2-[(2S,4R)-1-[4,4-bis(3-methylthiophen-2-yl)but-3-enyl]-4-hydroxy-4-(4-methoxyphenyl)pyrrolidin-2-yl]acetic acid | 1418177-92-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯烷类
• 英文名称: 2-[(2S,4R)-1-[4,4-bis(3-methylthiophen-2-yl)but-3-enyl]-4-hydroxy-4-(4-methoxyphenyl)pyrrolidin-2-yl]acetic acid
• CAS: 1418177-92-0
• 化学式: C₂₇H₃₁NO₄S₂
• 分子量: 497.679
• InChiKey: RKRLYDVNFNQHJQ-ZBLYBZFDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  34
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  127
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  methyl (2S)-1-benzyloxycarbonyl-4-oxopyrrolidin-2-acetate 在 palladium 10% on activated carbon 、 水 、 氢气 、 potassium carbonate 、 magnesium 、 三乙胺 、 potassium iodide 、 sodium hydroxide 作用下， 以 甲醇 、 乙醚 为溶剂， 反应 76.67h， 生成 2-[(2S,4R)-1-[4,4-bis(3-methylthiophen-2-yl)but-3-enyl]-4-hydroxy-4-(4-methoxyphenyl)pyrrolidin-2-yl]acetic acid
  参考文献：
  名称：

  Synthesis and biological evaluation of 4-hydroxy-4-(4-methoxyphenyl)-substituted proline and pyrrolidin-2-ylacetic acid derivatives as GABA uptake inhibitors

  摘要：

  A series of enantiomerically pure 4-hydroxy-4-(4-methoxyphenyl)-substituted proline and pyrrolidin-2-ylacetic acid derivatives have been synthesized starting from the respective N-protected 4-hydroxy derivatives via oxidation to the corresponding 4-oxo compounds, subsequent addition of organometallic reagents, final hydrolysis and deprotection. The major diastereoisomers obtained by the addition of the Grignard reagents were found to have opposite stereoconfigurations depending on whether cerium trichloride was present or absent as an additive. The final compounds were evaluated for their capability to inhibit the GABA transport proteins GAT1 and GAT3. 4-Hydroxyproline derivatives substituted with a tris(4-methoxyphenyl)methyloxyethyl residue at the nitrogen and a 4-methoxyphenyl group in 4-position showed, with the exception of the (2R,4R)-diastereomer, an improved inhibition at GAT3 compared to the derivatives missing the 4-methoxyphenyl group in 4-position. This may imply that an appropriate lipophilic group at the C-4 position of the proline moiety is beneficial for potent inhibition at GAT3. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2012.11.015

文献信息

• Synthesis and biological evaluation of 4-hydroxy-4-(4-methoxyphenyl)-substituted proline and pyrrolidin-2-ylacetic acid derivatives as GABA uptake inhibitors
  作者：Xueqing Zhao、Jörg Pabel、Georg C. Höfner、Klaus T. Wanner

  DOI：10.1016/j.bmc.2012.11.015

  日期：2013.1

  A series of enantiomerically pure 4-hydroxy-4-(4-methoxyphenyl)-substituted proline and pyrrolidin-2-ylacetic acid derivatives have been synthesized starting from the respective N-protected 4-hydroxy derivatives via oxidation to the corresponding 4-oxo compounds, subsequent addition of organometallic reagents, final hydrolysis and deprotection. The major diastereoisomers obtained by the addition of the Grignard reagents were found to have opposite stereoconfigurations depending on whether cerium trichloride was present or absent as an additive. The final compounds were evaluated for their capability to inhibit the GABA transport proteins GAT1 and GAT3. 4-Hydroxyproline derivatives substituted with a tris(4-methoxyphenyl)methyloxyethyl residue at the nitrogen and a 4-methoxyphenyl group in 4-position showed, with the exception of the (2R,4R)-diastereomer, an improved inhibition at GAT3 compared to the derivatives missing the 4-methoxyphenyl group in 4-position. This may imply that an appropriate lipophilic group at the C-4 position of the proline moiety is beneficial for potent inhibition at GAT3. (C) 2012 Elsevier Ltd. All rights reserved.