tert-butyl 4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidine-1-carboxylate | 1082950-48-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: tert-butyl 4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidine-1-carboxylate
• 英文别名: 4-[4-(4-fluoro-3-trifluoromethylphenyl)-1H-imidazol-2-yl]piperidine-1-carboxylic acid tert-butyl ester；tert-butyl 4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1H-imidazol-2-yl}piperidine-1-carboxylate；tert-butyl 4-[5-[4-fluoro-3-(trifluoromethyl)phenyl]-1H-imidazol-2-yl]piperidine-1-carboxylate
• CAS: 1082950-48-8
• 化学式: C₂₀H₂₃F₄N₃O₂
• 分子量: 413.415
• InChiKey: DLLYEBNXXOZNAR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  29
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  58.2
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  tert-butyl 4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidine-1-carboxylate 在 盐酸 作用下， 以 1,4-二氧六环 、 甲醇 为溶剂， 生成 4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidine hydrochloride
  参考文献：
  名称：

  [EN] NOVEL IMIDAZOLE AMINES AS MODULATORS OF KINASE ACTIVITY
  [FR] NOUVEAUX IMIDAZOLES AMINES EN TANT QUE MODULATEURS D'ACTIVITÉ KINASE

  摘要：

  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。

  公开号：

  WO2013040059A1
• 作为产物：
  描述：

  1-(3-三氟甲基-4-氟苯基)-2-氨基乙酮对甲苯磺酸盐 在 ammonium acetate 、 1-丙基磷酸酐 、 N,N'-羰基二咪唑 作用下， 以 四氢呋喃 、 甲醇 、 乙酸乙酯 为溶剂， 反应 88.5h， 生成 tert-butyl 4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidine-1-carboxylate
  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

• AKT AND P70 S6 KINASE INHIBITORS
  申请人：Shepherd Timothy Alan

  公开号：US20100120801A1

  公开（公告）日：2010-05-13

  The present invention provides AKT and p70 S6 kinase inhibitors of the formula: The present invention also provides pharmaceutical compositions comprising compounds of Formula I, uses of compounds of Formula I and methods of using compounds of Formula I.

  本发明提供了式子为AKT和p70 S6激酶抑制剂的药物。本发明还提供了包含式子I化合物的药物组合物，式子I化合物的用途以及使用式子I化合物的方法。
• Discovery of chiral dihydropyridopyrimidinones as potent, selective and orally bioavailable inhibitors of AKT
  作者：Saravanan Parthasarathy、Kenneth Henry、Huaxing Pei、Josh Clayton、Mark Rempala、Deidre Johns、Oscar De Frutos、Pablo Garcia、Carlos Mateos、Sehila Pleite、Yong Wang、Stephanie Stout、Bradley Condon、Sheela Ashok、Zhohai Lu、William Ehlhardt、Tom Raub、Mei Lai、Sandaruwan Geeganage、Timothy P. Burkholder

  DOI：10.1016/j.bmcl.2018.03.092

  日期：2018.6

  During the course of our research efforts to develop potent and selective AKT inhibitors, we discovered enatiomerically pure substituted dihydropyridopyrimidinones (DHP) as potent inhibitors of protein kinase B/AKT with excellent selectivity against ROCK2. A key challenge in this program was the poor physicochemical properties of the initial lead compound 5. Integration of structure-based drug design

  在我们开发有效和选择性AKT抑制剂的研究过程中，我们发现了对映体纯的取代的二氢吡啶并嘧啶酮（DHP）作为蛋白激酶B / AKT的有效抑制剂，对ROCK 2具有出色的选择性。该程序中的关键挑战是初始铅化合物5的理化性质较差。基于结构的药物设计和基于物理性质的设计相结合，导致高疏水性的多氟芳基环被简单的三氟甲基取代，从而鉴定出具有大大改善的理化性质的化合物6。随后的合成孔径雷达研究导致合成了新的吡喃类似物7具有增强的细胞效力。通过用适当的氟化烷基增加通透性来进一步优化药物代谢动力学特性，导致化合物8作为有效的选择性AKT抑制剂，在体内阻断GSK3β的磷酸化，并且在U87MG肿瘤异种移植模型中具有强大的，剂量和浓度依赖性。
• P70 S6 kinase inhibitors
  申请人：Eli Lilly and Company

  公开号：US08093383B2

  公开（公告）日：2012-01-10

  The present invention provides p70 S6 kinase inhibitors of the formula: pharmaceutical formulations comprising them, and methods for their use.

  本发明提供了式为p70 S6激酶抑制剂的制剂：包括它们的药物制剂，以及使用它们的方法。
• P70 S6 KINASE INHIBITOR AND EGFR INHIBITOR COMBINATION THERAPY
  申请人：Geeganage Sandaruwan

  公开号：US20110207752A1

  公开（公告）日：2011-08-25

  The present invention provides a combination therapy comprising the compound 4-[4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine, or a pharmaceutically acceptable salt thereof, and an EGFR inhibitor for use in the treatment of glioblastoma multiforme, adenocarcinomas of the colon, non-small-cell lung cancer, small-cell lung cancer, cisplatin-resistant small-cell lung cancer, ovarian cancer, leukemia, pancreatic cancer, prostate cancer, mammary carcinoma, renal cell carcimoma, multiple myeloma, Kaposis Sarcoma, Hodgkins lymphoma, lymphangioleiomyomatosis, Non-Hodgkins lymphoma or sarcoma.

  本发明提供一种联合治疗方案，包括化合物4-[4-[4-(4-氟-3-三氟甲基苯基)-1-甲基-1H-咪唑-2-基]-哌啶-1-基]-1H-吡唑并[3,4-d]嘧啶，或其药学上可接受的盐，以及一种EGFR抑制剂，用于治疗脑胶质母细胞瘤、结肠腺癌、非小细胞肺癌、小细胞肺癌、顺铂耐药小细胞肺癌、卵巢癌、白血病、胰腺癌、前列腺癌、乳腺癌、肾细胞癌、多发性骨髓瘤、卡波西肉瘤、霍奇金淋巴瘤、淋巴管平滑肌瘤病、非霍奇金淋巴瘤或肉瘤的治疗。
• P70 S6 KINASE INHIBITORS
  申请人：Dally Robert Dean

  公开号：US20120071490A1

  公开（公告）日：2012-03-22

  The present invention provides p70 S6 kinase inhibitors of the formula: pharmaceutical formulations comprising them, and methods for their use.

  本发明提供了公式为：p70 S6激酶抑制剂的制剂，以及包含它们的药物制剂和使用它们的方法。