摘要 |
A method of preparation of (S)-N-methyl-3-(1-naphthyloxy)-3-(2-mienyl)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-(l-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-thienyl)propylamine by action of an alkylchloroformate of formula ClCOOR (R = C-Calkyl, or C-Caryl or alkylaryl), especially phenyl, ethyl or methyl chloroformate, and 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 one uses, as the optically active substance in step (a), D-tartaric acid in the molar ratio 1:2 relative to the substance of formula (III), or an alkali metal acid D-tartrate or ammonium tartrate, or alternatively alkylammonium tartrate of formula (IV) in the molar ratio 1:1 relative to the substance of formula (III). |