di-tert-butyl 4-(benzylamino)-1H-pyrrole-1,3(2H,5H)-dicarboxylate | 341969-57-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯啉
• 英文名称: di-tert-butyl 4-(benzylamino)-1H-pyrrole-1,3(2H,5H)-dicarboxylate
• 英文别名: ditert-butyl 4-(benzylamino)-2,5-dihydropyrrole-1,3-dicarboxylate
• CAS: 341969-57-1
• 化学式: C₂₁H₃₀N₂O₄
• 分子量: 374.48
• InChiKey: CVXLHDAHGKZDEC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  27
• 可旋转键数：
  8
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  67.9
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  di-tert-butyl 4-(benzylamino)-1H-pyrrole-1,3(2H,5H)-dicarboxylate 在 10 percent Pd/C sodium tetrahydroborate 、 氢气 、 溶剂黄146 作用下， 以 甲醇 为溶剂， 反应 6.0h， 生成 di-tert-butyl cis-4-aminopyrrolidine-1,3-dicarboxylate
  参考文献：
  名称：

  Design, Synthesis, and Structural Analysis of Influenza Neuraminidase Inhibitors Containing Pyrrolidine Cores

  摘要：

  The discovery of (+/-)-(2S,3R,4R)-2-(trifluoroacetamido)methyl-3-amino-1-(N ' -ethyl-N ' -isopropylcarbamyl)pyrrolidine-4-earboxylic acid (A-192558, 20e) as a potent inhibitor of influenza neuraminidase (NA) is described. Efficient syntheses of two core structures, cis-3-(allyloxy-carbonyl)amino-1-(9 ' -fluorenylmethoxycarbonyl)pyrrolidine-4-carboxylic acid (7) and tert-butyl (+/-)(2S, 3R,4R)-2-aminomethyl-3-bis(tert-butyloxycarbonyl) amino-1-(N ' -ethyl-N ' -isopropylcarbamyl)pyrrolidine-4-carboxylate (18b), were developed. Starting with these core structures and using available structural information of the NA active site as the guide, analogues were synthesized in both the tri- and tetrasubstituted pyrrolidine series by means of high-throughput parallel synthesis in solid or solution phase for expeditious SAR. These studies accelerated the identification of(+/-)-(2S,3R,4R)-2-(trifluoroacetamido)methyl-3-amino-1-(N-ethyl-N-isopropylcarbamyl)pyrrolidine-4-carboxylate (20e, A-192558) as the most potent NA inhibitor in this series (IC50 = 0.2 muM against NA A and 8 muM against NA B). The X-ray crystallographic structure of A-192558 bound to NA revealed the predicted interaction of the carboxylic group with the positively charged pocket (Arg118, Arg292, Arg371) and interaction of the trifluoro-acetamino residue with the hydrophobic pocket (Ile222, Trp178) of the enzyme active site. Surprisingly, the ethyl and isopropyl groups of the urea functionality induced a conformational change of Glu276, turning the Glu276/Glu277 hydrophilic pocket, which normally accommodates the triglycerol side chain of substrate sialic acid, into an induced hydrophobic pocket.

  DOI：

  10.1021/jm000468c
• 作为产物：
  描述：

  丙烯酸叔丁酯 、 BOC-甘氨酸甲酯 、 苄基铵乙酸盐 在 potassium tert-butylate 、 溶剂黄146 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 25.5h， 以37 g的产率得到di-tert-butyl 4-(benzylamino)-1H-pyrrole-1,3(2H,5H)-dicarboxylate
  参考文献：
  名称：

  Design, Synthesis, and Structural Analysis of Influenza Neuraminidase Inhibitors Containing Pyrrolidine Cores

  摘要：

  The discovery of (+/-)-(2S,3R,4R)-2-(trifluoroacetamido)methyl-3-amino-1-(N ' -ethyl-N ' -isopropylcarbamyl)pyrrolidine-4-earboxylic acid (A-192558, 20e) as a potent inhibitor of influenza neuraminidase (NA) is described. Efficient syntheses of two core structures, cis-3-(allyloxy-carbonyl)amino-1-(9 ' -fluorenylmethoxycarbonyl)pyrrolidine-4-carboxylic acid (7) and tert-butyl (+/-)(2S, 3R,4R)-2-aminomethyl-3-bis(tert-butyloxycarbonyl) amino-1-(N ' -ethyl-N ' -isopropylcarbamyl)pyrrolidine-4-carboxylate (18b), were developed. Starting with these core structures and using available structural information of the NA active site as the guide, analogues were synthesized in both the tri- and tetrasubstituted pyrrolidine series by means of high-throughput parallel synthesis in solid or solution phase for expeditious SAR. These studies accelerated the identification of(+/-)-(2S,3R,4R)-2-(trifluoroacetamido)methyl-3-amino-1-(N-ethyl-N-isopropylcarbamyl)pyrrolidine-4-carboxylate (20e, A-192558) as the most potent NA inhibitor in this series (IC50 = 0.2 muM against NA A and 8 muM against NA B). The X-ray crystallographic structure of A-192558 bound to NA revealed the predicted interaction of the carboxylic group with the positively charged pocket (Arg118, Arg292, Arg371) and interaction of the trifluoro-acetamino residue with the hydrophobic pocket (Ile222, Trp178) of the enzyme active site. Surprisingly, the ethyl and isopropyl groups of the urea functionality induced a conformational change of Glu276, turning the Glu276/Glu277 hydrophilic pocket, which normally accommodates the triglycerol side chain of substrate sialic acid, into an induced hydrophobic pocket.

  DOI：

  10.1021/jm000468c

文献信息

• Design, Synthesis, and Structural Analysis of Influenza Neuraminidase Inhibitors Containing Pyrrolidine Cores
  作者：Gary T. Wang、Yuanwei Chen、Sheldon Wang、Robert Gentles、Thomas Sowin、Warren Kati、Steve Muchmore、Vincent Giranda、Kent Stewart、Hing Sham、Dale Kempf、W. Graeme Laver

  DOI：10.1021/jm000468c

  日期：2001.4.1

  The discovery of (+/-)-(2S,3R,4R)-2-(trifluoroacetamido)methyl-3-amino-1-(N ' -ethyl-N ' -isopropylcarbamyl)pyrrolidine-4-earboxylic acid (A-192558, 20e) as a potent inhibitor of influenza neuraminidase (NA) is described. Efficient syntheses of two core structures, cis-3-(allyloxy-carbonyl)amino-1-(9 ' -fluorenylmethoxycarbonyl)pyrrolidine-4-carboxylic acid (7) and tert-butyl (+/-)(2S, 3R,4R)-2-aminomethyl-3-bis(tert-butyloxycarbonyl) amino-1-(N ' -ethyl-N ' -isopropylcarbamyl)pyrrolidine-4-carboxylate (18b), were developed. Starting with these core structures and using available structural information of the NA active site as the guide, analogues were synthesized in both the tri- and tetrasubstituted pyrrolidine series by means of high-throughput parallel synthesis in solid or solution phase for expeditious SAR. These studies accelerated the identification of(+/-)-(2S,3R,4R)-2-(trifluoroacetamido)methyl-3-amino-1-(N-ethyl-N-isopropylcarbamyl)pyrrolidine-4-carboxylate (20e, A-192558) as the most potent NA inhibitor in this series (IC50 = 0.2 muM against NA A and 8 muM against NA B). The X-ray crystallographic structure of A-192558 bound to NA revealed the predicted interaction of the carboxylic group with the positively charged pocket (Arg118, Arg292, Arg371) and interaction of the trifluoro-acetamino residue with the hydrophobic pocket (Ile222, Trp178) of the enzyme active site. Surprisingly, the ethyl and isopropyl groups of the urea functionality induced a conformational change of Glu276, turning the Glu276/Glu277 hydrophilic pocket, which normally accommodates the triglycerol side chain of substrate sialic acid, into an induced hydrophobic pocket.