CN115353488B - 两类3-芳基异喹啉类化合物及其作为制备抗植物病原真菌杀菌剂的应用 - Google Patents

两类3-芳基异喹啉类化合物及其作为制备抗植物病原真菌杀菌剂的应用 Download PDF

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CN115353488B
CN115353488B CN202210286172.4A CN202210286172A CN115353488B CN 115353488 B CN115353488 B CN 115353488B CN 202210286172 A CN202210286172 A CN 202210286172A CN 115353488 B CN115353488 B CN 115353488B
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陈伟
张锐
陈阳
余坪槟
兰雨欣
许豪键
雷思敏
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Abstract

本发明涉及两类3‑芳基异喹啉类化合物及其作为制备抗植物病原真菌杀菌剂的应用。这两类异喹啉化合物的结构如式(I)和式(II)：其中，Ar为苯环、吡啶环、嘧啶环、三嗪环、萘环、呋喃环、噻吩环、咪唑环和三唑环等芳香性环结构；R1‑R4和R6‑R9为相同或者不同的氢、羟基、卤素、硝基、氰基、羧基、酯基、酰胺基、酰基、氨基、胺基、三氟甲基、二氟甲基、二氟甲氧基、C1‑C6的烷基或烷氧基、C2‑C6的链状烯烃或者炔烃、C3‑C5的环烷基或者杂环；R5为C1‑C6的烷基；X‑为卤素负离子、三氟甲磺酸根、硫酸根、碳酸根、磷酸根、磺酸根和四苯硼酸根。本发明所述化合物对多种植物病原真菌的具有显著的抑制活性，可用于制备杀菌剂。

Description

两类3-芳基异喹啉类化合物及其作为制备抗植物病原真菌杀 菌剂的应用
技术领域
本发明涉及农药杀菌剂领域，尤其是两类3-芳基异喹啉类化合物及其作为制备抗植物病原真菌杀菌剂的应用。
背景技术
季铵型异喹啉生物碱(Quaternary isoquinoline alkaloids,QQAs)是一类规模较小但生物活性突出的天然产物，结构中含有独特的C＝N+基团。血根碱(Sanguinarine)、白屈菜红碱(Cherythrine)和小檗碱(Berberine)作为QQAs的典型代表，不仅具有抗肿瘤、抗菌、镇痛、抗心律失常等多种医用活性，而且还表现出杀菌、杀虫、杀螨和抗病毒等农用活性，其开发和应用备受药物研究者重视。但天然的QQAs在自然界中含量少，分离提取困难；结构复杂，化学合成困难。近年来，周乐等以血根碱和白屈菜红碱为先导，制备了一系列N-芳基-3,4-二氢异喹啉盐，表现出杀螨、抑菌和抗癌等活性。但该类衍生物的与QQAs的相似性不高，并且C＝N+基团处于非共轭状态，致使其在空气中不稳定。因此，申请人期望可以制备出与天然产物结构相似性高、方便易得和结构稳定的QQAs类似物。
基于前期研究结果，申请人以血根碱、白屈菜红碱和小檗碱作为先导，采用仿生农药设计策略，简化先导的结构，合理利用合成方法学，设计并合成了一系列3-芳基异喹啉衍生物和相对应的3-芳基异喹啉-2-盐。结果证明，本发明中所涉及的两类异喹啉衍生物对多种植物病原真菌具有程度不等的抑菌活性。
本发明所涉及的两类异喹啉类化合物绝大多数都为未见文献报道的新化合物。之前，已有的文献报道都集中于该类化合物的合成方法研究，以及其在医药方面的抗肿瘤、抗炎活性等。本专利是申请人首次对这两类3-芳基异喹啉衍生物的抗植物病原真菌活性报道。
发明内容
本发明目的在于提供两类3-芳基异喹啉类化合物及其作为制备抗植物病原真菌杀菌剂的应用。
本发明所述的两类3-芳基异喹啉类化合物，其结构如式(I)和式(Ⅱ)，
式(I)和式(II)中，R1-R4选自氢、甲氧基；Ar选自苯环、萘环，具体结构如式(III)所示，
式(II)中，R5为甲基，中X－为三氟甲磺酸根。
式(III)中，R6-R9选自氢、卤素、硝基、甲氧基、甲氧羰基和三氟甲基，R10选自氢。
本发明提供了所述两类3-芳基异喹啉类化合物I、II的通用制备方法，其典型合成路线如下：
化合物I、II作为制备抗植物病原真菌药物的应用。对番茄早疫病菌(Alternariasolani)；小麦赤霉病菌(Fusahum graminearum)；梨黑斑病菌(Alternaria alternata)；黄瓜枯萎病菌(Fusarium oxysporum)；苹果轮纹病菌(Physalospora piricola)；马铃薯晚疫病菌(Phytophthora infestans)；油菜菌核病菌(Sclerotinia sclerotiorum)；水稻纹枯病菌(Rhizoctonia solani)；小麦纹枯病菌(Rhizotonia cerealis)；玉米小斑病菌(Helminthosporium maydis)具有显著的抑制活性。
与现有技术相比，本发明具有如下优点和效果：
本发明的目的是以天然异喹啉生物碱—血根碱、白屈菜红碱和小檗碱作为先导化合物，采用结构仿生模拟策略，以统一的仿生骨架3-芳基异喹啉为母核，设计并合成两类与先导化合物结构高度相似、结构稳定的3-芳基异喹啉类化合物。通过离体抗菌活性测试，证明两类化合物的抗植物病原真菌活性显著，优于天然先导血根碱，部分目标化合物和商品化杀菌剂百菌清，为这两类3-芳基异喹啉衍生物的合成和更广泛的生物活性研究提供基础资料。
具体实施方式
在本发明中，申请人设计并合成的两类3-芳基异喹啉类化合物的结构通式如下：
式(I)和式(II)中，R1-R4选自氢、甲氧基；Ar选自苯环、萘环，具体结构如式(III)所示，
式(II)中，R5为甲基，中X－为三氟甲磺酸根。
式(III)中，R6-R9选自氢、卤素、硝基、甲氧基、甲氧羰基和三氟甲基，R10选自氢。
两类3-芳基异喹啉类化合物作为制备抗植物病原真菌杀菌剂的应用，已知异喹啉类化合物对如下多种植物病原真菌具有中等到突出的抑菌活性：番茄早疫病菌(Alternariasolani；AS)；小麦赤霉病菌(Fusahum graminearum；FG)；梨黑斑病菌(Alternariaalternate；AA)；黄瓜枯萎病菌(Fusarium oxysporum；FO)；苹果轮纹病菌(Physalosporapiricola；PP)；马铃薯晚疫病菌(Phytophthora infestans；PI)；油菜菌核病菌(Sclerotinia sclerotiorum；SS)；水稻纹枯病菌(Rhizoctonia solani；RS)；小麦纹枯病菌(Rhizotonia cerealis；RC)；玉米小斑病菌(Helminthosporium maydis；HM)。
本发明所述的两类异喹啉类化合物I、II的通用合成方法按反应式1进行。以化合物I-1和II-1进行具体说明。
实施例1，化合物3-苯基-8-甲氧基异喹啉I-1的合成。
化合物I-1的合成路线如反应式2所示。
中间体3的合成：将2-氯-5-碘吡啶1(5mmol,1.20g)和二氯甲烷(10mL)置于密封反应管中，再加入三氟甲磺酸TfOH(20mmol，3.0g)，室温下搅拌5min，加入间氯过氧苯甲酸(mCPBA,7.5mmol，1.30g)和1,3,5-三甲苯2(5.5mmol，0.66g)，在60℃下搅拌反应30min。冷却至室温，减压浓缩，残余物中加入10mL乙醚，0℃下搅拌30min，过滤，用乙醚洗涤沉淀，得到灰色固体，即中间体3。
中间体4的合成：将化合物3(9.2mmol，6.05g)溶于70mL的无水甲苯中，依次加入呋喃(27.6mmol，1.88g)和叔丁醇钾tBuOK(36.8mmol，4.13g)，室温下搅拌15h，薄层色谱(TLC)监测至反应完全，过滤，甲苯洗涤沉淀，滤液浓缩，柱层析分离得到黄色液体，即中间体4。
中间体5的合成：将化合物4(25mmol，4.50g)溶解到80mL的无水二氯甲烷中，在氮气保护下，混合物在-78℃搅拌，通过注射器滴加BBr3的二氯甲烷溶液(25mmol，25mL)，混合物继续搅拌2.5h，用水淬灭反应，用乙酸乙酯EA：四氢呋喃THF＝4：1萃取，收集有机相，浓缩得到黄色固体，无需进一步处理，直接将固体溶于四氢呋喃中，加入碳酸钾和碘甲烷，加热回流约12h，TLC监测至反应完全，过滤沉淀，用四氢呋喃洗涤沉淀，浓缩滤液，柱层析分离得到白色固体，即中间体5。
目标化合物I-1的合成：将Pd(dba)2(5mol％，14.4mg)和X-Phos(10mol％，23.8mg)溶于4.4mL甲苯/水/乙醇(体积比，5:1:5)的混合溶剂中，接着加入苯硼酸频哪醇酯(0.6mmol，122.5mg)、中间体5(0.5mmol，96.8mg)和碳酸钠Na2CO3(2.5mmol，265mg)。在氮气保护下，混合物在110℃反应约12h，TLC监测至反应完全。冷却浓缩，柱层析分离得到黄色固体，即目标化合物I-1。
3-苯基-8-甲氧基异喹啉I-1：产率98％，黄色固体，m.p.168–170℃,1H NMR(400MHz,CDCl3)δ9.31(s,1H),8.48(s,1H),8.24–8.14(m,2H),7.60–7.49(m,4H),7.46–7.41(m,1H),7.02(dd,J＝7.6,1.0Hz,1H),4.06(s,3H).HRMS(ESI)calcd for C16H14NO[M+H]+236.1075,found 236.1066.
实施例2：目标化合物2-甲基-3-苯基-8-甲氧基异喹啉三氟甲磺酸盐II-1的合成。
化合物II-1的合成路线如反应式3所示。
目标化合物II-1的合成方法：将化合物I-1(0.5mmol，117.55mg)溶于3mL无水二氯甲烷中，氮气保护，冷却至0℃，滴加三氟甲磺酸甲酯CH3OTf(1.5mmol，246.15mg)，滴加完毕后，室温下反应约12h，TLC监测至反应完全。浓缩反应液，残渣用乙醚洗涤3-5次，再用乙酸乙酯洗涤沉淀2次，得到白色固体，即目标化合物II-1。
2-甲基-3-苯基-8-甲氧基异喹啉三氟甲磺酸盐II-1：产率74％，白色固体，m.p.134–136℃；1H NMR(400MHz,CDCl3)δ10.15(s,1H),8.42(s,1H),8.11(d,J＝8.4Hz,1H),7.85(t,J＝8.1Hz,1H),7.62–7.61(m,2H),7.60(d,J＝1.6Hz,1H),7.55–7.53(m,2H),7.41(d,J＝7.9Hz,1H),4.36(s,3H),4.07(s,3H).HRMS(ESI)calcd for C17H16NO[M-OTf]+250.1227,found 250.1217.
其余化合物I和II的合成方法同I-1和II-1。
部分代表性化合物的理化数据如下：
2-甲基-3-(4-氯苯基)-8-甲氧基异喹啉I-2：产率96％，黄色固体，m.p.94–96℃；1H NMR(400MHz,CDCl3)δ9.25(s,1H),8.39(s,1H),8.18–8.10(m,2H),7.53–7.56(m,1H),7.51–7.43(m,1H),7.22–7.13(m,2H),6.99(dd,J＝7.6,1.1Hz,1H),4.03(s,3H).HRMS(ESI)calcd for C16H13FNO[M+H]+254.0981,found 254.0972.
2-甲基-3-(4-氟苯基)-8-甲氧基异喹啉I-3：产率97％，黄色固体，m.p.116–118℃；1H NMR(400MHz,CDCl3)δ9.29(s,1H),8.45(s,1H),8.17–8.06(m,2H),7.60–7.51(m,2H),7.50(d,J＝2.0Hz,1H),7.48(d,J＝1.9Hz,1H),7.03(dd,J＝7.5,1.1Hz,1H),4.07(s,3H).HRMS(ESI)calcd for C16H13ClNO[M+H]+270.0686,found 270.0676.
2-甲基-3-(4-三氟甲基苯基)-8-甲氧基异喹啉I-4：产率91％，黄色固体，m.p.90–92℃；1H NMR(600MHz,CDCl3)δ9.28(s,1H),8.49(s,1H),8.29–8.25(m,2H),7.76–7.72(m,2H),7.56(m,1H),7.54–7.49(m,1H),7.01(dd,J＝7.6,1.0Hz,1H),4.04(s,3H).HRMS(ESI)calcd for C17H13F3NO[M+H]+304.0949,found 304.0939.
2-甲基-3-(4-硝基苯基)-8-甲氧基异喹啉I-5：产率90％，黄色固体，m.p.150–152℃；1H NMR(400MHz,CDCl3)δ9.30(s,1H),8.56(s,1H),8.34(s,4H),7.63–7.52(m,2H),7.06(dd,J＝6.7,1.9Hz,1H),4.07(s,3H).13C NMR(100MHz,CDCl3)δ154.98,152.21,148.09,145.89,129.02,128.42,127.60,127.53,124.07,124.03,119.32,112.73,108.25,55.76.HRMS(ESI)calcd for C16H13N2O3[M+H]+281.0926,found 281.0916.
2-甲基-3-(萘-2-基)-8-甲氧基异喹啉I-6：产率99％，黄色固体，m.p.105–107℃；1H NMR(400MHz,CDCl3)δ9.36(s,1H),8.73–8.69(m,1H),8.62(d,J＝1.0Hz,1H),8.32(dd,J＝8.6,1.8Hz,1H),8.07–7.96(m,2H),7.94–7.88(m,1H),7.60(d,J＝8.2Hz,1H),7.55–7.49(m,3H),7.04(d,J＝7.6Hz,1H),4.09(s,3H).HRMS(ESI)calcd for C20H16NO[M+H]+286.1232,found 286.1223.
2-甲基-3-(4-甲氧羰基苯基)-8-甲氧基异喹啉I-7：产率52％，黄色固体，m.p.98–100℃；1H NMR(400MHz,CDCl3)δ9.32(s,1H),8.55(s,1H),8.30–8.23(m,2H),8.20–8.15(m,2H),7.62–7.51(m,2H),7.05(dd,J＝7.4,1.1Hz,1H),4.08(s,3H),3.98(s,3H).HRMS(ESI)calcd for C18H16NO3[M+H]+294.1130,found 294.1119.
2-甲基-3-(3,4-二甲氧基苯基)-8-甲氧基异喹啉I-8：产率98％，黄色固体，m.p.110–112℃；1H NMR(400MHz,CDCl3)δ9.25(s,1H),8.37(s,1H),7.79(d,J＝2.0Hz,1H),7.70(dd,J＝8.4,2.1Hz,1H),7.52–7.54(m,1H),7.50–7.39(m,1H),7.00–6.96(m,2H),4.04(s,6H),3.95(s,3H).HRMS(ESI)calcd for C18H18NO3[M+H]+296.1287,found 296.1276.
2-甲基-3-(4-氟苯基)-8-甲氧基异喹啉三氟甲磺酸盐II-2：产率90％，黄色固体，m.p.152–154℃；1H NMR(400MHz,CDCl3)δ10.11(s,1H),8.42(s,1H),8.10(d,J＝8.3Hz,1H),7.87(t,J＝8.1Hz,1H),7.64–7.59(m,2H),7.43(d,J＝7.9Hz,1H),7.35–7.29(m,2H),4.37(s,3H),4.09(s,3H).HRMS(ESI)calcd for C17H15FNO[M-OTf]+268.1133,found 268.1121.
2-甲基-3-(4-氯苯基)-8-甲氧基异喹啉三氟甲磺酸盐II-3：产率83％，灰色固体，m.p.142–144℃；1H NMR(400MHz,CDCl3)δ10.11(s,1H),8.41(s,1H),8.10(d,J＝8.4Hz,1H),7.87(t,J＝8.1Hz,1H),7.62–7.54(m,4H),7.43(d,J＝7.9Hz,1H),4.37(s,3H),4.09(s,3H).HRMS(ESI)calcd for C17H15ClNO[M-OTf]+284.0837,found 284.0826.
2-甲基-3-(4-三氟甲基苯基)-8-甲氧基异喹啉三氟甲磺酸盐II-4：产率71％，白色固体，m.p.178–180℃；1H NMR(400MHz,CDCl3)δ10.14(s,1H),8.43(s,1H),8.12(d,J＝8.3Hz,1H),7.89(dd,J＝8.1,4.8Hz,3H),7.80(d,J＝8.1Hz,2H),7.45(d,J＝7.9Hz,1H),4.38(s,3H),4.09(s,3H).HRMS(ESI)calcd for C18H15F3NO[M-OTf]+318.1101,found318.1092.
2-甲基-3-(4-硝基苯基)-8-甲氧基异喹啉三氟甲磺酸盐II-5：产率89％，黄色固体，m.p.190–192℃；1H NMR(400MHz,MeOD)δ9.97(s,1H),8.62(s,1H),8.56–8.49(m,2H),8.09–8.04(m,2H),7.98(d,J＝2.1Hz,1H),7.96(d,J＝2.1Hz,1H),7.77–7.70(m,1H),4.32(s,3H),4.16(s,3H).HRMS(ESI)calcd for C17H15N2O3[M-OTf]+295.1078,found 295.1068.
2-甲基-3-(萘-2-基)-8-甲氧基异喹啉三氟甲磺酸盐II-6：：产率95％，黄色固体，m.p.150–152℃；1H NMR(400MHz,CDCl3)δ10.19(s,1H),8.50(s,1H),8.14(d,J＝8.3Hz,1H),8.05(d,J＝6.2Hz,2H),7.97(d,J＝9.0Hz,2H),7.86(t,J＝8.1Hz,1H),7.69–7.66(m,1H),7.65(s,1H),7.61–7.56(m,1H),7.41(d,J＝7.9Hz,1H),4.41(s,3H),4.07(s,3H).HRMS(ESI)calcd for C21H18NO[M-OTf]+300.1383,found 300.1374.
2-甲基-3-(4-甲氧羰基苯基)-8-甲氧基异喹啉三氟甲磺酸盐II-7：产率86％，黄色固体，m.p.136–138℃；1H NMR(400MHz,CDCl3)δ10.18(s,1H),8.44(s,1H),8.29(d,J＝1.8Hz,1H),8.27(d,J＝2.0Hz,1H),8.15(d,J＝8.3Hz,1H),7.90(t,J＝8.1Hz,1H),7.71(d,J＝1.9Hz,1H),7.69–7.68(m,1H),7.45(d,J＝7.9Hz,1H),4.39(s,3H),4.10(s,3H),4.01(s,3H).HRMS(ESI)calcd for C19H18NO3[M-OTf]+308.1282,found 308.1272.
2-甲基-3-(3,4-二甲氧苯基)-8-甲氧基异喹啉三氟甲磺酸盐II-8：产率90％，黄色固体，m.p.166–168℃；1H NMR(400MHz,CDCl3)δ10.04(s,1H),8.41(s,1H),8.06(d,J＝8.3Hz,1H),7.83(t,J＝8.1Hz,1H),7.38(d,J＝7.9Hz,1H),7.09(d,J＝1.8Hz,1H),7.06(d,J＝1.9Hz,1H),7.05(s,1H),4.38(s,3H),4.07(s,3H),3.97(s,3H),3.92(s,3H).HRMS(ESI)calcd for C19H20NO3[M-OTf]+310.1438,found 310.1428.
2-甲基-3-(呋喃-2-基)-8-甲氧基异喹啉三氟甲磺酸盐II-9：产率88％，黄色固体，m.p.118–120℃；1H NMR(400MHz,CDCl3)δ10.21(s,1H),8.70(s,1H),8.12(d,J＝8.3Hz,1H),7.85(t,J＝8.1Hz,1H),7.78(d,J＝1.3Hz,1H),7.41(d,J＝7.9Hz,1H),7.15(d,J＝3.3Hz,1H),6.72(dd,J＝3.6,1.8Hz,1H),4.65(s,3H),4.11(s,3H).HRMS(ESI)calcd forC15H14NO2[M-OTf]+240.1020,found 240.1012.
2-甲基-3-(5-甲基噻唑-2-基)-8-甲氧基异喹啉三氟甲磺酸盐II-10：产率73％，黄色固体，m.p.142–144℃；1H NMR(400MHz,CDCl3)δ10.25(s,1H),8.53(s,1H),8.15(d,J＝8.3Hz,1H),7.88(t,J＝8.1Hz,1H),7.43(d,J＝7.9Hz,1H),7.29(d,J＝4.0Hz,1H),6.95(d,J＝4.2Hz,1H),4.55(s,3H),4.11(s,3H),2.63(s,3H).HRMS(ESI)calcd for C16H16NOS[M-OTf]+270.0948,found 270.0938.
实施例3，目标化合物I、II的抗植物病原真菌活性的实验方法及结果。
本发明利用菌丝生长速率法测试了目标化合物I-1—I-8、II-1—I-8对番茄早疫病菌(AS)；小麦赤霉病菌(FG)；梨黑斑病菌(AA)；黄瓜枯萎病菌(FO)；苹果轮纹病菌(PP)；马铃薯晚疫病菌(PI)；油菜菌核病菌(SS)；水稻纹枯病菌(RS)；小麦纹枯病菌(RC)；玉米小斑病菌(HM)等10种常见农作物致病菌的离体活性，以百菌清(Chlorothalonil)和先导血根碱(Sanguinarine)作为对照药。将化合物溶于二甲基亚砜中，配成浓度为10mg·L-1的母液，用吐温溶液稀释成浓度为50mg·L-1的待测试液。取1mL上述溶液加入到9mL马铃薯葡萄糖琼脂(PDA)培养基中，待培养基完全凝固后接入供试菌种，以二甲基亚砜为空白对照，实验重复3次。在25℃避光的条件下培养3-4天后，取出培养皿，通过十字交叉法测量菌落直径。抗植物病原真菌测试结果见附表1。
结果表明，两类3-芳基异喹啉类化合物对10种植物病原真菌具有中等到显著的离体抑菌活性，且部分化合物活性优于先导化合物百菌清，与商品化药物百菌清相当。因此，本发明的两类3-芳基异喹啉类化合物可用于制备抗植物病原真菌的杀菌剂。
附表1目标化合物I-1—I-8、II-1—II-8的抗植物病原真菌活性实验数据

Claims (3)

1.两类3-芳基异喹啉类化合物，其结构如式(I)和式(Ⅱ)，
式(I)和式(II)中，Ar选自苯环、萘环，具体结构如式(III)所示，R1-R4选自氢、甲氧基；式(II)中，R5为甲基，中X－为三氟甲磺酸根；式(III)中，R6-R9选自氢、卤素、硝基、甲氧基、甲氧羰基和三氟甲基，R10选自氢；
2.根据权利要求1所述的两类3-芳基异喹啉类化合物在制备抗植物病原真菌药物的应用。
3.根据权利要求2所述的两类3-芳基异喹啉类化合物在制备抗植物病原真菌药物的应用，所述植物病原真菌选自番茄早疫病菌(Alternaria solani)；小麦赤霉病菌(Fusahumgraminearum)；梨黑斑病菌(Alternaria alternata)；黄瓜枯萎病菌(Fusariumoxysporum)；苹果轮纹病菌(Physalospora piricola)；马铃薯晚疫病菌(Phytophthorainfestans)；油菜菌核病菌(Sclerotinia sclerotiorum)；水稻纹枯病菌(Rhizoctoniasolani)；小麦纹枯病菌(Rhizotonia cerealis)；玉米小斑病菌(Helminthosporiummaydis)。
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