Study On Lipase-Catalyzed Resolution Of Ethyl Mandelate And Preparation Of Chiral Cyclandelate

Ethyl mandelate is an important pharmaceutical intermediate in the preparation of mandelic acid series drugs. At present, many studies were focused on resolution and synthesis of chiral (R)- mandelic acid and its series intermediates, but (S)- enantiomer was rarely reported. In this paper, (S)- ethyl mandelate was obtained through chiral resolution of racemic ethyl mandelate by lipase. Chiral cyclandelate was synthesized with (S)- mandelic acid hydrolyzed from (S)- ethyl mandelate.A method for determination of substrate and product with gas chromatography was established. Ethanol, ethyl mandelate and cyclandelate were analyzed by gas chromatography GC-14C with SE-30; and enantiomers of ethyl mandelate and cyclandelate were analyzed by GC-14C with chiral column CYCLOSILB 112-6632.Novozyme 435 was selected from 5 kinds of lipases for catalyzing chiral resolution of racemic ethyl mandelate in n-butanol media. The reaction was a transesterification reaction based on analysis results of gas chromatography - mass spectrograph. The catalytic behaviors of lipase Novozyme 435 were investigated, and the optimum reaction conditions were: 50mg Novozyme435, 0.4% water, 45℃, 150rpm shaking speed in 5ml reaction volume. After optimization, (S)-ethyl mandelate with 92.4% ee value was obtained when the substrate conversion rate reached 56%. The reaction kinetics showed that the substrate did not inhibit activity of enzyme and the affinity was very low between substrate and enzyme with 1022 mM Km value. A solvent-free system with high concentration substrate was benefited to improve reactive rate.(S)- mandelic acid with 94.5% ee value was obtained from hydrolyzation of ethyl mandelate catalyzed by sodium hydroxide.Chiral mandelic acid is used to esterify 3,3,5-trimethyl-cyclohexanol to chiral cyclandelate catalyzed by sodium bisulfate. The effects of reaction time, amount of...