The Organic Chemistry of Drug Synthesis V1.Pdf

The Organic Chemistry of Drug Synthesis Volume 1 DANIEL LEDNICER Chemical Research Mead Johnson & Co. Evansville, Indiana LESTER A. MITSCHER The University of Kansas School of Pharmacy Department of Medicinal Chemistry Lawrence, Kansas with a Glossary by Philip F. vonVoigtlander The Upjohn Company A WILEY-INTERSCIENCE PUBLICATION JOHN WILEY & SONS New York • Chichester • Brisbane • Toronto Copyright © 1977 by John Wiley & Sons, Inc. All rights reserved. Published simultaneously in Canada. Reproduction or translation of any part of this work beyond that permitted by Sections 107 or 108 of the 1976 United States Copyright Act without the permission of the copyright owner is unlawful. Requests for permission or further information should be addressed to the Permissions Department, John Wiley & Sons, Inc. Library of Congress Cataloging in Publication Data: Lednicer, Daniel, 1929- The organic chemistry of drug synthesis. "A Wiley-Interscience publication." 1. Chemistry, Medical and pharmaceutical. 2. Drugs. 3. Chemistry, Organic. I. Mitscher, Lester A., joint author. II. Title. RS421.L423 615M91 76-28387 ISBN 0-471-52141-8 Printed in the United States of America 10 9 To Beryle and Betty whose steadfastness made that which follows become real The three princes of Serendip, Balakrama, Vijayo, and Rajahsigha, as they traveled "...were always making discoveries, by accident and sagacity, of things they were not in quest of...n* ^Horace Walpole, in a letter of January 28, 1754, as quoted in "The Three Princes of Serendip," by E. J. Hodges, Atheneum, N.Y., 1!K)4 vii Preface There exists today an abundance of excellent texts covering the various aspects of organic chemistry. The student of medicinal chemistry can choose among any of a number of first-rate exposi- tions of that field. The reader who is primarily interested in the synthesis of some particular class of medicinal agents, however, will often find that he must consult either the original literature or some specialized review article. The same quandary faces the student who wishes to become acquainted with the biologic activity characteristic of some class of organic compounds. There thus seemed to be a place for a book that would cover specifically the chemical manipulations involved in the synthesis of medicinal agents. A book then was intended that would supplement both the available medicinal and organic chemistry texts. Comprehensive coverage of both the preparation and biologic activity of all organic compounds reported in the literature to show such activity would lead to a truly enormous treatise. In order to keep this book within bounds, we deliberately restricted our coverage to medicinal agents that have been assigned generic names. This means that at some time during the development of a drug, the sponsoring laboratory has felt the agent to have suf- ficient promise to apply to the USAN Council or its equivalent ;ibroad for the granting of such a name. By far, the majority of t he compounds in this volume denoted by generic names are marketed as drugs; some compounds, however, have either gotten only us far as clinical trial and failed, or are as yet in early pre- imirketing stages. We have not excluded the former since these .ire often closely related to drugs in clinical practice and thus serve as further illustration of molecular manipulation. We have further kept the book fairly current insofar as drugs available for sale in the United States are concerned. The informed reader will note that this book is not nearly as current when it comes to drugs available only outside this country—our own version of ix the drug lag. In order to sustain the chemical focus of the book, we departed in organization from the traditional texts in medicinal chemistry. The current volume is organized by structural classes rather than in terms of pharmacologic activities. This seems to allow for more natural treatment of the chemistry of many classes of compounds, such as the phenothiazines which form the nucleus for more than a single class of drugs. This framework has admit- tedly led to some seemingly arbitrary classifications. The sul- fonamides, for example, are all regarded as derivatives of p- aminobenzenesulfonamide even though this is sometimes the smallest moiety in a given sulfa drug; should these be classed as sulfon- amides or as a derivative of the appropriate heterocycle? In this case at least, since the biologic activity is well known to be associated with the sulfonamide portion—the pharmacophoric group—the compounds are kept together. Occasionally the material itself demanded a departure from a purely structural approach. The line of reasoning that leads from morphine to the 4-phenylpiperidines is so clear—if unhistoric—as to demand exposition in an integral chapter. The chronologically oriented chapter on the development of the local anesthetics is included specifically to give the reader some appreciation of one of the first approaches to drug development. We hope it is clear from the outset that the syntheses out- lined in this book represent only those published in the literature. In many cases this can be assumed to bear little relation to the processes used in actually producing the drugs on commercial scale. The latter are usually developed after it is certain the drug will be actually marketed. As in the case of all large- scale organic syntheses, they are changed from the bench-scale preparations in order to take into account such factors as eco- nomics and safety. Details of these are not usually readily available. Again in the interest of conciseness, the discussion of the pharmacology of the various drugs was cut to the bone. The activity is usually indicated by only a short general phrase. Com- parisons among closely related analogs as to differences in effi- cacy or side effects are usually avoided. Such discussion more properly belongs in a specialized text on clinical pharmacology. Since we do not presume that the reader is acquainted with biologic or medical terms, a glossary of the more common terms used in the book has been included following the last chapter. This glossary is intended more to provide simple definitions than in-depth pharmacologic discussion. We urge the reader interested in further study of such entries to consult any of the excellent refer- ence works in medicinal chemistry, such as Burger's "Medicinal Chemistry" or Rushig and Ehrhard's "Arzneimittel." This book assumes a good working knowledge of the more common organic reactions and a rudimentary knowledge of biology. We hope it will be of interest to all organic chemists curious about therapeutic agents, how these were developed, the synthetic oper- ations used in their preparation, and the types of structures that have proven useful as drugs. We hope further that this long look at what has gone before may provide food for thought not only to the practicing medicinal chemist but also to the organic chemist engaged in research in pure synthetic chemistry. Finally, we would like to express our most sincere appreciation to Ms. Carolyn Jarchow of The Upjohn Company. Among the press of daily responsibilities she not only found time for typ- ing this manuscript, but provided the mass of structural drawings .is well. Daniel Lednicer Kalamazoo, Michigan Lester A. Mitscher Lawrence, Kansas October 1975 Contents PAGE Chapter 1. Introduction 1 Chapter 2. A Case Study in Molecular Manipulation: The Local Anesthetics 4 1. Esters of Aminobenzoic Acids and Alkanol- amines 9 a. Derivatives of Ethanolamine 9 b. Modification of the Basic Ester Side Chain 12 2. Amides and Anilides 14 3. Miscellaneous Structures 18 References 21 Chapter 3. Monocyclic Alicyclic Compounds 23 1. Prostaglandins 23 2. Miscellaneous Alicyclic Compounds 35 References 38 Chapter 4. Benzyl and Benzhydryl Derivatives 40 1. Agents Based on Benzyl and Benzhydryl Amines and Alcohols 40 a. Compounds Related to Benzhydrol 40 b. Compounds Related to Benzylamine 50 c. Compounds Related to Benzhydrylamine 58 References 60 Chapter 5. Phenethyl and Phenylpropylamines 62 References 83 Chapter 6. Arylacetic and Arylpropionic Acids 85 xiii PAGE References 98 Chapter 7. Arylethylenes and Their Reduction Products 100 References 106 Chapter 8. Monocyclic Aromatic Compounds 108 1. Benzoic Acids 108 2. Anthranillic Acids 110 3. Anilines 111 4. Derivatives of Phenols 115 5. Derivatives of Arylsulfonic Acids 120 a. Sulfanilamides 120 b. Bissulfonamidobenzenes 132 c. Sulfonamidobenzoic Acids 134 d. Sulfonylureas 136 e. Diarylsulfones 139 References 141 Chapter 9. Polycyclic Aromatic Compounds 145 1. Indenes 145 a. Indenes with Basic Substituents 145 b. Indandiones 147 2. Dihydronaphthalenes 148 3. Dibenzocycloheptenes and Dibenzocyclohepta- dienes 149 4. Colchicine 152 References 154 Chapter 10. Steroids 155 1. Commercial Preparation of Estrogens, Androgens, and Progestins 156 2. Aromatic A-Ring Steroids 160 3. 19-Norsteroids 163 a. 19-Norprogestins 163 b. 19-Norsteroids by Total Synthesis 166 c. 19-Norandrogens 169 4. Steroids Related to Testosterone 172 5. Steroids Related to Progesterone 178 6. The Oral Contraceptives 186 7. Cortisone and Related Antiinflammatory Steroids 188 8. Miscellaneous Steroids 206 References 207 xiv PAGE Chapter 11. Tetracyclines 212 References 216 Chapter 12. Acyclic Compounds 218 References 225 Chapter 13. Five-Membered Heterocycles 226 1. Derivatives of Pyrrolidine 226 2. Nitrofurans 228 3. Oxazolidinediones and an Isoxazole 232 4. Pyrazolonones and Pyrazolodiones 234 5. Imidazoles 238 6. Imidazolines 241 7. Hydantoins 245 8. Miscellaneous Five-Membered Heterocycles 247 References 250 Chapter 14. Six-Membered Heterocycles 253 1. Pyridines 253 2. Derivatives of Piperidine 256 3. Morpholines 260 4. Pyrimidines 261 5. Barbituric Acid Derivatives 267 6. Pyrazines and Piperazines 277 7. Miscellaneous Monocyclic Hetexocycles 280 References 283 Chapter 15. Derivatives of Morphine, Morphinan, and Benzomorphan; 4-Phenylpiperidines 286 1. Morphine 287 2. Morphinans 292 3. Benzomorphans 296 4. 4-Phenylpiperidines 298 References 310 Chapter 16.

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