ethyl (3R,4R,5S)-4-acetamido-5-(tert-butoxycarbonylamino)-3-hydroxycyclohex-1-enecarboxylate | 1137726-89-6

• 英文名称: ethyl (3R,4R,5S)-4-acetamido-5-(tert-butoxycarbonylamino)-3-hydroxycyclohex-1-enecarboxylate
• 英文别名: ethyl (3R,4R,5S)-4-acetylamino-5-tert-butoxycarbonylamino-3-hydroxy-cyclohex-1-enecarboxylate；ethyl (3R,4R,5S)-4-acetamido-5-(tert-butylcarbonylamino)-3-hydroxycyclohex-1-enecarboxylate；(3R,4R,5S)-4-acetylamino-5-tert-butoxycarbonylamino-3-hydroxycyclohex-1-enecarboxylic acid ethyl ester；(3R,4R,5S)-4-Acetylamino-5-tert-butoxycarbonylamino-3-hydroxy-cyclohex-1-enecarboxylic acid ethyl ester；ethyl (3R,4R,5S)-4-acetamido-3-hydroxy-5-[(2-methylpropan-2-yl)oxycarbonylamino]cyclohexene-1-carboxylate
• CAS: 1137726-89-6
• 化学式: C₁₆H₂₆N₂O₆
• 分子量: 342.392
• InChiKey: XNUFADSYZLUVPF-YNEHKIRRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.4
• 重原子数：
  24
• 可旋转键数：
  7
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.69
• 拓扑面积：
  114
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  ethyl (3R,4R,5S)-4-acetamido-5-(tert-butoxycarbonylamino)-3-hydroxycyclohex-1-enecarboxylate 在 偶氮二甲酸二异丙酯 、 三乙胺 、 二甲基苯基磷 作用下， 以 二氯甲烷 为溶剂， 反应 0.17h， 以76%的产率得到(1S,5S,6R)-ethyl 7-acetyl-5-(tert-butoxycarbonylamino)-7-azabicyclo[4.1.0]hept-2-ene-3-carboxylate
  参考文献：
  名称：

  钡催化不对称Diels-Alder型反应合成达菲

  摘要：

  为了寻求更好的途径：开发了新的达菲催化不对称合成方法。关键的转变是钡/ F 2 -FujiCAPO络合物在存在CsF助催化剂的情况下催化1和2的不对称Diels-Alder型反应，从而构成了达菲的核心（见方案； TMS =三甲基甲硅烷基）。以克为单位，将产品分11步转化为达菲。

  DOI：

  10.1002/anie.200804777
• 作为产物：
  描述：

  (3aR,6S,7R,7aS)-7-acetylamino-6-tert-butoxycarbonylamino-2,2-dimethyl-3a,6,7,7a-tetrahydrobenzo[1,3]dioxole-4-carboxylic acid ethyl ester 在 乙醇 、 sodium ethanolate 作用下， 反应 0.08h， 以94%的产率得到ethyl (3R,4R,5S)-4-acetamido-5-(tert-butoxycarbonylamino)-3-hydroxycyclohex-1-enecarboxylate
  参考文献：
  名称：

  短时无化学酶叠氮化物的Oseltamivir（Tamiflu）合成：接近工艺效率的潜力

  摘要：

  通过一个简单的Dauben-Michno氧化转座和胺化反应以及丙烯酸酯的还原转座等关键步骤，实现了奥司他韦的短短的化学酶促合成和无叠氮化物合成。

  DOI：

  10.1002/adsc.200900844

文献信息

• Several Generations of Chemoenzymatic Synthesis of Oseltamivir (Tamiflu): Evolution of Strategy, Quest for a Process-Quality Synthesis, and Evaluation of Efficiency Metrics
  作者：Lukas Werner、Ales Machara、Bradford Sullivan、Ignacio Carrera、Michael Moser、David R. Adams、Tomas Hudlicky、John Andraos

  DOI：10.1021/jo2018872

  日期：2011.12.16

  Four generations of chemoenzymatic approaches to oseltamivir are presented. The first two generations relied on the use of cyclohexadiene-cis-diol derived enzymatically from bromobenzene. The third and fourth generation used the corresponding diol obtained from ethyl benzoate by fermentation with E. coli JM109(pDTG601a). Oseltamivir was obtained from ethyl benzoate by intersecting intermediate 39 (third-generation

  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。
• PROCESS AND COMPOUNDS FOR THE MANUFACTURE OF OSELTAMIVIR AND ANALOGS THEREOF, AND NEW ANTIVIRAL AGENTS
  申请人：Hudlicky Tomas

  公开号：US20120252890A1

  公开（公告）日：2012-10-04

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

  本申请涉及用于制造奥司他韦和奥司他韦的H3PO4盐的中间体的制备过程。该申请还涉及新型中间体和化合物以及奥司他韦类似物和包含该类似物化合物的制药组合物。该申请还涉及使用新型奥司他韦类似物治疗或预防流感的方法。
• Process and compounds for the manufacture of oseltamivir and analogs thereof, and new antiviral agents
  申请人：Hudlicky Tomas

  公开号：US08716333B2

  公开（公告）日：2014-05-06

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

  本申请涉及制备在制造奥司他韦和奥司他韦的H3PO4盐中有用的中间体的过程。本申请进一步涉及新颖的中间体和化合物、奥司他韦类似物以及包含该类似物化合物的制药组合物。本申请还涉及使用新颖的奥司他韦类似物治疗或预防流感的方法。
• [EN] PROCESS AND COMPOUNDS FOR THE MANUFACTURE OF OSELTAMIVIR AND ANALOGS THEREOF, AND NEW ANTIVIRAL AGENTS<br/>[FR] PROCÉDÉ ET COMPOSÉS POUR LA FABRICATION D'OSELTAMIVIR ET DE SES ANALOGUES, ET NOUVEAUX AGENTS ANTIVIRAUX
  申请人：UNIV BROCK

  公开号：WO2011047466A8

  公开（公告）日：2012-04-26
• An alternative synthesis of Tamiflu®: a synthetic challenge and the identification of a ruthenium-catalyzed dihydroxylation route
  作者：Kenzo Yamatsugu、Motomu Kanai、Masakatsu Shibasaki

  DOI：10.1016/j.tet.2009.05.077

  日期：2009.8

  Synthetic studies of Tamiflu (R) and the identification of a ruthenium-catalyzed dihydroxylation route are disclosed. This newly developed synthetic process circumvents the need for a Mitsunobu inversion step and the use of explosive reagents. This route, therefore, compares favorably to the previously developed synthetic process. (C) 2009 Elsevier Ltd. All rights reserved,