The Antidepressant Sertraline Hydrochloride Synthesis Process Research And Improvement

Sertraline hydrochloride is an antidepressant with permanence of effect and less side-effect. There is no paper on the total synthesis of it in China. In this paper, the intermediate 4-(3,4-dichlorophenyl)-l-tetralone was synthesized by one step Friedel-Crafts alkylation with alpha-naphthol and orthodichlorobenzene as raw materials and anhydrous aluminium as catalyzer. Then racemize sertraline hydrochloride was synthesized with the intermediate and methyl amine by reductive animation. After resolution of racemate, dextro-cis- sertraline hydrochloride was obtained.Orthodichlorobenzene was usually used as extraction reagent to synthesize the intermediate 4-(3,4-dichlorophenyl)-l-tetralone, which made operation difficult. After ethyl acetate acted as the substitute of orthodichlorobenzene, vacuum degree in decompression distillation was not strict. The system factors affecting the reaction were investigated and the optimal reaction conditions were obtained. The yield of synthesizing 4-(3,4-dichlorophenyl)-l-tetralone from alpha-naphthol and orthodichlorobenzene was 72.48%. Comparing with paper, the yield was improved by 11.48% and the half of the reaction time was saved. On the basis of the experiment, the mechanism and the reaction kinetic model were studied and conclusions were drawed that the reaction was a first-degree and reaction speed was a variable which was related with temperature and the concentration of alpha-naphthol.When the reductive amination between the intermediate 4-(3,4-dichlorophenyl)-l-tetralone and methyl amine was optimized, methanol solution of methyl amine was used as aminating agent for the first time. So, TiCl4 was not needed, and the reaction can run at room temperature. The factors affecting the reaction were investigated in the round, and the optimal reaction conditions were obtained. The yield of synthesizing racemize sertraline hydrochloride from 4-(3,4-dichlorophenyl)-l-tetralone and methyl amine was 36.4%. To getABSTRACThigher total yield of this step, trans- isomeric was innovatively converted to cis-isomeric by catalyzing of basic equilibration agent sodium tert.-butoxide. The converting yield was 44.56%.In conclusions, compared with alpha-naphthol, the total synthesis yield was 15.6%. The structure of the product was confirmed by melting-point, HPLC, optical activity analysis, element analysis, IR, H-NMR and et al.