endo-hydroxy-1-exo-hydroxymethyl3a,8b-cis-2,3,3a,8b-tetrahydro-1H-5-cyclopenta[b]benzofranyl]butyrate in 3.5 ml of anhydrous dimethylformamide cooled in an ice bath were added 140 mg of imidazole and 360 mg of t-butyldimethylsilyl chloride, and after the mixture was stirred for 3 hours at room temperature, dimethylformamide was removed under reduced pressure. The residue was dissolved in a mixture of 10 ml of acetic anhydride and 5 ml of pyridine. After the mixture was stirred for 2 hours at room temperature, the reaction mixture was concentrated. Then the residual oil was dissolved in 5 ml of acetic acid, and to the solution were added 5 ml of tetrahydrofuran and 2 ml of water. After the mixture was stirred for 14 hours at 50°C and concentrated, the residue was subjected to azeotropic operation two times with toluene. The residue was purified by column chromatography on silica gel using ethyl acetate-cyclohexane (1:2) to give 280 mg of the pure compound (yield; 70%). Methyl ester of 11,15-dideoxy-11-acetoxy-16-methyl-15-oxo-18,19tetradehydro-5,6,7-trinor-4,8-inter-m-phenylene PGI2: In 1.4 ml of a solution of 0.3 ml of pyridine in 10 ml of benzene was dissolved 178 mg of methyl 4-[2-endo-acetoxy-1-exo-hydroxymethyl-3a,8b-cis-
596
Bepotastine besilate
2,3,3a,8b-tetrahydro-1H-5- cyclopenta[b]benzofranyl]butyrate. To the solution were added 0.42 ml of the solution obtained by dissolving 0.14 ml of trifluoroacetic acid in 10 ml of dimethylsulfoxide and 320 mg of dicyclohexylcarbodiimide, and the mixture was stirred for 14 hours at room temperature. The precipitate was filtered and washed well with benzene. The filtrate was washed with water (3x3 ml), dried and concentrated to give 250 mg of crude aldehyde. In the next step, 118 mg of sodium hydride (55% dispersion in mineral oil) was suspended in 20 ml of dimethoxyethane under argon. To the suspension was added a solution of 689 mg of dimethyl 3-methyl-2-oxohept-5-ynephosphonate in 10 ml of dimethylformamide, and the mixture was stirred for 30 min at a room temperature. To the thus prepared mixture was added a solution of 250 mg of the abovementioned crude aldehyde in 5 ml of dimethoxyethane, and the mixture was stirred for 30 min at a room temperature. After neutralization (pH 7) with acetic acid the mixture was concentrated. The residue was dissolved in 10 ml of pentane and ether (1:1), and the precipitate was filtered, and the filtrate was concentrated to give 800 mg of an oily material. The oily material was purified by column-chromatography using ethyl acetate and cyclohexane (1:3) as an eluent to yield 162 mg of the pure captioned product (yield 70%). 11-Deoxy-11-acetoxy-16-methyl-18,19-tetradehydro-5,6,7-trinor-4,8-inter-mphenylene PGI2: To a stirred solution of 122 mg of 11,15-dideoxy-11-acetoxy-16-methyl-15oxo-18,19-tetradehydro-5,6,7-trinor- 4,8-inter-m-phenylene PGI2 in 10 ml of methanol was added 150 mg of cerium chloride heptahydrate, and then the solution was cooled in an ice bath, and 15 mg of sodium borohydride was added to the solution. After 10 min, to the mixture was added 2 ml of aqueous saturated solution of sodium hydrogen carbonate, and the mixture was further stirred for 10 min. After concentration of the reaction mixture, 5 ml of ethyl acetate was added to the residue, and the precipitate was filtered and washed with ethyl acetate (2x2 ml). The combined organic layers were washed with water and aqueous saturated solution of sodium chloride, dried and concentrated to give 130 mg of an oily material. The oily material was purified by column-chromatography on silica gel using ethyl acetate and cyclohexane (1:2) as eluent to give 54 mg of the captioned compound. Methyl ester of 16-methyl-18,19-tetradehydro-5,6,7-trinor-4,8-inter-mphenylene PGI2: To a solution of 54 mg of methyl ester of 11-deoxy-11-acetoxy-16-methyl18,19-tetradehydro-5,6,7-trinor-4,8-inter-m-phenylene PGI2 in 4.5 ml of anhydrous methanol was added 0.001 ml of 4.8 N sodium methoxide under argon, and the reaction mixture was stirred for 1.5 hours at room temperature. After addition of acetic acid to the reaction mixture and concentration of the mixture, the residue was dissolved in 20 ml of ethyl acetate, and the solution
Bepridil
597
was washed with aqueous saturated solution of sodium hydrogen carbonate, water and aqueous saturated solution of sodium chloride, dried and concentrated to afford 55 mg of an oily material. This oily material was purified by column chromatography using ethyl acetate and cyclohexane (3:1) as eluent to give 48 mg of the methyl ester of 16methyl-18,19-tetradehydro-5,6,7-trinor-4,8-inter-m-phenylene PGI2. References EP Appl. 84,856 Ohno Kiyotaka, Nagase Hiroshi, Matsumoto Kazuhisa, Nishio Shintaro; US Patent No. 4,474,802; October 2, 1984 ; Assigned to Toray Industries, Inc. (Tokyo, JP)
BEPRIDIL Therapeutic Function: Antianginal Chemical Name: 1-[2-(N-Benzylanilino)-3-isobutoxypropyl)pyrrolidine Common Name:Structural Formula:
Chemical Abstracts Registry No.: 49571-04-2 Trade Name Cordium Angopril Angopril
Manufacturer Riom Cerm Riom
Country France France France
Year Introduced 1981 -
Raw Materials N-Benzylaniline Sodium amide
1-(3-Isobutoxy-2-hydroxy)propyl pyrrolidine Thionyl chloride
Manufacturing Process The first step involves the preparation of 1-(3-isobutoxy-2-chloro)propyl
598
Bermoprofen
pyrrolidine as an intermediate. 345 ml of thionyl chloride dissolved in 345 ml of chloroform are added, drop by drop, to 275 g of 1-(3-isobutoxy-2hydroxy)propyl pyrrolidine dissolved in 350 ml of chloroform, while maintaining the temperature at approximately 45°. The reaction mixture is heated to reflux until gas is no longer evolved. The chloroform and the excess of thionyl chloride are removed under reduced pressure. The residue is poured on to 400 g of crushed ice. The reaction mixture is rendered alkaline with soda and the resulting mixture is extracted twice with 250 ml of diethyl ether. The combined ethereal extracts are dried over anhydrous sodium sulfate. After evaporation of the solvent the residue is distilled under reduced pressure. 220 g of product are obtained having the following properties: boiling point = 96°C/3 mm, nD24 = 1.4575. The final product is prepared as follows. 23.4 g of sodium amide is added little by little to a solution of 92 g of N-benzylaniline in 500 ml of anhydrous xylene. The reaction mixture is then heated at 130°-135°C for 6 hours. While maintaining the temperature at 110°C, 110 g of the product of the first step dissolved in 150 ml of xylene is added and the product heated for 6 hours at 120°C. The product having been allowed to cool to ambient temperature, 200 ml of cold water are added. The organic phase is separated and extracted with an aqueous solution of hydrochloric acid. After twice washing with 100 ml of diethyl ether, the aqueous phase is made alkaline with 50% caustic soda solution. The liberated base is twice extracted with 150 ml of diethyl ether. After the ether has been evaporated, the residue is distilled under reduced pressure and has a boiling point of 184°C/0.1 mm, nD20 = 1.5538. 77 g of the pure base in the form of a viscous liquid is thus obtained. The hydrochloride, which is prepared in conventional manner, has a melting point of 128°C. References Merck Index 1160 DFU 2 (11) 713 (1977) Kleeman and Engel p.93 OCDS Vol. 3 p. 46 (1984) DOT 18 (9) 422 (1982) I.N.p. 135 Mauvernay, R.Y., Busch, N., Moleyre, J., Monteil, A. and Simond, J.; US Patent 3,962,238; June 8,1976; assigned to Centre Europeen de Recherches Mauvernay "CERM"
BERMOPROFEN Therapeutic Function: Antiinflammatory, Antipyretic
Besipirdine hydrochloride
599
Chemical Name: 10,11-Dihydro-α,8-dimethyl-11-oxodibenz[b,f]oxepin-2acetic acid Common Name: Bermoprofen Structural Formula:
Chemical Abstracts Registry No.: 78499-27-1 Trade Name
Manufacturer
Country
Year Introduced
Bermoprofen
ZYF Pharm Chemical
-
-
Raw Materials DL-2-[4-(2'-Carboxymethyl-4'-methylphenoxy)phenyl]propionic acid Polyphosphoric acid Manufacturing Process A mixture of dl-2-[4-(2'-carboxymethyl-4'-methylphenoxy)phenyl]propionic acid (15.3 g) and polyphosphoric acid (92 g) was heated with stirring at 110120°C for 2 hours. To the reaction mixture was added water and the resulting mixture was extracted with chloroform. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated. The residue was chromatographed on silica gel (75 g) using chloroform as an eluent to give a crude product, which was recrystallized from toluene to give the dl-2-(8methyl-10,11-dihydro-11-oxodibenz[b,f]oxepin-2-yl)propionic acid (9.4 g, 65.3%), m.p. 128-129°C. References EP Appl. 3,893; Uno Hitoshi, Nagai Yasutaka, Nakamura Hideo; US Patent No. 4,238,620; Dec. 9, 1980; Assigned to Dainippon Pharmaceutical Co., Ltd. (Osaka, JP)
BESIPIRDINE HYDROCHLORIDE Therapeutic Function: Cognition activator Chemical Name: 1H-Indol-1-amine, N-propyl-N-4-pyridinyl-, monohydrochloride
600
Besipirdine hydrochloride
Common Name: Besipirdine Structural Formula:
Chemical Abstracts Registry No.: 130953-69-4 Trade Name
Manufacturer
Country
Year Introduced
Besipirdine hydrochloride
Hoechst-Roussel Pharmaceuticals, Inc.
-
-
Besipirdine hydrochloride
Aventis Pharmaceuticals, Inc.
-
-
Raw Materials N-(4-Pyridinyl)-1H-indol-1-amine 1-Bromopropane Hydrochloric acid
Sodium hydride Maleic acid
Manufacturing Process Part A: N-Propyl-N-(4-pyridinyl)-1H-indol-1-amine maleate: A solution of N-(4-pyridinyl)-1H-indol-1-amine (6 g) in 25 ml of dimethylformamide was slowly added to an ice-cooled suspension of NaH (1.3 g of 60% NaH dispersion in mineral oil was washed with hexanes, the liquid was decanted and the residual solid was dispersed in 5 ml of dimethylformamide). After anion formation, a solution of 1-bromopropane (4 g) in 5 ml of dimethylformamide was added. After one hour of stirring at ambient temperature, the reaction mixture was stirred with ice-water and extracted with dichloromethane. The organic extract was washed with water and saturated sodium chloride solution, was dried over anhydrous magnesium sulfate, filtered and concentrated to 8 g of oil. This oil was purified by HPLC (silica, ethyl acetate) and thereafter by column chromatography (alumina, ether) to give 6.4 g oil. This oil was converted to the maleate salt and recrystallized from methanol/ether to give 6.8 g of crystals, m.p. 115-116°C. Part B: N-Propyl-N-(4-pyridinyl)-1H-indol-1-amine hydrochloride: N-Propyl-N-(4-pyridinyl)-1H-indol-1-amine maleate was converted to the free base by action of alcaline agent. Then the free base oil was converted to the hydrochloride salt which was recrystallized from methanol; m.p. 212-214°C.
Betaine aspartate sodium
601
References Effland R.C., Klein J. T., Davis Larry Olsen, Gordon E.; US Patent No. 4,970,218; November 13, 1990; Hoechst-Roussel Pharmaceuticals Inc. (Somerville, NJ) Kongsamut S., Smith C. P., Woods A. T.; US Patent No. 5,356,910; October 18, 1994; Assigned to Hoechst-Roussel Pharmaceuticals Inc. (Somerville, NJ) Klein J.T., L. Davis, G.E. Olsen, G.S. Wong, M. Cornfeldt, F.P. Huger, C.P. Smith, W.W. Petko, J.C. Wilker, R.D. Blitzer, E. Landau, V. Hartoutunian, L.L. Martin and R.C. Effland. Synthesis and structure-activity relationships of N-propyl-N-(4-pyridinyl)-
BETAINE ASPARTATE SODIUM Therapeutic Function: Hepatoprotectant Chemical Name: L-aspartic acid, ion (1-), 1-carboxy-N,N,N-trimethylaminium sodium salt Common Name: Somatyl Structural Formula:
Chemical Abstracts Registry No.: 52921-08-1 Trade Name
Manufacturer
Country
Year Introduced
Somatyl
TEOFARMA Srl
-
-
Somatyl
Anphar-Rolland
-
-
Raw Materials Betaine L-Aspartic acid Manufacturing Process Betaine aspartate was prepared from betaine and L-aspartic acid (molar ratio 1:1) in aqueous solution at pH 5.7-5.0.
602
Betamethasone
In practice it is usually used as sodium salt. References Cote M.R.; FR Patent No. 1,356,945, Dec. 14, 1961 FR-M 2,462, Oct. 9, 1962
BETAMETHASONE Therapeutic Function: Glucocorticoid Chemical Name: 9-Fluoro-11β,17,21-trihydroxy-16β-methylpregna-1,4diene-3,20-dione Common Name: Structural Formula:
Chemical Abstracts Registry No.: 378-44-9 Trade Name
Manufacturer
Country
Year Introduced
Celestone
Schering
US
1961
Becort
Rachelle
US
-
Betacortil
Pfizer
US
-
Betalone
Firma
Italy
-
Betamamallet
Showa
Japan
-
Betapred
Glaxo
UK
-
Betasolon
Pharmax
Italy
-
Betnelan
Glaxo
UK
-
Betnesail
Glaxo
UK
-
Betnesol
Glaxo
UK
-
Celestan
Aesca
Austria
-
Celestene
Cetrane
France
-
Celestone
Essex
Spain
-
Cuantin
I.C.N.
Canada
-
Betamethasone acetate
603
Trade Name
Manufacturer
Country
Year Introduced
Dermovaleas
Valeas
Italy
-
Desacort-Beta
Caber
Italy
-
Diprosone
Byk-Essex
W. Germany
-
Diprosone
Unilabo
France
-
Diprostene
Centrane
France
-
Hormezone
Tobishi
Italy
-
Linosal
Wakamoto
Japan
-
Minisone
IDI
Japan
-
No-Rheumar
Janus
Italy
-
Pertene Vita
Vita
Italy
-
Rinderon
Shionogi
Japan
-
Sanbetason
Santen
Japan
-
Sclane
Promesa
Spain
-
Unicort
Unipharm
Israel
-
Valisone
Schering
US
-
Raw Materials Betamethasone acetate Hydrogen chloride Manufacturing Process Betamethasone acetate is converted to betamethasone by means of hydrochloric acid in a methanol-chloroform-water mixture as described in US Patent 3,164,618. References Merck Index 1196 Kleeman and Engel p.95 PDR p.1610 OCDS Vol.1 p.198 (1977) I.N. p.137 REM p.962 Amiard, G., Torelli, V. and Cerede, J.; US Patent 3,104,246; September 17, 1963; assigned to Roussei-UCLAF, SA, France Rausser, R. and Oliveto, E.P.; US Patent 3,164,618; January 5, 1965; assigned to Schering Corporation
BETAMETHASONE ACETATE Therapeutic Function: Glucocorticoid
604
Betamethasone acetate
Chemical Name: 9-Fluoro-11β,17,21-trihydroxy-16β-methylpregna-1,4diene-3,20-dione-21-acetate Common Name: Structural Formula:
Chemical Abstracts Registry No.: 987-24-6 Trade Name
Manufacturer
Country
Year Introduced
Celestone Soluspan
Schering
US
1965
Betafluorene
Lepetit
France
-
Celestone Cronodose
Essex
Italy
-
Raw Materials 17β,21-Dihydroxy-16β-methyl-4,9(11)-pregnadiene-3,20-dione 21acetate N-Bromosuccinimide Sodium methoxide Hydrogen fluoride Perchloric acid Acetic anhydride Selenium dioxide Manufacturing Process The synthesis is long and complex. For brevity, only the last steps are given here. Refer to the patents cited below for full details. Preparation of 9α-Bromo-11β,17α,21-Trihydroxy-16β-Methyl-4-Pregnene-3,20Dione 21-Acetate: To a mixture of 620 mg of 17α,21-dihydroxy-16β-methyl4,9(11)-pregnadiene-3,20-dione 21-acetate and 330 mg of Nbromosuccinimide in 10 ml of dioxane and 3.2 ml of water cooled to 10°C was added 1.8 ml of cold 1 M aqueous perchloric acid. The mixture was stirred at 15°C for 3 hours. Excess N-bromosuccinimide was destroyed by addition of aqueous sodium thiosulfate and most of the dioxane was removed in vacuo. About 30 ml of water was added and crystalline bromohydrin, 9α-bromo11β,17α,21-trihydroxy-16β-methyl-4-pregnene-3,20-dione 21-acetate, was
Betamethasone adamantoate
605
filtered, washed with water, and dried in air. Preparation of 9β,11β-Epoxy-17α-21-Dihydroxy-16β-Methyl-4-Pregnene-3,20Dione 21-Acetate: To a stirred solution of 100 mg of the 9α-bromo11β,17α,21-trihydroxy-16β-methyl-4-pregnene-3,20-dione 21-acetate in 3 ml of tetrahydrofuran and 1 ml of methanol under nitrogen was added 1.02 ml of 0.215N methanolic sodium methoxide. After 10 minutes at 25°C, 0.2 ml of acetic acid was added and the methanol removed in vacuo. The residue was acetylated with 1.00 ml of pyridine and 0.5 ml of acetic anhydride at 60°C for 70 minutes. The mixture was taken to dryness in vacuo, water added, and the product extracted into chloroform. The residue was crystallized from etheracetone to give pure 9β,11β-epoxy-17α,21-dihydroxy-16β-methyl-4-pregnene3,20-dione 21-acetate. Preparation of 9α-Fluoro-11β,17α,21-Trihydroxy-16β-Methyl-4-Pregnene-3,20Dione 21-Acetate: To a solution of 200 mg of 9β,11β-epoxy-17α,21-dihydroxy16β-methyl-4-pregnene-3,20-dione 21-acetate in 2 ml of chloroform and 2 ml of tetrahydrofuran in a polyethylene bottle at -60°C was added 2 ml of a 2:1 (by weight) mixture of anhydrous hydrogen fluoride and tetrahydrofuran. After 4 hours at -10°C the mixture was cooled to -60°C and cautiously added to a stirred mixture of 30 ml or 25% aqueous potassium carbonate and 25 ml of chloroform kept at -5°C. The aqueous phase was further extracted with chloroform and the latter phase washed with water and dried over magnesium sulfate. The residue on crystallization from acetone-ether gave pure 9α-fluoro11β,17α,21-trihydroxy-16β-methyl-4-pregnene-3,20-dione 21-acetate. Preparation of 9α-Fluoro-11β,17α,21-Trihydroxy-16β-Methyl-4-Pregnadiene3,20-Dione 21-Acetate 100 mg of 9α-fluoro-11β,17α,21-trihydroxy-16βmethyl-4-pregnene-3,20-dione 21-acetate was treated with selenium dioxide to produce the corresponding 9α-fluoro-11β,17α,21-trihydroxy-16β-methyl-4pregnadiene-3,20-dione 21-acetate. Alternately, Bacillus sphaericus may be utilized. References Merck Index 1196 Kleeman and Engel p.97 PDR p.1612 I.N. p.137 REM p.963 Taub, D., Wendler, N.L. and Slates, H.L.; US Patent 3,053,865; September 11, 1962; assigned to Merck and Co., Inc. Rausser, R. and Oliveto, E.P.; US Patent 3,164,618; January 5, 1965; assigned to Schering Corporation.
BETAMETHASONE ADAMANTOATE Therapeutic Function: Glucocorticoid Chemical Name: 9-Fluoro-11β,17-dihydroxy-16β-methylpregna-1,4-diene3,20-dione 21-(tricyclo(3.3.1.13,7)dec-1-ylformate)
606
Betamethasone adamantoate
Common Name: Betamethasone adamantoate Structural Formula:
Chemical Abstracts Registry No.: 40242-27-1 Trade Name
Manufacturer
Country
Year Introduced
Betamethasone Adamantoate
Zhejiang Xianju Pharmaceutical Co., Ltd.
-
-
Raw Materials Betamethasone Trifluorcacetic anhydride Pyridine
Adamantane carboxylic acid Sodium bicarbonate Triethylamine adamantane carbonyl chloride
Manufacturing Process 3 Methods of producing of betamethasone 21-adamantane-1'-carboxylate: 1. A suspension of betamethasone (740.0 mg) in dioxan (20 ml) was treated with adamantane carboxylic acid (1.96 g) and trifluorcacetic anhydride (0.75 ml). The mixture was stirred at room temperature for 23 h during which time the steroid completely dissolved. Addition of sodium bicarbonate (2.0 g) and water gave a waxy semi-solid which was separated from the supernatant liquid by decantation. Water and a little methanol were added to the solid and the resulting granular material was removed by filtration and washed well with water. Fractional crystallization from methanol afforded adamantane carboxylic anhydride as the less soluble component and betamethasone 21-adamantane1'-carboxylate as the more soluble component. 2. 9α-Fluoro-11β,17-dihydroxy-21-iodo-16β-methylpregna-1,4-diene-3,20dione (76.65 g) was dissolved in warm acetone (400 ml) and then adamantanecarboxylic acid (54.0 g) and triethylamine (52.5 ml) was added and washed in with more acetone (100 ml). The solution was refluxed for 1 h and then poured with good stirring into cold water (2.5 L). Filtration of the precipitated material and recrystallisation from aqueous methanol with charcoaling afforded betamethasone 21-admantane-1'-carboxylate showing extensive melting 245°-250°C.
Betamethasone benzoate
607
3. A solution of betamethasone (1.0 g) in dry tetrahydrofuran (40 ml) was treated with adamantane carbonyl chloride (about 2.2 equivalents) in dry tetrahydrofuran (5 ml) and then pyridine (0.8 ml) was added. The mixture was refluxed for 6 h and then most of the solvent was boiled off and the residue extracted with chloroform to afford a froth. The ether soluble portion of this froth was dissolved in chloroform and extracted repeatedly with dilute sodium bicarbonate solution. Evaporation of the chloroform layer gave a froth which was further purified by chromatography and crystallisation from chloroform-petroleum ether to yield betamethasone 21-adamantane-1'carboxylate melting point 256°-259°C (dec.). References Phillipps G.H., English A.F.; GB Patent No. 1,391,443; July 5, 1971; Assigned: Glaxo Laboratories Limited, a British Company, of Greenford, Middlesex
BETAMETHASONE BENZOATE Therapeutic Function: Glucocorticoid Chemical Name: 9-Fluoro-11β,17,21-trihydroxy-16β-methylpregna-1,4diene-3,20-dione-17-benzoate Common Name: Structural Formula:
Chemical Abstracts Registry No.: 22298-29-9 Trade Name
Manufacturer
Country
Year Introduced
Benisone
Warner Lambert
US
1973
Flurobate Gel
Texas Pharm
US
1973
Beben
Parke Davis
Italy
1974
Uticort Gel
Warner Lambert
US
1977
608
Betamethasone dihydrogen phosphate
Trade Name
Manufacturer
Country
Year Introduced
Benisone
Cooper Vision
US
1979
Bebate
Warner
UK
-
Beben
Vister
Italy
-
Dermizol
Roux-Ocefa
Argentina
-
Euvaderm
Sasse
W. Germany
-
Parbetan
Parke Davis
W. Germany
-
Skincort
Parke Davis
W. Germany
-
Uticort
Parke Davis
US
-
Raw Materials Betamethasone Methyl orthobenzoate Manufacturing Process A mixture of 50 g of betamethasone, 50 cc of dimethylformamide, 50 cc of methyl orthobenzoate and 1.5 g of p-toluenesulfonic acid is heated for 24 hours on oil bath at 105°C while a slow stream of nitrogen is passed through the mixture and the methanol produced as a byproduct of the reaction is distilled off. After addition of 2 cc of pyridine to neutralize the acid catalyst the solvent and the excess of methyl orthobenzoate are almost completely eliminated under vacuum at moderate temperature. The residue is chromatographed on a column of 1,500 g of neutral aluminum oxide. By elution with ether-petroleum ether 30 g of a crystalline mixture are obtained consisting of the epimeric mixture of 17α,21-methyl orthobenzoates. This mixture is dissolved without further purification, in 600 cc of methanol and 240 cc of methanol and 240 cc of aqueous 2N oxalic acid are added to the solution. The reaction mixture is heated at 40°-50°C on water bath, then concentrated under vacuum, The residue, crystallized from acetone-ether, gives betamethasone 17-benzoate, MP 225°-231°C. References Merck Index 1196 Kleeman and Engel p.98 PDR p.1393 DOT 10 (1) 9 (1974) I.N. p. 137 Ercoli, A. and Gardi, R.; US Patent 3,529,060; September 15, 1970; assigned to Warner-Lambert Pharmaceutical Co.
BETAMETHASONE DIHYDROGEN PHOSPHATE Therapeutic Function: Glucocorticoid
Betamethasone dihydrogen phosphate
609
Chemical Name: Pregna-1,4-diene-3,20-dione, 9-fluoro-11,17-dihydroxy-16methyl-21-(phosphonooxy)-, (11βa,16β)-, disodium salt Common Name: Bentelan; Betnesol; Celestan; Durabetason; VistaMethasone Structural Formula:
Chemical Abstracts Registry No.: 360-63-4 Trade Name
Manufacturer
Country
Year Introduced
Bentelan
Biofutura
-
-
Bentelan
Glaxo Wellcome
-
-
Celestan solubile
Essex
-
-
Raw Materials Bistriethylamine phosphate Phosphoric acid Silver phosphate Triethylamine Hydrogen chloride 9α-Fluoro-11β,17α,21-trihydroxy-16α-methyl-1,4-pregnadiene-3,20-dione 21-methanesulfonate Manufacturing Process A solution of bistriethylamine phosphate was prepared by slowly adding 2.36 ml of 85% phosphoric acid to 20 ml of acetonitrile containing 9.9 ml, of triethylamine at 20°C. This solution was added to a stirred mixture of 4.70 g of 9α-fluoro-11β,17α,21-trihydroxy-16α-methyl-1,4-pregnadiene-3,20-dione 21-methanesulfonate and 20 ml of acetonitrile. The mixture was heated under reflux for 4 h and then evaporated under reduced pressure to a volume of 12 ml. This mixture was a concentrated solution of 9α-fluoro-11β,17α,21trihydroxy-16α-methyl-1,4-pregnadiene-3,20-dione 21-phosphate triethylamine salt with some inorganic phosphate. The salt of 9α-fluoro-11β,17α,21-trihydroxy-16α-methyl-1,4-pregnadiene3,20-dione 21-phosphate may be converted to 9α-fluoro-11β,17α,21trihydroxy-16α-methyl-1,4-pregnadiene-3,20-dione 21-phosphate by treatment with acid (for example HCl).
610
Betamethasone dipropionate
References Metuchen J.M. Ch. et al.; US Patent No. 2,939,873; June 7, 1960; Assigned: Merck and Co., Inc., Rahway, N.J., a corporation of New Jersey
BETAMETHASONE DIPROPIONATE Therapeutic Function: Glucocorticoid Chemical Name: Pregna-1,4-diene-3,20-dione, 9-fluoro-11β,17,21trihydroxy-16β-methyl-, 17,21-dipropionate Common Name: Structural Formula:
Chemical Abstracts Registry No.: 5593-20-4 Trade Name
Manufacturer
Country
Year Introduced
Betnovate
Glaxo
UK
1961
Bentelan
Glaxo
Italy
1962
Betnesol
Glaxo
France
1963
Betnesol
Glaxo
W. Germany
1965
Diprosone
Schering
US
1975
Rinderon DP
Shionogi
Japan
1980
Diprolene
Schering
US
1983
Alphatrex
Savage
US
-
Beloderm
Belupo Ltd.
Yugoslavia
-
Diproderm
Essex Espana
Spain
-
Diproderm
Aesca
Austria
-
Diproderm
Schering
US
-
Diprogenta
Byk-Essex
W. Germany
-
Diprosalic
Unilabo
France
-
Betamethasone valerate
611
Trade Name
Manufacturer
Country
Year Introduced
Diprosalic
Schering
UK
-
Diprostene
Cetrane
France
-
Lortisone
Schering
US
-
Vanceril
Schering
US
-
Raw Materials 9α-Fluoro-11β-hydroxy-16β-methyl-17α,21-(1'-ethyl-1'-ethoxymethylenedioxy)pregna-1,4-diene-32,0-dione Acetic acid Propionyl chloride Manufacturing Process A solution of 9α-fluoro-11β-hydroxy-16β-methyl-17α,21-(1'-ethyl-1'ethoxymethylenedioxy)pregna-1,4-diene-3,20-dione (538 mg) in acetic acid (20 ml), containing 2 drops of water, was allowed to stand at room temperature for 5 hours. Dilution of the mixture with water gave a white solid (457 mg) which, after being filtered off and dried, was recrystallized from acetone to afford 9α-fluoro-11β,21-dihydroxy-16β-methyl-17αpropionyloxypregna-1,4-diene-3, 20-dione (361 mg), MP 230°-235°C. Bethmethasone 17-propionate (812 mg) in pyridine (10 ml) was treated with propionyl chloride (0.21 ml) at 0°C for 1 hour. Dilution with water and acidification with dilute hydrochloric acid gave the crude diester. Recrystallization from acetone-petroleum ether afforded betamethasone 17,21-dipropionate (649 mg), MP 117°C (decomposition). References Merck Index 1196 Kleeman and Engel p.99 PDR pp.888, 1429, 1601, 1614, 1631 I.N. p.138 Elks, J., May, P.J. and Weir, N.G.; US Patent 3,312,590; April 4, 1967; assigned to Glaxo Laboratories, Ltd.
BETAMETHASONE VALERATE Therapeutic Function: Corticosteroid Chemical Name: 9-Fluoro-11β,17,21-trihydroxy-16β-methylpregna-1,4diene-3,20-dione-17-valerate Common Name: Chemical Abstracts Registry No.: 33755-46-3; 38196-44-0 (Divalerate)
612
Betamethasone valerate
Structural Formula:
Trade Name
Manufacturer
Country
Year Introduced
Valisone
Schering
US
1967
Beta Dival
Fardeco
Italy
1978
Beta Val
Lemmon
US
1980
Cordel
Taisho
Japan
1981
Betatrex
Savage
US
1983
Betacort
ICN
Canada
-
Betacorten
Trima
Israel
-
Betaderm
K-Line
Canada
-
Betnesol
Glaxo
W. Germany
-
Betnelan
Glaxo
UK
-
Betnevate
Daiichi
Japan
-
Celestan
Schering
W. Germany
-
Celestoderm
Cetrane
France
-
Celestoderm
Essex Espana
Spain
-
Dermosol
Iwaki
Japan
-
Dermovaleas
Valeas
Italy
-
Ecoval
Glaxo
Italy
-
Metaderm
Riva
Canada
-
Muhibeta
Nippon Shoji
Japan
-
Novobetamet
Novopharm
Canada
-
Procto-Celestan
Byk-Essex
W. Germany
-
Recto-Betnesol
Glaxo
W. Germany
-
Retenema
Glaxo
UK
-
Rinderon
Shionogi
Japan
-
Rolazote
Lando
Argentina
-
Stranoval
Glaxo
Italy
-
Raw Materials Betamethasone Methyl orthovalerate
Betanidine sulfate
613
Manufacturing Process The valerate is made from betamethasone as a starting material as follows: A suspension of 9α-fluoro-11β,17α,21-trihydroxy-16β-methylpregna-1,4-diene3,20-dione(betamethasone) (2 grams) in sodium dried benzene (500 ml) was distilled vigorously for a few minutes, toluene-p-sulfonic acid monohydrate (30 mg) and methyl orthovalerate (5 ml) were added and distillation was continued for 10 minutes. The mixture was then boiled under reflux for 1.5 hours after which time unreacted betamethasone alcohol (400 mg) was removed by filtration. The benzene solution was treated with solid sodium .bicarbonate and a few drops of pyridine, filtered and evaporated to dryness at about 50°C. The residue, in ether, was filtered through grade III basic alumina (20grams) to remove traces of unreacted betamethasone alcohol, the ether removed in vacuo and the residue of crude betamethasone 17,21methyl orthovalerate was treated with acetic acid (20ml) and a few drops of water and left overnight at room temperature. The acetic acid solution was poured into water (100 ml) and extracted with chloroform. The chloroform extracts were washed in turn with water, saturated sodium bicarbonate solution and water, dried and evaporated in vacuo. The residual gum was triturated with ether and a white crystalline solid (1.16 grams) isolated by filtration. Recrystallization from ether (containing a small amount of acetone)-petroleum ether gave 9α-fluoro-11β,21-dihydroxy-16βmethyl-17α-valeryloxypregna-1,4-diene-3,20-dione (871 mg) as fine needles. References Merck Index 1196 Kleeman and Engel p.101 PDR pp.888, 1034, 1428, 1602, 1658 I.N. p.138 REM p. 963 Elks, J., May, P.J. and Weir, N.G.; US Patent 3,312,590; April 4, 1967; assigned to Glaxo Laboratories Limited, England
BETANIDINE SULFATE Therapeutic Function: Antihypertensive Chemical Name: Guanidine, 1-benzyl-2,3-dimethyl-, sulfate (2:1) Common Name: Betanidine sulfate; Bethanidine sulfate; Regulin Chemical Abstracts Registry No.: 55-73-2 (Base); 114-85-2 Raw Materials 2-Bromobenzylamine S-Methylthiouronium sulfate
614
Betaxolol hydrochloride
Structural Formula:
Trade Name
Manufacturer
Country
Year Introduced
Bendogen
Lagap Pharmaceuticals SA
-
-
Benzoxine
Plant Products
-
-
Bethanidine sulfate
Robins AH
-
-
Regulin
Gea
-
-
Regulin
Medica
-
-
Regulin
Nyco
-
-
Tenathan
Robins AH
-
-
Manufacturing Process A mixture of 2-bromobenzylamine (12.5 g) and S-methylthiouronium sulfate (10 g) in water (20 ml) was heated for 1.5 hours on a steam bath in a hood, during which methylmercaptan escaped (as evidenced by a foul odour). The reaction mixture was then cooled and diluted with ethanol (100 ml). A colourless solid of 2-bromobenzylguanidine sulfate was separeted, and washed with ethanol. This solid melted at 230-232°C; it was recrystallized from water and then melted at 247-248°C. By action of a basic agent the salt obtained may be converted into free base. References Walton E., Ruffell G.K.; GB Patent No. 973,882; Dec. 15, 1960; Assigned to the Wellcome Foundation Ltd., London
BETAXOLOL HYDROCHLORIDE Therapeutic Function: Beta-adrenergic blocker Chemical Name: 1-[4-[2-(Cyclopropylmethoxy)ethyl]phenoxy]-3-[(1methylethyl)amino]-2-propanol hydrochloride Common Name: -
Betaxolol hydrochloride
615
Structural Formula:
Chemical Abstracts Registry No.: 63659-18-7 Trade Name Kerlone Kerlon
Manufacturer Carriere Kramer
Country France Switz.
Year Introduced 1983 1983
Raw Materials Sodium hydroxide Hydrogen chloride Isopropylamine
4-[2-(Cyclopropylmethoxy)ethyl]phenol Epichlorohydrin
Manufacturing Process (1) 1 g of sodium hydroxide pellets (0.025 mol) is added to a suspension of 3.8 g of 4-[2-(cyclopropylmethoxy)-ethyl]-phenol in 30 ml of water. When the solution becomes homogenous, 2.3 ml of epichlorohydrin are added and the mixture is stirred for 8 hours. It is then extracted with ether and the extract is washed with water, dried over sodium sulfate and evaporated to dryness. The compound is purified by passing it over a silica column. 2.4 g of 1-[4-[2(cyclopropylmethoxy)ethyl]-phenoxy]-2,3-epoxy-propane are thus obtained. (2) 4.9 g of the preceding compound (0.02 mol) are condensed with 25 ml of isopropylamine by contact for 8 hours at ambient temperature and then by heating for 48 hours at the reflux temperature. After evaporation to dryness, the compound obtained is crystallized from petroleum ether. 5 g (yield 80%) of 2-[[4-(2-cyclopropylmethoxy)-ethyl]-phenoxy]-3-isopropylaminopropan-2-ol are thus obtained, melting point 70° to 72°C. The hydrochloride is prepared by dissolving the base in the minimum amount of acetone and adding a solution of hydrochloric acid in ether until the pH is acid. The hydrochloride which has precipitated is filtered off and is recrystallized twice from acetone, melting point 116°C. References Merck Index 1197 DFU 4 (12) 867 (1979) DOT 18 (10) 552 (1982) Manoury P.M.J., Cavero, I.A.G., Majer, H. and Guidicelli, D.P.R.L.; US Patent 4,252,984; February 24, 1981; assigned to Synthelabo
616
Betazole
BETAZOLE Therapeutic Function: Diagnostic aid (gastric secretion) Chemical Name: 1H-Pyrazole-3-ethanamine Common Name: β-Aminoethyipyrazole; Ametazole Structural Formula:
Chemical Abstracts Registry No.: 105-20-4; 138-92-1 (Dihydrochloride salt) Trade Name Histalog Betazol Histimin
Manufacturer Lilly Lilly Shionogi
Country US W. Germany Japan
Year Introduced 1953 -
Raw Materials γ-Pyrone Hydrazine hydrate Hydrogen Manufacturing Process A solution of 55 grams (1.1 mol) of hydrazine hydrate in 100 ml of methanol was cooled in a water bath and stirred while a solution of 48 grams (0.50 mol) of pure γ-pyrone in 100 ml of methanol was added over a period of about 15 minutes. After the addition was complete, the solution was allowed to stand at room temperature for about 1 hour, and was placed in a 1 liter hydrogenation bomb. 25 ml of liquid ammonia were added cautiously with stirring, followed by about 15 cc of Raney nickel catalyst. The bomb was charged with hydrogen to 1,800 pounds pressure, heated to 90°C and agitated. The quantity of hydrogen required to convert the hydrazone into the desired aminoethylpyrazole was taken up in about 3 hours. The bomb was cooled and opened, and the contents filtered. The filtrate was evaporated under reduced pressure to remove the methanol and the residual liquid was distilled under reduced pressure, whereby there were obtained 44.5 grams (81% yield) of 3-β-aminoethylpyrazole boiling at 118°-123°C at a pressure of 0.5 mm of Hg.
Bethanechol chloride
617
References Merck Index 1198 Kleeman and Engel p.102 I.N. p.139 REM p.1124 Jones, R.G.; US Patent 2,785,177; March 12, 1957; assigned to Eli Lilly and Company
BETHANECHOL CHLORIDE Therapeutic Function: Cholinergic Chemical Name: 2-[(Aminocarbonyl)oxyl-N,N,N-trimethyl-1-propanamium chloride Common Name: Carbamylmethylcholine chloride Structural Formula:
Chemical Abstracts Registry No.: 590-63-3 Trade Name
Manufacturer
Country
Year Introduced
Urecholine CI
MSD
US
1949
Urecholine CI
MSD
Switz.
-
Duvoid
Norwich Eaton
US
1978
Besacolin
Elsai
Japan
-
Bethachorol
Nichiiko
Japan
-
Mechothane
Farillon
UK
-
Mictone
Kenyon
US
-
Mictrol
Misemer
US
-
Mycholine
Glenwood
US
-
Myo Hermes
Hermes
Spain
-
Myotonachol
Glenwood
US
-
Myotonine
Glenwood
UK
-
Paracholin
Kanto
Japan
-
Perista
Nissin
Japan
-
Urocarb
Hamilton
Australia
-
Urolax
Century
US
-
618
Bevantolol hydrochloride
Raw Materials β-Methylcholine Chloride Phosgene Ammonia Manufacturing Process About 3 grams of β-methylcholine chloride are stirred at room temperature with an excess of phosgene dissolved in 50 grams of chloroform, for about 2 hours. Excess phosgene and hydrochloric acid are removed by distillation under vacuo. Additional chloroform is added to the syrup and the mixture is poured into excess ammonia dissolved in chloroform and cooled in solid carbon dioxide-acetone. The solid is filtered and extracted with hot absolute alcohol. The solid in the alcohol is precipitated with ether, filtered, and recrystallized from isopropanol. The carbaminoyl-β-methylcholine chloride obtained has a melting point of about 220°C. References Merck Index 1200 Kleeman and Engel p.102 PDR pp.830, 926, 1219, 1276 I.N. p.139 REM p.895 Major, R.T. and Bonnett, H.T.; US Patent 2,322,375; June 22, 1943; assigned to Merck and Co., Inc.
BEVANTOLOL HYDROCHLORIDE Therapeutic Function: Antiarrhythmic, Beta-adrenergic blocker Chemical Name: 2-Propanol, 1-((2-(3,4-dimethoxyphenyl)ethyl)amino)-3-(3methylphenoxy)-, hydrochloride Common Name: Bevantolol hydrochloride; Vantol Structural Formula:
Chemical Abstracts Registry No.: 59170-23-9 (Base); 42864-78-8
Bevantolol hydrochloride
619
Trade Name
Manufacturer
Country
Year Introduced
Bevantolol hydrochloride
Parke, Davis (Pfizer)
-
-
Raw Materials Epichlorohydrin 3-Cresol Sodium hydoxide β-(3,4-Dimethoxyphenyl)ethylamine Hydrogen chloride Manufacturing Process To a solution of 50 g (1.25 mol) of NaOH in 1200 ml H2O was added 108 g (1 mol) of m-cresol freshly distilled and at 15°C in one lot 117ml (1.5 mol) of epichlorohydrin. The emulsion was stirred at room temperature for 16 hours in a creased flask. The product was taken up in 1000 ml of toluene and washed with 500 ml water. Distillation yielded 135.7 g=82% of 3-(m-tolyloxy)-1,2epoxypropane, b.p. 61°C at 0.05 mm. Preparation of bevantolol hydrochloride: To a suitable reactor under a nitrogen blanket is added 13.7 kg of β-(3,4dimethoxyphenyl)ethylamine. The amine is cooled to 5°C and 12.5 kg of 3(m-tolyloxy)-1,2-epoxypropane is added maintaining the temperature between 5-10°C. After 10 hours, the mixture is seeded with bevantolol free base; seeding is repeated approximately every 2 hours until it is evident that crystallization has started. After stirring for 48 hours at 10°C, 26 L of hexane is added. The temperature is raised to 25°C and stirring is continued for 48 hours. The slurry is filtered and the collected solid is dried under vacuum. The product is dissolved in 60 L of isopropyl alcohol and the solution is filtered. The reactor and filter are rinsed with 186 L of isopropyl alcohol and 2.7 kg of anhydrous hydrogen chloride is added to the combined filtrate. The batch is heated to reflux for 2 hours. The temperature is adjusted to 65°C and the solution is seeded with bevantolol hydrochloride crystals. The mixture is held at this temperature with stirring until a heavy sand-like slurry is present. The mixture is allowed to cool to ambient temperature without stirring or artificial cooling. It is then cooled to 20°C. The slurry is centrifuged and the product rinsed with isopropyl alcohol until the filtrate is colorless. After being vacuum dried at 50-55°C the product is milled if necessary; yield of bevantolol hydrochloride 22.7 kg (78.6%); melting point 137-138°C. References Hoekstra M.S.; US Patent No. 4,994,618; February 19, 1991; Assigned to Warner-Lambert Company (Morris Plains, NJ) Holmes A., Meyer R.F.; US Patent No. 3,857,891; Dec. 31, 1974; Assigned to Parke, Davis and Vcompany, Detroit, Mich.
620
Bexarotene
BEXAROTENE Therapeutic Function: Antineoplastic Chemical Name: Benzoic acid, 4-(1-(5,6,7,8-tetrahydro-3,5,5,8,8pentamethyl-2-naphthalenyl)ethenyl)Common Name: Bexarotene Structural Formula:
Chemical Abstracts Registry No.: 153559-49-0 Trade Name
Manufacturer
Country
Year Introduced
LGD1069
Ligand Pharmaceuticals Inc. R.P. Scherer St. Petersburg Elan Pharmaceuticals, Inc.
-
-
USA
-
-
-
Ligand Pharmaceuticals Inc. Ligand Pharmaceuticals Inc.
USA
-
USA
-
Targretin Targretin Targretin Targrexin Raw Materials
Aluminum chloride 1,2-Dichloroethane 1,2,3,4-Tetrahydro-1,1,4,4,6-pentamethylnaphthalene 4-Carbomethoxybenzoyl chloride Potassium hexamethyldisilazide Methyltriphenylphosphonium bromide Manufacturing Process (a) Methyl [4-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) carbonyl]benzoate (1): To a suspension of aluminum chloride (1.10 g, 8.25 mmol) in 30 mL of 1,2dichloroethane under argon at room temperature was added a solution of 1,2,3,4-tetrahydro-1,1,4,4,6-pentamethylnaphthalene (1.52 g, 7.5 mmol) (Kagechika, H. et al., J. Med. Chem, 31:2182 (1988)) and 4carbomethoxybenzoyl chloride (1.57 g, 7.87 mmol) in 15 mL of 1,2-
Bexarotene
621
dichloroethane. The reaction mixture was stirred overnight and poured onto ice water and extracted with 40% ethyl acetate/hexane. The combined organic layers were washed with saturated aqueous NaHCO3and brine. The solution was dried over anhydrous MgSO4, filtered and concentrated to afford a brown solid (2.56 g). Flash chromatography (60% dichloromethane/hexane) yielded the desired product (1) as a white, crystalline solid (1.733 g, 64 %): m.p. 146°-149°C; Rf 0.11 (50% CH2Cl2/hexane). The structure of the product was also confirmed using IR, 1H NMR and mass spectroscopy. (b) [4-(5,6,7,8-Tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) carbonyl]benzoic acid (2): To a suspension of the ester (1) (0.120 g, 0.329 mmol) in 75% aqueous methanol (2 mL) was added potassium hydroxide (0.055 g). The reaction mixture was stirred at 60°C for 1 h during which time the material dissolved. The solution was cooled to room temperature, acidified with 1 N aqueous hydrochloric acid, and then extracted with 80% ethyl acetate/hexane. The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated to afford a white solid (0.109 g). Recrystallization from benzene/hexane afforded (2) as a white, crystalline solid (0.102 g, 89%): m.p. 209°-212°C. The structure of the product was also confirmed using IR, 1H NMR and mass spectroscopy. (c) Methyl 4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)-1ethenyl]benzoate (3): To a suspension of methyltriphenylphosphonium bromide (0.196 g, 0.55 mmol) in 1 mL of benzene under argon at room temperature was added a 0.5 M solution of potassium hexamethyldisilazide in toluene (1.2 mL, 0.6 mmol), and the yellow solution was stirred for 5 min. A solution of keto-ester (1) (0.1 g, 0.274 mmol) in 1.5 mL of benzene was added and the orange solution was stirred for 3 h at room temperature. The reaction mixture was filtered through a plug of silica gel with 40% ethyl acetate/hexane. The filtrate was concentrated to afford a solid. Flash chromatography (30%; 40% dichloromethane/hexane) yielded the desired product (3) as a white solid (0.077 g, 78%): m.p. 167°-168°C; Rf 0.4 (50% dichloromethane/hexane). The structure of the product was also confirmed using IR, 1H NMR and mass spectroscopy. (d) [4-[1-(5,6,7,8-Tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)-1ethenyl]benzoic acid (4): To a suspension of the ester (3) (0.058 g, 0.16 mmol) in 75% aqueous methanol (2 mL) was added one pellet of potassium hydroxide (0.1 g). The mixture was stirred at 70°C for 1 h during which time the material dissolved. The solution was cooled to room temperature, acidified with 1 N aqueous hydrochloric acid and then extracted with 80% ethyl acetate/hexane. The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated to afford a white solid. Recrystallization from dichloromethane/hexane afforded the desired acid (4) as a white, crystalline solid (42 mg, 91%): melting point 230°-231°C. The structure of the product was also confirmed using IR, 1H NMR and mass spectroscopy.
622
Bezafibrate
References Dawson M.L. et al.; US Patent No. 5,466,861; Nov., 14, 1995; Assigned: SRI International (Menlo Park, CA); La Jolla Cancer Research Foundation (La Jolla, CA)
BEZAFIBRATE Therapeutic Function: Antihyperlipidemic Chemical Name: Propanoic acid, 2-(4-(2-((4-chlorobenzoyl)amino)ethyl) phenoxy)-2-methylCommon Name: Bezafibrate; Detrex Structural Formula:
Chemical Abstracts Registry No.: 41859-67-0 Trade Name
Manufacturer
Country
Year Introduced
Bezafibrate
Eipico Co.
-
-
Bezalip
Glaxo Wellcom-Misr Co.
-
-
Cholestenorm
Natur Produkt
-
-
Azufibrat
Azupharma GmbH and Co. Hennig Arzneimittel GmbH and Co. KG
-
-
-
-
Befizal
Roche
-
-
Befizal
Boehringer Mannheim France Pharma SA
-
-
Beza 1 A Pharma
AbZ-Pharma GmbH
-
-
Beza 200 von ct
AbZ-Pharma GmbH
-
-
Beza AbZ
AbZ-Pharma GmbH
-
-
Bezabeta
Betapharm Arzneimittel GmbH
-
-
Bezacur
Hexal
-
-
Detrex
Vargas
-
-
Bezafibrate
Topharman Shanghai Co., Ltd.
-
-
Befibrat
Bezitramide
623
Raw Materials Tyramine Sodium
p-Chlorobenzoyl chloride 2-Bromo-2-methyl-propionic acid ethyl ester
Manufacturing Process 0.292 moles p-chlorobenzoyl chloride and 50 ml dry pyridine were added dropwise to 0.146 moles tyramine in 60 ml dry pyridine for 10 minutes. Then the mixture was poured in about 500 g of ice with water. The fallen-out crystals was filtered off, washed with diluted HCl, water and NaHCO3 solution and dried. It was recrystallized from acetone to give di(4-chlorobenzoyl) tyramine; yield 98 %; MP: 203°-205°C. 0.11 moles above product in 400 ml methanol was mixed with 130 ml 2 N KOH and heated at 40°-45°C for 1 hour. On cooling 130 ml 2 N HCl was added. The fallen-out precipitate was filtered off, filtrate was distilled off to dryness. The residue was washed with water, NaHCO3 solution and recrystallized from ethanol to give N-(4-chlorobenzoyl)tyramine; yield 91%; MP: 174°-176°C. 2.14 g sodium was dissolved in 50 ml of absolute methanol and mixed with 0.93 mole N-(4-chlorobenzoyl)tyramine. Methanol was removed in vacuum to dryness. The residue was slurried in 100 ml absolute toluene and 0.137 moles 2-bromo-2-methylpropionic acid ethyl ester was added. The suspension was heated for 25 hours at 80°C. Then it was distilled in vacuum to dryness and the residue was dissolved in CH2Cl2, washed with diluted HCl, NaOH and water, and dried over CaCl2. On removing of the solvent, the crude 2-{4-[2(4-chlorobenzoylamino)ethyl]phenoxy}-2-methylpropionic acid ethyl ester was obtained. After recrystallization from ether/ ligroin and acetone it had MP: 96°-97°C; yield 67 %. 0.1 mole above ester in 1.5 L of dioxane was slowly mixed with 200 ml 1 N KOH at ambient temperature and stood for 2 hours, then it was heated at 40°C for 1 hour. The substance was dissolved completely. On cooling the mixture was neutralized with 200 ml 1 N HCl. The solvents were removed in vacuum. The residue was washed with water and recrystallized from acetone to give 2-{4-[2-(4-chlorobenzoylamino)ethyl]phenoxy}-2-methylpropionic acid; yield 84%; MP: 186°C. References Witte E-Ch. et al; D.B. Patent No. 2,149,070; October 1, 1971; Assigned to Boehriger Mannheim GmbH, 6800 Mannheim
BEZITRAMIDE Therapeutic Function: Narcotic analgesic, Antitussive
624
Bezitramide
Chemical Name: 2-Benzimidazolinone, 1-(1-(3-cyano-3,3-diphenylpropyl)-4piperidyl)-3-propionylCommon Name: Bezitramide Structural Formula:
Chemical Abstracts Registry No.: 15301-48-1 Trade Name
Manufacturer
Country
Year Introduced
Bezitramide
ZYF Pharm Chemical
-
-
Raw Materials 4-Bromo-2,2-diphenylbutyronitrile 4-(2-Oxo-1-benzimidazolinyl)piperidine Propionic anhydride
Sodium carbonate Potassium iodide
Manufacturing Process A mixture of 6.9 parts 4-bromo-2,2-diphenylbutyronitrile, 5 parts 4-(2-oxo-1benzimidazolinyl)piperidine, 7.3 parts sodium carbonate, a few crystals of potassium iodide in 160 parts 4-methyl-2-pentanone is stirred and refluxed for 12 hours. After cooling the reaction mixture, 100 parts water is added. The aqueous layer is separated and extracted with 4-methyl-2-pentanone. The combined organic layer are dried over MgSO4 and evaporated. The oily residue is dissolved in a mixture of 24 parts diisopropylether and 24 parts isopropanol. After cooling overnight to -20°C, 5.3 parts product are obtained. This crop is boiled in 72 parts 4-methyl-2-pentanone and cooled to 0°C, yielding 1-(3-cyano-3,3-diphenylpropyl)-4-(2-oxo-1-benzimidazolinyl) piperidine, melting point 225-226°C, as a grey-white amorphous powder. A mixture of 5 parts 1-(3-cyano-3,3-diphenylpropyl)-4-(2-oxo-1benzimidazolinyl)piperidine, 7.5 parts propionic acid anhydride and 80 parts benzene is stirred and refluxed for 16 hours. After cooling, the reaction mixture is washed twice with 100 parts water. The aqueous layer is dried over potassium carbonate, filtered and evaporated. The residue is recrystallized from 60 parts of ether, yielding 4 parts crude 1-(3-cyano-3,3-diphenylpropyl)4-(2-oxo-3-propionyl-1-benzimidazolinyl)piperidine. This crop is recrystallized from 20 parts m-methyl-2-pentanone 4-ethyl-2-pentanone, yielding 1-(3-
Bialamicol
625
cyano-3,3-diphenylpropyl)-4-(2-oxo-3-propionyl-1-benzimidazolinyl)piperidine with melting point: 124.5-126°C as a pale yellow amorphous powder. References Janssen P.A.J.; US Patent No. 3,196,157; July 20, 1965; Assigned to Research Laboratorium Dr.C.Janssen N.V., a corporation of Belgium
BIALAMICOL Therapeutic Function: Antiamebic Chemical Name: 3,3'-Bis[(diethylamino)methyl]-5,5'-di-(2-propenyl)-[1,1biphenyl]-4,4'-diol Common Name: Biallylamicol Structural Formula:
Chemical Abstracts Registry No.: 493-75-4 Trade Name
Manufacturer
Country
Year Introduced
Camoform HCl
Parke Davis
US
1956
Raw Materials Paraformaldehyde Diethylamine 3,3'-Diallyl-4,4'-biphenol Manufacturing Process Paraformaldehyde (7.59) (0.25mol) and 18.3 g (0.25 mol) of diethylamine are mixed in 25 cc of alcohol and warmed until a clear solution is obtained. The
626
Bicalutamide
solution is cooled and mixed with 26.6 g (0.10 mol) of 3,3'-diallyl-4,4'biphenol in 25 cc of alcohol. After standing several hours, the solution is warmed for one hour on the steam bath, allowing the alcohol to boil off. The residue is then taken up in ether and water, the ether layer separated and washed with 2% sodium hydroxide solution and finally with water. The washed ether solution is dried over solid potassium carbonate, and filtered. After acidifying with alcoholic hydrogen chloride, the ether is distilled off and the alcoholic residue diluted with an equal volume of acetone. The crystalline hydrochloride is filtered off, triturated with alcohol, diluted with several volumes of acetone, filtered and dried; MP 209°-210°C. References Merck Index 1209 I.N. p.141 Rawlins, A.L., Holcomb, W.F., Jones, E.M., Tendick, F.H. and Burckhalter, J.H.; US Patent 2,459,338; January 18,1949; assigned to Parke, Davis and Co.
BICALUTAMIDE Therapeutic Function: Antitumor Chemical Name: Propanamide, N-(4-cyano-3-(trifluoromethyl)phenyl)-3-((4fluorophenyl)sulfonyl)-2-hydroxy-2-methyl- (racemic mixture) Common Name: Bicalutamide Structural Formula:
Chemical Abstracts Registry No.: 90357-06-5
Bicalutamide
627
Trade Name
Manufacturer
Country
Year Introduced
Bicalutamide
AstraZeneca
-
-
Biprosta
India
-
Calutide-50
Cytomed (A div. of Alembic) Cipla Limited
India
-
Casodex
AstraZeneca
-
-
Cosudex
AstraZeneca
-
-
Raffolutil
AstraZeneca
-
-
Raw Materials Bromal Dioxolanone 4-Fluorbenzenethiol Thionyl chloride
Citramalic acid 2-Mercaptopyridine-N-oxide 4-Amino-2-trifluoromethylbenzonitrile
Manufacturing Process [(4S)-4-Methyl-5-oxo-2-(tribromomethyl)-1,3-dioxolan-4-yl]acetic acid. Bromal (25.0 g; 89.1 mmol) and (S)-citramalic acid (11.0 g; 74.2 mmol) were cooled to 0°C under inert atmosphere. Sulfuric acid/acetic acid (1/1; 25 ml) was added dropwise with stirring. After 2 h the contents were a yellow solution with a white precipitate. The ice bath was removed and the reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with ice and extracted 4 times with ethyl acetate. The organic layer was back extracted with water and then was dried with MgSO4. After filtration, the filtrate was concentrated to an oil. The product was obtained as a white solid after crystallization from toluene/hexanes. Yield: 23.2 g (77%); mp 151°C (sublime). (5R)-5-(Bromomethyl)-5-methyl-2-(tribromo-methyl)-l,3-dioxolan-4-one. The above obtained [(4S)-4-Methyl-5-oxo-2-(tribromomethyl)-1,3-dioxolan-4yl]acetic acid (102.5 mg; 0.250 mmol) and 2-mercaptopyridine- N-oxide (34.4 mg; 0.280 mmol) were suspended in CBrCl3 (1.5ml). The reaction mixture was heated to reflux and a solution of dicyclohexyl carbodiimide (DCC) (103 mg; 0.500 mmol) in CBrCl3 (1.0 ml) was added slowly over the course of 30 min. The reaction mixture was stirred for an additional hour. The product was purified by silica gel chromatography (CH2Cl2/hexanes (1:2)) and was obtained as white needles from the same solvents. Yield: 72 mg (65%); mp 110-113°C. (2R)-3-[(4-Fluorophenyl)thio]-2-hydroxy-2-methyl-propanoic acid. The above prepared protected hydroxyacid (184 mg; 0.413 mmol) was dissolved in 4 ml of a 1:1 mixture of isopropanol:1 M NaOH. After 3 h, the reaction mixture was a solution and no starting material was detectable by TLC. 4-Fluorobenzenethiol (70 ml; 0.65 mmol) was then added and the reaction mixture was stirred overnight. The reaction mixture was then
628
Bietamiverine
adjusted to pH 8 with HCl and was extracted twice with CH2Cl2. The aqueous layer was then adjusted to pH 1 and was extracted with CH2Cl2. This organic layer was concentrated to an oil, which crystallized on standing. The hydroxyacid was either used in the next reaction without further purification or was recrystallized from chloroform/petroleum ether. Yield 76 mg (80%). (2R)-N-[4-Cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenul)thio]-2hydroxy-2-methylpropanamide was prepared from above hydroxyacid (1.89 g; 8.22 mmol) and 4-amino-2-trifluoromethylbenzonitrile (2.05 g; 11.0 mol) were in dry DMA (15 ml) under inert atmosphere. After the solution had been cooled to -10°C, the thionyl chloride (0.75 ml; 10 mmol) was added slowly. The reaction mixture was stirred for 15 min at -10°C and then the ice bath was removed. After stirring overnight at room temperature, the reaction mixture was deluted with CH2Cl2 and was extracted one time with saturated NaHCO3. The organic layer was dried with MgSO4 and concentrated. The product was purified by silica gel chromatography (6% ethyl acetate in CH2Cl2). Yield 1.38 g (42%). (2R)-N-[4-Cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2hydroxy-2-methylpropanamide. To a solution of the sulfide (1.27 g; 3.19 mmol) in CH2Cl2 (43 mL) was added mCPBA (1.65 g; 9.57 mmol). After stirring overnight at room temperature, the reaction mixture was diluted with ethyl acetate and extracted with Na2SO3 and NaHCO3 (2x). The organic layer was dried with MgSO4 and concentrated. After purification by silica gel chromatography using a step gradient of ethyl acetate in CHCl3, the product was obtained as white crystals from benzene/petroleum ether. Yield 1.29 g (94%); ee>>99%; mp 178°C. (2S)-N-[4-Cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2hydroxy-2-methylpropanamide ee>>99%. Product may be prepared from the starting materials. References James K.D., Ekwuribe N.N.; Tetrahedron, V. 58, Is. 29, pp.5905-5908, (2002) Tucker H.; US Patent No. 4,636,505; Jan. 13, 1987; Assigned: Imperial Chemical Industries PLC (London, GB2)
BIETAMIVERINE Therapeutic Function: Spasmolytic Chemical Name: 1-Piperidineacetic acid, alpha-phenyl-, 2-(diethylamino) ethyl ester Common Name: Bietamiverine; Dietamiverine
Bietaserpine
629
Structural Formula:
Chemical Abstracts Registry No.: 479-81-2 Trade Name
Manufacturer
Country
Year Introduced
Bietamiverine
Shanghai Lansheng Corporation Tokyo Tanabe
-
-
-
-
Sparine Raw Materials
Phenylchloroacetic acid Diethylaminoethanol Piperidine Manufacturing Process To a solution of 117 g of diethylaminoethanol in 1000 ml of benzene was added a solution of 94.5 g phenylchloroacetic acid in 400 ml benzene (time of addition 1 hour). Then the reaction mixture was refluxed for 2 hours. To the obtained solution was added an aqueous solution of sodium carbonate. Then to the solution which was dried with sodium sulfate was added 85 g of piperidine and the solution was refluxed for 2 hours. The obtained solution was washed with water, dried with sodium sulfate and distilled. Yield of αphenyl-1-piperidineacetic acid 2-diethylaminoethyl ester 115 g, Kp1 180°C. References Merck Index, Monograph number: 1252, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. Reez Th.; DE Patent No. 859,892; July 8, 1949; Assigned to Nord-Werke G.m.b.H., Hamburg
BIETASERPINE Therapeutic Function: Antihypertensive Chemical Name: 1-[2-(Diethylamino)ethyl]-11,17-dimethoxy-18-[(3,4,5trimethoxybenzoyl)oxy]yohimban-16-carboxylic acid methyl ester
630
Bietaserpine
Common Name: 1-[2-(Diethylamino)ethyl]reserpine Structural Formula:
Chemical Abstracts Registry No.: 53-18-9 Trade Name
Manufacturer
Country
Year Introduced
Tensibar
Lefranco
France
1967
Pleiatensin
Guidotti
Italy
-
Pleiatensin
Byla
France
-
Raw Materials Naphthalene Sodium
Diethylaminochloroethane Reserpine
Manufacturing Process The first stage is to prepare the naphthyl sodium solution in the following way: To a solution of 0.6 g naphthalene in 10 ml tetrahydrofurane, anhydrous, used as solvent, add 96 mg sodium under a nitrogen atmosphere. After a few minutes, an intensive dark green coloration develops, while the sodium dissolves. The reaction is completed after a period of time ranging between 30 and 60 minutes. Then add to the above solution a solution of 2.42 g reserpine in 60 ml anhydrous dioxan at 50°C. After heating for 15 minutes (which corresponds to carrying out reaction a), add 0.6 g, diethylaminochloroethane, while the mixture is kept boiling under reflux, for 6 hours. Reaction b is then completed. Then cool the mixture and evaporate the dioxan under reduced pressure. The pasty residue is dissolved in a mixture of 50 ml benzene and 20 ml ether, and washed several times with water. The aqueous solutions resulting from the washing are also extracted with
Bifemelane hydrochloride
631
ether, and the ether portions are added to the main ether-benzene solution. This solution is extracted several times with 5% acetic acid, until the silicotungstate test (an identification test for alkaloids) yields a negative result, and the acetic solutions are washed with 10 ml ether. After combining the acetic extracts, the solution is adjusted to a pH of 9 with sodium carbonate, which precipitates the base, which is insoluble in water. The oily suspension obtained in this way is extracted several times with chloroform. The chloroform solutions are then washed, each with 10 ml water, then they are combined and dried over anhydrous potassium carbonate. After filtering and evaporating the solvent under reduced pressure, the pasty residue, constituted by the enriched product, is diluted with 30 ml ether and in this way 0.225 g reserpine (which has not taken part in the reaction) is isolated by filtration. After evaporation of the ether under reduced pressure, 1.525 g of the crude resinous base is obtained, which constitutes the required product in a crude and impure condition. This product is purified in the following way: After dissolving in 15 ml of dry benzene, the resulting solution is filtered on an alumina column, which fixes the base. After consecutive elutions with pure benzene, and benzene containing increasing proportions of chloroform,0.748 g of 1-diethylaminoethylreserpineis isolated in the form of a resin. The crystalline acid bitartrate prepared in ethyl acetate melts at 145°-150°C, with decomposition. References Merck Index 1217 Kleeman and Engel p.105 I.N. p.142 Societe Nogentaise De Produits Chimiques and Buzas, A.; British Patent 894,866; April 26, 1962
BIFEMELANE HYDROCHLORIDE Therapeutic Function: Antidepressant, Antiulcer, Nootropic Chemical Name: N-Methyl-4-[2-(phenylmethyl)phenoxy]-1-butanamine hydrochloride Common Name: Bifemelane hydrochloride; Neurocine Chemical Abstracts Registry No.: 90293-01-9 (Base); 62232-46-6
632
Bifonazole
Structural Formula:
Trade Name Bifemelane hydrochloride
Manufacturer ABATRA Technology Co., Ltd.
Country -
Year Introduced -
Alnert Celeport Alemelano Cordinal Neurocine Neurolea
Fujisawa Eisai ELVETIUM-ALET Roemmers Armstrong Elea
-
-
Raw Materials Methylamine Sodium hydroxide
2-(5-Bromopentyloxy)diphenylmethane Hydrogen chloride
Manufacturing Process N-Methyl-4-[2-(phenylmethyl)phenoxy]-1-butanamine was prepared from 2(5-bromopentyloxy)diphenylmethane and of methylamine in ethanol is at 50°C in a sealed tube (heating for 3 hours). Ethanol and excess methylamine are distilled in vacuo, 2 N NaOH aqueous solution is added, and the reaction product is extracted with ether. Dry hydrogen chloride gas is passed into the ether solution, and the precipitate collected by filtration. Recrystallization from ethanol-ether gives N-methyl-4-[2-(phenylmethyl)phenoxy]-1-butanamine hydrochloride, m.p. 87.5-89.5°C. References Kikumoto Ryoji, Tobe Akihiro, Tonomura Shinji, Ikoma Hidenobu; US Patent No. 4,091,114; May 23, 1978; Assigned to Mitsubishi Chemical Industries Limited (Tokyo, JA) Tobe Akihiro, Tanaka Tadashi; EP No. 698,390; 1996-02-28; Assigned to MITSUBISHI CHEM CORP (JP)
BIFONAZOLE Therapeutic Function: Antifungal
Bifonazole
633
Chemical Name: 1-[(1,1'-Biphenyl)-4-yl-phenylmethyl]-1H-imidazole Common Name: (Biphenyl-4-yl)-imidazol-1-yl-phenylmethane Structural Formula:
Chemical Abstracts Registry No.: 60628-96-8 Trade Name Mycospor
Manufacturer Bayer
Country W. Germany
Year Introduced 1983
Raw Materials 4-Phenylbenzophenone Sodium borohydride
Imidazole Thionyl chloride
Manufacturing Process 38.8g (0.15 mol) of 4-phenylbenzophenone are dissolved in 200 ml of ethanol and 39 (0.075 mol) of sodium borohydride are added. After heating for 15 hours under reflux, and allowing to cool, the reaction mixture is hydrolyzed with water containing a little hydrochloric acid. The solid thereby produced is purified by recrystallization from ethanol. 36 g (89% of theory) of (biphenyl4-yl)-phenyl-carbinol [alternatively named as diphenyl-phenyl carbinol or α(biphenyl-4-yl)benzylalcohol] of melting point 72°-73°C are obtained. 13.6 g (0.2 mol) of imidazole are dissolved in 150 ml of acetonitrile and 3.5 ml of thionyl chloride are added at 10°C. 13 g (0.05 mol) of (biphenyl-4-yl)phenyl-carbinol are added to the solution of thionyl-bis-imidazole thus obtained. After standing for 15 hours at room temperature, the solvent is removed by distillation in vacuo. The residue is taken up in chloroform and the solution is washed with water. The organic phase is collected, dried over sodium sulfate and filtered and the solvent is distilled off in vacuo. The oily residue is dissolved in ethyl acetate and freed from insoluble, resinous constituents by filtration. The solvent is again distilled off in vacuo and the residue is purified by recrystallization from acetonitrile, 8.7 g (56% of theory) of (biphenyl-4-yl)-imidazol-1-yl-phenylmethane [alternatively named as diphenyl-imidazolyl-(1)-phenyl-methane or as 1-(α-biphenyl-4ylbenzyl)imidazole] of melting point 142°C are obtained. References Merck Index A-3 DFU 7 (2) 87 (1982)
634
Biotin
DOT 19 (6) 341 (1983) I.N. p.142 Regal, E., Draber, W., Buchel, K.H. and Plempel, M.; US Patent 4,118,487; October 3,1978; assigned to Bayer A.G.
BIOTIN Therapeutic Function: Vitamin Chemical Name: 1H-Thieno(3,4-d)imidazole-4-pentanoic acid, hexahydro-2oxo-, (3aS,4S,6aR)Common Name: Bios II; Biotin; Coenzym R; Skin factor; Vitamin B7; Vitamin Bw Structural Formula:
Chemical Abstracts Registry No.: 58-85-5 Trade Name Biotin Biotin Biotin Gabunat Medebiotin Priorin-Biotin
Manufacturer Solgar Nature's Way Twinlab Strathmann AG Medea Roche Nicholas
Country Germany France
Year Introduced -
Raw Materials 4,5-Dihydrothiophene Ammonium formate Sodium hydroxide Manufacturing Process 4-Carbomethoxy-2-(4,5-dihydrothiophen-3(2H)-one)valeric acid methyl ester was prepared from 4,5-dihydrothiophene as it was described in Baker et al., J. Org. Chem., 12, 167 (1947).
Biperiden
635
A solution of 60.0 g (0.182 mole) this ester in 550 ml absolute ethanol was treated with 91.6 g (1.45 moles) of ammonium formate. The reaction mixture refluxed for 5.0 hours. Then it was cooled, concentrated, and partitionated in a separatory funnel between 200 ml dichloromethane and 150 ml water. The aqueous phase was extracted three times with 50 ml portions of dichloromethane. The organic extracts were collected, dried over anhydrous sodium sulfate, and evaporated. 50 g (0.182 mole, 100%) 3-amino-4carbomethoxy-2,5-dihydro-2-thiophenevaleric acid methyl ester was obtained as a colorless oil. To a solution of 27.3 g (1 mole) of 3-amino-4-carbomethoxy-2,5-dihydro-2thiophenevaleric acid methyl ester in 250 ml dry methanol was added 4.0 g (0.1 mole) of sodium hydroxide pellets. The reaction mixture was refluxed 4.0 hrs, cooled and concentrated to a volume of 50 ml. The residue was taken up in 80 ml dichloromethane and transfered to a separatory funnel. After the addition of 150 ml of 10% by weight aqueous sodium bicarbonate solution, the aqueous layer was extracted twice with 50 ml portions of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and evaporated to yield 6.4 g (0.0234 mole) of recovered starting material. The aqueous phase was adjusted to pH 1 with 6 N hydrochloric acid and extracted three times with 75 ml portions of dichloromethane. The organic phases were pooled, dried over anhydrous sodium sulfate, and evaporated to yield 18.3 g (0.071 mole, 71%) of 3amino-4-carbomethoxy-2,5-dihydro-2-thiophenevaleric acid as a tan solid, upon trituration with pet. ether. The recovered starting material, 6.4 g (0.0234 mole) was dissolved in 70 ml dry methanol and treated with 1.0 g (0.025 mole) sodium hydroxide. The mixture was refluxed 5.0 hrs, cooled concentrated, and taken up in 80 ml dichloromethane. The organic phase was treated in a separatory funnel with 100 ml of 10% by weight aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with 40 ml portions of dichloromethane. The aqueous phase was acidified to pH 1 with 6 N hydrochloric acid and extracted two times with 50 ml portions of dichloromethane. The organic phases were cooled, dried over anhydrous sodium sulfate, and evaporated to dryness to afford an additional 5.3 g (0.021 mole, 21%) of 3-amino-4-carbomethoxy2,5-dihydro-2-thiophenevaleric acid; m.p. 98°-102°C. References Confalone et al.; US Patent No. 3,979,396; Sept. 7, 1976; Assigned: Hoffmann-La Roche Inc. (Nutley, NJ)
BIPERIDEN Therapeutic Function: Antiparkinsonian Chemical Name: α-Bicyclo[2.2.1]hept-5-en-2-yl-α-phenyl-1piperidinepropanol Common Name: -
636
Biperiden
Structural Formula:
Chemical Abstracts Registry No.: 514-65-8; 1235-82-1 (Hydrochloride salt) Trade Name Akineton HCl Akineton HCl Akineton HCl Akinophyl Akineton Akineton Akineton Dekinet Ipsatol Paraden Tasmolin
Manufacturer Knoll Knoll Knoll Biosedra Abbott Dainippon Medinsa Rafa Orion Yurtoglu Yoshitomi
Country US W. Germany Switz. France UK Japan Spain Israel Finland Turkey Japan
Year Introduced 1959 1970 -
Raw Materials Acetophenone Hydrogen chloride Magnesium
5-Chloro-2-norbomene Piperidine hydrochloride Formaldehyde
Manufacturing Process 65 grams of 3-piperidino-1-phenyl propanone-1 of the summary formula C14H29ON, produced according to Mannich's reaction by reacting acetophenone with formaldehyde and piperidine hydrochloride are dissolved in 300 cc of benzene. The resulting solution is added to an organo-magnesium solution prepared from 96 grams of [δ5-bicyclo-(2,2,1)-heptenyl-2]-chloride (also known as 5-chloro-2-norbomene) 18.5 grams of magnesium shavings, and 300 cc of ether. The reaction mixture is boiled for half an hour under reflux. Thereafter the ether is removed by distillation, until the inside temperature reaches 65°70°C. The resulting benzene solution is added to 95 cc concentrated hydrochloric acid containing ice for further processing. Thereby, 3-piperidino1-phenyl-1-[δ5-bicyclo-(2,2,1)-heptenyl-2]-propanol-1 of the summary formula C21H29ON is obtained. The compound melts at 101°C and its chlorohydrate has a melting point of about 238°C. The compound is difficultly soluble in water, slightly soluble in ethanol, and readily soluble in methanol.
Bisacodyl
637
References Merck Index 1231 Kleeman and Engel p.107 PDR p.975 OCDS Vol.1 p.47 (1977) DOT 18 (2) 90 (1982) I.N. p.144 REM pp.928, 929 Klavehr, W.; US Patent 2,789,110; April 16, 1957; assigned to Knoll AG Chemische Fabriken, Germany
BISACODYL Therapeutic Function: Laxative Chemical Name: 4,4'-(2-Pyridylmethylene)bisphenol diacetate Common Name: Structural Formula:
Chemical Abstracts Registry No.: 603-50-9 Trade Name Dulcolax Dulcolax Dulcolax Contalax Bicol Biscolax Theralax Alaxa Anan Bisacolax Biomit Brocalax
Manufacturer Boehringer Ingelheim Thomae Boehringer Ingelheim Riker Wampole Fleet Beecham Angelini Ono ICN Sampo BrocadesSteethman
Country US
Year Introduced 1958
W. Germany Switz.
-
France US US US Italy Japan Canada Japan Netherlands
1959 1974 1975 1976 -
638
Bisacodyl
Trade Name Cathalin Coditax Contalax Darmoletten Deficol Delco-Lax Durolax
Manufacturer Hokuriku Pharbil Fischer Omegin Vangard Delco Boehringer Ingelheim
Country Japan Belgium Israel W. Germany US US W. Germany
Year Introduced -
Endokolat Ercolax Ethanis Eulaxen Evac-Q-Kwik Godalax Hillcolax Ivilax Laco Laksodil Lax Laxadin Laxagetten Laxanin N Laxbene Laxematic Med-Laxan Metalax Mormalene Neodrast Neo-Salvilax Novolax Obstilax Organolax Perilax Prontolax Pyrilax Rytmil Sanvacual Satolax Serax Stadalax Telemin Toilax Toilex Ulcolax Vemas Vencoll Vinco
Weiskopf Erco Taisho Ferring Adria Pfleger Hillel Bieffe Paul Maney Uranium Kanto Teva Tempelhof Schwarzhaupt Merckle Kemifarma Med Star Montefarmaco Werner Schnur Para-Pharma Krka Zirkulin Azuchemie Nordex Streuli Berlin-Chemie Vicks Santos Sato Hameln Stada Funai Erco Protea Ulmer Nippon Zoki Maruko OTW
W. Germany Denmark Japan W. Germany US W. Germany Israel Italy Canada Turkey Japan Israel W. Germany W. Germany W. Germany Denmark W. Germany Finland Italy W. Germany Switz. Yugoslavia W. Germany W. Germany Norway Switz. E. Germany US Spain Japan W. Germany W. Germany Japan Denmark Australia US Japan Japan W. Germany
-
Bisantrene hydrochloride
639
Raw Materials α-Pyridine Aldehyde Phenol Acetic anhydride Manufacturing Process Preparation of (4,4'-Dihydroxy-Diphenyl)-(Pyridyl-2)-Methane 70.0 grams of α-pyridine aldehyde are fed portionwise with stirring and cooling to a mixture of 200 grams of phenol and 100 cc of concentrated sulfuric acid. The reaction mixture is allowed to stand for a while with repeated stirring, whereby it becomes syrupy, neutralized with sodium carbonate, dissolved in methanol and filtered. The filtrate is introduced into a large quantity of water and the resulting precipitate is recrystallized from a methanol/water mixture. Colorless crystals are obtained of MP 254°C. When using zinc chloride or tin tetrachloride and warming to a temperature of about 50°C, a corresponding result is obtained. Preparation of Bisacodyl: 5 grams of (4,4'-dihydroxy-diphenyl)-(pyridyl-2)methane are heated with 5 grams of anhydrous sodium acetate and 20 cc of acetic anhydride for three hours over a boiling water bath. The cooled reaction mixture is poured into water, whereby after a while a colorless substance precipitates, which is filtered off with suction, washed with water and recrystallized from aqueous ethanol. Colorless bright crystals, MP 138°C are obtained. References Merck Index 1238 Kleeman and Engel p.107 PDR pp.561, 677, 879, 1569 I.N. p.145 REM p.800 Kottler, A. and Seeger, E.; US Patent 2,764,590; September 25, 1956; assigned to Dr. Karl Thomae GmbH, Germany
BISANTRENE HYDROCHLORIDE Therapeutic Function: Antineoplastic Chemical Name: 9,10-Anthracenedicarboxaldehyde, bis((4,5-dihydro-1Himidazol-2-yl)hydrazone), dihydrochloride Common Name: Bisantrene hydrochloride Chemical Abstracts Registry No.: 78186-34-2 (Base); 71439-68-4
640
Bisantrene hydrochloride
Structural Formula:
Trade Name
Manufacturer
Country
Year Introduced
Bisantrene hydrochloride
ZYF Pharm Chemical
-
-
Raw Materials Hydrazine hydrate Hydrochloric acid Silver oxide
2-Methylthio-2-imidazoline hydroiodide 9,10-Anthracenedicarboxaldehyde
Manufacturing Process A 33.0 g (0.135 mole) of 2-methylthio-2-imidazoline hydroiodide is dissolved in 300 ml of water and treated with 8 ml (0.16 mole) of hydrazine hydrate. The mixture is stirred at room temperature for 20 hours and then taken to dryness under reduced pressure. The residue is dissolved in 250 ml of water and again taken to dryness under reduced pressure. The residue is redissolved in 250 ml of water and added to a mixture of 250 ml of water, 25 ml of concentrated hydrochloric acid and 25 g of silver oxide. The resulting mixture is stirred on a steam bath for 4 hours and then filtered. The filtrate is reduced to dryness under reduced pressure. The residue is dissolved in 300 ml of ethanol and 20 ml of water at the boil, clarified and cooled at -10°C. The precipitate is collected, washed with ethanol and ether and dried at 60°C and then 110°C under reduced pressure. Yield of the 2-hydrazino-2imidazoline hydrochloride 11.6 g, melting point 177-180°C. The 2-hydrazino-2-imidazoline monohydrochloride is converted to the dihydrochloride by treatment with ethanol and concentrated hydrochloric acid. A suspension of 3.46 g of the 2-hydrazino-2-imidazoline dihydrochloride and 2.34 g of 9,10-anthracenedicarboxaldehyde in 100 ml of ethanol is stirred and heated under reflux for two hours. The mixture is cooled and the solid is collected and washed with ethanol giving the desired product as a crystalline orange solid, m.p. 288-289°C (dec.). References Murdock Keith C., Durr; Frederick E.; US Patent No. 4,258,181; March 24, 1981; Assigned to American Cyanamid Company (Stamford, CT) Tomcufcik Andrew Stephen, Wilkinson Raymond George, Child Ralph Grassing; US Patent No. 3,931,152; January 6, 1976; Assigned to American Cyanamid Company (Stamford, CT)
Bismuth sodium triglycollamate
641
BISMUTH SODIUM TRIGLYCOLLAMATE Therapeutic Function: Lupus erythematosus suppressant Chemical Name: Nitrilotriacetic acid bismuth complex sodium salt Common Name: Structural Formula:
Chemical Abstracts Registry No.: 5798-43-6 Trade Name
Manufacturer
Country
Year Introduced
Bistrimate
Smith, Miller and Patch
US
1946
Raw Materials Bismuth Oxide Triglycollamic Acid Sodium carbonate Manufacturing Process A mixture of 2.33 g of bismuth oxide (Bi2O3), 3.71 g of anhydrous sodium carbonate, and 7.64 g of triglycollamic acid and 40 cc of water was heated at 80°C on the water bath until all was dissolved. The solution was evaporated on the water bath to a syrup. The syrup was allowed to cool, during which time partial solidification occurred. It was then triturated with 300 cc of alcohol, and the solid anhydrous salt was collected on a filter, washed with alcohol, ground fine, and dried in a vacuum desiccator. This substance has a water solubility at 25°C of 31,8% by weight. It decomposes on heating in the melting point bath. References Merck Index 1279 I.N. p. 147 Lehman, R.A. and Sproull, R.C.; US Patent 2,348984; May 16, 1944
642
Bisoprolol fumarate
BISOPROLOL FUMARATE Therapeutic Function: Beta-adrenergic blocker Chemical Name: 2-Propanol, 1-(4-((2-(1-methylethoxy)ethoxy)methyl) phenoxy)-3-((1-methylethyl)amino)-, (E)-2-butenedioate (2:1) (salt) Common Name: Bisoprolol fumarate Structural Formula:
Chemical Abstracts Registry No.: 104344-23-2 Trade Name Bilol Biso-BASF
Manufacturer Ecosol AG BC Biochemie Pharma GmbH
Country Switz. -
Year Introduced -
Bisobloc
Azupharma GmbH and Co. Rusan Healthcare Pvt. Ltd. Merck AG 1A Pharma Alpharma-Isis GmbH Merck AG E. Merck (India) Ltd. Merck AG AWD Pharma GmbH and Co. KG
-
-
India
-
Switz. India Switz. -
-
Procter and Gamble
Germany
-
Bisocar HT Bisomerck Biso 1A Pharma Biso-Puren Concor Concor Concor Cor Cordalin Fondril Raw Materials
1-(p-2-Isopropoxyethoxymethylphenoxy)-2,3-epoxypropane Ammonia Nickel Raney Manufacturing Process A solution of 10 g of 1-(p-2-isopropoxyethoxymethylphenoxy)-3-
Bivalirudin
643
isopropylideneamino-propan-2-ol [obtainable by reacting 1-(p-2isopropoxyethoxymethylphenoxy)-2,3-epoxy propane with ammonia to give 1(p-2-isopropoxyethoxymethylphenoxy)-3-amino-propan-2-ol and subsequently reacting this with acetone] in 250 ml of ethanol was hydrogenated on 0.5 g of Raney nickel at 25°C under 1 atmosphere of pressure until 1 equivalent of H2 had been absorbed. The mixture was filtered and the filtrate evaporated to give 1-(p-2-iso-propoxyethoxymethyl-phenoxy)-3-isopropylamino-propan-2-ol, fumarate, m.p. 100°C (after addition of equimolecular quantity of fumaric acid). References Jonas R. et Patent Jonas R. et Patent
al.; US Patent No. 4,171,370; Oct. 16, 1979; Assigned: Merck Gesellschaft mit beschrankter Haftung (Darmstadt, DE) al.; US Patent No. 4,258,062; Mar. 24, 1981; Assigned: Merck Gesellschaft mit beschrankter Haftung (Darmstadt, DE)
BIVALIRUDIN Therapeutic Function: Anticoagulant Chemical Name: L-Leucine, D-phenylalanyl-L-prolyl-L-arginyl-Lprolylglycylglycylglycylglycyl-L-asparaginylglycyl-L-α-aspartyl-Lphenylalanyl-L-α-glutamyl-L-α-glutamyl-L-isoleucyl-L-prolyl-L-α-glutamylL-α-glutamyl-L-tyrosyl Common Name: Bivalirudin Chemical Abstracts Registry No.: 128270-60-0 Trade Name Angiomax Angiomax Bivalirudin Hirulog
Manufacturer Oryx Medicines Co. Medicines Co. Braine-L' Alleud
Country Belgium
Year Introduced -
Raw Materials BOC-L-Leucine-O-divinylbenzene resin BOC-L-Glutamic acid (γ-benzyl ester) BOC-L-Proline BOC-L-Phenylalanine BOC-L-Asparagine BOC-L-Arginine 4-Cresol Trifluoroacetic acid
BOC-O-2,6-Dichlorobenzyl tyrosine BOC-L-Aspartic acid (β-benzyl ester) BOC-L-Isoleucine BOC-Glycine BOC-L-Phenylalanine Hydrogen fluoride Ethylmethyl sulfate
644
Bivalirudin
Structural Formula:
Manufacturing Process A 20 amino acid polypeptide [1], bivalirudin (hirulog) is a synthetic version of hirudin. Its amino-terminal D-Phe-Pro-Arg-Pro domain, which interacts with the active site of thrombin, is linked via four Gly residues to a dodecapeptide analogue of the carboxy-terminal of hirudin. Like hirudin, bivalirudin also forms a 1:1 stoichiometric complex with thrombin. Once bound, however, the Arg-Pro bond at the amino-terminal of bivalirudin is cleaved by thrombin, thereby restoring active site functions of the enzyme complexes of α-thrombin [2]. Hirulog-8 has the formula: H-(D-Phe)-Pro-Arg-Pro-(Gly)4-Asn-Gly-Asp-PheGlu-Glu-Ile-Pro-Glu-Glu-Tyr-Leu-OH. Hirulog-8 was synthesized by conventional solid-phase peptide synthesis employing an Applied Biosystems 430 A Peptide Synthesizer. This peptide was synthesized using BOC-L-LeucineO-divinylbenzene resin. Additional t-BOC-amino acids (Peninsula Laboratories,
Bleomycin hydrochloride
645
Belmont, Calif.) used included BOC-O-2,6-dichlorobenzyl tyrosine, BOC-Lglutamic acid (γ-benzyl ester), BOC-L-proline, BOC-L-isoleucine, BOC-Lphenylalanine, BOC-L-aspartic acid (β-benzyl ester), BOC-glycine, BOC-Lasparagine, BOC-L-phenylalanine, and BOC-L-arginine. In order to achieve higher yields in synthesis, the (Gly)4 linker segment was attached in two cycles of manual addition of BOC-glycylglycine (Beckman Biosciences, Inc., Philadelphia, Pa.). After completion of synthesis, the peptide was fully deprotected and uncoupled from the divinylbenzene resin by treatment with anhydrous HF:p-cresol:ethylmethyl sulfate (10:1:1, v/v/v). Following removal from the resin, the peptide was lyophilized to dryness. Crude Hirulog-8 was purified by reverse-phase HPLC employing an Applied Biosystems 151A liquid chromatographic system and a Vydac C18 column (2.2x25 cm). The column was equilibrated in 0.1% TFA/water and developed with a linear gradient of increasing acetonitrile concentration from 0 to 80% over 45 minutes in the 0.1% TFA at a flow-rate of 4.0 ml/min. The effluent stream was monitored for absorbance at 229 nm and fractions were collected manually. We purified 25-30 mg of crude Hirulog-8 by HPLC and recovered 15-20 mg of pure peptide. The structure of purified Hirulog-8 was confirmed by amino acid and sequence analyses. References Maraganore J.M., Bourdon P., Jablonski J., Ramachandran K.L., Fenton J.W.; Design and characterization of hirulogs: a novel class of bivalent peptide inhibitors of thrombin. J. Clin. Invest. 1990;29:7095-101 Skrzypczak-Jankun E., Carperos V.E., Ravichandran K.G., Tulinsky A., Westbrook M., Maraganore J.M.; Structure of the hirugen and hirulog 1 complexes of alpha-thrombin. J. Mol. Biol. 1991;221:1379-93 Maraganore J. et al.; US Patent No. 5,196,404; Mar. 23, 1993; Assigned Biogen, Inc., Cambridge, Mass.; Health Research, Inc., Albany, N.Y.
BLEOMYCIN HYDROCHLORIDE Therapeutic Function: Antibiotic Chemical Name: Bleomycin B1, mixture of several derivatives which differ from each other in the terminal amino function Common Name: Bleomicina hydrochloride; Bleomycin hydrochloride Chemical Abstracts Registry No.: 67763-87-5; 11056-06-7 (Base) Trade Name Bleomycin Hydrochloride
Manufacturer Nippon Kayaku, Co.
Country Japan
Year Introduced -
646
Bleomycin hydrochloride
Structural Formula:
Raw Materials 3-Amino-propyldimethylsulfonium bromide hydrobromate Streptomyces verticillus (ATCC No 15003) Millet jelly Soybean powder Glucose Manufacturing Process To a medium having a composition of 6.4 % of millet jelly, 0.5 % of glucose, 3.5 % of soybean powder, 0.75 % of corn steep liquor, 0.3 % of sodium chloride, 0.1 % of potassium secondary phosphate, 0.05 % of zinc sulfate, 0.01 % of copper sulfate, 0.2 % of sodium nitrate and 0.01 % of Toho No. 1 (trade name for a surface active agent composed of polyoxyethylene manufactured by Toho Chemical Industry Co. Ltd., Japan) was added 3-aminopropyl-dimethylsulfonium bromide hydrobromate in a proportion of 0.4 mg/ml to adjust the pH of the medium to 6.5. Each 100 ml of the thus treated medium was separately charged into a Sakaguchi flask and was then sterilized. Subsequently, Streptomyces verticillus (ATCC No. 15003) was inoculated in the medium and was cultured at 27°C for 8 days with stirring at 130 r.p.m. Thereafter, the culture liquors (4.5 L) were collected and filtered to obtain 3.0 L of a filtrate (potency 38.8 mg/ml, total potency 416.4 mg). This culture filtrate was passed through and adsorbed on a column packed with 200 ml of Amberlite IRC-50 and was washed with water and was eluted with 0.5 N hydrochloric acid. 1.0 L of the eluate was neutralized, was passed through and adsorbed on a column packed with 100 ml of active carbon, was washed and was then eluted by use of a 1:1 (by volume) mixture of acetone - 0.02 N aqueous hydrochloric acid solution, and fractions active to Mycobacterium 607 were collected and concentrated to dryness. The resulting residue was dissolved in 5 ml of an 80 % aqueous methanol solution and was charged into a column packed with 30 ml of neutral alumina, followed by elution with an 80 % aqueous methanol solution. Subsequently, bleomycin-containing fractions were collected and concentrated to dryness to obtain 195 mg of bleomycin hydrochloride (potency 650.7 mcg/mg, total potency 172 mg). The yield from the culture filtrate was 30.5 %.
Blonanserin
647
References Products of Toho Chemical Industry Co Ltd., Japan Patent Specification (London), 1,038,242, Aug 10, 1966 Umezawa H. et al.; US Patent No. RE30,451; Dec. 16, 1980; Assigned: Zaidan Jojin Biseibutsu Kagaku Kenkyu Kai (Tokyo, JP)
BLONANSERIN Therapeutic Function: Antipsychotic Chemical Name: Cycloocta[b]pyridine, 2-(4-ethyl-1-piperazinyl)-4-(1fluorophenyl)-5,6,7,8,9,10-hexahydroCommon Name: Blonanserin; AD 5423 Structural Formula:
Chemical Abstracts Registry No.: 132810-10-7 Trade Name
Manufacturer
Country
Year Introduced
Lonasen
Dainippon Pharmaceutical Almirall
-
-
-
-
Blonanserin Raw Materials
2-Chloro-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine N-Ethylpiperazine Potassium iodide Manufacturing Process Preparation of 2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10hexahydrocyclooc ta[b]pyridine:
648
Bluensomycin
A mixture of 2-chloro-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta [b]pyridine (2.0 g), N-ethylpiperazine (2.4 g), and potassium iodide (1.1 g) is stirred at 170°C for 5 hours. After cooling, the reaction mixture is dissolved in ethyl acetate and water. The organic layer is washed with water and extracted with 5% hydrochloric acid. The extract is made alkaline with potassium carbonate, and extracted with ethyl acetate. The extract is washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. (a) The residue is recrystallized from acetonitrile to give the desired product (1.2 g), MP: 123°-124°C. This product obtained in the above (a) is converted to the following salt thereof by treating the product with various acids. References Hino K.; US Patent No. 5,021,421; June 4. 1991; Assigned to Dainippon Pharmaceutical Co., Ltd., Osaka, Japan
BLUENSOMYCIN Therapeutic Function: Antibiotic Chemical Name: Antibiotic obtained from cultures of Streptomyces verticillus, or the same substance produced by any other means Common Name: Bluensomycin; Glebomycin Structural Formula:
Chemical Abstracts Registry No.: 11011-72-6
Bluensomycin Trade Name Bluencomycin Glebomycin Glebomycin
649
Manufacturer Shanghai Lansheng Corporation Banyu Pharm. Co., Ltd.
Country -
Year Introduced -
-
-
DSMZ-Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH
-
-
Raw Materials Streptomyces bluensis NRRL 2876 Polyacrylic acid cation exchange resin Sea sand, adsorbent cotton and fossil flour Carbon Manufacturing Process Bluensomycin was obtained from cultures of Streptomyces verticillus, or the same substance produced by any other means. For example antibiotic was prepared by growing of Streptomyces bluensis NRRL 2876 biological way and isolation from cultural solution by adsorption with a cation-exchange resin or a capillary adsorption method by elution with water-acid solution at pH from 1 to 6 or acidic water solution of acetone. 5350 L of cultivating liquid with pH 8.2 was mixed with 16 kg oxalic acid acidified with 1 N sulfuric acid to pH 2.9 and was filtered through about 160 kg fossil flour and washed with 500 L water. The filtrate (about 5400 L) was alkalified to pH 7.8-8 with 10% sodium hydroxide and was filtered through fossil flour filter. Then it was passed through two column with polyacrylic acid cation exchange resin in sodium form (US Patent No. 2,915,432). Each column was 35 cm in diameter and contained 0.126 kg of above resin. The filtrate (5300 L) was passed with rate 19 L/minute. Then the columns were washed with deionized water, 1 N sulfuric acid to pH 1.2-1.5, and at last eluted with 4x100 L water. About 200 L of column effluent was alkalifed to pH 6.4 with 10% sodium hydroxide. The 1-st column effluent was mixed with 1200 g of activated carbon, the second effluent was mixed with 850 g of coal (1 g coal per 1 g dissolved product). The mixture was thoroughly stirred and filtered. Each coal precipitate was washed 3x10 L with water and 200 L 15% water acetone. Water acetone effluent from the 1-st column (187 L) was dried and gave 1034 g of bluensomycin, the second gave 777 g. The portions of antibiotic were combined and purified by chromatography. The column (high 1.2 m, volume 155 L, with sea sand, adsorbent cotton and fossil flour as the carrier) was used. It was washed with 150 L of deionized water and 300 L 10% water acetone (rate 410 ml per minute). A fraction 101-127 L water acetone gave 640 g bluensomycin after drying. The IR and UV spectra, element analysis confirmed the structure of prepared product and its purity.
650
Bolandiol
References Eble T.E., Johnson L-R, E.; D.B. Patent No. 1,183,631; July 19, 1962; the Upjion Company, Kalamazoo, Mich. (V.St. A.)
BOLANDIOL Therapeutic Function: Anabolic Chemical Name: (3β,17β)-Estr-4-ene-3,17-diol Common Name: Bolandiol Structural Formula:
Chemical Abstracts Registry No.: 19793-20-5 Trade Name 19-Norandrostenediol
Manufacturer Epochem Co., Ltd.
Country -
Year Introduced -
Raw Materials 19-Nortestosterone Lithium aluminum hydride Manufacturing Process To a suspension of 6 parts of lithium aluminum hydride in 2100 parts of ether there are added, with stirring, 7.2 parts of 19-nortestosterone in 700 parts of ether. The mixture is stirred with heating on the steam bath for 45 min, after which the unreacted lithium aluminum hydride is decomposed by addition of acetone. The mixture is diluted with water and the organic layer is separated and washed with water and saturated aqueous sodium chloride solution. After drying over anhydrous sodium sulfate, the ether solution is evaporated under vacuum and the residue is dissolved in benzene and thus applied to a chromatography column containing 760 parts of silica gel. The column is developed with benzene and then with 5 and 10% solutions of ethyl acetate in benzene. Further elution with a 15% solution of ethyl acetate in benzene and concentration of the eluate yields a residue which is recrystallized from acetone and water, ethyl acetate and petroleum ether, and again from acetone and water to yield the 4-estrene-3β,17β-diol, melting point 169°-172°C.
Bolasterone
651
References Colton F.B.; US Patent No. 2,843,608; July 15, 1958; Assigned: G.D. Searle and Co., Chicago, III., a corporation of Delsaware
BOLASTERONE Therapeutic Function: Anabolic Chemical Name: Androst-4-en-3-one, 17-hydroxy-7,17-dimethyl-, (7α,17β)Common Name: Bolasterone; Dimethyltestosterone Structural Formula:
Chemical Abstracts Registry No.: 1605-89-6 Trade Name
Manufacturer
Country
Year Introduced
Myagen
Upjohn
-
-
Bolasterone
ThermoLife
-
-
Methosarb
Upjohn
-
-
Raw Materials Copper chloride Methyl magnesium bromide Hydrochloric acid 6-Dehydro-17-methyltestosterone Sodium carbonate Manufacturing Process A mixture of 0.4 g of cuprous chloride, 20 ml of 4 M methylmagnesium bromide in ether and 60 ml of redistilled tetrahydrofuran was stirred and cooled in an ice bath during the addition of a mixture of 2.0 g of 6-dehydro17-methyltestosterone, 60 ml of redistilled tetrahydrofuran and 0.2 g of cuprous chloride. The ice bath was removed and stirring was continued for 4 h. Ice and water were than carefully added, the solution acidified with 3 N hydrochloric acid and extracted several times with ether. The combined ether extracts were washed with a brine-sodium carbonate solution, brine and then
652
Boldenone undecylenate
dried over anhydrous magnesium sulfate, filtered and then poured over a 75.0 g column of magnesium silicate (Florisil) packed wet with hexanes (Skellysolve B). The column was eluted with 250 ml of hexanes, 0.5 liter of 2% acetone, two liters of 4% acetone and 3.5 L of 6% acetone in hexanes. The residues from fractions 8 to 16 were combined and rechromatographed over a 125.0 g column of magnesium silicate. The column was eluted with 6% acetone in hexanes. Fractions 18 to 29 were combined and dissolved in acetone, decolorized with charcoal, and recrystallized from acetone. 1.0 g of a crystalline mixture of the 7-epimers of 7,17-dimethyltestosterone was obtained melting at 120° to 140°C. The 7α-isomer are separated according to following procedure: To obtain the 7(α)-isomer of 7,17-dimethyltestosterone the crystalline mixture of the 7 stereoisomers of 7,17-dimethyltestosterone was refluxed in tertiary butyl alcohol with recrystallized chloranil under nitrogen. The reaction mixture was concentrated under a fast stream of nitrogen, diluted with methylene chloride and the solution washed with dilute sodium hydroxide, water and then dried, filtered and the solvent removed. The residue, was combined with the product from an identical run and chromatographed through a magnesium silicate column developed with solvent of the following composition and order: two each of hexane hydrocarbons (Skellysolve B), hexanes plus 4% acetone, hexanes plus 8% acetone, hexanes plus 12% acetone, hexanes plus 14% acetone, hexanes plus 16% acetone, hexanes plus 18% acetone, hexanes plus 20% acetone, hexanes plus 24% acetone, hexanes plus 28% acetone, and two of acetone. The residues, eluted with mixture: water-acetone, were combined and chromatographed through a 50 g 1:1 charcoal (Darco)-diatomaceous earth (Celite) column. The column was developed with solvent of the following composition and order: methanol, a 1:1 mixture of methanol and acetone, a 1:2 mixture of methanol and acetone, acetone and a 1:4 mixture of acetone and methylene chloride. Fractions, containing 7(α)-epimer were combined, the solvent evaporated and the residue crystallized from acetone to give the 7α,17-dimethyltestosterone, melting point at 163° to 165°C. References Babcock J.C., Campbell J.A.; US Patent No. 3,341,557; Sept. 12, 1967; Assigned: The Upjohn Company, Kalamazoo, Mich a corporation of Delaware
BOLDENONE UNDECYLENATE Therapeutic Function: Anabolic Chemical Name: Androsta-1,4-dien-3-one, 17β-hydroxy-, 10-undecenoate Common Name: Boldenone undecylenate; Boldone; Vebonol
Boldenone undecylenate
653
Structural Formula:
Chemical Abstracts Registry No.: 13103-34-9 Trade Name Boldenone undecylenate
Manufacturer Country Shandong Xinfa Pharmaceutical Co., Ltd. Epochem Co., Ltd. -
Year Introduced -
Equipoise Equipoise Bold 200 Boldane Vebonol
Genfar Squibb Quality Vet Squibb Ciba-Geigy Agrochemicals
-
-
Vebonol Pace Parenabol
Ciba-Geigy Jurox Labs Ciba
-
-
Boldenone undecylenate
-
Raw Materials L-Dehydrotestosterone Undecylene chloride Manufacturing Process To a solution 5 g of L-dehydrotestosterone in 25 ml of benzene was added 3 ml of pyridine and 7.1 ml undecylene chloride. The mixture was heated for 2 heurs at 70°C. After cooling pyridine hydrochloride was filtered off. The filtrat was purified via chromatography on neutral aluminum oxide. Benzenic eluate was concentrated to obtain 1-dehydrotestosteron 17-undecylenate (boldenone undecylenate) as an oil; λmax 243-244 nm. References Belg. Patent No. 623,277, Oct. 10, 1961; Assigned to E. Merck Aktiengesellschaft, Darmstadt, Germany
654
Bopindolol
BOPINDOLOL Therapeutic Function: Beta-adrenergic blocker Chemical Name: 2-Propanol, 1-((1,1-dimethylethyl)amino)-3-((2-methyl-1Hindol-4-yl)oxy)-, benzoate (ester), (+/-)Common Name: Bopindolol; Sandonorm; Wandonorm Structural Formula:
Chemical Abstracts Registry No.: 62658-63-3 Trade Name Bopindolol
Manufacturer Country Sandoz (Novartis) -
Year Introduced -
Raw Materials Benzoic acid Hexamethylphosphoric acid triamide 1-t-Butylamino-3-(2-methyl-indole-4-yloxy)-2-propanol Benzoic acid anhydride Tartaric acid Manufacturing Process 4-(2-Benzoyloxy-3-t-butylaminopropoxy)-2-methyl-indole: 26 g of benzoic acid are dissolved, while heating, in 50 ml of hexamethylphosphoric acid triamide and 3.5 g of 1-t-butylamino-3-(2-methylindole-4-yloxy)-2-propanol are added. After cooling, 3.0 g of benzoic acid anhydride are added and stirred for 20 hours at room temperature. The resulting clear, yellow solution is poured onto ice 0.5 liters of ether are added and stirred for 2 hours. After making the liquid alkaline with concentrated ammonia, the ether phase is separated, shaken out with tartaric acid, made alkaline with caustic soda solution while cooling with ice and extracted with methylene chloride. After evaporating the solvent, the residue is crystallized with 1 mol of fumaric acid from methanol and acetone.
Bornaprolol hydrochloride
655
References Troxler F. et al.; US Patent No. 4,340,541; July 20, 1982; Assigned to Sandoz Ltd., Basel, Switzerland
BORNAPROLOL HYDROCHLORIDE Therapeutic Function: Beta-adrenergic blocker Chemical Name: 1-(Isopropylamino)-3-(o-2-exo-norbornylphenoxy)-2propanol hydrochloride Common Name: Bornaprolol hydrochloride Structural Formula:
Chemical Abstracts Registry No.: 66451-06-7 (Base); 69319-47-7 Trade Name Bornaprolol hydrochloride
Manufacturer Onbio Inc.
Country -
Year Introduced -
Raw Materials 2-(2-Norbornylexo)phenol Epichlorohydrin
Sodium Isopropylamine
Manufacturing Process 1-Isopropylamino-3-[2-(2-norbornylexo)phenoxy]propan-2-ol: 24.5 g (0.13 moles) 2-(2-norbornylexo)phenol (L. A. KHEIFITS and A. E. GOL'DOVSKII, Zh. Obshch. Khim., 1963, 33, 2048), 350 ml anhydrous toluene and 3 g (0.13 mole) metallic sodium are introduced into a three-neck flask through which a stream of nitrogen flows. The reaction mixture is refluxed until the liberation of hydrogen ceases, then the solvent is driven off under reduced pressure and the residue is taken up in 250 ml tetrahydrofuran. 24 g (0.26 mole) epichlorohydrin are then added and the mixture is heated under reflux for 6 hours. An extraction with ether is then undertaken, the organic phase is washed with water, dried and the solvent is evaporated. 25 g 2-(2norbornylexo)-1-phenoxy-2,3-epoxypropane are thus obtained in the form of
656
Bosentan
an oil. 15 g (0.06 mole) of the preceding product are dissolved in 50 ml isopropylamine. After 4 days contact, the excess amine is evaporated under reduced pressure, then an extraction with ether is carried out. After washing with water and drying, the ethereal phase is saturated with gaseous hydrochloric acid. The precipitate formed is washed abundantly with ether then crystallized from an acetone/ethanol mixture (3/2). 16 g of the desired product in the form of the hydrochloride are thus obtained, having a melting point of 189°-191°C. References Mardiguuian J.; US Patent No. 4,157,400; June 5, 1979; Assigned to MARPHA, Societe d'Etude et d'Explotation de Marques, Paris, France
BOSENTAN Therapeutic Function: Endothelin receptor antagonist Chemical Name: Benzenesulfonamide, 4-(1,1-dimethylethyl)-N-(6-(2hydroxyethoxy)-5-(2-methoxyphenoxy)(2,2'-bipyrimidin)-4-yl)Common Name: Bosentan; Tracleer Structural Formula:
Chemical Abstracts Registry No.: 147536-97-8 Trade Name Bosentan
Manufacturer Roche
Country -
Year Introduced -
Raw Materials Pyrimidine-2-carboxamidine hydrochloride 5-(2-Methoxyphenoxy)-2-(pyrimidin-2-yl)tetrahydropyrimidine-4,6-dione 4,6-Dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine 4-t-Butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(pyrimidin-2-yl)pyrimidin-4-yl]benzenesulfonamide
Botiacrine
657
Sodium Ethylene glycol Tartaric acid Manufacturing Process A solution of 0.11 g of sodium in 3.0 ml of ethylene glycol and equivalent of 4-t-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(pyrimidin-2-yl)-pyrimidin-4yl]benzenesulphonamide were heated to 100°C, cooled for a further 4 hours, poured on to ice and adjusted to pH 3 with 1 M tartaric acid. The suspension obtained was extracted with ethyl acetate, the organic extracts were combined, washed with water, dried with sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on silica gel with CH2Cl2-ethyl acetate 9:1 and yielded 4-t-butyl-N-[6-(2-hydroxyethoxy)-5-(2methoxyphenoxy)-2-(pyrimidin-2-yl)-pyrimidin-4-yl]benzenesulphonamide as a solid. Sodium salt melted at 195°-198°C. The 4-t-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-pyrimidin-2-yl)-pyrimidin4-yl]benzenesulfonamide was prepared starting from pyrimidine-2carboxamidine hydrochloride via rac-5-(2-methoxyphenoxy)-2-(pyrimidin-2yl)tetrahydropyrimidine-4,6-dione and 4,6-dichloro-5-(2-methoxyphenoxy)2,2'-bipyrimidine. References Burri K. et al.; US Patent No. 5,292,740; March 8, 1994; Assigned to Hoffmann-La Roche Inc., Nutley, N.J.
BOTIACRINE Therapeutic Function: Antiparkinsonian Chemical Name: 10-Acridancarbothioic acid, 9,9-dimethyl-, S-(2(dimethylamino)ethyl) ester Common Name: Botiacrine Structural Formula:
Chemical Abstracts Registry No.: 4774-53-2
658
Boxidine
Trade Name Botiacrine
Manufacturer ZYF Pharm Chemical
Country -
Year Introduced -
Raw Materials Dimethylaminoethanethiol 9,9-Dimethylacridan Phosgene Manufacturing Process To 1 gramm-equivalent (g-eq) of dimethylaminoethanethiol in 150 ml of ether, a suspension of g-eq of 50% sodium hydride in 50-ml of anhydrous ether was added. After boiling for 1 hour, the reaction mixture was cooled to 0°C, whereupon g-eq of 9,9-dimethylacridan-10-carboxylic acid chloride (prepared from 9,9-dimethylacridan and phosghene - cf. Swiss Specification No. 426,821) were added and the mixture was heated for a further 6 hours to boiling temperature. After cooling to ambient temperature, the precipitated sodium chloride was filtered in a Buchner funnel fitted with a filter cell. The corresponding 9,9-dimethylacridan-10-carboxylic aciddimethylaminoethanethiol ester was immediately precipitated out of filtrate as base, which melted at 110.5°-111°C. Ethanesulphonic acid salt melted at 147°-150°C. References Molnar I. et al.; US Patent No. 3,630,918; August 20, 1974; Assigned to Siegfried Aktiengesellschaft, Zofingen, Switzerland
BOXIDINE Therapeutic Function: Antihyperlipidemic Chemical Name: Pyrrolidine, 1-(2-((4'-(trifluoromethyl)(1,1'-biphenyl)-4-yl) oxy)ethyl)Common Name: Boxidine Structural Formula:
Chemical Abstracts Registry No.: 10355-14-3
Boxidine Trade Name Boxidine
Manufacturer Onbio Inc.
Country -
659
Year Introduced -
Raw Materials p-Iodobenzotrifluoride Copper 2-Pyrrolidinylethyl chloride p-Bromobenzotrifluoride Methyl iodide Nitrobenzene
p-Iodoanisole Hydrobromic acid 4-Hydroxy-4'-trifluoromethylbiphenyl 4-Methoxycyclohexanone Palladium on carbon
Manufacturing Process The title compound may be prepared 2 ways: 1). 1-(2-[4'-(Trifluoromethyl)-4-biphenylyloxy]ethyl)pyrrolidine: A suspension consisting of 89.8 g (0.33 mole) of p-iodobenzotrifluoride, 132.5 g (0.65 mole) of p-iodoanisole, and 322.7 g of Cu powder in DMF (175 ml) was heated (225-230°C) with stirring in a resin pot for about 5 days. After cooling, the solid reaction mass was pulverized and continuously extracted (heptane) for 2 days. Evaporation of the solvent left a dark brown residue (ca. 50 g) which was dissolved (heptane, 200 ml), decolorized (charcoal), and concentrated to 100 ml. On standing ca. 20 g of impure 4,4'dimethoxybiphenyl were deposited as colorless crystals. Fractional crystallization was continued until the crops of crystalline material were free of impurities by TLC (80:20 heptane-ethyl acetate). Pure 4-methoxy-4'trifluoromethylbiphenyl was isolated as colorless granules, 21.6 g (26%), MP: 124-126°C. A solution consisting of 21.6 g (0.09 moles) of 4-methoxy-4'trifluoromethylbiphenyl dissolved in glacial acetic acid and HBr (48%) was refluxed for approximately 24 hr. After cooling the acetic reaction mixture was poured into H2O (1.5 L) and the solid which separated was collected and air dried. 18.0 g (83%) of the crude product was isolated and taken up in Et2O (100 ml), decolorized (charcoal), filtered, and concentrated to one-third of the original volume. The material which separated from the Et2O solution (m.p. 147-148°C) was pure enough for the next synthetic step (structure verified by NMR). 1.5.6 g (0.06 mole) of the sodium derivative of 4-hydroxy-4'trifluoromethylbiphenyl (prepared from 4-hydroxy-4'-trifluoromethylbiphenyl and sodium hydride) allowed to react with 8.0 g (0.06 mole) of 2pyrrolidinylethyl chloride in refluxing DMF (100 ml) for 18 hr. The resulting suspension was cooled, filtered, and the clear filtrate was concentrated to semisolid residue. Two 100 ml portions of water were used to triturate the crude product which was then dissolved in benzene; the solution was decolorized (char coal) and dried (Na2SO4) and the benzene was removed. Several fractional crystallizations from acetone afforded 9.8 g (49%) of pure 1-1 2- [4'-(trifluoromethyl)-4-biphenylyloxy]ethyl)pyrrolidine MP: 109-110°C. 2). p-Bromobenzotrifluoride (1.37 g, 0.7 mole) and ca. 1.0 g of MeI dissolved in dry Et2O (200 ml) was added to 19 g (0.8 g-atom) of 11 g suspended in Et2O (20 ml) under the usual conditions. Addition of the aromatic halide was regulated to maintain a gentle reflux and refluxing was continued an
660
Bretazenil
additional 1 hr after addition was complete. 4-Methoxycyclohexanone (64 g, 0.5 mole) dissolved in 75 ml of dry Et2O was added to the freshly formed Grignard reagent with vigorous stirring and, after addition of the ketone was complete, the reaction mixture was refluxed with stirring for approximately 1 hr. Decomposition of the Grignard reagent-ketone addition product was achieved by adding excess cold, aqueous ammonia chloride (53 g in 1 L of H2O), and the crude product was removed using two 100-ml portions of Et2O. The combined extracts were decolorized (charcoal), filtered, and dried (Na2SO4). Removal of the Et2O left a brown, oily residue which was distilled in vacuum affording 51.3 g (38%) of 1-(p-trifluoromethylphenyl)-4methoxycyclohexanol, b.p. 121-122°C (0.4-0.5 mm), m.p. 53-54°C. The 4-methoxycyclohexanol derivative (27 g, 0.1 mole), purified as described above, was added to a vigorously stirred concentrated H2SO2-glacial acetic acid (10:40 ml) solution. When a clear solution resulted (ca. 2 min), the reaction mixture was poured all at once into a previously cooled (5-10% mixture of H2O (300 ml) covered with Et2O (300 ml)). The Et2O layer was separated, dried (Na2SO4), and concentrated to a brown, oily residue. Fractionation of the crude oil yielded 18.3 g (717) of 1-(ptrifluoromethylphenyl)-4-methoxycyclohexene, b.p. 104-103°C (0.3-0.4 mm). Dehydrogenation of the purified 4-methoxycyclohexene derivative, obtained as described above, was accomplished using a modification of the method described by Anisworth (J.A.C.S., 76, 4446 (1954)). A suspension consisting of 1-(p-trifluoromethylphenyl)-4-methoxycyclohexene (500 g, 1.95 moles), 166 g of Pd/C and nitrobenzene was refluxed for 22 hr. Aliquots of the reaction mixture taken periodically and analyzed by TLC (heptane-ethyl acetate (4:1) solvent system) indicated that aromatization was complete after this period of time, Removal of the nitrobenzene under reduced pressure left 442 g (89.9%) of the crude biphenyl derivative. Two recrystallizations (petroleum ether) produced material identical with that obtained from the 1 procedure described above. References Bach FL et al.; J. Med. Chem.; 1968, 11, 987
BRETAZENIL Therapeutic Function: Anxiolytic Chemical Name: (S)-8-Bromo-11,12,13,13a-tetrahydro-9-oxo-9Himidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylic acid 1,1dimethylethyl ester Common Name: Bretazenil Chemical Abstracts Registry No.: 84379-13-5
Bretazenil
661
Structural Formula:
Trade Name
Manufacturer
Country
Year Introduced
Bretazenil
Hoffman-La Roche, Inc.
-
-
Raw Materials 6-Bromoisatoic acid anhydride Sodium hydride Potassium t-butylate
Proline, LDiethylchlorophosphate t-Butyl isocyanoacetate
Manufacturing Process 50.6 mmol of 6-bromoisatoic acid anhydride are stirred at 110°C for 2 hours with 50.6 mmol of L-proline in 80 ml of dimethyl sulphoxide. The solution is evaporated and the residue is crystallized from ethyl acetate. There is obtained (S)-6-bromo-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1c][1,4]benzodiazepine-5,11(10H)-dione. A suspension of 29.8 mmol of sodium hydride (55 percent oil dispersion) in 40 ml of dry dimethylformamide is treated at 20-30°C with 27.1 mmol of (S)-6bromo-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11(10H)dione, the mixture is stirred in the above temperature range for 45 min and then at -35°C 27.1 mmol of diethylchlorophosphate are added dropwise thereto. Separately, 3.0 g (27.1 mmol) of potassium t-butylate are dissolved in 9.0 ml of dry dimethylformamide, cooled in an acetone/dry-ice bath, treated with 3.9 g (27.1 mmol) of t-butyl isocyanoacetate and the solution obtained is added dropwise at -15°C to the mixture obtained according to the preceding paragraph. The mixture is warmed to 15°C, neutralized with 1.5 ml of glacial acetic acid, poured into 100 ml of water and extracted four times with methylene chloride. The methylene chloride solution is washed twice with water, dried over magnesium sulfate, evaporated and the crude product obtained is chromatographed on silica gel using ethyl acetate for the elution. By recrystallization from ethyl acetate/n-hexane there is obtained t-butyl (S)8-bromo-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1c][1,4]benzodiazepine-1-carboxylate. References Hunkeler W., Kyburz E.; US Patent No. 4,353,827; October 12, 1982; Assigned to Hoffmann-La Roche Inc. (Nutley, NJ)
662
Bretylium tosylate
BRETYLIUM TOSYLATE Therapeutic Function: Adrenergic blocker; Antiarrhythmic Chemical Name: 2-Bromo-N-ethyl-N,N-dimethylbenzenemethanaminium 4methylbenzene sulfonate Common Name: Structural Formula:
Chemical Abstracts Registry No.: 61-75-6 Trade Name Bretylate Bretylate Bretylol Critifib Darenthin
Manufacturer Wellcome Wellcome Am. Crit. Care Arnar-Stone BurroughsWellcome
Country UK France US US US
Year Introduced 1973 1974 1978 -
Raw Materials N-o-Bromobenzyl-N,N-dimethylamine Ethyl-p-toluene sulfonate Manufacturing Process N-o-Bromobenzyl-N,N-dimethylamine (100g) and ethyl p-toluenesulfonate (94 g) were mixed and warmed to 50°-60°C; after standing for either (a) a minimum of 96 hours at 15°-20°C or (b) a minimum of 18 hours at 50°-60°C and cooling to room temperature, a hard, crystalline mass was formed. Recrystallization of this product from acetone (2.0 ml/g of crude solid), followed by filtration and drying to 60°C gave N-o-bromobenzyl-N-ethyl-N,Ndimethylammonium p-toluenesulfonate as a white, crystalline solid, MP 97°99°C. For this procedure it was necessary that the reactants were substantially colorless and of a high purity.
Brimonidine
663
References Merck Index 1348 PDR p.574 OCDS Vol.1 p.55 (1977) DOT 16 (10) 359 (1980) I.N. p.152 REM p. 860 Copp, F.C. and Stephenson, D.; US Patent 3,038,004; June 5, 1962; assigned to Burroughs Wellcome and Co.
BRIMONIDINE Therapeutic Function: Antiglaucoma Chemical Name: 6-Quinoxalinamine, 5-bromo-N-(4,5-dihydro-1H-imidazol-2yl)Common Name: Brimonidine Structural Formula:
Chemical Abstracts Registry No.: 59803-98-4 Trade Name Alphagan P Brimonidine
Manufacturer Allergan Ratiopharm
Country Australia -
Year Introduced -
Raw Materials 6-Aminoquinoxaline Thiophosgene Sodium bisulfite
Bromine Ethylenediamine
Manufacturing Process 6-Aminoquinoxaline (2.08 g, 14.4 mmol) was dissolved in 11.5 ml glacial acetic acid. The solution was cooled in water while a solution of bromine (0.74 ml, 2.3 g, 14.4 mmol) in 1.5 ml glacial acetic acid was added slowly over 15 min. After stirring for an additional 30 min. the orange red solid formed was filtered off and washed thoroughly with dry ether. The solid was dried in vacuo overnight to yield 4.44 g crude product (a yield of 100%). The compound, 6amino-5-bromoquinoxaline hydrobromide, had no definite melting point. A
664
Brimonidine
phase change (from fine powder to red crystals) was noticed at about 220°C. Decomposition was observed at about 245°C. It was used directly for the next step. The crude 6-amino-5-bromoquinoxaline from above was dissolved in water and saturated sodium bisulfite solution was added until the resulting solution tested negative with starch-iodide paper. The solution was then basified with 2 N sodium hydroxide and extracted thoroughly with ethyl acetate. The organic extract was dried over magnesium sulfate and concentrated under reduced pressure to give the free base. The crude product was recrystallized from boiling benzene to give yellow crystals, m.p. 155°-156°C. Using various analytical procedures, the yellow crystals were determined to be 6-amino-5bromoquinoxaline. The yield was 82%. The crude hydrobromide product previously noted (4.27 g, 14.0 mmol) was dissolved in 60 ml of water and thiophosgene (1.28 ml, 16.8 mmol) was added in small portions with vigorous stirring. After 2 hours, the red color of the solution was discharged. The solid formed was filtered off and washed thoroughly with water. After drying in vacuo at 25°C 3.38 g (a yield of 90%) of brick red crystals was obtained, m.p. 157°-158°C. A portion of this material was further purified by column chromatography to give white crystals, m.p. 157°-158°C. Using various analytical procedures, these crystals were determined to be 5-bromo-6-isothiocyanatoquinoxaline. A solution of the isothiocyanate (3.25 g, 12.2 mmol) in 145 ml benzene was added to a solution of ethylenediamine (5.43 g, 90.0 mmol) in 18 ml benzene at 25°C over 2 hours. After stirring for a further 30 min., the supernatant was poured off. The oil which remained was washed by swirling with dry ether three times and used directly for the next step. A portion of this product was further purified by column chromatography (SiO2, CHCl3) for characterization. A white solid was decomposed at 175°C. This white solid was determined to be 5-bromo-6-(N-2-(aminoethyl)thioureido)quinoxaline. The crude product from above was dissolved in 100 ml dry methanol and the brown solution was refluxed for 19 hours until hydrogen sulfide gas was no longer evolved. The mixture was cooled to room temperature and concentrated to about 50 ml. The yellow solid was filtered off and dried in vacuo; weight 2.52 g (a yield of 70%), m.p. 242°-244°C. As the crude product was insoluble in most common organic solvents, initial purification was achieved by an acid-base extraction procedure. 23 g of the crude product was dissolved in 100 ml 0.5 N hydrochloric acid. The turbid yellow solution was filtered to give a clear orange yellow solution which was extracted twice with ethyl acetate (2x10 ml). The aqueous phase was cooled to 0°C and basified with 6 N sodium hydroxide, keeping the temperature of the solution below 15°C at all times. The yellow solid which precipitated was filtered off and washed thoroughly with water until the washings were neutral to pH paper. The solid was dried overnight in vacuo to give 1.97 g yellow solid, m.p. 249°-250°C. The recovery was about 88%. Further purification was achieved by recrystallization as described below. The partially purified product from above was dissolved in N,N-dimethylformamide (about 17 ml/g) at 100°C with vigorous stirring. The solution was filtered hot and set aside to cool overnight. The bright yellow crystals were collected by filtration, m.p. 252°-253°C. Recovery was from 65-77%. Using various
Brinzolamide
665
analytical procedures the bright yellow solid was determined to be 5-bromo-6(2-imidazolin-2-ylamino)quinoxaline. References Danielewicz J.C. et al.; US Patent No. 3,890,319; June 17, 1975; Assigned: Pfizer Inc., NewYork, N.Y. Burke J.A. et al.; US Patent no. 5,756,503; May 26, 1998; Assigned: Allergan (Waco, TX)
BRINZOLAMIDE Therapeutic Function: Antiglaucoma Chemical Name: (R)-4-Ethylamino-2-(3-methoxypropyl)-3,4-dihydro-2Hthieno[3,2-e]-1,2-thiazine-6-sulfonamide-1,1-dioxide Common Name: Brinzolamide Structural Formula:
Chemical Abstracts Registry No.: 138890-62-7 Trade Name
Manufacturer
Country
Year Introduced
Azopt
Alcon
-
-
Raw Materials 3-(2,5,5-Trimethyl-1,3-dioxane2-yl)thiophene 2-Bromoethyl methylether 2-(Bromomethyl)ethyl methyl ether Propylamine
Sulfur dioxide Hydroxylamine-O-sulfonic acid Pyridinium bromide perbromide Sodium borohydride Butyl lithium
Manufacturing Process To a solution of 3-(2,5,5-trimethyl-1,3-dioxane-2-yl)thiophene (2.5 g, 11.7 mmol) in hexane (30 mL) cooled to 0°C was added via syringe n-butyl lithium in hexane (2.5 M, 10.3 mL, 25.7 mmol) over 5 min. The mixture was stirred at 0°C for 20 min, the ice bath was removed and the stirring was continued for 30 min. At this time a white precipitate formed. The mixture was cooled to
666
Brinzolamide
-60°C and THF (20 mL) was added. Sulfur dioxide was then passed through the surface of the mixture for 30 min. The mixture was warmed to ambient temperature and stirred for an additional 15 min. The volatiles were evaporated and to the residue was added water (50 mL) and sodium acetate trihydrate (9.55 g, 70.2 mmol). The solution was cooled on an ice bath and hydroxylamine-O-sulfonic acid (4.62 g, 40.9 mmol) was added. The mixture was stirred at ambient temperature for 1 h, extracted with ethyl acetate (3x100 mL) and the combined extracts were washed with a sodium bicarbonate solution, brine and dried over molecular sieves. Evaporation to dryness gave a viscous liquid (4.93 g), which was chromatographed (silica, eluting with 33% ethyl acetate-hexane) to give a solid 3-(2,5,5-trimethyl-1,3dioxane-2-yl)-2-thiophenesulfonamide (2.47 g, 72%): m.p. 200°-202°C. The last compound (9.45 g, 32.5 mmol) and 1 N HCl (100 mL) in THF (100 mL) was heated at reflux for 1 h. The THF was evaporated and the aqueous solution was made basic by the addition of sodium bicarbonate. The mixture was cooled using an ice bath and the precipitate was filtered, washed with cold water and dried in vacuo to give 5.83 g (88%) of a solid 3-acetyl-2thiophenesulfonamide: m.p. 193°-196°C. The last product (5.73 g, 28.0 mmol) was dissolved in hot THF (200 mL). The solution was cooled to 10°C and pyridinium bromide perbromide (10.73 g, 33.5 mmol) was added. The mixture was allowed to stir at ambient temperature for 1 h. The volatiles were evaporated and the residue was mixed with water. The precipitate was filtered, washed with cold water and dried in vacuo overnight to give 7.77 g of a solid. A portion of this solid (3.49 g, 12.3 mmol) was suspended in ethanol (100 mL) and treated with sodium borohydride (266 mg, 7.04 mmol). The suspension turned clear after 10 min and was heated at reflux for 1 h. The ethanol was evaporated and the residue was extracted with ethyl acetate, washed with brine and evaporated to give 3,4-dihydro-4-hydroxy-2H-thieno[3,2-e]-1,2-thiazine 1,1-dioxide (1.80 g, 71%): m.p. 138°-140°C. A solution of the above product (19.2 g, 0.093 mol) in DMF (125 mL) was added to a suspension of sodium hydride (3.08 g, 80% oil dispersion, 0.103 mol) in DMF at 006. When the addition was completed the ice bath was removed and the reaction 20 mixture stirred at ambient temperature for 1 h. The reaction mixture was cooled to 0°C and 2-bromoethyl methylether (13.6 mL, 0.14 mol) was added. The reaction mixture was stirred at ambient temperature for 18 h after which time it was evaporated to dryness. The residue was suspended in brine (100 mL) and extracted with methylene chloride (4x80 mL). The combined extracts were dried (MgSO4), filtered and evaporated to a solid which was recrystallized from ethyl acetate to give the desired subject (17.4 g). Chromatography of the mother liquor (silica, 3% ethanol/methylene chloride) furnished more subject which was combined with the first batch to give a total of 19.3 g (78%) of 3,4-dihydro-4-hydroxy-2-(2methoxy)ethyl-2H-thieno[3,2-e]-1,2-thiazine 1,1-dioxide. 3,4-Dihydro-4-hydroxy-2-(2-methoxy)ethyl-2H-thieno[3,2-e]-1,2-thiazine 1,1dioxide (4.9 g, 50 18.6 mmol) was converted to the 4-(1-ethoxy)ethoxy-3,4dihydro-2-(2-methoxy)ethyl-2H-thieno[3,2-e]-1,2-thiazine 1,1-dioxide (6.2 g, 99%) using the reaction with p-toluensulfonic acid and ethylvinyl ether at 0°C in tetrahydrofuran for 2 hrs.
Bromazepam
667
The last one (6.2 g, 18.4 mmol) was converted into 3,4-dihydro-4-hydroxy-2(2-methoxy)ethyl-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide (4.87 g, 77%) m.p. 187°C by using the reaction with n-butyl lithium in anhydrous THF at -40°C for 40 min, and then bubbling sulfur dioxide gas for 20 min after which time the mixture was warmed to room temperature. After 30 min at room temperature the mixture was concentrated the residue was dissolved in water, cooled (0°C), sodium acetate trihydrate was added followed by hydroxylamine-O-sulfonic acid. The reaction mixture was stirred at room temperature for 18 h after which time was basified with solid sodium bicarbonate and extracted with ethyl acetate. 3,4-Dihydro-2-(2-methoxy)ethyl-4-propylamino-2H-thieno[3,2-e]-1,2-thiazine6-sulfonamide-1,1-dioxide hydrochloride was obtained by the reaction of 3,4dihydro-4-hydroxy-2-(2-methoxy)ethyl-2H-thieno[3,2-e]-1,2-thiazine-6sulfonamide-1,1-dioxide in THF containing triethylamine with tosyl chloride at -16°C and the next stirring for 18 hrs at room temperature. After which time the mixture was cooled to 0°C and propylamine was added, the desired product (0.57 g, 46%) was obtained: m.p. 178°-181°C. The desired 4-ethylamino-3,4-dihydro-2-(3-methoxy)propyl-2H-thieno[3,2-e]1,2-thriazine-6-sulfonamide-1,1-dioxide was prepared according to described above procedure for 3,4-dihydro-4-hydroxy-2-(2-methoxy)ethyl-2Hthieno[3,2-e]-1,2-thiazine-6-sulfonamide-1,1-dioxide substituting 2bromoethylmethylether for 2-(bromomethyl)ethyl-methylether. References Dean T.R. et al.; US Patent No. 5,240,923; Aug. 31, 1993; Assigned: Alcon Laboratories, Inc. (Fort Worth, TX)
BROMAZEPAM Therapeutic Function: Tranquilizer Chemical Name: 7-Bromo-1,3-dihydro-5-(2-pyridinyl)-2H-1,4-benzodiazepin2-one Common Name: Structural Formula:
Chemical Abstracts Registry No.: 1812-30-2
668
Bromazepam
Trade Name Lexotan Lexotan Lexotanil Lexotanil Lexomil Lexotan Compedium Creosidin Lectopam Lenitin Lexaurin Lexilium Normoc
Manufacturer Roche Roche Roche Roche Roche Roche Polifarma Osiris Hoffmann - La Roche Inc. Ikapharm Krka Alkaloid Merckle
Country Italy Japan W. Germany Switz. France UK Italy Argentina US
Year Introduced 1975 1977 1977 1977 1981 1982 -
Israel Yugoslavia Yugoslavia W. Germany
-
Raw Materials 2-(2-Aminobenzoyl)pyridine Bromine Bromoacetyl bromide Ammonia
Acetic anhydride Hydrogen chloride Water
Manufacturing Process Example: 32.8 grams of 2-(2-aminobenzoyl)-pyridine and 200 cc of acetic anhydride were stirred at room temperature for 3 hours and then permitted to stand overnight. Evaporation to dryness and digestion of the residue with 200 cc of water containing a little sodium bicarbonate to make the pH slightly alkaline gave 2-(2-acetamidobenzoyl)-pyridine as a light tan powder, which upon crystallization from methanol formed colorless crystals melting at 151°153°C. A solution of 8.6 cc of bromine in 100 cc of acetic acid was added slowly over a 3.5 hour period to a stirred solution of 38.5 grams of 2-(2acetamidobenzoyl)-pyridinein 250 cc of acetic acid. The dark solution was stirred for another 3 hours, permitted to stand over night, stirred for 1 hour with N2 sweeping, and evaporated at diminished pressure in the hood. The gummy residue (75 grams) was treated with water and ether, made alkaline with dilute sodium bicarbonate solution, and separated. Both phases contained undissolved product which was filtered off. Additional crops were obtained by further extraction of the aqueous phase with ether and evaporation of the resulting ether solutions. All these materials were recrystallized from methanol (decolorizing carbon added) yielding 2-(2-acetamido-5-bromobenzoyl)pyridineas yellow crystals melting at 131.5°-133°C. 20.85 grams of 2-(2-acetamido-5-bromobenzoyl)-pyridinein 250 cc of 20% hydrochloric acid in ethanol were heated to reflux for 2 hours. 100 cc of alcohol were added after one hour to maintain fluidity. The mixture stood overnight, was chilled and filtered to give 20.5 grams of colorless crystalline 2-(2-amino-5-bromobenzoyl)-pyridinehydrochloride. Digestion of this
Bromazepam
669
hydrochloride with 0.5liter hot water hydrolyzed this product to the free base, 2-(2-amino-5-bromobenzoyl)-pyridine which formed yellow crystals, melting at 98°-100°C. Evaporation of the alcoholic mother liquor, water digestion of the residue, and alkalization of the water digests afforded additional crops of 2-(2-amino-5-bromobenzoyl)pyridine. 0.145 kg of 2-(2-amino-5-bromobenzoyl)-pyridine, was dissolved in 2.0 liters of glacial acetic acid. The resultant solution was placed in a 3 liter, 3-necked, round bottom flask fitted with a stirrer, thermometer and dropping funnel. The system was protected by a drying tube filled with anhydrous calcium chloride. To the solution, with stirring at room temperature, were carefully added 46.7 ml of bromoacetyl bromide. After the addition was completed, the stirring was continued for two hours. The mixture was then warmed to 40°C, stirred at that temperature for 1.5 hours, chilled and filtered. The residue, after being washed with glacial acetic acid, was dried in vacuo over flake potassium hydroxide to give 2-(2-bromoacetamido-5-bromobenzoyl)pyridinehydrobromide orange crystals, MP 205°-206°C, dec. The hydrobromide was hydrolyzed to the free base as follows: 0.119 kg of 2(2-bromoacetamido-5-bromobenzoyl)-pyridine hydrobromide was stirred with 1.2 liters of cold water for 3.5 hours. The mixture was chilled and filtered, and the residue washed with cold water and dried to give 2-(2-bromoacetamido-5bromobenzoyl)-pyridine, MP 101°C (sinters), 103°-106°C, dec. 93.0 grams of 2-(2-bromoacetamido-5-bromobenzoyl)-pyridinewas carefully added to 0.5 liter of anhydrous ammonia in a 1 liter, 3-necked, round bottom flask equipped with stirrer and reflux condenser and cooled by a Dry Iceacetone bath. The system was protected from moisture by a drying tube containing anhydrous calcium chloride. After stirring for 2 hours, the cooling bath was removed. The mixture was then stirred for 6 hours, during which time the ammonia gradually boiled off. 0.4 liter of water was added to the solid residue and stirrind was resumed for about 2 hours. The solid was then filtered off, washed with water and dried in vacuo over potassium hydroxide flakes. The residue was dissolved on a steam bath in 1.4 liters of ethyl alcohol-acetonitrile (1:1) (decolorizing charcoal added). The solution was filtered hot and the filtrate chilled overnight. The crystalline deposit was filtered off, washed with cold ethyl alcohol and dried in vacuo over flake potassium hydroxide to give 54.2 grams. 7-Bromo-1,3-dihydro-5-(2-pyridyl)2H-1,4-benzodiazepin-2-one, MP 238°C (sinters), 239°-240.5°, dec. Further processing of the mother liquor yielded additional product. References Merck Index 1357 Kleeman and Engel p.110 DOT 9 (6) 238 (1973) and 11 (1) 31 (1975) I.N. p. 154 REM p. 1064 Fryer, R.I., Schmidt, R.A. and Sternbach, L.H.; US Patent 3,100,770; August 13, 1963; assigned to Hoffmann-LaRoche Inc. Fryer, R.I., Schmidt, R.A. and Sternbach, L.H.; US Patent 3,182,065; May 4, 1965; assigned to Hoffmann-LaRoche Inc. Fryer, R.I., Schmidt, R.A. and Sternbach, L.H.; US Patent 3,182,067; May 4, 1965; assigned to Hoffmann-LaRoche Inc.
670
Bromelain
BROMELAIN Therapeutic Function: Antiinflammatory Chemical Name: Complex proteolytic enzyme Common Name: Structural Formula: Complex protein, molecular weight 33,000 Chemical Abstracts Registry No.: 9001-00-7 Trade Name Ananase Bromelain Resolvit Ananase Ananase Extranase Bromelain Ananase Ananase Bromelain Dayto Anase Inflamen Mexase Pinase Proteolvis Resolvit Rogorin Traumanase
Manufacturer Rorer Nadrol Mepha Rorer Rorer Rorer Towa Yakuhin Pharmax Yamanouchi Permicutan Dayton Hokuriku Ciba Geigy Dainippon Benvegna Mepha Saba Arznei MullerRorer
Country US W. Germany Switz. Italy UK France Japan UK Japan W. Germany US Japan France Japan Italy Switz. Italy W. Germany
Year Introduced 1962 1965 1965 1965 1966 1969 1981 -
Raw Materials Pineapple Juice Acetone Manufacturing Process According to US Patent 3,002,891, the following describes pilot plant production of bromelain. Stripped pineapple stumps were passed four times through a three roll sugar mill press, In the second and following passes through the press, water was added to the pulp to increase the efficiency of the extraction procedure. The crude juice was screened to remove the coarse particles. Hydrogen sulfide gas was bled into the collected juice to partially saturate it. The pH was adjusted to pH 4.8 and then the juice was centrifuged. To 50 gallons of juice were added 30 gallons of cold acetone. The precipitate which formed was removed by centifuging in a Sharples centrifuge. This
Bromfenac sodium
671
precipitate was discarded. To the supernatant liquor an additional 35 gallons of acetone was added and the precipitate was collected in a Sharples centrifuge. The wet precipitate was dropped into fresh acetone, mixed well, and then recovered by settling. The paste was then dried in a vacuum oven at a shelf temperature of 110°F. Yield: 8 pounds of enzyme per 100 gallons of juice. Activity: 4,000 MCU/g. References Merck Index 1360 Kleeman and Engel p.112 PDR p.831 I.N. p.154 REM p.1038 Gibian, H. and Bratfisch, G.; US Patent 2,950,227; August 23, 1960; assigned to Schering AG, Germany Heinicke, R.M.; US Patent 3,002,891; October 3, 1961; assigned to Pineapple Research Institute of Hawaii
BROMFENAC SODIUM Therapeutic Function: Analgesicá Antiinflammatory Chemical Name: 2-Amino-3-(4-bromobenzoyl)benzeneacetic acid, sodium salt Common Name: Bromfenac sodium Structural Formula:
Chemical Abstracts Registry No.: 91714-93-1; 91714-94-2 (Base) Trade Name Duract Xibrom
Manufacturer Wyeth-Ayerst ISTA Pharmaceuticals, Inc.
Country -
Year Introduced -
Raw Materials (2-Aminophenyl)-(4-bromophenyl)methanone t-Butyl hypochlorite
Methylsulfanylacetic acid ethyl ester Nickel Raney
672
Bromhexine
Manufacturing Process Reaction of (2-aminophenyl)-(4-bromophenyl)-methanone with methylsulfanylacetic acid ethyl ester and tert-butyl hypochlorite gives a corresponding sulfonium salt. This salt was transformed to initially to the betaine. Electrocyclic rearrangement of that transient intermediate leads, after rearomatization, to the homoanthranilic acid. Internal ester-amine interchange leads then to 4-bromophenyl-(3-(methylthio)indolin-7-yl)methanone. The thiomethyl group is then removed with Raney nickel to give 4-bromophenyl(indolin-7-yl)methanone. Saponification of this intermediate affords the (2amino-3-(4-bromobenzoyl)-phenyl)-acetic acid (Bromfenac). In practice it is usually used as sodium salt. References Merck Index, Monograph number: 1411, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. Walsh D.A. et al.; J. Med. Chem.; 1984, 27, 1379 Gassman P.G. et al.; J. Amer. Chem. Soc.; 1973, 95, 6508
BROMHEXINE Therapeutic Function: Expectorant; Mucolytic Chemical Name: 2-Amino-3,5-dibromo-N-cyclohexyl-N-methylbenzenemethanamine Common Name: N-(2-Amino-3,5-dibromobenzyl)-N-methyl-cyclohexylamine Structural Formula:
Chemical Abstracts Registry No.: 3572-43-8; 611-75-6 (Hydrochloride salt) Trade Name Bisolvon Bisolvon Bisolvon Bisolvon
Manufacturer Boehringer Ingelheim Thomae Boehringer Ingelheim Boehringer Ingelheim
Country Switz. W. Germany Italy UK
Year Introduced 1963 1963 1968 1968
Bromindione Trade Name Bisolvon Lebelon L-Customed Aletor Auxit Bendogen Bromeksin Broncokin Bronkese Dakryo Fulpen Mucovin Ophthosol Solvex Viscolyt
Manufacturer Boehringer Ingelheim Towa Yakuhin Roha Cantabria Heyden Gea Mulda, Yurtoglu Geymonat Lennon Basotherm Sawai Leiras Winzer Ikapharm Gea
Country France Japan W. Germany Spain W. Germany Denmark Turkey Italy S. Africa W. Germany Japan Finland W. Germany Israel Denmark
673
Year Introduced 1969 1981 1982 -
Raw Materials 2-Nitrobenzyl bromide Hydrazine
Cyclohexylmethylamine Bromine
Manufacturing Process In initial steps, 2-nitrobenzylbromide and cyclohexylmethylamine are reacted and that initial product reacted with hydrazine to give N-(2-aminobenzyl)-Nmethyl-cyclohexylamine. A solution of 29.3 g of bromine in 50 cc of glacial acetic acid was slowly added dropwise to a solution of 159 g of N-(2-aminobenzyl)-N-methylcyclohexylamine, accompanied by stirring. The glacial acetic acid was decanted from the precipitate formed during the addition of the bromine solution, and the precipitate was thereafter shaken with 200 cc of 2N sodium hydroxide and 600cc of chloroform until all of the solids went into solution. The chloroform phase was allowed to separate from the aqueous phase. The chloroform phase was decanted, evaporated to dryness and the residue was dissolved in absolute ether. The resulting solution was found to be a solution of N-(2-amino-3,5-dibromobenzyl)-N-methyl-cyclohexylamine in ethanol. Upon introducing hydrogen chloride into this solution, the hydrochloride of N-(2amino-3,5-dibromobenzyl)-N-methyl-cyclohexylamine precipitated out. It had a melting point of 232°-235°C (decomposition). References Merck Index 1361 Kleeman and Engel p.113 OCDS Vol.2 p.96 (1980) I.N. p. 154 Keck, J.; US Patent 3,336,308; August 15, 1967; assigned to Boehringer Ingelheim G.m.b.H.
674
Bromisovalum
BROMINDIONE Therapeutic Function: Anticoagulant Chemical Name: 2-p-Bromophenylindandione Common Name: Bromindione; Bromophenindione; Brophenadione Structural Formula:
Chemical Abstracts Registry No.: 1146-98-1 Trade Name
Manufacturer
Country
Year Introduced
Bromindione
Chemical Formulations
-
-
Raw Materials Sodium Phthalide
Ethanol p-Bromobenzaldehyde
Manufacturing Process To a solution of 1.85 g of sodium in 40 ml of ethanol, was added 10 g of phthalide and 14.0 g of p-bromobenzaldehyde, and the reaction mixture was heated on the steam bath for one hour. Water was then added, and the alcohol was distilled off. Then after adding additional water, the reaction mixture was acidified with hydrochloric acid to precipitate the crude product, which was filtered off, dried and recrystallized from methanol. The 2-pbromophenylindandione is in the form of dark red crystals, having a melting point of 133-135°C. References Merck Index, Monograph number: 1414, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. Freedman L. et al.; US Patent No. 2,847,474; Aug. 12, 1958; Assigned to U.S. Vitamin Corporation, New York
BROMISOVALUM Therapeutic Function: Sedative, Hypnotic
Bromisovalum
675
Chemical Name: 2-Bromo-3-methylbutyrylurea Common Name: Bromisoval; Bromisovalerianyl carbamidum; Bromyl; Bromovalcarbamide; Bromovalharnstoff; Bromovaluree; Bromvaletone; Bromvalerocamidum; Bromvalerylurea Structural Formula:
Chemical Abstracts Registry No.: 496-67-3 Trade Name Bromisovalum Albroman Bromisoval Milocardin Sedual Alluval Bromural Bromoval Calmotin Dormigene Isobromyl Isoval Pivadorm Sedural Somnol Somnurol Valural
Manufacturer Linhai Duqiao Fine Chemical Factory Chinoin Slovakofarma Polpharma Pharmed Berlin-Chemie Knoll Sicomed Takeda Pharmaceutical Company Ltd.
Country -
Year Introduced -
-
-
Pharmacobel Clin-Comar-Byla Mission Specia Rekah Pharmaceutical Industry Ltd. Grindex Synochem Medica
-
-
-
-
Raw Materials 2-Bromoisovalerylbromide Urea Manufacturing Process A mixture of 2 kg 2-bromoisovalerylbromide and 1 kg dry urea is heated at 70°C. Then to the reaction mixture is added sodium hydrogen carbonate. 2Bromo-3-methylbutyrylurea is recrystallized from toluene or water, melting point 149°C.
676
Bromocriptine
References Merck Index, Monograph number: 1418, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. DE Patent No. 185,962; Mar 3, 1907; Assigned to Knoll and Ludwigschafen
BROMOCRIPTINE Therapeutic Function: Prolactin inhibitor Chemical Name: 2-Bromo-12'-hydroxy-2'-(1-methylethyl)-5'α-(2methylpropyl)ergotaman-3',6',18-trione Common Name: 2-Bromoergocryptine Structural Formula:
Chemical Abstracts Registry No.: 25614-03-3; 22260-51-1 (Mesylate salt) Trade Name
Manufacturer
Country
Year Introduced
Parlodel
Sandoz
UK
1975
Pravidel
Sandoz
W. Germany
1977
Parlodel
Sandoz
Switz.
1977
Parlodel
Sandoz
US
1978
Parlodel
Sandoz
France
1978
Parlodel
Sandoz
Japan
1979
Parlodel
Sandoz
Italy
1979
Bromergon
Lek
Yugoslavia
-
Raw Materials N-Bromosuccinimide Ergocryptine
Bromodiphenhydramine
677
Manufacturing Process A solution of 3.4 grams of N-bromosuccinimide in 60 cc of absolute dioxane is added drop wise in the dark, during the course of 5 minutes, to a stirred solution, heated to 60°C, of 9.2 grams of ergocryptine in 180 cc of absolute dioxane. The reaction mixture is stirred at this temperature for 70 minutes and is concentrated to a syrup-like consistency in a rotary evaporator at a bath temperature of 50°C. The reaction mixture is subsequently diluted with 300 cc of methylene chloride, is covered with a layer of about 200 cc of a 2 N sodium carbonate solution in a separating funnel and is shaken thoroughly. The aqueous phase is extracted thrice with 100 cc amounts of methylene chloride. The combined organic phases are washed once with 50 cc of water, are dried over sodium sulfate and the solvent is removed under a vacuum. The resulting brown foam is chromatographed on a 50-fold quantity of aluminum oxide of activity II-III with 0.2% ethanol in methylene chloride as eluant, whereby the compound indicated in the heading is eluted immediately after a secondary fraction which migrates somewhat more rapidly than the fractions containing the heading compound. The last fractions to leave the aluminum oxide contain varying amounts of starting material together with the heading compound, and may be subjected directly, as mixed fractions, to an afterbromination in accordance with the method described above. The fractions containing the pure heading compound are combined and crystallized from methyl ethyl ketonehopropy1 ether. Melting point 215°-218°C (decomp.), [α]D20-195° (c = 1 in methylene chloride). References Merck Index 1386 Kleeman and Engel p.114 PDR p.1589 DOT 12 (3) 87 (1976) I.N. p.155 REM pp.929, 955 Fluckiger, E., Troxler, F. and Hofmann, A.; US Patent 3,752,814; August 14, 1973; assigned to Sandoz Ltd., Switzerland Fluckiger, E., Troxler, F. and Hofmann, A.; US Patent 3,752,888; August 14, 1973; assigned to Sandoz Ltd., Switzerland
BROMODIPHENHYDRAMINE Therapeutic Function: Antihistaminic Chemical Name: p-Bromo-α-phenylbenzyloxy-N,N-dimethylethylamine Common Name: Bromazine; Bromdiphenhydraminum; Histabromazine; Bromodiphenhydramine Chemical Abstracts Registry No.: 118-23-0
678
Bromodiphenhydramine
Structural Formula:
Trade Name
Manufacturer
Country
Year Introduced
Bromazine
-
-
Ambodryl
Shanghai Lansheng Corporation Parke Davis and Co. Ltd.
-
-
Bromo-Benadryl
Parke Davis and Co. Ltd.
-
-
Raw Materials p-Bromobenzhydrylbromide Ethylene chlorohydrin Calcined sodium carbonate Dimethylethylamine Manufacturing Process 28.1 parts of p-bromobenzhydrylbromide are heated to boiling, under reflux and with stirring, with 50 parts of ethylene chlorohydrin and 5.3 parts of calcined sodium carbonate. The reaction product is extracted with ether and the etheral solution washed with water and dilute hydrochloric acid. The residue from the solution in ether [p-bromobenzhydryl(β-chloroethyl)ether]. 28.1 parts of this ether are heated with 12 parts of dimethylethylamine in a sealed tube for 4 hours at 110°C. The product of the reaction is extracted several time with dilute hydrochloric acid. The acid solution made alkaline, in the cold, with concentrated caustic soda solution, and the base which separates taken up in ether. The ether extract is washed with concentrated potassium carbonate solution, evaporated down, and the residue distilled in vacuo. Boiling point of p-bromo-α-phenylbenzyloxy)-N,N-dimethylethylamine 151-154°C under 0.3 mm. p-Bromo-α-phenylbenzyloxy)-N,N-dimethylethylamine may be used as a hydrochloride. References GB Patent No. 670,622; April 23, 1952; Assigned to Parke Davis and Corporation, USA
Bromopride
679
BROMOPRIDE Therapeutic Function: Antiemetic Chemical Name: 4-Amino-4-bromo-N-[2-(diethylamino)ethyl]-2methoxybenzamide Common Name: Structural Formula:
Chemical Abstracts Registry No.: 4093-35-0 Trade Name
Manufacturer
Country
Year Introduced
Praiden
Italchemi
Italy
1977
Valopride
Vita
Italy
1977
Cascapride
Cascan
W. Germany
1978
Artomey
Syncro
Argentina
-
Emepride
Roche
Switz.
-
Emoril
Roemmers
Argentina
-
Opridan
Locatelli
Italy
-
Plesium
Chiesi
Italy
-
Viaben
Schurholz
W. Germany
-
Raw Materials Bromine Dimethyl sulfate Methanol
4-Aminosalicylic acid Acetic anhydride
Manufacturing Process To 119 g (0.45 mol) of N-(2-diethylaminoethyl)-2-methoxy-4-aminobenzamide dissolved in 200 cc of acetic acid are added in the cold in small portions 69 g of acetic anhydride (0.45 mol + 50% excess). The starting material is made by esterifying 4-aminosalicylic acid with methanol, then acetylating with acetic anhydride and then methylating with dimethyl sulfate. The solution obtained is heated for 2 hours on a water bath and then boiled for 15 minutes. It is cooled at 25°C. While agitating constantly and maintaining the temperature between 25° and 30°C, there is added to the solution drop by drop 72 g of bromine dissolved in 60 cc of acetic acid. It is agitated for one hour. The
680
Brompheniramine maleate
mixture obtained is added to one liter of water and the base is precipitated by the addition of 30% soda, The precipitated base is extracted with 40 cc of methylene chloride. After evaporation of the solvent, the residue is boiled for two hours with 390 g of concentrated hydrochloric acid in 780 cc of water. It is cooled, diluted with one liter of water, 12 g of charcoal are added, and the mixture filtered. The base is precipitated with 30% soda. The N-(2diethylaminoethyl)-2-methoxy-4-amino-5-bromobenzamide formed crystallizes, is centrifuged and washed with water. A yield of 85 g of base having a melting point of 129°-130°C is obtained. To produce the dihydrochloride, the free base is dissolved in 110 cc of absolute alcohol, 9.6 g of dry hydrochloric acid dissolved in 35 cc of alcohol are added, followed by 2.8 cc of water. The dihydrochloride precipitates, is centrifuged, washed, and dried at 40°C. It was a solid white material having a melting point of 134°-135°C. References Merck Index 1404 Kleeman and Engel p.115 DOT 14 (5) 193 (1978) I.N. p. 156 Thominet, M.L.; US Patents 3,177,252; April 6, 1965; 3,219,528; November 23,1965; 3,357,978; December 12, 1967; all assigned to Societe d'Etudes Scientifiques et Industrielles de I'lle-de-France
BROMPHENIRAMINE MALEATE Therapeutic Function: Antihistaminic Chemical Name: (4-Bromophenyl)-N,N-dimethyl-2-pyridinepropanamine maleate Common Name: Parabromdylamine Structural Formula:
Brompheniramine maleate
681
Chemical Abstracts Registry No.: 980-71-2; 86-22-6 (Base) Trade Name
Manufacturer
Country
Year Introduced
Dimetane
Robins
US
1957
Dimegan
Dexo
France
1962
Symptom 3
WL/PD
US
1977
Brombay
Bay
US
1983
Antial
Ellem
Italy
-
Atronist
Adams
US
-
Bromfed
Muro
US
-
Bromphen
Schein
US
-
Bromrun
Hokuriku
Japan
-
Dimetapp
Scheurich
W. Germany
-
Dimotane
Robins
UK
-
Drauxin
Francia
Italy
-
Dura-Tap
Dura
US
-
Ebalin
Allergo Pharma
W. Germany
-
E .N .T. Syrup
Springbok
US
-
Febrica
Dexo
France
-
Gammistin
IBP
Italy
-
Ilvico
Bracco
Italy
-
Ilvin
Merck
W. Germany
-
Martigene
Martinet
France
-
Nagemid Chronule Ortscheit
W. Germany
-
Poly Histine
Bock
US
-
Probahist
Legere
US
-
Rupton
Dexo
France
-
Velzane
Lannett
US
-
Raw Materials Sulfuric acid Dimethylaminoethyl chloride 2-Chloropyridine
Sodium amide 4-Bromobenzyl cyanide Maleic acid
Manufacturing Process Initially, 4-bromobenzyl-cyanide is reacted with sodium amide and 2chloropyridine to give bromophenyl-pyridyl acetonitrile. This is then reacted with sodium amide then dimethyl amino ethyl chloride to give 4-bromophenyldimethylaminoethyl-pyridyl acetonitrile. This intermediate is then hydrolyzed and decarboxylated to bromphenirame using 80% H2SO4 at 140°-150°C for 24 hours. The brompheniramine maleate may be made by reaction with maleic acid in ethanol followed by recrystallization from pentanol.
682
Bronopol
References Merck Index 1417 Kleeman and Engel p.116 PDR pp.555, 674, 865, 993, 1033, 1268, 1454, 1606, 1735 OCDS Vol.1 p.77 (1977) I.N. p.157 REM p.1126 Sperber, N., Papa, D. and Schwenk, E.; US Patent 2,567,245; September 11, 1951; assigned to Schering Corporation Sperber, N., Papa, D. and Schwenk, E.; US Patent 2,676,964; April 27, 1954; assigned to Schering Corporation
BRONOPOL Therapeutic Function: Antiseptic Chemical Name: 2-Bromo-2-nitropropane-1,3-diol Common Name: Structural Formula:
Chemical Abstracts Registry No.: 52-51-7 Trade Name
Manufacturer
Country
Year Introduced
Bronosol
Green Cross
Japan
1977
Bronopol
Boots
UK
-
Raw Materials Nitromethane Formaldehyde Bromine Manufacturing Process A mixture of 441 g (3 mols) of calcium chloride dihydrate, 61 g (1 mol) of nitromethane, 163 g (2 mols) of formalin (37% formaldehyde solution) and 470 ml of water was cooled to 0°C and mixed with 5 g of calcium hydroxide while stirring. The temperature thereby rose to 30°C. As soon as the temperature had fallen again, a further 32 g of calcium hydroxide (total of 0.5
Broperamole
683
mol) were added. The mixture was then cooled to 0°C and with intensive cooling and stirring, 159.8 g (1 mol, 51 ml) of bromine were dropped in at a rate so that the temperature remained at around 0°C. After the addition was ended, the mixture was stirred for a further 2 hours, when the reaction product separated in crystalline form. The product was quickly filtered on a suction filter and the crystalline sludge obtained was taken up in 450 ml of ethylene chloride and dissolved at reflux. Then by addition of magnesium sulfate, undissolved inorganic salts were separated and the solution was slowly cooled whereby 140 g (70% yield) of 2-bromo-2-nitropropane-1,3-diol precipitated in colorless crystals melting at 123°-124°C. References Merck Index 1421 I.N. p.158 Wessendorf, R.; US Patents 3,658,921; April 25, 1972; and 3,711,561; January 16, 1973; both assigned to Henkel and Cie G.m.b.H.
BROPERAMOLE Therapeutic Function: Antiinflammatory Chemical Name: Piperidine, 1-(3-(5-(3-bromophenyl)-2H-tetrazol-2-yl)-1oxopropyl)Common Name: Broperamole Structural Formula:
Chemical Abstracts Registry No.: 33144-79-5 Trade Name
Manufacturer
Country
Year Introduced
Broperamole
Onbio Inc.
-
-
Raw Materials 3-[5'-(3"-Bromophenyl)-2'H-tetrazole]propionic acid Thionyl chloride Piperidine
684
Brotizolam
Manufacturing Process A mixture of 32 g (0.108 mole) of 3-[5'-(3"- bromophenyl)-2'Htetrazole]propionic acid and 80 g of thionyl chloride in 250 ml of dry chloroform was stirred under reflux for 16 hours. Evaporation of the solvent and excess reagent under reduced pressure gave a tan oil which was redissolved in 300 ml of dry tetrahydrofuran. To this was added 20 ml of redistilled piperidine in 100 ml of dry tetrahydrofuran. The mixture was stirred for 15 min at room temperature. The tetrahydrofuran was then removed under reduced pressure and the residue well triturated with one liter of 0.1 N hydrochloric acid. The resulting semi-solid was taken up in 700 ml of ether and extracted with 300 ml of 3% aqueous sodium bicarbonate solution. The ether solution was then dried over calcium chloride, filtered, and cooled in the refrigerator. This deposited 25 g (69 %) of tan needles of N-3-[5'-(3"bromophenyl)-2'H-tetrazole]propionyl piperidine; melting point 69°C. References Buckler R. Th.; US Patent No. 3,681,336; Aug. 1, 1972; Assigned to Miles Laboratories, Inc., Elkhart, Ind.
BROTIZOLAM Therapeutic Function: Psychotropic Chemical Name: 8-Bromo-6-(o-chlorophenyl)-1-methyl-4H-s-triazolo-[3,4c]thieno-[2,3e]-1,4-diazepine Common Name: Structural Formula:
Chemical Abstracts Registry No.: 57801-81-7 Trade Name
Manufacturer
Country
Year Introduced
Lendormin
Boehringer Ingelheim
Switz.
1983
Lendorm
Boehringer Ingelheim
Switz.
-
Broxyquinoline
685
Raw Materials 7-Bromo-5-(o-chlorophenyl)-3H-[2,3-e]thieno-1,4-diazepin-2-one Phosphorus pentasulfide Hydrazine hydrate Manufacturing Process (a) 11.5 g of 7-bromo-5-(o-chlorophenyl)-3H-[2,3e]-thieno-1,4-diazepin-2one (see German Patent 2,221,623), were heated at 55° to 60°C with 100 cc of absolute pyridine and 6.5 g of phosphorus pentasulfide for 4 hours while stirring. The mixture was allowed to cool and was then poured into 100 cc of saturated ice-cold NaCl solution. The precipitate was collected by suction filtration, washed with water, dissolved in 100 cc of methylene chloride, the solution was dried and evaporated, and the residue was treated with a little methylene chloride. After suction filtration, 6 g of brown crystalline 7-bromo5-(o-chlorophenyl)-3H-[2,3e]-thieno-1,4-diazepine-2-thione, melting point 214°C (decomposition) were obtained. (b) 6.0 g of this compound were suspended in 100 cc of tetrahydrofuran, and the suspension was stirred at room temperature with 1.2 g of hydrazine hydrate for 20 minutes. After evaporation to about 10 cc, 20 cc of ether were added, and the crystals were collected by suction filtration. Yield: 5.2 g of 7bromo-5-(o-chlorophenyl)-2-hydrazino-3H-[2,3e]-thieno-1,4-diazepine, melting point about 300°C (decomposition). (c) 5.2 g of this compound were suspended in 50 cc of orthotriethyl acetate, and the suspension was heated to 80°C. After about 30 minutes a clear solution was first formed from which later colorless crystals separated out. The mixture was allowed to cool, and the crystals were collected by suction filtration and washed with ether. Yield: 5 g of the compound, melting point 211° to 213°C. References Merck Index 1423 DFU 4 (2) 85 (1979) I.N. p.159 Weber, K.H., Bauer,A., Danneberg, P. and Kunn, F.J.; US Patent 4,094,984; June 13, 1978; assigned to Boehringer Ingelheim GmbH
BROXYQUINOLINE Therapeutic Function: Antibacterial Chemical Name: 5,7-Dibromo-8-hydroxyquinoline Common Name: Bromoxine; Broxichinolium; Broxychinolinum; Broxyquinoline; Dibromohydroxyquinoline
686
Bucainide maleate
Structural Formula:
Chemical Abstracts Registry No.: 521-74-4 Trade Name Brodiar Colepur Fenilor Intensopan Enterin Paramibe Paramibe Starogyn
Manufacturer Intervet Draco UCB Sandoz Leiras Ucepha Cid Co. Oy Leiras Finland Ab
Country -
Year Introduced -
Raw Materials 8-Hydroxyquinoline Bromine Hydrobromic acid Manufacturing Process To a suspension of 14.5 g of 8-hydroxyquinoline in 400 ml of water was added dropwise a solution of 32.3 g bromine and 30 g 8% aqueous hydrobromide in 30 ml water. A temperature of reaction mixture decreased to 33°C. Stirring was continued for 30 min, a fine yellow 5,7-dibromo-8-hydroxyquinoline was collected by filtration, washed with water and dried; yield 29.8 g (98.4%), melting point 201°C. References Merck Index, Monograph number: 1474, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. Jenkner H., DE Patent No. 2,515,476; Oct. 21, 1976; Assigned to Chemische Fabrik Kalk GmbH, 5000 Koeln
BUCAINIDE MALEATE Therapeutic Function: Antiarrhythmic Chemical Name: 1-Propanamine, N-((4-hexyl-1-piperazinyl) phenylmethylene)-2-methyl-, maleate (1:2)
Bucainide maleate
687
Common Name: Bucainide maleate Structural Formula:
Chemical Abstracts Registry No.: 51481-62-0 (Base); 51481-63-1 Trade Name
Manufacturer
Country
Year Introduced
Bucainide maleate
ZYF Pharm Chemical
-
-
Raw Materials N-Hexylpiperazine N-Isobutyl-benzimidoyl chloride Maleic acid Manufacturing Process To a solution of 13.6 g (0.08 mol) of N-hexylpiperazine and 8.1 g (11.2 ml), (0.08 mol) of triethylamine in 120 ml toluene, was added 15.6 g (0.08 mol) of N-isobutyl-benzimidoyl chloride over a period of 15 minutes. The reaction mixture was stirred at room temperature for a period of 2 hours. The triethylamine hydrochloride was filtered off and the filtrate concentrated under vacuum. The residual oily base was washed with 20 ml water, extracted with 50 ml ether and dried over anhydrous magnesium sulfate. The dry ethereal solution was then added to a solution of 18.6 g (0.16 mol) maleic acid in 800 ml ether to obtain the dimaleate salt. Two recrystallizations from ethanol yielded 22.5 g (50.2%) of N-[(4-hexyl-1-piperazinyl)phenylmethylene]-2methyl-1-propanamine product, M.P. 175°-176°C. References Shroff J.R. et al.; US Patent No. 3,793,322; February 19, 1974; Assigned to USV Pharmaceutical Corporation, Tuckahoe, N.Y.
688
Bucetin
BUCETIN Therapeutic Function: Analgesic Chemical Name: Butanamide, N-(4-ethoxyphenyl)-3-hydroxyCommon Name: Bucetin Structural Formula:
Chemical Abstracts Registry No.: 1083-57-4 Trade Name Bucetin
Manufacturer ZYF Pharm Chemical
Country -
Year Introduced -
Raw Materials Acetoacetic acid p-phenetidide Nickel Raney
Nickel on kiesel-guhr Aluminum amalgam
Manufacturing Process Bucetin may be prepared from acetoacetic acid p-phenetidide as follows: 5.5 parts of acetoacetic acid p-phenetidide, suspended in 600 parts by volume of methanol, are hydrogenated at 80°-85°C with a nickel catalyst supported on kiesel-guhr. When the theoretical quantity of hydrogen has been absorbed, the solution is cooled, then filtered, and the filtrate is concentrated. The solid residue is recrystallized from six times its weight of isopropanol. βHydroxybutyric acid p-phenetidide is obtained in an almost quantitative yield in the form of white crystals which melt at 160°C. 55 parts of acetoacetic acid p-phenetidide, suspended in 500 parts by volume of methanol, are hydrogenated with Raney nickel at 70°C. When the theoretical quantity of hydrogen has been absorbed, the solution is cooled, then filtered, and the filtrate is concentrated. The solid residue is recrystallized from six times its weight of isopropanol. 51 parts (93 % of the theoretical yield) of β-hydroxybutyric acid p-phenetidide are obtained in the form of white crystals, which are sparingly soluble in water and melt at 160°C. A mixture of 5 g of aluminum amalgam, 5 g of acetoacetic acid p-phenetidide and 50 ml of ethanol are gently heated for 30 minutes. After filtering off the reducing agent with suction, water is added to the filtrate, and the latter is then acidified with 2 N hydrochloric acid. β-Hydroxybutyric acid p-phenetidide melting at 160°C crystallizes in almost quantitative yield in the form of white crystals.
Buciclovir
689
References Ehrhart G. et al.; US Patent No. 2,830,087; April 8, 1975; Assigned to Farbwerke Hoechst Aktiengesellschaft vormals Meister Lucius and Bruning, Frankfurt am Main, Germany
BUCICLOVIR Therapeutic Function: Antiviral Chemical Name: 6H-Purin-6-one, 2-amino-9-(3,4-dihydroxybutyl)-1,9dihydro-, (R)Common Name: Buciclovir Structural Formula:
Chemical Abstracts Registry No.: 86304-28-1 Trade Name
Manufacturer
Country
Year Introduced
Buciclovir
Astra Lakemedel
-
-
Buciclovir
ZYF Pharm Chemical
-
-
Raw Materials Dimethyl maleate, R-, (+)Perchloric acid N-Bromosuccinimide
Lithium aluminum hydride Triphenylphosphine 2-Amino-6-chloropurine
Manufacturing Process Preparation of R-(+)-9-(3,4-dihydroxybutyl)guanine: Step A: preparation of R-(+)-1,2,4-butantriol: R-(+)-Dimethyl maleate (1.62, 10 mmol), prepared according to Boger, D.L. and Panek, J.S., J. Org. Chem. 1981, 46, 1208-10, was dissolved in THF (10 ml) and added dropwise to a prewarmed suspension of lithium aluminium hydride (0.63 g, 16.5 mmol) in THF (15 ml). The reaction mixture was stirred overnight at 55°C. After sequential addition of water (0.62 ml), 10% sodium hydroxide (1.20 ml) and water (1.90 ml) the mixture was filtered and the solid residue was boiled twice with THF (2x20 ml) and filtered. The combined
690
Buciclovir
filtrates were pooled and evaporated under reduced pressure (30°C) leaving crude 1,2,4-butantriol (0.7 g, 6.6 mmol) 66%. Step B: preparation of R-(+)-isopropylidenbutan 1,2,4-triol: R-(+)-1,2,4-butantriol (0.7 g, 6.6 mmol), prepared as described in step (a) above, was stirred for 1.5 hr in acetone (50 ml) containing 3 drops of conc. perchloric acid a satured solution of sodium bicarbonate in water (5 ml) was added and the stirring was continued for additional 10 min. The precipitate was filtered off and the filtrate evaporated under reduced pressure [2.7 kPa,(20 mm Hg), 30°C]. The residue was taken up in ethyl acetate, washed with satured aqueous sodium bicarbonate (5 ml) and brine (5 ml), and dried over magnesium sulfate. Evaporation of the solvent and distillation gave the title compound as a colourless oil (0.3 g, 2.05 mmol, 31%): b.p. 104°106°C/20 mm Hg; nD20=1.4390. Step C: preparation of R-(+)-4-bromo-isopropylidenebutan-1,2-diol: R-(+)-Isopropylidene-butan-1,2,4-triol (0.3 g, 2.05 mmol) and triphenylphosphine (0.63 g, 2.4 mmol) were dissolved in methylene chloride (5 ml) and cooled to 0°C. N-Bromosuccinimide (0.38 g, 2.16 mmol) was added in small portions with stirring at 0°C. After additional 1 hr of stirring at 0°C hexane (15 ml) was added and the resulting precipitate was removed by filtration and washed twice with hexane (2x5 ml). The combined hexane solution was passed through a short column of silica gel (5 g). Elution with hexane (15 ml) gave after evaporation and distillation the title compound as a colorless oil (0.2 g, 0.96 mmol, 47%): b.p. 74°-76°C/20 mm Hg, nD20=1.4630. [α]D20=+27.7° (C=20, CHCl3). Step D: preparation of R(+)-4-(2-amino-6-chloropurin-9-yl)isopropylidenebutane-1,2-diol: 2-Amino-6-chloropurin (162 mg, 0.96 mmol), R-(+)-4-bromo-isopropylidenebutandiol (200 mg, 0.96 mmol) and potassium carbonate (132 mg) was mixed in DMF (10 ml). After stirring for 16 hr the reaction mixture was filtered through celite and the solvent evaporated under reduced pressure [13 Pa (0.1 mm Hg), 50°C]. The residue was triturated with warm chloroform (5 ml) and undissolved material was filtered off. Evaporation of the solvent gave a pale yellow crystalline solid consisting mainly of the 9- and 7-isomers. These were separated by silica gel flash chromatography. Elution with chloroform/methanol (15:1) gave the title compound in pure form (106 mg, 0.36 mmol, 37%): MP: 129°-130°C, [α]D21 =+57.5° (C=6.97, CHCl3). Step E: preparation of R-(+)-9-(3,4-dihydroxybutyl)guanine: R-(+)-4-(2-Amino-6-chloropurin-9-yl)isopropylidene-butane-1,2-diol (100 mg, 0.33 mmol) prepared according to step (d) above was dissolved in hydrochloric acid (1 mol/L) and refluxed for 1 hr. The solution was concentrated in vacuum and the residue dissolved in water (5 ml) and made alkaline by addition of aqueous ammonium hydroxide. After evaporation the solid residue was recrystallized from water giving the title compound as white needles (40 mg, 0.17 mmol, 51%). [α]D21=+30.8° (C=0.25, water). (+/-)Form had MP: 260°-261°C.
Bucillamine
691
References Hugberg C-E. et al.; January 22, 1985; Assigned to Astra Lakemedel Aktiebolag, Sodertalje, Sweden
BUCILLAMINE Therapeutic Function: Antirheumatic, Immunomodulator Chemical Name: L-Cysteine, N-(2-mercapto-2-methyl-1-oxopropyl)Common Name: Bucillamine; Tiobutarit Structural Formula:
Chemical Abstracts Registry No.: 65002-17-7 Trade Name
Manufacturer
Country
Year Introduced
Bucillamine
ZYF Pharm Chemical
-
-
Bucillamine
Bioray Pharma LLC
-
-
Rimatil
Santen Pharmaceutical Co., Ltd.
-
-
Raw Materials S-Benzyl-L-cysteine Thionyl chloride Sodium
2-Benzylmercaptoisobutyric acid Ammonia
Manufacturing Process Preparation of N-(2-benzylmercaptoisobutyryl)-S-benzyl-L-cysteine: 1). 73.9 g of S-benzyl-L-cysteine were dissolved in 700 ml of 1 N sodium hydroxide solution. The solution was cooled in an ice bath and stirred. 2Benzylmercaptoisobutyryl chloride, which was obtained by reacting 63.1 g of 2-benzylmercaptoisobutyric acid with 39.3 g of thionyl chloride, was added dropwise to this solution. The resulting mixture was then stirred for one hour, acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried over sodium sulfate and evaporated to dryness. The residue was chromatographed on silica gel with benzene/ethylacetate (1:1) as an eluant. The eluate was evaporated to dryness and an oily residue
692
Bucindolol hydrochloride
weighing 46.9 g, representing a yield of 74%, was obtained. 2). The obtained in (1) above were dissolved in 500 ml of liquid ammonia and 21.1 g of metallic sodium were added slowly with stirring. After completion of reaction, 59.4 g of ammonium chloride were added and thereafter the ammonia was removed by distillation. Water was added to the residue to dissolve the solid. The resulting water layer was separated, washed with ethyl acetate, and acidified with hydrochloric acid under cooling. The precipitates thus obtained were extracted with ethyl acetate. The extract was washed with water, dried over sodium sulfate and evaporated to dryness. The product weighed 43.6 g, representing a yield of 88%. After recrystallization from ethyl acetate, the desired compound, melting at 139°-140°C, was obtained. [α]D25=+32.3° (c=1.0, ethanol). References Fujita T. et al.; US Patent No. 4,305,958; December 15, 1981; Assigned to Santen Pharmaceutical Co., Ltd., Osaka, Japan
BUCINDOLOL HYDROCHLORIDE Therapeutic Function: Antihypertensive Chemical Name: Benzonitrile, 3-(2-hydroxy-3-((2-(1H-indol-3-yl)-1,1dimethylethyl)amino)propoxy)- monohydrochloride Common Name: Bucindolol hydrochloride Structural Formula:
Chemical Abstracts Registry No.: 70369-47-0 Trade Name
Manufacturer
Country
Year Introduced
Bucindolol hydrochloride
Bristol Myers (BMS)
-
-
Bucindolol hydrochloride
693
Raw Materials 2-Cyanophenol Sodium hydroxide 2-Nitropropane Nickel Raney
Epichlorohydrin Gramine Acetic acid Hydrazine hydrate
Manufacturing Process A solution of 2-cyanophenol (25.0 g, 0.21 mole), epichlorohydrin (117.0 g, 1.26 mole), and piperidine (10 drops) was stirred and heated at 115-120°C in an oil bath for 2 h. The reaction mixture was then concentrated (90/30 mm) to remove unreacted epichlorohydrin. The residue was diluted with toluene and taken to dryness twice to help remove the last traces of volatile material. The residual oil was dissolved in 263 ml of THF, and the solution stirred at 4050°C for 1 h with 263 ml of 1 N NaOH. The organic layer was separated and concentrated to give an oil which was combined with the aqueous phase. The mixture was extracted with CH2Cl2 and the extract dried (MgSO4) and concentrated to give 36.6 g (100%) of 2-[(2,3-epoxy)propoxy]benzonitrile as oil, which slowly crystallized to a waxy solid. A mixture of gramine (120.0 g, 0.69 mole), 2-nitropropane (443 ml), and NaOH (28.8 g, 0.72 mole) was stirred and gradually heated to reflux under N2. After a 6.5 h reflux period, the reaction mixture was allowed to stand at room temperature overnight, and then diluted with 600 ml of 10% aqueous AcOH. The mixture was extracted with 1.5 l of Et2O and the organic layer washed with H2O (4x 500 ml). Concentration of the Et2O solution in vacuum gave an oil which was dissolved in 500 ml of 95% EtOH. This solution was diluted with 300 ml of H2O. After cooling, the yellow solid was collected on a filter to give 105.0 g (70%) of nitro intermediate, melting point 72-74°C. The nitro compound was dissolved in 1.3 L of 95% EtOH, and Raney nickel (70.0 g, EtOH-washed) and added. The mixture was heated to reflux, and a solution of 85% hydrazine hydrate (116.0 g, 2.3 mole) in 95% EtOH (110 ml) was added dropwise at a rate to maintain gentle reflux. The mixture was then heated at reflux for an additional 1.5 h, cooled, and filtered. Concentration of the filtrate gave crude product as a solid. A solution of the solid in 400 ml of EtOAc was diluted with 500 ml of (i-Pr)2O and cooled. The white, cottony solid which separated was collected on a filter to give 91.0 g (100%) of 2-(3indolyl)-1,1-dimethylethylamine, melting point 122-126°C. A solution of 2-[(2,3-epoxy)propoxy]benzonitrile (18.3 g, 0.10 mole) and 2(3-indolyl)-1,1-dimethylethylamine (15.2 g, 0.08 mole), in 500 ml of abs. EtOH was stirred at reflux overnight. After concentration of the reaction mixture to approximately 200 ml and seeding, crude product began to precipitate. The mixture was then cooled and the precipitate separated by filtration to give 24.8 g of the free base form of the product, white solid, melting point 120-123°C. The crude solid was dissolved in 400 ml of boiling MeOH, and the solution was cooled with stirring, as a by-product 1,1’-[[1,1dimethyl-2-(1H-indol-3-yl]ethyl]imino]bis-[3-(2-cyanophenoxy)-2-propanol] precipitated. The by-product was collected on a filter and air dried to give 2.2 g, of 2-[2-hydroxy-3-[[2-(3-indolyl)-1,1-dimethylethyl]amino]propoxy] benzonitrile, melting point 180-187°C.
694
Buclizine hydrochloride
In practice it is usually used as hydrochloride. References Kreighbaum W.E., Comer W.T.; US Patent No. 4,234,595; November 18, 1980; Assigned: Mead Johnson and Company, Evansville
BUCLIZINE HYDROCHLORIDE Therapeutic Function: Antihistaminic, Antiallergic, Antinauseant, Tranquilizer, Appetite stimulant Chemical Name: Piperazine, 1-((4-chlorophenyl)phenylmethyl)-4-((4-(1,1dimethylethyl)phenyl)methyl)-, hydrochloride Common Name: Buclizine hydrochloride; Histabutazine; Histabutizine Structural Formula:
Chemical Abstracts Registry No.: 129-74-8; 82-95-1 (Base) Trade Name
Manufacturer
Country
Year Introduced
Longifine
UCB
-
-
Longifene
Bios-Coutelier
-
-
Buclina
Sanofi Winthrop
-
-
Posdel
UCB
-
-
Postafen
Rhodia
-
-
Vibazine
Pfizer
-
-
Bucladin-S
Stuart Pharms
-
-
Buclizine Dihydrochloride
Toronto Research Chemicals Inc. (TRC)
-
-
Aphilan R
UCB Pharma
-
-
Histalon
Majer-Meyer
-
-
Postafeno
GSK
-
-
Quantum
Andromaco
-
-
Buclosamide
695
Raw Materials 4-Chlorobenzhydryl chloride Piperazine 1-carboxylic acid ethyl ester 4-tert-Butylbenzyl chloride Manufacturing Process 1 mol 4-chlorobenzhydril chloride was heated in toluene to reflux with 1 mol ethyl ester of piperazine 1-carboxylic acid at about 150°C in a presence of an excess of triethyl amine. On cooling the triethyl amine hydrochloride was filtered off, a solvent was removed in vacuum and the residue [(4-chlorophenyl)-phenyl-methyl]piperazine carboxylic acid ethyl ester was boiled straight away with potassium hydroxide in ethanol for 48 hours. After removing ethanol in vacuum to dryness, the residue was dissolved in benzene and washed with water. The benzene solution was dried, benzene removed in vacuum. The residue was distilled to give 4-chlorobezhydryl-piperazine. It had given the desired 1-(p-tert-butylbenzyl)-4-(p-chloro-α-phenylbenzyl)piperazine, buclizine, by a reaction with 4-tert-butylbenzyl chloride in the presence of any halogen hydrochloride acceptor (triethyl amine, sodium or potassium carbonate and so on). The obtained product had BP: 230°240°C/0.001 mm Hg. References Morren H.; DB Patent No. 964048; Feb. 15, 1951; Forest-Brussel (Belgium)
BUCLOSAMIDE Therapeutic Function: Antifungal Chemical Name: N-Butyl-4-chlorosalicylamide Common Name: Buclosamide Structural Formula:
Chemical Abstracts Registry No.: 575-74-6
696
Bucloxic acid
Trade Name Fungit Jadit
Manufacturer Dragon Hoechst
Country -
Year Introduced -
Raw Materials 4-Chloro-2-hydroxy-benzoic acid n-butyl-ester n-Butylamine Manufacturing Process 4-Chloro-2-hydroxy-benzoic acid n-butyl-amide A mixture consisting of 114 g of 4-chloro-2-hydroxy-benzoic acid n-butylester, 64 grams of methanol and 130 g of n-butyl-amine is heated for 22 hours at 80°C; then the parts volatile up to 130°C are distilled off under reduced pressure. The residue crystallizing in the cold is dissolved in 200 ml of methanol and the solution obtained is slowly added dropwise and while stirring into dilute hydrochloric acid, if necessary, after treatment with animal charcoal. The precipitate which is at first semi-solid soon crystallizes completely. It is filtered with suction, washed with dilute hydrochloric acid, then thoroughly washed again with water, and the product obtained in good yield is dried in the air. After having been recrystallized twice from carbon tetrachloride the 4-chloro-2-hydroxybenzene acid n-butylamide melts at 9092°C. References Merck Index, Monograph number: 1485, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. Ruschig H. et al.; US Patent No. 2,923,737; Feb. 2, 1960; Assigned to Farbwerke Hoechst Aktiengesellschaft vormais Meister Lucius and Bruning, Frankfurt am Main, Germany
BUCLOXIC ACID Therapeutic Function: Antiinflammatory Chemical Name: 3-Chloro-4-cyclohexyl-α-oxo-benzenebutanoic acid Common Name: 4-(4-Cyclohexyl-3-chlorophenyl)-4-oxobutyric acid Structural Formula:
Bucromarone
697
Chemical Abstracts Registry No.: 32808-51-8 Trade Name
Manufacturer
Country
Year Introduced
Esfar
Clin Midy
France
1974
Raw Materials Phenylcyclohexane Succinic anhydride Chlorine Manufacturing Process Phenylcyclohexane and succinic acid (Bernstein Acid) anhydride are reacted in the presence of AlCl3to give 4-(4'-cyclohexylphenyl)-4-keto-n-butyric acid. 177 grams of anhydrous aluminum chloride are introduced into a 3-necked 1 liter flask. A hot solution of 144 grams of 4-(4'-cyclohexylphenyl)-4-keto-nbutyric acid in 330 ml of methylene chloride is added slowly from a dropping funnel. Slight reflux is observed during this addition. 33.2ml of liquefied chlorine are then introduced slowly, drop by drop. This addition requires 5 hours. The solution is then poured on to 1 kg of ice containing 100 ml of concentrated hydrochloric acid. The aqueous phase is extracted twice, each time with 200 ml of methylene chloride, the organic phase is washed with water to pH 6.5 and dried and the organic solvent then evaporated. The desired acid is recrystallized from 500 ml of toluene. The yield is 64%. MP: 159°C. References Merck Index 1431 Kleeman and Engel p.118 OCDS Vol.2 p.126 (1980) DOT 10 (11) 294 (1974) British Patent 1,315,542; May 2, 1973;assigned to Ets Clinbyla, France
BUCROMARONE Therapeutic Function: Antiarrhythmic, Coronary vasodilator Chemical Name: 4H-1-Benzopyran-4-one, 2-(4-(3-(dibutylamino)propoxy)3,5-dimethylbenzoyl)Common Name: Bucromarone Chemical Abstracts Registry No.: 78371-66-1
698
Bucromarone
Structural Formula:
Trade Name
Manufacturer
Country
Year Introduced
Bucromarone
Transphyto
-
-
Raw Materials Aluminum chloride Hydrochloric acid Potassium carbonate
2,6-Dimethylphenol 2-Carboxylic chromone acid chloride 3-N,N-Dibutylamino-1-chloropropane
Manufacturing Process 1.2 mol of an electrophilic catalyst, advantageously aluminum chloride, was slowly added to a solution of 48.8 g (0.4 mol) of 2,6-dimethyl phenol in 400 ml of dichloroethane and agitated at room temperature for an hour. The mixture was cooled to 0°C and a solution of 84.0 g (0.4 mol) of 2-carboxylic chromone acid chloride in 400 ml of a dichloroethane, was slowly added. Agitation was continued at 0°C for 5 h and then at room temperature for 4 days. The reaction mixture was poured into 1.6 L of iced 50% hydrochloric acid. The resulting precipitate was filtered, washed with water, dried and 106.0 g (72% yield) of 2-(3,5-dimethyl-4-hydroxybenzoyl)chromone, melting point 216°C (recrystallised from dioxane) were obtained. 6.9 g (0.05 mol) of potassium carbonate was added to a solution of 29.4 g (0.1 mol) of 2-(3,5-dimethyl-4-hydroxybenzoyl)chromone in 250 ml of dimethyl formamide and kept at 100°C for an hour. A solution of 20.5 g (0.1 mol) of 3-N,N-dibutylamino-1-chloropropane in 100 ml of diethyl formamide was then added and the resulting solution heated to 130°C for 3 h. The solution was filtered, the dimethyl formamide was concentrated, dissolved in 300 ml water and extracted twice with 200 ml of benzene. The organic phase was dried on magnesium sulfate and the hydrochloride was precipitated by adding hydrochloric ether. 40.0 g (yield 80%) of 2-[4-(3-N,N-dibutylaminopropoxy)-3,5-dimethylbenzoyl]chromone were obtained (recrystallised from an acetone/ether mixture). References Chibret H.; US Patent No. 4,220,645; September 2, 1980; Assigned: Thea (Therapeutique et Applications) SA, France
Bucumolol hydrochloride
699
BUCUMOLOL HYDROCHLORIDE Therapeutic Function: Beta-adrenergic blocker Chemical Name: 8-(2-Hydroxy-3-t-butylaminopropoxy)-5-methyl coumarin hydrochloride Common Name: Structural Formula:
Chemical Abstracts Registry No.: 58409-59-9 (Base) Trade Name
Manufacturer
Country
Year Introduced
Bucumarol
Sankyo
Japan
1982
Raw Materials t-Butylamine 8-(2-Hydroxy-3-chloropropoxy)-5-methyl coumarin Manufacturing Process A mixture of 3 g of 8-(2-hydroxy-3-chloropropoxy)-5-methyl coumarin, 4.3 g of t-butylamine and 60 ml of ethanol is heated at 100°C in a sealed tube for 15 hours. The reaction mixture is concentrated under reduced pressure to dryness. The residue is recrystallized from a mixture of ethanol and ether to give 2.1 g of the desired product melting at 226° to 228°C (with decomposition). In practice it is usually used as hydrochloride. References Merck Index 1434 DFU 3 (9) 638 (1978) DOT 19 (1) 10 (1983) Sato, Y., Kobayashi, Y., Taragi, H., Kumakura, S., Nakayama, K. and Oshima, T.; US Patent 3,663,570; May 16, 1972; assigned to Sankyo Co., Ltd.
700
Budesonide
BUDESONIDE Therapeutic Function: Corticosteroid Chemical Name: Pregna-1,4-diene-3,20-dione, 16,17-(butylidenebis(oxy))11,21-dihydroxy-, (11β,16α)Common Name: Budesonide Structural Formula:
Chemical Abstracts Registry No.: 51333-22-3 Trade Name Budecort Budesonide Busonid Entocort EC Pulmicort Respules Ribujet
Manufacturer AstraZeneca Genpharm Inc. Biosintetica AstraZeneca AstraZeneca Chiesi Wasserman
Country -
Year Introduced -
Raw Materials Desonide (16α-hydroxyprednisolone-16,17-acetonide) Butyraldehyde Hydrofluoric acid Manufacturing Process 50 grams of desonide (16α-hydroxyprednisolone-16,17-acetonide) and immediately thereafter 12.5 ml of butyraldehyde were added to 500 ml of 70% hydrofluoric acid solution at -5°C, and the mixture was stirred at 0°C one hour and then poured into 5 liters of demineralized water at 0°C. The precipitate was filtered, washed to neutrality with water and dried under vacuum to give 51 g of pure budesonide with an A/B epimer ratio of 9/91. References Brattsand R.L. et al.; US Patent No. 3,983,233; Sept. 28, 1976; Assigned: AB Bofors (Bofors, SW)
Budipine
701
Brattsand R.L. et al.; US Patent No. 3,929,768; Dec., 30, 1975; Assigned: AB Bofors, Bofors, Sweden
BUDIPINE Therapeutic Function: Antiparkinsonian, Antidepressant Chemical Name: Piperidine, 1-(1,1-dimethylethyl)-4,4-diphenylCommon Name: Budipine Structural Formula:
Chemical Abstracts Registry No.: 57982-78-28 Trade Name
Manufacturer
Country
Year Introduced
Budipine
Byk Gulden (Altana)
-
-
Parkinsan
Promonta
-
-
Raw Materials 1-(tertiary Butyl)-4-hydroxy-4-phenylpiperidine Aluminum chloride Sodium hydroxide Manufacturing Process 24.4 g of 1-(t-butyl)-4-hydroxy-4-phenylpiperidine are suspended in 150 ml of anhydrous benzene. 61.5 g of finely pulverized anhydrous aluminum chloride are added in portions thereto within 25 min while stirring. The reaction temperature increases on starting addition of aluminum chloride to about 45°C. After about 20 min the temperature is increased to and maintained at about 50° to 55°C for about 1 hour. The resulting reaction solution is cooled to about 20°C and is poured into a mixture of ice and concentrated hydrochloric acid. After warming the mixture to room temperature, the hydrochloric acid layer together with the dark oil formed on decomposition is separated from the benzene layer and is washed with benzene. Water is added to said hydrochloric acid -oil phase, while stirring, in portions and in an amount sufficient to produce an almost clear solution. Said acid solution is rendered alkaline by the addition of 40% sodium hydroxide solution whereby
702
Budotitane
the mixture is well cooled. The alkalized mixture is repeatedly extracted with ether. The combined ether extracts are dried over anhydrous potassium carbonate and are concentrated by evaporation of the ether. 24 g of the crude base are obtained as residue in the form of yellowish oil. A water clear oil boiling at 129-131°C/0.005 mm Hg is recovered by distillation of said crude oil in a high vacuum. The oil solidifies to crystals on standing for a short period of time. After recrystallization from aqueous dimethylformamide, the resulting 1-methyl-4,4-diphenylpiperidine has a melting point of 72-74°C. Its hydrochloride is produced by dissolving the base in acetic acid ethyl ester and adding an ethereal hydrochloric acid solution thereto. After recrystallization from acetic acid ethyl ester, the melting point of the hydrochloride is 152-154°C. References Menge Heinz Gunter, Klosa Josef; US Patent No. 4,016,280; April 5, 1977; Assigned to Byk Gulden Lomberg Chemische Fabrik GmbH (DT)
BUDOTITANE Therapeutic Function: Antineoplastic Chemical Name: Diethoxybis(1-phenyl-1,3-butanedionato-O,O')titanium Common Name: Budotitane Structural Formula:
Chemical Abstracts Registry No.: 85969-07-9 Trade Name
Manufacturer
Country
Year Introduced
Budotitane
ZYF Pharm Chemical
-
-
Raw Materials Titantetraethoxid Benzoylaceton
Budralazine
703
Manufacturing Process 11.4 g (0.05 mol) of titantetraethoxid were mixed with solution of 15.8 g (0.097mol) of benzoylaceton in 200 ml n-hexan. Reaction mixture was mixed for 2 h at heating in N2 atmosphere. The precipitate obtained was filtered, then the product was washed with hexan also and filtered. So there was obtained the diethoxybis-(1-phenyl-1,3-butandionato)-titan, melting point 110°C. References Keller H.J. et al.; WO Patent 84/03042; February 9, 1983; Assigned: BYK GULDEN LOMBERG CHEMISCHE FABRIK GESELLSCHAFT MIT BESCHRaNKTER HAFTUNG [DE/DE]; Byk-Gulden-Strasse 2, D-7750 Konstanz (DE)
BUDRALAZINE Therapeutic Function: Antihypertensive Chemical Name: 1(2H)-Phthalazinone-(1,3-dimethyl-2-butenylidene)hydrazone Common Name: Mesityl oxide (1-phthalazinyl) hydrazone Structural Formula:
Chemical Abstracts Registry No.: 36798-79-5 Trade Name
Manufacturer
Country
Year Introduced
Buterazine
Daiichi Seiyaku
Japan
1983
Raw Materials 1-Hydrazinophthalazine HCl Mesityl oxide Manufacturing Process A mixture of 2.0 g of 1-hydrazinophthalazine hydrochloride, 1.1 g of mesityl oxide (isoproplyideneacetone) and 100 ml of ethanol, was refluxed for 3 hours. The reaction mixture was concentrated in vacuo and the residue was
704
Bufenadrine
dissolved in water. The water solution was neutralized with sodium bicarbonate, salted out and the product was extracted with benzene. The benzene layer was passed through a comparatively short column of alumina and the solvent was removed. The residue was crystallized from ether to give 0.7 g of 1-(1,3-dimethyl-2-butenylidene) hydrazinophthalazine, melting point 131°-132°C. References Merck Index 1437 DFU 2 (12) 788 (1977) DOT 18 (10) 553 (1982) and 19 (10) 582 (1983) Ueno, K., Miyazaki, S. and Akashi, A.; US Patent 3,840,539; October 8, 1974; assigned to Daiichi Seiyaku Co., Ltd.
BUFENADRINE Therapeutic Function: Antiemetic, Antihistaminic, Antiparkinsonian Chemical Name: 2-[[2-(1,1-Dimethylethyl)phenyl]phenylmethoxy]-N,Ndimethylethanamine Common Name: Bufenadinum; Bufenadrine Structural Formula:
Chemical Abstracts Registry No.: 604-74-0 Trade Name
Manufacturer
Country
Year Introduced
Bufenadrine
Onbio Inc.
-
-
Raw Materials ο-t-Butyl-α-phenylbenzyl alcohol Sodium hydride N,N-Dimethylmonochloroacetamide Lithium aluminum hydride
Bufeniode
705
Manufacturing Process The ο-t-butyl-α-phenylbenzyl alcohol and N,N-dimethylmonochloroacetamide are dissolved in anhydrous diethyl ether. Portionwise 50% sodium hydride in the form of an oily suspension is added to the solution with stirring. After all the sodium hydride is added, the mixture is stirred at room temperature for another 3 h and then water is added to decompose excess sodium hydride. The ethereal layer is separated, dried with sodium sulfate, filtered and concentrated by removal of the solvent. The residue crystallizes upon addition of petroleum ether (boiling range 80-100°C) to which some diethyl ether is added. There is obtained 2-[ο-t-butyl-α-phenylbenzyl)oxy]-N,N-dimethyl acetamide, melting point 90-91°C (81% yield). To a solution of 2-[ο-t-butyl-α-phenylbenzyl)oxy]-N,N-dimethyl acetamide in anhydrous diethyl ether is added portionwise with stirring and while refiuxing lithium aluminum hydride. After the addition is completed, refluxing is continued overnight. The reaction mixture still contains some lithium aluminum hydride which is decomposed by the addition of water. The mixture is filtered, the ethereal solution separated and dried over sodium sulfate. Diethyl ether is removed from the ethereal solution by distillation. There is obtained 2-[(ο-t-butyl-α-phenylbenzyl)oxy]-N,N-dimethylethylamine. References Stelt C.; US Patent No. 3,463,815; August 26, 1969; Assigned: N.V. Koninklijke Pharmaceutische Fabrieken v/h Brocades-Stheeman and Pharmacia Amsterdam, Netherlands, a corporation of the Netherlands
BUFENIODE Therapeutic Function: Antihypertensive Chemical Name: 4-Hydroxy-3,5-diiodo-α-[1-[(1-methyl-3-phenylpropyl) amino]ethyl]benzyl alcohol Common Name: Diiodobuphenine Structural Formula:
Chemical Abstracts Registry No.: 22103-14-6
706
Bufetolol hydrochloride
Trade Name
Manufacturer
Country
Year Introduced
Proclival
Houde
France
1970
Bufeniod
Weiskopf
W. Germany
1974
Diastal
Bayropharm
Italy
1982
Raw Materials 4-Hydroxypropiophenone Hydrogen Bromide
3-Butyl-1-phenylamine Benzyl chloride Iodine
Manufacturing Process Buphenine is the starting material. See under the alternative name "Nylidrin" in this publication for synthesis. 24 grams of buphenine hydrochloride are suspended in a mixture of 440 ml of 34% ammonia (specific gravity = 0.89) and 315 ml of water. 41 grams of iodine dissolved in 1,080 ml of 96% alcohol are added little by little, with good stirring. During this addition, effected in about 30 min, buphenine hydrochloride dissolves fairly rapidly, and then the diiodobuphenine precipitates out as a crystalline powder. Stirring is continued for a further hour. The precipitate is suction filtered, and then washed with water, with alcohol and with ether and is finally dried in vacuo in the exsiccator in the presence of phosphoric anhydride. Thus, about 23 grams of diiodobuphenine solvated with 1 mol of ethanol are obtained in the form of a microcrystalline white powder. MP (slow) = 185°C (dec.). MP (inst.): 212°C. References Merck Index 1440 Kleeman and Engel p.119 DOT 7 (2) 52 (1971) and 11 (8) 306 (1975) I.N. p.161 South African Patent 680,046; January 3, 1968; assigned to Laboratoires Houde, France
BUFETOLOL HYDROCHLORIDE Therapeutic Function: Antiarrhythmic, Beta-adrenergic blocker Chemical Name: Propanol, 1-(1,1-(dimethylethyl)amino)-3-(2-((tetrahydro2-furanyl)methoxy)phenoxy)-, hydrochloride Common Name: Bufetolol hydrochloride; Bufuronol hydrochloride Chemical Abstracts Registry No.: 35108-88-4
Bufetrol
707
Structural Formula:
Trade Name
Manufacturer
Country
Year Introduced
Bufetolol hydrochloride
ZYF Pharm Chemical
-
-
Raw Materials 1-Bromo-3-[2-(tetrahydro-furan-2-yloxy)phenoxy]propan-2-ol t-Butylamine Fumaric acid Manufacturing Process To a solution of 1 gramm equivalent (g-eq.) of 1-bromo-3-[2(tetrahydrofuran-2-yloxy)phenoxy]propan-2-ol in 30 ml of ethanol is added 1 g-eq. of t-butylamine, the mixture is refluxed for 6 hours, and then the ethanol is distilled off. The residue is dissolved in benzene and the solution is extracted twice with 5% oxalic acid. The aqueous extract is made alkaline with potassium hydroxide and the isolated oil is extracted with benzene. The benzene extract is dried over potassium carbonate and the benzene is distilled off to give of oily 1-(t-butylamino)-3-(o-((tetrahydrofurfuryl)oxy)phenoxy)-2propanol. The corresponding acid fumarate melts at 128°-132°C. References Nakanishi M. et al.; US Patent No. 3,723,476; March 27, 1973; Assigned to Yoshitomi Pharmaceutical Industries Ltd., Osaka, Japan
BUFETROL Therapeutic Function: Antiarrhythmic Chemical Name: 1-(tert-Butylamino)-3-[2-[(tetrahydro-2-furanyl)methoxy] phenoxy]-2-propanol Common Name: Bufetolol Chemical Abstracts Registry No.: 53684-49-4
708
Bufetrol
Structural Formula:
Trade Name
Manufacturer
Country
Year Introduced
Adobiol
Yoshitomi
Japan
1974
Raw Materials 2-(2-Tetrahydrofurfuryloxy)phenol Epichlorohydrin t-Butylamine Manufacturing Process The preparation of a similar compound in which a methoxyethoxy group replaces the tetrahydrofurfuryloxy group in Bufetrol is described in the following example. Nine grams of o-(2-methoxyethoxy)phenol is suspended in 50 milliliters of water containing 3.7 grams of potassium hydroxide, and 5.5 grams of epichlorhydrin is added thereto with stirring. The mixture is stirred at room temperature for 7 hours, and then extracted with two 50 milliliter portions of benzene. The extract is washed with water, dried over anhydrous magnesium sulfate and the benzene is distilled off to give 8.5 grams of oily 1(2,3-epoxypropoxy)-2-(2-methoxyethoxy)benzene showing nD20 = 1.5257. This compound has the methoxyethoxy group in place of the 2tetrahydrofurfuryloxy group in Bufetrol. To a solution of 1-(2,3-epoxypropoxy)-2-(2-tetrahydrofurfuryloxy)benzene in methanol are added tert-butylamine and water, the mixture is allowed to stand at 25°-30°C for 72 hours, and then the methanol is distilled off. The residue is dissolved in toluene and the solution is extracted twice with 5% oxalic acid. The aqueous extract is dried over potassium carbonate and concentrated to give Bufetrol. References Merck Index 1441 Kleeman and Engel p.119 DOT 10 (12) 332 (1974) I.N. p.161 Nakanishi. M.. Muro, T., Imamura, H. and Yamaguchi, N.; US Patent 3,723,476; March 27, 1973; assigned to Yoshitomi Pharmaceutical Industries, Ltd., Japan
Bufexamac
709
BUFEXAMAC Therapeutic Function: Antiinflammatory, Analgesic, Antipyretic Chemical Name: 4-Butoxy-N-hydroxybenzeneacetamide Common Name: Structural Formula:
Chemical Abstracts Registry No.: 2438-72-4 Trade Name
Manufacturer
Country
Year Introduced
Parfenac
Lederle
UK
1973
Feximac Cream
Nicholas
UK
1973
Parfenac
Lederle
France
1974
Parfenac
Cyanamid
Italy
1975
Parfenac
Cyanamid
W. Germany
1976
Parfenac
Opopharma
Switz.
1976
Anderm
Lederle-Takeda
Japan
1977
Droxan
Continental Pharma
Belgium
-
Droxarol
Continental Pharma
W. Germany
-
Flogocid
Continental Pharma
-
-
Malipuran
Scheurich
W. Germany
-
Norfemac
Nordic
Canada
-
Paraderm
Continental Pharma
Belgium
-
Viafen
Zyma
Switz.
-
Raw Materials p-Hydroxyacetophenone Sodium hydroxide Butyl bromide Ethanol
Sulfur Hydroxylamine hydrochloride Morpholine
Manufacturing Process (1) 136 g of p-hydroxyacetophenone, 140 g of butyl bromide, 152 g of potassium carbonate, 17 g of potassium iodide and 275 cc of ethanol are mixed and then refluxed for 48 hours. The reaction mixture is cooled, diluted with water, then extracted with ether. The ethereal phase is washed with a
710
Bufezolac
10% sodium hydroxide solution, then with water, followed by drying, ether is evaporated and the product distilled under reduced pressure. 168 g of pbutyloxyacetophenone are obtained with yield of 87% (160°-162°C at 11 mm Hg). (2) 192 g of p-butyloxyacetophenone, 42 g of sulfur and 130 g of morpholine are mixed and then refluxed for 14 hours. The resulting solution is poured into water and stirred until crystallization of the sulfurated complex. The latter is filtered, washed with water and dried, Production: 270 g (88% yield). (3) 200 g of sodium hydroxide are dissolved in 1,500 cc of ethanol and then 293 g of the thus-obtained sulfurated complex are added. The mixture is refluxed overnight, The mixture is distilled to separate the maximum of the alcohol and then diluted with water. The resulting solution is acidified with hydrochloric acid, and extracted with ether. The ethereal phase is washed with water, followed by extraction with a 10% sodium carbonate solution. The carbonated solution is acidified with 10% hydrochloric acid, and the resulting precipitate of p-n-butyloxyphenylacetic acid is filtered and dried. 100 g of this product are obtained (70% yield). (4) 208 g of p-n-butyloxyphenylacetic acid, 368 g of ethanol and 18 cc of sulfuric acid are refluxed for 5 hours. The mixture is diluted with water, after which it is extracted with ether. The ethereal phase is successively washed with water, then with carbonate, and again with water, following which it is dried and distilled to remove solvent. The ester is then distilled at a reduced pressure. 200 g of ethyl p-butyloxyphenylecetate are thus obtained with yield of 61% (186°C at 8 mm Hg). (5) 7 g of hydroxylamine hydrochloride are dissolved in 100 cc of methanol. A solution of 5 g of sodium in 150 cc of methanol is added and the salt precipitate is separated by filtration. 22 g of ethyl p-n-butyloxyphenylacetate are added to the filtrate and the mixture is refluxed for 1 hour. The mixture is cooled and acidified with 20% hydrochloric acid. 14.7 g of p-nbutyloxyphenylacetohydroxamic acid are thus obtained with yield of 71% (melting point: 153°-155°C). References Merck Index 1442 Kleeman and Engel p. 120 DOT 12 (11) 435 (1976) I.N. p.161 Buu-Hoi, N.P., Lambelin, G., Lepoivre, C., Gillet, C. and Thiriaux, J.; US Patent 3,479,396; November 18, 1969; assigned to Madan A.D.
BUFEZOLAC Therapeutic Function: Antiinflammatory Chemical Name: 1-(2-Methylpropyl)-3,4-diphenyl-1H-pyrazole-5-acetic acid
Bufezolac
711
Common Name: Bufezolac; LM 22070 Structural Formula:
Chemical Abstracts Registry No.: 50270-32-1 Trade Name
Manufacturer
Country
Year Introduced
Bufezolac
Onbio Inc.
-
-
Raw Materials Maleic anhydride Isobutylamine Sodium nitrite Perchloric acid Sodium carbonate
Triethylamine Hydrochloric acid Acetic anhydride Diphenylacetylene
Manufacturing Process 50.0 g of maleic anhydride and 180 ml of methanol are heated for 1 h under reflux while stirring. The reaction mixture is cooled to room temperature and the excess methanol is evaporated under reduced pressure. 67.0 g of monomethyl maleate are obtained. The monomethyl maleate is then cooled to 0°C after which 90 ml of triethylamine and then 34.0 g of isobutylamine are introduced over a period of 1 h. The reaction mixture is heated under reflux for 1 h, then cooled to 50°C and 200 ml of acetone added; as a result of filtering off the crystals which separate there are obtained 73.7 g of methyl Nisobutyl-β-aspartate, melting point 250°C. Over a period of 10 min 860 ml of concentrated hydrochloric acid are added to a suspension of 340.0 g of methyl N-isobutyl-β-aspartate in 860 ml of water whilst stirring. The solution is cooled to 0°C and 128.0 g of sodium nitrite dissolved in 280 ml of water are introduced over a period of 1 h 20 min. The reaction mixture is stirred for 2 h at 0°C and extraction is then carried out thrice with a total of 3000 ml of diethyl ether. The organic phase is thrice washed with a total of 1500 ml of water, dried over magnesium sulfate and the ether evaporated under reduced pressure. The residue, when dissolved in a mixture of 1400 ml of petroleum ether and 230 ml of ether, gives, after cooling to 3°C, 325.0 g of methyl N-isobutyl-N-nitroso-β-aspartate, melting point 95°C.
712
Buflomedil
Over a period of 15 min and whilst stirring 158.0 g of methyl N-isobutyl-Nnitroso-β-aspartate are added to 340 ml of acetic anhydride and then, drop by drop, 0.95 ml of 70% perchloric acid. The reaction mixture is then stirred for 2 h at room temperature. The acetic anhydride is evaporated under reduced pressure, and the residue is then successively dissolved once in 100 ml of chloroform, thrice in 100 ml of benzene each time and twice in 100 ml of diethyl ether each time, the solvent being evaporated each time under reduced pressure. 155.0 g of red oil are obtained which are dissolved in 2 volumes of hot di-isopropyl ether and cooled. After 1 min at 3°C the crystals which separate are filtered and there are thus obtained 78.0 g of methyl 3isobutyl-4-sydnonyl acetate, melting point 39°C. 120.0 g of methyl 3-isobutyl-4-sydnonylacetate and 110.0 g of diphenylacetylene dissolved in 600 ml of xylene are heated under reflux whilst being stirred for 70 h. The solution is cooled to room temperature and the xylene is evaporated under reduced pressure. The residue is dissolved in a mixture of 800 ml of 1 N sodium carbonate and 800 ml of acetone. The resulting solution is heated under reflux for 4 h whilst stirring and is then cooled to room temperature and separated. The aqueous phase has 1000 ml of water added thereto and is then extracted thrice with a total of 900 ml of benzene. The aqueous phase is then made acid by the addition of 68 ml of concentrated hydrochloric acid. The oil which separates from the acidified mixture is extracted using a total of 1000 ml of chloroform in five extractions. The combined chloroform extracts are dried over magnesium sulfate and the chloroform is evaporated under reduced pressure. 78.0 g of a brown oil are obtained which are submitted to chromatography upon silica gel using a mixture of chloroform-methanol 99:1 parts. So the 1-isobutyl-3,4diphenylpyrazolyl-5-acetic acid, melting point 181°C (recrystallisation from acetonitrile) is obtained. References Gueremy C., Renault C.; GB Patent No. 1,387,306; March 12, 1975; Aassigned: SOCIETE GENERALE DE RECHERCHES ET D'APPLICATIONS SCIENTIFIQUES SOGERAS, a Franch Body Corporate of 10, Rue Clement Marot, 75008 Paris, France
BUFLOMEDIL Therapeutic Function: Vasodilator Chemical Name: 4-(1-Pyrrolidinyl)-1-(2,4,6-trimethoxyphenyl)-1-butanone Common Name: Chemical Abstracts Registry No.: 55837-25-7; 35543-24-9 (Hydrochloride salt)
Buflomedil
713
Structural Formula:
Trade Name
Manufacturer
Country
Year Introduced
Fonzylane
Lafon
France
1976
Loftyl
Abbott
Italy
1981
Bufedil
Abbott
W. Germany
1982
Loftyl
Abbott
Switz.
1983
Buflan
Pierrel
Italy
-
Irrodan
Biomedica Foscama
Italy
-
Raw Materials 4-Chlorobutyronitrile Pyrrolidine 1,3,5-Trimethoxybenzene Manufacturing Process Introduce 33.6 g (0.2 mol) of 1,3,5-trimethoxybenzene and 100 ml of chlorobenzene into a 500 ml three-neck flask with stirrer, hydrochloric acid bubbler and condenser. Stir to dissolve and add 27.7 g of 4pyrrolidinobutyronitrile (from 4-chlorobutyronitrile and pyrrolidine). Cool to about 15°-20°C and bubble hydrochloric acid gas in for 4 hours. Cool to about 5°C and add 200 cm3 of water. Stir. Decant the aqueous layer, wash again with 150 cm3 of water. Combine the aqueous layers, drive off the traces of chlorobenzene by distilling 150 cm3 of water, and heat under reflux for one hour. Cool and render alkaline by means of 60 ml of sodium hydroxide solution of 36° Baume. Extract twice with 100 ml of ether. Wash the ether with 100 ml of water. Dry the ether over sodium sulfate and slowly run in 50 ml of 5N hydrogen chloride solution in ether, at the boil. Cool in ice. Filter, wash with ether and dry in a vacuum oven. 33.6 g of crude product are obtained. Recrystallize from 200 ml of isopropanol in the presence of 3 SA carbon black. Filter. Wash and dry in a vacuum oven. 26.9 g of a white, crystalline water-soluble powder are obtained. Yield: 39.2%. Instantaneous melting point: 192°-193°C. References Merck Index 1443 Kleeman and Engel p.121 DOT 11 (9) 339 (1975) I.N. p. 161 Lafon, L: US Patent 3,895,030; July 15, 1975; assigned to Orsymonde
714
Buformin hydrochloride
BUFORMIN HYDROCHLORIDE Therapeutic Function: Antidiabetic Chemical Name: N-Butylimidodicarbonimidic diamide hydrochloride Common Name: Butyldiguanide Structural Formula:
Chemical Abstracts Registry No.: 692-13-7 (Base) Trade Name
Manufacturer
Country
Year Introduced
Silubin
Protochemie
Switz.
-
Sindiatil
Bayer
Italy
1979
Adebit
Chinoin
Hungary
-
Andere
Toyama
Japan
-
Biforon
Meiji
Japan
-
Bigunal
Nikken
Japan
-
Bufonamin
Kaken
Japan
-
Bulbonin
Sankyo
Japan
-
Dibetos
Kodama
Japan
-
Gliporai
Grossmann
Mexico
-
Insulamin
Iwaki
Japan
-
Panformin
Shionogi
Japan
-
Ziavetine
Teikoku Kagaku
Japan
-
Raw Materials n-Butylamine HCl Dicyandiamide Manufacturing Process 105.6 g of n-butylamine hydrochloride and 79.3 g of dicyandiamide were ground intimately and mixed. The mixture was heated by means of an oil bath, gradually with stirring, and after thirty minutes when the internal temperature had reached 150°C, an exothermic reaction ensued with internal pressure rising to 178°C. The reaction mixture was removed from the oil bath until the internal temperature had fallen to 150°C and then heating was resumed at 150°C for one hour. The cooled fusion mixture was dissolved in 3 liters of acetonitrile and on cooling n-butyl-biguanide hydrochloride
Bufuralol hydrochloride
715
precipitated. References Merck index 1445 OCDS Vol.1 p.221 (1977); 2, 21 (1980) I.N. p. 162 Shapiro, S.L.; US Patent 2,961,377; November 22, 1960; assigned to US Vitamin and Pharmaceutical Corp.
BUFURALOL HYDROCHLORIDE Therapeutic Function: Beta-adrenergic blocker Chemical Name: α-[[(1,1-Dimethylethyl)amino]methyl]-7-ethyl-2benzofuranmethanol hydrochloride Common Name: Bufuralol hydrochloride; Angium Structural Formula:
Chemical Abstracts Registry No.: 54340-62-4 (Base); 59652-29-8 Trade Name
Manufacturer
Country
Year Introduced
Bururalol hydrochloride
Onbio Inc.
-
-
Raw Materials Trimethyl-phenyl-ammonium perbromide 5-Bromo-2-acetyl-7-ethylbenzofuran 2-Propanamine, 2-methylPalladium on carbon
Sodium borohydride Hydrochloric acid Sodium hydroxide Hydrogen
Manufacturing Process 68.3 g (0.182 mol) of trimethyl-phenyl-ammonium perbromide were added in a single portion at 20°C to a stirred solution of 48.5 g (0.182 mol) of 5bromo-2-acetyl-7-ethylbenzofuran in 400 ml of dry tetrahydro-furan. The
716
Bumadizon
resulting mixture was stirred at 20°C for 3 h, during which time trimethylphenyl-ammonium bromide precipitated out. The mixture was then poured into water and extracted 3 times with ether. The combined ether extracts were washed successively with water, saturated sodium bicarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The solid residue was recrystallized from ethanol to yield 43.1 g of 5-bromo-2-bromoacetyl-7-ethylbenzofuran as yellow crystals, melting point 101-102°C. 1.35 g of sodium borohydride were added portion-wise at room temperature over a period of 20 min to a stirred solution of 17.3 g (0.05 mol) of 5-bromo2-bromoacetyl-7-ethylbenzofuran in 100 ml of dioxane and 25 ml of water. The mixture was stirred at room temperature for 3 h, then dioxane was removed by evaporation at 40°C under reduced pressure and the residue was diluted with water and extracted 3 times with ether. The combined ether extracts were worked up in the usual manner to yield 16.0 g of crude 5bromo-2-(2-bromo-1-hydroxyethyl)-7-ethyl-benzofuran as a viscous oil. 16.0 g of crude 5-bromo-2-(2-bromo-1-hydroxyethyl)-7-ethylbenzofuran and 37.0 g of t-butylamine were heated at 100°C in a sealed autoclave for 24 h. After cooling, excess t-butylamine was evaporated off and the residue was taken up in dilute aqueous hydrochloric acid. The aqueous solution was washed twice with ether, basified with dilute aqueous sodium hydroxide solution and extracted twice with ether. The combined ether extracts were washed with water and with brine, dried over anhydrous sodium sulfate, filtered and evaporated. The solid residue was crystallized from petroleum ether (boiling point 60-80°C) to yield 4.7 g of 5-bromo-2-(2-t-butylamino-1hydroxyethyl)-7-ethylbenzofuran as buff crystals, melting point 101-103°C. 4.8 g of 5-bromo-2-(2-t-butylamino-1-hydroxyethyl)-7-ethylbenzofuran in 50 ml of ethanol were hydrogenated at room temperature and atmospheric pressure in the presence of 0.3 g of 5% palladium-on-carbon catalyst. After the uptake of one equivalent of hydrogen, the hydrogenation was terminated, catalyst was filtered off and the filtrate was evaporated to dryness. The residue was basified and extracted twice with ether. The combined ether extracts were worked up in the usual manner to give 2-(2-t-butylamino-1hydroxyethyl)-7-ethylbenzofuran in the form of an oil. In practice it is usually used as hydrochloride. References Fothergill G.A. et al.; US Patent No. 3,929,836; December 30, 1975; Assigned: Hoffmann-La Roche Inc., Nutley, N.J.
BUMADIZON Therapeutic Function: Analgesic, Antipyretic, Antirheumatic Chemical Name: Butylpropanedioic acid mono-(1,2-diphenylhydrazide)
Bumadizon
717
Common Name: Butylmalonic acid diphenylhydrazide Structural Formula:
Chemical Abstracts Registry No.: 3583-64-0 Trade Name
Manufacturer
Country
Year Introduced
Eumotol
Byk Gulden
W. Germany
1972
Eumotol
Iromedica
Switz.
1972
Eumotol
Valpan
France
1976
Eumotol
Byk Gulden
Italy
1976
Dibilan
Byk Gulden
-
-
Rheumatol
Tosse
W. Germany
-
Raw Materials Dicyclohexylcarbodiimide n-Butylmalonic acid ethyl ester Hydrazobenzene Manufacturing Process (a) A solution of 22.4 grams of dicyclohexylcarbodiimide in 120 ml of absolute tetrahydrofuran is added dropwise at 5°-10°C in an atmosphere of nitrogen to a solution of 20 grams of n-butylmalonic acid monoethyl ester and 19.6 grams of freshly recrystallized hydrazobenzene in 320 ml of anhydrous tetrahydrofuran. The mixture is then stirred for 15 hr at 25°C in an atmosphere of nitrogen, then the precipitated dicyclohexyl urea is filtered off and the filtrate, after the addition of 3 drops of glacial acetic acid, is evaporated to dryness in vacuo. The residue is dissolved in 1 liter of ether, the ethereal solution is extracted twice with 2 N potassium bicarbonate solution and twice with 2 N hydrochloric acid, whereupon it is washed with water until the washing water is neutral. The ethereal solution is dried over sodium sulfate and concentrated in vacuo. The residue is fractionally distilled under high vacuum whereupon the ester is obtained as a yellow oil. BP 170°C at 0.05 torr vacuum. Crystals which melt at 63°-65°C are obtained from cyclohexane. (b) A suspension of 7.1 grams of the ester obtained according to (a) in 40 ml of aqueous 0.5 N sodium hydroxide solution is refluxed for 24 hours in an atmosphere of nitrogen. The solution is filtered and traces of hydrazobenzene are removed by extraction with ether. The aqueous solution is made acid to
718
Bumetanide
Congo paper at 10°C with concentrated hydrochloric acid, the oil which separates is dissolved in 40 ml of ethyl acetate, the ethyl acetate solution is isolated, and washed neutral with water. The solution is then extracted twice with 36 ml of 0.5 N sodium bicarbonate solution each time. The separate extracts are made acid to Congo paper with concentrated HCl, extracted with ethyl acetate, the extracts are washed neutral with a little water, dried and concentrated under vacuum. The colorless oil which remains is recrystallized twice from ether/petroleum ether, whereupon n-butylmalonic acid-N,N'-diphenylhydrazide is obtained in the form of short needles which melt at 116°-118°C. References Merck Index 1451 Kleeman and Engel p.121 DOT 9 (1) 14 (1973) I.N. p.162 Pfister, R., Sallmann, A. and Hammerschmidt, W.; US Patent 3,455,999; July 16,1969; assigned to Geigy Chemical Corporation
BUMETANIDE Therapeutic Function: Diuretic Chemical Name: 3-(Aminosulfonyl)-5-(butylamino)-4-phenoxybenzoic acid Common Name: Structural Formula:
Chemical Abstracts Registry No.: 28395-03-1 Raw Materials Sodium bicarbonate Hydrogen Phenol
4-Chloro-3-nitro-5-sulfamyl benzoic acid n-Butanol
Bumetanide
719
Trade Name
Manufacturer
Country
Year Introduced
Burinex
Leo
UK
1973
Fordiuran
Thomae
W. Germany
1976
Lunetoron
Sankyo
Japan
1976
Burinex
Sigma Tau
Italy
1977
Lixil
Leo
France
1978
Fontego
Polifarma
Italy
1979
Bumex
Hoffmann - La Roche Inc.
US
1983
Aquazone
Prodes
Spain
-
Butinat
Gerardo Ramon
Argentina
-
Cambiex
Bernabo
Argentina
-
Farmadiuril
Alter
Spain
-
Poliurene
Lepetit
-
-
Primex
Medica
Finland
-
Salurex
Byk Gulden
-
-
Salurin
Yurtoglu
Turkey
-
Segurex
Ricar
Argentina
-
Yurinex
Hemofarm
Yugoslavia
-
Manufacturing Process Preparation of 3-Nitro-4-Phenoxy-5-Sulfamylbenzoic Acid: A mixture of 4chloro-3-nitro-5-sulfamylbenzoic acid (140 grams), phenol (100 grams), sodium hydrogencarbonate (170 grams), and water (1.000 ml) was heated to 85°C while stirring and kept at this temperature for 16 hours. After cooling to 4°C, the precipitated sodium salt of 3-nitro-4-phenoxy-5-sulfamylbenzoic acid was filtered off and washed with ice water. The sodium salt was dissolved in boiling water (3,000 ml), and the 3-nitro-4-phenoxy-5-sulfamylbenzoic acid was precipitated by addition of 4N hydrochloric acid. After cooling, the acid was isolated by suction and dried. The melting point was 255°-256°C. Preparation of 3-Amino-4-Phenoxy-5-Sulfamylbenzoic Acid: A suspension of 3nitro-4-phenoxy-5-sulfamylbenzoic acid (20 grams) in water (100 ml) was adjusted to pH 8 by addition of 1N lithium hydroxide. The resulting solution was hydrogenated at room temperature and 1.1 atmospheres hydrogen pressure after addition of Pd on carbon catalyst (0.6 grams catalyst containing 10% Pd). After the hydrogen uptake had become negligible, the catalyst was removed by filtration, and the 3-amino-4-phenoxy-5-sulfamylbenzoic acid was precipitated from the filtrate by addition of 4N hydrochloric acid to pH 2.5. After recrystallization from aqueous ethanol and drying, the melting point was 255°-256°C. Preparation of 3-n-Butylamino-4-Phenoxy-5-Sulfamylbenzoic Acid: To a suspension of 3-amino-4-phenoxy-5-sulfamyibenzoic acid (10 grams) in nbutanol (200 ml), concentrated sulfuric acid (2 ml) was added while stirring. The reaction mixture was heated under reflux under conditions in which the water formed during the reaction could be removed. When, after dilution with
720
Bumetrizole
n-butanol, the NMR-spectrum of a sample of the reaction mixture showed at the two doublets of the aromatic protons in ring A that the butyl-3-amino-4phenoxy-5-sulfamylbenzoate formed as an intermediate was more than 90% converted to the corresponding 3-n-butylaminobenzoate, 2 N sodium hydroxide (200 ml) was added and the boiling was continued for 45 minutes. After the saponification, the reaction mixture was neutralized to pH 8 by addition of concentrated hydrochloric acid. By cooling, the sodium salt of 3-n-butylamino-4-phenoxy-5-sulfamylbenzoic acid precipitated. It was filtered off and recrystallized from water (100 ml). The sodium salt, crystallizing with 3 molecules of water, was then dissolved in boiling water (200 ml), 1N hydrochloric acid was added to pH 2.5, and after cooling the precipitated 3-n-butylamino-4-phenoxy-5-sulfamylbenzoic acid was collected by filtration. After recrystallization from aqueous ethanol and drying, the pure compounds were obtained with melting point 230°-231°C. References Merck Index 1452 Kleeman and Engel p.121 PDR p.1479 OCDS Vol.2 p.87 (1980) DOT 8 (6) 238 (1972) and 9 (11) 449 (1973) I.N. p.162 Felt, P.W.; US Patent 3,634,583; January 11, 1972; assigned to Lovens Kemiske Fabrik Produktionsaktieselskab. Denmark
BUMETRIZOLE Therapeutic Function: Sunscreen agent Chemical Name: Phenol, 2-(5-chloro-2H-benzotriazol-2-yl)-6-(1,1dimethylethyl)-4-methylCommon Name: Bumetrizole Structural Formula:
Chemical Abstracts Registry No.: 3896-11-5 Trade Name
Manufacturer
Country
Year Introduced
Bumetrizole
Onbio Inc.
-
-
Bunaftine
721
Raw Materials 2'-Hydroxy-3'-t-butyl-5'-methyl-5-chloro-2-nitroazobenzene Sodium hydroxide Zinc Hydrochloric acid Manufacturing Process To a 2000 ml 3-necked, round-bottomed flask equipped with an agitator, reflux condenser, nitrogen inlet and thermometer were charged 140.5 g of 2'hydroxy-3'-t-butyl-5'-methyl-5-chloro-2-nitroazobenzene, 119 g of isopropanol and 80 g of Amsco mineral spirits. A stream of nitrogen was introduced over the surface of the contents of the flask and the nitrogen atmosphere was then maintained throughout the remainder of the reduction process. 13.7 g of 50% aqueous sodium hydroxide solution and 222 g of water were added and the temperature of the contents of the flask were adjusted to 55°C. The ratio of the moles of alkali to moles of o-nitroazobenzene intermediate used was is 0.848/1. 104 g of zinc dust was added in 5 portions over a 2 hours period with the temperature of the flask being held at 55-60°C with some slight external cooling. The total concentration of iron impurities from all reactants less than 150 ppm based on zinc used. After all the zinc was added, the temperature was raised to 60°C and held at this temperature until a spot test indicated no more o-nitroazobenzene intermediate was present. The temperature was then raised to 65°C and held there for 4 to 5 hours or until TLC analysis indicated that no more of the N-oxy-intermediate was present. 62.6 g of anhydrous sodium sulfate and 35.6 g of water were then added, the batch was heated to 70°C and stirred for 15 min. The material was then allowed to stand and separate into three liquid phases plus unreacted zinc dust. The top two layers containing the desired product were transferred to another flask. The remaining aqueous zinc slurry was washed at 65-70°C with three successive 16 g portions of Amsco mineral spirits: isopropanol 50:50. The combined product layers and wash liquids were then washed once at 70°C with an aqueous hydrochloric acid solution made from 130 g of water and 40 g of 32% hydrochloric acid to remove cleavage amine by-products. A second and third wash followed at 70°C with aqueous hydrochloric acid solutions made each from 65 g of water and 20 g of 32% hydrochloric acid. The last wash was essentially colorless. 14 g of 32% hydrochloric acid and 220 g of isopropanol were added to the solution of the product. The batch was allowed to crystallize slowly. The solid product form was filtered and washed with isopropanol at 0°C to give 110 g of 5-chloro-2-(2-hydroxy-3-t-butyl-5methylphenyl)-2H-benzotriazole with a melting point of 140-141°C. References White Howard L.; US Patent No. 4,041,044; August 9, 1977; Assigned to Ciba-Geig Corporation (Ardsley, NY)
BUNAFTINE Therapeutic Function: Antiarrhythmic
722
Bunaprolast
Chemical Name: N-Butyl-N-[2-(diethylamino)ethyl]-1-naphthalenecarboxamide Common Name: Bunaftine; Bunaphtide; Meregon Structural Formula:
Chemical Abstracts Registry No.: 32421-46-8 Trade Name
Manufacturer
Country
Year Introduced
Bunaftine
Malesci
-
-
Raw Materials 1-Naphthoic acid chloride N,N-2-Diethylamine-ethyl-N'(n-butyl)amine
Hydrochloric acid Potassium carbonate
Manufacturing Process Into a solution containing α-naphthoic acid chloride in benzene with agitation and cooling for 0.5 h a benzene solution of N,N-diethylamine-ethyl-N'-(nbutyl)amine is dropped. As the dropping is ended, the solution is kept under agitation in a water bath for 3 h. After cooling the benzene solution is extracted with 10% hydrochloric acid; then the aqueous solution is saturated with potassium carbonate. The separated oil is extracted with ether and, after drying on sodium sulfate, the solvent is removed and the residue is vacuum distilled. So the N-(2diethylamino-ethyl)-N-(n-butyl)-1-naphthalenecarboxamide, boiling point 178°C/0.1 mm/Hg. References Giannini M.; US Patent No. 3,704,322; November 28, 1972; Assigned: Malesci S.A.S. Istituto Farmacobiologico, Florence, Italy
BUNAPROLAST Therapeutic Function: Anti-asthmatic Chemical Name: 1-Naphthalenol, 2-butyl-4-methoxy-, acetate
Bunaprolast
723
Common Name: Bunaprolast Structural Formula:
Chemical Abstracts Registry No.: 99107-52-5 Trade Name
Manufacturer
Country
Year Introduced
Bunaprolast
ZYF Pharm Chemical
-
-
Raw Materials Chromium hexacarbonyl Phenyl lithium Acetic anhydride Triethylamine
Trimethyloxonium tetrafluoroborate(1-) 1-Hexyne Acetylene
Manufacturing Process Preparation of pentacarbonyl[phenyl(methoxy)carbene]chromium: To a suspension of 22 g (0.1 mole) of chromium hexacarbonyl in ether is slowly added phenyllithium (51 ml, 0.1 mole, cyclohexane/ether solution) via syringe over a period of 15-20 minutes under argon at room temperature, and the resulting deep red solution is stirred at room temperature for 1 hour. The solvent is removed under reduced pressure (bath temperature should be below 40°C), and the black residue is dissolved in 200 ml water. (CH3)3O·BF4 (about 15 g) is added portionwise to the solution until it becomes slightly acidic (pH 5.5). The aqueous layer is extracted three times with 200 ml of ether, and the combined etheral extracts are washed once with 300 ml of saturated brine solution, once with 300 ml of saturated sodium carbonate solution, and three times with 300 ml of saturated brine solution, dried over anhydrous sodium sulfate and filtered. The solvent is removed using a rotary evaporator. The deep red tarry residue is purified using flash chromatography by a silica gel column (200 g). Elution by 10% ether in n-hexane gives a deep red syrup, which is solidified upon cooling. Recrystallization from pet-ether at -70°C gives 25.12 g (80.5%) of pentacarbonyl[phenyl(methoxy)carbene] chromium as deep red crystalline. The physical properties of the product are consistent with those described in the literature. 2-Butyl-4-methoxy-1-naphthalenol, acetate:
724
Bunazosin hydrochloride
Reaction of pentacarbonyl[phenyl(methoxy)carbene ]chromium with 1hexyne: Part A. A mixture of the carbene complex (1.0 g, 3.2 mmole), 1-hexyne (2.6 equivalents), acetic anhydride (1.0 eq.) and triethylamine (1.0 eq.) in tetrahydrofuran (90 ml) is heated at 65°C under an argon atmosphere for 1 hour. The solution is cooled and concentrated to give a black residue, which is chromatographed through a silica gel (200 g) column using a flash chromatography. Elution by10% ether in n-hexane gives 71 5 mg (82.2%) of the title product, which solidified. Recrystallization from pet-ether gave white crystals of 2-butyl-4-methoxy-1-naphthalenol acetate; MP: 49°C. Part B. Alternatively, a mixture of 2.0 g (6.4 mmole) of the carbene complex, acetylene (2.6 eq.) and acetic acid in tetrahydrofuran is heated at 65°C for 2 hours under argon atmosphere. After cooling the reaction solution is concentrated and the black residue is loaded on a silica gel (200 g) column for a flash chromatography. Elution by 10% ether in n-hexane gives 895 mg (51.4%) of the title product. References Yamashita A.; European Patent No. 0,146,348; December 13, 1984; The Upjohn Company, Michigan, USA
BUNAZOSIN HYDROCHLORIDE Therapeutic Function: Antihypertensive Chemical Name: 1-(4-Amino-6,7-dimethoxy-2-quinazolinyl)hexahydro-4-(1oxobutyl)-1H-1,4-diazepine monohydrochloride Common Name: Bunazosin hydrochloride; Andante; Bunatenon Structural Formula:
Bunitrolol
725
Chemical Abstracts Registry No.: 52712-76-2 Trade Name
Manufacturer
Country
Year Introduced
Andante
Boehringer-Ingelh.
-
-
Bunazosin hydrochloride
Eisai
-
-
Raw Materials 2-Chloro-4-amino-6,7-dimethoxyquinazoline N-Formylhomopiperazine 2-Butylcarboxylic acid chloride Manufacturing Process 17.0 g of 2-chloro-4-amino-6,7-dimethoxyquinazoline and 18.2 g of Nformylhomopiperazine are added to 170 ml of butanol and the whole is refluxed with stirring for 3 h. After completion of the reaction, the mixture is cooled, and the crystals thus precipitated are filtered out, washed with a small quantity of ethanol and air-dried. 25.0 g of crude 2-homopiperazino-4-amino6,7-dimethoxyquinazoline are obtained. A solution of 2-homopiperazino-4-amino-6,7-dimethoxyquinazoline in 60 ml of acetone is added dropwise to a solution of 2-butylcarboxylic acid chloride in acetone under stirring and ice-cooling. After completion of the addition, the stirring is continued for additional 1 h to complete the reaction. The crystals thus precipitated are filtered out and the 1-(4-amino-6,7-dimethoxy-2quinazolinyl)hexahydro-4-(1-oxobutyl)-1H-1,4-diazepine, melting point 280282°C (recrystallized from a mixture of methanol-ethanol) is obtained. References Takahashy T., Sugimoto H.; US Patent No. 3,920,636; November 18, 1975; Assigned: Eisai Co., Ltd., Tokyo, Japan
BUNITROLOL Therapeutic Function: Antianginal Chemical Name: 2-[3-[(1,1-Dimethylethyl)amino]-2-hydroxypropoxy]benzonitrile Common Name: Chemical Abstracts Registry No.: 34915-68-9
726
Bunitrolol
Structural Formula:
Trade Name
Manufacturer
Country
Year Introduced
St resson
Boehringer Ingelheim
W. Germany
1976
Betriol
Boehringer Ingelheim
Italy
1981
Betrilol
Boehringer Ingelheim
Japan
1983
Betrilol
TANABE SEIYAKU
Japan
1983
Raw Materials Epichlorohydrin 2-Cyanophenol t-Butylamine Manufacturing Process Epichlorohydrin and 2-cyanophenol are first reacted to give 1-(2cyanophenoxy)-2,3-epoxypropane. 15 g (0.085 mol) of 1-(2-cyanophenoxy)-2,3-epoxy propane were dissolved in 100 ml of ethanol and 18.6 g (0.255 mol) of t-butylamine were added thereto. After standing for 1 hour at room temperature, the solution was heated at 60°-70°C for 2 hours after which the volatile constituents were distilled off in vacuo. The residue was digested with dilute HCl, and the insoluble constituents were vacuum filtered off. Then the filtrate was made alkaline with NaOH and the precipitating base was taken up in ether. After the ether solution had been dried over MgSO4, the ether was distilled off and the residue was dissolved in ethanol and by addition of ethereal HCl, the hydrochloride was precipitated there from in crystalline form which after recrystallization from ethanol with an addition of ether gave9.8 g of 1-(2cyanophenoxy)-2-hydroxy-3-t-butylamino propane hydrochloride having a melting point of 163°-165°C. References Merck Index 1457 DFU 1 (5) 210 (1976) Kleeman and Engel p.123 OCDS Vol. 2 pp.106, 110 (1980) DOT 13 (1) 15 (1977) I.N. p.163 Koppe, H., Engelhardt, A. and Zelle, K.; US Patents 3,541,130; November 17, 1970; 3,940,489; February 24, 1976; and 3,961,071 ; June 1, 1976; all assigned to Boehringer Ingelheim GmbH
Buphenine hydrochloride
727
BUPHENINE HYDROCHLORIDE Therapeutic Function: Vasodilator Chemical Name: 4-Hydroxy-α-[1-[(1-methyl-3-phenylpropyl)amino]ethyl] benzenemethanol hydrochloride Common Name: Buphenine hydrochloride; Nylidrine hydrochloride Structural Formula:
Chemical Abstracts Registry No.: 849-55-8 Trade Name
Manufacturer
Country
Year Introduced
Buphenine hydrochloride
Troponwerke
-
-
Opino
Bayropharm
-
-
Pervadil
Empire
-
-
Verina
Daiichi
-
-
Raw Materials 1-Phenyl-3-aminobutane Hydrogen Acetic acid
p-Benzoxy-α-bromopropiophenone Palladium hydroxide on barium sulfate
Manufacturing Process The p-benzoxy-α-bromopropiophenone and 1-phenyl-3-amino-butane were heating for an hour on the water bath in the absence of solvents. A solid crystalline cake was obtained. After being extracted with boiling acetic acid, the hydrobromide of 1-(p-hydroxyphenyl)-2-(β-phenylbutylamino)propanone-1 was obtained. The hydrobromide of 1-(p-hydroxyphenyl)-2-(β-phenylbutylamino)propanone1 was suspended in very pure methanol and shaken with a 10% palladium hydroxide barium sulfate catalyst in contact with, hydrogen. After rather more than 2 mols of hydrogen had been taken-up the hydrogenation stopped. The 1-(p-hydroxyphenyl)-2-(3-phenylbutylamino)propanol-1, was filtered, washed with methanol and evaporated, melting point 110-111°C.
728
Bupicomide
References Kulz F. et al.; US Patent No. 2,661,373; December 1, 1953; Assigned: Fritz Kulz, and Clemens Schopf, Darmstadt, Germany
BUPICOMIDE Therapeutic Function: Antihypertensive Chemical Name: 5-Butyl-2-pyridinecarboxamide Common Name: Bupicomide Structural Formula:
Chemical Abstracts Registry No.: 22632-06-0 Trade Name
Manufacturer
Country
Year Introduced
Bupicomide
ZYF Pharm Chemical
-
-
Raw Materials Methyl vinylketone Hydroxylamine Thionyl chloride Potassium carbonate
Acetic acid Selenium dioxide Ammonia
Manufacturing Process 3-n-Butyl-6-methyl-3,4-dihydro-1,2-pyran was obtained and isolated from the reaction mixture by fractional distillation in vacuum to separate a by-product formed by cyclodimerisation of methyl vinylketone. The yield of the3-n-butyl6-methyl-3,4-dihydro-1,2-pyran was 47% (boiling point 106-107°C. The saponification of the 3-n-butyl-6-methyl-3,4-dihydro-1,2-pyran was accomplished by heating for 0.5 h in a mixture with acetic acid. The 1-methyl4-n-butyl-1,5-dicarbonyl acid formed not isolated from the reaction mixture was added to hydroxylamine. The reaction with hydroxylamine was carried out by gradual addition of acetic acid solution of 1,5-dicarbonyl compound to the stirring refluxing suspension of hydroxylamine in glacial acetic acid. By usual treatment was fractionned in vacuum to yield 37.5% of 2-methyl-5-nbutylpyridine, boiling point 105°C.
Bupivacaine
729
The 2-methyl-5-n-butylpyridine was oxidated by selenium dioxide in pyridine to 5-n-butyl-2-pyridine carboxylic (fusarinic) acid, melting point 100-101°C. 25.0 g of the 5-n-butyl-2-pyridine carboxylic (fusarinic) acid and 25 ml of thionyl chloride were mixed; after all of the acid is dissolved, concentrate (in vacuo) the mixture and take up the mixture in 500 ml of anhydrous benzene; with cooling add the mixture to a solution of excess ammonia in 1 l of benzene, concentrate (in vacuo) the resulting mixture; add water and potassium carbonate and extract the amide with ether; dry and concentrate the ether extract and 5-n-butyl-2-pyridine carboxamide was obtained (recrystallize from acetonitrile). References Symchowicz S., Sherlock M.H.; US Patent No. 3,519,717; July 7, 1970; Assigned: Schering Corporation, Bloomfield, N.J.., a corporation of a New Jersey Chumakov Yu.I., Sherstyuk V.P.; Tetrahedron Letters N 2, pp.129-135, 1965
BUPIVACAINE Therapeutic Function: Local anesthetic Chemical Name: dl-1-Butyl-2',6'-pipecoloxylidide Common Name: Structural Formula:
Chemical Abstracts Registry No.: 2180-92-9; 18010-40-7 (Hydrochloride salt) Raw Materials 2,6-Dimethylaniline Formic acid Zinc
Nitrosyl chloride Diethyl malonate n-Butyl bromide
730
Bupivacaine
Trade Name
Manufacturer
Country
Year Introduced
Carbostesin
Astra
W. Germany
1967
Carbostesin
Giobopharm
Switz.
1967
Marcain
Duncan Flockhart
UK
1968
Marcain
Yoshitomi
Japan
1969
Marcaina
Pierrel
Italy
1971
Marcaine
Winthrop-Breon
US
1973
Marcaine
Cook-Waite
US
-
Sensorcaine
Astra
US
1981
Bupivan
Abbott
US
-
Meaverin
Woelm Pharma
W. Germany
-
Manufacturing Process 121 parts by weight of 2.6-xylidine are heated with 400 parts of diethylmalonate at 160°C for 1 hour, and the alcohol formed by the reaction is allowed to distill off. Thereafter the reaction mass is cooled to 80°C, and 500 parts of alcohol are added. After cooling the dixylidide is sucked off, and the alcohol solution with malonic ester monoxylidide is poured into 2,000 parts of water. The monoxylidide precipitates, is filtered off and washed with water, and recrystallized in diluted alcohol. Nitrosation thereafter takes place by dissolving the dried monoxylidide in chloroform and by introducing nitrosyl chloride at 0°C until the nitrosation is completed. The isonitrosomalonic ester xylidide is filtered off and dried. Thereafter the reduction takes place with zinc powder and formic acid at 90°-100°C. The formic acid is distilled off, and the remainder dissolved in warm benzene and washed with a bicarbonate solution to a neutral reaction. After the benzene has been distilled off, the aminomalonic ester xylidide is obtained. This is treated with an equal quantity of sodium ethylate and boiled with twice the theoretical quantity of tetramethylene bromide in absolute alcohol. After 6 hours of boiling, the sodium bromide formed is separated, and the mixture is steamdistilled in order to remove the excess of tetramethylene bromide. The remaining oil, which mainly consists of deltabromobutylaminomalonic ester xylidide is separated from the water and boiled with 3 parts of concentrated hydrochloric acid for 3 hours. Thereafter carbonfiltering and evaporation to dryness under vacuum takes place. The residue is dissolved in water, and the pH adjusted with sodium hydroxide to 5.5. The solution is extracted twice with ether, and the water is made strongly alkaline with sodium hydroxide. The oil precipitates and is crystallized after a time. The crystals are separated and dried under vacuum. The pipecolyl-2,6-xylidide produced is alkylated by boiling for 10-20 hours with 0.6 part n-butylbromide in an n-butanol solution in the presence of 0.5 part potassium carbonate. The potassium carbonate is filtered off and the butanol is distilled off in vacuum. The residue is dissolved in diluted hydrochloric acid and carbon treated, after which the base is precipitated with sodium hydroxide in the form of white crystals, which are filtered off and washed with water. The base obtained, which consists of N-n-
Bupranolol
731
butyl-pipecolyl-2,6-xylidide is sufficiently pure for the production of salts. References Merck Index 1462 Kleeman and Engel p.124 PDR pp.596, 825, 1915 OCDS Vol.1 p.17 (1977) DOT 3 (3) 88 (1967) I.N. p.164 REM p.1050 Thuresson, B. and Egner, B.P.H.; US Patent 2,792,399; May 14, 1957; assigned to AB Bofors, Sweden Thuresson, B. and Pettersson, B.G.; US Patent 2,955,111; October 4, 1960; assigned to AB Bofors, Sweden
BUPRANOLOL Therapeutic Function: Antiarrhythmic Chemical Name: 1-(tert-Butylamino)-3-[(6-chloro-m-tolyl)oxy]-2-propanol Common Name: Bupranol Structural Formula:
Chemical Abstracts Registry No.: 14556-46-8; 15146-80-8 (Hydrochloride salt) Trade Name
Manufacturer
Country
Year Introduced
Betadrenol
Pharma-Schwarz
W. Germany
1969
Betadrenol
Adrosanol
Switz.
1969
Betadran
Logeais
France
1972
Looser (Lucer)
Kaken
Japan
1974
Panimit
Nattermann
W. Germany
-
Ophtorenin
Dr. Winzer
W. Germany
-
Raw Materials Epichlorohydrin 2-Chloro-5-methylphenol t-Butylamine
732
Bupropion hydrochloride
Manufacturing Process A mixture of 16.3 g of (2-chloro-5-methylphenyl)glycidic ether (from epichlorohydrin and 2-chloro-5-methylphenol) and 6.2 g of t-butylamine in 50 ml of ethanol is heated at reflux for 6 hours. The solvent is removed, the residue is washed with water and then extracted with benzene. The dried extract is evaporated to give 1-t-butylamino-3-(2-chloro-5-methylphenoxy)-2propanol. Treatment of the free base in benzene solution with dry hydrogen chloride yields the hydrochloride salt. References Merck Index 1463 Kleeman and Engel p.125 I.N. p.164 Kunz, W., Jacobi, H., Koch, C. and Geus, R.J.; US Patent 3,309,406; March 14, 1967
BUPROPION HYDROCHLORIDE Therapeutic Function: Antidepressant; Smoking cessation aid Chemical Name: 1-Propanone, 1-(3-chlorophenyl)-2-((1,1-dimethylethyl) amino)-, (+/-)-, hydrochloride Common Name: Amfebutamone hydrochloride; Bupropion hydrochloride Structural Formula:
Chemical Abstracts Registry No.: 34911-55-2 (Base); 31677-93-7 Trade Name
Manufacturer
Country
Year Introduced
Bupropion hydrochloride
AroKor Holdings Inc.
-
-
Wellbutrin
Glaxo-Wellcome
-
-
Zyban
Glaxo-Wellcome
-
-
Bupropion hydrochloride
Shanghai BR Chemical Co., Ltd.
-
Bupropion hydrochloride
733
Raw Materials Ethyl magnesium bromide Hydrochloric acid t-Butylamine
m-Chlorobenzonitrile Bromine Sodium hydroxide
Manufacturing Process To ethyl magnesium bromide (2 L, 3 M) was added over 45 min with stirring and cooling m-chlorobenzonitrile (688.0 g, 5 mole) in ether (2.5 L). The resultant solution was heated under gentle reflux for 5 h. The reaction mixture was hydrolyzed with cold dilute hydrochloric acid, the ether was distilled off, and the aqueous solution was heated at 90°C for 1 h. The flask was then cooled. The solid ketone that separated was washed with cold water and recrystallized from methanol. The recrystallized m-chloropropiophenone, melting point 39°-40°C, weighed 750.0 g. In methylene chloride (3 L) was dissolved m-chloropropiophenone (698.0 g; 4.15 mole). The solution was stirred with charcoal (Darco) and magnesium sulfate for 2 h and filtered. To it was added with stirring (662.0 g) of bromine in methylene chloride (1 L). When the bromine color had faded completely, the solvent was evaporated in vacuum and m-chloro-α-bromopropiophenone was obtained as oil. The m-chloro-α-bromopropiophenone was dissolved in acetonitrile (1300 ml). To this, t-butylamine (733.0 g) in acetonitrile (1300 ml) was added while keeping the temperature below 32°C. The reaction mixture was allowed to stand over night. It was then partitioned between water (4200 ml) and ether (2700 ml). The aqueous layer was extracted with a further portion of ether (1300 ml). The combined ethereal layers were then washed with water (4200 ml) to which hydrochloric acid was added until the pH of the aqueous layer was 9. The aqueous layer was separated and washed with ether (500 ml) and then discarded. The combined ethereal layers were then stirred with ice (560.0 g) and concentrated hydrochloric acid (324 ml). The ethereal layer was separated and again washed with water (200 ml) and concentrated hydrochloric acid (50 ml). These last two acid layers were combined and concentrated in vacuum until crystals appeared. The solution was then chilled to 5°C and filtered. The product was sucked dry, washed with acetone and recrystallized from a mixture of isopropanol (3 L) and absolute ethanol (800 ml). The DL-m-chloro-α-t-butylaminopropiophenone hydrochloride so was obtained, melting point 233°-234°C. The DL-m-chloro-α-t-butylaminopropiophenone was obtained by treatment of DL-m-chloro-α-t-butylaminopropiophenone hydrochloride with sodium hydroxide. References Nariman B.M.; US Patent No. 3,819,706; June 25, 1974; Assigned: Burroughs Wellcome Co., Research Triangle Park, N.C.
734
Buquineran
BUQUINERAN Therapeutic Function: Coronary vasodilator Chemical Name: N-Butyl-N'-[1-(6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl] urea Common Name: Buquineran; BDPU Structural Formula:
Chemical Abstracts Registry No.: 59184-78-0 Trade Name
Manufacturer
Country
Year Introduced
Buquineran
Pfizer Central Research
-
-
Raw Materials Triethylamine 4-Chloro-6,7-dimethoxyquinazoline Sodium hydroxide 4-(3-n-Butylureido)piperidine hydrochloride Manufacturing Process 4-Chloro-6,7-dimethoxyquinazoline (45.0 g), 4-(3-n-butylureido)piperidine monhydrochloride (80.0 g) and triethylamine (140 ml) were refluxed in ethanol (450 ml) for 1.25 h. The mixture was then concentrated in vacuo and the resultant solid was stirred in water which was then basified to pH 11 with 5 N NaOH solution. The suspension was shaken with chloroform and the organic layer was separated, dried (Na2CO3) and evaporated to dryness in vacuo to give a yellow oily solid. Trituration with ether followed by recrystallization from ethanol gave the product (37.0 g) with small traces of impurities, wich were removed by running a chloroform solution of it down a glass column packed with "Florisil" and eluting with 10% isopropanol in chloroform. After evaporation, appropriate fractions were bulked to give a pure 4-(4-[3-nbutylureido]piperidino)-6,7-dimethoxyquinazoline, melting point 204-205°C (21.0 g; recrystallized from ethanol).
Buquiterine
735
References Danilewicz J.C. et al.; US Patent No. 4,001,422; January 4, 1977; Assigned: Pfizer Inc., New York, N.Y.
BUQUITERINE Therapeutic Function: Bronchodilator Chemical Name: 2-[(1,1-Dimethylethyl)amino]-6,7-dihydro-9,10-dimethoxy4H-pyrimido[6,1-a]isoquinolin-4-one Common Name: Buquiterine Structural Formula:
Chemical Abstracts Registry No.: 76536-74-8 Trade Name
Manufacturer
Country
Year Introduced
Buquiterine
ZYF Pharm Chemical
-
-
Raw Materials Sodium hydroxide t-Butylamine 9,10-Dimethoxy-2-chloro-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-4one Manufacturing Process A solution of 9,10-dimethoxy-2-chloro-6,7-dihydro-4H-pyrimido[6,1a]isoquinolin-4-one (3.0 g) and t-butylamine (10 ml) in chloroform (75 ml) is heated under reflux for 16 h. The solvent is evaporated under reduced pressure and the residue triturated with a dilute solution of sodium hydroxide to give a white precipitate of 9,10-dimethoxy-2-t-butylamino-6,7-dihydro-4Hpyrimido[6,1-a]isoquinolin-4-one. References Lal B., et al.; US Patent No. 4,482,556; November 13, 1984; Assigned: Hoechst Aktiengesellschaft, Frankfurt am Main, Fed. Rep. of Germany
736
Buspirone hydrochloride
BURAMATE Therapeutic Function: Anticonvulsant, Tranquilizer Chemical Name: (Phenylmethyl)carbamic acid 2-hydroxyethyl ester Common Name: Buramate; Hyamate Structural Formula:
Chemical Abstracts Registry No.: 4663-83-6 Trade Name
Manufacturer
Country
Year Introduced
Buramate
Chauny and Cirey
-
-
Raw Materials Cyclic carbonate of glycol Benzylamine Manufacturing Process Into a vessel provided with efficient stirring means there are gradually introduced, while maintaining the temperature at 40°C, 535.0 g of benzylamine and 440.0 g of cyclic carbonate of glycol. The mass obtained is maintained at a temperature 40-50°C for about 12 h. Upon cooling, there is obtained a glycol benzylcarbamate as a white crystalline, melting point at 40°C, yield 92%. References GB Patent No. 689,705; April 1, 1953; Assigned: Societe Anonyme des Manufactures des Glaces et Produits Chimiques de Saint-Gobain, Chauny et Cirey, a Company organized under the laws of the French Republic, of 1 bis Place des saussaies, Paris VIIIe, Franc
BUSPIRONE HYDROCHLORIDE Therapeutic Function: Anxiolytic Chemical Name: 8-Azaspiro[4.5]decane-7,9-dione, 8-(4-(4-(2-pyrimidinyl)1-piperazinyl)butyl), monohydrochloride
Buspirone hydrochloride
737
Common Name: Buspirone hydrochloride Structural Formula:
Chemical Abstracts Registry No.: 33386-08-2 Trade Name Ansial Anxiolan Bespar Buspar Buspirone hydrochloride
Manufacturer Bristol-Myers Squibb Medochemie Ltd. Bristol-Myers Squibb Bristol-Myers Squibb Alexis Biochemicals
Country -
Year Introduced -
Busirone
Bristol-Myers Squibb
-
-
Raw Materials 3-Chloropropionitrile Cyclohexane Nickel Raney
3,3-Tetramethyleneglutaric anhydride 1-(2-Pyrimidinyl)piperazine Hydrazine hydrate
Manufacturing Process There is the 3 methods for preparing of 8-azaspiro(4.5)decane-7,9-dione, 8(4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl) monohydrochloride (U.S. Patent 3,717,634). One of them is follows: a mixture of 0.1 mole of the substituted glutaric anhydride, 0.1 mole of l-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine (U.S. Pat. 3,398151), and 300 ml of pyridine was refluxed until imide formation was completed. The degree of reaction was readily followed by taking an aliquot portion of the reaction mixture, removing the solvent, and obtaining the infrared absorption spectrum of the residue. When reaction is complete, the spectrum exhibited typical infrared imide bands at 1701 and 1710 cm-1 whereas if incomplete, the infrared spectrum contains amide and carboxyl absorption bands at 1680, 1760 and 3300 cm-1. 1-(3-Cyanopropyl)-4-(2-pyrimidinyl)-piperazine. A mixture of 1-(2pyrimidinyl)piperazine (6.0 g, 0.04 mole), 4.6 g (0.044 mole) of 3chloropropionitrile and sodium carbonate (4.24 g, 0.04 mole) in 50 ml of nbutanol was gently refluxed for 16 hours. The reaction mixture was concentrated in vacuo and the residual oil dissolved in about 100 ml of cyclohexane. On standing a white crystalline material separated which was crystallized from cyclohexane to provide 6.5 g (yield 70%) of the cyano
738
Busulfan
intermediate, m.p. 56.6-58°C. A solution of 11.5 g (0.05 mole) of 1-(3cyanopropyl)-4-(2-pyrimidinyl)piperazine in 150 ml of absolute ethanol was saturated with ammonia. W-6 Raney nickel catalyst was added and the mixture hydrogenated under 1200 p.s.i. When the hydrogenation was completed the mixture was filtered and the residual oil distilled under reduced pressure to provide 8.2 g (70% ) of 1-(4-aminobutyl)-4-(2pyrimidinyl)piperazine, b.p. 143-146°C at 0.1 mm. (nD26 = 1.5582). The azospiroalkenedione 8-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-8azaspiro[4.5]decane-7,9-dione was purified as free base by stripping off the pyridine solvent and crystallizing the residue from a suitable solvent or by vacuum distillation thereof hydrochloric salt of it was prepared by treating of an ethanol solution of free base with equimolar amount of HCl. References Yao Hua Wu et al.; US Patent No. 3,717,634; Feb. 20, 1973; Assigned: Mead Johnson and Company (Evansville, IN) Yao Hua Wu et al.; US Patent No. 3,976,776; Aug. 24, 1976; Assigned: Mead Johnson and Company (Evansville, IN)
BUSULFAN Therapeutic Function: Antineoplastic Chemical Name: 1,4-Butanediol dimethanesulfonate Common Name: Structural Formula:
Chemical Abstracts Registry No.: 55-98-1 Trade Name
Manufacturer
Country
Year Introduced
Myleran
US
1954
Misulban
BurroughsWellcome Techni-Pharma
France
1955
Myleran
Wellcome
Switz.
1955
Myleran
Wellcome
W. Germany
1955
Mablin
Takeda
Japan
-
Mielucin
Farmasimes
Spain
-
Myeleukon
Arzneimittelwerk Dresden Spofa
E. Germany
-
Czechoslovakia
-
Mylecytan
Butabarbital sodium
739
Raw Materials 1,4-Butanediol Methanesulfonyl chloride Manufacturing Process 3.6 grams of redistilled 1,4-butanediol were dissolved in 10 ml of pyridine and the solution was cooled in ice and water. 9.6 grams of redistilled methanesulfonyl-chloride were added dropwise at such a rate that the temperature did not rise above 20°C. The solution was then allowed to stand at room temperature to; 30 minutes, during which time the temperature rose to 60°C. A thick precipitate of pyridine hydrochloride was formed. The mass was cooled in ice water and was treated with 30 ml of ice cold water. On agitation, a white crystalline precipitate was formed. This was filtered off and washed well with ice cold water and allowed to drain on the pump. It weighed 7.8 grams and had a melting point of 100°C. 3.5 grams of the material were recrystallized from acetone and ether to give small white needles, having a melting point of 106°-107°C, unchanged by further recrystallization. References Merck Index 1470 Kleeman and Engel p.125 PDR p.754 I.N. p.165 REM p.1144 Timmis, G.M.; US Patent 2,917,432; December 15, 1959; assigned to Burroughs Wellcome and Co., Inc.
BUTABARBITAL SODIUM Therapeutic Function: Hypnotic Chemical Name: Barbituric acid, 5-sec-butyl-5-ethyl-, sodium salt Common Name: Butabarbital sodium; Butabarbitone sodium; Secbutabarbital sodium; Secbutobarbitone sodium Structural Formula:
Chemical Abstracts Registry No.: 143-81-7
740
Butacaine
Trade Name Butisol sodium Butisol sodium
Manufacturer Wallace Labs Acura Pharmaceuticals, Inc.
Country USA -
Year Introduced -
Raw Materials Diethyl ester of malonic acid Sodium ethylate Urea
Ethyl bromide 2-Butyl bromide
Manufacturing Process 5-sec-Butyl-5-ethylbarbituric acid was prepared from diethyl ester of malonic acid in 3 steps. At the above malonic ester was reacted with C2H5Br and sodium ethylate producing the diethyl ester of ethylmalonic acid, which after a reaction with sodium ethylate and 2-butylbromide gave the ethyl-(2-butyl)malonic acid diethyl ester. The last one produced the 5-sec-butyl-5-ethylbarbituric acid after a reaction with urea and sodium ethylate. 23 g sodium (1 mol) was dissolved in 300 ml alcohol. To this solution was added a solution of 5-sec-butyl-5-ethyl-barbituric acid (1 mol) in 800 ml alcohol. To a mixture was added 1000 ml benzene, which precipitated the sodium salt of the barbituric acid (butabarbital sodium). The product was filtered and dried. References Whitmore F.C. et al.; US Patent No. 2,161,212; June 6, 1939 Shonle H.A. et al.; US Patent No. 1,856,792; May 3, 1932 Pharmazeitishe Wirkstoffe, A. Kleeman und J. Engel, N.I. 1982
BUTACAINE Therapeutic Function: Local anesthetic Chemical Name: 1-Propanol, 3-(dibutylamino)-, p-aminobenzoate (ester) Common Name: Butacaine; Butaprobenz; Butocaina Chemical Abstracts Registry No.: 149-16-6 Trade Name Butelline Butyn Dental
Manufacturer ALK-Abello Abbott
Country -
Year Introduced -
Raw Materials p-Nitro-gamma-bromo-propylbenzoate Hydrochloric acid
Dibutylamine Iron filings
Butadiazamide
741
Structural Formula:
Manufacturing Process 40 g p-nitro-gamma-bromo-propylbenzoate and 40 g dibutylamine are heated together at 60°C, for four hours. The excess dibutyl amine is removed by washing the product with water and then steam distilling the residue. The material remaining in the flask is taken up in benzene and treated with aqueous hydrochloric acid. Part of the p-nitrobenzoyl-gamma-di-nbutylamminopropanol hydrochloride thus formed goes into the water layer, while most of it separates as a heavy oily layer. This, together with the water layer, is separated from the benzene layer, made alkaline, and the resulting base taken up in benzene. Upon removal of the solvent, the desired pnitrobenzoyl-gamma-di-n-butylamminopropanol is obtained. The p-nitrobenzoyl-gamma-di-n-butylamminopropanol is reduced by warming to about 60°C with an excess of iron filings and a small amount of hydrochloric acid for four hours. The material is then allowed to cool, neutralized with dilute sodium hydroxide solution, and extracted with ether. Upon the removal of the ether, the free base, para-aminobenzoyl-gamma-din-butylaminopropanol, remains behind as an oil. It is exactly neutralized with aqueous hydrochloric acid and the resulting solid salt purified by recrystallization from water or a suitable organic solvent. It melts at 151°152°C (corr.) after drying at 100°C. References Merck Index, Monograph number: 1531, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. Adams R., Volwiler E.H.; US Patent No. 1,358,751; Nov. 16, 1920 Adams R., Volwiler E.H.; US Patent No. 1,676,470; July 10, 1928
BUTADIAZAMIDE Therapeutic Function: Oral hypoglycemic Chemical Name: N-(5-Butyl-1,3,4-thiadiazol-2-yl)-4-chlorobenzenesulfonamide
742
Butalamine hydrochloride
Common Name: Butadiazamide Structural Formula:
Chemical Abstracts Registry No.: 7007-88-7 Trade Name
Manufacturer
Country
Year Introduced
Butadiazamide
Onbio Inc.
-
-
Raw Materials 5-Amino-2-n-butyl-1:3:4-thiadiazole p-Chlorobenzene sulfonyl chloride Hydrochloric acid Manufacturing Process 15.7 g of 5-amino-2-n-butyl-1:3:4-thiadiazole (0.1 mol) was dissolved in 150 ml dry pyridine and treated with 21.1 g of ρ-chlorobenzene sulfonyl chloride (0.1 mol). The mixture was heated on a steam bath for 4 h and the pyridine removed by distillation under reduced pressure. The residue was treated with 50 ml 2 N hydrochloric acid, and after filtration the 2-n-butyl-5-ρchlorobenzenesulfonamido-1:3:4-thiadiazole as colourless prisms, melting point 129-130°C (recrystallised from benzene) was obtained. References Macrae F.J., Drain D.J.; GB Patent No. 824,978; December 9, 1959; Assigned: T.J. Smith and Nephew Limited, a British Company, of Neptune Street, Kingston-upon-Hull, Yorkshire
BUTALAMINE HYDROCHLORIDE Therapeutic Function: Vasodilator Chemical Name: N,N-Dibutyl-N'-(3-phenyl-1,2,4-oxadiazol-5-yl)-1,2ethanediamine hydrochloride Common Name: -
Butalamine hydrochloride
743
Structural Formula:
Chemical Abstracts Registry No.: 22131-35-7 (Base); 28875-47-0 (Hydrochloride salt) Trade Name
Manufacturer
Country
Year Introduced
Surheme
Aron
France
1969
Surheme
Spemsa
Italy
1974
Adrevil
Zyma-Blaes
W. Germany
1975
Oxadilene
Leurquin
France
-
Surem
Cepa
Spain
-
Raw Materials Benzaldehyde Dibutylaminoethyl chloride Cyanamide
Chlorine Hydroxylamine Sodium amide
Manufacturing Process Benzaldehyde and hydroxylamine may be reacted, the product chlorinated and then reacted with cyanamide to give 5-amino-3-phenyl-1,2,4-oxadiazole. 32 grams of 3-phenyl-5-amino-1,2,4-oxadiazole dissolved in about 150 ml of anhydrous benzene, 7.8 grams of sodium amide are added and the reaction mixture heated at the boiling point with stirring for 2 hours. A solution of 38.3 grams of dibutylaminoethyl chloride in benzene is then added and the mixture heated to boiling under reflux for four hours. The sodium chloride is separated as previously described, the benzene removed by vacuum distillation and 56 grams of 3-phenyl-5-(dibutylaminoethylamino)-1,2,4-oxadiazole is obtained in the form of an oil which is then converted directly to the crystalline hydrochloride. This is accomplished by dissolving the oil in ethanol and adding the stoichiometric equivalent of anhydrous ethyl ether saturated with gaseous hydrogen chloride. The recrystallized salt is found to have a melting point of 145°C. References Merck Index 1477 Kleeman and Engel p.126 I.N. p.166 Aron-Samuel, J.M.D. and Sterne, J.J.; US. Patent 3,338,899; August 29, 1967
744
Butalbital
BUTALBITAL Therapeutic Function: Hypnotic, Sedative Chemical Name: 2,4,6(1H,3H,5H)-Pyrimidinetrione, 5-(2-methylpropyl)-5-(2propenyl)Common Name: Alisobumalum; Allylbarbital; Butalbital; Itobarbital; Tetrallobarbital Structural Formula:
Chemical Abstracts Registry No.: 77-26-9 Trade Name Axocet Esgic-Esgic Plus Zyban Fiorinal Floricet Sandoptal Medigesic Pacaps Phrenilin Repan Sedacap Tenake Tencon
Manufacturer Savage Labs Forest Glaxo-Wellcome Sandoz Sandoz Sandoz US Pharmaceutical Corporation Lunsco Canrick Labs Everett Lab Merz Pharmaceuticals
Country -
Year Introduced -
-
-
Seatrace Pharmaceuticals Intarnational Ethical Labs
-
-
-
-
Raw Materials Sodium Ethyl malonic acid ester Urea Allyl bromide
Alcohol 2-Isobutyl bromide Potassium hydroxide
Manufacturing Process 1 mole of sodium is dissolved in 10 to 12 times its weight of absolute alcohol
Butamirate citrate
745
under a reflux condenser. To this are added 1 mole of ethyl malonic acid ester, and then gradually about 1.1 moles of 2-isobutyl bromide. The mixture is gently refluxed for some hours, or until it no longer shows alkaline reaction to moist litmus paper. Most of the alcohol is removed by vacuum distillation, leaving an oily residue. Water is added to this residue to dissolve the sodium bromide; and the oily layer, which is ethyl isopropyl-carbinyl malonic acid ester, is separated and dried. It is purified by fractional distillation in vacuum. When thus purified, ethyl isopropyl-carbinyl malonic acid ester is a colorless or pale yellow liquid, having a boiling point of 103°-105°C at about 4 mm pressure, and a refractive index at 25°C. 3 moles of sodium are dissolved in 10 to 12 times its weight of absolute alcohol under a reflux condenser. To this are added 1.6 moles of urea and 1 mole of ethyl isopropyl-carbinyl malonic acid ester. The mixture is gently refluxed for 2-4 h, after which most of the alcohol is removed by vacuum distillation. The residue is dissolved in water, and a sufficient amount of dilute acid is added to completely precipitate the isopropyl-carbinyl barbituric acid. The precipitate is filtered off, dried, and recrystallized from dilute alcohol. 1 mole of isopropyl-carbinyl barbituric acid is dissolved in a suitable vessel in a 10%-35% aqueous solution of 1 mole of potassium hydroxide. To this are added somewhat in excess of 1 mole of allyl bromide, and alcohol equal to about 10% of the total volume of the solution. The vessel is agitated for 5075 h. At the end of this time, the solution, which may still exhibit two layers, is concentrated to about one-half its volume, to remove the excess allyl bromide and the alcohol. On cooling, an oily layer, which is isopropyl-carbinyl allyl barbituric acid, separates out as a sticky viscous mass. It is dried, washed with petroleum ether, and dissolved in the minimum amount of benzene. Any unreacted isopropyl-carbinyl barbituric acid, which does not dissolve, is filtered off. The addition of petroleum ether to the clear filtrate causes the isopropyl-carbinyl allyl barbituric acid to precipitate as an oily mass. This is separated, washed with petroleum ether, and dried in vacuum. References Shonle H.A.; US Patent No. 1,954,429; April 10, 1934; Assigned: Eli Lilly and Company, Indianapolis, Ind., a Corporation of Indiana
BUTAMIRATE CITRATE Therapeutic Function: Antitussive Chemical Name: α-Ethylbenzeneacetic acid 2-[2-(diethylamino)ethoxy]ethyl ester citrate Common Name: Butamyrate Chemical Abstracts Registry No.: 18109-81-4; 18109-80-3 (Base)
746
Butamirate citrate
Structural Formula:
Trade Name
Manufacturer
Country
Year Introduced
Sinecod
Hommel
Switz.
1967
Sinecod
Karlspharma
W. Germany
1967
Sinecod
Bonomelli
Italy
1969
Acodeen
Hommel
Switz.
-
Acodfen
Klimitschek
Austria
-
Codesin-F
Hommel
Switz.
-
Intussin
Spofa
Czechoslovakia
-
Sincoden
Hommel
Switz.
-
Sincodix
Beta
Argentina
-
Sinecod
Abello
Spain
-
Pertix-Hommel
Hommel
W. Germany
-
Raw Materials α-Phenylbutyric acid chloride Diethylaminoethoxyethanol Citric acid Manufacturing Process 18.2 grams of α-phenylbutyric acid chloride are dissolved in 25 ml of toluene. To this solution, there is slowly added a solution of 16.1 grams of diethylaminoethoxyethanol in 25 ml of toluene, the reaction mixture thereby becoming hot. It is then heated for 8 hr under reflux. The reaction mixture, after cooling, is carefully poured onto 75 grams of ice and made alkaline with dilute ammonia. After thorough shaking of the solution, the toluene layer is removed and washed until neutral with water. The toluene solution is treated with carbon and dried over sodium sulfate. The toluene is distilled off from the filtered solution. The residue is α-phenylbutyric acid diethylaminoethoxyethyl ester. The basic ester is purified by distillation in a high vacuum. 10 grams of ester are added to a solution of 7 grams of citric acid in 30 ml of warm acetone. After standing for some time, the citrate of the ester crystallizes out. After suction filtration
Butamisole hydrochloride
747
and washing with acetone the ester citrate is recrystallized from acetone. The melting point of the citrate is 75°C. References Merck Index 1481 Kleeman and Engel p.127 OCDS Vol.2 p.76 (1980) DOT 9 (7) 280 (1973) I.N. p. 166 Heusser, J.; US Patent 3,349,114; October 24, 1967; Assigned to Hommel AG, Switzerland
BUTAMISOLE HYDROCHLORIDE Therapeutic Function: Anthelmintic Chemical Name: (S)-2-Methyl-N-[3-(2,3,5,6-tetrahydroimidazo[2,1b]thiazol-6-yl)phenyl]propanamide monohydrochloride Common Name: Butamisole hydrochloride; Styquin Structural Formula:
Chemical Abstracts Registry No.: 54400-62-3 Trade Name
Manufacturer
Country
Year Introduced
Butamisole hydrochloride
American Cyanamid (AHP)
-
-
Raw Materials 3'-Acetylacetanilide 2-Amino-2-thiazoline Isobutyric anhydride Sodium hydroxide Ammonium hydroxide
Bromine Sodium borohydride Sulfuric acid Hydrochloric acid
Manufacturing Process To a stirred solution of 110.0 g (0.62 mole) of 3'-acetylacetanilide in 2400 ml of chloroform is added dropwise a solution of 33.0 ml (102.9 g; 0.644 mole)
748
Butamisole hydrochloride
of bromine in 240 ml of chloroform. The solution is stirred 1 h and the resultant precipitate is then filtered, washed with ether and dried. The solid is stirred in a large volume of water to give an oily precipitate which crystallizes on further stirring. The solid is filtered, washed with water and then 2propanol, dried to give 148.34 g of the 3'-bromacetylacetanilide, melting point 108.5-110°C (recrystallized from 2-propanol). A solution of 5.12 g (0.020 mole) of 3'-bromoacetylacetanilide in 70 ml of acetone is added to a stirred solution of 2.04 g (0.020 mole) of 2-amino-2thiazoline in 30 ml of acetone. The mixture is stirred 1.5 h and the precipitate then filtered, washed with acetone and dried to give 6.00 g of 3'-[(2-imino-3thiazolidinyl)acetyl]acetaniIide hydrobromide, meltng point 275-277°C (recrystallization from water). To a stirred slurry of 63.47 g (0.177 mole) of 3'-[(2-imino-3-thiazolidinyl) acetyl]acetanilide hydrobromide in 1 L of 95% ethanol, maintained at 5°C, is added 5.70 g (0.15 mole) of sodium borohyride. After stirring 40 min an additional 4.10 g of sodium borohydride is added and the mixture is acidified with hydrochloric acid and evaporated under reduced pressure. The residue is partitioned between chloroform and dilute aqueous ammonium hydroxide. Two further chloroform extracts are combined with the original, washed with brine, dried (sodium sulfate) and evaporated to give an oil. Treatment with acetone gives 6.77 g (48%) of 3'-[l-hydroxy-2-(2-imino-3thiazolidinyl)ethyl]acetanilide hydrochloride as white crystalline, melting point 235-237°C. Addition of 5.00 g (0.0158 mole) of 3'-[1-hydroxy-2-(2-imino-3thiazolidinyl)ethyl]acetanilide hydrochloride to 15 ml of concentrated sulfuric icid is carried out in small increments over 0.5 h. The orange solution is stirred an additional 1 h, poured onto ice and made basic with concentrated ammonium hydroxide. The aqueous base is extracted twice with chloroform and the combined organic layers washed with water, brine, dried (sodium sulfate) and evaporated at reduced pressure to give 3.32 g (80% crude yield) of the 3'-(2,3,5,6-tetrahydroimidazo[2,1-b]thiazol-6-yl)acetanilide, melting point 164-166°C (recrystallization from 2-propanol). A solution of 1.00 g (0.0038 mole) of 3'-(2,3,5,6-tetrahydroimidazo[2,1b]thiazol-6-yl)acetanilide in 17 ml of 6 N hydrochloric acid is heated at reflux for 2.5 h and then allowed to stand overnight at room temperature. The solution is concentrated at reduced pressure, made basic with concentrated aqueous sodium hydroxide while cooling and then extracted with 3 portions of chloroform. The combined organic layers are washed with brine, dried (sodium sulfate) and evaporated to give 0.84 g of an oil, i.e., 6-(m-aminophenyl)2,3,5,6-tetrahydroimidazo[2,1-b]thiazole free base. The oil is dissolved in hot methanol and strongly acidified with hydrogen chloride in 2-propanol. Evaporation of the solution give the 6-(m-aminophenyl)-2,3,5,6tetrahydroimidazo[2,1-b]thiazole dihydrochloride, melting point 198-201°C (crystallization from 2-propanol). 2.2 g (0.010 mole) of 6-(m-aminophenyl)-2,3,5,6-tetrahydroimidazo[2,1b]thiazole dihydrochloride is disolved in a mixture of 15 ml methanol and 15 ml water and the pH is adjusted to about 6 with an aqueous hydrochloric acid solution. This solution is then added to 3.2 g (0.020 mole) of isobutyric anhydride. The mixture is allowed to stand at room temperature for 12 h. The
Butanilicaine
749
reaction mixture is then added to a mixture of 100 ml methylene chloride and 50 ml water and then made basic (pH 10) with an aqueous sodium hydroxide. The methylene chloride layer is removed and the water layer is washed twice with 75 ml of fresh methylene chloride. The methylene chloride extract are then combined, dried over magnesium sulfate, and the methylene chloride evaporated leaving a tacky solid. The free base of the product is recrystallized from a chloroformethyl ether mixture. The yield of the 3'-(2,3,5,6tetrahydroimidazo[2,1-b]thiazol-6-yl)isobutyranilide is 1.6 g (55%). References Spicer L.D., Hand J.J.; US Patent No. 3,899,583; August,1975; Assigned: American Cyanamid Company, Stamford, Conn.
BUTANILICAINE Therapeutic Function: Local anesthetic Chemical Name: 2-(Butylamino)-6'-chloro-o-acetoluidide Common Name: Butacetoluide; Butanilicaine Structural Formula:
Chemical Abstracts Registry No.: 3785-21-5 Trade Name
Manufacturer
Country
Year Introduced
Butanilicaine
Enreco, INC
-
-
Raw Materials 4-Bromo-2-methylaniline n-Butylamine
Chloroacetyl chloride Hydrochloric acid
Manufacturing Process To a solution of 4-bromo-2-methylaniline is added 13 g of chloroacetyl chloride. After the reaction is finished to the mixture id added a solution of 33 g sodium acetate in 138 ml of water. Chloroacetic acid 4-bromo-2methylanilide is filtered; yield 24 g, M.P. 135°C (crystallization from ethanol). 20 g of chloroacetic acid 4-bromo-2-methylanilide is dissolved in 200 ml of
750
Butanixin
butylamine. After about 15 hours to the solution is added 2 N hydrochloric acid. Butylaminoacetic acid 4-bromo-2-methylanilide hydrochloride is removed by suction and washed with water; yield 90%, M.P. 252-253°C (from methanol). References Merck Index, Monograph number: 1542, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. Walter A. et al., DE Patent No. 1,009,633; 1957.06.06; Assigned to Hoechst AG
BUTANIXIN Therapeutic Function: Analgesic, Antiinflammatory Chemical Name: 2-(p-Butanilino)nicotinic acid Common Name: Butanixin Structural Formula:
Chemical Abstracts Registry No.: 55285-35-3 Trade Name
Manufacturer
Country
Year Introduced
Butanixin
ZYF Pharm Chemical
-
-
Raw Materials 2-Chloronicotinic acid p-n-Butyl aniline Manufacturing Process 5 g 2-chloronicotinic acid and 9.4 g p-n-butyl aniline were heated for 1 hour at 160°C by vigorous stirring under a nitrogen atmosphere. Then the mixture was dissolved in 2 N sodium hydroxide and extracted with benzene. The water layer was acidified and a precipitate obtained was filtered off, washed with water and dried. 5 g 2-[(4-butylphenyl)amino]-3-pyridinecarboxylic acid yielded. MP: 171°-173°C (deg.).
Butantrone
751
References Stampa A.; D.E. Patent No. 2,409,260; January 30, 1975; Laboratorios Hermes S.A. Barcelona (Spain)
BUTANTRONE Therapeutic Function: Antipsoriatic Chemical Name: 1,8-Dihydroxy-10-(1-oxobutyl)-9(10H)-anthracenone Common Name: Butantrone Structural Formula:
Chemical Abstracts Registry No.: 75464-11-8 Trade Name
Manufacturer
Country
Year Introduced
Butantrone
Onbio Inc.
-
-
Raw Materials Anthralin Pyridine Butyryl chloride Manufacturing Process To a solution of 56.6 g (0.25 mol) of anthralin in 1750 ml of absolute toluene and 27.3 ml of pyridine, 31.5 ml (0.3 mol) of butyryl chloride was added with stirring over 30 min at room temperature. The reaction mixture was then heated to 85°C for 1 hour. After this mixture had recooled to room temperature, 27.3 ml of pyridine and 31.5 ml of butyryl chloride were again added. The suspension obtained was then heated to 85-90°C for 1 hour. The precipitated pyridinium hydrochloride was eliminated by filtration then washed with toluene. The toluene filtrates were concentrated to around 500 ml under reduced pressure, washed several times with water then dried over magnesium sulfate. The product was then fractionated by chromatography on
752
Butaperazine
silica gel, using toluene and then a mixture of toluene and ethyl acetate as the mobile phase. The different fractions containing the 1,8-dihydroxy-10-(1oxobutyl)-9(10H)-anthracenone were then concentrated and recrystallized from a toluene-hexane mixture. In this way 25 g of yellow crystals of 1,8dihydroxy-10-(1-oxobutyl)-9(10H)-anthracenone having a melting point of 138°C was obtained. References Shroot Braham, Lang Gerard, Maignan Jean; US Patent No. 4,696,941; September 29, 1987; Assigned to Groupement d'Interet Economique dit: Centre International 'de Recherches (Valbonne, FR)
BUTAPERAZINE Therapeutic Function: Neuroleptic, Antiemetic Chemical Name: 1-Butanone, 1-(10-(3-(4-methyl-1-piperazinyl)propyl)-10Hphenothiazin-2-yl)Common Name: Butaperazine; Butyrylperazine Structural Formula:
Chemical Abstracts Registry No.: 653-03-2 Trade Name
Manufacturer
Country
Year Introduced
Bayer 1362
Bayer
-
-
Repoise
Robins
-
-
Butyrylperazine
Robins
-
-
Randolectil
Bayer
-
-
AHR 712
Robins
-
-
Raw Materials Sodium amide 2-Buterylphenothiazine Sodium hydroxide
Butedronic acid
753
Manufacturing Process To a suspension of sodamide in liquid ammonia is added of 2buterylphenothiazine. After stirring for one hour, there is added 1-bromo-3chloropropane. The ammonia is allowed to evaporate and the residue is diluted with the water. The mixture is extracted with ether and the ether solution is dried over anhydrous sodium sulfate, filtered and concentrated. The residue consists of crude 10-(3-chloropropyl)-2-buterylphenothiazine as viscous oil and is used in the next step without further purification. A mixture of 1-methylpiperazine and crude 10-(3-chloropropyl)-2buterylphenothiazine is heated on a steam bath for 18 hours. The mixture is diluted with the water and extracted with ether. The ether solution is extracted with dilute hydrochloric acid. The aqueous acid solution is made alkaline with sodium hydroxide and the product is extracted with ether. The ether extracts are dried and concentrated to a residue consisting of the free base 2-butyryl-10-(3-(4-methyl-1-piperazinyl)propyl)phenothiazine. References Merck Index, Monograph number: 1543, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. Sheriock M.H. et al.; US Patent No. 2,985,654; May 23, 1961; Assigned to Schering Corporation, Bloomfield, N.Y., a corporation of New Jersey
BUTEDRONIC ACID Therapeutic Function: Diagnostic aid Chemical Name: (Diphosphonomethyl)butanedioic acid Common Name: Butedronic acid Structural Formula:
Chemical Abstracts Registry No.: 51395-42-7 Trade Name
Manufacturer
Country
Year Introduced
Butedronic acid
Bayer A.G.
-
-
754
Butenafine hydrochloride
Raw Materials Methylene diphosphonic acid tetraethyl ester Maleic acid diethyl ester Sodium ethylate Acetic acid Hydrochloric acid Manufacturing Process 0.5 mole of methylene diphosphonic acid tetraethyl ester is heated for 6 h to 110°C with 0.5 mole of maleic acid diethyl ester in the presence of 25 ml of a saturated sodium ethylate solution. The sodium ethylate is then neutralized with acetic acid and the reaction mixture is quickly distilled invacuo in order to avoid decomposition. The crude distillate is redistillated, the main fraction accumulating in the range from 190-213°C at a pressure of 0.05 Torr, yield 50%. The ester is hydrolyzed by boiling with concentrated hydrochloric acid. 1,1Diphosphonopropane-2,3-dicarboxylic acid crystallizes out after purification with active carbon and concentration of the hydrolysis product, yield 100%. References Heins A. et al.; US Patent No. 3,923,876; December 2, 1975; Assigned: Bayer Aktiengesellschaft, Leverkusen, Germany
BUTENAFINE HYDROCHLORIDE Therapeutic Function: Antifungal Chemical Name: 1-Naphthalenemethanamine, N-((4-(1,1-dimethylethyl) phenyl)methyl)-N-methyl-, hydrochloride Common Name: Butenafine hydrochloride Structural Formula:
Chemical Abstracts Registry No.: 101827-46-7
Buterizine
755
Trade Name
Manufacturer
Country
Year Introduced
Butenafine Hydrochloride
Shenzhen Fangye Industries Co., Ltd.
China
-
KP-363
Shenzhen Fangye Industries Co., Ltd.
China
-
Lotrimin Ultra
Schering-Plough HealthCare Products, Inc.
-
Mentax-TC
Bertek
-
-
Raw Materials N-Methyl-1-naphtylmethylamine hydrochloride p-tret-Butylbenzyl bromide Manufacturing Process N-Methyl-1-naphtylmethylamine hydrochloride (2.1 g, 0.01 mole) was dissolved in 50 ml of dry dimethylformamide, and 3.71 g (0.035 mole) of anhydrous sodium carbonate was added, then 2.49 g (0.011 mole) of p-tbutylbenzyl bromide was added by stirring and the mixture was reacted at 30° to 40°C for 5 hours. Ice water was added, and the mixture was extracted with toluene. The organic layer was washed with water, and toluene was evaporated. The residue was chromatographed on silica gel column, and eluated with 5% ethyl acetate/n-hexane. The eluate was concentrated to give 2.98 g (yield 94%) of an oily substance. Hydrochloric acid/ethanol was added to 1 g of this oily product, and the mixture was concentrated. The residue was recrystallized from methanol/acetic acid to give 0.95 g of desired 1naphthalenemethanamine, N-((4-(1,1-dimethylethyl)phenyl)methyl)-Nmethyl-, hydrochloride having melting point 200° to 202°C. References Arita et al.; US Patent No. 4,822,822; Apr. 18, 1989; Assigned Mitsui Toatsu Chemicals, Inc., Tokyo, Japan
BUTERIZINE Therapeutic Function: Vasodilator Chemical Name: 2-Butyl-5-[[4-(diphenylmethyl)-1-piperazinyl]methyl]-1ethyl-1H-benzimidazole Common Name: Buterizine Chemical Abstracts Registry No.: 68741-18-4
756
Buterizine
Structural Formula:
Trade Name
Manufacturer
Country
Year Introduced
Buterizine
Shanghai Chemfrom Chemical Co., Ltd.
-
-
Raw Materials 1-Chloro-4-(chloromethyl)-2nitrobenzene Nickel Raney Sodium hydroxide Pentyl ethanimidate hydrochloride
1-(Diphenylmethyl)piperazine Ethanamine Hydrogen Acetic acid
Manufacturing Process A mixture of 10.3 parts of 1-chloro-4-(chloromethyl)-2-nitrobenzene, 25.2 parts of 1-(diphenylmethyl)piperazine and 120 parts of ethanol is stirred and refluxed for 4 h. The reaction mixture is cooled and evaporated. The residue is taken up in about 100 parts of water and the product is extracted with methylbenzene. The extract is washed with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using trichloromethane as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of 2,2'oxybispropane and hexane (1:2 by volume). The product is filtered off, washed with hexane and dried, yielding 19.6 parts of 1-(4-chloro-3nitrophenylmethyl)-4-(diphenylmethyl)piperazine; melting point 101.6°C. During 20 h, gaseous ethanamine is bubbled through a stirred and hot (6070°C) mixture of 1-(4-chloro-3-nitrophenylmethyl)-4(diphenylmethyl)piperazine and dimethylsulfoxide. The reaction mixture is cooled and poured onto ice-water. The precipitated product is filtered off, washed with water and taken up in methylbenzene. The latter is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol as eluent. The pure fractions are collected and the eluent is evaporated, yielding 4-[4(diphenylmethyl)-1-piperazinylmethyl]-N-ethyl-2-nitrobenzenamine; melting point 128.2°C (crystallized from 2,2'-oxybispropane). A solution of 4-[4-(diphenylmethyl)-1-piperazinylmethyl]-N-ethyl-2nitrobenzenamine in methanol is hydrogenated at normal pressure and at room temperature with Raney-nickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated,
Butetamate citrate
757
yielding 4-[4-(diphenylmethyl)-1-piperazinylmethyl]-N1-ethyl-1,2benzenediamine. A mixture of 4-[4-(diphenylmethyl)-1-piperazinylmethyl]-N1-ethyl-1,2benzenediamine and acetic acid is stirred at room temperature till all solid enters solution. Then there are added pentyl ethanimidate hydrochloride and stirring is continued first for 1 h at room temperature and further for 1 h at reflux. The reaction mixture is evaporated and the residue is stirred in water. The whole is alkalized with a sodium hydroxide solution and the product is extracted with dichloromethane. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol as eluent. The pure fractions are collected and the eluent is evaporated. The product is filtered off and dried, yielding 5-[4-(diphenylmethyl)-1-piperazinylmethyl]-1-ethyl-2-butyl-1Hbenzimidazole; melting point 124.8°C (crystallized from 4-methyl-2pentanone). References Raeymaekers A.H.M. et al.; US Patent No. 4,179,505; December 18, 1979; Assigned: Janssen Pharmaceutica N.V. Beers, Belgium
BUTETAMATE CITRATE Therapeutic Function: Anticholinergic, Spasmolytic, Antitussive Chemical Name: 2-(Diethylamino)ethyl-2-phenylbutyrate, citrate salt Common Name: Butetamate citrate; Phenethylamincitrat; Butethamate citrate Structural Formula:
Chemical Abstracts Registry No.: 14007-64-8
758
Butethamine
Trade Name
Manufacturer
Country
Year Introduced
Butetamatdihydrogencitrat
-
-
Convenil
Chemische Werke Hommel GmbH and Co.KG Hommel
-
-
Convenal
Hommel
-
-
Hicoseen
Klimitschek
-
-
Phenetin
Alpinapharm
-
-
Aspectonetten
Krewel Meuselbach -
-
CAM
Rybar-Ireland
-
-
Raw Materials alpha-Phenylbutiric acid beta-Diethylaminoethylchloride hydrochloride Potassium carbonate Manufacturing Process 16.4 parts of alpha-phenylbutiric acid, 17.5 parts of betadiethylaminoethylchloride hydrochloride and 35 parts of dry potassium carbonate in 60 parts diisopropyl ether was stirred for 18 hours under reflux. To the reaction mixture at 40°C was added 120 parts of the water. Organic layer was washed with the water. The solvent was removed and the 2(diethylamino)ethyl-2-phenylbutyrate was distilled at 167-168°C/10 mm; melting point of hydrochloride 167-169°C. In practice it is usually used as citrate. References Schweizerische Patent No. 291,375; Sept. 16, 1953; Assigned to Aktiengesellschaft Hommels Haematogen, Zurich
BUTETHAMINE Therapeutic Function: Local anesthetic Chemical Name: 2-[(2-Methylpropyl)amino]ethanol 4-aminobenzoate Common Name: Ibylcaine Structural Formula:
Butethamine
759
Chemical Abstracts Registry No.: 2090-89-3; 553-68-4 (Hydrochloride salt) Trade Name
Manufacturer
Country
Year Introduced
Monoceine
Novocol
US
1941
Dentocaine
Amer. Chem.
US
-
Raw Materials Isobutylaminoethanol Tin
4-Nitrobenzoyl chloride Hydrochloric acid
Manufacturing Process The preparation of the normal butyl analog is as follows: 10 g of isobutylaminoethanol, 16 g of p-nitrobenzoyl chloride and 5 g of sodium hydroxide in 175 cc of water were allowed to react. The temperature was maintained between 30°-40°C during reaction. The reaction mixture was extracted with ether, the ether evaporated, and the resultant oil washed with water to remove any unreacted secondary amino alcohol and then dried. The yield was 21 g or 91% of theory. The compound responded positively when tested for the presence of the amine configuration and also the nitro group. The yellow viscous oil which was formed was isobutylaminoethyl pnitrobenzoate. 20 g of this latter material was directly reduced with 15 g of tin and 50 cc of concentrated hydrochloric acid. The temperature of the reduction was controlled by addition from time to time of small quantities of cold water to maintain the temperature at or near 70°C. When the reaction was completed 150 cc of sodium hydroxide was added and the solution then cooled to 15°C. The oil which gradually formed combined with undissolved tin to form a pasty mass which soon settled. The supernatant liquid was decanted and the residue washed two or three times with water to remove all traces of alkali. The oily mass, freed from most of its water, was then extracted with ether and filtered. The filtrate was evaporated to dryness and the yield of the base obtained was 13 g or 73.5% of theory. In order to get the melting point of the base, the monohydrochloride was first formed and purified, then the hydrochloride was dissolved in water and just neutralized with ammonia water. The colorless oil formed soon crystallized into a white solid, which after filtration and air drying, had a melting point of 74°-74.5°C. The hydrochloride was made when the oily base was dissolved in propyl alcohol and the calculated quantity of aqueous hydrochloric acid added to form the monohydrochloride of this compound. After repeated recrystallizations, a white needle crystal was formed which had a melting point at 146°C. References Merck Index 1492 Kleeman and Engel p.128 DOT 15 (7) 368 (1979) I.N. p.168 Goldberg, S.D.; US Patent 2,139,818; December 13, 1938; assigned to Novocol Chemical Mfg. Co., Inc.
760
Buthiazide
BUTHIAZIDE Therapeutic Function: Diuretic, Antihypertensive Chemical Name: 6-Chloro-3,4-dihydro-3-(2-methylpropyl)-2H-1,2,4benzothiadiazine-7-sulfonamide-1,1-dioxide Common Name: Thiabutazide; Butizide; Isobutylhydrochlorothiazide Structural Formula:
Chemical Abstracts Registry No.: 2043-38-1 Trade Name
Manufacturer
Country
Year Introduced
Saltucin
Boehringer Mannheim
W. Germany
1961
Eunephran
Servier
France
-
Intensain
Boehringer Mannheim
W. Germany
-
Modenol
Boehringer Mannheim
W. Germany
-
Sembrina
Boehringer Mannheim
W. Germany
-
Raw Materials 3-Chloraniline Ammonia
Chlorosulfonic acid Isovaleraldehyde
Manufacturing Process Chlorsulfonic acid and 3-chloroaniline react to give an intermediate which when treated with ammonia yields 5-chloro-2,4-disulfamylaniline. 20 g of 5-chloro-2,4-disulfamylaniline in 15 cc of diethyleneglycol-dimethyl ether with 0.9 g of isovaleraldehyde are reacted in the presence of 0.5 cc of a saturated solution of hydrochloric acid in ethyl acetate at 80°-90°C. The reaction mixture is concentrated under reduced pressure, an oily product precipitates on the addition of water, the latter is decanted and ethanol added to the remaining oil. 3-Isobutyl-6-chloro-7-sulfamyl-3,4-dihydro-1,2,4benzothiadiazine-1,1-dioxide crystallizes and, after recrystallization from dimethylformamide and water, melts at 241°-245°C. References
Butibufen
761
Merck Index 1494 Kleeman and Engel p.129 DOT 14 (3) 119 (1978) I.N. p.169 Ciba, Ltd.; British Patents 861,367; February 22, 1961 and 885,078; December 20, 1961
BUTIBUFEN Therapeutic Function: Antiinflammatory, Analgesic Chemical Name: 2-(p-Isobutylphenyl)butyric acid Common Name: Butilopan Structural Formula:
Chemical Abstracts Registry No.: 55837-18-8 Raw Materials Trade Name Butibufen Butilopan Butilopan
Manufacturer Onbio Inc. Juste Merck
Paraformaldehyde Hydrogen chloride Sodium amide Sodium hydroxide Hydrochloric acid
Country -
Year Introduced -
Zinc chloride Sodium cyanide Ethyl iodide Sodium
Manufacturing Process 1st method: 4-Isobutylphenylbenzyl chloride was prepared by passing a stream of hydrogen chloride into a suspension of p-bromoaldehyde and anhydrous zinc chloride in isobutylbenzene. A mixture of 137 g (0.75 mol) of 4-isobutylbenzyl chloride thus prepared, 44.1 g (0.90 mol) of sodium cyanide, 216 g of 99% ethanol, and 81.3 g of water was heated refluxed for 6 hours. The mixture became reddish-black in color. From this mixture, 215 ml of ethanol and water
762
Butibufen
was then distilled and the residue was filtered. The solids that were separated by filtration were washed with 100 ml of diethyl ether and the ether washings were combined with the original filtrate, to which 800 ml of water was then added. The organic phase was then separated from the aqueous phase, washed with five 400 ml portions of water and dried over anhydrous sodium sulfate. The ether was evaporated from the dried organic phase by vacuum distillation and the residue which distilled between 130°C and 132°C at a pressure of 7 mm of mercury was collected. The yields of 4-isobutylbenzene cyanide 100-113 g. To a solution of 6.7 g of sodium amide in 100 ml of anhydrous diethyl ether was added dropwise 26 g of 4-isobutylbenzene cyanide while the mixture was stirred and heated under gentle reflux. After all of the 4-isobutylbenzene cyanide had been added, the mixture was heated under gentle reflux for 15 min, after which 23.4 g of ethyl iodide was slowly added dropwise thereto from the dropping funnel. After completion of the addition of the ethyl iodide, the mixture was heated under gentle reflux for an initial period of 15 min, after which it was diluted with an equal volume of water and shaken. The two layers that formed were separated and the aqueous layer was then extracted with two 50 ml portions of diethyl ether. The ether extracts were combined and then washed with two 80 ml portions of water and dried over anhydrous magnesium sulfate. The dried ether extract was then distilled at a subatmospheric pressure. In this manner, 25 g of a clear transparent uncolored liquid having a boiling point of 118-122°C at a pressure of 1mm of mercury, which consisted of 2-(4-isobutylphenyl)butyronitrile, was collected. This yield was equivalent to 83% of the theoretical. A mixture of 40 g (0.2 mol) of 2-(4-isobutylphenyl)butyronitrile and 78 ml of a freshly prepared solution of sodium hydroxide that was prepared by dissolving 28 g of sodium hydroxide in 25 ml of distilled water and the volume of which was brought to 100 ml by addition thereto of methanol, was heated under gentle reflux in a flask provided with a stirrer and reflux condenser while the mixture was stirred during a period of 9 hours. From the mixture the methanol and a portion of the water were distilled and the mixture was then cooled, the crystals began to separate. The mixture was then diluted with 150 ml of water and extracted with two 25 ml portions of diethyl ether. The remaining aqueous solution containing the sodium salt of 2-(4isobutylphenyl)butyric acid was then saturated with sodium chloride until the salt started to precipitate. The solution was then cooled to 5°C and the precipitated salt was separated by filtration, recrystallized from isopropanol, and dried in a vacuum desiccator at a pressure of 1 mm of mercury until it had attained a constant weight. In this manner, 32 g of sodium 2-(4isobutylphenyl)butyrate having a melting point of 188-191°C, which is equivalent to a yield of 67% of the theoretical, was obtained. Dilute hydrochloric acid (19% by weight of hydrogen chloride) was slowly added to a cold solution of 25 g of the sodium 2-(4-isobutylphenyl)butyrate thus prepared in 100 ml of water until the solution corresponded to pH of 1.0. The oil which precipitated was then allowed to solidify to a white solid by standing in a refrigerator. The white solid was then separated by filtration, dried, and recrystallized from petroleum ether. It had a melting point of 5052°C, and its elementary analysis corresponded to the 2-(4isobutylphenyl)butyric acid.
Butibufen
763
2nd method: 5.0 g of small pellets of sodium metal were added slowly with stirring to 150 ml of absolute ethanol, while a current of nitrogen gas was passed there through so as to blanket the solution from the atmosphere. After all of the sodium metal had been dissolved and while the solution was maintained at a temperature of 50°C, a solution of 52 g of ethyl 2-(4isobutylphenyl)cyanoacetate in 50 ml of absolute ethanol was added dropwise while the mixture was stirred. Subsequently, 81 g of ethyl iodide was gradually added to the mixture with stirring, after which the introduction of nitrogen gas into the mixture was discontinued and the mixture was heated for a period of 2.5 hours under gentle reflux. Thereafter, the ethanol and excess ethyl iodide were distilled from the mixture and the residue was then diluted with three times its volume of water and shaken therewith. The 2-(4isobutylphenyl)-2-(ethoxycarbonyl)butyronitrile was then extracted from the mixture with three 50 ml portions of diethyl ether, the extracts were combined, washed with a 20% aqueous solution of sodium bisulfate and dried over anhydrous magnesium sulfate. The ether was then expelled from the extract by distillation and the residue was distilled at a subatmospheric pressure, yielding 45 g of a fraction containing 2-(4-isobutylphenyl)-2(ethoxycarbonyl)butyronitrile having a boiling point of 150-155°C/3 mm of mercury (78% of the theoretical yield). In a 2-liter flask provided with a stirrer and reflux condenser a solution of 129 g of 2-(4-isobutylphenyl)-2-(ethyoxycarbonyl)butyronitrile in 980 ml of a 20% solution of potassium hydroxide in methanol was heated with stirring at 40°C for a period of 1 hour. The mixture was then heated under gentle reflux with stirring for an additional period of 3 hours, during which a white solid precipitated. This mixture was then poured into 1.5 liters of water and acidified with an aqueous solution of hydrochloric acid (concentrated hydrochloric acid diluted with an equal volume of water) to a hydrogen ion concentration corresponding to a pH of 2.5, while carbon dioxide was evolved therefrom. The aqueous mixture was then extracted with diethyl ether. The extracts were washed successively with a saturated solution of sodium bicarbonate and water, dried over anhydrous magnesium sulfate, and distilled at a subatmospheric pressure, to yield 86.5 g of a fraction consisting of 2-(4isobutylphenyl)butyronitrile having a boiling point of 124-128°C at a pressure of 1.5 mm of mercury, which is equivalent to approximately 0.43 mol and a yield of 91% of the theoretical based on the original 2-(4-isobutylphenyl)-2(ethoxycarbonyl)butyronitrile. The 2-(4-isobutylphenyl)butyronitrile was converted to sodium 2-(4isobutylphenyl)butyrate and subsequently to 2-(4-isobutylphenyl)butyric acid in the same manner as described in Method 1 hereinbefore. References Aparicio Luis, Gayo Nenesio, Carretero Jose, Martin Jose Luis, Ron Armando; US Patent No. 4,031,243; June 21, 1977; Assigned to Juste, S.A. Quimico-Farmaceutica (Madrid, ES)
764
Butinazocine
BUTINAZOCINE Therapeutic Function: Analgesic Chemical Name: (-)-3-(3-Butynyl)-1,2,3,4,5,6-hexahydro-11,11-dimethyl2,6-methano-3-benzazocine-6,8-diol Common Name: Butinazocine Structural Formula:
Chemical Abstracts Registry No.: 93821-75-1 Trade Name
Manufacturer
Country
Year Introduced
Butinazocine
ZYF Pharm Chemical
-
-
Raw Materials 2-(4-Methoxybenzyl)-1,3,3-trimethyl4-piperidone hydrochloride Sodium hydroxide Ammonia Lithium aluminum hydride Toluene-4-sulfonic acid but-3-ynyl ester Methyliodide
Nitrobenzene Aluminum trichloride Hydrochloric acid Cyanogen bromide Sodium hydride Calcium carbonate Ethanethiol
Manufacturing Process A mixture of 59.5 g (0.2 mol) 2-(4-methoxybenzyl)-1,3,3-trimethyl-4piperidone hydrochloride and 53.8 g (0.4 mol) of aluminum trichloride and 54.0 g of nitrobenzene in 1500 ml of dry benzene are boiled under reflux for 1 h. After cooling the reaction mixture is extracted with 750 ml 4 N sodium hydroxide solution, the temperature being maintained below 35°C. The organic phase is separated and extracted with 750 ml 1 N hydrochloric acid. The acid aequeous phase is rendered alkali by the addition of 100 ml 25% ammonia and extracted three times with 250 ml chloroform. The collected chloroformic phases are dried with sodium sulfate and evaporated under reduced pressure. The residue, 46.7 g, is converted into the hydrochloride by reaction with iso-propanol/HCl and crystallized from a mixture of methanol and ethylacetate. 44.6 g of the 5-hydroxy-2’-methoxy-2,9,9-trimethyl-6,7benzomorphan hydrochloride are obtained, melting point 233-236° C (dec.).
Butinazocine
765
21.8 g (0.5 mol) of a 55% dispersion of sodium hydride in oil are added to 52.2 g (0.2 mol) of 5-hydroxy-2’-methoxy-2,9,9-trimethyl-6,7-benzomorphan in 500 ml of dry peroxide-free tetrahydrofuran, followed by the drop-wise addition over 45 min of 142.0 g (1.0 mol) of methyliodide, and the mixture is stirred for 4 h at room temperature, 9 ml of water are added carefully to the obtained reaction mixture and the tetrahydrofuran is evaporated off under reduced pressure. After addition of 250 ml of water the residue is extracted 3 times with 250 ml of chloroform. The combined chloroformic phases are dried over sodium sulfate and concentrated under reduced pressure. The residue is converted into the hydrochloride, washed with toluene to remove paraffin oil and crystallized form methanol/ethylacetate. There are obtained 53.5 g of the 2’,5-dimethoxy-2,9,9-trimethoxy-6,7-benzomorphan hydrochloride, melting point 212-214°C (dec.). A solution of 4.68 g (44 mmol) cyanogenbromide in 28 ml chloroform are added drop-wise within 5 min to a solution of 8.25 g (30 mmol) 2’,5dimethoxy-2,9,9-trimethyl-6,7-benzomorphan in 20 ml dry ethanol free chloroform. After boiling for 4 h under reflux the solution is concentrated under reduced pressure, the residue dissolved in 150 ml toluene, washed twice with 50 ml 2 N hydrochloric acid and once with water, dried over sodium sulfate and evaporated to dryness under reduced pressure to yield 7.82 g 2cyano-2’,5-dimethoxy-2,9,9-trimethyl-6,7-benzomorphan. The obtained residue is dissolved in 40 ml of dry peroxide-free tetrahydrofuran and the solution added drop-wise under a nitrogen atmosphere over a period of 20 min to a suspension of 2.10 g (61.7 mmol) of lithium aluminum hydride in 85 ml tetrahydrofuran. After boiling for 3 h under reflux and cooling, 2.1 ml water, 1.6 ml 4 N sodium hydroxide solution, 7.3 ml water and 85 ml chloroform are added sequentially. After stirring for 30 min the obtained hydroxide is filtered off over hyflo. The precipitate is stirred 3 times with 50 ml chloroform/butanol (9:1). The filtrate washed with water, dried over sodium sulfate and concentrated under reduced pressure. The residue is converted into the hydrochloride and crystallized from methanol/ethylacetate to yield 4.9 g of the 2’,5-dimethoxy-9,9-dimethyl-6,7-benzomorphan hydrochloride, melting point 220-222°C (dec.). A solution of ethanethiol in dimethylformamide (DMF) are added dropwise to a suspension of sodium hydride (55% suspension in oil) in dry DMF. The obtained suspension is stirred for a further 45 min and a solution of 2’,5dimethoxy-9,9-dimethyl-6,7-benzomorphan in 190 ml of dry DMF are added dropwise over 20 min. The initially formed volatile components are distilled off and the reaction mixture heated until the DMF boils. After boiling for 6 h under reflux the reaction mixture is concentrated under reduced pressure and the residue taken up in toluene and 2 N hydrochloric acid. The acid aqueous phase is made alkaline with 25% ammonia and extracted 3 times with chloroform/butanol (8:2). After evaporation of the organic phase, the residue is converted into the 9,9-dimethyl-2’,5-dihydroxy-6,7-benzomorphan hydrochloride, (crystallized from isopropanol). A mixture of 9,9-dimethyl-2’,5-dihydroxy-6,7-benzomorphan hydrochloride, calcium carbonate and toluene-4-sulfonic acid but-3-ynyl ester in dimethylformamide is heated and subsequently concentrated under reduced pressure. The residue is taken up in a mixture of water and chloroform (1:1) and the aequeous phase extracted twice with chloroform/butanol (9:1). The combined organic phases are concentrated under reduced pressure to give the
766
Butirosin
2-butynyl-9,9-dimethyl-2’,5-dihydroxy-6,7-benzomorphan (crystallized from methanol/ethylacetate). References Akkerman A.M. et al.; US Patent No. 4,425,353; January 10, 1984; Assigned: ACF Chemiefarma NV, Maarssen, Netherlands
BUTIROSIN Therapeutic Function: Chemical Name: N1-(4-Amino-2-hydroxybutyryl)-4-O-2,6-diamino-2,6didexy-D-glucopyranosyl)-5-O-D-xelofuranosyl-2-deoxystreptamine (mixture of A- and B-form) Common Name: Ambutyrosin; Butirosin Structural Formula:
Chemical Abstracts Registry No.: 12772-35-9 Trade Name
Manufacturer
Country
Year Introduced
Butirosin
SigmaAldrich
-
-
Butirosin
767
Raw Materials Amberlite Carbobenzoxy chloride N-Hydroxysuccinimide Palladium on charcoal
5-β-D-Xylofuranosylneamine L-(-)-γ-Amino-α-hydroxybutyric acid Dicyclohexylcarbodiimide
Manufacturing Process Ambutyrosin is the another name of butirosin. Ambutyrosin obtained from fermentation broths of Bacillus circulans contains a major proportion of N1-(4amino-2-hydroxybutyryl)-4-O-2,6-diamino-2,6-didexy-D-glucopyranosyl)-5-OD-xelofuranosyl-2-deoxystreptamine (ambutyrosin A) and a minor proportion (up to 10-15%) of N1-(4-amino-2-hydroxybutyryl)-4-O-2,6-diamino-2,6didexy-D-glucopyranosyl)-5-O-D-ribofuranosyl-2-deoxystreptamine (ambutyrosine B). A process for preparation of ambutyrosin by semisynthetic procedure of acylating of 5-β-D-xylofuranosylneamine or 5-βribofuranosylneamine is described below. Preparation of 5-β-D-pentofuranosyIneamine: ambutyrosin A (1.0 g) in 30 ml of 0.5 N sodium hydroxide solution was refluxed for one hour, then neutralized with 6 N hydrochloric acid and applied on a column of Amberlite CG-50 (NH4+ form, 30 ml). The column was washed with water (ca. 100 ml) until the ninhydrin test became negative, and then eluted with 0.2 N ammonium hydroxide. Biologically active fractions were collected, concentrated in vacuum to 5 ml and treated with 5 ml of methanol to induce precipitation. It was further purified by re-precipitation from aqueous methanol to yield 607 mg (65%) of deacylated ambutyrosin A hereafter referred to as DA1. The wash water of the above CG-50 column was adjusted to pH 7.0 and applied on a column of Amberlite IR-120 (H+ form, 30 ml). The column was washed with water and then eluted with 1 N ammonium hydroxide. Ninhydrinpositive fractions were combined, treated with active carbon and neutralized with IRC-50 resin (H+ form). The solution was concentrated to a small volume, treated with ethanol, and kept in the cold overnight to yield 160 mg (75%) of γ-amino-α-hydroxybutyric acid as colorless needles which melted at 217°C-218°C. [α]D23= -30.3° (c=1.0%, H2O). The above experiments were also carried out on 1.0 g of ambutyrosin B yielding 579 mg (62%) of deacylated ambutyrosin B, hereafter called DA2. L-(-)-γ-benzyloxycarbonylamino-α-ydroxybutyric acid: L-(-)-γ-amino-αhydroxybutyric acid (7.4 g, 0.062 mole) was added to 50 ml of aqueous sodium 3 hydroxide solution (5.2 g, 0.13 mole). To the solution was added dropwise 11.7 g (0.068 mole) of carbobenzoxy chloride with stirring at 0°C to 5°C for one hour. The reaction mixture was washed with 50 ml of ether, adjusted to pH 2 with dilute hydrochloric acid, and extracted with four 80-ml portions of ether. The extracts were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated in vacuum, and the residue was crystallized from benzene to give 11.6 g (74%) of 4 colorless plates. M.P: 78.5°-79.5°C. N-Hydroxysuccinimide ester of L-(-)-γ-benzyloxycarbonylamino-α-
768
Butirosin
hydroxybutyric acid: a solution of L-(-)-γ-benzyloxycarbonylamino-αhydroxybutyric acid (10.6 s g, 0.042 mole) and N-hydroxysuccinimide (4.8 g, 0.042 mole) in 200 ml of ethyl acetate was cooled to 0°C and added to 8.6 g (0.042 mole) of dicyclohexylearbodiimide. The mixture was stirred overnight at 5°C. The dicyclohexylurea which separated was removed by filtration, and the filtrate was concentrated in vacuum. The product was obtained as colorless plates. Yield: 13.4 g (92%). M.P: 117°-118°C [α]D23= +1.5° (c= 2.0%, CHCl3). N-(Benzyloxycarbonyloxy)succinimide: N-hydroxysuccinimide (23 g, 0.2 mole) was dissolved in 200 ml of aqueous NaOH solution (9 g, 0.22 mole). To the stirred solution was added dropwise 34 g (0.2 mole) of carbobenzoxy chloride with water-cooling. The mixture was stirred overnight at room temperature, and the precipitate which separated was collected by filtration, washed with water, and air dried. Yield: 41.1 g (82%). Recrystallization from benzene-nhexane (10:1) gave colorless prisms melting at 78°-79°C. 6'-Carbobenzoxy-DA1 and 1,6'-dicarbobenzoxy-DA1: To a solution of 9.1 g (20 mmoles) of above prepared DA1 in 150 ml of water and 60 ml of tetrahydrofuran (THF) was slowly added, under vigorous stirring and cooling (5°C), a solution of 5.17 g (20.8 mmoles) of N(benzyloxycarbonyloxy)succinimide in 60 ml of THF. The mixture was stirred for 24 hours at 5°C and for an additional 16 hours at room temperature and then concentrated in vacuum to dryness. The crude product thus obtained was roughly separated into two fractions by a preparative counter-current distributor (52 tubes, 100 ml/tube) using a solvent system of n-BuOHCHCl3·H2O (4:1:5). Tube No. 1-15 were combined and evaporated in vacuum to give 9.75 g of solid. The solid was dissolved in 20 ml of water and applied on a column of amberlite CG-50 (NH4+ form, 120 ml). The column was washed with water and then eluted with aqueous 0.1 N ammonium hydroxide collecting each 20-ml fraction. Fractions No 62-93 were combined and concentrated in vacuum to give 5.75 g (49%) of 6'-carbobenzoxy-DA1 as a white solid. NMR in D2O and elememtal analysis confirmed its structure. Tubes No. 36-49 from the above current distribution were combined and evaporated in vacuum to give 2.91 g of solid. The solid was further purified by silica gel column chromatography developed with methanol-ethyl acetate (4:1) to yield 1.11 g (7.5%) of 1,6'-dicarbobenzoxy-DA1. TLC [silica gel plate, MeOAc-n-PrOH-28% NH4OH (45:105:60)]. Rf=0.44. 1-[L-(-)-γ-Amino-α-hydroxybutyryl]-DA1: a solution of 6'-carbobenzoxy-DA1 (588 mg, 1 mmole) in 10 ml of water and 5 ml of THF was added dropwise to a solution of N-hydroxysuccinimide ester of L-(-)-γ-benzyloxycarbonylamino-αhydroxybutyric acid (350 mg, 1 mmole) in 5 ml of THF with stirring and cooling (5°C). The mixture was stirred overnight at room temperature and then concentrated in vacuum to dryness. The residue was shaken with a mixture of n-butanol-ethyl acetate-water (4:1:5). The upper layer of the solvent mixture was separated and evaporated in vacuum to dryness. The solid thus obtained was dissolved in 30% aqueous ethanol and hydrogenated over 250 mg of 10% palladium-on-charcoal at room temperature. The reaction mixture was filtered to remove the palladium catalyst, and the filtrate
Butixocort
769
was concentrated in vacuum to dryness. The residual solid was dissolved in 10 ml of water and chromatographed on a column of CG-50 (NH4+ form, 40 ml). The column was washed by water and then eluted fractionally with aqueous 0.5 N NH4OH. Biologically active fractions which showed Rf=0.20 by TLC were collected, concentrated in vacuum and lyophilized to give 94 mg (14%) of product as a white solid, which was identified with ambutyrosin A in every respect. It melts with decomposition over a wide range beginning at about 149°C. [α]D25= +26°C (1.4%, water). Ambutyrosin B was prepared in a similar manner. It melts with decomposition at about 146°C [α]D25=+33° (1.5%, water). References Kawaguchi H. et al.; US Pataent No. 3,792,037; February 12, 1974; Assigned to Bristol-Myers Company, New York, N.Y. Woo P.W.K. et al.; US Patent No. 3,541,078; November 17, 1970; Assigned to Parke, Davis and Company, Detroit, Mich., a corporation of Michigan
BUTIXOCORT Therapeutic Function: Glucocorticoid Chemical Name: 11β,17-Dihydroxy-21-mercaptopregn-4-ene-3,20-dione 17butyrate Common Name: Butixocort; Tixocortol butyrate Structural Formula:
Chemical Abstracts Registry No.: 120815-74-9 Trade Name
Manufacturer
Country
Year Introduced
Butixocort
Jouveinal
-
-
Butixocort
Onbio Inc.
-
-
Raw Materials S-Thioacetic acid Hexametapol
Sodium methylate methanolic solution Cortisol-21-mesylate-17-butyrate
770
Butoconazole nitrate
Manufacturing Process 3,20-Dione-11β-hydroxypregn-4-ene-21-thioacetate-17-butyrate (or hydrocortisone): 10.0 g (0.129 mole) of S-thioacetic acid and 220 ml of hexametapol are introduced into a reactor 27.7 ml of a 4.65 N sodium methylate methanolic solution (0.129 mole) are introduced, accompanied by stirring, at a temperature close to 20°C and then the beige solution is stirred for 1 hour at ambient temperature. Within 10 minutes, a solution of 44.0 g (0.086 mole) of cortisol-21-mesylate-17-butyrate is introduced into 440 ml of hexametapol. The solution is stirred for 2.5 hours at ambient temperature. The orange solution is precipitated in 8 liters of ice water. The insoluble substances formed are filtered and then taken up in methyl ether. The ethereal solution is extracted twice with 250 ml of 1 N sodium hydroxide solution and then three times with 500 ml of saturated sodium chloride solution. After drying the ethereal phase, the solvent is eliminated by distillation. The residue (39 g) is purified by column chromatography with the aid of 1 kg of "Florisil''. Elution by a mixture of dichloromethane and acetone 95:5 (v/v) makes it possible to collect 21 g of purified product. This product is finally recrystallized in 170 ml of a mixture of methanol and water 8:2 (v/v). Weight=19 g. Yield=44.3%. Melting point: 130°C; the structure of prepared compound is confirmed by NMR spectrum. References Aubard et al; US Patent No. 4,933,331; June 12, 1990; Assigned to Jouveinal, S.A., Paris, France
BUTOCONAZOLE NITRATE Therapeutic Function: Antifungal Chemical Name: 1H-Imidazole, 1-(4-(4-chlorophenyl)-2-((2,6dichlorophenyl)thio)butyl)-, mononitrate Common Name: Butoconazole nitrate Structural Formula:
Chemical Abstracts Registry No.: 64872-77-1 Trade Name
Manufacturer
Country
Year Introduced
Butoconazole nitrate
Cipla Limited
India
-
Butoconazole nitrate
771
Trade Name
Manufacturer
Country
Year Introduced
Femstat
Hoffmann - LaRoche Inc.
-
-
Femstat 3
Procter and Gamble
-
-
Femstat 3
Roche
-
-
Gynazole-1
KV Pharmaceutical Co.
USA
-
Gynomyk
Will-Pharma B.V.
Netherlands
-
Raw Materials Imidazole Glycidyl tosylate, (+/-)Triethylamine Methanesulfonyl chloride
4-Chloromagnesium chloride Sodium hydride Dilithium tetrachlorocuprate(II) 2,6-Dichlorobenzenethiol
Manufacturing Process 1H-Imidazole, 1-(4-(4-chlorophenyl)-2-((2,6-dichlorophenyl)thio)butyl)-, (+/)-, mononitrate may be prepared by the same way as described below for enantiomers. To a solution of Li2CuCl4 (0.10 M, 8.8 ml, 0.88 mmol) in dry THF (75 ml) was added dropwise a solution of 4-chloromagnesium chloride (17.5 mmol) in ether (15 ml) at -35°C. After stirring for 45 min, a pre-cooled (-35°C) solution of (S)-(+)-glycydil tosylate (2.0 g, 8.8 mmol) in THF (5 ml) was added via syringe. After 2 h at -35°C, the mixture was quenched with saturated NH4Cl and extracted with ether. The organic layer was dried (Na2SO4), evaporated to dryness and purificated by flash chromatography affording (2S)-1-(ptoluenesulphonyloxy)-4-(4-chlorophenyl)butan-2-ol, as a white solid (1.9 g, 77%), m.p. 72.7-74°C. (2S)-1-[2-Hydroxy-4-(4-chlorophenyl)butyl]-1H-imidazole was prepared as follows: to a solution of imidasole (0.52 g, 7.61 mmol) in dry DMF (5 ml) at 0°C under N2 was added NaH (60% dispersion in oil, 0.3 g, 7.61 mmol). The reaction mixture was warmed to room temperature and stirred for 30 min. A solution of (2S)-1-(p-toluenesulphonyloxy)-4-(4chlorophenyl)butan-2-ol in DMF (15 ml) was then added dropwise over 15 min. The reaction mixture was heated at 75°C for 24 h, cooled poured into water and extracted with ethyl acetate. The organic phase was dried and evaporated and was the residue purified by flash chromatography. Gradient elution (1-5% MeOH/CH2Cl2) afforded (2S)-1-[2-hydroxy-4-(4-chlorophenyl)butyl]-1H-imidazole which was recrystallized from EtOAc/Et2O (236 mg, 67%), m.p. 128°-131°C; [α]D2523.23 (c 0.4, CHCl3). (2S)-1-[2-Hydroxy-4-(4-chlorophenyl)butyl]-1H-imidazole nitrate was prepared as follows. To a solution of (2S)-1-(p-toluenesulphonyloxy)-4-(4chlorophenyl)butan-2-ol (250 mg, 1 mmol) in THF (5 ml) at 0°C was added triethylamine (0.28 ml, 2.0 mmol), followed by methanesulfonyl chloride (0,15 ml, 2.0 mmol). The reaction mixture was was warmed to room temperature and stirred for 1 h. The mixture was poured into aq. NaHCO3, extracted with EtOAC, and the organic phase dried and evaporated to dryness. The resulting mesylate was dissolved in acetone (50 ml), then 2,6-dichlorobenzenethiol
772
Butofilolol
(464 mg, 2.6 mmol) and K2CO3 (568 mg, 4.1 mmol) were added. The mixture was heated at reflux under N2, cooled to room temperature, evaporated to dryness and partionated between water and EtOAc. The organic phase was dried (Na2SO4), evaporated, and residue purified by flash chromatography (12% MeOH/CH2Cl2 gradient elution) to give an oil which was converted to nitrate salt. Recrystallization from EtOAc/Et2O gave 260 mg (55%) (2S)-1-[2hydroxy-4-(4-chlorophenyl)butyl]-1H-imidazole nitrate, m.p. 120°-124°C; [α]D25+22.68 (c 0.4, EtOH). The R enantiomer was prepared the same way from (-)-glycidyl tosylate. References Walker K.A.M. et al.; US Patent No. 4,036,970; July 19, 1977; Assigned: Syntex (U.S.A.) Inc. (Palo Alto, CA) Tetrahedron, v.4, No 7, pp. 1521-1526, 1993, D.M. Rotstein, K.A.M. Walker
BUTOFILOLOL Therapeutic Function: Beta-adrenergic blocker Chemical Name: 1-[2-[3-[(1,1-Dimethylethyl)amino]-2-hydroxypropoxy]-5fluorophenyl]-1-butanone Common Name: Structural Formula:
Chemical Abstracts Registry No.: 64552-17-6 Trade Name
Manufacturer
Country
Year Introduced
Cafide
Clin Midy
France
1982
Raw Materials 5-Fluorosalicylaldehyde Propyl Magnesium Bromide Hydrogen chloride
1-Chloro-2-hydroxy-3-t-butylaminopropane Sodium hydride
Butofilolol
773
Manufacturing Process (a) 5-Chloromethyl-3-tert-butyl-2-(2-hydroxy-5-fluorophenyl)oxazolidine: 5Fluorosalicylaldehyde (1.4 g, 0.01 mol) is dissolved in anhydrous benzene (20 ml) in the presence of a crystal of p-toluenesulfonic acid in a Dean-Stark apparatus. 1-Chloro-2-hydroxy-3-tert-butylaminopropane (2.08 g, approximately 1 equivalent, purity 75%) is then added within a period of 10 hours in portions of 250 mg at a time at the reflux temperature of benzene and the mixture is allowed to stand overnight. An insoluble substance is precipitated on addition of ether after which the solution is filtered, concentrated and distilled. A fraction is obtained having a boiling point of 118°-123°C/10-3 mm of mercury. A mixture of 1.03 g (yield 43%) of isomeric oxazolidines is obtained which solidifies. This is crystallized once from hexane. Melting point 75°-78°C. (b) 8-Aza-4,9-dioxa-11l-fluoro-8-tert-butyl-2,3-benzobicyclo[4.2.1]octane: The product of the previous stage (620 mg) is dissolved in anhydrous dimethylformamide (10 ml) and two quantities each of 300 mg of 50% sodium hydride is added within 2 hours. The mixture is then left for 24 hours at 25°C while being stirred mechanically and is then heated for 2 minutes on a water bath (80°-90°C). The mixture is poured into water, the product extracted with ether, the ethereal extract dried over anhydrous sodium sulfate and the organic phase then concentrated and filtered through a short column of activated alumina. A mixture of light petroleum and diethyl ether (75:25) is used to elute 186 mg of pure product from the column. Melting point 85°86°C (after recrystallization from diisopropyl ether). (c) 1-(2-Formyl-4-fluorophenoxy)-2-hydroxy-3-tert-butylaminopropane: The compound obtained as described above (50 mg) is dissolved in a solution of 1N hydrochloric acid (0.5 ml). The mixture is then heated on a water bath (80°-90°C) for several hours. After complete hydrolysis, which requires approximately 8 hours, the mixture is poured into an excess of water which has been basified, the solid base thus formed is extracted with ether, dried and recrystallized from diisopropyl ether. Melting point 103°-105°C. (d)1-[2(1-Hydroxybutyl)-4-fluorophenoxy]-2-hydroxy-3-tertbutylaminopropane: To a solution of propylmagnesium bromide prepared from 195 mg (8.1 X 10-3 mol) of magnesium, 1.08 g (8.1 X 10-3 mol) of bromopropane and a crystal of iodine in 10 ml of anhydrous diethyl ether under nitrogen is added a solution of the previously prepared aldehyde (197 mg, 0.73 x 10-3 mol) in 4 ml of an ether/tetrahydrofuran mixture (1:3 by volume) and the mixture is heated to reflux for 70 minutes. The mixture is poured into water, extracted with diethyl ether, dried over anhydrous sodium sulfate and 208 mg of an oil which is homogeneous, as shown by thin-layer chromatography, is isolated. (e) CM 6805 (Butofilolol): The previously prepared base (200 mg, 0.66 X mol) is dissolved in purified acetone (8 ml). A drop of sulfuric acid solution (prepared from 35 ml of concentrated sulfuric acid and 65 ml of water) is added and the mixture heated on a water bath for 1 minute. When the solution has cooled to 5° to 10°C a solution of chromic acid (66 mg, 1 equivalent) dissolved in 2 ml of the same acid solution is quickly added and the resulting mixture is stirred while cold. The mixture is then poured into a saturated solution of sodium carbonate, the acetone is evaporated under
774
Butopamine
reduced pressure on a water bath, and the organic phase is extracted with diethyl ether. After drying and evaporating the solvent an oil is obtained (172 mg) all of which solidifies. Recrystallization is carried out from diisopropyl ether. 122 mg of CM 6805 is obtained (yield 61%). Melting point 88°-89°C. References Merck Index 1500 DFU 7 (2) 96 (1982) DOT 18 (10) 551 (1982) and 19 (2)112 (1983) I.N. p.169 Demame, H.; US Patent 4,252,825; February 24, 1981; assigned to C.M. Industries.
BUTOPAMINE Therapeutic Function: Cardiotonic Chemical Name: 4-Hydroxy-α-[[[3-(4-hydroxyphenyl)-1-methylpropyl] amino]methyl]benzenemethanol Common Name: Butopamine Structural Formula:
Chemical Abstracts Registry No.: 66734-12-1 Trade Name
Manufacturer
Country
Year Introduced
Butopamine
ZYF Pharm Chemical
-
-
Butopamine
Lilly
-
-
Raw Materials Ammonia Hydrochloric acid Palladium on carbon Sodium hydroxide
Methyl 2-(4-benzyloxyphenyl)ethyl ketone Hydrogen 1-(4-Hydroxyphenyl)-2-aminoethanol
Manufacturing Process A solution of 32.8 g (0.2 m) of methyl 2-(4-hydroxyphenyl)ethyl ketone and 42.6 g (0.2 m) of 1-(4-hydroxyphenyl)-2-aminoethanol in 380 ml of ethanol
Butorphanol
775
containing 3.8 g of 5% palladium on carbon was stirred for 16 h at 60°C under hydrogen at 55 psi. The reaction mixture was then filtered, and the filtrate was diluted by addition of 350 ml of water. The aqueous mixture was concentrated to a volume of about 400 ml, and then washed with dichloromethane. The aqueous mixture was acidified by addition of 50 ml of conc. hydrochloric acid. After standing at room temperature for 2 h, the aqueous acid mixture was filtered and the filter cake was washed with 40 ml of ice water and dried at 50°C in vacuum to provide 47.0 g of 1-(4-hydroxyphenyl-2propylamino]ethanol hydrochloride, melting point 124-129°C. The 1-(4-hydroxyphenyl)-2-[1-methyl-3-(4-hydroxyphenyl)propylamino] ethanol was obtained by treatment of 1-(4-hydroxyphenyl-2propylamino]ethanol hydrochloride with sodium hydroxide. References Anderson D.B. et al.; US Patent No. 4,690,951; September 1, 1987; Assigned: Eli Lilly and Company, Indianapolis, Ind.
BUTORPHANOL Therapeutic Function: Analgesic, Antitussive Chemical Name: N-Cyclobutylmethyl-3,14-dihydroxymorphinan Common Name: Structural Formula:
Chemical Abstracts Registry No.: 42408-82-2 Trade Name
Manufacturer
Country
Year Introduced
Stadol
Bristol-Myers
US
1978
Stadol
Bristol-Myers
UK
1980
Moradol
Galenika
Yugoslavia
-
Raw Materials N-Cyclobutylmethyl-14-hydroxy-3-methoxymorphinan Hydrogen bromide
776
Butoxamine hydrochloride
Manufacturing Process A mixture of 1.0 g (2.58 mmols) of N-cyclobutylmethyl-14-hydroxy-9methoxymorphinan and 10 ml of 48% HBr was refluxed, under a nitrogen atmosphere, during five minutes. After cooling, the reaction mixture was diluted with water and made basic with aqueous ammonium hydroxide. The aquous basic mixture was extracted with chloroform and the combined chloroform extracts were dried over anhyrous sodium sulfate. After evaporation of the solvent, the residual oil (730 mg) was taken up in dry ether and the resulting solution filtered through celite-charcoal. The filtrate was treated with a saturated solution of hydrogen chloride in dry ether. The hydrochloride salt thus obtained was collected by filtration and recrystallized from a methanol-acetone mixture to yield 565 mg (56.5%)of Butorphanol hydrochloride crystals melting at 272°-274°C (decomposition). References Merck Index 1503 DFU 2 (4) 231 (1977) and 3 (5) 330 (1978) Kleeman and Engel p.129 PDR p.713 OCDS Vol.2 p.325 (1980) DOT 14 (5)197 (1978) I.N. p.170 REM p.1107 Monkovic, I. and Conway, T.T.; US Patent 3,775,414; November 27, 1973; Monkovic, I., Wong, H. and Lim, G.; US Patent 3,980,641; September 14, 1976; Pachter, I.J., Belleau, B.R. and Monkovic, I.; US Patent 3,819,635; June 25, 1974; and Lim, G. and Hooper,
BUTOXAMINE HYDROCHLORIDE Therapeutic Function: Oral hypoglycemic, Antihyperlipidemic Chemical Name: Benzenemethanol, α-(1-((1,1-dimethylethyl)amino)ethyl)2,5-dimethoxy-, (R*,S*)-(+-)-, hydrochloride Common Name: Butaxamine hydrochloride; Butoxamine hydrochloride Structural Formula:
Butriptyline
777
Chemical Abstracts Registry No.: 5696-15-1 Trade Name
Manufacturer
Country
Year Introduced
Butoxamine hydrochloride
SigmaAldrich
-
-
Raw Materials Butylamine Platinum Hydrochloric acid
2,5-Dimethoxy-α-bromopropiophenone Hydrogen Sodium hydroxide
Manufacturing Process 548.0 g (2 mol) of 2,5-dimethoxy-α-bromopropiophenone was dissolved in 500 ml of acetanitrile and 365.0 g (5 mol) of t-butylamine was added. The solution was allowed to stand at room temperature for 64 h and was then diluted with 2 L of anhydrous ether. The precipitated t-butylamine hydrobromide was filtered off and washed with ether. The filtrate and washings were concentrated in vacuo using a water-bath kept at 40°C. When most of the solvent had been removed, the residual material was dissolve in cold methanol and acidified with hydrochloric acid. The solution was then taken down to dryness in vacuo on the steam bath and the 1-(2,5dimethoxyphenyl)-2-(t-butylamino)propiophenone was obtained, melting point 175-176°C (recrystallised from an ethanol ether mixture). The bulk of the 1-(2,5-dimethoxyphenyl)-2-(t-butylamino)propiophenone was dissolved in methanol and hydrogenated over platinum (Adams' catalyst). After removal of the catalyst, the solvent was removed in vacuo and the residual solid was dissolved in water and the solution was washed with ether. The aqueous layer was basified (dilute sodium hydroxide solution) and the base was taken into ether. After drying over anhydrous potassium carbonate, the ether was evaporated and the base was distille at 0.3 mm pressure. So the DL-erythro 1-(2,5-dimethoxyphenyl)-2-(t-butylamino)propanol, boiling point 127-128°C was obtained. References GB Patent No. 1,104,292; February 21, 1968; Assigned: The Wellcome Foundation Limited, of 183-193 Euston Road, London
BUTRIPTYLINE Therapeutic Function: Antidepressant Chemical Name: (+-)-10,11-Dihydro-N,N,β-trimethyl-5H-dibenzo[a,d] cycloheptene-5-propanamine
778
Butriptyline
Common Name: Structural Formula:
Chemical Abstracts Registry No.: 35941-65-2; 5585-73-9 (Hydrochloride salt) Trade Name Evadyne Evadene Centrolyse Evasidol
Manufacturer Ayerst Ayerst Ayerst Arcana
Country UK Italy Austria
Year Introduced 1975 1976 -
Raw Materials Dibenzo[a,e]cycloheptadiene Sodium hydride 2-Methyl-3-dimethylaminopropyl chloride Manufacturing Process A solution of dibenzo[a,e]cycloheptadiene in anhydrous xylene is added in a dropwise fashion with stirring to a suspension of sodium hydride in refluxing anhydrous xylene. The mixture is heated at reflux for two hours with continual agitation and there is then added dropwise a solution of 2-methyl-3dimethylaminopropyl chloride in an equal volume of xylene. The mixture is then heated for fifteen hours, after which time it is cooled and decomposed by the cautious addition of ice water. The layers are separated and the aqueous layer extracted with ether. The combined organic layers are next extracted with 10% hydrochloric acid and the acidic extracts then rendered alkaline by the addition of ammonium hydroxide. The precipitated oil is extracted three times with chloroform. The chloroform extracts are dried and concentrated in vacuo, the residue being distiiled to yield the product. References Merck Index 1506 Kleeman and Engel p.131 OCDS Vol.1 p.151 (1977) DOT 9 (6) 219 (1973) and 10 (7) 235 (1974) I.N. p.170 Villani, F.J.; US Patent 3,409,640; November 5, 1968; assigned to Schering Corporation
Butropium bromide
779
BUTROPIUM BROMIDE Therapeutic Function: Spasmolytic Chemical Name: [3(S)-endo]-8-[(4-Butoxyphenyl)methyl]-3-(3-hydroxy-1oxo-2-phenylpropoxy)-8-methyl-8-azoniabicyclo[3.2.1]octane bromide Common Name: Structural Formula:
Chemical Abstracts Registry No.: 29025-14-7 Trade Name
Manufacturer
Country
Year Introduced
Coliopan
Eisai
Japan
1974
Raw Materials Hyoscyamin Butoxybenzyl bromide Manufacturing Process To 100 ml of an isopropanol solution containing 11.8 grams of hyoscyamine base were added drop by drop with stirring 10 ml of an isopropanol solution containing 11 grams of p-n-butoxybenzyl bromide. After a while, the reaction mixture had a turbid appearance followed by separation of white crystals. After stirring for 5 hours at room temperature, the crystals were recovered by filtration, which were then recrystallized from 120 ml of isopropanol. There was obtained 15.8 grams of white needles having the melting point of 158°160°C. References Merck Index 1507
780
Butylscopolamine bromide
Kleeman and Engel p.131 OCDS Vol.2 p.308 (1980) DOT 10 (11) 292 (1974) I.N. p.170 Tanaka, S.and Hasimoto, K.; US Patent 3,696,110; October 3, 1972; assigned to Eisai, KK, Japan
BUTYLSCOPOLAMINE BROMIDE Therapeutic Function: Anticholinergic, Spasmolytic Chemical Name: 1-alpha-H,5-alpha-H-Tropanium, 8-butyl-6-beta,7-betaepoxy-3-alpha-hydroxy-, bromide, (-)-tropate Common Name: Butylscopolamin(e) bromide; Butylscopolamini bromidum; Butylscopolammonium bromide; Hyoscine butyl bromide; Scopolamine butyl bromide; Scopolaminium butylbromatum Structural Formula:
Chemical Abstracts Registry No.: 149-64-4; 7182-53-8 (Base) Trade Name
Manufacturer
Country
Year Introduced
Butylscopolamine bromide
China Pharm Chemical Co., Ltd.
-
Scopolamine Nbutyl bromide
Andard-Mount Company Limited
-
-
Butylscopolamine bromide
Shchem Corporation
-
-
Scopolamine Butylbromide BP98
Shanghai Lancheng Corporation
-
-
Buscopan
-
-
Antispasmin
Boehringer Ingelheim Vetmedica, Inc. Green Cross
-
-
BS-ratiopharm
Ratiopharm
-
-
Butylscopolamine bromide
781
Trade Name
Manufacturer
Country
Year Introduced
Buscol
Pliva
-
-
Buscolysin
-
-
Buscolysin
PharmachimHolding AD Sopharma
-
-
Buscolysin
Pharmachim S.A
-
-
Buscopan
Boehringer Ingelheim Pharma
-
-
Buscovital
Vitalia K SA
-
-
Buscovital
Omega Pharma
-
-
Buspin
Intas
-
-
Buspon
Toyo Pharmar
-
-
Butilescopolamina Duncan
Duncan
-
-
Butipolan
Tobishi
-
-
Butopan
-
-
-
-
-
-
Cifespasmo
Biofarma Ilac San. ve Tic. A.S. Hokuriku Seiyaku Co. Ltd. Kobayashi Kako Co. Ltd. Northia
-
-
Colobolina
Fabra
-
-
Cryopina
Highnoon Laboratories Limited
-
-
Dhacopan
-
-
Dividol Remedica
Haw Par Healthcare Ltd. Remedica Ltd.
-
-
Espa-butyl
Innopharm
-
-
Hioscina
Veinfar
-
-
Hioscina, butilbromuro Hioscina
Fabra
-
-
Zimaia
-
-
Hioscina Fada
Fada Pharma
-
-
Hioscina N-butyl bromuro N-Butylbromuro de hioscina
Bussie S.A.
-
-
Laboratorios Synthesis -
-
Hioscina N-Butil
Richmond
-
-
Hybropan
Binex
-
-
Hyospan
Howards/LCPW
-
-
Hyospasmol
Pharmacare Limited
-
-
Hyospasmol
Lennon
-
-
Hyospasmol
Aspen Pharmacare
-
-
Hyscopan
M/s. Indus, Karachi.
-
-
Butylpan Butysco
782
Butylscopolamine bromide
Trade Name
Manufacturer
Country
Year Introduced
Hyscopan
Armoxindo Farma
-
-
Hysopan
Rephco Laboratories Ltd.
-
-
Hysopan
Lahore Chemical and Pharmaceutical Works (LCPW) (PVT.) Ltd.
-
-
Luar G
Klonal
-
-
Pasmodina
Drawer
-
-
Rupe N
Bioquim
-
-
Scobut
Laboratoarele Magistra
-
-
Scobutil
Sicomed S.A.
-
-
Scopex
Propan
-
-
Scopinal
Julphar
-
-
Scopolan
Herbapol Wroclaw
-
-
Selpiran-S
Laboratorios Diba, S. A.
-
-
Sparicon
Masung and Co., Ltd.
-
-
Spasman scop.
Merckle
-
-
Spasmopan
APM
-
-
Spasmopan
LEX LECIVA a.s
-
-
Spasmowern
Pharma Wernigerode
-
-
Raw Materials Scopolamine n-Butyl bromide Manufacturing Process 1300 g of scopolamine base and 350 g of n-butylbromide in 600 ml acetonitrile is heated at 65°C for 160 hours. The oil obtained is dissolved in methanol. The solution is cooled and crystalline scopolamine N-n-butylbromide is filtered. After recrystallization from methanol was obtained scopolamine Nn-butylbromide with melting point 142-144°C and [α]d20 = -20.5° (3% solution in water); yield 65%. References Merck Index, Monograph number: 1624, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. Adickes F., DE Patent No. 856,890; 1952.11.24; Assigned to Boenhringer Sohn Ingelheim
C
CABERGOLINE Therapeutic Function: Prolactin inhibitor Chemical Name: 1-((6-Allylergolin-8β-yl)carbonyl)-1-(3-(dimethylamino) propyl)-3-ethylurea Common Name: Cabergoline Structural Formula:
Chemical Abstracts Registry No.: 81409-90-7 Trade Name
Manufacturer
Country
Year Introduced
Destinex
Farmitalia Carlo Erba
Italy
-
Cabergoline
Pharmacia and Upjohn
-
-
Raw Materials 6-Methyl-8β-carboxy-ergoline N-(3-Dimethylaminopropyl)-N-ethyl carbodiimide Sodium hydroxide Manufacturing Process A mixture of 6-(2-propenyl)-8β-carboxy-ergoline and N-(3dimethylaminopropyl)-N-ethyl carbodiimide in tetrahydrofuran were refluxed, with stirring and under nitrogen, for 24 h. The resultant solution was evaporated in vacuo to dryness and the residue taken up with chloroform and
783
784
Cafaminol
5% sodium hydroxide solution. The organic phase was separated, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica (eluant chloroform with 1% methanol) to give the title compound N-(3-(dimethylamino)propyl)-N-((ethylamino)carbonyl)-8βcarboxamide-6-(2-propenyl)ergoline. References Salvati P. et al; US Patent No. 4,526,892; July 2, 1985; Assigned: Farmitalia Carlo Erba, S.p.A., Milan, Italy
CAFAMINOL Therapeutic Function: Nasal decongestant Chemical Name: 3,7-Dihydro-8-[(2-hydroxyethyl)methylamino]-1,3,7trimethyl-1H-purine-2,6-dione Common Name: Methylcoffanolamine Structural Formula:
Chemical Abstracts Registry No.: 30924-31-3 Trade Name
Manufacturer
Country
Year Introduced
Rhinoptil
Promonta
W. Germany
1974
Rhinetten
Arzneimittelwerk Dresden
E. Germany
-
Raw Materials 8-Chlorocaffeine beta-N-Methylaminoethanol Manufacturing Process 21 g 8-chlorocaffeine and 15 g beta-N-methylaminoethanol are heated to 140°-160°C for 30 minutes. Then the temperature is increased for 15-20 minutes to 165°-170°C. On cooling a colorless mass of crystals results. This is boiled with 50-60 ml ethanol and crystallized. Colorless crystals result which
Cafedrine
785
are soluble in water up to about 6%; pH of the aqueous solution is 6.9. The yield is 19 g while the MP is 162°-164°C. References Merck Index 1603 I.N. p. 173 Klosa, J.; US Patent 3,094,531; June 18,1963; assigned to Delmar Chemicals Ltd. (Canada)
CAFEDRINE Therapeutic Function: Analeptic Chemical Name: Theophylline, 7-(2-(beta-hydroxy-alpha-methylphenethylamino)ethyl)Common Name: Cafedrine; Kafedrin; Norephedrinoethyltheophylline Structural Formula:
Chemical Abstracts Registry No.: 78396-34-6 Trade Name
Manufacturer
Country
Year Introduced
Praxinor
Merck Lipha Sante
-
-
Cafedrine
Merck
-
-
Cafedrine
Shanghai Lancheng Corporation
-
-
Cafedrine
Gennapharm, Inc.
-
-
Akrinor
Adcock Ingram Ltd.
-
-
Akrinor
AWD Pharma GmbH and Co. KG
-
-
Bifort
Finadiet
-
-
786
Caffeine
Raw Materials 7-(2-Bromethyl)theophylline 1-Norphedrine Manufacturing Process 7.5 g 7-(2-bromethyl)theophylline, 11.3 g 1-norphedrine and 12.5 ml isopropanol were refluxed with stirring for 6 hours. Then 30 ml ethanol and HCl in ethanol to pH 5-6 were added. The mixture stood for 2 days. 9.6 g of 7-(2-(beta-hydroxy-alpha-methylphenethylamino)ethyl)theophylline hydrochloride was filtered off and dried. MP 243°-244°C. In practice it is usually used as free base. References Kohlstaedt E. et al.; D. B. Patent No. 1,095,285; 25 Sept. 1956; Assigned to Chemiewerk Homburg Zweigniedererlassung der Deutschen Gold- und Silber-Scheideanstalt vormals Roessler Franffurt/Main
CAFFEINE Therapeutic Function: Neurotropic, Central stimulant Chemical Name: 3,7-Dihydro-1,3,7-trimethyl-1H-purine-2,6-dione Common Name: Cafeina; Caféine; Caffeine; Coffein; Guaranine; Kafeiyin; Kaffein; Koffein; Mateina; Methyltheobromine; Thein Structural Formula:
Chemical Abstracts Registry No.: 58-08-2 Trade Name Caffedrine Caffeine Koffein Vivarin
Manufacturer Thompson Med. Prolab Prolab GlaxoSmithKline Consumer Healthcare, L.P.
Country USA
Year Introduced -
Calcifediol
787
Raw Materials Theophylline Dimethyl sulfoxide Dimethyl sulfate Manufacturing Process Caffeine was synthesized by the reaction N-chloromethylation of theophylline by action dimethylsulphate in dimethylsulfoxide. References DBP 834105 (Boehringer Ing.; Anm. 1949)
CALCIFEDIOL Therapeutic Function: Calcium regulator Chemical Name: 9,10-Secocholesta-5,7,10(19)-triene-3,25-diol Common Name: 25-Hydroxyvitamin D3; 25-Hydroxycholecalciferol Structural Formula:
Chemical Abstracts Registry No.: 19356-17-3 Trade Name
Manufacturer
Country
Year Introduced
Dedrogyl
Roussel
France
1976
Delakmin
Roussel
W. Germany
1978
Calderol
Upjohn
US
1980
Didrogyl
Roussel Maestretti Italy
1980
Dedrogyl
Hoechst
Switz.
1982
Hidroferol
Juventus
Spain
-
Calderol
Organon
US
-
788
Calcifediol
Raw Materials Cholesta-5,7-diene-3β,25-diol Manufacturing Process A solution of 125 mg of cholesta-5,7-diene-3β,25-diol in 125 ml of benzene and 10 ml of absolute ethanol is placed in a photo reactor equipped with a quartz lamp well cooled with water and a nitrogen inlet. The reaction mixture is cooled to about 16°C, and purged with N2. A Hanovia 8A36, 100-watt lamp, centered in the lampwell 2.5 cm from the internal surface of the reaction mixture, is turned on for 15 minutes, including the 5-6 minutes required for the lamp to reach full brilliance. The lamp is a typical actinic energy source suitable for the irradiation step in the known synthesis of Vitamin D, and can be replaced by any such available lamp. The specific lamp used is a 100-watt high-pressure quartz mercury-vapor lamp, producing approximately 11.5 watts total radiated energy distributed over the range of 220-1400 nm. A fast stream of water is necessary to keep the outlet water temperature below 20°C. The reaction mixture is concentrated to dryness in a rotary evaporator below room temperature. The semisolid residue is triturated with 5 ml of 35% ethyl acetate-65% Skellysolve B hexanes mixture and filtered and another 5 ml of the same solvent is used for wash. The solid contains unreacted starting material and the liquor contains the product. The liquor is poured onto a 40 g column containing TLC grade Florisil, 150-200 mesh packed wet with 35% ethyl acetate-Skellysolve B hexanes, and the products are eluted with the same solvent mixture collecting 10 ml fractions. The fractions containing the product, located by spotting on a TLC plate, are combined and evaporated to dryness below room temperature to give an oily residue. A few drops of absolute ether are added and removed under vacuum to give 25hydroxyprecholecalciferol as a fluffy foam; yield 60 mg. A solution of about 300 mg of 25-hydroxyprecholecalciferol prepared as described above in 5 ml of chloroform is heated for 3.5 hours at 70°-75°C under N2 in a sealed flask. The solvent is evaporated and the residue is chromatographed through a 60 g column containing TLC grade Florisil, 150200 mesh packed wet with 35% ethyl acetate in Skellysolve B hexanes. The column is eluted with the same solvent mixture, collecting 10 ml fractions. The fractions which crystallize on trituration with aqueous methanol are combined and recrystallized twice from aqueous methanol to give 25hydroxycholecalciferol hydrate; yield 120 mg, MP 81°-83°C (sinters 75°C). A solution of 20 mg of 25-hydroxycholecalciferol hydrate, prepared as described above, in 20 ml of methylene chloride is dried with 200 mg of anhydrous sodium sulfate. The solution is filtered and the filtrate is evaporated to yield 25-hydroxycholecalciferol essentially anhydrous as an amorphous oil. References Merck Index 1610 Kleeman and Engel p. 133 PDR p. 1285 OCDS Vol. 3 p. 101 (1984)
Calcipotriol
789
DOT 13 (6) 225 (1977) I.N. p. 174 Babcock, J.C. and Campbell, J.A.; US Patent 3,833,622; September 3, 1974; assigned to The Upjohn Company Saimond, W.G.; US Patent 4,001,096; January 4, 1977; assigned to The Upjohn Company
CALCIPOTRIOL Therapeutic Function: Antipsoriatic Chemical Name: 9,10-Secochola-5,7,10(19),22-tetraene-1,3,24-triol, 24cyclopropyl-, (1α,3β,5Z,7E,22E,24S)Common Name: Calcipotriene; Calcipotriol; Dovonex; MC 903 Structural Formula:
Chemical Abstracts Registry No.: 112965-21-6 Trade Name
Manufacturer
Country
Year Introduced
Psorcutan
KOHLPHARMA
-
-
Raw Materials (1S,3R)-Bis-(tert-butyldimethylsilyloxy)-(20S)-formyl-9.10-secopregna(5E,7E,10(19))triene (Cyclopropyl)(triphenylphosphoranylidene)ketone Cerium (III) chloride Cyclopropyl magnesium bromide Anthracene Sodium borohydride Triethylamine Tetrabutylammonium fluoride
790
Calcitonin
Manufacturing Process (1S,3R)-Bis-(t-butyldimethylsilyloxy)-(20S)-formyl-9,10-secopregna(5E,7E,10 (19))triene (Calverley Tetrahedron 43.4609 (1967) and (cyclopropyl)(triphenylphoshoranylidene)ketone are stirred in dimethyl sulfoxide under nitrogen. The reaction mixture is then diluted at room temperature with ethyl acetate and washed with common salt solution. The organic phase is dried on sodium sulfate and filtered. After removal of the solvent, the residue is filtered with toluene through silica gel. Evaporation of the solvent and gradient chromatography (toluene/hexane (1:1)-toluene) of the residue on silica gel yield (5E,7E,22E),(1S,3R)-1,3-bis-(t-butyldimethylsilyloxy)-24-cyclopropyl9,10-secochola-5,7,10(19),22-tetraene-24-one. (5E,7E,22E),(1S,3R)-1,3-Bis-(t-butyldimethylsilyloxy)-24-cyclopropyl-9,10secochola-5,7,10(19),22-tetraene-24-one in tetrahydrofuran and methanol are mixed with a 0.4 M methanol CeCl3·7H2O solution. Sodium borohydride is added by portions under nitrogen with ice cooling. The suspension is stirred with ice cooling and then put into ice/common salt solution. The aqueous phase is extracted with ethyl acetate, the organic phase is washed neutral with water and dried on sodium sulfate. Filtration and removal of the solvent yield oil. By chromatography on silica gel with ethyl acetate/hexane (1:9). The (5E,7E,22E),(1S,3R,24S)-1,3-bis-(t-butyldimethylsilyloxy)-24-cyclopropyl9,10-secochola-5,7,10(19),22-tetraene-24-ol is obtained. (5E,7E,22E),(1S,3R,24S)-1,3-Bis-(t-butyldimethylsilyloxy)-24-cyclopropyl9,10-secochola-5,7,10(19),22-tetraene-24-ol is dissolved in toluene and after addition of anthracene and 1 drop of triethylamine it is radiated at room temperature with a high pressure mercury vapor lamp (Heraeus TQ 150) through Pyrex glass. The reaction mixture is concentrated by evaporation and the residue a mixture of (5Z,7E,22E),(1S,3R,24S)-1,3-bis-(tbutyldimethylsilyloxy)-24-cyclopropyl-9,10-secochola-5,7,10(19),22-tetraene24-ol and anthracene - is directly reacted with tetrabutylammonium fluoride. (5Z,7E,22E),(1S,3R,24S)-1,3-Bis-(t-butyldimethylsilyloxy)-24-cyclopropyl9,10-secochola-5,7,10(19),22-tetraene-24-ol in tetrahydrofuran is kept with a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran under nitrogen. For working up, the cooled reaction mixture is poured into cold sodium bicarbonate solution and then extracted with ethyl acetate. After drying of the organic phase on sodium sulfate, filtration and evaporation of the solvent yields a resin-like residue. Chromatography on silica gel with ethyl acetate/hexane (2:1) yields (5Z,7E,22E),(1S,3R,24S)-24-cyclopropyl-9,10secochola-5,7,10(19),22-tetraene-1,3,24-triol. References Kircsch G. et al.; US Patent No. 5,665,716; Sept. 9, 1997; Assigned to Schering Aktiengesellscaft, Berlin, Germany
CALCITONIN Therapeutic Function: Calcium regulator
Calcitonin
791
Chemical Name: Complex hormone of molecular weight about 4,500 Common Name: Thyrocalcitonin Structural Formula: H-L-Cys-L-Ser-L-Asp(NH2)-L-Leu-L-Ser-L-Thr-L-Cys-LVal-L-Leu-Gly-L-Lys-L-Leu-L-Ser-L-Glu(NH2)-L-Glu-L-Leu-L-His-L-Lys-L-Leu-LGlu(NH2)-L-Thr-L-Tyr-L-Pro-L-Arg-L-Thr-L-Asp(NH2)-L-Thr-Gly-L-Ser-Gly-L-ThrL-Pro-NH2 (Disulfide bridge: 1-7) Chemical Abstracts Registry No.: 9007-12-9 Trade Name
Manufacturer
Country
Year Introduced
Calcitar
Yamanouchi
Japan
1978
Cibacalcin
Ciba Geigy
Switz.
1978
Elcitonin
Toyo Jozo
Japan
1981
Calcimar
Armour
US
-
Calcitonin-Sandoz
Sandoz
Switz.
-
Calsyn
Armour
UK
-
Calsynar
Armour
UK
-
Miacalcic
Sandoz
Switz.
-
Staporos
Roussel
France
-
Raw Materials C-cell-rich thyroid gland carcinoma Manufacturing Process The process for the manufacture of human calcitonin in pure form from C-cell rich medulla carcinoma of the thyroid gland or from C-cell metastasis material is one wherein medullar carcinoma of the thyroid gland or C-cell metastasis material, which has been defatted, for example with acetone or ether, and which may have been first purified with alcohol or with aqueous trichloroacetic acid, is extracted one or more times with a solvent system containing water and an alkanol having at most 5 carbon atoms, at a pH of from about 1 to 6, and the extracted product subjected to gel chromatography using aqueous formic acid as eluant. The calcitonin may be separated into its constituents by countercurrent distribution, for example by Craig distribution using a solvent system advantageously containing n-butanol and acetic acid. References Merck Index 1611 DFU 8 (2) 105 (1983) PDR p. 1809 DOT 14 (4) 139 (1978) I.N. p. 174 REM p. 979 Ciba-Geigy A.G.; British Patent 1,270,595; April 12, 1972
792
Calcitriol
CALCITRIOL Therapeutic Function: Calcium regulator Chemical Name: 9,10-Secocholesta-5,7,10(19)-triene-1,3,25-triol Common Name: 1α,25-Dihydroxycholecalciferol; 1α,25-Dihydroxyvitamin D3 Structural Formula:
Chemical Abstracts Registry No.: 32222-06-3 Trade Name
Manufacturer
Country
Year Introduced
Rocaltrol
Roche
US
1978
Rocaltrol
Roche
W. Germany
1980
Rocaltrol
Roche
UK
1980
Rocaltrol
Roche
Switz.
1980
Rocaltrol
Roche
Italy
1981
Raw Materials 1α,25-Diacetoxyprecholecalciferol Potassium hydroxide Manufacturing Process 1α,25-Dihydroxyprecholecalciferol: A solution of 1α,25diacetoxyprecholecalciferol (0.712 g, 1.42 mmols), potassium hydroxide (2.0 g, 35.6 mmols) and methanol (40 ml) was stirred at room temperature under argon for 30 hours. The reaction mixture was concentrated under reduced pressure. Water (50 ml) was added to the residue and the mixture was extracted with methylene chloride (3 x 100 ml). The combined organic extracts were washed with saturated sodium chloride solution (3 x 50 ml), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give 0.619 g of 1alpha,25-dihydroxyprecholecalciferol as a thick oil. 1α,25-Dihydroxycholecalciferol: A solution of 1α,25-dihydroxyprecholecalciferol [0.619 g in dioxane (30 ml)] was heated under reflux for 30 minutes under an atmosphere of argon. The reaction mixture was concentrated under reduced
Calcium pantothenate
793
pressure and the residue was purified with a Waters Associates liquid chromatograph model 202 using a 8 foot * 3/8 inch Porasil A column and a 5:1 mixture of ethyl acetate-n-hexane as the eluent to give 0.474 g (80% yield based on 1α,25-diacetoxyprecholecalciferol) of pure 1α,25dihydroxycholecalciferol. Recrystallization from methyl formate afforded 0.340 g of 1α,25-dihydroxcholecalciferol as colorless crystals, MP 113°-114°C. References Merck Index 1612 Kleeman and Engel p. 134 PDR p. 1498 OCDS Vol. 3 p. 103 (1984) DOT 16 (5) 149 (1980) I.N. p. 175 REM p. 1012 Uskokovic, M.R., Narwid, T.A., Iacobelli, J.A. and Baggiolini, E.; US Patent 3,993,675; November 23, 1976; assigned to Hoffmann-La Roche, Inc.
CALCIUM PANTOTHENATE Therapeutic Function: Vitamin Chemical Name: β-Alanine, N-(2,4-dihydroxy-3,3-dimethyl-1-oxobutyl)-, calcium salt (2:1), (R)Common Name: Calcium D-panthothenate; Calcium pantothenate Structural Formula:
Chemical Abstracts Registry No.: 137-08-6 Trade Name Calcium D-Pantothenate Calcium pantothenate
Manufacturer Country Arocor Holdings Inc. Mallinckrodt Baker, Inc.
Year Introduced -
Calcium pantothenate Detro Calcium Pantothenate
Epochem Co., Ltd. Shandong Xinfa Parmaceutical Co., Ltd.
-
-
Calcium pantothenate Calcium pantothenate
ICN Natura Sanat BV
-
-
794
Calcium pantothenate
Trade Name
Manufacturer
Country
Year Introduced
Calcium pantothenate
Pharmeta BV
-
-
Calcipan T
Spencer Pharma
-
-
Calcipan
M/s. Fisons, Karachi
-
-
Calcipan
Tabros Pharma
-
-
Calpan
Pharm Chemical
-
-
Calpan
Metagenics, Inc.
-
-
Cal Pan
Fertrell Company products
-
-
Calpanate
Hangzhou Minsheng Bio-Tech Co., Ltd.
-
Kerato Biciron (N) S and K PHARMA
-
-
Pantogen
Pantogen
-
-
Pantonate
Oasis
-
-
Eagle Pantonate
-
-
Pantothen
Eagle Pharmaceuticals Linz
-
-
Pantothen-Streuli
Streuli
-
-
Raw Materials Isobutyraldehyde Sodium cyanide β-Alanine Brucine
Formaldehyde Sodium methoxide Diethylamine
Manufacturing Process A mixture of 288 g (4 mols) of isobutyraldehyde, 288 g of methanol was cooled to 10°C and 170 g (2 mols) of 36.6% formalin containing 8.5 g (3% based on isobutyraldehyde) of sodium hydroxide was added dropwise over a 55 minute period to produce alpha,alpha-dimethyl-beta-hydroxypropionaldehyde. The mixture was stirred for an additional 2 hours at 10-15°C and then contacted with acetic acid to neutralize the catalyst. The excess isobutyraldehyde and methanol were stripped off at a kettle temperature of 50°C at 25 mm. To the residual α,α-dimethyl-beta-hydroxypropionaldehyde a mixture of 260 ml of methanol and 2 g (0.75%) sodium cyanide was added and the solution cooled to 10°C before adding 59.4 g (2.2 mols) of hydrogen cyanide dropwise over a 35 minute period to produce α,γ-dihydroxy-β,βdimethylbutyronitrile. The mixture was stirred at 10°C for one hour period and then contacted with acetic acid to neutralize the catalyst before stripping off the excess methanol to a kettle temperature of 45°C at 18 mm. The crude cyanohydrin was then hydrolysed by heating with 4 mols of concentrated hydrochloric acid at 80°C for 2 hours, then diluting with an equal volume of water and heating at 100°C for an additional 8 hours. The aqueous mixture was extracted continuously with ethylene dichloride. The solvent was
Calfactant
795
removed, and pantolactone (B. P. 131°C/19 mm, M.P. 61-77°C, 96.5% purity by saponification) was obtained by distillation in 71.5% yield based on formaldehyde and 55% efficiency based on isobutyraldehyde. 26 grams of racemic pantolactone (0.2 mol) and 1.1 grams of sodium methoxide (0.02 mol) contained in 30 ml of methanol, were added to 78.8 grams of 1-brucine (0.2 mol) contained in 156 ml of methanol. The resulting mixture was refluxed for 1.5 hours and allowed to stand at room temperature overnight. After centrifuging, washing with methanol and drying, 65.4 grams of D-(-)-pantolactone 1-brucine (62% of theory based upon all of the racemic pantolactone) melting at 203° to 206°C were obtained. Upon chilling the mother liquor, 13.46 grams of additional complex melting at 175° to 177°C were obtained. D-(-)-Pantolactone was obtained from the complex in the following manner. The 65.4 grams of complex obtained above were treated with 65 ml of chloroform and 5.35 grams of sodium hydroxide contained in 35 ml of water for one hour at room temperature. The aqueous layer was extracted 6 times with 20 ml portions of chloroform in order to remove the brucine. The sodium pantoate contained in the aqueous layer was relactonized by treatment with 11 ml of concentrated hydrochloric acid. Extraction of the crude D-(-)pantolactone yielded 15.29 grams. This material was then recrystallized from 7 ml of methyl isobutyl ketone and 7 ml hexane thereby yielding 9.77 grams of D-(-)-pantolactone (37% of theory). The αD25 was -44.8°. Into a vessel equipped with an agitator and reflux condenser are placed approximately 52 parts by weight of α-hydroxy-β,β-di-methyl-γ-butyrolactone, approximately 36 parts by weight of β-alanine, about 40 parts by weight of diethylamine and about 100 parts by weight of anhydrous methanol. The mixture is stirred and refluxed for about 12 hours until the reaction is complete as evidenced by the dissolution of the β-alanine. To this resulting mass is gradually added 8 parts by weight of calcium metal nodules or pellets and refluxing continued until the metal is dissolved. The diethylamine and alcohol are distilled off until the residue becomes viscous. The viscous residue is dried under vacuum at 100°C. The solid residue recovered, as biologically assayed, indicated a 91% yield of calcium pantothenate. References Lynn J.W.; US Patent No. 2,863,878; Dec. 9, 1958; Assigned to Unione Carbide Corporation, a corporation of New York Bckmann C.O. et al.; US Patent No. 2,967,869; Jan. 10, 1961; Assigned to Nopco Chemical Company Harrison, N.J., a corporation of New Jersey Lekberg R.D. et al.; US Patent No. 2,809,213; Oct. 8, 1957; Assigned to Chemik Laboratorics Inc., a corporation of Illinois
CALFACTANT Therapeutic Function: Lung surfactant Chemical Name: Calfactant
796
Calusterone
Common Name: Infasurf Structural Formula: Mixture of phospholipids Chemical Abstracts Registry No.: 183325-78-2 Trade Name
Manufacturer
Country
Year Introduced
Infasurf
Forest Pharmaceuticals, Inc.
USA
-
Raw Materials Calf lungs Aqueous solution NaCl (0.15 M) Manufacturing Process Calfactant is purified surfactant phospholipids extracted from calf lungs and purified by gel permeation chromatography. Calfactant include phospholipids, neutral lipides, and hydrophobic surfactant - three biophysically active proteins SP-A, SP-B, and SP-C. It contained no preservatives. References Egan E.A. et al.; US Patent No. 6,458,759; Oct. 1, 2002; Assigned: Ony, Inc. (Amherst, NY) http://www.fda.gov/cder/foi/label/1998/20521lbl.pdf http://www.infasurf.com/Infasurf_pi.pdf
CALUSTERONE Therapeutic Function: Antineoplastic Chemical Name: 17β-Hydroxy-7β,17-dimethylandrost-4-en-3-one Common Name: 7,17-Dimethyltestosterone Structural Formula:
Calusterone
797
Chemical Abstracts Registry No.: 17021-26-0 Trade Name
Manufacturer
Country
Year Introduced
Methosarb
Upjohn
US
1973
Riedemil
Upjohn
US
-
Raw Materials 6-Dehydro-17-methyltestosterone Methyl magnesium bromide Manufacturing Process As described in US Patent 3,029,263, one possibility is a multistep synthesis starting from 3β,17β-dihydroxy-17α-methyl-5-androstene. Alternatively, as described in US Patent 3,341,557, 6-dehydro-17methyltestosterone may be used as the starting material. A mixture of 0.4 g of cuprous chloride, 20 ml of 4M methylmagnesium bromide in ether and 60 ml of redistilled tetrahydrofuran was stirred and cooled in an ice bath during the addition of a mixture of 2.0 g of 6-dehydro-17-methyltestosterone, 60 ml of redistilled tetrahydrofuran and 0.2 g of cuprous chloride. The ice bath was removed and stirring was continued for four hours. Ice and water were then carefully added, the solution acidified with 3 N hydrochloric acid and extracted several times with ether. The combined ether extracts were washed with a brine-sodium carbonate solution, brine and then dried over anhydrous magnesium sulfate, filtered and then poured over a 75-g column of magnesium silicate (Florisil) packed wet with hexanes (Skellysolve B). The column was eluted with 250 ml of hexanes, 0.5 liter of 2% acetone, two liters of 4% acetone and 3.5 liters of 6% acetone in hexanes. Four 250-ml fractions were collected followed by 150 ml fractions. The residues from fractions 8 to 16 were combined and rechromatographed over a 125-g column of magnesium silicate. The solumn was eluted with 6% acetone in hexanes which was collected in 150 ml portions. Fractions 18 to 29 were combined and dissolved in acetone, decolorized with charcoal, and recrystallized from acetone. One gram of a crystalline mixture of the 7epimers of 7,17-dimethyltestosterone was obtained melting at 120° to 140°C. References Merck Index 1701 Kleeman and Engel p. 138 OCDS Vol. 2 p. 154 (1980) DOT 10 (3) 85 (1974) I.N.p. 177 REM p. 1001 Campbell, J.A. and Babcock, J.C.; US, Patents 3,029,263; April 10, 1962 and 3,341,557; September 12, 1967; both assigned to The Upjohn Company
798
Camazepam
CAMAZEPAM Therapeutic Function: Anxiolytic Chemical Name: 3-N,N-Dimethylcarbamoyloxy-1-methyl-7-chloro-5-phenyl1,3-dihydro-2H-1,4-benzodiazepin-2-one Common Name: Structural Formula:
Chemical Abstracts Registry No.: 36104-80-0 Trade Name
Manufacturer
Country
Year Introduced
Albego
Simes
Italy
1977
Albego
W. Germany
1978
Albego
Boehringer Ingelheim Inpharzam
Switz.
1978
Albego
Farmasimes
Spain
-
Limpidon
Crinos
Italy
-
Raw Materials 7-Chloro-5-phenyl-1-methyl-3-hydroxy-1,3-dihydro-2H-1,4benzodiazepine-2-one Phenyl chlorocarbonate Dimethylamine Manufacturing Process A suspension of 100 g of 7-chloro-5-phenyl-1-methyl-3-hydroxy-1,3-dihydro2H-1,4-benzodiazepin-2-one in 700 ml of anhydrous pyridine, kept stirred between 0°C and +5°C, is slowly treated, during 20 to 30 minutes, with 54.5 ml phenyl chlorocarbonate. The temperature is gradually allowed to rise to 20°-25°C and stirring is maintained at this temperature during 24 hours. 2 l of water are then slowly added (during about 30 minutes) and stirring is maintained during 1 hour. The precipitate which has been formed is collected on a filter, washed thoroughly with water, dried in a vacuo at 50°C and recrystallized by dissolving it at 60°C in 1,400 ml dioxane, the solution thus
Candesartan cilexetil
799
obtained being evaporated under reduced pressures to one-half of its volume, and 1,700 ml of ligroin (BP 80°C to 120°C) being added thereto. 7-chloro-5-phenyl-1-methyl-3-phenoxycarbonyloxy-1,3-dihydro-2H-1,4benzodiazepin-2-one is thus obtained, with a melting point of 162°C to 164°C. A suspension of 45 g 3-phenoxycarbonyloxy-1-methyl-7-chloro-5-phenyl-1,3dihydro-2H-1,4benzodiazepin-2-one in 450 ml methanol is treated with stirring, with 43 ml of a solution of dimethylamine in methanol (containing 31 g dimethylamine in 100 ml). Stirring is maintained at 20°C to 25°C during 5 hours. The reaction mixture is filtered, and the filtrate is diluted with 450 ml water. The precipitate thus formed, is 3-(N,N-dimethylcarbamoyloxy)-1methyl-7-chloro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one, which is collected on a filter, dried and recrystallized from ethyl acetate, and has a melting point of 173°C to 174°C. References Merck Index 1703 DFU 1 (10) 458 (1976) Kleeman and Engel p. 139 DOT 11 (5) 182 (1975); 13 (12) 521 (1977) I.N. p. 177 Ferrari, G. and Casagrande, C.; US Patent 3,799,920; March 26, 1974; assigned to Siphar SA
CANDESARTAN CILEXETIL Therapeutic Function: Antihypertensive Chemical Name: 1H-Benzimidazole-7-carboxylic acid, 2-ethoxy-1-((2'-(1Htetrazol-5-yl)(1,1'-biphenyl)-4-yl)methyl)-, 1-(((cyclohexyloxy)carbonyl) oxy)ethyl ester Common Name: Candesartan cilexetil Structural Formula:
Chemical Abstracts Registry No.: 145040-37-5
800
Candesartan cilexetil
Trade Name
Manufacturer
Country
Year Introduced
Amias
Microlab
-
-
Amias
AstraZeneca
-
-
Amias
Takeda
USA
-
Atacand
Astra Merck, Inc.
-
-
Atacand
AstraZeneca
-
-
Raw Materials 3-Nitrophthalic acid Sulfuric acid Potassium carbonate Sodium azide Sodium hydroxide
Trimethyltin azide Trityl chloride 4-(2-Cyanophenyl)benzyl bromide Cyclohexyl 1-iodoethyl carbonate Stannous dichloride dihydrate
Manufacturing Process 3-Nitrophthalic acid (35 g) in 300 ml ethanol and 20 ml concentrated sulfuric acid was heated under reflux for 24 hours. The solvent was evaporated in vacuo and the residue was poured into 700 ml cold water. The mixture was extracted with ethyl acetate. The aqueous layer was made acidic with hydrochloric acid and the mixture was extracted with methylene chloride. After evaporation of methylene chloride was obtained 29 g (74%) ethyl 2carboxy-3-nitrobenzoate. A mixture of 23.9 g ethyl 2-carboxy-3-nitrobenzoate and 12 ml thionyl chloride in 150 ml benzene were heated under reflux for 3 hours. The reaction mixture was concentrated to dryness. The resultant acid chloride (26 g) was dissolved in 20 ml. The solution was added to a mixture of sodium azide (9.75 g) in 20 ml DMF with stirring. The reaction mixture was poured into 200 ml a mixture of ether-hexane (3:1). The organic layer was washed with water and evaporated. The residue was dissolved in 200 ml tert-butanol and the solution was heated gradually with stirring, followed by heating under reflux for 2 hours. The reaction mixture was concentrated to give an oily ethyl 2butoxycarbonylamino-3-nitrobenzoate (30 g). To a solution of ethyl 2-butoxycarbonylamino-3-nitrobenzoate (29 g) in 50 ml THF was added, while stirring under ice-cooling, sodium hydride (60% dispersion in mineral oil, 2.8 g). After 20 min to the mixture were added 18 g 4-(2-cyanophenyl)benzyl bromide and 0.36 g potassium iodide. After heating for 10 hours under reflux the solvent was evaporated and the residue was partitioned between 250 ml water and 200 ml ether. The organic layer was washed with water, dried and concentrated to give yellow syrup. The syrup was dissolved in a mixture of 60 ml trifluoroacetic acid and 40 ml methylene chloride and the solution was stirred for 2 hour at room temperature. The reaction mixture was concentrated to dryness and to residue was added 200 ml ethyl ether to give crystals of ethyl 2-[(2'-cyanobiphenyl-4yl)methylamino]nitrobenzoate (22.1 g, 85%), M.P. 118-119°C. To a solution of 10.4 g ethyl 2-[(2'-cyanobiphenyl-4-yl)methylamino] nitrobenzoate in 50 ml ethanol was added 28.1 g stannous dichloride dihydrate and the mixture was stirred for 2 hours at 80°C. The solvent was
Candesartan cilexetil
801
evaporated. To the ice-cooling mixture of the residue in 300 ml ethyl acetate was added dropwise 2 N NaOH (500 ml). The aqueous layer was extracted with ethyl acetate (200 ml x 2). The organic layers were combined and evaporated to dryness. Product was purified by column chromatography on silica gel. Recrystallization from ethyl acetate-hexane gave colorless crystals ethyl-3-amino-2-[[(2'-cyanobiphenyl-4-yl)methyl]amino]benzoate (7.3 g, 79%), M.P. 104-105°C. Acetic acid (0.2 g) was added to a solution of ethyl-3-amino-2-[[(2'cyanobiphenyl-4-yl)methyl]amino]benzoate (1 g) in ethylorthocarbonate (5 ml). The mixture was stirred at 80°C for 1 hours. The reaction mixture was concentrated. The solution was washed with an aqueous solution of NaHCO3 and water. The solvent was evaporeted to give crystals. Recrystallization from ethyl acetate-benzene afforded colorless crystals 1-[(2'-cyanobiphenyl-4yl)methyl]-2-ethoxybenzimidazole-7-carboxylate (0.79 g, 69%), M.P. 131132°C. A mixture of 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-ethoxybenzimidazole-7carboxylate (0.7 g) and trimethyltin azide (0.7 g) in toluene (15 ml) was heated under reflux for 4 days. The reaction mixture was concentrated, and to the residue were added methanol (20 ml) and 1 N HCl (10 ml). The solution was stirred at room temperature for 30 minutes and adjusted to pH 3-4 with 1 N NaOH. After removal of the solvent, the residue was partitioned between chloroform and water. The organic layer was evaporated to dryness to dive a syrup. The syrup was purified by column chromatography on silica gel to give crystals. Recrystallization from ethyl acetate-benzene afforded colorless crystals ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (0.35 g, 45%), M.P. 158-159°C. Ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]-methyl]benzimidazole7-carboxylate (0.24 g) was stirred with 1 N NaOH (1.5 ml) in ethanol (4 ml) for 1 hours at 80°C. The reaction mixture was concentrated, and the concentrate was exrtacted with water and ethyl acetate. The aqueous layer was adjusted to pH 3-4 with 1 N HCl to give crystals. Recrystallization from ethyl acetate-benzene afforded colorless crystals of 2-ethoxy-1-[[2'-(1Htetrazol-5-yl)biphenyl-4-yl]-methyl]benzimidazole-7-carboxylic acid (0.15 g, 67%), M.P. 183-185°C. To a solution of 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid (2.07 g) in methylene chloride (10 ml) were added trityl chloride (1.59 g) and triethylamine (0.8 ml). The mixture was stirred at room temperature for 1 hour. The mixture was washed with water and concentrated to dryness. The residue was purified by column chromatography on silica gel to give crystals. Recrystallization from ethyl acetate-benzene afforded colorless crystals 2-ethoxy-1-[[2'-(Ntriphenylmethyltetrazol-5-yl)biphenyl-4-yl]-methyl]benzimidazole-7-carboxylic acid (2.12 g, 66%), M.P. 168-170°C. To a solution 2-ethoxy-1-[[2'-(N-triphenylmethyltetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid (0.5 g) in DMF (5 ml) were added potassium carbonate (0.12 g) and cyclohexyl 1-iodoethyl carbonate (0.26 g). The mixture was stirred at room temperature for 1 hour. To the mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried. After removal of the solvent, the
802
Candicidin
residue was dissolved in methanol (10 ml) and to solution was added 1 N HCl (2 ml). The mixture was stirred at room temperature for 1 hour. After removal of the solvent, the residue was purified by column chromatography on silica gel to give colorless powder (0.21 g), M.P. 103-106°C. The mixture was stirred for 3 hours at room temperature. To the powder (1 g) obtained as above was added ethanol (6 ml). The mixture was stirred for 3 hours at room temperature and allowed to stand under ice-cooling. The mixture was then stirred for 1 hour at temperature not higher than 10°C. Resultant crystals were collected and washed with cold ethanol. The crystals were dried at 25°C for 9 hours under reduced pressure, then at 35°C for further 18 hours to obtain white powdery crystal 1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-benzimidazole-7-carboxylate (0.94 g, M.P. 158-166°C). References Naka T., Nishikawa K., Kato T.; US Patent No. 5,196,444; 03.23.1993; Assigned to Takeda Chemical Industries, Ltd.
CANDICIDIN Therapeutic Function: Topical antifungal Chemical Name: Heptaene macrolide antibiotic Common Name: Structural Formula:
Chemical Abstracts Registry No.: 1403-17-4 Trade Name
Manufacturer
Country
Year Introduced
Candeptin
Schmidt
US
1964
Candimon
Averst
US
-
Prostatin
Schmidt
US
-
Vanobid
Merrell Dow
US
-
Candicidin
803
Raw Materials Yeast-glucose medium Streptomyces Griseus No. 3570 bacterium Manufacturing Process Hubert Lechevalier et al were the first to describe "Candicidin, a New Antifungal Antibiotic," in Mycologia XLV, No. 2, 155-171, March-April 1953. They produced candicidin by growing a culture of the organism streptomyces griseus No. 3570 on a yeast-glucose medium, isolating a "crude candicidin" from the resulting broth and purifying it. An improved extraction and purification method is described in US Patent 2,872,373 and is shown in the flow diagram below.
804
Canrenoate potassium
Another extraction and separation process is described in US Patent 2,992,162. References I.N. p. 178 REM p. 1226 Siminoff, P.; US Patent 2,872,373; February 3, 1959; assigned to S.B. Penick and Company, Inc. Waksman, S.A. and Lechevalier, H.A.; US Patent 2,992,162; July 11, 1961; assigned to Rutgers Research and Educational Foundation
CANRENOATE POTASSIUM Therapeutic Function: Aldosterone antagonist, Diuretic Chemical Name: 17-Hydroxy-3-oxo-17α-pregna-4,6-diene-21 carboxylic acid potassium salt Common Name: Structural Formula:
Chemical Abstracts Registry No.: 2181-04-6; 976-71-6 (Canrenone base) Trade Name
Manufacturer
Country
Year Introduced
Spiroctan
Switz.
1968
Soldactone
Boehringer Mannheim Diethelm
Switz.
1968
Osyrol
Hoechst
W. Germany
1968
Soludactone
Searle
France
1971
Venactone
Lepetit
Italy
1978
Spiroctan-M
MCP Pharm.
UK
1981
Soldacton
Dainippon
Japan
1981
Capecitabine
805
Trade Name
Manufacturer
Country
Year Introduced
Aldactone
W. Germany
-
Aldatense
Boehringer Mannheim Searle
France
-
Aldatense
SPA
Italy
-
Phanurane
Specia
France
-
Sincomen
Schering
W. Germany
-
Soldactone
Searle
US
-
Raw Materials 17α-Carboxyethyl-17β-hydroxyandrost 4-en-3-one lactone Chloranil Manufacturing Process The lactone is prepared as follows: A solution of 5 parts of 17α-carboxyethyl17β-hydroxyandrost-4-en-3-one lactone and 5 parts of chloranil in 400 parts of xylene containing a trace of p-toluenesulfonic acid is heated at the boiling point of the solvent under reflux overnight. The solution is then cooled and filtered through approximately 200 parts of silica gel. The gel is successively washed with 5%, 10%, and 15% ethyl acetate-benzene solutions, and the washings comprising 15% ethyl acetate are thereupon purified by chromatography on a further quantity of silica gel, using benzene and ethyl acetate as developing solvents. From the 15% ethyl acetate eluate there is obtained pure 17α-carboxyethyl-17β-hydroxyandrost-4,6-dien-3-one lactone, melting at 148° to 151°C. The product solidifies above this melting point and melts again at 165°C. References Merck Index 1726 Kleeman and Engel p. 507 OCDS Vol. 2 p. 174 (1980) DOT 12 (2)45 (1976) I.N. p. 178 Cella, J.A.; US Patent 2,900,383; August 18, 1959; assigned to G.D. Searle and Co.
CAPECITABINE Therapeutic Function: Antitumor Chemical Name: 5'-Deoxy-5-fluoro-N4-(4-(n-pentyloxy)carbonyl)cytidine Common Name: Capecitabine Chemical Abstracts Registry No.: 154361-50-9; 158798-73-3
806
Capreomycin
Structural Formula:
Trade Name
Manufacturer
Country
Year Introduced
Xeloda
Hoffmann - La Roche Inc.
USA
-
Raw Materials 2',3'-Bis-O-(tert-butyldimethylsilyl)-5'-deoxy-5-fluorocytidine n-Pentylchloroformate Tetrabutylammonium fluoride Manufacturing Process 5-Deoxy-5-fluoro-N4-((n-pentyloxy)carbonyl)cytidine may be prepared according to US Patent No. 6,114,520. From 2',3'-bis-O-(tert-butyldimethylsilyl)-5'-deoxy-5-fluorocytidine and npentylchloroformate in dichloromethane and pyridine may be obtained 2',3'bis-O-(tert-butyldimethylsilyl)-5'-deoxy-5-fluoro-N4-((pentyloxy)carbonyl) cytidine.From 2',3'-bis-O-(tert-butyldimethylsilyl)-5'-deoxy-5-fluoro-N4((pentyloxy)carbonyl)cytidineand tetrabutylammonium fluoride in tetrahydrofuran at room temperature for 2 hours may be prepared the product which by hydrolyses may be converted to 5-deoxy-5-fluoro-N4((pentyloxy)carbonyl)cytidine. Purification of the product may be carried out by silica gel chromatography (using dichloromethane:methanol = 20:1 as an eluent). References Hattory K. et al.; US Patent No. 6,114,520; Sep. 5, 2000; Assigned to Hoffmann-La, RocHe Inc. Fujii M. et al.; US Patent No. 4,966,891, Oct. 30, 1990; Assigned to Hoffmann-La, RocHe Inc.
CAPREOMYCIN Therapeutic Function: Antibacterial, Antitubercular
Capreomycin
807
Chemical Name: Mixture of Capreomycin I A with Capreomycin I B and small quantities of Capreomycin II A and II B Common Name: Capreomicina, Capreomycin, Capromycin Structural Formula:
Chemical Abstracts Registry No.: 11003-38-6 Trade Name
Manufacturer
Country
Year Introduced
Capastat
Dista
-
-
Capastat
Eli Lilly
-
-
Raw Materials Culture of NRRL 2773 Vegetative culture medium (Soluble starch, Peptones, Beef extract, Sodium chloride, Yeast extract, water) Manufacturing Process Preparation of Capreomycin
808
Capreomycin
A culture of NRRL 2773 is produced by growing the organism on a nutrient agar slant having the following composition: Tomato paste 20 g, Pre-cooked oatmeal 20 g, Agar 15 g and tap water up to 1 L. The slant is inoculated for 10 days at about 30°C. The culture growth on the slant is covered with 6 ml of nutrient broth, and the slant is scraped gently to remove the organisms to provide an aqueous suspension. Employing aseptic techniques, the inocolum obtained is used to inoculate a 2 L Erlenmeyer flask containing a 500 ml portion of a sterilized vegetative culture medium having the following composition: Soluble starch 10 g, Peptones 5 g, Beef extract 5 g, Sodium chloride 5 g, Yeast extract 2.5 g and tap water 1100 ml. The incubation is carried out at 28°C for 48 hours; during which time the flasks are shaken at the rate of 250 cycles per minute on a rotary shaker having a 1-inch stroke. To produce a larger quantity of vegetative inocolum, 500 ml of the vegetative inocolum is added aseptically to a stainless steel 350-gallon fermentation tank containing 250 gallons of sterile medium having following composition (weight/volume): Glucose 1.5%, Yeast 1.5%, Antifoam ("Polyglycol No 2000" sold by Dow Chemical Co) 0.02%. The inoculum is allowed to grow for 22 hours at 30°C. Throughout the growth period, the medium is aerated with sterile air at the rate of 17 cubic feet per minute and is agitated with 16-inch impeller rotating at 160 revolution per minute. To a 1700-gallon stainless steel fermentor are added 1100 gallons of a medium having following composition (weight/volume): Glucose 2.5%, Molasses 1.0%, Peptones 4.0%, Calcium carbonate 0.2%, Hydrolyzed casein 0.6%, Antifoam ("Polyglycol No 2000" sold by Dow Chemical Co) 0.005%. The medium after sterilization is inoculated with 100 gallons of the inoculum grown in the fermentation tank. The fermentation is carried on at 30°C for 5 days. The foam is controlled by the addition, when needed, of "Larex No 1" (an antifoam product sold by Swift and Co.). Throughout the fermentation, the medium is aerated with sterile air at the rate of 17 cubic feet per minute and is agitated with 22-inch impeller rotating at 140 revolution per minute. At the end of the fermentation, 240 pounds of "Dicalite 476" (a perlite filler product sold by Great Lakes Carbon Corporation) are added 1000 gallons or the antibiotic broth, and the mixture is stirred and filtered. The filter cake is washed with tap water and the filtrates are combined to provide a total volume of 1000 gallons. To 500 gallons of the combined liquids are added 132 pounds of "Darco G-60". The mixture is filtered, and the filtrate is discarded. The carbon filter cake is washed with 200 L of tap water, the wash water being discarded. The washed carbon cake on which the capreomycin is adsorbed is washed with 200 L of 0.05 N aqueous hydrochloric acid. The acid wash is discarded. The washed carbon cake is eluted during a one-hour period with 400 L of an aqueous acetone containing 1.65 L of 11.7 N hydrochloric acid and 80 L of acetone. The filter cake is further eluted by washing the cake with 200 L of an aqueous acetone containing 825 ml of 11.7 N hydrochloric acid and 40 L of acetone during a 15-minute period. The combined eluates, having a total volume 575 L, are concentrated in vacuo to 52.5 L. The concentrate is added
Capreomycin sulfate
809
with stirring to 525 L of acetone and the acetone mixture is permitted to stand overnight at room temperature, during which time an oily precipitate of capreomycin separates. The supernatant is decanted and discarded, and the oily precipitate which remains is dissolved in 20 L of distilled water. The aqueous solution is filtered. The filtrate is added to 240 L of methanol. The methanolic solution is acidified by the addition of 1 L of 10 N sulfuric acid, whereupon the precipitation of the capreomycin disulfate commences. The mixture is permitted to stand overnight. The supernant is removed by decantation and filtering. The precipitate is washed with 10 L of methanol, yield Capreomycin 2510 g. References Herr E.B. et al.; US Patent No. 3,143,468; 04.08.1964; Assigned to Eli Lilly and Company; W.S. Marsh et al.; US Patent No. 2,633,445; 31.03.1953; Assigned to Ciba Pharm. Products
CAPREOMYCIN SULFATE Therapeutic Function: Antitubercular Chemical Name: Cyclic polypeptide antibiotic Common Name: Caprolin Structural Formula:
Chemical Abstracts Registry No.: 1405-37-4 Trade Name
Manufacturer
Country
Year Introduced
Capastat
Lilly
UK
1966
810
Capreomycin sulfate
Trade Name
Manufacturer
Country
Year Introduced
Capastat
Serum Impfinst.
Switz.
1967
Ogostac
Lilly
W. Germany
1967
Capastat
Lilly
US
1971
Capastat
Lilly
Italy
1973
Capastat
Shionogi
Japan
-
Raw Materials Glucose Culture of NRRL 2773 Manufacturing Process A culture of NRRL 2773 is produced by growing the organism on a nutrient agar slant having the following composition: Oatmeal-Tomato Paste Agar
Tomato paste Precooked oatmeal Agar
Grams 20 20 15
Tap water, added to make a final volume of 1 liter. The slant is inoculated with spores of NRRL 2773 and is incubated for 10 days at about 30°C. The culture growth on the slant is covered with 6 ml of nutrient broth, and the slant is scraped gently to remove the organisms to provide an aqueous suspension. Employing aseptic techniques, the inoculum obtained from one 1-inch agar slant is used to inoculate a 2-liter Erlenmeyer flask containing a 500-ml portion of a sterilized vegetative culture medium having the following composition: soluble starch, 10 g; peptones, 5 g; beef extract, 5 g; sodium chloride, 5 g; yeast extract, 2.5 g; and tap water, 1,100 ml. The incubation is carried on at 28°C for 48 hours with shaking at 250 cycles per minute on a rotary shaker having a 1-inch stroke. To produce a larger quantity of vegetative inoculum, 500 ml of the vegetative inoculum is added aseptically to a stainless steel 350-gallon fermentation tank containing 250 gallons of sterile medium having the following composition (weight/volume): glucose, 1.5%; yeast, 1.5%; and antifoam (Polyglycol No. 2000, Dow Chemical Co.), 0.02%. The inoculum is allowed to grow for about 22 hours at a temperature of 30°C. Throughout the growth period, the medium is aerated with sterile air at the rate of 17 cfm and is agitated with two 16-inch impellers rotating at 160 revolutions per minute. To a 1,700gallon stainless steel fermentor are added 1,100 gallons of a medium having the following composition (weight/volume): Peptone No. 159 Medium
Capreomycin sulfate
Glucose Molasses Peptones Calcium carbonate Hydrolyzed casein
811
Percent 2.5 1.0 4.0 0.2 0.6
Antifoam (Polyglycol No. 2000, Dow Chemical Co.) 0.005 The medium after sterilization is inoculated with 100 gallons of the inoculum grown in the fermentation tank. The fermentation is carried on at 30°C for about five days. The foam is controlled by the addition, when needed, of Larex No. 1 (an antifoam product, Swift and Co.). Throughout the fermentation, the medium is aerated by the addition of sterile air at the rate of 96 cfm and is agitated with two 22-inch impellers operated at 140 revolutions per minute. At the end of the fermentation, 240 lb of Dicalite 476 (a perlite filter product, Great Lakes Carbon Corporation) are added to 1,000 gallons of the antibiotic broth, and the mixture is stirred and filtered. The filter cake is washed with tap water and the wash water and the filtrate are combined to provide a total volume of 1,000 gallons. To 500 gallons of the combined liquids are added 132 lb of Darco G-60. The mixture is stirred thoroughly and filtered, and the filtrate is discarded, The carbon filter cake is washed with 200 liters of tap water, the wash water being discarded. The washed carbon cake on which the capreomycin is adsorbed is further washed with 200 liters of 0.05 N aqueous hydrochloric acid. The acid wash is discarded. The washed carbon cake is eluted during a one-hour period with 400 liters of an aqueous acetone mixture containing 1.65 liters of 11.7 N hydrochloric acid and 80 liters of acetone. The filter cake is further eluted by washing the cake with 200 liters of an aqueous acetone mixture containing 825 ml of 11.7 N hydrochloric acid and 40 liters of acetone during a 15minute period. The combined eluates, having a total volume of 575 liters, are concentrated in vacuo to 52.5 liters. The concentrate is added with stirring to 525 liters of acetone and the acetone mixture is permitted to stand overnight at room temperature, during which time an oily precipitate of capreomycin separates. The supernatant is decanted and discarded, and the oily precipitate which remains is dissolved in 20 liters of distilled water. The aqueous solution is concentrated in vacuo to 12 liters to remove any residual acetone. The aqueous concentrate containing capreomycin is filtered to remove a small amount of a precipitate, which is discarded. The filtrate containing the capreomycin is added to 240 liters of methanol with stirring. The methanolic solution of capreomycin is acidified by the addition of one liter of 10 N sulfuric acid, whereupon the precipitation of the sulfuric acid addition salt of capreomycin commences. The mixture is permitted to stand overnight for more complete precipitation. The supernatant is removed by decanting and filtering. The precipitate, consisting of the capreomycin disulfate, is washed with 10 liters of methanol and is dried in vacuo. Yield: 2,510 grams.
812
Captodiamine
References Merck Index 1732 Kleeman and Engel p. 141 PDR p. 1039 DOT 1 (1) 33 (1965) I.N. p. 179 REM p. 1202 Herr, E.B., Jr., Hamill, R.L. and McGuire, J.M.; US Patent 3,143,468; August 4, 1964; assigned to Eli Lilly and Company
CAPTODIAMINE Therapeutic Function: Sedative Chemical Name: 2-[[[4-(Butylthio)phenyl]phenylmethyl]thio]-N,Ndimethylethanamine Common Name: Captodiam; Captodramine Structural Formula:
Chemical Abstracts Registry No.: 486-17-9; 904-04-1 (Hydrochloride salt) Trade Name Covatine Suvren Covatix
Manufacturer Bailly Ayerst Lundbeck
Country France US Denmark
Year Introduced 1958 1958 -
Raw Materials Thiourea Sodium hydroxide Diethylaminoethyl chloride
4-Butylmercaptobenzhydryl chloride Sodium
Manufacturing Process p-Butylmercaptobenzhydryl chloride was boiled with thiourea in alcohol
Captopril
813
thereby yielding p-butylmercaptobenzhydrylisothiouronium chloride which was then subjected to hydrolysis with dilute aqueous sodium hydroxide solution whereupon p-butylmercaptobenzhydryl mercaptan was formed. p-Butylmercaptobenzhydryl mercaptan (28.5 g) was added to a solution of sodium (2.3 g) in absolute alcohol (75 ml), followed by the addition of a solution of diethylaminoethyl chloride (13.6 g) in toluene (50 ml). The mixture was boiled on a steam bath for 3 hours and the sodium chloride which separated out was removed by filtration. The filtrate was concentrated to onethird of its volume and dissolved in ether. The ether solution was shaken with 2N hydrochloric acid (100 ml), and the resulting middle oily layer was separated, dissolved in water and the resulting aqueous solution was washed with ether, then treated with aqueous sodium hydroxide solution to precipitate an oil. The latter was dissolved in ether, dried with anhydrous potassium carbonate, filtered and then treated with anhydrous hydrogen chloride whereupon the desired p-butylmercaptobenzhydryl 2-diethylaminoethyl sulfide hydrochloride precipitated as a white, crystalline substance which was filtered and dried in a desiccator. The melting point of the product was 124°C. References Merck Index 1746 Kleeman and Engel p. 141 OCDS Vol. 1 p. 44 (1977) I.N. p. 179 Hubner, O.F. and Petersen, P.V.; US Patent 2,830,088; April 8, 1958
CAPTOPRIL Therapeutic Function: Antihypertensive Chemical Name: 1-(3-Mercapto-2-D-methylpropanoyl)-L-proline Common Name: Structural Formula:
Chemical Abstracts Registry No.: 62571-86-2 Trade Name
Manufacturer
Country
Year Introduced
Lopirin
Von Heyden
W. Germany
1980
814
Captopril
Trade Name
Manufacturer
Country
Year Introduced
Capoten
Squibb
US
1981
Lopirin
Squibb
Switz.
1981
Capoten
Squibb
UK
1981
Capoten
Squibb
Italy
1981
Lopril
Squibb
France
1982
Captoril
Sankyo
Japan
1983
Dilabar
Vita
Spain
-
Isopresol
Elea
Argentina
-
Raw Materials L-Proline Benzyloxycarbonyl chloride Ammonia Trifluoroacetic acid
Isobutylene Hydrogen 3-Acetylthiomethyl propanoic acid
Manufacturing Process The first step is the manufacture of L-proline tert-butyl ester. L-proline (230 g) is dissolved in a mixture of water (1 l) and 5 N sodium hydroxide (400 ml). The solution is chilled in an ice bath, and under vigorous stirring, 5 N sodium hydroxide (460 ml) and benzyloxycarbonyl chloride (340 ml) are added in five equal aliquots during a half-hour period. After one hour stirring at room temperature, the mixture is extracted twice with ether and acidified with concentrated hydrochloric acid. The precipitate is filtered and dried. Yield is 442 g; MP 78°C to 80°C. The benzyloxycarbonyl-L-proline thus obtained (180 g) is dissolved in a mixture of dichloromethane (300 ml), liquid isobutylene (800 ml) and concentrated sulfuric acid (7.2 ml). The solution is shaken in a pressure bottle for 72 hours. The pressure is released, the isobutylene is allowed to evaporate and the solution is washed with 5% sodium carbonate, water, dried over magnesium sulfate and concentrated to dryness in vacuo, to obtain benzyloxycarbonyl-L-proline tert-butyl ester, yield 205 g. Benzyloxycarbonyl-L-proline tert-butyl ester (205 g) is dissolved in absolute ethanol (1.2 l) and hydrogenated at normal pressure with 10% Pd on carbon (10 g) until only a trace of carbon dioxide is observed in the hydrogen exit gas (24 hours). The catalyst is filtered off and the filtrate is concentrated in vacuo at 30 mm Hg. The residue is distilled in vacuo, to obtain L-proline tertbutyl ester, BP1mm 50°C to 51°C. The next step yields 1-(3-acetylthio-2-methylpropanoyl)-L-proline tert-butyl ester. L-proline tert-butyl ester (5.1 g) is dissolved in dichloromethane (40 ml) and the solution stirred and chilled in an ice bath. Dicyclohexylcarbodiimide (15 ml) is added followed immediately by a solution of 3-acetylthio-2methylpropanoic acid (4.9 g) in dichloromethane (5 ml). After 15 minutes stirring in the ice bath and 16 hours at room temperature, the precipitate is filtered off and the filtrate is concentrated to dryness in vacuo. The residue is dissolved in ethyl acetate and washed neutral. The organic phase is dried over
Caramiphen edisylate
815
magnesium sulfate and concentrated to dryness in vacuo. The residue 1-(3acetylthio-2-methylpropanoyl)-L-proline tert-butyl ester is purified by column chromatography (silica gel-chloroform), yield 7.9 g. Then, 1-(3-acetylthio-2-methylpropanoyl)-L-proline is produced. The 1-(3acetylthio-3-methylpropanoyl)-L-proline tert-butyl ester (7.8 g) is dissolved in a mixture of anisole (55 ml) and trifluoroacetic acid (110 ml). After one hour storage at room temperature the solvent is removed in vacuo and the residue is precipitated several times from ether-hexane. The residue (6.8 g) is dissolved in acetonitrile (40 ml) and dicyclohexylamine (4.5 ml) is added. The crystalline salt is boiled with fresh acetonitrile (100 ml), chilled to room temperature and filtered, yield 3.8 g, MP 187°C to 188°C. This material is recrystallized from isopropanol [α]D-67° (C 1.4, EtOH). The crystalline dicyclohexylamine salt is suspended in a mixture of 5% aqueous potassium bisulfate and ethyl acetate. The organic phase is washed with water and concentrated to dryness. The residue is crystallized from ethyl acetate-hexane to yield the 1-(3-acetylthio-2-D-methylpropanoyl)-L-proline, MP 83°C to 85°C. Finally, Captopril is produced. The thioester (0.85 g) is dissolved in 5.5 N methanolic ammonia and the solution is kept at room temperature for 2 hours. The solvent is removed in vacuo and the residue is dissolved in water, applied to an ion exchange column on the H+ Cycle (Dowex 50, analytical grade) and eluted with water. The fractions that give positive thiol reaction are pooled and freeze dried. The residue is crystallized from ethyl acetate-hexane, yield 0.3 g. The 1-(3-mercapto-2-D-methylpropanoyl)-L-proline has a melting point of 103°C to 104°C. References Merck Index 1747 DFU 3 (11) 795 (1978) Kleeman and Engel p. 142 PDR p. 1736 OCDS Vo1.3 p. 128 (1984) DOT 17 (6) 233 (1981); 18 (10) 554 (1982) I.N. p. 180 REM p. 850 Ondetti, M.A. and Cushman, D.W.; US Patent 4,046,889; September 6, 1977; assigned to E.R. Squibb and Sons, Inc. Ondetti, M.A. and Cushman, D.W.; US Patent 4,105,776; August 8, 1978; assigned to E.R. Squibb and Sons, Inc. Ondetti, M.A. and Cushman, D.W.; US Patent 4,154,840; May 15,1979; assigned to E.R. Squibb and Sons, Inc.
CARAMIPHEN EDISYLATE Therapeutic Function: Antitussive Chemical Name: 1-Phenylcyclopentanecarboxylic acid 2-(diethylamino)-ethyl ester 1,2-ethanedisulfonate
816
Caramiphen edisylate
Common Name: Structural Formula:
Chemical Abstracts Registry No.: 125-86-0 Trade Name
Manufacturer
Country
Year Introduced
Panparnit
Geigy
US
1949
Toryn
Smith Kline
US
1953
Tuss-Ade
Schein
US
-
Tuss-Ornade
Smith Kline
US
-
Raw Materials 1-Phenylcyclopentyl-1-carboxylic acid chloride Diethylaminoethanol Ethanedisulfonic acid Manufacturing Process 20.8 parts of 1-phenylcyclopentyl-1-carboxylic acid chloride, obtained from the acid (cf. Am. Soc. 1934, 56, 715) by means of thionyl chloride, are dissolved in 250 parts by volume of absolute ether, then, while stirring and cooling with a mixture of common salt and ice a solution of 12 parts of diethylaminoethanol in 50 parts by volume of absolute ether is allowed to drop there into, the temperature being maintained below 0°C, whereupon stirring is continued during 2 hours at room temperature. The whole is then twice shaken out with water and once with diluted hydrochloric acid, the combined aqueous solutions are made alkaline with a potassium carbonate solution and shaken out with ether. The ethereal solution is washed with water, dried over potassium carbonate and the solvent is distilled off. The base boils at a pressure of 0.07 mm at 112°C to 115°C.
Carazolol
817
The base may then be converted to the hydrochloride or to the ethanedisulfonic acid salt (edisylate). References Merck Index 1750 PDR pp. 1606,1730 OCDS Vol. 1 pg. 90 (1977) I.N. p. 180 Martin, H. and Hafliger, F.; US Patent 2,404,588; July 23, 1946; assigned to J.R. Geigy A.G. (Switzerland)
CARAZOLOL Therapeutic Function: Beta-adrenergic blocker Chemical Name: 4-(3-Isopropylamino-2-hydroxypropoxy)carbazole Common Name: Structural Formula:
Chemical Abstracts Registry No.: 57775-29-8 Trade Name
Manufacturer
Country
Year Introduced
Conducton
Klinge
W. Germany
1980
Raw Materials Hydroxycarbazole Epichlorohydrin Isopropylamine Manufacturing Process The 4-(2,3-epoxypropoxy)carbazole used as starting material is prepared as follows. A solution of 16.3 g 4-hydroxycarbazole in a mixture of 190 ml dioxan and 98 ml 1 N sodium hydroxide is, after the addition of 66 ml epichlorohydrin, stirred for 2 hours at 40°C to 45°C. The reaction mixture is
818
Carbachol
then diluted with water and shaken out with methylene chloride. The methylene chloride phase is washed with water, dried over anhydrous sodium sulfate and evaporated. There are obtained 16.8 g 4-(2,3epoxypropoxy)carbazole. A solution of 3.5 g 4-(2,3-epoxypropoxy)carbazole in 50 ml absolute alcohol is mixed with 30 ml isopropylamine and heated for 3 hours under reflux. When the reaction is finished, the reaction mixture is evaporated to dryness. The residue obtained is taken up in methylene chloride and chromatographed over an aluminum oxide column (300 g basic aluminum oxide, activity stage IV; eluent methylene chloride). The eluted fractions are evaporated and the residue is dissolved in methanol and acidified with 2 N ethereal hydrochloric acid. The precipitate obtained is filtered off and recrystallized from methanol. There are obtained 3.1 g (62% of theory) 4-(3-isopropylamino-2-hydroxypropoxy) carbazole hydrochloride; MP 234°C to 235°C. References Merck Index 1753 DFU 2 (11) 715 (1977) Kleeman and Engel p. 143 DOT 17 (2) 53 (1981) and 18 (10) 551 (1982) I.N. p. 180 Boehringer Mannheim GmbH; British Patent 1,369,580; October 9, 1974
CARBACHOL Therapeutic Function: Cholinergic Chemical Name: 2-[(Aminocarbonyl)oxy]-N,N,N-trimethyl-ethanaminium chloride Common Name: Carbocholine Structural Formula:
Chemical Abstracts Registry No.: 51-83-2 Trade Name Miostat Atonyl
Manufacturer Alcon Ferrosan
Country US Denmark
Year Introduced 1979 -
Carbachol
819
Trade Name
Manufacturer
Country
Year Introduced
Cacholitin
Vaise
Denmark
-
Carbacel
Warner Lambert
US
-
Carbamiotin
Tilden Yates
US
-
Carbyl
Tubi Lux Pharma
Italy
-
Carcholin
Merck Sharp and Dohme
US
-
Doryl
Merck
W. Germany
-
Iricoline
Lematte/Boinot
France
-
Isopto-Carbachol
Alcon
US
-
Jestryl
Ankerwerk
E. Germany
-
Lentin
Merck
W. Germany
-
Lentivasan
Kwizda
Austria
-
Mistura
Lederle
US
-
Moryl
Savory and Moore UK
-
Oftan-Karbakol
Star
Finland
-
P.V. Carbachol
Allergan
US
-
Rilentol
Richter
Austria
-
Secretin
Streuli
Switz.
-
Spersacarbachol
Dispersa
Switz.
-
Tonocholin
A.F.I.
Norway
-
Raw Materials Choline chloride Phosgene Manufacturing Process About 14 g of choline chloride are stirred with a solution of about 20 g of phosgene in 100 g of chloroform for about two hours at room temperature. The mixture becomes a two-phase liquid mixture. Hydrochloric acid and excess phosgene are removed by distillation in vacuo. Chloroform is added to the syrup, and the mixture is then added to a solution of excess ammonia in chloroform which was cooled with solid carbon dioxide-acetone. The mixture is filtered, and the solid is extracted with hot absolute alcohol. The solid in the alcoholic solution is precipitated with ether, and filtered. It is recrystallized from a methyl alcohol-ether mixture; the carbaminoyl-choline chloride obtained has a melting point of about 208°-210°C. References Merck Index 1754 Kleeman and Engel p. 144 I.N. p. 180 REM p. 896
820
Carbadox
Major, R.T. and Bonnett, H.T.; US Patent 2,374,367; April 24, 1945; assigned to Merck and Co., Inc.
CARBADOX Therapeutic Function: Antibacterial Chemical Name: Hydrazinecarboxylic acid, (2-quinoxalinylmethylene)-, methyl ester, N,N'-dioxide Common Name: Carbadox; Enterodox; Getroxel Structural Formula:
Chemical Abstracts Registry No.: 6804-07-5 Trade Name
Manufacturer
Country
Year Introduced
Carbadox
Agrimex
-
-
Carbadox
Intraco LTD
-
-
Carbadox
Impextraco
-
-
Carbamix
Zineb
-
-
Enterodox
Orffa
-
-
Enterodox
Dox-Al Australia PTY Ltd.
-
-
Addi-dox
Addi-tech BVBA
-
-
Mecadox
Orffa
-
-
Mecadox
Pfizer Inc.
-
-
Raw Materials Methylcarbazate 2-Formylquinoxaline-1,4-dioxide Manufacturing Process A solution of methylcarbazate (48.0 mg) in methanol (250 ml) is added all at once at room temperature to a well stirred solution of 2-formylquinoxaline1,4-dioxide (100 g) in methanol (2.5 liters). Two drops of concentrated hydrochloric acid are added. The mixture is stirred for 3 hours then filtered to
Carbamazepine
821
remove the yellow crystalline product. The crystals of (2quinoxalinylmethylene)hydrazinecarboxylic acid methyl ester are washed with methanol then air dried; M.P. 234.5-236°C (dec.). Yield=121.8 g. The product is purified by refluxing in chloroform for 2 hours, followed by filtration and air drying; M.P. 239.5-240°C (dec.). The ultraviolet absorption spectrum (water) exhibits maxima at 236, 251, 303, 366 and 373 nm with extinction coefficients of 11,000, 10,900, 36,400, 16,100 and 16,200, respectively. References James David Johnston, Old Saybrook; US Patent No. 3,433,871; Mar. 18, 1962; Assigned to Chas. Pfizer and Co., Inc., New York, N.Y., a corporation of Delaware
CARBAMAZEPINE Therapeutic Function: Analgesic, Anticonvulsant Chemical Name: 5H-Dibenz[b,f]azepine-5-carboxamide Common Name: 5-Carbamyl iminostilbene Structural Formula:
Chemical Abstracts Registry No.: 298-46-4 Trade Name
Manufacturer
Country
Year Introduced
Tegretol
Geigy
W. Germany
1964
Tegretol
Geigy
UK
1964
Tegretol
Geigy
France
1964
Tegretol
Geigy
US
1968
Tegretol
Geigy
Italy
1972
Biston
Spofa
Czechoslovakia
-
Convuline
Protea
Australia
-
Finlepsin
Arzneimittelwerk Dresden
E. Germany
-
822
Carbamazepine
Trade Name
Manufacturer
Country
Year Introduced
Hermolepsin
Laake
Finland
-
Lexin
Fujinaga
Japan
-
Mazepine
ICN
Canada
-
Neuritol
Eczacibasi
Turkey
-
Neurotol
Farmos
Finland
-
Nordotol
Farmos
Finland
-
Servimazepine
Servipharm
Switz.
-
Stazepine
Polfa
Poland
-
Telesmin
Yoshitomi
Japan
-
Temporol
Orion
Finland
-
Teril
Taro
Israel
-
Timonil
Desitin
W. Germany
-
Raw Materials Iminostilbene Phosgene Ammonia Manufacturing Process 19.3 parts of iminostilbene are dispersed in 100 parts by volume of toluene. Phosgene is then introduced whereupon the temperature of the reaction mixture rises to 70°C. While boiling under reflux, further phosgene is introduced until all the iminostilbene has dissolved and the hydrogen chloride development is complete. The reaction mixture is then cooled and the 5chlorocarbonyl iminostilbene which has crystallized out is filtered off under suction. It melts at 168° to 169°C. 12.8 parts of 5-chlorocarbonyl iminostilbene are dispersed in 128 parts by volume of absolute ethanol and ammonia gas is introduced for three hours into this mixture while stirring at boiling temperature. The reaction is complete after this time; the reaction mixture is cooled and the crystals which precipitate are filtered off under suction. The ammonium chloride is washed from the crystals with water and the residue is recrystallized first from absolute ethanol and then from benzene. 5-carbamyl iminostilbene is obtained which melts at 204° to 206°C. References Merck Index 1758 Kleeman and Engel p. 144 PDR p. 900 OCDS Vol. 1 p. 403 (1977) DOT 1 (3) 82 (1965) I.N. p. 181 REM p. 1077 Schindier, W.; US Patent 2,948,718; August 9, 1960; assigned to Geigy Chemical Corporation
Carbaspirin calcium
823
CARBASPIRIN CALCIUM Therapeutic Function: Analgesic, Antipyretic, Antirheumatic Chemical Name: 2-(Acetyloxy)benzoic acid calcium salt Common Name: Calcium aspirin; Calcium acetylsalicylate Structural Formula:
Chemical Abstracts Registry No.: 69-46-3 Trade Name
Manufacturer
Country
Year Introduced
Calurin
Dorsey
US
1959
Iromin
Iromedica
Switz.
-
Soluspan
UPSA
France
1983
Iromin
Omegin
W. Germany
-
Fiogesic
Sandoz
US
-
Ursinus
Dorsey
US
-
Raw Materials Acetylsalicylic acid Calcium carbonate Manufacturing Process 500 g of finely powdered acetylsalicylic acid and 160 g of calcium carbonate (precipitated chalk), are intimately mixed and 3,000 cc of water are added. The mixture is stirred for 15 minutes or until the reaction is completed, which is indicated by the cessation of the liberation of carbon dioxide. The temperature is desirably maintained below 20°C by any suitable means. The mass is allowed to settle until the supernatant liquor is almost clear; this usually takes about 5 minutes, and the mixture is then filtered to remove unreacted material. This part of the process is carried out as quickly as possible so as to minimize any tendency of the calcium aspirin to hydrolyze in the solution. The filtrate is cooled to about 10°C and 1 to 1.5 volumes of 97%
824
Carbazochrome
methanol, or pure wood alcohol is added. This causes the calcium aspirin to precipitate and the mass is then filtered to remove as thoroughly as possible the mother liquor. The residue of calcium aspirin is then suspended in a quantity of methanol equivalent to the volume previously used as a precipitant, and it is allowed to stand there for one hour or more with occasional or continuous agitation. The mass is again filtered, the filtrate being employed for the precipitation of calcium aspirin in a later batch. After the filtering of the first wash liquor, the calcium aspirin is again suspended in another quantity of methanol of an equivalent volume. This constitutes the second wash and it is carried out in the same way as the first wash. The filtrate is employed as a first wash in a later batch and this filtrate in turn is used, as is the filtrate of the first wash, for the precipitation of more calcium aspirin. Fresh alcohol is used as a new wash in a later batch and the washes are carried out in series. After the second wash the calcium aspirin is dried in a suitable manner, as by passing dry warm air over it, the temperature not being allowed to rise to such an extent as to decompose the aspirin; preferably the temperature is not permitted to rise above 50°C, but should be high enough to avoid deposition of water vapor, and the drying is completed when there is no longer an odor of methanol. References Merck Index 1615 Kleeman and Engel p. 145 PDR p. 1583 Lawrence, W.H., Jr.; US Patent 2,003,374; June 4, 1935; assigned to Lee Laboratories, Inc.
CARBAZOCHROME Therapeutic Function: Hemostatic Chemical Name: 3-Hydroxy-1-methyl-5,6-indolinedione semicarbazone Common Name: Adrenochrome Structural Formula:
Chemical Abstracts Registry No.: 69-81-8; 13051-01-9 (Salicylate)
Carbenicillin disodium
825
Trade Name
Manufacturer
Country
Year Introduced
Adrenosem
Beecham
US
1953
Adrestat
Organon
US
1957
Adrenoxyl
Labaz
France
1957
Adrenoxyl
Nordmark
W. Germany
-
Anaroxyl
Organon
US
-
Cromosil
Zambeletti
Italy
-
Cromoxin
R. Rius
Spain
-
Meronyl
Santen
Japan
-
Raw Materials Adrenalin Silver oxide Semicarbazide hydrochloride Manufacturing Process A suspension containing 1 part by weight of adrenalin and 2 to 6 parts by weight of silver oxide in 150 to 250 parts by weight of methanol or ethanol is stirred for about 10 minutes. The alcoholic adrenochrome solution obtained is separated by draining and the filtrate is quickly evaporated to dryness at low temperature and in vacuo. The red crystals of adrenochrome obtained are dissolved in 45 to 55 parts by weight of water. To this solution, 2 parts of sodium acetate dissolved in 2 to 3 parts of water and 2 parts of semicarbazide hydrochloride dissolved in 2 to 3 parts of water are added. The formed precipitate consisting of red-orange prismatic needles is separated by filtration and recrystallized from diluted ethanol. There is obtained 0.30 to 0.40 part by weight of adrenochrome monosemicarbazone dihydrate, melting at 203°C with decomposition. References Merck Index 1767, 1768 Kleeman and Engel p. 146 I.N. p. 182 REM p. 832 Dechamps, G., Le Bihan, H. and Baudet, C.; US Patent 2,506,794; May 2, 1950; assigned to Societe Belge de l'azote et des Produits Chimiques du Marly (Belgium)
CARBENICILLIN DISODIUM Therapeutic Function: Antibacterial Chemical Name: N-(2-Carboxy-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0]hept-6-yl)-2-phenylmalonamic acid sodium salt
826
Carbenicillin disodium
Common Name: Carboxybenzylpenicillin sodium salt Structural Formula:
Chemical Abstracts Registry No.: 4800-94-6; 4697-36-3 (Base) Trade Name
Manufacturer
Country
Year Introduced
Pyopen
Beecham
Switz.
1968
Pyopen
Beecham
UK
1968
Carindapen
Pfizer
W. Germany
1968
Pyopen
Beecham
US
1970
Geopen
Roerig
US
1970
Gripenin
Fujisawa
Japan
1970
Geopen
Pfizer Taito
Japan
1971
Pyocianil
Farmitalia
Italy
1972
Anabactyl
Beecham
W. Germany
-
Carbapen
C.S.L.
Australia
-
Carbecin
Beecham
-
-
Fugacillin
Astra
Sweden
-
Microcillin
Bayer
W. Germany
-
Rexcilina
Wolner
Spain
-
Raw Materials Phenylmalonic acid Benzyl alcohol Thionyl chloride 6-Amino penicillanic acid Hydrogen Sodium bicarbonate Manufacturing Process The required monobenzyl phenylmalonate, MP 68°C, was prepared by treating a mixture of phenylmalonic acid (18 g) and benzyl alcohol (13 g) in carbon tetrachloride (80 ml) with dry hydrogen chloride. Monobenzyl phenylmalonate (13.3 g) in dry benzene (100 ml) was refluxed
Carbenicillin indanyl sodium
827
with thionyl chloride (6.45 g) for 90 minutes, then concentrated in vacuo. The residual oil was dissolved in dry acetone (50 ml) and added to a stirred, icecooled solution of 6-aminopenicillanic acid (9.7 g) in N sodium bicarbonate solution (135 ml), water (150 ml), and acetone (300 ml). The mixture was stirred for 30 minutes at 0°C and then for 90 minutes at room temperature, then concentrated under reduced pressure to remove acetone. The aqueous solution was brought to pH 2 with dilute hydrochloric acid and extracted with ether (3 x 100 ml). The ether solution was washed with water and then itself extracted with sufficient N sodium bicarbonate solution to give an aqueous phase of pH 7.5. The aqueous layer was separated and evaporated at low temperature and pressure to leave the impure sodium salt of alpha(benzyloxycarbonyl) benzylpenicillin. This crude product (15.8 g) in water (360 ml) was added to a prehydrogenated suspension of 10% palladium on charcoal (4 g) in water (400 ml), and hydrogenation was continued for 30 minutes. The catalyst was removed and the filtrate was adjusted to pH 7.5 with sodium bicarbonate, then evaporated at low temperature and pressure. The residue was purified by chromatography on a column of cellulose powder, eluting first with butanol/ethanol/water mixture and then with acetone/isopropanol/water. The main fraction was evaporated at low temperature and pressure to give a 32% yield of the sodium salt of alpha-carboxybenzylpenicillin as a white powder. The product was estimated by monometric assay with penicillinase to be 58% pure. References Merck Index 1773 Kleeman and Engel p. 147 PDR p. 1404 OCDS Vol. 1 p. 414 (1977) and 2 p. 437 (1980) DOT 4 (3) 96 (1968) I.N. p. 183 REM p. 1194 Brain, E.G. and Nayler, J.H.C.; US Patents 3,282,926; November 1, 1966 and 3,492,291; January 27, 1970; both assigned to Beecham Group Limited, England
CARBENICILLIN INDANYL SODIUM Therapeutic Function: Antibacterial Chemical Name: N-(2-Carboxy-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0]hept-6-yl)-2-phenylmalonamic acid, 1-(5-indanyl ester), monosodium salt Common Name: Carindacillin; Indanylcarbenicillin Chemical Abstracts Registry No.: 26605-69-6; 35531-88-5 (Base)
828
Carbenicillin indanyl sodium
Structural Formula:
Trade Name
Manufacturer
Country
Year Introduced
Geocillin
Roerig
US
1972
Carindapen
Pfizer
W. Germany
1973
Geopen
Pfizer
Switz.
1973
Geopen-U
Pfizer Taito
Japan
1976
Unipen
Pfizer-Roerig
US
-
Urobac
Pfizer-Roerig
-
-
Raw Materials Phenylmalonic acid 6-Aminopenicillanic acid Triethylamine
5-Indanyl alcohol Phosphorus pentachloride
Manufacturing Process (A) Preparation of Phenylchlorocarbonyl Ketene: To phenylmalonic acid (20 g) in ethyl ether (100 ml) there is added phosphorus pentachloride (46 g). A vigorous reaction occurs. The reaction mixture is refluxed for 4 hours then the ether partially removed by heating on a steam bath. The reaction mixture becomes black when about half the ether is removed and the remaining ether is removed under reduced pressure (at 100 mm). The residue is distilled under vacuum and the fraction boiling at 75° to 90°C at 1.5 to 4 mm collected. The product, a yellow liquid, is redistilled at 74°C and 1.5 mm. It shows a strong peak in the infrared region of the spectrum at 4.69 mu. Repetition of this procedure but using 10 g of phenylmalonic acid instead of 20 g produces a less vigorous reaction on addition of the phosphorus pentachloride. The same product is obtained. (B) Acylation of 6-Aminopenicillanic Acid: To a solution of the aryl halocarbonyl ketene (0.1 mol) in methylene chloride (sufficient to provide a clear solution and generally from about 5 to 10 ml per gram of ketene) there is added the proper alcohol R2OH (0.1 mol), in this case 5-indanyl alcohol. The reaction mixture is maintained under an atmosphere of nitrogen and stirred for a period of from 20 minutes to 3 hours, care being taken to
Carbenoxolone
829
exclude moisture. The temperature may range from about -70° to about 20°C. The infrared spectrum of the mixture is then taken to determine and confirm the presence of the ketene ester. A solution of 6-aminopenicillanic acid-triethylamine salt (0.1 mol) in methylene chloride (50 ml) is added and the mixture stirred at -70° to -20°C for 10 minutes. The cooling bath is then removed and the reaction mixture stirred continuously and allowed to warm to room temperature. Various isolation methods are then spelled out in US Patent 3,679,801. References Merck Index 1823 Kleeman and Engel p. 155 PDR p. 1524 DOT 8 (8) 310 (1972 and 9 (4)128 (1973) I.N. p. 189 REM p. 1195 Butler,K.; US Patents 3,557,090; January 19, 1971; 3,574,189; April 6, 1971; and 3,679,801; July 25, 1962; all assigned to Chas. Pfizer and Co., Inc.
CARBENOXOLONE Therapeutic Function: Antiinflammatory (gastric) Chemical Name: 3β-Hydroxy-11-oxo-20β-olean-12-en-29-oic acid hydrogen butanedioate Common Name: Glycyrrhetinic acid hydrogen succinate Structural Formula:
Chemical Abstracts Registry No.: 5697-56-3; 7421-40-1 (Sodium salt)
830
Carbenoxolone
Trade Name
Manufacturer
Country
Year Introduced
Biogastrone
Winthrop
UK
1963
Biogastrone
Homburg
W. Germany
1970
Gastrausil
Italseber
Italy
1971
Biogastrone
Richardson-Merrell Switz.
1978
Biogastron
Shionogi
Japan
1979
Biogastrone
Abic
Israel
-
Bioral
Biorex, Berk
UK
-
Duogastrone
Merrell
France
-
Duogastrone
Abic
Israel
-
Karbenol
Yurtoglu
Turkey
-
Neogel
Homburg
W. Germany
-
Neutrogastrol Ulcus Pyrogastone
Septa
Spain
-
Winthrop
UK
-
Sanodin
Leo
Spain
-
Sustac
Sintyal
Argentina
-
Terulcon
ISF
Italy
-
Ulcofer
Mulda
Turkey
-
Ulcus-Tablinen
Sanorania
W. Germany
-
Ulkon
Eczacibasi
Turkey
-
Ventroxol
Medica
Finland
-
Raw Materials Glycyrrhetinic acid Succinic anhydride Manufacturing Process 23.5 g of glycyrrhetinic acid were dissolved in 50 cc of dry pyridine. A solution of 6.0 g of succinic anhydride in 30 cc of dry pyridine was added, followed by 30 cc of dry triethylamine and then, for washing purposes, 5 cc of dry pyridine. The solution was heated on a boiling water bath for ten hours and then poured into excess of dilute hydrochloric acid and ice. The fine gray precipitate formed was filtered off, washed with water, dissolved in chloroform, and the solution repeatedly extracted with dilute hydrochloric acid and later with water. It was dried over sodium sulfate and evaporated to dryness. Crystallization from methanol, using charcoal to effect decolorization, gave the hydrogen succinate as cream-colored crystals, MP 291° to 294°C, with previous softening. One molecular proportion of glycyrrhetinic acid hydrogen succinate was ground with a dilute (5%) aqueous solution containing two molecular proportions of sodium hydroxide. The solution was filtered and evaporated in vacuum over concentrated sulfuric acid. The sodium salt is then obtained as a creamy white water-soluble solid. Glycyrrhetinic acid is obtainable from licorice root.
Carbidopa
831
References Merck Index 1774 Kleeman and Engel p. 147 I.N. p. 183 Gottfried,S. and Baxendale, L.; US Patent 3,070,623; December 25, 1962; assigned to Biorex Laboratories Limited, England
CARBIDOPA Therapeutic Function: Muscle relaxant, Antiparkinsonian Chemical Name: S-α-Hydrazino-3,4-dihydroxy-α-methylbenzenepropanoic acid monohydrate Common Name: Methyldopahydrazine Structural Formula:
Chemical Abstracts Registry No.: 38821-49-7; 28860-95-9 (Anhydrous) Trade Name
Manufacturer
Country
Year Introduced
Sinemet
Merck Sharp and Dohme
Italy
1974
Sinemet
Merck Sharp and Dohme
UK
1974
Nacom
Sharp and Dohme W. Germany
1975
Sinemet
Chibret
France
1975
Lodosyn
Merck Sharp and Dohme
US
1977
Menesit
Merck-Banyu
Japan
1980
Neo-Dopaston
Sankyo
Japan
1980
Raw Materials Vanillin Potassium cyanide
Nitroethane Hydrazine hydrate
832
Carbidopa Butylamine Iron Hydrobromic acid
Acetic acid Hydrogen chloride Hydrochloric acid
Manufacturing Process To a solution of vanillin in toluene is added nitroethane, butylamine and glacial acetic acid. The mixture is refluxed and the water of reaction is steadily azeotropically removed by distillation. After the theoretical amount of water is distilled out, distillation is continued to remove excess reactants. The last trace of excess reactants is then removed at room temperature under a vacuum. The product is then triturated with a hydrocarbon solvent such as Skellysolve B and is thus obtained in a crystalline state. In general, however, it is preferred to dissolve the residue directly in toluene for use in the next step, without isolating the 1-(2-nitropropen-1-yl)-4-hydroxy-3methoxybenzene. A mixture of iron, ferric chloride and water is added to the toluene solution. The mixture is heated to reflux and concentrated hydrochloric acid is added dropwise at a rate calculated to keep the mixture refluxing vigorously. After the hydrochloric acid is all added, the refluxing is continued by the application of heat for several hours. A siliceous filter aid is then added to the cooled reaction mixture and the material is removed by filtration. The filter cake is washed four times, each time with 90 ml of benzene. The organic layer is then separated from the filtrate. The water layer is acidified to a pH of 2 and extracted three times with 90 ml portions of benzene. These extracts are then combined with the organic solvent layer and the combined organic phase is extracted four times with 100 ml portions of water. It is then stirred for an hour with 230 ml of 10% sodium bisulfite solution. The organic solvent phase is then separated, washed seven times with 100 ml portions of water and dried over magnesium sulfate. Evaporation of the solvent gives 1-(4-hydroxy-3-methoxyphenyl)-2-propanone in the form of an oil. A mixture of 59.5 g of that oily product, 1.85 liters of benzene and 1 kg of potassium bisulfite in 200 liters of water is stirred at room temperature for two hours. The precipitated bisulfite addition product of the ketone is isolated by filtration and washed with isopropanol and then with ether. Five hundred grams of the adduct is mixed with 119.5 g of potassium cyanide, 292 ml of 85% hydrazine hydrate and 910 ml of water. The mixture is stirred overnight at room temperature after which the product is isolated by filtration. The product is washed 3 times with 250 ml portions of water and then 3 times with 230 ml portions of ether. It is then air dried and vacuum dried at room temperature. Fifty cubic centimeters of concentrated hydrochloric acid is saturated with hydrogen chloride gas at -10°C. To the solution is then added 2.5 g of the intermediate product, of the formula shown above, slowly with vigorous stirring. The mixture is allowed to stir overnight while warming at room temperature gradually. It is then concentrated in vacuo to a syrup. To the residual syrup is added 100 ml of 48% hydrobromic acid. The reaction vessel is purged with nitrogen and the reaction mixture is then refluxed for 3 hours after which it is concentrated in vacuo to a mixture of a syrup and a solid. The
Carbimazole
833
residue is taken up in sufficient water to form a clear solution. Activated charcoal is added and the mixture is heated to boiling and filtered. The filtrate is concentrated to dryness in vacuo and the residue is taken up in 25 cc of ethanol. The residual ammonium bromide is removed by filtration and to the filtrate there is added sufficient diethylamine to change the pH to 6.4. The mixture is warmed to 60°C and then cooled to room temperature. It is then allowed to stand overnight to effect complete crystallization. It is then cooled to 0°C and the product is isolated by filtration, washed with methanol and air dried. The product (α-hydrazino-α-methyl-β-(3,4-dihydroxyphenyl)propionic acid) is recrystallized once from water using a proportion of 15 cc water per gram of product. References Merck Index 1778 Kleeman and Engel p. 148 PDR p. 1210 OCDS Vol. 2p. 119 (1980) DOT 10 (9) 322 (1974) I.N. p. 184 REM p. 929 Chemerda, J.M., Sletzinger, M. and Bollinger, F.W.; US Patent 3,462,536; August 19, 1969; assigned to Merck and Co., Inc.
CARBIMAZOLE Therapeutic Function: Thyroid inhibitor Chemical Name: Ethyl 3-methyl-2-thioimidazoline-1-carboxylate Common Name: Athyromazole; Carbimazole; Kabimazuo Structural Formula:
Chemical Abstracts Registry No.: 22232-54-8 Trade Name Carbimazol Carbimazol Carbimazol
Manufacturer Cid Co. Henning Berlin Slovakofarma
Country -
Year Introduced -
834
Carbimazole
Trade Name
Manufacturer
Country
Year Introduced
Carbimazol
Genfarma
-
-
Carbimazol
Pharbita
-
-
Carbimazol
Pharmachemie
-
-
Carbist AD
Stada
-
-
Neo-Carbimazole
Landerlan
-
-
Neo-mercazole
Roche
-
-
Neo-mercazole
-
-
Neo-mercazole
Pharmacare Limited Nicholas Piramal
-
-
Neo-mercazole
Macleods
-
-
Neo-mercazole
Lagamed
-
-
Neo-mercazole
Nicholas
-
-
Neo-mercazole
Ferraz, Lynce
-
-
Neo-mercazole
Nicholas/Meda
-
-
Neo-Thyreostat
Herbrand
-
-
Neo-Tomizol
Robert
-
-
Thyrostat
NI-THE
-
-
Tyrazol
Orion Oy
-
-
Tyrazol
Algol Pharma Oy
-
-
Raw Materials 1-Methyl-2-mercaptoglyoxaline Ethyl chloroformate Pyridine Manufacturing Process 0.1 mol of 1-methyl-2-mercaptoglyoxaline is dissolved in the minimum quantity of pyridine at 0°C 0.1 mol of ethyl chloroformate is added drop wise with stirring. More pyridine is added, if necessary, to keep the mixture semifluid. The sludge is then placed in an ice bath for 30 minutes. The crystals are filtered off and washed firstly with a little ethanol and secondly with ethanol and water. The non-basic desired ethyl 3-methyl-2-thioimidazoline-1carboxylate is the colourless needles having a melting point of 122°-123°C. References Rimington C. et al.; US Patent No. 2,815,349; Dec. 3, 1957; Assigned to National Research Development Corporation, London, England, a British corporation Rimington C. et al.; US Patent No. 2,671,088; Mar. 2, 1954; Assigned to National Research Development Corporation, London, England, a British corporation Baker J.A., J. Chem. Soc. 1958, p. 2387
Carbinoxamine maleate
835
CARBINOXAMINE MALEATE Therapeutic Function: Antihistaminic Chemical Name: 2-[(4-Chlorophenyl)-2-pyridinyl-methoxy]-N,Ndimethylethanamine maleate Common Name: Structural Formula:
Chemical Abstracts Registry No.: 3505-38-2; 486-16-8 (Base) Trade Name Clistin Allergefon Polistin Cardec Cibelon Hislosine Histex Histine Lergefin Polistine Rondec Ziriton
Manufacturer McNeil Lafon Trommsdorff Schein Taisho Toho Sigma Pharbil Larma Pharbil Boss Importex
Country US France W. Germany US Japan Japan Australia Belgium Spain Netherlands US Italy
Year Introduced 1953 1962 1963 -
Raw Materials p-Bromochlorobenzene 2-Pyridine aldehyde 2-Dimethylaminoethyl chloride
Magnesium Sodium metal
Manufacturing Process As described in US Patent 2,800,485 a solution of p-chlorophenylmagnesium bromide is prepared by adding dropwise a solution of 230 g (1.2 mols) of pbromochlorobenzene in 900 cc of anhydrous ether to 26.7 g (1.1 g-atoms) of
836
Carbocysteine
magnesium suspended in 100 cc of anhydrous ether containing a small crystal of iodine. To this solution, 107 g (1 mol) of 2-pyridinealdehyde are added slowly with stripping at a rate to maintain refluxing. The reaction mixture is then stirred for one hour at room temperature. The mixture is then poured onto an equal volume of crushed ice and water and acidified with concentrated hydrochloric acid. The ether layer is removed. The aqueous layer is made basic with ammonia and extracted with ether. The ether solution is evaporated and the residue dried by addition of benzene and removal by distillation to give 208 g (95%) of solid alpha-(p-chlorophenyl)-2-pyridinemethanol melting at 78° to 80°C. The p-chlorophenyl pyridinemethanol may alternatively be prepared from 4-chloroacetophenone, pyridine and granular aluminum as described in US Patent 2,606,195. In either case, the synthesis then proceeds as described in US Patent 2,800,485. A solution of 219 g (1 mol) of α-(p-chlorophenyl)-2-pyridinemethanol in one liter of dry toluene is heated to 100°C with stirring. Twenty-three grams (1 gatom) of sodium are then added in portions. After all the sodium has reacted, a dried solution of 2-dimethylaminoethyl chloride in benzene is added. This benzene solution is prepared by dissolving 173 g (1.2 mols) of 2dimethylaminoethyl chloride hydrochloride in the minimum amount of water, adding 500 cc of benzene followed by 300 g of sodium carbonate decahydrate, stirring, separating the benzene layer and drying. The mixture is refluxed with stirring for ten hours, cooled and filtered. The filtrate is extracted three times with 200 cc portions of 6 N acetic acid. The aqueous acetic acid solution is then made strongly basic with 10% sodium hydroxide solution, and extracted three times with 200 cc portions of ether. The ether extract is dried with anhydrous sodium sulfate, stirred with 5 g of activated carbon and filtered to provide 2-[p-chloro-α(2-dimethylaminoethoxy) benzyl]pyridine in solution. Addition of a solution of 116 g (1 mol) of maleic acid in 1,500 cc of ether gives 323 g (79%) of solid which, on recrystallization from ethyl acetate, gives white solid 2-[p-chloro-α(2-dimethylaminoethoxy) benzyl]pyridine maleate melting at 117° to 119°C. References Merck Index 1780 Kleeman and Engel p. 150 PDR pp.1561, 1606 OCDS Vol. 1 p.43 (1977) and 2 p. 32 (1980) I.N.p. 184 REM p. 1126 Tilford. C.H. and Shelton, R.S.; US Patent 2,606,195; August 5, 1952; assigned to The Wm. S. Merrell Company Swain, A.P.; US Patent 2,800,485; July 23, 1957; assigned to McNeil Laboratories, Inc.
CARBOCYSTEINE Therapeutic Function: Mucolytic, Expectorant, Nasal antiinfective
Carbocysteine
837
Chemical Name: S-(Carboxymethyl)-L-cysteine Common Name: Structural Formula:
Chemical Abstracts Registry No.: 638-23-3 Trade Name
Manufacturer
Country
Year Introduced
Rhinathiol
Kramer
Switz.
-
Rhinathiol
Joullie
France
1961
Mucodyne
Berk
UK
1963
Transbronchin
Homburg
W. Germany
1975
Lisomucil
Lirca
Italy
1975
Mucodyne
Kyorin
Japan
1981
Actithiol
Funk
Spain
-
Bronchette
S. Africa
-
Bronchipect
Continental Ethicals Mepros
Netherlands
-
Bronchokod
Genekod
France
-
Broncodeterge
Valderrama
Spain
-
Carbocit
C.T.
Italy
-
Flemex
Parke Davis
US
-
Fluifort
Lampugnani
Italy
-
Loviscol
Robins
US
-
Muciclar
Parke Davis
US
-
Mucocaps
Berk
UK
-
Mucocis
Crosara
Italy
-
Mucolex
Warner Lambert
US
-
Mucopront
Mack
W. Germany
-
Mucosirop
Berk
UK
-
Mucospect
Lennon
S. Africa
-
Mucoliz
Yurtoglu
Turkey
-
Pectox
Infar-Nattermann
Spain
-
Pulmoclase
UCB
Belgium
-
Reodyn
Remeda
Finland
-
Reomucil
Tosi
Italy
-
Siroxyl
Sopar
Belgium
-
Solvopact
Mepros
Netherlands
-
838
Carbomycin
Raw Materials L-Cysteine Sodium metal Chloroacetic acid Manufacturing Process There were placed 120g of L-cysteine (0.5 mol) in a 2 liter three-necked flask equipped with a stirrer thermometer and methanol/dry ice cooling and 1.5 liters of liquid ammonia were allowed to enter at -40°C. Then there were added under continuous cooling 50 g (2.17 mols) of sodium metal in portions of 1 to 2 g during the course of one hour. The end of the reaction was recognized by the continuation of the blue color. After the end of the reaction the excess sodium was destroyed by the addition of ammonium chloride and the ammonia vaporized at normal pressure. The residue was taken up in 500 ml of water and concentrated in a vacuum to 200 ml in order to remove residual ammonia, and again treated with 300 ml of water. The entire operations were carried out under a nitrogen atmosphere. The aqueous solution of the disodium salt of L-cysteine obtained is then reacted at 20°C to 30°C under a nitrogen atmosphere in the course of 30 minutes with stirring with a solution of 104 g of chloroacetic acid (1.1 mols) and 4 g of sodium pyrosulfite in 200 ml of water. It is also allowed to post react for 15 minutes at 20°C, the solution clarified over activated carbon and the filtrate treated with 90 ml of concentrated hydrochloric acid to a pH of 2.5. Thereby the S-carboxymethyl-L-cysteine precipitates out in crystalline form. The product is filtered off with suction, well stirred in 500 ml of water, again filtered with suction and dried in a vacuum at 70°C. The yield is 92% based on L-cysteine. References Merck Index 1785 Kleeman and Engel p. 151 I.N. p. 185 Maierhofer, A. and Wagner. H.; US Patent 4,129,593; December 12, 1978: assigned to Deutsche Gold und Silber-Scheideanstalt vormals Roessler (Germany)
CARBOMYCIN Therapeutic Function: Antibiotic Chemical Name: 9-Deoxy-12,13-epoxy-9-oxo-leucomycin V-3-acetate-4B-(3methylbutanoate) Common Name: -
Carbomycin
839
Structural Formula:
Chemical Abstracts Registry No.: 4564-87-8 Trade Name
Manufacturer
Country
Year Introduced
Magnamycin
Pfizer
US
1953
Raw Materials Nutrient broth Streptomyces halsredii bacterium Manufacturing Process A selected strain of Streptomyces halstedii was cultivated in an aqueous nutrient medium under aerobic conditions and the resulting broth containing carbomycin antibiotics was filtered. The solutions was extracted twice at pH 6.5 with one-quarter volume of methyl isobutyl ketone. The combined extracts were concentrated to one-tenth volume under vacuum, and the antibiotics were extracted into water adjusted to a pH of about 2 with sulfuric acid. After adjusting the separated aqueous solution to pH 6.5, the antibiotic was extracted into benzene and the solution was concentrated to a small volume. Addition of hexane resulted in the separation of a solid product containing the benzene complexes of carbomycin A and carbomycin B, present in the fermentation broth. References Merck Index 1790 I.N.p. 186 Tanner, F.W. Jr., Lees, T.M. and Routien, J.B.; US Patent 2,771,392; November 20, 1956; assigned to Chas. Pfizer and Co., Inc.
840
Carboplatin
Friedman, I.J., Martin, E.G., Taylor, R.J. and Wagner, R.L. Jr.; US Patent 2,960,438; November 15, 1960; assigned to Chas. Pfizer and Co., Inc.
CARBOPLATIN Therapeutic Function: Antitumor Chemical Name: Platinum, diammine(1,1-cyclobutanedicarboxylato(2-)O,O')-, (SP-4-2)Common Name: Carboplatin Structural Formula:
Chemical Abstracts Registry No.: 41575-94-4 Trade Name
Manufacturer
Country
Year Introduced
Blastocarb
Lemery
Mexico
-
Carboplatin
Teva
Israel
-
Carboplatin
Yunnan Gejiu Biochemical Pharmaceutical Factory
China
-
Carboplatin
Pharmacia and Upjohn
Australia
-
Carboplatin-Ebewe Ebewe
Australia
-
Carboplatin-Teva
Pharmachemie
Netherlands
-
Cycloplatin
Pliva-Lachema
Czech Republic
-
Paraplatin
Bristol-Myers Squibb
Italy
-
Raw Materials cis-Diammine platinum diiodide Silver sulfate Barium salt of 1,1-cyclobutanedicarboxylic acid Manufacturing Process cis-Diammine platinum diiodide was reacted with silver sulfate to give cis-
Carboprost tromethamine
841
diaquodiammine platinum sulfate. This was reacted with the barium salt of 1,1-cyclobutanedicarboxylic acid to yield Carboplatin. References Harrison R.C. et al.; Inorg. Chem. Acta, 46, L15 (1980)
CARBOPROST TROMETHAMINE Therapeutic Function: Oxytocic Chemical Name: Prosta-5,13-dien-1-oic acid, 9,11,15-trihydroxy-15-methyl-, (5Z,9α,11α,13E,15S)-, compd. with 2-amino-2-(hydroxymethyl)-1,3propanediol (1:1) Common Name: Carboprost Trometamol; Carboprost Tromethamine; Prostodin Structural Formula:
Chemical Abstracts Registry No.: 58551-69-2 Trade Name
Manufacturer
Country
Year Introduced
Hemabate
Pharmacia and Upjohn Company
-
-
Prostinfenem
Pfizer
-
-
Prostin 15M
Pharmacia and Upjohn Company
-
-
Prostodin
AstraZeneca
-
-
Deviprost
Dr. Reddy`s Laboratories Ltd.
-
-
842
Carboprost tromethamine
Raw Materials (+)-2β,4β-Dihydroxy-3α-iodo-5α(methoxymetyl)cyclopentane-1βacetic acid γ-lactone Lithium aluminum hydride (2-Oxoheptyl)phosphonate Methyl magnesium bromide Diisobutylaluminum hydride Carboxybutyltriphenylphosphonium bromide
Benzoyl chloride Tributyltin chloride Boron trifluoride Sodium hydride Sodium hydroxide Sodium bisulfate Diazomethane 2-Amino-2-(hydroxymethyl)1,3-propanediol
Manufacturing Process (+)-2β4β-Dihydroxy-3α-iodo-5α-(methoxymetyl)cyclopentane-1β-acetic acid γlactone 4-benzoate: To a stirred solution at 20°C of 75 g of (+)-2β,4β-dihydroxy-3α-iodo-5α (methoxymetyl)cyclopentane-1β-acetic acid γ-lactone (M.P. 101-102°C, [α]D = -50° (c 0.98, CHCl3) in 135 ml of dry pyridine was added 30.4 ml of benzoyl chloride. After 30 min, 250 ml of toluene was added and the resulting solution evaporated to dryness under reduced pressure. The residue was dissolved in 1000 ml of ethyl acetate. The organic solution was washed with 200 ml 20% of aqueous sulfuric acid and 200 ml of brine. The aqueous solution was washed with 200 ml of ethyl acetate. The ethyl acetate solution was dried and evaporated under reduced pressure to give 95 g of oil which crystallized. The crude product was recrystallized to give 90 g of the white solid, M.P. 84-86°C, [α]D = +5° (c 1.03, CHCl3). (-)-3α,5α-Dihydroxy-2β-(methoxymethyl)cyclopentane-1-α-acetic acid γlactone 3-benzoate: To a solution of 4.2 g of lithium aluminum hydride in 420 ml of ether under a nitrogen atmosphere and cooled in a ice bath was added dropwise a solution of 99 g of tributyltin chloride in 210 ml of ether. The cooling bath was removed and stirring continued at ambient temperature for 1.5 hours. To the cooled solution was added 260 ml of water. The organic layer was washed with water and dried. This solution was added slowly at 15°C to a solution of (+)-2β,4β-dihydroxy-3α-iodo-5α-(methoxymethyl)cyclopentane-1β-acetic acid γ-lactone 4-benzoate in 240 ml of benzene. Then the solution was evaporated and the product was stirred with water. Yield of (-)-3α,5α-dihydroxy-2β(hydroxymethyl)cyclopentane-1α-acetic acid γ-lactone 3-benzoate 93%. (-)-3α,5α-Dihydroxy-2β-(methoxymethyl)cyclopentane-1α-acetic acid γ-lactone 3-benzoate: To a solution of 20 g of (-)-3α,5α-dihydroxy-2β-(hydroxymethyl)cyclopentane1α-acetic acid γ-lactone 3-benzoate in 320 ml of methylene chloride under nitrogen atmosphere and cooled in an ice bath was added dropwise 24.8 ml of boron trifluoride in 320 ml of methylene chloride. After 1 hour to the solution was added 78 g of sodium carbonate in 200 ml of water and then 66 g of solid sodium chloride. The aqueous phase was extracted with ethyl acetate. Yield of (-)-3α,5α-dihydroxy-2β-(methoxymethyl)cyclopentane-1α-acetic acid
Carboprost tromethamine
843
γ-lactone 3-benzoate 95%, M.P. 116-118°C. (-)-3α,5α-Dihydroxy-2β-(3-oxo-trans-1-octenyl)cyclopentane-1α-acetic acid γlactone 3-benzoate: To a mixture of 1.75 g of sodium hydride and 2509 ml of tetrahydrofuran at 5°C was added 8.0 g of (2-oxoheptyl)phosphonate. After 2.5 hours a thick white precipitate formed (ilide mixture). To a stirred mixture of 11 g of anhydrous cromium trioxide and 150 ml of methylene chloride under nitrogene atmosphere and cooled in an ice bath was added 17 g of anhydrous pyridine. The mixture was stirred for 15 min at 0°C for 2 hours at room temperature, then at 0°C again. A solution of 5.0 g of (-)-3α,5α-dihydroxy-2β(methoxymethyl)cyclopentane-1α-acetic acid γ-lactone 3-benzoate in 150 ml methylene chloride was added to at 0°C to a to the cold Collins oxidant solution. The resulting black mixture was stirred 5 min. After addition of 100 ml of benzene, the mixture was filtered through Celite, washing with benzene. The filtrate was concentrated to 50 ml under reduced pressure and then diluted with 100 ml of benzene. This solution was added to the cold ilide mixture. The resulting dark mixture was stirred for 1.5 hours at room temperature. After dropwise addition of 3 ml of acetic acid the mixture was concentrated to dryness. The residue was dissolved in 400 ml of ethyl acetate. The solution was washed with water and then with brine. Organic phase was dried and evaporated to give dark oil. This oil was purified on silica gel, yield of (-)-3α,5α-dihydroxy-2β-(3-oxo-trans-1-octenyl)cyclopentane-1α-acetic acid γ-lactone 3-benzoate 48%, M.P. 63-63.8°C, [α]D = -113° (c 1.18, CHCl3). (-)-3α,5α-Dihydroxy-2β-[(3RS)-3-hydroxy-3-methyl-trans-octenyl] cyclopentane-1α-acetic acid γ-lactone 3-benzoate: To a solution of 0.20 g of (-)-3α,5α-dihydroxy-2β-(3-oxo-trans-1-octenyl) cyclopentane-1α-acetic acid γ-lactone 3-benzoate in 15 ml of tetrahydrofuran at -78°C under nitrogen was added dropwise 3 ml etheral solution 3 M methylmagnesium bromide. The solution became heterogeneous after 2 hours, to the mixture was added 10 ml of saturated aqueous ammonium chloride and then ether and water. Organic extract was washed with brine, dried over sodium sulfate, and evaporated to give 0.21 g of (-)-3α,5αdihydroxy-2β-[(3RS)-3-hydroxy-3-methyl-trans-octenyl]cyclopentane-1α-acetic acid γ-lactone 3-benzoate as a colorless oil; [α]D = -80° (c 1.0, CHCl3). (-)-3α,5α-Dihydroxy-2β-[3-(RS)-3-hydroxy-3-methyl-trans-octenyl] cyclopentane-1α-acetaldehyde γ-lactol 3-benzoate: To a solution of 0.50 g of (-)-3α,5α-dihydroxy-2β-[(3RS)-3-hydroxy-3-methyltrans-octenyl]cyclopentane-1α-acetic acid γ-lactone 3-benzoate in 15 ml of tetrahydrofuran at -78°C under nitrogen was added 10 ml of 10% diisobutylaluminum hydride in toluene. After a gas evolution was ceased, the reaction was quenched by addition of 10 ml of saturated aqueous ammonium chloride. The resulting mixture was stirred at room temperature, filtered through Celite, and extracted with ethyl acetate. Extract was evaporated to give 0.48 g of (-)-3α,5α-dihydroxy-2β-[3-(RS)-3-hydroxy-3-methyl-transoctenyl]cyclopentane-1-α-acetaldehyde γ-lactol 3-benzoate as an oil. (15R)- and (15S)-15-methyl-PGF2α methyl esthers:
844
Carboquone
A mixture of 0.23 g sodium hydride (50% dispersion in mineral oil) and 10 ml of dimethyl sulfoxide stirred under nitrogene at 70-75°C. After 1 hours, gas evolution had ceased. After 0.5 hour, the mixture was cooled to room temperature. To the mixture was added 1.06 g 4carboxybutyltriphenylphosphonium bromide and the resulting dark red solution stirred 0.5 hour. To this solution was added a solution of 0.48 g of (-)-3α,5α-dihydroxy-2β-[3-(RS)-3-hydroxy-3-methyl-trans-octenyl] cyclopentane-1α-acetaldehyde γ-lactol 3-benzoate in 15 ml of dimethyl sulfoxide. The resulting dark orange mixture was stirred at room temperature for 12 hours. Another 1.2 mmol of freshly prepared ilide in 3.6 ml of solution (prepared as above) was added. After 24 hours, the reaction was quenched by addition to 15 ml of 2 M sodium bisulfate (diluted with ice water) and 25 ml of ether. The organic extract was washed with 5 ml of 1 N sodium hydroxide, and twice with water. The aqueous washings were combined (pH £ 11) and acidified with sodium bisulfate to pH about 1 in the presence of ether. The aqueous phase was extracted with ether. The extract was evaporated to give 0.45 g of dark oily solid. The crude product was dissolved in a mixture of methylene chloride, ether and methanol and treated with excess etheral diazomethane. Evaporation gave 0.40 g of dark oil. The crude product was chromatographed on 10 g of silica gel. Fraction 9-12 contained a mixture of epimers (15R)- and (15S)-15-methyl-PGF2α-methyl esthers, yield 160 mg (35%) as an oil. The structure of product was confirmed by 1H-NMR spectrum. (15S)-15-methyl-PGF2α methyl esthers: 1 g of the mixture of epimers was chromatographed on 100 g (eluent acetone-methylene chloride). It was obtained 150 mg of pure (15S)-15methyl-PGF2α methyl esthers; M.P. 55-56°C, [α]D = +24° (c 0.81, ethanol). Carboprost tromethamine: The drug was prepared by mixing of (15S)-15-methyl-PGF2α methyl esthers with 2-amino-2-(hydroxymethyl)-1,3-propanediol (1:1). References Yankee E.W. et al.; J. Amer. Chem. Soc.; 1974, 96, 5865 US Patent No. 6,211,233; Apr. 3, 2001; Assigned to Nixon S.A., Paris (FR)
CARBOQUONE Therapeutic Function: Antineoplastic Chemical Name: 2,5-Bis(1-aziridinyl)-3-(1-methoxy-2-carbamoyloxyethyl)-6methyl-1,4-benzoquinone Common Name: Carbazilquinone Chemical Abstracts Registry No.: 24279-91-2
Carbromal
845
Structural Formula:
Trade Name
Manufacturer
Country
Year Introduced
Esquinon
Sankyo
Japan
1974
Raw Materials 2-Methyl-5-(1-methoxy-2-carbamoyloxyethyl)-1,4-benzoquinone Aziridine Manufacturing Process In 10 ml of ethanol was dissolved with heating 200 mg of 2-methyl-5-(1methoxy-2-carbamoyloxyethyl)-1,4-benzoquinone and the resulting solution was cooled. To the cooled solution was added 0.5 ml of aziridine and then the resulting mixture was allowed to stand in a refrigerator at 5°C to 8°C for 4 days. Thereafter, the crystalline substance which precipitated in situ was recovered by filtration and washed with ethanol to give 50 mg of the desired product as red crystals melting at 200°C (with decomposition). References Merck Index 1806 Kleeman and Engel p. 151 DOT 11 (9) 344 (1975) I.N. p. 186 Nakao, H., Arakawa, M. and Nakamura, T.; US Patent 3,631,026; December 28, 1971; assigned to Sankyo Co., Ltd.
CARBROMAL Therapeutic Function: Hypnotic, Sedative Chemical Name: Urea, (2-bromo-2-ethylbutyryl)Common Name: Bromacetocarbamidum; Bromdiaethylacetylcarbamidum; Bromadal; Carbromal Chemical Abstracts Registry No.: 77-65-6
846
Carbutamide
Structural Formula:
Trade Name
Manufacturer
Country
Year Introduced
Antineuralgiae
Jelfa
-
-
Seduan
Pharmed
-
-
Adalin
Bayer
-
-
Diacid
Daro
-
-
Addisomnol
Synochem
-
-
CARBRITAL
WARNER-LAMBERT CO.
-
-
CARBROMAL
-
-
Adabrom
Shanghai Lancheng Corporation Hosco
-
-
Carbalin
Arochem Industries
-
-
Dulcipan
Cl Ocana
-
-
P.R.
Boots
-
-
Sedadorm
Pharma Funcke
-
-
Sedamon
Sapic
-
-
Raw Materials Urea 2-Bromo-2-ethyl-butyrylbromide Manufacturing Process 120 parts urea and 258 parts 2-bromo-2-ethylbutyrylbromide was mixed and stood at room temperature for 12 hours; then the mixture was heated about 3 hours on water bath and adjusted to alkaline pH with sodium bicarbonate after cooling. The unreacted products was dissolved in brine, the insoluble part was filtered off. The recrystallization from ethanol gave the title product (2-bromo-2-ethyl-butyryl)urea as the colorless, odorless crystals. MP 114°118°C. References Bayer F.; D.R. Patent No. 225,710; 10 July 1909; Assigned to Farbenfabriken F. Bayer and Co. in Elberfeld
CARBUTAMIDE Therapeutic Function: Oral hypoglycemic
Carbutamide
847
Chemical Name: Benzenesulfonamide, 4-amino-N-((butylamino)carbonyl)Common Name: Aminophenurobutane; Butylcarbamide; Carbutamide; Glybutamide; Sulfabutylharnstoff Structural Formula:
Chemical Abstracts Registry No.: 339-43-5 Trade Name Carbutamide Carbutamide
Manufacturer Servier Shanghai Lancheng Corporation
Country -
Year Introduced -
Bucarban Glucidoral Oranil Glucofren Invenol Nadisan Bucarban Bucarban Diabetin Diabeton Diabex Diabex Diaboral Diabutan Dibefanil Glucidoral Insoral Insoral Norboral Orabetic Orabetic Orabetic Orabetic Oranil Oranil
Chinoin Servier Berlin-Chemie Cophar Hoechst Boehringer, Mann Chinoin Sanofi Diasan Servier Dambergis Alphapharm PHARMEX G. Streuli and Co. AG Mepha Pharma AG Servier Valeas Elvetium S.A. Silanes Lilly Biotech Cathay Mibe GmbH Arzneimittel AGRINDUSTRIAL, S.A. A.Menarini Pharmaceutical Industre's Group Ltd.
-
-
848
Carbuterol
Raw Materials Sodium salt of acetylsulfaniamide N-Butyl isothiocyanate Sodium nitrite Manufacturing Process 223 g of the sodium salt of acetylsulfaniamide are stirred with 223 ml of triethylene glycol. 118 g of n-butyl isothiocyanate are added to the resulting homogeneous mixture. The resulting syrup is heated to 85°C for 4 hours. The mixture is then stirred with 1000 ml of chloroform and 1000 ml of water. The chloroform layer is twice shaken with water, each time with 250 ml. The aqueous extracts are combined and rendered weakly alkaline to phenolphthalein by addition of hydrochloric acid. Unreacted acetyl sulfanilamide precipitates and filtered off. The filtrate is acidified to a pH of 6.5 by the addition of HCl. An oily precipitate settles from the reaction solution and is separated therefrom. N-Butyl acetyl sulfanilylthiourea is precipitated from mother liquors obtained thereby by addition of HCl until Congo paper changes its color to blue. 210 g N-butyl acetyl sulfanilylthiourea are dissolved in 1400 ml of acetone while heating. The solution is mixed with 500 ml of water. A solution of 63 g of sodium nitrite in 120 ml of water is added thereto within about 45 minutes while stirring and cooling to 15°-20°C. A suspension of crystals is obtained. 240 ml of 25% glacial acid are added thereto within 30 minutes. Stirring of the mixture is continued for 6 hours. NButyl acetyl sulfanilylurea mixed with sulfur is precipitated and filtered off. The crude reaction product is suspended in 1000 ml of water and is rendered weakly alkaline to phenolphthalein. Undissolved sulfur is filtered off. The filtrate is acidified by the addition of HCl. 250 g of N-butyl acetyl sulfanilylthiourea having a melting point of 186°-189°C are obtained. It is heated with 500 ml of 5 N potassium hydroxide solution to a temperature of 92°C for 2 hours while stirring. The solid reaction product is dissolved by heating with 750 ml of water and is purified by means of activated charcoal. The resulting solution is heated to 60°C and acidified by addition of HCl. 187 g of N-butyl acetyl sulfanilylthiourea melting at 139°-141°C obtained thereby. References Haak E. et al.; US Patent No. 2,907,692; Oct.6, 1959; Assigned to C.F. Boehringer and Soehne G.m.b.H., Mannheim-Waldhof, Germany, a corporation of Germany
CARBUTEROL Therapeutic Function: Bronchodilator Chemical Name: [5-[2-[(1,1-Dimethylethyl)amino]-1-hydroxyethyl]-2hydroxyphenyl]urea Common Name: -
Carbuterol
849
Structural Formula:
Chemical Abstracts Registry No.: 34866-47-2 Trade Name Bronsecur Bronsecur Pirem Dilabron Rispan
Manufacturer SK and F SK and F Sasse Warner Lambert SK and F
Country W. Germany Italy W. Germany -
Year Introduced 1980 1980 1982 -
Raw Materials 3-Amino-4-benzyloxyacetophenone Ammonia N-Benzyl-N-t-butylamine
Phosgene Bromine Hydrogen
Manufacturing Process A stirred solution of 40 g (0.41 m) of phosgene in 150 ml of toluene is held at 25°C with a cooling bath while a mixture of 252 g (0.105 m) of 3-amino-4benzyloxyacetophenone and 220 ml of toluene are added slowly. The mixture is heated to reflux and continued for 30 minutes. Nitrogen is passed through the mixture and then concentrated in vacuo to give a crystalline isocyanate, MP 105°-106°C. A stirred solution of the isocyanate (28.0 g) in 500 ml of dry benzene is saturated with ammonia. After one hour, the mixture is cooled to give the crystalline 4-benzyloxy-3-ureidoacetophenone, MP 184°-186°C. To a stirred solution of 5.7 g (0.02 m) of 4-benzyloxy-2-ureidoacetophenone in 100 ml of chloroform is added 32 g (0.02 m) of bromine. The mixture is stirred at room temperature for about 45 minutes and the solution is concentrated in vacuo at 25°-30°C. The amorphous residue (hydrobromide salt of 4-benzyloxy-α-bromo-3-ureidoacetophenone) is dissolved in 80 ml of acetonitrile and 98 g (0.06 m) of N-benzyl-N-t-butylamine is added. The mixture is stirred and refluxed for 1.5 hours, then it is cooled to 0°C in an ice bath. Crystalline N-benzyl-N-t-butylamine hydrobromide is filtered. The filtrate is acidified with ethereal hydrogen chloride. The semicrystalline product is filtered after diluting the mixture with a large excess of ether. Trituration of the product with 60 ml of cold ethanol gives 4-benzyloxy-α-(N-benzyl-N-tbutylamino)-3-ureidoacetophenone hydrochloride, MP 200°-221°C (decomposition). A solution of 10.5 g (0.0218 m) of 4-benzyloxy-α-(N-benzyl-N-t-butylamino)-
850
Carfecillin sodium
3-ureidoacetophenone hydrochloride in 65 ml of methanol and 25 ml of water is added to a suspension of 1.5 g of 10% palladium-on-carbon in 10 ml of water. The mixture is hydrogenated on the Parr apparatus at room temperature, using an initial pressure of 60 psi of hydrogen. After 4 hours about 80% of the theoretical volume of hydrogen has been absorbed. The mixture is filtered, an additional 1.5 g of 10% palladium-on-carbon is added and the mixture is again hydrogenated on the Parr apparatus under the same conditions. After hydrogenating for an additional 3 hours, the mixture is filtered and the filtrate is concentrated in vacuo. The residue is stripped twice with toluene and crystallized with ether-ethanol to give α-(tbutylaminomethyl)-4-hydroxy-3-ureidobenzyl alcohol hydrochloride, MP 214°215°C. References Merck Index 1817 DFU 1 (9) 412 (1976) Kleeman and Engel p. 153 OCDS Vol. 2 p. 41 (1980) DOT 12 (2) 483 (1976) I.N. p. 187 Kaiser, C. and Ross, S.T.; US Patent 3,763,232; October 2, 1973; assigned to Smith Kline and French Laboratories Kaiser, C. and Ross, S.T.; US Patent 3,917,847; November 4, 1975; assigned to Smith Kline Corp.
CARFECILLIN SODIUM Therapeutic Function: Antibiotic Chemical Name: Malonamic acid, N-(2-carboxy-3,3-dimethyl-7-oxo-4-thia-1azabicyclo(3.2.0)hept-6-yl)-2-phenyl-, 1-phenyl ester monosodium salt Common Name: Carbenicillin phenyl sodium; Carfecillin sodium Structural Formula:
Chemical Abstracts Registry No.: 21649-57-0
Carfecillin sodium
851
Trade Name
Manufacturer
Country
Year Introduced
Carfecillin sodium
Beecham (GSK)
-
-
Raw Materials Phenylmalonic acid Thionyl chloride Phenol 6-Aminopenicillanic acid Manufacturing Process Phenylmalonic acid (27 g) was mixed with dry ether (80 ml) and treated with thionyl chloride (17.85 g, 10.9 ml) and dimethylformamide (4 drops). The mixture was refluxed for 3 hours on a hot water bath. The solvent was evaporated under reduced pressure and the residue dissolved in fresh dry ether (80 ml). Phenol (14.1 g) was added all at once and the mixture refluxed for 2 hours. The reaction was cooled to room temperature, washed with water (25 ml) and extracted with saturated sodium bicarbonate solution until the extracts were alkaline. The combined aqueous extracts were washed with ether (100 ml) and acidified with 5 N HCl. The precipitated oil was extracted with methylene chloride. The combined organic extracts were washed thoroughly with water (6x120 ml) dried over anhydrous magnesium sulphate and evaporated. The solid residue was crystallised from benzene to give monophenyl phenylmalonate, a colourless crystalline solid 30.2 g (78.7 %) MP 115-117°C. This product (5.12 g, 0.02 m) was mixed with thionyl chloride (20 ml) and heated in a water bath at 75°C for 1 hour. The excess thionyl chloride was evaporated under reduced pressure. The residue was mixed with dry benzene (10 ml) and again evaporated to dryness to remove residual thionyl chloride. The final residue was dissolved in dry acetone (100 ml) and added, with stirring, to a solution of 6-aminophenicillanic acid (4.32) in water (100 ml), 1 N sodium hydroxide (20 ml), 1 N sodium bicarbonate solution (30 ml) and acetone (50 ml) cooled to 12°C. The reaction mixture was stirred for 2 hours. The resulting mixture was stirred at room temperature for 2 hours. The resulting solution was extracted with ether (3x60 ml) and the extracts discarded. The aqueous layer was covered with ether (60 ml) and acidified with 1 N HCl to pH 2. The ether layer was separated and the aqueous layer extracted with ether (2x60 ml). The combine ether extracts were washed with water (20 ml) and extracted with 1 N sodium bicarbonate solution to pH 7. The neutral aqueous extract was evaporated under reduced temperature and pressure. The residue was dried over phosphorous pentoxide in vacuo to give 6.7 (70.4%) of penicillin salt as an amorphous solid. The solid, when dissolved in ethanol (50 ml) at room temperature gave on standing 30 min the penicillin salt as a colorless crystalline solid 5.23 g (78.1 %). References Hardy K. et al.; US Patent No. 3,853,849; Dec. 10, 1974; Assigned to Beecham Group Limited, Brentford Middlesex, England
852
Cargutocin
CARGUTOCIN Therapeutic Function: Oxytocic Chemical Name: 1-Butanoic acid-7-glycine-1,6-dicarbaoxytocin Common Name: Structural Formula:
Chemical Abstracts Registry No.: 33065-67-3 Trade Name
Manufacturer
Country
Year Introduced
Statocin
Yoshitomi
Japan
1982
Raw Materials Cyclic polypeptide Hydrogen Manufacturing Process To a suspension of Z-Tyr(Bz)-Ile-Gln-Asn-Asu(OTCP)-Gly-Leu-Gly-NH2 (1,310 mg) in DMF (350 ml) is added a suitable amount of palladium black. Hydrogen gas is introduced with stirring at room temperature (25°C) for about 40 hours. After stirring the mixture at 30°-35°C for several hours, the catalyst is filtered off and the filtrate is concentrated under reduced pressure. A large amount of ether is added to the residue, and the white coagulum is collected
Carisoprodol
853
by filtration, washed with ether and dried. This is dissolved in water (30 ml), and the solution is filtered. The filtrate is passed through a column (3 x 11.5 cm) of Amerlite IR-45 (OH-form). The fractions which show a UV-absorption maximum at 280 nm are combined and passed through a column (3 x 125 cm) of CM-Sephadex C-25 to remove the noncyclic compound and obtain neutral parts. The detection of the objective compound is made by UVabsorption at 280 nm. The aqueous solution of the neutral parts is concentrated below 35°C, under reduced pressure, and the concentrate is lyophilized to give 504 mg of the crude title compound in the form of 5 hydrate. References Merck Index 1822 DFU 8 (3) 188 (1983) DOT 19 (3) 130 (1983) Sakakibara, S. and Yamanaka, T.; US Patent 3,749,705; July 31, 1973; as signed to Yoshitomi Pharmaceutical Industries Ltd. (Japan)
CARISOPRODOL Therapeutic Function: Muscle relaxant Chemical Name: (1-Methylethyl)carbamic acid 2-([(aminocarbonyl)oxy] methyl)-2-methylpentyl ester Common Name: Isopropyl meprobamate Structural Formula:
Chemical Abstracts Registry No.: 78-44-4 Trade Name Soma Rela Sanoma Flexartal
Manufacturer Wallace Schering Heilit Clin Midy
Country US US W. Germany France
Year Introduced 1959 1959 1961
854
Carisoprodol
Trade Name
Manufacturer
Country
Year Introduced
Caprodat
Ferrosan
Denmark
-
Carisol
AFI
Norway
-
Carisoma
Wallace
US
-
Diolene
Italy
-
Erbasoma
Pharma. Farm. Spec. Erba
Italy
-
Meprodat
Star
Finland
-
Mioril
Rossini
Italy
-
Mioxom
Dessy
Italy
-
Myobutazolidin
Fujisawa
Japan
-
Relasom
Rafa
Israel
-
Relaxo-Powel
Erba
Italy
-
Soma
Horner
Canada
-
Soma
Guidotti
Italy
-
Somadril
Dumex
Denmark
-
Somalgit
Wallace
US
-
Somalgit Simple
Inibsa
Spain
-
Somanil
Banyu
Japan
-
Soprodol
Schein
US
-
Raw Materials Isopropylamine Phosgene
2-Methyl-2-propyl-1,3-propanediol Sodium cyanate
Manufacturing Process A cooled 10% solution of 1 mol of phosgene in toluene was added with stirring to a cooled solution of 1 mol of 2-methyl-2-propyl-1,3-propanediol and 2 mols of dimethylaniline also dissolved in toluene, at such a rate that the temperature of the mixture was maintained at about 25°C. The mixture was allowed to remain at this temperature for several hours, then cooled and extracted with cold 5% hydrochloric acid solution to remove the dimethylaniline. The toluene layer was dried using a suitable drying agent and the 2-methyl-2-propyl-3-hydroxypropyl chlorocarbonate used in subsequent reactions in the form of its solution in anhydrous toluene. A quantity of solution obtained as described containing 0.1 mol of the chlorocarbonate was treated with 0.2 mol of anhydrous isopropylamine and allowed to react at ordinary room temperature. The solution was cooled, extracted with dilute hydrochloric acid and the organic layer concentrated by evaporation of the solvent. The crude monocarbamate was purified by distilling at 86° to 88°C at about 0.01 mm. It was a clear, viscous liquid. 21.7 g (0.1 mol) of N-isopropyl-2-methyl-2-propyl-3-hydroxypropylcarbamate and 7.5 g (0.11 mol) of anhydrous sodium cyanate are stirred in 200 ml anhydrous chloroform in a suitable vessel equipped with a gas inlet tube,
Carmofur
855
stirrer and thermometer. While cooling the vessel, anhydrous hydrogen chloride is passed into the stirred mixture slowly for 5 hours maintaining the temperature between 0° and 5°C. Alternatively ethyl urethane in the presence of aluminum isopropylate as a catalyst may be used in place of the sodium cyanates and HCl. The mixture is then allowed to stand at room temperature overnight. The solid material is separated by filtration and the chloroform solution concentrated to an oil under reduced pressure. The oil is dissolved in 50 ml of trichloroethylene, the solution treated with charcoal, filtered and the filtrate added to 125 ml of hexane. The crystalline material which forms on standing at refrigerator temperature is removed by filtration, washed with light petroleum ether and dried at about 50°C. Approximately 20 g of product are obtained. On recrystallizing from trichloroethylene-hexane, 17.8 g of purified compound are obtained, MP 89° to 91°C. References Merck Index 1824 Kleeman and Engel p. 155 PDR pp. 830, 1606,1883 OCDS Vol. 1 p. 219 (1977) I.N.p. 189 REM p. 926 Berger, F.M. and Ludwig, B.J.; US Patent 2,937,119; May 17, 1960; assigned to Carter Products, Inc.
CARMOFUR Therapeutic Function: Antineoplastic Chemical Name: 5-Fluoro-N-hexyl-3,4-d-dihydro-2,4-dioxo-1(2H)pyrimidinecarboxamide Common Name: HCFU Structural Formula:
Chemical Abstracts Registry No.: 61422-45-5
856
Carmustine
Trade Name Mifurol Yamafur
Manufacturer Mitsui Yamanouchi
Country Japan Japan
Year Introduced 1981 1981
Raw Materials 5-Fluorouracil n-Hexyl isocyanate Manufacturing Process 13.0 g (0.10 mol) of 5-fluorouracil was suspended in 60 ml of dimethyl acetamide, then 14.0 g (0.11 mol) of n-hexyl isocyanate was added thereto at room temperature and stirred at 50°C for 8 hours. After the reaction mixture was concentrated under reduced pressure, the residue was poured into 400 ml of water and resultant precipitate was filtered off. The precipitate was washed and dried and 19.3 g (75.0% yield) of 5-fluoro-1-(n-hexylcarbamoyl)uracil was obtained. The product was recrystallized from ether and there were obtained white crystals melting at 283°C (decomposition). References Merck Index 1828 DFU 1 (4) 235 (1982) DOT 18 (9) 424 (1982) I.N. p. 190 Ozaki, S. and Mori, H.; US Patent 4,071,519; January 31, 1978; assigned to Mitsu Toatsu Chemicals, Inc.
CARMUSTINE Therapeutic Function: Antitumor Chemical Name: Urea, 1,3-bis(2-chloroethyl)-1-nitrosoCommon Name: Carmustine Structural Formula:
Chemical Abstracts Registry No.: 154-93-8
Carnitine
857
Trade Name
Manufacturer
Country
Year Introduced
BCNU
Gencorp Aerojet
US
-
BCNU
Bristol-Myers Squibb
-
-
BiCNU
Bristol-Myers Squibb
-
-
Gliadel Wafer
Rhone-Poulenc Rorer
-
-
Raw Materials N,N'-Bis-(2-chloroether)-urea Sodium nitrite Formic acid Manufacturing Process A solution of sodium nitrite (6.9 g, 0.10 mole) in water (60 ml) was added dropwise to a cold (0-5°C), stirred solution of 1,3-bis(2-chloroethyl)urea (8.0 g, 0.044 mole) in formic acid (50 ml). The reaction mixture was stirred further at 0°C until the pale yellow oil that had formed solidified. The nitrosourea was collected and washed quickly with cold water (2 x 10 ml), and dried in vacuum; yield 6.7 g. (71%). References Johnston T.P. et.al.; J. Med. Chem. 6, 669, (1963) Bastian H., Justus Liebigs, Ann. Chem., 566, 210 (1950)
CARNITINE Therapeutic Function: Gastric stimulator, Pancreatic stimulator Chemical Name: 3-Carboxy-2-hydroxy-N,N,N-trimethyl-1-propanaminium hydroxide, inner salt Common Name: Structural Formula:
Chemical Abstracts Registry No.: 461-06-3; 5842-94-8 (Hydrochloride salt)
858
Carnitine
Trade Name Flatistine Carnetina Nefrocarnit Carnitene Abedine Bicarnesine Carn Carnitan Carnitine Carnitolo Entomin Metina Monocamin Polycartin
Manufacturer Sauba Sigma Tau Nefro Pharma Refarmed SA Nippon Zoki Labaz Benvegna Kakenyaku Kako Tyson Sirt-B.B.P. Maruko Francia Tanabe Daigo Eiyo
Country France Italy W. Germany Switz. Japan France Italy Japan US Italy Japan Italy Japan Japan
Year Introduced 1978 1981 1983 1983 -
Raw Materials Trimethylamine Epichlorohydrin
Sodium cyanide Hydrogen chloride
Manufacturing Process 9.3 g of epichlorohydrin was added at a temperature of 40°-50°C under stirring to 9.6 g of trimethylamine hydrochloride dissolved in 10 cc of water. Continuing the reaction for an hour at the above temperature, the reaction product was concentrated under reduced pressure to obtain the crystals of 3chloro-2-oxypropyl trimethyl ammonium chloride which were recrystallized with 25 cc of ethanol. The crystals obtained by concentrating the mother liquor were also recrystallized. The yield was 17.4 g (MP 190°C, yield 91.5%). This substance occurs as white, somewhat hygroscopic crystals and is readily soluble in water or alcohol, but insoluble in benzene, toluene, ether, acetone or chloroform. The result of analysis assuming (C6H15C10N)+Cl--calculated value: N, 7.45%; total Cl, 37.7%; Cl-, 18.88%. Observed value: N, 7.36%; total Cl, 37.54%; Cl-, 18.98%. 18.8 g of 3-chloro-2-oxypropyl trimethyl ammonium chloride was dissolved in a mixed solvent composed of 19 cc of methanol and 1 cc of water. 5.1 g of sodium cyanide dissolved in 8 cc of water was dropped into the solution at 50°C under stirring. After dropping, the mixture was held at this temperature for 30 minutes under stirring. The reaction product was then neutralized with 6 N hydrochloric acid toward pH 5, and, after cooling, sodium chloride separated out and was filtered. The filtrate was concentrated to dryness under reduced pressure, and the residue was washed with small quantity of ethanol. Drying the residue, dissolving in hot methanol, filtering off insoluble matters, and cooling mother liquor, the crystals of 3-cyano-2-axypropyl trimethyl ammonium chloride which deposited out were filtered and dried. Yield 16.7 g [MP (decomposition) 220°-223°C, yield 93.4%].
β-Carotene
859
12.5 cc of concentrated hydrochloric acid was added to 17.9 g of 3-cyano-2oxypropyl trimethyl ammonium chloride. Gradually heating the mixture on a water bath under stirring, so bringing the temperature up to 98°C at the end of about 3 hours, 9 cc of water was added. After cooling, free hydrochloric acid was neutralized with 3 cc of 6 N sodium hydroxide, and then by adding 1 g of active charcoal, the reaction product was decolorized and filtered. The filtrate was concentrated to almost dryness under reduced pressure. Then, this concentrate was, after washing with 10 cc of ethanol, dried. Yield 24.7 g. The dried product was dissolved in 46.5 cc of glacial acetic acid by heating on a boiling water bath. The insoluble matter is removed by filtering hot, and on cooling the mother liquor, crystals of carnitine hydrochloride separated out. The crystals were filtered, washed with 10 cc of ethanol, and dried. Recrystallizing 19.7 g of the crude carnitine with methanol, 17 g of the refined carnitine was obtained [MP 195°-198°C (decomposing point), yield 86%], The overall yield of the refined carnitine through whole steps was about 74%. Carnitine thus prepared was an odorless, white, crystalline powder, having a strong acid taste. References Merck Index 1833 Kleeman and Engel p. 156 PDR p. 1807 DOT 19 (4) 185 (1983) I.N. p. 190 Noguchi, J. and Sakota, N.; US Patent 3,135,788; June 2, 1964; assigned to Nihon Zoki Seiyaku Kabushikikaisha (Japan)
β-CAROTENE Therapeutic Function: Vitamin A precursor, Sunscreen agent Chemical Name: β-Carotene Common Name: Structural Formula:
Chemical Abstracts Registry No.: 7235-40-7
860
β-Carotene
Trade Name Carotaben Solatene Vitacarotene Beta-carotene
Manufacturer Hermal Roche Pellestier Solgar
Country W. Germany US Spain US
Year Introduced 1975 1975 -
Raw Materials 3,8-Dimethyl-3,5,7-decatrien-1,9-diyne Phenyl lithium 4-(2,6,6-Trimethyl-1-cyclohexen-1-yl)-2-methyl-2-buten-1-al Hydrogen Manufacturing Process 3.6 g (0.023 mol) of 3,8-dimethyl-3,5,7-decatrien-1,9-diyne were dissolved in 50 ml of absolute ether, and to the solution was added 0.05 mol of ethereal phenyl-lithium solution. The mixture was refluxed for 30 minutes. Then a solution of 11 g (0.05 mol) of 4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2-methyl2-buten-1-al in 100 ml of ether was added dropwise, and the reaction mixture was boiled for 2 hours. The reaction mixture was then hydrolyzed with aqueous ammonium acetate solution, and the ethereal layer was separated, dried and concentrated. The residue, i.e., 1,18-di(2,6,6-trimethyl-1cyclohexen-1-yl)-3,7,12,16-tetramethyl-4,15-dihydroxy-2,7,9,11,16octadecapentaen-5,13-diyne, was a resinous product (having 1.9 active hydrogen atoms and absorption maxima in the ultraviolet spectrum at 326 and 341 nm) which was used for the next step without any further purification. The resin was dissolved in 200 ml of methylene chloride, 10 ml of glacial acetic acid were added to the solution, and the mixture was cooled to 40°C in a carbon dioxide atmosphere, while stirring. Then, 9 ml of aqueous hydrobromic acid (60%) were added in one portion, the mixture was stirred at -35°C for 1.5 minutes, and subsequently 200 ml of ice water were run into the mixture. After further stirring the mixture for 2 hours at 0°C, the methylene chloride layer was separated, washed with water and sodium bicarbonate solution, dried with Na2SO4 andconcentrated in vacuo. The residue, i.e., 11,12-11',12'-bisdehydro-betta-carotene, was a tough resin or a foamy solid (having no active hydrogen atoms and possessing absorption maxima in the ultraviolet spectrum at 334 and 408 nm). This product can be purified by chromatography. The crude product can also be used for the next step without any preliminary purification. 11.4 g of 11,12-11',12'-bisdehydro-β-carotene were dissolved in 100 ml of petroleum ether (boiling range 80° to100°C), and the solution was hydrogenated under normal conditions after the addition of 0.5 ml of quinoline and 5 g of a lead-poisoned palladium catalyst. After the calculated amount of hydrogen had been absorbed, the catalyst was removed by filtration and the filtrate was extracted with dilute sulfuric acid to remove the quinoline. By concentrating the solution in the usual manner there was obtained 11,1211',12'-di-cis-carotene. The product was purified by recrystallization from benzene-alcohol. The purified product melts at 154°C; absorption maxima in the ultraviolet spectrum at 276, 334, 338, 401 and 405 nm. The isomerization was effected by heating the product for 10 hours at 90 to 100°C in highboiling petroleum ether in a carbon dioxide atmosphere. The resulting and
Caroxazone
861
carotene melted at 180°C; ultraviolet absorption maxima at 452 and 480 nm. Preparation of the intermediates for the above chemical synthesis are also described in US. Patent 2,917,539. The other patents cited below describe a fermentation route. US Patent 2,848,508 describes preparation from carrots. References Merck Index 1837 PDR pp. 1501, 1734 I.N.P. 136 REM p. 1005 Barnett, H.M., Hartmann, M.L., Mosher, R.C. and Espoy, H.M.; US Patent 2,848,508; August 19, 1958; assigned to Barnett Isler, O., Montavon, M., Ruegg, R. and Zeller, P.; US Patent 2,917,539; December 15, 1959; assigned to Hoffmann - La Roche Inc. Zajic, J.E.; US Patents 2,959,521 and 2,959,522; November 8, 1960; both assigned to Grain Processing Corp. Miescher, G.M., US Patent 3,001,912; September 26, 1961; assigned to Commercial Solvents Cow. Zajic, J.E.; US Patent 3,128,236; April 7, 1964; assigned to Grain Processing Corp.
CAROXAZONE Therapeutic Function: Antidepressant Chemical Name: 2-Oxo-2H-1,3-benzoxazine-3(4H)-acetamide Common Name: Structural Formula:
Chemical Abstracts Registry No.: 18464-39-6 Trade Name
Manufacturer
Country
Year Introduced
Timostenil
Farmitalia
Italy
1975
Raw Materials Ethyl glycinate HCl Salicylic aldehyde Ammonia
Hydrogen Phosgene
862
Carphenazine maleate
Manufacturing Process 37.9 g of ethyl glycinate hydrochloride were dissolved in 400 cc of ethanol and 33.5 g of salicylic aldehyde were added. It is refluxed for half an hour and cooled. 38 cc of triethylamine and 25 g of Raney nickel are then added where after hydrogenation is carried out at room temperature and under atmospheric pressure. After hydrogen adsorption was complete, the mixture was filtered and the alcohol evaporated off. The residue was taken up with acidified water, extracted with ether to eliminate part of the by-products, consisting mainly of o-cresol, then made alkaline with ammonia and extracted with ethyl acetate. The solvent was removed in vacuo and the residue crystallized from ether/petroleum ether. 36.7 g of o-hydroxybenzylaminoacetic acid ethyl ester melting at 47°C are obtained. 20 g of this compound were dissolved in 100 cc of tetrahydrofuran and 100 cc of a 30% solution of phosgene in tetrahydrofuran solution were added. After one night at room temperature, the reaction mixture was dried, taken up with 150 cc of anhydrous pyridine and allowed to stand overnight. The pyridine was then removed in vacuo and the residue dissolved in benzol was washed several times with water and chromatographed over 250 g of alumina. Elution with benzene/petroleum ether yielded 16 g of 4H-3-carboethoxymethyl-1,3benzoxazine-2-one, melting at 90°-91°C. 5 g of this last compound were dissolved in 120 cc of absolute ethanol and saturated with NH3 at 0°C. It was allowed to stand overnight where after 1.5 g of 4H-3-carboxamidomethyl-1,3-andenzoxazine-2-one, melting at 205°C, were obtained. By evaporation from the mother liquors further quantities of the same product were obtained. References Merck Index 1842 Kleeman and Engel p. 157 OCDS Vol. 3 p. 191 (1984) DOT 12 (6) 236 (1976) I.N. p. 190 Bernardi, L., Coda, S., Pegrassi, L. and Suchowsky, G.K.; US Patent 3,427,313; February 11, 1969; assigned to Societa Farmaceutici Italia (Italy)
CARPHENAZINE MALEATE Therapeutic Function: Tranquilizer Chemical Name: 1-[10-[3-[4-(2-Hydroxyethyl)-1-piperazinyl]propyl]-10Hphenothiazin-2-yl]-1-propanone dimaleate Common Name: Carfenazine maleate Chemical Abstracts Registry No.: 2975-34-0; 2622-30-2 (Base)
Carphenazine maleate
863
Structural Formula:
Trade Name
Manufacturer
Country
Year Introduced
Proketazine
Wyeth
US
1962
Raw Materials 2-Propionylphenothiazine N-(2-Hydroxyethyl)piperazine
Sodium hydride Trimethylene chlorobromide
Manufacturing Process As described in US Patent 3,023,146, in a round-bottomed flask were placed 35 g of 2-propionyl phenothiazine (0.14 mol) 7 g of 50% sodium hydride in mineral oil (0.14 mol), and 240 cc of dimethyl formamide dried over sodium hydride. The resultant solution was stirred at room temperature for 2 hours, and then 88 g (0.56 mol) of trimethylene chlorobromide was added at once. The mixture was stirred for 2 hours, heated at 60 to 70°C for 1 hour and poured into 2 liters of H2O. The resulting suspension was extracted with ether, the ether layer separated and the ether removed under vacuum. A gummy mass remained which was dissolved in decalin and the solution was partly distilled to remove excess chlorobromide. After removal of most of the decalin under vacuum, the residue was treated with a large excess of N-(βhydroxyethyl)-piperazine and heated on a steam bath for 2 hours. This material was extracted with dilute aqueous HCl, this acid layer neutralized with aqueous base and the resulting oil extracted into ether. The ether layer was washed with water until the washings were neutral and dried over anhydrous potassium carbonate. On treatment with maleic acid in ether a yellow solid separated which was recrystallized from isopropanol. This yellow solid had MP 175° to 177°C. References Merck Index 1844 Kleeman and Engel p. 154
864
Carprofen
OCDS Vol. 1 p.383 (1977) I.N. p. 188 REM p. 1086 Tislow, R.F., Bruce, W.F. and Page, J.A.; US Patent 3,023,146; February 27, 1962; assigned to American Home Products Corporation Sherlock, M.H. and Sperber, N.; US Patent 2,985,654; May 23, 1961; assigned to Schering Corporation
CARPROFEN Therapeutic Function: Antiinflammatory Chemical Name: 6-Chloro-α-methylcarbazole-2-acetic acid Common Name: Structural Formula:
Chemical Abstracts Registry No.: 53716-49-7 Trade Name Imadyl Imadyl Imafen Rimadyt
Manufacturer Roche Roche Roche Roche
Country Switz. W. Germany -
Year Introduced 1981 1982 -
Raw Materials 6-Chloro-α-methyl-1,2,3,4-tetrahydrocarbazole-2-acetic acid ethyl ester p-Chloranil Sodium hydroxide Hydrogen chloride Manufacturing Process A mixture of 34.9 g of 6-chloro-α-methyl-1,2,3,4-tetrahydrocarbazole-2-acetic acid ethyl ester (mixture of diastereomers), 350 ml CP xylene and 56.0 g of p-chloranil was stirred and heated under an atmosphere of dry nitrogen. The reaction flask was wrapped in aluminum foil in order to keep out any extraneous light. After the reaction mixture had stirred at reflux temperature for 6 hours, heating and stirring were stopped and the reaction mixture was left overnight at room temperature. The supernatant liquid was decanted
Carteolol
865
through a filter. The residue was triturated with 100 ml of warm benzene and the supernatant liquid was decanted through a filter. This process was repeated three more times. Ether (300 ml) was added to the combined filtrates. The solution was extracted with cold 2 N sodium hydroxide (3 x 100 ml), washed by extraction with water until neutral and dried over anhydrous magnesium sulfate. Following filtration of the desiccant and evaporation of the solvent, a residue of 35.5 g remained. Crystallization from 50 ml of methanol gave 14.8 g of 6-chloro-α-methylcarbazole-2-acetic acid ethyl ester, MP 106°107.5°C (43.2%). A stirred mixture of 11 g of 6-chloro-α-methylcarbazole-2-acetic acid ethyl ester, 100 ml ethanol and 100 ml of 3 N sodium hydroxide was heated (N2 atmosphere). After 2 hours at reflux, the reaction mixture was concentrated to dryness under reduced pressure. Water (300 ml) and ice (200 g) were added to the residue and concentrated hydrochloric acid was added until the mixture was strongly acid. The acidic mixture was extracted with ether (3 x 200 ml). The ether extracts were combined, washed by extraction with water (3 x 100 ml) and dried over anhydrous magnesium sulfate. Following filtration of the desiccant and evaporation of the solvent, a yield of 9.89 (98.2%) was obtained. Crystallization from CHCl3 yielded 6.2 g (62.0%) of 6-chloro-αmethylcarbazole-2-acetic acid, MP 197°-198°C. A second crop of 1.6 g, MP 195°-199°C was obtained from the mother liquors. References Merck Index 1846 DFU 2 (1) 15 (1977) OCDS Vol. 3 p. 169 (1984) DOT 18 (4) 172 (1982) I.N. p. 191 Berger, L. and Corraz, A.J.; US Patent 3,896,145; July 22, 1975; assigned to Hoffmann-LaRoche, Inc.
CARTEOLOL Therapeutic Function: Beta-adrenergic blocker Chemical Name: 5-(3-tert-Butylamino-2-hydroxypropoxy)-3,4dihydrocarbostyril Common Name: Structural Formula:
866
Carticaine
Chemical Abstracts Registry No.: 51781-06-7 Trade Name Mikelan Endak
Manufacturer Otsuka Madaus
Country Japan W. Germany
Year Introduced 1981 1982
Raw Materials 5-Hydroxy-3,4-dihydrocarbostyril Epibromohydrin t-Butylamine Manufacturing Process A mixture of 1.63 g of 5-hydroxy-3,4-dihydrocarbostyril, 2.5 g of epibromohydrin and 2 drops of piperidine was heated at a temperature of 95°C to 100°C for a period of 4 hours with stirring. The reaction mixture was then concentrated to dryness under reduced pressure and the residue was recrystallized from acetone to obtain 1.2 g of 5-(2,3-epoxy)propoxy-3,4dihydrocarbostyril as a colorless powder having a melting point of 172°C to 173°C. A mixture of 0.75 g of 5-(2,3-epoxy)propoxy-3,4-dihydrocarbostyril, 1.0 g of tert-butylamine and 25 ml of ethanol was stirred at a temperature of from 50°C to 55°C for a period of 4 hours. Ethanol and unreacted tert-butylamine were distilled off under reduced pressure and the resulting residue was dissolved in acetone. References Merck Index 1850 DFU 2 (5) 288 (1977) Kleeman and Engel p. 158 OCDS Vol. 3 p. 183 (1984) DOT 18 (10) 551 (1982) and 19 (7) 413 (1983) I.N. p. 191 Tamura, Y., Nakagawa, K., Yoshizaki, S. and Murakami, N.; US Patent 3,910,924; October 7, 1975; assigned to Otsuka Pharmaceutical Co., Ltd.
CARTICAINE Therapeutic Function: Local anesthetic Chemical Name: 4-Methyl-3-[[1-oxo-2-(propylamino)propyl]amino]-2thiophene carboxylic acid methyl ester Common Name: Chemical Abstracts Registry No.: 23964-58-1; 23964-57-0 (Hydrochloride salt)
Carvedilol
867
Structural Formula:
Trade Name
Manufacturer
Country
Year Introduced
Ultracain
Hoechst
W. Germany
1976
Ultracain
Hoechst
France
1981
Raw Materials 3-Amino-2-carbomethoxy-4-methyl thiophene Chloropropionyl chloride n-Propylamine Manufacturing Process 3-α-Chloropropionylamino-2-carbomethoxy-4-methylthiophene (prepared from 3-amino-2-carbomethoxy-4-methylthiophene and chloropropionyl chloride) was dissolved in toluene and n-propylamine added. The whole mixture was heated to boiling for 6 to 7 hours. After cooling, the propylamine hydrochloride that had formed was removed by washing with water, The toluene phase was dried with sodium sulfate, and then the solvent and excess propylamine were removed by distillation. The oily residue was taken up in ether. The hydrochloride of 3-n-propylamino-α-propionylamino-2carbomethoxy-4-methylthiophene was obtained by introducing hydrogen chloride gas or by means of methanolic hydrogen chloride. The base boils at 162°C to 167°C under 0.3 mm of mercury pressure and the hydrochloride melts at 177°C to 178°C. References Merck Index 1853 Kleeman and Engel p. 158 DOT 12 (4) 132 (1976) Ruschig, H., Schorr, M., Muschaweck, R. and Rippel, R .; U.S. Patent 3,855,243; December 17, 1974; assigned to Farbwerke Hoechst AG (Germany)
CARVEDILOL Therapeutic Function: Beta-adrenergic blocker Chemical Name: 2-Propanol, 1-(9H-carbazol-4-yloxy)-3-((2-(2methoxyphenoxy)ethyl)amino)-
868
Carvedilol
Common Name: Carvedilol; Karvedilol Structural Formula:
Chemical Abstracts Registry No.: 72956-09-3 Trade Name
Manufacturer
Country
Year Introduced
Coreg
Roche
-
-
Coreg
GlaxoSmithKline
UK
-
Coropres
Roche
-
-
Dimitone
Roche
-
-
Eucardic
Roche
-
-
Raw Materials Epichlorohydrin 4-Hydroxycarbazole o-Methoxyphenoxyethylamine Manufacturing Process 1-(9H-Carbazol-4-yloxy)-3-((2-(2-methoxyphenoxy)ethyl)amino)-2-propanol may be synthesized by the method of preparation of S-(-)-(1-carbazol-4yloxy)-3-[2-(2-methoxyphenoxy)]ethylaminopropan-2-ol (Patent US 4,697,022 and 4,824,963). 27.5 g 4-hydroxycarbazole are dissolved in a mixture of 150 ml 1 N aqueous sodium hydroxide solution and 70 ml dimethylsulfoxide. To this is added at ambient temperature 13.9 g epichlorohydrin, followed by stirring for 18 hours at ambient temperature. 280 ml water are then added thereto, followed by stirring for 15 min and filtering off with suction. The filter residue is washed with 0.1 N aqueous sodium hydroxide solution and water and subsequently dissolved in methylene chloride. The methylene chloride solution is dried over anhydrous sodium sulfate, treated with active charcoal and floridin and evaporated. 4-(2,3-Epoxypropoxy)-carbazole is purified by recrystallising twice from ethyl acetate. From the mother liquors there are isolated a further 4(2,3-epoxypropoxy)-carbazole. 10 g 4-(2,3-epoxypropoxy)-carbazole are, together with 13.97 g omethoxyphenoxyethylamine, heated under reflux in 70 ml isopropanol for 2 hours. The solvent is evaporated off and the residue is stirred for 2 hours with a mixture of 115 ml toluene, 35 ml cyclohexane and 40 ml ethyl acetate. After filtering off with suction, the (1-carbazol-4-yloxy)-3-[2-(2-
Cefaclor
869
methoxyphenoxy)]-ethylaminopropan-2-ol is recrystallised from 150 ml ethyl acetate. References Leinert H., US Patent No. 4,697,022; Sep. 29, 1987; Assigned to Boehringer Mannheim GmbH Leinert H., US Patent No. 4,824,963; Apr. 25, 1989; Assigned to Boehringer Mannheim GmbH
CEFACLOR Therapeutic Function: Antibiotic Chemical Name: 7-(D-α-Phenylglycylamido)-3-chloro-3-cephem-4-carboxlic acid Common Name: Structural Formula:
Chemical Abstracts Registry No.: 53994-73-3 Trade Name Ceclor Panoral Distaclor Ceclor Alfatil Panacef Kefral Kefolor
Manufacturer Lilly Lilly Dista Lilly Lilly Lilly Shionogi Lilly
Country US W. Germany UK Switz. France Italy Japan -
Year Introduced 1979 1979 1979 1980 1980 1981 1982 -
870
Cefaclor
Raw Materials p-Nitrobenzyl-7-amino-3-chloro3-cephem-4-carboxylate HCl Methyl chloroformate
Hydrogen N,O-Bis-(trimethylsilyl)acetamide Methyl-3α-carboxybenzylaminocrotonate sodium salt
Manufacturing Process Preparation of 7-amino-3-chloro-3-cephem-4-carboxylic acid: To a solution of 750 mg (185 mmol) of p-nitrobenzyl 7amino-3-chloro-3cephem-4-carboxylate hydrochloride in 20 ml of tetrahydrofuran and 40 ml of methanol was added a suspension of 750 mg of prereduced 5% palladium on carbon catalyst in 20 ml of ethanol and the suspension was hydrogenated under 50 psi of hydrogen at room temperature for 45 minutes. The catalyst was filtered and washed with THF and water. The filtrate and catalyst washes were combined and evaporated to dryness, The residue was dissolved in a water-ethyl acetate mixture and the pH adjusted to pH 3. The insoluble product was filtered and triturated with acetone. The product was then dried to yield 115 mg of 7amino-3-chloro-3-cephem-4-carboxylic acid. Preparation of 7-(D-α-phenylglycylamido)-3-chloro-3-cephem-4-carboxylic acid: To a suspension of 280 mg (1.2 mmol) of 7-amino-3-chloro-3-cephem4-carboxylic acid in 14 ml of acetonitrile was added with stirring at room temperature 0.5 ml of N,O-bis-(trimethylsilyl)acetamide to form the soluble disilylmethyl derivative thereof. The solution was cooled to 0 C and was slowly added to a solution of the mixed anhydride formed by reacting 408 mg (1.5 mmol) of methyl-3-α-carboxybenzylaminocrotonate sodium salt with 161 mg (1.7 mmol) of methyl chloroformate in the presence to 2 drops of N,Ndimethylbenzyl amine in 7 ml of acetonitrile. The mixture was stirred at ice bath temperature for 2 hours, 1 ml of methanol was added and the mixture was filtered to remove insoluble impurities. Two milliliters of water were added to the filtrate and the pH was adjusted momentarily to pH 1.5, to effect removal of the enamine block, and then to pH 4.5 with triethylamine. After stirring for an additional hour at ice bath temperature the reaction product, 7-(D-α-phenylglycylamido)-3-chloro-3cephem-4-carboxylic acid (zwitterion) precipitated from the reaction mixture as a crystalline solid. The product was filtered, washed with acetonitrile and dried in vacuo to yield 200 mg. References Merck Index 1896 DFU 2 (6) 368 (1977) Kleeman and Engel p. 160 OCDS Vol. 3 p. 209 (1984) DOT 15 (7) 311 (1979) I.N. p. 193 REM p. 1184 Chauvette, R R.; British Patent 1,461,323; January 13, 1977; assigned to Eli Lilly and Co. Chauvette, R.R.; US Patent 3,925,372; December 9, 1975; assigned to Eli Lilly and Co.
Cefadroxil
871
CEFADROXIL Therapeutic Function: Antibacterial Chemical Name: 7-[[Amino-(4-hydroxyphenyl)acetyl]amino]-3-methyl-8oxo-5-thia-1-aza-bicyclo[4.2.0]- act-2-ene-2-carboxylic acid monohydrate Common Name: p-Hydroxycephalexine monohydrate Structural Formula:
Chemical Abstracts Registry No.: 50370-12-2 Trade Name
Manufacturer
Country
Year Introduced
Oracefal
Bristol
France
1977
Duricef
Mead Johnson
US
1978
Ultracef
Bristol
US
1980
Duracef
Ciba Geigy
Switz.
1980
Cephamox
Bristol
W. Germany
1980
Duracef
Bristol
Italy
1980
Sedral
Banyu
Japan
1982
Baxan
Bristol
UK
1982
Bidocef
Bristol-Myers
-
-
Cefos
C.T.
Italy
-
Droxicef
Alfa Farm.
Italy
-
Raw Materials Sodium N-(1-methoxycarbonyl-1-propen-2-yl)-D(-)-α-amino-(4hydroxyphenyl)acetate Ethyl chlorocarbonate 7-Amino-3-methyl-3-cephem-4-carboxylic acid Manufacturing Process 1.8 g of sodium N-(1-methoxycarbonyl-1-propen-2-yl)-D(-)-α-amino-(4hydroxyphenyl)acetate was suspended in 10 ml of acetone, and one droplet of N-methylmorpholine was added thereto, and the mixture was cooled to -15°C.
872
Cefamandole nafate sodium salt
There was added 0.85 g of ethyl chlorocarbonate thereto, and the mixture was reacted at -13°C to -10°C for 30 minutes, and then the reaction solution was cooled to -20°C. On the other hand, 1 g of 7-amino-3-methyl-3-cephem-4-carboxylic acid was suspended in 20 ml of methanol, and 1.4 g of triethylamine was added thereto to be dissolved, and 0.4 ml of acetic acid was further added thereto. This solution was cooled to -20°C and the mixed acid anhydride prepared previously was added thereto. After the mixture was reacted at -20°C for 1 hour, the temperature of the reaction mixture was raised to 0°C over a period of 1 hour, and the mixture was reacted for 3 hours at the same temperature. After the reaction, 1 ml of water was added to the reaction mixture, and the mixture was adjusted to a pH of 1.0 with concentrated hydrochloric acid while being cooled, and then stirred for 30 minutes, The insoluble matters were filtered off, and the filtrate was adjusted to a pH of 5.5 with triethylamine. This solution was concentrated under reduced pressure, and the residue was diluted with 20 ml of acetone to precipitate white crystals. The crystals were collected by filtration and washed with ethanol to obtain 1.46 g of white crystals of 7-[D(-)-α-amino-(4-hydroxyphenyl)acetamido]-3-methyl-3cephem-4-carboxylic acid having a decomposition point of 197°C. References Merck Index 1897 Kleeman and Engel p. 161 PDR pp.716, 1124 OCDS Vo1. 2 p. 440 (1980) DOT 13 (3) 126 (1977) and 13 (11) 471 (1977) I.N. p. 194 REM p. 1185 Ishimaru, T. and Kodama. Y.: US Patent 3,864,340; February 4, 1975; assigned to Toyama Chemical Co. Ltd. (Japan) Crast, L.B. Jr. and Gottstein, W.J.; US Patent 3,985,741; October 12, 1976; assigned to Bristol-Myers Co.
CEFAMANDOLE NAFATE SODIUM SALT Therapeutic Function: Antibiotic Chemical Name: Sodium 7-(D-2-formyloxy-2-phenylacetamido)-3-(1-methyl1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylate Common Name: Chemical Abstracts Registry No.: 42540-40-9; 34444-01-4 (Base) Trade Name Mandokef Kefadol
Manufacturer Lilly Lilly
Country W. Germany UK
Year Introduced 1977 1978
Cefamandole nafate sodium salt
873
Trade Name
Manufacturer
Country
Year Introduced
Mandol
Lilly
US
1978
Kefandol
Lilly
France
1978
Mandokef
Lilly
Italy
1981
Cedol
Tiber
Italy
-
Cefam
Magis
Italy
-
Cefman
I.B.P.
Italy
-
Cemado
Farmochimica
Italy
-
Cemandil
S.I.T.
Italy
-
Fado
Errekappa
Italy
-
Lampomandol
A.G.I.P.S.
Italy
-
Mandolsan
San Carlo
Italy
-
Neocefal
Gibipharma
Italy
-
Structural Formula:
Raw Materials Mandelic acid, DFormic acid Thionyl chloride Monotrimethyl silyl acetamide Sodium 2-ethylhexanoate 7-Amino-3-(1-methyl-1H-tetrazol-5-yl-thiomethyl)-3-cephem-4-carboxylic acid Manufacturing Process To 21.6 kg (17.8 l) of 98% formic acid was added 1.14 kg (7.5 mols) of D-(-)mandelic acid and the reaction mixture was heated for 4 hours at 70°C with stirring. The excess formic acid was evaporated off in vacuo and the residual syrup was dissolved in 6 l of benzene. The solution was washed twice with 6 l portions of water and was dried over magnesium sulfate. The drying agent was filtered and washed with 1.5 l of benzene, the washes being added to the filtrate. The dried filtrate was evaporated in vacuo to obtain the D-(-)mandelic acid formate ether as a syrup. The product can be crystallized from cyclohexane to yield material melting at about 55°C to 58°C.
874
Cefatrizine
The mandelic acid formate ester obtained as a syrup as described above is stirred for 2 hours with 2.9 kg (~1.75 l) of thionyl chloride at a temperature of about 70°C. The excess thionyl chloride is removed by evaporation and the residual green solution is vacuum distilled. The product, O-formyl mandeloyl chloride, distills over at 127°C to 130°C (15 mm) or at 108°C to 112°C (7 mm). To 13 l of ethyl acetate were added 85.1 g (2.59 mols) of 7-amino-3-(1methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid and 1,361 g (10.37 mols) of monotrimethylsilyl acetamide, and the mixture was stirred at 50°C until a clear solution was obtained. The solution was cooled to 20°C and 514 g (2.59 mold of O-formyl mandeloyl chloride was added at a rate such that the temperature of the reaction solution was maintained between about 20°C to 25% with ice-cooling. The reaction mixture was stirred for 1.5 hours at about room temperature after the addition of the mandeloyl chloride was completed. Five liters of water were then added to the reaction mixture and the diluted mixture was stirred for about 10 minutes. The organic layer was separated and was washed twice with water. The combined washes are extracted with 1.5 l of ethyl acetate and the extract is combined with the washed organic layer. The whole was dried over magnesium sulfate, filtered and evaporated in vacuo on a 25°C water bath to yield 1,460 g of product, 7-(D-2-formyloxy-2phenylacetamido)-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4carboxylic acid, as a yellow foam. The product was dissolved in 5 l of acetone and the solution was mixed with a solution of 430 g (2.59 mols) of sodium 2-ethylhexanoate in 5.4 l of acetone. The combined solutions were seeded and stirred in an ice bath for 1.5 hours. The crystalline precipitate of sodium 7-(D-2-formyloxy-2-phenylacetamido)-3(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylate was filtered and washed with 5 l of acetone. The crystalline salt was dried overnight in a vacuum oven at 40°C to yield 1,060 g (80%)of product, melting at 182°C to 184°C. References Merck Index 1898 DFU 2 (10) 646 (1977) Kleeman and Engel p. 166 PDR p. 1059 OCDS Vol. 2 p. 441 (1980) and 14 (4) 151 (1978) DOT 12 (5) 177 (1976) I.N.p. 196 REM p. 1185 Greene, J.M. and Indelicato, J.M.; US Patent 3,928,592; December 23, 1975; assigned to Eli Lilly and Co.
CEFATRIZINE Therapeutic Function: Antibiotic
Cefatrizine
875
Chemical Name: 7-[D-α-Amino-α-(p-hydroxyphenyl)acetamido]-3-(1,2,3triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid Common Name: Structural Formula:
Chemical Abstracts Registry No.: 51627-14-6 Trade Name
Manufacturer
Country
Year Introduced
Bricef
Bristol Banyu
Japan
1980
Cepticol
Banyu
Japan
1980
Cefatrix
Ausonia
Italy
1982
Latocef
Dukron
Italy
1982
Raw Materials 7-[D-α-t-Butoxycarbonylamino-α-(p-hydroxyphenyl)acetamido]-3-(1,2,3triazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid Formic acid Manufacturing Process A total 6.5 g (1 1.55 mmol) of 7-[D-α-t-butoxycarbonylamino-α-(phydroxyphenyl)acetamido]-3-(1,2,3-triazol-5-ylthiomethyl)-3-cephem-4carboxylic acid was dissolved in 175 ml (98 to 100% formic acid under anhydrous conditions. The mixture was stirred at room temperature for 2.5 hours. Part of the solution, 125 ml, was evaporated under reduced pressure to an amber oil. The oil was then azeotroped 3 times with 70 ml of toluene under reduced pressure. The residue was suspended in an 80:20 H2O-CH3OH solution (700 ml) and stirred for 0.5 hour until most of the solid dissolved, then filtered. The filtration was treated with 1.59 of (Darko) charcoal for about 20 minutes. The charcoal was filtered off through a Celite pad. The solution was then freeze-dried in 9 separate 100 ml round bottom flasks. The freezedried material weighed 2.415 g. It was recrystallized in batches of 0.200 g as described above to yield a total of 0.923 g 7-[D-α-amino-α-(p-hydroxyphenyl) acetamidol-3-(1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid. NMR was consistent, indicating the presence of 0.33 mol of CH3OH.
876
Cefazedone sodium
References Merck Index 1899 DFU 2 (10) 653 (1977) OCDS Vol. 3 p. 211 (1984) DOT 12 (5)183 (1976) I.N. p. 197 Kaplan, M.A. and Granatek, A.P.; US Patent 3,970,651; July 20, 1976; assigned to Bristol-Myers Co.
CEFAZEDONE SODIUM Therapeutic Function: Antibiotic Chemical Name: 5-Thia-1-azabicyclo(4.2.0)oct-2-ene-2-carboxylic acid, 7(((3,5-dichloro-4-oxo-1(4H)-pyridinyl)acetyl)amino)-3-(((5-methyl-1,3,4thiadiazol-2-yl)thio)methyl)-8-oxo-, (6R-trans)-, sodium salt Common Name: Cefazedone sodium Structural Formula:
Chemical Abstracts Registry No.: 63521-15-3; 56187-47-4 (Base) Trade Name Cefazedone Sodium Cefazedone Sodium Cefazedone Sodium
Manufacturer Arocor Holdings Inc.
Country -
Yick-Vic Chemicals and Pharmaceuticals (HK) Ltd. CKD Pharm -
-
Refosporen
Teva Pharmaceuticals
-
-
Raw Materials tert-Butyl ester of 7-aminocephalosporanic acid Dicyclohexylcarbodiimide 3,5-Dichloro-4-pyridone-1-acetic acid Trifluoroacetic acid 5-Methyl-1,3,4-thiadiazole-2-thiol
Year Introduced -
-
Cefazolin sodium
877
Manufacturing Process A solution of 1 eq. of the tert-butyl ester of 7-aminocephalosporanic acid and 1 eq. of dicyclohexylcarbodiimide in 100 ml of methylene chloride/DMF (1:1) is cooled to 0°C. The mixture is combined with 1 eq. of 3,5-dichloro-4pyridone-1-acetic acid; after 5 min the ice bath is removed and the mixture agitated for another 30 min at 25°C. The thus-formed urea is filtered off and the filtrate filtered over silica gel (eluent: ethyl acetate/1% methanol). The solvent is concentrated by evaporation, and the thus-obtained tert-butyl ester of 7-(3,5-dichloro-1,4-dihydro-4-oxo-1-pyridylacetamido)cephalosporanic acid is crystallized from ether. 1 eq. of the tert-butyl ester is dissolved in 30 ml of trifluoroacetic acid. After 30 minutes, the solution is evaporated and the thus-produced 7-(3,5-dichloro1,4-dihydro-4-oxo-1-pyridylacetamido)cephalosporanic acid crystallized from ether. 1 eq. of the obtained 7-(3,5-dichloro-1,4-dihydro-4-oxo-1-pyridylacetamido) cephalosporanic acid is dissolved in 60 ml of saturated aqueous sodium bicarbonate solution at a pH of below 7 and combined with 1 eq. of 5-methyl1,3,4-thiadiazole-2-thiol in 20 ml of acetone. The reaction solution is agitated for 2 hours at 80°C and at a pH of 6.3 under a nitrogen atmosphere. The acetone is thereupon removed, the solution is washed with ether and acidified to pH 2. The thus-obtained 3-(1-methyltetrazolyl-5-mercaptomethyl)-7-(3,5dichloro-1,4-dihydro-4-oxo-1-pyridylacetamido)-3-cephem-4-carboxylic acid is filtered off and dried. IR spectrum confirmed the structure of cefazedone. In practice it is usually used as sodium salt. References Gericke R.; US Patent No. 4,153,693; May 8, 1979; Assigned to Merck Patent Gesellschaft mit beschrankter Haftung, Darmstadt, Fed. Rep. of Germany
CEFAZOLIN SODIUM Therapeutic Function: Antibacterial Chemical Name: (6R-trans)-3-([(5-Methyl-1,3,4-thiadiazol-2-yl)thio]methyl)8-oxo-7-([(1-H-tetrazol-1-yl)acetyl]amino)-5-thia-1-azabicyclo[4.2.0]oct2-ene-2-carboxylic acid sodium salt Common Name: Chemical Abstracts Registry No.: 27164-46-1; 25953-19-9 (Base)
878
Cefazolin sodium
Structural Formula:
Trade Name
Manufacturer
Country
Year Introduced
Cefamedin
Fujisawa
Japan
1971
Kefzol
Lilly
US
1973
Ancef
SKF
US
1973
Totacef
Bristol
Italy
1973
Grammaxin
W. Germany
1974
Kefzol
Boehringer Mannheim Lilly
UK
1974
Kefzol
Serum Impfinst.
Switz.
1974
Cefacidal
Allard
France
1976
Kefzol
Lilly
France
1976
Acef
Tiber
Italy
-
Areuzolin
Areu
Spain
-
Atirin
Intersint
Italy
-
Biazolina
Panthox and Burck Italy
-
Bor-Cefazol
Proter
Italy
-
Brizolina
Bristol-Myers
-
-
Caricef
Antibioticos
Spain
-
Cefacene
Centrum
Spain
-
Cefalomicina
Marxer
Argentina
-
Cefamezin
Fujisawa
Japan
-
Cefazina
Chemil
Italy
-
Celmetin
A.L.
Norway
-
Cromezin
Crosara
Italy
-
Elzogram
Lilly
W. Germany
-
Fidesporin
Fides
Spain
-
Firmacel
Firma
Italy
-
Kurgan
Normon
Spain
-
Legemzolina
Legem
Spain
-
Lifezolina
Lifepharma
Spain
-
Liviclina
Sierochimica
Italy
-
Maksipor
Fako
Turkey
-
Neofazol
Rubio
Spain
-
Vifazolin
Vianex
Greece
-
Zolicef
Bristol-Myers
W. Germany
-
Cefdinir
879
Raw Materials 7-Aminocephalosporanic acid 5-Methyl-1,3,4-thiadiazole-2-thiol Sodium bicarbonate
1H-Tetrazole-1-acetyl chloride Sodium hydroxide
Manufacturing Process 7-Aminocephalosporanic acid is converted to its sodium salt and acylated with 1H-tetrazole-1-acetyl chloride. The acetoxy group is then displaced by reaction with 5-methyl-1,3,4-thiadiazole-2-thiol in buffer solution. The product acid is converted to the sodium salt by NaHCO3. References Merck Index 1901 Kleeman and Engel p. 168 PDR pp. 1058, 1701 OCDS Vol. 3 p. 442 (1984) DOT 7 (5) 146, 167, 181 (1971) I.N. p. 197 REM p. 1185 Takano, T., Kurita, M., Nikaido, H., Mera, M., Konishi, N. and Nakagawa, R.; US Patent 3,516,997; June 23, 1970; assigned to Fujisawa Pharmaceutical Co., Ltd., Japan
CEFDINIR Therapeutic Function: Antibiotic Chemical Name: 5-Thia-1-azabicyclo(4.2.0)oct-2-ene-2-carboxylic acid, 7(((2Z)-(2-amino-4-thiazolyl)(hydroxyimino)acetyl)amino)-3-ethenyl-8oxo-, (6R,7R)Common Name: Cefdinir; Cefdinyl Structural Formula:
Chemical Abstracts Registry No.: 91832-40-5
880
Cefdinir
Trade Name Manufacturer
Country
Year Introduced
Adcef
Torrent Pharmaceuticals Ltd. Sarabhai Piramal Pharmaceuticals Ltd.
India
-
India
-
Cefdiel
Ranbaxy Laboratories Limited
India
-
Cefzon
Fujisawa Pharmaceutical Co., Ltd.
-
-
Oceph Cap
Emcure Pharmaceuticals Ltd.
India
-
Omnicef
Hikma
-
-
Omnicef
Abbott Laboratories
-
-
Sefdin
Unichem Laboratories Ltd.
India
-
Zefdinir
German Remedies Limited
Germany
-
Cednir
Raw Materials 7-Amino-8-oxo-3-vinyl-5-thia-1-azabicyclo(4.2.0)oct-2-ene-2-carboxylic acid 4-methoxyphenyl ester 4-Bromoacetyl bromide Sodium nitrite Trifluoroacetic acid Manufacturing Process By interaction of 7-amino-8-oxo-3-vinyl-5-thia-1-azabicyclo(4.2.0)oct-2-ene2-carboxylic acid 4-methoxyphenyl ester with 4-bromoacetyl bromide was prepared 7-(4-bromo-3-oxo-butyrylamino)-8-oxo-3-vinyl-5-thia-1-azabicyclo (4.2.0)oct-2-ene-2-carboxylic acid 4-methoxyphenyl ester. The active methylene group in that product was then nitrosated with sodium nitrite. The initial product spontaneously tautomerizes to afford 7-(4-bromo-2hydroxyimino-3-oxo-butyrylamino)-8-oxo-3-vinyl-5-thia-1-azabicyclo(4.2.0) oct-2-ene-2-carboxylic acid 4-methoxyphenyl ester. By the reaction of that compound with thiourea and then with trifluoroacetic acid was obtained (6R,7R)-7-(2-(2-amino-4-thiazolyl)glyoxylamido)-8-oxo-3-vinyl-5-thia-1azabicyclo(4.2.0)oct-2-ene-2-carboxylic acid sodium nitrite, (Z)-oxime (Cefdinir sodium nitrile). In practice it is usually used as free acid. Synthesis of 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-(trytiloxyimino)acetamido]-3vinyl-3-cephem-4-carboxylic acid x p-toluenesulfonic acid x 2 N,Ndimethylacetamide (the precursor of Cefdinir) was described in Patent US 6,093,814. References Inamoto Y. et al., J. Antibiotics, 1988, V. 41, P. 828 Org. Chem. Drug. Synth., V.6, P.170
Cefditoren pivoxil
881
Gwan S.L. et al.; US Patent No. 6,093,814; Jul 25, 2000; Assigned to Hanmi Pharmaceutical Co, Ltd., Rep. Korea
CEFDITOREN PIVOXIL Therapeutic Function: Antibiotic Chemical Name: 5-Thia-1-azabicyclo(4.2.0)oct-2-ene-2-carboxylic acid, 7(((2Z)-(2-amino-4-thiazolyl)(methoxyimino)acetyl)amino)-3-((1Z)-2-(4methyl-5-thiazolyl)ethenyl)-8-oxo-, (2,2-dimethyl-1-oxopropoxy)methyl ester, (6R,7R)Common Name: Cefditoren pivoxil; Cefoviten pivoxil Structural Formula:
Chemical Abstracts Registry No.: 117467-28-4 Trade Name Meiact Spectracef Spectracef
Manufacturer Meiji Seika TAP Pharmaceuticals Abbott Laboratories
Country Japan -
Year Introduced -
Raw Materials (Z)-(2-Aminothiazol-4-yl)methoxyimino acetic acid Bis-(2-oxo-oxazolidinyl)phosphinic chloride 2-Mercapto-5-phenyl-1,3,4-oxadiazole 7-Amino-3-[(Z)-2-(methyl-5-thiazolyl)vinyl]-3-cephem-4-carboxylic acid Triethylamine Manufacturing Process A mixture of THF (250 ml) and water (150 ml) was stirred under inert atmosphere. At 0°-1°C, 7-amino-3-[(Z)-2-(methyl-5-thiazolyl)vinyl]-3-
882
Cefepime
cephem-4-carboxylic acid (25.0 g) and 2-mercapto-5-phenyl-1,3,4oxadiazolyl-(Z)-2-(2-aminothiazol-4-yl)-2-methoxyimino acetate (33.3 g) were added. Triethylamine (10.5 g) was slowly added to reaction by maintaining the pH between 7.5 to 8.5. The reaction was monitored by HPLC. After 4-5 hrs., the reaction mixture was extracted by methylene chloride. The aqueous layer is subjected for charcoal (0.125 g) treatment. Ethylacetate was added to the filtrate and the solution was acidified with diluted HCl at 10°C to pH 3.0. The solid separated was filtered, washed with water and ethylacetate and then dried under vacuum at 40-45°C to get 3-[(Z)-2-(4-methyl-5-thiazolyl)vinyl]-7[(Z)-(2-aminothiazolyl-4-yl)-2-(methoxyimino)acetamido]-3-cephem-4carboxylic acid (Cefditoren acid), 35.0 g (yield 90%), HPLC (purity)=96-98%. In practice it is often used as Cefditoren pivoxil. References Deshpande P. B., Luthra P. K.; US Patent No. 6,713,625; August 27, 2002; Assigned to Orchid Chemicals and Pharmaceuticals Ltd. Yasui K. et al.; US Patent No. 6,441,162; August 27, 2002; Assigned to Meiji Seika Kaisha, Ltd. (Tokyo, JP)
CEFEPIME Therapeutic Function: Antibiotic Chemical Name: Pyrrolidinium, 1-(((6R,7R)-7-(((2Z)-(2-amino-4-thiazolyl) (methoxyimino)acetyl)amino)-2-carboxy-8-oxo-5-thia-1-azabicyclo(4.2.0) oct-2-en-3-yl)methyl)-1-methyl-, inner salt Common Name: Cefepime Structural Formula:
Chemical Abstracts Registry No.: 88040-23-7 Trade Name Ceficad Forpar
Manufacturer Cadila Pharmaceuticals Ltd. Cipla Limited
Country India India
Year Introduced -
Cefepime
883
Trade Name
Manufacturer
Country
Year Introduced
Ivipime
VHB Life Sciences
India
-
Maxicef
Aristo Pharmaceutical Ltd.
India
-
Maxipime
Bristol-Myers Squibb
USA
-
Maxipime
EPI
USA
-
Ultipime
Recon Healthcare Ltd.
India
-
Zwiter
Lyka Hetro Labs. Ltd.
India
-
Raw Materials Ethyl (Z)-2-hydroxyimino-2-(2-tritylaminothiazol-4-yl) acetate Methyliodide 7-Phenylacetimidocephalosporanic acid sodium salt Diphenyldiazomethane Bis(trimethylsilyl)acetamide Potassium carbonate Phosphorus pentachloride Manufacturing Process A mixture of ethyl (Z)-2-hydroxyimino-2-(2-tritylaminothiazol-4-yl) acetate (5 g, 10.9 mmoles), methyliodide (2.04 ml, 32.8 mmoles) and K2CO3 (4.54 g, 32.8 mmoles) in dry DMSO (100 ml) was stirred at room temperature overnight and then poured into water (250 ml). The precipitate was collected, washed with water and dried to give 2-methoxyimino-2-(2-tritylaminothiazol4-yl) acetate (1.15 g, melting point 115°C (dec.)) Ethyl (Z)-2-hydroxyimino-2-(2-tritylaminothiazol-4-yl) acetate (6 g, 12.7 mmol) in ethanol was treated with 2 N NaOH (12.7 ml) at room temperature overnight. The mixture was adjusted to pH 8 by the addition of powdered dry ice and the solvent evaporated. The residue was dissolved in water (100 ml) and was added to the solution which was acidified with 1 N HCl to pH 2 and then extracted with ethyl acetate. Extract was evaporated, the residue was crystallized from ethyl acetate-hexane to afford ethyl (Z)-2-hydroxyimino-2(2-tritylaminothiazol-4-yl)acetic acid (5.56 g, melting point 138-143°C (dec.)). To a suspension of phosphate buffer (pH 7, 162.5 ml) and wheat bran (20 g, dry) at room temperature was added 7-phenylacetimidocephalosporanic acid sodium salt (5 g). After 5 hours the suspension was filtered to remove wheat bran and the filtrate was cooled to 5-10°C, then was added methylene chloride (32 ml) and 0.5 M solution of diphenyldiazomethane in methylene chloride (24 ml). The pH was then adjusted to 3.0 with 28% phosphoric acid. After 1 hour the mixture was allowed to rise to 20°C. Heptane was slowly added (56 ml) and was recovered benzhydryl 3-hydroxymethyl-7phenylacetamido-3-cephem-4-carboxylate (3.0 g, 50%). The mixture of PCl5(8.3 g) and pyridine (3.2 g) in CH2Cl2 was added to benzhydryl 3-hydroxymethyl-7-phenylacetamido-3-cephem-4-carboxylate (5.1 g) at -40°C. The mixture was stirred at -10°C for 15 minutes and allowed to stand at -15-10°C for 7 hours. To the solution at -20°C was added propane1,3-diol (10 ml) and the mixture was allowed to stand at -20°C for 16 hours
884
Cefepime
and then at room temperature for 20 minutes. The resulting solution was washed with ice-water and saturated aqueous NaCl (10 ml), dried and concentrated. The gummy residue (12 g) was dissolved in CHCl3-hexane (2:1), and subjected to chromatography using silica gel column and the same solvent as eluant. After evaporation of the solvents was obtained benzhydryl7-amino-3-chloromethyl-3-cephem-4-carboxylate (2.1 g, 51%, melting point >110°C(dec.)). Benzhydryl 7-amino-3-chloromethyl-3-cephem-4-carboxylate (2.29 g) was treated with bis(trimethylsilyl)acetamide (4.06 ml) at room temperature for 50 min to give a clear solution. Top the solution was added an acid chloride solution, which was prepared from (Z)-2-hydroxyimino-2-(2tritylaminothiazol-4-yl)acetic acid (2.04 g) and PCl5 (1.15 g) in methylene chloride (20 ml). The mixture was stirred at room temperature for 30 min, poured in cold water (200 ml) and extracted with ethyl acetate (100 ml x 3). After evaporation of the solution was obtained the syrup (4 g) which was chromatographed on a silica gel column by eluting with 10:1 and 3:1 mixture of toluene and ethyl acetate successively. After evaporation of the solvents was obtained benzhydryl 3-chloromethyl-7-[(Z)-2-methoxyimino-2-(2tritylaminothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (2.62 g, 68%). A mixture of the benzhydryl 3-chloromethyl-7-[(Z)-2-methoxyimino-2-(2tritylaminothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (1.50 g, 1.79 mmoles) and NaI (1.34 g, 8.93 mmoles) in methyl ethyl ketone (30 ml) was stirred at room temperature for 1 hour. After evaporation of the solvent the residue was dissolved in ethyl acetate (100 ml) and washed with water, aqueous Na2S2O3 and aqueous NaCl, dried and evaporated to give 7-[(Z)-2ethoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-iodomethyl-3-cephem4-carboxilate (1.47 g, 89%) as an amorphous powder. A mixture of 7-[(Z)-2-ethoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3iodomethyl-3-cephem-4-carboxilate (4.5 g, 4.83 mmoles) and Nmethylpyrrolidine (0.65 ml, 6.28 mmoles) in CH2Cl2 (45 ml) was stirred at room temperature for 20 min. Ether (300 ml) was added to the mixture to separate the quaternary salt of the blocked cephalosporin, which was collected by filtration and treated with 90% trifluoroacetic acid (TFA) (40 ml) at room temperature for 1 hour. The mixture was then evaporated under reduced pressure below 20°C. The residue was triturated with ether to give the TFA salt of 7-[(Z)-2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[(1methyl-1-pyrrolidinium)methyl]-3-cephem-4-carboxylate (2.40 g), which was dissolved in methanol (5 ml) and treated with 1 M solution of sodium-2ethylhexoate in ethyl acetate (8 ml) at room temperature for 30 min. After the addition of ethyl acetate (100 ml), the precipitate (1.94 g) formed was collected by filtration. HPLC analysis showed that the crude product was 7% pure with a 1:8 ratio of the δ3 isomer to the δ2 isomer. Purification of the product by HPLC was repeated three times (Lichrosorb RP-18, eluted with 5% aqueous methanol or 0.01 M ammonium phosphate buffer (pH 7.2 containing 5% of methanol) to give 35 mg (1.5%) of the title product as a colorless powder of 7-[(Z)-2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[(1methyl-1-pyrrolidinium)methyl]-3-cephem-4-carboxylate. Estimated purity (by HPLC) 90%. M.p. 150°C (dec.).
Cefixime
885
References Aburaki Sh. et al.; US Patent No. 4,406,899; 09.27.1983; Assigned to BristolMyers Company
CEFIXIME Therapeutic Function: Antibiotic Chemical Name: 5-Thia-1-azabicyclo(4.2.0)oct-2-ene-2-carboxylic acid, 7(((2Z)-(2-amino-4-thiazolyl)(carboxymethoxy)imino)acetylamino)-3ethenyl-8-oxo-, (6R,7R)Common Name: Cefixime; Cefvixime Structural Formula:
Chemical Abstracts Registry No.: 79350-37-1 Trade Name
Manufacturer
Country
Year Introduced
Acrotex
Acron Pharmaceuticals
India
-
Biotax-O
Biochem Pharma Industries
-
-
Cebay D. Syp.
Leben Laboratories Pvt. Ltd.
India
-
Cefaden-O
Eden Healthcare
India
-
Cefex
Talent Laboratories
India
-
Cefixime
Rhone-Poulenc Rorer
-
-
Cefnax
Andromaco
-
-
Cefspan
Hikma Pharmaceuticals
Iordania
-
Cefspan
Glaxo Smithkline
-
-
Ceftiwin
Parenteral Drugs (India) Ltd. India
-
Defender
Skymax Laboratories Pvt. Ltd.
India
-
Evacef O
Neon Laboratories Ltd.
India
-
Excef-DT
Ind-Swift Ltd.
India
-
886
Cefmenoxime
Trade Name Exime Fixx Lyceft-O Ocef Omnatax-O O-Powercef Pancef-O Pedixim Suprax Suprax
Manufacturer J.K. Drugs and Pharmaceuticals Ltd. Unichem Laboratories Ltd. Lyka Hetro Labs. Ltd. Osper Pharmanautics Pvt. Ltd.
Country India
Year Introduced -
India India India
-
Nicholas Piramal India Ltd. (Npil) Wockhardt Ltd. Aglowmed Limited Biological E. Limited Hikma Pharmaceuticals Aventis Pharma
India
-
India India India Iordania -
-
Raw Materials 7-Amino-3-vinyl-3-cephem-4-carboxylic acid 2-(Aminothiazol-4-yl)-2-(tert-butoxycarbonylmethoxyimino)acetic acid Smercaptobenzothiazole ester Triethylamine Manufacturing Process To a suspension of 7-amino-3-vinyl-3-cephem-4-carboxylic acid (11.25 g), 2(aminothiazol-4-yl)-2-(tert-butoxycarbonylmethoxyimino)acetic acid Smercaptobenzothiazole ester (23.88 g) in ethylacetate (266 ml) and water (9 ml) at 2°C is added triethylamine. After completion of the reaction, water is added and pH is adjusted to 2.1 with diluted sulfuric acid. The phases are separated and the aqueous phase is extracted with ethylacetate. The organic extracts are combined and concentrated to a volume of 120 ml, then acetonitrile (100 ml) and formic acid (22 ml) are added. The mixture is stirred at 30-35°C for 1 hour. The mixture is cooled to 2°C, the precipitate is filtered, washed with acetonitrile and dried to obtain 20.86 g of 5-thia-1azabicyclo(4.2.0)oct-2-ene-2-carboxylic acid, 7-(((2Z)-(2-amino-4thiazolyl)(carboxymethoxy)imino)acetylamino)-3-ethenyl-8-oxo-, (6R,7R)(Cefixime). References Carbi W. et al.; WO03040148, Nov. 9, 2001
CEFMENOXIME Therapeutic Function: Antibacterial Chemical Name: 7β-[α-Methoxyimino-α-(2-aminothiazol-4-yl)acetamido]-3(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid
Cefmenoxime
887
Common Name: Structural Formula:
Chemical Abstracts Registry No.: 65085-01-0 Trade Name Tacef Bestcall
Manufacturer Takeda Takeda
Country W. Germany Japan
Year Introduced 1983 1983
Raw Materials 7β-[α-Methoxyimino-α-(2-aminothiazol-4-yl)acetamido] cephalosporanicacid trifluoroacetic acid salt 1-Methyl-5-mercapto-1H-tetrazole Manufacturing Process 7β-[α-Methoxyimino-α-(2-aminothiazol-4-yl)acetamido]cephalosporanicacid trifluoroacetic acid salt is dissolved in a solution of 272 mg of 1-methyl-5mercapto-1H-tetrazole, 555 mg of sodium bicarbonate and 68 mg of triethylbenzylammonium bromide in 10 ml of water. The solution is heated at 60°C in nitrogen atmosphere for 6 hours. After cooling, the reaction solution is passed through a column of Amberlite XAD-2 and eluted with water and then with 2.5% ethanol. The procedure yields sodium 7β-[α-methoxyimino-α(2-aminothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3cephem-4-carboxylate, MP 174°C to 175°C (decomposition). References Merck Index 1902 DFU 5 (3) 146 and (12) 635 (1980) (as SCE-1365) DOT 19 (6) 335 and (8) 429 (1983) I.N. p. 198 REM p. 1189 Ochiai, M., Okada, T., Aki, O., Morimoto, A., Kawakita, K. and Matsushita, Y.; US Patent 4,098,888; July 4, 1978; assigned to Takeda Chemical Industries, Ltd.
888
Cefoperazone
CEFOPERAZONE Therapeutic Function: Antibiotic Chemical Name: 7-[D-(-)-α-(4-Ethyl-2,3-dioxo-1-piperazinecarboxamido)-α(4-hydroxyphenyl)acetamido]-3-[(1-methyl-1H-tetrazol-5-yl)thiomethyl]3-cephem-4-carboxylic acid Common Name: Structural Formula:
Chemical Abstracts Registry No.: 62893-19-0; 62893-20-3 (Sodium Salt) Trade Name
Manufacturer
Country
Year Introduced
Cefobid
Pfizer
W. Germany
1981
Cefobine
Pfizer
France
1981
Cefobis
Pfizer
Switz.
1981
Cefoperazin
Pfizer Taito
Japan
1982
Cefobid
Roerig
US
1982
Raw Materials 7-[D-(-)-α-Amino-p-hydroxyphenylacetamido]-3-[5-(1-methyl-1,2,3,4tetrazolyl)-thiomethyl]-δ(3)-cephem-4-carboxylic acid 4-Ethyl-2,3-dioxo-1-piperazinocarbonyl chloride Manufacturing Process To a suspension of 3.0 g of 7-[D-(-)-α-amino-p-hydroxyphenylacetamido]-3[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-∆3-cephem-4-carboxylic acid in 29 ml of water was added 0.95 g of anhydrous potassium carbonate. After the solution was formed, 15 ml of ethyl acetate was added to the solution, and 1.35 g of 4-ethyl-2,3-dioxo-1-piperazinocarbonyl chloride was added to the resulting solution at 0°C to 5°C over a period of 15 minutes, and then the mixture was reacted at 0°C to 5°C for 30 minutes. After the reaction, an aqueous layer was separated off, 40 ml of ethyl acetate and 10 ml of acetone
Cefotaxime sodium
889
were added to the aqueous layer, and then the resulting solution was adjusted to a pH of 2.0 by addition of dilute hydrochloric acid. Thereafter, an organic layer was separated off, the organic layer was washed two times with 10 ml of water, dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was dissolved in 10 ml of acetone, and 60 ml of 2-propanol was added to the solution to deposit crystals. The deposited crystals were collected by filtration, washed with 2propanol, and then dried to obtain 3.27 g of 7-[D-(-)-α-(4-ethyl-2,3-dioxo)-1piperazinocarbonylamino)-p-hydroxyphenylacetamido]-3-[5-(1-methyl1,2,3,4-tetrazolyl)thiomethyl]-∆3-cephem-4-carboxylicacid, yield 80.7%. The product forms crystals, MP 188°C to 190°C (with decomposition). References Merck Index 1905 DFU 4 (9) (675) and (12) 911 (1979) (as T-1551) Kleeman and Engel p. 169 PDR p. 1521 DOT 17 (12) 535 (1981) I.N. p. 198 REM p. 1185 Saikawa, I., Takano, S., Yoshida, C., Takashima, O., Momonoi, K., Kuroda, S., Komatsu, M., Yasuda, T. and Kodama, Y.; British Patent 1,508,071; April 19, 1978;assigned to Toyama Chemical Co., Ltd. and US Patent 4,110,327; August 29, 1978; also assigned to
CEFOTAXIME SODIUM Therapeutic Function: Antibiotic Chemical Name: Sodium 3-acetoxymethyl-7-[2-(2-amino-4-thiazolyl)-2methoxyimino]-acetamido-3-cephem-4-carboxylate Common Name: Structural Formula:
890
Cefotaxime sodium
Chemical Abstracts Registry No.: 64485-93-4; 63527-52-6 (Base) Trade Name Claforan Claforan Claforan Zariviz Claforan Claforan Cefotax Claforan Pretor Primafen Ralopar Tolvcar
Manufacturer Hoechst-Roussel Roussel Maestretti Roussel Hoechst Roussel-Hoechst Roussel Roussel Hoechst Hoechst Hoechst Hoechst Hoechst
Country W. Germany Italy France Italy Switz. UK Japan US -
Year Introduced 1980 1980 1980 1980 1981 1981 1981 1981 -
Raw Materials Sodium bicarbonate 3-Acetoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]ceph-3-em-4-carboxylic acid (Cefotaxime) Manufacturing Process A solution of 8 g of sodium bicarbonate in about 20 ml of ethanol was progressively added to 45.55 g of pure 3-acetoxymethyl-7-[2-(2-amino-4thiazolyl)-2-methoxyiminoacetamido]-ceph-3-eme-4-carboxylic acid in 100 ml of distilled water and another 80 ml of ethanol and 4.5 g of activated carbon were added thereto. The mixture was stirred for 5 minutes and was filtered. The filter was rinsed with ethanol and the filtrate was evaporated to dryness under reduced pressure. The residue was taken up in 100 ml of ethanol and evaporated to dryness again. The residue was dissolved in 100 ml of methanol and the solution was poured into 2 l of acetone. The mixture was vigorously stirred and was vacuum filtered. The recovered product was rinsed with acetone and then ether and dried under reduced pressure to obtain 43.7 g of a white product which rehydrated in air to obtain a final weight of 45.2 g of sodium 3-acetoxymethyl-7-[2-(2-amino-4-thiazolyl)-2methoxyiminoacetamido]-ceph-3-eme-4-carboxylate. References Merck Index 1907 DFU 3 (12) 905 (1978) Kleeman and Engel p. 171 PDR p. 935 OCDS Vol. 3 p. 216 (1984) DOT 17 (1) 16 (1981) I.N.p. 198 REM p. 1186 Heymes, R. and Lutz, A.; US Patent 4,152,432; May 1, 1979; assigned to Roussel Uclaf
Cefotiam
891
CEFOTIAM Therapeutic Function: Antibiotic Chemical Name: 5-Thia-1-azabicyclo(4.2.0)oct-2-ene-2-carboxylic acid, 7(((2-amino-4-thiazolyl)acetyl)amino)-3-(((1-(2-(dimethylamino)ethyl)1H-tetrazol-5-yl)thio)methyl)-8-oxo-, (6R-trans)Common Name: Cefotiam; Ceftiazole Structural Formula:
Chemical Abstracts Registry No.: 61622-34-2 Trade Name
Manufacturer
Country
Year Introduced
Cefotiam
Qingdao Ftz United International Inc.
-
-
Cefotiam
Terio Corporation
-
-
Cefotiam
Arocor Holdings Inc.
-
-
Ceradolan
Takeda
-
-
Halospor
Novartis
-
-
Halospor
Ciba-Geigy
-
-
Sporidyn
Zoja
-
-
Spizef
Grunenthal
-
-
Pansporin
Takeda
-
-
Taketiam
Takeda
-
-
Texodil
Cassenne
-
-
Raw Materials 7-Acetamindocephalosporinic acid 1-(2-Dimethylaminoethyl-1Htetrazol-5-thiol 2-(2-Aminothiazol-4-yl)acetic acid
Hydroxylamine hydrochloride N-Hydroxysuccinimide Triethylamine Amberlite
892
Cefoxitin sodium
Manufacturing Process 2 mmol of 7-acetamindocephalosporinic acid in phosphate buffer (pH 7), 2 mmol of 1-(2-dimethylaminoethyl-1H-tetrazol-5-thiol and 2.2 mmol of sodium hydrogen carbonate are mixed and resulting solution was stirred at 60°-65°C for 16 hours. After cooling the mixture was adjusted pH 3.6 and hydrochloride of NH2OH was added to give 7-amino-3-[2-(2-dimethylaminoethyl)-2Htetrazol-5-ylsulfanylmethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2carboxylic acid. 0.4 g (2 mmol) of 2-(2-aminothiazol-4-yl)acetic acid hydrochloride in 10 ml of dimethylformamide are dissolved, 0.25 g (2.2 mmol) of N-hydroxysuccinimide and 0.412 g (2 mmol) of dicyclohexylcarbodiimide and the solution is allowed to stand at room temperature for 3 hours. The reaction mixture is subjected to filtration under suction to remove the precipitate of N,N'-dicyclohexylurea. The filtrate is added at a stroke to a solution of 2 mmol of above prepared 7amino-3-[2-(2-dimethylaminoethyl)-2H-tetrazol-5-ylsulfanylmethyl]-8-oxo-5thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 0.404 g (4 mmol) of triethylamine in 20 ml of dichloromethane and the mixed solution is stirred for 24 hours at room temperature. The solvent is distilled off under reduced pressure and the residue is adjusted pH from to 6 to 7 by adding a 10% aqueous solution of sodium hydrogen carbonate. The resultant solution is chromatographed on column of polystyrene resin (Amberlite XAD-2) and developed with water. The fractions containing the desired product are pooled and freeze-dried to obtain the title product. References Numata M. et al.; US Patent No. 4,517,361; May 14, 1985; Assigned to Takeda Chemical Industries, Ltd., Osaka, Japan Tsushima S. et al.; US Patent No. 4,245,088; Jan. 13, 1981; Assigned to Takeda Chemical Industries, Ltd., Osaka, Japan
CEFOXITIN SODIUM Therapeutic Function: Antibiotic Chemical Name: 3-Carbamoyloxymethyl-7-α-methoxy-7β-(2thienylacetamido)decephalosporanic acid sodium salt Common Name: Structural Formula:
Cefoxitin sodium
893
Chemical Abstracts Registry No.: 33654-30-6; 35607-66-0 (Base) Trade Name
Manufacturer
Country
Year Introduced
Mefoxin
Merck Sharp and Dohme
US
1978
Mefoxitin
Sharp and Dohme
W. Germany
1978
Mefoxin
MSD
UK
1978
Mefoxitin
MSD
Switz.
1979
Mefoxin
MSD
Italy
1979
Cenomicin
Daiichi Seiyaku
Japan
1980
Mefoxin
MSD
France
1980
Merkicin
Merck-Banyu
Japan
1980
Betacel
Firma
Italy
-
Boncefin
MSD
-
-
Cefaxicina
Cefa
Spain
-
Cefoctin
Teva
Israel
-
Farmoxin
Farm. Carlo Erba
Italy
-
Raw Materials Benzhydryl 3-carbamyloxymethyl-7α-hydroxy-7β-(2-thienylacetamino)decephalosporanate Sodium hydride Dimethyl sulfate Trifluoroacetic acid Manufacturing Process Benzhydryl 3-carbamoyloxymethyl-7α-hydroxy-7β-(2-thienylacetamido) decephalosporanate, 543 mg, is stirred in 15 ml dry DMSO. Sodium hydride, 24 mg (48 mg of a 50% suspension of NaH in mineral oi1, which has been washed with hexane to remove the oil), is added. When hydrogen evolution has ceased, 126 mg dimethyl sulfate is added. The solution is stirred for one hour at room temperature, diluted with 100 ml benzene and washed six times with water; the last wash is made to pH 8, if necessary, by adding sodium bicarbonate. The solution is dried over MgSO4, filtered and evaporated, leaving benzhydryl 3-carbamoyloxymethyl-7β-(2-thienylacetamido)-7αmethoxydecephalosporanate, which may be purified if desired by chromatography on silica gel, eluting with 25:1 chloroformethyl acetate. Other methylating agents may be used in place of methyl sulfate, e.g., an equimolar amount of methyl iodide, bromide or chloride, using the same conditions, or methyl trifluoromethylsulfonate or trimethyloxonium trinitrobenzenesulfonate. The solvent in the lat
