2,5-二甲氧基异烟醛 | 867267-25-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 中文名称: 2,5-二甲氧基异烟醛
• 英文名称: 2,5-dimethoxyisonicotinaldehyde
• 英文别名: 2,5-dimethoxypyridine-4-carbaldehyde
• CAS: 867267-25-2
• 化学式: C₈H₉NO₃
• mdl: MFCD11100753
• 分子量: 167.164
• InChiKey: SCZSXGWZEONLMA-UHFFFAOYSA-N

物化性质

• 熔点：
  98-100 °C
• 沸点：
  295.3±35.0 °C(Predicted)
• 密度：
  1.174±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.6
• 重原子数：
  12
• 可旋转键数：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  48.4
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2,5-二甲氧基异烟醛 在 sodium methylate 作用下， 以 甲醇 、 xylene 为溶剂， 反应 3.0h， 生成 4,7-dimethoxy-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid methyl ester
  参考文献：
  名称：

  A Regioselective Route to 5- and 6-Azaindoles

  摘要：

  成功以区域选择性的方法合成了4,7-二甲氧基5-和6-氮杂吲哚，这是一种在最近开发的抗HIV-1药物中存在的结构单元。所开发的策略基于在锂介导的甲酰化步骤中适当选择保护基团，随后进行叠氮丙烯酸酯的热环化。

  DOI：

  10.1055/s-2005-871946
• 作为产物：
  描述：

  5-羟基-2-甲氧基吡啶 在 盐酸 、 甲基锂 、 sodium hydride 、 potassium carbonate 、 二异丙胺 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 14.0h， 生成 2,5-二甲氧基异烟醛
  参考文献：
  名称：

  A Regioselective Route to 5- and 6-Azaindoles

  摘要：

  成功以区域选择性的方法合成了4,7-二甲氧基5-和6-氮杂吲哚，这是一种在最近开发的抗HIV-1药物中存在的结构单元。所开发的策略基于在锂介导的甲酰化步骤中适当选择保护基团，随后进行叠氮丙烯酸酯的热环化。

  DOI：

  10.1055/s-2005-871946

文献信息

• Synthetic Studies to Help Elucidate the Metabolism of the Preclinical Candidate TBAJ-876—A Less Toxic and More Potent Analogue of Bedaquiline
  作者：Peter J. Choi、Daniel Conole、Hamish S. Sutherland、Adrian Blaser、Amy S.T. Tong、Christopher B. Cooper、Anna M. Upton、Brian D. Palmer、William A. Denny

  DOI：10.3390/molecules25061423

  日期：——

  Bedaquiline is a novel drug approved in 2012 by the FDA for treatment of drug-resistant tuberculosis (TB). Although it shows high efficacy towards drug-resistant forms of TB, its use has been limited by the potential for significant side effects. In particular, bedaquiline is a very lipophilic compound with an associated long terminal half-life and shows potent inhibition of the cardiac potassium hERG channel, resulting in QTc interval prolongation in humans that may result in cardiac arrhythmia. To address these issues, we carried out a drug discovery programme to develop an improved second generation analogue of bedaquiline. From this medicinal chemistry program, a candidate (TBAJ-876) has been selected to undergo further preclinical evaluation. During this evaluation, three major metabolites arising from TBAJ-876 were observed in several preclinical animal models. We report here our synthetic efforts to unequivocally structurally characterize these three metabolites through their independent directed synthesis.

  贝达昆林是一种新型药物，2012年获得FDA批准用于治疗耐药结核病（TB）。尽管它对耐药结核病表现出高效性，但由于潜在的严重副作用，其使用受到限制。特别是，贝达昆林是一种非常亲脂性的化合物，具有长的终末半衰期，并且对心脏钾通道hERG表现出强效抑制作用，导致人体QTc间期延长，可能导致心律失常。为了解决这些问题，我们进行了一项药物发现计划，以开发改进的第二代贝达昆林类似物。从这个药物化学计划中，已选择了一个候选药物（TBAJ-876）进行进一步的临床前评估。在这个评估过程中，在几种临床前动物模型中观察到了TBAJ-876产生的三种主要代谢物。我们在这里报告了我们的合成努力，通过它们的独立定向合成来明确结构表征这三种代谢物。
• Solvent-dependent oxidations of 5- and 6-azaindoles to trioxopyrrolopyridines and functionalised azaindoles
  作者：Zahia Mahiout、Thierry Lomberget、Sylvie Goncalves、Roland Barret

  DOI：10.1039/b719776d

  日期：——

  towards BBr3-mediated selective monodemethylation and oxidative demethylation reactions were also investigated. The regioselectivity of the deprotection was confirmed using a chemical approach. Oxidation reactions were then carried out on either dimethoxy- or hydroxymethoxyazaindoles, in different solvents, using [bis(trifluoroacetoxy)iodo]benzene. In acetonitrile-water, trioxopyrrolopyridines 12 were obtained

  的4,7-二甲氧基-5-和6-氮杂吲哚2所述的区域选择性合成已经实现，基于邻位定向或邻排斥基团在吡啶环的甲酰化的合适的选择。本文描述了甲酰化步骤的区域选择性和叠氮基丙烯酸酯中间体4的制备的研究。还研究了5和6氮杂吲哚结构对BBr3介导的选择性单脱甲基和氧化脱甲基反应的反应性。使用化学方法证实了脱保护基的区域选择性。然后使用[双（三氟乙酰氧基）碘]苯在不同的溶剂中对二甲氧基-或羟基甲氧基氮杂吲哚进行氧化反应。在乙腈水中，制得三氧杂吡咯烷吡啶12 而在乙腈-甲醇中观察到官能化的氮吲哚17的形成。X射线衍射分析证明了三氧杂吡咯并吡啶的互变异构结构。
• 3,5-Dialkoxypyridine analogues of bedaquiline are potent antituberculosis agents with minimal inhibition of the hERG channel
  作者：Hamish S. Sutherland、Amy S.T. Tong、Peter J. Choi、Adrian Blaser、Daniel Conole、Scott G. Franzblau、Manisha U. Lotlikar、Christopher B. Cooper、Anna M. Upton、William A. Denny、Brian D. Palmer

  DOI：10.1016/j.bmc.2019.02.026

  日期：2019.4

  Bedaquiline is a new drug of the diarylquinoline class that has proven to be clinically effective against drugresistant tuberculosis, but has a cardiac liability (prolongation of the QT interval) due to its potent inhibition of the cardiac potassium channel protein hERG. Bedaquiline is highly lipophilic and has an extremely long terminal half-life, so has the potential for more-than-desired accumulation in tissues during the relatively long treatment durations required to cure TB. The present work is part of a program that seeks to identify a diarylquinoline that is as potent as bedaquiline against Mycobacterium tuberculosis, with lower lipophilicity, higher clearance, and lower risk for QT prolongation. Previous work led to the identification of compounds with greatly-reduced lipophilicity compounds that retain good anti-tubercular activity in vitro and in mouse models of TB, but has not addressed the hERG blockade. We now present compounds where the C-unit naphthalene is replaced by a 3,5dialkoxy- 4-pyridyl, demonstrate more potent in vitro and in vivo anti-tubercular activity, with greatly attenuated hERG blockade. Two examples of this series are in preclinical development.
• A Regioselective Route to 5- and 6-Azaindoles
  作者：Roland Barret、Thierry Lomberget、Sylvie Radix

  DOI：10.1055/s-2005-871946

  日期：——

  The synthesis of 4,7-dimethoxy 5- and 6-azaindoles, a structural unit that is present in recently developed anti-HIV-1 agents, was achieved in a regioselective manner. The developed strategy is based on the appropriate choice of a protecting group during a lithium-mediated formylation step, followed by thermal cyclization of azidoacrylates.

  成功以区域选择性的方法合成了4,7-二甲氧基5-和6-氮杂吲哚，这是一种在最近开发的抗HIV-1药物中存在的结构单元。所开发的策略基于在锂介导的甲酰化步骤中适当选择保护基团，随后进行叠氮丙烯酸酯的热环化。