Toward a Practical, Two-Step Process for Molnupiravir: Direct Hydroxamination of Cytidine Followed by Selective Esterification

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 byproduct, molnupiravir isobutyryl oxime ester (4), into the final API. Both reactions proceed in >90% assay yield, and crystallization procedures are used to afford intermediates and active pharmaceutical ingredients in purities above 99% with an overall yield of 60%. Excellent throughput and sustainability are achieved by limiting the total concentration to 7 volumes of solvent in the course of the two reactions with an overall PMI of 26 including work-up and isolation. Environmentally friendly solvents, water and 2-methyl tetrahydrofuran, enhance sustainability of the operation.