Transition Metal-Catalyzed Couplings in Process Chemistry - Case 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 thisbook 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.

Inhaltsverzeichnis

FOREWORD 1 FOREWORD 2 FOREWORD 3 INTRODUCTION COPPER-CATALYZED COUPLING FOR A GREEN PROCESSIntroductionSynthesis of Amino Acid 14 Copper-Catalyzed Cyclization Sustainability Summary EXPERIENCES WITH NEGISHI COUPLINGS ON TECHNICAL SCALE IN EARLY DEVELOPMENT Introduction Synthesis of LBT613 via Pd-Catalyzed Negishi Coupling Elaboration of a Negishi Coupling in the Synthesis of PDE472Ni-Catalyzed Negishi Coupling with Catalytic Amounts of ZnCl2 Conclusions DEVELOPING PALLADIUM-CATALYZED ARYLATIONS OF CARBONYL-ACTIVATED C - H BONDS IntroductionSuzuki Approach to Side Chain Installation Arylation of Carbonyl-Activated C - H BondsPd Purging from API Conclusions DEVELOPMENT OF A PRACTICAL SYNTHESIS OF NAPHTHYRIDONE P38 MAP KINASE INHIBITOR MK-0913 Introduction Medicinal Chemistry Approach to 1Results and Discussion Conclusions PRACTICAL SYNTHESIS OF A CATHEPSIN S INHIBITOR Introduction Synthetic Strategy Syntheses of Building Blocks Sonogashira Coupling and Initial Purification of 1Salt Selection Conclusions C - N COUPLING CHEMISTRY AS A MEANS TO ACHIEVE A COMPLICATED MOLECULAR ARCHITECTURE: THE AR-A2 CASE STORY A Novel Chemical Entity Evaluation of Synthetic Pathways: Finding the Best Route Enabling C - N Coupling by Defining the Reaction Space From Synthesis to ProcessConcluding Remarks PROCESS DEVELOPMENT AND SCALE-UP OF PF-03941275, A NOVEL ANTIBIOTIC Introduction Medicinal Chemistry Synthesis of PF-03941275 Synthesis of 5-Bromo-2,4-difluorobenzaldehyde (1) Synthesis of Amine 3 Miyaura Borylation Reaction Suzuki - Miyaura Coupling Barbituric Acid Coupling Chlorination and API Isolation Conclusions DEVELOPMENT OF A PRACTICAL NEGISHI COUPLING PROCESS FOR THE MANUFACTURING OF BILB 1941, AN HCV POLYMERASE INHIBITOR Introduction and Background Stille Coupling Suzuki CouplingNegishi Coupling Comparison of Three Coupling Processes APPLICATION OF A RHODIUM-CATALYZED, ASYMMETRIC 1,4-ADDITION TO THE KILOGRAM-SCALE MANUFACTURE OF A PHARMACEUTICAL INTERMEDIATE Introduction Early Development Process Optimization Process Scale-up Recent Developments Conclusions COPPER-CATALYZED C - N COUPLING ON LARGE SCALE: AN INDUSTRIAL CASE STUDY Introduction Process Development of the C - N Bond Formation Choice of Catalytic System Choice of Base: Inorganic Versus Organic Choice of Solvent Optimized Conditions for C - N Bond Formation to 1 Purging Residual Copper from 1 Conclusions DEVELOPMENT OF A HIGHLY EFFICIENT REGIO- AND STEREOSELECTIVE HECK REACTION FOR THE LARGE-SCALE MANUFACTURE OF AN A4B2 NNR AGONIST Introduction Process Optimization Conclusions COMMERCIAL DEVELOPMENT OF AXITINIB (AG-013736): OPTIMIZATION OF A CONVERGENT PD-CATALYZED COUPLING ASSEMBLY AND SOLID FORM CHALLENGES Introduction First-Generation Synthesis of Axitinib Early Process Research and Development Commercial Route Development Conclusions LARGE-SCALE SONOGASHIRA COUPLING FOR THE SYNTHESIS OF AN MGLUR5 NEGATIVE ALLOSTERIC MODULATOR Introduction Background Process Development of the Sonogashira CouplingLarge-Scale Sonogashira Coupling and API Purification Conclusions PALLADIUM-CATALYZED BISALLYLATION OF ERYTHROMYCIN DERIVATIVES Introduction Discovery of 6,11-O,O-Bisallylation of Erythromycin DerivativesProcess Development of 6,11-O,O-Bisallylation of Erythromycin Derivatives Discovery and Optimization of 3,6-Bicyclolides Conclusions ROUTE SELECTION AND PROCESS DEVELOPMENT FOR THE VANILLOID RECEPTOR-1 ANTAGONIST AMG 517 Introduction Retrosynthesis and Medicinal Chemistry Route Optimization of Medicinal Chemistry Route Identification of the Process Chemistry Route Optimization of the Suzuki - Miyaura Reaction Postcampaign Improvements Summary TRANSITION METAL-CATALYZED COUPLING REACTIONS IN THE SYNTHESIS OF TARANABANT: FROM INCEPTION TO PILOT IMPLEMENTATIONIntroduction Development of Pd-Catalyzed Cyanations Development of Pd-Catalyzed Amidation ReactionsConclusions RING-CLOSING METATHESIS IN THE LARGE-SCALE SYNTHESIS OF SB-462795 Background The RCM Disconnection The RCM of Diene 5 DEVELOPMENT OF MIGITA COUPLINGS FOR THE MANUFACTURE OF A 5-LIPOXYGENASE INHIBITOR Introduction Evaluation of the Sulfur Source for Initial Migita Coupling Selection of Metal Catalyst and Coupling PartnersDevelopment of a One-Pot, Two-Migita Coupling Process Crystallization of 1 with Polymorph Control Final Commercial Process on Multikilogram Scale Conclusions PREPARATION OF 4-ALLYLISOINDOLINE VIA A KUMADA COUPLING WITH ALLYLMAGNESIUM CHLORIDE IntroductionKumada Coupling of 4-Bromoisoindoline WorkupIsolation ConclusionsMICROWAVE HEATING AND CONTINUOUS-FLOW PROCESSING AS TOOLS FOR METAL-CATALYZED COUPLINGS: PALLADIUM-CATALYZED SUZUKI - MIYAURA, HECK, AND ALKOXYCARBONYLATION REACTIONS Introduction Coupling Reactions Performed Using Microwave Heating or Continuous-Flow Processing ConclusionsAPPLYING THE HYDROPHOBIC EFFECT TO TRANSITION METAL-CATALYZED COUPLINGS IN WATER AT ROOM TEMPERATURE Introduction: the Hydrophobic Effect under Homogeneous and Heterogeneous Conditions Micellar Catalysis Using Designer Surfactants First Generation: PTS Heck Couplings in Water at rt Olefin Metathesis Going Green Adding Ammonia Equivalents onto Aromatic and Heteroaromatic RingsCouplings with Moisture-Sensitive Organometallics in Water A New, Third-Generation Surfactant: 'Nok' Summary, Conclusions, and a Look Forward LARGE-SCALE APPLICATIONS OF TRANSITION METAL REMOVAL TECHNIQUES IN THE MANUFACTURE OF PHARMACEUTICALS Introduction Methods that Precipitate or Capture/Extract the Metal while Maintaining the Coupling Product in SolutionMethods that Precipitate the Coupling Product while Purging the Metal to the FiltratesMiscellaneous Methods Other Methods for Metal Removal Conclusions INDEX

Über den Autor / die Autorin

Javier Magano received his Bachelor's Degree in organic chemistry from Complutense University in Madrid in 1987 and a Master s Degree in chemistry from the University of Michigan in 1990. After working for the oil industry in Spain for 3 years, he obtained a Master s Degree in rubber and polymer science from the School of Plastics and Rubber at the Center for Advanced Scientific Research in Madrid. In 1995 he moved back to the United States to carry out graduate work at the University of Michigan. In 1998 he joined Pfizer Inc. to work in the Chemical Research & Development group in Ann Arbor, MI, and currently in Groton, CT as senior scientist developing scalable processes for the production of drug candidates.

Joshua R. Dunetz received his B.A. degree in Chemistry from Haverford College in 2000 under the guidance of Professor Karin S. Åkerfeldt and his Ph.D. degree in Organic Chemistry from MIT in 2005 under the direction of Professor Rick L. Danheiser. After graduate school, Joshua conducted postdoctoral studies with Professor William R. Roush at Scripps Florida. In early 2008, Joshua assumed his current position at Pfizer in Groton, CT, with the process development group (Chemical R&D).

Zusammenfassung

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.

Bericht

"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)

Produktdetails

• Autoren: Joshua R. Dunetz, Javier Magano
• Mitarbeit: Joshua Dunetz (Herausgeber), Joshua R. Dunetz (Herausgeber), Javie Magano (Herausgeber), Javier Magano (Herausgeber), R Dunetz (Herausgeber), R Dunetz (Herausgeber)
• Verlag: Wiley-VCH
• Sprache: Englisch, Deutsch
• Produktform: Fester Einband
• Erschienen: 01.09.2013
• EAN: 9783527332793
• ISBN: 978-3-527-33279-3
• Seiten: 401
• Abmessung: 175 mm x 247 mm x 25 mm
• Gewicht: 1010 g
• Illustration: 285 SW-Abb., 43 Tabellen
• Themen: Naturwissenschaften, Medizin, Informatik, Technik > Chemie; Chemie, pharmazeutische industrie, chemistry, Industrial Chemistry, Technische u. Industrielle Chemie, Pharmaceutical & Medicinal Chemistry, Pharmazeutische u. Medizinische Chemie, Methods - Synthesis & Techniques, Organische Chemie / Methoden, Synthesen, Verfahren, PHARMAZEUTISCHE CHEMIE, Industrielle Chemie