CN110156808A - 具有杀菌活性的防己诺林碱-氨基甲酸酯类衍生物 - Google Patents

具有杀菌活性的防己诺林碱-氨基甲酸酯类衍生物 Download PDF

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CN110156808A
CN110156808A CN201910547717.0A CN201910547717A CN110156808A CN 110156808 A CN110156808 A CN 110156808A CN 201910547717 A CN201910547717 A CN 201910547717A CN 110156808 A CN110156808 A CN 110156808A
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徐胜臻
曹敏惠
王齐
汤保贺
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Huazhong Agricultural University
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Abstract

本发明属于化学农药合成技术领域，具体涉及一种具有杀菌活性的化合物防己诺林碱‑氨基甲酸酯类衍生物。该化合物通过天然产物防己诺林碱与烷基或芳基异氰酸酯于室温下在二氯甲烷和三乙胺中经一步加成反应制得，产率高，经抑菌活性筛选试验证实，防己诺林碱‑氨基甲酸酯类衍生物对于小麦赤霉菌或茶树拟茎点菌有较好的抑制作用，抑制活性优于或相当于使用量较大的杀菌农药嘧菌酯。

Description

具有杀菌活性的防己诺林碱-氨基甲酸酯类衍生物
技术领域
本发明属于化学农药合成技术领域，具体涉及一种具有杀菌活性的防己诺林碱-氨基甲酸酯类衍生物的合成方法与应用。
背景技术
粉防己碱(又叫汉防己甲素)和防己诺林碱(又叫汉防己乙素)是从汉防己根块中提取出来的一类生物碱。防己诺林碱自1973年Kupchan等人确定了其结构后，关于它的药理方面的研究也随之兴起(Kupchan,S M.Recent advances in the chemistry of tumorinhibitors of plant origin..Transactions of the New York Academy of Sciences,2012,32(1Series II):85-106)。防己诺林碱对大鼠甲醛性关节炎有一定的抗炎作用，也具有一定的降压作用(季宇彬.中药有效成分药理与应用.人民卫生出版社,2010)；防己诺林碱能够抑制氧自由基的产生，并增强其自清除作用，从而保护肝脏缺血再灌注损伤(刘正,李端,刘锡玖.汉防己乙素对大鼠肝脏缺血再灌注损伤脂质过氧化动态变化的影响.皖南医学院学报,2004,23(3):172-175)。
图1防己诺林碱和粉防己碱的结构式
北京大学张永鹤等报道改性的粉防己碱具有较好的治疗抑郁症的作用(CN201410437058.2；US20150025099)，也有专利报道改性的粉防己碱对糖尿病和肝病具有一定的治疗作用(US20140275138；WO2016023404A1)。防己诺林碱同粉防己碱相比，虽然各方面的药理活性均偏低，但是结构上有较活泼的酚羟基，对其进行结构改造的也比较多。2012年王锋鹏等将7-OH酯化形成-OCOEt结构，同时在5、13、14、5’碳上部分引入卤素，发现对肝癌Bel7402和直肠癌HCT8细胞株均有较好的抑制效果(He P,Sun H,Jian X.X,ChenQ.H,Chen D.L,Liu G.T,Wang F.P.Partial synthesis and biological evaluation ofbisbenzylisoquinoline alkaloids derivatives:potential modulators of multidrugresistance in cancer.J Asian Nat Prod Res,2012,14(6):564-576)；在2014年，潘卫东等对7-OH进行修饰改造，同时又在5、10、13、14碳上部分引入卤素，对人肝癌PLC/PRF/5细胞株、肺腺癌A549细胞株以及白血病K562细胞株均有较好的抑制活性(Liu Y.Z,Huang L,SunQ.Y,Zhang M.S,Li T.L,Liang G.L,Pan,W.D.Syntheses and anti-cancer activitiesof derivatives of tetrandrine and fangchinoline.Chem Res Chinese Univ,2014,30(6):937-940)；2017年刘玉法等对7-OH进行酯化修饰，发现其抗癌活性有了较大提升(LiD.C,Liu H.Z,Liu Y.F,Zhang Q.K,Liu C,Zhao S.H,Jiao B.Design,synthesis andbiological activities of tetrandrine and fangchinoline derivatives asantitumer agents.Bioorg Med Chem Lett,2017,27(3):533-536)。最近，邓洪斌等对7-OH进行修饰引入烷基、酰基、磺酰胺等，其抗炎活性也显著提高(Liu T,Zeng Q.X,Zhao X.Q,Wei W,Li Y.H,Deng H.B,Song D.Q.Synthesis and biological evaluation ofFangchinoline derivatives as anti-inflammatory agents through inactivation ofinflammasome.Molecules 2019,24,1154；doi:10.3390/molecules24061154)。防己诺林碱结构修饰改造较多，但将防己诺林碱与异氰酸酯发生加成反应得到防己诺林碱-氨基甲酸酯类衍生物作为农用杀菌剂无文献报道。
发明内容
本发明的目的在于提供一种具有杀菌活性的含有防己诺林碱结构片段的氨基甲酸酯类化合物。
为了实现上述目的，本发明采用以下技术方案：
一种杀菌剂防己诺林碱-氨基甲酸酯类衍生物，具有如通式(I)所示的结构：
式中R1为烷基或芳基。
进一步地，所述的烷基为乙基、丙基、异丙基或叔丁基。
进一步地，所述的芳基为苯基、邻甲基苯基、间甲基苯基、对甲基苯基、对甲氧基苯基、对氯苯基、对三氟甲基苯基或对三氟甲氧基苯。
进一步地，式中R1为乙基、丙基、异丙基、叔丁基、苯基、邻甲基苯基、间甲基苯基、对甲基苯基、对甲氧基苯基、对三氟甲基苯基、对三氟甲氧基苯基。
防己诺林碱-氨基甲酸酯类衍生物的制备方法，包括下列反应式所示的步骤：
在上述反应式中：防己诺林碱(II)与烷基或芳基异氰酸酯于室温下在二氯甲烷和三乙胺中经一步加成反应即得到目标化合物(I)。
防己诺林碱-氨基甲酸酯类衍生物的应用：作为小麦赤霉菌或茶树拟茎点菌杀菌剂的有效成份。
与现有技术相比，本发明的优点及有益效果在于：
本发明是基于具有新颖结构的天然产物防己诺林碱为先导化合物，经一步加成反应得到含防己诺林碱片段的氨基甲酸酯类化合物，合成得到的系列化合物结构新颖，反应一步完成，且产率高。
本发明所述的防己诺林碱-氨基甲酸酯类衍生物对于小麦赤霉菌或茶树拟茎点菌的抑制活性优于或相当于使用量较大的商品化品种嘧菌酯。
附图说明
图1：是本发明制备的化合物(I-a)的核磁共振氢谱(1H NMR)谱图。
图2：是本发明制备的化合物(I-a)的核磁共振碳谱(13C NMR)谱图。
图3：是本发明制备的化合物(I-b)的核磁共振氢谱(1H NMR)谱图。
图4：是本发明制备的化合物(I-b)的核磁共振碳谱(13C NMR)谱图。
图5：是本发明制备的化合物(I-c)的核磁共振氢谱(1H NMR)谱图。
图6：是本发明制备的化合物(I-c)的核磁共振碳谱(13C NMR)谱图。
图7：是本发明制备的化合物(I-d)的核磁共振氢谱(1H NMR)谱图。
图8：是本发明制备的化合物(I-d)的核磁共振碳谱(13C NMR)谱图。
图9：是本发明制备的化合物(I-e)的核磁共振氢谱(1H NMR)谱图。
图10：是本发明制备的化合物(I-e)的核磁共振碳谱(13C NMR)谱图。
图11：是本发明制备的化合物(I-f)的核磁共振氢谱(1H NMR)谱图。
图12：是本发明制备的化合物(I-f)的核磁共振碳谱(13C NMR)谱图。
图13：是本发明制备的化合物(I-g)的核磁共振氢谱(1H NMR)谱图。
图14：是本发明制备的化合物(I-g)的核磁共振碳谱(13C NMR)谱图。
图15：是本发明制备的化合物(I-h)的核磁共振氢谱(1H NMR)谱图。
图16：是本发明制备的化合物(I-h)的核磁共振碳谱(13C NMR)谱图。
图17：是本发明制备的化合物(I-i)的核磁共振氢谱(1H NMR)谱图。
图18：是本发明制备的化合物(I-i)的核磁共振碳谱(13C NMR)谱图。
图19：是本发明制备的化合物(I-j)的核磁共振氢谱(1H NMR)谱图。
图20：是本发明制备的化合物(I-j)的核磁共振碳谱(13C NMR)谱图。
图21：是本发明制备的化合物(I-k)的核磁共振氢谱(1H NMR)谱图。
图22：是本发明制备的化合物(I-k)的核磁共振碳谱(13C NMR)谱图。
图23：是本发明制备的化合物(I-l)的核磁共振氢谱(1H NMR)谱图。
图24：是本发明制备的化合物(I-l)的核磁共振碳谱(13C NMR)谱图。
具体实施方式
实施例1化合物I-a的制备
本实施例制备的化合物I-a具有如下式所示的结构：
合成方法：将汉防己乙素(2.53g，4.16mmol)溶解在二氯甲烷(CH2Cl2,15mL)中，然后加入三乙胺(NEt3，1.26g，12.47mmol)和乙基异氰酸酯(12.47mmol)并将混合物升温至室温，在N2气氛中搅拌24小时。将反应混合物用冰水淬灭，并用二氯甲烷(CH2Cl2，3×20mL)萃取。将合并的有机相用盐水洗涤(2×30mL)，并经无水硫酸钠(Na2SO4)干燥过夜。在真空中除去溶剂后，将粗产物在硅胶上色谱分离(石油醚：乙酸乙酯＝10：1，v/v)，得到目标化合物I-a。
红外光谱(IR)测定所用仪器为美国Nicolet公司生产的AVATAR 330型红外光谱仪(KBr压片法)，核磁共振谱(1H NMR，13C NMR)测定所用仪器为瑞士Bruker公司AV-600MHz型核磁共振仪(以CDCl3为溶剂，TMS为内标)。测试数据如下：
I-a:黄色粉状固体；产率89％；熔点:154-155℃；IR:1739(C＝O)；HRMS(ESI),m/z:680.3386[M+H]+(calcd for C40H46N3O7:680.3330)；1H NMR(600MHz,CDCl3)δ:7.29(1H,dd,J＝8.2,2.2Hz),7.13(1H,dd,J＝8.2,2.6Hz),6.90(1H,d,J＝7.4Hz),6.85(1H,d,J＝8.2Hz),6.79(1H,dd,J＝8.2,2.6Hz),6.51(2H,s),6.34(1H,s),6.24(1H,dd,J＝8.2,2.2Hz),5.96(1H,s),3.92(3H,s),3.81(1H,d,J＝7.8Hz),3.74(3H,s),3.72-3.52(3H,m),3.39(3H,s),3.03-3.09(2H,m),3.01-2.86(4H,m),2.80-2.70(3H,m),2.62(3H,s),2.55(1H,d,J＝14.0Hz),2.47(1H,d,J＝15.8Hz),2.35(3H,s),1.07(3H,t,J＝7.2Hz).13C NMR(150MHz,CDCl3)δ:153.8,153.1(C＝O),150.7,149.3,148.7,148.1,147.0,143.1,135.0,132.5,130.5,130.2,130.1,128.3,122.8,122.6,122.1,122.0,120.4,120.2,116.3,112.3,111.5,105.5,63.8,61.3,56.1,56.0,55.7,45.4,43.9,42.6,42.2,41.7,37.1,36.1,25.9,22.1,15.0.
实施例2化合物I-b～I-l的制备
化合物I-b～I-l的合成方法同I-a，其中的乙基异氰酸酯换成对应的R1基团，R1分别为：丙基，异丙基，叔丁基，苯基，邻甲基苯基，间甲基苯基，对甲基苯基，对甲氧基苯基，对氯苯基，对三氟甲基苯基，对三氟甲氧基苯基。所合成的化合物理化性质见下表1。
表1化合物I-a～I-l的理化性质
I-a:黄色粉状固体；产率89％；熔点::154-155℃；IR:1739(C＝O)；HRMS(ESI),m/z:680.3386[M+H]+(calcd for C40H46N3O7:680.3330)；1H NMR(600MHz,CDCl3)δ:7.29(1H,dd,J＝8.2,2.2Hz),7.13(1H,dd,J＝8.2,2.6Hz),6.90(1H,d,J＝7.4Hz),6.85(1H,d,J＝8.2Hz),6.79(1H,dd,J＝8.2,2.6Hz),6.51(2H,s),6.34(1H,s),6.24(1H,dd,J＝8.2,2.2Hz),5.96(1H,s),3.92(3H,s),3.81(1H,d,J＝7.8Hz),3.74(3H,s),3.72-3.52(3H,m),3.39(3H,s),3.03-3.09(2H,m),3.01-2.86(4H,m),2.80-2.70(3H,m),2.62(3H,s),2.55(1H,d,J＝14.0Hz),2.47(1H,d,J＝15.8Hz),2.35(3H,s),1.07(3H,t,J＝7.2Hz).13C NMR(150MHz,CDCl3)δ:153.8,153.1(C＝O),150.7,149.3,148.7,148.1,147.0,143.1,135.0,132.5,130.5,130.2,130.1,128.3,122.8,122.6,122.1,122.0,120.4,120.2,116.3,112.3,111.5,105.5,63.8,61.3,56.1,56.0,55.7,45.4,43.9,42.6,42.2,41.7,37.1,36.1(NH-C),25.9,22.1,15.0(CH2-C).
I-b:黄色粉状固体；产率84％；熔点:135-138℃；IR:1736(C＝O)；HRMS(ESI),m/z:694.3514[M+H]+(calcd for C41H48N3O7:694.3487)；1H NMR(600MHz,CDCl3)δ:7.30(1H,d,J＝8.2Hz),7.12(1H,d,J＝8.0Hz),6.88(1H,d,J＝8.0Hz),6.85(1H,d,J＝6.8Hz),6.78(1H,d,J＝8.0Hz),6.51(2H,s),6.33(1H,s),6.24(1H,d,J＝7.2Hz),5.96(1H,s),3.92(3H,s),3.84-3.76(1H,m),3.73(3H,s),3.55-3.51(1H,m),3.39(3H,s),3.37-3.34(1H,m),3.23-3.19(5H,m),2.98-2.90(5H,m),2.85(1H,d,J＝10.2Hz),2.79-2.69(3H,m),2.60(3H,s),2.55(1H,d,J＝14.0Hz),2.45(1H,d,J＝16.2Hz),2.34(3H,s),1.47-1.38(2H,m),0.87(3H,t,J＝7.4Hz).13C NMR(150MHz,CDCl3)δ:153.8,153.2,150.6,149.3,148.7,148.1,147.0,143.1,135.0,132.5,134.9,130.5,130.1,128.3,122.7,122.1,122.0,116.3,112.3,11.5,105.5,76.8,63.8,61.3,60.4,56.1,556.0,55.7,45.4,43.9(NH-C),43.0,42.6,42.2,41.7,37.3,25.9,23.1(CH3-C),22.1,11.2(CH2-C).
I-c:白色粉状固体；产率83％；熔点:139-141℃；IR:1735(C＝O)；HRMS(ESI),m/z:694.3522[M+H]+(calcd for C41H48N3O7:694.3487)；1H NMR(600MHz,CDCl3)δ:7.29(1H,d,J＝8.1Hz),7.12(1H,d,J＝2.6Hz),6.88(1H,d,J＝9.0Hz),6.84(1H,d,J＝8.2Hz),6.78(1H,dd,J＝8.3,2.6Hz),6.51(2H,d,J＝10.0Hz),6.34(1H,s),6.25(1H,d,J＝7.6Hz),5.95(1H,s),3.92(3H,s),3.80-3.78(1H,m),3.73(3H,s),3.65-3.60(1H,m),3.56-3.50(1H,m),3.37(3H,s),3.23-3.20(1H,m),2.94-2.90(3H,m),2.84(1H,d,J＝11.2Hz),2.77-2.69(4H,m),2.61(3H,s),2.56(1H,d,J＝14.0Hz),2.45(1H,d,J＝15.6Hz),2.34(3H,s),1.08(6H,dd,J＝28.0,6.4Hz).13C NMR(150MHz,CDCl3)δ:153.8(C＝O),152.3,152.3,150.6,149.3,148.6,147.0,143.3,132.5,130.0,122.7,121.9,120.3,116.3,112.5,111.5,105.6,63.8,61.4,60.4,56.1,56.0,55.7,45.5(NH-C),44.0,43.3,42.8,42.2,41.7,37.5,26.0,23.1(CH-C),22.8,22.6.
I-d:白色粉状固体；产率83％；熔点:145-146℃；IR:1750(C＝O)；HRMS(ESI),m/z:708.3676[M+H]+(calcd for C42H50N3O7:708.3643)；1H NMR(600MHz,CDCl3)δ:7.30(1H,dd,J＝8.2,2.2Hz),7.12(1H,dd,J＝8.0,2.6Hz),6.88(1H,dd,J＝8.2,2.0Hz),6.85(1H,d,J＝8.2Hz),6.79(1H,dd,J＝8.2,2.6Hz),6.52(1H,d,J＝1.8Hz),6.50(1H,s),6.32(1H,s),6.27(1H,dd,J＝8.2,2.2Hz),5.95(1H,s),3.92(3H,s),3.80-3.77(1H,m),3.73(s,3H),3.56-3.50(1H,m),3.42-3.40(1H,m),3.39(3H,s),3.56-3.50(1H,m),2.97-2.81(4H,m),2.78-2.68(3H,m),2.62(3H,s),2.57(1H,d,J＝14.0Hz),2.45(1H,dd,J＝15.6,5.2Hz),2.33(3H,s),1.20(9H,s).13C NMR(150MHz,CDCl3)δ:153.8(C＝O),149.3,148.6,147.4,147.1,142.3,138.8,137.1,134.4,132.8,132.5,131.2,130.1,128.8,127.8,124.6,122.9,122.1,122.0,120.4,119.3,116.3,115.8,112.6,112.0,111.5,63.5,61.6,61.1,56.1(NH-C),55.5,45.3,43.6,42.2,42.0,41.2,37.1,29.7,29.3(C-C),25.7,22.8,21.5.
I-e:黄色粉状固体；产率72％；熔点:146-149℃；IR:1735(C＝O)；HRMS(ESI),m/z:728.3363[M+H]+(calcd for C44H46N3O7:728.3330)；1H NMR(600MHz,CDCl3)δ:7.29(2H,d,J＝8.0Hz),7.27(1H,s),7.22(1H,dd,J＝8.2,2.2Hz),7.09(1H,dd,J＝8.0,2.6Hz),7.05-7.03(1H,m),6.90(1H,dd,J＝8.2,1.8Hz),6.85(1H,d,J＝8.2Hz),6.76(1H,dd,J＝8.2,2.6Hz),6.51(1H,d,J＝1.8Hz),6.50(1H,s),6.37(1H,s),6.33(1H,s),6.20(1H,dd,J＝8.2,2.2Hz),5.95(1H,s),3.91(3H,s),3.77(1H,d,J＝9.8Hz),3.74(3H,s),3.64-3.61(1H,m),3.57-3.51(1H,m),3.43(3H,s),3.30-3.26(1H,m),3.14-3.11(1H,m),2.99-2.92(2H,m),2.75-2.67(2H,m),2.54(1H,d,J＝14.0Hz),2.46(1H,dd,J＝15.6,5.0Hz),2.36(6H,s).13C NMR(150MHz,CDCl3)δ:153.7,150.6(C＝O),149.9,149.3,148.7,148.0,147.0,142.9,137.5(ph),135.0,134.9,132.5,131.0,130.1,128.8(ph),128.3(ph),127.7(ph),123.4,122.7,122.0(ph),121.9(ph),120.6,118.6,116.3,112.3,111.5,105.5,63.5,61.3,56.1,56.0,55.7,45.3,43.9,42.3,42.2,41.7,37.4,25.7,22.0.
I-f:黄色粉状固体；产率60％；熔点:152-155℃；IR:1756(C＝O)；HRMS(ESI),m/z:742.3528[M+H]+(calcd for C45H48N3O7:742.3487)；1H NMR(600MHz,CDCl3)δ:7.23(1H,dd,J＝8.2,2.2Hz),7.17(1H,d,J＝7.8Hz),7.09(1H,dd,J＝8.0,2.6Hz),7.06(2H,d,J＝8.2Hz),6.89(1H,dd,J＝8.2,1.8Hz),6.84(1H,d,J＝8.2Hz),6.76(1H,dd,J＝8.2,2.6Hz),6.51(1H,d,J＝1.8Hz),6.50(1H,s),6.36(1H,s),6.20(1H,dd,J＝8.2,2.2Hz),6.18(1H,s),5.95(1H,s),3.91(3H,s),3.76(1H,d,J＝9.8Hz),3.73(3H,s),3.64-3.61(1H,m),3.57-3.51(1H,m),3.42(3H,s),3.32-3.27(1H,m),3.14-3.11(1H,m),2.99-2.91(2H,m),2.74-2.66(5H,m),2.54(1H,d,J＝14.0Hz),2.45(1H,dd,J＝15.8,5.0Hz),2.37(3H,s),2.35(3H,s),2.30(3H,s).13C NMR(150MHz,CDCl3)δ:153.7,150.6,150.0(C＝O),149.3,148.6,148.1,147.0,142.9,135.1,135.0,134.9(ph),132.9,132.5,130.9(ph),130.1(ph),129.3(ph),128.8,128.4,127.8,125.9(ph),122.0,122.7,121.9,120.5,118.7,116.3(ph),112.3,111.5,105.5,63.6,61.3,56.1,56.0,55.7,45.3,43.9,42.4,42.2,41.7,37.6,25.7,22.1,21.0,20.8,14.2(ph-C).
I-g:黄色粉状固体；产率62％；熔点:152-150℃；IR:1754(C＝O)；HRMS(ESI),m/z:742.3524[M+H]+(calcd for C45H48N3O7:742.3487)；1H NMR(600MHz,CDCl3)δ:7.23(1H,dd,J＝8.2,2.2Hz),7.13(1H,d,J＝7.6Hz),7.10(1H,dd,J＝8.0,2.6Hz),7.06(1H,d,J＝8.2Hz),6.90(1H,d,J＝8.0Hz),6.86(2H,t,J＝6.6Hz),6.76(1H,dd,J＝8.2,2.6Hz),6.51(1H,d,J＝1.8Hz),6.50(1H,s),6.20(1H,dd,J＝8.2,2.2Hz),5.96(1H,s),3.92(3H,s),3.77(1H,d,J＝9.4Hz),3.74(3H,s),3.66-3.63(1H,m),3.57-3.52(1H,m),3.43(3H,s),3.32-3.28(1H,m),3.16-3.13(1H,m),3.00-2.92(2H,m),2.75-2.68(2H,m),2.54(1H,d,J＝14.0Hz),2.47(1H,d,J＝16.0Hz),2.37(3H,s),2.36(3H,s),2.31(3H,s).13C NMR(150MHz,CDCl3)δ:153.8,150.6,149.8(C＝O),149.3,148.7,148.0,147.0,143.0,138.7(ph),137.4,135.0(ph),132.5,131.0,130.1,128.8(ph),128.7,127.8,125.4(ph),124.2(ph),122.7,122.0,121.9,120.6,119.1(ph),116.3,115.6,112.3,111.5,105.5,63.6,61.3,56.1,56.0,55.7,45.4,43.9,42.4,42.2,41.7,37.8,25.6,22.1,21.5(ph-C).
I-h:黄色粉状固体；产率62％；熔点:154-155℃；IR:1736(C＝O)；HRMS(ESI),m/z:742.3532[M+H]+(calcd for C45H48N3O7:742.3487)；1H NMR(600MHz,CDCl3)δ:7.24(1H,d,J＝2.2Hz),7.18-7.15(1H,m),7.11(1H,dd,J＝8.0,2.6Hz),7.09(1H,d,J＝7.4Hz),6.89(1H,t,J＝7.4Hz),6.90(1H,dd,J＝8.2,1.8Hz),6.85(1H,d,J＝8.2Hz),6.77(1H,dd,J＝8.2,2.6Hz),6.53(1H,d,J＝1.8Hz),6.48(1H,s),6.37(1H,s),6.20(1H,dd,J＝8.2,2.2Hz),5.98(2H,d,J＝7.6Hz),5.99(1H,s),5.98(1H,s),3.92(3H,s),3.81-3.76(1H,m),3.74(3H,s),3.59-3.53(2H,m),3.44(3H,s),3.26-3.22(1H,m),3.14-3.11(1H,m),3.00-2.91(2H,m),2.76-2.54(6H,m),2.48-2.44(1H,m),2.36(3H,s),2.25(3H,s),2.13(3H,s).13C NMR(150MHz,CDCl3)δ:153.7,150.0(C＝O),149.3,148.5,148.0,147.0,142.8,135.6(ph),135.1,135.0(ph),134.9,132.5,130.9,130.2,130.1(ph),129.0,127.9,126.7,123.8,122.7,122.0,121.9(ph),120.5,116.3,112.4,111.5,105.6,63.6,61.3,56.1,56.055.7,45.3,43.9,42.2,41.7,38.00,37.6,25.6,22.1,21.1(ph-C).
I-i:黄色粉状固体；产率64％；熔点:142-144℃；IR:1744(C＝O)；HRMS(ESI),m/z:758.3468[M+H]+(calcd for C45H48N3O8:758.3436)；1H NMR(600MHz,CDCl3)δ:7.26-7.19(3H,m),7.10(1H,dd,J＝8.0,2.4Hz),6.90(1H,d,J＝8.0Hz),6.85(1H,dd,J＝8.2,1.0Hz),6.81(2H,d,J＝8.6Hz),6.77(1H,dd,J＝8.2,2.6Hz),6.51(2H,d,J＝2.0Hz),6.36(1H,s),6.20(1H,dd,J＝8.2,2.2Hz),5.95(1H,s),3.92(3H,s),3.79(3H,s),3.76(1H,s),3.74(3H,s),3.71-3.64(1H,m),3.54(1H,m),3.43(3H,s),3.30-3.28(1H,m),3.16-3.14(1H,m),2.99-2.92(2H,m),2.81-2.69(6H,m),2.54(1H,d,J＝14.0Hz),2.42(3H,s),2.36(3H,s).13CNMR(150MHz,CDCl3)δ:155.9(ph),153.8,149.3(C＝O),147.0,143.0,135.0,134.7,132.48,130.9,130.7,130.1(ph),128.6,122.9,122.8(ph),122.0,120.6,116.3,114.0(ph),112.3,111.5,105.6,67.1,63.5,61.3,60.4,56.1,55.5(O-C),45.2,43.9,42.3,41.7,37.1,29.7,29.3,26.4,25.7,23.2,23.1,22.1.
I-j:黄色粉状固体；产率67％；熔点:131-132℃；IR:1749(C＝O)；HRMS(ESI),m/z:762.2943[M+H]+(calcd for C44H45ClN3O7:762.2941)；1H NMR(600MHz,CDCl3)δ7.27(1H,s),7.24-7.19(3H,m),7.09(1H,dd,J＝8.0,2.6Hz,),6.90(1H,dd,J＝8.2,1.8Hz),6.84(1H,d,J＝8.2Hz),6.76(1H,dd,J＝8.2,2.6Hz),6.51-6.46(3H,m),6.36(1H,s),6.19(1H,dd,J＝8.3,2.2Hz),5.92(1H,s),3.91(3H,s),3.77(1H,d,J＝9.8Hz),3.73(3H,s),3.70-3.62(1H,m),3.57-3.50(1H,m),3.42(3H,s),3.29-3.22(1H,m),3.14-3.10(1H,m),3.00-2.91(2H,m),2.78-2.67(5H,m),2.52(1H,d,J＝14.0Hz),2.43(3H,s),2.35(3H,s).13C NMR(150MHz,CDCl3)δ:153.7,150.5(C＝O),150.0,149.3,148.7,147.9,147.0,142.8,136.3(ph),135.0,134.8,132.5(ph),131.2,130.1,128.8(ph),128.7,128.5,128.3,127.6(ph),122.7,122.0,121.9,120.5,120.0,116.3,112.2,111.5,105.6,63.4,61.3,60.4,56.1,56.0,55.6,45.1,43.8,42.4,42.2,41.7,36.1,26.0,22.0.
I-k:橙色粉状固体；产率53％；熔点:146-149℃；IR:1735(C＝O)；HRMS(ESI),m/z:796.3234[M+H]+(calcd for C45H45F3N3O7:796.3204)；1H NMR(600MHz,CDCl3)δ:7.52(2H,d,J＝8.4Hz),7.46(2H,d,J＝8.4Hz),7.21(1H,dd,J＝8.2,2.2Hz),7.09(1H,dd,J＝8.0,2.6Hz),6.91(1H,dd,J＝8.2,1.8Hz),6.85(1H,d,J＝8.2Hz),6.76(1H,dd,J＝8.2,2.6Hz),6.50(1H,d,J＝1.8Hz),6.48(1H,s),6.37(1H,s),6.19(1H,dd,J＝8.2,2.2Hz),5.92(1H,s),3.91(3H,s),3.77(1H,d,J＝9.8Hz),3.74(3H,s),3.64-3.61(1H,m),3.56-3.51(1H,m),3.43(3H,s),3.26-3.20(1H,m),3.13-3.10(1H,m),2.97-2.92(3H,m),2.76-2.66(5H,m),2.52(1H,d,J＝14.0Hz),2.42(3H,s),2.36(3H,s).13C NMR(150MHz,CDCl3)δ:153.8,150.5(C＝O),149.9,149.3,148.8,147.8,147.1,142.8,140.9(ph),135.0,134.8,132.5(ph),131.3,130.1,128.7,128.1,127.5,126.0,125.3(ph),125.1,125.0(C-F),123.3,122.9,122.8,122.0(ph),120.0,120.5,118.3,116.3,112.2,111.5,105.6,63.4,61.3,56.1,56.0,55.6,45.1,43.9,42.4,42.2,41.7,35.8,26.1,22.0.
I-l:黄色粉状固体；产率49％；熔点:139-141℃；IR:1737(C＝O)；HRMS(ESI),m/z:812.3189[M+H]+(calcd for C45H45F3N3O8:812.3153)；1H NMR(600MHz,CDCl3)δ:7.40-7.32(2H,m),7.22(1H,dd,J＝8.2,2.2Hz),7.12(2H,d,J＝8.6Hz),7.10(1H,dd,J＝8.0,2.6Hz),6.91(1H,d,J＝8.2Hz),6.85(1H,d,J＝8.2Hz),6.76(1H,dd,J＝8.2,2.6Hz),6.50(1H,d,J＝1.8Hz),6.49(1H,s),6.37(1H,s),6.19(1H,dd,J＝8.2,2.2Hz),5.93(1H,s),3.92(3H,s),3.77(1H,d,J＝11.2Hz),3.74(3H,s),3.64(1H,s),3.56-3.52(1H,m),3.43(3H,s),3.28-3.23(1H,m),3.14-3.11(1H,m),2.99-2.92(2H,m),2.76-2.64(5H,m),2.53(1H,d,J＝14.0Hz),2.47(1H,d,J＝16.4Hz),2.42(3H,s),2.36(3H,s).13C NMR(150MHz,CDCl3)δ:153.8,150.6(C＝O),145.0,149.3,148.8,147.9,147.1(ph),144.7,142.8,136.7,135.0,132.5,131.2(ph),130.1(C-F),127.6,122.8(ph),122.1,121.7,121.4,120.5,119.7,116.3(ph),112.2,111.5,105.6,63.5,61.3,56.1,56.0,55.7,45.2,43.8,42.4,42.2,41.7,22.1.
实施例3抑菌活性初筛试验
供试菌株：小麦赤霉菌(Gibberella zeae)，茶树茎点菌(Phoma adianticola)，茶树拟茎点菌(Phomopsis adianticola)，茶树链格孢菌(Altermaria alternata)，茶树炭疽菌(Colletotrichum fructicola)，茶树拟盘多毛孢菌(Pestalotiopsis theae)。
制作培养基：马铃薯洗净去皮，切块，称取400g于容器中，加水煮沸，并保持微沸15-20min，适度搅拌，停止加热。用三层纱布过滤于烧杯中，加入40g葡萄糖和40g琼脂，搅拌溶解，转入2000mL的容量瓶中定容至2000mL。往10个250mL锥形瓶分别加入滤液198mL，用无菌封口膜包扎，用报纸再次封口，用立式压力蒸汽灭菌器在101℃排空气，121℃下灭菌30min备用。所有需要的培养皿和枪头均在相同条件下灭菌，烘干备用。
配药和接菌：用电子分析天平(0.00001g)称取适量的供试药，加入适量的丙酮溶解，配成10g/L的母液。接菌前，将需要用到的培养皿、枪头、接种针、打孔器等物品提前放入超净工作台内，紫外灭菌30min。取2mL配制好的供试药剂加入到198mL融化的PDA培养基中，混匀，供试药的最终浓度为100mg/L。将加有供试药剂的培养基倒在90mm的玻璃培养皿上，待冷却后，用直径为5mm的打孔器在活化的菌种外围打孔，用接种针将菌饼轻轻挑出置于培养基正中央，盖上盖子，用保鲜膜封好周围缝隙。整个实验以加丙酮的马铃薯琼脂培养基为空白对照组，加有嘧菌酯或乙霉威的实验组为阳性对照组，每一化合物做两个平行对照。
培养与记录：将接好菌和密封好的培养皿放入生化培养箱中，于25±1℃温度条件下培养，直至空白对照组菌落直径长到60mm以上，采用十字交叉法测量菌落直径，做好记录，计算抑制率：I＝[(C-T)]/[(C-0.5)]×100％，其中C代表空白组PDA上真菌生长的直径，T代表药物处理组PDA上真菌的直径，I代表抑制率。其中直径均为2个平行组四个测量结果的平均值。
以平板法(体外菌丝生长速率法)，在100mg/L浓度下初筛测定防己诺林碱-氨基甲酸酯类衍生物I-a～I-l、防己诺林碱、粉防己碱等化合物对茶树链格孢菌、茶树茎点菌、茶树拟茎点菌、茶树拟盘多毛孢菌、茶树炭疽菌和小麦赤霉菌共6种真菌的抑菌活性，以商品化的杀菌剂嘧菌酯和乙霉威为阳性对照物，初筛结果如下表2所示。
表2目标化合物(100mg/L)对真菌的抑制效果
在100mg/L浓度下，化合物I-e，I-g，I-h，I-k对茶树茎点菌的抑制率分别为73.2％，70.2％，70.5％，68.9％，均优于嘧菌酯；化合物I-e，I-g，I-h和I-k对小麦赤霉菌的抑制率分别为68.0％，64.0％，82.8％，68.8％，均优于嘧菌酯，其中I-h对小麦赤霉菌的抑制活性最好，达到82.8％；化合物I-g，I-h，I-k对茶树拟茎点菌的抑制率分别为73.3％，71.3％和79.1％，其中I-k的抑制活性优于嘧菌酯，I-g，I-h的抑制活性与嘧菌酯相当。
实施例4抑菌活性复筛试验
制作培养基和灭菌，点菌，培养和记录等操作同初筛实验，在配制实验用药部分：用电子天平分别称取足量的供试药物，用丙酮作溶剂配制成2×104mg/L的母液，再依次稀释成1×104、5×103、2.5×103、1.25×103mg/L浓度的试样，加入到融溶的PDA培养基后最终浓度梯度为200、100、50、25、12.5mg/L，EC50的计算使用IBM SPSS 22.0版本。
表3筛选出的化合物对6种真菌的EC50
对于小麦赤霉菌，化合物I-e、I-f、I-g、I-h、I-k有非常好的抑制效果，EC50分别为76.6、33.1、56.1、12.5、42.9mg/L，抑制活性优于商品化品种嘧菌酯；对于茶树拟茎点菌，化合物I-d、I-f、I-g、I-h、I-i、I-k的EC50均小于40mg/L，抑制效果明显好于乙霉威，化合物I-g和I-h的活性与嘧菌酯相当。

Claims (6)

1.一种杀菌剂防己诺林碱-氨基甲酸酯类衍生物，其特征在于，该杀菌剂具有如通式(I)所示的结构：
式中R1为烷基或芳基。
2.根据权利要求1所述防己诺林碱-氨基甲酸酯类衍生物，其特征在于，所述的烷基为乙基、丙基、异丙基或叔丁基。
3.根据权利要求1所述防己诺林碱-氨基甲酸酯类衍生物，其特征在于，所述的芳基为苯基、邻甲基苯基、间甲基苯基、对甲基苯基、对甲氧基苯基、对氯苯基、对三氟甲基苯基或对三氟甲氧基苯基。
4.根据权利要求1所述防己诺林碱-氨基甲酸酯类衍生物，其特征在于，式中R1为乙基、丙基、异丙基、叔丁基、苯基、邻甲基苯基、间甲基苯基、对甲基苯基、对甲氧基苯基、对三氟甲基苯基、对三氟甲氧基苯基。
5.权利要求1所述防己诺林碱-氨基甲酸酯类衍生物的制备方法，包括下列反应式所示的步骤：
在上述反应式中：防己诺林碱(II)与烷基或芳基异氰酸酯于室温下在二氯甲烷和三乙胺中经一步加成反应即得到目标化合物(I)。
6.权利要求1至4中任一项所述的防己诺林碱-氨基甲酸酯类衍生物的应用，其特征是作为小麦赤霉菌或茶树拟茎点菌杀菌剂的有效成份。
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