(+)-2-(7-chloro-1,8-naphthyridin-2-yl)-3S-(5-methyl-2-oxohexyl)-1-isoindolinone

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: (+)-2-(7-chloro-1,8-naphthyridin-2-yl)-3S-(5-methyl-2-oxohexyl)-1-isoindolinone
• 英文别名: pagoclone；CI-1043；(3R)-2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-3H-isoindol-1-one
• 化学式: C₂₃H₂₂ClN₃O₂
• 分子量: 407.9
• InChiKey: HIUPRQPBWVEQJJ-LJQANCHMSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  29
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  63.2
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-3H-isoindol-1-one 在 麻黄素 、 水 、 N,N'-羰基二咪唑 、 potassium hydroxide 作用下， 以 四氢呋喃 、 乙二醇二甲醚 、 乙醇 、 二氯甲烷 、 水 为溶剂， 反应 30.5h， 生成 (+)-2-(7-chloro-1,8-naphthyridin-2-yl)-3S-(5-methyl-2-oxohexyl)-1-isoindolinone
  参考文献：
  名称：

  An Efficient and Cost-Effective Synthesis of Pagoclone

  摘要：

  The compound (+)-2-(7-chloro-1,8-naphthyridin-2-yl)-3S-(5-methyl-2-oxohexyl)-1-isoindolinone (pagoclone) shows anxiolytic activity due to partial agonism of the benzodiazepine site of the GABA(A) receptor. We describe the development of an economical and practical process for a 100+ kg pilot plant production used to supply development needs. For the key reaction, a beta-keto phosphonium salt was prepared by selectively reacting a primary alpha-bromo ketone with triphenylphosphine in the presence of a secondary alpha-bromo ketone. A novel Wittig reaction with a 1-isoindolinone was used to produce racemic pagoclone. The enantiomerically pure drug substance was prepared by hydrolyzing a gamma-lactam and resolving the resulting enantiomeric carboxylic acids with (+)-ephedrine hemihydrate. An alternate resolution, involving chiral multicolumn chromatography (MCC) was also developed. The synthesis was completed by a racemization-free lactam formation to afford pagoclone.

  DOI：

  10.1021/op034060b

文献信息

• An Efficient and Cost-Effective Synthesis of Pagoclone
  作者：Timothy L. Stuk、Bryce K. Assink、Ronald C. Bates,、David T. Erdman、Victor Fedij、Sandra M. Jennings、Jennifer A. Lassig、Randy J. Smith、Traci L. Smith

  DOI：10.1021/op034060b

  日期：2003.11.1

  The compound (+)-2-(7-chloro-1,8-naphthyridin-2-yl)-3S-(5-methyl-2-oxohexyl)-1-isoindolinone (pagoclone) shows anxiolytic activity due to partial agonism of the benzodiazepine site of the GABA(A) receptor. We describe the development of an economical and practical process for a 100+ kg pilot plant production used to supply development needs. For the key reaction, a beta-keto phosphonium salt was prepared by selectively reacting a primary alpha-bromo ketone with triphenylphosphine in the presence of a secondary alpha-bromo ketone. A novel Wittig reaction with a 1-isoindolinone was used to produce racemic pagoclone. The enantiomerically pure drug substance was prepared by hydrolyzing a gamma-lactam and resolving the resulting enantiomeric carboxylic acids with (+)-ephedrine hemihydrate. An alternate resolution, involving chiral multicolumn chromatography (MCC) was also developed. The synthesis was completed by a racemization-free lactam formation to afford pagoclone.