Abstract Process Economics Program Report 232 CHIRAL INTERMEDIATES (March 2001) Chiral chemicals are a unique class of compounds that, although chemically identical, exist as mirror images of each other called enantiomers. Chiral compounds touch many aspects of everyday life. The chirality of a compound affects how food tastes, how drugs interact in the body, and how quickly products decompose in the environment. Major identified markets for chiral compounds include: Pharmaceuticals. Agricultural chemicals. Food and feed additives. Polymers. Production methods for chiral compounds encompass many diverse technologies. This report reviews three major technologies for the production of chiral compounds: Resolution by crystallization of diastereomers. Resolution by enzymes. Asymmetric synthesis by biocatalysis. PEP 98 RGB/TFM
CONTENTS GLOSSARY... xiii 1 INTRODUCTION... 1-1 2 SUMMARY... 2-1 NAPROXEN RESOLUTION BY CRYSTALLIZATION... 2-1 1-PHENYLETHYLAMINE BY ENZYMATIC RESOLUTION...2-2 D-PHENYLALANINE BY BIOCATALYTIC CONVERSION...2-2 ECONOMICS... 2-2 PROCESS MATURITY...2-4 TOTAL FIXED CAPITAL... 2-4 CONCLUSIONS... 2-5 3 INDUSTRY STATUS...3-1 PHARMACEUTICALS... 3-1 AGROCHEMICALS... 3-2 FOOD, FLAVORS, AND FEED ADDITIVES...3-2 SPECIALTY POLYMERS... 3-2 PRODUCERS OF CHIRAL CHEMICALS AND THEIR TECHNOLOGIES... 3-2 4 CHEMISTRY... 4-1 INTRODUCTION...4-1 HISTORY AND NOMENCLATURE... 4-1 Enantiomeric Excess...4-2 Racemization... 4-3 Chiral Sources...4-3 Chiral Pool... 4-3 Resolution by Crystallization... 4-3 Production of Resolving Agent... 4-4 Reaction of Resolving Agent and Naproxen...4-5 iii
CONTENTS (Continued) 4 CHEMISTRY (Concluded) Recovery of Resolving Agent...4-6 Recovery of Product...4-7 Racemization of R-Naproxen...4-7 ENZYMATIC RESOLUTION OF RACEMIC MIXTURES... 4-7 Enzyme Catalysis...4-8 D-PHENYLALANINE SYNTHESIS BY BIOCATALYSIS... 4-9 5 NAPROXEN RESOLUTION BY CRYSTALLIZATION... 5-1 INTRODUCTION...5-1 PROCESS REVIEW...5-1 Classical Resolution...5-1 Crystallization of Conglomerates... 5-1 Crystallization of Racemic Compounds... 5-3 PROCESS DESCRIPTION... 5-5 Overview of the Process... 5-5 Section 100 Resolution and Racemization...5-6 Recrystallization... 5-6 Racemization and Recycle... 5-7 Section 200 Regeneration of Resolving Agent... 5-7 Section 300 Product Recovery...5-7 PROCESS DISCUSSION...5-18 Product Recovery...5-19 Racemization... 5-19 Waste Generation... 5-19 Materials of Construction... 5-19 CAPITAL AND PRODUCTION COSTS... 5-19 Capital Costs... 5-20 Production Costs... 5-20 iv
CONTENTS (Continued) 6 SEPARATION OF CHIRAL AMINES BY ENZYMATIC TRANSFORMATION... 6-1 INTRODUCTION...6-1 CHEMISTRY... 6-1 Enzyme Catalysis...6-1 PROCESS REVIEW...6-3 Hydrolysis of Amide... 6-3 Racemization... 6-4 PROCESS DESCRIPTION... 6-5 Enzymatic Resolution... 6-5 Acylation... 6-5 Separations...6-5 Amide Hydrolysis...6-6 Re-Esterification... 6-6 Racemization... 6-6 PROCESS DISCUSSION...6-21 Acylation...6-21 Distillation/Separation... 6-21 Amide Hydrolysis...6-21 Ester Regeneration... 6-21 Waste Streams...6-21 Liquid...6-21 Solid... 6-22 Gaseous...6-22 Materials of Construction... 6-22 Uncertainties... 6-22 Enzyme Consumption... 6-22 CAPITAL AND OPERATING COSTS...6-22 v
CONTENTS (Continued) 7 D-PHE SYNTHESIS BY BIOCATALYSIS...7-1 PROCESS REVIEW...7-1 Synthesis of Amino Acids... 7-1 Unnatural Amino Acids...7-1 Production of Starting Materials...7-4 Biocatalyst... 7-6 Other Processes... 7-6 PROCESS DESCRIPTION... 7-8 Section 100 Fermentation and Biomass Separation... 7-8 Preparation of Growth Media...7-8 Fermentor Sterilization...7-9 Fermentor Inoculation... 7-9 D-Phenylalanine Production... 7-9 Separation of Biomass...7-10 Section 200 Product Recovery...7-10 Ion-Exchange Step... 7-10 Concentration... 7-10 Section 300 Crystallization and Packaging... 7-10 PROCESS DISCUSSION...7-21 Biocatalyst Production... 7-21 Raw Materials... 7-21 Bioconversion... 7-21 Acidification of Fermentation Broth...7-22 Removal of Biomass...7-22 Recovery of Amino Acid by Ion-Exchange... 7-22 Concentration of Eluant...7-22 Solids Recovery... 7-23 vi
CONTENTS (Continued) 7 D-PHE SYNTHESIS BY BIOCATALYSIS (Concluded) Waste Generation... 7-23 Aqueous Wastes...7-23 Gaseous Wastes...7-23 Solid Wastes... 7-23 Materials of Construction... 7-23 COST ESTIMATES... 7-24 Capital Costs... 7-24 Production Costs... 7-24 8 CHIRAL CHEMICALS FROM ENANTIOSELECTIVE CATALYSIS...8-1 INTRODUCTION...8-1 WHEN TO USE CATALYSIS?... 8-1 Chiral Intermediate Strategy... 8-1 Homogenous vs. Heterogeneous Catalysis...8-3 Catalyst/Ligand Recovery...8-3 Water-Soluble Chiral Phosphine Ligands...8-4 PRODUCTION-SCALE CATALYTIC REACTIONS... 8-5 Metolachlor Example Development of an Industrial Asymmetric Synthesis...8-5 Process for Producing Racemic Metolachlor... 8-6 Selection of Synthesis Route...8-6 Development of Catalytic System... 8-7 Other Production-Scale Catalytic Reactions...8-8 Hydrogenation of a Dehydroamino Acid Derivative for an L-Dopa Intermediate.. 8-8 Synthetic Route for L-Phenyl-Alanine [Enichem]...8-9 Intermediate for Vitamin E [Takasago]...8-9 Intermediate for Biotin (Vitamin) [Lonza]...8-10 Intermediate for Benazepril [Solvias]... 8-10 Intermediate for S-Oxfloxazin (Bactericide) [Takasago]...8-10 Intermediate for Antibiotic Carbapenem [Takasago]...8-11 Intermediate for Antibiotic Carbapenem [NSC Technologies]...8-11 vii
CONTENTS (Concluded) 8 CHIRAL CHEMICALS FROM ENANTIOSELECTIVE CATALYSIS (Concluded) Epoxidation...8-11 Intermediate for Disparlure Pheromone [J.T. Baker]...8-11 Chiral Building Block [PPG-Sipsy]... 8-12 Intermediate for Protease Inhibitor [Merck/Chirex (Sepracor)]...8-13 Cyclopropanation...8-13 Intermediate for Cilastatin (Dehydropetidase) [Sumitomo]...8-13 Isomerization... 8-13 Intermediate for L-Menthol and Citronellol [Takasago]...8-13 Structure of Selected Ligands Used in Chiral Synthesis...8-14 Example of Synthesis of Chiral Ligand (DuPhos)...8-15 Future Directions in Asymmetric Catalysis... 8-15 9 EMERGING CHIRAL SEPARATION TECHNIQUES...9-1 INTRODUCTION...9-1 CHIRAL CHROMATOGRAPHY...9-1 FACILITATED TRANSPORT (FACILIMAX )...9-2 SUMMARY... 9-4 APPENDIX A: PATENT SUMMARY TABLES...A-1 APPENDIX B: DESIGN AND COST BASES... B-1 APPENDIX C: CITED REFERENCES... C-1 APPENDIX D: PATENT REFERENCES BY COMPANY... D-1 APPENDIX E: PROCESS FLOW DIAGRAMS...E-1 viii
ILLUSTRATIONS 4.1 Opposite Bending of Polarized Light by Different Crystals in Solution...4-1 4.2 Fischer Projection... 4-2 4.3 Cahn-Ingold-Prelog Convention...4-2 4.4 Chemical Schematic for S-Naproxen... 4-4 4.5 Conceptual Diagram of Enzyme Catalysis... 4-8 5.1 Conglomerate Mixture... 5-2 5.2 Resolution of Conglomerate Mixture... 5-2 5.3 Racemic Compound... 5-3 5.4 Crystallization of Racemic Mixture with Resolving Agent...5-4 6.1 Enantioselective Enzyme-Catalyzed Acylation...6-2 6.2 Conceptual Diagram of Enzyme Catalysis...6-2 6.3 Ketone-Amine Racemization Chemistry...6-4 6.4 Separation of Chiral Amines by Enzymatic Transformation: Block Flow Diagram...6-7 9.1 True Moving Bed Schematic...9-2 9.2 Simulated Moving Bed Schematic... 9-3 9.3 Facilimax Schematic... 9-4 ix
TABLES 2.1 Chiral Compounds: Manufacturing Cost Summaries...2-3 2.2 Chiral Compounds: Total Fixed Capital...2-4 2.3 Chiral Compounds: Utility Costs Per Pound...2-5 2.4 Chiral Compounds: Conversion Costs Per Pound...2-5 3.1 Chiral Synthesis Technologies... 3-3 5.1 Classical Resolution by Crystallization: Patent Summary...A-3 5.2 Resolving Agent Summary... 5-5 5.3 Naproxen Resolution by Crystallization: Design Bases and Assumptions...5-8 5.4 Naproxen Resolution by Crystallization: Stream Flows...5-11 5.5 Naproxen Resolution by Crystallization: Utilities Summary... 5-15 5.6 Naproxen Resolution by Crystallization: Major Equipment...5-16 5.7 Naproxen Resolution by Crystallization: Total Capital Investment... 5-21 5.8 Naproxen Resolution by Crystallization: Capital Investment by Section... 5-22 5.9 Naproxen Resolution by Crystallization: Production Costs...5-23 5.10 Naproxen Resolution by Crystallization: Direct Costs by Section... 5-25 6.1 Separation of Chiral Amines by Enzymatic Transformation: Patent Summary... A-5 6.2 Separation of Chiral Amines by Enzymatic Transformation: Design Bases and Assumptions... 6-8 6.3 Separation of Chiral Amines by Enzymatic Transformation: Stream Flows... 6-9 6.4 Separation of Chiral Amines by Enzymatic Transformation: Major Equipment...6-17 6.5 Separation of Chiral Amines by Enzymatic Transformation: Utilities Summary...6-20 6.6 Separation of Chiral Amines by Enzymatic Transformation: Total Capital Investment... 6-24 6.7 Separation of Chiral Amines by Enzymatic Transformation: Capital Investment by Section... 6-25 6.8 Separation of Chiral Amines by Enzymatic Transformation: Production Costs...6-26 7.1 D-Phenylalanine by Biocatalytic Conversion: Patent Summary... A-7 x
TABLES (Concluded) 7.2 Amino Acids and Corresponding Keto Acids... 7-3 7.3 Typical Batch Growth Media...7-9 7.4 D-Phenylalanine by Biocatalytic Conversion: Design Bases and Assumptions... 7-12 7.5 D-Phenylalanine by Biocatalytic Conversion: Stream Flows... 7-14 7.6 D-Phenylalanine by Biocatalytic Conversion: Major Equipment... 7-18 7.7 D-Phenylalanine by Biocatalytic Conversion: Utilities Summary...7-20 7.8 D-Phenylalanine by Biocatalytic Conversion: Total Capital Investment... 7-25 7.9 D-Phenylalanine by Biocatalytic Conversion: Capital Investment by Section... 7-26 7.10 D-Phenylalanine by Biocatalytic Conversion: Production Costs...7-27 7.11 D-Phenylalanine by Biocatalytic Conversion: Direct Costs by Section...7-29 8.1 Strengths and Weaknesses of Chiral Production Methods...8-2 8.2 Industrial Status of Various Enantiomeric Catalytic Reaction Classes...8-5 8.3 Effect of Substituent Groups on Iridium-Ferrocenyldiphosphine- Catalyzed Hydrogenation of MEA-Imine...8-7 xi