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 chi- ral compounds include: • Pharmaceuticals. • Agricultural chemicals. • Food and feed additives. • Polymers. Production methods for chiral compounds encompass many diverse technologies. This re- port 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 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