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

– Javier Magano

For Cynthia, for Caitlin.

– Joshua R. Dunetz

Foreword 1

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

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

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

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

Stephen L. Buchwald

Camille Dreyfus Professor of Chemistry

Massachusetts Institute of Technology

Foreword 2

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

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

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

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

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

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

Trevor Laird

Scientific Update LLP

Editor, Organic Process Research and Development

Foreword 3

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

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

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

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

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

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

Neal G. Anderson

Anderson's Process Solutions LLC

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

Note

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

References

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

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

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

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

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

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

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

List of Contributors

Murat Acemoglu

Novartis Pharma

Chemical & Analytical Development

4002 Basel

Switzerland

David J. Ager

DSM Innovative Synthesis B.V.

950 Strickland Road, Suite 103

Raleigh, NC 27615

USA

Markus Baenziger

Novartis Pharma

Chemical & Analytical Development

4002 Basel

Switzerland

Carl A. Busacca

Boehringer Ingelheim Pharmaceuticals, Inc.

Chemical Development

900 Ridgebury Road

Ridgefield, CT 06877

USA

Weiling Cai

Pfizer Worldwide Research & Development

Chemical Research and Development

Eastern Point Road

Groton, CT 06340

USA

Brian Chekal

Pfizer Worldwide Research & Development

Chemical Research and Development

Eastern Point Road

Groton, CT 06340

USA

John Y.L. Chung

Merck Research Laboratories

Global Process Chemistry

126 E. Lincoln Ave

Rahway, NJ 07065

USA

David Damon

Pfizer Worldwide Research & Development

Chemical Research and Development

Eastern Point Road

Groton, CT 06340

USA

Xiaohu Deng

Janssen Research & Development LLC

3210 Merryfield Row

San Diego, CA 92121

USA

Johannes G. de Vries

DSM Innovative Synthesis B.V.

6160 MD Geleen

The Netherlands

Joshua R. Dunetz

Pfizer Worldwide Research & Development

Chemical Research & Development

Eastern Point Road

Groton, CT 06340

USA

Vittorio Farina

Boehringer Ingelheim Pharmaceuticals, Inc.

Chemical Development

900 Ridgebury Road

Ridgefield, CT 06877

USA

and

Janssen Pharmaceutica

Department of Pharmaceutical Development and Manufacturing Sciences

Turnhoutseweg 30

2340 Beerse

Belgium

Roger M. Farr

Wyeth Pharmaceuticals

Department of Chemical and Pharmaceutical Development

401 N. Middletown Rd.

Pearl River, NY 10965

USA

Hans-Jürgen Federsel

AstraZeneca

Pharmaceutical Development

Silk Road Business Park

Macclesfield Cheshire SK10 2NA

UK

Mousumi Ghosh

Wyeth Pharmaceuticals

Department of Chemical and Pharmaceutical Development

401 N. Middletown Rd.

Pearl River, NY 10965

USA

Martin Hedberg

SP Technical Research Institute of Sweden

SP Process Development AB

15121 Södertälje

Sweden

Kevin E. Henegar

Pfizer Worldwide Research & Development

Chemical Research & Development

Eastern Point Road

Groton, CT 06340

USA

Rolf Herter

Boehringer Ingelheim Pharmaceuticals, Inc.

Chemical Development

900 Ridgebury Road

Ridgefield, CT 06877

USA

Azad Hossain

Boehringer Ingelheim Pharmaceuticals, Inc.

Chemical Development

900 Ridgebury Road

Ridgefield, CT 06877

USA

Timothy A. Johnson

Pfizer Veterinary Medicine Research & Development

Medicinal Chemistry

333 Portage Street

Kalamazoo, MI 49007

USA

Christoph M. Krell

Novartis Pharma

Chemical & Analytical Development

4002 Basel

Switzerland

Danny LaFrance

Pfizer Worldwide Research & Development

Chemical Research and Development

Eastern Point Road

Groton, CT 06340

USA

Nicholas E. Leadbeater

University of Connecticut

Department of Chemistry

55 North Eagleville Road

Storrs, CT 06269

USA

Kyle Leeman

Pfizer Worldwide Research & Development

Chemical Research and Development

Eastern Point Road

Groton, CT 06340

USA

Guisheng Li

Boehringer Ingelheim Pharmaceuticals, Inc.

Chemical Development

900 Ridgebury Road

Ridgefield, CT 06877

USA

Jimmy Liang

Janssen Research & Development LLC

3210 Merryfield Row

San Diego, CA 92121

USA

Bruce H. Lipshutz

University of California

Department of Chemistry & Biochemistry

Santa Barbara, CA 93106

USA

Bruce Z. Lu

Boehringer Ingelheim Pharmaceuticals, Inc.

Chemical Development

900 Ridgebury Road

Ridgefield, CT 06877

USA

Javier Magano

Pfizer Worldwide Research & Development

Chemical Research & Development

Eastern Point Road

Groton, CT 06340

USA

Neelakandha S. Mani

Janssen Research & Development LLC

3210 Merryfield Row

San Diego, CA 92121

USA

Wolfgang Marterer

Novartis Pharma

Chemical & Analytical Development

4002 Basel

Switzerland

Carlos Mojica

Pfizer Worldwide Research & Development

Chemical Research and Development

Eastern Point Road

Groton, CT 06340

USA

Andrew Palm

Pfizer Worldwide Research & Development

Chemical Research and Development

Eastern Point Road

Groton, CT 06340

USA

Alexandra Parker

AstraZeneca

Pharmaceutical Development

Silk Road Business Park, Charter Way

Macclesfield, Cheshire SK10 2NA

UK

Xiaowen Peng

Enanta Pharmaceuticals, Inc.

Chemistry Department

500 Arsenal Street

Watertown, MA 02472

USA

Fredrik R. Qvarnström

AstraZeneca

Pharmaceutical Development

15185 Södertälje

Sweden

Arianna Ribecai

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

Research & Development

Viale Milano 26

36075 Montecchio Maggiore (VI)

Italy

Frank Roschangar

Boehringer Ingelheim Pharmaceuticals, Inc.

Chemical Development

900 Ridgebury Road

Ridgefield, CT 06877

USA

Per Ryberg

AstraZeneca

Pharmaceutical Development

Chemical Science

Forskargatan 18

15185 Södertälje

Sweden

Chris H. Senanayake

Boehringer Ingelheim Pharmaceuticals, Inc.

Chemical Development

900 Ridgebury Road

Ridgefield, CT 06877

USA

Janice Sieser

Pfizer Worldwide Research & Development

Chemical Research and Development

Eastern Point Road

Groton, CT 06340

USA

Robert A. Singer

Pfizer Global Research & Development

Chemical Research & Development

Eastern Point Road

Groton, CT 06340

USA

Jeffrey B. Sperry

Pfizer Worldwide Research & Development

Chemical Research & Development

Eastern Point Road

Groton, CT 06340

USA

Paolo Stabile

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

Research & Development

Viale Milano 26

36075 Montecchio Maggiore (VI)

Italy

Michael St. Pierre

Pfizer Worldwide Research & Development

Chemical Research and Development

Eastern Point Road

Groton, CT 06340

USA

Karen Sutherland

Pfizer Worldwide Research & Development

Chemical Research and Development

Eastern Point Road

Groton, CT 06340

USA

Datong Tang

Enanta Pharmaceuticals, Inc.

Chemistry Department

500 Arsenal Street

Watertown, MA 02472

USA

Jason S. Tedrow

Amgen

Chemical Process Research and Development

One Amgen Center Drive

Thousand Oaks, CA 91320-1799

USA

Oliver R. Thiel

Amgen

Chemical Process Research and Development

One Amgen Center Drive

Thousand Oaks, CA 91320-1799

USA

Wei Tian

AstraZeneca

Pharmaceutical Development

15185 Södertälje

Sweden

Rajappa Vaidyanathan

Pfizer Worldwide Research & Development

Chemical Research and Development

Eastern Point Road

Groton, CT 06340

USA

John Van Alsten

Pfizer Worldwide Research & Development

Chemical Research and Development

Eastern Point Road

Groton, CT 06340

USA

Brian Vanderplas

Pfizer Worldwide Research & Development

Chemical Research and Development

Eastern Point Road

Groton, CT 06340

USA

Carrie Wager

Pfizer Worldwide Research & Development

Chemical Research and Development

Eastern Point Road

Groton, CT 06340

USA

Debra J. Wallace

Merck Research Laboratories

Global Process Chemistry

Rahway, NJ 07065

USA

Guoqiang Wang

Enanta Pharmaceuticals, Inc.

Chemistry Department

500 Arsenal Street

Watertown, MA 02472

USA

Huan Wang

GlaxoSmithKline

API Chemistry & Analysis

709 Swedeland Road

King of Prussia, PA 19406

USA

Gerald Weisenburger

Pfizer Worldwide Research & Development

Chemical Research and Development

Eastern Point Road

Groton, CT 06340

USA

Greg Withbroe

Pfizer Worldwide Research & Development

Chemical Research and Development

Eastern Point Road

Groton, CT 06340

USA

Shu Yu

Pfizer Worldwide Research & Development

Chemical Research and Development

Eastern Point Road

Groton, CT 06340

USA

Michael J. Zacuto

Merck Research Laboratories

Global Process Chemistry

Rahway, NJ 07065

USA

Introduction

Joshua R. Dunetz and Javier Magano

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

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

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

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

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

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

References

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

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

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

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

List of Abbreviations

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