4-(6-chloro-5-methylpyrimidin-4-yloxy)-3-fluorobenzonitrile | 1417392-67-6

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 4-(6-chloro-5-methylpyrimidin-4-yloxy)-3-fluorobenzonitrile
• 英文别名: 4-(6-Chloro-5-methylpyrimidin-4-yl)oxy-3-fluorobenzonitrile；4-(6-chloro-5-methylpyrimidin-4-yl)oxy-3-fluorobenzonitrile
• CAS: 1417392-67-6
• 化学式: C₁₂H₇ClFN₃O
• 分子量: 263.658
• InChiKey: NLUJUEXPHXPGCF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  18
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.08
• 拓扑面积：
  58.8
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  4-(6-chloro-5-methylpyrimidin-4-yloxy)-3-fluorobenzonitrile 、 tert-butyl 2,6-Diazatricyclo[3.3.1.1^3,7]decane-2-carboxylate 在 碳酸氢钠 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 18.0h， 以126.7 mg的产率得到Tert-butyl 6-[6-(4-cyano-2-fluorophenoxy)-5-methylpyrimidin-4-yl]-2,6-diazatricyclo[3.3.1.13,7]decane-2-carboxylate
  参考文献：
  名称：

  Design and Synthesis of Diazatricyclodecane Agonists of the G-Protein-Coupled Receptor 119

  摘要：

  A series of GPR119 agonists based on a 2,6-diazatricyclo[3.3.1.1 similar to 3,7,similar to]decane ring system is described. Also provided is a detailed account of the development of a multigram scale synthesis of the diazatricyclic ring system, which was achieved using a Hofmann-Loffler-Freytag reaction as the key step. The basis for the use of this complex framework lies in an attempt to constrain one end of the molecule in the "agonist conformation" as was previously described for 3-oxa-7-aza-bicyclo[3.3.1]nonanes. Optimization of carbamate analogues of the diazatricylic compounds led to the identification of 32i as a potent agonist of the GPR119 receptor with low unbound human liver microsomal clearance. The use of an agonist response weighted ligand lipophilic efficiency (LLE) termed AgLLE is discussed along with the issues of applying efficiency measures to agonist programs. Ultimately, solubility limited absorption and poor exposure reduced further interest in these molecules.

  DOI：

  10.1021/jm301626p
• 作为产物：
  描述：

  4,6-二氯-5-甲基嘧啶 、 3-氟-4-羟基苯腈 在 caesium carbonate 作用下， 以 乙腈 为溶剂， 反应 18.0h， 生成 4-(6-chloro-5-methylpyrimidin-4-yloxy)-3-fluorobenzonitrile
  参考文献：
  名称：

  Design and Synthesis of Diazatricyclodecane Agonists of the G-Protein-Coupled Receptor 119

  摘要：

  A series of GPR119 agonists based on a 2,6-diazatricyclo[3.3.1.1 similar to 3,7,similar to]decane ring system is described. Also provided is a detailed account of the development of a multigram scale synthesis of the diazatricyclic ring system, which was achieved using a Hofmann-Loffler-Freytag reaction as the key step. The basis for the use of this complex framework lies in an attempt to constrain one end of the molecule in the "agonist conformation" as was previously described for 3-oxa-7-aza-bicyclo[3.3.1]nonanes. Optimization of carbamate analogues of the diazatricylic compounds led to the identification of 32i as a potent agonist of the GPR119 receptor with low unbound human liver microsomal clearance. The use of an agonist response weighted ligand lipophilic efficiency (LLE) termed AgLLE is discussed along with the issues of applying efficiency measures to agonist programs. Ultimately, solubility limited absorption and poor exposure reduced further interest in these molecules.

  DOI：

  10.1021/jm301626p