N_im-trityl-L-histidine N'-methylamide | 145695-69-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 三苯基化合物
• 英文名称: N_im-trityl-L-histidine N'-methylamide
• 英文别名: (S)-2-Amino-N-methyl-3-(1-trityl-1H-imidazol-4-yl)propanamide；(2S)-2-amino-N-methyl-3-(1-tritylimidazol-4-yl)propanamide
• CAS: 145695-69-8
• 化学式: C₂₆H₂₆N₄O
• 分子量: 410.519
• InChiKey: SURIMOCYPMTPNV-DEOSSOPVSA-N

物化性质

• 沸点：
  631.5±55.0 °C(Predicted)
• 密度：
  1.15±0.1 g/cm3(Predicted)
• 溶解度：
  可溶于氯仿、可溶于二氯甲烷、甲醇

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  31
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.15
• 拓扑面积：
  72.9
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  N_im-trityl-L-histidine N'-methylamide 在 盐酸 、 六甲基磷酰三胺 、 四甲基乙二胺 、 4 A molecular sieve 、 碳酸氢钠 、 sodium carbonate 、 potassium carbonate 、 lithium diisopropyl amide 作用下， 以 二氯甲烷 、 甲苯 为溶剂， 反应 114.5h， 生成 (2R,4S)-3-benzoyl-2-(1,1-dimethylethyl)-4-(fluoromethyl)-4-(4'-imidazolylmethyl)-1-methyl-1,3-imidazolidin-5-one
  参考文献：
  名称：

  A novel stereoselective route to (S)-(+)-.alpha.-(fluoromethyl)histidine: .alpha.-halomethylation of (2R,4S)-3-benzoyl-2-(1,1-dimethylethyl)-1-methyl-4-[(N-tritylimidazol-4-yl)methyl]-1,3-imidazolidin-5-one. Synthesis and proton NMR spectroscopy

  摘要：

  A method is described for the alpha-enantioretentive methylation of L-histidine (S) to give (S)-(+)-alpha-(fluoromethyl)histidine (8). The synthesis involves the conversion of N(im)-trityl-L-histidine methyl ester (1) to both the ''trans''-(2S,4S)- and ''cis''-(2R,4S)-2-(1,1-dimethylethyl)-l-methyl-1,3-imidazolidin-5-one analogs 4 and 5. The cis isomer was regioselectively alkylated with chlorofluoromethane to give a single diastereomer 6 with retention of the original absolute configuration of the histidine alpha-position (S). .Deprotection and hydrolysis of the 1,3-imidazolidin-5-one intermediate 6 yielded the desired (S)-(+)-alpha-(fluoromethyl)histidine (8). Additionally, this reaction sequence was repeated using bromochloromethane as the alkylating agent to yield (S)-(+)-alpha-(chloromethyl)histidine (8a). Yields of this product, however, were very low due to an intramolecular alkylation reaction to give 3-benzoyl-2-(1,1-dimethylethyl)-l-methylspiro[imidazolidine-4,6'(7'H)-[5H]pyrrolo[1,2-c]imidazol]5-one (9). The structure and stereochemistry of the trans and cis 1,3-imidazolidin-5-one intermediates, as well as other members of the series, were confirmed using H-1 NMR spectroscopy, including two-dimensional NOE correlation spectroscopy (2D NOESY). The existence of slow chemical exchange in solution was detected for several members of the series based on the appearance of both positive and negative cross-peaks in the 2D NOESY spectra.

  DOI：

  10.1021/jo00055a027
• 作为产物：
  描述：

  N-Fmoc-N'-三苯甲基-L-组氨酸 在 哌啶 、 1-羟基苯并三唑 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 1.17h， 生成 N_im-trityl-L-histidine N'-methylamide
  参考文献：
  名称：

  在人血清中稳定的新型肌肽衍生物作为潜在的神经保护剂的合成，理化特性和生物活性

  摘要：

  描述了一系列具有不同亲脂性的酰胺基烷基取代基上的肌肽酰胺的合成及其理化和生物学特性。所有合成的产品均具有类似肌肽的特性，因其较高的血清稳定性而不同于铅。它们能够以与肌肽相同的化学计量比在生理pH下络合Cu 2+离子。新合成的化合物显示出高度显着的铜离子螯合能力，并且能够保护LDL免受Cu 2+离子催化的氧化，其中活性最高的化合物是亲水性最高的化合物。所有合成的酰胺都显示出很强的肌肽样HNE猝灭活性；特别是7d，该研究的系列成员之一，能够穿越血脑屏障（BBB）并保护原代小鼠海马神经元免受HNE诱导的死亡。这些产物可被认为是肌肽的代谢稳定的类似物，作为潜在的神经保护剂值得进一步研究。

  DOI：

  10.1021/jm101394n

文献信息

• Structure–activity relationships of imidazole-derived 2-[N-carbamoylmethyl-alkylamino]acetic acids, dual binders of human insulin-degrading enzyme
  作者：Julie Charton、Marion Gauriot、Jane Totobenazara、Nathalie Hennuyer、Julie Dumont、Damien Bosc、Xavier Marechal、Jamal Elbakali、Adrien Herledan、Xiaoan Wen、Cyril Ronco、Helene Gras-Masse、Antoine Heninot、Virginie Pottiez、Valerie Landry、Bart Staels、Wenguang G. Liang、Florence Leroux、Wei-Jen Tang、Benoit Deprez、Rebecca Deprez-Poulain

  DOI：10.1016/j.ejmech.2014.12.005

  日期：2015.1

  the structure-activity study, that required the synthesis of 48 analogues. We found that while the carboxylic acid, the imidazole and the tertiary amine were critical for activity, the methyl ester was successfully optimized to an amide or a 1,2,4-oxadiazole. Along with improving their activity, compounds were optimized for solubility, lipophilicity and stability in plasma and microsomes. The docking

  胰岛素降解酶（IDE）是一种锌金属蛋白酶，可降解小的淀粉样肽，例如β-淀粉样蛋白和胰岛素。到目前为止，IDE特异性药理抑制剂的缺乏影响了对其在阿尔茨海默氏病生理病理学中的作用，淀粉样蛋白-α清除及其作为潜在治疗靶点的验证的了解。击中1以前是通过高通量筛选发现的。在这里，我们描述了结构活性研究，该研究需要合成48个类似物。我们发现，尽管羧酸，咪唑和叔胺对于活性至关重要，但甲酯已成功优化为酰胺或1,2,4-恶二唑。除了提高活性外，还优化了化合物在血浆和微粒体中的溶解度，亲脂性和稳定性。一些化合物在IDE的外位或催化位点上的对接或共结晶为IDE抑制提供了结构基础。在体内测定了最佳化合物44和46的药代动力学特性。结果是44（BDM43079）其甲酯前体48（BDM43124）是探索IDE作用的有用化学探针。
• Synthesis, Physicochemical Characterization, and Biological Activities of New Carnosine Derivatives Stable in Human Serum As Potential Neuroprotective Agents
  作者：Massimo Bertinaria、Barbara Rolando、Marta Giorgis、Gabriele Montanaro、Stefano Guglielmo、M. Federica Buonsanti、Valentina Carabelli、Daniela Gavello、Pier Giuseppe Daniele、Roberta Fruttero、Alberto Gasco

  DOI：10.1021/jm101394n

  日期：2011.1.27

  The synthesis and the physicochemical and biological characterization of a series of carnosine amides bearing on the amido group alkyl substituents endowed with different lipophilicity are described. All synthesized products display carnosine-like properties differentiating from the lead for their high serum stability. They are able to complex Cu2+ ions at physiological pH with the same stoichiometry

  描述了一系列具有不同亲脂性的酰胺基烷基取代基上的肌肽酰胺的合成及其理化和生物学特性。所有合成的产品均具有类似肌肽的特性，因其较高的血清稳定性而不同于铅。它们能够以与肌肽相同的化学计量比在生理pH下络合Cu 2+离子。新合成的化合物显示出高度显着的铜离子螯合能力，并且能够保护LDL免受Cu 2+离子催化的氧化，其中活性最高的化合物是亲水性最高的化合物。所有合成的酰胺都显示出很强的肌肽样HNE猝灭活性；特别是7d，该研究的系列成员之一，能够穿越血脑屏障（BBB）并保护原代小鼠海马神经元免受HNE诱导的死亡。这些产物可被认为是肌肽的代谢稳定的类似物，作为潜在的神经保护剂值得进一步研究。
• A novel stereoselective route to (S)-(+)-.alpha.-(fluoromethyl)histidine: .alpha.-halomethylation of (2R,4S)-3-benzoyl-2-(1,1-dimethylethyl)-1-methyl-4-[(N-tritylimidazol-4-yl)methyl]-1,3-imidazolidin-5-one. Synthesis and proton NMR spectroscopy
  作者：Karl G. Grozinger、Richard W. Kriwacki、Scott F. Leonard、T. Phil Pitner

  DOI：10.1021/jo00055a027

  日期：1993.1

  A method is described for the alpha-enantioretentive methylation of L-histidine (S) to give (S)-(+)-alpha-(fluoromethyl)histidine (8). The synthesis involves the conversion of N(im)-trityl-L-histidine methyl ester (1) to both the ''trans''-(2S,4S)- and ''cis''-(2R,4S)-2-(1,1-dimethylethyl)-l-methyl-1,3-imidazolidin-5-one analogs 4 and 5. The cis isomer was regioselectively alkylated with chlorofluoromethane to give a single diastereomer 6 with retention of the original absolute configuration of the histidine alpha-position (S). .Deprotection and hydrolysis of the 1,3-imidazolidin-5-one intermediate 6 yielded the desired (S)-(+)-alpha-(fluoromethyl)histidine (8). Additionally, this reaction sequence was repeated using bromochloromethane as the alkylating agent to yield (S)-(+)-alpha-(chloromethyl)histidine (8a). Yields of this product, however, were very low due to an intramolecular alkylation reaction to give 3-benzoyl-2-(1,1-dimethylethyl)-l-methylspiro[imidazolidine-4,6'(7'H)-[5H]pyrrolo[1,2-c]imidazol]5-one (9). The structure and stereochemistry of the trans and cis 1,3-imidazolidin-5-one intermediates, as well as other members of the series, were confirmed using H-1 NMR spectroscopy, including two-dimensional NOE correlation spectroscopy (2D NOESY). The existence of slow chemical exchange in solution was detected for several members of the series based on the appearance of both positive and negative cross-peaks in the 2D NOESY spectra.