Duloxetine Intermediates In The Synthesis

Duloxetine, (s)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl)-l-propanamine, is used as an antidpresssant by inhibiting the reuptake of norepinephrine and serotonin.3-methylamino-l-(2-thienyl)-propanol is the most important intermediate during synthesis of Duloxetine. According to start material, there are three synthesis routines. Primary work has been done to the routine which start from thiophene. Starting from thiophene and 3-chloropropinylchloride, 3-methylamino-l-(2-thienyl) -propanol was prepared by Friedel-crafts acylation, reduction, iodization and aminelysisKey study focused on routine starting from Friedel-crafts acylation of thiophene. Catalyzed by Aluminium trichloride, 3-chloro-l-(2-thienyl)-propanone was prepared through the acylation between thiophene and 3-chloropropinylchloride. After practice, optimized conditions achieved: at 0℃, react 2 hr, CH₂Cl₂ as solvent , more rate AlCl₃: 3-chloropropionyl chloride: thiophene=1.5:l:l. After the addition of hydrochloric gas, improvement has obtained greatly in Yield, because of transformation of by-product to main product. Finally, the Yield is 87%, higher than the original reported literature. The product will go to next reaction without any purification. We still study on other reaction steps and achieve optimized conditions.Aminelysis in high pressure reactor was taken for avoid iodization and cut cost. The overall Yield is higher than the routine mentioned above. Compared to original routine, this method not only reduce cost, but also simplify the operation, therefore it was suitable for industrialize use.