Two short approaches to the COVID-19 drug -d-N⁴-hydroxycytidine and its prodrug molnupiravir

Molnupiravir, the prodrug for beta-d-N-4-hydroxycytidine (NHC), is marketed by Merck as Lagevrio (TM) 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.