Resolução cinética do rac-2-cloro-1-(2,4-diclorofenil)etanol utilizando CAL-A e estudo de racemização do correspondente (R)-enantiômero

Abstract

Dynamic Kinetic Resolution (DKR) is a technique that allows the conversion of up to 100% of a racemate into an optically pure enantiomer. This process combines the action of lipases with organometallic racemization catalysts and is widely used for the synthesis of high-value chiral intermediates, especially in the pharmaceutical industry. An example is (S)-2-chloro-1-(2,4-dichlorophenyl)ethanol (S-3), a key intermediate in the chemoenzymatic synthesis of Luliconazole (R-1), the active ingredient in antifungal ointments used to treat fungal infections. In this work, a new synthetic route for obtaining R-1 from the DKR of the racemate rac-3 is proposed. Initially, 2-chloro-1-(2,4-dichlorophenyl)ethanone (2) was reduced with sodium borohydride to generate rac-3. Subsequently, the enzymatic kinetic resolution of rac-3 was carried out via acetylation, catalyzed by Candida antarctica lipase type A immobilized on Immobead 150, recombinantly expressed in Aspergillus oryzae (CAL-A), using acetonitrile as the solvent and vinyl acetate as the acyl donor. After 48-72 hours of reaction, S-3 was obtained with an enantiomeric excess (e.e.) greater than 99%. Subsequently, S-3 was subjected to racemization tests using the Shvo catalyst (cat-10), chlorocarbonyl(1,2,3,4,5-pentamethylcyclopentadienyl)ruthenium(II) (cat-11), chlorocarbonyl(1,2,3,4,5-pentamethylcyclopentadienyl)ruthenium(II) (cat-12), and vanadyl sulfate (cat-43). The racemization studies were conducted under an inert nitrogen (N₂) atmosphere and in toluene as the solvent. Cat-10 was tested in the absence and presence of t-BuOK at 70 °C. In the presence of t-BuOK, a 23% decrease in e.e. was observed after 72 hours, while in the absence of the base, the reduction was less significant. Cat-11, activated in the presence of t-BuOK, showed a 10% decrease in e.e. in just 10 minutes. Cat-12, also activated by t-BuOK, exhibited a decay of only 4% in e.e. after 1 hour. Cat-43 did not demonstrate any activity in the racemization of (S)-3 at temperatures of 40-75 °C and in solvents such as heptane, toluene, cyclohexane, and acetonitrile. These results suggest that, although the catalysts exhibited racemization activity, the decreases in enantiomeric excess were not close to zero. Therefore, optimization of reaction conditions, such as temperature, catalyst ratio, and reaction time, is necessary to improve the efficiency of the racemization process.