SYNTHESIS OF LOVASTATIN WITH IMMOBILIZED CANDIDA-RUGOSA LIPASE IN ORGANIC-SOLVENTS - EFFECTS OF REACTION CONDITIONS ON INITIAL RATES

Lipase from Candida rugosa immobilized on a nylon support has been use d to synthesize lovastatin, a drug which lowers serum cholesterol leve ls, by the regioselective acylation of a diol lactone precursor with 2 -methylbutyric acid in mixtures of organic solvents. Analogs of lovast atin having a different side chain were also obtained through this met hod by reacting the diol substrate with different carboxylic acids. Th e selection of reaction conditions that maximize the initial reaction rate is investigated. Since the diet substrate has very low solubility in non-polar solvents, reaction solvents consisting of mixtures of he xane with a different, more polar cosolvent are considered. For each o f the cosolvent mixtures studied, the reaction rate is maximum for an intermediate percentage of cosolvent in hexane. With total concentrati ons of the diol lactone in the range 6.25-12.5 mM maximum initial rate s correspond approximately to those cosolvent concentrations that perm it a complete solubilization of the substrate. At higher cosolvent con centrations, lower rates are obtained. When considering the same disso lved substrate concentration, the reaction rate was found to increase with increasing values of logP(mix) and decreasing values of the diele ctric constant, when varying the composition of a binary solvent mixtu re. However, when comparing different cosolvents, no general trend wit h respect to these properties was observed. (C) 1997 John Wiley & Sons , Inc.