Can Molnupiravir be synthesized in a more efficient and economical way? Molnupiravir (EIDD-2801) is a new generation of oral antiviral drug for COVID-19, which has been reported to effectively reduce the hospitalization and mortality rates of infected patients. This drug has advantages such as high metabolic stability, high bioavailability, high lung distribution rate, and broad-spectrum low toxicity. Originally developed by Merck, the synthesis route of this compound was completed in 2019 with 5 steps and a maximum yield of only 17%. Professor Zhiyu Li's team from the School of Pharmacy, China Pharmaceutical University, published a short communication in the English journal "Acta Pharmaceutica Sinica B" in the November 2021 issue, studying the synthesis process of molnupiravir in order to obtain a more easily scalable, operationally simple, and more economical route. The research route in the paper starts with readily available uridine as the raw material, and through four steps of reaction, a total yield of 58% is obtained for hundred-gram level EIDD-2801. During the research process, by exploring the reaction conditions, the key hydroxylamine intermediate can be obtained through a one-step condensation reaction, avoiding the problem of complex operation and low yield in the original route. In addition, during the final deprotection of the protecting group, the authors discovered that trifluoroacetic acid can selectively remove the acetone group with high yield and high selectivity. The final synthetic route has the advantages of readily available raw materials, mild reaction conditions, simple operation, high yield, and ease of industrial production. Furthermore, the authors also calculated the optimal conditions for reaction reagents, temperature, and reaction time in key steps through Shapley value and DTR regression decision tree models, which are expected to be applied in kilogram-scale synthesis processes. Reference Preparing anti-SARS-CoV-2 agent EIDD-2801 by a practical and scalable approach, and quick evaluation via machine learning Zhen Qin, Bin Dong, Renbing Wang, Dechun Huang, Jubo Wang*, Xi Feng, Jinlei Bian*, Zhiyu Li* Acta Pharm Sin B 2021;11(11):3678-3682 查看更多
胰酶细胞消化液的应用及注意事项？ 背景 [1-3] 胰酶细胞消化液是一种含有酚红的溶液，成分包括0.25%胰酶、0.02%EDTA和酚红，pH值为7.2-7.8。该消化液经过过滤除菌，可直接用于细胞和组织的消化。 贴壁细胞的消化： 1、用无菌的PBS、Hanks液或无血清培养液洗涤细胞，去除残余的血清。 2、加入适量的胰酶细胞消化液，略盖过细胞，放置一段时间。消化时间因细胞类型而异。 3、观察细胞收缩和形态变化，或用枪吹打细胞，若细胞可被吹打下来，则吸除消化液，加入含血清的培养液。 4、若消化不足，可重新加入胰酶细胞消化液。 5、若消化时间过长，细胞已脱落，可用胰酶细胞培养液将细胞吹打下来，离心沉淀后加入含血清的培养液。 组织的消化时间因组织类型而异，通常以充分打散组织为宜。 注意事项： 1、使用胰酶细胞消化液时要避免细菌污染。 2、胰酶细胞消化液的消化时间不宜过长，否则细胞生长状况会受到影响。 应用 [4][5] 胰酶/EDTA两种消化液对携带水痘-带疱疹病毒的2BS细胞消化效果的比较研究 本研究比较了胰酶和EDTA两种消化液对冻融后携带水痘-带疱疹病毒的2BS细胞的消化效果。实验中分别配制了0.125%和0.25%的胰酶，以及0.01%和0.02%的EDTA溶液，加入预先培养好的2BS细胞中进行消化。消化后，观察细胞形态，离心、浓缩、冻融并检测病毒滴度。 结果显示，与0.125%和0.25%胰酶、0.01%EDTA，0.25%胰酶和0.02%EDTA混合消化液相比，使用0.02%EDTA消化液消化水痘-带疱疹病毒的2BS细胞后，冻融后的病毒滴度提高了1.3～0.8个log值。因此，使用0.2%EDTA消化液消化含有水痘病毒的细胞可以获得最佳的病毒滴度。 参考文献 [1]Establishment and Maintenance of Human Embryonic Stem Cell Lines on Human Feeder Cells Derived from Uterine Endometrium under Serum-Free Condition1[J].Jung Bok Lee,Jeoung Eun Lee,Jong Hyuk Park,Sun Jong Kim,Moon Kyoo Kim,Sung Il Roh,Hyun Soo Yoon.Biology of Reproduction.2005(1) [2]Wnt signalling inhibits neural differentiation of embryonic stem cells by controlling bone morphogenetic protein expression[J].Lorenz Haegele,Barbara Ingold,Heike Naumann,Ghazaleh Tabatabai,Birgit Ledermann,Sebastian Brandner.Molecular and Cellular Neuroscience.2003(3) [3]Id proteins in development,cell cycle and cancer[J].Marianna B.Ruzinova,Robert Benezra.Trends in Cell Biology.2003(8) [4]BMP Induction of Id Proteins Suppresses Differentiation and Sustains Embryonic Stem Cell Self-Renewal in Collaboration with STAT3[J].Qi-Long Ying,Jennifer Nichols,Ian Chambers,Austin Smith.Cell.2003(3) [5]郝鹏博,谢秋红,杜岩,杨蕾蕾.比较胰酶/EDTA两种消化液对携带水痘-带疱疹病毒的2BS消化效果分析[J].中国实用医药,2011,6(21):60-61. 查看更多
2,4,5-三氟苯甲酰乙酸乙酯的合成方法是什么? 2,4,5-三氟苯甲酰乙酸乙酯，英文名为Ethyl 2,4,5-trifluorobenzoylacetate，是一种常温常压下为白色至灰白色固体的化合物。它主要用作有机合成和医药化学中间体，特别是在新型氟喹诺酮类广谱抗菌药物分子德拉沙星的合成中起到重要作用。 合成方法 图1 展示了2,4,5-三氟苯甲酰乙酸乙酯的合成路线。合成过程中，首先在反应器中加入2,4,5-三氟苯甲酸、甲苯和N,N-二甲基甲酰胺，然后加入亚硫酰氯。将混合物加热至60±5度，直到起始原料酸被消耗掉。反应结束后，通过真空蒸馏得到溶液。接着加入新鲜的甲苯进行第二次蒸馏。在另一个反应器中，加入乙基丙二酸钾、氯化镁和甲苯，然后向混合物中加入四氢呋喃和三乙胺。将悬浮液加热并搅拌反应，最后通过盐酸提取得到目标产物。 用途 2,4,5-三氟苯甲酰乙酸乙酯常用作医药化学和有机合成中间体。它可以用于合成新型氟喹诺酮类广谱抗菌药物分子德拉沙星。德拉沙星是一种新型的氟喹诺酮类广谱抗菌药，具有阴离子特性，在酸性条件下具有较好的抗菌活性。它通过抑制细菌DNA的复制过程来杀菌。对革兰氏阳性菌、革兰氏阴性菌和厌氧菌都具有较好的抗菌活性。此外，在有机合成转化中，2,4,5-三氟苯甲酰乙酸乙酯的结构中的羰基和酯基之间的亚甲基可以在碱性条件下生成碳负离子，从而进行后续的衍生化反应。 参考文献 [1] Barnes, David M. et al Organic Process Research & Development, 10(4), 803-807; 2006 查看更多
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