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

Edited by
Javier Magano and
Joshua R. Dunetz
Transition Metal-Catalyzed
Couplings in Process
Chemistry


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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
Pfizer 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



VII

Contents
Foreword 1 XV
Foreword 2 XVII
Foreword 3 XIX
List of Contributors XXIII
Introduction XXIX
List of Abbreviations XXXIII
1
1.1
1.2
1.2.1
1.2.2
1.3
1.3.1
1.3.2
1.4

1.5

2

2.1
2.2
2.3
2.4
2.5

Copper-Catalyzed Coupling for a Green Process 1
David J. Ager and Johannes G. de Vries
Introduction 1
Synthesis of Amino Acid 14 4
Asymmetric Hydrogenation Approach 4
Enzymatic Approaches 5
Copper-Catalyzed Cyclization 6
C–N Bond Formation 6
INDAC (1) Synthesis 8
Sustainability 10
Summary 10
References 11
Experiences with Negishi Couplings on Technical Scale in Early
Development 15
Murat Acemoglu, Markus Baenziger, Christoph M. Krell,
and Wolfgang Marterer
Introduction 15
Synthesis of LBT613 via Pd-Catalyzed Negishi
Coupling 16
Elaboration of a Negishi Coupling in the Synthesis of

PDE472 19
Ni-Catalyzed Negishi Coupling with Catalytic Amounts
of ZnCl2 21
Conclusions 22
References 23


VIII

Contents

3

3.1
3.2
3.3
3.4
3.5

4

4.1
4.2
4.3
4.3.1
4.3.2
4.3.3
4.3.4
4.3.5
4.4

5
5.1
5.2
5.3
5.4
5.5
5.6

6

6.1
6.2
6.3
6.3.1
6.3.2
6.3.3
6.3.4
6.3.5

Developing Palladium-Catalyzed Arylations of Carbonyl-Activated
C–H Bonds 25
Carl A. Busacca and Chris H. Senanayake
Introduction 25
Suzuki Approach to Side Chain Installation 26
Arylation of Carbonyl-Activated C–H Bonds 30
Pd Purging from API 36
Conclusions 37
References 37
Development of a Practical Synthesis of Naphthyridone p38

MAP Kinase Inhibitor MK-0913 39
John Y.L. Chung
Introduction 39
Medicinal Chemistry Approach to 1 40
Results and Discussion 42
ADC Route to 21 42
Tandem Heck–Lactamization Route to 23 47
Suzuki–Miyaura Coupling 48
Preparation of Grignard 22 for Endgame Couplings 49
Coupling of Organomagnesium 22 and Naphthyridones 19–21 50
Conclusions 54
References 54
Practical Synthesis of a Cathepsin S Inhibitor 57
Xiaohu Deng, Neelakandha S. Mani, and Jimmy Liang
Introduction 57
Synthetic Strategy 59
Syntheses of Building Blocks 59
Sonogashira Coupling and Initial Purification of 1 63
Salt Selection 65
Conclusions 70
References 70
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 Tian
A Novel Chemical Entity 73
Evaluation of Synthetic Pathways: Finding the Best Route 73
Enabling C–N Coupling by Defining the Reaction Space 76
First Experiences 76
Setbacks and Problem Solutions 78

Scoping Out Key Parameters for Best Reaction Performance 79
Ligand Screening 79
Finding the Best Base 80


Contents

6.3.6
6.3.7
6.3.8
6.4
6.4.1
6.4.2
6.4.3
6.5

Optimizing the Ligand/Metal Ratio 81
Temperature Effect 82
Optimizing the Catalyst Loading 82
From Synthesis to Process 83
Demonstration on Scale 83
Environmental Performance 85
Impurity Tracking 86
Concluding Remarks 88
References 88

7

Process Development and Scale-up of PF-03941275, a Novel
Antibiotic 91

Kevin E. Henegar and Timothy A. Johnson
Introduction 91
Medicinal Chemistry Synthesis of PF-03941275 91
Synthesis of 5-Bromo-2,4-difluorobenzaldehyde (1) 93
Synthesis of Amine 3 93
Miyaura Borylation Reaction 95
Suzuki–Miyaura Coupling 97
Barbituric Acid Coupling 101
Chlorination and API Isolation 101
Conclusions 104
References 104

7.1
7.2
7.3
7.4
7.5
7.6
7.7
7.8
7.9

8

8.1
8.2
8.3
8.4
8.4.1
8.4.2

8.4.3
8.5

9

9.1
9.2
9.3
9.3.1

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
Introduction and Background 105
Stille Coupling 107
Suzuki Coupling 107
Negishi Coupling 109
Initial Investigation 109
Negishi Coupling Optimization 110
Negishi Coupling Process Scale-up 118
Comparison of Three Coupling Processes 119
References 119
Application of a Rhodium-Catalyzed, Asymmetric 1,4-Addition to the
Kilogram-Scale Manufacture of a Pharmaceutical Intermediate 121
Alexandra Parker
Introduction 121
Early Development 122
Process Optimization 126
Manufacturability 127

IX


X

Contents

9.3.2
9.4
9.5
9.6

Rhodium Removal 129
Process Scale-up 131
Recent Developments 133
Conclusions 133
References 134

10

Copper-Catalyzed C–N Coupling on Large Scale: An Industrial
Case Study 135
Arianna Ribecai and Paolo Stabile
Introduction 135
Process Development of the C–N Bond Formation 137
Choice of Catalytic System 140
Choice of Base: Inorganic Versus Organic 141
Choice of Solvent 142
Optimized Conditions for C–N Bond Formation to 1 142

Purging Residual Copper from 1 143
Conclusions 144
References 144

10.1
10.2
10.3
10.4
10.5
10.6
10.7
10.8

11

11.1
11.2
11.2.1
11.2.2
11.2.3
11.2.4
11.2.5
11.2.6
11.2.7
11.2.8
11.3

12

12.1

12.2
12.3
12.4

Development of a Highly Efficient Regio- and Stereoselective
Heck Reaction for the Large-Scale Manufacture
of an a4b2 NNR Agonist 147
Per Ryberg
Introduction 147
Process Optimization 149
Selectivity in the Heck Reaction 149
Identification of Selective Conditions for the Heck Coupling 149
Investigation of the Mechanism of the Heck Step 152
Identification of a Solution to the Pd Mirror Problem 153
Development of a Backup Method for Residual Pd Removal 156
Effect of Water on the Reaction 157
Development of a Semicontinuous Process Based on Catalyst
Recycling 159
Application on Large Scale 160
Conclusions 162
References 162
Commercial Development of Axitinib (AG-013736): Optimization of a
Convergent Pd-Catalyzed Coupling Assembly and Solid Form
Challenges 165
Robert A. Singer
Introduction 165
First-Generation Synthesis of Axitinib 165
Early Process Research and Development 167
Commercial Route Development 169

Contents

12.4.1
12.4.2
12.4.3
12.4.4
12.5

13

13.1
13.2
13.3
13.3.1
13.3.2
13.3.3
13.4
13.5

14
14.1
14.2
14.3
14.4
14.5

15

15.1

15.2
15.3
15.4
15.5
15.6
15.7

Development of the Migita Coupling (Step 1) and
Iodination (Step 2) 169
Control of Impurities after Iodination through Recrystallization
(Step 2R) 172
Development of the Heck Reaction 173
Control of Solid Form 176
Conclusions 178
References 179
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
Introduction 181
Background 181
Process Development of the Sonogashira Coupling 183
Solvent Screening 183
Catalyst Loading 185
Stoichiometry of 2-Ethynylpyridine (6) 185
Large-Scale Sonogashira Coupling and API Purification 186
Conclusions 187
References 188
Palladium-Catalyzed Bisallylation of Erythromycin Derivatives 189
Xiaowen Peng, Guoqiang Wang, and Datong Tang

Introduction 189
Discovery of 6,11-O,O-Bisallylation of Erythromycin
Derivatives 192
Process Development of 6,11-O,O-Bisallylation of Erythromycin
Derivatives 195
Discovery and Optimization of 3,6-Bicyclolides 199
Conclusions 200
References 200
Route Selection and Process Development for the Vanilloid Receptor-1
Antagonist AMG 517 201
Oliver R. Thiel and Jason S. Tedrow
Introduction 201
Retrosynthesis and Medicinal Chemistry Route 202
Optimization of Medicinal Chemistry Route 204
Identification of the Process Chemistry Route 207
Optimization of the Suzuki–Miyaura Reaction 208
Postcampaign Improvements 213
Summary 214
References 215

XI


XII

Contents

16

16.1

16.2
16.3
16.4

17

17.1
17.2
17.2.1
17.2.2
17.3
17.3.1
17.3.2
17.3.3

18

18.1
18.2
18.3
18.4
18.5
18.6
18.7

19

19.1
19.2
19.3

Transition Metal-Catalyzed Coupling Reactions in the Synthesis of
Taranabant: from Inception to Pilot Implementation 217
Debra J. Wallace
Introduction 217
Development of Pd-Catalyzed Cyanations 217
Development of Pd-Catalyzed Amidation Reactions 224
Conclusions 230
References 230
Ring-Closing Metathesis in the Large-Scale Synthesis of
SB-462795 233
Huan Wang
Background 233
The RCM Disconnection 233
Synthesis of the Azepanone Core: Amino Alcohols 2 and 3 233
Comparison of the Two RCM Reactions 235
The RCM of Diene 5 239
General Considerations: Solvent, Catalyst, and Temperature 239
Impact of Impurities in Diene 5 243
Large-Scale Performance 249
References 250
Development of Migita Couplings for the Manufacture of a
5-Lipoxygenase Inhibitor 253
Weiling Cai, Brian Chekal, David Damon, Danny LaFrance,
Kyle Leeman, Carlos Mojica, Andrew Palm, Michael St. Pierre,
Janice Sieser, Karen Sutherland, Rajappa Vaidyanathan,
John Van Alsten, Brian Vanderplas, Carrie Wager, Gerald Weisenburger,
Greg Withbroe, and Shu Yu
Introduction 253
Evaluation of the Sulfur Source for Initial Migita

Coupling 254
Selection of Metal Catalyst and Coupling Partners 255
Development of a One-Pot, Two-Migita Coupling Process 256
Crystallization of 1 with Polymorph Control 262
Final Commercial Process on Multikilogram Scale 263
Conclusions 265
References 265
Preparation of 4-Allylisoindoline via a Kumada Coupling with
Allylmagnesium Chloride 267
Michael J. Zacuto
Introduction 267
Kumada Coupling of 4-Bromoisoindoline 268
Workup 273


Contents

19.4
19.5

Isolation 275
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
Introduction 279
Microwave Heating in Preparative Chemistry 279
Continuous-Flow Processing in Preparative Chemistry 280
Coupling Reactions Performed Using Microwave Heating or
Continuous-Flow Processing 281
Suzuki–Miyaura and Heck Reactions 281
Batch Microwave Heating for Suzuki–Miyaura and Heck
Couplings 281
Continuous-Flow Processing for Suzuki–Miyaura and Heck
Couplings 286
Alkoxycarbonylation Reactions 287
Use of Batch Microwave Heating for Alkoxycarbonylation
Reactions 287
Continuous-Flow Processing for Alkoxycarbonylation
Reactions 291
Conclusions 294
References 295

20.1
20.1.1
20.1.2
20.2
20.2.1
20.2.1.1
20.2.1.2
20.2.2
20.2.2.1
20.2.2.2
20.3

21

21.1
21.2
21.3
21.4
21.5
21.6
21.7
21.7.1
21.7.2
21.8
21.9

Applying the Hydrophobic Effect to Transition Metal-Catalyzed
Couplings in Water at Room Temperature 299
Bruce H. Lipshutz
Introduction: the Hydrophobic Effect under Homogeneous and
Heterogeneous Conditions 299
Micellar Catalysis Using Designer Surfactants 300
First Generation: PTS 300
Heck Couplings in Water at rt 302
Olefin Metathesis Going Green 302
Adding Ammonia Equivalents onto Aromatic and
Heteroaromatic Rings 304
Couplings with Moisture-Sensitive Organometallics
in Water 305
Negishi-like Couplings 305
Organocopper-Catalyzed Conjugate Additions 307

A New, Third-Generation Surfactant: “Nok” 308
Summary, Conclusions, and a Look Forward 309
References 311

XIII


XIV

Contents

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
22.2.1
Extraction Methods 316
22.2.1.1 Sodium Bisulfite 316
22.2.1.2 Ethanolamine 317
22.2.1.3 Trimercaptotriazine 318
22.2.1.4 Ethylenediaminetetraacetic Acid Sodium Salts 322
22.2.1.5 Citric Acid 323
22.2.1.6 Cysteine 324
22.2.1.7 2-Mercaptonicotinic Acid 326

22.2.1.8 Ammonium Hydroxide 326
22.2.1.9 Tri-n-butylphosphine 328
22.2.1.10 Potassium Dihydrogenphosphate 330
22.2.2
Adsorption Methods 330
22.2.2.1 Activated Carbon 330
22.2.2.2 Macroporous Polystyrene Trimercaptotriazine 332
22.2.2.3 Smopex 333
22.2.2.4 Polymer-Bound DIAION CR20 Resin 335
22.2.2.5 Deloxan Resin 336
22.2.2.6 SiliaBond Thiol 337
22.2.2.7 Cysteine on Silica–Alumina 340
22.2.2.8 Chromatography on Alumina 341
22.3
Methods that Precipitate the Coupling Product while Purging the
Metal to the Filtrates 341
22.3.1
Tri-n-butylphosphine 341
22.3.2
Triethylamine 342
22.3.3
Ethylenediamine 343
22.3.4
N-Acetylcysteine 343
22.3.5
Phosphine/Amine Combination 345
22.3.6
N,N-Dimethylglycine 346
22.4
Miscellaneous Methods 347

22.4.1
BH3ÁMe3N 347
22.5
Other Methods for Metal Removal 348
22.6
Conclusions 349
References 350
Index 357


XV

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.


XVI

Foreword 1

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.
Camille Dreyfus Professor of Chemistry
Massachusetts Institute of Technology

Stephen L. Buchwald


XVII

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


XVIII

Foreword 2

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.
Scientific Update LLP
Editor, Organic Process Research and Development

Trevor Laird


XIX

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.
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 [1]. Many

of these APIs could be manufactured by

reaction of amines with the commercially
available 40 -(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].

MgCl
ZnCl2
THF, 0 °C
CN

+ Cl

Ni(acac)2 (7.5 mol%,
5 wt% H2O)
P(O-iPr)3 (15 mol%)

CN

THF, 40 °C, 6 h

ZnCl

OTBN (89%)

bromination

Cl
N
HO
N

N N
N NK

Br

CN

4'-(bromomethyl)biphenyl-2-carbonitrile
losartan potassium


XX

Foreword 3

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 moisturesensitive 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


Foreword 3

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

Neal G. Anderson

References
1 Yet, L. (2007) Chapter 9: Angiotensin AT1

4 Buchwald, S.L. and Bolm, C. (2009) Angew.
antagonists for hypertension, in The Art of
Chem., Int. Ed., 48, 5586.
Drug Synthesis (eds D.S. Johnson and J.J. Li), 5 Arvela, R.K., Leadbeater, N.E., Sangi, M.S.,
Williams, V.A., Granados, P., and Singer,
John Wiley & Sons, Inc., New York,
R.D. (2005) J. Org. Chem., 70, 161.
pp 129–141.
2 (a) Miller, J.A. and Farrell, R.P. (1998)
6 For some examples, see Corbet, J.-P. and
Tetrahedron Lett., 39, 6441; (b) Miller, J.A. and
Mignani F G. (2006) Chem. Rev., 106, 2651.
7 Magano, J. and Dunetz, J.R. (2011) Chem.
Farrell, R.P. (2001) US Patent 6,194,599
Rev., 111, 2177.
(to Catalytica, Inc.).
3 Laird, T. (2009) Org. Process Res. Dev., 13,
823.

XXI



XXIII

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


XXIV

List of Contributors

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

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 S€
odert€alje

Sweden

and

Kevin E. Henegar
Pfizer Worldwide Research &
Development
Chemical Research & Development
Eastern Point Road
Groton, CT 06340
USA

Janssen Pharmaceutica
Department of Pharmaceutical
Development and Manufacturing
Sciences
Turnhoutseweg 30
2340 Beerse
Belgium

Rolf Herter
Boehringer Ingelheim
Pharmaceuticals, Inc.
Chemical Development
900 Ridgebury Road
Ridgefield, CT 06877
USA

Roger M. Farr
Wyeth Pharmaceuticals

Department of Chemical and
Pharmaceutical Development
401 N. Middletown Rd.
Pearl River, NY 10965
USA

Azad Hossain
Boehringer Ingelheim
Pharmaceuticals, Inc.
Chemical Development
900 Ridgebury Road
Ridgefield, CT 06877
USA

Hans-J€
urgen Federsel
AstraZeneca
Pharmaceutical Development
Silk Road Business Park
Macclesfield
Cheshire SK10 2NA
UK

Timothy A. Johnson
Pfizer Veterinary Medicine Research
& Development
Medicinal Chemistry
333 Portage Street
Kalamazoo, MI 49007
USA

List of Contributors

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

XXV