Chemoenzymatic Synthesis of Apremilast: A Study Using Ketoreductases and Lipases
AUTOR(ES)
Vega, Kimberly B.; Cruz, Daniel M. V.; Oliveira, Artur R. T.; Silva, Marcos R. da; Lemos, Telma L. G. de; Oliveira, Maria C. F.; Bernardo, Ricardo D. S.; Sousa, Jackson R. de; Zanatta, Geancarlo; Nasário, Fábio D.; Marsaioli, Anita J.; Mattos, Marcos C. de
FONTE
J. Braz. Chem. Soc.
DATA DE PUBLICAÇÃO
2021-05
RESUMO
The key step in the chemoenzymatic synthesis of apremilast was to produce the chiral alcohol (R)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanol, (R)-3. Two enzymatic approaches were evaluated to obtain (R)-3, one using ketoreductases and the other lipases. Bioreduction of 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanone (2), using ketoreductase KRED-P2-D12, led to (R)-3 with 48% conversion and 93% enantiomeric excess (ee). Kinetic resolution of rac-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl acetate (rac-4), via hydrolysis reaction, with 20% of n-butanol, catalyzed by lipase from Aspergillus niger yielded (R)-3 with > 99% ee, 50% conversion and E-value (enantiomeric ratio) > 200. The reaction between enantiomerically pure (R)-3 and 4-acetylamino-isoindol-1,3-dione (8) afforded apremilast in 65% yield and 67% ee.
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