art of drug synthesis
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8/12/2019 Art of drug synthesis
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C2NTENNIAL 3
1 8 7
WILEY
2 7
re
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2
r
THE ART OF DRUG
SYNTHESIS
Edited by
Douglas S. Johnson
Jie Jack Li
Pfizer Global Research and Development
ICENTENNIAL
WILEY INTERS IEN E
A J O H N W I L E Y S O N S , IN C . , P U B L IC A T IO N
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C O N T E N T S
Foreword i
Preface iii
Contributors v
1 THE ROLE OF MEDICINAL CHEMISTRY IN DRUG DISCOVERY John A. Lowe III
1.1 Introduction 1.2 Hurdles in the Drug Discovery Process
1.3 The Tools of Medicinal Chemistry 1.3.1 In Silico Modeling 1.3.2 Structure-Based Drug Design SBDD) 1.4 The Role of Synthetic Chemistry in Drug Discovery References 2 PROCESS RESEARCH: HOW MUCH? HOW SOON? 1Neal G. Anderson
2.1 Introduction 1
2.2 Considerations for Successful Scale-up to Tox Batchesand Phase I Material 5
2.3 Considerations for Phase 2 Material and Beyond 62.3.1 Reagent Selection 62.3.2 Solvent Selection 82.3.3 Unit Operations 9
2.3.4 Developing Simple, Effective, Efficient Work-ups and Isolations 22.3.5 The Importance of Physical States 32.3.6 Route Design and Process Optimization to Minimize COG 42.4 Summary 6
eferen es 6
I CANCER AND INFECTIOUS DISEASES
3 AROMATASE INHIBITORS FOR BREAST CANCER: EXEMESTANE
AROMASIN® ), ANASTROZOLE ARIMIDEX® ), AND LETROZOLE
FEMARA® 1
Jie Jack Li
3.1 Introduction 2
3.2 Synthesis of Exemestane 53.3 Synthesis of Anastrozole 63.4 Synthesis of Letrozole 7References 8
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vi O N TEN TS
4 QUINOLONE ANTIBIOTICS: LEVOFLOXACIN LEVAQUIN ® ,
MOXIFLOXACIN AVELOX® ), GEMIFLOXACIN FACTIVE®),
AND GARENOXACIN T-3811) 9Chris Limberakis
4.1 Introduction 0
4.1.1 Mechanism of Action 34.1.2 Modes of Resistance 44.1.3 Structure–Activity Relationship SAR) and Structure–Toxicity
Relationship STR) 44.1.4 Pharmacokinetics 5
4.1.5 Synthetic Approaches 64.2 Levofloxacin 7
4.3 Moxifloxacin 7
4.4 Gemifloxacin 04.5 Garenoxacin T-3811): A Promising Clinical Candidate 4References 6
5 TRIAZOLE ANTIFUNGALS: ITRACONAZOLE SPORANOX® ,
FLUCONAZOLE DIFLUCAN® ), VORICONAZOLE VFEND®),
AND FOSFLUCONAZOLE PRODIF® 1
Andrew S. Bell
5.1 Introduction 2
5.2 Synthesis of Itraconazole 45.3 Synthesis of Fluconazole 65.4 Synthesis of Voriconazole 75.5 Synthesis of Fosfluconazole 0References 1
6 NON-NUCLEOSIDE HIV REVERSE TRANSCRIPTASE
INHIBITORS 3
Arthur Harms
6.1 Introduction 4
6.2 Synthesis of Nevirapine 5
6.3 Synthesis of Efavirenz 76.4 Synthesis of Delavirdine Mesylate 0References 2
7 NEURAMINIDASE INHIBITORS FOR INFLUENZA: OSELTAMIVIR
PHOSPHATE TAMIFLU® ) AND ZANAMIVIR RELENZA® 5
Douglas S. Johnson and Jie Jack Li
7.1 Introduction 5
7.1.1 Relenza 7
7.1.2 Tamiflu 7
7.2 Synthesis of Oseltamivir Phosphate Tamiflu® 97.3 Synthesis of Zanamivir Relenza® 1 0
References 1 3
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CONTENTS ii
II CARDIOVASCULAR AND METABOLIC DISEASES
8 PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR
PPAR) AGONISTS FOR TYPE 2 DIABETES 17Jin Li
8.1 Introduction 1 7
8.1.1 Insulin 1 8
8.1.2 Sulfonylurea Drugs 1 9
8.1.3 Meglitinides 1 9
8.1.4 Biguanides 1 9
8.1.5 Alpha-Glucosidase Inhibitors 20
8.1.6 Thiazolidinediones 20
8.2 Synthesis of Rosiglitazone 21
8.3 Synthesis of Pioglitazone 22
8.4 Synthesis of Muraglitazar 24 eferen es 25
9 ANGIOTENSIN AT i ANTAGONISTS FOR
HYPERTENSION 29
Larry Yet
9.1 Introduction 30
9.2 Losartan Potassium 32
9.2.1 Introduction to Losartan Potassium 32
9.2.2 Synthesis of Losartan Potassium 33
9.3 Valsartan 34
9.3.1 Introduction to Valsartan 34
9.3.2 Synthesis of Valsartan 34
9.4 Irbesartan 35
9.4.1 Introduction to Irbesartan 35
9.4.2 Synthesis of Irbesartan 35
9.5 Candesartan Cilexetil 36
9.5.1 Introduction to Candesartan Cilexetil 36
9.5.2 Synthesis of Candesartan Cilexetil 3 6
9.6 Olmesartan Medoxomil 37
9.6.1 Introduction to Olmesartan Medoxomil 379.6.2 Synthesis of Olmesartan Medoxomil 37
9.7 Eprosartan Mesylate 38
9.7.1 Introduction to Eprosartan Mesylate 38
9.7.2 Synthesis of Eprosartan Mesylate 3 8
9.8 Telmisartan 3 9
9.8.1 Introduction to Telmisartan 39
9.8.2 Synthesis of Telmisartan 39
eferen es 40
10 LEADING ACE INHIBITORS FOR HYPERTENSION 43Victor J. Cee and Edward J. Olhava
10.1 Introduction 44
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viii O N TEN TS
10.2 Synthesis of Enalapril Maleate 46
10.3 Synthesis of Lisinopril 47
10.4 Synthesis of Quinapril 48
10.5 Synthesis of Benazepril 5 0
10.6 Synthesis of Ramipril 51
10.7 Synthesis of Fosinopril Sodium 5 4
References 5 6
11 DIHYDROPYREDINE CALCIUM CHANNEL BLOCKERS FOR
HYPERTENSION 59
Daniel P. Christen
11.1 Introduction 60
11.2 Synthesis of Nifedipine Adalat® 62
11.3 Synthesis of Felodepine Plendil ® 63
11.4 Synthesis of Amlodipine Besylate Norvasc® 64
11.5 Synthesis of Azelnidipine Calblock® 65
References 66
12 SECOND-GENERATION HMG-CoA REDUCTASE
INHIBITORS 69
Jeffrey A Pfefferkorn
12.1 Introduction 70
12.2 Synthesis of Fluvastatin Lescol® 71
12.3 Synthesis of Rosuvastatin Crestor® 7412.4 Synthesis of Pitavastatin Livalo® 77
References 81
13 CHOLESTEROL ABSORPTION INHIBITORS: EZETIMIBE
ZETIA® 83
Stuart B. Rosenblum
13.1 Introduction 8 3
13.2 Discovery Path to Ezetimibe 8 4
13.3 Synthesis of Ezetimibe Zetia® 8 7
References 95
III CENTRAL NERVOUS SYSTEM DISEASES
14 DUAL SELECTIVE SEROTONIN AND NOREPINEPHRINE
REUPTAKE INHIBITORS SSNRIs) FOR DEPRESSION 99Marta Pifieiro-Nifiez
14.1 Introduction 00
14.2 Synthesis of Venlafaxine 03
14.3 Synthesis of Milnacipran 05
14.4 Synthesis of Duloxetine 07
References 1 2
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