Patent ID: 8269023
Filing Date: 2012-09-18
Classification: C07D

Abstract:
1. A novel process for synthesis of duloxetine hydrochloride of formula (1), the process comprising the steps of: i) reaction of (RS)—N.N-di methyl-3-hydroxy-3-(2-thienyl)propanamine (2, racemic hydroxy compound) of formula (2), with 1-fluoronaphthalene of formula (3), in aprotic polar organic solvent in presence of a base selected from sodamide, potassium amide, potassium bis(trimethylsilyl)amide to obtain (RS)—N.N-di methyl-3-(1-naphthyloxy)-3-(2-thienyl)propanamine (racemic condensed compound) of formula 4, ii) optionally isolation of racemic condensed compound as acid addition salt of organic or inorganic acid of formula (5), where HA is organic or inorganic acid, iii) conversion of acid salt (5) to free base (R,S)—N.N-di methyl-3-(1-naphthyloxy)-3-(2-thienyl)propanamine of formula (6a+6b), by treatment with organic or inorganic base in aqueous or organic or mixture of aqueous and water immiscible organic solvent, iv) optical resolution of racemic condensed compound free base (6a+6b) with dibenzoyl-L-tartaric acid (DBTA) of formula (7) wherein R=H, or di-p-anisoyl-L-tartaric acid (DATA) of formula (7) wherein R=OCH is carried out in organic solvent selected from aromatic hydrocarbons; lower alcohols; lower aliphatic ketones; aliphatic esters; ethers; acetonitrile, or mixtures thereof to get crude corresponding (S)-isomer tartarate salt of formula (8a or 9a), respectively, v) optionally purification of (S)-isomer tartarate salt (8a or 9a) by crystallization from a suitable organic solvent or mixture of two or more solvents, vi) conversion of (S)-isomer tartarate salt (8a or 9a) to free base (S)—N.N-di methyl-3-(1-naphthyloxy)-3-(2-thienyl)propanamine of formula (6a), by treatment with organic or inorganic base in aqueous or organic or mixture of aqueous and water immiscible organic solvent, vii) demethylation of free base (6a) by treatment with phenyl chloroformate in presence of diisopropylethyl amine in toluene to get carbamate intermediate of formula (10), viii) hydrolysis of carbamate intermediate (10) with sodium hydroxide in polar aprotic solvent to give duloxetine base of formula (11), ix) conversion of duloxetine base (11) to duloxetine hydrochloride (1) in an organic solvent or mixture of organic solvents, and x) optionally purification of duloxetine hydrochloride (1) by crystallization.