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

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 epimeriza

SUBMITTER: Ghosh AK 

PROVIDER: S-EPMC10526638 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature