Study Of Synthesizing Antidepressant Sertraline

Sertraline is a novel antidepressant, which has fire-new specialties in the field of curative effect, side-effect and so on. Pfizer Co. in U.S.A. developed and put it into the market in early 1990s. It firstly obtained the certificate of FDA as the PMDD medicament and clinic used in many countries. However until now there was no production of Sertraline at home, so the study on their synthesis was of great practical significance. The synthesis of Sertraline was the major work of this paper. The final products were identified by rotation, IR, 1H-NMR and HPLC.4-(3,4-dichlorophenyl)-3,4-dihydronaphthalen-1-(2H)-one was treated with methylamine to afford intermediate N-(4-(3,4-dichlorophenyl)-3,4-dihydronaphthalen-1-(2H)-ylidene)-methyl amine . Influences of catalyst, dosage of solvent, reaction time and temperature were studied. In the optimum reaction condition, the yield was up to 94.28% and the purity was 99.18%. The route had advantages of high yield, mild conditions and easy operation, and it laid an elementary foundation for industrialized production.4-(3,4-dichlorophenyl)-N-methyl-1,2,3,4-tetrahydronaphthalen-1-amine (Sertraline racemate) was synthesized from the former intermediate by catalytic hydrogenation. The product Sertraline racemate having high cis/trans ratio about 12:1 was prepared with the present of palladium catalyst at 0.35MPa hydrogen pressure. In the optimum reaction condition, the cis-isomer was obtained through recrystallization and the yield was up to 62.01 %.Cis-Sertraline is resolved by D-mandelic acid as resolution agent. Firstly, salt of cis-1S,4S- sertralin D-mandelic was separated from salt of cis-1R,4R-sertralin D-mandelic using the difference of two salts in solubility, and then optically active cis-1S,4S-sertralin hydrochloride was acquired by hydrolysis and hydrochlorinated. By this method general yield of cis-1S,4S-sertralin hydrochloride is 34.22% with optical purity more than 97%. In this paper, the optimal resolution parameters of Cis-Sertraline were also determined.The resolution of raw material was studied. The resolution agent (1S)-10-mercaptoisoborneol was prepared through three steps. D-camphorsulphonic acid was chloridized with thionyl chloride to afford (+)-10-D-camphorsulfonyl chloride, which was then reduced by triphenyl phosphate and then NaBH4. The whole yield was up to 65.88%.