含三氟甲硫基的酮、烯烃及芳烃的合成研究及生物活性测试

发布时间：2018-03-05 09:01

本文选题：三氟甲硫基化　切入点：末端炔　出处：《华东理工大学》2017年博士论文　论文类型：学位论文

【摘要】：三氟甲硫基(CF_3S)具有强的电负性和亲酯性,向药物分子中引入CF_3S基团能够增强药物的膜穿透性以及代谢稳定性,从而达到提高药效的作用。因此,含三氟甲硫基化合物在医药、农药、材料等领域有着广泛的用途。近年来,高效合成含CF_3S基团的化合物也成为有机合成和有机氟化学的研究热点。本论文以α-CF_3S取代酮、烯基三氟甲硫基醚、芳基三氟甲硫基醚三类化合物的合成为研究目标,通过三氟甲硫基化试剂的选择、反应条件的筛选、底物的选择,分别经亲电、自由基、以及氧化三氟甲硫基化反应,研究出这三类化合物高效、新颖的合成方法,并提出相应的反应机理。我们还对部分目标产物进行了初步的生物活性测试。1.在第二章中,我们研究了一种以亲电性的PhNHSCF_3为三氟甲硫基化试剂,在乙酰氯存在下,室温时将酮类化合物α-氢进行三氟甲硫基化的反应。该反应具有较好的底物拓展性、官能团耐受性以及区域选择性,避免了底物预先官能团化等优点。该方法能够以中等到较好的收率得到目标产物。另外,我们还对合成的31个化合物进行了细胞毒性测试,发现部分化合物对HepG2细胞具有很强的抑制活性,其中化合物3y、3k比对照药白藜芦醇的活性高将近3倍。2.在第三章中,我们研究了在AgSCF_3/K_2S_2O_8体系下,由末端炔烃制备烯基三氟甲硫基醚的反应。通过条件的改变,我们能以中等到较好的收率分别得到单一性反马氏和马氏加成的三氟甲硫基化烯烃。在对反马氏选择氢化三氟甲硫基化反应的机理研究中,我们通过一系列氘代实验发现产物中的两个氢分别来自于水和溶剂DMF。另外结合自由基验证实验、动力学同位素实验以及对照实验,我们推测该反应机理是经由自由基途径进行的。该反应为合成烯基三氟甲硫基醚类化合物提供了另一种的途径。3.在第四章中,我们研究了一种以10 mol%CuI为催化剂、20 mol%bpy为配体、AgSCF_3为三氟甲硫基源和氧化剂,对芳基硼酸进行直接三氟甲硫基化的反应。该反应具有较好的底物拓展性和官能团耐受性。反应过程中无须额外氧化剂的加入。通过一系列对照实验,我们证实了 AgSCF_3既是三氟甲硫基源又是氧化剂,还证明了反应机理是经过(bpy)CuSCF_3活性物种。该反应的优势在于避免了将AgSCF_3转变成亲电的三氟甲硫基化试剂或提前制备(bpy)CuSCF_3。我们还对合成的21个化合物进行了细胞毒性测试,发现部分化合物对HepG2细胞具有较强的抑制活性。
[Abstract]:CF3S) has strong electronegativity and lipophilicity. The introduction of CF_3S group into the drug molecule can enhance the membrane penetration and metabolic stability of the drug, thereby improving its efficacy. Therefore, the trifluoromethylthioyl compound is used in medicine. Pesticides, materials and other fields have been widely used. In recent years, the highly efficient synthesis of compounds containing CF_3S groups has also become a research hotspot in organic synthesis and organic fluorochemistry. The synthesis of three kinds of aryl trifluoromethyl thioether compounds was studied. Through the selection of trifluoromethylthionization reagent, reaction conditions, substrate selection, electrophilic reaction, free radical reaction and trifluoromethylthionylation reaction, The efficient and novel synthesis methods of these three kinds of compounds have been studied, and the corresponding reaction mechanism has been put forward. We have also carried out a preliminary bioactivity test for some target products. In Chapter 2, In the presence of acetyl chloride, a trifluoromethylthionylation reaction of ketones 伪 -hydrogen at room temperature with electrophilic PhNHSCF_3 as trifluoromethylthionization reagent has been studied. Functional group tolerance and regioselectivity can avoid the advantages of substrate prefunctionalization. This method can obtain the target product in medium to better yield. In addition, we have also tested the cytotoxicity of 31 synthesized compounds. It was found that some of the compounds had strong inhibitory activity on HepG2 cells, and the activity of compound 3yt3k was nearly 3 times higher than that of the control drug resveratrol. In Chapter 3, we studied the activity of resveratrol in AgSCF_3/K_2S_2O_8 system. The preparation of alkyltrifluoromethyl thioether from terminal alkynes. We can obtain the trifluoromethylthioalkenes with the unique anti-Markov and Mahalanobenzene addition in moderate to better yields. In the mechanism of the anti-Markov selective hydrogenation of trifluoromethyl sulphide, we have studied the mechanism of the sulfidation of trifluoromethyl trifluoromethyltrifluoromethylthionates. Through a series of deuterium experiments, we found that two of the hydrogen in the product came from water and solvent DMF, respectively. In addition, we combined the free radical verification experiment, the kinetic isotope experiment and the control experiment. We speculate that the reaction mechanism is carried out by free radical pathway. This reaction provides another way for the synthesis of trifluoromethyl thioether compounds. 3. In Chapter 4th, Using 10 mol%CuI as catalyst and 20 mol%bpy as ligand, AgSCF3 was used as trifluoromethylthio source and oxidant. The reaction of direct trifluoromethylthiylation of aryl boric acid was carried out. The reaction had good substrate expansibility and functional group tolerance. No additional oxidant was needed during the reaction. A series of controlled experiments were carried out. We have confirmed that AgSCF_3 is both a trifluoromethylthio source and an oxidant. It has also been proved that the reaction mechanism is through the active species of CuSCF3. The advantage of this reaction is that it avoids the conversion of AgSCF_3 to electrophilic trifluoromethylthionization reagents or the preparation of pyridine CuSCFs in advance. We have also tested the cytotoxicity of the 21 compounds synthesized. It was found that some of the compounds had strong inhibitory activity on HepG2 cells.
【学位授予单位】：华东理工大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：O621.25

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