(3R,4R)-3-(1-tert-butoxycarbonyl-4-fluoropiperidin-3-yl)-6-fluoroindole-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: (3R,4R)-3-(1-tert-butoxycarbonyl-4-fluoropiperidin-3-yl)-6-fluoroindole-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester
• 英文别名: 1-O-tert-butyl 2-O-methyl 6-fluoro-3-[(3R,4R)-4-fluoro-1-[(2-methylpropan-2-yl)oxycarbonyl]piperidin-3-yl]indole-1,2-dicarboxylate
• 化学式: C₂₅H₃₂F₂N₂O₆
• 分子量: 494.536
• InChiKey: KFRAPOWFCXXKLM-IAGOWNOFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5
• 重原子数：
  35
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  87.1
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  (3R,4R)-3-(1-tert-butoxycarbonyl-4-fluoropiperidin-3-yl)-6-fluoroindole-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester 在 90percent aq. formic acid 作用下， 反应 2.5h， 生成 6-Fluoro-3-((3R,4R)-4-fluoro-piperidin-3-yl)-1H-indole-2-carboxylic acid methyl ester
  参考文献：
  名称：

  3-(4-Fluoropiperidin-3-yl)-2-phenylindoles as High Affinity, Selective, and Orally Bioavailable h5-HT_2A Receptor Antagonists

  摘要：

  The development of very high affinity, selective, and bioavailable h5-HT2A receptor antagonists is described. By investigation of the optimal position for the basic nitrogen in a series of 2-phenyl-3-piperidylindoles, it was found that with the basic nitrogen at the S-position of the piperidine it was not necessary to further substitute the piperidine in order to obtain good binding at h5-HT2A receptors. This meant the compounds no longer had high affinity at the IKr potassium channel, an issue with previous series of 2-aryl-3-(4-piperidyl)indoles. Improvements could be made to oral bioavailability in this series by reduction of the pK(a) of the basic nitrogen, by adding a fluorine atom to the piperidine ring, leading to 3-(4-fluoropiperidin-3-yl)-2-phenyl-1H-indole (17). Metabolic studies with this compound identified oxidation at the B-position of the indole as a major route in vitro and in vivo in rats. Blocking this position with a fluorine atom led to 6-fluoro-3-(4-fluoropiperidin-3-yl)-2-phenyl-1H-indole (22), an antagonist with 0.06 nM affinity for h5-HT2A receptors, with bioavailability of 80% and half-life of 12 h in rats.

  DOI：

  10.1021/jm0004998
• 作为产物：
  描述：

  氰基甲酸甲酯 、 tert-butyl 6-fluoro-3-[(3R,4R)-4-fluoro-1-[(2-methylpropan-2-yl)oxycarbonyl]piperidin-3-yl]indole-1-carboxylate 在 2,2,6,6-tetramethylpiperidinyl-lithium 作用下， 以 四氢呋喃 、 正己烷 为溶剂， 反应 3.0h， 生成 (3R,4R)-3-(1-tert-butoxycarbonyl-4-fluoropiperidin-3-yl)-6-fluoroindole-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester
  参考文献：
  名称：

  3-(4-Fluoropiperidin-3-yl)-2-phenylindoles as High Affinity, Selective, and Orally Bioavailable h5-HT_2A Receptor Antagonists

  摘要：

  The development of very high affinity, selective, and bioavailable h5-HT2A receptor antagonists is described. By investigation of the optimal position for the basic nitrogen in a series of 2-phenyl-3-piperidylindoles, it was found that with the basic nitrogen at the S-position of the piperidine it was not necessary to further substitute the piperidine in order to obtain good binding at h5-HT2A receptors. This meant the compounds no longer had high affinity at the IKr potassium channel, an issue with previous series of 2-aryl-3-(4-piperidyl)indoles. Improvements could be made to oral bioavailability in this series by reduction of the pK(a) of the basic nitrogen, by adding a fluorine atom to the piperidine ring, leading to 3-(4-fluoropiperidin-3-yl)-2-phenyl-1H-indole (17). Metabolic studies with this compound identified oxidation at the B-position of the indole as a major route in vitro and in vivo in rats. Blocking this position with a fluorine atom led to 6-fluoro-3-(4-fluoropiperidin-3-yl)-2-phenyl-1H-indole (22), an antagonist with 0.06 nM affinity for h5-HT2A receptors, with bioavailability of 80% and half-life of 12 h in rats.

  DOI：

  10.1021/jm0004998