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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
401 pages
October 2013
Transition Metal-Catalyzed Couplings in Process Chemistry: Case Studies From the Pharmaceutical Industry (3527332790) cover image


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.
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Table of Contents

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 CH 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 CN Coupling Chemistry as a Means to Achieve a Complicated Molecular Architecture: the AR-A2 Case Story 73
Hans-Jurgen Federsel, Martin Hedberg, Fredrik R. Qvarnstrom, 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 CN 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 SuzukiMiyaura, 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

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Author Information

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.
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“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)

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