Process for preparing scopine ester of di-(2-thienyl)glycolic acid, intermediate in synthesis of tiotropium bromide and novel form thereof kolovÚ

摘要

The present invention relates to a process for the preparation of a di- (2-thienyl) glycol acid scopine ester of Formula I. The scopine ester of Formula I is an important intermediate in the synthesis of tiotropium bromide, the chemical name chemical (1R, 2R, 4S, 5S, 7S) -7- (2-hydroxy) -2,2-di (thiophen-2-yl) acetoxy) -9,9-dimethyl-3-oxa-9-azatricyclo [3.3.1.0. II. The process consists of the following steps: a) reacting scopine of formula III with acid derivatives of the formula XIII wherein X is F, Cl, Br, I and R is X or O-tert-butyl, O-methyl, N-pyrrolidinyl, N - morpholinyl and N-imidazolyl, in the presence of a weak base and a catalyst in an inert organic solvent to give a derivative of formula XIV, b) reacting a derivative of formula XIV with at least 2 equivalents of 2-thienylmagnesium bromide of formula XV, c) then recovering the scopine ester of formula I and crystallizes from a crystallization solvent.