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Synthesis and crystal characteristics of nirmatrelvir
Reaction Chemistry & Engineering ( IF 3.4 ) Pub Date : 2023-03-29 , DOI: 10.1039/d3re00019b Bibo Jiang 1 , Gang Li 1 , Jun Yu 1 , Xiaoyan Xu 1 , Hongjuan Pan 1 , Chuanmeng Zhao 1 , Jialiang Zhong 1 , Fuli Zhang 1
Reaction Chemistry & Engineering ( IF 3.4 ) Pub Date : 2023-03-29 , DOI: 10.1039/d3re00019b Bibo Jiang 1 , Gang Li 1 , Jun Yu 1 , Xiaoyan Xu 1 , Hongjuan Pan 1 , Chuanmeng Zhao 1 , Jialiang Zhong 1 , Fuli Zhang 1
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Several synthetic routes of nirmatrelvir (the ingredient of a new drug to treat COVID-19 made by Pfizer) have been reported. We focused on a second route to improve the synthetic method of nirmatrelvir with a methodology that included different steps. The first step was an analysis of reaction byproducts using acetonitrile as a solvent of the condensation reaction to improve the inversion rate. Then, we used isobutyl acetate as a crystalline solvent to obtain the key intermediate as a solvate, which was a stable crystal product with high purity. Complementarily, we also used trifluoroacetic anhydride as the primary-amide dehydrating agent, and 2-methyl tetrahydrofuran as the solvent to prepare nirmatrelvir, which led to an overall yield of 48% via four steps and a purity of 99.5% according to high-performance liquid chromatography. We also investigated the crystal form of nirmatrelvir: the single-crystal features and transformation from a crystal form to nirmatrelvir were dependent upon temperature. Our data have great value for study of the synthetic method and crystal stability of nirmatrelvir.
中文翻译：
尼马曲韦的合成及晶体特性
已经报道了nirmatrelvir（辉瑞公司生产的一种治疗COVID-19的新药的成分）的几种合成路线。我们专注于第二条路线，通过包括不同步骤的方法改进尼马曲韦的合成方法。第一步是分析使用乙腈作为缩合反应溶剂以提高转化率的反应副产物。然后，我们使用乙酸异丁酯作为结晶溶剂，得到关键中间体溶剂化物，这是一种稳定的高纯度结晶产物。作为补充，我们还使用三氟乙酸酐作为伯酰胺脱水剂，2-甲基四氢呋喃作为溶剂制备了nirmatrelvir，总收率为48%四步，高效液相色谱法测定纯度为99.5%。我们还研究了 nirmatrelvir 的晶体形式：单晶特征和从晶体形式到 nirmatrelvir 的转变取决于温度。我们的数据对于研究尼马曲韦的合成方法和晶体稳定性具有重要价值。
更新日期：2023-03-29
中文翻译：
尼马曲韦的合成及晶体特性
已经报道了nirmatrelvir（辉瑞公司生产的一种治疗COVID-19的新药的成分）的几种合成路线。我们专注于第二条路线，通过包括不同步骤的方法改进尼马曲韦的合成方法。第一步是分析使用乙腈作为缩合反应溶剂以提高转化率的反应副产物。然后，我们使用乙酸异丁酯作为结晶溶剂，得到关键中间体溶剂化物，这是一种稳定的高纯度结晶产物。作为补充，我们还使用三氟乙酸酐作为伯酰胺脱水剂，2-甲基四氢呋喃作为溶剂制备了nirmatrelvir，总收率为48%四步，高效液相色谱法测定纯度为99.5%。我们还研究了 nirmatrelvir 的晶体形式：单晶特征和从晶体形式到 nirmatrelvir 的转变取决于温度。我们的数据对于研究尼马曲韦的合成方法和晶体稳定性具有重要价值。
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