4-Amino-5-benzyloxycarbonylmethyl-2,5-dihydro-pyrrole-1,3-dicarboxylic acid 1-benzyl ester 3-tert-butyl ester | 341969-87-7

• 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: 4-Amino-5-benzyloxycarbonylmethyl-2,5-dihydro-pyrrole-1,3-dicarboxylic acid 1-benzyl ester 3-tert-butyl ester
• 英文别名: 1-O-benzyl 3-O-tert-butyl 4-amino-5-(2-oxo-2-phenylmethoxyethyl)-2,5-dihydropyrrole-1,3-dicarboxylate
• CAS: 341969-87-7
• 化学式: C₂₆H₃₀N₂O₆
• 分子量: 466.534
• InChiKey: KMNWGDFGZZWDEF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  34
• 可旋转键数：
  11
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  108
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  4-Amino-5-benzyloxycarbonylmethyl-2,5-dihydro-pyrrole-1,3-dicarboxylic acid 1-benzyl ester 3-tert-butyl ester 在 10 percent Pd/C 4-二甲氨基吡啶 、 氢气 、 溶剂黄146 作用下， 以 二氯甲烷 为溶剂， 20.0 ℃ 、405.33 kPa 条件下， 生成 C₂₁H₃₆N₂O₈
  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：

  在 ammonium acetate 、 N,N-二异丙基乙胺 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 53.0h， 生成 4-Amino-5-benzyloxycarbonylmethyl-2,5-dihydro-pyrrole-1,3-dicarboxylic acid 1-benzyl ester 3-tert-butyl ester
  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