ethyl 2-(3,5-bis(trifluoromethyl)phenyl)-2-diazoacetate | 1070764-19-0

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: ethyl 2-(3,5-bis(trifluoromethyl)phenyl)-2-diazoacetate
• 英文别名: Ethyl [3,5-bis(trifluoromethyl)phenyl](diazo)acetate；ethyl 2-[3,5-bis(trifluoromethyl)phenyl]-2-diazoacetate
• CAS: 1070764-19-0
• 化学式: C₁₂H₈F₆N₂O₂
• 分子量: 326.198
• InChiKey: WYPFMNMKFWNDLP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  22
• 可旋转键数：
  4
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  28.3
• 氢给体数：
  0
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  ethyl 2-(3,5-bis(trifluoromethyl)phenyl)-2-diazoacetate 、 tert-butyl (3aR,4R,5S,7aS)-5-hydroxy-4-(2-methylphenyl)octahydro-2H-isoindole-2-carboxylate 在 dirhodium tetraacetate 作用下， 以 苯 为溶剂， 反应 8.0h， 以70%的产率得到tert-butyl (3aR,4R,5S,7aS)-5-{1-[3,5-bis(trifluoromethyl)phenyl]-2-ethoxy-2-oxoethoxy}-4-(2-methylphenyl)-octahydro-2H-isoindole-2-carboxylate
  参考文献：
  名称：

  2-[(3aR,4R,5S,7aS)-5-{(1S)-1-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxyethoxy}-4-(2-methylphenyl)octahydro-2H-isoindol-2-yl]-1,3-oxazol-4(5H)-one: A Potent Human NK₁ Receptor Antagonist with Multiple Clearance Pathways

  摘要：

  Hydroisoindoline 2 has been previously identified as a potent, brain-penetrant NK1 receptor antagonist with a long duration of action and improved profile of CYP3A4 inhibition and induction compared to aprepitant. However, compound 2 is predicted, based on data in preclinical species, to have a human half-life longer than 40 h and likely to have drug-drug-interactions (DDI), as 2 is a victim of CYP3A4 inhibition caused by its exclusive clearance pathway via CYP3A4 oxidation in humans. We now report 2-[(3aR4R,5S,7aS)-5-{(1S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxyethoxy}-4-(2-methylphenypoctahydro-2H-isoindol-2-yl]-1,3-oxazol-4(5H)-one (3) as a next generation NK1 antagonist that possesses an additional clearance pathway through glucuronidation in addition to that via CYP3A4 oxidation. Compound 3 has a much lower propensity for drug drug interactions and a reduced estimated human half-life consistent with once daily dosing. In preclinical species, compound 3 has demonstrated potency, brain penetration, and a safety profile similar to 2, as well as excellent pharmacokinetics.

  DOI：

  10.1021/jm400751p
• 作为产物：
  描述：

  3,5-双(三氟甲基)苯乙酸 在 4-二甲氨基吡啶 、 对甲苯磺酰叠氮 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 作用下， 以 二氯甲烷 、 乙腈 为溶剂， 反应 0.75h， 生成 ethyl 2-(3,5-bis(trifluoromethyl)phenyl)-2-diazoacetate
  参考文献：
  名称：

  WO2008/124143

  摘要：

  公开号：

文献信息

• Synthesis of Aryldiazoacetates through Palladium(0)-Catalyzed Deacylative Cross-Coupling of Aryl Iodides with Acyldiazoacetates
  作者：Fei Ye、Chengpeng Wang、Yan Zhang、Jianbo Wang

  DOI：10.1002/anie.201407653

  日期：2014.10.20

  Palladium(0)‐catalyzed deacylative cross‐coupling of aryl iodides and acyldiazocarbonyl compounds can be achieved at room temperature under mild reaction conditions. The coupling reaction represents a highly efficient and general method for the synthesis of aryldiazocarbonyl compounds, which have found wide and increasing applications as precursors for generating donor/acceptor‐substituted metallocarbenes

  钯（0）催化的芳基碘化物和酰基重氮羰基化合物的脱酰基交叉偶联可在室温下在温和的反应条件下实现。偶联反应代表了合成芳基重氮羰基化合物的一种高效且通用的方法，该方法作为生成供体/受体取代的金属碳烯的前体已得到越来越广泛的应用。
• Palladium-Catalyzed C–H Functionalization of Acyldiazomethane and Tandem Cross-Coupling Reactions
  作者：Fei Ye、Shuanglin Qu、Lei Zhou、Cheng Peng、Chengpeng Wang、Jiajia Cheng、Mohammad Lokman Hossain、Yizhou Liu、Yan Zhang、Zhi-Xiang Wang、Jianbo Wang

  DOI：10.1021/ja513275c

  日期：2015.4.8

  favorable. The reaction instead proceeds through Ag2CO3 assisted deprotonation and subsequently reductive elimination to afford the products with diazo functionality remained. This C-H functionalization transformation can be further combined with the recently evolved palladium-catalyzed cross-coupling reaction of diazo compounds with aryl iodides to develop a tandem coupling process for the synthesis of α,α-diaryl

  已经开发了钯催化的 CH 与芳基碘化物的酰基重氮甲烷官能化。该反应的特点是在转化过程中保留了重氮官能团，从而构成了一种将重氮官能团引入有机分子的新方法。与实验结果一致，密度泛函理论（DFT）计算表明，重氮乙酸乙酯（Pd-EDA）配合物通过双氮挤出在催化循环中形成Pd-卡宾物种不太有利。相反，反应通过 Ag2CO3 辅助的去质子化和随后的还原消除进行，以提供具有重氮官能团的产物。这种 CH 官能化转化可以进一步与最近发展的钯催化重氮化合物与芳基碘化物的交叉偶联反应相结合，以开发合成 α,α-二芳基酯的串联偶联方法。DFT 计算支持 Pd-卡宾作为催化循环中的反应中间体的参与，它通过具有低能垒 (3.8 kcal/mol) 的轻松卡宾迁移插入。
• Isolation of a Reactive Tricoordinate α-Oxo Gold Carbene Complex
  作者：Abdallah Zeineddine、Feriel Rekhroukh、E. Daiann Sosa Carrizo、Sonia Mallet-Ladeira、Karinne Miqueu、Abderrahmane Amgoune、Didier Bourissou

  DOI：10.1002/anie.201711647

  日期：2018.1.26

  decomposition at −40 °C. It is the first α‐oxo gold carbene complex to be characterized. Its crystallographic structure was determined and DFT calculations have been performed, unraveling the key influence of the chelating (P,P) ligand. The gold center is tricoordinate and the electrophilicity of the carbene center is decreased. Complex 3 mimics transient α‐oxo gold carbenes in a series of catalytic

  [（P，P）Au = C（Ph）CO 2 Et] +配合物3 [其中（P，P）是邻-甲碳烷基二膦配体]是通过在-40°C下重氮分解制备的。这是第一个被表征的α-氧代金卡宾络合物。确定了其晶体结构并进行了DFT计算，揭示了螯合（P，P）配体的关键影响。金中心是三坐标的，卡宾中心的亲电性降低。配合物3在一系列催化转化中模拟了瞬态α-氧羰金，并为亲电性在苯酚功能化的化学选择性（OH与CH插入）中的关键作用提供了支持。
• HYDROXYMETHYL ETHER HYDROISOINDOLINE TACHYKININ RECEPTOR ANTAGONISTS
  申请人：DeVita Robert J.

  公开号：US20100105747A1

  公开（公告）日：2010-04-29

  The present invention is directed to certain hydroxymethyl ether hydroisoindoline compounds which are useful as neurokinin-1 (NK-1) receptor antagonists, and inhibitors of tachykinin and in particular substance P. The invention is also concerned with pharmaceutical formulations comprising these compounds as active ingredients and the use of the compounds and their formulations in the treatment of certain disorders, including emesis, urinary incontinence, LUTS, depression, and anxiety.

  本发明涉及某些羟甲基醚羟异吲哚烷化合物，其作为神经激肽-1（NK-1）受体拮抗剂和快速激肽，特别是物质P的抑制剂有用。本发明还涉及包含这些化合物作为活性成分的制药配方，以及这些化合物和它们的配方在治疗某些疾病，包括恶心、尿失禁、下尿路症状、抑郁症和焦虑症中的使用。
• Hydroxymethyl ether hydroisoindoline tachykinin receptor antagonists
  申请人：Merck Sharp & Dohme Corp.

  公开号：US08124633B2

  公开（公告）日：2012-02-28

  The present invention is directed to certain hydroxymethyl ether hydroisoindoline compounds which are useful as neurokinin-1 (NK-1) receptor antagonists, and inhibitors of tachykinin and in particular substance P. The invention is also concerned with pharmaceutical formulations comprising these compounds as active ingredients and the use of the compounds and their formulations in the treatment of certain disorders, including emesis, urinary incontinence, LUTS, depression, and anxiety.

  本发明涉及某些羟甲基醚羟异吲哚烷化合物，其作为神经激肽-1（NK-1）受体拮抗剂和快速激肽，特别是物质P的抑制剂而有用。本发明还涉及包含这些化合物作为活性成分的制药配方以及这些化合物和它们的配方在治疗某些疾病，包括恶心、尿失禁、下泌尿道症状、抑郁和焦虑方面的用途。