Transition Metal-Catalyzed Couplings in Process Chemistry

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
Conclusio