Toward a Practical, Two-Step Process for Molnupiravir from Cytidine
2021
A two-step synthesis of molnupiravir (1) is presented. This work focuses on the development of
practical reaction and purification conditions toward a manufacturing
route. The sequence commences from
highly available cytidine (2), and
molnupiravir is formed through direct hydroxamination of the cytosine ring and
esterification of the sugar’s primary alcohol without use of protecting or
activating groups. A highly crystalline
hydrate of N-hydroxycytidine (3) resulted in an easily purified
intermediate, and a practical, off-the-shelf enzyme was selected for the
acylation. The yield was increased
through a chemically-promoted, selective ester cleavage which converted a by-product,
molnupiravir isobutyryl oxime ester (4),
into the final API. Both reactions
proceed in >90% assay yield and crystallization procedures are used to
afford intermediate and active pharmaceutical ingredient in purities above 99%
with an overall yield of 60%. Excellent
throughput and sustainability is achieved by limiting the total concentration
to 7 volumes of solvent in the course of the two reactions with an overall PMI
of 41 including work-up and isolation. Environmentally
friendly solvents, water and 2-methyl tetrahydrofuran, enhance sustainability
of the operation.
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