Transition metal catalyzed couplings in process chemistry case studies from the pharmaceutical industry

Dunetz P fizer Inc., Chemical Research and Development Eastern Point Road Groton, CT 06340 USA All books published by Wiley-VCH are carefully produced.. Chemical Research and DevelopmentE

Edited by

Javier Magano andJoshua R Dunetz

Transition Metal-CatalyzedCouplings in ProcessChemistry

Related Titles

de Meijere, A., Br€ase, S.,

Oestreich, M (eds.)

Metal Catalyzed

Cross-Coupling Reactions and More

Second, Completely Revised Edition

2011 ISBN: 978-3-527-32598-6

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

on Industrial ScaleChallenges, 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 Industry2010

ISBN: 978-3-527-32418-7

Nugent, T C (ed.)Chiral Amine SynthesisMethods, Developmentsand Applications

2010 ISBN: 978-3-527-32509-2

Edited by Javier Magano and Joshua R Dunetz

Transition Metal-Catalyzed Couplings

in Process Chemistry

Case Studies from the Pharmaceutical Industry

The Editors

Javier Magano

Pfizer Inc.,

Chemical Research and Development

Eastern Point Raod

Groton, CT 06340

USA

Dr Joshua R Dunetz

P fizer Inc.,

Chemical Research and Development

Eastern Point Road

Groton, CT 06340

USA

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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

List of Abbreviations XXXIII

1 Copper-Catalyzed Coupling for a Green Process 1

David J Ager and Johannes G de Vries

1.1 Introduction 1

1.2 Synthesis of Amino Acid14 4

1.2.1 Asymmetric Hydrogenation Approach 4

Murat Acemoglu, Markus Baenziger, Christoph M Krell,

and Wolfgang Marterer

3 Developing Palladium-Catalyzed Arylations of Carbonyl-Activated

C–H Bonds 25

Carl A Busacca and Chris H Senanayake

3.1 Introduction 25

3.2 Suzuki Approach to Side Chain Installation 26

3.3 Arylation of Carbonyl-Activated C–H Bonds 30

3.4 Pd Purging from API 36

3.5 Conclusions 37

References 37

4 Development of a Practical Synthesis of Naphthyridone p38

MAP Kinase Inhibitor MK-0913 39

John Y.L Chung

4.1 Introduction 39

4.2 Medicinal Chemistry Approach to1 40

4.3 Results and Discussion 42

4.3.1 ADC Route to21 42

4.3.2 Tandem Heck–Lactamization Route to 23 47

4.3.3 Suzuki–Miyaura Coupling 48

4.3.4 Preparation of Grignard22 for Endgame Couplings 49

4.3.5 Coupling of Organomagnesium22 and Naphthyridones 19–21 504.4 Conclusions 54

References 54

5 Practical Synthesis of a Cathepsin S Inhibitor 57

Xiaohu Deng, Neelakandha S Mani, and Jimmy Liang

5.1 Introduction 57

5.2 Synthetic Strategy 59

5.3 Syntheses of Building Blocks 59

5.4 Sonogashira Coupling and Initial Purification of 1 63

5.5 Salt Selection 65

5.6 Conclusions 70

References 70

6 C–N Coupling Chemistry as a Means to Achieve a Complicated Molecular

Architecture: the AR-A2 Case Story 73

Hans-J€urgen Federsel, Martin Hedberg, Fredrik R Qvarnstr€om, and Wei Tian6.1 A Novel Chemical Entity 73

6.2 Evaluation of Synthetic Pathways: Finding the Best Route 73

6.3 Enabling C–N Coupling by Defining the Reaction Space 76

6.3.1 First Experiences 76

6.3.2 Setbacks and Problem Solutions 78

6.3.3 Scoping Out Key Parameters for Best Reaction Performance 796.3.4 Ligand Screening 79

6.3.5 Finding the Best Base 80

VIII Contents

6.3.6 Optimizing the Ligand/Metal Ratio 81

6.3.7 Temperature Effect 82

6.3.8 Optimizing the Catalyst Loading 82

6.4 From Synthesis to Process 83

7.7 Barbituric Acid Coupling 101

7.8 Chlorination and API Isolation 101

7.9 Conclusions 104

References 104

8 Development of a Practical Negishi Coupling Process for the

Manufacturing of BILB 1941, an HCV Polymerase Inhibitor 105

Bruce Z Lu, Guisheng Li, Frank Roschangar, Azad Hossain, Rolf Herter,Vittorio Farina, and Chris H Senanayake

8.1 Introduction and Background 105

8.2 Stille Coupling 107

8.3 Suzuki Coupling 107

8.4 Negishi Coupling 109

8.4.1 Initial Investigation 109

8.4.2 Negishi Coupling Optimization 110

8.4.3 Negishi Coupling Process Scale-up 118

8.5 Comparison of Three Coupling Processes 119

References 119

9 Application of a Rhodium-Catalyzed, Asymmetric 1,4-Addition to the

Kilogram-Scale Manufacture of a Pharmaceutical Intermediate 121

10.2 Process Development of the C–N Bond Formation 137

10.3 Choice of Catalytic System 140

10.4 Choice of Base: Inorganic Versus Organic 141

10.5 Choice of Solvent 142

10.6 Optimized Conditions for C–N Bond Formation to 1 142

10.7 Purging Residual Copper from1 143

10.8 Conclusions 144

References 144

11 Development of a Highly Efficient Regio- and Stereoselective

Heck Reaction for the Large-Scale Manufacture

of ana4b2 NNR Agonist 147

Per Ryberg

11.1 Introduction 147

11.2 Process Optimization 149

11.2.1 Selectivity in the Heck Reaction 149

11.2.2 Identification of Selective Conditions for the Heck Coupling 14911.2.3 Investigation of the Mechanism of the Heck Step 152

11.2.4 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 157

11.2.7 Development of a Semicontinuous Process Based on Catalyst

Recycling 159

11.2.8 Application on Large Scale 160

11.3 Conclusions 162

References 162

12 Commercial Development of Axitinib (AG-013736): Optimization of a

Convergent Pd-Catalyzed Coupling Assembly and Solid FormChallenges 165

Robert A Singer

12.1 Introduction 165

12.2 First-Generation Synthesis of Axitinib 165

12.3 Early Process Research and Development 167

12.4 Commercial Route Development 169

X Contents

12.4.1 Development of the Migita Coupling (Step 1) and

Iodination (Step 2) 169

12.4.2 Control of Impurities after Iodination through Recrystallization

(Step 2R) 172

12.4.3 Development of the Heck Reaction 173

12.4.4 Control of Solid Form 176

12.5 Conclusions 178

References 179

13 Large-Scale Sonogashira Coupling for the Synthesis of an mGluR5

Negative Allosteric Modulator 181

Jeffrey B Sperry, Roger M Farr, Mousumi Ghosh,

and Karen Sutherland

14 Palladium-Catalyzed Bisallylation of Erythromycin Derivatives 189

Xiaowen Peng, Guoqiang Wang, and Datong Tang

15.2 Retrosynthesis and Medicinal Chemistry Route 202

15.3 Optimization of Medicinal Chemistry Route 204

15.4 Identification of the Process Chemistry Route 207

15.5 Optimization of the Suzuki–Miyaura Reaction 208

15.6 Postcampaign Improvements 213

References 215

Contents XI

16 Transition Metal-Catalyzed Coupling Reactions in the Synthesis of

Taranabant: from Inception to Pilot Implementation 217

Debra J Wallace

16.1 Introduction 217

16.2 Development of Pd-Catalyzed Cyanations 217

16.3 Development of Pd-Catalyzed Amidation Reactions 224

Weiling Cai, Brian Chekal, David Damon, Danny LaFrance,

Kyle Leeman, Carlos Mojica, Andrew Palm, Michael St Pierre,Janice Sieser, Karen Sutherland, Rajappa Vaidyanathan,

John Van Alsten, Brian Vanderplas, Carrie Wager, Gerald Weisenburger,Greg Withbroe, and Shu Yu

18.1 Introduction 253

18.2 Evaluation of the Sulfur Source for Initial Migita

Coupling 254

18.3 Selection of Metal Catalyst and Coupling Partners 255

18.4 Development of a One-Pot, Two-Migita Coupling Process 25618.5 Crystallization of1 with Polymorph Control 262

18.6 Final Commercial Process on Multikilogram Scale 263

19.4 Isolation 275

19.5 Conclusions 276

References 276

20 Microwave Heating and Continuous-Flow Processing as

Tools for Metal-Catalyzed Couplings: Palladium-Catalyzed

Suzuki–Miyaura, Heck, and Alkoxycarbonylation

Reactions 279

Nicholas E Leadbeater

20.1 Introduction 279

20.1.1 Microwave Heating in Preparative Chemistry 279

20.1.2 Continuous-Flow Processing in Preparative Chemistry 280

20.2 Coupling Reactions Performed Using Microwave Heating or

Continuous-Flow Processing 281

20.2.1 Suzuki–Miyaura and Heck Reactions 281

20.2.1.1 Batch Microwave Heating for Suzuki–Miyaura and Heck

21 Applying the Hydrophobic Effect to Transition Metal-Catalyzed

Couplings in Water at Room Temperature 299

21.4 Heck Couplings in Water at rt 302

21.5 Olefin Metathesis Going Green 302

21.6 Adding Ammonia Equivalents onto Aromatic and

Heteroaromatic Rings 304

21.7 Couplings with Moisture-Sensitive Organometallics

in Water 305

21.7.1 Negishi-like Couplings 305

21.7.2 Organocopper-Catalyzed Conjugate Additions 307

21.8 A New, Third-Generation Surfactant:“Nok” 308

21.9 Summary, Conclusions, and a Look Forward 309

References 311

Contents XIII

22 Large-Scale Applications of Transition Metal Removal Techniques

in the Manufacture of Pharmaceuticals 313

Javier Magano

22.1 Introduction 313

22.2 Methods that Precipitate or Capture/Extract the Metal while

Maintaining the Coupling Product in Solution 316

22.3 Methods that Precipitate the Coupling Product while Purging the

Metal to the Filtrates 341

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 demonstrated

on a large scale gives industrial chemists increased confidence about employing it

in their own work in pharmaceutical process chemistry and manufacturingsettings

Catalytic chemistry as practiced today offers synthetic chemists a wide array ofdifferent 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 series

of 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 and

an 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

XV

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 avoidinghigh dilution reactions, and problems with reaction workup on scale) may holdthe key to whether a given process might be applicable in thefinal manufacturingroute

It is clear that catalytic methods will have an ever more important role in themanufacturing offine chemicals Both societal and economic pressures will place

an 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 working

to 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 up

by 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 rities in raw materials or solvents and lack of reproducibility can sometimes ensue.The temptation to abandon this chemistry andfind 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

impu-Process chemists are expert at examining the effect of changing reactionparameters 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 used

to 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 theprocess chemist with regard to product workup and isolation, since the often toxic

XVII

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 providefascinating 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

Editor, 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 widely

prescribed to treat hypertension Losartan

potassium was marketed in 1995, and at

least five other antihypertensive agents with

ortho-substituted, unsymmetrical biaryl

moi-eties have been marketed since [1] Many

of these APIs could be manufactured by

reaction of amines with the commercially available 40-(bromomethyl)biphenyl-2-carbo- nitrile, 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].

N N N

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 and

to 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 preparingtens 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 fromacademia 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 selection

of 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 2011review “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

Author of“Practical Process Research &

Development– A Guide for Organic Chemists”

References

1 Yet, L (2007) Chapter 9: Angiotensin AT 1

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,

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.

Foreword 3 XXI

Chemical Research and Development

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Brian ChekalPfizer Worldwide Research &

DevelopmentChemical Research and DevelopmentEastern Point Road

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John Y.L ChungMerck Research LaboratoriesGlobal Process Chemistry

126 E Lincoln AveRahway, NJ 07065USA

David DamonPfizer Worldwide Research &

DevelopmentChemical Research and DevelopmentEastern Point Road

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Xiaohu DengJanssen Research & Development LLC

3210 Merryfield RowSan Diego, CA 92121USA

XXIII

Chemical Research & Development

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401 N Middletown Rd

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Kevin E HenegarPfizer Worldwide Research &Development

Chemical Research & DevelopmentEastern Point Road

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Rolf HerterBoehringer IngelheimPharmaceuticals, Inc

Chemical Development

900 Ridgebury RoadRidgefield, CT 06877USA

Azad HossainBoehringer IngelheimPharmaceuticals, Inc

Chemical Development

900 Ridgebury RoadRidgefield, CT 06877USA

Timothy A JohnsonPfizer Veterinary Medicine Research

& DevelopmentMedicinal Chemistry

333 Portage StreetKalamazoo, MI 49007USA

XXIV List of Contributors

Chemical Research and Development

Eastern Point Road

Chemical Research and Development

Eastern Point Road

BiochemistrySanta Barbara, CA 93106USA

Bruce Z LuBoehringer IngelheimPharmaceuticals, Inc

Chemical Development

900 Ridgebury RoadRidgefield, CT 06877USA

Javier MaganoPfizer Worldwide Research &

DevelopmentChemical Research & DevelopmentEastern Point Road

Groton, CT 06340USA

Neelakandha S ManiJanssen Research & Development LLC

3210 Merryfield RowSan Diego, CA 92121USA

Wolfgang MartererNovartis PharmaChemical & Analytical Development

4002 BaselSwitzerlandCarlos MojicaPfizer Worldwide Research &

DevelopmentChemical Research and DevelopmentEastern Point Road

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List of Contributors XXV

Andrew Palm

Pfizer Worldwide Research &

Development

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Chris H SenanayakeBoehringer IngelheimPharmaceuticals, Inc

Chemical Development

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Janice SieserPfizer Worldwide Research &

DevelopmentChemical Research and DevelopmentEastern Point Road

Groton, CT 06340USA

Robert A SingerPfizer Global Research & DevelopmentChemical Research & DevelopmentEastern Point Road

Groton, CT 06340USA

Jeffrey B SperryPfizer Worldwide Research &

DevelopmentChemical Research & DevelopmentEastern Point Road

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Paolo StabileF.I.S.– Fabbrica ItalianaSintetici S.p.A

Research & DevelopmentViale Milano 26

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XXVI List of Contributors

Michael St Pierre

Pfizer Worldwide Research &

Development

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DevelopmentChemical Research and DevelopmentEastern Point Road

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Pfizer Worldwide Research &

DevelopmentChemical Research and DevelopmentEastern Point Road

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Brian VanderplasPfizer Worldwide Research &

DevelopmentChemical Research and DevelopmentEastern Point Road

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Carrie WagerPfizer Worldwide Research &

DevelopmentChemical Research and DevelopmentEastern Point Road

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Debra J WallaceMerck Research LaboratoriesGlobal Process ChemistryRahway, NJ 07065USA

Guoqiang WangEnanta Pharmaceuticals, Inc

Chemistry Department

500 Arsenal StreetWatertown, MA 02472USA

List of Contributors XXVII

Chemical Research and Development

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Chemical Research and Development

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Shu YuPfizer Worldwide Research &Development

Chemical Research and DevelopmentEastern Point Road

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Michael J ZacutoMerck Research LaboratoriesGlobal Process ChemistryRahway, NJ 07065USA

XXVIII List of Contributors

Joshua R Dunetz and Javier Magano

When faced with life’s common maladies, such as the occasional headache, musclesoreness, 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 bythe Boots Pure Drug Company and patented in the 1960s [1] For several decades,the Boots synthesis would serve as the established method for the industrialmanufacture of this pharmaceutical compound (Scheme I.1) This process, whichhas supplied millions of pounds of ibuprofen throughout the years, comprises sixsteps and has the disadvantage of generating substantial amounts of industrialwaste Much of the waste stems from an indirect approach to the carboxylic acidmoiety through a series of functional group manipulations From a process safetyperspective, this route also suffers from intermediates and reagents containingpotentially hazardous, high-energy functional groups such as epoxide2, oxime 3,and hydroxylamine

In light of the pending patent expiration for ibuprofen in the mid-1980s, theBoots Company teamed with Hoechst Celanese Corporation to develop animproved synthesis of ibuprofen that addresses the inefficiencies of the originalroute 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 theimproved synthesis is a Pd-catalyzed carbonylation as thefinal step The reaction ofalcohol 5 with carbon monoxide, Pd catalyst, and phosphine ligand in acidicaqueous media (e.g., aq HCl) directly installs the carboxylic acid and avoids thearduous sequence of functional group manipulations from the original synthesis.This innovative application of transition metal catalysis provides a more efficientmanufacturing 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 tostreamline the synthesis of pharmaceuticals [4] These coupling technologies arecontinuously evolving to accommodate the increasing structural complexities ofAPIs (active pharmaceutical ingredients) Large-scale applications of transitionmetal catalysis for the manufacture of drug ingredients require processes that aresafe, efficient, and reliable Process chemists are also tasked with developingsynthetic routes that provide API with very high purity

XXIX

This book is not intended as a cursory overview of transition metal-catalyzedcouplings Rather, this book contains the personal accounts of process chemistsdescribing their own development of robust coupling processes for the synthesis ofpharmaceuticals Each case study details the optimization of a coupling reactionwhile elaborating on issues such as design of experiments, scalability andthroughput, product isolation, metal purging, process safety, cost efficiency, wastemanagement, and overall environmental impact The chapters span a wide range ofnamed coupling reactions: Suzuki–Miyaura, Negishi, Heck, Buchwald–Hartwig,Sonogashira, Kumada–Corriu, Tsuji–Trost, Migita, and Hayashi–Miyaura Othercase studies discuss the process development of metal-catalyzed cyanations,borylations, enolate arylations, carbonylations, and ring-closing metathesis Two ofthe threefinal chapters cover emerging technologies: the potential for large-scalecatalysis using continuous-flow processing and microwave heating, and applica-tions of designer surfactants for green catalysis in aqueous media The finalchapter reviews metal scavengers used for the removal of residual catalyst metalsfrom coupling products on process scale.

In editing this book, we had the privilege of collaborating with talented processchemists from pharmaceutical companies throughout the world, as well as twoinnovative professors at the forefront of developing creative solutions to processchemistry challenges The case studies we received are arranged alphabetically withrespect to the corresponding author; grouping chapters by reaction would havebeen problematic as some chapters discuss more than one type of coupling

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

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

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

XXX Introduction

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 40

-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.

References XXXI

nyl-2,20-diolBIPHEP 2,20-bis(diphenylphosphino)-1,10-biphenyl

phosphino]ethane

HIV human immunodeficiency virus

IMesHCl 1,3-bis(2,4,6-trimethylphenyl)imidazolium

chloride

(R,R)-MeDuPhos (–)-1,2-bis[(2R,5R)-2,5-dimethylphospholano]

benzene

NNRTI non-nucleoside reverse transcription inhibitor

stabilization, and initiation

-binaphthyl}[(2S)-(þ)-1,1-bis(4-meth-RuPhos 2-dicyclohexylphosphino-20,60

-diisopropoxybiphenyl

XXXVI List of Abbreviations

SPhos 2-dicyclohexylphosphino-20,60-dimethoxy-1,10

-biphenyl

TrixiePhos ()-2-di-t-butylphosphino-1,10-binaphthyl

triisopropylbiphenyl

List of Abbreviations XXXVII

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 Theincorporation 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 thissubstitution 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 canplay an important role Familiar technology helps not only in the planning stage butalso 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 elementcan be reduced if many technologies are accessible, as too many choices can makethe selection of a specific process difficult [2]

The general concepts for route selection were applied to the synthesis of indoline carboxylic acid (1), commonly called INDAC (Figure 1.1) This compound

(S)-2-is a component of angiotensin 1-converting enzyme (ACE) inhibitors indolapril (2)and perindopril (3)

A new process was required, as the existing manufacturing route had seven stepsand 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 Toachieve an efficient resolution, some functional group modifications were requiredthat added steps to the synthesis For example, the indole synthesis gives the ethylester6 that has to be hydrolyzed, while the nitrogen has to be acylated to stop itfrom interfering in the resolution

To increase the efficiency of the synthesis, a number of different strategiescan be envisioned for construction of the indole and the chiral center Indeed,other approaches had already been reported as well as different variations ofthe route shown in Scheme 1.1 These include classical resolution of theacid 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

1

Transition Metal-Catalyzed Couplings in Process Chemistry: Case Studies from the Pharmaceutical Industry,

First Edition Edited by Javier Magano and Joshua R Dunetz

Ó 2013 Wiley-VCH Verlag GmbH & Co KGaA Published 2013 by Wiley-VCH Verlag GmbH & Co KGaA.

which an aniline displaces an a-chlorocarboxylic acid, in turn derived from

an asymmetric reduction of the corresponding a-keto acid with sodiumborohydride in the presence of D-proline [16] The use of a chiral base toperform a kinetic resolution by acylation of a 2-substituted indole has alsobeen 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 accessthe 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 theapproaches require that the stereochemical integrity of the amine functionality

is retained during the N-arylation step Other work on the preparation ofarylamines 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 beingavailable [19]

A rapid entry to INDAC (1) would be to prepare the corresponding indoleand then perform an asymmetric reduction The hydrogenation of 2-substituted indoles has been achieved with Rh in the presence of (R,R)-2,200-bis[(S)-1-(diphenylphosphino)ethyl]-1,100-biferrocene ((S,S)-(R,R)-Ph-TRAP, 26)

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

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

2 1 Copper-Catalyzed Coupling for a Green Process