CN110156678A - 一种2,8-双(三氟甲基)喹啉类4-位修饰的衍生物在防治植物病害中的用途 - Google Patents

一种2,8-双(三氟甲基)喹啉类4-位修饰的衍生物在防治植物病害中的用途 Download PDF

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CN110156678A
CN110156678A CN201910443528.9A CN201910443528A CN110156678A CN 110156678 A CN110156678 A CN 110156678A CN 201910443528 A CN201910443528 A CN 201910443528A CN 110156678 A CN110156678 A CN 110156678A
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刘映前
杨冠洲
燕银芳
李虎
朱佳凯
高建梅
尹晓丹
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Lanzhou University
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Abstract

本发明公开了一种2,8‑双(三氟甲基)喹啉类4‑位修饰的衍生物及其制备方法和在防治植物病害中的用途。试验结果表明：该类化合物对油菜菌核病菌、立枯丝核菌、小麦赤霉菌、稻瘟病菌、玉米叶点霉、灰霉病菌、西瓜蔓枯病菌和棉花枯萎病菌具有优异的防治效果。本发明制备工艺简单、原料廉价易得，产品纯度高，杀菌谱广泛，有望开发为新的杀菌剂。

Description

一种2,8-双(三氟甲基)喹啉类4-位修饰的衍生物在防治植物 病害中的用途
技术领域
本发明属于天然药物化学领域和农药技术领域，公开了一种2,8-双(三氟甲基)喹啉类4-位修饰的衍生物的一种新用途，具体涉及喹啉类化合物在防治由菌油菜菌核菌(Sclerotinia sclerotiorum)、立枯丝核菌(Rhizoctonia solani)、小麦赤霉菌(FusaHumgraminearum)、稻瘟病菌(Magnaporthe oryzae)、玉米叶点霉(Phyllosticta zeae)、灰霉病菌(Botrytis cinerea)、西瓜蔓枯病菌(Mycosphaerlla melonis)和棉花枯萎病(Fusarium oxysporum f.sp.vasinfectum)引起的植物病害。
背景技术
真菌引起的植物病害可给农业造成重大损失，对全球粮食安全构成严重威胁。真菌病原体常常导致作物腐烂，甚至产生对人和动物有害的真菌毒素。为了控制这些植物病害，生产了多种化学杀菌剂。然而，重复和单独使用化学类杀菌剂往往会增加病原体的化学抗性，对非目标生物产生不良影响，并对人类健康和环境污染造成潜在风险。因此，寻找具有生物活性的天然产物并将其开发成新型的抗真菌药物以有效控制这些农业病害就显得尤为重要。
以天然产物为先导，运用药物合成和优化策略，创制具有自主知识产权和实际应用价值的杀菌剂是目前农药创新的有效途径。奎宁及其类似物因其特有的生物活性、潜在的研究价值、稳定的化学性质、便宜的价格和易于修饰等优点，可作为农业杀菌剂的先导结构。我们通过对奎宁类化合物的抗真菌活性筛选，发现均具有一定的抗菌活性，值得进一步结构优化和探索。在后期不断地优化过程中，我们以提高活性和降低应用成本为目标，以期开发出新型植物源喹啉类杀菌剂。
奎宁是非常著名的生物碱类天然药物，俗称金鸡纳碱，最早是从茜草科植物金鸡纳树(Cinchona ledgeriana(Howard)Moens ex Trim)及其同属植物的树皮中提取得到的。奎宁是治疗疟疾的特效药，它的发现及应用曾经挽救了无数疟疾病人的生命。课题组前期首次发现奎宁对植物病原真菌的抑制活性，设计合成了一系列新的喹啉类化合物(专利申请号：201810291712.1)。本发明在前期研究的基础上，进一步其喹啉类化合物进行结构优化与衍生合成，并测定了对不同植物病原真菌的活性。以上研究结果表明，喹啉类化合物抗菌谱广泛，抗菌活性较强，田间防效显著，发展前景广阔，可被开发为一类全新的广谱杀菌剂。
发明内容
本发明的目的是提供一种2,8-双(三氟甲基)喹啉类4-位修饰的衍生物在防治农业病害方面的应用。
本发明提供了如下技术方法：
一种针对油菜菌核病菌、立枯丝核菌、小麦赤霉菌、稻瘟病菌、玉米叶点霉、灰霉病菌、西瓜蔓枯病菌和棉花枯萎病菌引起的植物病害的新农药分子，其中含有治疗有效量的任一化合物结构通式如下所示。
其中：
R1为氨基，(C1-C6)烷基，(C3-C6)环烷基，5-10元饱和或部分饱和的杂环基，(C2-C6)卤代烷基，(C2-C6)醇羟基，(C1-C6)芳香苄基。
R2为卤素，羟基，三氟甲基，三氟甲氧基，羧基，氨基，硝基，氰基，5元杂环。
R3为O、S、N原子，(C1-C6)氮烷基，芳香胺基。
R4为(C1-C8)烷基，(C1-C8)不饱和烷基，(C1-C8)卤代烷基，芳基，含有1-3个选自O,N或S的杂原子3-6元杂芳基。
R5为(C1-C8)烷基，(C1-C8)环烷基，(C1-C8)卤代烷基。
R6为(C1-C8)烷基，(C1-C8)环烷基，(C1-C8)卤代烷基。
R7为(C1-C8)烷基，芳基，不同位置被卤素、三氟甲基、三氟甲氧基和硝基取代的芳基。
n可代表0，1，2，3，4，5个碳原子。R8和R9为(C1-C4)烷基，含有1-3个选自O，N或S的杂原子杂芳基。
本发明中“卤素”是指氟、氯、溴或碘等；“烷基”是指直链或支链的烷基；“环烷基”是指取代或未取代的环烷基；“芳基”是指无取代基或连有取代基的苯基；“杂芳基”是指含有一个或多个选自N，O或S杂原子的单环或多环的环状体系。
本发明所述的一种2,8-双(三氟甲基)喹啉类4-位修饰的衍生物合成方法见实施例，经多次硅胶柱层析等常规方法分离获得纯品，经质谱和核磁共振等波谱技术，确定了权利要求的喹啉类化合物。经活性筛选结果表明，本发明所述的喹啉衍生物对油菜菌核病菌、立枯丝核菌、小麦赤霉菌、稻瘟病菌、玉米叶点霉、灰霉病菌、西瓜蔓枯病菌和棉花枯萎病菌表现出较强的抑制作用，可用于制备杀菌剂。
下面通过具体的实施例来进一步描述本发明，本领域技术人员应该理解，下面的实施例仅为了更好地理解本发明，并不用来对本发明进行任何限制。
具体实施方式
实施例旨在阐述而不是限制本发明的范围。以下通过具体实施方式对本发明效果做进一步说明。
实施例1：3a系列化合物的合成方法及化学结构
在100mL的干燥圆底烧瓶中，加入2,8-双(三氟甲基)-4-羟基喹啉，然后再加入适量的三氯化磷，室温下搅拌3小时，然后减压旋蒸除去三氯化磷。将冰水缓慢的滴加入圆底烧瓶，并用二氯甲烷多次萃取所得的化合物。收集有机相，用无水硫酸镁干燥除去溶剂中的水，悬干后直接进行下一步实验。
将上步所得的反应物与不同的取代基化合物用乙醇溶解并在100mL圆底烧瓶中回流，并加入微量三乙胺作为催化剂，反应约3小时，用TLC监测反应。待反应完成后，冷却至室温，加入少量的稀盐酸，并将溶液在室温下搅拌5分钟，然后用二氯甲烷作为有机相进行萃取。收集有机相，用无水硫酸镁干燥除去溶剂中的水，减压旋蒸至固体，然后柱层析纯化获得代表性化合物3a-1～3a-7。
将不同长度烷基醇取代的喹啉加入到100mL的干燥圆底烧瓶中，用干燥的二氯甲烷溶解，然后加入过量的二氯亚砜，在室温下搅拌3小时，然后减压旋蒸除去二氯亚砜。将冰水缓慢的滴加入冰水，并用二氯甲烷多次萃取所得的化合物。收集有机相，用无水硫酸镁干燥除去溶剂中的水，旋干后直接进行下一步实验。
将上步所得的反应物与不同的取代基化合物用乙醇溶解并在100mL圆底烧瓶中回流，并加入微量三乙胺作为催化剂，反应约3小时，用TLC监测反应。待反应完成后，冷却至室温，加入少量的稀盐酸，并将溶液在室温下搅拌5分钟，然后用二氯甲烷作为有机相进行萃取。收集有机相，用无水硫酸镁干燥除去溶剂中的水，减压旋蒸至固体，然后柱层析纯化获得代表性化合物3a-9～3a-13。
化合物3a-9～3a-13的化学结构及结构表征如下：
化合物3a-1
白色固体,产率85.76％,；1H NMR(400MHz,DMSO-d6)δ8.65(d,J＝8.4Hz,1H),8.15(d,J＝7.3Hz,1H),7.68(t,J＝7.9Hz,1H),6.86(s,1H),3.44(td,J＝7.3,5.4Hz,2H),1.30(t,J＝7.2Hz,3H).13C NMR(100MHz,DMSO-d6)δ152.63(2C),148.21,130.05,129.46,129.35,127.45,124.87,120.76,119.81,94.52,94.50,37.78,13.79.MS-ESI m/z:309.108[M+H]+.
化合物3a-2
白色固体,产率81.47％；1H NMR(400MHz,Chloroform-d)δ8.03(d,J＝7.3Hz,1H),7.92(d,J＝8.5Hz,1H),7.51(t,J＝7.8Hz,1H),6.77(s,1H),5.23(s,1H),3.33(td,J＝7.2,5.1Hz,2H),1.82(h,J＝7.4Hz,2H),1.10(t,J＝7.4Hz,3H).13C NMR(100MHz,Chloroform-d)δ151.15(2C),144.39,128.83,128.47,128.41,124.59,123.45,122.44,119.15,95.08,45.14,22.04,11.54.MS-ESI m/z:323.10[M+H]+.
化合物3a-3
白色固体,产率83.59％；1H NMR(400MHz,DMSO-d6)δ8.66(d,J＝8.6Hz,1H),8.15(d,J＝7.3Hz,1H),7.97(t,J＝5.4Hz,1H),7.68(t,J＝7.9Hz,1H),6.86(s,1H),3.43–3.36(m,2H),1.68(p,J＝7.3Hz,2H),1.43(h,J＝7.3Hz,2H),0.95(t,J＝7.4Hz,3H).13C NMR(100MHz,DMSO-d6)δ152.78(2C),144.32,129.42,129.37,127.46,126.95,124.87,123.13,119.83,94.55,42.73,30.14,20.20,14.17.MS-ESI m/z:337.12[M+H]+.
化合物3a-4
浅棕色固体,产率65.23％；1H NMR(400MHz,DMSO-d6)δ8.73(d,J＝8.6Hz,1H),8.15(d,J＝7.3Hz,1H),7.66(t,J＝7.9Hz,1H),7.59(d,J＝7.8Hz,1H),6.92(s,1H),3.70(s,1H),1.99(s,2H),1.78(s,2H),1.49–1.38(m,4H),1.22(q,J＝11.9,9.9Hz,2H).13C NMR(100MHz,DMSO-d6)δ151.79(2C),144.32,129.42,129.37,127.77,126.95,124.70,123.13,119.84,94.78,51.60,32.10(2C),25.76,25.07(2C).MS-ESI m/z:363.13[M+H]+.
化合物3a-5
淡黄色固体,产率76.28％；1H NMR(400MHz,DMSO-d6)δ8.79–8.66(m,2H),8.18(d,J＝7.3Hz,1H),7.73(t,J＝7.9Hz,1H),7.41(d,J＝7.1Hz,2H),7.35(s,1H),7.29–7.24(m,1H),6.80(s,1H),4.70(d,J＝5.9Hz,2H).13C NMR(101MHz,DMSO-d6)δ152.78(2C),144.26,138.18,129.58,129.52,129.04(2C),127.64,127.45(2C),127.39,127.03,125.25,123.34,119.95,95.45,46.07.MS-ESI m/z:371.10[M+H]+.
化合物3a-6
黄色固体，产率76.28％；1H NMR(400MHz,DMSO-d6)δ9.35(s,1H),8.54(d,J＝8.5Hz,1H),8.13(d,J＝7.3Hz,1H),7.63(t,J＝7.9Hz,1H),7.37(s,1H),4.77(s,2H).13CNMR(100MHz,DMSO-d6)δ156.40,152.32,151.89,130.05,129.46,129.35,127.45,124.87,120.76,119.81,94.52.MS-ESI m/z:296.06[M+H]+.
化合物3a-7
白色固体,产率56.79％；1H NMR(400MHz,DMSO-d6)δ8.65(d,J＝8.6Hz,1H),8.16(d,J＝7.3Hz,1H),8.01(t,J＝5.7Hz,1H),7.68(t,J＝7.9Hz,1H),6.96(s,1H),4.92(s,1H),3.70(d,J＝5.8Hz,2H),3.51(d,J＝5.8Hz,2H).13C NMR(100MHz,DMSO-d6)δ153.11(2C),144.34,129.41,129.35,129.11,127.44,124.84,120.78,119.86,94.82,59.29,45.70.MS-ESI m/z:325.08[M+H]+.
化合物3a-8
白色固体,产率59.56％；1H NMR(400MHz,DMSO-d6)δ8.65(d,J＝8.6Hz,1H),8.20(dd,J＝11.8,6.4Hz,2H),7.72(t,J＝7.9Hz,1H),7.05(s,1H),5.77(s,1H),3.92(dd,J＝6.7,5.0Hz,2H),3.85(t,J＝5.6Hz,2H).13C NMR(100MHz,DMSO-d6)δ152.63(2C),144.29,129.58,129.53,127.32,127.06,126.77,125.23,123.08,119.81,95.16,44.59,43.01.MS-ESI m/z:343.04[M+H]+.
化合物3a-9
白色固体,产率45.89％；1H NMR(400MHz,Chloroform-d)δ8.03(dd,J＝11.1,7.9Hz,2H),7.54(t,J＝7.9Hz,1H),7.26(s,0H),6.34(s,1H),3.39–3.30(m,2H),2.74(t,J＝5.9Hz,2H),2.34(s,6H).13C NMR(100MHz,DMSO-d6)δ152.63(2C),144.29,129.58,129.53,127.32,127.06,126.77,125.23,123.08,119.81,95.16,60.50,47.21,46.79(2C).MS-ESI m/z:352.12[M+H]+.
化合物3a-10
橘黄色固体,产率43.57％；1H NMR(400MHz,DMSO-d6)δ8.65(d,J＝8.5Hz,1H),8.16(d,J＝7.3Hz,1H),8.02(t,J＝5.6Hz,1H),7.69(t,J＝7.9Hz,1H),6.94(s,1H),3.57(d,J＝6.1Hz,2H),2.85(t,J＝6.7Hz,2H),2.65(s,4H),1.76–1.70(m,4H).13C NMR(100MHz,DMSO-d6)δ152.71(2C),144.31,129.49,129.43,127.49,126.68,125.00,120.75,119.84,94.84,54.13(2C),53.72,41.92,23.53(2C).MS-ESI m/z:378.14[M+H]+.
化合物3a-11
白色固体,产率48.96％；1H NMR(400MHz,DMSO-d6)δ8.60(d,J＝8.6Hz,1H),8.16(d,J＝7.3Hz,1H),7.90(t,J＝5.5Hz,1H),7.69(t,J＝7.9Hz,1H),6.96(s,1H),3.51(q,J＝6.3Hz,2H),2.60(t,J＝6.7Hz,2H),2.44(t,J＝5.3Hz,4H),1.50(q,J＝5.6Hz,4H),1.41–1.35(m,2H).13C NMR(100MHz,DMSO-d6)δ152.80(2C),144.30,129.43,129.37,127.28,126.70,124.96,120.77,119.79,94.97,57.04,54.64(2C),40.88,26.03(2C),24.40.MS-ESI m/z:392.15[M+H]+.
化合物3a-12
白色固体,产率54.08％；1H NMR(400MHz,DMSO-d6)δ8.60(d,J＝8.6Hz,1H),8.16(d,J＝7.3Hz,1H),7.89(t,J＝5.5Hz,1H),7.69(t,J＝8.0Hz,1H),6.96(s,1H),3.65–3.49(m,6H),2.64(t,J＝6.6Hz,2H),2.48(s,4H).13C NMR(100MHz,DMSO-d6)δ152.79(2C),144.29,129.46,129.34,127.33,125.01,123.50,123.11,119.79,94.98,66.67(2C),56.68,53.84(2C).MS-ESI m/z:394.14[M+H]+.
化合物3a-13
白色固体,产率57.09％；1H NMR(400MHz,DMSO-d6)δ8.60(d,J＝8.5Hz,1H),8.16(d,J＝7.3Hz,1H),7.89(s,1H),7.69(t,J＝7.9Hz,2H),6.96(s,1H),3.51(d,J＝6.1Hz,2H),2.63(t,J＝6.6Hz,2H),2.51(p,J＝1.8Hz,4H),2.34(s,4H),2.16(s,3H).13C NMR(100MHz,DMSO-d6)δ152.80(2C),144.29,129.46,129.34,127.32,125.01,125.00,123.10,119.79,95.02,56.30,55.15(2C),53.19(2C),46.12.MS-ESI m/z:407.17[M+H]+.
实施例2：3b系列化合物的合成方法及化学结构
在100mL的干燥圆底烧瓶中，加入2,8-双(三氟甲基)-4-羟基喹啉，再加入适量的三氯化磷，室温下搅拌3小时，然后减压旋蒸除去三氯化磷。将冰水缓慢的滴加入圆底烧瓶，并用二氯甲烷多次萃取所得的化合物。收集有机相，用无水硫酸镁干燥除去溶剂中的水，旋干后直接进行下一步实验。
先将氢化钠溶解在无水四氢呋喃(若反应产率很低，则将溶剂换为DMF)中，然后在冰浴条件下缓慢加入不同的胺，活化一段时间，最加入上步所得化合物，并在常温下搅拌反应，TLC监测。待反应完成后，将冰水缓慢的滴加入圆底烧瓶，并用二氯甲烷多次萃取所得的化合物。收集有机相，用无水硫酸镁干燥除去溶剂中的水，旋干有机相后用柱层析方法纯化获得代表性化合物3b-1～3b-6。
化合物3b-1～3b-6的化学结构及结构表征如下：
化合物3b-1
黄色固体,产率35.29％；1H NMR(400MHz,DMSO-d6)δ9.75(s,1H),8.83(d,J＝8.6Hz,1H),8.28(d,J＝7.3Hz,1H),7.84(t,J＝7.9Hz,1H),7.56(td,J＝7.9,1.7Hz,1H),7.47(ddd,J＝7.5,4.7,2.0Hz,2H),7.38(ddd,J＝9.0,6.5,2.4Hz,1H),6.64(d,J＝2.8Hz,1H).13C NMR(101MHz,DMSO-d6)δ158.47,156.01,151.71,144.50,130.15,129.18,129.10,128.79,127.75,127.21,126.92,126.38,126.12,120.41,120.14,117.54,97.30.MS-ESIm/z:375.07[M+H]+.
化合物3b-2
白色固体,产率35.29％；1H NMR(400MHz,DMSO-d6)δ9.82(s,1H),8.77(d,J＝8.6Hz,1H),8.28(d,J＝7.3Hz,1H),7.83(t,J＝7.9Hz,1H),7.54(q,J＝7.8Hz,1H),7.36–7.17(m,3H),7.10(td,J＝8.8,2.1Hz,1H).13C NMR(102MHz,DMSO-d6)δ164.44,162.01,150.92(2C),144.77,131.91,131.89,130.18,127.82,127.19,126.09,120.80,119.63,112.54,110.86,110.63,98.06.MS-ESI m/z:375.07[M+H]+.
化合物3b-3
黄色固体,产率47.87％；1H NMR(400MHz,DMSO-d6)δ9.74(s,1H),8.79(d,J＝8.6Hz,1H),8.26(d,J＝7.3Hz,1H),7.81(t,J＝7.9Hz,1H),7.52–7.32(m,4H),6.96(s,1H).13C NMR(101MHz,DMSO-d6)δ161.54,159.12,151.99(2C),144.72,130.08,127.70,127.20,125.84(2C),123.21,123.02,120.46,120.33,117.25,117.02,96.73.MS-ESI m/z:375.07[M+H]+.
化合物3b-4
黄色固体，产率57.98％；1H NMR(400MHz,DMSO-d6)δ9.78(s,1H),8.78(d,J＝8.6Hz,1H),8.27(d,J＝7.3Hz,1H),7.82(t,J＝7.9Hz,1H),7.59–7.53(m,2H),7.50–7.42(m,2H),7.13(s,1H).13C NMR(100MHz,DMSO-d6)δ161.54,159.12,151.99(2C),144.72,130.08,127.70,127.20,125.84(2C),123.21,123.02,120.46,120.33,117.25,117.02,96.73.MS-ESI m/z:391.04[M+H]+.
化合物3b-5
淡黄色固体,产率58.47％；1H NMR(400MHz,DMSO-d6)δ9.84(s,1H),8.74–8.68(m,1H),8.30(d,J＝7.3Hz,1H),7.86(t,J＝7.9Hz,1H),7.52(d,J＝1.8Hz,2H),7.44(t,J＝1.8Hz,1H),7.35(s,1H).13C NMR(100MHz,DMSO-d6)δ161.54,159.12,151.99(2C),144.72,130.08,127.70,127.20,125.84(2C),123.21,123.02,120.46,120.33,117.25,117.02,96.73.MS-ESI m/z:425.00[M+H]+.
化合物3b-6
白色固体,产率49.47％；1H NMR(400MHz,DMSO-d6)δ10.01(s,1H),9.06(s,1H),8.94(d,J＝8.7Hz,1H),8.44(dd,J＝5.1,2.0Hz,1H),8.29(d,J＝7.3Hz,1H),7.86(dtd,J＝9.0,4.8,2.5Hz,2H),7.47(d,J＝8.3Hz,1H),7.12(dd,J＝7.2,5.0Hz,1H).13C NMR(100MHz,DMSO-d6)δ154.56,148.26,147.73,147.62,144.46,138.85,129.87,127.86,127.32,126.20,125.73,120.95,120.66,118.78,114.93,102.38.MS-ESI m/z:358.08[M+H]+.
实施例3：3c系列化合物的合成方法及化学结构
在100mL的干燥圆底烧瓶中，加入2,8-双(三氟甲基)-4-羟基喹啉，然后再加入适量的三氯化磷，室温下搅拌3小时，然后减压旋蒸除去三氯化磷。将冰水缓慢的滴加入圆底烧瓶，并用二氯甲烷多次萃取所得的化合物。收集有机相，用无水硫酸镁干燥除去溶剂中的水，旋干后直接进行下一步实验。
将上步所得的反应物与不同的胺类用乙醇溶解并在100mL圆底烧瓶中回流，并加入微量三乙胺作为催化剂，反应约3小时，用TLC监测反应。待反应完成后，冷却至室温，加入少量的稀盐酸，并将溶液在室温下搅拌5分钟，然后用二氯甲烷作为有机相进行萃取。收集有机相，用无水硫酸镁干燥除去溶剂中的水，减压旋蒸至固体，然后柱层析纯化获得代表性化合物3c-1～3c-5。
化合物3c-1～3c-5的化学结构及结构表征如下：
化合物3c-1
白色固体,产率42.57％；1H NMR(400MHz,Chloroform-d)δ8.20(dd,J＝8.6,1.4Hz,1H),8.10(d,J＝7.2Hz,1H),7.64(t,J＝7.9Hz,1H),7.24(s,1H),3.63–3.46(m,4H),3.04–2.88(m,4H).13C NMR(101MHz,Chloroform-d)δ159.70,148.88,145.31,129.21,128.83,128.78,127.78,125.83,124.98,124.59,106.15,54.92(2C),27.83(2C).MS-ESIm/z:367.07[M+H]+.
化合物3c-2
黄色固体,产率58.96％；1H NMR(400MHz,DMSO-d6)δ8.55–8.50(m,1H),8.42(d,J＝7.3Hz,1H),8.17(s,1H),7.97(t,J＝7.9Hz,1H),3.81–3.77(m,4H),3.76–3.72(m,2H),3.53(m,J＝4.9Hz,2H).13C NMR(101MHz,DMSO-d6)δ157.31,151.32,144.54,131.10,128.85,127.51,126.89,125.36,124.05,119.97,110.64,66.11(2C),45.40,44.64.MS-ESI m/z:351.09[M+H]+.
化合物3c-3
浅棕色固体,产率58.96％；1H NMR(400MHz,DMSO-d6)δ8.36(d,J＝8.5Hz,1H),8.26(d,J＝7.3Hz,1H),7.80(t,J＝7.9Hz,1H),7.40(s,1H),3.39–3.31(m,8H),2.31(s,3H).13CNMR(101MHz,DMSO-d6)δ159.42,1513.25,144.83,131.10,129.78,127.51,126.57,125.36,123.96,119.97,105.50,54.76(2C),52.17(2C),46.12.MS-ESI m/z:364.12[M+H]+.
化合物3c-4
橘黄色固体,产率52.68％；1H NMR(400MHz,DMSO-d6)δ8.46(d,J＝8.5Hz,1H),8.28(d,J＝7.2Hz,1H),7.83(t,J＝7.9Hz,1H),7.47(s,1H),7.28(t,J＝7.8Hz,2H),7.05(d,J＝8.1Hz,2H),6.85(t,J＝7.2Hz,1H),3.52(dd,J＝7.0,3.2Hz,4H),3.49–3.45(m,4H).13C NMR(100MHz,DMSO-d6)δ159.32,151.17,147.90,144.82,129.98,129.92,129.81,129.52(2C),126.70(2C),124.00,119.78(2C),116.11(2C),105.67,52.13(2C),48.58(2C).MS-ESI m/z:426.14[M+H]+.
化合物3c-5
白色固体,产率52.68％；1H NMR(400MHz,Chloroform-d)δ8.26–8.19(m,1H),8.09(d,J＝7.2Hz,1H),7.63(t,J＝7.9Hz,1H),7.20(s,1H),4.12–3.96(m,2H),3.50–3.33(m,2H),2.71(dd,J＝12.1,10.2Hz,2H),1.29(d,J＝6.2Hz,6H).13C NMR(100MHz,Chloroform-d)δ158.42(2C),145.30,129.17,128.75,128.69,127.94,125.64,124.25,119.95,105.33,71.60(2C),57.99(2C),18.84(2C).MS-ESI m/z:379.12[M+H]+.
实施例4：3d系列化合物的合成方法及化学结构
将2,8-双(三氟甲基)-4-羟基-喹啉用无水丙酮溶解于100mL的干燥圆底烧瓶中，向其中加入适量无水碳酸钾，并加热到30℃混合均匀，然后逐滴加入1.5倍当量的碘代烷烃，混合物回流12h。将反应混合物冷却至室温并过滤，将滤液减压旋干，并将所得固体溶于乙酸乙酯中，进行萃取。收集有机相，用无水硫酸镁干燥除去溶剂中的水，减压旋蒸至固体，然后通过柱层析法纯化得到代表性化合物3d-1～3d-7。
将化合物3d-7与不同的胺类用乙醇溶解并在100mL圆底烧瓶中回流，并加入微量三乙胺作为催化剂，反应约3小时，用TLC监测反应。待反应完成后，冷却至室温，加入少量的稀盐酸，并将溶液在室温下搅拌5分钟，然后用二氯甲烷作为有机相进行萃取。收集有机相，用无水硫酸镁干燥除去溶剂中的水，减压旋蒸至固体，然后柱层析纯化获得代表化合物3d-8～3d-11。
化合物3d-1～3d-11的化学结构及结构表征如下：
化合物3d-1
白色固体,产率52.68％；1H NMR(400MHz,DMSO-d6)δ8.49(dd,J＝8.4,1.4Hz,1H),8.30(d,J＝7.3Hz,1H),7.83(t,J＝7.9Hz,1H),7.56(s,1H),4.20(s,3H).13C NMR(100MHz,DMSO-d6)δ164.53,148.99,143.89,130.43,127.47,127.24,126.87,125.53,122.24,120.24,98.82,57.80.MS-ESI m/z:296.05[M+H]+.
化合物3d-2
白色固体,产率67.98％；1H NMR(400MHz,DMSO-d6)δ8.48(dd,J＝8.5,1.4Hz,1H),8.29(d,J＝7.3Hz,1H),7.82(t,J＝7.9Hz,1H),7.51(s,1H),4.47(q,J＝6.9Hz,2H),1.51(t,J＝7.0Hz,3H).13C NMR(100MHz,DMSO-d6)δ163.66,149.31,143.97,130.38,127.35,126.86,125.54,122.98,122.26,120.24,99.14,66.19,14.50.MS-ESI m/z:310.06[M+H]+.
化合物3d-3
白色固体,产率71.23％；1H NMR(400MHz,DMSO-d6)δ8.51(dd,J＝8.8,5.3Hz,1H),8.30(d,J＝6.8Hz,1H),7.86–7.79(m,1H),7.54(s,1H),4.38(td,J＝6.4,2.7Hz,2H),1.92(q,J＝7.0Hz,2H),1.09(t,J＝7.4Hz,3H).13C NMR(100MHz,DMSO-d6)δ163.80,149.33,143.97,130.42,127.43,127.28,126.89,125.55,122.32,120.25,99.21,71.63,22.09.MS-ESI m/z:324.08[M+H]+.
化合物3d-4
白色固体,产率67.57％；1H NMR(400MHz,DMSO-d6)δ8.44(dd,J＝8.5,1.4Hz,1H),8.26(d,J＝7.3Hz,1H),7.79(t,J＝7.9Hz,1H),7.51(s,1H),4.38(t,J＝6.4Hz,2H),1.93–1.80(m,2H),1.60–1.46(m,2H),0.97(t,J＝7.4Hz,3H).13C NMR(100MHz,DMSO-d6)δ163.72,149.31,143.93,130.28,127.16,126.88,125.51,122.96,122.26,120.22,99.10,69.93,30.45,19.13,14.02.MS-ESI m/z:338.10[M+H]+.
化合物3d-5
粘稠状液体,产率54.78％；1H NMR(400MHz,DMSO-d6)δ8.46(d,J＝8.4Hz,1H),8.27(d,J＝7.4Hz,1H),7.81(t,J＝7.9Hz,1H),7.52(s,1H),4.38(t,J＝6.5Hz,2H),1.87(p,J＝6.8Hz,2H),1.54–1.44(m,2H),1.28–1.24(m,4H),0.84(d,J＝6.0Hz,3H).13C NMR(100MHz,DMSO-d6)δ163.73,149.33,143.96,130.30,127.33,126.92,125.51,122.80,122.29,120.23,99.14,70.22,31.65,28.80,28.58,25.82,22.43,14.28.MS-ESI m/z:380.14[M+H]+.
化合物3d-6
白色固体,产率57.98％；1H NMR(400MHz,DMSO-d6)δ8.54(dd,J＝8.5,1.4Hz,1H),8.31(d,J＝7.3Hz,1H),7.85(t,J＝7.9Hz,1H),7.57(s,1H),6.19(ddt,J＝17.3,10.5,5.2Hz,1H),5.57(dq,J＝17.3,1.7Hz,1H),5.41(dq,J＝10.6,1.5Hz,1H),5.05(dt,J＝5.3,1.6Hz,2H).13CNMR(100MHz,DMSO-d6)δ163.27,149.22,144.04,132.40,130.53,127.54,126.61,125.53,122.96,122.33,120.22,119.15,99.69,70.49.MS-ESI m/z:322.06[M+H]+.
化合物3d-7
白色固体,产率47.98％；1H NMR(400MHz,DMSO-d6)δ8.59(dd,J＝8.6,1.4Hz,1H),8.32(d,J＝7.3Hz,1H),7.85(t,J＝7.9Hz,1H),7.61(s,1H),4.56(t,J＝5.9Hz,2H),3.93(t,J＝6.4Hz,2H),2.38(q,J＝6.2Hz,2H).13C NMR(100MHz,DMSO-d6)δ163.57,149.34,143.97,130.48,127.49,126.86,125.54,122.90,122.28,120.23,99.34,67.24,42.29,31.69.MS-ESI m/z:358.04[M+H]+.
化合物3d-8
白色固体,产率45.96％；1H NMR(400MHz,DMSO-d6)δ8.49(dd,J＝8.5,1.4Hz,1H),8.32(d,J＝7.3Hz,1H),8.22(s,1H),7.86(t,J＝7.9Hz,1H),7.74(s,1H),7.55(s,1H),4.70(t,J＝6.8Hz,2H),4.46(t,J＝5.8Hz,2H),2.51(d,J＝2.0Hz,2H).13C NMR(100MHz,DMSO-d6)δ163.55,149.13,143.96,133.81,130.50,127.59,127.40,126.83,125.43,122.97,122.26,120.22,99.27,67.50,46.85,29.49.MS-ESI m/z:391.10[M+H]+.
化合物3d-9
白色固体,产率45.96％；1H NMR(400MHz,DMSO-d6)δ8.58(s,1H),8.50(dd,J＝8.5,1.4Hz,1H),8.32(d,J＝7.3Hz,1H),8.00(s,1H),7.85(t,J＝7.9Hz,1H),7.55(s,1H),4.48(dt,J＝15.0,6.3Hz,4H),2.48–2.42(m,2H).13C NMR(100MHz,DMSO-d6)δ163.58,152.00,148.96,144.70,143.95,130.48,129.11,127.39,126.54,122.97,122.28,120.23,99.27,67.57,46.22,29.04.MS-ESI m/z:391.10[M+H]+.
化合物3d-10
白色固体,产率51.59％；1H NMR(400MHz,DMSO-d6)δ8.52(d,J＝8.4Hz,1H),8.30(d,J＝7.3Hz,1H),7.84(t,J＝7.9Hz,1H),7.55(s,1H),4.48(t,J＝6.2Hz,2H),3.57(t,J＝4.5Hz,4H),2.57–2.51(m,2H),2.40(t,J＝4.6Hz,4H),2.06(p,J＝6.6Hz,2H).13C NMR(100MHz,DMSO-d6)δ163.81,148.98,143.98,131.95,130.42,129.10,127.43,126.59,122.35,120.25,99.22,68.60,66.64(2C),55.07,53.81(2C),25.83MS-ESI m/z:409.13[M+H]+.
化合物3d-11
白色固体,产率52.37％；1H NMR(400MHz,DMSO-d6)δ8.52(d,J＝8.2Hz,1H),8.31(d,J＝7.1Hz,1H),7.85(t,J＝7.9Hz,1H),7.55(d,J＝3.7Hz,1H),4.46(q,J＝5.0,3.6Hz,2H),2.47(t,J＝7.2Hz,2H),2.34(s,4H),2.04(p,J＝6.7Hz,2H),1.48(p,J＝5.5Hz,4H),1.37(d,J＝7.0Hz,2H).13C NMR(100MHz,DMSO-d6)δ163.84,149.32,143.99,131.95,130.45,129.11,127.44,126.59,122.36,120.25,99.22,68.77,55.36,54.56(2C),26.25,26.04(2C),24.57.MS-ESIm/z:409.13[M+H]+.
实施例5：3e系列化合物的合成方法及化学结构
将原料2,8-二三氟甲基喹啉加入到100ml圆底烧瓶瓶中，用20ml丙酮溶解，先加入2倍当量碳酸钾，然后加入2倍当量的相应酰氯，加热回流3小时，冷却到室温后用乙酸乙酯萃取，收集有机相用无水硫酸镁干燥，蒸去溶剂，用柱层析纯化(乙酸乙酯:石油醚＝1:5)得白色固体。获得代表性化合物3e-1～3e-5。
化合物3e-1～3e-5的化学结构及结构表征如下：
化合物3e-1
白色固体,产率84.97％；1H NMR(400MHz,DMSO-d6)δ8.52–8.47(m,1H),8.45(d,J＝7.3Hz,1H),8.34(s,1H),8.00(t,J＝7.9Hz,1H),4.33(t,J＝6.6Hz,2H),1.78(h,J＝7.1Hz,2H),1.00(t,J＝7.4Hz,3H).13C NMR(101MHz,DMSO-d6)δ156.58,151.59,148.28,144.58,131.39,129.32,127.26,127.05,123.42，122.58,119.87,110.87,71.81,21.80,10.49.MS-ESIm/z:368.07[M+H]+.
化合物3e-2
白色固体,产率86.89％；1H NMR(400MHz,DMSO-d6)δ8.46(t,J＝7.7Hz,2H),8.34(s,1H),8.00(t,J＝7.9Hz,1H),5.02(h,J＝6.2Hz,1H),1.41(d,J＝6.3Hz,6H).13C NMR(100MHz,DMSO-d6)δ156.56,150.97,148.62,144.57,131.37,129.33,127.27,127.02,123.42,122.61,119.88,110.81,75.34,21.79(2C).MS-ESI m/z:368.07[M+H]+.
化合物3e-3
白色固体,产率89.84％；1H NMR(400MHz,DMSO-d6)δ8.46(dd,J＝17.3,7.9Hz,2H),8.34(s,1H),7.99(t,J＝7.9Hz,1H),4.15(d,J＝6.6Hz,2H),2.06(hept,J＝6.7Hz,1H),0.99(d,J＝6.7Hz,6H).13C NMR(100MHz,DMSO-d6)δ156.57,151.59,148.45,144.58,131.34,129.34,127.27,127.03,123.43,122.58,119.86,110.92,75.91,27.66,19.05(2C).MS-ESIm/z:382.09[M+H]+.
化合物3e-4
白色固体,产率82.59％；1H NMR(400MHz,DMSO-d6)δ8.50–8.41(m,2H),8.32(s,1H),7.98(t,J＝7.9Hz,1H),4.36(t,J＝6.6Hz,2H),1.81–1.66(m,2H),1.49–1.37(m,2H),0.94(t,J＝7.4Hz,3H).13C NMR(101MHz,DMSO-d6)δ156.56,151.56,148.62,144.57,131.30,129.29,127.27,127.01,125.28,123.39,119.86,110.81,70.12,30.33,18.85,13.93.MS-ESIm/z:382.09[M+H]+.
化合物3e-5
白色固体,产率82.59％；1H NMR(400MHz,DMSO-d6)δ8.46(dd,J＝12.5,7.9Hz,2H),8.35(s,1H),7.99(t,J＝7.9Hz,1H),5.26(p,J＝4.2Hz,1H),2.00–1.88(m,4H),1.77–1.71(m,2H),1.65(dd,J＝8.9,5.6Hz,2H).13C NMR(100MHz,DMSO-d6)δ156.61,151.15,148.62,144.57,131.38,129.32,127.27,127.10,123.45,122.62,119.89,110.93,84.02,32.51(2C),23.68(2C).MS-ESI m/z:394.09[M+H]+.
实施例6：3f系列化合物的合成方法及化学结构
将2,8-双(三氟甲基)4-氯喹啉和相当量的硫脲加入到干燥的圆底烧瓶中用无水乙醇充分溶解，然后将混合物加热回流1小时。滤出所得固体产物，用水洗涤，用乙醇重结晶，得到橙色结晶得到目标化合物3f-1。
将化合物3f-1加入到100mL圆底烧瓶瓶中，用20ml丙酮溶解，先加入2倍当量碳酸钾，然后加入2倍当量的相应酰氯，加热回流3小时，冷却到室温后用乙酸乙酯萃取，收集有机相用无水硫酸镁干燥，蒸去溶剂，用柱层析纯化(乙酸乙酯:石油醚＝1:5)得代表性化合物3f-2～3f-5。
化合物3f-1～3f-5的化学结构及结构表征如下：
化合物3f-1
淡黄色固体,产率34.10％.1H NMR(400MHz,DMSO-d6)δ8.78(d,J＝8.5Hz,1H),8.45(d,J＝7.3Hz,1H),8.23(s,1H),8.10(s,1H),8.03(d,J＝8.1Hz,1H).13C NMR(100MHz,DMSO-d6)δ149.27,147.14,142.82,131.20,129.32,129.12,127.83,127.48,125.24,122.55,116.03.MS-ESIm/z:298.01[M+H]+.
化合物3f-2
淡黄色固体,产率31.94％.；1H NMR(400MHz,DMSO-d6)δ8.79(d,J＝8.6Hz,1H),8.47(d,J＝6.9Hz,1H),8.25(s,1H),8.14–8.03(m,1H),1.92(s,3H).13C NMR(100MHz,DMSO-d6)δ172.46,148.64,142.82,131.35,129.74,129.51,129.05,127.70,127.32,125.15,122.36,115.73,21.51.MS-ESI m/z:340.02[M+H]+.
化合物3f-3
白色固体,产率31.89％.1H NMR(400MHz,DMSO-d6)δ8.79(d,J＝8.6Hz,1H),8.47(d,J＝6.9Hz,1H),8.25(s,1H),8.14–8.03(m,1H),4.59,(q,1H),1.57(d,3H).13C NMR(100MHz,DMSO-d6)δ171.45,148.65,142.82,131.29,129.74,129.50,129.06,127.71,127.32,125.15,122.36,115.73,53.78,21.87.MS-ESI m/z:388.00[M+H]+.
化合物3f-4
白色固体,产率28.97％,1H NMR(400MHz,DMSO-d6)δ8.79(d,J＝8.5Hz,1H),8.47(d,J＝7.3Hz,1H),8.25(s,1H),8.07(t,J＝8.0Hz,1H),3.67(t,J＝6.5Hz,2H),2.38(t,J＝7.2Hz,2H),1.95(p,J＝6.8Hz,3H).13C NMR(100MHz,DMSO-d6)δ174.10,148.60,146.93,142.81,131.32,129.49,129.00,127.67,127.53,122.55,119.81,115.68,45.07,31.26,28.03.MS-ESIm/z:368.05[M+H]+.
化合物3f-5
白色固体,产率25.86％.1H NMR(400MHz,DMSO-d6)δ8.79(d,J＝8.5Hz,1H),8.47(d,J＝7.3Hz,1H),8.25(s,1H),8.07(t,J＝8.0Hz,1H),3.65(t,J＝6.5Hz,2H),2.26(t,J＝7.3Hz,2H),1.79-1.69(m,2H),1.67-1.55(m,2H).13C NMR(100MHz,DMSO-d6)δ174.65,148.57,146.94,142.82,131.24,129.47,129.29,128.96,127.84,127.66,127.54,119.16,115.63,45.48,33.23,31.89,22.35.MS-ESI m/z:416.03[M+H]+.
实施例7：3g系列化合物的合成方法及化学结构
将2,8-双(三氟甲基)4-羟基喹啉加入到100ml圆底烧瓶瓶中，用20ml丙酮溶解，先加入2倍当量碳酸钾，然后加入2倍当量的相应磺酰氯，加热回流，TLC检测反应，待反应完全后，冷却到室温后用乙酸乙酯萃取，收集有机相用无水硫酸镁干燥，蒸去溶剂，用柱层析纯化(乙酸乙酯:石油醚＝1:5)得到代表性化合物3g-1～3g-7。
化合物3g-1～3g-7的化学结构及结构表征如下：
化合物3g-1
白色固体,产率74.23％,1H NMR(400MHz,CDCl3)δ8.33(d,J＝8.5Hz,1H),8.19(d,J＝7.3Hz,1H),7.80(s,1H),7.76(s,1H),3.36(s,3H).13C NMR(100MHz,CDCl3)δ153.9,149.4,145.4,130.3,130.2,129.3,128.3,125.8,123.4,121.8,109.3,39.2.ESI-MS m/z:360.06[M+H]+.
化合物3g-2
白色固体,产率79.86％,1H NMR(400MHz,CDCl3)δ8.14–8.07(m,2H),7.93–7.87(m,2H),7.69(td,J＝7.4,1.4Hz,1H),7.62(t,J＝7.9Hz,1H),7.57–7.50(m,3H).13C NMR(100MHz,CDCl3)δ154.5,149.2,145.3,135.4,134.5,130.1,130.1,130.0,129.8,129.1,128.7,128.5,128.0,126.0,124.5,123.6,109.6.ESI-MS m/z:444.06[M+Na]+.
化合物3g-3
白色固体,产率75.68％,1H NMR(400MHz,DMSO-d6)δ8.72(dd,J＝8.6,1.3Hz,1H),8.48(d,J＝7.3Hz,1H),8.29(d,J＝7.2Hz,1H),8.24–8.15(m,1H),8.07(s,1H),8.00(t,J＝7.9Hz,1H),7.89-7.75(m,1H),7.28(s,1H).13C NMR(100MHz,DMSO-d6)δ161.32,149.37,149.02,144.96,131.33,131.27,128.88,127.78,127.44,127.37,127.01,125.48,123.75,123.37,119.91,107.05,101.53.ESI-MS m/z:489.05[M+Na]+.
化合物3g-4
白色固体,产率75.68％；1H NMR(400MHz,DMSO-d6)δ8.52(d,J＝8.4Hz,1H),8.41(t,J＝7.4Hz,1H),8.29(d,J＝7.6Hz,1H),7.91(d,J＝7.5Hz,1H),7.80(t,J＝7.9Hz,1H),7.70(d,J＝7.9Hz,1H),7.61(t,J＝7.7Hz,1H),7.30(s,1H).13C NMR(100MHz,DMSO-d6)δ161.32,149.87,149.02,144.79,133.30,132.34,130.50,129.99,129.73,129.62,127.75,127.14,126.63,125.91,125.61,125.57,122.40,101.50.ESI-MS m/z:512.05[M+Na]+.
化合物3g-5
白色固体,产率79.67％；1H NMR(400MHz,DMSO-d6)δ8.52(d,J＝8.4Hz,1H),8.30(dt,J＝11.2,6.1Hz,2H),8.08(d,J＝8.2Hz,1H),7.95–7.87(m,1H),7.82(d,J＝8.2Hz,1H),7.71(d,J＝8.0Hz,1H),7.30(s,1H).13C NMR(100MHz,DMSO-d6)δ152.64,149.87,149.02,144.79,130.51,130.34,129.99,129.79,129.42,129.11,127.76,127.03,126.79,126.63,125.35,125.31,122.40,101.49.ESI-MS m/z:512.05[M+Na]+.
化合物3g-6
白色固体,产率75.28％；1H NMR(400MHz,DMSO-d6)δ8.43(d,J＝7.3Hz,1H),8.29(d,J＝8.4Hz,1H),8.08(dt,J＝8.1,2.2Hz,1H),7.98–7.88(m,3H),7.79–7.71(m,2H).13CNMR(101MHz,DMSO-d6)δ164.08,163.62,161.13,154.44,144.79,133.01,131.72,129.76,127.12,125.63,125.60,123.98,123.84,122.10,116.58,116.33,111.51.ESI-MS m/z:462.05[M+Na]+.
化合物3g-7
白色固体,产率75.28％,1H NMR(400MHz,DMSO-d6)δ8.43(d,J＝7.3Hz,2H),7.79(d,J＝8.0Hz,1H),7.70–7.62(m,2H),7.29(s,1H),7.18–7.07(m,2H).13C NMR(101MHz,DMSO-d6)δ167.97,164.08,154.55,144.80,132.65,131.71,129.92,129.74,128.34,127.77,127.08,126.62,123.85,118.18,117.95,114.67,101.53.ESI-MS m/z:462.05[M+Na]+.
实施例8：3h系列化合物的合成方法及化学结构
将原料2,8-二三氟甲基喹啉加入到100ml圆底烧瓶瓶中，用20ml丙酮溶解，先加入2倍当量碳酸钾，然后加入2倍当量氯乙(丙)酰氯，加热回流3小时，冷却到室温后用乙酸乙酯萃取，收集有机相用无水硫酸镁干燥，蒸去溶剂，用柱层析纯化(乙酸乙酯:石油醚＝1:5)得无色晶体。
再将收到的化合物加入到100ml圆底烧瓶瓶中，用20ml乙醇溶解，先加入2倍当量碳酸钾，然后加入2倍当量相应的胺，加热回流3小时，冷却到室温后用乙酸乙酯萃取，收集有机相用无水硫酸镁干燥，蒸去溶剂，用柱层析纯化(乙酸乙酯:石油醚＝1:5)得到代表性化合物3h-1～3h-8。
化合物3h-1～3h-8的化学结构及结构表征如下：
化合物3h-1
白色固体,产率67.84％,1H NMR(400MHz,DMSO-d6)δ8.54–8.48(m,1H),8.42(d,J＝7.3Hz,1H),8.17(s,1H),7.97(t,J＝7.9Hz,1H),3.80–3.72(m,6H),3.53(t,J＝4.9Hz,2H).13C NMR(100MHz,DMSO-d6)δ157.3,151.3,148.5,144.5,131.2,128.9,128.9,127.5,126.9,124.0,122.6,110.6,66.1(2C),45.4,44.6.MS-ESI m/z:395.08[M+H]+.
化合物3h-2
粘稠状液体,产率46.78％,1H NMR(400MHz,Chloroform-d)δ8.52(m,1H),8.07(d,J＝7.2Hz,1H),7.56(t,J＝7.8Hz,1H),6.85(s,1H),3.76(dd,J＝5.6,3.8Hz,4H),2.98(dd,J＝5.7,3.7Hz,4H),1.26(s,2H).13C NMR(100MHz,DMSO-d6)δ158.4,151.4,148.8,144.9,131.2,129.9,128.9,127.5,126.9,124.6,122.6,110.6,67.4(2C),58.2,45.8(2C).MS-ESIm/z:409.10[M+H]+.
化合物3h-3
粘稠状液体,产率42.69％,1H NMR(400MHz,DMSO-d6)δ8.51(d,J＝8.4Hz,1H),8.21(d,J＝7.3Hz,1H),7.71(t,J＝7.8Hz,1H),7.13(s,1H),3.63–3.56(m,6H),2.74–2.61(m,2H),2.55–2.52(m,4H).13C NMR(100MHz,DMSO-d6)δ158.4,151.4,148.8,144.9,131.2,129.9,128.9,127.5,126.9,124.6,122.6,110.6,67.4(2C),55.8(2C),58.2,33.5.MS-ESIm/z:423.11[M+H]+.
化合物3h-4
粘稠状液体,产率48.97％,1H NMR(400MHz,DMSO-d6)δ8.43(d,J＝8.1Hz,1H),7.99(d,J＝7.2Hz,1H),7.42(t,J＝7.8Hz,1H),6.67(s,1H),3.17(s,2H),2.31(d,J＝11.9Hz,8H),2.19(s,3H).13C NMR(100MHz,DMSO-d6)δ158.4,151.4,148.8,144.9,131.2,129.9,128.9,127.5,126.9,124.6,122.6,110.6,57.9,57.3(2C),55.6,(2C),46.6.MS-ESI m/z:422.13[M+H]+.
化合物3h-5
粘稠状液体,产率41.58％；1H NMR(400MHz,DMSO-d6)δ8.52–8.47(m,1H),8.45(d,J＝7.3Hz,1H),8.34(s,1H),8.00(t,J＝7.9Hz,1H),4.33(t,J＝6.6Hz,2H),3.34(s,2H),1.78(q,J＝7.1Hz,8H),1.00(t,J＝7.4Hz,3H).13C NMR(100MHz,DMSO-d6)δ156.6,151.6,148.3,144.6,131.4,131.3,129.3,128.9,127.1,123.4,122.6,110.9,71.8(4C),39.7,21.8,10.5..MS-ESIm/z:436.14[M+H]+.
化合物3h-6
粘稠状液体,产率46.78％；1H NMR(400MHz,DMSO-d6)δ8.49(d,J＝9.0Hz,1H),8.06(d,J＝7.3Hz,1H),7.51(d,J＝8.1Hz,1H),6.83(s,1H),3.62(s,2H),3.47–3.30(m,4H),1.48(m,J＝32.7Hz,6H).13C NMR(100MHz,DMSO-d6)δ156.6,151.6,148.3,144.6,131.4,131.3,129.3,128.9,127.1,123.4,122.6,110.9,58.2,56.5(2C),26.5(2C),24.5.MS-ESIm/z:407.12[M+H]+.
化合物3h-7
,产率36.98％,粘稠状液体；1H NMR(400MHz,DMSO-d6)δ8.50–8.40(m,1H),8.07(d,J＝7.2Hz,1H),7.53(t,J＝7.8Hz,1H),6.84(s,1H),3.45–3.37(m,2H),3.11(t,J＝7.3Hz,2H),2.73(t,J＝7.3Hz,2H),2.09(s,2H),1.63(dq,J＝34.0,5.9Hz,6H).13C NMR(100MHz,DMSO-d6)δ156.6,151.6,148.3,144.6,131.4,131.3,129.3,128.9,127.1,123.4,122.6,110.9,56.8(2C),52.8,33.5,25.9(2C),24.5.MS-ESI m/z:421.13[M+H]+.
化合物3h-8
粘稠状液体,产率46.78％；1H NMR(400MHz,DMSO-d6)δ8.43(d,J＝8.3Hz,1H),7.96(d,J＝7.2Hz,1H),7.39(t,J＝7.7Hz,1H),6.61(s,1H),3.3(s,2H),2.64(m,4H),1.19(m,6H).13C NMR(100MHz,DMSO-d6)δ165.35,148.89,148.56,145.02,130.25,130.20,128.02,126.66,126.00,125.74,124.78,123.15,101.69,49.33,47.95(2C),11.43,9.41.MS-ESIm/z:395.12[M+H]+.
实施例9:目标化合物室内抑菌活性测定及结果
1)实验材料：
本实验中所用的植物病原菌为实验室4℃保存的菌种，采用的培养基为马铃薯培养基(简称PDA)。
PDA培养基配方:马铃薯(去皮)200g，葡萄糖20g，琼脂15g，自来水1000mL，自然PH。
配制方法：将马铃薯洗净去皮，称200g切成小块，加水煮烂(煮沸20-30分钟，能被玻璃棒戳破即可)，用八层纱布过滤于烧杯中，根据实验需要加15-20g琼脂，加入20g葡萄糖，搅拌均匀，充分溶解后稍冷却补足水至1000mL，分装后121℃灭菌20分钟，冷却后备用。
2)实验方法
采用生长速率法。
1、先将5种植物病原菌在PDA平板上25℃培养6d左右待用。
2、将PDA培养基加热溶化，冷却至45-50℃，分别加入不同浓度的喹啉类衍生物制成含100和50μg/mL药液的培养基，并分别倒入培养皿中冷却。
3、以无菌操作手续，用打孔器在培养6d的各菌株菌丝边缘(生长状况尽量一致)打取圆形菌饼(直径0.50cm)，再用接种针挑至含药平板中央，然后将培养皿倒置于培养箱(25℃)中培养。
4、于处理后不同时间观察测定菌丝的生长情况，并采用十字交叉法测得直径并处理数据，计算抑制率。
5、抑制率(％)＝(对照菌丝直径-处理菌丝直径)/对照菌丝直径×100
6、每个处理重复3次。
对油菜菌核病菌、立枯丝核菌、小麦赤霉菌、稻瘟病菌、玉米叶点霉、灰霉病菌、西瓜蔓枯病菌和棉花枯萎病菌活性测定参照生测标准方法NY/T1156.2-2006，采用生长速率法进行室内生物活性测定，明确了目标化合物对这8种病菌的抑制活性，结果见表1-4。
表1 3a～3g系列化合物对油菜菌核、玉米叶点霉、番茄灰霉病和小麦赤霉病的体外抗菌活性
表2 3a～3g系列化合物对棉花枯萎病、立枯丝核菌、稻瘟病菌和西瓜蔓枯病菌的体外抗菌活性
表3 3h系列化合物对油菜菌核、玉米叶点霉、番茄灰霉病和小麦赤霉病植物病的抗菌活性
表4 3h系列化合物对棉花枯萎病、立枯丝核菌、稻瘟病菌和西瓜蔓枯病菌的抗菌活性

Claims (10)

1.本发明所述的一种2,8-双(三氟甲基)喹啉类4-位修饰的衍生物含有治疗有效量的任一化合物结构通式如下所示。
其中：
R1为氨基，(C1-C6)烷基，(C3-C6)环烷基，5-10元饱和或部分饱和的杂环基，(C2-C6)卤代烷基，(C2-C6)醇羟基，(C1-C6)芳香苄基。
R2为卤素，羟基，三氟甲基，三氟甲氧基，羧基，氨基，硝基，氰基，5元杂环。
R3为O、S、N原子，(C1-C6)氮烷基，芳香胺基。
R4为(C1-C8)烷基，(C1-C8)不饱和烷基，(C1-C8)卤代烷基，芳基，含有1-3个选自O，N或S的杂原子3-6元杂芳基。
R5为(C1-C8)烷基，(C1-C8)环烷基，(C1-C8)卤代烷基。
R6为(C1-C8)烷基，(C1-C8)环烷基，(C1-C8)卤代烷基。
R7为(C1-C8)烷基，芳基，不同位置被卤素、三氟甲基、三氟甲氧基和硝基取代的芳基。
n可代表0，1，2，3，4，5个碳原子。R8和R9为(C1-C4)烷基，含有1-3个选自O，N或S的杂原子杂芳基。
本发明中“卤素”是指氟、氯、溴或碘等；“烷基”是指直链或支链的烷基；“环烷基”是指取代或未取代的环烷基；“芳基”是指无取代基或连有取代基的苯基；“杂芳基”是指含有一个或多个选自N，O或S杂原子的单环或多环的环状体系。
2.权利要求1所述的一种2,8-双(三氟甲基)喹啉类4-位修饰的衍生物，其特征在于所述化合物可作为制备防治农业真菌病害药物中的应用。
3.根据权利要求1所述的2,8-双(三氟甲基)喹啉类4-位修饰的衍生物在制备防治或抗油菜菌核病的药物中的应用。
4.根据权利要求1所述的2,8-双(三氟甲基)喹啉类4-位修饰的衍生物在制备防治或抗立枯丝核菌的药物中的应用。
5.根据权利要求1所述的2,8-双(三氟甲基)喹啉类4-位修饰的衍生物在制备防治或抗小麦赤霉菌的药物中的应用。
6.根据权利要求1所述的2,8-双(三氟甲基)喹啉类4-位修饰的衍生物在制备防治或抗稻瘟病的药物中的应用。
7.根据权利要求1所述的2,8-双(三氟甲基)喹啉类4-位修饰的衍生物在制备防治或抗玉米叶点霉菌的药物中的应用。
8.根据权利要求1所述的2,8-双(三氟甲基)喹啉类4-位修饰的衍生物在制备防治或抗西瓜蔓枯病菌的药物中的应用。
9.根据权利要求1所述的2,8-双(三氟甲基)喹啉类4-位修饰的衍生物在制备防治或抗番茄灰霉病的药物中的应用。
10.根据权利要求1所述的2,8-双(三氟甲基)喹啉类4-位修饰的衍生物在制备防治或抗棉花枯萎病的药物中的应用。
CN201910443528.9A 2019-05-27 2019-05-27 一种2,8-双(三氟甲基)喹啉类4-位修饰的衍生物在防治植物病害中的用途 Pending CN110156678A (zh)

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CN112608275A (zh) * 2020-12-29 2021-04-06 兰州大学 一种2,8-双(三氟甲基)-4-羟基喹啉衍生物在制备和防治农业病害中的用途
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CN115466212B (zh) * 2022-10-26 2023-09-22 河南农业大学 一种2-三氟甲基喹啉类化合物及其合成方法和应用

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