CN112493244A - 喹啉2-位衍生物在制备防治农业植物病害药物中的应用 - Google Patents

喹啉2-位衍生物在制备防治农业植物病害药物中的应用 Download PDF

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CN112493244A
CN112493244A CN201910872525.7A CN201910872525A CN112493244A CN 112493244 A CN112493244 A CN 112493244A CN 201910872525 A CN201910872525 A CN 201910872525A CN 112493244 A CN112493244 A CN 112493244A
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刘映前
杨余东
张智军
赵中敏
彭静文
杨程杰
孙钰
吴天琳
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Abstract

本发明涉及农药化学技术领域，公开了一种喹啉2‑位衍生物的新用途，具体涉及喹啉2‑位衍生物在制备防治油菜菌核病菌、水稻纹枯病菌、番茄灰霉病菌、小麦赤霉病菌和稻瘟病菌中的应用。本发明中的化合物是易于合成的、结构简单的小分子化合物，有望开发为新型农业杀菌剂。

Description

喹啉2-位衍生物在制备防治农业植物病害药物中的应用
技术领域
本发明属于农药化学技术领域，公开了喹啉2-位衍生物的一种新用途，具体涉及喹啉2-位衍生物在制备防治油菜菌核病菌、水稻纹枯病菌、番茄灰霉病菌、小麦赤霉病菌和稻瘟病菌中的应用。
背景技术
近年来，由于甲氧基丙烯酸酯类、三唑类、琥珀酸脱氢酶抑制剂类农业杀菌剂的长期大量使用，导致植物病源真菌对已上市药物出现的耐药问题显得日益严峻。水稻纹枯病、油菜菌核病、灰霉病、小麦赤霉病、稻瘟病等农业性疾病也严重影响着粮食作物和农产品的产量与质量。因此，研究开发新型杀菌剂已刻不容缓。
酰肼是农药医药中的活性基团，代表有抗结核药异烟肼、抗抑郁药异唑肼、单胺氧化酶抑制剂异丙烟肼。在化学方法学中其可发生多种化学反应，作为构建各式杂环化合物的必需基团，以实现结构复杂的化合物的合成与方法学研究。在药物化学中其可合成多种类型的衍生物，如腙、脲、酰胺、磺酰胺、1,3,4-噁二唑(噻二唑)类化合物，具有杀虫、除草、抗细菌、抗真菌、抗寄生虫、抗肿瘤、抗病毒等多种生理活性，代表药物有抗高血压药奈沙地尔、抗HIV药雷特格韦等。喹啉是一种具有多种生物活性的含氮稠杂环，自生物碱奎宁从金鸡纳树皮中被人类发现用于治疗疟疾后，其母核始终是科研工作者发现的新型化合物中最常见的杂环之一，也表现出特殊的药理活性和生物活性，如农药中的杀菌剂苯氧喹啉、8-羟基喹啉铜，医药中的抗疟药氯喹、甲氟喹、伯氨喹，因此喹啉环在药物化学中占有重要的地位。本发明将酰肼引入喹啉2位形成喹啉-2-甲酰肼，并以其为合成子进行基于喹啉核心骨架的新型化合物的设计合成和喹啉-2-甲酰肼衍生物的设计合成，以期发现活性优异的喹啉2-位取代的杀菌候选药物。
发明内容
本发明目的是为农业生产提供一种杀菌剂，是以喹啉-2-甲酰肼为合成子的喹啉2-位衍生物的新用途，即喹啉2-位衍生物作为农药在防治油菜菌核病菌、水稻纹枯病菌、番茄灰霉病菌、小麦赤霉病菌和稻瘟病菌中的应用。
为实现上述目的，本发明提供了如下技术方法：一种抗油菜菌核病菌、水稻纹枯病菌、番茄灰霉病菌、小麦赤霉病菌和稻瘟病菌的药物，喹啉2-位衍生物的结构通式如式(Ⅰ)-(Ⅵ)所示：
Figure BDA0002203273300000021
其中：
R为氢、甲基，乙基，环丙基，叔丁基，氨基，羟基，巯基，饱和或不饱和烷基取代的巯基及其氧化物，呋喃基，噻吩基，吡啶基；以及含有一个或多个甲基、乙基、甲氧基、三氟甲基、三氟甲氧基、硝基、氰基、卤素取代的苯基，取代的苄基。
X为氧或硫原子。
可以用下列表1中列出的化合物来说明本发明的喹啉2-位衍生物，但不限定于本发明。
表1化合物表
Figure BDA0002203273300000022
Figure BDA0002203273300000031
Figure BDA0002203273300000041
Figure BDA0002203273300000051
进一步地，本发明所述的喹啉2-位衍生物是按照文献((1)J.Agric.FoodChem.2018,66,9598-9607；(2)Bioorg.Med.Chem.16(2008)9660–9667；(3)Med.Chem.Commun.2015,6,2023–2028；(4)J.Agric.Food Chem.2011.59,2,628-634)报道的合成方法获得的化合物，经硅胶柱层析等常规方法分离获得纯品，经核磁共振波谱等技术，确定了权利要求的喹啉2-位衍生物。经活性筛选结果表明，本发明所述的喹啉2-位衍生物对油菜菌核病菌、水稻纹枯病菌、番茄灰霉病菌、小麦赤霉菌和稻瘟病菌表现出一定的抑制作用，可用于制备杀菌剂。
为了更好地理解本发明，以下通过具体实施方式，对本发明的上述内容做进一步的详细说明。但不应将此理解为对本发明的限制。
具体实施方式
实施例1:2a的合成
Figure BDA0002203273300000052
其具体合成操作如下：将喹啉-2-羧酸(2.31mmol)溶于5ml氯化亚砜中，在80℃下反应4h。反应完成后旋干溶剂，加入5ml无水二氯甲烷溶解，转移至恒压滴液漏斗中备用。将叔丁基肼盐酸盐(4.62mmol)溶于15ml二氯甲烷中，在0℃下向其中滴加5ml氢氧化钠(6.93mmol)水溶液，反应15min。后开始缓慢滴加中间体的二氯甲烷液，滴加完成后在0℃下反应30min，后升温至室温继续反应3h。反应完成后加入30ml二氯甲烷稀释，用水和卤水洗涤有机相，有机相用无水硫酸钠干燥。旋干有机相得固体，以二氯甲烷/丙酮为洗脱剂经柱层析纯化得黄色固体产品2a，产率28％。合成化合物的熔点、核磁共振波谱数据为：mp:90-92℃；1H NMR(400MHz,CDCl3)δ:8.27–8.16(m,2H),8.03(d,J＝8.5Hz,1H),7.79(d,J＝8.2Hz,1H),7.68(t,J＝7.6Hz,1H),7.58–7.49(t,J＝7.4Hz,1H),1.15(s,9H)；13C NMR(100MHz,CDCl3)δ:162.10,148.07,145.54,136.41,129.09,128.79,128.32,126.88,126.71,117.82,54.55,26.32.
实施例2:2b的合成
Figure BDA0002203273300000061
实验步骤与实施例1同，仅以苯肼盐酸盐代替叔丁基肼盐酸盐。黄色固体，产率57％。合成化合物的熔点、核磁共振波谱数据为：mp:188-199℃；1H NMR(400MHz,CDCl3)δ:9.71(s,1H),8.29–8.17(m,2H),8.07(d,J＝8.5Hz,1H),7.83(d,J＝8.3Hz,1H),7.73(t,J＝8.5Hz,1H),7.58(t,J＝8.1Hz,1H),7.18(t,J＝7.2Hz,2H),6.92(d,J＝8.1Hz,2H),6.86(t,J＝7.4Hz,1H),6.23(s,1H)；13C NMR(100MHz,CDCl3)δ:163.17,147.73,146.91,145.55,136.60,129.32,128.81,128.57,128.20,127.25,126.79,120.32,117.90,112.79.
实施例3:2c的合成
Figure BDA0002203273300000062
实验步骤与实施例1同，仅以4-甲基苯肼盐酸盐代替叔丁基肼盐酸盐。黄色固体，产率39％。合成化合物的熔点、核磁共振波谱数据为：mp:162-163℃；1H NMR(400MHz,CDCl3)δ:9.71(s,1H),8.27–8.15(m,2H),8.05(d,J＝8.5Hz,1H),7.80(d,J＝8.1Hz,1H),7.71(t,J＝7.6Hz,1H),7.56(t,J＝7.5Hz,1H),6.97(d,J＝7.9Hz,2H),6.82(d,J＝8.0Hz,2H),2.18(s,3H)；13C NMR(100MHz,CDCl3)δ:164.16,148.85,146.56,145.61,137.62,130.75,130.33,129.83,129.73,129.58,128.25,127.83,118.96,114.12,20.61.
实施例4:2d的合成
Figure BDA0002203273300000063
实验步骤与实施例1同，仅以2-氟苯肼盐酸盐代替叔丁基肼盐酸盐。黄色固体，产率61％。合成化合物的熔点、核磁共振波谱数据为：mp:173-174℃；1H NMR(400MHz,CDCl3)δ:9.76(s,1H),8.33(d,J＝8.5Hz,1H),8.26(d,J＝8.5Hz,1H),8.15(d,J＝8.5Hz,1H),7.90(d,J＝8.1Hz,1H),7.80(t,J＝8.4Hz,1H),7.66(t,J＝7.5Hz,1H),7.11–6.96(m,3H),6.89–6.82(m,1H),6.46(s,1H)；13C NMR(100MHz,CDCl3)δ:164.24,152.89,150.50,148.61,146.58,137.68,136.05(d,J＝10.5Hz),130.41,129.84,129.64,128.10(d,J＝51.1Hz),124.51(d,J＝3.6Hz),121.24(d,J＝7.0Hz),118.91,115.25(d,J＝18.2Hz),114.82(d,J＝2.5Hz).
实施例5:2e的合成
Figure BDA0002203273300000071
实验步骤与实施例1同，仅以4-氟苯肼盐酸盐代替叔丁基肼盐酸盐。黄色固体，产率42％。合成化合物的熔点、核磁共振波谱数据为：mp:155-156℃；1H NMR(400MHz,CDCl3)δ:9.74(s,1H),8.25–8.14(m,2H),8.04(d,J＝8.5Hz,1H),7.79(d,J＝8.1Hz,1H),7.70(t,J＝7.6Hz,1H),7.55(t,J＝7.5Hz,1H),6.83(d,J＝6.5Hz,4H)；13C NMR(100MHz,CDCl3)δ:164.39,159.19,156.82,148.63,146.52,144.11,137.72,130.43,129.77,129.60,128.36,127.85,118.91,115.85,115.62,115.24(d,J＝7.9Hz).
实施例6:7a的合成
Figure BDA0002203273300000072
其具体合成操作如下：1的合成：将喹啉-2-羧酸(23.10mmol)溶于30ml N,N-二甲基甲酰胺中，加入无水碳酸钾(23.10mmol)和碘甲烷(46.20mmol)，在室温下反应24h。后倒入300ml水中，抽滤得固体，干燥后溶解于40ml无水甲醇中，加入水合肼(92.40mmol)，在66℃下反应8h。反应完成后抽滤得固体，用水洗涤，干燥，无水甲醇重结晶得白色固体产品1，产率68％。合成化合物的熔点、核磁共振波谱数据为：mp:141-142℃；1H NMR(400MHz,DMSO-d6)δ:10.03(s,1H),8.55(d,J＝8.5Hz,1H),8.09–8.05(m,3H),7.86(t,J＝8.4Hz,1H),7.75–7.66(t,J＝8.2Hz,1H)；13C NMR(100MHz,DMSO-d6)δ:163.37,150.53,146.54,138.16,130.89,129.69,129.12,128.52,128.38,119.10.
3a的合成：将中间体1(2.14mmol)、甲酸(2.14mmol)、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(4.27mmol)、1-羟基苯并三唑(3.21mmol)、N-甲基吗啉(4.91mmol)溶于30ml二氯甲烷中，在室温下反应24h。反应完成后加入30ml二氯甲烷稀释，先后用水、1mol/L稀盐酸和饱和碳酸氢钠水溶液洗涤，有机相用无水硫酸钠干燥。旋干有机相得固体，以二氯甲烷/丙酮为洗脱剂经柱层析纯化得白色固体产品3a，产率60％。合成化合物的熔点、核磁共振波谱数据为：mp:209-211℃；1H NMR(400MHz,DMSO-d6)δ:11.08(s,1H),10.71(s,1H),10.22(s,1H),8.60(d,J＝8.4Hz,1H),8.18–8.07(m,3H),7.91(t,J＝7.6Hz,1H),7.76(t,J＝7.3Hz,1H)；13C NMR(100MHz,DMSO-d6)δ:163.30,160.16,149.54,146.49,138.44,131.16,129.72,129.39,128.84,128.63,119.29.
7a的合成：将3a(0.93mmol)溶于10ml氯化亚砜中，在107℃下反应12h。反应完成后冷却，缓慢倒入100g碎冰中，用二氯甲烷反复萃取，合并有机相，再用饱和碳酸氢钠水溶液洗涤，有机相用无水硫酸钠干燥。旋干有机相得固体，以石油醚/乙酸乙酯为洗脱剂经柱层析纯化得白色固体产品7a，产率40％。合成化合物的熔点、核磁共振波谱数据为：mp:163-165℃；1H NMR(400MHz,CDCl3)δ:8.64(s,1H),8.37(s,2H),8.27(d,J＝8.5Hz,1H),7.92(d,J＝8.2Hz,1H),7.83(t,J＝7.7Hz,1H),7.68(t,J＝7.6Hz,1H)；13C NMR(100MHz,CDCl3)δ:153.78,147.89,142.97,137.69,130.91,130.76,130.13,128.83,128.53,127.83,119.85.
实施例7:7b的合成
Figure BDA0002203273300000081
实验步骤与实施例6同，仅以乙酸代替甲酸。白色固体，产率63％。合成化合物的熔点、核磁共振波谱数据为：mp:157-158℃；1H NMR(400MHz,DMSO-d6)δ:10.58(s,1H),10.09(s,1H),8.59(d,J＝8.4Hz,1H),8.18–8.07(m,3H),7.94–7.86(m,1H),7.75(t,J＝8.1Hz,1H),1.96(s,3H)；13C NMR(100MHz,DMSO-d6)δ:168.59,163.31,149.70,146.47,138.40,131.13,129.72,129.37,128.79,128.61,119.25,21.10.
Figure BDA0002203273300000082
白色固体，产率51％。合成化合物的熔点、核磁共振波谱数据为：mp:175-176℃；1HNMR(400MHz,CDCl3)δ:8.33(s,2H),8.26(d,J＝8.5Hz,1H),7.89(d,J＝8.0Hz,1H),7.80(t,J＝8.0Hz,1H),7.65(t,J＝7.6Hz,1H),2.72(s,3H)；13C NMR(100MHz,CDCl3)δ:165.16,164.44,147.79,143.41,137.54,130.58,130.01,128.68,128.25,127.79,119.64,11.40.
实施例8:7c的合成
Figure BDA0002203273300000091
实验步骤与实施例6同，仅以丙酸代替甲酸。白色固体，产率87％。合成化合物的熔点、核磁共振波谱数据为：mp:182-184℃；1H NMR(400MHz,DMSO-d6)δ:10.58(s,1H),10.05(s,1H),8.59(d,J＝8.5Hz,1H),8.12(m,3H),7.89(t,J＝8.4Hz,1H),7.74(t,J＝8.1Hz,1H),2.25(q,J＝7.6Hz,2H),1.09(t,J＝7.6Hz,3H)；13C NMR(100MHz,DMSO-d6)δ:172.44,163.33,149.72,146.47,138.38,131.11,129.72,129.36,128.77,128.60,119.22,27.00,10.13.
Figure BDA0002203273300000092
白色固体，产率53％。合成化合物的熔点、核磁共振波谱数据为；mp:94-96℃；1HNMR(400MHz,CDCl3)δ:8.33(s,2H),8.26(d,J＝8.5Hz,1H),7.89(d,J＝8.4Hz,1H),7.80(t,J＝8.2Hz,1H),7.65(t,J＝7.6Hz,1H),3.07(q,J＝7.6Hz,2H),1.51(t,J＝7.6Hz,3H)；13CNMR(100MHz,CDCl3)δ:169.33,164.32,147.84,143.57,137.50,130.54,130.05,128.68,128.22,127.80,119.74,19.40,10.88.
实施例9:7d的合成
Figure BDA0002203273300000093
实验步骤与实施例6同，仅以环丙甲酸代替甲酸。白色固体，产率88％。合成化合物的熔点、核磁共振波谱数据为：mp:203-204℃；1H NMR(400MHz,DMSO-d6)δ:10.63(s,1H),10.31(s,1H),8.59(d,J＝8.5Hz,1H),8.16–8.08(m,3H),7.90(t,J＝8.4Hz,1H),7.75(t,J＝8.5Hz,1H),1.77–1.69(m,1H),0.82–0.76(m,4H)；13C NMR(100MHz,DMSO-d6)δ:172.44,163.42,149.72,146.48,138.40,131.14,129.73,129.37,128.80,128.62,119.25,12.61,7.17.
Figure BDA0002203273300000094
白色固体，产率40％。合成化合物的熔点、核磁共振波谱数据为：mp:95-97℃；1HNMR(400MHz,CDCl3)δ:8.34–8.23(m,3H),7.88(d,J＝8.0Hz,1H),7.79(t,J＝7.9Hz,1H),7.63(t,J＝7.5Hz,1H),2.37–2.26(m,1H),1.36–1.31(m,2H),1.26–1.20(m,2H)；13C NMR(100MHz,CDCl3)δ:170.17,163.68,147.82,143.44,137.48,130.54,129.97,128.61,128.18,127.78,119.63,8.97,6.60.
实施例10:7e的合成
Figure BDA0002203273300000101
其具体合成操作如下：将中间体1(1.34mmol)溶于约12ml的1,4-二氧六环/水中(1:5)，再加入碳酸氢钠(2.00mmol)和溴氰(2.00mmol)，在室温下反应8h。反应完成后过滤，用水洗涤固体，干燥，无水甲醇重结晶得白色固体7e，产率43％。合成化合物的熔点、核磁共振波谱数据为：mp:278-279℃；1H NMR(400MHz,DMSO-d6)δ:8.51(d,J＝8.6Hz,1H),8.12(d,J＝8.7Hz,1H),8.09–8.01(m,2H),7.83(t,J＝8.2Hz,1H),7.68(t,J＝8.1Hz,1H),7.59(s,2H)；13C NMR(100MHz,DMSO-d6)δ:165.36,158.12,147.56,143.98,137.94,131.03,129.43,128.58,128.24,128.09,118.92.
实施例11:7f的合成
Figure BDA0002203273300000102
其具体合成操作如下：将三光气(0.66mmol)加至圆底烧瓶中，用5ml二氯甲烷溶解。将中间体1(1.87mmol)溶于10ml二氯甲烷并加至滴液漏斗中，慢慢滴加至圆底烧瓶中。在40℃下反应2h。反应完成后过滤，少许二氯甲烷洗涤，干燥，无水甲醇重结晶得白色固体7f，产率38％。合成化合物的熔点、核磁共振波谱数据为：mp:194-195℃；1H NMR(400MHz,DMSO-d6)δ:12.92(s,1H),8.54(d,J＝8.6Hz,1H),8.11(d,J＝8.4Hz,1H),8.06(d,J＝8.2Hz,1H),8.01(d,J＝8.6Hz,1H),7.86(t,J＝7.8Hz,1H),7.71(t,J＝7.6Hz,1H)；13C NMR(100MHz,DMSO-d6)δ:154.99,153.88,147.42,143.52,138.18,131.26,129.66,128.61,128.57,118.46,49.06.
实施例12:7g的合成
Figure BDA0002203273300000111
其具体合成操作如下：将中间体1(1.60mmol)溶于10ml无水乙醇中，然后加入氢氧化钾(2.40mmol)，二硫化碳(3.21mmol)，在80℃下反应8h。旋干反应液，加水溶解固体，缓慢滴加2mol/L的稀盐酸调PH至固体不再析出。过滤得固体，干燥，无水甲醇重结晶得淡黄色固体7g，产率84％。合成化合物的熔点、核磁共振波谱数据为：mp:214-216℃；1H NMR(400MHz,DMSO-d6)δ:14.91(s,1H),8.60(d,J＝8.6Hz,1H),8.16(d,J＝8.5Hz,1H),8.13–8.05(m,2H),7.90(t,J＝8.4Hz,1H),7.75(t,J＝8.5Hz,1H)；13C NMR(100MHz,DMSO-d6)δ:178.53,160.22,147.49,142.26,138.54,131.50,129.77,129.03,128.81,128.67,119.27.
实施例13:7h的合成
Figure BDA0002203273300000112
实验步骤与实施例6同，仅以苯甲酸代替甲酸。白色固体，产率82％。合成化合物的熔点、核磁共振波谱数据为：mp:230-231℃；1H NMR(400MHz,CDCl3)δ:8.30–8.23(m,2H),8.21–8.17(m,3H),7.80(d,J＝7.8Hz,1H),7.71(t,J＝7.8Hz,1H),7.55(t,J＝7.5Hz,1H),7.52–7.43(m,3H)；13C NMR(100MHz,CDCl3)δ:164.81,163.13,146.92,142.35,136.36,131.02,129.49,129.08,128.00,127.64,127.22,126.74,126.41,122.57,118.80.
Figure BDA0002203273300000113
白色固体，产率59％。合成化合物的熔点、核磁共振波谱数据为：mp:169-170℃；1HNMR(400MHz,CDCl3)δ:8.26(q,J＝8.6Hz,2H),8.21–8.17(m,3H),7.80(d,J＝7.8Hz,1H),7.71(t,J＝7.8Hz,1H),7.55(t,J＝7.5Hz,1H),7.52–7.43(m,3H)；13C NMR(100MHz,CDCl3)δ:164.81,163.13,146.92,142.35,136.36,131.02,129.49,129.08,128.00,127.64,127.22,126.74,126.41,122.57,118.80.
实施例14:7i的合成
Figure BDA0002203273300000121
实验步骤与实施例6同，仅以4-甲基苯甲酸代替甲酸。白色固体，产率72％。合成化合物的熔点、核磁共振波谱数据为：mp:209-210℃；1H NMR(400MHz,DMSO-d6)δ:10.79(s,1H),10.57(s,1H),8.62(d,J＝8.4Hz,1H),8.20–8.15(m,2H),8.12(d,J＝8.2Hz,1H),7.95–7.85(m,3H),7.77(t,J＝7.6Hz,1H),7.34(d,J＝7.8Hz,2H),2.39(s,3H)；13C NMR(100MHz,DMSO-d6)δ:165.94,163.93,149.83,146.53,142.32,138.43,131.15,130.23,129.78,129.49,129.40,128.82,128.63,128.02,119.30,21.51.
Figure BDA0002203273300000122
白色固体，产率65％。合成化合物的熔点、核磁共振波谱数据为：mp:175-176℃；1HNMR(400MHz,CDCl3)δ:8.29–8.15(m,3H),8.09–8.02(d,J＝7.6Hz,2H),7.78(d,J＝8.2Hz,1H),7.71(t,J＝7.5Hz,1H),7.53(t,J＝7.3Hz,1H),7.25(d,J＝7.8Hz,2H),2.34(s,3H)；13CNMR(100MHz,CDCl3)δ:164.95,162.89,146.90,142.43,141.63,136.30,129.43,129.06,128.70,127.59,127.14,126.72,126.36,119.78,118.77,20.66.
实施例15:7j的合成
Figure BDA0002203273300000123
实验步骤与实施例6同，仅以2-甲氧基苯甲酸代替甲酸。白色固体，产率91％。合成化合物的熔点、核磁共振波谱数据为：mp:144-146℃；1H NMR(400MHz,DMSO-d6)δ:10.87(s,1H),10.19(s,1H),8.61(d,J＝8.5Hz,1H),8.20–8.15(m,2H),8.11(d,J＝8.1Hz,1H),7.91(t,J＝8.3Hz,1H),7.84(dd,J＝7.6,1.9Hz,1H),7.79–7.73(m,1H),7.58–7.52(m,1H),7.20(d,J＝8.4Hz,1H),7.11(t,J＝7.5Hz,1H),3.94(s,3H)；13C NMR(100MHz,DMSO-d6)δ:169.47,168.00,162.42,154.48,151.28,143.23,143.11,138.15,135.87,134.53,134.14,133.56,133.36,126.52,125.78,124.01,117.37,61.16.
Figure BDA0002203273300000131
白色固体，产率64％。合成化合物的熔点、核磁共振波谱数据为：mp:142-143℃；1HNMR(400MHz,CDCl3)δ:8.43–8.25(m,3H),8.13(d,J＝7.8Hz,1H),7.89(d,J＝8.2Hz,1H),7.80(t,J＝8.5Hz,1H),7.64(t,J＝8.1Hz,1H),7.54(t,J＝8.8Hz,1H),7.17–7.05(m,2H),4.03(s,3H)；13C NMR(100MHz,CDCl3)δ:164.60,163.93,158.22,148.01,143.65,137.33,133.39,130.97,130.42,130.22,128.67,128.15,127.76,120.71,119.93,112.83,111.88,56.09.
实施例16:7k的合成
Figure BDA0002203273300000132
实验步骤与实施例6同，仅以3-甲氧基苯甲酸代替甲酸。白色固体，产率74％。合成化合物的熔点、核磁共振波谱数据为：mp:199-200℃；1H NMR(400MHz,CDCl3)δ:8.37(m,2H),8.29(d,J＝8.5Hz,1H),7.94–7.76(m,4H),7.66(t,J＝8.3Hz,1H),7.47(t,J＝8.0Hz,1H),7.13(d,J＝8.4Hz,1H),3.93(s,3H)；13C NMR(100MHz,CDCl3)δ:165.84,164.22,160.00,148.01,143.44,137.40,130.53,130.19,130.16,128.71,128.28,127.78,124.76,119.96,119.89,118.74,111.90,55.62.
Figure BDA0002203273300000133
白色固体，产率49％。合成化合物的熔点、核磁共振波谱数据为：mp:153-155℃；1HNMR(400MHz,CDCl3)δ:8.37(q,J＝8.5Hz,2H),8.29(d,J＝8.5Hz,1H),7.94–7.76(m,4H),7.66(t,J＝8.3Hz,1H),7.47(t,J＝8.0Hz,1H),7.13(d,J＝8.4Hz,1H),3.93(s,3H)；13C NMR(100MHz,CDCl3)δ:165.84,164.22,160.00,148.01,143.44,137.40,130.53,130.19,130.16,128.71,128.28,127.78,124.76,119.96,119.89,118.74,111.90,55.62.
实施例17:7l的合成
Figure BDA0002203273300000141
实验步骤与实施例6同，仅以4-甲氧基苯甲酸代替甲酸。白色固体，产率61％。合成化合物的熔点、核磁共振波谱数据为：mp:250-252℃；1H NMR(400MHz,DMSO-d6)δ:10.79(s,1H),10.51(s,1H),8.62(d,J＝8.5Hz,1H),8.20–8.15(m,2H),8.12(d,J＝8.2Hz,1H),8.00–7.88(m,3H),7.76(t,J＝7.5Hz,1H),7.08(d,J＝8.2Hz,2H),3.85(s,3H)；13C NMR(100MHz,DMSO-d6)δ:165.58,163.98,162.52,149.86,146.55,138.44,131.16,129.91,129.79,129.41,128.83,128.64,125.17,119.30,114.21,55.89.
Figure BDA0002203273300000142
白色固体，产率62％。合成化合物的熔点、核磁共振波谱数据为：mp:189-190℃；1HNMR(400MHz,CDCl3)δ:8.36(q,J＝8.6Hz,2H),8.28(d,J＝8.5Hz,1H),8.22(d,J＝8.4Hz,2H),7.90(d,J＝8.2Hz,1H),7.82(t,J＝7.2Hz,1H),7.64(t,J＝7.5Hz,1H),7.05(d,J＝8.7Hz,2H),3.90(s,3H)；13C NMR(100MHz,CDCl3)δ:165.87,163.80,162.66,147.99,143.60,137.35,130.47,130.11,129.31,128.66,128.16,127.78,119.86,116.14,114.50,55.49.
实施例18:7m的合成
Figure BDA0002203273300000143
实验步骤与实施例6同，仅以2-氟苯甲酸代替甲酸。白色固体，产率94％。合成化合物的熔点、核磁共振波谱数据为：mp:166-167℃；1H NMR(400MHz,DMSO-d6)δ:10.90(s,1H),10.49(s,1H),8.62(d,J＝8.5Hz,1H),8.20–8.16(m,2H),8.12(d,J＝8.2Hz,1H),7.92(t,J＝7.6Hz,1H),7.80–7.69(m,2H),7.62(t,J＝6.9Hz,1H),7.41–7.33(m,2H)；13C NMR(100MHz,DMSO-d6)δ:163.68(d,J＝2.7Hz),161.03,158.53,149.69,146.53,138.44,133.55(d,J＝8.4Hz),131.16,130.68(d,J＝2.9Hz),129.78,129.41,128.85,128.63,125.04(d,J＝3.6Hz),122.76(d,J＝14.7Hz),119.29,116.80(d,J＝21.8Hz).
Figure BDA0002203273300000151
白色固体，产率52％。合成化合物的熔点、核磁共振波谱数据为：mp:165-167℃；1HNMR(400MHz,CDCl3)δ:8.42–8.33(m,2H),8.29(d,J＝8.5Hz,1H),8.25(t,J＝7.5Hz,1H),7.90(d,J＝8.4Hz,1H),7.81(t,J＝8.0Hz,1H),7.65(t,J＝7.8Hz,1H),7.62–7.54(m,1H),7.41–7.24(m,2H)；13C NMR(100MHz,CDCl3)δ:164.37,162.55(d,J＝5.1Hz),161.60,159.03,148.04,143.24,137.43,133.82(d,J＝8.5Hz),130.52,130.24(d,J＝7.7Hz),128.74,128.33,127.75,124.66(d,J＝3.9Hz),119.88,117.04(d,J＝20.8Hz),112.28(d,J＝11.7Hz).
实施例19:7n的合成
Figure BDA0002203273300000152
实验步骤与实施例6同，仅以3-氟苯甲酸代替甲酸。白色固体，产率64％。合成化合物的熔点、核磁共振波谱数据为：mp:240-242℃；1H NMR(400MHz,DMSO-d6)δ:10.89(s,1H),10.76(s,1H),8.62(d,J＝8.5Hz,1H),8.21–8.16(m,2H),8.12(d,J＝8.2Hz,1H),7.92(t,J＝8.3Hz,1H),7.83(d,J＝7.7Hz,1H),7.80–7.72(m,2H),7.66–7.58(m,1H),7.52–7.45(m,1H)；13C NMR(100MHz,DMSO-d6)δ:164.74(d,J＝2.5Hz),163.93,163.65,161.22,149.71,146.54,138.47,135.27(d,J＝6.9Hz),131.29(d,J＝8.0Hz),131.17,129.77,129.43,128.86,128.64,124.18(d,J＝2.9Hz),119.32(d,J＝7.3Hz),114.76(d,J＝22.9Hz).
Figure BDA0002203273300000153
白色固体，产率47％。合成化合物的熔点、核磁共振波谱数据为：mp:154-156℃；1HNMR(400MHz,CDCl3)δ:8.42–8.32(m,2H),8.29(d,J＝8.5Hz,1H),8.08(d,J＝7.7Hz,1H),7.98(d,J＝8.8Hz,1H),7.91(d,J＝8.6Hz,1H),7.82(t,J＝8.4Hz,1H),7.66(t,J＝7.5Hz,1H),7.59–7.51(m,1H),7.33–7.25(m,1H)；13C NMR(100MHz,CDCl3)δ:164.84(d,J＝3.4Hz),164.42,164.08,161.62,148.01,143.21,137.45,130.90(d,J＝8.1Hz),130.38(d,J＝43.6Hz),128.75,128.38,127.79,125.54(d,J＝8.8Hz),123.23(d,J＝3.2Hz),119.87,119.13(d,J＝21.2Hz),114.46(d,J＝24.3Hz).
实施例20:7o的合成
Figure BDA0002203273300000161
实验步骤与实施例6同，仅以4-氟苯甲酸代替甲酸。白色固体，产率69％。合成化合物的熔点、核磁共振波谱数据为：mp:207-208℃；1H NMR(400MHz,DMSO-d6)δ:10.87(s,1H),10.70(s,1H),8.62(d,J＝8.5Hz,1H),8.20–8.15(m,2H),8.12(d,J＝8.2Hz,1H),8.08–8.01(m,2H),7.92(t,J＝8.4Hz,1H),7.77(t,J＝7.6Hz,1H),7.42–7.37(m,2H)；13C NMR(100MHz,DMSO-d6)δ:165.70,165.07,163.98,163.72,149.76,146.55,138.47,131.18,130.72(d,J＝9.2Hz),129.79,129.43,128.87,128.64,119.31,116.02(d,J＝22.0Hz).
Figure BDA0002203273300000162
白色固体，产率52％。合成化合物的熔点、核磁共振波谱数据为：mp:177-178℃；1HNMR(400MHz,CDCl3)δ:8.32–8.24(m,2H),8.23–8.16(m,3H),7.82(d,J＝8.2Hz,1H),7.74(t,J＝8.5Hz,1H),7.57(t,J＝8.0Hz,1H),7.17(t,J＝8.5Hz,2H)；13C NMR(100MHz,CDCl3)δ:165.28,164.02,163.20,162.76,146.96,142.31,136.39,129.53,129.09,128.77(d,J＝9.0Hz),127.69,127.28,126.77,118.98(d,J＝3.3Hz),118.82,115.51,115.28.
实施例21:7p的合成
Figure BDA0002203273300000163
实验步骤与实施例6同，仅以2,6-氟苯甲酸代替甲酸。白色固体，产率55％。合成化合物的熔点、核磁共振波谱数据为：mp:220-221℃；1H NMR(400MHz,CDCl3)δ:8.36–8.26(m,2H),8.21(d,J＝8.5Hz,1H),7.83(d,J＝8.2Hz,1H),7.73(t,J＝8.5Hz,1H),7.58(t,J＝7.9Hz,1H),7.54–7.45(m,1H),7.06(t,J＝8.4Hz,2H)；13C NMR(100MHz,CDCl3)δ:164.89,162.22(d,J＝5.1Hz),159.65(d,J＝5.1Hz),157.88(d,J＝3.6Hz),148.02,143.05,137.55,133.87(t,J＝10.4Hz),130.60,130.31,128.81,128.44,127.77,119.89,112.51(d,J＝21.2Hz),112.28(d,J＝20.4Hz),103.12(t,J＝16.7Hz).
Figure BDA0002203273300000171
黄色固体，产率54％。合成化合物的熔点、核磁共振波谱数据为：mp:170-172℃；1HNMR(400MHz,CDCl3)δ:8.36–8.26(m,2H),8.21(d,J＝8.5Hz,1H),7.83(d,J＝8.2Hz,1H),7.73(t,J＝8.5Hz,1H),7.58(t,J＝7.9Hz,1H),7.54–7.45(m,1H),7.06(t,J＝8.4Hz,2H)；13C NMR(100MHz,CDCl3)δ:164.89,162.22(d,J＝5.1Hz),159.65(d,J＝5.1Hz),157.88(d,J＝3.6Hz),148.02,143.05,137.55,133.87(t,J＝10.4Hz),130.60,130.31,128.81,128.44,127.77,119.89,112.39(dd,J＝21.2,3.6Hz),103.12(t,J＝16.7Hz).
实施例22:7q的合成
Figure BDA0002203273300000172
实验步骤与实施例6同，仅以2,3,4,5,6-氟苯甲酸代替甲酸。白色固体，产率33％。合成化合物的熔点、核磁共振波谱数据为：mp:210-211℃；1H NMR(400MHz,DMSO-d6)δ:11.12(m,2H),8.63(d,J＝8.5Hz,1H),8.16(m,3H),7.93(t,J＝8.0Hz,1H),7.78(t,J＝7.6Hz,1H)；13C NMR(100MHz,DMSO-d6)δ:163.48,156.42,149.40,146.54,138.48,131.19,129.75,129.46,128.92,128.64,119.32.
Figure BDA0002203273300000173
黄色固体，产率41％。合成化合物的熔点、核磁共振波谱数据为：mp:170-172℃；1HNMR(400MHz,CDCl3)δ:8.31(s,2H),8.20(d,J＝8.5Hz,1H),7.84(d,J＝8.1Hz,1H),7.75(t,J＝8.4Hz,1H),7.65–7.57(m,1H)；13C NMR(100MHz,CDCl3)δ:160.53,143.28,137.78,132.93,126.15,126.02,125.55,124.16,124.07,123.95,123.05,115.12.
实施例23:7r的合成
Figure BDA0002203273300000181
实验步骤与实施例6同，仅以2-氯苯甲酸代替甲酸。白色固体，产率68％。合成化合物的熔点、核磁共振波谱数据为：mp:164-165℃；1H NMR(400MHz,DMSO-d6)δ:10.89(s,1H),10.60(s,1H),8.62(d,J＝8.5Hz,1H),8.21–8.16(m,2H),8.14–8.09(d,J＝8.0Hz,1H),7.92(t,J＝8.3Hz,1H),7.76(t,J＝8.1Hz,1H),7.66–7.42(m,4H)；13C NMR(100MHz,DMSO-d6)δ:165.86,163.64,149.67,146.53,138.44,135.04,132.01,131.17,131.03,130.40,129.97,129.77,129.42,128.86,128.63,127.61,119.28.
Figure BDA0002203273300000182
白色固体，产率47％。合成化合物的熔点、核磁共振波谱数据为：mp:141-143℃；1HNMR(400MHz,DMSO-d6)δ:8.65(d,J＝8.6Hz,1H),8.34(d,J＝8.6Hz,1H),8.19(d,J＝8.5Hz,1H),8.15–8.08(m,2H),7.89(t,J＝7.4Hz,1H),7.80–7.58(m,4H)；13C NMR(100MHz,DMSO-d6)δ:164.47,163.55,147.70,143.18,138.60,133.95,132.56,132.04,131.65,131.44,129.88,128.98,128.89,128.70,128.40,122.88,120.19.
实施例24:7s的合成
Figure BDA0002203273300000183
实验步骤与实施例6同，仅以4-氯苯甲酸代替甲酸。白色固体，产率89％。合成化合物的熔点、核磁共振波谱数据为：mp:204-205℃；1H NMR(400MHz,CDCl3)δ:8.31–8.23(m,2H),8.19(d,J＝8.5Hz,1H),8.12(d,J＝8.5Hz,2H),7.81(d,J＝8.2Hz,1H),7.73(t,J＝8.4Hz,1H),7.57(t,J＝8.2Hz,1H),7.45(d,J＝8.5Hz,2H)；13C NMR(100MHz,CDCl3)δ:163.99,163.24,146.91,142.18,137.36,136.42,129.56,129.06,128.42,127.67,127.32,126.76,121.05,118.81.
Figure BDA0002203273300000191
白色固体，产率44％。合成化合物的熔点、核磁共振波谱数据为：mp:188-189℃；1HNMR(400MHz,CDCl3)δ:8.31–8.23(m,2H),8.19(d,J＝8.5Hz,1H),8.12(d,J＝8.5Hz,2H),7.81(d,J＝8.2Hz,1H),7.73(t,J＝8.4Hz,1H),7.60–7.54(t,J＝8.2Hz,1H),7.48–7.42(m,2H)；13C NMR(100MHz,CDCl3)δ:163.99,163.24,146.91,142.18,137.36,136.42,129.56,129.06,128.42,127.67,127.32,126.76,121.05,118.81.
实施例25:7t的合成
Figure BDA0002203273300000192
实验步骤与实施例6同，仅以2,6-氯苯甲酸代替甲酸。白色固体，产率42％。合成化合物的熔点、核磁共振波谱数据为：mp:190-192℃；1H NMR(400MHz,DMSO-d6)δ:10.97(s,1H),10.93(s,1H),8.63(d,J＝8.5Hz,1H),8.24–8.10(m,3H),7.93(t,J＝8.7Hz,1H),7.77(t,J＝8.0Hz,1H),7.61–7.46(m,3H)；13C NMR(100MHz,DMSO-d6)δ:163.78,163.17,162.70,149.80,149.66,146.52,138.45,135.02,132.37,132.12,131.17,129.74,129.41,128.85,128.69,128.64,119.27.
Figure BDA0002203273300000193
白色固体，产率42％。合成化合物的熔点、核磁共振波谱数据为：mp:234-235℃；1HNMR(400MHz,CDCl3)δ:8.36(d,J＝8.5Hz,1H),8.31(d,J＝8.3Hz,1H),8.20(d,J＝8.1Hz,1H),7.84(d,J＝8.2Hz,1H),7.73(t,J＝7.9Hz,1H),7.59(t,J＝7.8Hz,1H),7.40(s,3H)；13CNMR(100MHz,CDCl3)δ:164.16,160.02,146.92,142.06,136.60,135.71,132.09,129.64,129.15,127.82,127.45,127.19,126.78,123.25,118.85.
实施例26:7u的合成
Figure BDA0002203273300000201
实验步骤与实施例6同，仅以2-溴苯甲酸代替甲酸。白色固体，产率86％。合成化合物的熔点、核磁共振波谱数据为：mp:173-174℃；1H NMR(400MHz,DMSO-d6)δ:10.88(s,1H),10.60(s,1H),8.62(d,J＝8.5Hz,1H),8.19(m,2H),8.12(d,J＝8.0Hz,1H),7.92(t,J＝7.9Hz,1H),7.79–7.71(m,2H),7.60(d,J＝7.6Hz,1H),7.54(t,J＝7.2Hz,1H),7.45(t,J＝8.0Hz,1H)；13C NMR(100MHz,DMSO-d6)δ:166.67,163.61,149.67,146.53,138.45,137.11,133.56,132.13,131.17,130.03,129.77,129.42,128.86,128.63,128.07,119.91,119.28.
Figure BDA0002203273300000202
白色固体，产率57％。合成化合物的熔点、核磁共振波谱数据为：mp:167-169℃；1HNMR(400MHz,CDCl3)δ:8.42–8.34(m,2H),8.29(d,J＝8.6Hz,1H),8.08(d,J＝8.0Hz,1H),7.91(d,J＝7.9Hz,1H),7.81(m,2H),7.65(t,J＝7.5Hz,1H),7.50(t,J＝7.6Hz,1H),7.43(t,J＝7.7Hz,1H)；13C NMR(100MHz,CDCl3)δ:164.63,164.56,148.04,143.23,137.51,134.52,132.73,131.97,130.58,130.28,128.77,128.38,127.78,127.59,125.20,122.12,119.87.
实施例27:7v的合成
Figure BDA0002203273300000203
实验步骤与实施例6同，仅以呋喃-2-甲酸代替甲酸。白色固体，产率91％。合成化合物的熔点、核磁共振波谱数据为：mp:204-205℃；1H NMR(400MHz,DMSO-d6)δ:10.80(s,1H),10.53(s,1H),8.61(d,J＝8.5Hz,1H),8.17(t,J＝8.5Hz,2H),8.12(d,J＝8.2Hz,1H),7.97–7.87(m,2H),7.76(t,J＝7.5Hz,1H),7.30(d,J＝3.5Hz,1H),6.72–6.69(m,1H)；13CNMR(100MHz,DMSO-d6)δ:164.01,157.60,149.73,146.79,146.53,146.24,138.44,131.16,129.76,129.41,128.85,128.64,119.33,115.11,112.39.
Figure BDA0002203273300000211
白色固体，产率60％。合成化合物的熔点、核磁共振波谱数据为：mp:150-152℃；1HNMR(400MHz,CDCl3)δ:8.41–8.33(m,2H),8.29(d,J＝8.6Hz,1H),7.91(d,J＝8.1Hz,1H),7.82(t,J＝8.5Hz,1H),7.72(d,J＝1.7Hz,1H),7.66(t,J＝8.2Hz,1H),7.39(d,J＝3.6Hz,1H),6.67–6.65(m,1H)；13C NMR(100MHz,CDCl3)δ:163.48,158.59,147.98,146.16,143.07,139.24,137.48,130.59,130.17,128.74,128.37,127.79,119.89,115.20,112.34.
实施例28:7w的合成
Figure BDA0002203273300000212
实验步骤与实施例6同，仅以噻吩-2-甲酸代替甲酸。白色固体，产率73％。合成化合物的熔点、核磁共振波谱数据为：mp:224-225℃；1H NMR(400MHz,DMSO-d6)δ:10.87(s,1H),10.66(s,1H),8.62(d,J＝8.5Hz,1H),8.17(t,J＝8.6Hz,2H),8.12(d,J＝8.5Hz,2H),7.93(m,2H),7.88(d,J＝5.0Hz,1H),7.80–7.74(m,1H),7.24(t,J＝5.4Hz,1H)；13C NMR(100MHz,DMSO-d6)δ:164.08,161.04,149.73,146.53,138.46,137.89,132.14,131.18,129.77,129.54,129.43,128.86,128.66,119.34.
Figure BDA0002203273300000213
白色固体，产率75％。合成化合物的熔点、核磁共振波谱数据为：mp:191-193℃；1HNMR(400MHz,CDCl3)δ:8.41–8.32(m,2H),8.28(d,J＝8.5Hz,1H),8.00(d,J＝3.9Hz,1H),7.90(d,J＝8.2Hz,1H),7.82(t,J＝7.8Hz,1H),7.68–7.61(m,2H),7.28–7.21(m,1H)；13CNMR(100MHz,CDCl3)δ:163.62,162.14,147.97,143.23,137.44,130.81,130.79,130.57,130.13,128.71,128.31,128.26,127.80,124.89,119.89.
实施例29:7x的合成
Figure BDA0002203273300000221
实验步骤与实施例6同，仅以吡啶-3-甲酸代替甲酸。白色固体，产率53％。合成化合物的熔点、核磁共振波谱数据为：mp:213-215℃；1H NMR(400MHz,DMSO-d6)δ:10.91(d,J＝23.0Hz,2H),9.12(s,1H),8.80(d,J＝8.0Hz,1H),8.63(d,J＝8.5Hz,1H),8.30(d,J＝7.9Hz,1H),8.22–8.15(m,2H),8.13(d,J＝8.3Hz,1H),7.92(t,J＝8.4Hz,1H),7.77(t,J＝8.2Hz,1H),7.60(t,J＝7.9Hz,1H)；13C NMR(100MHz,DMSO-d6)δ:164.70,163.93,153.01,149.67,148.96,146.54,138.49,135.75,131.20,129.77,129.44,128.88,128.70,128.65,124.19,119.32.
Figure BDA0002203273300000222
白色固体，产率41％。合成化合物的熔点、核磁共振波谱数据为：mp:177-179℃；1HNMR(400MHz,CDCl3)δ:9.50(s,1H),8.83(d,J＝8.2Hz,1H),8.55(d,J＝8.0Hz,1H),8.44–8.35(m,2H),8.29(d,J＝8.6Hz,1H),7.92(d,J＝8.2Hz,1H),7.83(t,J＝7.8Hz,1H),7.67(t,J＝7.6Hz,1H),7.52(t,J＝7.2Hz,1H)；13C NMR(100MHz,CDCl3)δ:164.62,163.80,152.72,148.40,147.98,143.05,137.55,134.59,130.68,130.14,128.79,128.48,127.82,123.77,120.21,119.88.
实施例30:7y的合成
Figure BDA0002203273300000223
实验步骤与实施例6同，仅以4-甲氧基苯基乙酸代替甲酸。白色固体，产率88％。合成化合物的熔点、核磁共振波谱数据为：mp:171-173℃；1H NMR(400MHz,CDCl3)δ:8.32–8.26(m,J＝1.2Hz,2H),8.24(d,J＝8.5Hz,1H),7.86(d,J＝8.2Hz,1H),7.78(t,J＝8.5Hz,1H),7.62(t,J＝8.1Hz,1H),7.37–7.30(d,J＝8.4Hz,2H),6.92–6.84(d,J＝8.5Hz,2H),4.32(s,2H),3.78(s,3H)；13C NMR(100MHz,CDCl3)δ:167.13,164.63,159.03,147.82,143.41,137.44,130.52,130.06,130.04,128.66,128.24,127.77,125.64,119.73,114.34,55.29,31.13.
Figure BDA0002203273300000231
白色固体，产率70％。合成化合物的熔点、核磁共振波谱数据为：mp:141-142℃；1HNMR(400MHz,CDCl3)δ:8.32–8.26(m,J＝1.2Hz,2H),8.24(d,J＝8.5Hz,1H),7.86(d,J＝8.2Hz,1H),7.78(t,J＝8.5Hz,1H),7.62(t,J＝8.1Hz,1H),7.37–7.30(d,J＝8.4Hz,2H),6.92–6.84(d,J＝8.5Hz,2H),4.32(s,2H),3.78(s,3H)；13C NMR(100MHz,CDCl3)δ:167.13,164.63,159.03,147.82,143.41,137.44,130.52,130.05(d,J＝2.0Hz),128.66,128.24,127.77,125.64,119.73,114.34,55.29,31.13.
实施例31:4a的合成
Figure BDA0002203273300000232
其具体合成操作如下：将中间体1(1.60mmol)溶于5ml无水吡啶，加入甲基磺酰氯(1.60mmol)，在室温下反应3h。反应完成后旋干溶剂，加入40ml二氯甲烷溶解，用水和卤水洗涤有机相，有机相用无水硫酸钠干燥。旋干有机相得固体，以二氯甲烷/丙酮为洗脱剂经柱层析纯化得黄色固体4a，产率64％。合成化合物的熔点、核磁共振波谱数据为：mp:203-205℃；1H NMR(400MHz,DMSO-d6)δ:10.98(s,1H),9.69(s,1H),8.61(d,J＝8.5Hz,1H),8.22–8.07(m,3H),7.91(t,J＝8.4Hz,1H),7.76(t,J＝8.1Hz,1H),3.10(s,3H)；13C NMR(100MHz,DMSO-d6)δ:164.56,149.53,146.49,138.41,131.16,129.78,129.42,128.92,128.61,119.45,41.22.
实施例32:4b的合成
Figure BDA0002203273300000233
实验步骤与实施例32同，仅以乙基磺酰氯代替甲基磺酰氯。白色固体，产率82％。合成化合物的熔点、核磁共振波谱数据为：mp:201-202℃；1H NMR(400MHz,DMSO-d6)δ:10.91(s,1H),9.64(s,1H),8.61(d,J＝8.5Hz,1H),8.21–8.07(m,3H),7.91(t,J＝8.3Hz,1H),7.76(t,J＝8.1Hz,1H),3.19(q,J＝7.3Hz,2H),1.36(t,J＝7.3Hz,3H)；13C NMR(100MHz,DMSO-d6)δ:164.57,149.54,146.48,138.42,131.16,129.77,129.41,128.92,128.61,119.42,46.95,8.50.
实施例33:4c的合成
Figure BDA0002203273300000241
实验步骤与实施例32同，仅以2-氟苯基磺酰氯代替甲基磺酰氯。白色固体，产率85％。合成化合物的熔点、核磁共振波谱数据为：mp:225-227℃；1H NMR(500MHz,DMSO-d6)δ:10.95(s,1H),10.40(s,1H),8.53(d,J＝8.5Hz,1H),8.13(d,J＝8.5Hz,1H),8.07(d,J＝8.2Hz,1H),7.92(d,J＝8.5Hz,1H),7.88(t,J＝8.2Hz,1H),7.82(t,J＝7.8Hz,1H),7.76–7.67(m,2H),7.43(t,J＝8.0Hz,1H),7.30(t,J＝7.6Hz,1H)；13C NMR(125MHz,DMSO-d6)δ:164.21,160.63,158.60,149.32,146.47,138.40,136.20(d,J＝8.7Hz),131.17,130.71,129.79,129.38,128.94,128.59,124.76(d,J＝3.5Hz),119.27,117.65(d,J＝21.0Hz).
实施例34:4d的合成
Figure BDA0002203273300000242
实验步骤与实施例32同，仅以4-氟苯基磺酰氯代替甲基磺酰氯。白色固体，产率87％。合成化合物的熔点、核磁共振波谱数据为：mp:172-173℃；1H NMR(500MHz,DMSO-d6)δ:10.89(s,1H),10.23(s,1H),8.53(d,J＝8.6Hz,1H),8.14(d,J＝8.5Hz,1H),8.07(d,J＝8.2Hz,1H),7.96–7.87(m,4H),7.74(t,J＝8.1Hz,1H),7.40(t,J＝8.0Hz,2H)；13C NMR(125MHz,DMSO-d6)δ:166.07,164.07,163.99,149.38,146.49,138.41,136.20(d,J＝3.2Hz),131.24,131.16,129.82,129.40,128.92,128.58,119.28,116.63,116.45.
实施例35:4e的合成
Figure BDA0002203273300000243
实验步骤与实施例32同，仅以2-氯苯基磺酰氯代替甲基磺酰氯。白色固体，产率89％。合成化合物的熔点、核磁共振波谱数据为：mp:190-192℃；1H NMR(400MHz,DMSO-d6)δ:10.93(s,1H),10.28(s,1H),8.53(d,J＝8.6Hz,1H),8.13(d,J＝8.5Hz,1H),8.08(d,J＝8.3Hz,1H),8.02(d,J＝8.0Hz,1H),7.95(d,J＝8.5Hz,1H),7.88(t,J＝7.8Hz,1H),7.74(t,J＝7.5Hz,1H),7.71–7.62(m,2H),7.46(t,J＝7.6Hz,1H)；13C NMR(100MHz,DMSO-d6)δ:164.30,149.33,146.44,138.39,138.03,134.72,132.47,132.20,131.43,131.14,129.76,129.37,128.92,128.58,127.61,119.29.
实施例36:4f的合成
Figure BDA0002203273300000251
实验步骤与实施例32同，仅以4-氯苯基磺酰氯代替甲基磺酰氯。白色固体，产率90％。合成化合物的熔点、核磁共振波谱数据为：mp:169-171℃；1H NMR(500MHz,DMSO-d6)δ:10.93(s,1H),10.31(s,1H),8.54(d,J＝8.4Hz,1H),8.15(d,J＝8.2Hz,1H),8.08(d,J＝8.3Hz,1H),7.93(d,J＝8.5Hz,1H),7.91–7.85(m,3H),7.74(t,J＝8.1Hz,1H),7.67–7.62(m,2H)；13C NMR(125MHz,DMSO-d6)δ:164.08,149.39,146.49,138.91,138.42,138.34,131.16,130.03,129.82,129.51,129.41,128.93,128.59,119.31.
实施例37:4g的合成
Figure BDA0002203273300000252
实验步骤与实施例32同，仅以4-三氟甲基苯基磺酰氯代替甲基磺酰氯。白色固体，产率82％。合成化合物的熔点、核磁共振波谱数据为：mp:177-179℃；1H NMR(400MHz,DMSO-d6)δ:11.00(s,1H),10.47(s,1H),8.53(d,J＝8.5Hz,1H),8.14(d,J＝8.5Hz,1H),8.11–8.06(m,3H),7.99–7.86(m,4H),7.75(d,J＝7.6Hz,1H)；13C NMR(100MHz,DMSO-d6)δ:164.23,149.34,146.49,144.16,138.39,131.13,129.79,129.40,129.01,128.92,128.57,126.54,126.51,119.28,55.34.
实施例38:4h的合成
Figure BDA0002203273300000253
实验步骤与实施例32同，仅以4-三氟甲氧基苯基磺酰氯代替甲基磺酰氯。白色固体，产率91％。合成化合物的熔点、核磁共振波谱数据为：mp:168-170℃；1H NMR(500MHz,DMSO-d6)δ:10.95(s,1H),10.33(s,1H),8.54(d,J＝8.4Hz,1H),8.14(d,J＝8.5Hz,1H),8.07(d,J＝8.2Hz,1H),8.04–7.98(m,2H),7.93–7.87(m,2H),7.74(t,J＝8.2Hz,1H),7.60–7.52(m,2H)；13C NMR(125MHz,DMSO-d6)δ:164.13,151.73,149.40,146.49,138.92,138.40,131.15,130.74,129.81,129.40,128.93,128.59,121.53,119.25.
实施例39:5a的合成
Figure BDA0002203273300000261
其具体合成操作如下：将中间体1(1.34mmol)和4-乙基苯甲醛(2.00mmol)溶于10ml无水乙醇，加入0.1ml冰醋酸，在80℃下反应8h。反应冷却后过滤，固体用少许无水乙醇洗涤，必要时用无水乙醇重结晶得白色固体5a，产率69％。合成化合物的熔点、核磁共振波谱数据为：mp:136-137℃；1H NMR(400MHz,CDCl3)δ:11.06(s,1H),8.33–8.26(m,2H),8.22(d,J＝8.5Hz,1H),8.03(d,J＝8.5Hz,1H),7.78(d,J＝8.2Hz,1H),7.68(m,3H),7.54(t,J＝7.5Hz,1H),7.15(m,2H),2.57(q,J＝7.4Hz,2H),1.16(t,J＝7.6Hz,3H)；13C NMR(100MHz,CDCl3)δ:159.12,148.07,148.04,146.16,145.28,136.67,130.14,129.28,128.53,128.45,127.19,127.16,126.91,126.82,118.10,27.83,14.25.
实施例40:5b的合成
Figure BDA0002203273300000262
实验步骤与实施例39同，仅以4-氰基苯甲醛代替4-乙基苯甲醛。白色固体，产率80％。合成化合物的熔点、核磁共振波谱数据为：mp:236-237℃；1H NMR(400MHz,DMSO-d6)δ:12.45(s,1H),8.80(s,1H),8.64(d,J＝8.5Hz,1H),8.23(d,J＝8.5Hz,2H),8.13(d,J＝8.1Hz,1H),7.96–7.90(m,5H),7.77(t,J＝7.6Hz,1H)；13C NMR(100MHz,DMSO-d6)δ:161.41,149.99,147.91,146.44,139.25,138.61,133.28,131.23,129.69,129.50,128.95,128.70,128.22,119.61,119.12,112.51.
实施例41:5c的合成
Figure BDA0002203273300000263
实验步骤与实施例39同，仅以2-硝基苯甲醛代替4-乙基苯甲醛。白色固体，产率71％。合成化合物的熔点、核磁共振波谱数据为：mp:204-205℃；1H NMR(400MHz,DMSO-d6)δ:12.66(s,1H),9.16(s,1H),8.63(d,J＝8.5Hz,1H),8.23(t,J＝8.4Hz,2H),8.18(t,J＝7.9Hz,1H),8.15–8.08(m,2H),7.93(t,J＝8.2Hz,1H),7.86(t,J＝8.0Hz,1H),7.77(t,J＝8.1Hz,1H),7.71(t,J＝7.8Hz,1H)；13C NMR(100MHz,DMSO-d6)δ:161.65,150.04,148.91,146.47,144.80,138.55,134.18,131.30,131.18,129.72,129.49,129.16,128.93,128.68,128.52,125.08,119.66.
实施例42:5d的合成
Figure BDA0002203273300000271
实验步骤与实施例39同，仅以4-硝基苯甲醛代替4-乙基苯甲醛。白色固体，产率81％。合成化合物的熔点、核磁共振波谱数据为：mp:241-242℃；1H NMR(400MHz,DMSO-d6)δ:12.51(s,1H),8.86(s,1H),8.64(d,J＝8.5Hz,1H),8.33(d,J＝8.7Hz,2H),8.24(d,J＝8.5Hz,2H),8.14(d,J＝8.2Hz,1H),8.05–8.00(m,2H),7.94(t,J＝7.3Hz,1H),7.78(t,J＝7.6Hz,1H)；13C NMR(100MHz,DMSO-d6)δ:161.49,149.96,148.43,147.41,146.45,141.08,138.63,131.25,129.70,129.52,128.97,128.71,128.60,124.61,119.64.
实施例43:5e的合成
Figure BDA0002203273300000272
实验步骤与实施例39同，仅以4-甲氧苯甲醛代替4-乙基苯甲醛。白色固体，产率87％。合成化合物的熔点、核磁共振波谱数据为：mp:153-155℃；1H NMR(400MHz,DMSO-d6)δ:12.08(s,1H),8.67(s,1H),8.62(d,J＝8.5Hz,1H),8.22(d,J＝8.5Hz,2H),8.12(d,J＝8.0Hz,1H),7.91(t,J＝7.6Hz,1H),7.79–7.68(m,3H),7.05(d,J＝8.8Hz,2H),3.83(s,3H)；13C NMR(100MHz,DMSO-d6)δ:161.44,160.88,150.39,149.72,146.44,138.49,131.12,129.68,129.39,129.33,128.75,128.65,127.33,119.52,114.86,55.79.
实施例44:5f的合成
Figure BDA0002203273300000273
实验步骤与实施例39同，仅以2-氟苯甲醛代替4-乙基苯甲醛。白色固体，产率48％。合成化合物的熔点、核磁共振波谱数据为：mp:169-170℃；1H NMR(400MHz,DMSO-d6)δ:12.46(s,1H),9.01(s,1H),8.63(d,J＝8.5Hz,1H),8.23(d,J＝8.3Hz,2H),8.13(d,J＝8.2Hz,1H),8.02(t,J＝7.7Hz,1H),7.93(t,J＝8.5Hz,1H),7.77(t,J＝8.2Hz,1H),7.57–7.48(m,1H),7.37–7.29(m,2H)；13C NMR(100MHz,DMSO-d6)δ:162.64,161.30,160.16,150.11,146.46,142.59(d,J＝4.8Hz),138.53,132.61(d,J＝8.4Hz),131.17,129.69,129.46,128.77(d,J＝20.1Hz),126.92(d,J＝2.8Hz),125.42(d,J＝3.3Hz),122.44(d,J＝9.8Hz),119.59,116.52(d,J＝20.8Hz).
实施例45:5g的合成
Figure BDA0002203273300000281
实验步骤与实施例39同，仅以4-氟苯甲醛代替4-乙基苯甲醛。白色固体，产率57％。合成化合物的熔点、核磁共振波谱数据为：mp:176-177℃；1H NMR(400MHz,DMSO-d6)δ:12.22(s,1H),8.74(s,1H),8.62(d,J＝8.5Hz,1H),8.22(d,J＝8.4Hz,2H),8.12(d,J＝8.2Hz,1H),7.92(t,J＝8.5Hz,1H),7.87–7.80(m,2H),7.76(t,J＝7.8Hz,1H),7.36–7.30(m,2H)；13C NMR(100MHz,DMSO-d6)δ:164.91,162.45,161.12,150.23,148.73,146.44,138.53,131.41(d,J＝3.0Hz),131.16,129.87(d,J＝8.6Hz),129.68,129.43,128.82,128.67,119.55,116.55,116.33.
实施例46:5h的合成
Figure BDA0002203273300000282
实验步骤与实施例39同，仅以2-氯苯甲醛代替4-乙基苯甲醛。白色固体，产率70％。合成化合物的熔点、核磁共振波谱数据为：mp:208-209℃；1H NMR(400MHz,DMSO-d6)δ:12.59(s,1H),9.17(s,1H),8.63(d,J＝8.5Hz,1H),8.24(t,J＝8.7,Hz,2H),8.15–8.06(m,2H),7.93(t,J＝8.4Hz,1H),7.76(t,J＝8.1Hz,1H),7.58–7.52(m,1H),7.52–7.42(m,2H)；13C NMR(100MHz,DMSO-d6)δ:161.47,150.15,146.48,145.77,138.51,133.91,132.24,132.06,131.16,130.42,129.70,129.46,128.87,128.68,128.08,127.48,119.63.
实施例47:5i的合成
Figure BDA0002203273300000283
实验步骤与实施例39同，仅以4-氯苯甲醛代替4-乙基苯甲醛。白色固体，产率59％。合成化合物的熔点、核磁共振波谱数据为：mp:182-183℃；1H NMR(400MHz,DMSO-d6)δ:12.28(s,1H),8.74(s,1H),8.63(d,J＝8.5Hz,1H),8.22(d,J＝8.6Hz,2H),8.12(d,J＝8.2Hz,1H),7.92(t,J＝8.5Hz,1H),7.83–7.73(m,3H),7.59–7.53(m,2H)；13C NMR(100MHz,DMSO-d6)δ:161.18,150.17,148.54,146.44,138.55,135.13,133.74,131.17,129.68,129.46,129.37,129.30,128.85,128.68,119.57.
实施例48:5j的合成
Figure BDA0002203273300000291
实验步骤与实施例39同，仅以2,6-二氯苯甲醛代替4-乙基苯甲醛。白色固体，产率64％。合成化合物的熔点、核磁共振波谱数据为：mp:226-227℃；1H NMR(400MHz,CDCl3)δ:11.31(s,1H),8.62(s,1H),8.36–8.28(m,2H),8.11(d,J＝8.5Hz,1H),7.85(d,J＝8.2Hz,1H),7.75(t,J＝7.7Hz,1H),7.60(t,J＝7.5Hz,1H),7.31(d,J＝8.1Hz,2H),7.18(d,J＝7.7Hz,1H)；13C NMR(100MHz,CDCl3)δ:160.46,148.82,146.38,144.12,137.88,135.36,130.47,130.45,129.64,128.78,128.42,127.92,119.24.
实施例49:5k的合成
Figure BDA0002203273300000292
实验步骤与实施例39同，仅以4-溴苯甲醛代替4-乙基苯甲醛。白色固体，产率66％。合成化合物的熔点、核磁共振波谱数据为：mp:185-186℃；1H NMR(500MHz,DMSO-d6)δ:12.29(s,1H),8.73(s,1H),8.63(d,J＝8.4Hz,1H),8.23(d,J＝8.5Hz,2H),8.13(d,J＝8.1Hz,1H),7.93(t,J＝7.8Hz,1H),7.77(t,J＝7.6Hz,1H),7.74–7.68(m,4H)；13C NMR(125MHz,DMSO-d6)δ:161.21,150.16,148.64,146.45,138.57,134.08,132.39,131.19,129.70,129.54,129.46,128.87,128.69,123.95,119.58.
实施例50:5l的合成
Figure BDA0002203273300000293
实验步骤与实施例39同，仅以2-三氟甲基苯甲醛代替4-乙基苯甲醛。白色固体，产率68％。合成化合物的熔点、核磁共振波谱数据为：mp:184-186℃；1H NMR(400MHz,DMSO-d6)δ:12.50(s,J＝5.2Hz,1H),9.12(s,1H),8.47(d,J＝8.2Hz,1H),8.39(d,J＝7.5Hz,1H),8.31–8.23(m,2H),8.00(d,J＝7.7Hz,1H),7.85(t,J＝7.3Hz,1H),7.70(m,3H),7.57(t,J＝7.2Hz,1H)；13C NMR(100MHz,DMSO-d6)δ:161.62,149.76,146.52,144.99,137.85,132.73,132.32,130.51,129.92,129.68,129.4,128.43,128.18,127.61,125.78,122.97,119.43,78.66(t,J＝32.8Hz).
实施例51:5m的合成
Figure BDA0002203273300000301
实验步骤与实施例39同，仅以4-三氟甲基苯甲醛代替4-乙基苯甲醛。白色固体，产率63％。合成化合物的熔点、核磁共振波谱数据为：mp:195-196℃；1H NMR(400MHz,DMSO-d6)δ:12.13(d,J＝11.1Hz,1H),8.74(d,J＝11.3Hz,1H),8.44(t,J＝11.5Hz,1H),8.27–8.15(m,2H),8.00–7.90(m,3H),7.86–7.76(m,1H),7.70–7.62(m,3H)；13C NMR(100MHz,DMSO-d6)δ:161.17,149.60,147.86,146.44,138.26,137.99,130.60,129.63,129.45,128.48,128.22,127.94,125.71,125.67,119.32,78.77(t,J＝32.3Hz).
实施例52:5n的合成
Figure BDA0002203273300000302
实验步骤与实施例39同，仅以2-三氟甲氧基苯甲醛代替4-乙基苯甲醛。白色固体，产率57％。合成化合物的熔点、核磁共振波谱数据为：mp:172-173℃；1H NMR(400MHz,DMSO-d6)δ:12.63(s,1H),9.08(s,1H),8.64(d,J＝8.4Hz,1H),8.29–8.21(m,2H),8.14(t,J＝7.9Hz,2H),7.93(t,J＝7.6Hz,1H),7.77(t,J＝7.8Hz,1H),7.65–7.45(m,3H)；13C NMR(100MHz,DMSO-d6)δ:161.54,150.18,147.38,146.49,142.92,138.54,132.25,131.16,129.72,129.48,128.88,128.69,128.55,128.09,127.18,122.34,119.70.
实施例53:5o的合成
Figure BDA0002203273300000303
实验步骤与实施例39同，仅以4-三氟甲氧基苯甲醛代替4-乙基苯甲醛。白色固体，产率54％。合成化合物的熔点、核磁共振波谱数据为：mp:176-177℃；1H NMR(400MHz,DMSO-d6)δ:12.30(s,1H),8.77(s,1H),8.64(d,J＝8.6Hz,1H),8.25–8.21(m,2H),8.13(d,J＝7.7Hz,1H),7.91(m,3H),7.81–7.74(m,1H),7.49(d,J＝8.0Hz,2H)；13C NMR(100MHz,DMSO-d6)δ:161.23,150.15,149.83,148.27,146.44,138.57,134.08,131.20,129.68,129.55,129.46,128.88,128.69,121.85,119.58.
实施例54:6a的合成
Figure BDA0002203273300000311
其具体合成操作如下：将中间体1(1.87mmol)和硫氰酸钾(7.48mmol)溶于10ml无水乙醇，加入1ml浓盐酸，在80℃下反应48h。冷却后过滤，固体用少许无水乙醇洗涤，干燥。固体不经纯化溶于20ml的2mol/L的氢氧化钠水溶液中，在100℃下反应48h。反应冷却后滴加浓盐酸酸化，过滤，固体用水洗涤，无水甲醇重结晶得白色固体6a，产率69％。合成化合物的熔点、核磁共振波谱数据为：mp:303-305℃；1H NMR(400MHz,DMSO-d6)δ:14.10(s,1H),13.89(s,1H),8.52(d,J＝8.6Hz,1H),8.12–8.03(m,3H),7.85(t,J＝8.2Hz,1H),7.69(t,J＝7.6Hz,1H)；13C NMR(100MHz,DMSO-d6)δ:168.39,150.95,147.35,145.01,138.19,131.06,129.41,128.61,128.46,128.23,118.54.
实施例55:6b的合成
Figure BDA0002203273300000312
其具体合成操作如下：将中间体1(1.60mmol)溶于10ml无水乙醇，然后加入氢氧化钾(2.40mmol)，二硫化碳(2.40mmol)，在80℃下反应48h。冷却后过滤，固体用少许无水乙醇洗涤，干燥。将固体加至15ml水合肼中，在120℃下反应4d。冷却后加入20ml水稀释，缓慢滴加浓盐酸酸化，过滤，固体用水洗涤，干燥，无水乙醇重结晶得白色固体6b，产率32％。合成化合物的熔点、核磁共振波谱数据为：mp:209-210℃；1H NMR(400MHz,DMSO-d6)δ:14.21(s,1H),8.59(d,J＝7.6Hz,1H),8.18(d,J＝8.6Hz,1H),8.15–8.04(m,2H),7.90(d,J＝8.0Hz,1H),7.74(d,J＝7.7Hz,1H),6.68(s,2H)；13C NMR(100MHz,DMSO-d6)δ:164.71,146.86,146.35,146.02,138.23,131.21,129.55,128.59,128.57,128.24,120.23.
实施例56:8a的合成
Figure BDA0002203273300000321
其具体合成操作如下：将3a(1.60mmol)和劳森试剂(1.60mmol)溶于10ml四氢呋喃，在66℃下反应12h。旋干反应液，加入40ml二氯甲烷溶解固体，用饱和碳酸氢钠洗涤，有机相用无水硫酸钠干燥。旋干有机相得固体，以石油醚/乙酸乙酯为洗脱剂经柱层析纯化得白色固体产品8a，产率75％。合成化合物的熔点、核磁共振波谱数据为：mp:124-125℃；1HNMR(500MHz,CDCl3)δ:9.15(s,1H),8.40(d,J＝8.4Hz,1H),8.23(d,J＝8.5Hz,1H),8.05(d,J＝8.4Hz,1H),7.79(d,J＝8.1Hz,1H),7.69(t,J＝7.8Hz,1H),7.53(t,J＝7.5Hz,1H)；13CNMR(125MHz,CDCl3)δ:170.84,153.90,148.75,147.96,137.41,130.36,129.59,128.89,127.91,127.84,118.59.
实施例57:8b的合成
Figure BDA0002203273300000322
实验步骤与实施例56同，仅以3b代替3a。白色固体，产率58％。合成化合物的熔点、核磁共振波谱数据为：mp:177-178℃；1H NMR(400MHz,CDCl3)δ:8.42(d,J＝8.5Hz,1H),8.28(d,J＝8.6Hz,1H),8.11(d,J＝8.3Hz,1H),7.86(d,J＝8.2Hz,1H),7.75(t,J＝8.4Hz,1H),7.59(t,J＝8.2Hz,1H),2.86(s,3H)；13C NMR(100MHz,CDCl3)δ:171.20,167.46,149.26,147.91,137.18,130.18,129.54,128.73,127.79,127.65,118.31,15.93.
实施例58:8c的合成
Figure BDA0002203273300000323
实验步骤与实施例56同，仅以3d代替3a。白色固体，产率63％。合成化合物的熔点、核磁共振波谱数据为：mp:121-122℃；1H NMR(400MHz,CDCl3)δ:8.41–8.34(m,1H),8.24(d,J＝8.97Hz,1H),8.08(d,J＝8.9Hz,1H),7.83(d,J＝8.5Hz,1H),7.72(t,J＝8.1Hz,1H),7.56(t,J＝7.6Hz,1H),2.53–2.45(m,1H),1.34–1.14(m,4H)；13C NMR(100MHz,CDCl3)δ:176.18,169.01,149.30,147.88,137.10,130.15,129.46,128.66,127.78,127.56,118.24,12.16,12.08.
实施例59:8d的合成
Figure BDA0002203273300000331
其具体合成操作如下：将中间体1(1.60mmol)溶于10ml无水乙醇中，然后加入氢氧化钾(2.40mmol)，二硫化碳(3.21mmol)，在80℃下反应8h。反应冷却后过滤，固体用少量无水乙醇洗涤，干燥。固体加至5ml浓硫酸中，室温反应2h。将反应液倒入大量碎冰中，待冰全部融化后过滤得固体，用水洗涤。固体用10％氢氧化钠水溶液溶解，过滤除去不溶物，滤液用浓盐酸酸化，过滤得固体，干燥，无水甲醇重结晶得黄色固体8e，产率46％。合成化合物的熔点、核磁共振波谱数据为：mp:237-238℃；1H NMR(400MHz,DMSO-d6)δ:15.02(s,1H),8.61(d,J＝8.6Hz,1H),8.18(d,J＝8.5Hz,1H),8.13–8.08(m,2H),7.91(t,J＝7.8Hz,1H),7.76(t,J＝7.6Hz,1H)；13C NMR(100MHz,DMSO-d6)δ:178.50,160.25,147.49,142.27,138.53,131.48,129.77,129.02,128.80,128.67,119.27.
实施例60:8e的合成
Figure BDA0002203273300000332
实验步骤与实施例56同，仅以3e代替3a。白色固体，产率89％。合成化合物的熔点、核磁共振波谱数据为：mp:202-203℃；1H NMR(400MHz,CDCl3)δ:8.47(d,J＝8.6Hz,1H),8.28(d,J＝8.5Hz,1H),8.12(d,J＝8.5Hz,1H),8.14–8.05(m,2H),7.85(d,J＝8.3Hz,1H),7.75(t,J＝7.7Hz,1H),7.59(t,J＝7.5Hz,1H),7.54–7.48(m,3H)；13C NMR(100MHz,CDCl3)δ:170.45,170.42,149.18,147.97,137.19,131.29,130.32,130.26,129.53,129.23,128.80,128.04,127.82,127.74,118.36.
实施例61:8f的合成
Figure BDA0002203273300000333
实验步骤与实施例56同，仅以3g代替3a。白色固体，产率61％。合成化合物的熔点、核磁共振波谱数据为：mp:205-206℃；1H NMR(500MHz,CDCl3)δ:8.61(d,J＝8.3Hz,1H),8.53(d,J＝8.5Hz,1H),8.28(d,J＝8.5Hz,1H),8.17(d,J＝8.4Hz,1H),7.86(d,J＝8.1Hz,1H),7.76(t,J＝7.3Hz,1H),7.59(t,J＝7.5Hz,1H),7.29(t,J＝7.5Hz,1H),7.16(t,J＝7.6Hz,1H),7.08(d,J＝8.3Hz,1H),4.09(s,3H)；13C NMR(125MHz,CDCl3)δ:170.64,164.16,156.30,150.12,148.03,137.07,132.32,130.09,129.54,128.78,128.72,127.83,127.47,121.25,119.40,118.61,111.37,55.82.
实施例62:8g的合成
Figure BDA0002203273300000341
实验步骤与实施例56同，仅以3g代替3a。白色固体，产率83％。合成化合物的熔点、核磁共振波谱数据为：mp:186-188℃；1H NMR(400MHz,CDCl3)δ:8.52–8.46(m,2H),8.29(d,J＝8.5Hz,1H),8.15(d,J＝8.5Hz,1H),7.86(d,J＝8.1Hz,1H),7.76(t,J＝8.0Hz,1H),7.59(t,J＝7.8Hz,1H),7.55–7.47(m,1H),7.34(t,J＝7.8Hz,1H),7.27(t,J＝8.3Hz,1H)；13CNMR(100MHz,CDCl3)δ:171.58(d,J＝4.8Hz),162.52(d,J＝7.7Hz),161.04,158.53,149.27,148.00,137.20,132.72(d,J＝8.7Hz),130.26,129.60,129.07(d,J＝2.1Hz),128.82,127.80,127.73,124.90(d,J＝3.4Hz),118.43,116.29(d,J＝21.8Hz).
实施例63:8h的合成
Figure BDA0002203273300000342
实验步骤与实施例56同，仅以3m代替3a。白色固体，产率81％。合成化合物的熔点、核磁共振波谱数据为：mp:216-217℃；1H NMR(400MHz,CDCl3)δ:8.47(d,J＝8.5Hz,1H),8.30(d,J＝8.5Hz,1H),8.13(d,J＝8.5Hz,1H),8.10–8.04(m,2H),7.87(d,J＝8.1Hz,1H),7.77(t,J＝7.6Hz,1H),7.61(t,J＝7.7Hz,1H),7.27–7.18(m,2H)；13C NMR(100MHz,CDCl3)δ:170.55,169.19,165.80,163.29,149.07,147.97,137.24,130.31,130.05(d,J＝8.6Hz),129.53,128.83,127.81(d,J＝4.2Hz),126.67,118.34,116.44(d,J＝22.1Hz).
实施例64:8i的合成
Figure BDA0002203273300000351
实验步骤与实施例56同，仅以3l代替3a。白色固体，产率67％。合成化合物的熔点、核磁共振波谱数据为：mp:202-204℃；1H NMR(500MHz,CDCl3)δ:8.53(d,J＝8.5Hz,1H),8.33(d,J＝8.5Hz,1H),8.15(d,J＝8.5Hz,1H),7.89(d,J＝8.3Hz,1H),7.77(t,J＝8.2Hz,1H),7.61(t,J＝8.0Hz,1H),7.53–7.46(m,1H),7.13(t,J＝8.5Hz,2H)；13C NMR(125MHz,CDCl3)δ:172.03,161.33(d,J＝5.5Hz),159.29(d,J＝5.6Hz),158.04(d,J＝5.6Hz),149.06,148.02,137.34,132.40(t,J＝10.6Hz),130.33,129.61,128.94,127.87(d,J＝2.8Hz),118.49,112.47(d,J＝3.7Hz),112.30(d,J＝3.9Hz).
实施例65:8j的合成
Figure BDA0002203273300000352
实验步骤与实施例56同，仅以3o代替3a。白色固体，产率86％。合成化合物的熔点、核磁共振波谱数据为：mp:198-199℃；1H NMR(400MHz,CDCl3)δ:8.50(d,J＝8.6Hz,1H),8.43–8.39(m,1H),8.30(d,J＝8.5Hz,1H),8.15(d,J＝8.5Hz,1H),7.87(d,J＝8.1Hz,1H),7.76(t,J＝7.8Hz,1H),7.62–7.54(m,2H),7.47–7.42(m,2H)；13C NMR(100MHz,CDCl3)δ:171.59,165.81,149.28,148.01,137.23,132.89,131.71,131.14,130.69,130.27,129.61,129.23,128.84,127.82,127.76,127.36,118.48.
实施例66:8k的合成
Figure BDA0002203273300000353
实验步骤与实施例56同，仅以3p代替3a。白色固体，产率58％。合成化合物的熔点、核磁共振波谱数据为：mp:255-257℃；1H NMR(500MHz,CDCl3)δ:8.49(d,J＝8.6Hz,1H),8.32(d,J＝8.7Hz,1H),8.14(d,J＝8.6Hz,1H),8.03(d,J＝8.3Hz,2H),7.89(d,J＝8.2Hz,1H),7.79(t,J＝7.8Hz,1H),7.62(t,J＝7.5Hz,1H),7.51(d,J＝8.3Hz,2H)；13C NMR(125MHz,CDCl3)δ:170.80,169.23,149.04,148.02,142.61,142.48,137.47,137.31,130.36,129.56,129.21,128.89,128.83,127.87,118.38.
实施例67:8l的合成
Figure BDA0002203273300000361
实验步骤与实施例56同，仅以3r代替3a。白色固体，产率47％。合成化合物的熔点、核磁共振波谱数据为：mp:196-198℃；1H NMR(500MHz,CDCl3)δ:8.51(d,J＝8.5Hz,1H),8.32(d,J＝8.5Hz,1H),8.24(d,J＝8.0Hz,1H),8.16(d,J＝8.4Hz,1H),7.88(d,J＝8.2Hz,1H),7.80–7.75(m,2H),7.61(t,J＝7.4Hz,1H),7.49(t,J＝7.6Hz,1H),7.37(t,J＝7.8Hz,1H)；13C NMR(125MHz,CDCl3)δ:171.62,167.37,149.25,148.04,137.28,134.11,131.89,131.82,131.30,130.30,129.63,128.87,127.86,127.84,127.81,122.70,118.50.
实施例68:8m的合成
Figure BDA0002203273300000362
实验步骤与实施例56同，仅以3v代替3a。白色固体，产率94％。合成化合物的熔点、核磁共振波谱数据为：mp:150-152℃；1H NMR(500MHz,CDCl3)δ:8.41(d,J＝8.5Hz,1H),8.25(d,J＝8.5Hz,1H),8.04(d,J＝8.5Hz,1H),7.83(d,J＝8.1Hz,1H),7.72(t,J＝7.3Hz,1H),7.56(t,J＝7.5Hz,1H),7.29(d,J＝8.5Hz,2H),6.29(d,J＝8.3Hz,2H),4.42(s,2H),3.80(s,3H)；13C NMR(125MHz,CDCl3)δ:173.29,171.46,159.02,149.25,147.90,137.18,130.20,130.04,129.48,129.37,128.74,127.79,127.67,118.24,114.46,55.32,35.96.
实施例69:9a的合成
Figure BDA0002203273300000371
其具体合成操作如下：将7g(1.31mmol)溶于5ml N,N-二甲基甲酰胺中，加入无水碳酸钾(1.31mmol)和碘甲烷(2.62mmol)，在室温下反应24h。后倒入100ml水中，抽滤得固体，以石油醚/乙酸乙酯为洗脱剂经柱层析纯化得白色固体产品9a，产率96％。合成化合物的熔点、核磁共振波谱数据为：mp:129-130℃；1H NMR(400MHz,CDCl3)δ:8.25–8.22(m,3H),7.88(d,J＝8.1Hz,1H),7.80(t,J＝8.5Hz,1H),7.64(t,J＝8.1Hz,1H),2.83(s,3H)；13C NMR(100MHz,CDCl3)δ:167.21,165.30,147.83,143.11,137.47,130.58,130.04,128.64,128.25,127.77,119.54,14.73.
实施例70:9b的合成
Figure BDA0002203273300000372
实验步骤与实施例69同，仅以碘乙烷代替碘甲烷。白色固体，产率87％。合成化合物的熔点、核磁共振波谱数据为：mp:88-89℃；1H NMR(500MHz,CDCl3)δ:8.32–8.27(m,2H),8.25(d,J＝8.6Hz,1H),7.88(d,J＝8.2Hz,1H),7.80(t,J＝7.7Hz,1H),7.64(t,J＝7.5Hz,1H),3.39(q,J＝7.4Hz,2H),1.55(t,J＝7.4Hz,3H)；13C NMR(125MHz,CDCl3)δ:166.59,165.16,147.85,143.15,137.47,130.58,130.06,128.64,128.24,127.78,119.54,27.08,14.64.
实施例71:9c的合成
Figure BDA0002203273300000373
实验步骤与实施例69同，仅以1,2-二溴乙烷代替碘甲烷。白色固体，产率74％。合成化合物的熔点、核磁共振波谱数据为：mp:110-111℃；1H NMR(500MHz,CDCl3)δ:8.27–8.15(m,3H),7.82(d,J＝8.1Hz,1H),7.73(t,J＝8.4Hz,1H),7.58(t,J＝8.2Hz,1H),3.75(m,2H),3.72–3.67(m,2H)；13C NMR(125MHz,CDCl3)δ:165.56,165.26,147.86,142.88,137.58,130.70,130.08,128.73,128.41,127.82,119.54,34.13,29.16.
实施例72:9d的合成
Figure BDA0002203273300000381
实验步骤与实施例69同，仅以1-碘代丙烷代替碘甲烷。白色固体，产率81％。mp:57-59℃；1H NMR(400MHz,CDCl3)δ:8.36–8.22(m,3H),7.89(d,J＝8.2Hz,1H),7.80(t,J＝8.3Hz,1H),7.64(t,J＝8.1Hz,1H),3.35(t,J＝7.2Hz,2H),1.97–1.86(m,2H),1.10(t,J＝7.3Hz,3H)；13C NMR(100MHz,CDCl3)δ:166.83,165.12,147.85,143.16,137.46,130.57,130.06,128.64,128.24,127.77,119.55,34.54,22.64,13.20.
实施例73:室内抑菌活性测定及结果
1)实验材料：
结构式如式(Ⅰ)-(Ⅵ)的喹啉2-位衍生物为本实验室合成。
本实验中所用的植物病源菌为实验室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，称取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2种植物病源菌在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骆驼宁碱A衍生物制成含100ppm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。
3)喹啉2-位衍生物对油菜菌核病菌、水稻纹枯病菌、番茄灰霉病菌、小麦赤霉病菌和稻瘟病菌五种植物病源菌菌丝生长的抑菌效果
1、油菜菌核病菌、水稻纹枯病菌、番茄灰霉病菌、小麦赤霉病菌和稻瘟病菌参照生测标准方法NY/T1156.2-2006，采用生长速率法进行室内生物活性测定，明确了喹啉2-位衍生物对这五种病菌的抑制活性。表2为喹啉2-位衍生物对五种植物病源真菌的抑制活性测试结果。
表2喹啉2-位衍生物在浓度100ppm下对五种植物病源真菌的抑制活性试验结果
Figure BDA0002203273300000391
Figure BDA0002203273300000401
Figure BDA0002203273300000411
Figure BDA0002203273300000421
注:试验中每个处理设三次重复，表中数据为三次重复的平均值。
由表2结果可知，本发明制备的喹啉2-位衍生物对油菜菌核病菌、水稻纹枯病菌、番茄灰霉病菌、小麦赤霉病菌和稻瘟病菌表现有一定的抑制活性，其中部分化合物在100ppm下对前四种病菌抑制活性达80％以上，甚至表现出更好的活性，因此本发明所述的化合物可用于制备农药中的用途。综上所述，本发明所述的喹啉2-位衍生物结构简单，易于合成，且部分化合物对四种植物病源菌表现出显著的抑制活性，具有进一步研究的价值，有开发成为新型小分子农业杀菌剂的潜力。

Claims (7)

1.本发明涉及一种喹啉2-位衍生物在制备防治或抗农业病害的药物中的应用，是喹啉2-位衍生物的新用途。
2.根据权利要求1所述的喹啉2-位衍生物具有的结构通式如式(Ⅰ)-(Ⅵ)所示：
Figure FDA0002203273290000011
其中：
R为氢、甲基，乙基，环丙基，叔丁基，氨基，羟基，巯基，饱和或不饱和烷基取代的巯基及其氧化物，呋喃基，噻吩基，吡啶基；以及含有一个或多个甲基、乙基、甲氧基、三氟甲基、三氟甲氧基、硝基、氰基、卤素取代的苯基，取代的苄基。
X为氧或硫原子。
可以用下列表1中列出的化合物来说明本发明的喹啉2-位衍生物，但不限定于本发明。
表1 化合物表
Figure FDA0002203273290000012
Figure FDA0002203273290000021
Figure FDA0002203273290000031
Figure FDA0002203273290000041
3.根据权利要求2所述的喹啉2-位衍生物任一化合物在制备防治或抗油菜菌核病菌的药物中的应用。
4.根据权利要求2所述的喹啉2-位衍生物任一化合物在制备防治或抗水稻纹枯病菌的药物中的应用。
5.根据权利要求2所述的喹啉2-位衍生物任一化合物在制备防治或抗番茄灰霉病菌的药物中的应用。
6.根据权利要求2所述的喹啉2-位衍生物任一化合物在制备防治或抗小麦赤霉病菌的药物中的应用。
7.根据权利要求2所述的喹啉2-位衍生物任一化合物在制备防治或抗稻瘟病菌病的药物中的应用。
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