Ethyl 3-(6-nitro-3-oxo-1,4-benzoxazin-4-yl)propanoate | 475469-73-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并恶嗪类
• 英文名称: Ethyl 3-(6-nitro-3-oxo-1,4-benzoxazin-4-yl)propanoate
• CAS: 475469-73-9
• 化学式: C₁₃H₁₄N₂O₆
• 分子量: 294.264
• InChiKey: BTHNEHATCMDSTH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  21
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  102
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  Ethyl 3-(6-nitro-3-oxo-1,4-benzoxazin-4-yl)propanoate 在 lithium aluminium tetrahydride 、 palladium 10% on activated carbon 、 氢气 、 sodium hydride 作用下， 以 四氢呋喃 、 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 4.0h， 生成 N-(3,4,10,10a-terhydro-2H-1,9-dioxa-4a-azaphenanthrene-6-yl)methane sulfonamide-N1-carbamic acid
  参考文献：
  名称：

  Synthesis of N-(3,4,10,10a-Tetrahydro-2H-1,9-dioxa-4aazaphenanthrene- 6-yl)alkyl and Aryl Sulfonamides

  摘要：

  市售的2-氨基-4-硝基苯酚（1）与氯乙酰氯反应，得到6-硝基-4H-苯并[1,4]噁嗪-3,2-酮（2）。后者与乙基3-溴丙酸酯反应，得到3-(6-硝基-3-氧代-2,3-二氢苯并[1,4]噁嗪-4-基)丙酸乙酯（3），再经锂铝氢化物处理，经过还原环化反应得到6-硝基-3,4,10,10a-四氢-2H-1,9-二氧代-4a-氮蒽（4）。化合物4与含有二叔丁基碳酸酯(Boc)2O的H2/Pd-C在THF中反应，得到(3,4,10,10a-四氢-2H-1,9-二氧代-4a-氮蒽-6-基)氨基酸酯的叔丁基酯（5）。后者与在NaH存在下的烷基或芳基磺酰氯反应，得到N-(3,4,10,10a-四氢-2H-1,9-二氧代-4a-氮蒽-6-基)烷基或芳基磺酰胺-N1-氨基酸酯的叔丁基酯（6）。化合物6中的N-Boc基团用碳酸铯/咪唑在乙腈中去保护，得到作为潜在抗菌剂的N-(3,4,10,10a-四氢-2H-1,9-二氧代-4a-氮蒽-6-基)烷基或芳基磺酰胺（7）。上述反应序列中获得的所有新产品均已通过光谱数据得到充分表征。

  DOI：

  10.14233/ajchem.2014.17017
• 作为产物：
  描述：

  2-氨基-4-硝基苯酚 在 potassium carbonate 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 14.0h， 生成 Ethyl 3-(6-nitro-3-oxo-1,4-benzoxazin-4-yl)propanoate
  参考文献：
  名称：

  Synthesis of N-(3,4,10,10a-Tetrahydro-2H-1,9-dioxa-4aazaphenanthrene- 6-yl)alkyl and Aryl Sulfonamides

  摘要：

  市售的2-氨基-4-硝基苯酚（1）与氯乙酰氯反应，得到6-硝基-4H-苯并[1,4]噁嗪-3,2-酮（2）。后者与乙基3-溴丙酸酯反应，得到3-(6-硝基-3-氧代-2,3-二氢苯并[1,4]噁嗪-4-基)丙酸乙酯（3），再经锂铝氢化物处理，经过还原环化反应得到6-硝基-3,4,10,10a-四氢-2H-1,9-二氧代-4a-氮蒽（4）。化合物4与含有二叔丁基碳酸酯(Boc)2O的H2/Pd-C在THF中反应，得到(3,4,10,10a-四氢-2H-1,9-二氧代-4a-氮蒽-6-基)氨基酸酯的叔丁基酯（5）。后者与在NaH存在下的烷基或芳基磺酰氯反应，得到N-(3,4,10,10a-四氢-2H-1,9-二氧代-4a-氮蒽-6-基)烷基或芳基磺酰胺-N1-氨基酸酯的叔丁基酯（6）。化合物6中的N-Boc基团用碳酸铯/咪唑在乙腈中去保护，得到作为潜在抗菌剂的N-(3,4,10,10a-四氢-2H-1,9-二氧代-4a-氮蒽-6-基)烷基或芳基磺酰胺（7）。上述反应序列中获得的所有新产品均已通过光谱数据得到充分表征。

  DOI：

  10.14233/ajchem.2014.17017

文献信息

• Synthesis and Structure–Activity Relationship Studies of Benzo[ <i>b</i> ][1,4]oxazin‐3(4 <i>H</i> )‐one Analogues as Inhibitors of Mycobacterial Thymidylate Synthase X
  作者：Jakub Modranka、Jiahong Li、Anastasia Parchina、Michiel Vanmeert、Shrinivas Dumbre、Mayla Salman、Hannu Myllykallio、Hubert F. Becker、Roeland Vanhoutte、Lia Margamuljana、Hoai Nguyen、Rania Abu El‐Asrar、Jef Rozenski、Piet Herdewijn、Steven De Jonghe、Eveline Lescrinier

  DOI：10.1002/cmdc.201800739

  日期：2019.3.22

  report herein an optimization campaign of a novel series of inhibitors with a unique inhibition profile. The inhibitors display competitive inhibition toward the methylene tetrahydrofolate cofactor of ThyX, enabling us to generate a model of the compounds bound to their target, thus offering insight into their structure-activity relationships.

  由于发现了人类中不存在的黄素依赖性胸苷酸合酶（ThyX或FDTS），但对于多种病原体中的DNA生物合成至关重要，该酶一直被用于开发针对结核分枝杆菌的新型抗菌剂。广泛的传染病结核病（TB）的病原体。为了响应对更有效的抗结核药物的日益增长的需求，我们在之前的筛选工作基础上，在此报告了一系列具有独特抑制谱的新型抑制剂的优化方案。抑制剂对ThyX的亚甲基四氢叶酸辅因子表现出竞争性抑制作用，使我们能够生成与目标结合的化合物模型，从而深入了解其结构与活性之间的关系。
• Synthesis and vasorelaxant activity of new 1,4-benzoxazine derivatives potassium channel openers
  作者：Giuseppe Caliendo、Elisa Perissutti、Vincenzo Santagada、Ferdinando Fiorino、Beatrice Severino、Roberta d'Emmanuele di Villa Bianca、Laura Lippolis、Aldo Pinto、Raffaella Sorrentino

  DOI：10.1016/s0968-0896(02)00091-3

  日期：2002.8

  As part of a search for new potassium channel openers, the synthesis and vasorelaxant activity of new 1,4-benzoxazine derivatives derived from transformation of the benzopyran skeleton of cromakalim were described. Several new 1,4-benzoxazine derivatives were provided with significant vasorelaxant activity with an overall pharmacological behavior similar to CRK (1f, 1i, 2d, 2e, 2f and 2i).

  作为寻找新的钾通道开放剂的一部分，描述了衍生自克罗马卡林的苯并吡喃骨架的新的1,4-苯并恶嗪衍生物的合成和血管舒张活性。几种新的1,4-苯并恶嗪衍生物具有明显的血管舒张活性，其总体药理行为类似于CRK（1f，1i，2d，2e，2f和2i）。
• Synthesis by microwave irradiation of a substituted benzoxazine parallel library with preferential relaxant activity for guinea pig trachealis
  作者：Giuseppe Caliendo、Elisa Perissutti、Vincenzo Santagada、Ferdinando Fiorino、Beatrice Severino、Donatella Cirillo、Roberta d’Emmanuele di Villa Bianca、Laura Lippolis、Aldo Pinto、Raffaella Sorrentino

  DOI：10.1016/j.ejmech.2004.05.003

  日期：2004.10

  An efficient, facile, and practical parallel combinatorial synthesis of substituted-benzoxazines under microwave irradiation was described. The procedure involved the use of a microwave oven especially designed for organic synthesis suitable for parallel synthesis of solution libraries. A demonstration 19-membered library of substituted N,N-dimethyl- and N-methyl-benzoxazine amide derivatives, structurally related to the potassium channel opener cromakalim, was generated by both conventional and microwave procedures, achieving a reduction from 7 h to 30-36 min in library generation time for the microwave approach. All the synthesized compounds were tested using the in vitro models of rat aorta and guinea pig trachea rings pre-contracted with phenylephrine and carbachol, respectively. All N,N-dimethyl amide derivatives showed a relaxant activity higher on guinea pig trachea rings than on rat aorta rings. (C) 2004 Elsevier SAS. All rights reserved.
• Synthesis of N-(3,4,10,10a-Tetrahydro-2H-1,9-dioxa-4aazaphenanthrene- 6-yl)alkyl and Aryl Sulfonamides
  作者：V. Rajachandrasekhar、B. George Vineel、S. Venkataiaha、P.K. Dubey

  DOI：10.14233/ajchem.2014.17017

  日期：——

  Commercially available 2-amino-4-nitrophenol (1) was treated with chloroacetyl chloride to obtain 6-nitro-4H-benzo[1,4]oxazine-3,2-one (2). The latter was reacted with ethyl 3-bromopropionate to obtain 3-(6-nitro-3-oxo-2,3-dihydrobenzo[1,4]oxazine-4-yl)propionic acid ethyl ester (3), which on treatment with lithium aluminiumhydride gave 6-nitro-3,4,10,10a-tetrahydro-2H-1,9-dioxo-4a-azaphenanthrene (4) by reductive cyclization. Compound, 4 was treated with H2/Pd-C containing di-tert-butyldicarbonate (Boc)2O in THF to obtain the (3,4,10,10a-tetrahydro-2H-1,9-dioxa-4a-azaphenanthrene-6-yl)carbamic acid tert-butyl ester (5). The latter, on treatment with alkyl or arylsulfonyl chlorides in the presence of NaH gave N-(3,4,10,10a-tetrahydro-2H-1,9-dioxa-4a-azaphenanthrene-6-yl) alkyl or aryl sulfonamide-N1-carbamic acid tert-butyl ester (6). N-Boc group of 6 was de-protected with Cs2CO3/imidazole in acetonitrile to give the title compounds N-(3,4,10,10a-tetrahydro-2H-1,9-dioxa-4a-azaphenanthrene-6-yl) alkyl or aryl sulfonamides (7) as potential anti-bacterial agents. All the new products obtained in the above sequences of reactions have been adequately characterized by spectral data.

  市售的2-氨基-4-硝基苯酚（1）与氯乙酰氯反应，得到6-硝基-4H-苯并[1,4]噁嗪-3,2-酮（2）。后者与乙基3-溴丙酸酯反应，得到3-(6-硝基-3-氧代-2,3-二氢苯并[1,4]噁嗪-4-基)丙酸乙酯（3），再经锂铝氢化物处理，经过还原环化反应得到6-硝基-3,4,10,10a-四氢-2H-1,9-二氧代-4a-氮蒽（4）。化合物4与含有二叔丁基碳酸酯(Boc)2O的H2/Pd-C在THF中反应，得到(3,4,10,10a-四氢-2H-1,9-二氧代-4a-氮蒽-6-基)氨基酸酯的叔丁基酯（5）。后者与在NaH存在下的烷基或芳基磺酰氯反应，得到N-(3,4,10,10a-四氢-2H-1,9-二氧代-4a-氮蒽-6-基)烷基或芳基磺酰胺-N1-氨基酸酯的叔丁基酯（6）。化合物6中的N-Boc基团用碳酸铯/咪唑在乙腈中去保护，得到作为潜在抗菌剂的N-(3,4,10,10a-四氢-2H-1,9-二氧代-4a-氮蒽-6-基)烷基或芳基磺酰胺（7）。上述反应序列中获得的所有新产品均已通过光谱数据得到充分表征。