diethyl (3R,4R,5S)-4-acetamido-5-azido-3-(1-ethylpropoxy)-1-cyclohexene-1-phosphonate

• 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: diethyl (3R,4R,5S)-4-acetamido-5-azido-3-(1-ethylpropoxy)-1-cyclohexene-1-phosphonate
• 英文别名: diethyl (3R,4R,5S)-5-azido-4-acetamido-3-(1-ethylpropoxy)cyclohexene-1-phosphonate；diethyl (3R,4R,5S)-4-acetamido-5-azido-3-(1-ethylpropoxy)-1-cyclohexene phosphonate；Diethyl (3R,4R,5S)-4-acetamido-5-azido-3-(1-ethylpropoxy)-1-cyclohexene-1-phosphonate；N-[(1R,2R,6S)-6-azido-4-diethoxyphosphoryl-2-pentan-3-yloxycyclohex-3-en-1-yl]acetamide
• 化学式: C₁₇H₃₁N₄O₅P
• 分子量: 402.431
• InChiKey: VOTUJRYIRDXPLW-GVDBMIGSSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  27
• 可旋转键数：
  11
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.82
• 拓扑面积：
  88.2
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  diethyl (3R,4R,5S)-4-acetamido-5-azido-3-(1-ethylpropoxy)-1-cyclohexene-1-phosphonate 在 三甲基溴硅烷 、 氢气 、 三乙胺 、 三氟乙酸 、 mercury dichloride 作用下， 以 乙醇 、 二氯甲烷 、 氯仿 、 N,N-二甲基甲酰胺 为溶剂， 反应 41.0h， 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：

  D-GlcNAc 在 吡啶 、 4-二甲氨基吡啶 、 1H-咪唑-1-磺酰叠氮 、 sodium tetrahydroborate 、 sodium periodate 、 sodium azide 、 copper(ll) sulfate pentahydrate 、 硫酸 、 palladium on activated charcoal 、 三氟化硼乙醚 、 氢气 、 四氯化钛 、 sodium hydride 、 potassium carbonate 、 溶剂黄146 、 三乙胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 乙醚 、 乙醇 、 正己烷 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 丙酮 、 甲苯 、 mineral oil 为溶剂， 反应 121.33h， 生成 diethyl (3R,4R,5S)-4-acetamido-5-azido-3-(1-ethylpropoxy)-1-cyclohexene-1-phosphonate
  参考文献：
  名称：

  Synthesis of oseltamivir and tamiphosphor from N-acetyl-d-glucosamine

  摘要：

  以N-乙酰-D-葡萄糖胺为起始材料，通过醛中间体8合成抗流感药物奥司他韦和塔米福韦。使用了一个分子内Horner-Wadsworth-Emmons反应来构建高度官能化的环己烯环。现有的N-乙酰基被转化为叠氮基，以进行后续的氮杂环化反应，随后植入所需立体化学的3-戊氧基团。

  DOI：

  10.1039/c3ob41622d

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。
• Synthesis of oseltamivir containing phosphonate congeners with anti-influenza activity
  申请人：Academia Sinica

  公开号：US07888337B2

  公开（公告）日：2011-02-15

  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.

  本文介绍了一种新型膦酸盐化合物。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合成途径，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，还通过简单的11步反应和>20%的总收率，从易得的发酵产物（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。大部分反应中间体均为晶体，无需繁琐的纯化步骤。关键转化包括最初的区域和立体选择性的溴化酰胺化反应，以及最终的钯催化的羰基化和膦化反应。
• [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
• Synthesis of Tamiflu and its Phosphonate Congeners Possessing Potent Anti-Influenza Activity
  作者：Jiun-Jie Shie、Jim-Min Fang、Shi-Yun Wang、Keng-Chang Tsai、Yih-Shyun E. Cheng、An-Suei Yang、Shih-Chia Hsiao、Ching-Yao Su、Chi-Huey Wong

  DOI：10.1021/ja073992i

  日期：2007.10.1

  Using D-xylose as an appropriate chiral precursor, we have synthesized active neuraminidase inhibitor oseltamivir, antiflu drug Tamiflu, and novel phosphonate congeners that exhibit even stronger antiflu activities by inhibiting the neuraminidases of the wildtype and H274Y mutant of H1N1 and H5N1 viruses. Molecular modeling of the neuraminidase-phosphonate complex indicates a pertinent binding mode of the phosphonate with three arginine residues in the active site. Discovery of such potent neuraminidase inhibitors will offer an opportunity to the development of new anti-influenza drugs.