Liu Zhi-Jin, Liu Han, Chen Xuan-Wen, Lin Min, Hu Yu, Tuo Xun, Yuan Zhong-Yi, Sun Xiao-Xia
College of Chemistry, Nanchang University, Nanchang, China.
Jiangxi Key Laboratory of Functional Organic Molecules, Jiangxi Normal University of Science and Technology, Nanchang, China.
Chirality. 2018 Mar;30(3):268-274. doi: 10.1002/chir.22790. Epub 2017 Dec 12.
Numbers of resolving factors were investigated to improve resolution of venlafaxine 1. An effective resolving agent, O,O'-di-p-toluoyl-(R, R)-tartaric acid 2, was screened using similar method of 'Dutch resolution' from tartaric acid derivatives. The resolution efficiency was up to 88.4%, when the ratio of rac-1 and 2 was 1:0.8 in THF with little water (10:1 v/v). Enantiomerically pure venlafaxine was prepared with 99.1% ee in 82.2% yield. The chiral resolution mechanism was first explained through X-ray crystallographic study. One diastereomeric salt with well solubility forms a columnar supramolecular structure as the acidic salt (R)-1·2, while the other diastereomeric salt with less solubility forms a multilayered sandwich supramolecular structure by enantio-differentiation self-assembly as the neutral salt 2(S)-1·2. The water molecules play a key role in the optical resolution, as indicated by the special structures of the diastereomeric salts.
研究了拆分因子的数量以提高文拉法辛1的拆分效果。使用类似“荷兰拆分”的方法从酒石酸衍生物中筛选出一种有效的拆分剂，即O,O'-二对甲苯甲酰基-(R,R)-酒石酸2。当外消旋体1与2的比例在含少量水（10:1 v/v）的四氢呋喃中为1:0.8时，拆分效率高达88.4%。制备得到对映体纯的文拉法辛，对映体过量值（ee）为99.1%，收率为82.2%。首次通过X射线晶体学研究解释了手性拆分机理。一种具有良好溶解性的非对映体盐以酸性盐(R)-1·2的形式形成柱状超分子结构，而另一种溶解性较差的非对映体盐以中性盐2(S)-1·2的形式通过对映体差异化自组装形成多层夹心超分子结构。如非对映体盐的特殊结构所示，水分子在光学拆分中起关键作用。
