Pharmaceutical Process Chemistry

Covering the whole area of process chemistry in the pharmaceutical industry, this monograph provides the essential knowledge on the basic chemistry needed for future development and key industrial techniques, as well as morphology, engineering and regulatory compliances.
Application-oriented and well structured, the authors include recent examples of excellent industrial production of active pharmaceutical ingredients.

Takayuki Shioiri is Emeritus Professor of Nagoya city University and President of the Japanese Society for Process Chemistry (JSPC). After working at University of Tokyo as research Associate, Assistant Professor, and then Associate Professor, he was appointed Professor at Faculty of Pharmaceutical Sciences, Nagoya city University in 1977. After retirement, he became Professor of Meijo University and retired again in 2007. Throughout his career, he explored a number of reagents including DPPA ((C₆H₅O)₂P(O)N₃) as well as Me₃SiCHN₂, and utilized these for the synthesis of a number of biologically interesting natural products, especially aquatic ones. By these works, he was awarded the Pharmaceutical Society of Japan Award and the Japanese Peptide Society Award. He was an Executive Editor of tetrahedron and President of the Japanese Peptide Society. he is an author/collaborator on over 400 articles, book chapters, and scientific presentations.

Kunisuke Izawa received his Ph.D. from Osaka University. In 1973, he joined Ajinomoto Co. to develop a new catalytic process. After carrying out postdoctoral research at MIT for two years, he returned in 1981 to the same company aiming at discovery of new methodology for pharmaceuticals. In 1990, he moved to the Process research as a general manager. Since then, he engaged in the process development of pharmaceutical fine chemicals in Ajinomoto. In 1999, he became a corporate executive fellow and an advisor of present. He is also serving as a vice president in the Society of Synthetic Organic Chemistry, Japan in 2009-2010 and an auditor of JSPC. His research interest is in the field of organic synthesis utilizing amino acids and nucleosides. He published over 200 scientific papers and patents.

Toshiro Konoike received his Ph.D from Kyoto University in 1976, and joined Shionogi research Laboratories to develop a Synthetic method of 1-oxacephems. After spending two years at University of Pittsburgh as a postdoctoral fellow, he returned to Shionogi to discover a new drug as a medicinal chemist. He started his career of a process chemist in 2997 as a general manager of the chemical Development Laboratories, and he is currently a research advisor of Shionogi CMC Development Laboratories. His research interest covers process chemistry and new manufacturing Methodology. He is the fellow of the chemical Society of Japan and a board member of JSPC. He received the Chemical technology Award from the Kinki Chemical Society. He published 40 scientific papers and filed 30 patents.

Preface.

List of Contributors.

1 From Milligrams to Tons: The Importance of Synthesis and Process Research in the Development of New Drugs (Martin Karpf).

1.1 Introduction.

1.2 The Synthetic Development of the Monoamine Oxidase-B Inhibitor Lazabemide

1.3 The Synthetic Development of the Lipase Inhibitor Tetrahydrolipstatin (Xenical).

1.4 The Synthetic Development of the HIV Protease Inhibitor Saquinavir (Invirase).

1.5 The Synthetic Development of the Influenza Neuraminidase Inhibitor Oseltamivir Phosphate (Tamiflu).

References.

2 Design of Dynamic Salt Catalysts Based on Acid–Base Combination Chemistry (Kazuaki Ishihara).

2.1 Introduction.

2.2 Dehydrative Condensation Catalysts Pharmaceutical Process Chemistry (Takayuki Shioiri, Kunisuke Izawa, and Toshiro Konoike).

2.3 Asymmetric Mannich-Type Catalysts.

References.

3 Asymmetric Oxidation with Hydrogen Peroxide, an Effective and Versatile Oxidant (Tsutomu Katsuki).

3.1 Introduction.

3.2 Asymmetric Epoxidation.

3.3 Asymmetric Oxidation of Sulfides.

3.4 Conclusion.

References.

4 Development of Palladium Catalysts for Chemoselective Hydrogenation (Hironao Sajiki and Yasunari Monguchi).

4.1 Catalyst Poisons and Chemoselective Heterogeneous Catalysts.

4.2 Catalyst Supports and Chemoselective Heterogeneous Catalysts.

4.3 Summary.

Acknowledgment.

References.

5 Silicon-Based Carbon–Carbon Bond Formation by Transition Metal Catalysis (Yoshiaki Nakao and Tamejiro Hiyama).

5.1 Introduction.

5.2 Cross-Coupling Reactions.

5.3 Carbonyl Addition Reaction.

5.4 Recent Developments in Catalytic Preparation of Organosilanes.

References.

6 Direct Reductive Amination with Amine Boranes (Karl Matos and Elizabeth R. Burkhardt).

6.1 Introduction.

6.2 Types of Amine Boranes.

6.3 Comparison to Sodium Triacetoxyborohydride (STAB).

6.4 Primary Amine Synthesis.

6.5 Stereoselective Reductive Amination.

6.6 Reaction Solvents.

6.7 Reaction Workup.

6.8 Conclusion.

References.

7 Industrial Synthesis of Perfluorinated Building Blocks by Liquid-Phase Direct Fluorination (Takashi Okazoe).

7.1 Introduction.

7.2 History of Direct Fluorination.

7.3 Synthetic Methods Using Perfluorinated Acyl Fluorides for Industrially Important Perfluorinated Monomers.

7.4 Synthesis of Perfluorinated Building Blocks by the PERFECT Method.

7.5 Conclusion.

References.

8 Cross-Linked Enzyme Aggregates as Industrial Biocatalysts (Roger A. Sheldon).

8.1 Introduction.

8.2 Cross-Linked Enzyme Aggregates.

8.3 CLEAs from Hydrolases.

8.4 Oxidoreductases.

8.5 Lyases.

8.6 Combi-CLEAs and Cascade Processes.

8.7 Reactor Design.

8.8 Conclusions and Prospects.

References.

9 Application of Whole-Cell Biocatalysts in the Manufacture of Fine Chemicals (Michael Schwarm).

9.1 Introduction: Early Applications of Biocatalysis for Amino Acid Manufacture at Evonik Degussa.

9.2 Hydantoinase Biocatalysts.

9.3 Amino Acid Dehydrogenase Biocatalysts.

9.4 Alcohol Dehydrogenase Biocatalysts.

9.5 Summary.

Acknowledgments.

References.

10 Process Development of Amrubicin Hydrochloride, an Anthracycline Anticancer Drug (Kazuhiko Takahashi and Mitsuharu Hanada).

10.1 Introduction.

10.2 Original Synthetic Route for Amrubicin.

10.3 Amrubicin Bulk Production Synthetic Method.

10.4 Conclusion.

References.

11 Process Development of HIV Integrase Inhibitor S-1360 (Toshiro Konoike and Sumio Shimizu).

11.1 Introduction.

11.2 Discovery of Integrase Inhibitor S-1360.

11.3 Synthesis of Two Starting Materials for S-1360.

11.4 Process Chemistry of S-1360 and Scale-Up of THP Route.

11.5 Process Development of S-1360 and Commercial Route by Methoxyisopropyl (MIP) Protection.

11.6 Summary and Outlook.

Acknowledgments.

References.

12 An Efficient Synthesis of the Protein Kinase Cβ Inhibitor JTT-010 (Takashi Inaba).

12.1 Introduction.

12.2 Synthetic Strategies.

12.3 Key Intermediate Synthesis.

12.4 Replacement of the Hydroxyl Group of 1 with an Amino Group.

12.5 Construction of JTT-010.

12.6 Conclusion.

References.

13 Process Development of Oral Carbapenem Tebipenem Pivoxil, TBPM-PI (Takao Abe and Masataka Kitamura).

13.1 Introduction.

13.2 Discovery of TBPM-PI.

13.3 Synthetic Process of Side Chain on the C2-Position of TBPM, TAT.

13.4 Synthetic Process of TBPM-PI from 4-Nitrobenzyl (1R,5R,6S)-2-diphenylphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate, MAP.

13.5 Summary and Outlook.

Acknowledgments.

References.

14 Some Progress in Organic Synthesis of Pharmaceuticals in China (Delong Liu and Wanbin Zhang).

14.1 Introduction.

14.2 Industrial Synthesis of Chinese Herbal Medicines.

14.3 New Agents Derived from Chinese Herbal Medicines.

14.4 Process Chemistry for l-Ascorbic Acid and Biotin.

14.5 Conclusion and Perspectives.

Abbreviations.

References.

15 The Use of Continuous Processing to Make AZD 4407 Intermediates (Andrew S. Wells).

15.1 Green Chemistry and the Drive for Sustainability.

15.2 Advantages of Chemistry in Continuous-Flow Reactors.

15.3 Introduction to AZD 4407.

15.4 Comparison of the Synthetic Routes Used to Prepare AZD 4407.

15.5 Conversion of Batch to a Flow Process.

15.6 Conclusions.

Acknowledgments.

References.

16 Sustainable Processes Based on Enzymes Enabling 100% Yield and 100% ee Concepts (Oliver May).

16.1 Introduction.

16.2 Asymmetric Synthesis.

16.3 Enzymatic Desymmetrization.

16.4 Enzymatic Deracemization.

16.5 Dynamic Kinetic Resolution.

16.6 Summary and Outlook.

References.

17 Development of a Novel Synthetic Method for RNA Oligomers (Tadaaki Ohgi and Junichi Yano).

17.1 Introduction.

17.2 Synthesis of CEM Amidites.

17.3 Synthesis of RNA Oligomers from CEM Amidites.

Acknowledgments.

References.

18 Process Research with Explosive Reactions (Hiromu Kawakubo).

18.1 Introduction.

18.2 Safety Evaluation of an Explosive Chemical Process.

18.3 Standard Procedures for Risk Assessment.

18.4 Safety Evaluation of Nitroacetic Acid Ethyl Ester.

18.5 Development of an Efficient Method for the Synthesis of Nitrobenzene Derivatives.

References.

19 Scientific Strategy for Optical Resolution by Salt Crystallization: New Methodologies for Controlling Crystal Shape, Crystallization, and Chirality of Diastereomeric Salt (Rumiko Sakurai and Kenichi Sakai).

19.1 Introduction.

19.2 Control of Crystal Shape: Crystal Habit Modification.

19.3 Control of Crystallization: Concept of Space Filler.

19.4 Control of Chirality: Dielectrically Controlled Optical Resolution (DCR).

19.5 Conclusion and Prospect.

References.

20 Development of New Drug and Crystal Polymorphs (Mitsuhisa Yamano).

20.1 Introduction.

20.2 Scope of Crystal Polymorphs.

20.3 Late-Appearing Polymorphs.

20.4 Late-Appearing Polymorphs as a Process Research Issue.

20.5 Drug Substance Form Selection.

20.6 Polymorph Screening.

20.7 Thermodynamically Stable Polymorphs.

20.8 Polymorph Control.

20.9 Primary Nucleation.

20.10 Summary.

Acknowledgments.

References.

21 Development of LIPOzymes Based on Biomembrane Process Chemistry (Hiroshi Umakoshi, Toshinori Shimanouchi, and Ryoichi Kuboi).

21.1 Introduction.

21.2 From ‘‘Process Chemistry’’ to ‘‘Biomembrane Process Chemistry’’.

21.3 Recognition (Separation) Function of Liposomes.

21.4 LIPOzyme: Liposome with Enzyme-Like Activity?

21.4.1 Break-Down Type LIPOzyme.

21.4.2 Build-Up Type LIPOzyme.

21.5 Biomembrane Interference.

21.6 Summary.

Acknowledgments.

References.

22 Matching Chemistry with Chemical Engineering for Optimum Design and Performance of Pharmaceutical Processing (Amit V. Mahulkar, Parag R. Gogate, and Aniruddha B. Pandit).

22.1 Concept of Molecule to Money.

22.2 Steps Involved in Bringing Molecule to Market.

22.3 Interrelation in Each Step and Concept of Unit Operations.

22.4 Unit Operations.

22.5 Scale-up Problems.

22.6 Optimization and Intensification of Unit Operations.

22.7 Summary.

References.

23 The Integration of Safety, Health, and Environmental Considerations into Process Development (Wesley White, Vyv Coombe, and Jonathan Moseley).

23.1 Introduction.

23.2 Process Safety.

23.3 Health.

23.4 Environment.

23.5 The Use of Risk Assessment.

23.6 Conclusion.

Acknowledgments.

References.

Index.