Transition Metal-Catalyzed Couplings in Process ChemistryCase Studies From the Pharmaceutical Industry
Transition metal-catalyzed coupling reactions have a rich history that led to the awarding of the 2010 Nobel Prize in Chemistry to Professors Suzuki, Heck, and Negishi for their pioneering contributions to the field. The coming of age of this active area of research is showcased in this book through case studies in which process chemists from the pharmaceutical industry share their personal experiences developing their own transition metal-catalyzed couplings for the large-scale manufacture of active pharmaceutical ingredients. Authors from Pfizer, Merck, Boehringer-Ingelheim, Novartis, Amgen, GSK, AstraZeneca, and other companies describe the evolution of robust coupling processes from inception through early and late development, including commercial routes where applicable. This book covers a wide range of coupling transformations while capturing the lessons learned from each process. Every case study details the optimization of at least one transition metal-catalyzed coupling while elaborating on issues such as design of experiments, scalability and throughput, product purification, process safety, and waste management. The important issue of metal removal and the different technologies available to accomplish this goal are also addressed. Finally, a section covers novel technologies for cross-coupling with high potential for future applications on a large scale, such as microwave and flow chemistry as well as green cross-couplings performed in water. With Forewords by Stephen L. Buchwald, Massachusetts Institute of Technology, Trevor Laird, Editor of Organic Process Research and Development and Neal G. Anderson, Anderson's Process Solutions LLC.
Foreword 1 XV Foreword 2 XVII Foreword 3 XIX List of Contributors XXIII Introduction XXIX List of Abbreviations XXXIII 1 Copper-Catalyzed Coupling for a Green Process 1 David J. Ager and Johannes G. de Vries 1.1 Introduction 1 1.2 Synthesis of Amino Acid 14 4 1.3 Copper-Catalyzed Cyclization 6 1.4 Sustainability 10 1.5 Summary 10 References 11 2 Experiences with Negishi Couplings on Technical Scale in Early Development 15 Murat Acemoglu, Markus Baenziger, Christoph M. Krell, and Wolfgang Marterer 2.1 Introduction 15 2.2 Synthesis of LBT613 via Pd-Catalyzed Negishi Coupling 16 2.3 Elaboration of a Negishi Coupling in the Synthesis of PDE472 19 2.4 Ni-Catalyzed Negishi Coupling with Catalytic Amounts of ZnCl2 21 2.5 Conclusions 22 References 23 3 Developing Palladium-Catalyzed Arylations of Carbonyl-Activated C–H Bonds 25 Carl A. Busacca and Chris H. Senanayake 3.1 Introduction 25 3.2 Suzuki Approach to Side Chain Installation 26 3.3 Arylation of Carbonyl-Activated C–H Bonds 30 3.4 Pd Purging from API 36 3.5 Conclusions 37 References 37 4 Development of a Practical Synthesis of Naphthyridone p38 MAP Kinase Inhibitor MK-0913 39 John Y.L. Chung 4.1 Introduction 39 4.2 Medicinal Chemistry Approach to 1 40 4.3 Results and Discussion 42 4.4 Conclusions 54 References 54 5 Practical Synthesis of a Cathepsin S Inhibitor 57 Xiaohu Deng, Neelakandha S. Mani, and Jimmy Liang 5.1 Introduction 57 5.2 Synthetic Strategy 59 5.3 Syntheses of Building Blocks 59 5.4 Sonogashira Coupling and Initial Purification of 1 63 5.5 Salt Selection 65 5.6 Conclusions 70 References 70 6 C–N Coupling Chemistry as a Means to Achieve a Complicated Molecular Architecture: the AR-A2 Case Story 73 Hans-J€urgen Federsel, Martin Hedberg, Fredrik R. Qvarnstr€om, and Wei Tian 6.1 A Novel Chemical Entity 73 6.2 Evaluation of Synthetic Pathways: Finding the Best Route 73 6.3 Enabling C–N Coupling by Defining the Reaction Space 76 6.4 From Synthesis to Process 83 6.5 Concluding Remarks 88 References 88 7 Process Development and Scale-up of PF-03941275, a Novel Antibiotic 91 Kevin E. Henegar and Timothy A. Johnson 7.1 Introduction 91 7.2 Medicinal Chemistry Synthesis of PF-03941275 91 7.3 Synthesis of 5-Bromo-2,4-difluorobenzaldehyde (1) 93 7.4 Synthesis of Amine 3 93 7.5 Miyaura Borylation Reaction 95 7.6 Suzuki–Miyaura Coupling 97 7.7 Barbituric Acid Coupling 101 7.8 Chlorination and API Isolation 101 7.9 Conclusions 104 References 104 8 Development of a Practical Negishi Coupling Process for the Manufacturing of BILB 1941, an HCV Polymerase Inhibitor 105 Bruce Z. Lu, Guisheng Li, Frank Roschangar, Azad Hossain, Rolf Herter, Vittorio Farina, and Chris H. Senanayake 8.1 Introduction and Background 105 8.2 Stille Coupling 107 8.3 Suzuki Coupling 107 8.4 Negishi Coupling 109 8.5 Comparison of Three Coupling Processes 119 References 119 9 Application of a Rhodium-Catalyzed, Asymmetric 1,4-Addition to the Kilogram-Scale Manufacture of a Pharmaceutical Intermediate 121 Alexandra Parker 9.1 Introduction 121 9.2 Early Development 122 9.3 Process Optimization 126 9.4 Process Scale-up 131 9.5 Recent Developments 133 9.6 Conclusions 133 References 134 10 Copper-Catalyzed C–N Coupling on Large Scale: An Industrial Case Study 135 Arianna Ribecai and Paolo Stabile 10.1 Introduction 135 10.2 Process Development of the C–N Bond Formation 137 10.3 Choice of Catalytic System 140 10.4 Choice of Base: Inorganic Versus Organic 141 10.5 Choice of Solvent 142 10.6 Optimized Conditions for C–N Bond Formation to 1 142 10.7 Purging Residual Copper from 1 143 10.8 Conclusions 144 References 144 11 Development of a Highly Efficient Regio- and Stereoselective Heck Reaction for the Large-Scale Manufacture of an a4b2 NNR Agonist 147 Per Ryberg 11.1 Introduction 147 11.2 Process Optimization 149 11.3 Conclusions 162 References 162 12 Commercial Development of Axitinib (AG-013736): Optimization of a Convergent Pd-Catalyzed Coupling Assembly and Solid Form Challenges 165 Robert A. Singer 12.1 Introduction 165 12.2 First-Generation Synthesis of Axitinib 165 12.3 Early Process Research and Development 167 12.4 Commercial Route Development 169 12.5 Conclusions 178 References 179 13 Large-Scale Sonogashira Coupling for the Synthesis of an mGluR5 Negative Allosteric Modulator 181 Jeffrey B. Sperry, Roger M. Farr, Mousumi Ghosh, and Karen Sutherland 13.1 Introduction 181 13.2 Background 181 13.3 Process Development of the Sonogashira Coupling 183 13.4 Large-Scale Sonogashira Coupling and API Purification 186 13.5 Conclusions 187 References 188 14 Palladium-Catalyzed Bisallylation of Erythromycin Derivatives 189 Xiaowen Peng, Guoqiang Wang, and Datong Tang 14.1 Introduction 189 14.2 Discovery of 6,11-O,O-Bisallylation of Erythromycin Derivatives 192 14.3 Process Development of 6,11-O,O-Bisallylation of Erythromycin Derivatives 195 14.4 Discovery and Optimization of 3,6-Bicyclolides 199 14.5 Conclusions 200 References 200 15 Route Selection and Process Development for the Vanilloid Receptor-1 Antagonist AMG 517 201 Oliver R. Thiel and Jason S. Tedrow 15.1 Introduction 201 15.2 Retrosynthesis and Medicinal Chemistry Route 202 15.3 Optimization of Medicinal Chemistry Route 204 15.4 Identification of the Process Chemistry Route 207 15.5 Optimization of the Suzuki–Miyaura Reaction 208 15.6 Postcampaign Improvements 213 15.7 Summary 214 References 215 16 Transition Metal-Catalyzed Coupling Reactions in the Synthesis of Taranabant: from Inception to Pilot Implementation 217 Debra J. Wallace 16.1 Introduction 217 16.2 Development of Pd-Catalyzed Cyanations 217 16.3 Development of Pd-Catalyzed Amidation Reactions 224 16.4 Conclusions 230 References 230 17 Ring-Closing Metathesis in the Large-Scale Synthesis of SB-462795 233 Huan Wang 17.1 Background 233 17.2 The RCM Disconnection 233 17.3 The RCM of Diene 5 239 References 250 18 Development of Migita Couplings for the Manufacture of a 5-Lipoxygenase Inhibitor 253 Weiling Cai, Brian Chekal, David Damon, Danny LaFrance, Kyle Leeman, Carlos Mojica, Andrew Palm, Michael St. Pierre, Janice Sieser, Karen Sutherland, Rajappa Vaidyanathan, John Van Alsten, Brian Vanderplas, Carrie Wager, Gerald Weisenburger, Greg Withbroe, and Shu Yu 18.1 Introduction 253 18.2 Evaluation of the Sulfur Source for Initial Migita Coupling 254 18.3 Selection of Metal Catalyst and Coupling Partners 255 18.4 Development of a One-Pot, Two-Migita Coupling Process 256 18.5 Crystallization of 1 with Polymorph Control 262 18.6 Final Commercial Process on Multikilogram Scale 263 18.7 Conclusions 265 References 265 19 Preparation of 4-Allylisoindoline via a Kumada Coupling with Allylmagnesium Chloride 267 Michael J. Zacuto 19.1 Introduction 267 19.2 Kumada Coupling of 4-Bromoisoindoline 268 19.3 Workup 273 19.4 Isolation 275 19.5 Conclusions 276 References 276 20 Microwave Heating and Continuous-Flow Processing as Tools for Metal-Catalyzed Couplings: Palladium-Catalyzed Suzuki–Miyaura, Heck, and Alkoxycarbonylation Reactions 279 Nicholas E. Leadbeater 20.1 Introduction 279 20.2 Coupling Reactions Performed Using Microwave Heating or Continuous-Flow Processing 281 20.3 Conclusions 294 References 295 21 Applying the Hydrophobic Effect to Transition Metal-Catalyzed Couplings in Water at Room Temperature 299 Bruce H. Lipshutz 21.1 Introduction: the Hydrophobic Effect under Homogeneous and Heterogeneous Conditions 299 21.2 Micellar Catalysis Using Designer Surfactants 300 21.3 First Generation: PTS 300 21.4 Heck Couplings in Water at rt 302 21.5 Olefin Metathesis Going Green 302 21.6 Adding Ammonia Equivalents onto Aromatic and Heteroaromatic Rings 304 21.7 Couplings with Moisture-Sensitive Organometallics in Water 305 21.8 A New, Third-Generation Surfactant: “Nok” 308 21.9 Summary, Conclusions, and a Look Forward 309 References 311 22 Large-Scale Applications of Transition Metal Removal Techniques in the Manufacture of Pharmaceuticals 313 Javier Magano 22.1 Introduction 313 22.2 Methods that Precipitate or Capture/Extract the Metal while Maintaining the Coupling Product in Solution 316 22.3 Methods that Precipitate the Coupling Product while Purging the Metal to the Filtrates 341 22.4 Miscellaneous Methods 347 22.5 Other Methods for Metal Removal 348 22.6 Conclusions 349 References 350 Index 357
“So, if you have any interest in transition metal-catalyzed cross-coupling reactions this book is for you.” (Organic Process Research & Development Journal, 1 January 2014)
Javier Magano was born in Madrid, Spain. He received a B.S. in organic chemistry from Complutense University in Madrid in 1987 and a M.Sc. degree in chemistry from the University of Michigan in 1990. After working for the oil industry in Spain for several years, he obtained a M.Sc. degree in rubber and polymer science at the Center for Advanced Scientific Research in Madrid. After moving back to the United States, he joined the early process chemistry group at Pfizer in 1998 in Ann Arbor, MI, where he spent nine years developing scalable processes for the preparation of drug candidates. In 2007, he moved to Groton, CT to continue his work as a process chemist and, during this period, he has also worked in the area of biologics for 1.5 years on the preparation of linkers for bioconjugation processes. Javier currently holds a position in the Chemical Technology group at Pfizer, where he is involved in the applications of high-throughput screening to transition metal-catalyzed couplings. His research interests also include the development of catalytic processes that employ non-precious metals in coupling reactions. Joshua R. Dunetz graduated from Haverford College in 2000 with a B.A. in Chemistry after undergraduate research with Professor Karin ?kerfeldt. He received his Ph.D. in Organic Chemistry from MIT in 2005 under the guidance of Professor Rick Danheiser, and then completed postdoctoral studies with Professor William Roush at Scripps Florida. In early 2008, Joshua assumed his current position with Pfizer Chemical R&D in which he develops processes for the GMP manufacture of small molecules on gram to multikilogram scale.
Transition metal-catalyzed coupling reactions have a rich history that led to the awarding of the 2010 Nobel Prize in Chemistry to Professors Suzuki, Heck, and Negishi for their pioneering contributions to the field. The coming of age of this active area of research is showcased in this book through case studies in which process chemists from the pharmaceutical industry share their experiences developing transition metal-catalyzed couplings for the large-scale manufacture of active pharmaceutical ingredients. Authors from Pfizer, Merck, Boehringer-Ingelheim, Novartis, Amgen, GSK, AstraZeneca, and other companies describe the evolution of robust coupling processes from inception through early and late development, including commercial routes where applicable. The book covers a wide range of coupling transformations while capturing the lessons learned from each process. Every case study details at least one transition metal-catalyzed coupling while elaborating on issues such as design of experiments, scalability and throughput, product purification, process safety, and waste management. The important issue of metal removal and the different technologies available to accomplish this goal are also addressed. Finally, a section covers novel technologies for cross-coupling with high potential for future applications on a large scale, such as microwave and flow chemistry as well as green cross-couplings performed in water.
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