ethyl 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}-4H-[5,1-c][1,4]benzoxazin-3-carboxylate | 876922-82-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: ethyl 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}-4H-[5,1-c][1,4]benzoxazin-3-carboxylate
• 英文别名: ethyl 6-{2-[4-(2-methylquinolin-5-yl)piperazin-1-yl]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazine-3-carboxylate；ethyl 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazine-3-carboxylate；ethyl 6-[2-[4-(2-methylquinolin-5-yl)piperazin-1-yl]ethyl]-4H-imidazo[5,1-c][1,4]benzoxazine-3-carboxylate
• CAS: 876922-82-6
• 化学式: C₂₉H₃₁N₅O₃
• 分子量: 497.597
• InChiKey: ULXBTCAXCQWKDE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  37
• 可旋转键数：
  7
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.34
• 拓扑面积：
  72.7
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  ethyl 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}-4H-[5,1-c][1,4]benzoxazin-3-carboxylate 在 sodium methylate 作用下， 以 甲醇 、 formamide 为溶剂， 以86%的产率得到6-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxamide
  参考文献：
  名称：

  Development of an Efficient Large-Scale Synthesis for a 4H-imidazo[5,1-c][1,4]benzoxazine-3-carboxamide Derivative for Depression and Anxiety

  摘要：

  The development and scale-up of an optimized synthesis for a novel drug candidate for depression and anxiety is presented. The updated synthesis represents a convergent and efficient four-stage approach to the API, overcoming high cost of goods (COG), general lack of convergence, and low yield of previous routes. A lower cost of goods resulted from using 3-nitrosalicylaldehyde as a starting material and introducing the expensive side chain (2-methyl-5-(piperazin-1-yl)quinoline) at a later stage. Green chemistry principles were applied when a direct amidation enabled a straightforward conversion of the 4H-imidazo[5,1-c][1,4]benzoxazine-3-carboxylate to the corresponding amide in the last step. In addition, the total number of stages was reduced from seven to four, and solvent usage was greatly minimized. The modified synthesis NUS demonstrated on a kilogram pilot scale, allowing the isolation of the API in 17% overall yield with the required purity.

  DOI：

  10.1021/op100103v
• 作为产物：
  描述：

  2-methyl-5-(1-piperazinyl)quinoline 在 三乙酰氧基硼氢化钠 作用下， 以 二氯甲烷 为溶剂， 反应 1.33h， 以5.75 kg的产率得到ethyl 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}-4H-[5,1-c][1,4]benzoxazin-3-carboxylate
  参考文献：
  名称：

  Development of an Efficient Large-Scale Synthesis for a 4H-imidazo[5,1-c][1,4]benzoxazine-3-carboxamide Derivative for Depression and Anxiety

  摘要：

  The development and scale-up of an optimized synthesis for a novel drug candidate for depression and anxiety is presented. The updated synthesis represents a convergent and efficient four-stage approach to the API, overcoming high cost of goods (COG), general lack of convergence, and low yield of previous routes. A lower cost of goods resulted from using 3-nitrosalicylaldehyde as a starting material and introducing the expensive side chain (2-methyl-5-(piperazin-1-yl)quinoline) at a later stage. Green chemistry principles were applied when a direct amidation enabled a straightforward conversion of the 4H-imidazo[5,1-c][1,4]benzoxazine-3-carboxylate to the corresponding amide in the last step. In addition, the total number of stages was reduced from seven to four, and solvent usage was greatly minimized. The modified synthesis NUS demonstrated on a kilogram pilot scale, allowing the isolation of the API in 17% overall yield with the required purity.

  DOI：

  10.1021/op100103v

文献信息

• [EN] FUSED TRICYCLIC DERIVATIVES FOR THE TREATMENT OF PSYCHOTIC DISORDERS<br/>[FR] DERIVES TRICYCLIQUES ACCOLES POUR LE TRAITEMENT DE TROUBLES PSYCHOTIQUES
  申请人：GLAXO GROUP LTD

  公开号：WO2006024517A1

  公开（公告）日：2006-03-09

  Compounds of formula (I) wherein R1, R2, X, A, Y, B, Z1, Q, p, r and s are defined in the specification for treating inter alia psychotic disorders, depressive disorders, anxiety disorders and sexual dysfunctions.

  式中R1、R2、X、A、Y、B、Z1、Q、p、r和s在说明书中定义的用于治疗精神疾病、抑郁障碍、焦虑障碍和性功能障碍的(I)式化合物。
• FUSED TRICYCLIC DERIVATIVES FOR THE TREATMENT OF PSYCHOTIC DISORDERS
  申请人：Bentley Jonathan

  公开号：US20120022056A1

  公开（公告）日：2012-01-26

  Compounds of formula (I) wherein R 1 , R 2 , X, A, Y, B, Z 1 , Q, p, r and s are defined in the specification for treating inter alia psychotic disorders, depressive disorders, anxiety disorders and sexual dysfunctions.

  式(I)中的化合物，其中R1、R2、X、A、Y、B、Z1、Q、p、r和s在规范中定义，用于治疗精神疾病、抑郁症、焦虑症和性功能障碍等疾病。
• Design and Synthesis of Novel Tricyclic Benzoxazines as Potent 5-HT_1A/B/D Receptor Antagonists Leading to the Discovery of 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}-4<i>H</i>-imidazo[5,1-<i>c</i>][1,4]benzoxazine-3-carboxamide (GSK588045)
  作者：Steven M. Bromidge、Roberto Arban、Barbara Bertani、Silvia Bison、Manuela Borriello、Paolo Cavanni、Giovanna Dal Forno、Romano Di-Fabio、Daniele Donati、Stefano Fontana、Massimo Gianotti、Laurie J. Gordon、Enrica Granci、Colin P. Leslie、Luca Moccia、Alessandra Pasquarello、Ilaria Sartori、Anna Sava、Jeannette M. Watson、Angela Worby、Laura Zonzini、Valeria Zucchelli

  DOI：10.1021/jm100482n

  日期：2010.8.12

  Bioisoteric replacement of the metabolically labile N-methyl amide group of a series of benzoxazinones with small heterocyclic rings has led to novel series of fused tricyclic benzoxazines which are potent 5-HT1A/B/D receptor antagonists with and without concomitant human serotonin transporter (hSerT) activity. Optimizing against multiple parameters in parallel identified 6-2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazine-3-carboxamide (GSK588045) as a potent 5-HT1A/B/D receptor antagonist with a high degree of selectivity over human ether-a-go-go related gene (hERG) potassium channels, favorable pharmacokinetics, and excellent activity in vivo in rodent pharmacodynamic (PD) models. On the basis of its outstanding overall profile, this compound was progressed as a clinical candidate with the ultimate aim to assess its potential as a faster acting antidepressant/anxiolytic with reduced side-effect burden.
• Organic Process Research and Development 2010, 14, 859-867
  作者：

  DOI：——

  日期：——
• Development of an Efficient Large-Scale Synthesis for a 4<i>H</i>-imidazo[5,1-<i>c</i>][1,4]benzoxazine-3-carboxamide Derivative for Depression and Anxiety
  作者：Nicola Giubellina、Paolo Stabile、Gilles Laval、Alcide D. Perboni、Zadeo Cimarosti、Pieter Westerduin、Jason W. B. Cooke

  DOI：10.1021/op100103v

  日期：2010.7.16

  The development and scale-up of an optimized synthesis for a novel drug candidate for depression and anxiety is presented. The updated synthesis represents a convergent and efficient four-stage approach to the API, overcoming high cost of goods (COG), general lack of convergence, and low yield of previous routes. A lower cost of goods resulted from using 3-nitrosalicylaldehyde as a starting material and introducing the expensive side chain (2-methyl-5-(piperazin-1-yl)quinoline) at a later stage. Green chemistry principles were applied when a direct amidation enabled a straightforward conversion of the 4H-imidazo[5,1-c][1,4]benzoxazine-3-carboxylate to the corresponding amide in the last step. In addition, the total number of stages was reduced from seven to four, and solvent usage was greatly minimized. The modified synthesis NUS demonstrated on a kilogram pilot scale, allowing the isolation of the API in 17% overall yield with the required purity.