CN116283867A - 氮杂取代苍耳亭或氯代苍耳亭类衍生物及其应用 - Google Patents
氮杂取代苍耳亭或氯代苍耳亭类衍生物及其应用 Download PDFInfo
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- CN116283867A CN116283867A CN202310261782.3A CN202310261782A CN116283867A CN 116283867 A CN116283867 A CN 116283867A CN 202310261782 A CN202310261782 A CN 202310261782A CN 116283867 A CN116283867 A CN 116283867A
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Abstract
本发明涉及氮杂取代苍耳亭或氯代苍耳亭类衍生物及其应用。以苍耳亭为原料，通过不同的化学反应对苍耳亭七元环环外侧链进行多样化的结构修饰，得到具有如下结构通式的苍耳亭类衍生物；抗菌活性测试结果表明衍生物1、8和27对供试植物病原真菌菌丝具有广谱高效的抑制活性，衍生物1、2、8、9、20和27对供试植物病原真菌孢子显示出强烈的抑制萌发作用，故有望用于制备高效、广谱的新型农用抗菌剂。
Description
技术领域
本发明属于杀菌剂合成及其应用技术领域，具体涉及氮杂取代苍耳亭或氯代苍耳亭类衍生物及其制备方法和应用。
背景技术
苍耳亭(Xanthatin)是一种从菊科苍耳属植物苍耳中(Xanthium strumarium L.)分离得到的天然倍半萜内酯类物质，因其具备广泛的生物活性而成为近年来的研究焦点。特别是发现该化合物拥有优良的杀虫和抑菌活性，使其在农业领域的应用具备了一定的前景。其中，文献[孟学英,沈慧敏.苍耳提取物苍耳亭的结构修饰及其杀虫活性测定,甘肃农业学学报,2015,(3):102-112.]报道了苍耳亭及其部分衍生物不仅对二斑叶螨雌成螨有很好的触杀活性，而且对东方粘虫还有良好的触杀、胃毒以及拒食作用。文献[Kawazu K,Nakajima S,Ariwa M.Xanthumin and 8-epi-xanthatin as insect developmentinhibitors from Xanthium canadense Mill.Experientia,1979,35(10):1294-1295.]报道了一个苍耳亭类似物对果蝇幼虫具有生长抑制作用。文献[胡冬燕.苍耳化学成分的分离、鉴定及抑菌活性的研究.甘肃农业大学,2012.]发现苍耳亭对辣椒丝核菌以及番茄灰霉菌均具有一定的抑制生长作用。文献[Saha D,Kumar R,Ghosh S,et al.Control offoliar diseases of tea with Xanthium strumarium leaf extract.IndustrialCrops&Products,2012,37(1):376-382.]研究了苍耳亭对茶叶叶斑病菌、叶枯病菌、褐斑病菌以及灰斑病菌的抗真菌活性，抑制效果最好的是对叶斑病菌，其次是褐斑病菌。文献[Pinel B,Landreau A,Seraphin D,et al.Synthesis of reduced xanthatinderivatives and in vitro evaluation of their antifungal activity.Journal ofEnzyme Inhibition and Medicinal Chemistry,2005,20(6):575-579.]报道了苍耳亭对光滑念珠菌、白色念珠菌、烟曲霉菌的体外抗真菌活性。此外，文献[Zhi X Y,Song L L,Liang J,et al.Synthesis and in vitro antifungal activity of new Michael-typeamino derivatives of xanthatin,a natural sesquiterpene lactone from Xanthiumstrumarium L.Bioorganic&Medicinal Chemistry Letters.2022,55:128481]和文献[ZhiX Y,Jiang L Y,Li T,et al.Natural product-based semisynthesis and biologicalevaluation of thiol/amino-Michael adducts of xanthatin derived from Xanthiumstrumarium as potential pesticidal agents.Bioorganic Chemistry,2020,97:103696.]报道了苍耳亭五元环环外双键修饰得到的产物对部分植物病原真菌孢子显示出较强的抑制萌发活性。
综上可以发现，现阶段尽管已有文献报道了苍耳亭及其部分衍生物的抗菌活性，但是其依然存在抗菌作用较弱，抗菌活性谱较窄，尤其缺乏对苍耳亭七元环环外侧链上羰基修饰的衍生物及其抑菌作用的研究，从而极大地制约了对该类物质及其衍生物抑菌作用的深入研究和开发利用。
发明内容
本发明所要解决的技术问题为：如何提供一种对苍耳亭进行修饰，从而提高苍耳亭衍生物的抑菌活性或广谱性。
本发明的技术方案为：苍耳亭类衍生物或其药学上可接受的盐，所述衍生物具有式Ⅰ所示结构式：
式Ⅰ中，X、R1和Y为以下(1)～(27)组合中的任一种：
(1):X＝N,R1＝OH,Y＝H(E式构型)；
(2):X＝N,R1＝a,Y＝H(E式构型)；
(3):X＝N,R1＝b,Y＝H(E式构型)；
(4):X＝N,R1＝c,Y＝H(E式构型)；
(5):X＝N,R1＝d,Y＝H(E式构型)；
(6):X＝N,R1＝f,Y＝H(E式构型)；
(7):X＝N,R1＝g,Y＝H(E式构型)；
(8):X＝N,R1＝OH,Y＝H(Z式构型)；
(9):X＝N,R1＝a,Y＝H(Z式构型)；
(10):X＝N,R1＝b,Y＝H(Z式构型)；
(11):X＝N,R1＝c,Y＝H(Z式构型)；
(12):X＝N,R1＝d,Y＝H(Z式构型)；
(13):X＝N,R1＝f,Y＝H(Z式构型)；
(14):X＝N,R1＝f,Y＝H(Z式构型)；
(15):X＝N,R1＝g,Y＝H(E式构型)；
(16):X＝N,R1＝h,Y＝H(E式构型)；
(17):X＝N,R1＝i,Y＝H(E式构型)；
(18):X＝N,R1＝j,Y＝H(E式构型)；
(19):X＝N,R1＝k,Y＝H(E式构型)；
(20):X＝N,R1＝g,Y＝H(Z式构型)；
(21):X＝N,R1＝h,Y＝H(Z式构型)；
(22):X＝N,R1＝i,Y＝H(Z式构型)；
(23):X＝N,R1＝j,Y＝H(Z式构型)；
(24):X＝N,R1＝k,Y＝H(Z式构型)；
(25):X＝N,R1＝l,Y＝H(E式构型)；
(26):X＝N,R1＝m,Y＝H(E式构型)；
(27):X＝O,Y＝Cl(E式构型)；
其中，a-m分别为以下基团：
优选地，所述衍生物为以下结构式中的任一种：
苍耳亭类衍生物或其药学上可接受的盐在抗植物病原真菌上的应用。
进一步地，所述植物病原真菌为苹果树腐烂病菌(Cytospora mandshurica)、小麦赤霉病菌(Fusarium graminearum)、番茄早疫病菌(Alternaria solani)、腐皮镰刀病菌(Fusariu m solani)、黄瓜炭疽病菌(Colletotrichum orbiculare)、辣椒枯萎病菌(Fusarium oxysporu m)或番茄灰霉病菌(Botrytis cinerea)中的任一种。
一种制剂，含有上述所述的苍耳亭类衍生物或其药学上可接受的盐。
与现有技术相比，本发明具有以下有益效果：
1、本发明将不同的取代基团导入苍耳亭的七元环环外侧链，从而制备得到了若干结构丰富新颖的苍耳亭类衍生物，填补了对苍耳亭七元环环外侧链系统结构修饰的研究空白，极大地丰富了此类化合物的结构多样性。制备得到的部分苍耳亭类衍生物具有较高的杀菌活性，尤其是衍生物1、8和27对供试植物病原真菌菌丝具有广谱且高效的抑制活性，衍生物1、2、8、9、20和27对部分供试植物病原真菌孢子表现出强烈的抑制萌发作用，上述衍生物具备较大的应用潜力。
2、本发明涉及的部分苍耳亭类衍生物，相比于母体苍耳亭而言其抗菌活性有所提高，从而证实了对苍耳亭的七元环环外侧链进行改造有助于提高此物质的抑菌活性，为进一步深入研究开发该类化合物作为新型农用杀菌剂提供了思路。主要有：衍生物3、5、6、8、10、12、13、25和27对苹果树腐烂病菌具有较强的抑制菌丝生长作用，抑菌作用高于底物苍耳亭；衍生物8和27对小麦赤霉病菌的抑制作用高于母体苍耳亭；衍生物1、8、10、12、25和27对番茄早疫病菌的抑制活性优于苍耳亭；衍生物27对腐皮镰刀病菌菌丝的抑制生长活性高于母体苍耳亭；衍生物1、5、9、11、12、25和27对黄瓜炭疽病菌的抑制活性高于苍耳亭；衍生物1、8、9和27对辣椒枯萎病菌的抑制活性高于苍耳亭。此外，衍生物2、4、9、15和27对腐皮镰刀病菌孢子的抑制萌发作用要强于母体化合物苍耳亭；衍生物1、8、9和20对番茄灰霉病菌孢子的抑制萌发活性优于苍耳亭；衍生物1和8对黄瓜炭疽病菌孢子的抑制萌发活性也高于苍耳亭。
附图说明
图1为化合物1的核磁共振氢谱；
图2为化合物1的核磁共振碳谱；
图3为化合物8的核磁共振氢谱；
图4为化合物8的核磁共振碳谱；
图5为化合物25的核磁共振氢谱；
图6为化合物25的核磁共振碳谱；
图7为化合物27的核磁共振氢谱；
图8为化合物27的核磁共振碳谱。
具体实施方式
下述实施例中的实验方法，如无特殊说明，均为常规方法。下述实施例中所用的试验材料，如无特殊说明，均为从商业渠道购买得到的。
实施例1
本发明的氮杂取代苍耳亭/氯代苍耳亭类衍生物的制备路线及结构表征数据
以下为衍生物1和8的制备路线：
取一定量的苍耳亭(1mmol)和一定量的盐酸羟胺(5mmol)溶于无水乙醇中(6mL)中，室温下搅拌4.5h后反应完全，制备硅胶薄层色谱分离即得到所需目标产物1和8。
反应式如下：
化合物1的理化性质如下：
1)白色固体，熔点123.9-124.5℃，收率44.1％；
2)该化合物的核磁共振图谱特征：
以氘代氯仿为溶剂，TMS为内标，其中各峰归属为：–1H NMR(500MHz,CDCl3):δ＝6.48(d,J＝16.5Hz,1H,2-H),6.32(d,J＝16.5Hz,1H,3-H),6.19(d,J＝3.0Hz,1H,13-H),6.03(dd,J＝3.5,9.0Hz,1H,5-H),5.48(d,J＝3.0Hz,1H,13-H),4.26–4.31(m,1H,8-H),3.12–3.16(m,1H,9-H),2.69–2.75(m,1H,10-H),2.51–2.57(m,1H,7-H),2.34–2.38(m,1H,6-H),2.15–2.21(m,1H,6-H),2.06(s,3H,15-H),1.81–1.87(m,1H,9-H),1.17(d,J＝7.5Hz,3H,14-H).–13CNMR(125MHz,CDCl3):δ＝170.01,156.86,145.31,139.53,138.51,131.57,123.08,118.75,81.88,47.80,36.71,29.12,26.81,18.88,9.75；
3)该化合物的高分辨质谱特征：
采用电喷雾电离：m/z＝262.1448(calcd.262.1443for C15H20NO3,[M+H]+)。
化合物8的理化性质如下：
1)白色固体，熔点171.4-172.3℃，收率42.1％；
2)该化合物的核磁共振图谱特征：
以氘代氯仿为溶剂，TMS为内标，其中各峰归属为：–1H NMR(500MHz,CDCl3):δ＝7.06(d,J＝16.5Hz,1H,2-H),6.53(d,J＝16.5Hz,1H,3-H),6.20(d,J＝3.5Hz,1H,13-H),6.12(dd,J＝3.5,9.5Hz,1H,5-H),5.48(d,J＝3.0Hz,1H,13-H),4.27–4.32(m,1H,8-H),3.20–3.25(m,1H,9-H),2.71–2.77(m,1H,10-H),2.52–2.57(m,1H,7-H),2.36–2.40(m,1H,6-H),2.17–2.23(m,1H,6-H),2.05(s,3H,15-H),1.82–1.88(m,1H,9-H),1.19(d,J＝7.5Hz,3H,14-H).–13CNMR(125MHz,CDCl3):δ＝169.90,153.42,145.81,141.63,139.44,133.76,118.76,114.24,81.80,47.71,36.66,28.97,26.91,18.87,16.99；
3)该化合物的高分辨质谱特征：
采用电喷雾电离：m/z＝262.1444(calcd.262.1443for C15H20NO3,[M+H]+)。
以下为衍生物2-7和9-14的制备路线：
取一定量的化合物1/8(1mmol)，一定量的卤代烃(2mmol)，一定量的氢氧化钠(2mmol)和催化量的碘化钾(0.1mmol)溶于N,N-二甲基甲酰胺中(DMF，2mL)中，冰盐浴下搅拌反应，TLC跟踪检测，反应完全后制备硅胶薄层色谱分离即得到所需目标产物2-7和9-14。
反应式如下：
化合物2-7和9-14与取代基R2的序号一一对应。
化合物2的理化性质如下：
1)白色固体，熔点104.7-105.6℃，收率70.5％；
2)该化合物的核磁共振图谱特征：
以氘代氯仿为溶剂，TMS为内标，其中各峰归属为：–1H NMR(400MHz,CDCl3):δ＝6.46(d,J＝16.0Hz,1H,2-H),6.33(d,J＝16.4Hz,1H,3-H),6.19(d,J＝3.2Hz,1H,13-H),6.02(dd,J＝3.6,9.2Hz,1H,5-H),5.47(d,J＝2.8Hz,1H,13-H),4.25–4.31(m,1H,8-H),3.92(s,3H,-OCH3),3.13–3.19(m,1H,9-H),2.67–2.74(m,1H,10-H),2.50–2.56(m,1H,7-H),2.33–2.38(m,1H,6-H),2.14–2.21(m,1H,6-H),1.99(s,3H,15-H),1.80–1.87(m,1H,9-H),1.16(d,J＝7.2Hz,3H,14-H).–13C NMR(100MHz,CDCl3):δ＝169.96,155.77,145.41,139.53,138.07,131.31,123.24,118.66,81.88,61.84,47.80,36.66,29.05,26.76,18.85,10.23；
3)该化合物的高分辨质谱特征：
采用电喷雾电离：m/z＝276.1597(calcd.276.1600for C16H22NO3,[M+H]+)。
化合物3的理化性质如下：
1)浅黄色固体，熔点70.5-71.4℃，收率34.5％；
2)该化合物的核磁共振图谱特征：
以氘代氯仿为溶剂，TMS为内标，其中各峰归属为：–1H NMR(400MHz,CDCl3):δ＝6.45(d,J＝16.4Hz,1H,2-H),6.35(d,J＝16.4Hz,1H,3-H),6.19(d,J＝3.6Hz,1H,13-H),6.01(dd,J＝3.6,9.2Hz,1H,5-H),5.47(d,J＝2.8Hz,1H,13-H),4.25–4.31(m,1H,8-H),4.14(t,J＝7.2Hz,2H),3.14–3.19(m,1H,9-H),2.67–2.74(m,1H,10-H),2.50–2.56(m,1H,7-H),2.32–2.37(m,1H,6-H),2.13–2.21(m,1H,6-H),2.00(s,3H,15-H),1.79–1.86(m,1H,9-H),1.63–1.70(m,2H),1.38–1.45(m,2H),1.16(d,J＝7.2Hz,3H,14-H),0.96(t,J＝7.6Hz,3H,-CH3).–13C NMR(100MHz,CDCl3):δ＝169.98,155.51,145.49,139.55,137.82,131.14,123.48,118.65,81.91,74.09,47.82,36.66,31.21,29.04,26.75,19.20,18.86,13.93,10.34；
3)该化合物的高分辨质谱特征：
采用电喷雾电离：m/z＝340.1895(calcd.340.1889for C19H27NO3Na,[M+Na]+)。
化合物4的理化性质如下：
1)白色固体，熔点62.9-63.7℃，收率19.8％；
2)该化合物的核磁共振图谱特征：
以氘代氯仿为溶剂，TMS为内标，其中各峰归属为：–1H NMR(400MHz,CDCl3):δ＝6.44(d,J＝16.4Hz,1H,2-H),6.33(d,J＝16.4Hz,1H,3-H),6.19(d,J＝3.2Hz,1H,13-H),6.01(dd,J＝3.2,9.2Hz,1H,5-H),5.47(d,J＝2.8Hz,1H,13-H),4.25–4.31(m,1H,8-H),4.12(t,J＝6.8Hz,2H),3.12–3.19(m,1H,9-H),2.67–2.74(m,1H,10-H),2.50–2.56(m,1H,7-H),2.32–2.37(m,1H,6-H),2.13–2.21(m,1H,6-H),1.99(s,3H,15-H),1.79–1.86(m,1H,9-H),1.64–1.71(m,2H),1.29–1.35(m,6H),1.16(d,J＝7.2Hz,3H,14-H),0.90(t,J＝6.8Hz,3H,-CH3).–13C NMR(100MHz,CDCl3):δ＝169.98,155.44,145.49,139.56,137.68,131.04,123.57,118.65,81.91,74.36,47.83,36.66,31.64,29.09,29.04,26.74,25.65,22.59,18.86,14.03,10.33；
3)该化合物的高分辨质谱特征：
采用电喷雾电离：m/z＝346.2383(calcd.346.2382for C21H32NO3,[M+H]+)。
化合物5的理化性质如下：
1)淡黄色液体，收率20.4％；
2)该化合物的核磁共振图谱特征：
以氘代氯仿为溶剂，TMS为内标，其中各峰归属为：–1H NMR(400MHz,CDCl3):δ＝6.45(d,J＝16.4Hz,1H,2-H),6.34(d,J＝16.4Hz,1H,3-H),6.19(d,J＝3.2Hz,1H,13-H),6.01(dd,J＝3.2,8.8Hz,1H,5-H),5.47(d,J＝3.2Hz,1H,13-H),4.25–4.31(m,1H,8-H),4.21(t,J＝6.4Hz,2H),3.49(t,J＝6.4Hz,2H),3.34(s,3H,-OCH3),3.13–3.19(m,1H,9-H),2.67–2.74(m,1H,10-H),2.50–2.56(m,1H,7-H),2.33–2.38(m,1H,6-H),2.14–2.21(m,1H,6-H),2.00(s,3H,15-H),1.97(t,J＝6.4Hz,2H),1.79–1.87(m,1H,9-H),1.16(d,J＝7.2Hz,3H,14-H).–13C NMR(100MHz,CDCl3):δ＝169.98,155.72,145.46,139.54,137.87,131.18,123.44,118.67,81.90,71.04,69.50,58.65,47.82,36.66,29.43,29.05,26.75,18.86,10.35；
3)该化合物的高分辨质谱特征：
采用电喷雾电离：m/z＝356.1841(calcd.356.1838for C19H27NO4Na,[M+Na]+)。
化合物6的理化性质如下：
1)黄色固体，熔点94.2-95.2℃，收率28.0％；
2)该化合物的核磁共振图谱特征：
以氘代氯仿为溶剂，TMS为内标，其中各峰归属为：–1H NMR(400MHz,CDCl3):δ＝6.45(d,J＝16.0Hz,1H,2-H),6.34(d,J＝16.4Hz,1H,3-H),6.19(d,J＝3.2Hz,1H,13-H),6.01(dd,J＝3.6,9.2Hz,1H,5-H),5.47(d,J＝3.2Hz,1H,13-H),4.25–4.31(m,1H,8-H),3.94(d,J＝7.2Hz,2H),3.14–3.19(m,1H,9-H),2.67–2.74(m,1H,10-H),2.50–2.57(m,1H,7-H),2.33–2.38(m,1H,6-H),2.14–2.21(m,1H,6-H),2.03(s,3H,15-H),1.79–1.87(m,1H,9-H),1.17–1.22(m,1H),1.16(d,J＝7.6Hz,3H,14-H),0.53–0.58(m,2H),0.27–0.31(m,2H).–13C NMR(100MHz,CDCl3):δ＝169.98,155.55,145.48,139.55,137.83,131.12,123.53,118.67,81.91,78.90,47.83,36.66,29.04,26.75,18.87,10.45,10.23,3.04,3.01；
3)该化合物的高分辨质谱特征：
采用电喷雾电离：m/z＝316.1917(calcd.316.1913for C19H26NO3,[M+H]+)。
化合物7的理化性质如下：
1)白色固体，熔点68.5-69.3℃，收率70.2％；
2)该化合物的核磁共振图谱特征：
以氘代氯仿为溶剂，TMS为内标，其中各峰归属为：–1H NMR(500MHz,CDCl3):δ＝7.34–7.38(m,4H,Ar-H),7.28–7.31(m,1H,Ar-H),6.45(d,J＝16.5Hz,1H,2-H),6.33(d,J＝16.5Hz,1H,3-H),6.18(d,J＝3.5Hz,1H,13-H),6.01(dd,J＝3.5,9.5Hz,1H,5-H),5.46(d,J＝3.0Hz,1H,13-H),5.16(s,2H,-OCH2-),4.25–4.30(m,1H,8-H),3.11–3.17(m,1H,9-H),2.67–2.73(m,1H,10-H),2.50–2.55(m,1H,7-H),2.32–2.36(m,1H,6-H),2.13–2.20(m,1H,6-H),2.04(s,3H,15-H),1.79–1.85(m,1H,9-H),1.15(d,J＝7.5Hz,3H,14-H).–13C NMR(125MHz,CDCl3):δ＝169.94,156.26,145.45,139.53,138.17,137.81,131.33,128.37,127.93,127.80,123.31,118.64,81.87,76.08,47.80,36.64,29.03,26.75,18.85,10.58；
3)该化合物的高分辨质谱特征：
采用电喷雾电离：m/z＝352.1916(calcd.352.1913for C22H26NO3,[M+H]+)。
化合物9的理化性质如下：
1)白色固体，熔点113.0-113.8℃，收率40.7％；
2)该化合物的核磁共振图谱特征：
以氘代氯仿为溶剂，TMS为内标，其中各峰归属为：–1H NMR(500MHz,CDCl3):δ＝6.94(d,J＝16.5Hz,1H,2-H),6.50(d,J＝16.5Hz,1H,3-H),6.19(d,J＝3.5Hz,1H,13-H),6.10(dd,J＝3.5,9.5Hz,1H,5-H),5.48(d,J＝3.0Hz,1H,13-H),4.26–4.31(m,1H,8-H),3.89(s,3H,-CH3),3.16–3.22(m,1H,9-H),2.70–2.76(m,1H,10-H),2.51–2.56(m,1H,7-H),2.36–2.39(m,1H,6-H),2.16–2.23(m,1H,6-H),2.03(s,3H,15-H),1.81–1.86(m,1H,9-H),1.18(d,J＝7.5Hz,3H,14-H).–13C NMR(125MHz,CDCl3):δ＝169.89,152.65,145.84,141.55,139.45,133.69,118.76,114.76,81.81,61.59,47.73,36.66,28.92,26.90,18.89,17.00；
3)该化合物的高分辨质谱特征：
采用电喷雾电离：m/z＝276.1604(calcd.276.1600for C16H22NO3,[M+H]+)。
化合物10的理化性质如下：
1)淡黄色液体，收率21.4％；
2)该化合物的核磁共振图谱特征：
以氘代氯仿为溶剂，TMS为内标，其中各峰归属为：–1H NMR(400MHz,CDCl3):δ＝6.96(d,J＝16.4Hz,1H,2-H),6.50(d,J＝16.8Hz,1H,3-H),6.20(d,J＝3.2Hz,1H,13-H),6.10(dd,J＝3.6,9.2Hz,1H,5-H),5.48(d,J＝2.8Hz,1H,13-H),4.26–4.32(m,1H,8-H),4.11(t,J＝6.8Hz,2H),3.15–3.20(m,1H,9-H),2.70–2.77(m,1H,10-H),2.51–2.58(m,1H,7-H),2.36–2.41(m,1H,6-H),2.15–2.23(m,1H,6-H),2.03(s,3H,15-H),1.81–1.88(m,1H,9-H),1.64–1.71(m,2H),1.37–1.45(m,2H),1.18(d,J＝7.2Hz,3H,14-H),0.97(t,J＝7.2Hz,3H,-CH3).–13C NMR(100MHz,CDCl3):δ＝169.91,152.40,145.84,141.39,139.44,133.47,123.55,118.76,114.99,81.81,73.86,47.71,36.68,31.21,28.97,26.91,19.23,17.04,13.98；
3)该化合物的高分辨质谱特征：
采用电喷雾电离：m/z＝318.2074(calcd.318.2069for C19H28NO3,[M+H]+)。
化合物11的理化性质如下：
1)白色固体，熔点51.3-51.9℃，收率20.2％；
2)该化合物的核磁共振图谱特征：
以氘代氯仿为溶剂，TMS为内标，其中各峰归属为：–1H NMR(500MHz,CDCl3):δ＝6.96(d,J＝16.5Hz,1H,2-H),6.50(d,J＝16.5Hz,1H,3-H),6.19(d,J＝3.5Hz,1H,13-H),6.10(dd,J＝3.5,9.5Hz,1H,5-H),5.48(d,J＝3.0Hz,1H,13-H),4.27–4.32(m,1H,8-H),4.10(t,J＝6.5Hz,2H),3.16–3.20(m,1H,9-H),2.70–2.76(m,1H,10-H),2.51–2.56(m,1H,7-H),2.36–2.40(m,1H,6-H),2.16–2.23(m,1H,6-H),2.04(s,3H,15-H),1.82–1.87(m,1H,9-H),1.65–1.71(m,2H),1.30–1.37(m,6H),1.18(d,J＝7.5Hz,3H,14-H),0.90(t,J＝7.0Hz,3H,-CH3).–13C NMR(125MHz,CDCl3):δ＝169.87,152.43,145.84,141.37,139.45,133.47,118.73,115.02,81.79,74.15,47.72,36.68,31.64,29.05,28.97,26.91,25.66,22.60,18.86,17.02,14.01；
3)该化合物的高分辨质谱特征：
采用电喷雾电离：m/z＝346.2381(calcd.346.2382for C21H32NO3,[M+H]+)。
化合物12的理化性质如下：
1)淡黄色液体，收率75.2％；
2)该化合物的核磁共振图谱特征：
以氘代氯仿为溶剂，TMS为内标，其中各峰归属为：–1H NMR(400MHz,CDCl3):δ＝6.95(d,J＝16.4Hz,1H,2-H),6.50(d,J＝16.8Hz,1H,3-H),6.20(d,J＝3.2Hz,1H,13-H),6.10(dd,J＝3.6,9.2Hz,1H,5-H),5.48(d,J＝3.2Hz,1H,13-H),4.26–4.32(m,1H,8-H),4.18(t,J＝6.4Hz,2H),3.50(t,J＝6.4Hz,2H),3.34(s,3H,-OCH3),3.16–3.21(m,1H,9-H),2.70–2.77(m,1H,10-H),2.50–2.57(m,1H,7-H),2.36–2.41(m,1H,6-H),2.16-2.23(m,1H,6-H),2.03(s,3H,15-H),1.93–2.00(m,2H),1.81–1.88(m,1H,9-H),1.18(d,J＝7.6Hz,3H,14-H).–13C NMR(100MHz,CDCl3):δ＝169.90,152.64,145.81,139.43,137.84,133.55,131.16,123.46,118.77,114.93,81.80,69.61,58.64,47.71,36.67,29.43,26.91,18.87,10.35；
3)该化合物的高分辨质谱特征：
采用电喷雾电离：m/z＝356.1835(calcd.356.1838for C19H27NO4Na,[M+Na]+)。
化合物13的理化性质如下：
1)淡黄色固体，熔点102.1-102.7℃，收率24.3％；
2)该化合物的核磁共振图谱特征：
以氘代氯仿为溶剂，TMS为内标，其中各峰归属为：–1H NMR(400MHz,CDCl3):δ＝7.00(d,J＝16.4Hz,1H,2-H),6.51(d,J＝16.4Hz,1H,3-H),6.20(d,J＝3.2Hz,1H,13-H),6.10(dd,J＝3.6,9.2Hz,1H,5-H),5.48(d,J＝3.2Hz,1H,13-H),4.27–4.33(m,1H,8-H),3.92(d,J＝6.8Hz,2H,-OCH2-),3.17–3.24(m,1H,9-H),2.70–2.77(m,1H,10-H),2.51–2.57(m,1H,7-H),2.37–2.41(m,1H,6-H),2.16–2.24(m,1H,6-H),2.04(s,3H,15-H),1.81–1.89(m,1H,9-H),1.14–1.22(m,1H),1.19(d,J＝7.6Hz,3H,14-H),0.53–0.58(m,2H),0.28–0.32(m,2H).–13C NMR(100MHz,CDCl3):δ＝169.91,152.50,145.89,141.46,139.44,133.50,123.55,118.76,115.05,81.83,78.68,47.73,36.67,28.95,26.90,18.89,17.09,10.27,3.08；
3)该化合物的高分辨质谱特征：
采用电喷雾电离：m/z＝316.1909(calcd.316.1913for C19H26NO3,[M+H]+)。
化合物14的理化性质如下：
1)淡黄色液体，收率37.9％；
2)该化合物的核磁共振图谱特征：
以氘代氯仿为溶剂，TMS为内标，其中各峰归属为：–1H NMR(500MHz,CDCl3):δ＝7.34–7.39(m,4H,Ar-H),7.29–7.32(m,1H,Ar-H),6.99(d,J＝16.5Hz,1H,2-H),6.50(d,J＝16.5Hz,1H,3-H),6.19(d,J＝3.5Hz,1H,13-H),5.98–6.09(m,1H),5.47(d,J＝3.0Hz,1H,13-H),5.14(s,2H,-OCH2-),4.25–4.30(m,1H,8-H),3.15–3.17(m,1H,9-H),2.67–2.75(m,1H,10-H),2.50–2.55(m,1H,7-H),2.33–2.37(m,1H,6-H),2.16–2.22(m,1H,6-H),2.04(s,3H,15-H),1.80–1.85(m,1H,9-H),1.16(d,J＝7.0Hz,3H,14-H).–13C NMR(125MHz,CDCl3):δ＝169.92,153.20,145.84,141.77,139.45,138.01,133.77,131.37,128.39,128.08,123.35,118.79,115.00,81.82,75.89,47.72,36.67,28.95,26.93,18.90,17.09,10.62；
3)该化合物的高分辨质谱特征：
采用电喷雾电离：m/z＝352.1911(calcd.352.1913for C22H26NO3,[M+H]+)。
以下为衍生物15-19和20-24的制备路线：
取一定量的化合物1/8(1mmol)和相应的取代芳香异氰酸酯(1.2mmol)溶于丙酮中(2mL)中，56℃下搅拌反应，TLC跟踪检测，反应完全后制备硅胶薄层色谱分离即得到所需目标产物15-19和20-24。
反应式如下：
化合物15-19和20-24与取代基R3的序号一一对应。
化合物15的理化性质如下：
1)白色固体，熔点62.1-63.0℃，收率77.4％；
2)该化合物的核磁共振图谱特征：
以氘代氯仿为溶剂，TMS为内标，其中各峰归属为：–1H NMR(500MHz,CDCl3):δ＝8.23(s,1H,-NH-),7.31–7.34(m,2H,Ar-H),7.24(t,J＝7.5Hz,1H,Ar-H),6.95(d,J＝7.5Hz,1H,Ar-H),6.69(d,J＝16.5Hz,1H,2-H),6.40(d,J＝16.5Hz,1H,3-H),6.21(d,J＝3.5Hz,1H,13-H),6.15(dd,J＝3.5,9.0Hz,1H,5-H),5.50(d,J＝3.0Hz,1H,13-H),4.28–4.33(m,1H,8-H),3.17–3.21(m,1H,9-H),2.74–2.80(m,1H,10-H),2.53–2.58(m,1H,7-H),2.38–2.42(m,1H,6-H),2.36(s,3H,-CH3),2.21–2.25(m,4H,6-H and 15-H),1.85–1.90(m,1H,9-H),1.21(d,J＝7.5Hz,3H,14-H).–13C NMR(125MHz,CDCl3):δ＝169.83,160.55,151.98,145.04,142.67,139.32,139.09,136.96,134.22,128.96,125.08,121.25,120.23,118.93,116.71,81.65,47.67,36.69,29.1226.94,21.53,18.93,11.95；
3)该化合物的高分辨质谱特征：
采用电喷雾电离：m/z＝417.1790(calcd.417.1790for C23H26N2O4Na,[M+Na]+)。
化合物16的理化性质如下：
1)淡黄色固体，熔点74.1-75.0℃，收率71.5％；
2)该化合物的核磁共振图谱特征：
以氘代氯仿为溶剂，TMS为内标，其中各峰归属为：–1H NMR(500MHz,CDCl3):δ＝8.20(s,1H,-NH-),7.40(s,1H,Ar-H),7.38(s,1H,Ar-H),7.15(s,1H,Ar-H),7.14(s,1H,Ar-H),6.68(d,J＝16.5Hz,1H,2-H),6.40(d,J＝16.5Hz,1H,3-H),6.21(d,J＝3.5Hz,1H,13-H),6.14(dd,J＝3.5,9.5Hz,1H,5-H),5.49(d,J＝3.0Hz,1H,13-H),4.28–4.33(m,1H,8-H),3.17–3.21(m,1H,9-H),2.74–2.79(m,1H,10-H),2.53–2.58(m,1H,7-H),2.38–2.42(m,1H,6-H),2.32(s,3H,-CH3),2.22(s,3H),2.19–2.25(m,1H),1.84–1.90(m,1H,9-H),1.21(d,J＝7.5Hz,3H,14-H).–13C NMR(125MHz,CDCl3):δ＝169.80,160.49,152.11,145.02,142.59,139.30,134.44,134.15,133.87,129.61,121.26,119.72,118.89,81.62,47.64,36.66,29.09,26.91,20.82,18.89,11.89；
3)该化合物的高分辨质谱特征：
采用电喷雾电离：m/z＝417.1790(calcd.417.1790for C23H26N2O4Na,[M+Na]+)。
化合物17的理化性质如下：
1)淡黄色固体，熔点66.9-67.8℃，收率77.5％；
2)该化合物的核磁共振图谱特征：
以氘代氯仿为溶剂，TMS为内标，其中各峰归属为：–1H NMR(400MHz,CDCl3):δ＝8.15(s,1H,-NH-),7.42(s,1H,Ar-H),7.40(s,1H,Ar-H),6.89(s,1H,Ar-H),6.87(s,1H,Ar-H),6.68(d,J＝16.4Hz,1H,2-H),6.40(d,J＝16.0Hz,1H,3-H),6.20(d,J＝3.6Hz,1H,13-H),6.14(dd,J＝3.2,9.2Hz,1H,5-H),5.49(d,J＝2.8Hz,1H,13-H),4.27–4.33(m,1H,8-H),3.80(s,3H,-OCH3),3.14–3.20(m,1H,9-H),2.73–2.80(m,1H,10-H),2.52–2.58(m,1H,7-H),2.37–2.42(m,1H,6-H),2.22(s,3H),2.19–2.25(m,1H),1.83–1.90(m,1H,9-H),1.21(d,J＝7.6Hz,3H,14-H).–13C NMR(100MHz,CDCl3):δ＝169.82,160.50,156.52,152.47,145.01,142.58,139.30,134.15,130.06,121.64,121.25,118.90,114.29,81.63,55.51,53.45,47.64,36.66,29.10,26.91,18.89,11.88；
3)该化合物的高分辨质谱特征：
采用电喷雾电离：m/z＝433.1721(calcd.433.1734for C23H26N2O5Na,[M+Na]+)。
化合物18的理化性质如下：
1)淡黄色固体，熔点79.8-81.4℃，收率70.0％；
2)该化合物的核磁共振图谱特征：
以氘代氯仿为溶剂，TMS为内标，其中各峰归属为：–1H NMR(500MHz,CDCl3):δ＝8.19(s,1H,-NH-),7.14(s,2H,Ar-H),6.76(s,1H,Ar-H),6.68(d,J＝16.0Hz,1H,2-H),6.39(d,J＝16.5Hz,1H,3-H),6.21(d,J＝3.0Hz,1H,13-H),6.14(dd,J＝3.0,9.0Hz,1H,5-H),5.49(d,J＝3.0Hz,1H,13-H),4.28–4.32(m,1H,8-H),3.17–3.21(m,1H,9-H),2.73–2.79(m,1H,10-H),2.53–2.58(m,1H,7-H),2.38–2.42(m,1H,6-H),2.31(s,6H,Ar-(CH 3)2),2.22(s,3H),2.18–2.25(m,1H),1.84–1.90(m,1H,9-H),1.21(d,J＝7.5Hz,3H,14-H).–13C NMR(125MHz,CDCl3):δ＝169.81,160.46,151.94,145.04,142.61,139.34,138.86,136.88,134.16,126.01,121.29,118.89,117.35,81.64,47.67,36.69,29.14,26.94,21.40,18.92,11.93；
3)该化合物的高分辨质谱特征：
采用电喷雾电离：m/z＝431.1949(calcd.431.1947for C24H28N2O4Na,[M+Na]+)。
化合物19的理化性质如下：
1)白色固体，熔点70.4-71.2℃，收率40.0％；
2)该化合物的核磁共振图谱特征：
以氘代氯仿为溶剂，TMS为内标，其中各峰归属为：–1H NMR(400MHz,CDCl3):δ＝8.28(s,1H,-NH-),7.48(s,1H,Ar-H),7.46(s,1H,Ar-H),7.32(s,1H,Ar-H),7.30(s,1H,Ar-H),6.70(d,J＝16.4Hz,1H,2-H),6.39(d,J＝16.4Hz,1H,3-H),6.21(d,J＝3.2Hz,1H,13-H),6.16(dd,J＝3.2,9.2Hz,1H,5-H),5.50(d,J＝3.2Hz,1H,13-H),4.27–4.33(m,1H,8-H),3.15–3.20(m,1H,9-H),2.73–2.81(m,1H,10-H),2.53–2.59(m,1H,7-H),2.38–2.43(m,1H,6-H),2.23(s,3H),2.18–2.26(m,1H),1.84–1.91(m,1H,9-H),1.21(d,J＝7.2Hz,3H,14-H).–13C NMR(100MHz,CDCl3):δ＝169.79,160.88,151.89,144.98,142.95,139.26,135.67,134.43,129.13,120.99,120.80,118.93,81.59,47.62,36.66,29.11,26.93,18.89,11.94；
3)该化合物的高分辨质谱特征：
采用电喷雾电离：m/z＝437.1250(calcd.437.1244for C22H23N2O4 35ClNa,[M+Na]+)；439.1236(calcd.439.1215for C22H23N2O4 37ClNa,[M+Na]+)。
化合物20的理化性质如下：
1)白色固体，熔点60.3-61.2℃，收率66.3％；
2)该化合物的核磁共振图谱特征：
以氘代氯仿为溶剂，TMS为内标，其中各峰归属为：–1H NMR(500MHz,CDCl3):δ＝8.36(s,1H,-NH-),7.30–7.34(m,2H,Ar-H),7.24(t,J＝7.5Hz,1H,Ar-H),7.05(d,J＝16.0Hz,1H,2-H),6.94(d,J＝7.5Hz,1H,Ar-H),6.68(d,J＝16.5Hz,1H,3-H),6.20–6.21(m,2H),5.48(d,J＝3.0Hz,1H,13-H),4.28–4.32(m,1H,8-H),3.23–3.25(m,1H,9-H),2.74–2.79(m,1H,10-H),2.51–2.56(m,1H,7-H),2.38–2.42(m,1H,6-H),2.36(s,3H,-CH3),2.23(s,1H),2.19(s,3H,-CH3),1.81–1.87(m,1H,9-H),1.18(d,J＝7.5Hz,3H,14-H).–13C NMR(125MHz,CDCl3):δ＝169.75,157.21,152.17,145.49,142.64,139.28,136.46,134.19,128.91,125.03,121.21,118.81,116.78,114.37,81.62,47.55,36.49,28.83,27.00,21.49,18.87,17.17,11.91；
3)该化合物的高分辨质谱特征：
采用电喷雾电离：m/z＝395.1970(calcd.395.1971for C23H27N2O4,[M+H]+)。
化合物21的理化性质如下：
1)白色固体，熔点85.3-85.9℃，收率66.3％；
2)该化合物的核磁共振图谱特征：
以氘代氯仿为溶剂，TMS为内标，其中各峰归属为：–1H NMR(500MHz,CDCl3):δ＝8.33(s,1H,-NH-),7.39(s,1H,Ar-H),7.38(s,1H,Ar-H),7.16(s,1H,Ar-H),7.14(s,1H,Ar-H),7.05(d,J＝16.0Hz,1H,2-H),6.67(d,J＝16.5Hz,1H,3-H),6.21(s,1H),6.20(s,1H),5.48(d,J＝2.5Hz,1H,13-H),4.28–4.32(m,1H,8-H),3.19–3.24(m,1H,9-H),2.74–2.79(m,1H,10-H),2.51–2.56(m,1H,7-H),2.38–2.42(m,1H,6-H),2.32(s,3H,-CH3),2.22–2.26(m,1H,6-H),2.19(s,3H,15-H),1.81–1.86(m,1H,9-H),1.18(d,J＝7.5Hz,3H,14-H).–13C NMR(125MHz,CDCl3):δ＝169.75,157.18,152.33,145.64,145.44,139.28,136.44,134.49,133.85,129.59,119.81,118.81,114.38,81.62,47.55,36.49,28.81,26.99,20.83,18.86,17.17；
3)该化合物的高分辨质谱特征：
采用电喷雾电离：m/z＝417.1791(calcd.417.1790for C23H26N2O4Na,[M+Na]+)。
化合物22的理化性质如下：
1)淡黄色固体，熔点68.5-69.3℃，收率45.5％；
2)该化合物的核磁共振图谱特征：
以氘代氯仿为溶剂，TMS为内标，其中各峰归属为：–1H NMR(500MHz,CDCl3):δ＝8.26(s,1H,-NH-),7.41(s,1H,Ar-H),7.40(s,1H,Ar-H),7.06(d,J＝16.5Hz,1H,2-H),6.90(s,1H,Ar-H),6.88(s,1H,Ar-H),6.67(d,J＝16.5Hz,1H,3-H),6.20(s,1H,Ar-H),6.19(s,1H),5.48(d,J＝3.5Hz,1H,13-H),4.27–4.32(m,1H,8-H),3.80(s,3H,-OCH3),3.24(s,1H,9-H),2.74–2.79(m,1H,10-H),2.51–2.56(m,1H,7-H),2.39–2.41(m,1H,6-H),2.22–2.26(m,1H,6-H),2.19(s,3H,15-H),1.81–1.86(m,1H,9-H),1.18(d,J＝7.5Hz,3H,14-H).–13CNMR(125MHz,CDCl3):δ＝169.74,157.16,156.53,152.68,145.66,145.42,139.29,136.41,130.10,121.75,118.80,114.40,114.29,81.62,55.51,47.55,36.49,28.83,27.00,18.86,17.16；
3)该化合物的高分辨质谱特征：
采用电喷雾电离：m/z＝433.1740(calcd.433.1739for C23H26N2O5Na,[M+Na]+)。
化合物23的理化性质如下：
1)淡黄色固体，熔点72.9-73.6℃，收率77.4％；
2)该化合物的核磁共振图谱特征：
以氘代氯仿为溶剂，TMS为内标，其中各峰归属为：–1H NMR(500MHz,CDCl3):δ＝8.32(s,1H,-NH-),7.14(s,2H,Ar-H),7.05(d,J＝16.0Hz,1H,2-H),6.77(s,1H,Ar-H),6.68(dd,J＝3.2,16.5Hz,1H,5-H),6.21(s,1H),6.20(s,1H),5.49(d,J＝3.0Hz,1H,13-H),4.28–4.33(m,1H,8-H),3.24–3.25(m,1H,9-H),2.74–2.79(m,1H,10-H),2.51–2.56(m,1H,7-H),2.39–2.42(m,1H,6-H),2.31(s,6H,Ar-(CH3)2),2.22(s,1H,6-H),2.19(s,3H,15-H),1.81–1.88(m,1H,9-H),1.18(d,J＝7.5Hz,3H,14-H).–13C NMR(125MHz,CDCl3):δ＝169.76,160.43,157.11,152.15,145.45,142.59,139.28,138.82,136.43,134.17,125.97,121.23,118.82,117.42,114.39,81.63,47.55,36.48,28.81,26.99,21.38,18.87,17.17,11.91；
3)该化合物的高分辨质谱特征：
采用电喷雾电离：m/z＝409.2127(calcd.409.2127for C24H29N2O4,[M+H]+)。
化合物24的理化性质如下：
1)白色固体，熔点61.6-62.5℃，收率90.0％；
2)该化合物的核磁共振图谱特征：
以氘代氯仿为溶剂，TMS为内标，其中各峰归属为：–1H NMR(500MHz,CDCl3):δ＝8.42(s,1H,-NH-),7.48(s,1H,Ar-H),7.46(s,1H,Ar-H),7.31(s,1H,Ar-H),7.30(s,1H,Ar-H),7.03(d,J＝16.0Hz,1H,2-H),6.69(d,J＝16.0Hz,1H,3-H),6.22(s,1H),6.20(s,1H),5.49(d,J＝3.0Hz,1H,13-H),4.28–4.33(m,1H,8-H),3.22–3.24(m,1H,9-H),2.74–2.80(m,1H,10-H),2.52–2.56(m,1H,7-H),2.39–2.42(m,1H,6-H),2.23(s,1H,6-H),2.19(s,3H,15-H),1.81–1.87(m,1H,9-H),1.18(d,J＝7.5Hz,3H,14-H).–13C NMR(125MHz,CDCl3):δ＝169.71,157.55,152.07,145.79,145.62,142.93,139.27,136.70,135.75,134.41,129.11,120.88,118.83,114.24,81.58,47.55,36.51,28.87,27.03,18.87,17.15,11.94；
3)该化合物的高分辨质谱特征：
采用电喷雾电离：m/z＝415.1427(calcd.415.1425for C22H24N2O4 35Cl,[M+H]+)；417.1407(calcd.417.1395for C22H24N2O4 37Cl,[M+H]+)。
以下为衍生物25和26的制备路线：
取一定量的苍耳亭(1mmol)和硫代氨基脲(1mmol)溶于无水乙醇中(5mL)中，滴加两滴冰乙酸，80℃下搅拌反应3.5h，之后通过制备硅胶薄层色谱分离即得到所需目标产物25；
取一定量的化合物25(1mmol)和2-溴苯乙酮(1.2mmol)溶于无水乙醇中(3mL)中，75℃下搅拌反应0.5h，之后通过制备硅胶薄层色谱分离即得到所需目标产物26。
反应式如下：
化合物25的理化性质如下：
1)淡黄色固体，熔点112.1-113.0℃，收率91.8％；
2)该化合物的核磁共振图谱特征：
以氘代氯仿为溶剂，TMS为内标，其中各峰归属为：–1H NMR(400MHz,CDCl3):δ＝8.75(s,1H,-NH-),7.30(s,1H),6.57(d,J＝16.4Hz,1H,2-H),6.47(s,1H),6.32(d,J＝16.0Hz,1H,3-H),6.20(d,J＝3.2Hz,1H,13-H),6.09(dd,J＝3.2,9.2Hz,1H,5-H),5.49(d,J＝2.8Hz,1H,13-H),4.26–4.33(m,1H,8-H),3.11–3.18(m,1H,9-H),2.71–2.78(m,1H,10-H),2.52–2.58(m,1H,7-H),2.36–2.41(m,1H,6-H),2.16–2.24(m,1H,6-H),2.05(s,3H,15-H),1.82–1.89(m,1H,9-H),1.19(d,J＝7.2Hz,3H,14-H).–13C NMR(100MHz,CDCl3):δ＝178.67,169.87,148.91,145.22,140.29,139.35,132.98,125.37,118.85,81.71,47.70,36.66,29.13,26.88,18.89,11.54；
3)该化合物的高分辨质谱特征：
采用电喷雾电离：m/z＝320.1434(calcd.320.1433for C16H22N3O2S,[M+H]+)。
化合物26的理化性质如下：
1)橘色固体，熔点110.1-111.0℃，收率31.7％；
2)该化合物的核磁共振图谱特征：
以氘代氯仿为溶剂，TMS为内标，其中各峰归属为：–1H NMR(400MHz,CDCl3):δ＝7.75(d,J＝1.2Hz,1H,Ar-H),7.73(s,1H,Ar-H),7.39–7.43(m,2H,Ar-H),7.31–7.34(m,1H,Ar-H),6.83(s,1H),6.41–6.50(m,2H),6.20(d,J＝3.2Hz,1H,13-H),6.06(dd,J＝3.2,9.2Hz,1H,5-H),5.48(d,J＝2.8Hz,1H,13-H),4.27–4.33(m,1H,8-H),3.19–3.25(m,1H,9-H),2.69–2.76(m,1H,10-H),2.52–2.58(m,1H,7-H),2.37–2.42(m,1H,6-H),2.16–2.24(m,1H,6-H),2.09(s,3H,15-H),1.82–1.89(m,1H,9-H),1.20(d,J＝7.2Hz,3H,14-H).–13C NMR(100MHz,CDCl3):δ＝169.97,169.34,150.25,148.72,145.54,139.51,137.68,131.50,128.75,128.13,125.96,118.71,103.45,81.90,47.84,36.67,29.70,29.09,26.80,21.34,18.92,11.68；
3)该化合物的高分辨质谱特征：
采用电喷雾电离：m/z＝420.1739(calcd.420.1740for C24H26N3O2S,[M+H]+)。
以下为衍生物27的制备路线：
取一定量的苍耳亭(1mmol)和N-氯代丁二酰亚胺(NCS，2mmol)溶于无水四氢呋喃中(THF，3mL)中，70℃下搅拌反应3h，之后通过制备硅胶薄层色谱分离即得到所需目标产物27；
反应式如下：
化合物27的理化性质如下：
1)橙色蜡状液体，收率67.1％；
2)该化合物的核磁共振图谱特征：
以氘代氯仿为溶剂，TMS为内标，其中各峰归属为：–1H NMR(400MHz,CDCl3):δ＝7.27(s,1H,2-H),6.31(dd,J＝3.2,8.4Hz,1H,5-H),6.21(d,J＝3.2Hz,1H,13-H),5.50(d,J＝2.8Hz,1H,13-H),4.27–4.33(m,1H,8-H),2.98–3.04(m,1H,9-H),2.76–2.83(m,1H,10-H),2.62–2.68(m,1H,7-H),2.46(s,3H,15-H),2.31–2.38(m,1H,6-H),2.20–2.26(m,1H,6-H),1.90–1.97(m,1H,9-H),1.20(d,J＝7.6Hz,3H,14-H).–13C NMR(100MHz,CDCl3):δ＝193.34,169.78,141.47,139.45,133.30,129.98,119.02,81.41,47.07,36.85,33.01,29.70,27.10,26.92,18.93；
3)该化合物的高分辨质谱特征：
采用电喷雾电离：m/z＝303.0771(calcd.303.0764for C15H17 35ClO3Na,[M+Na]+)；305.0742(calcd.305.0735for C15H17 37ClO3Na,[M+Na]+)。
实施例2
本发明的抗菌活性测定试验：
本实施例为实施例1制备得到的氮杂取代苍耳亭/氯代苍耳亭类衍生物(1-27)的抗菌活性试验：
1、供试植物病原真菌：苹果树腐烂病菌(Cytospora mandshurica)、小麦赤霉病菌(Fusarium graminearum)、番茄早疫病菌(Alternaria solani)、腐皮镰刀病菌(Fusariumsolani)、黄瓜炭疽病菌(Colletotrichum orbiculare)、辣椒枯萎病菌(Fusariumoxysporum)以及番茄灰霉病菌(Botrytis cinerea)。
2、供试样品及试剂：
供试样品：实施例1制备得到的氮杂取代苍耳亭/氯代苍耳亭类衍生物1-27；
对照药剂：原料苍耳亭(xanthatin)、99％恶霉灵原药、98％吡唑醚菌酯原药和98％苯醚甲环唑原药；
溶剂：DMSO(二甲基亚砜，色谱纯)、丙酮(分析纯)，乳化剂为吐温-80(优级纯)。
3、抗菌活性测试方法及结果：
(1)采用菌丝生长速率测定法测试实施例1制备得到的苍耳亭七元环环外侧链修饰衍生物对六种植物病原真菌菌丝生长的抑制效果：将所有供试样品用丙酮溶解后同融化的PDA培养基混匀，倒入无菌培养皿中，每皿约15mL，制成浓度为100μg/mL的含药培养基(含药培养基中丙酮的含量不超过0.5％，v/v)。待培养基冷却凝固后，将事先活化好的供试菌种沿菌落边缘打制成直径为4mm的菌饼，接种于含药培养基的正中央，每个药剂重复3次，同时设置不含药剂的空白对照试验。适宜温度下培养至空白对照组菌落直径达到培养皿直径的2/3时为止，采用十字交叉法测量各处理组和对照组的菌落直径，依照公式-1计算各药剂处理组的菌丝生长抑制率，同时计算相应的标准偏差等。测定结果见表-1所示。
菌丝生长抑制率＝(对照组平均菌落直径-处理组平均菌落直径)/(对照组平均菌落直径-4mm)×100％(公式-1)
表-1氮杂取代苍耳亭/氯代苍耳亭类衍生物(1-27)对六种植物病原真菌菌丝生长的抑制活性
由表-1可以发现，抑制菌丝生长试验中，在100μg/mL的供试浓度下，衍生物3、5、6、8、10、12、13、25和27对苹果树腐烂病菌显示出强烈的抑制菌丝生长作用，其抑菌率均大于90％，优于阳性对照药剂恶霉灵，且与阳性对照药剂吡唑醚菌酯的抑菌率相当；衍生物8和27对小麦赤霉病菌的抑菌活性最为突出，其抑菌率高于两种阳性对照药剂；衍生物27对腐皮镰刀病菌的抑制率高达94％左右，优于母体苍耳亭和阳性对照药剂恶霉灵及吡唑醚菌酯；衍生物1、8、11和27对黄瓜炭疽病菌的抑菌活性较为突出，其抑菌率优于苍耳亭和恶霉灵，尤其是衍生物27的抑菌率高达100％，与对照药剂吡唑醚菌酯相当；此外，1、8和27对辣椒枯萎病菌的抑菌率较高，特别是化合物27的抑菌活性远高于母体苍耳亭和两种阳性对照药剂。
综上可以发现，大多数供试衍生物对苹果树腐烂病菌均表现出了一定的抑制作用，尤其以衍生物1、8及27的抑菌活性最为突出，其对6种供试植物病原真菌菌丝均显示出较强的抑制生长作用，说明其具备广谱且高效的抑菌作用，故有望进一步开发用于制备新型农用抗菌剂。
(2)采用孢子萌发法测试实施例1中制备得到的苍耳亭七元环环外侧链修饰衍生物对四种植物病原真菌孢子的抑制萌发活性：a.孢子悬浮液的制备：将病原菌在25±1℃下，在PDA培养基上培养2周，然后刮刀将菌落轻轻刮下，无菌水冲洗，双层纱布过滤除去菌丝和培养基，无菌水反复洗涤3次，最终用无菌水稀释到所需孢子浓度(100倍显微镜下，每个视野大约有20-40个孢子)即可；b.药剂配制：将待测样品溶解于一定量的DMSO中，用0.1％的吐温-80无菌水溶液稀释制备1mg/mL原液，再根据药剂活性，设置5-7个系列质量浓度，有机溶剂最终含量不超过2％(v/v)；c.药剂处理：将配制好的样品溶液与孢子悬浮液等体积混合均匀得到所需的最终浓度。以2％DMSO加0.1％的吐温-80无菌水溶液作为对照组。用微量加样器吸取上述混合液滴于凹玻片中，放于带有浅层水的培养皿中，加盖后置于适宜温度的培养箱中培养。显微镜下观察载玻片上孢子的萌发情况。待孢子萌发后的芽管大于孢子短径时，即为萌发，当空白对照的孢子萌发率大于90％时，观察并计算各处理组的孢子萌发率(公式-2)，同时采用公式-3计算各处理组的校正孢子萌发抑制率，并求出各化合物的抑制中浓度，95％的置信区间等，测定结果见表-2。
孢子萌发率＝萌发孢子数/统计孢子总数×100％(公式-2)；
校正孢子萌发抑制率＝(对照组平均孢子萌发率-处理组平均孢子萌发率)/对照组平均孢子萌发率×100％(公式-3)。
表-2氮杂取代苍耳亭/氯代苍耳亭类衍生物(1-27)对四种植物病原真菌孢子的抑制萌发作用
通过表-2结果可得知，衍生物2、9和27对腐皮镰刀病菌孢子的抑制萌发作用尤为强烈，其抑制中浓度分别为31.75、11.06和18.79μg/mL-1，抑制活性高于母体苍耳亭，且远远高于阳性对照药剂苯醚甲环唑；衍生物1、2、8、9及20对番茄灰霉病菌孢子的抑制萌发作用较强，特别是衍生物1对番茄灰霉病菌孢子的抑制萌发中浓度仅有1.11μg/mL-1，远优于商品化的阳性对照药剂苯醚甲环唑，具有强大的应用潜质；衍生物1、2、8、9及20对黄瓜炭疽病菌孢子的抑制中浓度分别为17.09、61.07、14.89、28.39和63.39μg/mL-1，抑制活性均高于苯醚甲环唑。综上可以得出，本发明制备的部分苍耳亭七元环环外侧链修饰衍生物对植物病原真菌孢子具有较强的抑制萌发活性，特别是衍生物1、2、8、9、20和27显示出了高效广谱的抑制作用，从而有望用于制备成新型农用真菌孢子萌发抑制剂。
Claims (5)
1.苍耳亭类衍生物或其药学上可接受的盐，其特征在于，所述衍生物具有式Ⅰ所示结构式：
式Ⅰ中，X、R1和Y为以下(1)～(27)组合中的任一种：
(1):X＝N,R1＝OH,Y＝H(E式构型)；
(2):X＝N,R1＝a,Y＝H(E式构型)；
(3):X＝N,R1＝b,Y＝H(E式构型)；
(4):X＝N,R1＝c,Y＝H(E式构型)；
(5):X＝N,R1＝d,Y＝H(E式构型)；
(6):X＝N,R1＝f,Y＝H(E式构型)；
(7):X＝N,R1＝g,Y＝H(E式构型)；
(8):X＝N,R1＝OH,Y＝H(Z式构型)；
(9):X＝N,R1＝a,Y＝H(Z式构型)；
(10):X＝N,R1＝b,Y＝H(Z式构型)；
(11):X＝N,R1＝c,Y＝H(Z式构型)；
(12):X＝N,R1＝d,Y＝H(Z式构型)；
(13):X＝N,R1＝f,Y＝H(Z式构型)；
(14):X＝N,R1＝f,Y＝H(Z式构型)；
(15):X＝N,R1＝g,Y＝H(E式构型)；
(16):X＝N,R1＝h,Y＝H(E式构型)；
(17):X＝N,R1＝i,Y＝H(E式构型)；
(18):X＝N,R1＝j,Y＝H(E式构型)；
(19):X＝N,R1＝k,Y＝H(E式构型)；
(20):X＝N,R1＝g,Y＝H(Z式构型)；
(21):X＝N,R1＝h,Y＝H(Z式构型)；
(22):X＝N,R1＝i,Y＝H(Z式构型)；
(23):X＝N,R1＝j,Y＝H(Z式构型)；
(24):X＝N,R1＝k,Y＝H(Z式构型)；
(25):X＝N,R1＝l,Y＝H(E式构型)；
(26):X＝N,R1＝m,Y＝H(E式构型)；
(27):X＝O,Y＝Cl(E式构型)；
其中，a-m分别为以下基团：
2.根据权利要求1所述的苍耳亭类衍生物或其药学上可接受的盐，其特征在于，所述衍生物为以下结构式中的任一种：
3.权利要求1或2所述的苍耳亭类衍生物或其药学上可接受的盐在抗植物病原真菌上的应用。
4.根据权利要求3所述的应用，其特征在于，所述植物病原真菌为苹果树腐烂病菌(Cytospora mandshurica)、小麦赤霉病菌(Fusarium graminearum)、番茄早疫病菌(Alternari a solani)、腐皮镰刀病菌(Fusarium solani)、黄瓜炭疽病菌(Colletotrichum orbiculare)、辣椒枯萎病菌(Fusarium oxysporum)或番茄灰霉病菌(Botrytis cinerea)中的任一种。
5.一种制剂，含有权利要求1或2所述的苍耳亭类衍生物或其药学上可接受的盐。
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