Preparation of chiral N-alkyl-N-methyl-3-hydroxy-3-(2-thienyl)-propylamine derivative, useful to prepare duloxetine, comprises asymmetric hydrogenation of prochiral 1-(N-alkyl-N-methylamino)-3-(2-thienyl)-propan-3-one

摘要

Preparation of a chiral N-alkyl-N-methyl-3-hydroxy-3-(2-thienyl)-propylamine derivative (I) and its acid addition salts comprises asymmetric hydrogenation of prochiral 1-(N-alkyl-N-methylamino)-3-(2-thienyl)-propan-3-one (II) in the presence of a catalyst system comprising rhodium, (2R, 4R)-4-(dicyclohexylphosphino)-2-(diphenylphosphino-methyl)-N-methyl-aminocarbonyl-pyrrolidine, optionally an inert diluent and a weak base. Preparation of a chiral N-alkyl-N-methyl-3-hydroxy-3-(2-thienyl)-propylamine derivative of formula (I) and its acid addition salts comprises subjecting prochiral 1-(N-alkyl-N-methylamino)-3-(2-thienyl)-propan-3-one of formula (II) and its acid addition salts to asymmetric hydrogenation in the presence of a catalyst system comprising rhodium, (2R, 4R)-4-(dicyclohexylphosphino)-2-(diphenylphosphino-methyl)-N-methyl-aminocarbonyl-pyrrolidine and optionally an inert diluent and a weak base. R11-6C alkyl (optionally substituted with phenyl). An independent claim is also included for the preparation of duloxetine comprising: (1) reacting (I) with 1-fluoronaphthalene and cleaving the alkyl group R1; or (2) cleaving the alkyl group R1 of (I) and reacting the product obtained with 1-fluoronaphthalene. [Image].