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

开发同时进行非对映异构体形成和外消旋反应的先进光学拆分工艺

基本信息

批准号：
16360380
负责人：
MATSUOKA Masakuni
金额：
$ 9.86万
依托单位：
Tokyo University of Agriculture and Technology
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2006
项目状态：
已结题

项目摘要

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

化学合成的外消旋物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分离工艺，但在批量操作后期，产品纯度往往会下降，因此在操作中需要防止不需要的异构体结晶。外消旋化合物的拆分采用非对映异构体的生成反应，需要解决的问题是提高光学纯度和产率以及拆分剂的寻找方法。为了防止优先结晶过程中纯度的降低，在光学显微镜和原子力显微镜下观察了种子晶体表面的成核行为，并分析了晶体组成和固相组成的变化。随着溶解的进行，不需要的同分异构体的数量增加，一旦过饱和度超过一定阈值，不需要的同分异构体就开始自发的表面成核。同时，发现种子晶体的表面形貌（即暴露在溶液中的晶体平面）对表面成核有很强的影响，可以很容易地通过溶剂洗涤种子晶体来改变表面成核。对于外消旋化合物混合物，在实验调查的条件下，在单个容器中进行非对映异构体形成和外消旋同时反应，所需的非对映异构体在其中结晶，从而获得更高的收率和更高的光学纯度。为此，对酸类、醛类等溶解剂和催化剂的选择、搅拌条件、溶解温度等进行了实验研究。在确定了整个反应动力学的基础上，模拟了反应过程，找到了最佳反应条件。然后对条件进行了实验检查，并显示出前所未有的产量和纯度。少

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

ラセミ化反応を伴う優先晶析によるL-ピリジルアラニンの製造法

优先结晶伴外消旋反应生产L-吡啶基丙氨酸的方法

DOI：
发表时间：
2004
期刊：
化学工学会第69回年会研究発表講演要旨集
影响因子：
0
作者：
H.Nishihara et al.;S.R.Mukai et al.;H.nishi hara et al.;S.R.Mukai et al.;H.Nishihara et al.;S.R.Mukai et al.;H.Nishihara et al.;S.R.Mukai et al.;田門肇;田門肇;H.Tamon;古賀敬一他4名
通讯作者：
古賀敬一他4名

ラセミ化反応を伴う優先晶析によるL-ピリジルアラニン(L-PA)の工業的晶析法の開発

开发L-吡啶丙氨酸（L-PA）的工业结晶方法，采用优先结晶伴随外消旋反应

DOI：
发表时间：
2004
期刊：
分離技術会年会2004技術・研究発表講演要旨集
影响因子：
0
作者：
H.Nishihara et al.;S.R.Mukai et al.;H.nishi hara et al.;S.R.Mukai et al.;H.Nishihara et al.;S.R.Mukai et al.;H.Nishihara et al.;S.R.Mukai et al.;田門肇;田門肇;H.Tamon;古賀敬一他4名;H.Tamon;古賀敬一他4名
通讯作者：
古賀敬一他4名

Preferential Crystallization of L-Pyridylalanine Accompanied by Racemization Reaction.

L-吡啶丙氨酸的优先结晶伴随外消旋化反应。