4-fluoro-3-fluoromethyl-but-2-enoic acid ethyl ester | 1810-37-3

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 脂肪酰基
• 英文名称: 4-fluoro-3-fluoromethyl-but-2-enoic acid ethyl ester
• 英文别名: γ-Fluor-β-fluormethyl-crotonsaeure-ethylester；4-Fluor-3-fluormethyl-crotonsaeure-ethylester；Ethyl 4-fluoro-3-(fluoromethyl)but-2-enoate；ethyl 4-fluoro-3-(fluoromethyl)but-2-enoate
• CAS: 1810-37-3
• 化学式: C₇H₁₀F₂O₂
• 分子量: 164.152
• InChiKey: OJYVEUSWPHJEMN-UHFFFAOYSA-N

物化性质

• 沸点：
  59-60 °C(Press: 10 Torr)
• 密度：
  1.080±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  11
• 可旋转键数：
  5
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  26.3
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  4-fluoro-3-fluoromethyl-but-2-enoic acid ethyl ester 在 水 、 氢气 、 lithium hydroxide 、 2,8,9-三异丙基-2,5,8,9-四硫唑嘌呤-1-磷杂二环[3.3.3]十一烷 作用下， 以 四氢呋喃 、 乙醇 为溶剂， 20.0 ℃ 、344.75 kPa 条件下， 反应 18.08h， 生成 3-(tert-butoxycarbonylamino-methyl)-4-fluoro-3-fluoromethyl-butyric acid
  参考文献：
  名称：

  N′-(Arylsulfonyl)pyrazoline-1-carboxamidines as Novel, Neutral 5-Hydroxytryptamine 6 Receptor (5-HT₆R) Antagonists with Unique Structural Features

  摘要：

  The 5-HT6 receptor (5-HT6R) has been in the spotlight for several years regarding CNS-related diseases. We set out to discover novel, neutral 5-HT6R antagonists to improve off-target selectivity compared to basic amine-containing scaffolds dominating the field. High-throughput screening identified the N'-(sulfonyl)pyrazoline-1-carboxamidine scaffold as a promising neutral core for starting hit-to-lead. Medicinal chemistry, molecular modeling, small molecule NMR and X-ray crystallography were subsequently applied to optimize the leads into antagonists (compounds 1-49) displaying high 5-HT6R affinity with optimal off-target selectivity. Unique structural features include a pseudoaromatic system and an internal hydrogen bond freezing the bioactive conformation. While physicochemical properties and CNS availability were generally favorable, significant efforts had to be made to improve metabolic stability. The optimized structure 42 is an extremely selective, hERG-free, high-affinity 5-HT6R antagonist showing good human in vitro metabolic stability. Rat pharrnacokinetic data were sufficiently good to enable further in vivo profiling.

  DOI：

  10.1021/jm200466r
• 作为产物：
  描述：

  1,3-二氟丙酮 、 乙氧甲酰基亚甲基三苯基膦 生成 4-fluoro-3-fluoromethyl-but-2-enoic acid ethyl ester
  参考文献：
  名称：

  Machleidt,H. et al., Justus Liebigs Annalen der Chemie, 1963, vol. 667, p. 35 - 47

  摘要：

  DOI：

文献信息

• Machleidt,H. et al., Justus Liebigs Annalen der Chemie, 1963, vol. 667, p. 35 - 47
  作者：Machleidt,H. et al.

  DOI：——

  日期：——
• <i>N</i>′-(Arylsulfonyl)pyrazoline-1-carboxamidines as Novel, Neutral 5-Hydroxytryptamine 6 Receptor (5-HT₆R) Antagonists with Unique Structural Features
  作者：Arnold van Loevezijn、Jennifer Venhorst、Wouter I. Iwema Bakker、Cor G. de Korte、Wouter de Looff、Stefan Verhoog、Jan-Willem van Wees、Martijn van Hoeve、Rob P. van de Woestijne、Martina A. W. van der Neut、Alice J. M. Borst、Maria J. P. van Dongen、Natasja M. W. J. de Bruin、Hiskias G. Keizer、Chris G. Kruse

  DOI：10.1021/jm200466r

  日期：2011.10.27

  The 5-HT6 receptor (5-HT6R) has been in the spotlight for several years regarding CNS-related diseases. We set out to discover novel, neutral 5-HT6R antagonists to improve off-target selectivity compared to basic amine-containing scaffolds dominating the field. High-throughput screening identified the N'-(sulfonyl)pyrazoline-1-carboxamidine scaffold as a promising neutral core for starting hit-to-lead. Medicinal chemistry, molecular modeling, small molecule NMR and X-ray crystallography were subsequently applied to optimize the leads into antagonists (compounds 1-49) displaying high 5-HT6R affinity with optimal off-target selectivity. Unique structural features include a pseudoaromatic system and an internal hydrogen bond freezing the bioactive conformation. While physicochemical properties and CNS availability were generally favorable, significant efforts had to be made to improve metabolic stability. The optimized structure 42 is an extremely selective, hERG-free, high-affinity 5-HT6R antagonist showing good human in vitro metabolic stability. Rat pharrnacokinetic data were sufficiently good to enable further in vivo profiling.