Process Optimization For The Synthesis Of Duloxetine Hydrochloride

Developed by Eli Lilly, Duloxetine hydrochloride is one of the specific dual serotonin and norepinephrine reuptake inhibitors (SNRIs) that increase the concentration in the synaptic cleft of both norepinephrine and serotonin. With unique features, Duloxetine is a relatively new compound that can effectively improve the symptoms of depression and somatic symptoms, and also can be used to treat other mental disorders such as anxiety.In recent years, several synthetic methods of duloxetine have been reported and can be classified mainly into three categories:(1) chemical resolution (2) enzymatic resolution (3) asymmetric synthesis. Based on considerations including the cost of production, environmental protection and accessibility of raw materials, synthetic route for duloxetine hydrochloride were finalized in this paper. Firstly thiophene as the starting material reacted with acetic anhydride via Freidel-Crafts acylation to prepare 2-acetyl thiophene, which was reacted with paraformaldehyde and dimethylamine hydrochloride via Mannich reaction to afford 3-(dimethylamino)-1-(thiophen-2-yl)propan-1-one hydrochloride. After steps of reduction by sodium borohydride, chiral resolution with S-(+) mandelic acid, etherication, demethylation, and salification, duloxetine hydrochloride was obtained with the total yield 22.9% and ee ?98%.The structure of intermediates and the target product were confirmed by LCMS,'H NMR and 13C NMR. The synthetic process was featured with easy-obtaining raw materials, simple steps, mild conditions and relatively high yield, therefore appropriate for industrial production.