methyl 4-[(5R)-methoxymethyl-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylate TFA salt | 1416987-11-5

• 分子结构分类: 有机化合物
• 英文名称: methyl 4-[(5R)-methoxymethyl-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylate TFA salt
• CAS: 1416987-11-5
• 化学式: C₂HF₃O₂*C₁₅H₂₇NO₄
• 分子量: 399.408
• InChiKey: KUHXXRWRAXQJLP-JANLATCWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.14
• 重原子数：
  27.0
• 可旋转键数：
  6.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.88
• 拓扑面积：
  94.09
• 氢给体数：
  2.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  methyl 4-[(5R)-methoxymethyl-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylate TFA salt 在 sodium methylate 、 碳酸氢钠 、 三甲基硅烷化重氮甲烷 作用下， 以 1,4-二氧六环 、 甲醇 、 水 、 苯 为溶剂， 反应 25.0h， 生成 methyl trans-4-[1-tert-butoxycarbonyl-(5R)-methoxymethyl-(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-(5R)-methoxymethylpyrrolidine 在 偶氮二甲酸二异丙酯 、 palladium 10% on activated carbon 、 Rh/Al₂O₃ 、 氢气 、 三苯基膦 、 三氟乙酸 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 为溶剂， 20.0 ℃ 、1.01 MPa 条件下， 反应 66.0h， 生成 methyl 4-[(5R)-methoxymethyl-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylate TFA salt
  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