2,4,6-三氟苯基丙二酸二乙酯 | 262609-07-4

• 物质功能分类: 化学试剂 - 有机试剂 - 酯类
• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: 2,4,6-三氟苯基丙二酸二乙酯
• 中文别名: 2-(2,4,6-三氟苯基)丙二酸二乙酯
• 英文名称: diethyl 2-(2,4,6-trifluorophenyl)malonate
• 英文别名: diethyl (2,4,6-trifluoro-phenyl)-malonate；Diethyl (2,4,6-trifluorophenyl)malonate；diethyl 2-(2,4,6-trifluorophenyl)propanedioate
• CAS: 262609-07-4
• 化学式: C₁₃H₁₃F₃O₄
• 分子量: 290.239
• InChiKey: VCCISIBKCNTCLR-UHFFFAOYSA-N

物化性质

• 熔点：
  46-49℃
• 稳定性/保质期：
  避氧化物

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  20
• 可旋转键数：
  7
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  52.6
• 氢给体数：
  0
• 氢受体数：
  7

安全信息

• 危险品标志：
  Xi
• 海关编码：
  2917399090
• 危险性防范说明：
  P264,P280,P302+P352,P337+P313,P305+P351+P338,P362+P364,P332+P313
• 危险性描述：
  H315,H319
• 储存条件：
  保存方法：密封存放于阴凉、通风干燥处。

反应信息

• 作为反应物：
  描述：

  2,4,6-三氟苯基丙二酸二乙酯 在 三正丁胺 、 sodium hydride 、 N,N-二异丙基乙胺 、 sodium hydroxide 、 三氯氧磷 作用下， 以 四氢呋喃 、 二甲基亚砜 、 N,N-二甲基甲酰胺 、 甲苯 、 mineral oil 为溶剂， 反应 9.0h， 生成 西维布林
  参考文献：
  名称：

  Brain-Penetrant, Orally Bioavailable Microtubule-Stabilizing Small Molecules Are Potential Candidate Therapeutics for Alzheimer’s Disease and Related Tauopathies

  摘要：

  Microtubule (MT) stabilizing drugs hold promise as potential treatments for Alzheimer's disease (AD) and related tauopathies. However, thus far epothilone D has been the only brain-penetrant MT-stabilizer to be evaluated in tau transgenic mice and in AD patients. Furthermore, this natural product exhibits potential deficiencies as a drug candidate, including an intravenous route of administration and the inhibition of the P-glycoprotein (Pgp) transporter. Thus, the identification of alternative CNS-active MT-stabilizing agents that lack these potential limitations is of interest. Toward this objective, we have evaluated representative compounds from known classes of non-naturally occurring MT-stabilizing small molecules. This led to the identification of selected triazolopyrimidines and phenylpyrimidines that are orally bioavailable and brain-penetrant without disruption of Pgp function. Pharmacodynamic studies confirmed that representative compounds from these series enhance MT-stabilization in the brains of wild-type mice. Thus, these classes of MT-stabilizers hold promise for the development of orally active, CNS-directed MT-stabilizing therapies.

  DOI：

  10.1021/jm5005623
• 作为产物：
  描述：

  1,3,5-三氟苯 在 iron(III) chloride 、 溴 、 sodium ethanolate 、 copper(I) bromide 作用下， 生成 2,4,6-三氟苯基丙二酸二乙酯
  参考文献：
  名称：

  A new Knoevenagel-type synthesis of fully substituted γ-hydroxybutenolides

  摘要：

  The synthesis of fully substituted gamma-hydroxybutenolides is possible by a Knoevenagel-type ring condensation of alpha-methyleneketones and alpha-ketoesters under basic conditions. This novel transformation allowed the preparation of di-aryl/heteroaryl substituted hydroxyfuranones, such as 20 and 27, which are important intermediates for pyridazine fungicides. As it turned out, a whole range of different substituents, such as alkyl, cycloalkyl, aryl, heteroaryl and ester groups could be linked to the butenolide scaffold, demonstrating the broad scope of the novel cyclization. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.tetlet.2012.05.125

文献信息

• 5-arylpyrimidines as anticancer agents
  申请人：Zhang Nan

  公开号：US20050075357A1

  公开（公告）日：2005-04-07

  This invention relates to certain 5-arylpyrimidine compounds or a pharmaceutically acceptable salt thereof, and compositions containing said compounds or a pharmaceutically acceptable salt thereof, wherein said compounds are anti-cancer agents useful for the treatment of cancer in mammals. This invention further relates to a method of treating or inhibiting the growth of cancerous tumor cells and associated diseases in a mammal and further provides a method for the treatment or prevention of cancerous tumors that express multiple drug resistance (MDR) or are resistant because of MDR, in a mammal in need thereof which method comprises administering to said mammal an effective amount of said compounds or a pharmaceutically acceptable salt thereof. More specifically, the present invention relates to a method of treating or inhibiting the growth of cancerous tumor cells and associated diseases in a mammal in need thereof by promotion of microtubule polymerization which comprises administering to said mammal an effective amount of said compounds and pharmaceutically acceptable salts thereof.

  这项发明涉及某些5-芳基嘧啶化合物或其药用盐，以及含有所述化合物或其药用盐的组合物，其中所述化合物是抗癌剂，可用于治疗哺乳动物的癌症。该发明还涉及一种治疗或抑制哺乳动物体内癌细胞和相关疾病生长的方法，并进一步提供了一种治疗或预防表达多药耐药性（MDR）或因MDR耐药的癌症肿瘤的方法，该方法包括向所述哺乳动物体内施用所述化合物或其药用盐的有效量。更具体地，本发明涉及通过促进微管聚合来治疗或抑制哺乳动物体内癌细胞和相关疾病的方法，该方法包括向所述哺乳动物体内施用所述化合物及其药用盐的有效量。
• Synthesis and SAR of 6-chloro-4-fluoroalkylamino-2-heteroaryl-5-(substituted)phenylpyrimidines as anti-cancer agents
  作者：Nan Zhang、Semiramis Ayral-Kaloustian、Thai Nguyen、Richard Hernandez、Judy Lucas、Carolyn Discafani、Carl Beyer

  DOI：10.1016/j.bmc.2008.11.016

  日期：2009.1

  ortho-position to the pyrimidyl core. The structure–activity relationship for the rest of the molecule in this 2-heteroarylpyrimidine series mimics that of the [1,2,4]triazolo[1,5-a]pyrimidine series. Like triazolopyrimidines and 2-cyanoaminopyrimidines, the 2-heteroarylpyrimidines retain the capability to overcome multidrug resistance due to Pgp. Mechanism of action studies showed that the lead compounds behaved

  描述了一系列的6-氯-4-氟烷基氨基-2-杂芳基-5-（取代）苯基嘧啶作为抗癌剂的合成和SAR。这一系列的2-杂芳基嘧啶是通过修饰我们先前报道的一系列抗肿瘤[1,2,4]三唑并[1,5- a ]嘧啶和2-氰基氨基嘧啶而开发的。对于2-杂芳基，当杂芳基在嘧啶基核的邻位具有氮原子时，可获得最佳活性。该2-杂芳基嘧啶系列中其余分子的结构-活性关系类似于[1,2,4]三唑[1,5- a ]的结构-活性关系]嘧啶系列。像三唑并嘧啶和2-氰基氨基嘧啶一样，2-杂芳基嘧啶保留克服由于Pgp引起的多药耐药性的能力。作用机理研究表明，先导化合物的行为与三唑并嘧啶和2-氰基氨基嘧啶相同。在体外和体内，该系列中的先导化合物比相应的三唑并嘧啶更有效。化合物21（PTI-868）在几种裸鼠异种移植模型中均显示出抑制肿瘤生长的作用，因此被选择进行临床前开发。
• Method for the production of substituted 2-aryl malonic acid esters
  申请人：Maywald Volker

  公开号：US20100056820A1

  公开（公告）日：2010-03-04

  The present invention relates to a process for preparing substituted 2-arylmalonic esters of the general formula I in which R is C 1 -C 6 -alkyl or C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl; Ar is phenyl or a heteroaromatic 5- or 6-membered ring; where each carbon atom present in the radicals mentioned above optionally carries a substituent R A ; R A is F, Cl, CN, NO 2 , C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, etc., or two adjacent substituents R A together with the carbon atoms to which they are attached form a ring; and where a malonic ester is reacted with a base and an aryl bromide in the presence of a copper salt, which comprises employing from 0.1 to 0.65 molar equivalents of the base per molar equivalent of the malonic ester.

  本发明涉及一种制备通式I的取代2-芳基丙二酸酯的方法，其中R为C1-C6-烷基或C1-C4-烷氧基-C1-C4-烷基；Ar为苯基或杂芳5-或6-成员环；上述基团中每个碳原子可选择携带取代基RA；RA为F、Cl、CN、NO2、C1-C4-烷基、C1-C4-卤代烷基、C1-C4-烷氧基、C1-C4-卤代烷氧基等，或者两个相邻的取代基RA与它们连接的碳原子一起形成一个环；以及将丙二酸酯与碱和芳基溴在铜盐存在下反应，其中每摩尔丙二酸酯的摩尔当量中使用0.1至0.65摩尔当量的碱。
• Evaluation of the Structure–Activity Relationship of Microtubule-Targeting 1,2,4-Triazolo[1,5-<i>a</i>]pyrimidines Identifies New Candidates for Neurodegenerative Tauopathies
  作者：Killian Oukoloff、Goodwell Nzou、Carmine Varricchio、Bobby Lucero、Thibault Alle、Jane Kovalevich、Ludovica Monti、Anne-Sophie Cornec、Yuemang Yao、Michael J. James、John Q. Trojanowski、Virginia M.-Y. Lee、Amos B. Smith、Andrea Brancale、Kurt R. Brunden、Carlo Ballatore

  DOI：10.1021/acs.jmedchem.0c01605

  日期：2021.1.28

  demonstrated that brain-penetrant microtubule (MT)-stabilizing compounds, including the 1,2,4-triazolo[1,5-a]pyrimidines, hold promise as candidate treatments for Alzheimer’s disease and related neurodegenerative tauopathies. Triazolopyrimidines have already been investigated as anticancer agents; however, the antimitotic activity of these compounds does not always correlate with stabilization of MTs in cells

  对 tau 和 Aβ 斑块转基因小鼠模型的研究表明，脑渗透性微管 (MT) 稳定化合物，包括 1,2,4-三唑[1,5- a]嘧啶，有望成为阿尔茨海默病和相关神经退行性 tau 蛋白病的候选治疗方法。三唑并嘧啶已作为抗癌剂进行了研究。然而，这些化合物的抗有丝分裂活性并不总是与细胞中 MTs 的稳定性相关。事实上，我们实验室以前的研究确定了在 C6 上连接的片段在确定三唑并嘧啶是否促进 MT 稳定或相反地破坏细胞中的 MT 完整性方面的关键作用。为了进一步阐明构效关系 (SAR) 并确定神经退行性疾病的潜在改善 MT 稳定候选物，设计、合成和评估了一套全面的 68 种三唑并嘧啶同系物，这些同系物在 C6 和/或 C7 处具有结构修饰。
• Tubulin inhibitor and process for its preparation
  申请人：Blum Michael David

  公开号：US20060281760A1

  公开（公告）日：2006-12-14

  The invention provides 6-chloro-5-2,6-difluoro-4-[3-(methylamino)propoxy]phenyl}-2-pyrazin-2-yl-N-[(1S)-2,2,2-trifluoro-1-methylethyl]pyrimidin-4-amine hemifumarate which is a tubulin inhibitor useful in the treatment of cancer and processes of making said hemifumarate.

  这项发明提供了一种对癌症治疗有用的微管抑制剂6-氯-5-2,6-二氟-4-[3-(甲胺基)丙氧基]苯基}-2-吡嗪-2-基-N-[(1S)-2,2,2-三氟-1-甲基乙基]嘧啶-4-胺富马酸盐，以及制备该富马酸盐的方法。