苯并吡唑类衍生物的设计、合成、杀虫活性及结合模式研究.pdf

研究论文doi:10.16801/j.issn.1008-7303.2023.0076苯并吡唑类衍生物的设计、合成、杀虫活性及结合模式研究施蔓,周聪,栗广龙,徐晓勇,邵旭升,李忠,程家高*(华东理工大学药学院，上海市化学生物学（芳香杂环）重点实验室，上海200237)摘 要：基于新报道的高活性介离子类 nAChR 调节剂结构，通过骨架跃迁策略设计、合成了30 个未见文献报道的苯并吡唑类化合物，所有化合物的结构均通过核磁共振氢谱(1HNMR)、碳谱(13CNMR)及高分辨质谱(HRMS)确证。杀虫活性测试结果表明，目标化合物 A1、A7、A16 和 A22 在 500mg/L 下对苜蓿蚜的致死率约为 40%，活性弱于先导结构化合物 1。初步分析，介离子结构与非介离子结构结合模式相近，其理化性质以及静电势表面的差异可能是导致目标化合物活性比化合物 1 低的主要原因。关键词:苯并吡唑；新烟碱；杀虫活性；烟碱乙酰胆碱受体；结合模式中图分类号：O622.26；TQ453文献标志码：ADesign,synthesis,insecticidal assay and binding mode study ofbenzopyrazole derivativesSHIMan,ZHOUCong,LIGuanglong,XUXiaoyong,SHAOXusheng,LIZhong,CHENGJiagao*(Shanghai Key Laboratory of Chemical Biology,School of Pharmacy,East China University ofScience and Technology,Shanghai 200237,China)Abstract:BasedontherecentlyreportedstructureofhighlyactivemesoionicnAChRmodulators,30novelbenzopyrazolecompoundsweredesignedandsynthesizedthroughscaffoldhopping.Theirstructureswereconfirmedby1HNMR,13CNMRandHRMS.InsecticidalactivityassaysrevealedcompoundsA1,A7,A16andA22showedabout40%mortalityagainstAphis craccivoraattheconcentrationof500mg/L,howeverstilllessactivethanleadcompound1.Preliminaryanalysissuggestssimilarbindingmodesformesoionicandnon-mesoionicstructures,andthedifferencesintheirphysicochemicalpropertiesandelectrostaticpotentialsurfacebetweenA1andcompound1maybethemainreasonfortheloweractivitiesofthetargetcompoundsthanthatofcompound1.Keywords:benzopyrazole;neonicotinoid;insecticidalactivities;nicotineacetylcholinereceptor;bindingmode收稿日期：2023-04-15；录用日期：2023-08-13；网络首发日期：2023-09-07.Received:April15,2023;Accepted:August13,2023;Published online:September7,2023.URL:https:/doi.org/10.16801/j.issn.1008-7303.2023.0076http:/ Journal of Pesticide ScienceE-mail:蚜虫是最常见的刺吸式害虫之一1，不仅可以从幼叶、茎组织和豆荚中吸取汁液，还能传播多种植物病毒2，导致作物产量损失。使用化学杀虫剂是防控蚜虫最有效的手段。新烟碱类杀虫剂是当前世界上使用最广泛的杀虫剂之一，约占全球杀虫剂市场的 25%3。自第一个新烟碱类杀虫剂吡虫啉(imidacloprid)4 问世以来，啶虫脒(acetamiprid)5、噻虫嗪(thiamethoxam)6、噻虫啉(thiacloprid)7、噻虫胺(clothianidin)8、呋虫胺(dinotefuran)9、烯啶虫胺(nitenpyram)10、氟啶虫胺腈(sulfoxaflor)11、氟吡呋喃酮(flupyradifurone)12、flupyrimin13以及国内研发的环氧虫啉(cycloxylidin)14、哌虫啶(paichongding)15、环氧虫啶(cycloxaprid)16-17和戊吡虫胍(guadipyr)18等新烟碱类杀虫剂陆续上市。然而，新烟碱类杀虫剂因频繁大量使用而面临严重的抗性问题19并引发了蜂群崩溃综合征等20生态环境风险。开发安全高效、生态友好以及作用机制新颖的新烟碱类杀虫剂已成为研究的主要方向之一。杜邦公司近年开发了两种介离子类新烟碱杀虫剂triflumezopyrim21和 dicloromezotiaz22(图式 1)。二者均作用于乙酰胆碱受体的正构位点，具有抑制烟碱乙酰胆碱受体(nicotineacetylcholinereceptor，nAChR)的功能，与传统杀虫剂无交互抗性23。因介离子化合物具有高效低毒、对环境友好等优点24，这两个介离子化合物一经报道就引起了广泛关注。其中，贵州大学基于介离子类新烟碱杀虫剂化学结构，设计合成了全新的化合物 125(图式 2)，在 100mg/L 下对蚜虫的致死率达到 100%。介离子结构因性质独特而受到广泛关注，然而对与其相应的非介离子结构的比较研究较少。本研究基于新报道的介离子化合物 1 进行骨架结构跃迁，在保留相关药效团基础上设计了相应的非介离子结构，合成了 30 个苯并吡唑类非介离子化合物。化合物设计思路见图式 2，合成路线见图式 3。开展了化合物理化性质预测、杀虫活性测试以及与乙酰胆碱结合蛋白(acetylcholinebindingprotein,AChBP)结合模式研究，以期考察介离子、非介离子结构间的性质差异对化合物活性的影响机制。1 实验部分 1.1 仪器、药剂与试剂BrukerAM-400核磁共振仪(德国 Bruker 公司，内标：TMS，氘代试剂：DMSO-d6或CDCl3)；MIicroMassGCTCA055 高分辨质谱仪(HRMS-EI-TOF，美国 Waters 公司)；ThermoFisherQ-Exactive(ESI-Orbitrap)液质联用仪(中国赛默飞世尔科技公司)；BchiMeltingPointB-540熔点仪(瑞士 Buchi 公司)。97%吡虫啉原药(imidacloprid)，NN+OOONNCF3NNOClClNSCltriflumezopyrimdicloromezotiaz图式 1 triflumezopyrim 和 dicloromezotiaz 的结构Scheme 1 The structures of triflumezopyrim anddicloromezotiazN+NOONSClO化合物 1贵州大学Compound 1Guizhou UniversityFNNOOR2R1=,NSClNCl苯并吡唑类化合物Benzopyrazole compounds骨架跃迁Scaffold hoppingR1图式 2 苯并吡唑类化合物的设计思路Scheme 2 Design strategy of benzopyrazole compounds1048农药学学报Vol.25购自江苏克胜集团有限公司。除特殊说明外，所用的试剂均为市售分析纯。1.2 化合物的合成1.2.1中间体 3a3o 的合成参考文献 26 方法合成：将吲唑-3-羧酸(1)(20mmol)和四氢呋喃(THF)(30mL)加入 250mL 圆底瓶中，室温搅拌下加入取代苯酚(2a2o)(20mmol)、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(EDCI)(24mmol)以及 4-二甲氨基吡啶(DMAP)(2mmol)，反应 16h，薄层色谱(TLC)V(正庚烷):V(乙酸乙酯)=2:1监测至反应完成。旋转蒸发除去四氢呋喃，用乙酸乙酯(30mL3)萃取。合并有机相，使用无水硫酸钠干燥，旋转蒸发除去乙酸乙酯，经硅胶柱层析V(正庚烷):V(乙酸乙酯)=3:1分离提纯，得中间体 3a3o，收率 70%83%。代表性中间体 4-氟苯基-1H-吲唑-3-羧酸酯(3a):1HNMR(400MHz,CDCl3)12.51(s,1H),8.47(dd,J=8.1,1.3Hz,1H),7.90(dd,J=8.3,1.3Hz,1H),7.67(td,J=7.6,1.3Hz,1H),7.57(td,J=7.4,1.2Hz,1H),7.507.45(m,2H),7.35(dd,J=7.3,5.8Hz,2H)。1.2.2目标化合物 A1A30 的合成参考文献 27方法合成：将中间体 3a3o(5mmol)和 N,N-二甲基甲酰胺(DMF)(10mL)加入 100mL 圆底瓶中，室温搅拌下加入 5-氯-2-(氯甲基)噻唑(4)(5.5mmol)或 2-氯-5-(氯甲基)吡啶(5)(5.5mmol)、碳酸钾(6mmol)和碘化钾(0.25mmol)，氩气氛围，搅拌加热至 65，反应 2h，TLCV(正庚烷):V(乙酸乙酯)=3:1监测至反应完成。用乙酸乙酯(20mL3)萃取。合并有机相，使用无水硫酸钠干燥，旋转蒸发除去乙酸乙酯，经硅胶柱层析V(正庚烷):V(乙酸乙酯)=3:1 分离提纯，得到目标化合物A1A30。4-氟苯基-1-(2-氯噻唑-5-基)甲基)-1H-吲唑-3-羧酸酯(A1):白色固体 832mg,收率 43%,m.p.153.2153.9;1HNMR(400MHz,CDCl3),8.15(dd,J=8.4,1.3Hz,1H),7.90(dd,J=8.5Hz,1.3Hz,1H),7.74(s,1H),7.48(td,J=8.3,1.4Hz,1H),7.41(td,J=8.2,1.4Hz,1H),7.337.29(m,2H),7.22(d,J=8.5Hz,2H),6.27(s,2H).13CNMR(100MHz,CDCl3),160.72(d,1JCF=244.1Hz),159.02,153.51,148.10,145.76(d,4JCF=2.8Hz),141.44,134.37,127.32,126.44,123.82,123.25(d,3JCF=8.6Hz),122.32,121.41,118.79,116.55(d,2JCF=23.6Hz),45.65.HRMS(ESI):C18H1135ClFN3O2S(M+H)+,计算值 388.0317,理论值 388.0323;C18H1137ClFN3O2S(M+H)+,计算值 390.0288,理论值 390.0289。4-氯苯基-1-(2-氯噻唑-5-基)甲基)-1H-吲唑-3-羧酸酯(A2)：白色固体 786mg,收率 39%,m.p.152.1153.0;1HNMR(400MHz,CDCl3),8.15(d,J=8.3Hz,1H),7.90(d,J=8.6Hz,1H),7.75(s,1H),7.537.46(m,3H),7.457.40(m,1H),7.29(d,J=8.9Hz,2H),6.26(s,2H).13CNMR(100MHz,CDCl3),158.93,154.73,153.92,148.57,148.23,141.55,132.32,130.08,129.69,127.61,126.72,123.97,123.32,121.55,118.91,49.27.HRMS(ESI):C18H1135Cl2N3O2S(M+NHNOOH+OHREDCI,DMAPTHF,16 h,r.t.12a-2oNNOORNSClNHNOORNSCl3a-3o4A1-A15NNOOR65,2 hNClCl5NClClA16-A303a,A1,A16:R=4-F;3b,A2,A17:R=4-Cl;3c,A3,A18:R=4-Br;3d,A4,A19:R=4-CH3;3e,A5,A20:R=4-OCH3;3f,A6,A21:R=2-F;3g,A7,A22:R=2-Cl;3h,A8,A23:R=2-Br;3i,A9,A24:R=2-CH3;3j,A10,A25:R=2-OCH3;3k,A11,A26:R=3-CF3;3l,A12,A27:R=3-F;3m,A13,A28:R=3-Cl;3n,A14,A29:R=3-CH3;3o,A15,A30:R=2,4-di-FK2CO3,KI,DMF,K2CO3,KI,DMF,65,2 h图式 3 苯并吡唑类化合物 A1A30 的合成路线Scheme 3 Synthetic route of benzopyrazole compounds A1-A30No.5施蔓等:苯并吡唑类衍生物的设计、合成、杀虫活性及结合模式研究1049H)+,计算值 404.0022,理论值 404.0020;C18H1135Cl37ClN3O2S(M+H)+,计算值 405.9992,理论值 405.9990;C18H1137Cl2N3O2S(M+H)+,计算值 407.9963,理论值 407.9960。4-溴苯基-1-(2-氯噻唑-5-基)甲基)-1H-吲唑-3-羧酸酯(A3)：白色固体 1028mg,收率 46%,m.p.143.8144.1;1HNMR(400MHz,CDCl3),8.14(d,J=8.2Hz,1H),7.90(d,J=8.7Hz,1H),7.74(s,1H),7.687.63(m,2H),7.48(ddd,J=8.4,6.8,1.3Hz,1H),7.457.39(m,1H),7.277.21(m,2H),6.27(s,2H).13CNMR(100MHz,CDCl3),152.15,149.01,148.11,142.62,141.44,134.33,132.88,127.33,126.51,123.84,123.55,122.22,121.35,118.82,117.26,49.15.HRMS(ESI):C18H1179Br35ClN3O2S(M+H)+,计算值 447.9517,理论值 447.9514;C18H1181Br35ClN3O2S(M+H)+,计算值449.9496，理论值 449.9492;C18H1179Br37ClN3O2S(M+H)+,计算值449.9496,理论值 449.9492;C18H1181Br37ClN3O2S(M+H)+,计算值451.9467,理论值 451.9461。对甲苯基-1-(2-氯噻唑-5-基)甲基)-1H-吲唑-3-羧酸酯(A4)：白色固体 635mg,收率 33%,m.p.129.8130.5;1HNMR(400MHz,CDCl3),8.26(dd,J=8.1,1.3Hz,1H),7.60(dd,J=8.3,1.3Hz,1H),7.54(s,1H)7.39(td,J=8.4,1.4Hz,1H),7.34(td,J=8.5,1.4Hz,1H),7.14(dd,J=7.3,1.2Hz,2H),7.006.94(m,2H),6.23(s,2H),2.34(d,J=1.4Hz,3H).13CNMR(100MHz,CDCl3),153.92,148.22,147.87,141.54,137.75,136.52,134.61,130.42,127.35,126.34,123.92,122.81,121.66,121.52,118.78,49.18,21.11.HRMS(ESI):C19H1435ClN3O2S(M+H)+,计算值 384.0568,理论值384.0565;C19H1437ClN3O2S(M+H)+,计算值 386.0539,理论值 386.0535。4-甲氧基苯基-1-(2-氯噻唑-5-基)甲基)-1H-吲唑-3-羧酸酯(A5)：白色固体 1077mg,收率 54%,m.p.136.1136.6;1HNMR(400MHz,CDCl3),8.17(d,J=8.4Hz,1H),7.89(d,J=8.6Hz,1H),7.75(s,1H),7.47(dd,J=8.8,6.7Hz,1H),7.437.37(m,1H),7.287.22(m,2H),7.077.00(m,2H),6.27(s,2H),3.89(s,3H).13CNMR(100MHz,CDCl3),159.42,157.89,153.50,148.09,143.41,141.42,134.50,127.28,126.25,123.79,122.55,121.56,118.66,116.10,114.88,55.76,49.07.HRMS(ESI):C19H1435ClN3O3S(M+H)+,计算值 384.0568,理论值 400.0517;C19H1437ClN3O3S(M+H)+,计算值 402.0488,理论值 402.0478。2-氟苯基-1-(2-氯噻唑-5-基)甲基)-1H-吲唑-3-羧酸酯(A6)：白色固体 836mg,收率 43%,m.p.131.5132.1;1HNMR(400MHz,CDCl3),8.26(dd,J=8.4,1.5Hz,1H),7.59(dd,J=8.2,1.5Hz,1H),7.43(s,1H),7.40(td,J=8.4,1.6Hz,1H),7.387.30(m,2H),7.157.11(m,2H),7.107.05(m,1H),6.24(s,2H).13CNMR(100MHz,CDCl3),157.86,154.45(d,1JCF=196.1Hz),152.94,148.11,141.44,134.30,127.83(d,2JCF=21.4Hz),127.29,126.48,124.77(d,4JCF=3.8Hz),124.46(d,3JCF=7.0Hz),124.04,123.86,123.07(d,3JCF=6.9Hz),121.98,118.73,117.05(d,2JCF=18.3Hz),49.08.HRMS(ESI):C18H1135ClFN3O2S(M+H)+,计算值 388.0318,理论值 388.0314;C18H1137ClFN3O2S(M+H)+,计算值390.0288,理论值 390.0284。2-氯苯基-1-(2-氯噻唑-5-基)甲基)-1H-吲唑-3-羧酸酯(A7)：白色固体 725.4mg,收率 36%,m.p.141.7142.5;1HNMR(400MHz,CDCl3),8.03(d,J=8.4Hz,1H),7.82(d,J=8.6Hz,1H),7.74(s,1H),7.42(d,J=7.5Hz,2H),7.327.23(m,2H),7.046.99(m,2H),6.25(s,2H).13CNMR(100MHz,CDCl3),153.29,147.95,141.48,141.23,140.14,136.00,134.80,130.74,128.08,127.83,127.34,127.04,126.51,125.65,123.02,118.73,118.42,48.88.HRMS(ESI):C18H1135Cl2N3O2S(M+H)+,计算值 404.0022,理论值404.0017;C18H1135Cl37ClN3O2S(M+H)+,计算值 405.9992,理论值 405.9987;C18H1137Cl2N3O2S(M+H)+,计算值407.9963,理论值 407.9957。2-溴苯基 1-(2-氯噻唑-5-基)甲基)-1H-吲唑-3-羧酸酯(A8)：白色固体983mg,收率 44%,m.p.125.1126.8;1HNMR(400MHz,CDCl3),8.288.24(m,1H),7.88(s,1H),7.797.74(m,2H),7.537.46(m,2H),7.467.41(m,1H),7.38(dd,J=8.1,1.5Hz,1H),7.32(d,J=1.6Hz,1H),6.29(s,2H).13CNMR(100MHz,CDCl3),155.64,152.49,150.62,143.12,142.38,136.89,135.11,133.71,128.64,128.57,125.50,123.01,122.33,121.88,121.66,115.57,111.52,50.47.HRMS(ESI):C18H1179Br35ClN3O2S(M+H)+,计算值 447.9517,理论值 447.9511;C18H1181Br35ClN3O2S(M+H)+,计算值 449.9496,理论值449.9490;C18H1179Br37ClN3O2S(M+H)+,计算值 449.9496,理论值 449.9490;C18H1181Br37ClN3O2S(M+H)+,计算值 451.9467,理论值 451.9460。邻甲苯基-1-(2-氯噻唑-5-基)甲基)-1H-吲唑-3-羧酸酯(A9)：白色固体 977mg,收率 51%,m.p.130.2131.3;1HNMR(400MHz,CDCl3),8.20(d,J=8.4Hz,1H),7.91(d,J=8.6Hz,1H),7.75(s,1H),7.517.45(m,1H),7.42(d,J=8.7Hz,1H),7.387.28(m,3H),7.24(d,J=8.2Hz,1H),6.29(s,2H),2.31(s,3H).13CNMR(100MHz,CDCl3),158.91,153.47,148.66,148.12,141.45,134.48,131.55,130.36,127.30,126.85,126.34,125.48,123.87,122.52,122.11,121.50,118.74,49.06,16.47.HRMS(ESI):C19H1435ClN3O2S(M+H)+,计算值 384.0568,理论值 384.0565;C19H1437ClN3O2S(M+H)+,计算值 386.0539,理论值 386.0535。2-甲氧基苯基-1-(2-氯噻唑-5-基)甲基)-1H-吲唑-3-羧酸酯(A10):白色固体 798mg,收率 40%,m.p.138.9139.5;1HNMR(400MHz,DMSO-d6),8.07(dd,J=8.3,1.3Hz,1H),7.89(dd,J=8.6,1.3Hz,1H),7.80(s,1H),7.47(ddd,J=8.5,6.8,1.3Hz,1H),7.447.40(m,1H),7.37(m,2H),7.25(dd,J=8.3,1.4Hz,1H),7.07(td,J=7.7,1.5Hz,1H),6.28(s,2H),3.79(s,3H).13CNMR(100MHz,DMSO-d6),158.03,152.14,151.35,147.71,142.04,139.01,135.80,128.10,127.68,126.63,123.65,123.58,122.87,121.69,121.26,1050农药学学报Vol.25118.89,113.56,56.39,49.28.HRMS(ESI):C19H1435ClN3O3S(M+H)+,计算值 400.0517,理论值 400.0506;C19H1437ClN3O3S(M+H)+,计算值 402.0488,理论值402.0473。3-(三氟甲基)苯基-1-(2-氯噻唑-5-基)甲基)-1H-吲唑-3-羧酸酯(A11):白色固体 1027mg,收率 47%,m.p.129.5130.9;1HNMR(400MHz,CDCl3),8.03(d,J=8.3Hz,1H),7.79(d,J=8.5Hz,1H),7.62(s,1H),7.55(d,J=5.4Hz,2H),7.52(s,1H),7.44(dt,J=6.2,2.6Hz,1H),7.397.29(m,2H),6.15(s,2H).13CNMR(100MHz,CDCl3),158.51,153.53,150.08,148.13,141.46,134.28,132.45(q,2JCF=33.1Hz),130.43,127.37,126.65,125.45,123.88,123.50(q,1JCF=270.8Hz),123.44(d,3JCF=3.6Hz),122.01,121.30,119.12(d,3JCF=4.0Hz),118.89,49.16.HRMS(ESI):C19H1135ClF3N3O2S(M+H)+,计算值 438.0285,理论值438.0281;C19H1137ClF3N3O2S(M+H)+,计算值 440.0256,理论值 440.0251。3-氟苯基-1-(2-氯噻唑-5-基)甲基)-1H-吲唑-3-羧酸酯(A12)：白色固体 1219mg,收率 63%,m.p.128.1129.0;1HNMR(400MHz,CDCl3),8.26(dd,J=8.3,1.3Hz,1H),7.91(s,1H),7.60(dd,J=8.5,1.3Hz,1H),7.41(td,J=8.4,1.5Hz,1H),7.337.28(m,2H),7.067.01(m,1H),6.89(dt,J=9.0,1.9Hz,1H),6.83(dt,J=7.5,1.9Hz,1H),6.18(s,2H).13CNMR(100MHz,CDCl3),163.02(d,1JCF=201.4Hz),155.93,152.94(d,3JCF=6.9Hz),151.53,143.12,142.63,135.76,135.03,130.14(d,3JCF=6.1Hz),128.36,123.49,122.54,121.72,115.13(d,4JCF=2.2Hz),112.50(d,2JCF=16.0Hz),111.48,109.54(d,2JCF=16.0Hz),50.47.HRMS(ESI):C18H1135ClFN3O2S(M+H)+,计算值 388.0314,理论值388.0317;C18H1137ClFN3O2S(M+H)+,计算值 390.0284,理论值 390.0288。3-氯苯基-1-(2-氯噻唑-5-基)甲基)-1H-吲唑-3-羧酸酯(A13)：白色固体 1189mg,收率 59%,m.p.130.5131.2;1HNMR(400MHz,CDCl3),8.26(dd,J=8.1,1.3Hz,1H),7.91(s,1H),7.60(dd,J=8.3,1.3Hz,1H),7.477.39(m,3H),7.36(td,J=8.3,1.5Hz,1H),7.25(s,1H),6.986.94(m,1H),6.21(s,2H).13CNMR(100MHz,CDCl3),155.93,152.49,151.23,143.12,142.38,136.89,135.11,134.34,130.86,128.57,125.78,123.01,122.33,121.88,121.80,120.69,111.52,50.47.HRMS(ESI):C18H1135Cl2N3O2S(M+H)+,计算值 404.0018,理论值 404.0022;C18H1135Cl37ClN3O2S(M+H)+,计算值 405.9988,理论值 405.9992;C18H1137Cl2N3O2S(M+H)+,计算值 407.9958,理论值 407.9963。间甲苯基-1-(2-氯噻唑-5-基)甲基)-1H-吲唑-3-羧酸酯(A14)：白色固体 900mg,收率 47%,m.p.129.7130.4;1HNMR(400MHz,CDCl3),8.21(dd,J=8.2,1.3Hz,1H),7.95(s,1H),7.56(dd,J=8.1,1.3Hz,1H),7.41(td,J=8.0,1.5Hz,1H),7.36(td,J=8.1,1.4Hz,1H),7.267.23(m,1H),7.077.03(m,1H),6.95(dd,J=5.9,1.9Hz,2H),4.99(s,2H),2.35(s,3H).13CNMR(100MHz,CDCl3),154.87,152.43,151.40,142.16,141.33,139.77,136.54,135.13,129.49,128.43,125.54,123.50,122.52,122.30,121.76,118.89,112.48,49.47,21.32.HRMS(ESI):C19H1435ClN3O2S(M+H)+,计算值 384.0561,理论值 384.0568;C19H1437ClN3O2S(M+H)+,计算值 386.0531,理论值 386.0539。2,4-二氟苯基-1-(2-氯噻唑-5-基)甲基)-1H-吲唑-3-羧酸酯(A15)：白色固体 997.5mg,收率 50%,m.p.148.7149.5;1HNMR(400MHz,CDCl3),8.16(d,J=8.4Hz,1H),7.92(d,J=8.5Hz,1H),7.75(s,1H),7.567.34(m,3H),7.177.02(m,2H),6.28(s,2H).13CNMR(100MHz,CDCl3),160.63(dd,JCF=248.4,10.4Hz),157.86,154.22(dd,JCF=252.8,12.5Hz),153.53,148.13,141.47,140.67,134.24,133.73(dd,JCF=12.6,3.9Hz),127.36,126.63,124.57124.34(m),124.06,121.38,118.82,111.65(dd,JCF=23.2,3.6Hz),105.51(dd,2JCF=26.9,22.2Hz),49.13.HRMS(ESI):C18H1035ClF2N3O2S(M+H)+,计算值 400.0659,理论值 400.0655;C18H1037ClF2N3O2S(M+H)+,计算值 402.0629,理论值 402.0625。4-氟苯基-1-(6-氯吡啶-3-基)甲基)-1H-吲唑-3-羧酸酯(A16):白色固体 1219.2mg,收率 64%,m.p.131.3132.7;1HNMR(400MHz,CDCl3),8.54(d,J=2.4Hz,1H),8.15(dd,J=8.4,1.3Hz,1H),7.91(dd,J=8.5,1.3Hz,1H),7.75(dd,J=8.3,2.5Hz,1H),7.48(td,J=8.3,1.2Hz,1H),7.41(td,J=8.6,1.3Hz,1H),7.30(d,J=8.3Hz,2H),7.25(d,J=8.3Hz,1H),7.19(d,J=8.5Hz,2H),6.14(s,2H).13CNMR(100MHz,CDCl3),160.68(d,1JCF=245.4Hz),158.81,151.53,149.69,148.05,145.77(d,4JCF=2.2Hz),138.93,130.59,127.19,126.33,124.39,124.01,123.23(d,3JCF=8.5Hz),122.62,121.43,118.75,116.48(d,2JCF=23.7Hz),53.62.HRMS(ESI):C20H1335ClFN3O2(M+H)+,计算值 382.0753,理论值382.0749;C20H1337ClFN3O2(M+H)+,计算值 384.0724,理论值 384.0719。4-氯苯基-1-(6-氯吡啶-3-基)甲基)-1H-吲唑-3-羧酸酯(A17):白色固体 1489mg,收率 75%,m.p.130.8131.5;1HNMR(400MHz,CDCl3),8.50(d,J=2.4Hz,1H),8.10(d,J=8.4Hz,1H),7.87(d,J=8.6Hz,1H),7.71(dd,J=8.3,2.5Hz,1H),7.467.42(m,3H),7.407.35(m,1H),7.26(d,J=8.3Hz,1H),7.237.19(m,2H),6.10(s,2H).13CNMR(100MHz,CDCl3),158.54,155.19,149.56,148.02,139.11,132.06,130.66,129.85,129.39,127.31,126.44,124.51,123.99,123.13,121.41,118.70,116.84,53.58.HRMS(ESI):C20H1335Cl2N3O2(M+H)+,计算值 398.0458,理论值398.0454;C20H1335Cl37ClN3O2(M+H)+,计算值 400.0428,理论值 400.0424;C20H1337Cl2N3O2(M+H)+,计算值 402.0399,理论值 402.0394。4-溴苯基-1-(6-氯吡啶-3-基)甲基)-1H-吲唑-3-羧酸酯(A18)：白色固体 1706mg,收率 77%,m.p.135.3136.5;1HNMR(400MHz,CDCl3),8.54(d,J=2.6Hz,1H),8.14No.5施蔓等:苯并吡唑类衍生物的设计、合成、杀虫活性及结合模式研究1051(dd,J=8.4,1.5Hz,1H),7.91(dd,J=8.5,1.4Hz,1H),7.75(dd,J=7.9,2.6Hz,1H),7.687.60(m,2H),7.48(td,J=8.7,1.5Hz,1H),7.41(td,J=8.5,1.4Hz,1H),7.31(d,J=8.0Hz,1H),7.227.16(m,2H),6.14(s,2H).13CNMR(100MHz,CDCl3),158.43,151.54,149.71,148.99,148.03,138.90,132.82,130.52,127.19,126.38,124.36,124.00,122.43,123.55,121.38,119.73,118.79,53.64.HRMS(ESI):C20H1379Br35ClN3O2(M+H)+,计算值 441.9952,理论值 441.9948;C20H1379Br37ClN3O2(M+H)+,计算值 443.9932,理论值 443.9918;C20H1381Br35ClN3O2(M+H)+，计算值 443.9932,理论值 443.9918;C20H1381Br37ClN3O2(M+H)+,计算值 445.9902,理论值 445.9888。对甲苯-1-(6-氯吡啶-3-基)甲基)-1H-吲唑-3-羧酸酯(A19):白色固体 1413.7mg,收率 75%,m.p.140.7141.5;1HNMR(400MHz,CDCl3),8.59(d,J=2.3Hz,1H),8.18(dd,J=8.4,1.1Hz,1H),7.90(dd,J=8.6,1.2Hz,1H),7.76(dd,J=7.8,2.3Hz,1H),7.47(td,J=7.7,1.1Hz,1H),7.40(td,J=7.6,1.3Hz,1H),7.31(d,J=7.9Hz,1H),7.28(d,J=8.1Hz,2H),7.16(d,J=8.1Hz,2H),6.15(s,2H),2.44(s,3H).13CNMR(100MHz,CDCl3),151.49,149.77,148.06,143.02,13