methyl (2S,4R)-1-(4,4-diphenylbut-3-en-1-yl)-4-hydroxypyrrolidine-2-carboxylate | 850741-32-1

• 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 (2S,4R)-1-(4,4-diphenylbut-3-en-1-yl)-4-hydroxypyrrolidine-2-carboxylate
• 英文别名: methyl (2S,4R)-1-(4,4-diphenyl-3-butenyl)-4-hydroxylpyrrolidine-2-carboxylate；methyl (2S,4R)-1-(4,4-diphenylbut-3-enyl)-4-hydroxypyrrolidine-2-carboxylate
• CAS: 850741-32-1
• 化学式: C₂₂H₂₅NO₃
• 分子量: 351.445
• InChiKey: PCMMFKILFYCYEQ-CTNGQTDRSA-N

物化性质

• 沸点：
  515.0±50.0 °C(Predicted)
• 密度：
  1.156±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  26
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  49.8
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  methyl (2S,4R)-1-(4,4-diphenylbut-3-en-1-yl)-4-hydroxypyrrolidine-2-carboxylate 在 草酰氯 、 二甲基亚砜 、 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 0.34h， 以87%的产率得到methyl (2S)-1-(4,4-diphenylbut-3-en-1-yl)-4-oxopyrrolidine-2-carboxylate
  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
• 作为产物：
  描述：

  (4-溴-1-苯基丁-1-烯基)苯 、 反式-4-羟基-L-脯氨酸甲酯盐酸盐 在 potassium carbonate 、 potassium iodide 作用下， 以 丙酮 为溶剂， 以52%的产率得到methyl (2S,4R)-1-(4,4-diphenylbut-3-en-1-yl)-4-hydroxypyrrolidine-2-carboxylate
  参考文献：
  名称：

  Synthesis and biological evaluation of new GABA-uptake inhibitors derived from proline and from pyrrolidine-2-acetic acid

  摘要：

  Several synthetic approaches to N-alkylated derivatives of 4-hydroxypyrrolidine-2-carboxylic acid and 4-hydroxypyrrolidine-2-acetic acid are described. The final compounds have been evaluated as potential inhibitors of the GABA transport proteins GAT-I and GAT-3. The biological assays used were based on bovine material or porcine brain. As compared to the corresponding 4-unsubstituted compounds, the 4-hydroxypyrrolidine-2-carboxylic acid and 4-hydroxypyrrolidine-2-acetic acid derivatives showed a significant decrease in the inhibitory potency at both GAT-1 and GAT-3 with only four compounds having reasonable affinity to GAT-1 (IC50: 5.1, 6.6 and 9.4 mu M) or GAT-3 (IC50:19.9 mu M), respectively. The biological data of the 4-hydroxypyrrolidine-2-acetic acid derivatives indicates that (2S)-configuration at the C-2 position for potent inhibition of GAT-1 and (4R)-configuration at the C-4 position for potent inhibition of GAT-3 may be crucial. (c) 2005 Elsevier SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2004.11.004

文献信息

• Synthesis and biological evaluation of 4-fluoroproline and 4-fluoropyrrolidine-2-acetic acid derivatives as new GABA uptake inhibitors
  作者：Weiping Zhuang、Xueqing Zhao、Gang Zhao、Lihe Guo、Yunyang Lian、Jingming Zhou、Dongsheng Fang

  DOI：10.1016/j.bmc.2009.08.010

  日期：2009.9

  Preparation for the N-alkylated derivatives of enantiomerically pure (2S)-4-fluoroproline and (2S)-4-fluoropyrrolidine-2-acetic acid is described. The final compounds were evaluated as potential GAT-1 uptake inhibitors via cultured cell lines expressing mouse GAT-1. Compared with their corresponding 4-hydroxy compounds, these derivatives exhibited slight improvement on their inhibitory potency, but still much weaker than their corresponding compounds with no substituents at the C-4 of the pyrrolidine moiety, with the most potent affinity being about 1/15 fold as that of Tiagabine. The drastic decrease of their affinity may arise from sharp reduction of their basicity due to strong inductive effect of the 4-fluorine. However the configuration of the C-4 linking fluorine did not have much influence on their affinity for GAT-1. (C) 2009 Elsevier Ltd. All rights reserved.
• 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.
• Synthesis and biological evaluation of new GABA-uptake inhibitors derived from proline and from pyrrolidine-2-acetic acid
  作者：Xueqing Zhao、Cornelia E. Hoesl、Georg C. Hoefner、Klaus T. Wanner

  DOI：10.1016/j.ejmech.2004.11.004

  日期：2005.3

  Several synthetic approaches to N-alkylated derivatives of 4-hydroxypyrrolidine-2-carboxylic acid and 4-hydroxypyrrolidine-2-acetic acid are described. The final compounds have been evaluated as potential inhibitors of the GABA transport proteins GAT-I and GAT-3. The biological assays used were based on bovine material or porcine brain. As compared to the corresponding 4-unsubstituted compounds, the 4-hydroxypyrrolidine-2-carboxylic acid and 4-hydroxypyrrolidine-2-acetic acid derivatives showed a significant decrease in the inhibitory potency at both GAT-1 and GAT-3 with only four compounds having reasonable affinity to GAT-1 (IC50: 5.1, 6.6 and 9.4 mu M) or GAT-3 (IC50:19.9 mu M), respectively. The biological data of the 4-hydroxypyrrolidine-2-acetic acid derivatives indicates that (2S)-configuration at the C-2 position for potent inhibition of GAT-1 and (4R)-configuration at the C-4 position for potent inhibition of GAT-3 may be crucial. (c) 2005 Elsevier SAS. All rights reserved.