Abstract
•A straightforward chemoenzymatic syntheses of propafenone hydrochloride enantiomers has been developed.•The key step involved obtaining both (R)- and (S)- β-chlorohydrins catalyzed by lipases.•Novozym® 435 proves to be a robust biocatalyst leading to chiral β-chlorohydrins.•The efficiency of Novozym® 435 was only achieved using 20% THF in phosphate buffer medium.•Lipase from Candida rugosa was efficient in hydrolyzing (R)-β-chlorohydrin acetate.
A straightforward chemoenzymatic synthesis of both enantiomers of propafenone hydrochloride has been developed. The key step involved the enzymatic kinetic resolution (KR) of rac-1-(chloromethyl)-2-[o-(3-phenylpropionyl)phenoxy]ethyl acetate (rac-5) with Novozym® 435 via a hydrolytic process. The best conditions for KR of rac-5 involved the use of a Novozym® 435:rac-5 ratio of 2:1 (m:m), in 0.1 M phosphate buffer:THF (8:2, v:v), at 35 °C, 250 rpm and 48 h of reaction. Alternatively, KR of rac-5 was performed at 50 °C within 24 h of reaction. Under these conditions, enantiomerically enriched halohydrin (S)-4, 1-{o-[(2S)-3-chloro-2-hydroxypropoxy]phenyl}-3-phenyl-propan-1-one were obtained with 47% yield and 95% ee; the remaining (1R)-1-(chloromethyl)-2-[o-(3-phenylpropionyl)phenoxy]ethyl acetate (R-5) yielded 46% with 96% ee. The latter was hydrolyzed by the lipase from Candida rugosa leading to corresponding chlorohydrin (R)-4 in quantitative yield and 96% ee. The last synthetic step consisted of the reaction of enantiomerically enriched chlorohydrins (S)-4 and (R)-4 with n-propylamine, followed by a hydrochloric acid solution treatment, leading to (R)- and (S)-propafenone hydrochloride with 95% and 96% ee, respectively.
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