methyl 4-[(5S)-benzyloxymethyl-1-tert-butoxycarbonyl-(2S)-pyrrolidinylmethoxy]benzoate | 317357-52-1

• 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: methyl 4-[(5S)-benzyloxymethyl-1-tert-butoxycarbonyl-(2S)-pyrrolidinylmethoxy]benzoate
• CAS: 317357-52-1
• 化学式: C₂₆H₃₃NO₆
• 分子量: 455.551
• InChiKey: HZJGKLUPIZYWTQ-VXKWHMMOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.84
• 重原子数：
  33.0
• 可旋转键数：
  8.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  74.3
• 氢给体数：
  0.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  methyl 4-[(5S)-benzyloxymethyl-1-tert-butoxycarbonyl-(2S)-pyrrolidinylmethoxy]benzoate 在 吡啶 、 palladium 10% on activated carbon 、 Rh/Al₂O₃ 、 氢气 、 sodium methylate 、 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 21.0h， 生成 methyl trans-4-[(5S)-acetoxymethyl-1-tert-butoxycarbonyl-(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,5S)-5-benzyloxymethyl-1-tert-butoxycarbonyl-2-hydroxymethylpyrrolidine 、 对羟基苯甲酸甲酯 在 偶氮二甲酸二异丙酯 、 三苯基膦 作用下， 反应 2.0h， 以80%的产率得到methyl 4-[(5S)-benzyloxymethyl-1-tert-butoxycarbonyl-(2S)-pyrrolidinylmethoxy]benzoate
  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