methyl 3-cyclohexyl-2-{2-[(2S)-oxiran-2-ylmethoxy]phenyl}-1H-indole-6-carboxylate | 886041-53-8

• 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 3-cyclohexyl-2-{2-[(2S)-oxiran-2-ylmethoxy]phenyl}-1H-indole-6-carboxylate
• 英文别名: 3-cyclohexyl-2-{2-[(2S)-oxiran-2-ylmethoxy]phenyl}-1H-indole-6-carboxylic acid methyl ester；methyl 3-cyclohexyl-2-[2-[[(2S)-oxiran-2-yl]methoxy]phenyl]-1H-indole-6-carboxylate
• CAS: 886041-53-8
• 化学式: C₂₅H₂₇NO₄
• 分子量: 405.494
• InChiKey: JYIGVOHKGIEQPC-SFHVURJKSA-N

物化性质

• 熔点：
  184-186 °C
• 沸点：
  577.2±50.0 °C(Predicted)
• 密度：
  1.226±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.8
• 重原子数：
  30
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  63.8
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  methyl 3-cyclohexyl-2-{2-[(2S)-oxiran-2-ylmethoxy]phenyl}-1H-indole-6-carboxylate 在 吡啶 、 叠氮基三甲基硅烷 、 palladium 10% on activated carbon 、 氢气 、 sodium cyanoborohydride 、 caesium carbonate 、 溶剂黄146 、 四丁基二氟三苯硅酸铵 、 三氟乙酸 、 原甲酸三甲酯 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 二氯甲烷 为溶剂， 20.0~65.0 ℃ 、101.33 kPa 条件下， 反应 109.0h， 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：

  Discovery of (7R)-14-Cyclohexyl-7-{[2-(dimethylamino)ethyl](methyl) amino}-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylic Acid (MK-3281), a Potent and Orally Bioavailable Finger-Loop Inhibitor of the Hepatitis C Virus NS5B Polymerase

  摘要：

  Infections caused by hepatitis C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand. The polymerase of HCV is responsible for the replication of viral genome and has been a prime target for drug discovery efforts. Here, we report on the further development of tetracyclic indole inhibitors, binding to an allosteric site on the thumb domain. Structure-activity relationship (SAR) studies around an indolo-benzoxazocine scaffold led to the identification of compound 33 (MK-3281), an inhibitor with good potency in the HCV subgenomic replication assay and attractive molecular properties suitable for a clinical candidate. The compound caused a consistent decrease in viremia in vivo using the chimeric mouse model of HCV infection.

  DOI：

  10.1021/jm1013105
• 作为产物：
  描述：

  2-溴-3-环己基-1H-吲哚-6-羧酸甲酯 在 bis-triphenylphosphine-palladium(II) chloride 、 sodium carbonate 、 cesium fluoride 作用下， 以 1,4-二氧六环 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 4.0h， 生成 methyl 3-cyclohexyl-2-{2-[(2S)-oxiran-2-ylmethoxy]phenyl}-1H-indole-6-carboxylate
  参考文献：
  名称：

  Discovery of (7R)-14-Cyclohexyl-7-{[2-(dimethylamino)ethyl](methyl) amino}-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylic Acid (MK-3281), a Potent and Orally Bioavailable Finger-Loop Inhibitor of the Hepatitis C Virus NS5B Polymerase

  摘要：

  Infections caused by hepatitis C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand. The polymerase of HCV is responsible for the replication of viral genome and has been a prime target for drug discovery efforts. Here, we report on the further development of tetracyclic indole inhibitors, binding to an allosteric site on the thumb domain. Structure-activity relationship (SAR) studies around an indolo-benzoxazocine scaffold led to the identification of compound 33 (MK-3281), an inhibitor with good potency in the HCV subgenomic replication assay and attractive molecular properties suitable for a clinical candidate. The compound caused a consistent decrease in viremia in vivo using the chimeric mouse model of HCV infection.

  DOI：

  10.1021/jm1013105

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：——