Asymmetric Catalysis on Industrial Scale E-Book

• Herausgeber: Wiley-VCH
• Kategorie: Fachliteratur
• Sprache: Englisch

Seitenzahl: 837

Veröffentlichungsjahr: 2011

Beschreibung

This second edition of the pioneering work on this hot topic captures the major trends and latest achievements in the art of asymmetric catalysis on an industrial scale. A number of completely new real-life case studies written by the world leaders in their respective areas provide a compact and qualified insight into this developing field. The resulting ready reference and handbook collates first-hand and valuable information within a context where it can be easily found.
The high-quality contributions illustrate the relevant environments and situations, such as time pressure, how the catalytic step fits into the overall synthesis, or competition with other synthetic approaches, as well as the typical problems encountered in the various phases, including finding/developing the catalyst and optimization of the process or choice of equipment. Both successful and unsuccessful approaches to solve these problems are described.

Leseprobe

Contents

List of Contributors

Introduction

Part I: New processes for Existing Active Compounds (APIs)

1: Some Recent Examples in Developing Biocatalytic Pharmaceutical Processes

1.1 Introduction

1.2 Levetiracetam (Keppra®)

1.3 Atorvastatin (Lipitor®)

1.4 Pregabalin (Lyrica®)

1.5 Conclusion

2: Enantioselective Hydrogenation: Applications in Process R&D of Pharmaceuticals

2.1 Introduction

2.2 Carbonyl Hydrogenations

2.3 Imine Hydrogenation

2.4 Conclusion

3: Chiral Lactones by Asymmetric Hydrogenation - a Step Forward in (+)-Biotin Production

3.1 Introduction: (+)-Biotin as an Example for the Industrial Production of Vitamins

3.2 Commercial Syntheses and Other Routes to (+)-Biotin by Total Synthesis

3.3 Catalytic Asymmetric Reduction of Cyclic Anhydride to D-Lactone

3.4 Conclusion

4: Biocatalytic Asymmetric Oxidation for the Production of Bicyclic Proline Peptidomimetics

4.1 Introduction

4.2 Development of Routes to 1 and 2

4.3 Asymmetric Biocatalytic Amine Oxidation

4.4 Enzyme Evolution - Current State of the Art

4.5 Amine Oxidase Evolution

4.6 Chemical Development

4.7 Optimization of Cyanation

4.8 Conclusion

5: The Asymmetric Reduction of Heterocyclic Ketones - a Key Step in the Synthesis of Potassium-Competitive Acid Blockers (P-CABs)

5.1 Potassium-Competitive Acid Blockers - a New Option for the Treatment of Acid-Related Diseases

5.2 Discovery and Development of 7H-8,9-Dihydropyrano[2,3-c]imidazo[1,2-a]pyridines as Potassium-Competitive Acid Blockers

5.3 Noyori-Type Catalysts for the Asymmetric Reduction of Prochiral Ketones

5.4 Research Overview

5.5 Asymmetric Reduction of Ketones Bearing the Imidazo[1,2-a]pyridine Skeleton

5.6 Asymmetric Reduction of Ketones Bearing the 3,6,7,8-Tetrahydrochromeno[7,8-d]imidazole Skeleton

5.7 Large-Scale Asymmetric Synthesis of the 3,6,7,8-Tetrahydrochromeno[7,8-d]imidazole BYK 405879

5.8 Conclusions

Part II: Processes for Important Buildings Blocks

6: Application of a Multiple-Enzyme System for Chiral Alcohol Production

6.1 Introduction

6.2 Construction of an Enzymatic Reduction System

6.3 Enzymatic Stereoinversion System

7: Chemoenzymatic Route to the Side-Chain of Rosuvastatin

7.1 Introduction

7.2 Route Selection

7.3 Process Development

7.4 Conclusion

8: Asymmetric Hydrogenation of a 2-Isopropylcinnamic Acid Derivative en Route to the Blood Pressure-Lowering Agent Aliskiren

8.1 Introduction

8.2 Development of Monodentate Phosphoramidites as Ligands for Asymmetric Hydrogenation

8.3 Instant Ligand Libraries of Monodentate BINOL-Based Phosphoramidites

8.4 Aliskiren™

8.5 High-Throughput Screening in Search of a Cheap Phosphoramidite Ligand

8.6 Mixtures of Ligands

8.7 Further Screening of Conditions

8.8 Validation and Pilot Plant Run

8.9 Instant Ligand Library Screening to Further Optimize Rate and ee

8.10 Validations

8.11 Recent Developments in the Asymmetric Hydrogenation of 3

8.12 Conclusion

9: Asymmetric Phase-Transfer Catalysis for the Production of Non-Proteinogenic α-Amino Acids

9.1 Background

9.2 Designer’s Chiral Phase-Transfer Catalysts

9.3 Synthesis of the C2-Symmetric Chiral Mono-1,1′-Binaphthyl-Derived Catalyst

9.4 Application of Enantiomers of 21 to the Industrial Production of NPAAs

9.5 Conclusion

10: Development of Efficient Technical Processes for the Production of Enantiopure Amino Alcohols in the Pharmaceutical Industry

10.1 Introduction

10.2 Phenylephrine

10.3 Adrenaline (Epinephrine)

10.4 Lobeline

10.5 Availability of the Catalyst

10.6 General Remarks on the Development of Industrial Processes for Asymmetric Hydrogenation

11: The Asymmetric Hydrogenation of Enones - Access to a New L-Menthol Synthesis

11.1 Introduction

11.2 Screening of Metal Complexes, Conditions, and Ligands

11.3 Scale-Up and Mechanistic Work

11.4 Catalyst Recycling and Continuous Processing

11.5 Conclusion

12: Eliminating Barriers in Large-Scale Asymmetric Synthesis

12.1 Introduction

12.2 Improvement of the Synthetic Route to Biaryl Ligands

12.3 Development of an Efficient Process En Route to Unprotected β-Amino Acids

12.4 Conclusion

13: Catalytic Asymmetric Ring Opening: A Transfer from Academia to Industry

13.1 Introduction

13.2 Catalyst Preparation and Initial Optimization

13.3 Further Optimization

13.4 Process Adaptation

13.5 Protecting Group Adaptation

13.6 Use of Benzoate as O-nucleophile

13.7 Chemical Elaboration

13.8 Conclusion

14: Asymmetric Baeyer-Villiger Reactions Using Whole-Cell Biocatalysts

14.1 Introduction

14.2 Chemistry

14.3 Biocatalysts

14.4 Process Screening and Design

14.5 Downstream Processing

14.6 Future Process Developments

14.7 Perspective

15: Large-Scale Applications of Hydrolases in Biocatalytic Asymmetric Synthesis

15.1 Introduction

15.2 Chemistry

15.3 Biocatalyst

15.4 Process Screening and Design

15.5 Downstream Processing and Purification

15.6 Future Process Developments

15.7 Perspectives

16: Scale-Up Studies in Asymmetric Transfer Hydrogenation

16.1 Background

16.2 Reaction Components

16.3 Case Studies

16.4 Conclusions

17: 2,2′,5,5′-Tetramethyl-4,4′-bis(diphenylphoshino)-3,3′-bithiophene: A Very Efficient Chiral Ligand for Ru-Catalyzed Asymmetric Hydrogenations on the Multi-Kilograms Scale

17.1 Introduction

17.2 Case Histories

17.3 Conclusion

18: The Power of Whole-Cell Reaction: Efficient Production of Hydroxyproline, Sugar Nucleotides, Oligosaccharides, and Dipeptides

18.1 Introduction

18.2 Production of Hydroxyproline by Asymmetric Hydroxylation of L-Proline

18.3 Oligosaccharide Production by Bacterial Coupling

18.4 Dipeptide Production Systems

18.5 Conclusion and Perspective

19: Enantioselective Ketone Hydrogenation: from Research to Pilot Scale with Industrially Viable Ru-(Phosphine-Oxazoline) Complexes

19.1 Introduction

19.2 Ligand Screening and Optimization of the Reaction Conditions

19.3 Quality Risks

19.4 Health and Safety

19.5 Catalyst Removal

19.6 Final Process

Part III: Processes for New Chemical Entities (NCEs)

20: Enabling Asymmetric Hydrogenation for the Design of Efficient Synthesis of Drug Substances

20.1 Introduction

20.2 Laropiprant

20.3 Taranabant

20.4 Sitagliptin

20.5 Conclusions and Outlook

21: Scale-up of a Telescoped Enzymatic Hydrolysis Process for an Intermediate in the Synthesis of a Factor Xa Inhibitor

21.1 Introduction

21.2 The Discovery Chemistry Synthesis

21.3 Optimization and Multi-Kilogram Supply of Monoacid (R,R)-2

21.4 Process Development of the N-Boc Approach

21.5 Scalable Enzymatic Monohydrolysis of the Diester (R,R)-1

21.6 Production - Experimental Part

21.7 Evaluation of an Enzymatic Alternative - the N-Difluoroethyl Approach

21.8 Discussion

22: An Efficient, Asymmetric Synthesis of Odanacatib, a Selective Inhibitor of Cathepsin K for the Treatment of Osteoporosis, Using an Enzyme-Mediated Dynamic Kinetic Resolution

22.1 Introduction

22.2 Fluoroleucine Synthesis Strategy

22.3 First-Generation Enzymatic Dynamic Kinetic Resolution: Batch Process

22.4 Development of Enzymatic Dynamic Kinetic Resolution: Towards a Manufacturing Process

22.5 Pilot Plant Runs

22.6 Conclusion

23: Biocatalytic Routes to the GPIIb/IIIa Antagonist Lotrafiban, SB 214857

23.1 Introduction

23.2 The Medicinal Chemistry Route of Synthesis

23.3 The First Biocatalytic Route - a Late-Stage Resolution

23.4 Early-Stage Resolution

23.5 Catalase for the Removal of Iodide

23.6 Other Synthetic Strategies to Chiral Lotrafiban Intermediates

23.7 The End Game

24: Discovery and Development of a Catalytic Asymmetric Conjugate Addition of Ketoesters to Nitroalkenes and Its Use in the Large-Scale Preparation of ABT-546

24.1 Introduction

24.2 Retrosynthetic Analysis of ABT-546

24.3 Early Asymmetric Syntheses

24.4 Synthesis of the Reaction Partners

24.5 Discovery of the Asymmetric Conjugate Addition Reaction

24.6 Completion of the Synthesis of ABT-546

24.7 Extension to Other Reaction Partners

24.8 Conclusion

25: The Kagan Oxidation - Industrial-Scale Asymmetric Sulfoxidations in the Synthesis of Two Related NK1/NK2 Antagonists

25.1 Introduction

25.2 Background and Introduction to ZD7944

25.3 Introduction to the ZD7944 CBz Sulfoxide Stage

25.4 Process Development of ZD7944 CBz Sulfoxide

25.5 Additional Investigations in the Development of ZD7944 CBz Sulfoxide

25.6 The Impact of Other Stages on the ZD7944 CBz Sulfoxide Process

25.7 Summary of ZD7944

25.8 Background and Introduction to ZD2249

25.9 Process Development of ZD2249 CBz Sulfoxide

25.10 Summary of ZD2249

25.11 Comparisons and Conclusions

26: Large-Scale Application of Asymmetric Phase-Transfer Catalysis for Amino Acid Synthesis

26.1 Introduction

26.2 Initial Strategy

26.3 Synthesis of 4,4′-Difluorobenzylhydryl Bromide

26.4 Initial Studies and Optimization

26.5 Scale-Up of the PTC Alkylation

26.6 Conclusion

26.7 Experimental

27: Application of Phase-Transfer Catalysis in the Organocatalytic Asymmetric Synthesis of an Estrogen Receptor Beta-Selective Agonist

27.1 Introduction

27.2 Medicinal Chemistry Synthesis and Revised Synthetic Plan

27.3 Preparation of the Phase-Transfer Substrate 11

27.4 Asymmetric Phase-Transfer Michael Addition

27.5 Ether Cleavage, Cyclization, and Chlorination

27.6 Conclusion

28: Asymmetric Synthesis of HCV and HPV Drug Candidates on Scale: The Choice Between Enantioselective and Diastereoselective Syntheses

28.1 Introduction

28.2 GSK260983A (1) for the HPV

28.3 GW873082X (2) for the HCV

28.4 Conclusion

Index

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ISBN: 978-3-527-32489-7

List of Contributors

Jean-Michel Adam

F. Hoffmann-La Roche Ltd. Pharma Research Basel Technical Sciences Chemical Synthesis Synthesis and Process Research Basel Switzerland

David M. Barnes

Abbott Laboratories PPD Process Research 1401 Sheridan Road North Chicago IL 60064 USA

A. John Blacker

Piramal Healthcare R&D Leeds Road Huddersfield HD1 9GA UK and University of Leeds Institute of Process Research Development School of Chemistry Leeds, LS2 9JT UK

Hans-Ulrich Blaser

Solvias AG P.O. Box CH-4002 Basel Switzerland

Werner Bonrath

DSM Nutritional Products Research and Development P.O. Box 2676 4002 Basel Switzerland

Jeroen A. F. Boogers

DSM Innovative Synthesis BV A unit of DSM Pharma Chemicals PO Box 18 6160 MD Geleen The Netherlands

Sharon A. Bowden

AstraZeneca PR&D Avlon Works Severn Road Hallen Bristol, BS10 7ZE UK

Z. Chen

Elevance Renewable Sciences 175 E. Crossroad Parkway Bolingbrook IL 60440 USA

Jeremy D. Cobb

GlaxoSmithKline Chemical Development 5 Moore Drive PO Box 13398 Research Triangle Park NC 27709-3398 USA

Bob E. Cooley

GlaxoSmithKline Chemical Development 5 Moore Drive PO Box 13398 Research Triangle Park NC 27709-3398 USA

Johannes G. de Vries

DSM Innovative Synthesis BV A unit of DSM Pharma Chemicals PO Box 18 6160 MD Geleen The Netherlands

André H. M. de Vries

DSM Innovative Synthesis BV A unit of DSM Pharma Chemicals PO Box 18 6160 MD Geleen The Netherlands

Bert Dielemans

DSM Innovative Synthesis BV A unit of DSM Pharma Chemicals PO Box 18 6160 MD Geleen The Netherlands

Pascal Dott

F. Hoffmann-La Roche Ltd. Pharma Research Basel Technical Sciences Chemical Synthesis Kilolab Basel Switzerland

Hans-Jürgen Federsel

Director of Science Pharmaceutical Development AstraZeneca 151 85 Södertälje Sweden

Ulfried Felfer

DSM Fine Chemicals Austria Nfg GmbH & Co Kg St.-Peter-Strasse 25 4021 Linz Austria

Rolf Fischer

F. Hoffmann-La Roche Ltd. Pharma Technical Development Basel Switzerland

Roy C. Flanagan

GlaxoSmithKline Chemical Development 5 Moore Drive PO Box 13398 Research Triangle Park NC 27709-3398 USA

Wolfgang Haap

F. Hoffmann-La Roche Ltd. Pharma Research Basel Discovery Chemistry Basel Switzerland

Junzo Hasegawa

Kaneka Corporation Frontier Biochemical and Medical Research Laboratories 1–8 Miyamae Takasago Hyogo 676-8688 Japan

Shin-ichi Hashimoto

Kyowa Hakko Bio Co. Ltd. Manufacturing Technology Division 1-6-1 Ohtemachi Chiyoda-ku Tokyo 100-8185 Japan

Christopher G. Henry

GlaxoSmithKline Chemical Development 5 Moore Drive PO Box 13398 Research Triangle Park NC 27709-3398 USA

Robert A. Holt

Piramal Healthcare Wilton Centre Redcar Cleveland TS104RF UK

David R. J. Hose

AstraZeneca PR&D Avlon Works Severn Road Hallen Bristol, BS10 7ZE UK

Hans Iding

F. Hoffmann-La Roche Ltd. Pharma Research Basel Technical Sciences Chemical Synthesis Biocatalysis Basel Switzerland

Masaya Ikunaka

Nagase & Co., Ltd. Fine Chemicals Department 5-1, Nihonbashi-Kobunacho Chuo-ku Tokyo 103-8355 Japan and Yasuda Women’s University Faculty of Pharmacy Department of Pharmaceutical Chemistry 6-13-1, Yasuhigashi Asaminami-ku Hiroshima 731-0153 Japan

Mary M. Jackson

GlaxoSmithKline Chemical Development 5 Moore Drive PO Box 13398 Research Triangle Park NC 27709-3398 USA

Christoph Jäkel

BASF SE GCB/C-M313 67056 Ludwigshafen Germany

Lynda A. Jones

GlaxoSmithKline Chemical Development 5 Moore Drive PO Box 13398 Research Triangle Park NC 27709-3398 USA

Reinhard Karge

DSM Nutritional Products Research and Development P.O. Box 2676 4002 Basel Switzerland

Franz Dietrich Klingler

Boehringer Ingelheim Pharma GmbH & Co. KG Department of Process Development 55216 Ingelheim am Rhein Germany

Satoshi Koizumi

Kyowa Hakko Bio Co. Ltd. Manufacturing Technology Division 1-6-1 Ohtemachi Chiyoda-ku Tokyo 100-8185 Japan

Martina Kotthaus

DSM Fine Chemicals Austria Nfg GmbH & Co Kg St.-Peter-Strasse 25 4021 Linz Austria

Shane Krska

Merck & Co., Inc. Department of Process Research Merck Research Laboratories Rahway NJ 07065 USA

James J. Lalonde

Codexis, Inc. 200 Penobscot Drive Redwood City CA 94063 USA

Stephan Lauper

F. Hoffmann-La Roche Ltd. Pharma Technical Development Basel Switzerland

Laurent Lefort

DSM Innovative Synthesis BV A unit of DSM Pharma Chemicals PO Box 18 6160 MD Geleen The Netherlands

Jack Liang

Codexis, Inc. 200 Penobscot Drive Redwood City CA 94063 USA

J. Liu

Elevance Renewable Sciences 175 E. Crossroad Parkway Bolingbrook IL 60440 USA

Keiji Maruoka

Kyoto University Graduate School of Science Department of Chemistry Sakyo Kyoto 606-8502 Japan

Richard T. Matsuoka

GlaxoSmithKline Chemical Development 5 Moore Drive PO Box 13398 Research Triangle Park NC 27709-3398 USA

Alan Millar

GlaxoSmithKline Chemical Development 5 Moore Drive PO Box 13398 Research Triangle Park NC 27709-3398 USA

Jonathan D. Moseley

AstraZeneca PR&D Avlon Works Severn Road Hallen Bristol, BS10 7ZE UK

Hirokazu Nanba

Kaneka Corporation Frontier Biochemical and Medical Research Laboratories 1–8 Miyamae Takasago Hyogo 676-8688 Japan

Frédéric Naud

Solvias AG P.O. Box CH-4002 Basel Switzerland

Thomas Netscher

DSM Nutritional Products Research and Development P.O. Box 2676 4002 Basel Switzerland

Thomas Oberhauser

F. Hoffmann-La Roche Ltd. Pharma Technical Development Basel Switzerland

Martin H. Osterhout

GlaxoSmithKline Chemical Development 5 Moore Drive PO Box 13398 Research Triangle Park NC 27709-3398 USA

Akio Ozaki

Kyowa Hakko Bio Co. Ltd. Manufacturing Technology Division 1-6-1 Ohtemachi Chiyoda-ku Tokyo 100-8185 Japan

Rocco Paciello

BASF SE GCB/H-M313 67056 Ludwigshafen Germany

Andreas Marc Palmer

Nycomed GmbH Department of Medicinal Chemistry Byk-Gulden-Strasse 2 78467 Konstanz Germany

Bharti Patel

AstraZeneca PR&D Avlon Works Severn Road Hallen Bristol, BS10 7ZE UK

Daniel E. Patterson

GlaxoSmithKline Chemical Development 5 Moore Drive PO Box 13398 Research Triangle Park NC 27709-3398 USA

Oreste Piccolo

Studio di Consulenza Scientifica Via Bornó 5 23896 Sirtori Italy

Kurt Püntener

F. Hoffmann-La Roche Ltd. Pharmaceuticals Division Synthesis Research & Catalysis 4070 Basel Switzerland

Reinhard Reents

F. Hoffmann-La Roche Ltd. Pharma Technical Development Basel Switzerland

Christopher D. Reeve

Piramal Healthcare Wilton Centre Redcar Cleveland TS104RF UK

Felix Roessler

DSM Nutritional Products Research and Development P.O. Box 2676 4002 Basel Switzerland

Thomas D. Roper

GlaxoSmithKline Chemical Development 5 Moore Drive PO Box 13398 Research Triangle Park NC 27709-3398 USA

Carsten Rueggeberg

Rohner AG Gempen strasse 6 CH-4133 Pratteln Switzerland

Takao Saito

Takasago International Corporation Fine Chemicals Division Nissay Aroma Square 17F 5-37-1 Kamata Ohta-ku Tokyo 144-8721 Japan

Rosa Maria Rodriguez Sarmiento

F. Hoffmann-La Roche Ltd. Pharma Research Basel Discovery Chemistry Basel Switzerland

Dirk Sartor

DSM Fine Chemicals Austria Nfg GmbH & Co Kg St.-Peter-Strasse 25 4021 Linz Austria

Noboru Sayo

Takasago International Corporation Corporate Research and Development Division Fine Chemical Laboratory 1-4-11 Nishi-yawata Hiratsuka City Kanagawa 254-0073 Japan

Michelangelo Scalone

F. Hoffmann-La Roche Ltd. Pharmaceuticals Division Synthesis Research & Catalysis 4070 Basel Switzerland

Andreas T. Schmidt

Rohner AG Gempen strasse 6 CH-4133 Pratteln Switzerland

Jeremy P. Scott

Merck Sharp & Dohme Research Laboratories Department of Process Research Hertford Road Hoddesdon Hertfordshire, EN11 9BU UK

Matthew J. Sharp

GlaxoSmithKline Chemical Development 5 Moore Drive PO Box 13398 Research Triangle Park NC 27709-3398 USA

Hideo Shimizu

Takasago International Corporation Corporate Research and Development Division Fine Chemical Laboratory 1-4-11 Nishi-yawata Hiratsuka City Kanagawa 254-0073 Japan

C. Scott Shultz

Merck & Co., Inc. Department of Process Research Merck Research Laboratories Rahway NJ 07065 USA

Dirk Spielvogel

Solvias AG PO Box 4002 Basel Switzerland

Felix Spindler

Solvias AG P.O. Box CH-4002 Basel Switzerland

Gerhard Steinbauer

DSM Fine Chemicals Austria Nfg GmbH & Co Kg St.-Peter-Strasse 25 4021 Linz Austria

Yongkui Sun

Merck & Co., Inc. Department of Process Research Merck Research Laboratories Rahway NJ 07065 USA

Junhua Tao

Elevance Renewable Sciences 175 E. Crossroad Parkway Bolingbrook IL 60440 USA

David M. Tellers

Merck & Co., Inc. Department of Process Research Merck Research Laboratories Rahway NJ 07065 USA

Peter Thompson

Piramal Healthcare R&D Leeds Road Huddersfield HD1 9GA UK

Jennifer F. Toczko

GlaxoSmithKline Chemical Development 5 Moore Drive PO Box 13398 Research Triangle Park NC 27709-3398 USA

Matthew D. Truppo

Merck & Co., Inc. Department of Process Research Merck Research Laboratories Rahway, NJ 07065 USA

Andy Wells

AstraZeneca Global Process R&D 42/2/2.0 Bakewell Road Loughborough Leicestershire, LE11 5RH UK

Beat Wirz

F. Hoffmann-La Roche Ltd. Pharma Research Basel Technical Sciences Chemical Synthesis Biocatalysis Basel Switzerland

Roland Wohlgemuth

Sigma-Aldrich Research Specialties Industriestrasse 25 9470 Buchs Switzerland

John M. Woodley

Technical University of Denmark Center for BioProcess Engineering Department of Chemical and Biochemical Engineering 2800 Lyngby Denmark

Shiping Xie

GlaxoSmithKline Chemical Development 5 Moore Drive PO Box 13398 Research Triangle Park NC 27709-3398 USA

Yoshihiko Yasohara

Kaneka Corporation Frontier Biochemical and Medical Research Laboratories 1–8 Miyamae Takasago Hyogo 676-8688 Japan

Antonio Zanotti-Gerosa

Johnson Matthey Catalysis and Chiral Technologies 28 Cambridge Science Park Cambridge, CB4 0FP United Kingdom

Xiaoming Zhou

GlaxoSmithKline Chemical Development 5 Moore Drive PO Box 13398 Research Triangle Park NC 27709-3398 USA

Part I

New processes for Existing Active Compounds (APIs)

1

Some Recent Examples in Developing Biocatalytic Pharmaceutical Processes

Junhua Tao, J. Liu, and Z. Chen

1.1 Introduction

A confluence of factors is driving biocatalysis into a premier platform for the production of pharmaceuticals. First, the technology itself is more practical than ever for commercialization as a result of easy access of biocatalyst tool boxes from the GenBank, efficient expression systems for their production, and robust protein engineering techniques to improve their specificity, selectivity, and stability. Second, to improve the therapeutic index and absorption, desorption, metabolism, excretion, and toxicity (ADMET) profile, new chemical entities (NCEs) as pharmaceutical ingredients are structurally increasingly more complex, which conversely demand more selective transformations for bond connection and disconnection, manipulation of functional groups, and stereoselectivity. Third, catalytic process technology is posed to be the most crucial component in commercializing drug substances and even drug products as drug innovators or branded pharmaceutical companies are entering the generic business by launching generic versions of branded drugs. The premium paid to ‘the first mover’ by a generic company will be significantly decreased. Not only is biocatalysis intrinsically process efficient under the principles of green chemistry, it also provides a stronghold to generate novel routes with freedom to operate (FTO) and/or proprietary intellectual property (IP). This chapter focuses on the development of three chemoenzymatic routes to illustrate the dynamics of the field and the importance of strategic integration of chemical and biological transformation to shorten synthetic sequences, reduce energy input, and enhance process safety.