Large-Scale Stereoselective Synthesis of 1,3-Oxathiolane Nucleoside, Lamivudine, via ZrCl4-Mediated N-Glycosylation,Organic Process Research & Development

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Large-Scale Stereoselective Synthesis of 1,3-Oxathiolane Nucleoside, Lamivudine, via ZrCl4-Mediated N-Glycosylation
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2020-03-03 , DOI: 10.1021/acs.oprd.9b00414
Umesh P. Aher ₁ , Dhananjai Srivastava ₁ , Harishchandra S. Jadhav ₁ , Girij P. Singh ₁ , Jayashree B. S. ₂ , Gautham G. Shenoy ₂

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A stereoselective large-scale synthetic process is described to produce 1,3-oxathiolane nucleoside, lamivudine. A mild, inexpensive, and readily available zirconium (IV) chloride (ZrCl₄) catalyst acts as a substrate activator for the key N-glycosylation step at room temperature. An optimum of 0.5 equiv of ZrCl₄ is required, which gives encouraging results with respect to chemical efficiency and stereoselectivity. The focus of this work was to develop a new Lewis acid catalyst for N-glycosylation reaction that permits mild and selective synthesis of lamivudine at a large scale. It allowed preferential formation of a single isomer of nucleoside out of four possible stereoisomers, starting from the corresponding 1,3-oxathiolane acetate substrate (racemic and/or diastereomeric mixture of isomers). The thermal behavior for the critical N-glycosylation step was also studied by differential scanning calorimetry and reaction calorimetry techniques.

中文翻译：

通过ZrCl ₄介导的N-糖基化大规模立体选择性合成1,3-氧杂硫杂环戊烷核苷拉米夫定

描述了一种立体选择性的大规模合成方法，可生产1,3-氧杂硫杂环戊烷核苷拉米夫定。温和，便宜且易于获得的氯化锆（IV）（ZrCl ₄）催化剂在室温下用作关键N-糖基化步骤的底物活化剂。ZrCl ₄的最佳含量为0.5当量，这在化学效率和立体选择性方面提供了令人鼓舞的结果。这项工作的重点是开发一种新的N路易斯酸催化剂-糖基化反应，允许温和且选择性地大规模合成拉米夫定。从相应的1，3-氧杂硫杂环戊烷乙酸酯底物（异构体的外消旋和/或非对映异构体混合物）开始，它允许从四种可能的立体异构体中优先形成单个核苷异构体。还通过差示扫描量热法和反应量热技术研究了关键的N-糖基化步骤的热行为。

更新日期：2020-03-03

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