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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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