Synthesis Of Chiral Venlafaxine By Phase-Transfer Catalysis

Depression is a common mental disorder that can lead to substantial impairments in an individual's ability to take care of his or her everyday responsibilities. Venlafaxine is one of the most prescribed antidepressant which can simultaneously inhibit the reuptake of 5-HT and norepinephrine in presynapse. Its two enantiomers have different pharmacodynamic and pharmacokinetic properties. We firstly synthesized (S)-venlafaxine by asymmetric phase-transfer catalysis. Our work mainly involves the following three steps:1. Five cinchona alkaloid-derived quatermary ammonium salts were prepared according to the reported procedures. They were respectively used as phase-transfer catalyst in the asymmetric aldol reaction of 4-methoxyphenylacetonitrile with cyclohexanone to afford (S)-1-[cyano-(4-methoxyphenyl)methyl]cycloalkanol. Various reaction conditions were screened and the best results (50.4% yield; 60.9% ee) were obtained under the optimised reaction condition(organic phase:p-toluene-chloroform(1:1); aqueous phase:30% KOH; 10%mol catalyst;-20℃; 18h).2. (S)-1-[cyano-(4-methoxyphenyl)methyl]cycloalkanol was converted into (S)-1-[2-amino-1-(4-methoxyphenyl)ethyl]cyclohexanol by catalytic hydrogenation with 5% Pd/C as the catalyst. The influence of different factors (including solvent, pressure, temperature and the catalyst load) on the reaction were examined. The product was obtained in 75.4% yield under the optimized reaction conditions (HAc-H2O(1.25:1); PH2=12 bar; 15%mol catalyst; 35℃;7h).3. (S)-1-[2-amino-1-(4-methoxyphenyl)ethyl]cyclohexanol was transformed into (S)-venlafaxine by Eschweiler-Clarke reaction in 72.0% yield. A new side-product was characterized by 1HNMR, upon which the synthetic procedure was improved.