[(3R,4R,5S)-4-acetamido-5-amino-3-pentan-3-yloxycyclohexen-1-yl]-ethoxyphosphinic acid | 1122748-00-8

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 有机膦酸及其衍生物
• 英文名称: [(3R,4R,5S)-4-acetamido-5-amino-3-pentan-3-yloxycyclohexen-1-yl]-ethoxyphosphinic acid
• CAS: 1122748-00-8
• 化学式: C₁₅H₂₉N₂O₅P
• 分子量: 348.379
• InChiKey: MAKSKQQRSUORDZ-RRFJBIMHSA-N

物化性质

• 密度：
  1.17±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -2.5
• 重原子数：
  23
• 可旋转键数：
  8
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.8
• 拓扑面积：
  111
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  [(3R,4R,5S)-4-acetamido-5-amino-3-pentan-3-yloxycyclohexen-1-yl]-ethoxyphosphinic acid 在 碳酸氢铵 作用下， 以 水 为溶剂， 反应 1.0h， 生成 ethyl (3R,4R,5S)-4-acetamido-5-tert-butoxy-carbonylamino-3-(1-ethylpropoxy)-1-cyclohexene phosphonate ammonium salt
  参考文献：
  名称：

  [EN] SYNTHESIS OF OSELTAMIVIR CONTAINING PHOSPHONATE CONGENERS WITH ANTI-INFLUENZA ACTIVITY
  [FR] SYNTHÈSE D'OSELTAMIVIR CONTENANT DES CONGÉNÈRES DE PHOSPHONATE AYANT UNE ACTIVITÉ ANTI-GRIPPALE

  摘要：

  公开号：

  WO2009029888A3
• 作为产物：
  描述：

  奥司他韦 在 4-二甲氨基吡啶 、 四(三苯基膦)钯 、 trifluoroiodoethane 、 碳酸氢钠 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 三乙胺 、 三氟乙酸 、 potassium hydroxide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 水 、 甲苯 为溶剂， 反应 13.0h， 生成 [(3R,4R,5S)-4-acetamido-5-amino-3-pentan-3-yloxycyclohexen-1-yl]-ethoxyphosphinic acid
  参考文献：
  名称：

  Tamiphosphor monoesters as effective anti-influenza agents

  摘要：

  Oseltamivir is a potent neuraminidase inhibitor for influenza treatment. By replacing the carboxylate group in oseltamivir with phosphonate monoalkyl ester, a series of tamiphosphor derivatives were synthesized and shown to exhibit high inhibitory activities against influenza viruses. Our molecular modeling experiments revealed that influenza virus neuraminidase contains a 371-cavity near the S1-site to accommodate the alkyl substituents of tamiphosphor monoesters to render appreciable hydrophobic interactions for enhanced affinity. Furthermore, guanidino-tamiphosphor (TPG) monoesters are active to the oseltamivir-resistant mutant. TPG monohexyl ester 4e having a more lipophilic alkyl substituent showed better cell permeability and intestinal absorption than the corresponding monoethyl ester 4c, but both compounds showed similar bioavailability. Intranasal administration of TPG monoesters at low dose greatly improved the survival rate of mice infected with lethal dose of H1N1 influenza virus, whereas 4c provided better protection of the infected mice than oseltamivir and other phosphonate congeners by oral administration. (C) 2014 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2014.04.082

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。
• Development of Oseltamivir Phosphonate Congeners as Anti-influenza Agents
  作者：Ting-Jen R. Cheng、Steven Weinheimer、E. Bart Tarbet、Jia-Tsrong Jan、Yih-Shyun E. Cheng、Jiun-Jie Shie、Chun-Lin Chen、Chih-An Chen、Wei-Che Hsieh、Pei-Wei Huang、Wen-Hao Lin、Shi-Yun Wang、Jim-Min Fang、Oliver Yoa-Pu Hu、Chi-Huey Wong

  DOI：10.1021/jm3008486

  日期：2012.10.25

  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.
• 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
• Tamiphosphor monoesters as effective anti-influenza agents
  作者：Chun-Lin Chen、Tzu-Chen Lin、Shi-Yun Wang、Jiun-Jie Shie、Keng-Chang Tsai、Yih-Shyun E. Cheng、Jia-Tsrong Jan、Chun-Jung Lin、Jim-Min Fang、Chi-Huey Wong

  DOI：10.1016/j.ejmech.2014.04.082

  日期：2014.6

  Oseltamivir is a potent neuraminidase inhibitor for influenza treatment. By replacing the carboxylate group in oseltamivir with phosphonate monoalkyl ester, a series of tamiphosphor derivatives were synthesized and shown to exhibit high inhibitory activities against influenza viruses. Our molecular modeling experiments revealed that influenza virus neuraminidase contains a 371-cavity near the S1-site to accommodate the alkyl substituents of tamiphosphor monoesters to render appreciable hydrophobic interactions for enhanced affinity. Furthermore, guanidino-tamiphosphor (TPG) monoesters are active to the oseltamivir-resistant mutant. TPG monohexyl ester 4e having a more lipophilic alkyl substituent showed better cell permeability and intestinal absorption than the corresponding monoethyl ester 4c, but both compounds showed similar bioavailability. Intranasal administration of TPG monoesters at low dose greatly improved the survival rate of mice infected with lethal dose of H1N1 influenza virus, whereas 4c provided better protection of the infected mice than oseltamivir and other phosphonate congeners by oral administration. (C) 2014 Elsevier Masson SAS. All rights reserved.