tert-butyl 8-chloro-6-fluoro-4-hydroxy-3,4-dihydrospiro[chromene-2,4'-piperidine]-1'-carboxylate | 1245739-02-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡喃
• 英文名称: tert-butyl 8-chloro-6-fluoro-4-hydroxy-3,4-dihydrospiro[chromene-2,4'-piperidine]-1'-carboxylate
• 英文别名: tert-butyl 8-chloro-6-fluoro-4-hydroxy-3,4-dihydro-1'H-spiro[chromene-2,4'-piperidine]-1'-carboxylate
• CAS: 1245739-02-9
• 化学式: C₁₈H₂₃ClFNO₄
• 分子量: 371.836
• InChiKey: SHEHLEPLNDLXQF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.06
• 重原子数：
  25.0
• 可旋转键数：
  0.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.61
• 拓扑面积：
  59.0
• 氢给体数：
  1.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  tert-butyl 8-chloro-6-fluoro-4-hydroxy-3,4-dihydrospiro[chromene-2,4'-piperidine]-1'-carboxylate 在 三乙基硅烷 、 三氟乙酸 、 水 、 碳酸氢钠 、 盐酸 作用下， 以 乙酸乙酯 为溶剂， 反应 20.0h， 以71%的产率得到8-chloro-6-fluoro-3,4-dihydrospiro[chromene-2,4'-piperidine] hydrochloride
  参考文献：
  名称：

  Synthesis and pharmacological evaluation of novel N-aryl-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidine]-1′-carboxamides as TRPM8 antagonists

  摘要：

  A novel series of N-aryl-3,4-dihydro-1'H-spiro[chromene-2,4'-piperidine]-1'-carboxamides was identified as transient receptor potential melastatin 8 (TRPM8) channel blockers through analogue-based rational design, synthesis and screening. Details of the synthesis, effect of aryl groups and their substituents on in-vitro potency were studied. The effects of selected functional groups on the 4-position of the chromene ring were also studied, which showed interesting results. The 4-hydroxy derivatives showed excellent potency and selectivity. Optical resolution and screening of alcohols revealed that (R)-(-)-isomers were in general more potent than the corresponding (S)-(+)-isomers. The isomer (R)-(-)-10e (IC50: 8.9 nM) showed a good pharmacokinetic profile upon oral dosing at 10 mg/kg in Sprague-Dawley (SD) rats. The compound (R)-(-)-10e also showed excellent efficacy in relevant rodent models of neuropathic pain. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2013.08.031
• 作为产物：
  描述：

  tert-butyl 8-chloro-6-fluoro-4-oxo-3,4-dihydrospiro[chromene-2,4'-piperidine]-1'-carboxylate 在 sodium tetrahydroborate 作用下， 以 乙醇 为溶剂， 反应 1.0h， 以87%的产率得到tert-butyl 8-chloro-6-fluoro-4-hydroxy-3,4-dihydrospiro[chromene-2,4'-piperidine]-1'-carboxylate
  参考文献：
  名称：

  Synthesis and pharmacological evaluation of novel N-aryl-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidine]-1′-carboxamides as TRPM8 antagonists

  摘要：

  A novel series of N-aryl-3,4-dihydro-1'H-spiro[chromene-2,4'-piperidine]-1'-carboxamides was identified as transient receptor potential melastatin 8 (TRPM8) channel blockers through analogue-based rational design, synthesis and screening. Details of the synthesis, effect of aryl groups and their substituents on in-vitro potency were studied. The effects of selected functional groups on the 4-position of the chromene ring were also studied, which showed interesting results. The 4-hydroxy derivatives showed excellent potency and selectivity. Optical resolution and screening of alcohols revealed that (R)-(-)-isomers were in general more potent than the corresponding (S)-(+)-isomers. The isomer (R)-(-)-10e (IC50: 8.9 nM) showed a good pharmacokinetic profile upon oral dosing at 10 mg/kg in Sprague-Dawley (SD) rats. The compound (R)-(-)-10e also showed excellent efficacy in relevant rodent models of neuropathic pain. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2013.08.031