3-乙氧基-5-甲基-4-苯基-1,2-恶唑 | 146197-26-4

• 分子结构分类: 有机化合物 - 有机氧化合物
• 中文名称: 3-乙氧基-5-甲基-4-苯基-1,2-恶唑
• 英文名称: 3-ethoxy-5-methyl-4-phenylisoxazole
• 英文别名: 3-ethoxy-5-methyl-4-phenyl-1,2-oxazole
• CAS: 146197-26-4
• 化学式: C₁₂H₁₃NO₂
• 分子量: 203.241
• InChiKey: NECKEUOMTKFPGD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  15
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  35.3
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  3-乙氧基-5-甲基-4-苯基-1,2-恶唑 在 N-溴代丁二酰亚胺(NBS) 、 sodium hydride 、 过氧化苯甲酰 作用下， 以 四氯化碳 、 N,N-二甲基甲酰胺 为溶剂， 反应 39.75h， 生成 2-Amino-3-(3-hydroxy-4-phenyl-isoxazol-5-yl)-propionic acid
  参考文献：
  名称：

  Synthesis and Pharmacology of 3-Isoxazolol Amino Acids as Selective Antagonists at Group I Metabotropic Glutamic Acid Receptors

  摘要：

  Using ibotenic acid (2) as a lead, two series of 3-isoxazolol amino acid ligands for (S)-glutamic acid (Glu, 1) receptors have been developed. Whereas analogues of (RS)-2-amino-3-(3-hydroxy5-methyl-4-isoxazolyl)propionic acid [AMPA, (RS)-3] interact selectively with ionotropic Glu receptors (iGluRs), the few analogues of (RS)-2-amino-3-(3-hydroxy-5-isoxazolyl)propionic acid [HIBO, (RS)-4] so far known typically interact with iGluRs as well as metabotropic Glu receptors (mGluRs). We here report the synthesis and pharmacology of a series of 4-substituted analogues of HIBO. The hexyl analogue 9 was shown to be an antagonist at group I mGluRs. The effects of 9 were shown to reside exclusively in (S)-9 (K-b = 30 muM at mGlu(1) and K-b = 61 muM at mGlu(5)). The lower homologue of 9, compound 8, showed comparable effects at mGluRs, but 8 also was a weak agonist at the AMPA subtype of iGluRs. Like 9, the higher homologue, compound 10, did not interact with iGluRs, but 10 selectively antagonized mGlu(1) (K-b = 160 muM) showing very weak antagonist effect at mGlu(5) (K-b = 990 muM). The phenyl analogue 11 turned out to be an AMPA agonist and an antagonist at mGlu(1) and mGlu(5), and these effects were shown to originate in (S)-11 (EC50 = 395 muM, K-b = 86 and 90 muM, respectively). Compound 9, administered icy, but not sc, was shown to protect mice against convulsions induced by N-methyl-D-aspartic acid (NMDA). Compounds 9 and 11 were resolved using chiral HPLC, and the configurational assignments of the enantiomers were based on X-ray crystallographic analyses.

  DOI：

  10.1021/jm000441t
• 作为产物：
  描述：

  3-乙氧基-5-甲基异噁唑 在 bis-triphenylphosphine-palladium(II) chloride 一氯化碘 、 碳酸氢钠 作用下， 以 乙二醇二甲醚 、 水 、 溶剂黄146 为溶剂， 反应 2.5h， 生成 3-乙氧基-5-甲基-4-苯基-1,2-恶唑
  参考文献：
  名称：

  通过钯催化的偶联反应方便地合成4-取代的3-乙氧基-5-甲基异恶唑

  摘要：

  使用3-乙氧基-4-碘-5-甲基异恶唑（4）作为关键中间体进行偶联反应。的耦合4铃木-宫浦或Stille条件下使用的Pd（PPh下3）2氯2和芳基硼酸或aryltin类似物，分别得到4-芳基取代的异恶唑在产率为49％，为3-吡啶基类似物14，至96 ％的4-吡啶类似物12。在Heck反应条件下使用Pd（PPh 3）2 Cl 2和4合成了在4-位含有乙烯基或炔基的3-乙氧基-5-甲基异恶唑的类似物，产率为58-98％。由4和异丙基溴化镁制得的3-乙氧基-5-甲基异恶唑-4-基溴化镁（19）与苯甲醛或苯甲酰氯平稳反应，得到所需的4- [羟基（苯基）甲基]类似物21和4-苯甲酰基- 3-乙氧基-5-甲基异恶唑（22）。的金属转移19与的ZnCl 2，并用的Pd（PPh后续处理3）2氯2和4-碘甲苯，得到3-乙氧基-5-甲基-4-（4-甲基苯基）异恶唑（23），产率为80％。

  DOI：

  10.1016/s0040-4020(01)00052-7

文献信息

• A convenient synthesis of 4-substituted 3-ethoxy-5-methylisoxazoles by palladium-catalyzed coupling reactions
  作者：Hasse Kromann、Frank A Sløk、Tommy N Johansen、Povl Krogsgaard-Larsen

  DOI：10.1016/s0040-4020(01)00052-7

  日期：2001.3

  The coupling reactions were performed using 3-ethoxy-4-iodo-5-methylisoxazole (4) as the key intermediate. Coupling of 4 under Suzuki–Miyaura or Stille conditions using Pd(PPh3)2Cl2 and arylboronic acids or aryltin analogues, respectively, gave 4-aryl substituted isoxazoles in yields ranging from 49% for the 3-pyridyl analogue 14, to 96% for the 4-pyridyl analogue 12. Under Heck reaction conditions

  使用3-乙氧基-4-碘-5-甲基异恶唑（4）作为关键中间体进行偶联反应。的耦合4铃木-宫浦或Stille条件下使用的Pd（PPh下3）2氯2和芳基硼酸或aryltin类似物，分别得到4-芳基取代的异恶唑在产率为49％，为3-吡啶基类似物14，至96 ％的4-吡啶类似物12。在Heck反应条件下使用Pd（PPh 3）2 Cl 2和4合成了在4-位含有乙烯基或炔基的3-乙氧基-5-甲基异恶唑的类似物，产率为58-98％。由4和异丙基溴化镁制得的3-乙氧基-5-甲基异恶唑-4-基溴化镁（19）与苯甲醛或苯甲酰氯平稳反应，得到所需的4- [羟基（苯基）甲基]类似物21和4-苯甲酰基- 3-乙氧基-5-甲基异恶唑（22）。的金属转移19与的ZnCl 2，并用的Pd（PPh后续处理3）2氯2和4-碘甲苯，得到3-乙氧基-5-甲基-4-（4-甲基苯基）异恶唑（23），产率为80％。
• Synthesis and Pharmacology of 3-Isoxazolol Amino Acids as Selective Antagonists at Group I Metabotropic Glutamic Acid Receptors
  作者：Ulf Madsen、Hans Bräuner-Osborne、Karla Frydenvang、Lise Hvene、Tommy N. Johansen、Birgitte Nielsen、Connie Sánchez、Tine B. Stensbøl、Francois Bischoff、Povl Krogsgaard-Larsen

  DOI：10.1021/jm000441t

  日期：2001.3.1

  Using ibotenic acid (2) as a lead, two series of 3-isoxazolol amino acid ligands for (S)-glutamic acid (Glu, 1) receptors have been developed. Whereas analogues of (RS)-2-amino-3-(3-hydroxy5-methyl-4-isoxazolyl)propionic acid [AMPA, (RS)-3] interact selectively with ionotropic Glu receptors (iGluRs), the few analogues of (RS)-2-amino-3-(3-hydroxy-5-isoxazolyl)propionic acid [HIBO, (RS)-4] so far known typically interact with iGluRs as well as metabotropic Glu receptors (mGluRs). We here report the synthesis and pharmacology of a series of 4-substituted analogues of HIBO. The hexyl analogue 9 was shown to be an antagonist at group I mGluRs. The effects of 9 were shown to reside exclusively in (S)-9 (K-b = 30 muM at mGlu(1) and K-b = 61 muM at mGlu(5)). The lower homologue of 9, compound 8, showed comparable effects at mGluRs, but 8 also was a weak agonist at the AMPA subtype of iGluRs. Like 9, the higher homologue, compound 10, did not interact with iGluRs, but 10 selectively antagonized mGlu(1) (K-b = 160 muM) showing very weak antagonist effect at mGlu(5) (K-b = 990 muM). The phenyl analogue 11 turned out to be an AMPA agonist and an antagonist at mGlu(1) and mGlu(5), and these effects were shown to originate in (S)-11 (EC50 = 395 muM, K-b = 86 and 90 muM, respectively). Compound 9, administered icy, but not sc, was shown to protect mice against convulsions induced by N-methyl-D-aspartic acid (NMDA). Compounds 9 and 11 were resolved using chiral HPLC, and the configurational assignments of the enantiomers were based on X-ray crystallographic analyses.