N-[benzotriazol-1-yloxy(oxolan-2-ylmethoxy)phosphoryl]-2-bromo-N-methylethanamine | 312719-32-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并三唑类
• 英文名称: N-[benzotriazol-1-yloxy(oxolan-2-ylmethoxy)phosphoryl]-2-bromo-N-methylethanamine
• CAS: 312719-32-7
• 化学式: C₁₄H₂₀BrN₄O₄P
• 分子量: 419.215
• InChiKey: JDRHDMJGVSCHTA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  24
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  78.7
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  N-[benzotriazol-1-yloxy(oxolan-2-ylmethoxy)phosphoryl]-2-bromo-N-methylethanamine 在 cacodylate buffer 作用下， 以 乙腈 为溶剂， 生成 tetrahydrofurfuryl dihydrogen phosphate 、 N-(2-hydroxyethyl)-N-methyl-(oxolan-2-ylmethoxy)phosphonamidic acid 、 tetrahydrofurfuryl 1-benzotriazolyl phosphate 、 [2-(benzotriazol-1-yloxy)-ethyl]-methyl-phosphoramidic acid mono-(tetrahydro-furan-2-ylmethyl) ester
  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
• 作为产物：
  描述：

  四氢糠醇 在 三乙胺 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 为溶剂， 反应 2.08h， 生成 N-[benzotriazol-1-yloxy(oxolan-2-ylmethoxy)phosphoryl]-2-bromo-N-methylethanamine
  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.