Resolução cinética da glicidil ftalimida: um intermediário para a produção da rivaroxabana

Abstract

This work describes the development of a new synthetic route for rivaroxaban, a chiral anticoagulant drug, through the enzymatic kinetic resolution of the racemic intermediate glycidyl phthalimide (5). The resolution step was optimized by systematically evaluating reaction parameters such as enzyme type, acyl donor, temperature, reaction time, and enzyme amount. Screening of eight different lipases identified Amano Lipase PS from Burkholderia cepacia as the most enantioselective. The optimized reaction conditions employed vinyl acetate as the acyl donor, methyl tert-butyl ether (TBME) as the solvent, and a temperature of 50 ºC, resulting in a product with an enantiomeric ratio greater than 200 in 8 hours. This result represents a significant advance compared to the literature, where the highest reported enantiomeric ratio was 32 in 24 hours. The developed methodology demonstrates potential for application in the enantioselective synthesis of rivaroxaban, with advantages such as reduced reaction time and increased enantioselectivity.