Synthesis of optically active SARS-CoV-2 Mpro inhibitor drug nirmatrelvir (Paxlovid): an approved treatment of COVID-19.
Synthesis of optically active SARS-CoV-2 Mpro inhibitor drug nirmatrelvir (Paxlovid): an approved treatment of COVID-19.
复制标题
光学活性 SARS-CoV-2 Mpro 抑制剂药物 nirmatrelvir (Paxlovid) 的合成：一种已批准的 COVID-19 治疗方法。
DOI：
10.1039/d3ob00653k
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发表时间：
2023
影响因子：
3.2
通讯作者：
Yadav,Monika
中科院分区：
文献类型：
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作者：
Ghosh,ArunK;Yadav,Monika
尼马瑞韦(Paxlovid)是FDA批准的针对SARS-COV-2 3CL蛋白水解酶的药物。我们报道了一种尼马瑞韦的光学活性合成方法，它避免了关键的异构化步骤。我们首次使用标准偶联剂EDC和HOBt将GEM-二甲基双环[3.1.0]脯氨酸甲酯与叔亮氨酸-三氟乙酰胺偶联，以极高的产率提供了相应的二肽衍生物，但在含有叔亮氨酸的手性中心观察到了显著的异构化。为了避免这一异构化问题，我们建立了氯化锌介导的Boc-衍生物的直接N-三氟乙酰化反应来合成尼马瑞韦。该方案已用于与其他酸酐形成N-酰基键，而不需要异构化。本合成路线可用于合成尼马瑞韦的结构变体，而不需要显著的异构化反应。
Nirmatrelvir (Paxlovid) is an FDA approved drug that targets SARS-COV-2 3CLprotease. We report an optically active synthesis of nirmatrelvir that avoids a critical epimerization step. Our initial coupling of gem-dimethyl bicyclo[3.1.0]proline methyl ester with tert-leucine-trifluoroacetamide using standard coupling reagents, EDC and HOBt, provided the corresponding dipeptide derivative in excellent yield, however, a significant epimerization was observed at the tert-leucine bearing chiral center. To circumvent this epimerization problem, we developed a ZnCl2-mediated direct N-trifluroacetylation of Boc-derivatives for the synthesis of nirmatrelvir. This protocol has been utilized for N-acyl bond formation with other anhydrides without epimerization. The present synthetic route can be useful for the synthesis of structural variants of nirmatrelvir without significant epimerization.