Synthesis of optically active SARS-CoV-2 Mpro inhibitor drug nirmatrelvir (Paxlovid): an approved treatment of COVID-19.
Org Biomol Chem
; 21(28): 5768-5774, 2023 07 19.
Article
em En
| MEDLINE
| ID: mdl-37293830
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
SARS-CoV-2
/
COVID-19
Limite:
Humans
Idioma:
En
Revista:
Org Biomol Chem
Assunto da revista:
BIOQUIMICA
/
QUIMICA
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
Estados Unidos