Lipase-catalyzed Kinetic Resolution Of Naproxen In Aqueous-organic Solvent Biphase System

Naproxen is a kind of anti-inflammatory, analgesic, anti rheumatic chiral drugs. The efficacy of the S configuration drug is 28 times higher than that of the R configuration drug. R-naproxen has negative effect on the human body. In order to ensure the safety of clinical medication, It is needed to obtain optical pure naproxen.This thesis explored the aqueous-organic solvent biphase system, Candida rugosa lipase has been used to catalyze the selective hydrolysis of naproxen methyl ester and generate S-Naproxen.The esterification was verified by thin layer chromatography, and the efficiency of the esterification was 100%. Naproxen methyl ester has been used as a following substrate.The lipase was screened with racemic naproxen methyl ester as substrate, under the condition of the same enzyme activity unit. The catalysis activity of Candida rugosa lipase (CRL), porcine pancreatic lipase (PPL), Immobilized antarctic Candida San lipase n435, Carica papaya lipase (CPL) were studied. The experimental results showed that the CRL has highest conversion and enantiomeric excess of product (eep). So CRL has been selected as following experiments.The eifect of the reaction time, reaction temperature, enzyme addition amount, the amount of buffer, the type of organic solvent, and the amount of lactose on the lipase catalyzed resolution reaction were studiedThe optimum conditions for the reaction system is below:25 mL of isooctane,1 mL of phosphate buffer (0.2 mol/L, pH7.0),250 mg, of racemic naproxen methyl ester 100 mg of Candida lipase (CRL),0.5 g of lactose. The reaction temperature is 35?, Reaction time is 96 h. The optimal enantiomer excess of product (eep) can reach above 98%..Based on the above results, the effect of microwave on the lipase-catalyzed Naproxen resolution reaction was studied. The effect of the reaction temperature, reaction time, enzyme addition amount, the amount of buffer on microwave reaction were studied. The experimental results showed that when the temperature is 45?, the amount of CRL is 125 mg, the adding amount of phosphate buffer (0.2 mol/L, pH 7.0) isl mL, the reaction time of 3 h is optimum. Under the optimum microwave reaction condition, the enantiomeric excess of product (eep) can reach more than 99%.Finally dynamic kinetic resolution was used to overcome the problem that enantiomeric excess of product (eep) should been reduced with the increase of yield in the kinetic resolution, To obtain higher yield with higher enantiomeric excess of product (eep), and to overcome the disadvantage of kinetic resolution, the dynamic kinetic resolution system under microwave was established, Theoretically, dynamic kinetic resolution can achieve 100% of conversionThe establishment of dynamic kinetic resolution system is as follows:first of all, the silicone rubber hose (wall thickness 0.6 mm, inner diameter of 7 mm) was fully swelled, In the inner of the silicone rubber hose, the addition amount of NaOH is 2 g, the addition amount of methanol and trimethylchlorosilane is 0.1 ml and 0.2 ml, respectively. In the outer of the silicone rubber hose, the addition amount of isooctane is 50 ml, the addition amount of racemic naproxen methyl ester is 0.115 g, the addition amount of CRL is 0.285 g, the addition amount of phosphate buffer solution (0.2 mol/L, pH 7.0) is1 ml.