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.

中文翻译：

---

迈向实用的 Molnupiravir 两步法：胞苷直接羟胺化，然后选择性酯化

提出了莫努匹拉韦 ( 1 )的两步合成。这项工作的重点是向制造路线发展实用的反应和纯化条件。该序列从高度可用的胞苷 ( 2 ) 开始，通过胞嘧啶环的直接异羟胺化和糖伯醇的酯化形成莫奈拉韦，无需使用保护或活化基团。N-羟基胞苷 ( 3 )的高度结晶水合物产生易于纯化的中间体，并且选择实用的现成酶进行酰化。通过化学促进的选择性酯裂解提高了产量，该裂解转化了副产物莫诺匹韦异丁酰肟酯 ( 4))，进入最终的 API。两个反应均以 > 90% 的分析产率进行，结晶程序用于提供纯度高于 99% 的中间体和活性药物成分，总产率为 60%。通过在两个反应过程中将总浓度限制为 7 体积溶剂来实现出色的通量和可持续性，总体 PMI 为 26，包括后处理和分离。环保溶剂、水和 2-甲基四氢呋喃，提高了运营的可持续性。