2-(chloroacetamido)-1,4-bis(methylcarbamyl)-3,6-dimethoxy-5-nitrobenzene | 143430-51-7

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 2-(chloroacetamido)-1,4-bis(methylcarbamyl)-3,6-dimethoxy-5-nitrobenzene
• 英文别名: 2-[(2-chloroacetyl)amino]-3,6-dimethoxy-1-N,4-N-dimethyl-5-nitrobenzene-1,4-dicarboxamide
• CAS: 143430-51-7
• 化学式: C₁₄H₁₇ClN₄O₇
• 分子量: 388.765
• InChiKey: PFJDUASABIXCTM-UHFFFAOYSA-N

物化性质

• 沸点：
  483.0±45.0 °C(Predicted)
• 密度：
  1.416±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.6
• 重原子数：
  26
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  152
• 氢给体数：
  3
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  2-(chloroacetamido)-1,4-bis(methylcarbamyl)-3,6-dimethoxy-5-nitrobenzene 在 palladium on activated charcoal 吡啶 、 sodium dithionite 、 ammonium cerium(IV) nitrate 、 硫酸 、 水 、 氢气 作用下， 以 甲醇 、 氯仿 、 水 、 溶剂黄146 、 二甲基亚砜 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 25.0~100.0 ℃ 、344.73 kPa 条件下， 反应 8.5h， 生成 2,3,7,8-tetramethylpyrimido<4,5-g>quinazoline-4,5,9,10(3H,8H)tetrone
  参考文献：
  名称：

  Design of pyrimido[4,5-g]quinazoline-based anthraquinone mimics. Structure-activity relationship for quinone methide formation and the influence of internal hydrogen bonds on quinone methide fate

  摘要：

  Pyrimido[4,5-g]quinazolinequinone derivatives were synthesized as a anthraquinone-like reductive alkylating agents. Like many naturally-occurring antibiotics, these quinone derivatives are designed to afford an alkylating quinone methide species upon reduction and leaving-group elimination. Kinetic studies of pyrimido[4,5-g]quinazoline hydroquinones provided evidence of quinone methide intermediate able to trap nucleophiles (alkylation) and protons (ketonization). The rate of quinone methide formation is determined by the hydroquinone free energy. Thus, a linear free energy relationship for quinone methide formation was obtained by plotting rates of quinone methide formation as the log versus the quinone reduction potential. The pyrimido[4,5-g]quinazoline quinone methides fall on this free energy plot, showing that these species are formed by the same mechanism as the other structurally-diverse quinone methides previously studied in this research group. Internal hydrogen bonds present in pyrimido[4,5-g]quinazoline derivatives influence the fate of the quinone methide species as well as the rate of hydroquinone oxidation in the presence of oxygen Such hydrogen bonds stabilize the hydroquinone species, thereby resulting in slow rates of hydroquinone oxidation to quinone in alkaline aerobic buffer. Stabilization of the hydroquinone also results in substantial nucleophile trapping by the quinone methide. Without internal hydrogen bonds, hydroquinone oxidations are rapid and the quinone methide traps only electrophiles.

  DOI：

  10.1021/jo00047a017
• 作为产物：
  描述：

  2,5-Dimethoxy-1,4-benzoldicarbonitril 在 palladium on activated charcoal 吡啶 、 sodium hydroxide 、 硫酸 、 氢气 、 双氧水 、 硝酸 、 乙酸酐 、 sodium nitrite 作用下， 以 甲醇 、 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 70.0 ℃ 、344.73 kPa 条件下， 反应 8.33h， 生成 2-(chloroacetamido)-1,4-bis(methylcarbamyl)-3,6-dimethoxy-5-nitrobenzene
  参考文献：
  名称：

  Design of pyrimido[4,5-g]quinazoline-based anthraquinone mimics. Structure-activity relationship for quinone methide formation and the influence of internal hydrogen bonds on quinone methide fate

  摘要：

  Pyrimido[4,5-g]quinazolinequinone derivatives were synthesized as a anthraquinone-like reductive alkylating agents. Like many naturally-occurring antibiotics, these quinone derivatives are designed to afford an alkylating quinone methide species upon reduction and leaving-group elimination. Kinetic studies of pyrimido[4,5-g]quinazoline hydroquinones provided evidence of quinone methide intermediate able to trap nucleophiles (alkylation) and protons (ketonization). The rate of quinone methide formation is determined by the hydroquinone free energy. Thus, a linear free energy relationship for quinone methide formation was obtained by plotting rates of quinone methide formation as the log versus the quinone reduction potential. The pyrimido[4,5-g]quinazoline quinone methides fall on this free energy plot, showing that these species are formed by the same mechanism as the other structurally-diverse quinone methides previously studied in this research group. Internal hydrogen bonds present in pyrimido[4,5-g]quinazoline derivatives influence the fate of the quinone methide species as well as the rate of hydroquinone oxidation in the presence of oxygen Such hydrogen bonds stabilize the hydroquinone species, thereby resulting in slow rates of hydroquinone oxidation to quinone in alkaline aerobic buffer. Stabilization of the hydroquinone also results in substantial nucleophile trapping by the quinone methide. Without internal hydrogen bonds, hydroquinone oxidations are rapid and the quinone methide traps only electrophiles.

  DOI：

  10.1021/jo00047a017

文献信息

• Synthesis and elucidation of pyrimido (4,5-Q) quinazoline derivatives
  申请人：Arizona Board of Regents acting on behalf of Arizona State University

  公开号：US05639881A1

  公开（公告）日：1997-06-17

  Pyrimido[4,5-g]quinazoline quinone derivatives were synthesized as anthranone-like reductive alkylating agents. Like many naturally-occurring antibiotics, these quinone derivatives are designed to afford an alkylating quinone methide species upon reduction and leaving group elimination. Kinetic studies of pyrimido[4,5-g]quinazoline hydroquinones provided evidence of quinone methide intermediates able to trap nucleophiles (alkylation) and protons. The rate of quinone methide formation is determined by the hydroquinone free energy. Thus, a linear free energy relationship for quinone methide formation was obtained by plotting rates of quinone methide formation, as the log, versus the quinone reduction potential. The pyrimido[4-5-g]quinazoline quinone methides fall on this free energy plot, showing that these species are formed by the same mechanism as the other structurally-diverse quinone methides previously studied in this research group. A drawback of many quinone antibiotics, particularly the anthracyclines, is the formation of toxic oxygen species by quinone/hydroquinone cycling. In the present invention pyrimido[4,5-g]quinazoline hydroquinones are found to be relatively stable toward oxygen, and thus cause little oxygen toxicity. Antitumor screening revealed that the disclosed pyrimido[4,5-g]quinazoline dione derivatives possess excellent inhibitory activity against selected human cancer cell lines. The pyrimido[4,5g]quinazoline-diones have the following structural formulae: ##STR1## wherein: R is H or CH.sub.3 ; and X is Cl or Br.

  合成了嘧啶并[4,5-g]喹唑啉醌衍生物作为类蒽醌还原烷基化试剂。与许多天然抗生素一样，这些醌衍生物旨在在还原和离去基消除后提供烷基化醌甲烷物种。嘧啶并[4,5-g]喹唑啉羟醌的动力学研究提供了醌甲烷中间体的证据，能够捕获亲核试剂（烷基化）和质子。醌甲烷形成的速率由羟醌自由能决定。因此，通过绘制醌还原电位的对数，以及醌甲烷形成速率，得到了醌甲烷形成的线性自由能关系。嘧啶并[4-5-g]喹唑啉醌甲烷落在这个自由能图上，表明这些物种是通过与先前在该研究小组中研究的其他结构多样的醌甲烷相同的机制形成的。许多醌类抗生素，特别是蒽环素的缺点是通过醌/羟醌循环形成有毒氧化物质。在本发明中，发现嘧啶并[4,5-g]喹唑啉羟醌相对稳定于氧气，因此产生的氧毒性很小。抗肿瘤筛选显示，所述的嘧啶并[4,5-g]喹唑啉二酮衍生物对选择的人类癌细胞系具有优异的抑制活性。嘧啶并[4,5-g]喹唑啉二酮的结构式为：其中：R为H或CH3；X为Cl或Br。
• Pyrimido(4,5-g)quinazoline derivatives with anti-tumour activity
  申请人：ARIZONA BOARD OF REGENTS

  公开号：EP0541404A2

  公开（公告）日：1993-05-12

  Pyrimido[4,5-g]quinazoline quinone derivatives were synthesized as anthraquinone-like reductive alkylating agents. Like many naturally-occurring antibiotics, these quinone derivatives are designed to afford an alkylating quinone methide species upon reduction and leaving group elimination. Kinetic studies of pyrimido[4,5-g]quinazoline hydroquinones provided evidence of quinone methide intermediates able to trap nucleophiles (alkylation) and protons. The rate of quinone methide formation is determined by the hydroquinone free energy. Thus, a linear free energy relationship for quinone methide formation was obtained by plotting rates of quinone methide formation, as the log, versus the quinone reduction potential. The pyrimido[4-5-g]quinazoline quinone methides fall on this free energy plot, showing that these species are formed by the same mechanism as the other structurally-diverse quinone methides previously studied in this research group. A drawback of many quinone antibiotics, particularly the anthracyclines, is the formation of toxic oxygen species by quinone/hydroquinone cycling. In the present invention pyrimido[4,5-g]quinazoline hydroquinones are found to be relatively stable toward oxygen, and thus cause little oxygen toxicity. Antitumor screening revealed that the disclosed pyrimid [4,5-g] quinazoline dione and tetione derivatives possess excellent inhibitory activity against selected human cancer cell lines.

  嘧啶并[4,5-g]喹唑啉醌衍生物被合成为类似蒽醌的还原烷化剂。与许多天然存在的抗生素一样，这些醌衍生物的设计目的是在还原和离去基团消除时产生一种烷基化的醌甲醚。对嘧啶并[4,5-g]喹唑啉对苯二酚的动力学研究证明，甲脒醌中间体能够捕获亲核物（烷基化）和质子。甲喹酮的形成速率由对苯二酚自由能决定。因此，通过绘制醌甲酰胺形成率（对数）与醌还原电位的关系图，可以得出醌甲酰胺形成的线性自由能关系。嘧啶并[4-5-g]喹唑啉醌甲苷就属于这种自由能关系，这表明这些物种的形成机制与本研究小组之前研究的其他结构多样的醌甲苷相同。许多醌类抗生素，尤其是蒽环类抗生素的一个缺点是，醌/氢醌循环会形成有毒的氧物种。本发明发现，嘧啶并[4,5-g]喹唑啉对氧相对稳定，因此几乎不会产生氧毒性。抗肿瘤筛选显示，所公开的嘧啶并[4,5-g]喹唑啉二酮和四酮衍生物对选定的人类癌细胞株具有极好的抑制活性。
• US5639881A
  申请人：——

  公开号：US5639881A

  公开（公告）日：1997-06-17
• Design of pyrimido[4,5-g]quinazoline-based anthraquinone mimics. Structure-activity relationship for quinone methide formation and the influence of internal hydrogen bonds on quinone methide fate
  作者：Robert H. Lemus、Edward B. Skibo

  DOI：10.1021/jo00047a017

  日期：1992.10

  Pyrimido[4,5-g]quinazolinequinone derivatives were synthesized as a anthraquinone-like reductive alkylating agents. Like many naturally-occurring antibiotics, these quinone derivatives are designed to afford an alkylating quinone methide species upon reduction and leaving-group elimination. Kinetic studies of pyrimido[4,5-g]quinazoline hydroquinones provided evidence of quinone methide intermediate able to trap nucleophiles (alkylation) and protons (ketonization). The rate of quinone methide formation is determined by the hydroquinone free energy. Thus, a linear free energy relationship for quinone methide formation was obtained by plotting rates of quinone methide formation as the log versus the quinone reduction potential. The pyrimido[4,5-g]quinazoline quinone methides fall on this free energy plot, showing that these species are formed by the same mechanism as the other structurally-diverse quinone methides previously studied in this research group. Internal hydrogen bonds present in pyrimido[4,5-g]quinazoline derivatives influence the fate of the quinone methide species as well as the rate of hydroquinone oxidation in the presence of oxygen Such hydrogen bonds stabilize the hydroquinone species, thereby resulting in slow rates of hydroquinone oxidation to quinone in alkaline aerobic buffer. Stabilization of the hydroquinone also results in substantial nucleophile trapping by the quinone methide. Without internal hydrogen bonds, hydroquinone oxidations are rapid and the quinone methide traps only electrophiles.