CHIRAL INTERMEDIATES (March 2001)

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