2-chloro-6-(3,5-dimethylphenoxy)pyridine

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 2-chloro-6-(3,5-dimethylphenoxy)pyridine
• 化学式: C₁₃H₁₂ClNO
• 分子量: 233.697
• InChiKey: FONCUKPUDDYFPX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  16
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.15
• 拓扑面积：
  22.1
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  2-chloro-6-(3,5-dimethylphenoxy)pyridine 在 正丁基锂 、 三乙胺 、 三氟乙酸 作用下， 以 1,4-二氧六环 、 乙二醇二甲醚 、 正己烷 、 二氯甲烷 、 水 为溶剂， 反应 29.34h， 生成
  参考文献：
  名称：

  Systematically Mitigating the p38α Activity of Triazole-based BET Inhibitors

  摘要：

  The Bromodomain and Extra Terminal (BET) family of proteins recognize post-translational N-ε-acetylated lysine modifications, regulating transcription as "reader" proteins. Bromodomain inhibitors are interesting targets for the development of potential cancer, inflammation, and heart disease treatments. Several dual kinase-bromodomain inhibitors have been identified by screening kinase inhibitor libraries against BET proteins. Although potentially useful from a polypharmacology standpoint, multitarget binding complicates deciphering molecular mechanisms. This report describes a systematic approach to mitigating kinase activity in a dual kinase-bromodomain inhibitor based on a 1,2,3-triazole-pyrimidine core. By modifying the triazole substituent and altering the pyrimidine core, this structure-activity relationship study enhanced BET activity while reducing the p38α kinase activity >90,000-fold. A BRD4-D1 cocrystal structure indicates that the 1,2,3-triazole is acting as a N-ε-acetylated lysine mimic. A BRD4 sensitive cell line, MM.1S, was used to demonstrate activity in cells, which is further supported by reduced c-Myc expression.

  DOI：

  10.1021/acsmedchemlett.9b00227
• 作为产物：
  描述：

  2,6-二氯吡啶 、 3,5-二甲基苯酚 在 N-苯基吡啶甲酰胺 、 铜 、 caesium carbonate 作用下， 以 1,4-二氧六环 为溶剂， 反应 24.0h， 以57%的产率得到2-chloro-6-(3,5-dimethylphenoxy)pyridine
  参考文献：
  名称：

  N- Picolinamides作为Ullman C–O型偶联反应中的配体

  摘要：

  铜催化的修饰的Ullmann偶联反应产生C–O键，包括二芳基醚或苯酚，对有机合成至关重要。合成的N-苯基-2-吡啶甲酰胺及其衍生物在形成各种二芳基醚和酚的过程中，与催化性铜源一起用作配体。在温和的反应条件下，将各种具有供电子和吸电子基团的芳基和杂芳基卤化物与各种苯酚反应，可提供中等至极好的收率。

  DOI：

  10.1016/j.tetlet.2017.07.099

文献信息

• N-Picolinamides as ligands in Ullman type C–O coupling reactions
  作者：Fehmi Damkaci、Cihad Sigindere、Thomas Sobiech、Erik Vik、Joshua Malone

  DOI：10.1016/j.tetlet.2017.07.099

  日期：2017.9

  modified Ullmann coupling reactions creating C–O bonds, including diaryl ethers or phenols, are vital to organic synthesis. Synthesized N-phenyl-2-pyridinecarboxamide and its derivatives were used as ligands in conjunction with catalytic copper sources in the formation of various diaryl ethers and phenols. Various aryl and heteroaryl halides with electron donating and withdrawing groups were reacted with

  铜催化的修饰的Ullmann偶联反应产生C–O键，包括二芳基醚或苯酚，对有机合成至关重要。合成的N-苯基-2-吡啶甲酰胺及其衍生物在形成各种二芳基醚和酚的过程中，与催化性铜源一起用作配体。在温和的反应条件下，将各种具有供电子和吸电子基团的芳基和杂芳基卤化物与各种苯酚反应，可提供中等至极好的收率。
• THERAPEUTIC COMPOUNDS AND METHODS OF USE THEREOF
  申请人：REGENTS OF THE UNIVERSITY OF MINNESOTA

  公开号：US20200377474A1

  公开（公告）日：2020-12-03

  The invention provides a compound of formula I: or a salt thereof, wherein R 1 , R 2 , R 3 , A, B, D, E, F and G have any of the values described in the specification, as well as compositions comprising a compound of formula I. The compounds are useful as bromodomain inhibitors.

  该发明提供了一个式I的化合物：或其盐，其中R1、R2、R3、A、B、D、E、F和G的取值可在规范中描述，以及包含式I的化合物的组合物。这些化合物可用作溴结构域抑制剂。
• Substituent Effects of 2-Pyridones on Selective O-Arylation with Diaryliodonium Salts: Synthesis of 2-Aryloxypyridines under Transition­-Metal-Free Conditions
  作者：Dong-Liang Mo、Xiao-Hua Li、Ai-Hui Ye、Cui Liang

  DOI：10.1055/s-0036-1591884

  日期：2018.4

  An efficient transition-metal-free strategy to synthesize 2-aryloxypyridine derivatives has been developed by a selective O-arylation of 2-pyridones with diaryliodonium salts. The reaction was compatible with a series of functional groups for 2-pyridones and diaryliodonium salts such as halides, nitro, cyano, and ester groups. The substituents at the C6-position of 2-pyridones favored O-arylation products because of steric hindrance. The reaction was easily performed on a gram-scale and 6-chloro-2-pyridone was a good precursor to access various unsubstituted 2-aryloxypyridines by dehalogenation. A P2Y1 lead compound analogue could be prepared in good yield over two steps.

  开发了一种高效的过渡金属自由策略，通过选择性的氧芳基化2-吡啶酮与二芳基碘盐合成2-芳氧基吡啶衍生物。该反应与一系列功能团对2-吡啶酮和二芳基碘盐兼容，如卤素、硝基、氰基和酯基等。2-吡啶酮的C6位取代基有利于氧芳基化产物的生成，因为存在立体位阻。该反应易于在克级规模上进行，并且6-氯-2-吡啶酮是通过去卤代法获得各种未取代的2-芳氧基吡啶的良好前体。通过两步反应可以以较高产率制备P2Y1前体类似物。
• Systematically Mitigating the p38α Activity of Triazole-based BET Inhibitors
  作者：Angela S. Carlson、Huarui Cui、Anand Divakaran、Jorden A. Johnson、Ryan M. Brunner、William C. K. Pomerantz、Joseph J. Topczewski

  DOI：10.1021/acsmedchemlett.9b00227

  日期：2019.9.12

  The Bromodomain and Extra Terminal (BET) family of proteins recognize post-translational N-ε-acetylated lysine modifications, regulating transcription as "reader" proteins. Bromodomain inhibitors are interesting targets for the development of potential cancer, inflammation, and heart disease treatments. Several dual kinase-bromodomain inhibitors have been identified by screening kinase inhibitor libraries against BET proteins. Although potentially useful from a polypharmacology standpoint, multitarget binding complicates deciphering molecular mechanisms. This report describes a systematic approach to mitigating kinase activity in a dual kinase-bromodomain inhibitor based on a 1,2,3-triazole-pyrimidine core. By modifying the triazole substituent and altering the pyrimidine core, this structure-activity relationship study enhanced BET activity while reducing the p38α kinase activity >90,000-fold. A BRD4-D1 cocrystal structure indicates that the 1,2,3-triazole is acting as a N-ε-acetylated lysine mimic. A BRD4 sensitive cell line, MM.1S, was used to demonstrate activity in cells, which is further supported by reduced c-Myc expression.