Resolução cinética do rac-2-cloro-1-(2,4-diclorofenil) etanol via acetilação, catalisada por lipases

Abstract

(S)-2-Chloro-1-(2,4-dichlorophenyl)ethanol (S-3) is a key intermediate in the chemoenzymatic synthesis of (R)-luliconazole (R-1), commercially known under the brand name Luzu. (R)-1 is an azole antifungal chiral drug used in the treatment of mycoses caused by dermatophytes such as Trichophyton rubrum and Epidermophyton floccosum, both agents responsible for tineas pedis, cruris and corporis and onychomycosis. In this work, we propose a biocatalytic route, in line with green chemistry, to obtain (S)-3 from the enzymatic kinetic resolution of 2-chloro-1-(2,4-dichlorophenyl)ethanol (rac-3), via acetylation reaction, catalyzed by lipases. A screening was performed using seven commercial lipases and six organic solvents, in the presence of vinyl acetate, as acyl donor. Among the evaluated lipases, Candida antarctica type A lipase (CAL-A) immobilized in immobead 150, recombined with Aspergillus oryzae was the most efficient enzyme in the kinetic resolution of rac-3. After the study of several parameters it was possible to establish the optimized conditions in the kinetic resolution of rac-3: 30 h, 40 °C, enzyme:substrate ratio of 2:1 (m:m) and acetonitrile as solvent. Under such reaction conditions, the kinetic resolution of rac-3 led to (S)-2-chloro-1-(2,4-dichlorophenyl)ethyl acetate (S-4) with an enantiomeric excess of 97% and the halohydrin remaining (R)-2-chloro-1-(2,4-dichlorophenyl)ethanol (R-3) with ee > 99%, with 50% conversion and enantiomeric ratio (E) > 200. (S)-2-chloro-1-(2,4-dichlorophenyl)ethanol (S-3) was efficiently obtained after enzymatic hydrolysis of (S)-4 in the presence of lipase CAL-B, with enantiomeric excess > 99%.