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Asymmetric Catalysis on Industrial Scale: Challenges, Approaches and Solutions, 2nd Edition

Asymmetric Catalysis on Industrial Scale: Challenges, Approaches and Solutions, 2nd Edition

Hans Ulrich Blaser (Editor), Hans-Jürgen Federsel (Editor)

ISBN: 978-3-527-64216-8

Aug 2011

580 pages



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.
List of Contributors.

Introduction. (Hans-Ulrich Blaser and Hans-Jürgen Federsel)

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.

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. (Kurt Püntener and Michelangelo Scalone)

2.1 Introduction.

2.2 Carbonyl Hydrogenations.

2.3 Imine Hydrogenation.

2.4 Conclusion.

3 Chiral Lactones in Assymetric Hydrogenation – a Step Forward in (+)-Biotin Production. (Werner Bonrath, Reinhard Karge, Thomas Netscher, Felix Roessler and Felix Spindler)

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. (James J. Lalonde and Jack Liang)

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 Reductions of Heterocyclic Ketones – A Key Step in the Synthesis of Potassium-competitive Acid Blockers (P-CABs). (Andreas Marc Palmer and Antonio Zanotti-Gerosa)

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-Tetrahydrochromenol[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 Building Blocks.

6 Application of a Multiple-Enzyme System for Chiral Alcohol Production. (Junzo Hasegawa, Hirokazu Nanba and Yoshihiko Yasohara)

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. (Robert A. Holt and Christopher D. Reeve)

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. (Jeroen A.F. Boogers, Dirk Sartor, Ulfried Felfer, Martina Kotthaus, Gerhard Steinbauer, Bert Dielemans, Laurent Lefort, André H.M. de Vries and Johannes G. de Vries)

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 AliskirenTM.

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 Assymmetric Phase-Transfer Catalysis for the Production of Non-Proteinogenic a-Amino Acids. (Masaya Ikunaka and Keiji Maruoka)

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. (Franz Dietrich Klingler)

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. (Christoph Jäkel and Rocco Paciello)

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. (Hideo Shimizu, Noboru Sayo, Takao Saito)

12.1 Introduction.

12.2 Improvement of the Synthetic Route to Biaryl Ligands.

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

12.4 Conclusion.

13 Catalytic Asymmetric Ring Opening: A Transfer from Academia to Industry. (Dirk Spielvogel)

13.1 Introduction.

13.2 Catalyst Preparation and Initial Optimization.

13.3 Further Optimization.

13.4 Process Adaptation.

13.5 Protecting Group Adaption.

13.6 Use of Benzoate as O-Nucleophile.

13.7 Chemical Elaboration.

13.8 Conclusion.

14 Asymmetric Baeyer–Villiger Reactions Using Whole-Cell Biocatalysts. (Roland Wohlgemuth and John M. Woodley)

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. (Roland Wohlgemuth)

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 Hyrdrogenation. (A. John Blacker and Peter Thompson)

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. (Oreste Piccolo)

17.1 Introduction.

17.2 Case Histories.

17.3 Conclusion.

18 The Power of Whole-Cell Reaction: Efficient Production of Hydropyroline, Sugar Nucleotides, Oligosaccharides and Dipeptides. (Shin-ichi Hashimoto, Satoshi Koizumi and Akio Ozaki)

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. (Frédéric Naud, Felix Spindler, Carsten Rueggeberg, Andreas T. Schimdt and Hans-Ulrich Blaser)

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 Hyrdogenation for the Design of Efficient Synthesis of Drug Substances. (Yongkui Sun, Shane Krska, Scott Shultz and David M. Tellers)

20.1 Introduction.

20.2 Laropiprant.

20.3 Taranabant.

20.4 Sitagliptin.

20.5 Conclusions and Outlook.

21 Scale-up of a Telescoped Enzymatic Hyrdrolysis Process for an Intermediate in the Synthesis of a Factor Xa Inhibitor. (Hans Iding, Beat Wirz, Jean-Michel Adam, Pascal Dott, Wolfgang Haap, Rosa Maria Rodríguez Sarmiento, Thomas Oberhauser, Reinhard Reents, Rolf Fischer and Stephan Lauper)

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, Assymetric Synthesis of Odanacatib, a Selective Inhibitor of Cathepsin K for the Treatment of Osteoporosis, Using an Enzyme-Mediated Dynamic Kinetic Resolution. (Matthew D. Truppo)

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. (Andy Wells)

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. (David M. Barnes)

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 Antagonists. (David R.J. Hose, Bharti Patel, Sharon A. Bowdenadn Jonathan D. Mosely)

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 Comparison and Conclusions.

26 Large-Scale Application of Asymmetric Phase-Transfer Catalysis for Amino Acid Synthesis. (Daniel E. Patterson, Shiping Xie, Lynda Jones, Martin H. Osterhout, Christopher G. Henry and Thomas D. Roper)

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. (Jeremy P. Scott)

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. (Jeremy D. Cobb, Bob E. Cooley, Roy C. Flanagan, Mary M. Jackson, Lynda A. Jones, Richard T. Matsuoka, Alan Millar, Daniel E. Patterson, Matthew J. Sharp, Jennifer F. Toczko, Shiping Xie and Xiaoming Zhou)

28.1 Introduction.

28.2 GSK260983A (1) for the HPV.

28.3 GSK873082X (2) for the HCV.

28.4 Conclusion.


"Overall, this book will be of interest to both industrial specialists and academics as it contains a good mix of chemistry and engineering. It provides comfort and inspiration to those working in this field through the numerous success stories told and is undoubtedly a useful source of potential contacts for those struggling with a particular asymmetric synthesis issue." (Platinum Metals Review, 2011)