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Copyright © 2011 by John Wiley & Sons, Inc All rights reserved Published by John Wiley & Sons, Inc., Hoboken, New Jersey Published simultaneously in Canada

No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mech prior written permission of the Publisher, or authorization through payment of the appropriate per-copy fee to the Copyright Clearance C 222 Rosewood Drive, Danvers, MA 01923, (978) 750-8400, fax (978) 750-4470, or on the web at www.Copyright.com Requests to the I permission should be addressed to the Permissions Department, John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, (201) 74 fax (201) 748-6008, or online at http://www.wiley.com/go/permission

Limit of Liability/Disclaimer of Warranty: While the publisher and author have used their best efforts in preparing this book, they make | representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any impl of merchantability or fitness for a particular purpose No warranty may be created or extended by sales representatives or written sales m The advice and strategies contained herein may not be suitable for your situation You should consult with a professional where appropri publisher nor author shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidents or other damages

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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

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2 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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