CN119490463A 一种β-三氮唑衍生物及其合成方法和应用 （华东师范大学）

三氮唑化合物、烷基化合物/醛/二硫醚/二硒醚发明所涉及的β三氮唑酮衍生物类化合物是一活性分析显示，部分化合物在10μM浓度下23其中，1为烷基化合物/醛/二硫醚/二硒醚在氧化剂和添加剂作用下生成的烷基自由1为烷基2为芳基9.如权利要求13之任一项所述的β三氮唑衍生物在制备抗肿瘤细胞活性的药物中的4的化学活化和区域选择性难以控制，催化实现烯烃的分子间双官能团化仍然是一个挑战。过芳香氮杂环自由基与自由基接力反应中的二级碳中心自由基偶联来构建β一三氮唑支架3为烷基53为苯基16[0018]其中，所述氧化剂的用量以烷基化合物/醛/二硫醚/二硒醚为基准，为烷基化合物/醛/二硫醚/二硒醚的摩尔量的100–150优选地，所述氧化剂的用量以烷基化合物/[0027]机理阐述：烷基化合物/醛/二硫醚/二硒醚在氧化剂和添加剂的作用下生成R1自不会进攻三氮唑的N1位生成化合物4'。7过氧叔丁醇或者过硫酸铵为氧化剂，在有机溶剂中，经过一步反应可以高选择性(100%N289(0.6mmol)溶于2ml二氯乙烷中，然后用注射器注入两口瓶中，最后置于50℃条件下反应(ESI)m/z:[M+H]+CalcdforC23H20N3O(M+H)+354.1603,Found:354.1606.Cu(CH3CN)4PF6(0.02mo22.9Hz),64.4,44.1.HRMS(ESI)m/z:[M+H]+CalcdforC23H19FN3O(M+H)+372.1497,Found:372.1502.Cu(CH3CN)4PF6(0.02mo44.0.HRMS(ESI)m/z:[M+H]+CalcdforC23H19ClN3O(M+H)+388.1248,Found:388.1247.Cu(CH3CN)4PF6(0.0219FNMR(376MHz,Chloroformd)δ21.7Hz),64.2,44.1.HRMS(ESI)m372.1505.15.6.HRMS(ESI)m/z:[M+H]+CalcdforC25H24N3O(M+H)+382.1918,Found:382.1919.CNMR(101MHz,Chloroformd)δ195.9,159.7,147.5,139.6,136.5,133.4,130.5,128.8,[0139]实施例73(4([1,1'联苯]4基)2H1,2,3三氮唑2基)1,3二苯基丙1127.0,126.7,126.3,64.3,44.1.HRMS(ESI)m/z:[M+H]+CalcdforC29H24N3O(M+H)+429.1836,Found:429.1839.(0.6mmol)溶于2ml二氯乙烷中，然后用注射器注入两口瓶中，最后置于50℃条件下反应44.1,31.3,25.2,22.3,13.8.HRMFound:334.1643.(0.6mmol)溶于2ml二氯乙烷中，然后用注射器注入两口瓶中，最后置于50℃条件下反应128.6,128.2,128.1,126.7,63.9,30.8,30.3.HRMS(ESI)m/z:[M+H]+CalcdforC21H24N3OS(M+H)+333.1865,Found:333.1873.128.8,128.6,128.3,128.2,126.7,126.2,126.0,121.5,64.1,44.1.HRMS(ESI)CalcdforC21H18N3OS(M+H)+360.1165,Found:360.1171.(101MHz,Chloroform一d)δ195.8,142.8,139.9,139.5,139.1,136.4,133.5,132.8,131.4,(ESI)m/z:[M+H]+CalcdforC25H20N3OS(M+H)+410.1266,Found:410.1260.(ESI)m/z:[M+H]+CalcdforC25H20N3OS(M+H)+394.1556,Found:394.1547.[0157]实施例131(3溴苯基)3苯基3(4苯基2H1,2128.9,128.8,128.4,128.3,126.7,126.6,126.1,123.1,64.1,44.1.HRMS(ESI)m/z:[M+H]+CalcdforC23H19BrN3O(M+H)+432.0730,Found:432.0721.(CH3CN)4PF6(0.02mol)然后换氮气三次，最后将3,4一二氯苯甲醛(0.4mmol),苯乙烯44.1.HRMS(ESI)m/z:[M+H]+CalcdforC23H18Cl2N3O(M+H)+422.0837,Found:422.0827.[0163]实施例151(4氟苯基)3苯基3(4苯基2H1,2FNMR(376MHz,Chloroformd)δ104.43.13CNMR(101MHz,Chloroformd)δ194.3,165.9z:[M+H]+CalcdforC23H19FN3O(M+H)+372.1497,Found:372.1502.[0166]实施例161(4氯苯基)3苯基3(4苯基2H1,2130.3,129.6,129.1,128.9,128.7,128.4,126.6,125.9,64.2,44.1.HRMS(ESI)m/z:[M+H]+CalcdforC23H19ClN3O(M+H)+388.1321,Found:388.1328.[0169]实施例171(4溴苯基)3苯基3(4苯基2H1,C23H19BrN3O(M+H)+432.0730,Found:432.0721.(CH3CN)4PF6(0.02mol)然后换氮气三次，最后将对三氟甲氧基苯甲醛(0.4mmol),苯乙烯FNMR2.0Hz),147.71,139.29,134.68,131.17,130.33,128.95,128.121.57,120.46,118.99,64.21,44.12.HRMS(ESI)m/z:[M+H]+CalcdforC2438.1421,Found:438.1429.(CH3CN)4PF6(0.02mol)然后换氮气三次，最后将对甲氧基苯甲醛(0.4mmol),苯乙烯131.1,130.5,130.5,129.5,128.8,128.7,128.3,128.2,126.7,126.1,113.8,64.3,55.5,43.7.HRMS(ESI)m/z:[M+H]+CalcdforC24H22F3N3O2(M+H+CalcdforC21H18N3OS(M+H)+360.1165,Found:360.1171.+CalcdforC21H18N3OS(M+H)+360.1165,Found:360.1171.[0184]实施例221(苯并噻吩2基)3苯基3(4(CH3CN)4PF6(0.02mol)然后换氮气三次，最后将苯并噻吩一2一甲醛(0.4mmol),苯乙烯forC25H20N3OS(M+H)+410.1357,Found:410.1348.[0187]实施例231(苯并呋喃2基)3苯基3(4苯基2H1,2,3三唑2基)(CH3CN)4PF6(0.02mol)然后换氮气三次，最后将苯并呋喃一2一甲醛(0.4mmol),苯乙烯124.0,123.4,113.4,112.5,63.9,44.3.HRMS(ESI)m/z:[M+H]+CalcdforC25H20N3O2(M+H)+394.1548,Found:394.1556.(0.6mmol)溶于2ml二氯乙烷中，然后用注射器注入两口瓶中，最后置于50℃条件下反应101.9,64.3,43.8.HRMS(ESI)m/z:[M+H]+CalcdforC25H20N3O2(M+H)+398.1512,Found:398.1505.13CNMR(101MHz,318.1598,Found:318.1606.(CH3CN)4PF6(0.02mo24.2,23.9,17.7.HRMS(ESI)m/z:[M+H]+CalcdforC21H22N3O(M+H)+332.1773,Found:332.1777.(CH3CN)4PF6(0.02moCNMR(101MHz,Chloroformd)δ208.7,28.6,28.4,25.9,25.9.HRMS(ESI)m/z:[M+H]+CalcdforC22H24N3O(M+H)+346.1919,Found:346.1909.(0.6mmol)溶于2ml二氯乙烷中，然后用注射器注入两口瓶中，最后置于50℃条件下反应CNMR(101MHz,Chloroformd)δ2131.1,130.5,128.8,128.8,128.4,128.3,126.6,125.9,64.1,47.8,45.2,17.1,13.6(ESI)m/z:[M+H]+CalcdforC20H22N3O(M+H)+320.1716,Found:320.1725.(0.6mmol)溶于2ml二氯乙烷中，然后用注射器注入两口瓶中，最后置于50℃条件下反应25.6,22.2,13.8.HRMS(ESI)m/z:[M+H]+CalcdforC21H24N3O334.1917,Found:334.1919.376.2399,Found:376.2404.[0211]实施例313(4氟苯基)1苯基3(4苯基2H1,2,3三氮唑2基)丙1酮Chloroformd)δ113.63.13CNMR(101MHz,Chloroformd)δ195.7,162.6(d,J＝247.2Hz),forC23H19FN3O372.1491,Found:372.1497.[0214]实施例323(4氯苯基)1苯基3(4苯基2H1,2,3三氮唑2基)丙1酮44.0.HRMS(ESI)m/z:[M+H]+CalcdforC23H19ClN3O(M+H)+387.1123,Found:387.1128.[0217]实施例333([1,1'联苯应18h，得到62％收率的β一三氮唑酮4ag.1HNMR(400MHz,ChlorofforC29H23N3O(M+H)+430.1945,Found:430.1949.(CH3CN)4PF6(0.02mol)然后换氮气三次，最后将苯甲醛(0.4mmol),对甲基苯乙烯CNMR(101MHz,Chloroformd)δ196.0,147.6,138.1,136.6,136.5,133.4,131.1,130.5,129.5,128.7,128.7,128.3,128.3,126.7,126.00,64.1,44.1,21.1.HRMS(ESI)CalcdforC24H22N3O(M+H)+368.1748,Found:368.1742.[0223]实施例353(萘2基)1苯基3(4苯基2H1,2,3三氮唑2基)丙1酮应18h，得到66％收率的β一三氮唑酮4ai.1HNMR(400MHz,Chloroform一44.1.HRMS(ESI)m/z:[M+H]+CalcdforC27H22N3O(M+H)+404.1767,Found:404.1763.(CH3CN)4PF6(0.02mol应18h，得到50％收率的β一三氮唑酮4aj.1HNMR(400MHz,Chloroform一d)130.4,129.3,128.9,128.7,128.7,128.5,128.3,128.2,128.0,127.8,127.4,125.9,70.8,58.5.HRMS(ESI)m/z:[M+H]+CalcdforC29H24N3O(M+H)+429.1887,Found:429.1881.[0229]实施例371(萘2基)3苯基3(4苯基2H1,2,3三氮唑2基)丙1酮126.0,123.8,64.4,44.2.HRMS(ESI)m/z:[M+H]+CalcdforC27H22N3O(M+H)+404.1767,Found:404.1763.(0.02mol)然后换氮气三次，最后将二苯硫醚(0.4mmol),苯乙烯(0.4mmol),(NH4)2S2O4(0.6mmol)溶于2ml二氯乙烷中，然后用注射器注入两口瓶中，最后置于80℃条件下反应128.4,127.1,127.1,126.1,68.6,40.1.(0.02mol)然后换氮气三次，最后将二苯硒醚(0.4mmol),苯乙烯(0.4mmol),(NH4)2S2O4(0.6mmol)溶于2ml二氯乙烷中，然后用注射器注入两口瓶中，最后置于80℃条件下反应CNMR(101MHz,Chloroform一d)δ147.7,138.8,133.9,131.1,130.5,129.2,12128.5,128.4,127.6,126.9,126.1,69.3,32.9.(CH3CN)4PF6(0.02mol)然后换氮气三次，最后将三氟甲磺酸钠(0.4mmol),苯乙烯65.01.[0251]6、同一孔450nm吸光光度值一620nm吸光光度值(背景吸光光度值)作为最终吸光细胞增殖和细胞毒性快速高灵敏度检测试剂)和药物溶液(药物溶液即指待测试的化合物4g,4l,4n,4o,4r,4t,4v,4w,4ae,4ai对骨肉瘤细胞HCT116表现出较好的抑制活性；化合物4a,4b,4c,4d,4e,4f,4g,4l,4n,4o,4r,4t,4u,4w,4x,4ae,对骨肉瘤细胞143B表现出比较好