ethyl 6-methyl-2-thioxo-4-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate | 394226-76-7

• 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 6-methyl-2-thioxo-4-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate
• 英文别名: ethyl 6-methyl-2-sulfanylidene-4-[4-(trifluoromethyl)phenyl]-3,4-dihydro-1H-pyrimidine-5-carboxylate
• CAS: 394226-76-7
• 化学式: C₁₅H₁₅F₃N₂O₂S
• 分子量: 344.358
• InChiKey: XBCVWKGNLMRWBL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  23
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  82.4
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  ethyl 6-methyl-2-thioxo-4-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate 在 potassium carbonate 、 eosin Y bis(tetrabutyl ammonium salt) 作用下， 以 甲醇 、 水 、 丙酮 为溶剂， 生成 ethyl 4-methyl-2-(methylthio)-6-(4-(trifluoromethyl)phenyl)pyrimidine-5-carboxylate
  参考文献：
  名称：

  Synthesis of 2-substituted pyrimidines and benzoxazoles via a visible-light-driven organocatalytic aerobic oxidation: enhancement of the reaction rate and selectivity by a base

  摘要：

  利用有机光催化剂藻红Y双(四丁基铵盐)(TBA-藻红Y)和廉价氧化剂分子氧，已经实现了各种2-取代二氢嘧啶和酚亚胺的高效可见光驱动光催化氧化反应。在碱的辅助下，从底物二氢嘧啶或酚亚胺到TBA-藻红Y激发态的显著增强的光诱导电子转移，使得空气氧化能够选择性地生成2-(甲硫基)嘧啶或2-芳基苯并噁唑。

  DOI：

  10.1039/c4gc00337c
• 作为产物：
  描述：

  4-(三氟甲基)苄醇 在 二甲基亚砜 、 1-丙基磷酸酐 作用下， 以 乙酸乙酯 为溶剂， 反应 7.75h， 生成 ethyl 6-methyl-2-thioxo-4-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate
  参考文献：
  名称：

  T3P®-DMSO介导的一锅串联方法，从醇中合成3,4-二氢嘧啶-2（1H）-酮/硫酮

  摘要：

  背景：Biginelli反应是最重要的多组分化学反应之一，可产生3,4-dihydropyrimidin-2（1H）-ones。尽管有一个世纪以来使用不同的底物报道了Biginelli反应的报道，但文献中仍缺乏使用醇作为底物的例子。迄今为止，尚未探索用另一官能团取代醛组分。 方法：在本研究中，我们已使用丙基膦酸酐（T3P®）-DMSO作为从芳香族醇一锅合成3,4-二氢嘧啶-2（1H）-酮/硫酮的高效温和试剂。 结果：在温和的条件下，醇被原位氧化为醛，然后与β-酮酸酯和脲/硫脲进行三组分反应，生成3,4-二氢嘧啶-2（1H）-1 /硫酮。 结论：首次在温和的反应条件下以良好的收率首次从醇类直接合成3,4-二氢嘧啶-2（1H）-酮/硫酮。操作简便，成本低廉，试剂毒性小是该方案的主要优点。

  DOI：

  10.2174/1570178614666170720115044

文献信息

• Organocatalytic Application of Ionic Liquids: [bmim][MeSO4] as a Recyclable Organocatalyst in the Multicomponent Reaction for the Preparation of Dihydropyrimidinones and -thiones
  作者：Asit Chakraborti、Sudipta Roy、Pradeep Jadhavar、Kapileswar Seth、Kulin Sharma

  DOI：10.1055/s-0030-1260067

  日期：2011.7

  substitution in the latter. The ionic liquid can be recovered and reused for five consecutive reactions without significant loss of catalytic efficiency. The applicability of the methodology for large-scale reaction highlights its potential for bulk synthesis. ionic liquid - organocatalyst - multicomponent reaction - dihydropyrimidinone - dihydropyrimidinethione

  已经研究了基于1-丁基-3-甲基咪唑鎓的室温离子液体的有机催化潜力，该反应通过单锅多组分反应（包括醛，β-酮酸酯或β-二酮）合成二氢嘧啶酮和-硫酮，尿素或硫脲在短时间内的收率很高。研究了影响离子液体作为催化剂效率的因素，例如阴离子和咪唑鎓阳离子，特别是后者中C2取代的影响。可以回收离子液体并将其重新用于五个连续的反应，而不会显着降低催化效率。该方法用于大规模反应的适用性突出了其本体合成的潜力。 离子液体-有机催化剂-多组分反应-二氢嘧啶酮-二氢嘧啶硫酮
• Specific TLR4 Blocking Effect of a Novel 3,4-Dihydropyrimidinone Derivative
  作者：Mingqian Zhou、Yiqi Wang、Xiaoying Lin、Jieping Wan、Chengping Wen

  DOI：10.3389/fphar.2020.624059

  日期：——

  Background: Toll-like receptor 4 (TLR4) initiates both innate and adaptive immune responses, which plays an important protective role in self-defense mechanisms. Excessive or inappropriate TLR4 activation causes the development of many autoimmune diseases. Dihydropyrimidinone derivatives are medicinally important molecules with diverse pharmacological activities, including anti-inflammatory activity. The present study focused on novel synthesized 3,4-dihydropyrimidinone derivatives and evaluated their inhibitory effects on TLR4.

  Methods: A series of 3,4-dihydropyrimidinone derivatives were recently synthesized and evaluated for their TLR4 inhibition activities and cytotoxic on HEK-Blue^TM hTLR4 cells with the help of QUANTI-Blue assay and MTS assay. Selected compound 3 was analyzed for its molecular docking with TLR4 by using Autodock vina 1.1.2. Its effect on the TLR4 pathway related cytokines was also evaluated in THP-1 cells and human peripheral blood mononuclear cells by using real-time PCR, ELISA and western blot.

  Results: Five compounds were synthesized and characterized for effectiveness based on 3,4-dihydropyrimidinone. Compound 3 was found to be the potent hybrid among the synthesized compounds, with high TLR4 inhibition activities and low cytotoxic activities against HEK-Blue^TM hTLR4 cells. Molecular docking analysis showed that two hydrogen bonds between compound 3 and residues Asp209(TLR4) and Asp99(MD-2) mainly contribute to the TLR4 inhibition. In addition, compound 3 suppressed LPS-induced of the mRNA expression of TLR4, IP-10, TNF-α, IL-6, IL-12A, and IL-12B, the protein expression of pIRF3 and pNFκB and the secretion of IP-10, TNF-α in THP-1 cell line. Compound 3 also inhibited LPS-induced expression of TNF-α, IL-6, and IL-1β but increased IP-10 at mRNA levels in human peripheral blood mononuclear cells.

  Conclusion: Our study reveals compound 3, a novel 3,4-dihydropyrimidinone derivative, is a potential TLR4 antagonist, which opens up new research avenues for the development of promising therapeutic agents for inflammatory and autoimmune diseases.

  背景：Toll样受体4（TLR4）启动先天和适应性免疫反应，对自我防御机制起着重要的保护作用。过度或不适当的TLR4激活会导致许多自身免疫性疾病的发展。二氢嘧啶酮衍生物是具有多种药理活性的药物重要分子，包括抗炎活性。本研究重点研究了新合成的3,4-二氢嘧啶酮衍生物，并评估了它们对TLR4的抑制作用。 方法：最近合成了一系列3,4-二氢嘧啶酮衍生物，并通过QUANTI-Blue和MTS试验评估了它们对HEK-BlueTM hTLR4细胞的TLR4抑制活性和细胞毒性。选择的化合物3通过使用Autodock vina 1.1.2与TLR4的分子对接进行分析。同时，通过实时PCR、ELISA和Western blot在THP-1细胞和人外周血单个核细胞中评估了其对TLR4通路相关细胞因子的影响。 结果：合成了五种基于3,4-二氢嘧啶酮的有效化合物。化合物3被发现是合成化合物中最有效的混合物，对HEK-BlueTM hTLR4细胞具有高的TLR4抑制活性和低的细胞毒性活性。分子对接分析显示，化合物3与残基Asp209（TLR4）和Asp99（MD-2）之间的两个氢键主要贡献于TLR4的抑制作用。此外，化合物3抑制了LPS诱导的TLR4、IP-10、TNF-α、IL-6、IL-12A和IL-12B mRNA表达，抑制了THP-1细胞中pIRF3和pNFκB蛋白表达及IP-10、TNF-α的分泌。化合物3还抑制了LPS诱导的人外周血单个核细胞中TNF-α、IL-6和IL-1β的表达，但增加了IP-10的mRNA水平。 结论：本研究揭示了化合物3，一种新型的3,4-二氢嘧啶酮衍生物，是潜在的TLR4拮抗剂，为开发有前途的治疗炎症和自身免疫性疾病的治疗药物开辟了新的研究途径。
• Abdollahi, Narges; Kiasat, Ali Reza; Saghanezhad, Seyyed Jafar, Revue Roumaine de Chimie, 2016, vol. 61, # 3, p. 159 - 167
  作者：Abdollahi, Narges、Kiasat, Ali Reza、Saghanezhad, Seyyed Jafar

  DOI：——

  日期：——
• Bio-Based Solvent Mediated Synthesis of Dihydropyrimidinthiones Via Biginelli Reaction
  作者：Zhen Xu、Yangyang Jiang、Shuang Zou、Yunyun Liu

  DOI：10.1080/10426507.2013.855767

  日期：2014.6.3

  The three-component Biginelli reaction using aldehyde, thiourea, and 1,3-dicarbonyl compounds was performed smoothly in ethyl lactate (EL) with the catalysis of trimethylsilyl chloride (TMSCl). A class of 3,4-dihydropyrimidinthiones (DHPMs) were synthesized in good to excellent yields via the bio-based solvent mediated catalytic protocol.
• Pd-catalyzed regioselective tandem C-S/C-N bond formation for modular synthesis of pyrimidine-fused benzothiazoles from o-dihaloarenes and 3,4-dihydropyrimidin-2-thiones
  作者：xuying hu、ruiqi Liu、shiwen Fu、Lianxu Shi、Chunxia Chen、Jinsong Peng

  DOI：10.1055/a-2311-3930

  日期：——

  A Pd-catalyzed annulation reaction for the synthesis of 4H-pyrimido[2,1-b]benzothiazole derivatives via regioselective tandem C-S/C-N bond formation was developed. With PdCl2(PPh3)2 as the precatalyst, Davephos as the ligand, and K2CO3 as the base, various 3,4-dihydropyrimidin-2-thiones with o-dihaloarenes proceeded smoothly, and the desired products were obtained in moderate to good yields