N-[(1R,2R,6R)-4-bromo-2-(1-ethylpropoxy)-6-hydroxycyclohex-3-en-1-yl]acetamide | 1122581-40-1

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: N-[(1R,2R,6R)-4-bromo-2-(1-ethylpropoxy)-6-hydroxycyclohex-3-en-1-yl]acetamide
• 英文别名: N-[(1R,2R,6R)-4-bromo-6-hydroxy-2-pentan-3-yloxycyclohex-3-en-1-yl]acetamide
• CAS: 1122581-40-1
• 化学式: C₁₃H₂₂BrNO₃
• 分子量: 320.227
• InChiKey: HHSFFVVWQODKOC-JHJVBQTASA-N

物化性质

• 熔点：
  102-104 °C(Solv: ethyl ether (60-29-7))
• 沸点：
  473.0±45.0 °C(Predicted)
• 密度：
  1.32±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  18
• 可旋转键数：
  5
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.77
• 拓扑面积：
  58.6
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  N-[(1R,2R,6R)-4-bromo-2-(1-ethylpropoxy)-6-hydroxycyclohex-3-en-1-yl]acetamide 在 三乙烯二胺 、 四(三苯基膦)钯 、 三甲基溴硅烷 、 叠氮磷酸二苯酯 、 氢气 、 三乙胺 、 三苯基膦 、 三氟乙酸 、 mercury dichloride 、 N,N'-二异丙基碳二亚胺 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 氯仿 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 77.0h， 生成 (3R,4R,5S)-4-acetamido-5-guanidino-3-(1-ethylpropoxy)-1-cyclohexene-1-phosphonic acid
  参考文献：
  名称：

  Development of Oseltamivir Phosphonate Congeners as Anti-influenza Agents

  摘要：

  Oseltamivir phosphonic acid (tamiphosphor, 3a), its monoethyl ester (3c), guanidino-tamiphosphor (4a), and its monoethyl ester (4c) are potent inhibitors of influenza neuraminidases. They inhibit the replication of influenza viruses, including the oseltamivir-resistant H275Y strain, at low nanomolar to picomolar levels, and significantly protect mice from infection with lethal doses of influenza viruses when orally administered with 1 mg/kg or higher doses. These compounds are stable in simulated gastric fluid, liver microsomes, and human blood and are largely free from binding to plasma proteins. Pharmacokinetic properties of these inhibitors are thoroughly studied in dogs, rats, and mice. The absolute oral bioavailability of these compounds was lower than 12%. No conversion of monoester 4c to phosphonic acid 4a was observed in rats after intravenous administration, but partial conversion of 4c was observed with oral administration. Advanced formulation may be investigated to develop these new anti-influenza agents for better therapeutic use.

  DOI：

  10.1021/jm3008486
• 作为产物：
  描述：

  (3aS,7aS)-4-bromo-2,2-dimethyl-3a,7a-dihydro-1,3-benzodioxole 在 盐酸 、 C₆H₁₆B*HLi 、 三氟化硼乙醚 、 溴化锡 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 甲醇 、 水 、 乙腈 为溶剂， 反应 26.0h， 生成 N-[(1R,2R,6R)-4-bromo-2-(1-ethylpropoxy)-6-hydroxycyclohex-3-en-1-yl]acetamide
  参考文献：
  名称：

  Development of Oseltamivir Phosphonate Congeners as Anti-influenza Agents

  摘要：

  Oseltamivir phosphonic acid (tamiphosphor, 3a), its monoethyl ester (3c), guanidino-tamiphosphor (4a), and its monoethyl ester (4c) are potent inhibitors of influenza neuraminidases. They inhibit the replication of influenza viruses, including the oseltamivir-resistant H275Y strain, at low nanomolar to picomolar levels, and significantly protect mice from infection with lethal doses of influenza viruses when orally administered with 1 mg/kg or higher doses. These compounds are stable in simulated gastric fluid, liver microsomes, and human blood and are largely free from binding to plasma proteins. Pharmacokinetic properties of these inhibitors are thoroughly studied in dogs, rats, and mice. The absolute oral bioavailability of these compounds was lower than 12%. No conversion of monoester 4c to phosphonic acid 4a was observed in rats after intravenous administration, but partial conversion of 4c was observed with oral administration. Advanced formulation may be investigated to develop these new anti-influenza agents for better therapeutic use.

  DOI：

  10.1021/jm3008486

文献信息

• SYNTHESIS OF OSELTAMIVIR CONTAINING PHOSPHONATE CONGENERS WITH ANTI-INFLUENZA ACTIVITY
  申请人：Wong Chi-Huey

  公开号：US20100113397A1

  公开（公告）日：2010-05-06

  Novel phosphonate compounds are described. The compounds have activity as neuraminidase inhibitors against wild-type and H274Y mutant of H1N1 and H5N1 viruses. The present disclosure also provides an enantioselective synthetic route to known neuraminidase inhibitors oseltamivir and the anti-flu drug Tamiflu®, as well as novel phosphonate compounds, via D-xylose. Another efficient and flexible synthesis of Tamiflu and the highly potent neuraminidase inhibitor Tamiphosphor was also achieved in 11 steps and >20% overall yields from the readily available fermentation product (1S-cis)-3-bromo-3,5-cyclohexadiene-1,2-diol. Most of the reaction intermediates were obtained as crystals without tedious purification procedures. The key transformations include an initial regio- and stereoselective bromoamidation of a bromoarene cis-dihydrodiol, as well as the final palladium-catalyzed carbonylation and phosphonylation.

  本文描述了新型膦酸盐化合物。这些化合物对H1N1和H5N1病毒的野生型和H274Y突变体具有神经氨酸酶抑制剂活性。本公开还提供了一种手性选择性的合成路线，可通过D-木糖合成已知的神经氨酸酶抑制剂奥司他韦和抗流感药物达菲®，以及新型膦酸盐化合物。另外，还通过11个步骤和>20％的总收率，从易得到的发酵产物（1S-cis）-3-溴-3,5-环己二烯-1,2-二醇中实现了达菲和高效神经氨酸酶抑制剂Tamiphosphor的有效灵活合成。大多数反应中间体都以晶体形式获得，无需繁琐的纯化程序。关键的转化包括最初的区域和立体选择性的溴胺化反应，以及最后的钯催化的羰基化和膦酸盐化反应。
• [EN] SYNTHESIS OF OSELTAMIVIR CONTAINING PHOSPHONATE CONGENERS WITH ANTI-INFLUENZA ACTIVITY<br/>[FR] SYNTHÈSE D'OSELTAMIVIR CONTENANT DES CONGÉNÈRES DE PHOSPHONATE AYANT UNE ACTIVITÉ ANTI-GRIPPALE
  申请人：WONG CHI-HUEY

  公开号：WO2009029888A3

  公开（公告）日：2009-05-07
• A Concise and Flexible Synthesis of the Potent Anti‐Influenza Agents Tamiflu and Tamiphosphor
  作者：Jiun‐Jie Shie、Jim‐Min Fang、Chi‐Huey Wong

  DOI：10.1002/anie.200801959

  日期：2008.7.21
• OSELTAMIVIR PHOSPHONATE DERIVATIVES WITH ANTI-INFLUENZA ACTIVITY AND SYNTHESIS THEREOF
  申请人：Academia Sinica

  公开号：EP2190439B1

  公开（公告）日：2016-03-09
• US7888337B2
  申请人：——

  公开号：US7888337B2

  公开（公告）日：2011-02-15