Toward a Practical, Two-Step Process for Molnupiravir from Cytidine
<p>A two-step synthesis of molnupiravir (<b>1</b>) 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 (<b>2</b>), 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 <i>N</i>-hydroxycytidine (<b>3</b>) 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 (<b>4</b>), 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. </p>