ethyl (3R,4R,5S)-4-N-acetylamino-3-(1-ethylpropoxy)-5-N-propylamino-1-cyclohexene-1-carboxylate

• 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: ethyl (3R,4R,5S)-4-N-acetylamino-3-(1-ethylpropoxy)-5-N-propylamino-1-cyclohexene-1-carboxylate
• 英文别名: ethyl (3R,4R,5S)-4-acetamido-3-pentan-3-yloxy-5-(propylamino)cyclohexene-1-carboxylate
• 化学式: C₁₉H₃₄N₂O₄
• 分子量: 354.49
• InChiKey: VTUQOZZXSFMLFP-RCCFBDPRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  25
• 可旋转键数：
  11
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.79
• 拓扑面积：
  76.7
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  ethyl (3R,4R,5S)-4-N-acetylamino-3-(1-ethylpropoxy)-5-N-propylamino-1-cyclohexene-1-carboxylate 在 三乙胺 、 mercury dichloride 、 sodium hydroxide 作用下， 以 甲醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 28.0h， 生成 (3R,4R,5S)-4-acetamido-3-(pentan-3-yloxy)-5-(1-propylguanidino)cyclohex-1-enecarboxylic acid trifluoroacetate salt
  参考文献：
  名称：

  Discovery of N-Substituted Oseltamivir Derivatives as Potent and Selective Inhibitors of H5N1 Influenza Neuraminidase

  摘要：

  To discover group-1-specific neuraminidase (NA) inhibitors that are especially involved in combating the H5N1 virus, two series of oseltamivir derivatives were designed and synthesized by targeting the 150-cavity. Among these, compound 20l was the most potent N1-selective inhibitor, with IC50 values of 0.0019, 0.0038, and 0.0067 mu M against NAs from three H5N1 viruses. These values are better than those of oseltamivir carboxylate. Compound 32 was another potent N1-selective inhibitor that exhibited a 12-fold increase in activity against the H274Y mutant relative to oseltamivir carboxylate. Molecular docking studies revealed that the 150-cavity was an auxiliary binding site that may contribute to the high selectivity of these compounds. The present work is a significant breakthrough in the discovery of potent group-1-specific neuraminidase inhibitors, which may be further investigated for the treatment of infection by the H5N1 virus.

  DOI：

  10.1021/jm500892k
• 作为产物：
  描述：

  ethyl (3R,4S,5R)-5-amino-3-(1-ethylpropoxy)-4-methanesulfonyloxy-1-cyclohexene-1-carboxylate 在 palladium on activated charcoal 甲烷磺酸 、 乙二醇 、 溶剂黄146 作用下， 以 乙醇 、 乙酸乙酯 为溶剂， 112.0 ℃ 、600.01 kPa 条件下， 反应 9.0h， 生成 ethyl (3R,4R,5S)-4-N-acetylamino-3-(1-ethylpropoxy)-5-N-propylamino-1-cyclohexene-1-carboxylate
  参考文献：
  名称：

  新的无叠氮化物的环氧化物转化为1,2-二氨基化合物：抗流感神经氨酸酶抑制剂磷酸奥司他韦（Tamiflu）的合成。

  摘要：

  描述了一种新的，无叠氮化物的关键前体环氧化合物6向流感神经氨酸酶抑制剂前药磷酸奥司他韦（1，Tamiflu）的无叠氮化物转化。该顺序代表环氧化物向没有潜在毒性和危险的叠氮化物试剂和中间体的1,2-二氨基化合物的新型高效转化，并且避免了还原和氢化条件。使用催化MgBr（2）.OEt（2）作为一种新的，廉价的路易斯酸，第一个氨基官能团的引入是通过用烯丙胺打开环氧乙烷环，然后Pd / C催化脱氨成氨基醇16。然后通过涉及多米诺序列的有效反应级联反应优选地利用瞬时亚氨基保护来完成第二个氨基的引入。

  DOI：

  10.1021/jo005702l

文献信息

• [EN] METHOD OF FORMING OSELTAMIVIR AND DERIVATIVES THEREOF<br/>[FR] PROCÉDÉ DE FORMATION D'OSELTAMIVIR ET DE SES DÉRIVÉS ET APPLICATIONS CORRESPONDANTES
  申请人：UNIV NANYANG

  公开号：WO2009078813A1

  公开（公告）日：2009-06-25

  A process is provided for the synthesis of 4,5-diamino cyclohexene carboxylate ester (1): or a pharmaceutically acceptable salt thereof. R1 - R3 are a silyl-, an aliphatic, alicyclic, aromatic, arylaliphatic, or an arylalicyclic group. R4, R11 and R12 are H, a silyl-group, an aliphatic, alicyclic, aromatic, arylaliphatic, or an arylalicyclic group. 3,4-Dihydropyran compound (9): with R5 and R6 being suitable protecting groups, is reacted to form aldehyde (4): which is oxidized and converted to N-substituted carbamate (3): with R7 being a suitable protecting group. (3) is, via oxazolinidone (13): converted to azido carboxylate ester (2): and then to 4,5-diamino cyclohexene carboxylate ester (1).

  提供了一种用于合成4,5-二氨基环己烯羧酸酯（1）或其药用可接受的盐的过程。R1 - R3是硅基、脂肪、脂环、芳香、芳脂或芳环基团。R4、R11和R12是H、硅基、脂肪、脂环、芳香、芳脂或芳环基团。将3,4-二氢吡喃化合物（9）与适当的保护基R5和R6反应，形成醛（4），氧化并转化为N-取代的碳酸酯（3），其中R7是适当的保护基。通过噁唑啉二酮（13）将（3）转化为偶氮羧酸酯（2），然后转化为4,5-二氨基环己烯羧酸酯（1）。
• METHOD OF FORMING OSELTAMIVIR AND DERIVATIVES THEREOF
  申请人：Liu Xuewei

  公开号：US20110021762A1

  公开（公告）日：2011-01-27

  A process is provided for the synthesis of 4,5-diamino cyclohexene carboxylate ester (1): or a pharmaceutically acceptable salt thereof. R 1 -R 3 are a silyl-, an aliphatic, alicyclic, aromatic, arylaliphatic, or an arylalicyclic group. R 4 , R 11 and R 12 are H, a silyl-group, an aliphatic, alicyclic, aromatic, arylaliphatic, or an arylalicyclic group. 3,4-Dihydropyran compound (9): with R 5 and R 6 being suitable protecting groups, is reacted to form aldehyde (4): which is oxidized and converted to N-substituted carbamate (3): with R 7 being a suitable protecting group. (3) is, via oxazolinidone (13): converted to azido carboxylate ester (2): and then to 4,5-diamino cyclohexene carboxylate ester (1).

  本发明提供了一种合成4,5-二氨基环己烯羧酸酯（1）或其药学上可接受的盐的方法。其中R1-R3是硅基，脂肪基，脂环基，芳香基，芳脂基或芳环脂基。R4，R11和R12是氢，硅基，脂肪基，脂环基，芳香基，芳脂基或芳环脂基。将带有R5和R6适当保护基的3,4-二氢吡喃化合物（9）反应生成醛（4），然后氧化并转化为带有R7适当保护基的N-取代氨基甲酸酯（3）。通过氧杂环丙氨酮（13）将（3）转化为偶氮羧酸酯（2），然后再转化为4,5-二氨基环己烯羧酸酯（1）。
• US8304553B2
  申请人：——

  公开号：US8304553B2

  公开（公告）日：2012-11-06
• Discovery of N-Substituted Oseltamivir Derivatives as Potent and Selective Inhibitors of H5N1 Influenza Neuraminidase
  作者：Yuanchao Xie、Dongqing Xu、Bing Huang、Xiuli Ma、Wenbao Qi、Fangyuan Shi、Xinyong Liu、Yingjie Zhang、Wenfang Xu

  DOI：10.1021/jm500892k

  日期：2014.10.23

  To discover group-1-specific neuraminidase (NA) inhibitors that are especially involved in combating the H5N1 virus, two series of oseltamivir derivatives were designed and synthesized by targeting the 150-cavity. Among these, compound 20l was the most potent N1-selective inhibitor, with IC50 values of 0.0019, 0.0038, and 0.0067 mu M against NAs from three H5N1 viruses. These values are better than those of oseltamivir carboxylate. Compound 32 was another potent N1-selective inhibitor that exhibited a 12-fold increase in activity against the H274Y mutant relative to oseltamivir carboxylate. Molecular docking studies revealed that the 150-cavity was an auxiliary binding site that may contribute to the high selectivity of these compounds. The present work is a significant breakthrough in the discovery of potent group-1-specific neuraminidase inhibitors, which may be further investigated for the treatment of infection by the H5N1 virus.
• New, Azide-Free Transformation of Epoxides into 1,2-Diamino Compounds:  Synthesis of the Anti-Influenza Neuraminidase Inhibitor Oseltamivir Phosphate (Tamiflu)
  作者：Martin Karpf、René Trussardi

  DOI：10.1021/jo005702l

  日期：2001.3.1

  amino function was accomplished by opening of the oxirane ring with allylamine followed by Pd/C-catalyzed deallylation to the amino alcohol 16. The introduction of the second amino group was then accomplished via an efficient reaction cascade involving a domino sequence preferably utilizing a transient imino protection. Selective acetylation of the resulting diamine 17 was achieved under acidic conditions

  描述了一种新的，无叠氮化物的关键前体环氧化合物6向流感神经氨酸酶抑制剂前药磷酸奥司他韦（1，Tamiflu）的无叠氮化物转化。该顺序代表环氧化物向没有潜在毒性和危险的叠氮化物试剂和中间体的1,2-二氨基化合物的新型高效转化，并且避免了还原和氢化条件。使用催化MgBr（2）.OEt（2）作为一种新的，廉价的路易斯酸，第一个氨基官能团的引入是通过用烯丙胺打开环氧乙烷环，然后Pd / C催化脱氨成氨基醇16。然后通过涉及多米诺序列的有效反应级联反应优选地利用瞬时亚氨基保护来完成第二个氨基的引入。