advanced practical medicinal chemistry

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Copyright 2004, New Age International (P) Ltd., Publishers Published by New Age International (P) Ltd., Publishers All rights reserved. No part of this ebook may be reproduced in any form, by photostat, microfilm, xerography, or any other means, or incorporated into any information retrieval system, electronic or mechanical, without the written permission of the publisher. All inquiries should be emailed to

ISBN (13) : 978-81-224-2553-6


NEW AGE INTERNATIONAL (P) LIMITED, PUBLISHERS 4835/24, Ansari Road, Daryaganj, New Delhi - 110002 Visit us at

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PREFACEThe art and skill for the preparation of newer drug molecules is a pivotal creative and an exceptionally great intellectual exercise that essentially serves as a fulcrum to plethora of specific areas of scientific research, ranging from the most applied to the most academic. Accordingly, the medicinal chemist, organic chemist, biologist, pharmacologist, biochemist, biotechnologist, phytochemist, genetic engineer, materials scientist, and polymer scientist, in an university or an industry, all must have genuinely encountered with the most challenging and intricate task of performing a reaction ultimately leading to an entirely new organic preparation exhibiting certain specific actions on the biological system to combat diseases in the ailing human beings. Invariably, the wonderful magic of modern organic synthesis, based on host of documented theories, hypothesis, organic name reactions (ONRs) amalgamated with logistic, scientific and assertive reaction mechanism(s), in fact, genuinely paved the way of complicated, notso-easy, cumbersome course of reactions much simpler and understandable. The advent of ever-more sophisticated and many supportive modern analytical techniques, such as : UV, IR, NMR, MS, ORD, CD, AAS, FES, GC, HPLC and the hyphenated techniques as well, have tremendously enhanced the confidence of medicinal chemists to such a magnitude as to maximize both the chances of success rate and probability factor. Besides, the use of organic and inorganic chemicals employed as reactants, catalysts, medium of reaction, purifying substances etc., are not only harmful but also hazardous in nature. Nevertheless, the various conditionalities of critical and specific reactions are sometimes articulated and spelled out so meticulously that one has to follow them just like gospel truth, to accomplish the right synthesis, and hence, the right product. It is, however, pertinent to mention here that the UG and PG students, associated with the myth and reality of drug synthesis should make an honest attempt to carry out a particular synthesis of a drug substance with a most tried and tested methodical, scientific and rational approach, so that one may get reproducible results under a particular reaction in a seamless manner. The copious volumes of textbooks, scientific research journals, monographs, review articles on related topics like : organic chemistry of drug synthesis, chiral chemistry, drug design, principles of medicinal chemistry, organic medicinal and pharmaceutical chemistry, and medicinal chemistry provide ample evidence and scope to suggest that the comprehensive in-depth knowledge together with utmost specialized state-of-the-art know-how of the various techniques is an absolute necessity and basic requirement to have a real understanding with regard to the practical aspects of Medicinal Chemistry. In Advanced Practical Medicinal Chemistry, an attempt has been made to stress the much needed requirement of both undergraduate and graduate students specializing in the field of Pharmaceutical Chemistry to learn how to synthesize drugs in the laboratory. Unfortunately, the common available textbooks ordinarily referred to by the Pharmacy Students

( viii ) mostly deal with the synthesis of pure organic compounds ; and hence, do not provide the real and much needed subject matter relevant to a budding Medicinal Chemist. The Advanced Practical Medicinal Chemistry comprises of four major chapters that are intimately associated with specific emphasis on the synthesis of a broad range of some typical and selected drugs commonly found in the therapeutic armamentarium. Chapter-1 deals with Safety in a Chemical Laboratory. It consists of various aspects, namely : guard against personal safety ; conduct in a chemistry laboratory ; neatness and cleanliness ; after-hours working ; guidelines for accident or injury ; storage of chemicals/reagents in a chemical laboratory ; glass ware ; waste disposal ; an ideal chemistry laboratory ; and toxicity and hazards of chemicals/reagents. Chapter-2 consists of Drug Synthesis. First, aspect beingConceptualization of a Synthesis viz., prime considerations in designing synthesis ; the Synthon Approach ; reaction specificity. Secondly, Reaction Variants, viz., structural variants ; interchangeability of functional moiety ; selectivity in reactions ; protection of functional moieties ; elimination of functional moieties ; annealation reactions ; fragmentation reactions. Thirdly, Stereochemistry, viz., nucleophilic substitutions (SN2), ionic additions to C-C double bonds ; catalytic hydrogenation ; acid or base promoted enolization of compounds, reductions of cyclohexane ; and cycloadditions. Chapter-3 comprises of Performing the Reactions. The wide range of latest laboratory techniques invariably employed in a reasonably well equipped chemical research laboratory or a chemical laboratory for actually performing the specifically desired reactions and other equally important operational measures have been dealt with in an explicit and lucid manner. The various aspects included in this chapter are, namely : solvent stills (with continuous still collecting head)-reactions performed at elevated temperatures-large scale reaction and slow addition of reagents-low temperature reactions-reaction above room temperature using a condensermechanical stirrer-mechanical shaker-crystallization at low temperature-distillation under reduced pressure-small scale distillation-performing the reaction, and -photolysis. Chapter-4 i.e., the last chapter, has been exclusively devoted toSynthesis of Medicinal Compounds which vary in length from the single-stage reaction to the multi-stage or projecttype synthesis. In fact, it is the backbone of the present textbook and specially designed to inculcate the sense of creativity, learning the art of synthesis, and above all inject the spirit of zeal and enthusiasm amongst the medicinal chemists to tackle most synthesis-related problems with great ease, confidence and fervour. It embraces three specific areas of interest confined to the synthesis of drugs, such as : (a) Types of Chemical Reactions e.g., acetylation methods-benzoylation methodssulphonation methods-bromination methods-condensation reactions ; and diazotization and coupling reactions ; (b) Organic Name Reactions (ONRs) e.g., Bart reaction-Diels-Alder reaction-FriedelCrafts reaction-Fries reaction-Grignard reaction-Hoesch reaction-Perkin reaction-Mannich reaction-Michael reaction, and Reimer-Tieman reaction ; (c) Selected Medicinal Compounds : It includes the synthesis of forty selected medicinal compounds having a wide variety of therapeutic action(s). An intensive and extensive care has been exercised painstakingly and meticulously to discuss in details each and every medicinal compound under the above mentioned three categories i.e., (a) through (c) in a particular original style of presentation that essentially includes :

( ix ) chemical structure-synonym(s)/chemical name(s)-theory-chemicals required-procedure-precautions-recrystallization-theoretical yield/practical yield-physical parameters-uses, and -questions for viva-voce. A subtle, but no less profound effect of this completely new approach as given in the Advanced Practical Medicinal Chemistry comprising of syntheses totalling eighty selected drug substances would not only benefit the undergraduate and graduate students in Pharmaceutical Chemistry in Indian Universities and other developing countries as well, but also go a along way to help the esteemed teachers involved in the handling of such courses who always genuinely felt the dire necessity of such a compilation for the academics in particular. The medicinal chemists involved in Bulk Drug Manufacturing Operations may also find this presentation as a handy reference book in the domain of their ever expanding and demanding profession. In case, the above outlined objectives have been duly achieved, actual users of this textbook must be able to accomplish their synthetic problems with greater ease and confidence. Synthesis of Medicinal Compounds is not only satisfying but also exciting, and provides an ample opportunity to explore an individuals inherent talent and enormous strength of real creativities. Ashutosh Kar

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CONTENTSPreface (vii) 1. SAFETY IN A CHEMISTRY LABORATORY 1 1.1. 1.2. Introduction 1 Guard Against Personal Safety 2 1.2.1. Protective Coat 2 1.2.2. Protection for Eyes 2 1.2.3. Conduct in a Chemistry Laboratory 3 1.2.4. Neatness and Cleanliness 3 1.2.5. After-Hours Working 6 1.2.6. Guidelines for Accident or Injury 6 1.2.7. Storage of Chemicals/Reagents in a Chemical Laboratory 7 1.2.8. Glassware 8 1.2.9. Waste Disposal 9 1.2.10. An Ideal Chemistry Laboratory 9 1.2.11. Toxicity and Hazards of Chemicals Reagents 10


DRUG SYNTHESIS 2.1. 2.2. Introduction 15 Conceptualization of a Synthesis 15 2.2.1. Prime Considerations in Designing Synthesis 16 2.2.2. The Synthon Approach 17 2.2.3. The Retro-Synthetic Approach 18 2.2.4. Materials Required 19 2.2.5. Reaction Specificity 20 2.2.6. Purity and Yield 21 Reaction Variants 21 2.3.1. Struc


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