2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-6-methoxyaniline | 63478-14-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: 2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-6-methoxyaniline
• 英文别名: 2-(2-amino-3-methoxyphenyl)-4,4-dimethyl-2-oxazoline；2-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-6-methoxy-aniline；2-(4,4-dimethyl-5H-1,3-oxazol-2-yl)-6-methoxyaniline
• CAS: 63478-14-8
• 化学式: C₁₂H₁₆N₂O₂
• 分子量: 220.271
• InChiKey: BXFBKNHDMOWOLV-UHFFFAOYSA-N

物化性质

• 熔点：
  113-114 °C(Solv: ethanol (64-17-5); water (7732-18-5))
• 沸点：
  356.1±32.0 °C(Predicted)
• 密度：
  1.18±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  16
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  56.8
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-6-methoxyaniline 在 盐酸 、 甲醇 、 sodium hydroxide 作用下， 生成 2-氨基-3-甲氧基苯甲酸
  参考文献：
  名称：

  有机合成中的新方法和试剂。92.替格伐林及其类似物的立体选择性合成

  摘要：

  Tilivalline（1a），肺炎克雷伯菌的一种代谢产物。催产素及其衍生物1已由叠氮基磷酸二苯酯，2-恶唑啉2，L-脯氨酸衍生物5和吲哚有效地和立体选择性地合成；关键步骤是伴随完全立体选择性引入吲哚的曼尼希型分子内环化反应。此外，通过使用这种新的曼尼希型环化反应，还由乙缩醛酰胺9a和各种亲核试剂合成了11个取代的5 H-吡咯并[2,1- c ] [1,4]苯并二氮杂-5-酮（16）。。

  DOI：

  10.1016/s0040-4020(01)80968-6
• 作为产物：
  描述：

  3-(4,4-dimethyloxazolin 2-yl)anisole 生成 2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-6-methoxyaniline
  参考文献：
  名称：

  有机合成中的新方法和试剂。65.替格伐林的立体选择性合成

  摘要：

  Tilivalline（1）是克雷伯氏菌的代谢物，已由叠氮基磷酸二苯酯（DPPA），2-恶唑啉2，L-脯氨酸衍生物5和吲哚有效地和立体选择性地合成：关键步骤是曼尼希型分子内环化反应并伴随同时并完全立体选择性地引入吲哚。

  DOI：

  10.1016/s0040-4039(00)85411-8

文献信息

• Identification, Design and Biological Evaluation of Bisaryl Quinolones Targeting <i>Plasmodium falciparum</i> Type II NADH:Quinone Oxidoreductase (PfNDH2)
  作者：Chandrakala Pidathala、Richard Amewu、Bénédicte Pacorel、Gemma L. Nixon、Peter Gibbons、W. David Hong、Suet C. Leung、Neil G. Berry、Raman Sharma、Paul A. Stocks、Abhishek Srivastava、Alison E. Shone、Sitthivut Charoensutthivarakul、Lee Taylor、Olivier Berger、Alison Mbekeani、Alasdair Hill、Nicholas E. Fisher、Ashley J. Warman、Giancarlo A. Biagini、Stephen A. Ward、Paul M. O’Neill

  DOI：10.1021/jm201179h

  日期：2012.3.8

  the selection of 2-bisaryl 3-methyl quinolones as a series for further biological evaluation. The lead compound within this series 7-chloro-3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(1H)-one (CK-2-68) has antimalarial activity against the 3D7 strain of P. falciparum of 36 nM, is selective for PfNDH2 over other respiratory enzymes (inhibitory IC50 against PfNDH2 of 16 nM), and demonstrates

  进行了一项计划来鉴定针对 NADH 的命中化合物：泛醌氧化还原酶 (PfNDH2)，这是一种疟疾寄生虫恶性疟原虫线粒体电子传递链的脱氢酶. PfNDH2 只有一种已知抑制剂，羟基-2-十二烷基-4-(1H)-喹诺酮 (HDQ)，它与一系列化学信息学方法一起用于合理选择 17000 种化合物以进行高通量筛选。确定并简要检查了 12 种不同的化学型，导致选择喹诺酮核心作为构效关系 (SAR) 发展的关键目标。广泛的结构探索导致选择 2-双芳基 3-甲基喹诺酮作为进一步生物学评价的系列。该系列中的先导化合物 7-chloro-3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(1H)-one (CK-2-68) 对 3D7 具有抗疟活性36 nM 的恶性疟原虫菌株对 PfNDH2 的选择性高于其他呼吸酶（抑制性 IC50对 PfNDH2
• 2-Pyridylquinolone antimalarials with improved antimalarial activity and physicochemical properties
  作者：Sitthivut Charoensutthivarakul、W. David Hong、Suet C. Leung、Peter D. Gibbons、Paul T. P. Bedingfield、Gemma L. Nixon、Alexandre S. Lawrenson、Neil G. Berry、Stephen A. Ward、Giancarlo A. Biagini、Paul M. O'Neill

  DOI：10.1039/c5md00062a

  日期：——

  2-Pyridylquinolones with improved solubility, an improved metabolic stability profile, reduced off-target toxicity and 12 nM Plasmodium falciparum antimalarial activity are described.

  描述了具有改善溶解性、改善代谢稳定性、减少非靶标毒性和12 nM Plasmodium falciparum 抗疟活性的2-吡啶基喹啉类化合物。
• New methods and reagents in organic synthesis. 65. A stereoselective synthesis of tilivalline
  作者：Shigehiro Mori、Toyohiko Aoyama、Takayuki Shioiri

  DOI：10.1016/s0040-4039(00)85411-8

  日期：——

  Tilivalline (1), a metabolite from Klebsiella, has been efficiently and stereoselectively synthesized from diphenyl phosphorazidate (DPPA), the 2-oxazoline 2, the L-proline derivative 5, and indole: the key step is a Mannich type intramolecular cyclization accompanied with simultaneous and completely stereoselective introduction of indole.

  Tilivalline（1）是克雷伯氏菌的代谢物，已由叠氮基磷酸二苯酯（DPPA），2-恶唑啉2，L-脯氨酸衍生物5和吲哚有效地和立体选择性地合成：关键步骤是曼尼希型分子内环化反应并伴随同时并完全立体选择性地引入吲哚。
• The displacement of methoxy by amino groups in aryloxazolines. A novel approach to o-amino, o-alkylamino, and o-dialkylaminobenzoic acids
  作者：A. I. Meyers、Richard Gabel

  DOI：10.1021/jo00435a036

  日期：1977.7
• Identification, Design and Biological Evaluation of Heterocyclic Quinolones Targeting <i>Plasmodium falciparum</i> Type II NADH:Quinone Oxidoreductase (PfNDH2)
  作者：Suet C. Leung、Peter Gibbons、Richard Amewu、Gemma L. Nixon、Chandrakala Pidathala、W. David Hong、Bénédicte Pacorel、Neil G. Berry、Raman Sharma、Paul A. Stocks、Abhishek Srivastava、Alison E. Shone、Sitthivut Charoensutthivarakul、Lee Taylor、Olivier Berger、Alison Mbekeani、Alasdair Hill、Nicholas E. Fisher、Ashley J. Warman、Giancarlo A. Biagini、Stephen A. Ward、Paul M. O’Neill

  DOI：10.1021/jm201184h

  日期：2012.3.8

  Following a program undertaken to identify hit compounds against NADH:ubiquinone oxidoreductase (PfNDH2), a novel enzyme target within the malaria parasite Plasmodium falciparum, hit to lead optimization led to identification of CK-2-68, a molecule suitable for further development. In order to reduce ClogP and improve solubility of CK-2-68 incorporation of a variety of heterocycles, within the side chain of the quinolone core, was carried out, and this approach led to a lead compound SL-2-25 (8b). 8b has IC(50)s in the nanomolar range versus both the enzyme and whole cell P. falciparum (IC50 = 15 nM PfNDH2; IC50 = 54 nM (3D7 strain of P. falciparum) with notable oral activity of ED50/ED90 of 1.87/4.72 mg/kg versus Plasmodium berghei (NS Strain) in a murine model of malaria when formulated as a phosphate salt. Analogues in this series also demonstrate nanomolar activity against the bc(1) complex of P. falciparum providing the potential added benefit of a dual mechanism of action. The potent oral activity of 2-pyridyl quinolones underlines the potential of this template for further lead optimization studies.