Study on the Simultaneous Enantioseparation of Racemic Acid and Amine Combinations

我们最近报道，在外消旋酸和胺组合的结晶中，砾岩形成的概率高达50%，通过非对映体盐方法可以实现对映体的有效分离。为了证实这一现象的普遍性，我们试图将结晶扩展到各种外消旋酸和胺的组合。然而，尽管进行了大量的文献检索，但只发现了几种高效分解的外消旋和对映不纯的酸和胺。因此，在检查之前，开发了适合本研究的新型溶解剂。设计合成了六种萘和/或硫代骨架的新型酸性溶解剂和四种苯并二甲苯和/或双羟基骨架的新型碱性溶解剂。利用文献报道和本研究开发的各种溶解剂，对外消旋酸和胺的组合进行结晶，以分析砾岩形成的概率。结果，我们发现，正如我们所报道的，对于各种各样的组合，概率也在50%左右。此外，明确了砾岩的测定不仅可以通过x射线晶体学分析，还可以通过红外光谱和熔点分析对外消旋酸和胺的结晶过程中获得的单晶和粉状微晶进行测定。

We have recently reported that the probability for conglomerate formation is as high as 50% in the crystallizations of racemic acid and amine combinations, for which efficient enantioseparation is achieved by the diastereomeric salt method. In order to confirm the generality of the phenomenon, we tried to extend the crystallization to various kinds of racemic acid and amine combinations. However, only a few racemic and enantiopure forms of acids and amines, which have been resolved with high efficiency, were found, despite of heavy bibliographic search. Therefore, novel resolving agents suitable for the present study were developed prior to the examination. Six kinds of novel acidic resolving agents, which have a naphthalene and/or phosphonothioic skeleton, and four kinds of novel basic resolving agents, which have a benzindanylene and/or bishydroxy skeleton, were designed and synthesized for the present study.Using various kinds of resolving agents, which were reported in literatures and developed in the present study, crystallizations of racemic acid and amine combinations were carried out in order to analyze the probability of the formation of conglomerate. As a result, we found that the probability was also about 50% for a wide variety of the combination, as we have reported. Furthermore, it was clarified that the determination of conglomerate could be carried out not only by X-ray crystallographic analysis but also by IR spectral and melting point analyzes of a single crystal and powdery micro crystals, which were obtained in the crystallization of a racemic acid and amine combination.