New chemical and chemo-enzymatic synthesis of (RS)-, (R)-, and (S)-esmolol

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Abstract

One of the β-adrenergic receptor blocking agents, esmolol, is synthesized in its racemic (RS) and enantio enriched forms (R and S) by a new chemical and chemo-enzymatic route. The enantio-pure intermediates (R) and (S)-methyl 3-(4-(3-chloro-2-hydroxypropoxy)phenyl)propanoate were synthesized from the corresponding racemic alcohol by enzymatic kinetic resolution. The commercially available lipases PCL and CRL showed complementary enantioselectivity in the transesterification reaction of racemic alcohol with vinyl acetate as the acyl donor. The reactions afforded the (R)-alcohol along with (S)-acetate and the (S)-alcohol along with (R)-acetate, respectively, indicating the enzymatic switch for reversal of enantioselectivity. Various reaction parameters such as substrate and enzyme concentration, type of reaction medium, duration of conversion and enantioselectivity were optimized. The (R)- and (S)-alcohols were converted to the (S)- and (R)-esmolol, respectively, on N-alkylation with isopropanolamine. The enzymatically obtained (R)- and (S)-acetates were chemically hydrolyzed to the corresponding alcohols and further converted to (S)- and (R)-esmolol by chemical reactions. These represent the new chemo-enzymatic synthesis of both the enantiomers of the drug. Using chemical routes, the (RS)/(R)/(S)-esmolol were also synthesized from (RS)/(R)/(S)-epichlorohydrin via the corresponding (RS)/(S)/(R)- methyl 3-(4-((oxiran-2-yl)methoxy)phenyl)propanoate and the (RS)/(R)/(S)-methyl 3-(4-(3-chloro-2-hydroxypropoxy)phenyl)propanoate intermediates. This process has given improved overall yield and better enantiomeric excess compared to the reported one.

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Banoth, L., & Banerjee, U. C. (2017). New chemical and chemo-enzymatic synthesis of (RS)-, (R)-, and (S)-esmolol. Arabian Journal of Chemistry, 10, S3603–S3613. https://doi.org/10.1016/j.arabjc.2014.03.011

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