A METHOD OF PREPARING THE SCOPINE ESTER OF DI-(2-THIENYL)GLYCOLIC ACID, AN INTERMEDIATE IN THE SYNTHESIS OF TIOTROPIUM BROMIDE, AND ITS NEW FORM

摘要

The invention relates to a preparation method of the scopine ester of di-(2- thienyl)glycolic acid of formula I. The scopine ester of formula I is an important intermediate in the synthesis of tiotropium bromide, the substance with the chemical name (1R,2R,4S,5S,7S)-7-(2-hydroxy-2,2-di(thiophen-2-yl)acetoxy)-9,9-dimethyl-3- oxa-9-azatricyclo[3.3.1.02'4]nonan-9-ium bromide of formula II. The method consists of the following steps, reaction of scopine of formula III with derivatives of oxalic acid of formula XIII, wherein X means F, CI, Br, I, and R is X or O-terf-butyl, O-methyl, A/-pyrrolidinyl, N-morpholinyl and /V-imidazolyl, in the presence of a weak base and a catalyst in an inert organic solvent, producing the derivative of formula XIV; reaction of the derivative of formula XIV with at least 2 equivalents of 2- thienylmagnesium bromide of formula XV; and isolating the resulting scopine ester of formula I is then and crystallization from a crystallization solvent.