(4R,5S)-5-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-4-(4-fluorophenyl)-2-pyrazin-2-yloctahydro-1H-isoindole | 1148156-40-4

• 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: (4R,5S)-5-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-4-(4-fluorophenyl)-2-pyrazin-2-yloctahydro-1H-isoindole
• 英文别名: (3aR,4R,5S,7aS)-5-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-4-(4-fluorophenyl)-2-pyrazin-2-yl-1,3,3a,4,5,6,7,7a-octahydroisoindole
• CAS: 1148156-40-4
• 化学式: C₂₈H₂₆F₇N₃O
• 分子量: 553.523
• InChiKey: LZWZHVNWDDYRHY-KODCPBCOSA-N

物化性质

• 沸点：
  527.7±50.0 °C(predicted)
• 密度：
  1.37±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  6.4
• 重原子数：
  39
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  38.2
• 氢给体数：
  0
• 氢受体数：
  11

反应信息

• 作为产物：
  描述：

  2-氯吡嗪 、 (3aR,4R,5S,7aS)-5-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-4-(4-fluorophenyl)octahydro-1H-isoindole 以 乙醇 为溶剂， 反应 5.0h， 以79%的产率得到(4R,5S)-5-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-4-(4-fluorophenyl)-2-pyrazin-2-yloctahydro-1H-isoindole
  参考文献：
  名称：

  Potent, Brain-Penetrant, Hydroisoindoline-Based Human Neurokinin-1 Receptor Antagonists

  摘要：

  3-[(3aR,4R,5S,7aS)-5-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-4-(4-fluorophenyl)octahydro-2H-isoindol-2-yl]-cyclopent-2-en-1-one (17) is a high affinity, brain-penetrant, hydroisoindoline-based neurokinin-1 (NK(1)) receptor antagonist with a long central duration of action in preclinical species and a minimal drug-drug interaction profile. Positron emission tomography (PET) studies in rhesus showed that this compound provides 90% NK(1) receptor blockade in rhesus brain at a plasma level of 67 nM, which is about 10-fold more potent than aprepitant, an NK(1) antagonist marketed for the prevention of chemotherapy-induced and postoperative nausea and vomiting (CINV and PONV). The synthesis of this enantiomerically pure compound containing five stereocenters includes a Diels-Alder condensation, one chiral separation of the cyclohexanol intermediate, an ether formation using a trichloroacetimidate intermediate, and bis-alkylation to form the cyclic amine.

  DOI：

  10.1021/jm8016514

文献信息

• Potent, Brain-Penetrant, Hydroisoindoline-Based Human Neurokinin-1 Receptor Antagonists
  作者：Jinlong Jiang、Jaime L. Bunda、Geoge A. Doss、Gary G. Chicchi、Marc M. Kurtz、Kwei-Lan C. Tsao、Xinchun Tong、Song Zheng、Alana Upthagrove、Koppara Samuel、Richard Tschirret-Guth、Sanjeev Kumar、Alan Wheeldon、Emma J. Carlson、Richard Hargreaves、Donald Burns、Terence Hamill、Christine Ryan、Stephen M. Krause、WaiSi Eng、Robert J. DeVita、Sander G. Mills

  DOI：10.1021/jm8016514

  日期：2009.5.14

  3-[(3aR,4R,5S,7aS)-5-(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-4-(4-fluorophenyl)octahydro-2H-isoindol-2-yl]-cyclopent-2-en-1-one (17) is a high affinity, brain-penetrant, hydroisoindoline-based neurokinin-1 (NK(1)) receptor antagonist with a long central duration of action in preclinical species and a minimal drug-drug interaction profile. Positron emission tomography (PET) studies in rhesus showed that this compound provides 90% NK(1) receptor blockade in rhesus brain at a plasma level of 67 nM, which is about 10-fold more potent than aprepitant, an NK(1) antagonist marketed for the prevention of chemotherapy-induced and postoperative nausea and vomiting (CINV and PONV). The synthesis of this enantiomerically pure compound containing five stereocenters includes a Diels-Alder condensation, one chiral separation of the cyclohexanol intermediate, an ether formation using a trichloroacetimidate intermediate, and bis-alkylation to form the cyclic amine.