Enhancement of enantioselectivity on the synthesis of (S)-naproxen morpholinoalkyl ester prodrugs in organic solvents using isopropanol-dried immobilized lipase

Enzymatic synthesis of a series of (S)-naproxen morpholinoalkyl ester prodrugs directly from racemic naproxen has been investigated. The decrease of enantioselectivity of the crude Candida rugosa lipase from 74.5 to 24 was observed with the increase of the straight alkyl chain length of hydroxyalkyl morpholines (acyl acceptor) from ethyl to butyl in the esterification reaction. The enantioselectivity for the isopropanol-dried immobilized lipase (IPA-dried IM-lipase) was all exceeded 100 for the different straight alkyl chain length of hydroxyalkyl morpholines in various organic solvents, but for the lyophilized IM-lipase was only reached about 11 in isooctane. The hydroxyalkyl morpholines still acts as an enzyme inhibitor at higher alcohol concentration and its optimal alcohol concentrations were ranged from 5 to 10 mM. In conclusion, IPA-dried IM-lipase shows good enzyme activity and excellent enantioselectivity in the synthesis of (S)-naproxen morpholinoalkyl ester prodrugs.