Chemoenzymatic Synthesis of Apremilast: A Study Using Ketoreductases and Lipases

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.

Resolution of Racemic Aryloxy-Propan-2-yl Acetates via Lipase-Catalyzed Hydrolysis: Preparation of Enantiomerically Pure/Enantioenriched Mexiletine Intermediates and Analogs

“…To the best of our knowledge, there is no general rule explaining the co-solvent's influence on the conversion and enantioselectivity of lipase-mediated hydrolysis reaction in a monophasic aqueous system containing a minor fraction of an organic solvent. It is a fact that co-solvent modifies the microenvironment of the active site of a lipase, altering its catalytic activity [21]. The way to achieve an ideal co-solvent in a KR lipase, catalyzed via hydrolysis reaction, is still an empirical process.…”

“…Both the remaining (S)-acetate and the (R)-alcohol were obtained with >99% ee. The latter was used in synthesizing apremilast, an effective drug in treating moderate to severe active psoriasis and psoriatic arthritis [21].…”