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.)
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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
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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.
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].
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
Ac |
acetyl |
acac |
acetylacetone |
ADC |
acetonedicarboxylate |
AIBN |
2,2′-azobis(2-methylpropionitrile) |
Am |
amyl |
AmPhos |
di-t-butyl(4-dimethylaminophenyl)phosphine |
API |
active pharmaceutical ingredient |
9-BBN |
9-borabicyclo[3.3.1]nonane |
BINAP |
(1,1′-binaphthalene-2,2′-diyl)bis(diphenylphosphine) |
Biphen |
5,5′,6,6′-tetramethyl-3,3′-di-t-butyl-1,1′-biphenyl-2,2′-diol |
BIPHEP |
2,2′-bis(diphenylphosphino)-1,1′-biphenyl |
Boc |
t-butyloxycarbonyl |
BTPP |
t-butylimino-tri(pyrrolidino)phosphorane |
Bu |
butyl |
t-BuDavePhos |
2-di-t-butylphosphino-2′-(N,N-dimethylamino)biphenyl |
cBRIDP |
di-t-butyl(2,2-diphenyl-1-methyl-1-cyclopropyl)phosphine |
Cbz |
carbobenzyloxy |
CDI |
1,1′-carbonyldiimidazole |
(S,S)-ChiraPHOS |
(2S,3S)-(−)-bis(diphenylphosphino)butane |
COD |
1,5-cyclooctadiene |
Cy |
cyclohexyl |
trans-CyDA |
(1R,2R)-trans-cyclohexyldiamine |
Cy-JohnPhos |
2-(dicyclohexylphosphino)biphenyl |
d |
day |
1,2-DAP |
1,2-diaminopropane |
DavePhos |
2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl |
dba |
dibenzylideneacetone |
DBU |
1,8-diazabicyclo[5.4.0]undec-7-ene |
DCE |
1,2-dichloroethane |
dcpe |
1,2-bis(dicyclohexylphosphino)ethane |
dcpm |
bis(dicyclohexylphosphino)methane |
DIAD |
diisopropyl 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]ethane |
DIPHOS |
1,2-bis(diphenylphosphino)ethane |
dippf |
di-i-propylphosphinoferrocene |
DIPT |
di-i-propyl tartrate |
DKR |
dynamic kinetic resolution |
DLS |
dynamic light scattering |
DMAc |
N,N-dimethylacetamide |
DMAP |
4-dimethylaminopyridine |
DMC |
dimethyl carbonate |
trans-DMCyDA |
(1R,2R)-N,N′-dimethylcyclohexyldiamine |
DME |
1,2-dimethoxyethane |
DMEDA |
N,N′-dimethylethylenediamine |
DMF |
N,N-dimethylformamide |
DMG |
N,N-dimethylglycine |
DMSO |
dimethyl sulfoxide |
DoE |
design of experiments |
DPEPhos |
bis[(2-diphenylphosphino)phenyl]ether |
dppb |
diphenylphosphinobutane |
dppe |
diphenylphosphinoethane |
dppf |
diphenylphosphinoferrocene |
dppm |
diphenylphosphinomethane |
dppp |
diphenylphosphinopropane |
dtbpf |
di-t-butylphosphinoferrocene |
EDTA |
ethylenediaminetetraacetic acid |
ee |
enantiomeric excess |
Et |
ethyl |
FDA |
Food and Drug Administration |
FT-IR |
Fourier transform infrared spectroscopy |
fur |
2-furfuryl |
GC |
gas chromatography |
GMP |
good manufacturing practice |
h |
hour |
HATU |
1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxid hexafluorophosphate |
HCV |
hepatitis C virus |
HDPE |
high-density polyethylene |
Hex |
hexyl |
HIV |
human immunodeficiency virus |
HMBC |
heteronuclear multiple-bond correlation |
HMDS |
hexamethyldisilazide |
HOAt |
1-hydroxy-7-azabenzotriazole |
HPLC |
high-performance liquid chromatography |
HRMS |
high-resolution mass spectrometry |
HST |
hydroboration–Suzuki–Tamao |
HTE |
high-throughput experimentation |
IMes·HCl |
1,3-bis(2,4,6-trimethylphenyl)imidazolium chloride |
IMS |
industrial methylated spirits |
INDAC |
(S)-2-indoline carboxylic acid |
IPA |
2-propanol |
IR |
infrared |
JohnPhos |
(2-biphenyl)di-t-butylphosphine |
KF |
Karl Fischer |
L |
ligand or liters |
LC |
liquid chromatography |
LOX |
lipoxygenase |
MAP |
mitogen-activated protein |
mCBA |
m-chlorobenzoic acid |
mCPBA |
m-chloroperbenzoic acid |
Me |
methyl |
(R,R)-MeDuPhos |
(–)-1,2-bis[(2R,5R)-2,5-dimethylphospholano]benzene |
MEK |
methyl ethyl ketone |
MePhos |
dicyclohexylphosphino-2′-methylbiphenyl |
Mes |
mesityl |
2-MeTHF |
2-methyltetrahydrofuran |
(R,R)-Me-ULLUPHOS |
(–)-1,2-bis[(2R,5R)-2,5-dimethylphospholano]benzene |
MIBK |
methyl isobutyl ketone |
min |
minute |
MP |
macroporous polystyrene |
Ms |
methanesulfonyl |
MS |
mass spectrometry |
MSZL |
metastable zone limit |
MTBE |
methyl t-butyl ether |
mv |
mean volume |
MVK |
methyl vinyl ketone |
MW |
microwave |
NAM |
negative allosteric modulator |
NBS |
N-bromosuccinimide |
NCE |
new chemical entity |
NCS |
N-chlorosuccinimide |
ND |
not detected |
NIXANTPHOS |
4,6-bis(diphenylphosphino)phenoxazine |
nm |
nanometer |
NMM |
N-methylmorpholine |
NMP |
1-methyl-2-pyrrolidone |
NMR |
nuclear magnetic resonance |
NNRTI |
non-nucleoside reverse transcription inhibitor |
NOE |
nuclear Overhauser effect |
Np |
neopentyl |
Nu |
nucleophile |
PAL |
phenylalanine ammonia lyase |
PCA |
principal component analysis |
PDE |
phosphodiesterase |
PEEK |
polyether ether ketone |
PEG |
polyethylene glycol |
Peppsi |
pyridine-enhanced precatalyst preparation, stabilization, and initiation |
Phen |
phenanthroline |
PLS |
projection to latent structure |
PMB |
p-methoxybenzyl |
PMI |
process mass intensity |
ppm |
parts per million |
Pr |
propyl |
PS |
polystyrene |
PTFE |
polytetrafluoroethylene |
PTS |
(polyoxoethanyl-α-tocopheryl)sebacate |
PXRD |
powder X-ray diffraction |
PyBOP |
(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate |
QPhos |
1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene |
QPT |
quinoline pyrimidine trione |
RA |
rheumatoid arthritis |
RCC |
renal cell carcinoma |
RCM |
ring-closing metathesis |
RSM |
response surface methodology |
rt |
room temperature |
RuCl2[(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) |
RuPhos |
2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl |
SFC |
supercritical fluid chromatography |
SPhos |
2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl |
TBAB |
tetra-n-butylammonium bromide |
TBAC |
tetra-n-butylammonium chloride |
TBS |
t-butyldimethylsilyl |
TEM |
transmission electron microscopy |
Tf |
trifluoromethylsulfonyl |
TFA |
trifluoroacetic acid |
THF |
tetrahydrofuran |
THP |
tetrahydropyran |
TIPS |
tri-i-propylsilyl |
(R)-TMBTP |
2,2′,5,5′-tetramethyl-4,4′-bis(diphenylphosphino)-3,3′-bithiophene |
TMEDA |
tetramethylethylenediamine |
TMG |
1,1,3,3-tetramethylguanidine |
TMHD |
2,2′,6,6′-tetramethylheptane-2,5-dione |
TMS |
trimethylsilyl |
TMT |
trimercaptotriazine |
tol |
tolyl |
TrixiePhos |
(±)-2-di-t-butylphosphino-1,1′-binaphthyl |
TRP |
transient receptor potential |
Ts |
toluenesulfonyl |
VEGF |
vascular endothelial growth factor |
VR |
vanilloid receptor |
wt |
weight |
Xantphos |
4,5-bis(diphenylphosphino)-9,9-dimethylxanthene |
XPhos |
2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl |
XRF |
X-ray fluorescence |