Process for preparing scopine ester of di-(2-thienyl)glycolic acid, an intermediate in the synthesis of tiotropium bromide

摘要

The present invention relates to a process for preparing tiotropium bromide of the general formula II, comprising the following steps: a) preparation of the scopine ester of the general formula I by transesterification of methyl di(2thienyl)glycolate of the general formula IV with scopine of the general formula III in the presence of a substoichiometric amount of a sterically hindered base selected from the group consisting of sodium or potassium salt of tert-butoxide, tert-pentoxide, isopropoxide in an inert solvent, wherein the transesterification is carried out at a temperature ranging from 80 to 130 degC and at a pressure in the range of 50 kPa to 30 kPa and under simultaneous distillation off of the liberated methanol; b) isolation of the scopine ester of the general formula I; and c) quaternization of the scopine ester of the general formula I with methyl bromide.