Transition Metal-Catalyzed Couplings in Process Chemistry E-Book

• Herausgeber: Wiley-VCH
• Kategorie: Fachliteratur
• Sprache: Englisch

Seitenzahl: 599

Veröffentlichungsjahr: 2013

Beschreibung

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.

Leseprobe

Contents

Cover

Related Titles

Title Page

Copyright

Foreword 1

Foreword 2

Foreword 3

List of Contributors

Introduction

List of Abbreviations

Chapter 1: Copper-Catalyzed Coupling for a Green Process

1.1 Introduction

1.2 Synthesis of Amino Acid 14

1.3 Copper-Catalyzed Cyclization

1.4 Sustainability

1.5 Summary

Acknowledgments

References

Chapter 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

Chapter 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

Chapter 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

4.4 Conclusions

References

Chapter 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

Acknowledgments

References

Chapter 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

6.4 From Synthesis to Process

6.5 Concluding Remarks

References

Chapter 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

Acknowledgments

References

Chapter 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

8.5 Comparison of Three Coupling Processes

References

Chapter 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

9.4 Process Scale-up

9.5 Recent Developments

9.6 Conclusions

Acknowledgments

References

Chapter 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

Chapter 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

11.3 Conclusions

Acknowledgments

References

Chapter 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

12.5 Conclusions

Acknowledgments

References

Chapter 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

13.4 Large-Scale Sonogashira Coupling and API Purification

13.5 Conclusions

Acknowledgments

References

Chapter 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

Acknowledgments

References

Chapter 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

Acknowledgments

References

Chapter 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

Chapter 17: Ring-Closing Metathesis in the Large-Scale Synthesis of SB-462795

17.1 Background

17.2 The RCM Disconnection

17.3 The RCM of Diene 5

Acknowledgments

References

Chapter 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

Acknowledgments

References

Chapter 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

Acknowledgments

References

Chapter 20: Microwave Heating and Continuous-Flow Processing as Tools for Metal-Catalyzed Couplings: Palladium-Catalyzed Suzuki–Miyaura, Heck, and Alkoxycarbonylation Reactions

20.1 Introduction

20.2 Coupling Reactions Performed Using Microwave Heating or Continuous-Flow Processing

20.3 Conclusions

Acknowledgments

References

Chapter 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

21.8 A New, Third-Generation Surfactant: “Nok”

21.9 Summary, Conclusions, and a Look Forward

References

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

22.1 Introduction

22.2 Methods that Precipitate or Capture/Extract the Metal while Maintaining the Coupling Product in Solution

22.3 Methods that Precipitate the Coupling Product while Purging the Metal to the Filtrates

22.4 Miscellaneous Methods

22.5 Other Methods for Metal Removal

22.6 Conclusions

Acknowledgments

References

Index

Related Titles

de Meijere, A., Bräse, S., Oestreich, M. (eds.)

Metal Catalyzed Cross-Coupling Reactions and More

2014

ISBN: 978-3-527-33154-3

Zaragoza Dörwald, F.

Lead Optimization for Medicinal Chemists

Pharmacokinetic Properties of Functional Groups and Organic Compounds

2012

ISBN: 978-3-527-33226-7

Shioiri, T., Izawa, K., Konoike, T. (eds.)

Pharmaceutical Process Chemistry

2011

ISBN: 978-3-527-32650-1

Yudin, A. K. (ed.)

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2011

ISBN: 978-3-527-32428-6

Hall, D. G. (ed.)

Boronic Acids

Preparation and Applications in Organic Synthesis, Medicine and Materials

Second, Completely Revised Edition

2011

ISBN: 978-3-527-32598-6

Blaser, H.-U., Federsel, H.-J. (eds.)

Asymmetric Catalysis on Industrial Scale

Challenges, Approaches and Solutions

Second Edition

2010

ISBN: 978-3-527-32489-7

Dunn, P., Wells, A., Williams, M. T. (eds.)

Green Chemistry in the Pharmaceutical Industry

2010

ISBN: 978-3-527-32418-7

Nugent, T. C. (ed.)

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Methods, Developments and Applications

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ISBN: 978-3-527-32509-2

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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Boschstr. 12, 69469 Weinheim, Germany

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Composition Thomson Digital, Noida, India

Cover Design Formgeber, Eppelheim

Print ISBN: 978-3-527-33279-3

ePDF ISBN: 978-3-527-65893-0

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oBook ISBN: 978-3-527-65890-9

To Kari, Ana, and Sonia, for their love and support. And to my parents, for their gift of a good education.

– Javier Magano

For Cynthia, for Caitlin.

– Joshua R. Dunetz

Foreword 1

The ever-increasing impact of transition metal catalysis on organic synthesis can be seen in our day-to-day reading of the top chemistry journals. The Nobel Prizes to Sharpless, Noyori, and Knowles (2001), Schrock, Grubbs, and Chauvin (2005), and Heck, Suzuki, and Negishi (2010) further highlighted the importance of catalytic processes in everyday synthetic chemistry. As the methodology matures, its application on larger scale in the pharmaceutical industry is investigated at an increasing rate. Key to success in this endeavor is the development of reliable and cost-effective protocols. Each example of the use of a given technique demonstrated on a large scale gives industrial chemists increased confidence about employing it in their own work in pharmaceutical process chemistry and manufacturing settings.

Catalytic chemistry as practiced today offers synthetic chemists a wide array of different approaches to effect the same bond disconnection. As can be seen in many of the examples described in this book, the synthetic route is something that evolves over time. Beginning with the medicinal chemistry route, process chemists look for improvements in terms of safety, yield, robustness, and, ultimately, cost. Even when the identities of the basic steps that will be utilized become clear, a significant amount of work remains. This is a result of the tremendous number of different catalysts, ligands, and reaction conditions that have been developed to accomplish almost any important transformation. Thus, a standard aspect of the synthetic chemists approach has been to screen a series of different reaction parameters in order to arrive at the optimal reaction conditions. The calculus of deciding, for example, which catalyst to utilize in a carbon–carbon cross-coupling reaction can be quite complex. In addition to the efficiency of the catalyst (in terms of both yield and volumetric productivity), the cost and availability of the ligand need to be considered. Moreover, the use of less expensive metals such as nickel, iron, or copper, rather than palladium, is often explored. In addition, there may be a benefit to using a simpler ligand and an aryl bromide (typically more expensive), rather than a more complex one that allows one to use an aryl chloride coupling partner. Superimposed on this is whether patent considerations limit the use of any given technology and, if so, how onerous are the licensing terms.

From the perspective of one who develops new catalysts and synthetic methods, an examination of case studies, such as the ones in this book, is most enlightening. Issues that are often not considered in depth in academic circles (e.g., the need to employ cryogenic conditions, the concentration of reagents, particularly avoiding high dilution reactions, and problems with reaction workup on scale) may hold the key to whether a given process might be applicable in the final manufacturing route.

It is clear that catalytic methods will have an ever more important role in the manufacturing of fine chemicals. Both societal and economic pressures will place an increasing emphasis on greener processes. In order to achieve success, the advent of new and more efficient catalysts and synthetic methods will be required. The lessons presented in this book will be invaluable to synthetic chemists working to develop more efficient processes. Specifically, chemists should make an effort to test their new reactions on increasingly complex substrates, particularly on heterocycle-containing ones. For it is here where their methods will have the greatest impact on the “real-world” practice of synthetic chemistry.

Stephen L. Buchwald

Camille Dreyfus Professor of Chemistry

Massachusetts Institute of Technology

Foreword 2

Industrial process chemists often rely on academic discoveries of new chemical reactions, catalysts, or ligands when designing novel synthetic routes to complex target molecules such as pharmaceuticals. The best chemistry is quickly taken up by industry and used in manufacturing processes, none more so than transition metal-catalyzed coupling reactions, which have proved so versatile in synthetic chemistry over the past 20 years. Many of these reactions have been named after their inventors, some of whom have been awarded the Nobel Prize for their discoveries and for their outstanding work.

A negative aspect of transition metal-catalyzed couplings for the process chemist is that the catalysts and ligands can be expensive and have the potential to increase process costs. So, for efficient manufacture of pharmaceuticals, the process chemist not only has to focus on obtaining a high yield but also has to study the reaction conditions in detail and examine catalyst turnover number and frequency, and in some cases catalyst/ligand recycling and reuse. Understanding the complex mechanism of these reactions leads to better process control and batch-to-batch consistency as well as process robustness for large-scale operation.

Many transition metal-catalyzed couplings can be adversely affected by impurities in raw materials or solvents and lack of reproducibility can sometimes ensue. The temptation to abandon this chemistry and find something more reproducible should be avoided since a detailed and painstaking study of the effect of small amounts of process impurities on catalyst performance usually results in an efficient and robust process – perseverance pays off! Understanding the detailed interactions, mechanisms, side reactions, and so on is part of the fascination of process chemistry.

Process chemists are expert at examining the effect of changing reaction parameters on yield and product quality; these days statistical methods of optimization such as design of experiments and principal component analysis (still surprisingly not taught in many university chemistry departments) are widely used to maximize yield, minimize impurity formation, and optimize space–time yield (a useful measure of process throughput) to produce an efficient, scalable, and robust process.

Transition metal-catalyzed couplings can also present unusual difficulties for the process chemist with regard to product workup and isolation, since the often toxic and usually homogeneous catalyst needs to be removed from the pharmaceutical product to ppm levels. Transition metals are notorious for liking to complex with the type of molecules used in the pharmaceutical industry, and special technologies and/or novel reagents need to be used in the workup and isolation strategies. Detailed crystallization studies may also be required to produce products within specification.

In the case studies presented in this unique book, the chapter authors provide fascinating stories of the innovative process research and development needed to convert a transition metal-catalyzed coupling reaction into an economic and robust manufacturing process for the manufacture of kilograms or even tons of complex products in high purity. The trials and tribulations are described for all to see. The editors and chapter authors are to be congratulated on producing an outstanding work that should be of value not only to process chemists but also to those teaching industrial applications of academic discoveries.

Trevor Laird

Scientific Update LLP

Editor, Organic Process Research and Development

Foreword 3

Selecting metals and designing ligands for transformations in organic chemistry, mostly hydrogenations and couplings, were largely academic pursuits for several decades. As these reactions became increasingly popular, chemists in industry applied them to the synthesis of many drug candidates. The value of transition metal-catalyzed cross-couplings was evident in the pharmaceutical industry since the 1990s with the manufacturing of the family of sartans, antihypertensive agents.1 The power of transition metal-catalyzed couplings was recognized with the Nobel Prize awarded in 2010 to Professors Heck, Negishi, and Suzuki.

Transition metal-catalyzed couplings are more complicated to optimize than many organic reactions, especially for researchers in industrial process R&D. On scale, the charges of expensive transition metals and ligands are minimized, as the benefits of any increased selectivity from the catalyst must be balanced with the overall contribution to the cost of goods and with any difficulties encountered during workup and isolation. On scale, the transition metals charged may be recovered and reused. The amount of water in a process often must be controlled, as water can activate or deactivate reactions and produce impurities such as those from protodeboronation in Suzuki couplings. Starting materials, for example, halides or sulfonates, may be chosen to promote reactivity and decrease excess charges needed; starting materials may also be selected to mitigate reactivity or minimize the formation of by-products, such as those from olefin migration. Processes must be well understood both to avoid the introduction of inhibitors and to control the generation of inhibitors, thus minimizing the charges of metal and ligands and making operations more rugged. Some transition metal-catalyzed reactions are driven by equilibrium, necessitating the development of practical workups to quench reactive conditions; simply pouring a reaction mixture onto a column of silica gel as is often done in the laboratory may be ineffective on scale. Last but not least, removing the metals to control the quality of the product can influence the workup and isolation of the product. These considerations are discussed in this book.

Many of the investigations in these chapters were oriented toward preparing tens to hundreds of kilograms of products from transition metal-catalyzed couplings. In the case studies, critical considerations ranged from selection of routes and starting materials to reducing cycle times on scale. Details of some manufacturing processes are also divulged. Routinely conducting processes on scale is the culmination of many efforts and demonstrates the thorough understanding of the process chemist and engineer.

In addition to the case studies in these chapters, two valuable chapters from academia are included. The chapter from Professor Leadbeater describes conditions using both microwave heating and continuous operations, which can be useful for making larger amounts of material with minimal process development. The chapter from Professor Lipshutz, recipient of a US Presidential Green Chemistry Award in 2011, describes the use of emulsions for running moisture-sensitive reactions in largely aqueous media. This area will also be fruitful for future transition metal-catalyzed scale-ups.

Cost considerations will become even more crucial to process development in industry. Environmental and toxicity considerations may make the selection of some solvents and transition metals less attractive, and these will affect the cost of goods and influence process development. The availability of some transition metals may be affected by international politics, resulting in increased costs. We will probably see the increased use of catalysts containing less expensive transition metals, perhaps doped with small amounts of other metals; examples might be iron catalysts containing palladium or copper [3,4]. With the use of different transition metals, different ligands will likely be designed. Extremely small charges of transition metals and ligands can be effective [5], making the recovery of metals no longer economical [6]. Thorough understanding will continue to be critical for developing rugged catalytic processes.

Javier Magano and Joshua Dunetz put a huge amount of work into their 2011 review “Large-scale applications of transition metal-catalyzed couplings for the synthesis of pharmaceuticals” [7]. Therein, they described details of the reaction sequences, workup conditions used to control the levels of residual metals, and critical analyses of the advantages and disadvantages of such processes run on scale. These considerations are evident in this book too, as Javier and Josh have extended the analyses for developing practical processes to scale up transition metal-catalyzed reactions. This book will also be important in the continuing evolution of chemical processes. I am sure that this valuable book will stimulate many thoughts for those involved in process R&D of transition metal-catalyzed processes.

Neal G. Anderson

Anderson's Process Solutions LLC

Author of “Practical Process Research & Development – A Guide for Organic Chemists”

Note

1. The “sartan” family of drugs is widely prescribed to treat hypertension. Losartan potassium was marketed in 1995, and at least five other antihypertensive agents with ortho -substituted, unsymmetrical biaryl moieties have been marketed since then [1]. Many of these APIs could be manufactured by reaction of amines with the commercially available 4′-(bromomethyl)biphenyl-2-carbonitrile, which can be derived by bromination of o -tolylbenzonitrile (OTBN). A group from Catalytica described Ni- and Pd-catalyzed preparations of OTBN using inexpensive components [2].

References

1. Yet, L. (2007) Chapter 9: Angiotensin AT1 antagonists for hypertension, in The Art of Drug Synthesis (eds D.S. Johnson and J.J. Li), John Wiley & Sons, Inc., New York, pp 129–141.

2. (a) Miller, J.A. and Farrell, R.P. (1998) Tetrahedron Lett., 39, 6441; (b) Miller, J.A. and Farrell, R.P. (2001) US Patent 6,194,599 (to Catalytica, Inc.).

3. Laird, T. (2009) Org. Process Res. Dev., 13, 823.

4. Buchwald, S.L. and Bolm, C. (2009) Angew. Chem., Int. Ed., 48, 5586.

5. Arvela, R.K., Leadbeater, N.E., Sangi, M.S., Williams, V.A., Granados, P., and Singer, R.D. (2005) J. Org. Chem., 70, 161.

6. For some examples, see Corbet, J.-P. and Mignani F G. (2006) Chem. Rev., 106, 2651.

7. Magano, J. and Dunetz, J.R. (2011) Chem. Rev., 111, 2177.

List of Contributors

Murat Acemoglu

Novartis Pharma

Chemical & Analytical Development

4002 Basel

Switzerland

David J. Ager

DSM Innovative Synthesis B.V.

950 Strickland Road, Suite 103

Raleigh, NC 27615

USA

Markus Baenziger

Novartis Pharma

Chemical & Analytical Development

4002 Basel

Switzerland

Carl A. Busacca

Boehringer Ingelheim Pharmaceuticals, Inc.

Chemical Development

900 Ridgebury Road

Ridgefield, CT 06877

USA

Weiling Cai

Pfizer Worldwide Research & Development

Chemical Research and Development

Eastern Point Road

Groton, CT 06340

USA

Brian Chekal

Pfizer Worldwide Research & Development

Chemical Research and Development

Eastern Point Road

Groton, CT 06340

USA

John Y.L. Chung

Merck Research Laboratories

Global Process Chemistry

126 E. Lincoln Ave

Rahway, NJ 07065

USA

David Damon

Pfizer Worldwide Research & Development

Chemical Research and Development

Eastern Point Road

Groton, CT 06340

USA

Xiaohu Deng

Janssen Research & Development LLC

3210 Merryfield Row

San Diego, CA 92121

USA

Johannes G. de Vries

DSM Innovative Synthesis B.V.

6160 MD Geleen

The Netherlands

Joshua R. Dunetz

Pfizer Worldwide Research & Development

Chemical Research & Development

Eastern Point Road

Groton, CT 06340

USA

Vittorio Farina

Boehringer Ingelheim Pharmaceuticals, Inc.

Chemical Development

900 Ridgebury Road

Ridgefield, CT 06877

USA

and

Janssen Pharmaceutica

Department of Pharmaceutical Development and Manufacturing Sciences

Turnhoutseweg 30

2340 Beerse

Belgium

Roger M. Farr

Wyeth Pharmaceuticals

Department of Chemical and Pharmaceutical Development

401 N. Middletown Rd.

Pearl River, NY 10965

USA

Hans-Jürgen Federsel

AstraZeneca

Pharmaceutical Development

Silk Road Business Park

Macclesfield Cheshire SK10 2NA

UK

Mousumi Ghosh

Wyeth Pharmaceuticals

Department of Chemical and Pharmaceutical Development

401 N. Middletown Rd.

Pearl River, NY 10965

USA

Martin Hedberg

SP Technical Research Institute of Sweden

SP Process Development AB

15121 Södertälje

Sweden

Kevin E. Henegar

Pfizer Worldwide Research & Development

Chemical Research & Development

Eastern Point Road

Groton, CT 06340

USA

Rolf Herter

Boehringer Ingelheim Pharmaceuticals, Inc.

Chemical Development

900 Ridgebury Road

Ridgefield, CT 06877

USA

Azad Hossain

Boehringer Ingelheim Pharmaceuticals, Inc.

Chemical Development

900 Ridgebury Road

Ridgefield, CT 06877

USA

Timothy A. Johnson

Pfizer Veterinary Medicine Research & Development

Medicinal Chemistry

333 Portage Street

Kalamazoo, MI 49007

USA

Christoph M. Krell

Novartis Pharma

Chemical & Analytical Development

4002 Basel

Switzerland

Danny LaFrance

Pfizer Worldwide Research & Development

Chemical Research and Development

Eastern Point Road

Groton, CT 06340

USA

Nicholas E. Leadbeater

University of Connecticut

Department of Chemistry

55 North Eagleville Road

Storrs, CT 06269

USA

Kyle Leeman

Pfizer Worldwide Research & Development

Chemical Research and Development

Eastern Point Road

Groton, CT 06340

USA

Guisheng Li

Boehringer Ingelheim Pharmaceuticals, Inc.

Chemical Development

900 Ridgebury Road

Ridgefield, CT 06877

USA

Jimmy Liang

Janssen Research & Development LLC

3210 Merryfield Row

San Diego, CA 92121

USA

Bruce H. Lipshutz

University of California

Department of Chemistry & Biochemistry

Santa Barbara, CA 93106

USA

Bruce Z. Lu

Boehringer Ingelheim Pharmaceuticals, Inc.

Chemical Development

900 Ridgebury Road

Ridgefield, CT 06877

USA

Javier Magano

Pfizer Worldwide Research & Development

Chemical Research & Development

Eastern Point Road

Groton, CT 06340

USA

Neelakandha S. Mani

Janssen Research & Development LLC

3210 Merryfield Row

San Diego, CA 92121

USA

Wolfgang Marterer

Novartis Pharma

Chemical & Analytical Development

4002 Basel

Switzerland

Carlos Mojica

Pfizer Worldwide Research & Development

Chemical Research and Development

Eastern Point Road

Groton, CT 06340

USA

Andrew Palm

Pfizer Worldwide Research & Development

Chemical Research and Development

Eastern Point Road

Groton, CT 06340

USA

Alexandra Parker

AstraZeneca

Pharmaceutical Development

Silk Road Business Park, Charter Way

Macclesfield, Cheshire SK10 2NA

UK

Xiaowen Peng

Enanta Pharmaceuticals, Inc.

Chemistry Department

500 Arsenal Street

Watertown, MA 02472

USA

Fredrik R. Qvarnström

AstraZeneca

Pharmaceutical Development

15185 Södertälje

Sweden

Arianna Ribecai

F.I.S. – Fabbrica Italiana Sintetici S.p.A.

Research & Development

Viale Milano 26

36075 Montecchio Maggiore (VI)

Italy

Frank Roschangar

Boehringer Ingelheim Pharmaceuticals, Inc.

Chemical Development

900 Ridgebury Road

Ridgefield, CT 06877

USA

Per Ryberg

AstraZeneca

Pharmaceutical Development

Chemical Science

Forskargatan 18

15185 Södertälje

Sweden

Chris H. Senanayake

Boehringer Ingelheim Pharmaceuticals, Inc.

Chemical Development

900 Ridgebury Road

Ridgefield, CT 06877

USA

Janice Sieser

Pfizer Worldwide Research & Development

Chemical Research and Development

Eastern Point Road

Groton, CT 06340

USA

Robert A. Singer

Pfizer Global Research & Development

Chemical Research & Development

Eastern Point Road

Groton, CT 06340

USA

Jeffrey B. Sperry

Pfizer Worldwide Research & Development

Chemical Research & Development

Eastern Point Road

Groton, CT 06340

USA

Paolo Stabile

F.I.S. – Fabbrica Italiana Sintetici S.p.A.

Research & Development

Viale Milano 26

36075 Montecchio Maggiore (VI)

Italy

Michael St. Pierre

Pfizer Worldwide Research & Development

Chemical Research and Development

Eastern Point Road

Groton, CT 06340

USA

Karen Sutherland

Pfizer Worldwide Research & Development

Chemical Research and Development

Eastern Point Road

Groton, CT 06340

USA

Datong Tang

Enanta Pharmaceuticals, Inc.

Chemistry Department

500 Arsenal Street

Watertown, MA 02472

USA

Jason S. Tedrow

Amgen

Chemical Process Research and Development

One Amgen Center Drive

Thousand Oaks, CA 91320-1799

USA

Oliver R. Thiel

Amgen

Chemical Process Research and Development

One Amgen Center Drive

Thousand Oaks, CA 91320-1799

USA

Wei Tian

AstraZeneca

Pharmaceutical Development

15185 Södertälje

Sweden

Rajappa Vaidyanathan

Pfizer Worldwide Research & Development

Chemical Research and Development

Eastern Point Road

Groton, CT 06340

USA

John Van Alsten

Pfizer Worldwide Research & Development

Chemical Research and Development

Eastern Point Road

Groton, CT 06340

USA

Brian Vanderplas

Pfizer Worldwide Research & Development

Chemical Research and Development

Eastern Point Road

Groton, CT 06340

USA

Carrie Wager

Pfizer Worldwide Research & Development

Chemical Research and Development

Eastern Point Road

Groton, CT 06340

USA

Debra J. Wallace

Merck Research Laboratories

Global Process Chemistry

Rahway, NJ 07065

USA

Guoqiang Wang

Enanta Pharmaceuticals, Inc.

Chemistry Department

500 Arsenal Street

Watertown, MA 02472

USA

Huan Wang

GlaxoSmithKline

API Chemistry & Analysis

709 Swedeland Road

King of Prussia, PA 19406

USA

Gerald Weisenburger

Pfizer Worldwide Research & Development

Chemical Research and Development

Eastern Point Road

Groton, CT 06340

USA

Greg Withbroe

Pfizer Worldwide Research & Development

Chemical Research and Development

Eastern Point Road

Groton, CT 06340

USA

Shu Yu

Pfizer Worldwide Research & Development

Chemical Research and Development

Eastern Point Road

Groton, CT 06340

USA

Michael J. Zacuto

Merck Research Laboratories

Global Process Chemistry

Rahway, NJ 07065

USA

Introduction

Joshua R. Dunetz and Javier Magano

When faced with life's common maladies, such as the occasional headache, muscle soreness, or fever, you may have reached for a pain reliever such as Advil, Motrin, or Nuprin. Ibuprofen, the active ingredient in these medicines, was discovered by the Boots Pure Drug Company and patented in the 1960s [1]. For several decades, the Boots synthesis would serve as the established method for the industrial manufacture of this pharmaceutical compound (Scheme I.1). This process, which has supplied millions of pounds of ibuprofen throughout the years, comprises six steps and has the disadvantage of generating substantial amounts of industrial waste. Much of the waste stems from an indirect approach to the carboxylic acid moiety through a series of functional group manipulations. From a process safety perspective, this route also suffers from intermediates and reagents containing potentially hazardous, high-energy functional groups such as epoxide 2, oxime 3, and hydroxylamine.

Scheme I.1 Original synthesis of ibuprofen by Boots Company.

In light of the pending patent expiration for ibuprofen in the mid-1980s, the Boots Company teamed with Hoechst Celanese Corporation to develop an improved synthesis of ibuprofen that addresses the inefficiencies of the original route. This joint venture led to the BHC Company that patented a greener, three-step process for the industrial production of ibuprofen (Scheme I.2) [2]. Key to the improved synthesis is a Pd-catalyzed carbonylation as the final step. The reaction of alcohol 5 with carbon monoxide, Pd catalyst, and phosphine ligand in acidic aqueous media (e.g., aq HCl) directly installs the carboxylic acid and avoids the arduous sequence of functional group manipulations from the original synthesis. This innovative application of transition metal catalysis provides a more efficient manufacturing route to ibuprofen, and this achievement was recognized with the 1997 Presidential Green Chemistry Challenge Award [3].

Scheme I.2 Improved synthesis of ibuprofen via Pd-catalyzed carbonylation.

This story of ibuprofen is not unique. The literature contains countless examples in which chemists have implemented transition metal-catalyzed couplings to streamline the synthesis of pharmaceuticals [4]. These coupling technologies are continuously evolving to accommodate the increasing structural complexities of APIs (active pharmaceutical ingredients). Large-scale applications of transition metal catalysis for the manufacture of drug ingredients require processes that are safe, efficient, and reliable. Process chemists are also tasked with developing synthetic routes that provide API with very high purity.

This book is not intended as a cursory overview of transition metal-catalyzed couplings. Rather, this book contains the personal accounts of process chemists describing their own development of robust coupling processes for the synthesis of pharmaceuticals. Each case study details the optimization of a coupling reaction while elaborating on issues such as design of experiments, scalability and throughput, product isolation, metal purging, process safety, cost efficiency, waste management, and overall environmental impact. The chapters span a wide range of named coupling reactions: Suzuki–Miyaura, Negishi, Heck, Buchwald–Hartwig, Sonogashira, Kumada–Corriu, Tsuji–Trost, Migita, and Hayashi–Miyaura. Other case studies discuss the process development of metal-catalyzed cyanations, borylations, enolate arylations, carbonylations, and ring-closing metathesis. Two of the three final chapters cover emerging technologies: the potential for large-scale catalysis using continuous-flow processing and microwave heating, and applications of designer surfactants for green catalysis in aqueous media. The final chapter reviews metal scavengers used for the removal of residual catalyst metals from coupling products on process scale.

In editing this book, we had the privilege of collaborating with talented process chemists from pharmaceutical companies throughout the world, as well as two innovative professors at the forefront of developing creative solutions to process chemistry challenges. The case studies we received are arranged alphabetically with respect to the corresponding author; grouping chapters by reaction would have been problematic as some chapters discuss more than one type of coupling.

We hope you learn as much from this book as we did.

References

1. Nicholson, J.S. and Adams, S.S. (1968) Phenyl propionic acids. US Patent 3,385,886.

2. (a) Elango, V., Murphy, M.A., Smith, B.L., Davenport, K.G., Mott, G.N., Zey, E.G., and Moss, G.L. (1991) Method for producing ibuprofen. US Patent 4,981,995; (b) Lindley, D.D., Curtis, T.A., Ryan, T.R., de la Garza, E.M., Hilton, C.B., and Kenesson, T.M. (1991) Process for the production of 4′-isobutylacetophenone. US Patent 5,068,448.

3.http://www.epa.gov/greenchemistry/pubs/pgcc/winners/gspa97.html.

4. (a) Crawley, M.L. and Trost, B.M. (eds) (2012) Applications of Transition Metal Catalysis in Drug Discovery and Development: An Industrial Perspective, John Wiley & Sons, Inc., Hoboken, NJ; (b) Busacca, C.A., Fandrick, D.R., Song, J.J., and Senanayake, C.H., (2011) Adv. Synth. Catal., 353, 1825; (c) Magano, J. and Dunetz, J.R. (2011) Chem. Rev., 111, 2177.

List of Abbreviations

AcacetylacacacetylacetoneADCacetonedicarboxylateAIBN2,2′-azobis(2-methylpropionitrile)AmamylAmPhosdi-t-butyl(4-dimethylaminophenyl)phosphineAPIactive pharmaceutical ingredient9-BBN9-borabicyclo[3.3.1]nonaneBINAP(1,1′-binaphthalene-2,2′-diyl)bis(diphenylphosphine)Biphen5,5′,6,6′-tetramethyl-3,3′-di-t-butyl-1,1′-biphenyl-2,2′-diolBIPHEP2,2′-bis(diphenylphosphino)-1,1′-biphenylBoct-butyloxycarbonylBTPPt-butylimino-tri(pyrrolidino)phosphoraneBubutylt-BuDavePhos2-di-t-butylphosphino-2′-(N,N-dimethylamino)biphenylcBRIDPdi-t-butyl(2,2-diphenyl-1-methyl-1-cyclopropyl)phosphineCbzcarbobenzyloxyCDI1,1′-carbonyldiimidazole(S,S)-ChiraPHOS(2S,3S)-(−)-bis(diphenylphosphino)butaneCOD1,5-cyclooctadieneCycyclohexyltrans-CyDA(1R,2R)-trans-cyclohexyldiamineCy-JohnPhos2-(dicyclohexylphosphino)biphenyldday1,2-DAP1,2-diaminopropaneDavePhos2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyldbadibenzylideneacetoneDBU1,8-diazabicyclo[5.4.0]undec-7-eneDCE1,2-dichloroethanedcpe1,2-bis(dicyclohexylphosphino)ethanedcpmbis(dicyclohexylphosphino)methaneDIADdiisopropyl azodicarboxylate(S,S)-DIOP(4S,5S)-(+)-O-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane(S,S)-DIPAMP(1S,2S)-(+)-bis[(2-methoxyphenyl)phenylphosphino]ethaneDIPHOS1,2-bis(diphenylphosphino)ethanedippfdi-i-propylphosphinoferroceneDIPTdi-i-propyl tartrateDKRdynamic kinetic resolutionDLSdynamic light scatteringDMAcN,N-dimethylacetamideDMAP4-dimethylaminopyridineDMCdimethyl carbonatetrans-DMCyDA(1R,2R)-N,N′-dimethylcyclohexyldiamineDME1,2-dimethoxyethaneDMEDAN,N′-dimethylethylenediamineDMFN,N-dimethylformamideDMGN,N-dimethylglycineDMSOdimethyl sulfoxideDoEdesign of experimentsDPEPhosbis[(2-diphenylphosphino)phenyl]etherdppbdiphenylphosphinobutanedppediphenylphosphinoethanedppfdiphenylphosphinoferrocenedppmdiphenylphosphinomethanedpppdiphenylphosphinopropanedtbpfdi-t-butylphosphinoferroceneEDTAethylenediaminetetraacetic acideeenantiomeric excessEtethylFDAFood and Drug AdministrationFT-IRFourier transform infrared spectroscopyfur2-furfurylGCgas chromatographyGMPgood manufacturing practicehhourHATU1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxid hexafluorophosphateHCVhepatitis C virusHDPEhigh-density polyethyleneHexhexylHIVhuman immunodeficiency virusHMBCheteronuclear multiple-bond correlationHMDShexamethyldisilazideHOAt1-hydroxy-7-azabenzotriazoleHPLChigh-performance liquid chromatographyHRMShigh-resolution mass spectrometryHSThydroboration–Suzuki–TamaoHTEhigh-throughput experimentationIMes·HCl1,3-bis(2,4,6-trimethylphenyl)imidazolium chlorideIMSindustrial methylated spiritsINDAC(S)-2-indoline carboxylic acidIPA2-propanolIRinfraredJohnPhos(2-biphenyl)di-t-butylphosphineKFKarl FischerLligand or litersLCliquid chromatographyLOXlipoxygenaseMAPmitogen-activated proteinmCBAm-chlorobenzoic acidmCPBAm-chloroperbenzoic acidMemethyl(R,R)-MeDuPhos(–)-1,2-bis[(2R,5R)-2,5-dimethylphospholano]benzeneMEKmethyl ethyl ketoneMePhosdicyclohexylphosphino-2′-methylbiphenylMesmesityl2-MeTHF2-methyltetrahydrofuran(R,R)-Me-ULLUPHOS(–)-1,2-bis[(2R,5R)-2,5-dimethylphospholano]benzeneMIBKmethyl isobutyl ketoneminminuteMPmacroporous polystyreneMsmethanesulfonylMSmass spectrometryMSZLmetastable zone limitMTBEmethyl t-butyl ethermvmean volumeMVKmethyl vinyl ketoneMWmicrowaveNAMnegative allosteric modulatorNBSN-bromosuccinimideNCEnew chemical entityNCSN-chlorosuccinimideNDnot detectedNIXANTPHOS4,6-bis(diphenylphosphino)phenoxazinenmnanometerNMMN-methylmorpholineNMP1-methyl-2-pyrrolidoneNMRnuclear magnetic resonanceNNRTInon-nucleoside reverse transcription inhibitorNOEnuclear Overhauser effectNpneopentylNunucleophilePALphenylalanine ammonia lyasePCAprincipal component analysisPDEphosphodiesterasePEEKpolyether ether ketonePEGpolyethylene glycolPeppsipyridine-enhanced precatalyst preparation, stabilization, and initiationPhenphenanthrolinePLSprojection to latent structurePMBp-methoxybenzylPMIprocess mass intensityppmparts per millionPrpropylPSpolystyrenePTFEpolytetrafluoroethylenePTS(polyoxoethanyl-α-tocopheryl)sebacatePXRDpowder X-ray diffractionPyBOP(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphateQPhos1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferroceneQPTquinoline pyrimidine trioneRArheumatoid arthritisRCCrenal cell carcinomaRCMring-closing metathesisRSMresponse surface methodologyrtroom temperatureRuCl2[(S)-xylbinap][(S)-daipen]dichloro{(S)-(−)-2,2′-bis[di(3,5-xylyl)phosphino]-1,1′-binaphthyl}[(2S)-(+)-1,1-bis(4-methoxyphenyl)-3-methyl-1,2-butanediamine]ruthenium(II)RuPhos2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenylSFCsupercritical fluid chromatographySPhos2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenylTBABtetra-n-butylammonium bromideTBACtetra-n-butylammonium chlorideTBSt-butyldimethylsilylTEMtransmission electron microscopyTftrifluoromethylsulfonylTFAtrifluoroacetic acidTHFtetrahydrofuranTHPtetrahydropyranTIPStri-i-propylsilyl(R)-TMBTP2,2′,5,5′-tetramethyl-4,4′-bis(diphenylphosphino)-3,3′-bithiopheneTMEDAtetramethylethylenediamineTMG1,1,3,3-tetramethylguanidineTMHD2,2′,6,6′-tetramethylheptane-2,5-dioneTMStrimethylsilylTMTtrimercaptotriazinetoltolylTrixiePhos(±)-2-di-t-butylphosphino-1,1′-binaphthylTRPtransient receptor potentialTstoluenesulfonylVEGFvascular endothelial growth factorVRvanilloid receptorwtweightXantphos4,5-bis(diphenylphosphino)-9,9-dimethylxantheneXPhos2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenylXRFX-ray fluorescence

1

Copper-Catalyzed Coupling for a Green Process

David J. Ager and Johannes G. de Vries

1.1 Introduction

Modern processes are trending toward green and sustainable chemistries. The incorporation of catalysis in synthesis is one of the principles of green chemistry [1]; the use of a stoichiometric reagent can then be avoided and the result of this substitution is often a reduction of cost. This chapter illustrates these concepts with a Cu-catalyzed cyclization reaction.

When looking at routes to new targets, or a new route to an old target, luck can play an important role. Familiar technology helps not only in the planning stage but also in the implementation of the process, as timelines can be reduced with little or no learning curve. An understanding of the technology reduces the risk of failure, especially if a large number of examples are known. Of course, the luck element can be reduced if many technologies are accessible, as too many choices can make the selection of a specific process difficult [2].

The general concepts for route selection were applied to the synthesis of (S)-2-indoline carboxylic acid (1), commonly called INDAC (Figure 1.1). This compound is a component of angiotensin 1-converting enzyme (ACE) inhibitors indolapril (2) and perindopril (3).

Figure 1.1 Structures of INDAC (1) and ACE inhibitors indolapril (2) and perindopril (3).

A new process was required, as the existing manufacturing route had seven steps and involved a classic resolution with a maximum yield of 50% for this step (Scheme 1.1) [3–6]. The approach was based on a Fisher indole synthesis. To achieve an efficient resolution, some functional group modifications were required that added steps to the synthesis. For example, the indole synthesis gives the ethyl ester 6 that has to be hydrolyzed, while the nitrogen has to be acylated to stop it from interfering in the resolution.

Scheme 1.1 Resolution-based synthesis of INDAC (1).

To increase the efficiency of the synthesis, a number of different strategies can be envisioned for construction of the indole and the chiral center. Indeed, other approaches had already been reported as well as different variations of the route shown in Scheme 1.1. These include classical resolution of the acid 1 [7–11] and enzymatic resolutions of esters derived from 1 [4,12–15]. Another approach uses a ring closure to prepare the five-membered ring in which an aniline displaces an α-chlorocarboxylic acid, in turn derived from an asymmetric reduction of the corresponding α-keto acid with sodium borohydride in the presence of D-proline [16]. The use of a chiral base to perform a kinetic resolution by acylation of a 2-substituted indole has also been reported [17].

Some of the possible retrosynthetic disconnections are shown in Figure 1.2 [18]. In addition, a number of enzyme-based approaches can be used to access the intermediate amino acid 14 (Figure 1.3). The formation of the aryl–nitrogen bond is strategic in a number of these routes, and some of the approaches require that the stereochemical integrity of the amine functionality is retained during the N -arylation step. Other work on the preparation of arylamines suggested that formation of the C–N bond was a viable option, with a number of potential routes to the amino acid precursor 14 also being available [19].

Figure 1.2 Representative examples for the retrosynthetic analysis of INDAC (1).

Figure 1.3 Enzyme-based approaches for the preparation of the amino acid 14.

A rapid entry to INDAC (1) would be to prepare the corresponding indole and then perform an asymmetric reduction. The hydrogenation of 2-substituted indoles has been achieved with Rh in the presence of (R, R)-2,2″-bis[(S)-1-(diphenylphosphino)ethyl]-1,1″-biferrocene ((S, S)-(R, R)-Ph-TRAP, 26) and Cs2CO3 [20]. A 95% yield in 95% ee (by HPLC) was achieved with the ester 24 (Figure 1.4) in IPA, at 60 °C and 500 bar H2, but the substrate/catalyst ratio was 100 : 1, which is not an economical proposition at scale [21]. In an effort to reduce the cost of the ligand, (S)-(+)-(3,5-dioxa-4-phosphacyclohepta[2,1-a;3,4-a ′]dinaphthalen-4-yl)piperidine ((S)-PipPhos, 27) was found to be effective in a Rh catalyst in CH2Cl2 at 40 °C and 25 bar H2, but Cs2CO3 was still required and the ee of the product 25 was only 74% [22].

Figure 1.4 Asymmetric hydrogenation catalysts and structures of substrate and product.

1.2 Synthesis of Amino Acid 14

Again, Figures 1.2 and 1.3 illustrate a variety of approaches to the amino acid 14 or a simple derivative. Each approach has its advantages and disadvantages and, for the current application, must be amenable to performing at scale [23,24].

1.2.1 Asymmetric Hydrogenation Approach

There are numerous catalyst and ligand systems available to prepare α-amino acids and derivatives from enamide 17 [25]. Our in-house experience using monodentate phosphoramidites such as 27 (Figure 1.4) and the low cost of these ligands led us to pursue catalysts based on this class of ligands [26–28].

The enamide substrate 17 for the asymmetric hydrogenation can be prepared by an Erlenmeyer or azlactone synthesis (Figure 1.2). This has been used at scale in the preparation of a number of unnatural amino acids [29–31]. The starting material for this is the aldehyde 15. However, the yield of the enamide is usually good rather than excellent. The alternative approach to 17 employs a Heck coupling with the appropriate dehydroalanine 20 (Figure 1.2) [32]. Although Pd is used, the catalyst loading can be reduced to a very small amount so that it is not a major cost contributor to the overall sequence and a ligand is not required [33,34]. The other component for the Heck method is a 1,2-dihalobenzene 19.

The drawback of using an asymmetric hydrogenation is the need for an N -acyl group that then has to be hydrolyzed to provide the desired product 14. This adds steps compared to the enzymatic method finally chosen. Furthermore, the cinnamic acid 23 needed for the enzymatic conversion is readily available.

Although a potential option at the planning stage, the use of serine (12) as the source of chirality (Figure 1.2) was not the subject of an in-depth laboratory study. Competing reactions during the cyclization of 13, such as the elimination of water to form a dehydroalanine derivative, were seen as potential problems.

1.2.2 Enzymatic Approaches

Three enzymatic methods are outlined in Figure 1.3. In addition, there are a number of other alternatives, such as the use of an amidase to hydrolyze an N -acyl group from just one enantiomer of the amino acid. The undesired isomer can be racemized and submitted to the same reaction to increase the overall yield [23,24], and a second enzyme, a racemase, can be introduced to effect the interconversion of the enantiomers in the reaction vessel. The use of a hydantoinase can circumvent this recycle problem as the epimerization can be performed in situ. The hydantoin 21 is obtained by reaction of a phenylacetaldehyde with cyanide and ammonium carbonate (the Bucherer–Bergs reaction [35]). Phenylacetaldehyde derivatives, however, are not as readily available as benzaldehyde derivatives. In addition, phenylacetaldehydes are not particularly stable compounds, which results in low yields during their synthesis as well as in subsequent reactions.

A similar problem exists for the use of an amino acid dehydrogenase; the required α-keto acids 22 are often difficult to access. In addition, these reactions to give the amino acids are in equilibria with a constant of ∼1, so an appropriate amino donor needs to be used to allow the by-product to be removed and drive the reaction to completion [36].

In contrast, the phenylalanine ammonia lyase (PAL) uses a cinnamic acid 23 as the substrate and it is available by a number of methods all employing cheap starting materials [37]. This method became the one of choice to prepare the amino acid 14 [18].

1.3 Copper-Catalyzed Cyclization

The key step was the cyclization of the amino acid 14 to the desired product 1. Some experience had already been obtained for the preparation of anilines from aryl halides (see below).

1.3.1 C–N Bond Formation

The traditional reaction for the conversion of an aryl halide and amines to anilines in the presence of a stoichiometric Cu catalyst at high temperature is the Ullmann reaction [38–42]. The harsh conditions of the Ullmann reaction led to the use of Pd-catalyzed reactions for the coupling of an aryl halide with an amine to form an aniline or N -aryl product [43–45]. One of the major drawbacks of Pd is the price of this metal. As a consequence, applications of catalytic Cu have been investigated and found to be effective for the preparation of N -aryl bonds [40,46–55]. Recent advances have been made that employ a variety of ligands, which allow the amount of Cu to be reduced and lower temperatures used [56,57].

The majority of the work in this area has used aryl iodides, a class of compounds that is more expensive than the corresponding bromides or chlorides. With the less reactive aryl bromides, the expensive base Cs2CO3 is typically required, and the results are often inferior to those seen in the iodide series [58–66] unless the amine is primary [67–69]. However, the use of diphenyl pyrrolidine-2-phosphonate does provide good yields for reaction between secondary amines and aryl bromides [70]. The use of Cu2O has been found to be effective for the N -arylation of a number of simple amides and amines even with aryl chlorides [71], while ionic organic bases, such as tetraalkylammonium and tetraalkylphosphonium carboxylates, have also been advocated with CuI [72].

As N -arylation is a common reaction, we needed to find conditions to allow the use of an aryl bromide or chloride as the substrate (Figure 1.5 and Table 1.1) [73,74]. The initial results with acetylacetone (28a) were not very successful. However, moving to the more lipophilic 2,2′,6,6′-tetramethylheptane-2,5-dione (TMHD, 28b) gave reasonable yields with aryl bromides (entries 1–5). TMHD had been used for Cu-catalyzed aromatic etherifications [75].

Figure 1.5 Ligands investigated for the copper N -arylation reaction.

Table 1.1 Copper-catalyzed amination reactions with 1.3–1.5 equiv amine, 25 mol% ligand, and 1 M concentration of aryl halide (unless otherwise noted) [73]

High-throughput experimentation (HTE) was used to screen the many reaction parameters [76]. We found that the source of the copper was not important and both Cu(I) and Cu(II) salts gave similar results. When moving from Cs2CO3 to K2CO3 to reduce the cost of the base, we observed that more concentrated reactions gave higher yields (Table 1.1, entries 9–12). (This is where luck played a role.) In addition, switching to K2CO3 allowed us to use the inexpensive ligand 28a with better results (entry 10). This concentration effect was also observed with heterocyclic amines, but to a lesser degree (entries 11–12). However, the reactions of aniline and secondary amines were still in need of improvement. Thus, ligands 29a–c and 30a–c were also investigated and the results showed that ligands 30a–c performed better than the other series. However, ortho -substituted aryl bromides and aryl chlorides did not give high yields (entries 6, 13, 20, and 25).

The studies also showed that aminations could be observed in the absence of a transition metal catalyst. These instances occurred when KOt -Bu was used as the base at high temperature and a benzyne mechanism could operate [77,78]. The other instances were when a strong electron-withdrawing group was ortho or para to the bromide so that an SNAr mechanism could account for the results.

These studies showed that aryl bromides could be used in amination reactions and that the cheaper base K2CO3 could replace Cs2CO3 [79]. In addition, other ligands for Cu are still being developed [56], as are alternative bases [80].

1.3.2 INDAC (1) Synthesis

As the halogen in the amino acid substrate 14 is substituted by the amine in the key step, the displaced halide becomes waste. The screening studies, therefore, were limited to the use of Br and Cl as the halogen. Our key to success was the ability to cyclize 14 to 1 without compromising the chirality already set. Arylation of amino acids via Cu catalysis without racemization was already precedented at the time of our study [43,46], whereas racemization in the presence of Pd is well documented [81–83]. Cu-catalyzed ring closures were known with simple amines [48,84–86] for the preparation of N -substituted indoles [87,88].

The initial experiments were performed with β-diketone ligands (see Section 1.3.1) [73]. However, it soon became apparent that a ligand was not required for our amination to proceed, which was consistent with another study on the arylation of amino acids via Cu catalysis [46]. In these cases, the assumption is that the amino acid acts as a ligand [89].

The results of the screening studies are summarized in Table 1.2. The initial experiment with amino acid 14b (X = Br) was run at 100 °C in NMP and 1 was formed in 93% yield with no loss of ee (entry 1). However, a longer reaction time resulted in a lower yield and racemization (entry 2). With less catalyst and a lower temperature, the reaction was essentially complete within 2 h with no loss of enantioselectivity (entry 3).

Table 1.2 Copper-catalyzed conversion of amino acid 14a–b to INDAC (1)

In our new INDAC (1) synthesis, the Cu-catalyzed cyclization follows an enzymatic method to prepare the amino acid 14. To avoid a solvent switch, water was tried as the solvent for the Cu reaction since others have observed that N -arylations could be performed in this solvent [90,91]. The reaction was still fast (2 h) and the stereochemistry was retained (entry 5). Even in the absence of Cu, the desired reaction was observed (entries 6 and 7)! It must be assumed that trace amounts of metal were present in the reaction as a low loading experiment (entry 8) gave excellent results after just 5 h.

With the chloro substrate 14a (entries 10–11), the cyclization reaction is slower, and in this case, no reaction was observed in the absence of Cu (entry 9). The use of 4 mol% of CuCl gave an excellent yield and stereochemical retention after 2 h with K2CO3 as base (entry 12). The ready availability of the chloro-substituted cinnamic acid made this the substrate of choice despite the slower reaction. The copper salts were removed during the aqueous workup [19], using standard methodologies [92].

Analysis of the amination mixture showed the presence of a dimeric compound 31 that was formed by the intermolecular N -arylation of the product 1 with 2-chlorophenylalanine (Figure 1.6) [93].

Figure 1.6 Structure of dimeric impurity from the Cu-catalyzed cyclization.

1.4 Sustainability

As noted in the introduction, sustainable and green chemistry is now playing an important role in synthesis design and implementation. The old synthesis comprising seven steps, which included a resolution, has now been replaced by a two-step process where the stereochemistry is set by an enzymatic reaction and no resolution is needed [93,94]. The environmental impact can be measured in a variety of ways [95–97]. A comparison of the old and new processes is summarized in Table 1.3.

Table 1.3 Sustainability comparison between old and new processes for the synthesis of INDAC (1)

Key parametersFirst- versus second-generation processes (% reduction)SustainabilityProcess mass intensity32Carbon footprint55Eco-indicator 9980EconomicsManufacturing costsSignificantCapacity−16a

a. That is, an increase.

The use of organic solvents was reduced significantly, as water is used as the reaction medium for both steps. Process mass intensity (PMI) is an indicator of the amount of material put into the reaction compared to the amount of desired product generated. However, water is not ignored in the PMI, which leads to only a modest reduction of this factor [98]. The carbon footprint, or life cycle analysis, takes into account the starting materials and energy that give rise to CO2 emission [99], while the Eco-indicator 99 is an all-inclusive measure that covers human health, impact on the ecosystem, and resource depletion [100].

1.5 Summary

An improved manufacturing process to INDAC (1) was developed building on previous knowledge and expertise for the preparation of unnatural amino acids by enzymatic processes and a Cu-catalyzed N -arylation method. The new process has only two steps compared with the traditional route that had seven and both are run in water. In addition to cost reduction, the new process is much more sustainable illustrating that both can be achieved without compromising either. The PAL enzyme and the Cu-catalyzed cyclization are currently being used on ton scale for the preparation of INDAC (1) [18,19,101,102].

Acknowledgments

The authors wish to thank the many people at DSM who have contributed to this chemistry over the years and who have developed it to become a flagship sustainable process.

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