%0 Journal Article %1 WOS:000634754700015 %A Vega, Kimberly B %A Cruz, Daniel M V %A Oliveira, Artur R T %A da Silva, Marcos R %A de Lemos, Telma L G %A Oliveira, Maria C F %A Bernardo, Ricardo D S %A de Sousa, Jackson R %A Zanatta, Geancarlo %A Nasario, Fabio D %A Marsaioli, Anita J %A de Mattos, Marcos C %C CAIXA POSTAL 26037, 05599-970 SAO PAULO, BRAZIL %D 2021 %I SOC BRASILEIRA QUIMICA %J JOURNAL OF THE BRAZILIAN CHEMICAL SOCIETY %K biocatalysis; enzymatic ketoreductases; kinetic lipases; resolution} {apremilast; %N 5 %P 1100-1110 %R 10.21577/0103-5053.20210012 %T Chemoenzymatic Synthesis of Apremilast: A Study Using Ketoreductases and Lipases %V 32 %X 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. 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.

@article{WOS:000634754700015, abstract = {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. 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.}, added-at = {2022-05-23T20:00:14.000+0200}, address = {CAIXA POSTAL 26037, 05599-970 SAO PAULO, BRAZIL}, author = {Vega, Kimberly B and Cruz, Daniel M V and Oliveira, Artur R T and da Silva, Marcos R and de Lemos, Telma L G and Oliveira, Maria C F and Bernardo, Ricardo D S and de Sousa, Jackson R and Zanatta, Geancarlo and Nasario, Fabio D and Marsaioli, Anita J and de Mattos, Marcos C}, biburl = {https://www.bibsonomy.org/bibtex/282f7523d0d65eea08bda23b5e3e00026/ppgfis_ufc_br}, doi = {10.21577/0103-5053.20210012}, interhash = {53fe06b4b729ff176a049a6e36fd4345}, intrahash = {82f7523d0d65eea08bda23b5e3e00026}, issn = {0103-5053}, journal = {JOURNAL OF THE BRAZILIAN CHEMICAL SOCIETY}, keywords = {biocatalysis; enzymatic ketoreductases; kinetic lipases; resolution} {apremilast;}, number = 5, pages = {1100-1110}, publisher = {SOC BRASILEIRA QUIMICA}, pubstate = {published}, timestamp = {2022-05-23T20:00:14.000+0200}, title = {Chemoenzymatic Synthesis of Apremilast: A Study Using Ketoreductases and Lipases}, tppubtype = {article}, volume = 32, year = 2021 }