Synthesis of optically active SARS-CoV-2 Mpro inhibitor drug nirmatrelvir (Paxlovid): an approved treatment of COVID-19?

Organic & Biomolecular Chemistry Pub Date: 2023-06-09 DOI: 10.1039/D3OB00653K

Abstract

Nirmatrelvir (Paxlovid) is an FDA approved drug that targets SARS-COV-2 3CLprotease. We report an optically active synthesis of nirmatrelvir that avoids a critical epimerization step. Our initial coupling of gem-dimethyl bicyclo[3.1.0]proline methyl ester with tert-leucine-trifluoroacetamide using standard coupling reagents, EDC and HOBt, provided the corresponding dipeptide derivative in excellent yield, however, a significant epimerization was observed at the tert-leucine bearing chiral center. To circumvent this epimerization problem, we developed a ZnCl2-mediated direct N-trifluroacetylation of Boc-derivatives for the synthesis of nirmatrelvir. This protocol has been utilized for N-acyl bond formation with other anhydrides without epimerization. The present synthetic route can be useful for the synthesis of structural variants of nirmatrelvir without significant epimerization.

Graphical abstract: Synthesis of optically active SARS-CoV-2 Mpro inhibitor drug nirmatrelvir (Paxlovid): an approved treatment of COVID-19
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