Development of An Advanced Optical Resolution Process with Simultaneous Diastereoisomer Formation and Racemization Reactions

2006 Fiscal Year Final Research Report Summary

• Project/Area Number: 16360380
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Properties in chemical engineering process/Transfer operation/Unit operation
• Research Institution: Tokyo University of Agriculture and Technology
• Principal Investigator: MATSUOKA Masakuni Tokyo University of Agriculture and Technology, Institute of Symbiotic Science and Technology, Professor, 大学院共生科学技術研究院, 教授 (40016671)
• Co-Investigator(Kenkyū-buntansha): TAKIYAMA Hiroshi Tokyo University of Agriculture and Technology, Institute of Symbiotic Science and Technology, Associate Professor, 大学院共生科学技術研究院, 助教授 (40251582) ; HADA Maiko Tokyo University of Agriculture and Technology, Institute of Symbiotic Science and Technology, Research Associate, 大学院共生科学技術研究院, 助手 (90365883)
• Project Period (FY): 2004 – 2006
• Keywords: optical resolution / diastereoisomer / racemization / optical purity

Research Abstract

Chemically synthesized racemates are classified into racemic compounds and racemic mixtures. While racemic mixtures can be crystallized as separate pure isomers, crystals of racemic compounds are always isomolar mixtures. Although preferential crystallization is a representative resolution process, the product purity often decreases in the later period of batch operation, hence prevention of crystallization of undesired isomers is needed in the operation. For the resolution of racemic compounds, formation reactions of diastereoisomers are adopted where improvements of optical purity and yields as well as search methods of resolving agents are the problems to be solved.
For the prevention of purity decrease in preferential crystallization, nucleation behavior on the seed crystal surfaces was observed under optical and atomic force microscopes as well as changes in compositions of crystal and solution phases were analyzed. It was found that the solution supersaturation with respect to the undesired isomer increased as the resolution proceeded and spontaneous surface nucleation of the undesired isomer started once the supersaturation exceeded a certain threshold. At the same time surface morphology (i.e., crystallographic planes exposed to the solution) of the seed crystal was found to have a strong effect on the surface nucleation, which can easily be modified by washing the seed crystals with solvents.
For racemic compound mixtures, higher yields as well as higher optical purity were achieved under the conditions surveyed experimentally where simultaneous reactions of diastereoisomer formation and racemization were carried out in a single vessel in which the desired diastereoisomer was crystallizing. For this purpose the selection of resolving agents and catalysts such as acids and aldehydes and stirring conditions, resolution temperatures were experimentally examined in detail. With the whole kinetics determined, the resolution process was simulated and optimal conditions found. The conditions were then experimentally examined and showed better yields and purities ever reported.