(1R,5S)-3-methyl-7-(pyridin-3-yl)-3-azabicyclo[3.3.1]non-6-ene | 1403377-14-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: (1R,5S)-3-methyl-7-(pyridin-3-yl)-3-azabicyclo[3.3.1]non-6-ene
• 英文别名: TC-8817；(1R,5S)-3-methyl-7-pyridin-3-yl-3-azabicyclo[3.3.1]non-6-ene
• CAS: 1403377-14-9
• 化学式: C₁₄H₁₈N₂
• 分子量: 214.31
• InChiKey: PWXQAVZNBKKQOF-NWDGAFQWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  16
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  16.1
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  (1R,5S)-3-methyl-7-(pyridin-3-yl)-3-azabicyclo[3.3.1]non-6-ene 、 对羟基苯甲酸 以 醋酸异丙酯 、 异丙醇 为溶剂， 生成 (1R,5S)-3-methyl-7-(pyridin-3-yl)-3-azabicyclo[3.3.1]non-6-ene p-hydroxybenzoate
  参考文献：
  名称：

  Development of a Scalable Synthesis of a Pyridinyl-3-azabicyclononene, a Novel Nicotinic Partial Agonist

  摘要：

  The process research and development of two syntheses of a novel nicotinic partial agonist, TC-8817 ((+)-5), are described. The original Medicinal Chemistry route had multiple flaws, making it unsuitable for further development. A second approach was explored which was more amenable to optimization. The key steps were an intramolecular Lewis acid-promoted cyclization, a dibromination/elimination sequence to provide a vinyl bromide, and subsequent Suzuki coupling with 3-pyridineboronic acid. The overall yield of similar to 3-16% over nine steps was offset by the low cost of goods and ease of synthesis. A major drawback was the need for simulated moving bed chiral separation on the penultimate intermediate to afford the subsequently desired single enantiomer version. A third-generation, asymmetric variation afforded a key intermediate in good yield and enantiomeric purity, providing proof of concept for a more efficient production of the desired (+)-enantiomer.

  DOI：

  10.1021/op400002r
• 作为产物：
  描述：

  3-环己烯甲醛 在 盐酸 、 1,1'-双(二苯基膦)二茂铁 、 lithium aluminium tetrahydride 、 甲酸 、 三氟化硼乙醚 、 盐酸羟胺 、 potassium tert-butylate 、 溴 、 palladium diacetate 、 sodium carbonate 、 sodium hydroxide 作用下， 以 四氢呋喃 、 2-甲基四氢呋喃 、 1,4-二氧六环 、 二氯甲烷 、 水 、 二乙胺 、 异丙醇 为溶剂， 反应 78.0h， 生成 (1R,5S)-3-methyl-7-(pyridin-3-yl)-3-azabicyclo[3.3.1]non-6-ene
  参考文献：
  名称：

  Development of a Scalable Synthesis of a Pyridinyl-3-azabicyclononene, a Novel Nicotinic Partial Agonist

  摘要：

  The process research and development of two syntheses of a novel nicotinic partial agonist, TC-8817 ((+)-5), are described. The original Medicinal Chemistry route had multiple flaws, making it unsuitable for further development. A second approach was explored which was more amenable to optimization. The key steps were an intramolecular Lewis acid-promoted cyclization, a dibromination/elimination sequence to provide a vinyl bromide, and subsequent Suzuki coupling with 3-pyridineboronic acid. The overall yield of similar to 3-16% over nine steps was offset by the low cost of goods and ease of synthesis. A major drawback was the need for simulated moving bed chiral separation on the penultimate intermediate to afford the subsequently desired single enantiomer version. A third-generation, asymmetric variation afforded a key intermediate in good yield and enantiomeric purity, providing proof of concept for a more efficient production of the desired (+)-enantiomer.

  DOI：

  10.1021/op400002r

文献信息

• Development of a Scalable Synthesis of a Pyridinyl-3-azabicyclononene, a Novel Nicotinic Partial Agonist
  作者：Scott R. Breining、John F. Genus、J. Pike Mitchener、Timothy J. Cuthbertson、Ronald Heemstra、Matt S. Melvin、Gary M. Dull、Daniel Yohannes

  DOI：10.1021/op400002r

  日期：2013.3.15

  The process research and development of two syntheses of a novel nicotinic partial agonist, TC-8817 ((+)-5), are described. The original Medicinal Chemistry route had multiple flaws, making it unsuitable for further development. A second approach was explored which was more amenable to optimization. The key steps were an intramolecular Lewis acid-promoted cyclization, a dibromination/elimination sequence to provide a vinyl bromide, and subsequent Suzuki coupling with 3-pyridineboronic acid. The overall yield of similar to 3-16% over nine steps was offset by the low cost of goods and ease of synthesis. A major drawback was the need for simulated moving bed chiral separation on the penultimate intermediate to afford the subsequently desired single enantiomer version. A third-generation, asymmetric variation afforded a key intermediate in good yield and enantiomeric purity, providing proof of concept for a more efficient production of the desired (+)-enantiomer.