The Organic Chemistry

490 Pages·2005·3.85 MB·German

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, how-
ever, 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 bio-
logic activity characteristic of some class of organic compounds.
There thus seemed to be a place for a book that would cover spe-
cifically 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 mar-
keted 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-phenyl-
piperidines 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 litera-
ture. In many cases this can be assumed to bear little relation
to the processes used in actually producing the drugs on commer-
cial 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 activ-
ity 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 biolo-
gic or medical terms, a glossary of the more common terms used in
the book has been included following the last chapter. This glos-
sary is intended more to provide simple definitions than in-depth
pharmacologic discussion. We urge the reader interested in fur-
ther 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 com-
mon 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 apprecia-
tion 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