(2-chloro-ethyl)-(6-oxo-(9ar)-tetrahydro-6λ⁵-[1,2,4]dioxazino[4,3-c][1,3,2]oxazaphosphinin-6t-yl)-amine | 53459-54-4

• 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: (2-chloro-ethyl)-(6-oxo-(9ar)-tetrahydro-6λ⁵-[1,2,4]dioxazino[4,3-c][1,3,2]oxazaphosphinin-6t-yl)-amine
• CAS: 53459-54-4；64858-45-3；64858-46-4
• 化学式: C₇H₁₄ClN₂O₄P
• 分子量: 256.626
• InChiKey: ZHKZPDCBWPNYKE-ZIDLFYJRSA-N

物化性质

• 沸点：
  326.4±52.0 °C(Predicted)
• 密度：
  1.43±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.93
• 重原子数：
  15.0
• 可旋转键数：
  3.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  60.03
• 氢给体数：
  1.0
• 氢受体数：
  4.0

反应信息

• 作为产物：
  描述：

  N-(2-chloro-ethyl)-N'-(2-methanesulfonyloxy-ethyl)-phosphorodiamidic acid but-3-enyl ester 在 sodium hydroxide 作用下， 以 氯仿 为溶剂， 生成 (2-chloro-ethyl)-(6-oxo-(9ar)-tetrahydro-6λ⁵-[1,2,4]dioxazino[4,3-c][1,3,2]oxazaphosphinin-6t-yl)-amine
  参考文献：
  名称：

  Studies on cyclophosphamide metabolites and their related compounds. 8. Synthesis and antitumor activity of preactivated isophosphamide analogs bearing modified alkylating functionalities

  摘要：

  In search of cancer chemotherapeutic agents with greater efficacy than cyclophosphamide, 4-hydroperoxyisophosphamide analogues bearing modified alkylating functionalities such as 2-bromoethyl, 2-iodoethyl, 2-methyl-sulfonyloxyethyl, and 2-ethylsulfonyloxyethyl groups were prepared by ozonolytic cyclization reaction of N,N'-substituted 3-butenyl phosphorodiamidates. Comparative cytotoxicity against L1210 cells and antileukemic life-span activity against L1210 implanted BDF1 mice of the newly synthesized compounds were tabulated. The 4-hydroperoxyisophosphamide analogues which have different alkylating groups in a molecule showed slightly greater cytoxicity in vitro than those with the same alkylating groups. Most of the compounds having different alkylating groups also showed high antileukemic activity in vivo. Among them, the highest efficacy was found for 2-[N-methyl-n-(2-chlorethyl)]amino-3-(2-methylsulfonyloxyethyl)-4-hydroperoxy-1,3,2-oxazaphosphorinane 2-xoide (NSC 280122D) whos life-span activity was also greater than that of 4-hydroperoxyisophosphamide, cyclophosphamide, and isoposphamide. The superiority of this compound was especially apparent by oral administration.

  DOI：

  10.1021/jm00200a013

文献信息

• Synthesis, stereochemistry and antitumor activity of 4-hydroperoxyisophosphamide (NSC-227114) and related compounds.
  作者：AKIRA TAKAMIZAWA、SAICHI MATSUMOTO、TSUYOSHI IWATA、ITSUO MAKINO

  DOI：10.1248/cpb.25.1877

  日期：——

  4-Hydroperoxyisophosphamide and its analogues were simply synthesized by ozonolysis reactions of O-(3-butenyl)-N, N'-bis (2-chloroethyl) phosphorodiamidate and related O-(3-butenyl) phosphoramidates. An acid-catalyzed isomerization of 4-hydroperoxyisophosphamide proceeded with inversion of its phosphorus configuration giving 2-epi-4-hydroperoxyisophosphamide. Both isomers readily afforded C4-substituted isophosphamide derivatives by reactions with nucleophilic agents and acid. L1210 antileukemic activities were tested for the isomers and some analogues revealing that the C4-hydroperoxylation of isophosphamide resulted in a marked enhancement of its activity and that the inverted stereochemistry of an alkylating functionality at the phosphorus atom is also effective in promoting the antitumor action as an alternative activated species of isophosphamide.

  4-羟基过氧化异磷酰胺及其类似物通过O-(3-丁烯基)-N,N'-双(2-氯乙基)磷酸二酰胺及相关O-(3-丁烯基)磷酰胺的臭氧化反应简单合成。4-羟基过氧化异磷酰胺在酸性催化下发生异构化，其磷构型反转生成2-表-4-羟基过氧化异磷酰胺。两种异构体均能通过与亲核试剂及酸反应生成C4取代的异磷酰胺衍生物。对这些异构体及其某些类似物进行了L1210抗白血病活性测试，结果显示，异磷酰胺的C4羟基过氧化改性显著增强了其活性，且磷原子上烷基化功能的立体构型反转同样有效促进了其抗肿瘤作用，作为异磷酰胺的替代激活形式。
• Takamizawa,A. et al., Heterocycles, 1977, vol. 7, p. 1091 - 1130
  作者：Takamizawa,A. et al.

  DOI：——

  日期：——