Lipase catalysis in the resolution of racemic intermediates of diltiazem synthesis in organic solvents

Abstract

The key intermediates of the diltiazem synthesis, methyl trans-3-(4-methoxyphenyl)glycidate 1 and methyl threo-2-hydroxy-3-(4-methoxyphenyl)-3-(2-nitrophenylthio)propionate 2, have been successfully resolved by using lipase catalysis in organic solvents. In the resolution of the glycidate 1, enzymatic enantioselectivity greatly depends on the solvent, tertiary alcohols leading to the highest optical purities of the products: e.e. close to 90% at 60% conversion for the unchanged (2R,3S)enantiomer and over 90% for the new (2S,3R)-ester, when the first 20% of the product is formed, can be obtained. Ester hydrolysis takes place simultaneously with ester alcoholysis. The enzymatic acylation of compound 2 with acid anhydrides or vinyl esters in THF tends to stop at 50% conversion, yielding the two enantiomers with an e.e. of the order of 100%. The enantiomers can be easily separated by flash chromatography.