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Transition Metal-Catalyzed Couplings in Process Chemistry: Case Studies From the Pharmaceutical Industry

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Transition Metal-Catalyzed Couplings in Process Chemistry: Case Studies From the Pharmaceutical Industry

Javier Magano (Editor), Joshua R. Dunetz (Editor)

ISBN: 978-3-527-33279-3 September 2013 401 Pages

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Description

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
FOREWORD 2
FOREWORD 3

INTRODUCTION

COPPER-CATALYZED COUPLING FOR A GREEN PROCESS
Introduction
Synthesis 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 PDE472
Ni-Catalyzed Negishi Coupling with Catalytic Amounts of ZnCl2
Conclusions

DEVELOPING PALLADIUM-CATALYZED ARYLATIONS OF CARBONYL-ACTIVATED C -
H BONDS
Introduction
Suzuki Approach to Side Chain Installation
Arylation of Carbonyl-Activated C -
H Bonds
Pd Purging from API
Conclusions

DEVELOPMENT OF A PRACTICAL SYNTHESIS OF NAPHTHYRIDONE P38 MAP KINASE INHIBITOR MK-0913
Introduction
Medicinal Chemistry Approach to 1
Results and Discussion
Conclusions

PRACTICAL SYNTHESIS OF A CATHEPSIN S INHIBITOR
Introduction
Synthetic Strategy
Syntheses of Building Blocks
Sonogashira Coupling and Initial Purification of 1
Salt 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 Process
Concluding 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 Coupling
Negishi 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 Coupling
Large-Scale Sonogashira Coupling and API Purification
Conclusions

PALLADIUM-CATALYZED BISALLYLATION OF ERYTHROMYCIN DERIVATIVES
Introduction
Discovery of 6,11-O,O-Bisallylation of Erythromycin Derivatives
Process 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 IMPLEMENTATION
Introduction
Development of Pd-Catalyzed Cyanations
Development of Pd-Catalyzed Amidation Reactions
Conclusions

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 Partners
Development 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
Introduction
Kumada Coupling of 4-Bromoisoindoline
Workup
Isolation
Conclusions

MICROWAVE 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
Conclusions

APPLYING 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 Rings
Couplings 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 Solution
Methods that Precipitate the Coupling Product while Purging the Metal to the Filtrates
Miscellaneous Methods
Other Methods for Metal Removal
Conclusions

INDEX

“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)