The Art of Drug Synthesis

Foreword xi

Preface xiii

Contributors xv

1 THE ROLE OF MEDICINAL CHEMISTRY IN DRUG DISCOVERY 1
John A. Lowe, III

1.1 Introduction 1

1.2 Hurdles in the Drug Discovery Process 2

1.3 The Tools of Medicinal Chemistry 3

1.4 The Role of Synthetic Chemistry in Drug Discovery 6

2 PROCESS RESEARCH: HOW MUCH? HOW SOON? 11
Neal G. Anderson

2.1 Introduction 11

2.2 Considerations for Successful Scale-up to Tox Batches and Phase I Material 15

2.3 Considerations for Phase 2 Material and Beyond 16

2.4 Summary 26

I CANCER AND INFECTIOUS DISEASES

3 AROMATASE INHIBITORS FOR BREAST CANCER: EXEMESTANE (AROMASIN), ANASTROZOLE (ARIMIDEX), AND LETROZOLE (FEMARA) 31
Jie Jack Li

3.1 Introduction 32

3.2 Synthesis of Exemestane 35

3.3 Synthesis of Anastrozole 36

3.4 Synthesis of Letrozole 37

4 QUINOLONE ANTIBIOTICS: LEVOFLOXACIN (LEVAQUIN), MOXIFLOXACIN (AVELOX), GEMIFLOXACIN (FACTIVE), AND GARENOXACIN (T-3811) 39
Chris Limberakis

4.1 Introduction 40

4.2 Levofloxacin 47

4.3 Moxifloxacin 57

4.4 Gemifloxacin 60

4.5 Garenoxacin (T-3811): A Promising Clinical Candidate 64

5 TRIAZOLE ANTIFUNGALS: ITRACONAZOLE (SPORANOX), FLUCONAZOLE (DIFLUCAN), VORICONAZOLE (VFEND), AND FOSFLUCONAZOLE (PRODIF) 71
Andrew S. Bell

5.1 Introduction 72

5.2 Synthesis of Itraconazole 74

5.3 Synthesis of Fluconazole 76

5.4 Synthesis of Voriconazole 77

5.5 Synthesis of Fosfluconazole 80

6 NON-NUCLEOSIDE HIV REVERSE TRANSCRIPTASE INHIBITORS 83
Arthur Harms

6.1 Introduction 84

6.2 Synthesis of Nevirapine 85

6.3 Synthesis of Efavirenz 87

6.4 Synthesis of Delavirdine Mesylate 90

7 NEURAMINIDASE INHIBITORS FOR INFLUENZA: OSELTAMIVIR PHOSPHATE (TAMIFLU) AND ZANAMIVIR (RELENZA) 95
Douglas S. Johnson and Jie Jack Li

7.1 Introduction 95

7.1.1 Relenza 97

7.1.2 Tamiflu 97

7.2 Synthesis of Oseltamivir Phosphate (Tamiflu) 99

7.3 Synthesis of Zanamivir (Relenza) 110

II CARDIOVASCULAR AND METABOLIC DISEASES

8 PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR (PPAR) AGONISTS FOR TYPE 2 DIABETES 117
Jin Li

8.1 Introduction 117

8.2 Synthesis of Rosiglitazone 121

8.3 Synthesis of Pioglitazone 122

8.4 Synthesis of Muraglitazar 124

9 ANGIOTENSIN AT1 ANTAGONISTS FOR HYPERTENSION 129
Larry Yet

9.1 Introduction 130

9.2 Losartan Potassium 132

9.3 Valsartan 134

9.4 Irbesartan 135

9.5 Candesartan Cilexetil 136

9.6 Olmesartan Medoxomil 137

9.7 Eprosartan Mesylate 138

9.8 Telmisartan 139

10 LEADING ACE INHIBITORS FOR HYPERTENSION 143
Victor J. Cee and Edward J. Olhava

10.1 Introduction 144

10.2 Synthesis of Enalapril Maleate 146

10.3 Synthesis of Lisinopril 147

10.4 Synthesis of Quinapril 148

10.5 Synthesis of Benazepril 150

10.6 Synthesis of Ramipril 151

10.7 Synthesis of Fosinopril Sodium 154

11 DIHYDROPYRIDINE CALCIUM CHANNEL BLOCKERS FOR HYPERTENSION 159
Daniel P. Christen

11.1 Introduction 160

11.2 Synthesis of Nifedipine (Adalat) 162

11.3 Synthesis of Felodepine (Plendil) 163

11.4 Synthesis of Amlodipine Besylate (Norvasc) 164

11.5 Synthesis of Azelnidipine (Calblock) 165

12 SECOND-GENERATION HMG-CoA REDUCTASE INHIBITORS 169
Jeffrey A. Pfefferkorn

12.1 Introduction 170

12.2 Synthesis of Fluvastatin (Lescol) 171

12.3 Synthesis of Rosuvastatin (Crestor) 174

12.4 Synthesis of Pitavastatin (Livalo) 177

13 CHOLESTEROL ABSORPTION INHIBITORS: EZETIMIBE (ZETIA) 183
Stuart B. Rosenblum

13.1 Introduction 183

13.2 Discovery Path to Ezetimibe 184

13.3 Synthesis of Ezetimibe (Zetia) 187

III CENTRAL NERVOUS SYSTEM DISEASES

14 DUAL SELECTIVE SEROTONIN AND NOREPINEPHRINE REUPTAKE INHIBITORS (SSNRIs) FOR DEPRESSION 199
Marta Pineiro-Nunez

14.1 Introduction 200

14.2 Synthesis of Venlafaxine 203

14.3 Synthesis of Milnacipran 205

14.4 Synthesis of Duloxetine 207

15 GABAA RECEPTOR AGONISTS FOR INSOMNIA: ZOLPIDEM (AMBIEN), ZALEPLON (SONATA), ESZOPICLONE (ESTORRA, LUNESTA), AND INDIPLON 215
Peter R. Guzzo

15.1 Introduction 216

15.2 Synthesis of Zolpidem 217

15.3 Synthesis of Zaleplon 219

15.4 Synthesis of Eszopiclone 220

15.5 Synthesis of Indiplon 221

16 Alpha2Delta LIGANDS: NEURONTIN (GABAPENTIN) AND LYRICA (PREGABALIN) 225
Po-Wai Yuen

16.1 Introduction 225

16.2 Synthesis of Gabapentin 227

16.3 Synthesis of Pregabalin 234

17 APPROVED TREATMENTS FOR ATTENTION DEFICIT HYPERACTIVITY DISORDER: AMPHETAMINE (ADDERALL), METHYLPHENIDATE (RITALIN), AND ATOMOXETINE (STRATERRA) 241
David L. Gray

17.1 Introduction 242

17.2 Synthesis of Amphetamine 244

17.3 Synthesis of Methylphenidate 247

17.4 Synthesis of Atomoxetine 253

References 257

Index 261