Enzymatic Method Before Open Distribution Ibuprofen Esters And Polymer Drug Synthesis

Enzyme catalysis offers large advantages in terms of mild reaction conditions, environment-friendly process, high enantioselectivity and catalytic efficiency.2-Arylpropionic acid drugs are a kind of important non-steroidal anti-inflammatory drugs(NSAIDs). Since the bioactivity of profens is mainly due to the (S)-enantiomer, obtaining the pure optical enantiomer through the enzymatic resolution has a profound significance for the enhancement of pesticide effect.In this paper, the synthesis of three kinds of2-aryl propionic acid vinyl esters were catalyzed by Hg(Ac)2/H2SO4with vinyl acetate as the acyl donor. Five kinds of ibuprofen esters were also obtained through the reactions of ibuprofen chloride and different alcohols and ester.Then the enzymatic hydrolysis of ibuprofen methyl ester was used as a model reaction, and the influence of enzyme sources, solvents, temperature were studied systematically. At25℃, the highest enantioselectivity (E～145) could be obtained when the reaction was catalyzed by lipase from Candida rugosa (CRL) in the mixed solvent of isooctane/PBS (5/5, v/v). The highest enantiomeric excess (eep%>98%) could be achieved when lipase from Candida cylindracea (L-AY30) was used as the catalyst in the mixed solvent of isooctane/PBS (1/9, v/v). While investigate the enantioselectivity of the hydrolysis of ibuprofen vinyl ester, which was catalyzed by CRL in different media, it was found that in single solvent systems, the linear Eyring plots were obtained with different Tr and the enantiopreferences were all S-selectivity in the experimental temperature (10～50℃). However, in the three mixed reaction media, the Eyring plots were non-linear intersecting at different Tinv. The introduction of solute-solvent cluster model could give a plausible explanation regarding the phenomenon above.The enzymatic method of preparing polymeric drug containing ibuprofen was developed. The results demonstrated that the ring opening polymerization of methyl3-(N-(2-ibuprofen ethyl ester)-N-(2-hydroxyethyl) amino)propanoate and ε-caprolactone could be effectively achieved by the two-step method catalyzed by Novozym435and alkaline protease from Bacillus subtilis (BSAP) successively, and the polymeric products were characterized by IR、1H NMR and GPC.