ABSTRACT
The present work describes the synthesis of molnupiravir by employing commercially available inexpensive materials in two steps with an overall yield of 85.7%. The synthetic methodology starts with an eco-friendly starting material, that is, cytidine and establishes an alternative way to avoid costly enzyme mediated reactions. This synthetic strategy involves a selective acylation of cytidine as the first key step followed by the second step, that is, hydroxamination reaction. The major advantage of this protocol is that it is completely free of protection and deprotection reactions. Chemoselective acylation of cytidine's primary alcohol was achieved using isobutyryl chloride, Et3N, and DMF solvent (89.3% yield). The aqueous phase transformation was achieved for the hydroxamination reaction with a 96% yield.
ABSTRACT
In view of recent global pandemic the 3-alkynyl substituted 2-chloroquinoxaline framework has been explored as a potential template for the design of molecules targeting COVID-19. Initial in silico studies of representative compounds to assess their binding affinities via docking into the N-terminal RNA-binding domain (NTD) of N-protein of SARS-CoV-2 prompted further study of these molecules. Thus building of a small library of molecules based on the said template became essential for this purpose. Accordingly, a convenient and environmentally safer method has been developed for the rapid synthesis of 3-alkynyl substituted 2-chloroquinoxaline derivatives under Cu-catalysis assisted by ultrasound. This simple and straightforward method involved the coupling of 2,3-dichloroquinoxaline with commercially available terminal alkynes in the presence of CuI, PPh3 and K2CO3 in PEG-400. Further in silico studies revealed some remarkable observations and established a virtual SAR (Structure Activity Relationship) within the series. Three compounds appeared as potential agents for further studies.