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

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 ZnCl 2 -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.