methyl (7R)-14-cyclohexyl-7-{[2-(1,3-dioxo-1,3dihydro-2H-isoindol-2-yl)ethyl]amino}-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate | 1267498-45-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: methyl (7R)-14-cyclohexyl-7-{[2-(1,3-dioxo-1,3dihydro-2H-isoindol-2-yl)ethyl]amino}-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate
• CAS: 1267498-45-2
• 化学式: C₃₅H₃₅N₃O₅
• 分子量: 577.68
• InChiKey: VVJNAFUTZZJEFY-XMMPIXPASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.79
• 重原子数：
  43.0
• 可旋转键数：
  6.0
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.34
• 拓扑面积：
  89.87
• 氢给体数：
  1.0
• 氢受体数：
  7.0

反应信息

• 作为反应物：
  描述：

  methyl (7R)-14-cyclohexyl-7-{[2-(1,3-dioxo-1,3dihydro-2H-isoindol-2-yl)ethyl]amino}-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate 在 一水合肼 作用下， 以 四氢呋喃 为溶剂， 以92%的产率得到methyl (7R)-7-[(2-aminoethyl)amino]-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate
  参考文献：
  名称：

  Mitsunobu Inversion of a Secondary Alcohol with Diphenylphosphoryl azide. Application to the Enantioselective Multikilogram Synthesis of a HCV Polymerase Inhibitor

  摘要：

  The development of a practical synthesis of the hepatitis C virus polymerase inhibitor 1 was necessary to support preclinical safety and human clinical studies. Significant challenges face the process chemist in developing a route to 1 that is amenable to multikilogram operation. In particular, an efficient construction of the eight-membered dihydroindolobenzoxazocine ring and enantioselective synthesis of the secondary amine stereocenter are required. This article describes our process development of a Mitsunobu protocol to achieve the latter goal which uses diphenylphosphoryl azide at ambient temperature to invert a scalemic secondary alcohol, The hazard evaluation performed to establish the safety of this protocol and allow pilot-plant introduction at > 8.0 kg scale is discussed. Overall, an enantioselective synthesis of 1 by way of seven isolated intermediates in 32% overall yield was developed from commercially available materials. This allowed us to prepare over 3 kg of the targeted drug candidate.

  DOI：

  10.1021/op200002u
• 作为产物：
  描述：

  苯二酰亚氨乙醛二乙基乙缩醛 在 盐酸 、 水 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 4.08h， 生成 methyl (7R)-14-cyclohexyl-7-{[2-(1,3-dioxo-1,3dihydro-2H-isoindol-2-yl)ethyl]amino}-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate
  参考文献：
  名称：

  Mitsunobu Inversion of a Secondary Alcohol with Diphenylphosphoryl azide. Application to the Enantioselective Multikilogram Synthesis of a HCV Polymerase Inhibitor

  摘要：

  The development of a practical synthesis of the hepatitis C virus polymerase inhibitor 1 was necessary to support preclinical safety and human clinical studies. Significant challenges face the process chemist in developing a route to 1 that is amenable to multikilogram operation. In particular, an efficient construction of the eight-membered dihydroindolobenzoxazocine ring and enantioselective synthesis of the secondary amine stereocenter are required. This article describes our process development of a Mitsunobu protocol to achieve the latter goal which uses diphenylphosphoryl azide at ambient temperature to invert a scalemic secondary alcohol, The hazard evaluation performed to establish the safety of this protocol and allow pilot-plant introduction at > 8.0 kg scale is discussed. Overall, an enantioselective synthesis of 1 by way of seven isolated intermediates in 32% overall yield was developed from commercially available materials. This allowed us to prepare over 3 kg of the targeted drug candidate.

  DOI：

  10.1021/op200002u

文献信息

• Org. Process Res. Dev. 2011, 15, 1116-1123
  作者：

  DOI：——

  日期：——