4-{4-[双(β-羟乙基)氨基]苯基}丁酸甲酯 | 130198-76-4

• 分子结构分类: 有机化合物 - 有机氮化合物
• 中文名称: 4-{4-[双(β-羟乙基)氨基]苯基}丁酸甲酯
• 中文别名: 4-{4-[双(β；4-[双(2-羟乙基)氨基]苯丁酸甲酯；4-{4-[双(&beta；4-(4-(双(2-羟基乙基)氨基)苯基)丁酸甲酯
• 英文名称: methyl 3-<4-phenyl>butyrate
• 英文别名: methyl 4-{4-[bis(2-hydroxyethyl)amino]phenyl}butyrate；methyl 4-{4-[bis(2-hydroxyethyl)amino]phenyl}butanoate；Methyl 4-[4-[bis(2-hydroxyethyl)amino]phenyl]butanoate
• CAS: 130198-76-4
• 化学式: C₁₅H₂₃NO₄
• 分子量: 281.352
• InChiKey: KCFBCMRTIRHVAE-UHFFFAOYSA-N

物化性质

• 沸点：
  457.1±45.0 °C(Predicted)
• 密度：
  1.166±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -0.5
• 重原子数：
  20
• 可旋转键数：
  10
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  70
• 氢给体数：
  2
• 氢受体数：
  5

安全信息

• 海关编码：
  2922509090

制备方法与用途

用途：瘤可宁的中间体。

生产方法：通过乙酰苯胺与琥珀酸酐在无水三氯化铝催化下缩合生成β-（对乙酰氨基苯甲酰基）丙酸，再与水合肼、氢氧化钾反应进行水解并还原处理。随后，以乙酸酸化得到4-（4-氨基苯基）丁酸；将其与甲醇在氯化氢作用下酯化并中和后，在常温和酸性条件下使用环氧乙烷进行羟乙基化，最终制得该产品。

反应信息

• 作为反应物：
  描述：

  4-{4-[双(β-羟乙基)氨基]苯基}丁酸甲酯 在 盐酸 、 三氯氧磷 作用下， 以 苯 为溶剂， 反应 1.67h， 生成 苯丁酸氮芥
  参考文献：
  名称：

  DNA-directed alkylating agents. 3. Structure-activity relationships for acridine-linked aniline mustards: consequences of varying the length of the linker chain

  摘要：

  Four series of acridine-linked aniline mustards have been prepared and evaluated for in vitro cytotoxicity, in vivo antitumor activity, and DNA cross-linking ability. The anilines were attached to the DNA-intercalating acridine chromophores by link groups (-O-, -CH2-, -S-, and -SO2-) of widely varying electronic properties, providing four series of widely differing mustard reactivity where the alkyl chain linking the acridine and mustard moieties was varied from two to five carbons. Relationships were sought between chain length and biological properties. Within each series, increasing the chain length did not alter the reactivity of the alkylating moiety but did appear to position it differently on the DNA, since cross-linking ability (measured by agarose gel assay) altered with chain length, being maximal with the C4 analogue. The in vivo antitumor activities of the compounds depended to some extent on the reactivity of the mustard, with the least reactive SO2 compounds being inactive. However, DNA-targeting did appear to allow the use of less reactive mustards, since the S-linked acridine mustards showed significant activity whereas the parent S-mustard did not. Within each active series, the most active compound was the C4 homologue, suggesting some relationship between activity and extent of DNA alkylation.

  DOI：

  10.1021/jm00173a016
• 作为产物：
  描述：

  3-(4-乙酰基氨基苯甲酰基)丙酸 在 氯化亚砜 、 水 、 一水合肼 、 溶剂黄146 、 potassium hydroxide 作用下， 以 二乙二醇 为溶剂， 反应 8.0h， 生成 4-{4-[双(β-羟乙基)氨基]苯基}丁酸甲酯
  参考文献：
  名称：

  一种抗肿瘤药苯丁酸氮芥的合成工艺

  摘要：

  本发明涉及一种抗肿瘤药苯丁酸氮芥（Chlorambucil）的合成工艺，包括以下步骤：(1)氨基保护反应；（2）酰基化反应；(3)还原反应；（4）羧基保护反应；（5）取代反应；（6）氯化反应；（7）脱保护反应。本发明采用醋酐保护氨基，再经过酰基化，还原，羧基保护，取代，氯化，盐酸水溶液水解得到苯丁酸氮芥。本发明具有成本低，反应条件温和，毒性低，工艺操作方便，适合工业化生产的特点。

  公开号：

  CN104447376B

文献信息

• Synthesis and pharmacokinetic profile of a quaternary ammonium derivative of chlorambucil, a potential anticancer drug for the chemotherapy of chondrosarcoma
  作者：Maryse Rapp、Isabelle Giraud、Jean-Claude Maurizis、Jean-Claude Madelmont

  DOI：10.1016/j.bmc.2003.09.006

  日期：2003.11

  As a part of our targeting program based on the affinity of the quaternary ammonium moiety for cartilage, our objective was to develop more selective anticancer drugs towards chondrosarcoma that would concentrate in this malignant cartilaginous tissue and so improve the therapeutic index through a reduction of side effects. For this purpose we have synthesized and labeled with C-14 a quaternary ammonium (QA) derivative of chlorambucil. Biological studies performed in rats showed that [C-14]-CQA and [C-14]-chlorambucil exhibited different pharmacokinetic profiles. The blood elimination of [C-14]-CQA was faster than that of parent compound. [C-14]-CQA was principally excreted by the fecal way. However, until 15 min after administration, levels of radioactivity were measured in cartilaginous tissues of rats given [C-14]-CQA which was not the case for the rats which had received [C-14]-chlorambucil. Although rates of radioactivity were quantified only during 15 min, these results prove that the functionalization of chlorambucil by a quaternary ammonium group allows the molecule to be carried selectively to cartilaginous tissues. (C) 2003 Elsevier Ltd. All rights reserved.
• VALU, KISIONE K.;GOURDIE, TRUDI A.;BORITZKI, THEODORE J.;GRAVATT, G. LANC+, J. MED. CHEM., 33,(1990) N1, C. 3014-3019
  作者：VALU, KISIONE K.、GOURDIE, TRUDI A.、BORITZKI, THEODORE J.、GRAVATT, G. LANC+

  DOI：——

  日期：——
• 一种抗肿瘤药苯丁酸氮芥的合成工艺
  申请人：平湖优康药物研发有限公司

  公开号：CN104447376B

  公开（公告）日：2016-10-05

  本发明涉及一种抗肿瘤药苯丁酸氮芥（Chlorambucil）的合成工艺，包括以下步骤：(1)氨基保护反应；（2）酰基化反应；(3)还原反应；（4）羧基保护反应；（5）取代反应；（6）氯化反应；（7）脱保护反应。本发明采用醋酐保护氨基，再经过酰基化，还原，羧基保护，取代，氯化，盐酸水溶液水解得到苯丁酸氮芥。本发明具有成本低，反应条件温和，毒性低，工艺操作方便，适合工业化生产的特点。
• DNA-directed alkylating agents. 3. Structure-activity relationships for acridine-linked aniline mustards: consequences of varying the length of the linker chain
  作者：Kisione K. Valu、Trudi A. Gourdie、Theodore J. Boritzki、G. Lance Gravatt、Bruce C. Baguley、William R. Wilson、Laurence P. G. Wakelin、Paul D. Woodgate、William A. Denny

  DOI：10.1021/jm00173a016

  日期：1990.11

  Four series of acridine-linked aniline mustards have been prepared and evaluated for in vitro cytotoxicity, in vivo antitumor activity, and DNA cross-linking ability. The anilines were attached to the DNA-intercalating acridine chromophores by link groups (-O-, -CH2-, -S-, and -SO2-) of widely varying electronic properties, providing four series of widely differing mustard reactivity where the alkyl chain linking the acridine and mustard moieties was varied from two to five carbons. Relationships were sought between chain length and biological properties. Within each series, increasing the chain length did not alter the reactivity of the alkylating moiety but did appear to position it differently on the DNA, since cross-linking ability (measured by agarose gel assay) altered with chain length, being maximal with the C4 analogue. The in vivo antitumor activities of the compounds depended to some extent on the reactivity of the mustard, with the least reactive SO2 compounds being inactive. However, DNA-targeting did appear to allow the use of less reactive mustards, since the S-linked acridine mustards showed significant activity whereas the parent S-mustard did not. Within each active series, the most active compound was the C4 homologue, suggesting some relationship between activity and extent of DNA alkylation.