Transition Metal-Catalyzed Couplings in Process Chemistry: Case Studies from the Pharmaceutical Industry -- Contents -- Foreword 1 -- Foreword 2 -- Foreword 3 -- List of Contributors -- Introduction -- List of Abbreviations -- 1 Copper-Catalyzed Coupling for a Green Process -- 1.1 Introduction -- 1.2 Synthesis of Amino Acid 14 -- 1.2.1 Asymmetric Hydrogenation Approach -- 1.2.2 Enzymatic Approaches -- 1.3 Copper-Catalyzed Cyclization -- 1.3.1 C-N Bond Formation -- 1.3.2 INDAC (1) Synthesis -- 1.4 Sustainability -- 1.5 Summary -- References -- 2 Experiences with Negishi Couplings on Technical Scale in Early Development -- 2.1 Introduction -- 2.2 Synthesis of LBT613 via Pd-Catalyzed Negishi Coupling -- 2.3 Elaboration of a Negishi Coupling in the Synthesis of PDE472 -- 2.4 Ni-Catalyzed Negishi Coupling with Catalytic Amounts of ZnCl2 -- 2.5 Conclusions -- References -- 3 Developing Palladium-Catalyzed Arylations of Carbonyl-Activated C-H Bonds -- 3.1 Introduction -- 3.2 Suzuki Approach to Side Chain Installation -- 3.3 Arylation of Carbonyl-Activated C-H Bonds -- 3.4 Pd Purging from API -- 3.5 Conclusions -- References -- 4 Development of a Practical Synthesis of Naphthyridone p38 MAP Kinase Inhibitor MK-0913 -- 4.1 Introduction -- 4.2 Medicinal Chemistry Approach to 1 -- 4.3 Results and Discussion -- 4.3.1 ADC Route to 21 -- 4.3.2 Tandem Heck-Lactamization Route to 23 -- 4.3.3 Suzuki-Miyaura Coupling -- 4.3.4 Preparation of Grignard 22 for Endgame Couplings -- 4.3.5 Coupling of Organomagnesium 22 and Naphthyridones 19-21 -- 4.4 Conclusions -- References -- 5 Practical Synthesis of a Cathepsin S Inhibitor -- 5.1 Introduction -- 5.2 Synthetic Strategy -- 5.3 Syntheses of Building Blocks -- 5.4 Sonogashira Coupling and Initial Purification of 1 -- 5.5 Salt Selection -- 5.6 Conclusions -- References.

6 C-N Coupling Chemistry as a Means to Achieve a Complicated Molecular Architecture: the AR-A2 Case Story -- 6.1 A Novel Chemical Entity -- 6.2 Evaluation of Synthetic Pathways: Finding the Best Route -- 6.3 Enabling C-N Coupling by Defining the Reaction Space -- 6.3.1 First Experiences -- 6.3.2 Setbacks and Problem Solutions -- 6.3.3 Scoping Out Key Parameters for Best Reaction Performance -- 6.3.4 Ligand Screening -- 6.3.5 Finding the Best Base -- 6.3.6 Optimizing the Ligand/Metal Ratio -- 6.3.7 Temperature Effect -- 6.3.8 Optimizing the Catalyst Loading -- 6.4 From Synthesis to Process -- 6.4.1 Demonstration on Scale -- 6.4.2 Environmental Performance -- 6.4.3 Impurity Tracking -- 6.5 Concluding Remarks -- References -- 7 Process Development and Scale-up of PF-03941275, a Novel Antibiotic -- 7.1 Introduction -- 7.2 Medicinal Chemistry Synthesis of PF-03941275 -- 7.3 Synthesis of 5-Bromo-2,4-difluorobenzaldehyde (1) -- 7.4 Synthesis of Amine 3 -- 7.5 Miyaura Borylation Reaction -- 7.6 Suzuki-Miyaura Coupling -- 7.7 Barbituric Acid Coupling -- 7.8 Chlorination and API Isolation -- 7.9 Conclusions -- References -- 8 Development of a Practical Negishi Coupling Process for the Manufacturing of BILB 1941, an HCV Polymerase Inhibitor -- 8.1 Introduction and Background -- 8.2 Stille Coupling -- 8.3 Suzuki Coupling -- 8.4 Negishi Coupling -- 8.4.1 Initial Investigation -- 8.4.2 Negishi Coupling Optimization -- 8.4.3 Negishi Coupling Process Scale-up -- 8.5 Comparison of Three Coupling Processes -- References -- 9 Application of a Rhodium-Catalyzed, Asymmetric 1,4-Addition to the Kilogram-Scale Manufacture of a Pharmaceutical Intermediate -- 9.1 Introduction -- 9.2 Early Development -- 9.3 Process Optimization -- 9.3.1 Manufacturability -- 9.3.2 Rhodium Removal -- 9.4 Process Scale-up -- 9.5 Recent Developments -- 9.6 Conclusions -- References.

10 Copper-Catalyzed C-N Coupling on Large Scale: An Industrial Case Study -- 10.1 Introduction -- 10.2 Process Development of the C-N Bond Formation -- 10.3 Choice of Catalytic System -- 10.4 Choice of Base: Inorganic Versus Organic -- 10.5 Choice of Solvent -- 10.6 Optimized Conditions for C-N Bond Formation to 1 -- 10.7 Purging Residual Copper from 1 -- 10.8 Conclusions -- References -- 11 Development of a Highly Efficient Regio- and Stereoselective Heck Reaction for the Large-Scale Manufacture of an α4β2 NNR Agonist -- 11.1 Introduction -- 11.2 Process Optimization -- 11.2.1 Selectivity in the Heck Reaction -- 11.2.2 Identification of Selective Conditions for the Heck Coupling -- 11.2.3 Investigation of the Mechanism of the Heck Step -- 11.2.4 Identification of a Solution to the Pd Mirror Problem -- 11.2.5 Development of a Backup Method for Residual Pd Removal -- 11.2.6 Effect of Water on the Reaction -- 11.2.7 Development of a Semicontinuous Process Based on Catalyst Recycling -- 11.2.8 Application on Large Scale -- 11.3 Conclusions -- References -- 12 Commercial Development of Axitinib (AG-013736): Optimization of a Convergent Pd-Catalyzed Coupling Assembly and Solid Form Challenges -- 12.1 Introduction -- 12.2 First-Generation Synthesis of Axitinib -- 12.3 Early Process Research and Development -- 12.4 Commercial Route Development -- 12.4.1 Development of the Migita Coupling (Step 1) and Iodination (Step 2) -- 12.4.2 Control of Impurities after Iodination through Recrystallization (Step 2R) -- 12.4.3 Development of the Heck Reaction -- 12.4.4 Control of Solid Form -- 12.5 Conclusions -- References -- 13 Large-Scale Sonogashira Coupling for the Synthesis of an mGluR5 Negative Allosteric Modulator -- 13.1 Introduction -- 13.2 Background -- 13.3 Process Development of the Sonogashira Coupling -- 13.3.1 Solvent Screening -- 13.3.2 Catalyst Loading.

13.3.3 Stoichiometry of 2-Ethynylpyridine (6) -- 13.4 Large-Scale Sonogashira Coupling and API Purification -- 13.5 Conclusions -- References -- 14 Palladium-Catalyzed Bisallylation of Erythromycin Derivatives -- 14.1 Introduction -- 14.2 Discovery of 6,11-O,O-Bisallylation of Erythromycin Derivatives -- 14.3 Process Development of 6,11-O,O-Bisallylation of Erythromycin Derivatives -- 14.4 Discovery and Optimization of 3,6-Bicyclolides -- 14.5 Conclusions -- References -- 15 Route Selection and Process Development for the Vanilloid Receptor-1 Antagonist AMG 517 -- 15.1 Introduction -- 15.2 Retrosynthesis and Medicinal Chemistry Route -- 15.3 Optimization of Medicinal Chemistry Route -- 15.4 Identification of the Process Chemistry Route -- 15.5 Optimization of the Suzuki-Miyaura Reaction -- 15.6 Postcampaign Improvements -- 15.7 Summary -- References -- 16 Transition Metal-Catalyzed Coupling Reactions in the Synthesis of Taranabant: from Inception to Pilot Implementation -- 16.1 Introduction -- 16.2 Development of Pd-Catalyzed Cyanations -- 16.3 Development of Pd-Catalyzed Amidation Reactions -- 16.4 Conclusions -- References -- 17 Ring-Closing Metathesis in the Large-Scale Synthesis of SB-462795 -- 17.1 Background -- 17.2 The RCM Disconnection -- 17.2.1 Synthesis of the Azepanone Core: Amino Alcohols 2 and 3 -- 17.2.2 Comparison of the Two RCM Reactions -- 17.3 The RCM of Diene 5 -- 17.3.1 General Considerations: Solvent, Catalyst, and Temperature -- 17.3.2 Impact of Impurities in Diene 5 -- 17.3.3 Large-Scale Performance -- References -- 18 Development of Migita Couplings for the Manufacture of a 5-Lipoxygenase Inhibitor -- 18.1 Introduction -- 18.2 Evaluation of the Sulfur Source for Initial Migita Coupling -- 18.3 Selection of Metal Catalyst and Coupling Partners -- 18.4 Development of a One-Pot, Two-Migita Coupling Process.

18.5 Crystallization of 1 with Polymorph Control -- 18.6 Final Commercial Process on Multikilogram Scale -- 18.7 Conclusions -- References -- 19 Preparation of 4-Allylisoindoline via a Kumada Coupling with Allylmagnesium Chloride -- 19.1 Introduction -- 19.2 Kumada Coupling of 4-Bromoisoindoline -- 19.3 Workup -- 19.4 Isolation -- 19.5 Conclusions -- References -- 20 Microwave Heating and Continuous-Flow Processing as Tools for Metal-Catalyzed Couplings: Palladium-Catalyzed Suzuki-Miyaura, Heck, and Alkoxycarbonylation Reactions -- 20.1 Introduction -- 20.1.1 Microwave Heating in Preparative Chemistry -- 20.1.2 Continuous-Flow Processing in Preparative Chemistry -- 20.2 Coupling Reactions Performed Using Microwave Heating or Continuous-Flow Processing -- 20.2.1 Suzuki-Miyaura and Heck Reactions -- 20.2.1.1 Batch Microwave Heating for Suzuki-Miyaura and Heck Couplings -- 20.2.1.2 Continuous-Flow Processing for Suzuki-Miyaura and Heck Couplings -- 20.2.2 Alkoxycarbonylation Reactions -- 20.2.2.1 Use of Batch Microwave Heating for Alkoxycarbonylation Reactions -- 20.2.2.2 Continuous-Flow Processing for Alkoxycarbonylation Reactions -- 20.3 Conclusions -- References -- 21 Applying the Hydrophobic Effect to Transition Metal-Catalyzed Couplings in Water at Room Temperature -- 21.1 Introduction: the Hydrophobic Effect under Homogeneous and Heterogeneous Conditions -- 21.2 Micellar Catalysis Using Designer Surfactants -- 21.3 First Generation: PTS -- 21.4 Heck Couplings in Water at rt -- 21.5 Olefin Metathesis Going Green -- 21.6 Adding Ammonia Equivalents onto Aromatic and Heteroaromatic Rings -- 21.7 Couplings with Moisture-Sensitive Organometallics in Water -- 21.7.1 Negishi-like Couplings -- 21.7.2 Organocopper-Catalyzed Conjugate Additions -- 21.8 A New, Third-Generation Surfactant: "Nok" -- 21.9 Summary, Conclusions, and a Look Forward -- References.

22 Large-Scale Applications of Transition Metal Removal Techniques in the Manufacture of Pharmaceuticals.