tert-butyl (1R,3'S)-3'-((2-chloro-3-(trifluoromethyl)benzyl)(cyclopropyl)carbamoyl)-5,6-difluoro-3-oxo-3H-spiro[isobenzofuran-1,4'-piperidine]-1'-carboxylate | 1360574-63-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 氮杂螺癸烷衍生物
• 英文名称: tert-butyl (1R,3'S)-3'-((2-chloro-3-(trifluoromethyl)benzyl)(cyclopropyl)carbamoyl)-5,6-difluoro-3-oxo-3H-spiro[isobenzofuran-1,4'-piperidine]-1'-carboxylate
• CAS: 1360574-63-5
• 化学式: C₂₉H₂₈ClF₅N₂O₅
• 分子量: 614.997
• InChiKey: SHYPRZGZJMPQQT-NGOKVRLYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.45
• 重原子数：
  42.0
• 可旋转键数：
  4.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  76.15
• 氢给体数：
  0.0
• 氢受体数：
  5.0

反应信息

• 作为反应物：
  描述：

  tert-butyl (1R,3'S)-3'-((2-chloro-3-(trifluoromethyl)benzyl)(cyclopropyl)carbamoyl)-5,6-difluoro-3-oxo-3H-spiro[isobenzofuran-1,4'-piperidine]-1'-carboxylate 在 锂硼氢 作用下， 以 四氢呋喃 为溶剂， 反应 8.0h， 以23%的产率得到tert-butyl (1R,3'S)-3'-((2-chloro-3-(trifluoromethyl)benzyl)(cyclopropyl)carbamoyl)-5,6-difluoro-3-hydroxy-3H-spiro[isobenzofuran-1,4'-piperidine]-1'-carboxylate
  参考文献：
  名称：

  Renin inhibitors for the treatment of hypertension: Design and optimization of a novel series of spirocyclic piperidines

  摘要：

  The discovery and SAR of a novel series of spirocyclic renin inhibitors are described herein. It was found that by restricting the northern aromatic plate to the bioactive conformation through spirocyclization, increase in renin potency and decrease in hERG affinity could both be realized. When early members of this series were found to be potent time-dependent CYP3A4 inhibitors, two distinct strategies to address this liability were explored and this effort culminated in the identification of compound 31 as an optimized renin inhibitor. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2011.10.013
• 作为产物：
  描述：

  2-溴-4,5-二氟苯甲酸 在 咪唑 、 ruthenium trichloride 、 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 sodium bromate 、 dimethyl sulfide borane 、 四丁基氟化铵 、 异丙基氯化镁 、 sodium hydride 、 sodium carbonate 作用下， 以 四氢呋喃 、 乙醇 、 水 、 N,N-二甲基甲酰胺 、 甲苯 、 乙腈 、 paraffin oil 为溶剂， 反应 69.5h， 生成 tert-butyl (1R,3'S)-3'-((2-chloro-3-(trifluoromethyl)benzyl)(cyclopropyl)carbamoyl)-5,6-difluoro-3-oxo-3H-spiro[isobenzofuran-1,4'-piperidine]-1'-carboxylate
  参考文献：
  名称：

  Renin inhibitors for the treatment of hypertension: Design and optimization of a novel series of spirocyclic piperidines

  摘要：

  The discovery and SAR of a novel series of spirocyclic renin inhibitors are described herein. It was found that by restricting the northern aromatic plate to the bioactive conformation through spirocyclization, increase in renin potency and decrease in hERG affinity could both be realized. When early members of this series were found to be potent time-dependent CYP3A4 inhibitors, two distinct strategies to address this liability were explored and this effort culminated in the identification of compound 31 as an optimized renin inhibitor. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2011.10.013