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

化学合成的外消旋体分为外消旋化合物和外消旋混合物。虽然外消旋混合物可以结晶为单独的纯异构体，但外消旋化合物的晶体总是等摩尔混合物。虽然优先结晶是一种代表性的拆分方法，但在间歇操作的后期，产品纯度往往会降低，因此在操作中需要防止不需要的异构体结晶。对于外消旋化合物的拆分，采用非对映异构体的形成反应，其中光学纯度和收率的提高以及拆分剂的寻找方法是需要解决的问题。在光学显微镜和原子力显微镜下观察了晶种表面的成核行为以及晶相和溶液相组成的变化。分析了结果表明，溶液过饱和度随温度的升高而增大， ...更多信息 不需要的异构体随着拆分的进行而增加，并且一旦过饱和度超过某一阈值，不需要的异构体的自发表面成核开始。同时表面形态（即，暴露于溶液的晶面）对表面成核有很强的影响，这可以通过用溶剂洗涤晶种而容易地改变。对于外消旋化合物混合物，在实验考察的条件下获得了更高的产率以及更高的光学纯度，其中非对映异构体形成和外消旋化的同时反应在单一容器中进行，所需的非对映异构体结晶。为此，对拆分剂和催化剂（如酸和醛）的选择、搅拌条件、拆分温度进行了详细的实验研究。在确定了整个动力学的基础上，对拆分过程进行了模拟，找到了最佳拆分条件，并对实验条件进行了考察，得到了较好的收率和纯度。少

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 … More 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. Less