tetrahydrofurfuryl N-methyl-N-(2-bromoethyl)phosphoramidate

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 有机磷酸及其衍生物
• 英文名称: tetrahydrofurfuryl N-methyl-N-(2-bromoethyl)phosphoramidate
• 英文别名: N-(2-bromoethyl)-N-methyl-(oxolan-2-ylmethoxy)phosphonamidic acid
• 化学式: C₈H₁₇BrNO₄P
• 分子量: 302.105
• InChiKey: OSWYGPCQSHQTCF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.3
• 重原子数：
  15
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  59
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  四氢糠醇 在 10percent Pd/C 氢气 、 三乙胺 、 三氯氧磷 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 2.16h， 生成 tetrahydrofurfuryl N-methyl-N-(2-bromoethyl)phosphoramidate
  参考文献：
  名称：

  Activation Mechanisms of Nucleoside Phosphoramidate Prodrugs

  摘要：

  A series of thymidine and tetrahydrofurfuryl phosphoramidates bearing haloethyl or piperidyl sulostituents was synthesized and used to investigate the activation mechanisms of nucleoside phosphoramidate prodrugs. Structure assignments for the tetrahydrofurfuryl reaction products were confirmed by comparison to authentic samples. Structural assignments for thymidine phosphoramidate reaction products were made by analogy to the tetrahydrofurfuryl products. Generation of the phosphoramidate anion leads to cyclization and subsequent nucleophilic attack at carbon and phosphorus of the resulting aziridinium ion intermediate to give the observed products. Nucleophilic attack by water at carbon and phosphorus occurs without selectivity, supporting a mechanism of action of haloethylamine nucleoside prodrugs involving intracellular release of the nucleotide. Activation of the benzotriazolyl piperidyl phosphoramidates is followed by P-N bond hydrolysis; this reaction is subject to specific acid catalysis and to nucleophilic catalysis by 1-hydroxybenzotriazole. These results suggest that the mechanism of action of the piperidyl nucleoside phosphoramidates involves the intracellular release of the active nucleotide following P-N bond cleavage, presumably by the action of an endogenous phosphoramidase.

  DOI：

  10.1021/jm000302b

文献信息

• Activation Mechanisms of Nucleoside Phosphoramidate Prodrugs
  作者：Caren L. Freel Meyers、Richard F. Borch

  DOI：10.1021/jm000302b

  日期：2000.11.1

  A series of thymidine and tetrahydrofurfuryl phosphoramidates bearing haloethyl or piperidyl sulostituents was synthesized and used to investigate the activation mechanisms of nucleoside phosphoramidate prodrugs. Structure assignments for the tetrahydrofurfuryl reaction products were confirmed by comparison to authentic samples. Structural assignments for thymidine phosphoramidate reaction products were made by analogy to the tetrahydrofurfuryl products. Generation of the phosphoramidate anion leads to cyclization and subsequent nucleophilic attack at carbon and phosphorus of the resulting aziridinium ion intermediate to give the observed products. Nucleophilic attack by water at carbon and phosphorus occurs without selectivity, supporting a mechanism of action of haloethylamine nucleoside prodrugs involving intracellular release of the nucleotide. Activation of the benzotriazolyl piperidyl phosphoramidates is followed by P-N bond hydrolysis; this reaction is subject to specific acid catalysis and to nucleophilic catalysis by 1-hydroxybenzotriazole. These results suggest that the mechanism of action of the piperidyl nucleoside phosphoramidates involves the intracellular release of the active nucleotide following P-N bond cleavage, presumably by the action of an endogenous phosphoramidase.