- Chemoenzymatic synthesis of apremilast: A study using ketoreductases and lipases
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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.
- Vega, Kimberly B.,Cruz, Daniel M. V.,Oliveira, Artur R. T.,Da Silva, Marcos R.,De Lemos, Telma L. G.,Oliveira, Maria C. F.,Bernardo, Ricardo D. S.,De Sousa, Jackson R.,Zanatta, Geancarlo,Nasário, Fábio D.,Marsaioli, Anita J.,De Mattos, Marcos C.
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p. 1100 - 1110
(2021/05/19)
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- Preparation method of 3-acetyl aminophthalimide
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The invention relates to a preparation method of 3-acetyl aminophthalimide, comprising the following steps: dissolving 3-nitro phthalic acid in sodium hydroxide aqueous solution, then adding a reducer and a catalyst, heating to 70 to 80 DEG C, stirring and reacting for 1 to 20 hours, and recrystallizing to obtain 3-amino phthalic acid; stirring with acetic anhydride and performing reflux reaction for 1 to 10 hours to obtain N-(1,3-Dioxo-1,3-dihydro-2-benzofuran-4-yl)acetamide; dissolving the N-(1,3-Dioxo-1,3-dihydro-2-benzofuran-4-yl)acetamide in an organic solvent, adding an amino donor, and stirring and refluxing for 1 to 10 hours, thus obtaining the 3-acetyl aminophthalimide. The method is simple in operation, high in yield, short in reaction route, less in the three wastes (waste gas industrial residue), and easy for industrial production.
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Paragraph 0037; 0038
(2016/10/07)
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