(2S)-benzyloxymethyl-1-tert-butoxycarobnyl-(5S)-fluoromethylpyrrolidine | 1416961-09-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: (2S)-benzyloxymethyl-1-tert-butoxycarobnyl-(5S)-fluoromethylpyrrolidine
• CAS: 1416961-09-5
• 化学式: C₁₈H₂₆FNO₃
• 分子量: 323.408
• InChiKey: NDJUEGCYYIKFLZ-HOTGVXAUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.94
• 重原子数：
  23.0
• 可旋转键数：
  5.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.61
• 拓扑面积：
  38.77
• 氢给体数：
  0.0
• 氢受体数：
  3.0

反应信息

• 作为反应物：
  描述：

  (2S)-benzyloxymethyl-1-tert-butoxycarobnyl-(5S)-fluoromethylpyrrolidine 在 偶氮二甲酸二异丙酯 、 palladium 10% on activated carbon 、 Rh/Al₂O₃ 、 氢气 、 sodium methylate 、 三苯基膦 、 三甲基硅烷化重氮甲烷 作用下， 以 甲醇 、 乙醇 、 正己烷 、 溶剂黄146 、 苯 为溶剂， 反应 20.5h， 生成 methyl trans-4-[1-tert-butoxycarbonyl-(5S)-fluoromethyl-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylate
  参考文献：
  名称：

  A novel, potent, and orally active VLA-4 antagonist with good aqueous solubility: trans-4-[1-[[2-(5-Fluoro-2-methylphenylamino)-7-fluoro-6-benzoxazolyl]acetyl]-(5S)-[methoxy(methyl)amino]methyl-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid

  摘要：

  We have carried out the optimization of substituents at the C-3 or the C-5 position on the pyrrolidine ring of VLA-4 antagonist 3 with 2-(phenylamino)-7-fluorobenzoxazolyl moiety for the purpose of improving in vivo efficacy while maintaining good aqueous solubility. As a result, we successfully increased in vitro activity in the presence of 3% human serum albumin and achieved an exquisite lipophilic and hydrophilic balance of compounds suitable for oral administrative regimen. The modification resulted in the identification of zwitterionic compound 7n with (5S)-[methoxy(methyl) amino] methylpyrrolidine, which significantly alleviated bronchial hyper-responsiveness to acetylcholine chloride at 12.5 mg/kg, p.o. in a murine asthma model and showed favorable aqueous solubility (JP1, 89 mu g/mL; JP2, 462 mu g/mL). Furthermore, this compound showed good oral bioavailability (F = 54%) in monkeys. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2012.11.003
• 作为产物：
  描述：

  (2S)-benzyloxymethyl-1-tert-butoxycarbonyl-(5S)-methansulfonyloxymethylpyrrolidine 在 四丁基氟化铵 作用下， 以 四氢呋喃 为溶剂， 反应 8.0h， 以68%的产率得到(2S)-benzyloxymethyl-1-tert-butoxycarobnyl-(5S)-fluoromethylpyrrolidine
  参考文献：
  名称：

  A novel, potent, and orally active VLA-4 antagonist with good aqueous solubility: trans-4-[1-[[2-(5-Fluoro-2-methylphenylamino)-7-fluoro-6-benzoxazolyl]acetyl]-(5S)-[methoxy(methyl)amino]methyl-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid

  摘要：

  We have carried out the optimization of substituents at the C-3 or the C-5 position on the pyrrolidine ring of VLA-4 antagonist 3 with 2-(phenylamino)-7-fluorobenzoxazolyl moiety for the purpose of improving in vivo efficacy while maintaining good aqueous solubility. As a result, we successfully increased in vitro activity in the presence of 3% human serum albumin and achieved an exquisite lipophilic and hydrophilic balance of compounds suitable for oral administrative regimen. The modification resulted in the identification of zwitterionic compound 7n with (5S)-[methoxy(methyl) amino] methylpyrrolidine, which significantly alleviated bronchial hyper-responsiveness to acetylcholine chloride at 12.5 mg/kg, p.o. in a murine asthma model and showed favorable aqueous solubility (JP1, 89 mu g/mL; JP2, 462 mu g/mL). Furthermore, this compound showed good oral bioavailability (F = 54%) in monkeys. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2012.11.003