Enzymatic synthesis of metronidazole esters and their monosaccharide ester derivatives

An efficient enzymatic method for preparation of lipophilic metronidazole ester bearing with a long chain acyl group and hydrophilic metronidazole-saccharide derivatives was developed in the paper. Transesterification reactions of metronidazole with fatty acid vinyl esters (from vinyl caprylate to vinyl stearate) and divinyl dicarboxylate (from divinyl butanedioate to divinyl decanedioate) in anhydrous tetrahydrofuran were catalyzed by Candida antarctica lipase acrylic resin and provided a series of lipophilic metronidazole ester. Subsequently, under the catalysis of alkaline protease from Bacillus subtilis, acylation of D-glucose and D-mannose with metronidazole vinyl ester was carried out in pyridine. Hydrophilic metronidazole-saccharide derivatives were regioselectivly synthesized. Reaction conditions including enzyme sources and solvents for the esterification of metronidazole were examined in detail. The result of enzyme screening showed that C. antarctica lipase acrylic resin in tetrahydrofuran exhibited the highest catalytic activity and the conversion ratio of metronidazole after 24 h was up to 97.4%. Polarity and substrate solubility of reaction solvents have great influence on the enzymatic transesterification. Polar solvents in which metronidazole has high solubility are favorable. (c) 2006 Elsevier Inc. All rights reserved.