Study On The Synthetic Technology Of Duloxetine Hydrochloride

Depression is one of common psychiatric illness.New antidepressant duloxetine hydrochloride is a dual reuptake inhibitor of the neurotransmitters serotonin and norepinephrine.It is mainly used for the treatment of major depressive disorder.It has the advantages of good curative efficacy,less side effects,chemically stable and low affinity to other acceptors.The synthesis of duloxetine hydrochloride was studied.After investigation of a series of synthetic routes of duloxetine hydrochloride,the best synthetic processes had been determined which was suitable for scale production.Through the analysis and comparison of the reported synthetic methods of duloxetine hydrochloride,the better synthetic processes was determined and established.N,N-dimethyl-3-hydroxy-3-（2-thienyl）propanamine was prepared by reaction of 2-acetyl-thiophene with dimethylamine hydrochloride and paraformaldehyde,and then using sodium borohydride via reduction reaction.（S）-N,N-dimethyl-3-hydroxy-3-（2-thienyl）propanamine was obtained by treatment N,N-dimethyl-3-hydroxy-3-（2-thienyl）propan-amine with（S）-（+）-mandelic acid by optical resolution.Duloxetine hydrochloride was obtained from（S）-N,N-dimethyl-3-hydroxy-3-（2-thienyl）propanamine with 1-fluoro-naphthalene by etherification,then removing one N-methyl group with phenyl chloroformate and salt formation.The total yield was 22.4%,higher than the literature reported.[α]_D²⁰=+126.5°（C=1,MeOH）.In the key intermediate of N,N-dimethyl-3-hydroxy-3-（2-thienyl）propanamine resolution process,it is necessary to utilize the left（R）-N,N-dimethyl-3-hydroxy-3-（2-thienyl）propanamine and（S）-（+）-mandelic acid.The recovery yield of（S）-（+）-mandelic was 67.6%.The racemic reaction of（R）-N,N-dimethyl-3-hydroxy-3-（2-thienyl）propanamine was studied,and the yield was 91.2%.The racemic product could be reused in the synthesis process of duloxetine hydrochloride,which could further increase the yield of duloxetine hydrochloride and reduce its production cost.The chemical structure of duloxetine hydrochloride had been characterized by means of ¹H-NMR,IR,and the specific rotation was consistent with the literature reported.