Art of Drug Synthesis

Douglas S. Johnson, PHD, is a Research Chemist at Pfizer Global Research and Development. Jie Jack Li, PHD, is a Research Chemist at Pfizer Global Research and Development.

• Foreword xiPreface xiiiContributors xv1 THE ROLE OF MEDICINAL CHEMISTRY IN DRUG DISCOVERY 1John A. Lowe, III1.1 Introduction 11.2 Hurdles in the Drug Discovery Process 21.3 The Tools of Medicinal Chemistry 31.4 The Role of Synthetic Chemistry in Drug Discovery 62 PROCESS RESEARCH: HOW MUCH? HOW SOON? 11Neal G. Anderson2.1 Introduction 112.2 Considerations for Successful Scale-up to Tox Batches and Phase I Material 152.3 Considerations for Phase 2 Material and Beyond 162.4 Summary 26I CANCER AND INFECTIOUS DISEASES3 AROMATASE INHIBITORS FOR BREAST CANCER: EXEMESTANE (AROMASIN), ANASTROZOLE (ARIMIDEX), AND LETROZOLE (FEMARA) 31Jie Jack Li3.1 Introduction 323.2 Synthesis of Exemestane 353.3 Synthesis of Anastrozole 363.4 Synthesis of Letrozole 374 QUINOLONE ANTIBIOTICS: LEVOFLOXACIN (LEVAQUIN), MOXIFLOXACIN (AVELOX), GEMIFLOXACIN (FACTIVE), AND GARENOXACIN (T-3811) 39Chris Limberakis4.1 Introduction 404.2 Levofloxacin 474.3 Moxifloxacin 574.4 Gemifloxacin 604.5 Garenoxacin (T-3811): A Promising Clinical Candidate 645 TRIAZOLE ANTIFUNGALS: ITRACONAZOLE (SPORANOX), FLUCONAZOLE (DIFLUCAN), VORICONAZOLE (VFEND), AND FOSFLUCONAZOLE (PRODIF) 71Andrew S. Bell5.1 Introduction 725.2 Synthesis of Itraconazole 745.3 Synthesis of Fluconazole 765.4 Synthesis of Voriconazole 775.5 Synthesis of Fosfluconazole 806 NON-NUCLEOSIDE HIV REVERSE TRANSCRIPTASE INHIBITORS 83Arthur Harms6.1 Introduction 846.2 Synthesis of Nevirapine 856.3 Synthesis of Efavirenz 876.4 Synthesis of Delavirdine Mesylate 907 NEURAMINIDASE INHIBITORS FOR INFLUENZA: OSELTAMIVIR PHOSPHATE (TAMIFLU) AND ZANAMIVIR (RELENZA) 95Douglas S. Johnson and Jie Jack Li7.1 Introduction 957.1.1 Relenza 977.1.2 Tamiflu 977.2 Synthesis of Oseltamivir Phosphate (Tamiflu) 997.3 Synthesis of Zanamivir (Relenza) 110II CARDIOVASCULAR AND METABOLIC DISEASES8 PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR (PPAR) AGONISTS FOR TYPE 2 DIABETES 117Jin Li8.1 Introduction 1178.2 Synthesis of Rosiglitazone 1218.3 Synthesis of Pioglitazone 1228.4 Synthesis of Muraglitazar 1249 ANGIOTENSIN AT1 ANTAGONISTS FOR HYPERTENSION 129Larry Yet9.1 Introduction 1309.2 Losartan Potassium 1329.3 Valsartan 1349.4 Irbesartan 1359.5 Candesartan Cilexetil 1369.6 Olmesartan Medoxomil 1379.7 Eprosartan Mesylate 1389.8 Telmisartan 13910 LEADING ACE INHIBITORS FOR HYPERTENSION 143Victor J. Cee and Edward J. Olhava10.1 Introduction 14410.2 Synthesis of Enalapril Maleate 14610.3 Synthesis of Lisinopril 14710.4 Synthesis of Quinapril 14810.5 Synthesis of Benazepril 15010.6 Synthesis of Ramipril 15110.7 Synthesis of Fosinopril Sodium 15411 DIHYDROPYRIDINE CALCIUM CHANNEL BLOCKERS FOR HYPERTENSION 159Daniel P. Christen11.1 Introduction 16011.2 Synthesis of Nifedipine (Adalat) 16211.3 Synthesis of Felodepine (Plendil) 16311.4 Synthesis of Amlodipine Besylate (Norvasc) 16411.5 Synthesis of Azelnidipine (Calblock) 16512 SECOND-GENERATION HMG-CoA REDUCTASE INHIBITORS 169Jeffrey A. Pfefferkorn12.1 Introduction 17012.2 Synthesis of Fluvastatin (Lescol) 17112.3 Synthesis of Rosuvastatin (Crestor) 17412.4 Synthesis of Pitavastatin (Livalo) 17713 CHOLESTEROL ABSORPTION INHIBITORS: EZETIMIBE (ZETIA) 183Stuart B. Rosenblum13.1 Introduction 18313.2 Discovery Path to Ezetimibe 18413.3 Synthesis of Ezetimibe (Zetia) 187III CENTRAL NERVOUS SYSTEM DISEASES14 DUAL SELECTIVE SEROTONIN AND NOREPINEPHRINE REUPTAKE INHIBITORS (SSNRIs) FOR DEPRESSION 199Marta Pineiro-Nunez14.1 Introduction 20014.2 Synthesis of Venlafaxine 20314.3 Synthesis of Milnacipran 20514.4 Synthesis of Duloxetine 20715 GABAA RECEPTOR AGONISTS FOR INSOMNIA: ZOLPIDEM (AMBIEN), ZALEPLON (SONATA), ESZOPICLONE (ESTORRA, LUNESTA), AND INDIPLON 215Peter R. Guzzo15.1 Introduction 21615.2 Synthesis of Zolpidem 21715.3 Synthesis of Zaleplon 21915.4 Synthesis of Eszopiclone 22015.5 Synthesis of Indiplon 22116 Alpha2Delta LIGANDS: NEURONTIN (GABAPENTIN) AND LYRICA (PREGABALIN) 225Po-Wai Yuen16.1 Introduction 22516.2 Synthesis of Gabapentin 22716.3 Synthesis of Pregabalin 23417 APPROVED TREATMENTS FOR ATTENTION DEFICIT HYPERACTIVITY DISORDER: AMPHETAMINE (ADDERALL), METHYLPHENIDATE (RITALIN), AND ATOMOXETINE (STRATERRA) 241David L. Gray17.1 Introduction 24217.2 Synthesis of Amphetamine 24417.3 Synthesis of Methylphenidate 24717.4 Synthesis of Atomoxetine 253References 257Index 261

“This is a most topical and useful short primer on estab1ished drugs and their synthesis.” (American Journal of Therapeutics, June 2009) "The book is very felicitous and closes a gap in the literature by covering the subject of drug development in this particular way." (Angewandte Chemie, June 23, 2008)"This book is a very entertaining read." (ChemMedChem, 2008, 3)"The editors and contriubting authros have certainly provided a most useful book for the medicinal and organic chemistry community." (Journal of Medicinal Chemistry, March 2008)"Where I see the book being very useful is as a starting point for student seminars or discussion groups... Also, it is highly illuminating just to dip into for a browse and to marvel at some of the excellent chemistry that goes on in the pharmaceutical industry." (Chemistry World, January 2008)