1-[3-[(2R)-2,3-dihydroxypropyl]-5-[3-(trifluoromethyl)-2H-pyrazolo[3,4-b]pyridin-4-yl]phenyl]cyclopropane-1-carbonitrile | 1620328-15-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: 1-[3-[(2R)-2,3-dihydroxypropyl]-5-[3-(trifluoromethyl)-2H-pyrazolo[3,4-b]pyridin-4-yl]phenyl]cyclopropane-1-carbonitrile
• CAS: 1620328-15-5
• 化学式: C₂₀H₁₇F₃N₄O₂
• 分子量: 402.376
• InChiKey: IMOQEWXBWXGJOX-CQSZACIVSA-N

物化性质

• 沸点：
  682.406±55.00 °C(Press: 760.00 Torr)(predicted)
• 密度：
  1.522±0.10 g/cm3(Temp: 25 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  29
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  106
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  1,3-二溴-5-氟苯 在 盐酸 、 potassium phosphate 、 tris-(dibenzylideneacetone)dipalladium(0) 、 lithium chloro-isopropyl-magnesium chloride 、 (S,S)-(+)-N,N'-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminocobalt(II) 、 四丁基溴化铵 、 水 、 copper(l) cyanide 、 sodium hydride 、 对甲苯磺酸 、 溶剂黄146 、 间氯过氧苯甲酸 、 lithium chloride 、 sodium hydroxide 、 tri tert-butylphosphoniumtetrafluoroborate 作用下， 以 四氢呋喃 、 N-甲基吡咯烷酮 、 二氯甲烷 、 水 、 二甲基亚砜 、 丙酮 、 甲苯 为溶剂， 反应 85.5h， 生成 1-[3-[(2R)-2,3-dihydroxypropyl]-5-[3-(trifluoromethyl)-2H-pyrazolo[3,4-b]pyridin-4-yl]phenyl]cyclopropane-1-carbonitrile
  参考文献：
  名称：

  Strategies for the modulation of phase II metabolism in a series of PKCε inhibitors

  摘要：

  Extensive phase II metabolism of an advanced PKC epsilon inhibitor resulted in sub-optimal pharmacokinetics in rat marked by elevated clearance. Synthesis of the O-glucuronide metabolite as a standard was followed by three distinct strategies to specifically temper phase II metabolic degradation of the parent molecule. In this study, it was determined that the introduction of proximal polarity to the primary alcohol generally curbed O-glucuronidation and improved PR and physical chemical properties while maintaining potency against the target. Utilization of a Jacobsen hydrolytic kinetic resolution to obtain optically enriched final compounds is also discussed. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2014.05.082

文献信息

• Strategies for the modulation of phase II metabolism in a series of PKCε inhibitors
  作者：Jeremy J. Clemens、Timothy Coon、Brett B. Busch、Juliana L. Asgian、Sarah Hudson、Andreas Termin、Tina B. Flores、Dao Tran、Peggy Chiang、Sam Sperry、Ray Gross、Jeffrey Abt、Roger Heim、Sandra Lechner、Heather Twin、John Studley、Guy Brenchley、Philip N. Collier、Francoise Pierard、Andrew Miller、Chau Mak、Vadims Dvornikovs、Juan-Miguel Jimenez、Dean Stamos

  DOI：10.1016/j.bmcl.2014.05.082

  日期：2014.8

  Extensive phase II metabolism of an advanced PKC epsilon inhibitor resulted in sub-optimal pharmacokinetics in rat marked by elevated clearance. Synthesis of the O-glucuronide metabolite as a standard was followed by three distinct strategies to specifically temper phase II metabolic degradation of the parent molecule. In this study, it was determined that the introduction of proximal polarity to the primary alcohol generally curbed O-glucuronidation and improved PR and physical chemical properties while maintaining potency against the target. Utilization of a Jacobsen hydrolytic kinetic resolution to obtain optically enriched final compounds is also discussed. (C) 2014 Elsevier Ltd. All rights reserved.