(1S,4R,6S,7Z,14S,18S)-14-cyclopentyloxycarbonylamino-18-(4-nitro-benzoyloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.0^4,6]nonadec-7-ene-4-carboxylic acid methyl ester | 912291-95-3

• 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: (1S,4R,6S,7Z,14S,18S)-14-cyclopentyloxycarbonylamino-18-(4-nitro-benzoyloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.0^4,6]nonadec-7-ene-4-carboxylic acid methyl ester
• 英文别名: methyl (1S,4R,6S,7Z,14S,18S)-14-(cyclopentyloxycarbonylamino)-18-(4-nitrobenzoyl)oxy-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylate
• CAS: 912291-95-3
• 化学式: C₃₂H₄₀N₄O₁₀
• 分子量: 640.69
• InChiKey: XYSMXUXGMLJSQN-LMESAXFESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  46
• 可旋转键数：
  8
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  186
• 氢给体数：
  2
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  (1S,4R,6S,7Z,14S,18S)-14-cyclopentyloxycarbonylamino-18-(4-nitro-benzoyloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.0^4,6]nonadec-7-ene-4-carboxylic acid methyl ester 在 N-甲基吡咯烷酮 、 4-二甲氨基吡啶 、 lithium hydroxide 、 caesium carbonate 、 三乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 、 甲苯 为溶剂， 反应 42.0h， 生成 (1S,4R,6S,7Z,14S,18R)-14-cyclopentyloxycarbonylamino-18-[2-(2-isopropylamino-thiazol-4-yl)-7-methoxy-quinolin-4-yloxy]-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.0^4,6]nonadec-7-ene-4-carboxylic acid methyl ester
  参考文献：
  名称：

  Efficient Large-Scale Synthesis of BILN 2061, a Potent HCV Protease Inhibitor, by a Convergent Approach Based on Ring-Closing Metathesis

  摘要：

  A multistep scalable synthesis of the clinically important hepatitis C virus (HCV) protease inhibitor BILN 2061 (1) is described. The synthesis is highly convergent and consists of two amide bond formations, one etherification, and one ring-closing metathesis (RCM) step, using readily available building blocks 2-5. The optimization of each step is described at length. The main focus of the paper is the study of the RCM step and the description of the main problems faced when scaling up to pilot scale this highly powerful but very challenging synthetic operation. Eventually, the RCM reaction was smoothly scaled up to produce > 400 kg of cyclized product.

  DOI：

  10.1021/jo060285j
• 作为产物：
  描述：

  Boc-L-羟脯氨酸 在 RuCl2(1,3-dimesityl-imidazolidin-2-yl)(PCy3)(=CHPh) 盐酸 、 偶氮二甲酸二异丙酯 、 1-羟基苯并三唑 、 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 、 N,N-二异丙基乙胺 、 三苯基膦 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 二氯甲烷 、 甲苯 、 乙腈 为溶剂， 反应 6.5h， 生成 (1S,4R,6S,7Z,14S,18S)-14-cyclopentyloxycarbonylamino-18-(4-nitro-benzoyloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.0^4,6]nonadec-7-ene-4-carboxylic acid methyl ester
  参考文献：
  名称：

  Efficient Large-Scale Synthesis of BILN 2061, a Potent HCV Protease Inhibitor, by a Convergent Approach Based on Ring-Closing Metathesis

  摘要：

  A multistep scalable synthesis of the clinically important hepatitis C virus (HCV) protease inhibitor BILN 2061 (1) is described. The synthesis is highly convergent and consists of two amide bond formations, one etherification, and one ring-closing metathesis (RCM) step, using readily available building blocks 2-5. The optimization of each step is described at length. The main focus of the paper is the study of the RCM step and the description of the main problems faced when scaling up to pilot scale this highly powerful but very challenging synthetic operation. Eventually, the RCM reaction was smoothly scaled up to produce > 400 kg of cyclized product.

  DOI：

  10.1021/jo060285j

文献信息

• Epimerization Reaction of a Substituted Vinylcyclopropane Catalyzed by Ruthenium Carbenes:  Mechanistic Analysis
  作者：Xingzhong Zeng、Xudong Wei、Vittorio Farina、Elio Napolitano、Yibo Xu、Li Zhang、Nizar Haddad、Nathan K. Yee、Nelu Grinberg、Sherry Shen、Chris H. Senanayake

  DOI：10.1021/jo061587o

  日期：2006.11.1

  A novel ruthenium carbene-catalyzed epimerization of vinylcyclopropanes is reported. The reaction rate strongly depends on the presence of ruthenium ligands in solution. When the first-generation Grubbs catalyst is employed, a 5.3:1 equilibrium ratio of epimers is established quickly, but when a first-generation Hoveyda catalyst is employed, epimerization is observed only if an additional phosphine

  报道了一种新型的钌卡宾催化的乙烯基环丙烷差向异构化反应。反应速率很大程度上取决于溶液中钌配体的存在。当使用第一代Grubbs催化剂时，迅速建立了5.3：1的差向异构体平衡比，但是当使用第一代Hoveyda催化剂时，仅在添加额外的膦或氮配体的情况下才观察到差向异构。NMR和动力学研究表明，异构化反应是通过钌环戊烯的中间体发生的。该观察结果表明，合成实用性的环丙基亚甲基钌卡宾可以通过经由其他途径获得的钌-环戊烯来获得。
• RCM Macrocyclization Made Practical:  An Efficient Synthesis of HCV Protease Inhibitor BILN 2061
  作者：Chutian Shu、Xingzhong Zeng、Ming-Hong Hao、Xudong Wei、Nathan K. Yee、Carl A. Busacca、Zhengxu Han、Vittorio Farina、Chris H. Senanayake

  DOI：10.1021/ol800183x

  日期：2008.3.1

  We report here that dramatic improvement of the key RCM reaction in the synthesis of HCV protease inhibitor BILN2061 can be achieved by N-substitution of the diene substrate with an electron-withdrawing group. Mechanistic studies using H-1 NMR spectroscopy showed an unprecedented switch of the initiation sites and the correlation between such switch and the results of RCM, from the unmodified to the modified substrates. We also provided theoretical evidence that such modification may also increase the thermodynamic preference of the macrocyclic product over the diene substrate.
• Efficient Large-Scale Synthesis of BILN 2061, a Potent HCV Protease Inhibitor, by a Convergent Approach Based on Ring-Closing Metathesis
  作者：Nathan K. Yee、Vittorio Farina、Ioannis N. Houpis、Nizar Haddad、Rogelio P. Frutos、Fabrice Gallou、Xiao-jun Wang、Xudong Wei、Robert D. Simpson、Xuwu Feng、Victor Fuchs、Yibo Xu、Jonathan Tan、Li Zhang、Jinghua Xu、Lana L. Smith-Keenan、Jana Vitous、Michael D. Ridges、Earl M. Spinelli、Michael Johnson、Kai Donsbach、Thomas Nicola、Michael Brenner、Eric Winter、Paul Kreye、Wendelin Samstag

  DOI：10.1021/jo060285j

  日期：2006.9.1

  A multistep scalable synthesis of the clinically important hepatitis C virus (HCV) protease inhibitor BILN 2061 (1) is described. The synthesis is highly convergent and consists of two amide bond formations, one etherification, and one ring-closing metathesis (RCM) step, using readily available building blocks 2-5. The optimization of each step is described at length. The main focus of the paper is the study of the RCM step and the description of the main problems faced when scaling up to pilot scale this highly powerful but very challenging synthetic operation. Eventually, the RCM reaction was smoothly scaled up to produce > 400 kg of cyclized product.