ethyl 4-(2,6-difluorophenyl)-2-methyl-3-oxobutanoate | 221121-48-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: ethyl 4-(2,6-difluorophenyl)-2-methyl-3-oxobutanoate
• CAS: 221121-48-8
• 化学式: C₁₃H₁₄F₂O₃
• 分子量: 256.249
• InChiKey: SEHOQOLCHASFSR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  18
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  43.4
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  ethyl 4-(2,6-difluorophenyl)-2-methyl-3-oxobutanoate 在 sodium ethanolate 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 29.0h， 生成 6-(2,6-difluorophenylmethyl)-3,4-dihydro-5-methyl-2-methylthiopyrimidin-4-one
  参考文献：
  名称：

  5-Alkyl-2-(alkylthio)-6-(2,6-dihalophenylmethyl)-3,4-dihydropyrimidin-4(3H)-ones:  Novel Potent and Selective Dihydro-alkoxy-benzyl-oxopyrimidine Derivatives

  摘要：

  Molecular modeling analysis of compounds belonging to the recently published series of dihydroalkoxy-benzyl-oxopyrimidines (DABOs), such as S-DABOs and DATNOs, gave support to the design of new 2,6-disubstituted benzyl-DABO derivatives as highly potent and specific inhibitors of the HIV-1 reverse transcriptase (RT). To follow up on the novel DABO derivatives, we decided to investigate the effect of electron-withdrawing substituents in the benzyl unit of the S-DABO skeleton versus their anti-HIV-1 activity. Such chemical modifications impacted the inhibitory activity, especially when two halogen units were introduced at positions 2 and 6 in the phenyl portion of the benzyl group bound to C-6 of the pyrimidine ring. Various 5-alkyl-2-(alkyl(or cycloalkyl)thio)-6-(2,B-dichloro(or 2, 6-difluoro)phenylmethyl)-3,4-dihydropyrimidin-4(3H)-ones were then synthesized and tested as anti-HIV-1 agents in both cell-based and enzyme (recombinant reverse transcriptase, rRT) assays. Among the various mono- and disubstituted phenyl derivatives, the most potent were those containing a 6-(2,6-difluorophenylmethyl) substituent (F-DABOs), which showed EC50's ranging between 40 and 90 nM and selectivity indexes up to greater than or equal to 5000. An excellent correlation was found between EC50 and IC50 values which confirmed that these compounds act as inhibitors of the HIV-1 RT. The structure-activity relationships of the newly synthesized pyrimidinones are presented herein.

  DOI：

  10.1021/jm980260f
• 作为产物：
  描述：

  2,6-二氟苯乙酸 在 三乙胺 、 magnesium chloride 作用下， 以 乙腈 为溶剂， 反应 2.0h， 生成 ethyl 4-(2,6-difluorophenyl)-2-methyl-3-oxobutanoate
  参考文献：
  名称：

  具有亚纳摩尔级抗HIV-1活性的新S-DABO衍生物的平行溶液相和微波辅助合成。

  摘要：

  已经建立了用于平行溶液相合成的简单而有效的方法，以获得一系列硫尿嘧啶，然后在微波辐射下选择性地将S-苄基化，得到新的S-DABO。生物筛选导致鉴定出对高度纯化的重组人免疫缺陷病毒1型（HIV-1）逆转录酶（RT）酶（野生型和突变型）和野生型（wt）和突变型HIV具有纳摩尔活性的化合物-1株。特别是，发现20种是迄今为止报道的最有效的S-DABO（针对分离的wt酶的ID50 = 26 nM），对wt和多抗性病毒（IRLL98）HIV-1菌株均具有亚纳摩尔活性（EC50 <0.14 nM和EC50分别为0.22 nM）。

  DOI：

  10.1021/jm050744t

文献信息

• Solution-phase parallel synthesis of S-DABO analogues
  作者：Andrea Togninelli、Caterina Carmi、Elena Petricci、Claudia Mugnaini、Silvio Massa、Federico Corelli、Maurizio Botta

  DOI：10.1016/j.tetlet.2005.10.142

  日期：2006.1

  A simple and straightforward methodology for the parallel, solution-phase synthesis of a new series of S-DABO derivatives 1 and 2, bearing aromatic substituents at the C2 and C6 positions, has been developed. Starting from potassium ethyl malonates 3, thiouracil intermediates 5 were prepared through parallel synthesis and isolated as pure products by simple extraction with ethyl acetate. Selective

  已经开发出一种简单，直接的方法，用于平行，溶液相合成一系列在C2和C6位置带有芳族取代基的S -DABO衍生物1和2。从丙二酸乙基钾3出发，通过平行合成制备硫尿嘧啶中间体5，并通过用乙酸乙酯简单萃取将其分离为纯产物。在微波辐射下，在几分钟内完成5的选择性S-苄基化反应，得到标题化合物1，与相应的砜2平行氧化。一些新化合物1 对HIV-1 RT显示出有效的抑制活性。
• Discovery of Dihydro-Alkyloxy-Benzyl-Oxopyrimidines as Promising Anti-Influenza Virus Agents
  作者：Mingyan Yu、Ailin Liu、Guanhua Du、Lieve Naesens、Evelien Vanderlinden、Erik De Clercq、Xinyong Liu

  DOI：10.1111/j.1747-0285.2011.01180.x

  日期：2011.10

  and A/H3N2 subtype, respectively) and influenza B viruses (EC50: 33 μm). The antiviral mechanism of action of these dihydro‐alkyloxy‐benzyl‐oxopyrimidine derivatives must be quite different from that of the currently approved anti‐influenza virus drugs that target the viral M2 or neuraminidase proteins. The dihydro‐alkyloxy‐benzyl‐oxopyrimidine derivatives represent a new avenue for further optimization

  合成了一系列新颖的二氢-烷氧基-苄基-氧嘧啶衍生物，并评估了它们在Madin-Darby犬肾细胞中对流感病毒的活性。四个二氢-烷氧基苄基oxopyrimidine衍生物（4A1，4A2，4A3，和4D1）显示对流感病毒有效的活性。其中，化合物4A3与抗流感A宽的活性最有前途的引线（抗病毒EC 50倍的图9和18的值 μ米分别用于A / H1N1和A / H3N2亚型）和B型流感病毒（EC 50：33  μ米）。这些二氢-烷氧基-苄基-氧嘧啶衍生物的抗病毒作用机制必须与目前批准的针对病毒M2或神经氨酸酶蛋白的抗流感病毒药物完全不同。二氢烷氧基苄基氧嘧啶衍生物代表了进一步优化和开发新型抗流感病毒剂的新途径。
• Synthesis and Biological Evaluation of 6-Substituted 5-Alkyl-2-(phenylaminocarbonylmethylthio)pyrimidin-4(3H)-ones as Potent HIV-1 NNRTIs
  作者：Mingyan Yu、Zhenyu Li、Shuai Liu、Erkang Fan、Christophe Pannecouque、Erik De Clercq、Xinyong Liu

  DOI：10.1002/cmdc.201000555

  日期：2011.5.2

  A series of new 5‐alkyl‐2‐phenylaminocarbonylmethylthiopyrimidin‐4(3H)‐ones bearing variously substituted arylmethyl moieties at the C6 position of the pyrimidine ring were synthesized and evaluated for anti‐HIV activity in MT‐4 cells. Most of these new congeners exhibited moderate to good activities against the wild‐type virus, with EC50 values in the range of 1.40–0.19 μM. Among them, 2‐[(4‐cyan

  合成了一系列新的5-烷基-2-苯基氨基羰基甲基硫嘧啶-4（3 H）-在嘧啶环的C6位带有不同取代的芳基甲基的部分，并评估了其在MT-4细胞中的抗HIV活性。大多数这些新的同系物表现出中度到对野生型病毒的创先争优活动，与EC 50个在1.40-0.19μ的范围值中号。其中2-[（（4-氰基苯基氨基）羰基甲硫基] -6-（2-氯-6-氟苄基）-5-乙基嘧啶-4（3 H）-一4 b6是被赋予最高的宽泛度的化合物之一。光谱HIV-1的抑制活性，以EC 50个为0.19±0.005μ值中号对野生型病毒，1.05±0.24μ中号（双重抵抗）的E138K应变，和2.38±0.13μ中号（4.5倍的抗性）压靠在Y181C菌株。此外，使用选定的衍生物进行了针对野生型HIV-1 RT的逆转录酶（RT）抑制试验，证实了这些化合物的主要靶标是HIV-1 RT，并且这些新的S -DABO类似物充当了非核苷RT。抑制
• Diarylpyrimidine−Dihydrobenzyloxopyrimidine Hybrids: New, Wide-Spectrum Anti-HIV-1 Agents Active at (Sub)-Nanomolar Level
  作者：Dante Rotili、Domenico Tarantino、Marino Artico、Maxim B. Nawrozkij、Emmanuel Gonzalez-Ortega、Bonaventura Clotet、Alberta Samuele、José A. Esté、Giovanni Maga、Antonello Mai

  DOI：10.1021/jm101626c

  日期：2011.4.28

  Here, we describe a novel small series of non-nucleoside reverse transcriptase inhibitors (NNRTIs) that combine peculiar structural features of diarylpyrimidines (DAPYs) and dihydro-alkoxy-benzyl-oxopyrimidines (DABOs). These DAPY−DABO hybrids (1−4) showed a characteristic SAR profile and a nanomolar anti-HIV-1 activity at both enzymatic and cellular level. In particular, the two compounds 4d and 2d

  在这里，我们描述了一个新颖的小系列非核苷类逆转录酶抑制剂（NNRTIs），该抑制剂结合了二芳基嘧啶（DAPYs）和二氢-烷氧基-苄基-氧嘧啶（DABOs）的独特结构特征。这些DAPY-DABO杂种（1 - 4）显示出特征的SAR轮廓和在两个酶活性和细胞水平纳摩尔的抗HIV-1活性。特别是，对野生型和临床相关的HIV-1突变株具有（亚）纳摩尔活性的两种化合物4d和2d被选作主要化合物，用于下一步的优化研究。
• Dihydro-alkylthio-benzyl-oxopyrimidines as Inhibitors of Reverse Transcriptase: Synthesis and Rationalization of the Biological Data on Both Wild-Type Enzyme and Relevant Clinical Mutants
  作者：Claudia Mugnaini、Maddalena Alongi、Andrea Togninelli、Harsukh Gevariya、Antonella Brizzi、Fabrizio Manetti、Cesare Bernardini、Lucilla Angeli、Andrea Tafi、Luca Bellucci、Federico Corelli、Silvio Massa、Giovanni Maga、Alberta Samuele、Marcella Facchini、Imma Clotet-Codina、Mercedes Armand-Ugón、José A. Esté、Maurizio Botta

  DOI：10.1021/jm0708230

  日期：2007.12.27

  A series of novel S-DABO analogues, characterized by different substitution patterns at positions 2, 5, and 6 of the heterocyclic ring, were synthesized in a straightforward fashion by means of parallel synthesis and evaluated as inhibitors of human immunodeficiency virus type-1 (HIV-1). Most of the compounds proved to be highly active on the wild-type enzyme both in enzymatic and cellular assays, with one of them emerging as the most active reverse transcriptase inhibitor reported so far (EC50wt = 25 pM). The general loss of potency displayed by the compounds toward clinically relevant mutant strains was deeply studied through a molecular modeling approach, leading to the evidence that the dynamic of the entrance in the non-nucleoside binding pocket could represent the basis of the inhibitory activity of the molecules.