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Library of Congress Cataloging-in-Publication Data: Harrington, Peter J Pharmaceutical process chemistry for synthesis : rethinking the routes to scale-up / Peter J Harrington p.;em Includes bibliographical references and index ISBN 978-0-470-57755-4 (cloth)
1 Pharmaceutical chemistry 2 Chemical processes I Title
[DNLM: 1 Chemistry, Pharmaceutical-methods 2 Chemistry Techniques, Analytical 3 Drug Discovery 4 Pharmaceutical Preparations-chemical synthesis 5 Technology, Pharmaceutical-methods QV 744 H311p 2011]
RS403.H37 2011 615'.19-de22
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CONTENTS
1 Introduction
Actos® (Pioglitazone Hydrochloride) Lexapro® (Escitalopram Oxalate)
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INTRODUCTION
1.1 INSPIRATION
This project was first conceptualized at a most unlikely place: at a visit to an Inspiring Impressionism exposition at the Denver Art Museum in 2008 The exhibition focused on the impre: students of earlier masters They immersed themselves in these earlier masterpieces and then incorporated the insights they had gained and added their own techniques to convey the same subject matter in pro- found new ways My 20 years as a process chemist at Syntex and Roche are much like the years the impressionis' camped out in front of the works of the masters The it gained could be conveyed by presenting the theory and concepts of process research and development, but there are many well-worn reference books that collectively accomplish that objective My experience has been that process chemistry is a roller-coaster ride, with tremendous highs and lows, where you learn theory and concepts, as needed, on the fly, from your colleagues and from those reference books (while meeting seemingly unattainable milestones and timelines) The aim of this book is to convey some of this experience by immersing the reader in the process chemistry of some of the most valuable pharmaceu- ticals we are fortunate to have available today The master- pieces in this book are the top-selling drugs in the United States in 2007-2008 These are Lipitor®, Nexium®, Advair Diskus®, Prevacid®, Plavix®, Singulair®, Seroquel®, Effex- or XR®, Lexapro®, and Actos®, all “blockbuster” drugs, generating more than $1 billion in revenue for their owners
each year (Figure 1.1).' onists 2
T have no previous detailed knowledge of chemistry of most of these drugs Why choos« subject matter? First, there is currently intense i process chemistry of these drugs Second, if I unpublished knowledge about these drugs, I wo by a secrecy agreement to discuss only inform in the public domain Third, having no financia of these drugs or their process technology, I can ly (and refreshingly) objective I am not “sellit of any target or proprietary technology to a pat a pharmaceutical manufacturer
After a detailed review of the process c Plavixđ and Nexium®, these will not be it
process chemistry for Plavix® is omitted be
published and patented process work and k knowledge of the manufacturing process for antiplatelet drug Ticlid® is an adenosine dipho: receptor inhibitor with the same thienopyri
Plavix® (Figure 1.2).2 The process chemistry is omitted because Prevacid® and Nexium® h
core and there is considerable overlap in |
chemistry Advair Diskus® has two active ing
meterol and fluticasone The process chemistry is included The process chemistry of fluticas« better presented “in context” with the process other valuable steroids
With this format, will this book touch on ev aspect of proc
Trang 102 INTRODUCTION ° Et 2 N oO ot HoT? Actos ) pioglitazone (hydrochloride) NC N $2.23billion o CH : Ny ` zZ^~*cng N= N(CH3)2 OH S F
Seroquel CHO Lexapro quetiapine (hemifumarate) 3 escitalopram (oxalate)
$2.52billion Effexor XR $2.3billion venlafaxine (hydrochloride) $2.46billion N CH3 ‘on Yu “~ OCH;CFs ovocks © Ỳ NO NY He N
Prevacid aie XO Singulair
lansoprazole S cl montelukast (sodium)
$3.320ilion Plavix $2 89blHon clopidogrel (hydrogen sulfate) $3.08bilion l ae So OH ro HO’ 0 “CH HO’ Advair Diskus oO Advair Diskus salmeterol (xinafoate) $3.30bilion : Ệ — ffutlcasone (propionate) No CH3 S~§ cs OCH3 OH OH O CHạƠ Noe H oy cm ‘OH Nexium esomeprazole Lipitor $4 36billion atorvastatin (calcium) $6.17billion
FIGURE 1.1 The top-selling drugs in the United States in 2007 expert? Most people would say no Would you be better Ox OCH3
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