4-溴-2-(四氢-2H-吡喃-2-基)-2H-吲唑 | 1266386-31-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡唑类
• 中文名称: 4-溴-2-(四氢-2H-吡喃-2-基)-2H-吲唑
• 英文名称: 4-bromo-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole
• 英文别名: 4-Bromo-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole；4-bromo-2-(oxan-2-yl)indazole
• CAS: 1266386-31-5
• 化学式: C₁₂H₁₃BrN₂O
• 分子量: 281.152
• InChiKey: JJJWAPQDJLALQV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  16
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  27
• 氢给体数：
  0
• 氢受体数：
  2

安全信息

• 海关编码：
  2934999090

反应信息

• 作为反应物：
  描述：

  4-溴-2-(四氢-2H-吡喃-2-基)-2H-吲唑 在 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 四(三苯基膦)钯 、 potassium acetate 、 sodium carbonate 作用下， 以 1,4-二氧六环 、 乙二醇二甲醚 、 水 为溶剂， 反应 34.0h， 生成 4-(4-(benzylthio)-6-(2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-yl)-1,3,5-triazin-2-yl)morpholine
  参考文献：
  名称：

  Discovery of Novel and Orally Bioavailable Inhibitors of PI3 Kinase Based on Indazole Substituted Morpholino-Triazines

  摘要：

  A new class of potent PI3K alpha inhibitors is identified based on aryl substituted morpholino-triazine scaffold. The identified compounds showed not only a high level of enzymatic and cellular potency in nanomolar range but also high oral bioavailability. The three lead molecules (based on their in vitro potency) when evaluated further for in vitro metabolic stability as well as pharmacokinetic profile led to the identification of 26, as a candidate for further development. The IC50 and EC50 value of 26 is 60 and 500 nM, respectively, for PI3Ka enzyme inhibitory activity and ovarian cancer (A2780) cell line. The identified lead also showed a high level of microsomal stability and minimal inhibition activity for CYP3A4, CYP2C19, and CYP2D6 at 10 mu M concentrations. The lead compound 26, demonstrated excellent oral bioavailability with an AUG of 5.2 mu M at a dose of 3 mpk in mice and found to be well tolerated in mice when dosed at 30 mpk BID for 5 days.

  DOI：

  10.1021/acsmedchemlett.5b00322
• 作为产物：
  描述：

  3-溴-2-甲基苯胺 在 potassium acetate 、 4-甲基苯磺酸吡啶 、 乙酸酐 作用下， 以 正庚烷 、 氯仿 、 甲苯 为溶剂， 反应 33.0h， 生成 4-溴-1-(氧杂-2-基)-1H-吲唑 、 4-溴-2-(四氢-2H-吡喃-2-基)-2H-吲唑
  参考文献：
  名称：

  通过非官能化的三芳基镁酸锂中间体在非低温条件下实用合成PI3K抑制剂

  摘要：

  我们报告了P​​I3K抑制剂GDC-0941的实用合成。使用收敛方法从噻吩并嘧啶中间体开始，通过一系列甲酰化和还原性胺化反应，然后进行Suzuki-Miyaura交叉偶联，实现了合成。噻吩并嘧啶中间体的金属化涉及三芳基镁酸酯的中间体，从而在非低温条件下进行甲酰化以产生相应的醛。我们还研究了通过苯并三唑基-哌嗪底物进行的氨基烷基化，作为还原性胺化途径的替代方法。我们评估了硼化和铃木-宫浦交叉偶联的钯和镍催化过程。最终的脱保护和盐的形成提供了API。

  DOI：

  10.1021/op3002992

文献信息

• 一种雌激素受体抑制剂吲哚类化合物的制备方法
  申请人：深圳扬厉医药技术有限公司

  公开号：CN116425727A

  公开（公告）日：2023-07-14

  本发明公开了一种雌激素受体抑制剂吲哚类化合物的制备方法，属于药物合成技术领域。所述制备方法为中间体化合物9依次经过磺酰化反应、Miyaura偶联反应、Suzuki偶联反应、脱保护反应制备得到雌激素受体抑制剂吲哚类化合物。本发明采用手性合成方式保留了目标产物的手性特征，同时将原合成路线的保护基THP变为二甲氨基磺酰基，优化了原路线的手性拆分纯化方式，解决了原路线工艺放大的瓶颈。另外，本发明将潜在基因毒性杂质反应步骤前置至起始物料，使得反应的质量可控性得到大大提升。并且，反应条件相对温和，并无超低温和危险性高的实验条件，各步骤反应产率也显著提高，有利于降低生产成本用于大规模工业生产。化合物9： 目标产物：
• Thatipally, Suresh; Acharyulu, Palle V.R.; Dubey, Asian Journal of Chemistry, 2011, vol. 23, # 1, p. 451 - 454
  作者：Thatipally, Suresh、Acharyulu, Palle V.R.、Dubey

  DOI：——

  日期：——
• Discovery of Novel and Orally Bioavailable Inhibitors of PI3 Kinase Based on Indazole Substituted Morpholino-Triazines
  作者：Sundeep Dugar、Frank P. Hollinger、Dinesh Mahajan、Somdutta Sen、Bilash Kuila、Reena Arora、Yogesh Pawar、Vaibhav Shinde、Mahesh Rahinj、Kamal K. Kapoor、Rahul Bhumkar、Santosh Rai、Rakesh Kulkarni

  DOI：10.1021/acsmedchemlett.5b00322

  日期：2015.12.10

  A new class of potent PI3K alpha inhibitors is identified based on aryl substituted morpholino-triazine scaffold. The identified compounds showed not only a high level of enzymatic and cellular potency in nanomolar range but also high oral bioavailability. The three lead molecules (based on their in vitro potency) when evaluated further for in vitro metabolic stability as well as pharmacokinetic profile led to the identification of 26, as a candidate for further development. The IC50 and EC50 value of 26 is 60 and 500 nM, respectively, for PI3Ka enzyme inhibitory activity and ovarian cancer (A2780) cell line. The identified lead also showed a high level of microsomal stability and minimal inhibition activity for CYP3A4, CYP2C19, and CYP2D6 at 10 mu M concentrations. The lead compound 26, demonstrated excellent oral bioavailability with an AUG of 5.2 mu M at a dose of 3 mpk in mice and found to be well tolerated in mice when dosed at 30 mpk BID for 5 days.
• A Practical Synthesis of a PI3K Inhibitor under Noncryogenic Conditions via Functionalization of a Lithium Triarylmagnesiate Intermediate
  作者：Qingping Tian、Zhigang Cheng、Herbert M. Yajima、Scott J. Savage、Keena L. Green、Theresa Humphries、Mark E. Reynolds、Srinivasan Babu、Francis Gosselin、David Askin、Isao Kurimoto、Norihiko Hirata、Mitsuhiro Iwasaki、Yasuharu Shimasaki、Takashi Miki

  DOI：10.1021/op3002992

  日期：2013.1.18

  We report a practical synthesis of PI3K inhibitor GDC-0941. The synthesis was achieved using a convergent approach starting from a thienopyrimidine intermediate through a sequence of formylation and reductive amination followed by Suzuki-Miyaura cross-coupling. Metalation of the thienopyrimidine intermediate involving the intermediacy of triarylmagnesiates allowed formylation under noncryogenic conditions

  我们报告了P​​I3K抑制剂GDC-0941的实用合成。使用收敛方法从噻吩并嘧啶中间体开始，通过一系列甲酰化和还原性胺化反应，然后进行Suzuki-Miyaura交叉偶联，实现了合成。噻吩并嘧啶中间体的金属化涉及三芳基镁酸酯的中间体，从而在非低温条件下进行甲酰化以产生相应的醛。我们还研究了通过苯并三唑基-哌嗪底物进行的氨基烷基化，作为还原性胺化途径的替代方法。我们评估了硼化和铃木-宫浦交叉偶联的钯和镍催化过程。最终的脱保护和盐的形成提供了API。