Preparing anti-SARS-CoV-2 agent EIDD-2801 by a practical and scalable approach, and quick evaluation via machine learning.
Preparing anti-SARS-CoV-2 agent EIDD-2801 by a practical and scalable approach, and quick evaluation via machine learning.
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通过实用且可扩展的方法制备抗SARS-CoV-2药物EIDD-2801，并通过机器学习进行快速评估
DOI：
10.1016/j.apsb.2021.10.011
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发表时间：
2021-11
期刊：
影响因子：
--
通讯作者：
Li Z
中科院分区：
文献类型：
--
作者：
Qin Z;Dong B;Wang R;Huang D;Wang J;Feng X;Bian J;Li Z
EIDD-2801是一种口服生物可利用的前药，将向美国食品和药物管理局申请紧急使用授权，用于治疗COVID-19。为了考察最佳工艺参数，通过四步合成优化了EIDD-2801，纯度为99.9%。羟胺化过程在一锅法中进行，最后一步对试剂、温度和反应时间进行了精确控制。与原路线相比，新路线的收率由原来的17%提高到58%。在十克规模上成功地确定了优化的合成：第一步为200 g，最后一步为20 g。此外，通过Shapley值解释和机器学习方法-决策树方法研究了脱保护步骤中温度、时间和试剂对收率的影响。结果表明，试剂对产率估计的影响最大，其次是温度。EIDD-2801在十克规模下通过四步合成得到总收率为58%。并通过Shapley值解释和机器学习方法-决策树方法对脱保护步骤的本质进行了研究。
EIDD-2801 is an orally bioavailable prodrug, which will be applied for emergency use authorization from the U.S. Food and Drug Administration for the treatment of COVID-19. To investigate the optimal parameters, EIDD-2801 was optimized via a four-step synthesis with high purity of 99.9%. The hydroxylamination procedure was telescoped in a one-pot and the final step was precisely controlled on reagents, temperature and reaction time. Compared to the original route, the yield of the new route was enhanced from 17% to 58% without column chromatography. The optimized synthesis has been successfully determinated on a decagram scale: the first step at 200 g and the final step at 20 g. Besides, the relationship between yield and temperature, time, and reagents in the deprotection step was investigated via Shapley value explanation and machine learning approach-decision tree method. The results revealed that reagents have the greatest impact on yield estimation, followed by the temperature. EIDD-2801 was optimized in a decagram scale with overall yield of 58% under a four-step synthesis. And the nature of deprotection step was investigated via Shapley value explanation and machine learning approach-decision tree method.
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影响因子：
28.3
作者：
Gorbalenya, Alexander E.;Baker, Susan C.;Ziebuhr, John
通讯作者：
Ziebuhr, John
DOI：
10.1016/j.trsl.2019.12.002
发表时间：
2020-04
期刊：
Translational research : the journal of laboratory and clinical medicine
影响因子：
--
作者：
Toots M;Yoon JJ;Hart M;Natchus MG;Painter GR;Plemper RK
通讯作者：
Plemper RK
影响因子：
4.9
作者：
Yoon, Jeong-Joong;Toots, Mart;Plemper, Richard K.
通讯作者：
Plemper, Richard K.
影响因子：
5.2
作者：
Jethava, Krupal P.;Fine, Jonathan;Chopra, Gaurav
通讯作者：
Chopra, Gaurav
影响因子：
7.3
作者：
Gil, Carmen;Ginex, Tiziana;Martinez, Ana
通讯作者：
Martinez, Ana