物理化学学报 >> 2016, Vol. 32 >> Issue (9): 2241-2254.doi: 10.3866/PKU.WHXB201606132

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手性尼莫地平绝对构型的确定和关联

郭栋1,宋嘉熙2,李丹1,陈嘉媚2,林丽榕1,鲁统部2,*(),章慧1,*()   

  1. 1 厦门大学化学化工学院化学系,福建厦门361005
    2 中山大学化学与化学工程学院,广州510275
  • 收稿日期:2016-05-12 发布日期:2016-09-08
  • 通讯作者: 鲁统部,章慧 E-mail:lutongbu@mail.sysu.edu.cn;huizhang@xmu.edu.cn
  • 基金资助:
    国家自然科学基金(21273175);国家自然科学基金(21331007);国家自然科学基金(21271150);广东省自然科学基金(S2012030006240)

Determination and Correlation of the Absolute Configurations of Chiral Nimodipine

Dong GUO1,Jia-Xi SONG2,Dan LI1,Jia-Mei CHEN2,Li-Rong LIN1,Tong-Bu LU2,*(),Hui ZHANG1,*()   

  1. 1 Department of Chemistry, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, Fujian Province, P. R. China
    2 School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275, P. R. China
  • Received:2016-05-12 Published:2016-09-08
  • Contact: Tong-Bu LU,Hui ZHANG E-mail:lutongbu@mail.sysu.edu.cn;huizhang@xmu.edu.cn
  • Supported by:
    National Natural Science Foundation of China(21273175);National Natural Science Foundation of China(21331007);National Natural Science Foundation of China(21271150);Natural Science Foundation of Guangdong Province, China(S2012030006240)

摘要:

概述了手性1, 4-二氢吡啶类(1, 4-DHPs)钙拮抗剂的立体化学结构及其药效与绝对构型的关系,以及尼莫地平(nimodipine)的多晶型现象。采用单晶X射线衍射与固体和溶液圆二色(ECD)光谱直接关联的方法,对自发拆分获得的一对尼莫地平外消旋聚集体进行了绝对构型确定,首次获得了手性1, 4-DHPs类化合物的固体和溶液ECD光谱图。本方法对确认有机小分子的绝对构型,以及关联系列手性1, 4-DHP衍生物的绝对构型具有重要参考价值,同时提供了有别于常规非手性方法鉴别优势手性药物晶型的有效手段。

关键词: 1, 4-二氢吡啶, 绝对构型关联, 尼莫地平, 多晶型, 原料药(API), 自发拆分, 电子圆二色

Abstract:

The stereochemical structures and absolute configuration-pharmacological activity relationship of chiral l, 4-dihydropyridines (1, 4-DHPs) calcium channel drugs were summarized. Additionally, the polymorphic forms of nimodipine were investigated. The absolute configurations of a pair of chiral nimodipines as a conglomerate prepared by spontaneous resolution under chiral crystallization were confirmed via X-ray crystallographic analysis directly correlated with their solid-state and solution electronic circular dichroism (ECD) spectra. The solid-state and solution ECD spectra of chiral l, 4-DHPs were obtained for the first time. This comprehensive method can be used to determine the absolute configurations of small organic molecules. Furthermore, it can be extended to correlate the absolute configurations of other series of chiral l, 4-DHP derivatives in the future. We also presented some effective techniques to distinguish polymorphs of chiral active pharmaceutical ingredients (APIs), which differ from the non-chiral conventional methods, to allow qualitative identification of different chiral crystalline states of APIs in pharmaceutical preparations.

Key words: 1, 4-Dihydropyridine, Absolute configuration correlation, Nimodipine, Polymorphism, Active pharmaceutical ingredient, Spontaneous resolution, Electronic circular dichroism

MSC2000: 

  • O641