methyl (7R)-7-azido-14-cyclohexyl-7,8-dihydro-6H-indolo-[1,2-e][1,5]benzoxazocine-11-carboxylate | 886041-63-0

• 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)-7-azido-14-cyclohexyl-7,8-dihydro-6H-indolo-[1,2-e][1,5]benzoxazocine-11-carboxylate
• 英文别名: methyl (7R)-7-azido-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate；methyl (10R)-10-azido-19-cyclohexyl-8-oxa-12-azatetracyclo[10.7.0.02,7.013,18]nonadeca-1(19),2,4,6,13(18),14,16-heptaene-15-carboxylate
• CAS: 886041-63-0
• 化学式: C₂₅H₂₆N₄O₃
• 分子量: 430.506
• InChiKey: HCWYTOZKVLDULI-GOSISDBHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.7
• 重原子数：
  32
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  54.8
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  methyl (7R)-7-azido-14-cyclohexyl-7,8-dihydro-6H-indolo-[1,2-e][1,5]benzoxazocine-11-carboxylate 在 一水合肼 、 N,N-二异丙基乙胺 、 三苯基膦 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 29.08h， 生成 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：

  3-环己基-2-(2-羟苯基)-1H-吲哚-6-羧酸甲酯 在 吡啶 、 叠氮基三甲基硅烷 、 caesium carbonate 、 cesium fluoride 、 四丁基二氟三苯硅酸铵 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 N,N-二甲基甲酰胺 为溶剂， 生成 methyl (7R)-7-azido-14-cyclohexyl-7,8-dihydro-6H-indolo-[1,2-e][1,5]benzoxazocine-11-carboxylate
  参考文献：
  名称：

  Development of a Scalable Chiral Synthesis of MK-3281, an Inhibitor of the Hepatitis C Virus NS5B Polymerase

  摘要：

  本报告介绍了 HCV NS5B 抑制剂 MK-3281 的可扩展手性合成方法。对几种替代路线进行了探索，现予以介绍。

  DOI：

  10.1055/s-0030-1260790

文献信息

• Development of a Scalable Chiral Synthesis of MK-3281, an Inhibitor of the Hepatitis C Virus NS5B Polymerase
  作者：Stefania Colarusso、Jörg Habermann、Immacolata Conte、Marcello Di Filippo、Caterina Ercolani、Angela Mackay、Maria Palumbi、Maria del Rosario Rico Ferreira、Ian Stansfield、Simone Zaramella、Frank Narjes

  DOI：10.1055/s-0030-1260790

  日期：2011.7

  The development of a scalable chiral synthesis for the HCV NS5B inhibitor MK-3281 is being reported. Several alternative routes were explored and are being described.

  本报告介绍了 HCV NS5B 抑制剂 MK-3281 的可扩展手性合成方法。对几种替代路线进行了探索，现予以介绍。
• Tetracyclic indole derivatives as antiviral agents
  申请人：Conte Immacolata

  公开号：US20060100262A1

  公开（公告）日：2006-05-11

  The present invention relates to tetracyclic indole compounds of formula (I): wherein R 1 , R 2 , A, Ar, W, X, Y and Z are defined herein, and pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising them, and their use for the treatment or prevention of infection by hepatitis C virus.

  本发明涉及公式（I）的四环吲哚化合物，其中R1、R2、A、Ar、W、X、Y和Z的定义如下，以及其药学上可接受的盐，包括它们的药物组成物，并用于治疗或预防丙型肝炎病毒感染的用途。
• WO2006/46030
  申请人：——

  公开号：——

  公开（公告）日：——
• Mitsunobu Inversion of a Secondary Alcohol with Diphenylphosphoryl azide. Application to the Enantioselective Multikilogram Synthesis of a HCV Polymerase Inhibitor
  作者：Jeremy P. Scott、Mahbub Alam、Nadine Bremeyer、Adrian Goodyear、Thientu Lam、Robert D. Wilson、George Zhou

  DOI：10.1021/op200002u

  日期：2011.9.16

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

  DOI：——

  日期：——