Practical Remdesivir Synthesis through One-Pot Organocatalyzed Asymmetric (S)-P-Phosphoramidation.
J Org Chem
; 86(7): 4977-4985, 2021 04 02.
Article
em En
| MEDLINE
| ID: mdl-33634692
ABSTRACT
Remdesivir, an inhibitor of RNA-dependent RNA polymerase developed by Gilead Sciences, has been used for the treatment of COVID-19. The synthesis of remdesivir is, however, challenging, and the overall cost is relatively high. Particularly, the stereoselective assembly of the P-chirogenic center requires recrystallization of a 11 isomeric p-nitrophenylphosphoramidate mixture several times to obtain the desired diastereoisomer (39%) for further coupling with the d-ribose-derived 5-alcohol. To address this problem, a variety of chiral bicyclic imidazoles were synthesized as organocatalysts for stereoselective (S)-P-phosphoramidation employing a 11 diastereomeric mixture of phosphoramidoyl chloridates as the coupling reagent to avoid a waste of the other diastereomer. Through a systematic study of different catalysts at different temperatures and concentrations, a mixture of the (S)- and (R)-P-phosphoramidates was obtained in 97% yield with a 96.1/3.9 ratio when 20 mol % of the chiral imidazole-cinnamaldehyde-derived carbamate was utilized in the reaction at -20 °C. A 10-g scale one-pot synthesis via a combination of (S)-P-phosphoramidation and protecting group removal followed by one-step recrystallization gave remdesivir in 70% yield and 99.3/0.7 d.r. The organocatalyst was recovered in 83% yield for reuse, and similar results were obtained. This one-pot process offers an excellent opportunity for industrial production of remdesivir.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Antivirais
/
Monofosfato de Adenosina
/
Alanina
Idioma:
En
Revista:
J Org Chem
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Taiwan