N-((1R,2S,4S)-2-bromomethyl-4-(2,5-difluorophenyl)-4-{[4-(trifluoromethyl)phenyl]sulfonyl}cyclohexyl)methanesulfonamide | 886061-01-4

• 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: N-((1R,2S,4S)-2-bromomethyl-4-(2,5-difluorophenyl)-4-{[4-(trifluoromethyl)phenyl]sulfonyl}cyclohexyl)methanesulfonamide
• 英文别名: N-[(1R,2S,4S)-2-(bromomethyl)-4-(2,5-difluorophenyl)-4-[4-(trifluoromethyl)phenyl]sulfonylcyclohexyl]methanesulfonamide
• CAS: 886061-01-4
• 化学式: C₂₁H₂₁BrF₅NO₄S₂
• 分子量: 590.43
• InChiKey: MFBWWOMOTFSCQV-GBLZOACLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  34
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  97.1
• 氢给体数：
  1
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  N-((1R,2S,4S)-2-bromomethyl-4-(2,5-difluorophenyl)-4-{[4-(trifluoromethyl)phenyl]sulfonyl}cyclohexyl)methanesulfonamide 在 正己基锂 、 二异丙胺 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 正己烷 为溶剂， 反应 4.33h， 生成 (3S,4aS,6S,8aR)-6-(2,5-Difluoro-phenyl)-3-ethyl-1-(4-methoxy-benzyl)-6-(4-trifluoromethyl-benzenesulfonyl)-octahydro-benzo[c][1,2]thiazine 2,2-dioxide
  参考文献：
  名称：

  Practical Asymmetric Synthesis of a γ-Secretase Inhibitor Exploiting Substrate-Controlled Intramolecular Nitrile Oxide−Olefin Cycloaddition

  摘要：

  A practical asymmetric synthesis of the gamma-secretase inhibitor (-)-1 is described. As the key transformation, a highly diastereoselective intramolecular nitrile oxide cycloaddition forms the hexahydrobenzisoxazole core of 3 in four operations. Other aspects of the route include a highly stereoselective reduction of an isoxazole to form a cis-gamma-amino alcohol, an efficient chemical resolution, a dianion cyclization to construct a sultam ring, and the alpha-alkylation of a sultam with excellent diastereoselectivity. In each instance, the relative stereochemistry was evolved by way of substrate-based induction with >= 96% ds. Kilogram quantities of the targeted drug candidate (-)-1 were obtained, without recourse to chromatography, by way of 10 isolated intermediates and in 13% overall yield.

  DOI：

  10.1021/jo060033i
• 作为产物：
  描述：

  Methanesulfonic acid (1S,2R,5S)-5-(2,5-difluoro-phenyl)-2-methanesulfonylamino-5-(4-trifluoromethyl-benzenesulfonyl)-cyclohexylmethyl ester 在 sodium bromide 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 7.0h， 以3.49 kg的产率得到N-((1R,2S,4S)-2-bromomethyl-4-(2,5-difluorophenyl)-4-{[4-(trifluoromethyl)phenyl]sulfonyl}cyclohexyl)methanesulfonamide
  参考文献：
  名称：

  Practical Asymmetric Synthesis of a γ-Secretase Inhibitor Exploiting Substrate-Controlled Intramolecular Nitrile Oxide−Olefin Cycloaddition

  摘要：

  A practical asymmetric synthesis of the gamma-secretase inhibitor (-)-1 is described. As the key transformation, a highly diastereoselective intramolecular nitrile oxide cycloaddition forms the hexahydrobenzisoxazole core of 3 in four operations. Other aspects of the route include a highly stereoselective reduction of an isoxazole to form a cis-gamma-amino alcohol, an efficient chemical resolution, a dianion cyclization to construct a sultam ring, and the alpha-alkylation of a sultam with excellent diastereoselectivity. In each instance, the relative stereochemistry was evolved by way of substrate-based induction with >= 96% ds. Kilogram quantities of the targeted drug candidate (-)-1 were obtained, without recourse to chromatography, by way of 10 isolated intermediates and in 13% overall yield.

  DOI：

  10.1021/jo060033i

文献信息

• Practical Asymmetric Synthesis of a γ-Secretase Inhibitor Exploiting Substrate-Controlled Intramolecular Nitrile Oxide−Olefin Cycloaddition
  作者：Jeremy P. Scott、Steven F. Oliver、Karel M. J. Brands、Sarah E. Brewer、Antony J. Davies、Andrew D. Gibb、David Hands、Stephen P. Keen、Faye J. Sheen、Robert A. Reamer、Robert D. Wilson、Ulf-H. Dolling

  DOI：10.1021/jo060033i

  日期：2006.4.1

  A practical asymmetric synthesis of the gamma-secretase inhibitor (-)-1 is described. As the key transformation, a highly diastereoselective intramolecular nitrile oxide cycloaddition forms the hexahydrobenzisoxazole core of 3 in four operations. Other aspects of the route include a highly stereoselective reduction of an isoxazole to form a cis-gamma-amino alcohol, an efficient chemical resolution, a dianion cyclization to construct a sultam ring, and the alpha-alkylation of a sultam with excellent diastereoselectivity. In each instance, the relative stereochemistry was evolved by way of substrate-based induction with >= 96% ds. Kilogram quantities of the targeted drug candidate (-)-1 were obtained, without recourse to chromatography, by way of 10 isolated intermediates and in 13% overall yield.