Patent ID: 8071791
Filing Date: 2011-12-06
Classification: C07D

Abstract:
1. A method of preparation of (S)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine of formula I and its pharmaceutically acceptable salts, comprising a) reaction of (RS)-N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine of formula III with optically active D-tartaric acid or an acid salt derived from D-tartaric acid forming a mixture of diastereoisomeric salts of N,N-dimethyl-3-(1-naphthyloxy)-3-(2- thienyl) propylamine and D-tartaric acid (2:1), b) isolation of the salt (S)-N,N-dimethyl-3-(naphthyloxy)-3-(2-thienyl) propylamine/D-tartrate (2:1) from the mixture of diastereoisomeric salts in an organic solvent, water or a mixture thereof and release of (S)-N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine of formula (S)-(III) by action of an inorganic or organic base c) demethylation of (S)-N,N-dimethyl-3-(1-naphthyloxy)-3-(2-hienyl)propylamine by action of an alkylchloroformate of formula ClCOOR, wherein R is a C d) hydrolytic release of the duloxetine base of formula I and optionally conversion of the base to a salt with the respective acid, or salt of a weak base, wherein the optically active substance in step (a) is D-tartaric acid in the molar ratio 1:2 relative to the substance of formula III, an alkali metal acid D-tartrate, ammonium tartrate, or alkylammonium tartrate of formula IV in the molar ratio 1:1 relative to the substance of formula III.