The Study Of The New Method For The Synthesis Of Duluoxetine

DuloxetineHydrochloride[(S)-N-metheyl-3-(naphthalenyloxy)-3-(2-thienyl)propylamine], trade name: Cymbalta, is a new kind of antidepressant. There are several methods tosynthesize duloxetine, and the reported data for product recovery are among 6.8%-16%. Thereason is the lower yield of the chiral resolution of theγ-amino alcohol (＜35%). Theasymmetric hydrogenation methods reported in the reference is very difficult to carry out,because of the inconvienence to get the catalyst or the materical. The purpose of this study isto seek a cheaper asymmetric catalyst for the asymmetric hydrogenation of theβ-aminoketones, as well the convienet operation, in roder to improve thesynthesis ofduloxetine.Key study focus on the synthesis of 3-(N-methyl-N-ethoxycarbonyl)amino-1-(2-thienyl)proanol. A commercial catalyst [(S,S)-Ts-DPEN-Ru] is found and the chiralγ-amino alcoholis synthesized from theβ-aminoketones in the mild system—HCOOH/Et₃N. The operatrinparameters such as reaction temperature etc., were evaluated and optimized, when the3-(N-methyl-N-acetyl)amino-1-(-2-thienyl) proanone is reduced. The optimal condition wasgot. temperature: 40℃, 5%DMF as the solvent,S/C=500:1, HCOOH/Et₃N=1.2: 1, under thecondition, 3-(N-methyl-N-ethoxycarbonyl)amino-1-(2-thienyl) proanone was transfer into(S)-3-(methyl-ethoxycarbonyl)amino-1-(2-thienyl) proanol in yield 93% and 96.5% ee. To ourknowledge, the method for the synthesis ofγ-amino alcohol has not been reported.After the (S)-3-(methyl-ethoxycarbonyl)amino-1-(2-thienyl) proanol was camethrought, the process of the total synthesis of duloxetine was studied from the thioene, byFriedel-crafts acylation, Mannich reaction, N group protected, asymmetri hedrogenatio-n-transfer, removing the protective function at alkali condition and condensation with1-fluoronaphthalene, resulting in the increase the yield of the final product from 8-16% to51.6%, comparing with reference. These intermediates and final product were characterizedby MS& ¹H-NMR, and the results are satisfied.