含2-甲基苯并咪唑基异黄酮衍生物的合成及抗氧化活性研究
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摘要
本论文报道一类苯并咪唑基异黄酮类衍生物的合成方法。以取代苯乙酸和间苯二酚为起始原料,用微波辐射法合成脱氧安息香(3),(3)与乙酸酐缩合生成2-甲基-7-乙酰氧基异黄酮(4),(4)在酸性条件下水解生成相应的异黄酮(5),化合物(5)分别与1,2-二溴乙烷和1,3-二溴丙烷反应生成(6)和(7),化合物(6)和(7)再分别与2-甲基苯并咪唑偶合生成目标化合物。本方法经5步反应合成了10种含苯并咪唑基异黄酮衍生物,包括中间体在内共合成了35种化合物,经IR,~1H NMR,~(13)C NMR,元素分析等对目标化合物及相关中间体结构进行了确证。经CA检索,10种目标化合物均未见文献报道。在合成这些目标化合物的过程中,优化了复杂结构中C-O键和C-N键建立的反应条件,同时把微波催化引入了多步反应过程中,使反应时间大大缩短。对10种目标化合物的抗氧化活性进行了初步研究,结果表明这10种目标化合物都具有较强的清除羟基自由基的能力。抗氧化活性实验结果还提示我们所合成的异黄酮衍生物清除羟基自由基能力的强弱,不仅与其所连的羟基的数目和7-位羟基所连的脂肪链的长短有关,而且与7-位羟基所连的其它基团的结构有关。10种目标化合物的其它活性有待进一步研究。
本论文主要包括以下三部分:
第1章综述了近年来异黄酮类衍生物的研究进展。主要分为两个方面:1)合成方法研究进展。合成异黄酮类衍生物的主要方法有:脱氧安息香法、重排反应法、Pd-催化交叉偶联法、一锅法、微波合成法等。其中脱氧安息香法由于其原料易得,反应条件温和而备受人们青睐,是目前应用最广泛的异黄酮合成法。2)药理活性研究概述。异黄酮类衍生物具有多种药理活性:如杀菌活性、抗癌作用、抗病毒作用、抗骨质疏松作用、治疗心血管疾病等。
第2章设计并合成了10种目标化合物:2-甲基-4′-氯-7-(2-(1-(2-甲基苯并咪唑基))乙氧基)异黄酮(1a)、2,4′-二甲基-7-(2-(1-(2-甲基苯并咪唑基))乙氧基)异黄酮(1b)、2-甲基-7-(2-(1-(2-甲基苯并咪唑基))乙氧基)异黄酮(1c)、2-甲基-4′-甲氧基7-(2-(1-(2-甲基苯并咪唑基))乙氧基)异黄酮(1d)、2-甲基-4′-羟基-7-(2-(1-(2-甲基苯并咪唑基))乙氧基)异黄酮(1e)、2-甲基-4′-氯-7-(3-(1-(2-甲基苯并咪唑基))丙氧基)异黄酮(2a)、2,4′-二甲基-7-(3-(1-(2-甲基苯并咪唑基))丙氧基)异黄酮(2b)、2-甲基-7-(3-(1-(2-甲基苯并咪唑基))丙氧基)异黄酮(2c)、2-甲基-4′-甲氧基-7-(3-(1-(2-甲基苯并咪唑基))丙氧基)异黄酮(2d)、2-甲基-4′-羟基-7-(3-(1-(2-甲基苯并咪唑基))丙氧基)异黄酮(2e)。经JR,~1H NMR,~(13)C NMR,元素分析等对其结构进行了表征,10种目标化合物均未见文献报道。
第3章目标化合物的抗氧化活性初步研究。本文采用番红花红T-Mn~(2+)-H_2O_2光度法测定了10种目标化合物清除羟基自由基的能力。实验结果表明2-甲基苯并咪唑基的引入,增强了异黄酮的生物活性,10种目标化合物都具有较强的清除羟基自由基的能力。其它生物活性有待进一步研究。
A method for the synthesis of 2-methyl-benzimidazolyl isoflavone derivatives have been reported.Deoxybenzoin(3) was prepareded by using the resorcinol and substituted phenylacetic as starting meterials in microwave-mediated.Then the compound(3) was reacted with acetic anhydride to produce(4).The compound(4) was hydrolyzed to convert compound(5) in the acid-mediated. The compound(5) was reacted with the 1,2-dibromo-ethane and 1,3-dibromo-propane in refluxed condition with acetone as solvent to give(6) or(7),respectively.Lastly,the title compounds were synthesized by refluxing(6) or(7) with 2-methyl-benzimidazole and potassium carbonate in acetone solution.In this method,thirty-five compounds including ten kinds of 2-methyl-benzimidazolyl isoflavone derivatives were synthesized via five steps.All the structures of target compounds were confirmed by IR,~1H NMR,~(13)C NMR,elemental analysis and so on.The target compounds have not been reported in documents so far by way of searching sciFinder Scholar.During synthesis of all target compounds,we not only have optimized the reaction condition of C-O bond and C-N bond but also have introduced successfully the microwave promoting method to our protocol which shortened the reaction time greatly.The antioxidative ability of ten target compounds have been investigated, all of them possess good scavenging capacity to free radical.The results of experiment on radical scavenging effect suggest that the ability of scavenging radical not only releted to the numbers of hydroxyl and the length of allyl-chain which join with 7-hydroxy but also possibly releted to the structure of the group which join with 7-hydroxy.The other actives of ten target compounds will be further undergoes in future.
This thesis is consisted of three parts as follows:
Chapter one,the researching progress in the derivatives of isoflavone was described.There are mainly involving two aspects:The section one is researching progress in synthetic methods.For example,deoxybenzoin method,oxidation rearrangement,Pd-catalyzed cross-coupling method, one-pot method and microwave-mediated synthesis et al.Currently,deoxybenzoin method is applied extensively because of facile materials and mild reaction condition.The section two is researching progress in the pharmacological effects of isoquinolinones such as disinfection,anticancer, antifungal,antiosteporosis and therapy vascular diseases.
Chapter two,ten target compounds were designed and synthesized by our protocol. 4'-chloro-2-methyl-7-(2-(1H-(2-methyl-benzimidazole)-1-yl)ethoxy) isoflavone(1a),2,4'-dimethyl -7-(2-(1H-(2-methyl-benzimidazole)-1-yl)ethoxy) isoflavone(1b),2-methyl-7-(2-(1H-(2-methyl-benzimidazole) -1-yl)ethoxy) isoflavone(1c),4'-methoxy-2-methyl-7-(2-(1H-(2-methyl-benzimidazole) -1-yl)ethoxy) isoflavone(1d),4'-hydroxy-2-methyl-7-(2-(1H-(2-methyl-benzimidazole) -1-yl)ethoxy) isoflavone(1e),4'-chloro-2-methyl-7-(3-(1H-(2-methyl-benzimidazole) -1-yl)propoxy) isoflavone(2a),2,4'-dimethyl-7-(3-(1H-(2-methyl-benzimidazole) -1-yl)propoxy) isoflavone(2b),2-methyl-7-(3-(1H-(2-methyl-benzimidazole)-1-yl)propoxy) isoflavone(2c),4'-methoxy-2-methyl-7-(3-(1H-(2-methyl-benzimidazole)-1-yl)propoxy) isoflavone (2d),4'-hydroxy-2-methyl-7-(3-(1H-(2-methyl-benzimidazole)-1-yl)propoxy) isoflavone(2e).All of these target compounds were never reported so far,and their structure were confirmed by IR,~1H NMR,~(13)C NMR,elemental analysis.
Chapter three,a pilot evaluation on their antioxidative activity of the title compounds was investigated by safranine T-Mn~(2+)-H_2O_2 system.The results indicated that the antioxidative activity has been enhanced by the introducing of 2-methyl-benzimidazolyl.All of the target compounds possess good scavenging capacity to free radical.The other activity of the compounds will be further investigated.
本论文主要包括以下三部分:
第1章综述了近年来异黄酮类衍生物的研究进展。主要分为两个方面:1)合成方法研究进展。合成异黄酮类衍生物的主要方法有:脱氧安息香法、重排反应法、Pd-催化交叉偶联法、一锅法、微波合成法等。其中脱氧安息香法由于其原料易得,反应条件温和而备受人们青睐,是目前应用最广泛的异黄酮合成法。2)药理活性研究概述。异黄酮类衍生物具有多种药理活性:如杀菌活性、抗癌作用、抗病毒作用、抗骨质疏松作用、治疗心血管疾病等。
第2章设计并合成了10种目标化合物:2-甲基-4′-氯-7-(2-(1-(2-甲基苯并咪唑基))乙氧基)异黄酮(1a)、2,4′-二甲基-7-(2-(1-(2-甲基苯并咪唑基))乙氧基)异黄酮(1b)、2-甲基-7-(2-(1-(2-甲基苯并咪唑基))乙氧基)异黄酮(1c)、2-甲基-4′-甲氧基7-(2-(1-(2-甲基苯并咪唑基))乙氧基)异黄酮(1d)、2-甲基-4′-羟基-7-(2-(1-(2-甲基苯并咪唑基))乙氧基)异黄酮(1e)、2-甲基-4′-氯-7-(3-(1-(2-甲基苯并咪唑基))丙氧基)异黄酮(2a)、2,4′-二甲基-7-(3-(1-(2-甲基苯并咪唑基))丙氧基)异黄酮(2b)、2-甲基-7-(3-(1-(2-甲基苯并咪唑基))丙氧基)异黄酮(2c)、2-甲基-4′-甲氧基-7-(3-(1-(2-甲基苯并咪唑基))丙氧基)异黄酮(2d)、2-甲基-4′-羟基-7-(3-(1-(2-甲基苯并咪唑基))丙氧基)异黄酮(2e)。经JR,~1H NMR,~(13)C NMR,元素分析等对其结构进行了表征,10种目标化合物均未见文献报道。
第3章目标化合物的抗氧化活性初步研究。本文采用番红花红T-Mn~(2+)-H_2O_2光度法测定了10种目标化合物清除羟基自由基的能力。实验结果表明2-甲基苯并咪唑基的引入,增强了异黄酮的生物活性,10种目标化合物都具有较强的清除羟基自由基的能力。其它生物活性有待进一步研究。
A method for the synthesis of 2-methyl-benzimidazolyl isoflavone derivatives have been reported.Deoxybenzoin(3) was prepareded by using the resorcinol and substituted phenylacetic as starting meterials in microwave-mediated.Then the compound(3) was reacted with acetic anhydride to produce(4).The compound(4) was hydrolyzed to convert compound(5) in the acid-mediated. The compound(5) was reacted with the 1,2-dibromo-ethane and 1,3-dibromo-propane in refluxed condition with acetone as solvent to give(6) or(7),respectively.Lastly,the title compounds were synthesized by refluxing(6) or(7) with 2-methyl-benzimidazole and potassium carbonate in acetone solution.In this method,thirty-five compounds including ten kinds of 2-methyl-benzimidazolyl isoflavone derivatives were synthesized via five steps.All the structures of target compounds were confirmed by IR,~1H NMR,~(13)C NMR,elemental analysis and so on.The target compounds have not been reported in documents so far by way of searching sciFinder Scholar.During synthesis of all target compounds,we not only have optimized the reaction condition of C-O bond and C-N bond but also have introduced successfully the microwave promoting method to our protocol which shortened the reaction time greatly.The antioxidative ability of ten target compounds have been investigated, all of them possess good scavenging capacity to free radical.The results of experiment on radical scavenging effect suggest that the ability of scavenging radical not only releted to the numbers of hydroxyl and the length of allyl-chain which join with 7-hydroxy but also possibly releted to the structure of the group which join with 7-hydroxy.The other actives of ten target compounds will be further undergoes in future.
This thesis is consisted of three parts as follows:
Chapter one,the researching progress in the derivatives of isoflavone was described.There are mainly involving two aspects:The section one is researching progress in synthetic methods.For example,deoxybenzoin method,oxidation rearrangement,Pd-catalyzed cross-coupling method, one-pot method and microwave-mediated synthesis et al.Currently,deoxybenzoin method is applied extensively because of facile materials and mild reaction condition.The section two is researching progress in the pharmacological effects of isoquinolinones such as disinfection,anticancer, antifungal,antiosteporosis and therapy vascular diseases.
Chapter two,ten target compounds were designed and synthesized by our protocol. 4'-chloro-2-methyl-7-(2-(1H-(2-methyl-benzimidazole)-1-yl)ethoxy) isoflavone(1a),2,4'-dimethyl -7-(2-(1H-(2-methyl-benzimidazole)-1-yl)ethoxy) isoflavone(1b),2-methyl-7-(2-(1H-(2-methyl-benzimidazole) -1-yl)ethoxy) isoflavone(1c),4'-methoxy-2-methyl-7-(2-(1H-(2-methyl-benzimidazole) -1-yl)ethoxy) isoflavone(1d),4'-hydroxy-2-methyl-7-(2-(1H-(2-methyl-benzimidazole) -1-yl)ethoxy) isoflavone(1e),4'-chloro-2-methyl-7-(3-(1H-(2-methyl-benzimidazole) -1-yl)propoxy) isoflavone(2a),2,4'-dimethyl-7-(3-(1H-(2-methyl-benzimidazole) -1-yl)propoxy) isoflavone(2b),2-methyl-7-(3-(1H-(2-methyl-benzimidazole)-1-yl)propoxy) isoflavone(2c),4'-methoxy-2-methyl-7-(3-(1H-(2-methyl-benzimidazole)-1-yl)propoxy) isoflavone (2d),4'-hydroxy-2-methyl-7-(3-(1H-(2-methyl-benzimidazole)-1-yl)propoxy) isoflavone(2e).All of these target compounds were never reported so far,and their structure were confirmed by IR,~1H NMR,~(13)C NMR,elemental analysis.
Chapter three,a pilot evaluation on their antioxidative activity of the title compounds was investigated by safranine T-Mn~(2+)-H_2O_2 system.The results indicated that the antioxidative activity has been enhanced by the introducing of 2-methyl-benzimidazolyl.All of the target compounds possess good scavenging capacity to free radical.The other activity of the compounds will be further investigated.
引文
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