CN108610286B - 一种2-芳基-4-喹诺酮衍生物及其制备方法和应用 - Google Patents

一种2-芳基-4-喹诺酮衍生物及其制备方法和应用 Download PDF

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CN108610286B
CN108610286B CN201810546037.2A CN201810546037A CN108610286B CN 108610286 B CN108610286 B CN 108610286B CN 201810546037 A CN201810546037 A CN 201810546037A CN 108610286 B CN108610286 B CN 108610286B
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程凯
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Abstract

本发明公开了一种2‑芳基‑4‑喹诺酮衍生物及其制备方法和应用，该2‑芳基‑4‑喹诺酮衍生物的结构如式(I)所示，式(I)中，R1独立地选自H、C1～C5烷基、卤素或C1～C5烷氧基中的一个或者多个，R2独立地选自H、C1～C5烷基、CF3、卤素或C1～C5烷氧基中的一个或者多个。试验结果表明，本发明的2‑芳基‑4‑喹诺酮衍生物具有较好的抑菌活性，可以作为一种抗菌剂进行使用。

Description

一种2-芳基-4-喹诺酮衍生物及其制备方法和应用
技术领域
本发明属于有机合成及其应用领域，具体涉及一种2-芳基-4-喹诺酮衍生物及其制备方法和应用。
背景技术
喹诺酮类药物是近年发展迅速的人工合成抗菌药，具有抗菌谱广、抗菌作用长、有较长PAE、口服吸收好、组织浓度高、与其他药物之间无交叉耐药性及不良反应相对少的优点，广泛应用于临床。喹诺酮类药物是一种有效的核酸合成抑制剂，作用的靶酶是敏感细菌的DNA回旋酶(DNA gyrase)，能与DNA回旋酶亚基A结合，通过形成药物-DNA-酶复合物而抑制酶反应，从而抑制回旋酶对DNA的断裂和再连接的功能，干扰DNA超螺旋结构的解旋，阻止DNA的复制和mRNA的转录而导致细菌死亡，呈现杀菌作用，故在分类上属慢效杀菌剂。代表性的喹诺酮包括萘啶酸、西诺沙星、诺氟沙星、环丙沙星、洛美沙星、氧氟沙星、左氧氟沙星、斯帕沙星、加替沙星、格帕沙星、曲伐沙星、莫西沙星、吉米沙星等。
喹诺酮类药物的结构如式(I)所示，喹诺酮类化合物的母核的来源依赖于人工合成，传统合成方法主要为取代芳胺与EMME缩合后成环；经苯环的亲核取代反应成环；经迪克曼缩合反应成环等。
Figure BDA0001673120830000011
最近，2-芳基-4-喹诺酮及其衍生物已经成为一系列疾病潜在的候选治疗药物，显示出抗疟疾性，抗病毒性和组织蛋白酶抑制剂活性，可以作为抗血小板抗体，抗糖尿病药物的黄嘌呤氧化酶活性检测剂，并具有积极的心脏作用。(T.Osawa,H.Ohta,K.Akimoto,K.Harada,H.Soga and Y.Jinno,4(1H)quinolone Derivatives,Eur.Pat.,0 343 574,1994.)
而2-芳基-4-喹诺酮及其衍生物在生物学上的特殊作用使其制备需要更加有效的合成策略。各种2-芳基-4-喹诺酮的合成途径得到了发展，比如Conrad–Limpach(A.Romekand T.Opatz,Eur.J.Org.Chem.,2010,5841)和Niementowski.(F.R.Alexandre,A.Berecibar and T.Besson,Tetrahedron Lett.,2002,43,3911)报道的方法。这些方法普遍集中精力于胺和羧酸衍生物的缩合反应，再经环化步骤生成2-芳基-4-喹诺酮。然而大多数方法都存在着诸多局限性，需要苛刻的反应条件，如高温和添加强酸强碱等，这都显著地限制了底物的范围。随后的研究采用了过渡金属催化剂来合成该类化合物。如钯催化的羰基化反应(V.N.Kalinin,M.V.Shostakovsky and A.B.Ponomaryov,Tetrahedron Lett.,1992,33,373)，钛促进的还原偶联(A.Furstner,A.Hupperts,A.Ptock and E.Janssen,J.Org.Chem.,1994,59,5215.)和钌催化的还原反应等。(S.Tollari,S.Cenini,F.Ragainiand L.Cassar,J.Chem.Soc.,Chem.Commun.,1994,1741.)
碱促进的邻酰氨基苯乙酮的环化反应(Camps环化)也是一种具有吸引力的并广泛应用的2-芳基-4-喹诺酮的合成方法(D.A.Pflum,Camps Quinolinol Synthesis,in NameReactions in Heterocyclic Chemistry,ed.J.J.Li and E.J.Corey,Wiley-Interscience,Hoboken,NJ,2005,p.386.)，然而受限于邻酰氨基苯乙酮本身的合成。2008年，Huang课题组发展了一种温和的一锅法合成2-芳基-4-喹诺酮，通过连续的Pd催化氨化和碱促进的环化过程(J.K.Huang,Y.Chen,A.O.King,M.Dilmeghani,R.D.Larsen andM.M.Faul,Org.Lett.,2008,10,2609.)2014年，Helaja课题组发展了一种金催化的策略合成2-芳基-4-喹诺酮，从芳基或者烷基取代的aniline-2-propynones(O.Seppa¨nen,M.Muuronen and J.Helaja,Eur.J.Org.Chem.,2014,4044.)。Marinelli课题组刚刚发展了邻碘苯胺同丙炔醇经Sonogashira偶联/氧化为邻氨基芳香炔酮，亚硝化环化为4-硝基喹啉，酸处理为2-芳基-4-喹诺酮。(N.D.Rodea,A.Arcadia,M.Chiarinib,F.Marinelli,Synthesis 2017,49,2501–2512)但是这些方法仍然需要特殊的底物，复杂的步骤和昂贵的过渡金属。本专利中发展了一种通过保护的邻氨基芳基甲酰甲酸，同芳乙烯基氟硼酸钾通过银/过硫酸钾体系促进的，反应可以在水相中进行，室温下反应即可顺利进行，底物适用范围广，催化体系价廉易得，反应选择性好。通过该方法制备了35种2-芳基-4-喹诺酮。
过渡金属催化的脱羧性反应以其近年来在碳碳键和碳杂键构筑方面的应用得到了方法关注(N.Rodriguez and L.J.Goossen,Chem.Soc.Rev.,2011,40,5030)。然而银/过硫酸盐体系催化的脱羧性反应仍然急需进一步发展。(Q.-Z.Zheng and N.Jiao,Chem.Soc.Rev.,2016,45,4590)。
银在化学的历史中扮演了重要角色，但是其应用主要是以光电性质(照相)和生物活性(对人体无毒的水分散系统中生物杀灭剂)为主，而其在有机化学中往往是化学计量用于阴离子复分解反应(阴离子交换，卤素清除剂)和氧化性反应中。随着过渡金属催化的偶联反应研究的发展，化学计量的银往往被作为助剂以提高金属离子反应活性(如钯，钌，铑等)，而银化合物作为单一过渡金属促进的偶联反应的应用却十分有限。近几年的研究表明，当量银促进的有机反应具有反应条件温和、试剂价廉易得(目前银价格仅为￥4.03/克)等特点，因此，探索银催化的偶联反应具有十分重要的现实意义(T.Liu,Q.Ding,Q.Zong,G.Qiu,Org.Chem.Front.,2015,2,670)。
银参与的偶联反应具有其自身的特点和优势。银兼具高亲电活性和路易斯酸的性质，可以与π共轭体系通过配位作用形成银-π络合物，活化亲电试剂。如果在适当位置上引入亲核性位点，就可以通过分子内环化反应来合成多样性的(杂)环类化合物。银催化剂可以在过硫酸盐的辅助下，选择性脱除离去基团，引发自由基历程，中间体经其他试剂捕获后得到偶联产物。(H.Wang,L.N.Guo and X.H.Duan,Adv.Synth.Catal.,2013,355,2222；)随着研究的不断深入，银催化的偶联反应在有机合成中的应用将会愈加广泛。
发明内容
本发明提供了一种2-芳基-4-喹诺酮衍生物及其制备方法和应用，该衍生物具有较好的抗菌活性，同时，该制备方法操作简单，反应收率高，所用的催化剂更加廉价。
一种2-芳基-4-喹诺酮衍生物，结构如式(I)所示：
Figure BDA0001673120830000041
式(I)中，R1独立地选自H、C1～C5烷基、卤素或C1～C5烷氧基中的一个或者多个；
R2独立地选自H、C1～C5烷基、CF3、卤素或C1～C5烷氧基中的一个或者多个。
作为优选，所述的R1独立地选自H、甲基、F、Cl、Br或甲氧基中的一个或者多个；
所述的R2独立地选自H、甲基、CF3、F、Cl、Br或甲氧基中的一个或者多个。
作为优选，所述的2-芳基-4-喹诺酮衍生物选自化合物Q1～Q35中的一个：
Figure BDA0001673120830000042
本发明还提供了一种所述的2-芳基-4-喹诺酮衍生物的应用，其特征在于，所述的2-芳基-4-喹诺酮衍生物用于制备抗菌剂。
作为优选，所述的抗菌剂用于抑制真菌或/和细菌。
作为优选，所述的抗菌剂用于抑制苦瓜枯萎病菌、杨树溃疡病菌、小麦赤霉病菌、番茄早疫病菌四种真菌；
或者用于抑制枯草芽孢杆菌、白色念珠菌、大肠杆菌、金黄色葡萄球菌四种细菌。
本发明还提供了一种所述的2-芳基-4-喹诺酮衍生物的制备方法，包括以下步骤：
在银催化剂和氧化剂的作用下，2-乙酰氨基芳甲酰甲酸类化合物和芳基乙烯三氟硼酸钾类化合物在有机溶剂中发生偶联关环反应，反应结束后经过后处理得到所述的2-芳基-4-喹诺酮衍生物；
所述的2-乙酰氨基芳甲酰甲酸类化合物的结构如式(II)所示：
Figure BDA0001673120830000051
所述的芳基乙烯三氟硼酸钾类化合物的结构如式(III)所示：
Figure BDA0001673120830000052
式(II)～(III)中，R1或R2的定义如权利要求1～3任一项所述。
作为优选，所述的银催化剂为AgOAc、Ag2CO3、AgOTf、AgBF4、AgOTs或AgNO3。
作为优选，所述的氧化剂为(NH4)2S2O8、Na2S2O8或K2S2O8。
作为优选，所述的有机溶剂为丙酮、乙腈、二氯甲烷、1,2-二氯乙烷中的一种与水的混合溶剂。
同现有技术相比，本发明的有益效果体现在：
(1)本发明的衍生物具有较好的抑菌活性，可以对真菌和细菌进行较好的抑制，可以作为一种抗菌剂进行使用；
(2)本发明的制备方法所用的催化剂价格低廉，同时，制备过程操作简单，底物适应性好。
具体实施方式
下面结合具体实施例对本发明做进一步的描述。
实施例1
向反应瓶中加入2-乙酰氨基苯甲酰甲酸(1.0mmol)、反式-苯乙烯三氟硼酸钾(1.0mmol)、硝酸银(0.1mmol)和过硫酸钾(1.0mmol)，然后加入反应溶剂(2mL，如果是混合溶剂，则体积比为1：1)，于25℃下搅拌进行反应，反应12小时后，加入二氯甲烷萃取，食盐水洗涤，有机相用无水硫酸钠干燥，然后进行硅胶柱层析，洗脱剂为石油醚和乙酸乙酯的混合溶剂，得到产品。反应条件和反应结果见表1，反应式如下：
Figure BDA0001673120830000061
表1实施例1的反应条件和反应结果
Figure BDA0001673120830000062
实施例2
向反应瓶中加入2-乙酰氨基苯甲酰甲酸(1.0mmol)、反式-苯乙烯三氟硼酸钾(1.0mmol)、银催化剂(0.1mmol)和氧化剂(1.0mmol)，然后加入乙腈和水的混合溶剂(1mL+1mL)，于25℃下搅拌进行反应，反应12小时后，加入二氯甲烷萃取，食盐水洗涤，有机相用无水硫酸钠干燥，然后进行硅胶柱层析，洗脱剂为石油醚和乙酸乙酯的混合溶剂，得到产品。反应条件和反应结果见表2，反应式如下：
Figure BDA0001673120830000071
表2实施例2的反应条件和反应结果
Figure BDA0001673120830000072
a银盐为硝酸银；
b氧化剂为K2S2O8
实施例3
向反应瓶中加入保护的2-氨基苯甲酰甲酸类化合物(1.0mmol)、反式-苯乙烯三氟硼酸钾(1.0mmol)、硝酸银(0.1mmol)和过硫酸钾(1.0mmol)，然后加入乙腈和水的混合溶剂(1mL+1mL)，于25℃下搅拌进行反应，反应12小时后，加入二氯甲烷萃取，食盐水洗涤，有机相用无水硫酸钠干燥，然后进行硅胶柱层析，洗脱剂为石油醚和乙酸乙酯的混合溶剂，得到产品。反应条件和反应结果见表3，反应式如下：
Figure BDA0001673120830000073
表3实施例3的反应条件和反应结果
Figure BDA0001673120830000074
Figure BDA0001673120830000081
实施例4
向反应瓶中加入2-乙酰氨基芳甲酰甲酸类化合物(1.0mmol)、芳基乙烯三氟硼酸钾类化合物(1.0mmol)、硝酸银(0.1mmol)和过硫酸钾(1.0mmol)，然后加入乙腈和水的混合溶剂(1mL+1mL)，于25℃下搅拌进行反应，反应12小时后，加入二氯甲烷萃取，食盐水洗涤，有机相用无水硫酸钠干燥，然后进行硅胶柱层析，洗脱剂为石油醚和乙酸乙酯的混合溶剂，得到产品。反应条件和反应结果见表4，反应式如下：
Figure BDA0001673120830000082
表4不同反应底物的反应结果
Figure BDA0001673120830000091
产物的结构和表征数据如下：
Figure BDA0001673120830000092
2-Phenyl-4-quinolone(Q2).beige solid.1H-NMR(400MHz,DMSO-d6):δ8.26(d,J＝8.1Hz,1H),7.69(m,4H),7.52(m,3H),7.38(m,1H),6.56(s,1H).13C-NMR(100MHz,DMSO-d6):δ180.3,153.0,141.5,135.0,133.3,131.6,129.9,128.2,125.7,125.4,125.1,119.4,108.4.HRMS Calculated for C15H12NO[M+H]+222.0913,found 222.0914.
Figure BDA0001673120830000101
6-Methyl-2-phenyl-1H-quinolin-4-one(Q7).off-white solid.1H-NMR(400MHz,DMSO-d6):δ11.7(s,1H),7.89(m,1H),7.84(dd,J1＝6.4Hz,J2＝3.6Hz,2H),7.67(d,J＝8.4Hz,1H),7.60–7.56(m,3H),7.51(dd,J1＝8.4Hz,J2＝1.9Hz,1H),6.30(s,1H),2.96(s,3H).13C-NMR(100MHz,DMSO-d6):δ171.5,154.6,141.1,135.6,133.1,132.5,130.3,128.8,127.1,123.8,119.1,107.4,20.6.HRMS Calculated for C16H14NO[M+H]+236.1070,found 236.1073.
Figure BDA0001673120830000102
7-Fluoro-2-phenyl-4-quinolone(Q3).cream-colored solid.1H-NMR(400MHz,CD3OD/CDCl3):δ8.27(dd,J＝9.1,6.1Hz,1H),7.72(m,2H),7.52(m,3H),7.36(dd,J＝9.8,2.4Hz,1H),7.10(ddd,J＝10.7,8.3,2.4Hz,1H),6.53(s,1H).13C-NMR(100MHz,CD3OD/CDCl3/CD2Cl2):δ179.8,166.1(d,JCF＝252Hz),153.6,143.1(d,JCF＝13Hz),134.9,131.7,130.0,129.0(d,JCF＝10Hz),128.2,122.4(d,JCF＝1.7Hz),114.1(d,JCF＝24Hz),108.6,104.6(d,JCF＝25Hz).HRMS Calculated for C15H11FNO[M+H]+240.0819,found240.0828.
Figure BDA0001673120830000103
7-Methoxy-2-phenyl-4-quinolone(Q4).off-white solid.1H-NMR(400MHz,DMSO-d6):δ11.53(s,1H),8.01(d,J＝8Hz,1H),7.83(m,2H),7.58(m,3H),7.21(s,1H),6.94(d,J＝8Hz,1H),6.27(s,1H),3.87(s,3H)；13C-NMR(100MHz,DMSO-d6):δ176.41,161.84,149.54,142.23,134.16,130.26,128.91,127.11,126.43,119.13,113.17,106.99,99.70,55.34.HRMS Calculated for C16H14NO2[M+H]+252.1019,found 252.1023.
Figure BDA0001673120830000111
6-Methyl-2-phenyl-1H-quinolin-4-one(Q5).colorless solid.1H-NMR(400MHz,DMSO-d6):δ11.6(s,1H),7.89(m,1H),7.83(dd,J1＝6.5Hz,J2＝3.7Hz,2H),7.67(d,J＝8.5Hz,1H),7.60–7.57(m,3H),7.50(dd,J1＝8.5Hz,J2＝1.9Hz,1H),6.31(s,1H),2.97(s,3H).13C-NMR(100MHz,DMSO-d6):δ171.4,154.7,141.0,135.6,133.0,132.5,130.2,128.9,127.2,123.9,119.1,107.3,20.7.HRMS Calculated for C16H14NO[M+H]+236.1070,found 236.1082.
Figure BDA0001673120830000112
7-Chloro-2-phenyl-1H-quinolin-4-one(Q6).white solid.1H-NMR(400MHz,DMSO-d6):δ11.73(s,1H),8.09(d,J＝8.6Hz,1H),7.85(m,4H),7.80(d,J＝1.9Hz,1H),7.70(dd,J1＝8.4Hz,J2＝1.0Hz,1H),7.61–7.57(m,7H),7.36(dd,J1＝8.6Hz,J2＝2.0Hz,1H),7.27(dd,J1＝7.7Hz,J2＝1.0Hz,1H),6.39(s,1H),
6.32(s,1H).13C-NMR(100MHz,DMSO-d6):δ176.6,151.0,141.9,136.7,134.5,
131.9,130.5,128.9,127.9,127.8,126.6,127.3,126.3,126.1,123.6,118.8,118.4,109.7,108.1.HRMS Calculated for[M+H]+256.0524；found 256.0529.
Figure BDA0001673120830000121
8-phenyl-3,4-dihydro-2H-[1,4]dioxepino[2,3-g]quinolin-10(7H)-one(Q7).off-white solid.1H-NMR(400MHz,DMSO-d6):δ11.52(s,1H),8.79(m,2H),7.57(m,4H),7.31(s,1H),6.03(s,1H),4.26(m,2H),4.18(m,2H),2.16(m,2H)；13C-NMR(100MHz,DMSO-d6):δ175.97,151.14,149.57,148.33,137.15,134.27,130.33,128.99,127.22,121.17,115.73,109.66,106.15,70.72,70.65,31.11.HRMS Calculated for C18H16NO3[M+H]+294.1124,found 294.1128.
Figure BDA0001673120830000122
2-(2'-methoxyphenyl)-4-quinolone(Q8).white solid.1H-NMR(400MHz,DMSO-d6):δ8.34–8.36(m,1H),8.14–8.16(m,1H),8.03–8.07(m,1H),7.76–7.80(m,1H),7.67–7.71(m,2H),7.34–7.36(m,1H),7.29(s,1H),7.23–7.26(m,1H),3.90(s,3H)；13C-NMR(100MHz,DMSO-d6):δ170.2,156.8,152.4,139.6,134.4,133.4,131.1,127.2,123.6,121.2,121.0,120.0,119.9,112.4,107.2,56.1.HRMS Calculated for[M+H]+C16H13NO2[M+]:251.0946；found:251.0947.
Figure BDA0001673120830000123
2-(4'-Chlorophenyl)-4-quinolone(Q9).white solid.1H-NMR(400MHz,DMSO-d6):δ11.77(s,1H),8.11(dd,J1＝8.1Hz,J2＝1.2Hz,1H),7.88(d,J＝8.6Hz,2H),7.76(d,J＝8.1Hz,1H),7.68-7.71(m,1H),7.66(d,J＝8.6Hz,2H),7.33-7.38(m,1H),6.38(s,1H)；13C-NMR(100MHz,DMSO-d6):δ177.3,149.1,140.9,135.6,133.4,132.3,129.6,129.4,128.1,125.0,123.8,119.1,107.8；HRMS Calculated for C15H11NOCl[M+H]+256.0523,found 256.0534.
Figure BDA0001673120830000131
2-(3’-Chlorophenyl)-4-quinolone(Q10).cream-colored solid.1H-NMR(400MHz,DMSO-d6):δ8.26(m,1H),7.76(m,1H),7.67(m,3H),7.50(m,2H),7.40(m,1H),6.55(s,1H).13C-NMR(100MHz,DMSO-d6):δ180.4,151.4,141.6,137.0,135.9,133.5,131.5,131.4,128.3,126.7,125.8,125.6,125.3,119.5,108.7.HRMS Calculated forC15H11NOCl[M+H]+256.0523,found 256.0531.
Figure BDA0001673120830000132
2-(2’-Chlorophenyl)-4-quinolone(Q11).off-white solid.1H-NMR(400MHz,DMSO-d6):δ11.97(s,1H),8.13(d,J＝8Hz,1H),7.68-7.55(m,6H),7.36(m,1H),6.03(s,1H)；13C-NMR(100MHz,DMSO-d6):δ176.60,148.30,140.10,133.89,131.88,131.61,131.42,131.07,129.78,127.48,124.79,124.74,123.30,118.38,109.72.HRMS Calculated forC15H11NOCl[M+H]+256.0523,found 256.0535.
Figure BDA0001673120830000133
2-(3-(trifluoromethyl)-phenyl)-quinolin-4(1H)-one(Q12).off-whitesolid.1H-NMR(400 MHz,DMSO-d6):δ11.91(s)8.24(s,1H),8.18(d,J＝7.8Hz,1H),8.10(dd,J＝
8.1,1.2Hz,1H),7.88(d,J＝7.7Hz,1H),7.78(t,J＝7.8Hz,1H),7.74(d,J＝8.3Hz,1H),7.62(t,J＝7.2Hz,1H),7.30(t,J＝7.4Hz,1H),6.48(s,1H).13C-NMR(100MHz,DMSO-d6):δ176.16,148.04,139.94,133.18,132.58,131.96,131.32,130.29,126.27,124.75,123.35,118.29,109.80.HRMS Calculated for C16H11F3NO[M+H]+:290.0793；found:290.0794.
Figure BDA0001673120830000141
2-(2-(trifluoromethyl)-phenyl)-quinolin-4(1H)-one(Q13).off-whitesolid.1H-NMR(400MHz,DMSO-d6):δ11.99(s,1H),8.13(d,J＝4Hz,1H),7.95(d,J＝8Hz,1H),7.86(t,J＝8Hz,1H),7.80(t,J＝8Hz,1H),7.74(d,J＝4Hz,1H),7.68(t,J＝8Hz,1H),7.58(d,J＝8Hz,1H),7.37(t,J＝8Hz,1H),5.97(s,1H)；13C-NMR(100MHz,DMSO-d6):δ176.15,148.04,139.95,133.18,132.57,131.96,131.33,130.29,126.28,124.75,123.36,118.29,109.81.HRMS Calculated for C16H11NOF3[M+H]+290.0787,found 290.0790.
Figure BDA0001673120830000142
2-(4'-Methoxyphenyl)-4-quinolone(Q14).off-white solid.1H-NMR(400MHz,DMSO-d6):δ11.82(br s,1H),8.20(dd,J1＝8.1Hz,J2＝1.2Hz,1H),8.10(s,0.6H),7.81(d,J＝8.8Hz,2H),7.75-7.79(m,2H),7.30-7.36(m,1H),7.14(d,J＝8.8Hz,2H),3.85(s,3H)；13C-NMR(100MHz,DMSO-d6):δ176.87,159.44,149.71,140.38,135.52,131.72,130.12,124.85,124.63,123.17,119.52,118.66,116.01,112.74,107.33,55.31.HRMS Calculatedfor C16H14NO2[M+H]+252.1019,found 252.1028.
Figure BDA0001673120830000151
2-(3'-Methoxyphenyl)-4-quinolone(Q15).off-white solid.1H-NMR(400MHz,DMSO-d6):δ11.70(s,1H),8.11(d,J＝8Hz,1H),7.78(d,J＝8Hz,1H),7.70(d,J＝8Hz,1H),7.51(m,1H),7.38(m,3H),7.16(m,1H),6.37(s,1H),3.88(s,3H).13C-NMR(100MHz,DMSO-d6):δ176.88,159.44,149.70,140.38,135.51,131.72,130.11,124.85,124.64,123.17,119.53,118.66,116.02,112.74,107.33,55.33.HRMS Calculated for C16H14NO2[M+H]+252.1019,found 252.1025.
Figure BDA0001673120830000152
2-(4'-Methylphenyl)-4-quinolone(Q16).off-white solid.1H-NMR(400MHz,DMSO-d6):δ11.69(s,1H),8.10(dd,J1＝8.1Hz,J2＝1.2Hz,1H),7.69-7.79(m,3H),7.63-7.67(m,1H),7.31-7.41(m,3H),6.34(s,1H),2.33(s,3H)；13C-NMR(100MHz,DMSO-d6):δ177.2,150.4,140.7,140.6,132.1,131.6,129.9,127.6,125.1,125.0,123.6,119.1,107.2,21.2；HRMS Calculated for C16H14NO[M+H]+236.1070,found 236.1084.
Figure BDA0001673120830000153
2-(3-Fluorophenyl)-4-quinolone(Q17).off-white solid.1H-NMR(400MHz,DMSO-d6):δ8.28(1H,d,J＝8.2Hz),7.79～7.75(2H,m),7.65～7.46(4H,m),7.31(1H,m),6.68(1H,s).13C-NMR(100MHz,DMSO-d6):δ178.84,163.77(d,J＝253.6Hz),152.10,141.35,136.64,133.86,131.88(d,J＝8.1Hz),125.68,125.55,124.66,124.23(d,J＝2.9Hz),119.51,118.62(d,J＝21.1Hz),115.35(d,J＝23.5Hz),107.94.HRMS Calculated forC15H11FNO[M+H]+,240.0825；found,240.0827.
Figure BDA0001673120830000161
2-(3,4-Dimethoxyphenyl)-4-quinolone(Q18).off-white solid.1H-NMR(400MHz,DMSO-d6):δ8.40(1H,d,J＝7.39Hz),7.88～7.77(2H,m),7.56～7.48(3H,m),7.21(1H,d,J＝8.44Hz),6.72(1H,s).4.12(3H,s),4.09(3H,s).13C-NMR(100MHz,DMSO-d6):δ180.13,152.65,152.18,150.19,141.36,133.05,127.44,125.63,125.34,124.84,121.38,119.09,112.38,111.33,107.78,56.56,56.46 HRMS Calculated for C17H16NO3[M+H]+282.1130；found,282.1127.
Figure BDA0001673120830000162
2-(3,4-dichlorophenyl)quinolin-4(1H)-one(Q19).off-white solid.1H-NMR(400MHz,DMSO-d6):δ11.78(s,1H),8.17(s,1H),8.10(d,J＝7.9Hz,1H),7.84(d,J＝8.2Hz,2H),7.75(d,J＝8.1Hz,1H),7.69(t,J＝7.2Hz,1H),7.36(t,J＝7.3Hz,1H),6.46(s,1H).13C-NMR(100MHz,DMSO-d6):δ180.14,152.65,152.18,150.17,141.36,133.04,127.44,125.62,125.34,124.83,121.38,119.08,112.38,111.34,107.78.HRMS Calculated forC15H10Cl2NO[M+H]+:290.0139；found:290.0145.
Figure BDA0001673120830000163
2-(3,5-difluorophenyl)quinolin-4(1H)-one(Q20).off-white solid.1H-NMR(400MHz,DMSO-d6):δ11.80(s,1H),8.10(d,J＝8.0Hz,1H),7.76(d,J＝8.3Hz,1H),7.69(s,1H),7.67(d,J＝7.6Hz,2H),7.46(t,J＝9.2Hz,1H),7.34(t,J＝7.4Hz,1H),6.51(s,1H).13C-NMR(100MHz,DMSO-d6):δ176.6,151.0,141.9,136.7,134.5,131.9,130.5,128.9,127.9,127.8,126.6,127.3,126.3,126.1,123.6,118.8,118.4,109.7,108.1.HRMSCalculated for C15H10F2NO[M+H]+:258.0730；found:258.0749.
Figure BDA0001673120830000171
2-(3',4',5'-Trimethoxyphenyl)-4-quinolone(Q21).off-white solid.1H-NMR(400MHz,DMSO-d6):δ11.62(s,1H),8.10(dd,J1＝8.1Hz,J2＝1.1Hz,1H),7.76(d,J＝7.8Hz,1H),7.64-7.71(m,1H),7.32-7.37(m,1H),7.11(s,2H),6.43(s,1H),3.91(s,6H),3.74(s,3H)；13C-NMR(100MHz,DMSO-d6):δ177.3,153.5,153.1,150.3,
140.8,139.5,132.1,130.0,125.1,123.6,119.0,107.6,105.4,60.5,56.5；HRMSCalculated for C18H18NO4[M+H]+312.1230,found 312.1225.
Figure BDA0001673120830000172
2-(4’-Pyridyl)-4-quinolone(Q22).beige solid.1H-NMR(400MHz,DMSO-d6):δ8.71(d,J＝5.0Hz,2H),8.27(dt,J＝8.2,1.1Hz,1H),7.70(m,4H),7.39(m,1H),6.60(s,1H).13C-NMR(100MHz,DMSO-d6):δ180.1,150.6,149.2,143.2,141.5,133.5,125.7,125.6,125.3,122.8,119.4,109.0.HRMS Calculated for C14H11N2O[M+H]+223.0865,found223.0871.
Figure BDA0001673120830000181
2-(3’-Pyridyl)-4-quinolone(Q23).off-white solid.1H-NMR(400MHz,DMSO-d6):δ11.85(s,1H),9.05(s,1H),8.76(d,J＝4Hz,1H),8.27(d,J＝8Hz,1H),8.12(d,J＝8Hz,1H),7.70-7.75(m,1H),7.62(m,1H),7.37(m,1H),6.43(s,1H)；13C-NMR(100MHz,DMSO-d6):δ176.79,151.79,151.04,148.59,148.04,140.49,135.12,131.85,130.08,124.64,123.73,123.41,118.67,107.83.HRMS Calculated
for C14H11N2O[M+H]+223.0865,found 223.0873.
Figure BDA0001673120830000182
2-(2’-Pyridyl)-4-quinolone(Q24).beige solid.1H-NMR(400MHz,DMSO-d6):δ8.77(ddd,J＝4.8,1.7,1.0Hz,1H),8.27(ddd,J＝8.3,1.5,0.6Hz,1H),8.09(d,J＝8.1Hz,1H),7.97(td,J＝7.6,1.8Hz,1H),7.78(ddd,J＝8.5,1.1,0.6Hz,1H),7.71(m,1H),7.50(ddd,J＝7.6,6.9,1.2Hz,1H),7.41(ddd,J＝8.2,6.9,1.2Hz,1H),6.98(s,1H).13C-NMR(100MHz,DMSO-d6):δ181.0,150.2,149.8,147.7,140.7,138.7,133.6,126.4,125.9,125.8,125.2,122.3,119.7,106.6.HRMS Calculated for C14H11N2O[M+H]+223.0865,found 223.0861.
Figure BDA0001673120830000183
2-(2’-Thiophenyl)-4-quinolone(Q25).beige solid.1H-NMR(400MHz,DMSO-d6):δ8.22(ddd,J＝8.2,1.4,0.6Hz,1H),7.76(dd,J＝3.8,1.1Hz,1H),7.66(m,2H),7.57(dd,J＝5.1,1.1Hz,1H),7.36(ddd,J＝8.1,6.7,1.4Hz,1H),7.19(dd,J＝5.1,3.8Hz,1H),6.60(s,1H).13C-NMR(100MHz,DMSO-d6):δ179.9,146.0,141.1,136.8,133.2,130.0,129.1,128.5,125.6,125.3,124.8,118.9,107.3.HRMS Calculated for C13H10NOS[M+H]+228.0478,found 228.0471.
Figure BDA0001673120830000191
2-(3’-Thiophenyl)-4-quinolone(Q26).beige solid.1H-NMR(400MHz,DMSO-d6):δ8.23(d,J＝8.0Hz,1H),8.01(s,1H),7.63(m,2H),7.55-7.33(m,3H),6.61(s,1H).13C-NMR(100MHz,DMSO-d6):δ180.7,147.8,141.6,136.2,133.5,128.6,127.2,126.9,125.9,125.7,125.2,119.4,107.6.HRMS Calculated for C13H10NOS[M+H]+228.0478,found228.0473.
Figure BDA0001673120830000192
2-(4-methylthiophen-3-yl)quinolin-4(1H)-one(Q27).off-white solid.1H-NMR(400MHz,DMSO-d6):δ11.72(s,1H),8.11(d,J＝8Hz,1H),7.68(m,3H),7.36(m,1H),7.12(d,J＝8Hz,1H),6.10(s,1H),2.37(s,3H)；13C-NMR(100MHz,DMSO-d6):δ176.48,143.96,140.30,137.52,131.84,131.18,129.34,127.16,124.68,123.35,118.44,109.68,14.65.HRMS Calculated for C14H12NOS[M+H]+242.0634,found 242.0644.
Figure BDA0001673120830000193
2-(3’-Furyl)-4-quinolone(Q28).off-white solid.1H-NMR(400MHz,DMSO-d6):δ11.97(br,1H),8.08(d,J＝8Hz,1H),8.00(s,1H),7.84(d,J＝8Hz,1H),7.65(m,1H),7.52(m,1H),7.32(t,J＝8Hz,1H),6.78(s,1H),6.52(s,1H)；13C-NMR(100MHz,DMSO-d6):δ175.89,147.26,145.45,140.90,140.30,131.59,124.94,124.46,123.05,119.20,112.64,111.74,103.25.HRMS Calculated for C13H10NO2
[M+H]+212.0707,found 212.0717.
Figure BDA0001673120830000201
6,7,8-Trimethoxy-2-(4'-chlorophenyl)-4-quinolone(Q29).white solid.1H-NMR(400MHz,DMSO-d6):δ7.93(d,2H,J＝8.0Hz),7.70(d,2H,J＝8.0Hz),7.34(s,1H),6.75(s,1H),3.94(s,3H),3.85(s,3H),3.81(s,3H).13C-NMR(100MHz,DMSO-d6):δ176.2,156.2,152.1,146.2,139.5,138.7,135.1,132.5,129.1,128.9,114.2,108.4,95.9,61.9,61.1,55.8.HRMS Calculated for C18H16NClO4[M+H]+:345.0768；found:345.0755.
Figure BDA0001673120830000202
6,7,8-Trimethoxy-2-(4'-methoxyphenyl)-4-quinolone(Q30).whitesolid.1H-NMR(400MHz,DMSO-d6):δ7.86–7.89(m,2H),7.38(s,1H),7.17–7.20(m,2H),6.73(s,1H),3.94(s,3H),3.86(s,3H),3.85(s,3H),3.81(s,3H).13C-NMR(100MHz,DMSO-d6):δ172.0,161.8,157.4,150.7,150.0,140.3,139.6,129.3,124.6,114.7,111.4,105.0,96.9,62.1,61.1,56.2,55.6.HRMS Calculated for C19H19NO5[M+H]+:341.1263；found:341.1268.
Figure BDA0001673120830000203
8-Methyl-2-(2'-methoxyphenyl)-4-quinolone(Q31).white solid.1H-NMR(400MHz,DMSO-d6):δ10.65(s,1H),7.99(d,J＝8.0Hz,1H),7.49-7.58(m,3H),7.20-7.26(m,2H),7.09-7.14(m,1H),6.16(s,1H),3.88(s,3H),2.54(s,3H)13C-NMR(100MHz,DMSO-d6):δ177.5,157.3,148.7,138.9,132.9,131.9,130.6,126.8,125.3,123.6,123.1.123.0,121.1,112.4,109.6,56.1,17.7；HRMS Calculated for C17H16NO2[M+H]+266.1176,found266.1171.
Figure BDA0001673120830000211
2-(2’-Chlorophenyl)-7-fluoro-4-quinolone(Q32).beige solid.1H-NMR(400MHz,DMSO-d6):δ8.30(dd,J＝9.0,6.0Hz,1H),7.53(m,1H),7.44(m,3H),7.22(dd,J＝9.6,2.4Hz,1H),7.11(ddd,J＝10.8,8.2,2.1Hz,1H),6.31(s,1H).13C-NMR(100MHz,DMSO-d6):δ179.4,165.8(d,JCF＝252Hz),150.9,142.4(d,JCF＝13Hz),134.2,133.2,132.1,131.3,130.8,128.9(d,JCF＝11Hz),127.8,122.2,114.1(d,JCF＝24Hz),111.1,104.2(d,JCF＝25Hz).HRMS Calculated for C15H10ClFNO[M+H]+274.0429,found 274.0422.
Figure BDA0001673120830000212
7-Fluoro-2-(3’-pyridyl)-4-quinolone(Q33).beige solid.1H-NMR(400MHz,DMSO-d6):δ8.93(s,br,1H),8.72(s,br,1H),8.29(dd,J＝9.0,6.0Hz,1H),8.14(d,J＝8.1Hz,1H),7.58(s,br,1H),7.34(dd,J＝9.6,2.4Hz,1H),7.13(ddd,J＝10.7,8.3,2.4Hz,1H),6.52(s,1H).13C-NMR(100MHz,DMSO-d6):δ179.4,166.1(d,JCF＝252Hz),151.7,150.2,148.4,143.5,136.7,131.8,129.0(d,JCF＝10Hz),125.2,122.5(d,JCF＝1.2Hz),114.4(d,JCF＝24Hz),109.2,104.8(d,JCF＝25Hz).HRMS Calculated for C14H10FNO2[M+H]+241.0772,found 241.0766.
Figure BDA0001673120830000221
6-Bromo-2-(4'-methoxyphenyl)-4-quinolone(Q34).beige solid.1H-NMR(400MHz,DMSO-d6):δ12.07(br s,1H),8.28(d,J＝2.1Hz,1H),8.17(s,1H),7.78-7.83(m,1H),7.83(d,J＝8.7Hz,2H),7.57(d,J＝9.0Hz,1H),7.15(d,J＝8.7Hz,2H),3.85(s,3H)；13C-NMR(100MHz,DMSO-d6):δ179.5,165.8,150.8,142.4,134.1,133.2,132.2,131.3,130.7,128.9,127.7,122.2,114.2,111.1,104.1,56.3.HRMS Calculated forC16H13BrNO2[M+H]+330.0124,found 330.0133.
Figure BDA0001673120830000222
7-Chloro-2-(2'-methoxyphenyl)-4-quinolone(Q35).beige solid.1H-NMR(400MHz,DMSO-d6):δ11.76(br s,1H),8.14(d,J＝8.7Hz,1H),7.97(s,1H),7.67(d,J＝2.0Hz,1H),7.48-7.57(m,3H),7.23(d,J＝8.1Hz,1H),7.09-7.14(m,1H),3.84(s,3H)；13C-NMR(100MHz,DMSO-d6):δ179.4,165.8,150.9,142.4,134.2,133.2,132.1,131.3,130.8,128.9,127.8,122.2,114.1,111.1,104.2,56.1.HRMS Calculated for C16H13ClNO2[M+H]+286.0629,found 286.0622.
测试例1样品的抗菌性能评价-抗真菌活性测定过程：
含有不同取代喹诺酮衍生物的培养基制备：将提取物溶于丙酮，配成浓度为1mg/mL的母液。分别吸取1mL母液与9mLMEA培养基于无菌试管中，充分振摇后倒入无菌培养皿中，使培养基中提取物的最终质量浓度为100g/mL，以等量丙酮作为空白对照。将活化的植物致病真菌用无菌打孔器打成直径为5mm的菌块，置于上述培养基，每处理重复3次，培养3-7d后，采用十字交叉法测量供试菌菌落直径。按如下公式计算抑制率：抑制率＝[(对照菌落直径－处理菌落直径)/(对照菌落直径-5mm)]×100％。结果见表5.
表5抗真菌平均抑制率(％)
Figure BDA0001673120830000231
3.抗菌性能
由表5知道，所有喹诺酮化合物对小麦赤霉病菌、番茄早疫病菌、杨树溃疡病菌、苦瓜枯萎病菌四种真菌都有一定的抑制活性，其中Q3,Q20,Q33对小麦赤霉病菌；Q7,Q13,Q33,Q35对番茄早疫病菌；Q3,Q27,Q32对杨树溃疡病菌；Q19,Q20,Q32对苦瓜枯萎病菌抑制率很好。表1为同种浓度(浓度为50μg/mL)下不同化合物对4种植物致病真菌的抑制作用。
测试例2
参照测试例1的方法，以小麦赤霉病菌、番茄早疫病菌、杨树溃疡病菌、苦瓜枯萎病菌四种菌为对象，把表5中抑菌效果好的九种化合物配置成不同浓度来做，并且得出了IC50(最小抑制浓度)值，结果见表6。表6中15个IC50值小于10μg/mL，其中Q19、Q20、Q33表现非常好。
表6.四种植物致病真菌的具体抑制效果
Figure BDA0001673120830000241
测试例3抗细菌活性测定过程：
将所有供试菌接种于牛肉膏蛋白胨液体培养基中，大肠杆菌于37℃，其它供试菌于28℃，150r/min，恒温摇床培养1-2d活化。将上述供试菌充分稀释至菌悬液浓度为1.5×108cfu/mL，并均匀涂布在牛肉膏蛋白胨培养基上。用移液枪吸取5mL药液滴加到直径7mm的无菌滤纸片上，待溶剂挥干后放入上述制备好的培养基中，置于28℃培养箱中培养1-2d，观察是否产生抑菌圈，并采用十字交叉法测量抑菌圈的直径。重复2次，同时以两性霉素作为白色念珠菌的阳性对照，硫酸庆大霉素作为供试细菌的阳性对照，结果见表7。
表7吡唑啉酮衍生物对四种致病细菌的生长抑制作用的抑菌圈直径(mm)
Figure BDA0001673120830000242
由表7可知，表5中抑菌效果好的九种化合物对大肠杆菌、枯草芽孢杆菌、金黄色葡萄球菌、白色念珠菌四种致病细菌也有一定的抑制作用，与阳性药相比较，Q13对大肠杆菌，Q32对枯草芽孢杆菌，Q13、Q27对金黄色葡萄球菌Q33对白色念珠菌表现出了比阳性药更好的抑制能力。
以上实验证明，吡唑啉酮衍生物对苦瓜枯萎病菌、杨树溃疡病菌、小麦赤霉病菌、番茄早疫病菌四种真菌都有一定的抑制活性，并且枯草芽孢杆菌、白色念珠菌、大肠杆菌、金黄色葡萄球菌四种细菌也有很好的抑制作用。

Claims (2)

1.一种2-芳基-4-喹诺酮衍生物的制备方法，其特征在于，包括以下步骤：
在银催化剂和氧化剂的作用下，2-乙酰氨基芳甲酰甲酸类化合物和芳基乙烯三氟硼酸钾类化合物在有机溶剂中发生偶联关环反应，反应结束后经过后处理得到所述的2-芳基-4-喹诺酮衍生物；
所述的2-乙酰氨基芳甲酰甲酸类化合物的结构如式（II）所示：
Figure DEST_PATH_IMAGE002
（II）
所述的芳基乙烯三氟硼酸钾类化合物的结构如式（III）所示：
Figure DEST_PATH_IMAGE004
（III）
式（II）~（III）中，R1独立地选自H、甲基、F、Cl、Br或甲氧基中的一个或者多个；
R2独立地选自H、甲基、CF3、F、Cl、Br或甲氧基中的一个或者多个；
所述的银催化剂为AgNO3；
所述的氧化剂为K2S2O8；
所述的有机溶剂为乙腈与水的混合溶剂，体积比为1：1。
2.根据权利要求1所述的2-芳基-4-喹诺酮衍生物的制备方法，其特征在于，所述的2-芳基-4-喹诺酮衍生物选自以下化合物：
Figure DEST_PATH_IMAGE006
。
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