N-[(1S,2R,5S,6S)-4-bromo-2-(1-ethylpropoxy)-5,6-(isopropylidenedioxy)cyclohex-3-en-1-yl]acetamide | 1062100-75-7

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: N-[(1S,2R,5S,6S)-4-bromo-2-(1-ethylpropoxy)-5,6-(isopropylidenedioxy)cyclohex-3-en-1-yl]acetamide
• 英文别名: N-((3aS,4S,5R,7aS)-7-bromo-2,2-dimethyl-5-(pentan-3-yloxy)-3a,4,5,7a-tetrahydrobenzo[d][1,3]dioxol-4-yl)acetamide；N1-[(3aS,4S,5R,7aS)-7-bromo-2,2-dimethyl-5-(1-ethylpropoxy)-3a,4,5,7a-tetrahydro-1,3-benzodioxol-4-yl]acetamide；N-[(3aS,4S,5R,7aS)-7-bromo-2,2-dimethyl-5-pentan-3-yloxy-3a,4,5,7a-tetrahydro-1,3-benzodioxol-4-yl]acetamide
• CAS: 1062100-75-7
• 化学式: C₁₆H₂₆BrNO₄
• 分子量: 376.291
• InChiKey: CQAQNEYLCOESCW-BARDWOONSA-N

物化性质

• 沸点：
  485.8±45.0 °C(Predicted)
• 密度：
  1.30±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  22
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.81
• 拓扑面积：
  56.8
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  N-[(1S,2R,5S,6S)-4-bromo-2-(1-ethylpropoxy)-5,6-(isopropylidenedioxy)cyclohex-3-en-1-yl]acetamide 在 吡啶 、 盐酸 、 四(三苯基膦)钯 、 叠氮化四丁基铵 、 三乙胺 作用下， 以 乙二醇二甲醚 、 乙醇 、 二氯甲烷 、 水 、 甲苯 为溶剂， -78.0~60.0 ℃ 、101.33 kPa 条件下， 反应 79.0h， 生成 ethyl (3R,4R,5R,6R)-4-acetamido-5-azido-6-(methylsulfonyloxy)-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate
  参考文献：
  名称：

  奥司他韦（达菲）的化学酶合成的几代人：策略的演变，寻求过程质量的合成，以及效率指标的评估

  摘要：

  介绍了四代奥司他韦的化学酶法。前两代依靠酶法衍生自溴苯的环己二烯-顺-二醇的使用。第三和第四代使用通过与大肠杆菌JM109（pDTG601a）发酵从苯甲酸乙酯获得的相应二醇。通过将中间体39（第三代合成物）和中间体45相交，从苯甲酸乙酯获得Oseltamivir（第四代合成）。这两种先进的方法都受益于对称性的考虑和丙烯酸酯双键的易位以及随之而来的C-1羟基的消除。通过使用效率指标评估合成的整体效率，并将其与奥司他韦的其他合成（学术和工业）进行比较。

  DOI：

  10.1021/jo2018872
• 作为产物：
  描述：

  (3aS,7aS)-4-bromo-2,2-dimethyl-3a,7a-dihydro-1,3-benzodioxole 在 三氟化硼乙醚 、 溴化锡 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 水 、 乙腈 为溶剂， 反应 14.5h， 生成 N-[(1S,2R,5S,6S)-4-bromo-2-(1-ethylpropoxy)-5,6-(isopropylidenedioxy)cyclohex-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

• [EN] PROCESSES AND INTERMEDIATES FOR THE PREPARATION OF OSELTAMIVIR AND ANALOGS THEREOF<br/>[FR] PROCÉDÉS ET INTERMÉDIAIRES POUR LA FABRICATION D'OSELTAMIVIR ET D'ANALOGUES DE CELUI-CI
  申请人：UNIV BROCK

  公开号：WO2009137916A1

  公开（公告）日：2009-11-19

  The present application relates to processes for the preparation of oseltamivir and the H3PO4 salt of oseltamivir, Tamiflu®. The application further relates to novel intermediate compounds and to pharmaceutical compositions containing said compounds. The application further relates to a method of using the novel intermediates to treat or prevent influenza.

  本申请涉及奥司他韦（Oseltamivir）及其H3PO4盐Tamiflu®的制备过程。该申请还涉及新型中间化合物以及含有这些化合物的药物组合物。该申请还涉及使用这些新型中间体来治疗或预防流感的方法。
• 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。
• PROCESSES AND INTERMEDIATES FOR THE PREPARATION OF OSELTAMIVIR AND ANALOGS THEREOF
  申请人：Hudlicky Tomas

  公开号：US20110201577A1

  公开（公告）日：2011-08-18

  The present application relates to processes for the preparation of oseltamivir and the H 3 PO 4 salt of oseltamivir, Tamiflu®. The application further relates to novel intermediate compounds and to pharmaceutical compositions containing said compounds. The application further relates to a method of using the novel intermediates to treat or prevent influenza.

  本申请涉及制备奥司他韦和奥司他韦的H3PO4盐（Tamiflu®）的过程。该申请还涉及新型中间体化合物和含有该化合物的制药组合物。该申请还涉及使用新型中间体治疗或预防流感的方法。
• [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