Abstract Process Economics Program Report 232 CHIRAL INTERMEDIATES (March 2001)

Transcription

1 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

2 CONTENTS GLOSSARY... xiii 1 INTRODUCTION SUMMARY NAPROXEN RESOLUTION BY CRYSTALLIZATION PHENYLETHYLAMINE BY ENZYMATIC RESOLUTION D-PHENYLALANINE BY BIOCATALYTIC CONVERSION ECONOMICS PROCESS MATURITY TOTAL FIXED CAPITAL CONCLUSIONS INDUSTRY STATUS PHARMACEUTICALS AGROCHEMICALS FOOD, FLAVORS, AND FEED ADDITIVES SPECIALTY POLYMERS PRODUCERS OF CHIRAL CHEMICALS AND THEIR TECHNOLOGIES CHEMISTRY INTRODUCTION HISTORY AND NOMENCLATURE Enantiomeric Excess Racemization Chiral Sources Chiral Pool Resolution by Crystallization Production of Resolving Agent Reaction of Resolving Agent and Naproxen iii

3 CONTENTS (Continued) 4 CHEMISTRY (Concluded) Recovery of Resolving Agent Recovery of Product Racemization of R-Naproxen ENZYMATIC RESOLUTION OF RACEMIC MIXTURES Enzyme Catalysis D-PHENYLALANINE SYNTHESIS BY BIOCATALYSIS NAPROXEN RESOLUTION BY CRYSTALLIZATION INTRODUCTION PROCESS REVIEW Classical Resolution Crystallization of Conglomerates Crystallization of Racemic Compounds PROCESS DESCRIPTION Overview of the Process Section 100 Resolution and Racemization Recrystallization Racemization and Recycle Section 200 Regeneration of Resolving Agent Section 300 Product Recovery PROCESS DISCUSSION Product Recovery Racemization Waste Generation Materials of Construction CAPITAL AND PRODUCTION COSTS Capital Costs Production Costs iv

4 CONTENTS (Continued) 6 SEPARATION OF CHIRAL AMINES BY ENZYMATIC TRANSFORMATION INTRODUCTION CHEMISTRY Enzyme Catalysis PROCESS REVIEW Hydrolysis of Amide Racemization PROCESS DESCRIPTION Enzymatic Resolution Acylation Separations Amide Hydrolysis Re-Esterification Racemization PROCESS DISCUSSION Acylation Distillation/Separation Amide Hydrolysis Ester Regeneration Waste Streams Liquid Solid Gaseous Materials of Construction Uncertainties Enzyme Consumption CAPITAL AND OPERATING COSTS v

5 CONTENTS (Continued) 7 D-PHE SYNTHESIS BY BIOCATALYSIS PROCESS REVIEW Synthesis of Amino Acids Unnatural Amino Acids Production of Starting Materials Biocatalyst Other Processes PROCESS DESCRIPTION Section 100 Fermentation and Biomass Separation Preparation of Growth Media Fermentor Sterilization Fermentor Inoculation D-Phenylalanine Production Separation of Biomass Section 200 Product Recovery Ion-Exchange Step Concentration Section 300 Crystallization and Packaging PROCESS DISCUSSION Biocatalyst Production Raw Materials Bioconversion Acidification of Fermentation Broth Removal of Biomass Recovery of Amino Acid by Ion-Exchange Concentration of Eluant Solids Recovery vi

6 CONTENTS (Continued) 7 D-PHE SYNTHESIS BY BIOCATALYSIS (Concluded) Waste Generation Aqueous Wastes Gaseous Wastes Solid Wastes Materials of Construction COST ESTIMATES Capital Costs Production Costs CHIRAL CHEMICALS FROM ENANTIOSELECTIVE CATALYSIS INTRODUCTION WHEN TO USE CATALYSIS? Chiral Intermediate Strategy Homogenous vs. Heterogeneous Catalysis Catalyst/Ligand Recovery Water-Soluble Chiral Phosphine Ligands PRODUCTION-SCALE CATALYTIC REACTIONS Metolachlor Example Development of an Industrial Asymmetric Synthesis Process for Producing Racemic Metolachlor Selection of Synthesis Route Development of Catalytic System Other Production-Scale Catalytic Reactions Hydrogenation of a Dehydroamino Acid Derivative for an L-Dopa Intermediate Synthetic Route for L-Phenyl-Alanine [Enichem] Intermediate for Vitamin E [Takasago] Intermediate for Biotin (Vitamin) [Lonza] Intermediate for Benazepril [Solvias] Intermediate for S-Oxfloxazin (Bactericide) [Takasago] Intermediate for Antibiotic Carbapenem [Takasago] Intermediate for Antibiotic Carbapenem [NSC Technologies] vii

7 CONTENTS (Concluded) 8 CHIRAL CHEMICALS FROM ENANTIOSELECTIVE CATALYSIS (Concluded) Epoxidation Intermediate for Disparlure Pheromone [J.T. Baker] Chiral Building Block [PPG-Sipsy] Intermediate for Protease Inhibitor [Merck/Chirex (Sepracor)] Cyclopropanation Intermediate for Cilastatin (Dehydropetidase) [Sumitomo] Isomerization Intermediate for L-Menthol and Citronellol [Takasago] Structure of Selected Ligands Used in Chiral Synthesis Example of Synthesis of Chiral Ligand (DuPhos) Future Directions in Asymmetric Catalysis EMERGING CHIRAL SEPARATION TECHNIQUES INTRODUCTION CHIRAL CHROMATOGRAPHY FACILITATED TRANSPORT (FACILIMAX ) SUMMARY 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

8 ILLUSTRATIONS 4.1 Opposite Bending of Polarized Light by Different Crystals in Solution Fischer Projection Cahn-Ingold-Prelog Convention Chemical Schematic for S-Naproxen Conceptual Diagram of Enzyme Catalysis Conglomerate Mixture Resolution of Conglomerate Mixture Racemic Compound Crystallization of Racemic Mixture with Resolving Agent Enantioselective Enzyme-Catalyzed Acylation Conceptual Diagram of Enzyme Catalysis Ketone-Amine Racemization Chemistry Separation of Chiral Amines by Enzymatic Transformation: Block Flow Diagram True Moving Bed Schematic Simulated Moving Bed Schematic Facilimax Schematic ix

9 TABLES 2.1 Chiral Compounds: Manufacturing Cost Summaries Chiral Compounds: Total Fixed Capital Chiral Compounds: Utility Costs Per Pound Chiral Compounds: Conversion Costs Per Pound Chiral Synthesis Technologies Classical Resolution by Crystallization: Patent Summary...A Resolving Agent Summary Naproxen Resolution by Crystallization: Design Bases and Assumptions Naproxen Resolution by Crystallization: Stream Flows Naproxen Resolution by Crystallization: Utilities Summary Naproxen Resolution by Crystallization: Major Equipment Naproxen Resolution by Crystallization: Total Capital Investment Naproxen Resolution by Crystallization: Capital Investment by Section Naproxen Resolution by Crystallization: Production Costs Naproxen Resolution by Crystallization: Direct Costs by Section Separation of Chiral Amines by Enzymatic Transformation: Patent Summary... A Separation of Chiral Amines by Enzymatic Transformation: Design Bases and Assumptions Separation of Chiral Amines by Enzymatic Transformation: Stream Flows Separation of Chiral Amines by Enzymatic Transformation: Major Equipment Separation of Chiral Amines by Enzymatic Transformation: Utilities Summary Separation of Chiral Amines by Enzymatic Transformation: Total Capital Investment Separation of Chiral Amines by Enzymatic Transformation: Capital Investment by Section Separation of Chiral Amines by Enzymatic Transformation: Production Costs D-Phenylalanine by Biocatalytic Conversion: Patent Summary... A-7 x

10 TABLES (Concluded) 7.2 Amino Acids and Corresponding Keto Acids Typical Batch Growth Media D-Phenylalanine by Biocatalytic Conversion: Design Bases and Assumptions D-Phenylalanine by Biocatalytic Conversion: Stream Flows D-Phenylalanine by Biocatalytic Conversion: Major Equipment D-Phenylalanine by Biocatalytic Conversion: Utilities Summary D-Phenylalanine by Biocatalytic Conversion: Total Capital Investment D-Phenylalanine by Biocatalytic Conversion: Capital Investment by Section D-Phenylalanine by Biocatalytic Conversion: Production Costs D-Phenylalanine by Biocatalytic Conversion: Direct Costs by Section Strengths and Weaknesses of Chiral Production Methods Industrial Status of Various Enantiomeric Catalytic Reaction Classes Effect of Substituent Groups on Iridium-Ferrocenyldiphosphine- Catalyzed Hydrogenation of MEA-Imine xi