4-[4-(4-fluoro-3-trifluoromethylphenyl)-1-methyl-1H-imidazol-2-yl]piperidine | 1083051-56-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 4-[4-(4-fluoro-3-trifluoromethylphenyl)-1-methyl-1H-imidazol-2-yl]piperidine
• 英文别名: 6-(4-4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl-piperidin-1-yl)pyrimidin-4-amine；4-(4-(4-Fluoro-3-(trifluoromethyl)phenyl)-1-methyl-1H-imidazol-2-yl)piperidine；4-[4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methylimidazol-2-yl]piperidine
• CAS: 1083051-56-2
• 化学式: C₁₆H₁₇F₄N₃
• 分子量: 327.325
• InChiKey: QPFXUEVSBFKNJV-UHFFFAOYSA-N

物化性质

• 沸点：
  459.1±45.0 °C(Predicted)
• 密度：
  1.35±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  23
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  29.8
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  4-[4-(4-fluoro-3-trifluoromethylphenyl)-1-methyl-1H-imidazol-2-yl]piperidine 在 2-双环己基膦-2',6'-二甲氧基联苯 、 palladium diacetate 、 potassium carbonate 、 caesium carbonate 作用下， 以 1,4-二氧六环 、 水 、 二甲基亚砜 为溶剂， 生成 6-{4-[4-(4-fluoro-3-trifluoromethylphenyl)-1-methyl-1H-imidazol-2-yl]piperidin-1-yl}-5-pyridin-4-ylpyrimidin-4-ylamine
  参考文献：
  名称：

  发现 4-氨基嘧啶类似物作为高效的双重 P70S6K/Akt 抑制剂

  摘要：

  PI3K/Akt/mTOR 激酶通路的激活与人类癌症有关。双重 p70S6K/Akt 抑制剂足以抑制强烈的肿瘤生长并阻止补偿性 Akt 反馈回路激活的负面影响。基于现有喹唑啉甲酰胺系列的支架对接策略确定了 4-氨基嘧啶类似物6，其在 p70S6K 和 Akt 酶测定中显示出个位数的纳摩尔和微摩尔效力。SAR 优化提高了 Akt 酶和 p70S6K 细胞的效力，降低了 hERG 的敏感性，并最终发现了有希望的候选者37，它在 p70S6K 和 Akt 生化分析中都表现出个位数的纳摩尔值，以及 hERG 活性（IC 50 = 17.4 微米）。该药物在抑制小鼠乳腺癌肿瘤生长方面表现出剂量依赖性功效，并且在 200 mg/kg po 的剂量下长达 24 小时覆盖超过 90% 的 pS6 抑制。

  DOI：

  10.1016/j.bmcl.2021.128352
• 作为产物：
  描述：

  5-溴-2-氟三氟甲苯 在 N-甲基吗啉 、 盐酸 、 ammonium acetate 、 异丙基氯化镁 、 溶剂黄146 、 1-丙基磷酸酐 作用下， 以 四氢呋喃 、 甲醇 、 乙酸乙酯 为溶剂， 反应 5.84h， 生成 4-[4-(4-fluoro-3-trifluoromethylphenyl)-1-methyl-1H-imidazol-2-yl]piperidine
  参考文献：
  名称：

  Rapid Development and Scale-Up of a 1H-4-Substituted Imidazole Intermediate Enabled by Chemistry in Continuous Plug Flow Reactors

  摘要：

  The development of reactions in a continuous fashion in plug flow tube reactors (PFR) offers unique advantages to the drug development and scale-up process and can also enable chemistry that would be difficult to perform via batch processing. Herein, we report the development of two different continuous flow approaches to a key 1H-4-substituted imidazole intermediate (5). In a first generation approach, rapid optimization and scale-up of a challenging cyclization reaction was demonstrated in a PFR under GMP conditions to afford 29 kg of protected product 2. This material was further processed in batch equipment to deliver di-HCl salt 4. This first generation approach highlights the rapid development of chemistry in research-scale PFRs and speed to material delivery through linear scale up to a pilot-scale PFR under GMP conditions. In a second generation effort, a more efficient synthetic route was developed, and PFRs with automated sampling, dilution, and analytical analysis allowed for rapid and data-rich reaction optimization of both a key cyclization reaction and thermal removal of a Boc protecting group. This work culminated in 1 kg demonstration runs in a 0.22 L PFR for both continuous steps and shows the potential of commercialization from a lab hood footprint (1-2 MT/year).

  DOI：

  10.1021/op200351g

文献信息

• [EN] NOVEL IMIDAZOLE AMINES AS MODULATORS OF KINASE ACTIVITY<br/>[FR] NOUVEAUX IMIDAZOLES AMINES EN TANT QUE MODULATEURS D'ACTIVITÉ KINASE
  申请人：MERCK PATENT GMBH

  公开号：WO2013040059A1

  公开（公告）日：2013-03-21

  The invention provides novel imidazole amine compounds according to Formula (I) and Formula (II) their manufacture and use for the treatment of hyperproliferative diseases, such as cancer.

  该发明提供了根据式（I）和式（II）的新型咪唑胺化合物，其制备和用于治疗高增殖性疾病，如癌症。
• Imidazole amines as modulators of kinase activity
  申请人：Lan Ruoxi

  公开号：US09145392B2

  公开（公告）日：2015-09-29

  The invention provides novel imidazole amine compounds according to Formula (I) and Formula (II) their manufacture and use for the treatment of hyperproliferative diseases, such as cancer.

  本发明提供了根据式(I)和式(II)的新型咪唑胺化合物，以及它们的制备方法和用于治疗增殖过度性疾病（如癌症）的用途。
• Novel Imidazole Amines as Modulators of Kinase Activity
  申请人：Merck Patent GmbH

  公开号：US20160000785A1

  公开（公告）日：2016-01-07

  The invention provides novel imidazole amine compounds according to Formula (I) and Formula (II) their manufacture and use for the treatment of hyperproliferative diseases, such as cancer.

  本发明提供了根据公式（I）和公式（II）的新型咪唑胺化合物，以及它们的制备和用于治疗高增殖性疾病，如癌症的用途。
• US20140343029A1
  申请人：——

  公开号：——

  公开（公告）日：——
• NOVEL IMIDAZOLE AMINES AS MODULATORS OF KINASE ACTIVITY
  申请人：Merck Patent GmbH

  公开号：EP2755965A1

  公开（公告）日：2014-07-23