N-methyl-N-(2-bromoethyl)phosphoramidic dichloride | 68175-51-9

• 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: N-methyl-N-(2-bromoethyl)phosphoramidic dichloride
• 英文别名: 2-bromo-N-dichlorophosphoryl-N-methylethanamine
• CAS: 68175-51-9
• 化学式: C₃H₇BrCl₂NOP
• 分子量: 254.878
• InChiKey: GOTGBRYDPISCGU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  9
• 可旋转键数：
  3
• 环数：
  0.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  20.3
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  四氢糠醇 、 N-methyl-N-(2-bromoethyl)phosphoramidic dichloride 在 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 为溶剂， 反应 0.83h， 以87%的产率得到tetrahydrofurfuryl N-methyl-N-(2-bromoethyl)phosphoramidochloridate
  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：

  N-甲基-N-(2-溴乙基)胺氢溴酸盐 在 三乙胺 、 三氯氧磷 作用下， 以 二氯甲烷 为溶剂， 以93%的产率得到N-methyl-N-(2-bromoethyl)phosphoramidic dichloride
  参考文献：
  名称：

  5-氟-2'-脱氧尿苷氨基磷酸酯类似物的合成和生物学评估。

  摘要：

  已经制备了一系列5-氟-2'-脱氧尿苷的烷基化氨基磷酸酯类似物，并在体外评估了它们对鼠L1210白血病和B16黑素瘤细胞的生长抑制活性。这些化合物被设计为可在胞内释放氨基磷酸酯阴离子，希望它们可作为胸苷酸合酶的不可逆抑制剂起作用。期望的是核苷部分的结合将随后经由氨基磷酸酯使酶烷基化。氯化物，溴化物，碘化物和甲苯磺酸酯类似物是L1210细胞增殖的高效抑制剂，在较高的药物浓度和较长的暴露时间下均观察到抑制作用增强。胸苷的添加完全逆转了所有化合物的抑制作用，提示这些化合物通过抑制胸苷酸合酶起作用。尽管非烷基化吗啉类似物1f为约。哌啶类似物1g的效力比甲基（氯乙基）氨基化合物低50倍，效力仅低2倍，这证明氮的碱性与烷基化基团的存在同样重要。胸苷的添加逆转了吗啉和哌啶类似物的生长抑制，表明这些化合物也可能经历细胞内转化为5-氟-2'-脱氧尿苷5'单磷酸酯。胸苷和脱氧尿苷衍生物2和3在L1210分析中

  DOI：

  10.1021/jm00014a019

文献信息

• Phosphoramidate analogs of 2'-deoxyuridine
  申请人：University of Rochester

  公开号：US05233031A1

  公开（公告）日：1993-08-03

  The present invention provides a series of cytotoxic phosphoramidate analogs of 5-fluoro-2'-deoxyuridine of the general formula (I): ##STR1## wherein R.sup.1 is H, F or (C.sub.1 -C.sub.4)alkyl; R.sup.2 is CH.sub.2 CH.sub.2 X wherein X is Cl, Br, I or p-toluenesulfonyl; R.sup.3 is (C.sub.1 -C.sub.4)alkyl or CH.sub.2 CH.sub.2 X wherein X is Cl, Br, I or p-toluenesulfonyl; or wherein R.sup.2 and R.sup.3, taken together with the N atom, can be a 5- or 6-membered heterocyclic ring which is aliphatic or aliphatic interrupted by a ring oxygen or a second ring nitrogen; R.sup.4 is H, one equivalent of a pharmaceutically-acceptable cation or (4,4,6-trimethyltetrahydro-1,3-oxazin-2-yl)ethyl, and the pharmaceutically-acceptable salts thereof.

  本发明提供了一系列细胞毒性的磷酰胺类似物5-氟-2'-脱氧尿嘧啶，其一般式为(I)：##STR1## 其中R^1为H，F或(C1-C4)烷基；R^2为CH2CH2X，其中X为Cl、Br、I或对甲苯磺酰基；R^3为(C1-C4)烷基或CH2CH2X，其中X为Cl、Br、I或对甲苯磺酰基；或者R^2和R^3与N原子结合形成5-或6-成员的杂环，该杂环是脂肪族的或被一个环氧原子或第二个环氮原子中断的脂肪族；R^4为H，一个药学上可接受的阳离子或(4,4,6-三甲基四氢-1,3-噁嗪-2-基)乙基，以及其药学上可接受的盐。
• Design, Synthesis, and Biological Evaluation of Indolequinone Phosphoramidate Prodrugs Targeted to DT-diaphorase
  作者：Marcy Hernick、Carolee Flader、Richard F. Borch

  DOI：10.1021/jm020191b

  日期：2002.8.1

  A series of 2- and 3-substituted indolequinone phosphoramidate prodrugs targeted to DT-diaphorase (DTD) have been synthesized and evaluated. These compounds are designed to undergo activation via quinone reduction by DTD followed by expulsion of the phosphoramide mustard substituent from the hydroquinone. Chemical reduction of the phosphoramidate prodrugs led to rapid expulsion of the corresponding phosphoramidate anions in both series of compounds. Compounds substituted at the 2-position are excellent substrates for human DTD (k(cat)/K-M = (2-5) x 10(6) M-1 s(-1)); however, compounds substituted at the 3-position are potent inhibitors of the target enzyme. Both series of compounds are toxic in HT-29 and BE human colon cancer cell lines in a clonogenic assay. There was a correlation found between cytotoxicity and DTD activity for the 2-series of phosphoramidates; however, there was no correlation between cytotoxicity and DTD activity in the 3-series of compounds. This finding suggests the presence of an alternative mechanism for the activation of these compounds.
• Synthesis and Biological Activity of Novel 5-Fluoro-2‘-deoxyuridine Phosphoramidate Prodrugs
  作者：Caren L. Freel Meyers、Liping Hong、Carolyn Joswig、Richard F. Borch

  DOI：10.1021/jm000301j

  日期：2000.11.1

  A series of novel haloethyl and piperidyl phosphoramidate FdUMP prodrug analogues has been synthesized, and the growth inhibitory activity of these compounds has been evaluated against L1210 mouse leukemia cells. All compounds exhibited potent inhibition of L1210 cell proliferation with IC50 values in the nanomolar range. Growth inhibition was reversed by the addition of 5 muM thymidine, suggesting a mechanism of action involving the intracellular release of FdUMP. P-31 NMR studies carried out on model haloethyl phosphoramidates confirm the release of nucleotide via cyclization of the phosphoramidate anion to the aziridinium ion intermediate followed by hydrolysis of the P-N bond. The data suggests that <50% of the prodrug is converted to FdUMP intracellularly by this pathway. Piperidyl phosphoramidate analogues are also converted to nucleotide intracellularly, presumably by the action of an endogenous phosphoramidase.
• Savignac,P. et al., Comptes Rendus des Seances de l'Academie des Sciences, Serie C: Sciences Chimiques, 1978, vol. 287, p. 35 - 38
  作者：Savignac,P. et al.

  DOI：——

  日期：——
• 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.