diethyl N-<2-pivaloylamino-4-chloro<(pyrrolo<2,3-d>pyrimidin-5-yl)ethynyl>benzoyl>-L-glutamate | 149765-17-3

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: diethyl N-<2-pivaloylamino-4-chloro<(pyrrolo<2,3-d>pyrimidin-5-yl)ethynyl>benzoyl>-L-glutamate
• 英文别名: diethyl N-{2-pivaloylamino-4-chloro[(pyrrolo[2,3-d]pyrimidin-5-yl)ethynyl]benzoyl}-L-glutamate
• CAS: 149765-17-3
• 化学式: C₂₉H₃₂ClN₅O₆
• 分子量: 582.056
• InChiKey: KDGYSQFSSZMLGI-FQEVSTJZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.0
• 重原子数：
  41.0
• 可旋转键数：
  9.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  152.37
• 氢给体数：
  3.0
• 氢受体数：
  8.0

反应信息

• 作为反应物：
  描述：

  diethyl N-<2-pivaloylamino-4-chloro<(pyrrolo<2,3-d>pyrimidin-5-yl)ethynyl>benzoyl>-L-glutamate 在 palladium on activated charcoal 氢气 作用下， 以 乙醇 、 二氯甲烷 为溶剂， 反应 4.0h， 以95%的产率得到diethyl N-<2-pivaloylamino-4-chloro<(pyrrolo<2,3-d>pyrimidin-5-yl)ethyl>benzoyl>-L-glutamate
  参考文献：
  名称：

  The Synthesis of N-{2-Amino-4-substituted [(Pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl}-L-glutamic Acids as Antineoplastic Agents

  摘要：

  A series of N-{2-amino-4-substituted[(pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl}-L-glutamic acids were synthesized. In this current synthesis, compound 2-amino-4-chloro-pyrrolo[2,3-d]pyrimidine (4) was selected as an important precursor for the preparation of key intermediates such as 5b, 10b, 15a and 15b. These highly functionalized pyrrolo[2,3-d]pyrimidines were then later coupled with either 4-ethynylbenzoylglutamate or 4-iodobenzoylglutamate in a palladium catalyzed Heck reaction and thus provided the basic skeleton of the targeted molecules. The availability of the chlorine atom at the 4-position of the pyrrolopyrimidine nucleus has allowed us to introduce different substituents at this position efficiently. By this approach, we were able to prepare a variety of 4-substituted pyrrolo[2,3d]pyrimidine based folate antagonists (2a-2g) which are closely related to the novel thymidylate synthase inhibitor LY231514. In vitro analysis has demonstrated that some of these agents are highly cytotoxic against human leukemic cells (CCRF-CEM) in culture.

  DOI：

  10.3987/com-92-s(t)65
• 作为产物：
  描述：

  2-氨基-4-羟基吡咯并[2,3-d]嘧啶 在 吡啶 、 N-碘代丁二酰亚胺 、 copper(l) iodide 、 四(三苯基膦)钯 、 三乙胺 、 三氯氧磷 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 7.5h， 生成 diethyl N-<2-pivaloylamino-4-chloro<(pyrrolo<2,3-d>pyrimidin-5-yl)ethynyl>benzoyl>-L-glutamate
  参考文献：
  名称：

  The Synthesis of N-{2-Amino-4-substituted [(Pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl}-L-glutamic Acids as Antineoplastic Agents

  摘要：

  A series of N-{2-amino-4-substituted[(pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl}-L-glutamic acids were synthesized. In this current synthesis, compound 2-amino-4-chloro-pyrrolo[2,3-d]pyrimidine (4) was selected as an important precursor for the preparation of key intermediates such as 5b, 10b, 15a and 15b. These highly functionalized pyrrolo[2,3-d]pyrimidines were then later coupled with either 4-ethynylbenzoylglutamate or 4-iodobenzoylglutamate in a palladium catalyzed Heck reaction and thus provided the basic skeleton of the targeted molecules. The availability of the chlorine atom at the 4-position of the pyrrolopyrimidine nucleus has allowed us to introduce different substituents at this position efficiently. By this approach, we were able to prepare a variety of 4-substituted pyrrolo[2,3d]pyrimidine based folate antagonists (2a-2g) which are closely related to the novel thymidylate synthase inhibitor LY231514. In vitro analysis has demonstrated that some of these agents are highly cytotoxic against human leukemic cells (CCRF-CEM) in culture.

  DOI：

  10.3987/com-92-s(t)65

文献信息

• Design, Synthesis, and Biological Activities of Classical <i>N</i>-{4-[2-(2-Amino-4-ethylpyrrolo[2,3-<i>d</i>]pyrimidin-5-yl)ethyl]benzoyl}-<scp>l</scp>-glutamic Acid and Its 6-Methyl Derivative as Potential Dual Inhibitors of Thymidylate Synthase and Dihydrofolate Reductase and as Potential Antitumor Agents
  作者：Aleem Gangjee、Jianming Yu、Roy L. Kisliuk、William H. Haile、Giulia Sobrero、John J. McGuire

  DOI：10.1021/jm0203534

  日期：2003.2.1

  3-d]pyrimidin-5-yl)ethyl]benzoyl]-l-glutamic acid (2) and N-[2-amino-4-ethyl-6-methyl[(pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-l-glutam ic acid (4), were designed and synthesized as potent dual inhibitors of thymidylate synthase (TS) and dihydrofolate reductase (DHFR) and as antitumor agents. Compound 2 had inhibitory potency against human DHFR similar to N-[4-[2-(amino-3,4-dihydro-4-oxo-7H-pyrrolo[2,

  两种新颖的类似物，N- [2-氨基-4-乙基[（吡咯并[2,3-d]嘧啶-5-基）乙基]苯甲酰基] -1-谷氨酸（2）和N- [2-氨基-设计并合成了4-乙基-6-甲基[（吡咯并[2,3-d]嘧啶-5-基）乙基]苯甲酰基] -1-谷氨酸（4），作为有效的胸苷酸合酶双重抑制剂（TS ）和二氢叶酸还原酶（DHFR）并用作抗肿瘤药。化合物2具有类似于N- [4- [2-（氨基-3,4-二氢-4-氧代-7H-吡咯并[2,3-d]嘧啶-5-基）乙基]苯甲酰基的对人DHFR的抑制能力。 ] -L-谷氨酸（LY231514）和1，而4对人DHFR没有活性。2和4都比LY231514更能抵抗大肠杆菌。抗人TS的功效比LY231514低7倍，而4表现出与LY231514相似的抑制活性。与2相比，它是人类草氨酸谷氨酸合成酶（FPGS）的有效底物，4是FPGS的不良底物。在标准的NCI临床前体外筛选中，化合物2