tert-butyl (5R)-5-[(1S,2S)-1-benzyloxy-3-(3,5-difluorophenyl)-2-methylpropyl]-2-oxomorpholine-4-carboxylate | 883442-71-5

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: tert-butyl (5R)-5-[(1S,2S)-1-benzyloxy-3-(3,5-difluorophenyl)-2-methylpropyl]-2-oxomorpholine-4-carboxylate
• 英文别名: (R)-5-[(1S,2S)-1-benzyloxy-2-dibenzylamino-3-(3,5-difluorophenyl)-propyl]-2-oxomorpholine-4-carboxylic acid tert-butyl ester；tert-butyl (5R)-5-[(1S,2S)-2-(dibenzylamino)-3-(3,5-difluorophenyl)-1-phenylmethoxypropyl]-2-oxomorpholine-4-carboxylate
• CAS: 883442-71-5
• 化学式: C₃₉H₄₂F₂N₂O₅
• 分子量: 656.77
• InChiKey: YMGSGRXIRDTFJZ-NIOPZXMRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.5
• 重原子数：
  48
• 可旋转键数：
  14
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  68.3
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  tert-butyl (5R)-5-[(1S,2S)-1-benzyloxy-3-(3,5-difluorophenyl)-2-methylpropyl]-2-oxomorpholine-4-carboxylate 在 sodium hydride 、 二异丁基氢化铝 作用下， 以 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 1.25h， 生成 tert-butyl (5R)-5-[(1S,2S)-1-benzyloxy-2-(dibenzylamino)-3-(3,5-difluorophenyl)propyl]-2-(cyclohexylmethoxy)morpholine-4-carboxylate
  参考文献：
  名称：

  Optimization of Hydroxyethylamine Transition State Isosteres as Aspartic Protease Inhibitors by Exploiting Conformational Preferences

  摘要：

  NMR conformational analysis of a hydroxyethylamine peptide isostere developed as an aspartic protease inhibitor shows that it is a flexible architecture. Cyclization to form pyrrolidines, piperidines, or morpholines results in a preorganization of the whole system in solution. The resulting conformation is similar to the conformation of the inhibitor in the active site of BACE-1. This entropic gain results in increased affinity for the enzyme when compared with the acyclic system. For morpholines 27 and 29, the combination of steric and electronic factors is exploited to orient substituents toward S1, S1', and S2' pockets both in the solution and in the bound states. These highly preorganized molecules proved to be the most potent compounds of the series. Additionally, the morpholines, unlike the pyrrolidine and piperidine analogues, have been found to be brain penetrant BACE-1 inhibitors.

  DOI：

  10.1021/acs.jmedchem.7b01304
• 作为产物：
  描述：

  在 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 18.0h， 生成 tert-butyl (5R)-5-[(1S,2S)-1-benzyloxy-3-(3,5-difluorophenyl)-2-methylpropyl]-2-oxomorpholine-4-carboxylate
  参考文献：
  名称：

  Optimization of Hydroxyethylamine Transition State Isosteres as Aspartic Protease Inhibitors by Exploiting Conformational Preferences

  摘要：

  NMR conformational analysis of a hydroxyethylamine peptide isostere developed as an aspartic protease inhibitor shows that it is a flexible architecture. Cyclization to form pyrrolidines, piperidines, or morpholines results in a preorganization of the whole system in solution. The resulting conformation is similar to the conformation of the inhibitor in the active site of BACE-1. This entropic gain results in increased affinity for the enzyme when compared with the acyclic system. For morpholines 27 and 29, the combination of steric and electronic factors is exploited to orient substituents toward S1, S1', and S2' pockets both in the solution and in the bound states. These highly preorganized molecules proved to be the most potent compounds of the series. Additionally, the morpholines, unlike the pyrrolidine and piperidine analogues, have been found to be brain penetrant BACE-1 inhibitors.

  DOI：

  10.1021/acs.jmedchem.7b01304

文献信息

• 3-(2-Acylamino-1-Hydroxyethyl)-Morpholine Derivatives and Their Use as Bace Inhibitors
  申请人：Broughton Barff Howard

  公开号：US20070225267A1

  公开（公告）日：2007-09-27

  The present invention provides BACE inhibitors of Formula (I); methods for their use and preparation, and intermediates useful for their preparation.

  本发明提供了化学式（I）的BACE抑制剂；以及它们的使用和制备方法，以及用于它们制备的中间体。
• 3-(2-acylamino-1-hydroxyethyl)-morpholine derivatives and their use as bace inhibitors
  申请人：Eli Lilly and Company

  公开号：US07745438B2

  公开（公告）日：2010-06-29

  The present invention provides BACE inhibitors of Formula (I); methods for their use and preparation, and intermediates useful for their preparation.

  本发明提供了式(I)的BACE抑制剂；其使用和制备方法，以及用于其制备的中间体。
• US7745438B2
  申请人：——

  公开号：US7745438B2

  公开（公告）日：2010-06-29