一种改进的卡巴拉汀制备工艺

An improved preparing process for rivastigmine

卡巴拉汀改进后的制备工艺如下:首先将间羟基苯乙酮(4)与甲乙氨基甲酰氯缩合得中间体(3),然后用科里-巴克什-柴田(CBS)手性还原得(R)-N-乙基-N-甲基氨基甲酸-3-(1-羟乙基)苯酯(2),再经甲基磺酰氯甲磺酰化,并用二甲胺气体原位亲核取代得终产物卡巴拉汀(1)。整个工艺最关键的步骤为手性还原中间体(3)生成手性中间体(2),该过程通过正交试验来理解和优化。改进后的卡巴拉汀制备工艺操作和纯化方便,三步总收率达到88%。

An improved manufacturing process for rivastigmine （1） was developed by performing the condensa- tion reaction of m-hydroxyacetophenone （4） with N-ethyl-N-methyl carbamoyl chloride, then Corey-Bakshi-Shibata （CBS） chiral reduction to （R）-3-（1-hydroxyethyl） phenyl ethyl （methyl） carbamate （2） and then mesylation with methanesulfonyl chloride and nueleophilic substitution with dimethylamine, respectively. To be successful, a crucial reductive process in the conversion of ketone （3） to chiralalcohol （2） had to be correctly understood and optimized via orthogonal experiment. The whole improved process was convenient for operation and purification, with completion of the synthesis of rivastigmine and an overall yield of 88%.