Studies on generalization of a new enantiomeric resolution phenomenon (Preferential Enrichment)

为了阐明优先富集机理，必须充分理解以下四点：(1)溶液中的超分子缔合结构；(2)由过饱和溶液动力学形成的亚稳晶相的晶体结构；(3)过饱和溶液中亚稳晶相向稳定相的多晶型转变的机理。为了理解(I)，进行了固体物质的溶解度和超溶解度的测量、溶液中的数平均相对分子质量的测量以及稳定的超分子缔合结构的分子动力学模拟。为了分离(II)中的亚稳晶体，使用种子晶体的外延结晶，或通过抑制不需要的稳定多晶型的成核或晶体生长过程来选择性地结晶所需的多晶型。此外，当单晶f…在没有X射线晶体分析的情况下，可以通过蒙特卡罗方法和随后的Rietveld精修，从粉末X射线衍射数据中解算出晶体结构。对于(III)来说，过饱和溶液的原位和实时空气红外测量或沉积晶体的DSC测量是有效的。通过比较亚稳态晶体结构和稳定晶体结构，可以合理地解释多晶型转变的机理。利用这些方法，得到了四个关于优先浓缩机理的结果：(1)在外消旋体优先富集的溶液中，均手性分子缔合优先于杂手性分子缔合。(2)优先富集外消旋晶体的性质被归类为由两个对映体组成的外消旋混合晶体。(3)优先富集机理与过饱和溶液结晶过程中发生的晶型转变密切相关。(4)通过比较相变前后的晶体结构，可以理解固-固型多晶型转变的机制。在此基础上，提出了独特的优先致富机制。较少

In order to elucidate the mechanism of Preferential Enrichment, the following four points must be fully understood; (i) the supramolecular association structure in solution, (ii) the crystal structure of the metastable crystalline phase formed kinetically from the supersaturated solution, (iii) the mechanism of polymorphic transition of the metastable crystalline phase into the stable form in the supersaturated solution. For the understanding of (i), the solubility and supersolubility measurement of the solid material, the number-averaged molecular weight measurement in solution, and the molecular dynamics simulation of the stable supramolecular association structure were carried out. For the isolation of the metastable crystals in (ii), the epitaxial crystallization by using seed crystals, or the selective crystallization of the desired polymorph by inhibition of the nucleation or crystal growth process of an undesired stable polymorph were used. In addition, when the single crystal f … More or X-ray crystallographic analysis was not available, the crystal structure was able to be solved from the powder X-ray diffraction data by the Monte Carlo method and the subsequent Rietveld refinement. For the aim of (iii), the in situ and real time AIR-IR measurement of the supersaturated solution or the DSC measurement of the deposited crystals was effective. It was also shown that the mechanism of polymorphic transition could be rationalized by comparison of the metastable and stable crystal structures. By using these methods, the following four results concerning the mechanism of Preferential Enrichment were obtained.(1) In a solution of the racemate showing Preferential Enrichment, the homochiral molecular association is preferred to the heterochial one.(2) The nature of the racemic crystal of the compound showing Preferential Enrichment has been classified as a fairly ordered racemic mixed crystal composed of the two enantiomers.(3) The mechanism of Preferential Enrichment is closely associated with the polymorphic transition occurring during crystallization from the supersaturated solution.(4) By comparison of the crystal structures before and after the phase transition, the mechanism of the solid-to-solid type of polymorphic transition can be understood. On the basis of this mechanism, the unique mechanism of Preferential Enrichment has been proposed. Less