Studies On The Asymmetric Synthesis Of Chiral Pharmaceutical Intermediate(R)-3,5-(trifluoro-dimethyl) Benzene Ethanol Via An Efficient Chiral Catalyst

(R)-3,5-(trifluoro-dimethyl)benzene ethanol was key intermediate for the synthesis of aprepitant,an chiral drug for Cancer antiemetic,the research on preparation of this compound has become one of hot and dificult topics woldwide.The above product shows good prospects in the market for medicine because the demand of this chiral alcohol,with high optical purity,used as a drug also increase with the increasing number of cancer patients.In this paper,the asymmetric transfer hydrogenation was applied to synthesize(R)-3,5-bis(trifluoromethyl)benzene-ethanol from 3,5-bis(trifluoromethyl)acetophenone was obtained in isopropyl alcohol at a certain temperature by using[RuCl2(C10H14)2]2 as catalyst and(1S,2R)-(-)-1-amino-2-indene alcohol as chiral ligand.In the exploration of the asymmetric reactions of hydrogenation for synthesis of(R)-3,5-bis(trifluoromethyl)benzene-ethanol,a method for the determination of the synthetic compounds was developed by chiral gas chromatography.By the single-factor experiments and orthogonal test,the main factors and the optimum reaction conditions were confirmed as follows:when based on 2.5g 3,5-Bis(trifluoromethyl)acetophenone,0.018 g catalyst needed,then the ratio of 1:1.75 for the catalyst and the ligand,0.15g KOH,the concentration of the substrate for 0.03826 mol/L,reaction at 25℃ for 6.5h,and as the experimental completed,optical purity of 91.94%ee and conversion rate of 99.46%were obtainedBy using silica gel column chromatography method,target compound was isolated and purified from raw materials and other impurities.The elution phase composition,a sample volume,silica gel volume and the eluent volume were primarily investigated,after the exploration the optimal conditions were obtained as follows:the volume ratio of 8.5:1 for etlyl acetate and petroleum ether,5.5 h of elution time,1.7L of eluent volume.By purifying and isolating,the purity of(R)-3,5-bis(trifluoromethyl)benzene-ethanol reached 99.99%.The enantiomer were separated by chiral resolution technology,DABCO was chosen as the resolution agent,n-heptane chosen as the solvent,experimental results gave optical purity of 94.2%(ee)and the total yield of 32.52%.After gotten the purified product,We determined the IR,1H NMR,melting point and optical rotation of(R)-3,5-bis(trifluoromethyl)benzene-ethanol and its standard,then analyzed the spectrums and other data,we found sequence analysis of two compounds identical to each other.