Two short approaches to the COVID-19 drug ß-D-N4-hydroxycytidine and its prodrug molnupiravir.

Molnupiravir, the prodrug for ß-D-N4-hydroxycytidine (NHC), is marketed by Merck as Lagevrio™ against mild-moderate COVID-19, under FDA emergency use authorization. It is the first oral drug against the disease. This work describes two synthetic approaches to NHC and molnupiravir by amide activation in uridine with a peptide-coupling agent and with a 4-chloropyrimidinone nucleoside intermediate.