Transition Metal-Catalyzed Couplings in Process...

Transition Metal-Catalyzed Couplings in Process Chemistry

Edited by Javier Magano and Joshua R. Dunetz

Case Studies from the Pharmaceutical Industry

Edited by

Javier Magano and

Joshua R. Dunetz

Transition Metal-CatalyzedCouplings in ProcessChemistry

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Edited by Javier Magano and Joshua R. Dunetz

Transition Metal-Catalyzed Couplingsin Process Chemistry

Case Studies from the Pharmaceutical Industry

The Editors

Javier MaganoPfizer Inc.,Chemical Research and DevelopmentEastern Point RaodGroton, CT 06340USA

Dr. Joshua R. DunetzPfizer Inc.,Chemical Research and DevelopmentEastern Point RoadGroton, CT 06340USA

All books published byWiley-VCH are carefully produced.Nevertheless, authors, editors, and publisher do notwarrant the information contained in these books,including this book, to be free of errors. Readers areadvised to keep in mind that statements, data, illustrations,procedural details or other items may inadvertently beinaccurate.

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Print ISBN: 978-3-527-33279-3ePDF ISBN: 978-3-527-65893-0ePub ISBN: 978-3-527-65892-3mobi ISBN: 978-3-527-65891-6oBook ISBN: 978-3-527-65890-9

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

– Javier Magano

For Cynthia, for Caitlin.

– Joshua R. Dunetz

Contents

Foreword 1 XVForeword 2 XVIIForeword 3 XIXList of Contributors XXIIIIntroduction XXIXList of Abbreviations XXXIII

1 Copper-Catalyzed Coupling for a Green Process 1David J. Ager and Johannes G. de Vries

1.1 Introduction 11.2 Synthesis of Amino Acid 14 41.2.1 Asymmetric Hydrogenation Approach 41.2.2 Enzymatic Approaches 51.3 Copper-Catalyzed Cyclization 61.3.1 C–N Bond Formation 61.3.2 INDAC (1) Synthesis 81.4 Sustainability 101.5 Summary 10

References 11

2 Experiences with Negishi Couplings on Technical Scale in EarlyDevelopment 15Murat Acemoglu, Markus Baenziger, Christoph M. Krell,and Wolfgang Marterer

2.1 Introduction 152.2 Synthesis of LBT613 via Pd-Catalyzed Negishi

Coupling 162.3 Elaboration of a Negishi Coupling in the Synthesis of

PDE472 192.4 Ni-Catalyzed Negishi Coupling with Catalytic Amounts

of ZnCl2 212.5 Conclusions 22

References 23

3 Developing Palladium-Catalyzed Arylations of Carbonyl-ActivatedC–H Bonds 25Carl A. Busacca and Chris H. Senanayake

3.1 Introduction 253.2 Suzuki Approach to Side Chain Installation 263.3 Arylation of Carbonyl-Activated C–H Bonds 303.4 Pd Purging from API 363.5 Conclusions 37

References 37

4 Development of a Practical Synthesis of Naphthyridone p38MAP Kinase Inhibitor MK-0913 39John Y.L. Chung

4.1 Introduction 394.2 Medicinal Chemistry Approach to 1 404.3 Results and Discussion 424.3.1 ADC Route to 21 424.3.2 Tandem Heck–Lactamization Route to 23 474.3.3 Suzuki–Miyaura Coupling 484.3.4 Preparation of Grignard 22 for Endgame Couplings 494.3.5 Coupling of Organomagnesium 22 and Naphthyridones 19–21 504.4 Conclusions 54

References 54

5 Practical Synthesis of a Cathepsin S Inhibitor 57Xiaohu Deng, Neelakandha S. Mani, and Jimmy Liang

5.1 Introduction 575.2 Synthetic Strategy 595.3 Syntheses of Building Blocks 595.4 Sonogashira Coupling and Initial Purification of 1 635.5 Salt Selection 655.6 Conclusions 70

References 70

6 C–N Coupling Chemistry as a Means to Achieve a Complicated MolecularArchitecture: the AR-A2 Case Story 73Hans-J€urgen Federsel, Martin Hedberg, Fredrik R. Qvarnstr€om, and Wei Tian

6.1 A Novel Chemical Entity 736.2 Evaluation of Synthetic Pathways: Finding the Best Route 736.3 Enabling C–N Coupling by Defining the Reaction Space 766.3.1 First Experiences 766.3.2 Setbacks and Problem Solutions 786.3.3 Scoping Out Key Parameters for Best Reaction Performance 796.3.4 Ligand Screening 796.3.5 Finding the Best Base 80

VIII Contents

6.3.6 Optimizing the Ligand/Metal Ratio 816.3.7 Temperature Effect 826.3.8 Optimizing the Catalyst Loading 826.4 From Synthesis to Process 836.4.1 Demonstration on Scale 836.4.2 Environmental Performance 856.4.3 Impurity Tracking 866.5 Concluding Remarks 88

References 88

7 Process Development and Scale-up of PF-03941275, a NovelAntibiotic 91Kevin E. Henegar and Timothy A. Johnson

7.1 Introduction 917.2 Medicinal Chemistry Synthesis of PF-03941275 917.3 Synthesis of 5-Bromo-2,4-difluorobenzaldehyde (1) 937.4 Synthesis of Amine 3 937.5 Miyaura Borylation Reaction 957.6 Suzuki–Miyaura Coupling 977.7 Barbituric Acid Coupling 1017.8 Chlorination and API Isolation 1017.9 Conclusions 104

References 104

8 Development of a Practical Negishi Coupling Process for theManufacturing of BILB 1941, an HCV Polymerase Inhibitor 105Bruce Z. Lu, Guisheng Li, Frank Roschangar, Azad Hossain, Rolf Herter,Vittorio Farina, and Chris H. Senanayake

8.1 Introduction and Background 1058.2 Stille Coupling 1078.3 Suzuki Coupling 1078.4 Negishi Coupling 1098.4.1 Initial Investigation 1098.4.2 Negishi Coupling Optimization 1108.4.3 Negishi Coupling Process Scale-up 1188.5 Comparison of Three Coupling Processes 119

References 119

9 Application of a Rhodium-Catalyzed, Asymmetric 1,4-Addition to theKilogram-Scale Manufacture of a Pharmaceutical Intermediate 121Alexandra Parker

9.1 Introduction 1219.2 Early Development 1229.3 Process Optimization 1269.3.1 Manufacturability 127

Contents IX

9.3.2 Rhodium Removal 1299.4 Process Scale-up 1319.5 Recent Developments 1339.6 Conclusions 133

References 134

10 Copper-Catalyzed C–N Coupling on Large Scale: An IndustrialCase Study 135Arianna Ribecai and Paolo Stabile

10.1 Introduction 13510.2 Process Development of the C–N Bond Formation 13710.3 Choice of Catalytic System 14010.4 Choice of Base: Inorganic Versus Organic 14110.5 Choice of Solvent 14210.6 Optimized Conditions for C–N Bond Formation to 1 14210.7 Purging Residual Copper from 1 14310.8 Conclusions 144

References 144

11 Development of a Highly Efficient Regio- and StereoselectiveHeck Reaction for the Large-Scale Manufactureof an a4b2 NNR Agonist 147Per Ryberg

11.1 Introduction 14711.2 Process Optimization 14911.2.1 Selectivity in the Heck Reaction 14911.2.2 Identification of Selective Conditions for the Heck Coupling 14911.2.3 Investigation of the Mechanism of the Heck Step 15211.2.4 Identification of a Solution to the Pd Mirror Problem 15311.2.5 Development of a Backup Method for Residual Pd Removal 15611.2.6 Effect of Water on the Reaction 15711.2.7 Development of a Semicontinuous Process Based on Catalyst

Recycling 15911.2.8 Application on Large Scale 16011.3 Conclusions 162

References 162

12 Commercial Development of Axitinib (AG-013736): Optimization of aConvergent Pd-Catalyzed Coupling Assembly and Solid FormChallenges 165Robert A. Singer

12.1 Introduction 16512.2 First-Generation Synthesis of Axitinib 16512.3 Early Process Research and Development 16712.4 Commercial Route Development 169

X Contents

12.4.1 Development of the Migita Coupling (Step 1) andIodination (Step 2) 169

12.4.2 Control of Impurities after Iodination through Recrystallization(Step 2R) 172

12.4.3 Development of the Heck Reaction 17312.4.4 Control of Solid Form 17612.5 Conclusions 178

References 179

13 Large-Scale Sonogashira Coupling for the Synthesis of an mGluR5Negative Allosteric Modulator 181Jeffrey B. Sperry, Roger M. Farr, Mousumi Ghosh,and Karen Sutherland

13.1 Introduction 18113.2 Background 18113.3 Process Development of the Sonogashira Coupling 18313.3.1 Solvent Screening 18313.3.2 Catalyst Loading 18513.3.3 Stoichiometry of 2-Ethynylpyridine (6) 18513.4 Large-Scale Sonogashira Coupling and API Purification 18613.5 Conclusions 187

References 188

14 Palladium-Catalyzed Bisallylation of Erythromycin Derivatives 189Xiaowen Peng, Guoqiang Wang, and Datong Tang

14.1 Introduction 18914.2 Discovery of 6,11-O,O-Bisallylation of Erythromycin

Derivatives 19214.3 Process Development of 6,11-O,O-Bisallylation of Erythromycin

Derivatives 19514.4 Discovery and Optimization of 3,6-Bicyclolides 19914.5 Conclusions 200

References 200

15 Route Selection and Process Development for the Vanilloid Receptor-1Antagonist AMG 517 201Oliver R. Thiel and Jason S. Tedrow

15.1 Introduction 20115.2 Retrosynthesis and Medicinal Chemistry Route 20215.3 Optimization of Medicinal Chemistry Route 20415.4 Identification of the Process Chemistry Route 20715.5 Optimization of the Suzuki–Miyaura Reaction 20815.6 Postcampaign Improvements 21315.7 Summary 214

References 215

Contents XI

16 Transition Metal-Catalyzed Coupling Reactions in the Synthesis ofTaranabant: from Inception to Pilot Implementation 217Debra J. Wallace

16.1 Introduction 21716.2 Development of Pd-Catalyzed Cyanations 21716.3 Development of Pd-Catalyzed Amidation Reactions 22416.4 Conclusions 230

References 230

17 Ring-Closing Metathesis in the Large-Scale Synthesis ofSB-462795 233Huan Wang

17.1 Background 23317.2 The RCM Disconnection 23317.2.1 Synthesis of the Azepanone Core: Amino Alcohols 2 and 3 23317.2.2 Comparison of the Two RCM Reactions 23517.3 The RCM of Diene 5 23917.3.1 General Considerations: Solvent, Catalyst, and Temperature 23917.3.2 Impact of Impurities in Diene 5 24317.3.3 Large-Scale Performance 249

References 250

18 Development of Migita Couplings for the Manufacture of a5-Lipoxygenase Inhibitor 253Weiling Cai, Brian Chekal, David Damon, Danny LaFrance,Kyle Leeman, Carlos Mojica, Andrew Palm, Michael St. Pierre,Janice Sieser, Karen Sutherland, Rajappa Vaidyanathan,John Van Alsten, Brian Vanderplas, Carrie Wager, Gerald Weisenburger,Greg Withbroe, and Shu Yu

18.1 Introduction 25318.2 Evaluation of the Sulfur Source for Initial Migita

Coupling 25418.3 Selection of Metal Catalyst and Coupling Partners 25518.4 Development of a One-Pot, Two-Migita Coupling Process 25618.5 Crystallization of 1 with Polymorph Control 26218.6 Final Commercial Process on Multikilogram Scale 26318.7 Conclusions 265

References 265

19 Preparation of 4-Allylisoindoline via a Kumada Coupling withAllylmagnesium Chloride 267Michael J. Zacuto

19.1 Introduction 26719.2 Kumada Coupling of 4-Bromoisoindoline 26819.3 Workup 273

XII Contents

19.4 Isolation 27519.5 Conclusions 276

References 276

20 Microwave Heating and Continuous-Flow Processing asTools for Metal-Catalyzed Couplings: Palladium-CatalyzedSuzuki–Miyaura, Heck, and AlkoxycarbonylationReactions 279Nicholas E. Leadbeater

20.1 Introduction 27920.1.1 Microwave Heating in Preparative Chemistry 27920.1.2 Continuous-Flow Processing in Preparative Chemistry 28020.2 Coupling Reactions Performed Using Microwave Heating or

Continuous-Flow Processing 28120.2.1 Suzuki–Miyaura and Heck Reactions 28120.2.1.1 Batch Microwave Heating for Suzuki–Miyaura and Heck

Couplings 28120.2.1.2 Continuous-Flow Processing for Suzuki–Miyaura and Heck

Couplings 28620.2.2 Alkoxycarbonylation Reactions 28720.2.2.1 Use of Batch Microwave Heating for Alkoxycarbonylation

Reactions 28720.2.2.2 Continuous-Flow Processing for Alkoxycarbonylation

Reactions 29120.3 Conclusions 294

References 295

21 Applying the Hydrophobic Effect to Transition Metal-CatalyzedCouplings in Water at Room Temperature 299Bruce H. Lipshutz

21.1 Introduction: the Hydrophobic Effect under Homogeneous andHeterogeneous Conditions 299

21.2 Micellar Catalysis Using Designer Surfactants 30021.3 First Generation: PTS 30021.4 Heck Couplings in Water at rt 30221.5 Olefin Metathesis Going Green 30221.6 Adding Ammonia Equivalents onto Aromatic and

Heteroaromatic Rings 30421.7 Couplings with Moisture-Sensitive Organometallics

in Water 30521.7.1 Negishi-like Couplings 30521.7.2 Organocopper-Catalyzed Conjugate Additions 30721.8 A New, Third-Generation Surfactant: “Nok” 30821.9 Summary, Conclusions, and a Look Forward 309

References 311

Contents XIII

22 Large-Scale Applications of Transition Metal Removal Techniquesin the Manufacture of Pharmaceuticals 313Javier Magano

22.1 Introduction 31322.2 Methods that Precipitate or Capture/Extract the Metal while

Maintaining the Coupling Product in Solution 31622.2.1 Extraction Methods 31622.2.1.1 Sodium Bisulfite 31622.2.1.2 Ethanolamine 31722.2.1.3 Trimercaptotriazine 31822.2.1.4 Ethylenediaminetetraacetic Acid Sodium Salts 32222.2.1.5 Citric Acid 32322.2.1.6 Cysteine 32422.2.1.7 2-Mercaptonicotinic Acid 32622.2.1.8 Ammonium Hydroxide 32622.2.1.9 Tri-n-butylphosphine 32822.2.1.10 Potassium Dihydrogenphosphate 33022.2.2 Adsorption Methods 33022.2.2.1 Activated Carbon 33022.2.2.2 Macroporous Polystyrene Trimercaptotriazine 33222.2.2.3 Smopex 33322.2.2.4 Polymer-Bound DIAION CR20 Resin 33522.2.2.5 Deloxan Resin 33622.2.2.6 SiliaBond Thiol 33722.2.2.7 Cysteine on Silica–Alumina 34022.2.2.8 Chromatography on Alumina 34122.3 Methods that Precipitate the Coupling Product while Purging the

Metal to the Filtrates 34122.3.1 Tri-n-butylphosphine 34122.3.2 Triethylamine 34222.3.3 Ethylenediamine 34322.3.4 N-Acetylcysteine 34322.3.5 Phosphine/Amine Combination 34522.3.6 N,N-Dimethylglycine 34622.4 Miscellaneous Methods 34722.4.1 BH3�Me3N 34722.5 Other Methods for Metal Removal 34822.6 Conclusions 349

References 350

Index 357

XIV Contents

Foreword 1

The ever-increasing impact of transition metal catalysis on organic synthesis can beseen in our day-to-day reading of the top chemistry journals. The Nobel Prizes toSharpless, Noyori, and Knowles (2001), Schrock, Grubbs, and Chauvin (2005), andHeck, Suzuki, and Negishi (2010) further highlighted the importance of catalyticprocesses in everyday synthetic chemistry. As the methodology matures, itsapplication on larger scale in the pharmaceutical industry is investigated at anincreasing rate. Key to success in this endeavor is the development of reliable andcost-effective protocols. Each example of the use of a given technique demonstratedon a large scale gives industrial chemists increased confidence about employing itin their own work in pharmaceutical process chemistry and manufacturingsettings.Catalytic chemistry as practiced today offers synthetic chemists a wide array of

different approaches to effect the same bond disconnection. As can be seen inmany of the examples described in this book, the synthetic route is somethingthat evolves over time. Beginning with the medicinal chemistry route, processchemists look for improvements in terms of safety, yield, robustness, and,ultimately, cost. Even when the identities of the basic steps that will be utilizedbecome clear, a significant amount of work remains. This is a result of thetremendous number of different catalysts, ligands, and reaction conditions thathave been developed to accomplish almost any important transformation. Thus,a standard aspect of the synthetic chemists approach has been to screen a seriesof different reaction parameters in order to arrive at the optimal reactionconditions. The calculus of deciding, for example, which catalyst to utilize in acarbon–carbon cross-coupling reaction can be quite complex. In addition to theefficiency of the catalyst (in terms of both yield and volumetric productivity), thecost and availability of the ligand need to be considered. Moreover, the use ofless expensive metals such as nickel, iron, or copper, rather than palladium, isoften explored. In addition, there may be a benefit to using a simpler ligand andan aryl bromide (typically more expensive), rather than a more complex one thatallows one to use an aryl chloride coupling partner. Superimposed on this iswhether 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 needto employ cryogenic conditions, the concentration of reagents, particularly avoidinghigh dilution reactions, and problems with reaction workup on scale) may holdthe key to whether a given process might be applicable in the final manufacturingroute.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 placean increasing emphasis on greener processes. In order to achieve success, theadvent of new and more efficient catalysts and synthetic methods will be required.The lessons presented in this book will be invaluable to synthetic chemists workingto develop more efficient processes. Specifically, chemists should make an effort totest their new reactions on increasingly complex substrates, particularly onheterocycle-containing ones. For it is here where their methods will have thegreatest impact on the “real-world” practice of synthetic chemistry.

Camille Dreyfus Professor of Chemistry Stephen L. BuchwaldMassachusetts Institute of Technology

XVI Foreword 1

Foreword 2

Industrial process chemists often rely on academic discoveries of new chemicalreactions, catalysts, or ligands when designing novel synthetic routes to complextarget molecules such as pharmaceuticals. The best chemistry is quickly taken upby industry and used in manufacturing processes, none more so than transitionmetal-catalyzed coupling reactions, which have proved so versatile in syntheticchemistry over the past 20 years. Many of these reactions have been named aftertheir inventors, some of whom have been awarded the Nobel Prize for theirdiscoveries 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 increaseprocess costs. So, for efficient manufacture of pharmaceuticals, the processchemist not only has to focus on obtaining a high yield but also has to study thereaction conditions in detail and examine catalyst turnover number and frequency,and in some cases catalyst/ligand recycling and reuse. Understanding the complexmechanism of these reactions leads to better process control and batch-to-batchconsistency as well as process robustness for large-scale operation.Many transition metal-catalyzed couplings can be adversely affected by impu-

rities in raw materials or solvents and lack of reproducibility can sometimes ensue.The temptation to abandon this chemistry and find something more reproducibleshould be avoided since a detailed and painstaking study of the effect of smallamounts of process impurities on catalyst performance usually results in anefficient and robust process – perseverance pays off! Understanding the detailedinteractions, mechanisms, side reactions, and so on is part of the fascination ofprocess chemistry.Process chemists are expert at examining the effect of changing reaction

parameters on yield and product quality; these days statistical methods ofoptimization such as design of experiments and principal component analysis (stillsurprisingly not taught in many university chemistry departments) are widely usedto maximize yield, minimize impurity formation, and optimize space–time yield (auseful measure of process throughput) to produce an efficient, scalable, and robustprocess.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 pharmaceuticalproduct to ppm levels. Transition metals are notorious for liking to complex withthe type of molecules used in the pharmaceutical industry, and special technologiesand/or novel reagents need to be used in the workup and isolation strategies.Detailed crystallization studies may also be required to produce products withinspecification.In the case studies presented in this unique book, the chapter authors provide

fascinating stories of the innovative process research and development needed toconvert a transition metal-catalyzed coupling reaction into an economic and robustmanufacturing process for the manufacture of kilograms or even tons of complexproducts in high purity. The trials and tribulations are described for all to see. Theeditors and chapter authors are to be congratulated on producing an outstandingwork that should be of value not only to process chemists but also to those teachingindustrial applications of academic discoveries.

Scientific Update LLP Trevor LairdEditor, Organic Process Research and Development

XVIII Foreword 2

Foreword 3

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

1) The “sartan” family of drugs is widelyprescribed to treat hypertension. Losartanpotassium was marketed in 1995, and atleast five other antihypertensive agents withortho-substituted, unsymmetrical biaryl moi-eties have been marketed since [1]. Manyof these APIs could be manufactured by

reaction of amines with the commerciallyavailable 40-(bromomethyl)biphenyl-2-carbo-nitrile, which can be derived by brominationof o-tolylbenzonitrile (OTBN). A group fromCatalytica described Ni- and Pd-catalyzedpreparations of OTBN using inexpensivecomponents [2].

N NKNNN

losartan potassium

OTBN (89%)

bromination

ZnCl2THF, 0 °C

4'-(bromomethyl)biphenyl-2-carbonitrile

Ni(acac)2 (7.5 mol%,5 wt% H2O)

P(O-iPr)3 (15 mol%)

THF, 40 °C, 6 h

Transition metal-catalyzed couplings are more complicated to optimize thanmany organic reactions, especially for researchers in industrial process R&D. Onscale, the charges of expensive transition metals and ligands are minimized, as thebenefits of any increased selectivity from the catalyst must be balanced with theoverall contribution to the cost of goods and with any difficulties encounteredduring workup and isolation. On scale, the transition metals charged may berecovered 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 thosefrom protodeboronation in Suzuki couplings. Starting materials, for example,halides or sulfonates, may be chosen to promote reactivity and decrease excesscharges needed; starting materials may also be selected to mitigate reactivity orminimize the formation of by-products, such as those from olefin migration.Processes must be well understood both to avoid the introduction of inhibitors andto control the generation of inhibitors, thus minimizing the charges of metal andligands and making operations more rugged. Some transition metal-catalyzedreactions are driven by equilibrium, necessitating the development of practicalworkups to quench reactive conditions; simply pouring a reaction mixture onto acolumn 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 caninfluence the workup and isolation of the product. These considerations arediscussed in this book.Many of the investigations in these chapters were oriented toward preparing

tens to hundreds of kilograms of products from transition metal-catalyzedcouplings. In the case studies, critical considerations ranged from selection ofroutes and starting materials to reducing cycle times on scale. Details of somemanufacturing processes are also divulged. Routinely conducting processes onscale is the culmination of many efforts and demonstrates the thoroughunderstanding 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 condi-tions using both microwave heating and continuous operations, which can beuseful for making larger amounts of material with minimal process development.The chapter from Professor Lipshutz, recipient of a US Presidential GreenChemistry Award in 2011, describes the use of emulsions for running moisture-sensitive reactions in largely aqueous media. This area will also be fruitful forfuture transition metal-catalyzed scale-ups.Cost considerations will become even more crucial to process development

in industry. Environmental and toxicity considerations may make the selectionof some solvents and transition metals less attractive, and these will affect thecost of goods and influence process development. The availability of sometransition metals may be affected by international politics, resulting inincreased costs. We will probably see the increased use of catalysts containingless expensive transition metals, perhaps doped with small amounts of othermetals; examples might be iron catalysts containing palladium or copper [3,4].With the use of different transition metals, different ligands will likely be

XX Foreword 3

designed. Extremely small charges of transition metals and ligands can beeffective [5], making the recovery of metals no longer economical [6].Thorough understanding will continue to be critical for developing ruggedcatalytic 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 thesynthesis of pharmaceuticals” [7]. Therein, they described details of the reactionsequences, workup conditions used to control the levels of residual metals, andcritical analyses of the advantages and disadvantages of such processes run onscale. These considerations are evident in this book too, as Javier and Josh haveextended the analyses for developing practical processes to scale up transitionmetal-catalyzed reactions. This book will also be important in the continuingevolution of chemical processes. I am sure that this valuable book will stimulatemany thoughts for those involved in process R&D of transition metal-catalyzedprocesses.

Anderson’s Process Solutions LLC Neal G. AndersonAuthor of “Practical Process Research &Development – A Guide for Organic Chemists”

References

1 Yet, L. (2007) Chapter 9: Angiotensin AT1antagonists for hypertension, in The Art ofDrug 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. andFarrell, 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. andMignani F G. (2006) Chem. Rev., 106, 2651.

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

Foreword 3 XXI

List of Contributors

Murat Acemoglu

Novartis PharmaChemical & Analytical Development4002 BaselSwitzerland

David J. Ager

DSM Innovative Synthesis B.V.950 Strickland Road, Suite 103Raleigh, NC 27615USA

Markus Baenziger

Carl A. Busacca

Boehringer IngelheimPharmaceuticals, Inc.Chemical Development900 Ridgebury RoadRidgefield, CT 06877USA

Weiling Cai

Pfizer Worldwide Research &DevelopmentChemical Research and DevelopmentEastern Point RoadGroton, CT 06340USA

Brian Chekal

John Y.L. Chung

Merck Research LaboratoriesGlobal Process Chemistry126 E. Lincoln AveRahway, NJ 07065USA

David Damon

Xiaohu Deng

Janssen Research & Development LLC3210 Merryfield RowSan Diego, CA 92121USA

Johannes G. de Vries

DSM Innovative Synthesis B.V.6160 MD GeleenThe Netherlands

Joshua R. Dunetz

Pfizer Worldwide Research &DevelopmentChemical Research & DevelopmentEastern Point RoadGroton, CT 06340USA

Vittorio Farina

Janssen PharmaceuticaDepartment of PharmaceuticalDevelopment and ManufacturingSciencesTurnhoutseweg 302340 BeerseBelgium

Roger M. Farr

Wyeth PharmaceuticalsDepartment of Chemical andPharmaceutical Development401 N. Middletown Rd.Pearl River, NY 10965USA

Hans-J€urgen Federsel

AstraZenecaPharmaceutical DevelopmentSilk Road Business ParkMacclesfieldCheshire SK10 2NAUK

Mousumi Ghosh

Wyeth PharmaceuticalsDepartment of Chemical andPharmaceutical Development401 N. Middletown Rd.Pearl River, NY 10965USA

Martin Hedberg

SP Technical Research Institute ofSwedenSP Process Development AB15121 S€odert€aljeSweden

Kevin E. Henegar

Rolf Herter

Azad Hossain

Timothy A. Johnson

Pfizer Veterinary Medicine Research& DevelopmentMedicinal Chemistry333 Portage StreetKalamazoo, MI 49007USA

XXIV List of Contributors

Christoph M. Krell

Danny LaFrance

Nicholas E. Leadbeater

University of ConnecticutDepartment of Chemistry55 North Eagleville RoadStorrs, CT 06269USA

Kyle Leeman

Guisheng Li

Jimmy Liang

Bruce H. Lipshutz

University of CaliforniaDepartment of Chemistry &BiochemistrySanta Barbara, CA 93106USA

Bruce Z. Lu

Javier Magano

Neelakandha S. Mani

Wolfgang Marterer

Carlos Mojica

List of Contributors XXV

Andrew Palm

Alexandra Parker

AstraZenecaPharmaceutical DevelopmentSilk Road Business Park, Charter WayMacclesfield, Cheshire SK10 2NAUK

Xiaowen Peng

Enanta Pharmaceuticals, Inc.Chemistry Department500 Arsenal StreetWatertown, MA 02472USA

Fredrik R. Qvarnstr€om

AstraZenecaPharmaceutical Development15185 S€odert€aljeSweden

Arianna Ribecai

F.I.S. – Fabbrica ItalianaSintetici S.p.A.Research & DevelopmentViale Milano 2636075 Montecchio Maggiore (VI)Italy

Frank Roschangar

Per Ryberg

AstraZenecaPharmaceutical DevelopmentChemical ScienceForskargatan 1815185 S€odert€aljeSweden

Chris H. Senanayake

Janice Sieser

Robert A. Singer

Pfizer Global Research & DevelopmentChemical Research & DevelopmentEastern Point RoadGroton, CT 06340USA

Jeffrey B. Sperry

Paolo Stabile

F.I.S. – Fabbrica ItalianaSintetici S.p.A.Research & DevelopmentViale Milano 2636075 Montecchio Maggiore (VI)Italy

XXVI List of Contributors

Michael St. Pierre

Karen Sutherland

Datong Tang

Jason S. Tedrow

AmgenChemical Process Researchand DevelopmentOne Amgen Center DriveThousand Oaks, CA 91320-1799USA

Oliver R. Thiel

AmgenChemical Process Research andDevelopmentOne Amgen Center DriveThousand Oaks, CA 91320-1799USA

Wei Tian

AstraZenecaPharmaceutical Development15185 S€odert€aljeSweden

Rajappa Vaidyanathan

John Van Alsten

Brian Vanderplas

Carrie Wager

Debra J. Wallace

Merck Research LaboratoriesGlobal Process ChemistryRahway, NJ 07065USA

Guoqiang Wang

List of Contributors XXVII

Huan Wang

GlaxoSmithKlineAPI Chemistry & Analysis709 Swedeland RoadKing of Prussia, PA 19406USA

Gerald Weisenburger

Greg Withbroe

Shu Yu

Michael J. Zacuto

Merck Research LaboratoriesGlobal Process ChemistryRahway, NJ 07065USA

XXVIII List of Contributors

Transition Metal-Catalyzed Couplings in Process...

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