盐酸西维美林半水合物的制备

Preparation of Cevimeline Hydrochloride Hemihydrate

在叔丁醇钠催化下,将3-喹咛环酮盐酸盐(Ⅱ)与三甲基碘化亚砜反应生成三亚甲基喹咛环氧化物(Ⅲ),再通入硫化氢开环加成得到3-羟基-3-巯基亚甲基喹咛(Ⅳ),化合物Ⅳ与乙缩醛缩合后生成西维美林碱基(Ⅴ),化合物Ⅴ再与消旋樟脑磺酸成盐,并经过多次精制得到高纯度西维美林樟脑磺酸盐(Ⅵ),化合物Ⅵ碱化后与氯化氢成盐得到目标产物盐酸西维美林半水合物(Ⅰ),总收率20.5%。该合成方法反应条件温和、操作简单、周期短、收率高,利于工业化生产。

CompoundⅢis obtained through the reaction between 3-quinuclidinone hydrochloride(Ⅱ)and trimethylsulfoxonium iodide in the presence of sodium tert-butoxide,then compoundⅣis obtained through ring-opening and addition of compoundⅢwith hydrogen sulfide,and compoundⅤis obtained through condensation of compoundⅣwith acetal.Moreover,high-purity compoundⅥis obtained from compoundⅤvia salt-forming reaction with racemic camphorsulfonic acid,recrystallization for resolution.Furthermore,Cevimeline hydrochloride hemihydrate(Ⅰ)is obtained from compoundⅥvia alkalization,salt-forming reaction with hydrogen chloride with the total yield of 20.5%.This synthetic method has advantages such as moderate conditions,simple operation,saving time,and high yield,which is favorable for industrial production.