CN109422745B - 苦参碱酰腙衍生物及其制备和在防治植物病虫害方面的应用 - Google Patents
苦参碱酰腙衍生物及其制备和在防治植物病虫害方面的应用 Download PDFInfo
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Abstract
Description
技术领域
本发明涉及苦参碱酰腙衍生物及其制备和在抗植物烟草花叶病毒,杀虫以及杀菌方面的应用。
背景技术
传统的合成酰腙方法是由酰肼与醛或酮化合物回流。现在已经发展了微波法,虽然利用微波技术进行有机合成存在单次反应产量小等缺点,但是微波反应具有反应速度快、副反应少、产率高、产品易纯化等优点,还可以节约能源,实现原子经济性合成和生态友好绿色合成等特点。
最早在1973年,杜邦公司研发出一些结构较为简单的二苯甲酮腙类化合物并报道了其优良的杀虫活性。随后巴斯夫、拜耳以及孟山等公司均投入到这类具有杀虫活性的化合物的研究当中(Wenderoth B,Brand S,Schuetz F,et al.Substituted hydrazones andfungicides co ntaining these compounds[P].US 4956387,1990-09-11;Heuer L,Schwamborn M,Erdelen C,et al. New hydrazone compounds[P].DE 4207400,1993-09-16;Phillion D.Oxime amides and hydrazone amides having fungicidal activity[P].US 6359156,2002-03-19.)。酰腙类化合物作为一种特殊的席夫碱化合物,由于含有一个活性亚结构基团(-CONHN=CH-),因而表现出良好的生物活性、较强的配位能力和多样的配位方式。研究人员发现,酰腙类化合物不仅具有杀菌活性(龙德清,李德江.新型三唑并嘧啶甲酰腙类化合物的合成及杀菌活性[J].化学试剂,2008,30(3):206-208.)、除草活性(武冬梅,二氮氧化喹喔啉甲醛-烃氧硫酰腙的合成及其除草活性研究[D],华中农业大学,2009.)、杀虫活性(邢家华,夏旭建,彭伟立,等.新型杀虫剂甲磺虫腙的合成与杀虫活性[J].农药学学报,2008,10(2):236-239.)、抗癌活性(倪振杰,薛思佳,王静,等.1-取代哌啶-4-酮芳甲酰腙的合成及其抗白血病活性[J].有机化学,2011,31(2):222-226.)等,还在分析检测领域方面具有广泛应用(刘建宁,张兵,尚虹,等.2,4-二羟基苯乙酮苯甲酰腙与Al3+的荧光反应及其应用[J].中国卫生检验杂志,2002,12(2):147-148.),2,4-二羟基苯乙酮酰腙(结构式见下式)已成功用于生理盐水、葡萄糖注射液、饮料和油条中铝的测定。
由于土壤污染与其他环境问题的日益严重,植物源农药的研究和开发利用无疑是最为诱人的领域之一。据统计地球上的植物最少有25万种,实际上可能达50万种,但迄今只有约10%的植物经过了化学成份研究,只是极小一部分。然而就这几万种植物的化学成份至今仍未能完全查明,因为植物体内的化学成份种类太多,尤其是要作为农药或医药来加以利用时,各种次生物质之间存在交互作用带来复杂的毒理学问题,不是很容易研究清楚的。据考证,昆虫与植物经过约几亿年的共同进化,植物体形成了多种能有效地防御植食性昆虫侵袭的机制,包括植物的形态行为以及体内所产生的次生物质。尽管次生物质的化学并未完全查明,但早已被注意和利用;其中作为农药利用的很多,除虫菊、烟草和鱼藤过去是最著名的三种植物性农药,植物源药物的研究利用已经有几千年之久。
苦参碱类生物碱广泛存在于豆科植物苦参(Sophora flavescens)、苦豆子(Sophora alopecuroides)及广豆根(Sophora subprostrara)中,是几种常用中草药的主要有效成分(国家医药管理局中草药情报中心站编.植物药有效成分手册[M].北京:人民卫生出版社,1986:700.)。《中华人民共和国药典》(国家药典委员会.中华人民共和国药典.一部[S].2010:188-189.) 苦参碱类化合物是从山豆根及山豆根地上部分提取的,也可以从豆科植物苦参的根、茎等利用乙醇等有机溶剂提取,为白色粉末。山豆根又名苦豆根、黄结、广豆根、芸豆根、山大豆根、柔枝槐等,含有多种生物碱类、黄酮类化合物及三萜类化合物如异黄酮、槐根碱、苦参碱、槐花二醇、臭豆碱、大豆皂醇等,主产于我国广西省。根茎呈不规则的结节状,顶端常残存茎基,其下着生根数条。质地坚硬,较难折断,断层呈浅棕色,外部为淡黄色。表面为棕色至棕褐色,有横长皮孔样突起以及不规则的纵皱纹。药理作用较多,有降血脂,抗心律失常,增加冠脉血流量,增加心肌收缩力,抗血栓,也可解热等。
粗提取物苦参总碱中,苦参碱(C15H24N2O)和氧化苦参碱(C15H24N2O2)的总量大于0.70%,其主要成分有苦参碱(Matrine)、氧化苦参碱(Oxymatrine)、槐果碱(Sophocarpine)、氧化槐果碱(Oxysophocarpine)、别苦参碱(allomatrine)等多种生物碱,结构式见附图1,以苦参碱、氧化苦参碱的含量最高。
苦参碱生物碱具有广谱的生物活性,如抗肿瘤(倪晨旭,齐阳,维恒,等.苦参碱衍生物M19对于肿瘤细胞转移的抑制作用[J].现代肿瘤医学,2016,21:3341-3344.)、抗氧化(李小花,程赣中,周凤华.苦参碱对慢性酒精性肝损伤大鼠血脂及抗氧化能力的影响[J].中国老年学杂志,2016,36:1838-1839.)、杀菌(姚红丽,张浩,叶嘉.苦参碱及氧化苦参碱对番茄灰霉菌的抑制效果[J].黑龙江农业科学,2016,11:72-76.)、杀虫(袁静,吕良忠,丛斌,等.苦参生物碱杀虫生物活性测定[J].农药,2004,43(6):284-287.)等。本课题组硕士李朝杰首次发现苦参碱具有良好的抗烟草花叶病毒活性,进行结构修饰后,发现15-脱氧-14-R-羟基甲基苦参碱(T-1)相比于15-脱氧-14-S-羟基甲基苦参碱(T-2)具有更好的抗病毒活性,从结构式可以看出15-脱氧-14-R-苦参碱(T-1)中有氢键,而15-脱氧-14-S-苦参碱(T-2)结构中没有氢键,推测是由于氢键作用使两个化合物活性出现较大差距,结构式见附图2。
本申请以苦参碱为先导化合物,开展了苦参碱的结构多样性衍生,设计合成含酰腙结构的苦参碱衍生物,系统研究了其在抗烟草花叶病毒病、杀菌、杀虫方面的应用。
发明内容
本发明的内容是关于14-及11-酰腙苦参碱衍生物(通式I)及其合成和在系统研究了其在抗烟草花叶病毒病、杀菌、杀虫方面的应用。
本发明所述的通式I中R代表芳香基:苯基,各种给电子和吸电子苯基,芳香杂环取代基;脂肪基:各种取代烷基。
本发明所述的特点在于三点:第一点,操作简单;第二点,原料廉价;第三点微波反应更加迅速,易于反应处理,产率较高。
本发明通式I所述的14-酰腙苦参碱衍生物可以通过方法一制备:14-酰肼苦参碱与各种醛类,在回流条件下,发生缩合反应。
本发明的再一个目的在于提供在天然产物中引入酰腙的的制备方法,其特点在于操作简单,反应条件温和,易于提纯。
本发明通式I所述的11-酰腙苦参碱衍生物可以通过方法二制备:11-酰肼苦参碱与各种醛类,在回流条件下,发生缩合反应。
两个系列酰腙类苦参碱能够作为抗烟草花叶病毒制剂直接使用,也可以加载体使用,还可以作为抗烟草花叶病毒剂和其他的抗烟草花叶病毒制剂复合使用。
本发明具有很大的优点:其特征在于它们具有很好的水溶性,热稳定性,有机溶剂溶解性和生物活性,易于合成,环境兼容性好,对非靶标生物安全。
附图说明:
图1 苦参总碱代表性化合物的结构
图2 15-脱氧苦参碱的结构。
图3 14-酰腙苦参碱衍生物的结构
图4 11-酰腙苦参碱衍生物的结构。
具体实施方式
实施例1 14-酰腙苦参碱衍生物中化合物1的合成
器向烧瓶中加入苦参碱(8.0g,32.2mmol)和碳酸二甲酯(3.5mL,41.9mmol)的四氢呋喃溶液(20mL),体系变为亮黄色,升至室温,搅拌一小时后,TLC监测反应完全,向体系中加入200mL饱和碳酸钠溶液,分液,水相用乙酸乙酯多次充分萃取,合并有机相,用饱和食盐水洗,用无水硫酸镁干燥,脱除溶剂,得黄色油状物9.32g,收率为94%。1H NMR(400MHz, CDCl3)δ4.43-4.34(m,1H,CONCH2),3.92-3.83(m,1H,CONCH2),3.76和3.74(a pair of s, 3H,OCH3),3.48(t,J=4.8Hz,0.41H,CONCH),3.28(dd,J=9.6,6.8Hz,0.58H,CONCH),3.10 (t,J=12.8Hz,1H,CH2N),2.81(dd,J=19.2,11.2Hz,2H,CH2N),2.22-2.16(m,1H,CH2N), 2.05-1.24(m,16H).13C NMR(100MHz,CDCl3)δ171.7,171.5,165.5,165.0,63.8,63.6,57.4, 57.3,53.4,53.3,52.6,52.4,49.9,48.8,43.6,43.0,42.1,41.8,35.5,35.4,27.9,27.8,26.5,26.4,23.7, 23.5,22.9,22.5,21.3,21.2,20.9,20.7,14.0,13.8.HRMS(ESI)calcd for[C17H26N2O3+Na]+ 329.1836.found 329.1837.
4.39-4.01(m,1H,COCHCO),3.92-3.79(m,1H,CONCH),3.59(s,2H,NH2),3.28(s,0.6H,NCH2),3.16-3.02(m,2H,NCH2),2.81(q,J=10.8Hz,2H,NCH2),2.42-2.37(m,0.48H,NCH2),2.11-1.86(m,6H),1.73-1.35(m,10H).13C NMR(100MHz,DMSO-d6)δ169.5,169.4,165.9,165.4,63.1,62.8,56.6,56.5,52.7,52.5,47.5,46.8,42.8,41.9,41.6,40.9,35.3,34.9,27.4,27.4, 25.9,25.8,25.2,25.1,22.5,21.9,20.7,20.6,20.2,14.0,13.6.HRMS(ESI)calcd for C16H26N4O2 [M+H]+307.2129,found 307.2133.
DMSO-d6)δ11.36(s,0.11H,CONH),11.35(s,0.20H,CONH),11.24(s,0.19H,CONH),11.15(s,0.23H,CONH),8.43(d,J=8.0Hz,0.33H,CH=N),8.22(s,0.17H,CH=N),8.18(s,0.20H,CH=N), 7.79-7.55(m,1H,Ph-H),6.66-6.53(m,2H,Ph-H),4.16(s,1H,CONCH),3.84(d,J=4.0Hz,3H, OCH3),3.81(s,3H,OCH3),3.09-2.93(m,1H,COCHCO),2.78-2.75(m,2H,CONCH2),2.33-2.16(m,3H,NCH2),2.00-1.78(m,5H,CH2,NCH2),1.57-1.45(m,8H,CH2),1.36-1.29(m,3H,CH2).HRMS(ESI)calcd for C25H34N4O4[M+H]+ 455.2653,found 455.2660.
实施例2 14-酰腙苦参碱衍生物中化合物2-25参照实施例1中的方法的合成(结构式见附图3)
化合物2
淡黄色固体0.40g,收率59%,Mp 170-171℃。1H NMR(400MHz,DMSO-d6)δ11.47(s,0.23H,CONH),11.46(s,0.18H,CONH),11.37(s,0.23H,CONH),11.27(s,0.25H,CONH),8.55(s,0.19H,CH=N),8.53(s,0.19H,CH=N),8.33(s,0.22H,CH=N),8.28(s,0.26H,CH=N),7.80-7.85(m,1H,Ar-H),7.42-7.38(m,1H,Ar-H),7.10-6.93(m,2H,Ar-H),4.15-4.11(m,1H, COCHCO),3.85-3.83(2s,3H,OCH3),3.25-3.07(m,1H,CONCH2),3.01-2.95(m,1H,CONCH), 2.77-2.71(m,2H,CONCH2,NCH2),2.18-1.86(m,8H),1.64-1.22(m,10H).HRMS(ESI)calcd for C24H32N4O3[M+H]+ 425.2547,found 425.2551.
化合物3
淡黄色固体0.45g,收率为66%,Mp 181-182℃。1H NMR(400MHz,DMSO-d6)δ11.35(s,0.22H,CONH),11.33(s,0.22H,CONH),11.30(s,0.23H,CONH),11.20(s,0.25H,CONH),8.16(s,0.22H,CH=N),8.13(s,0.21H,CH=N),7.96(s,0.22H,CH=N),7.89(s,0.29H,CH=N), 7.96-7.90(m,1H,Ar-H),7.66-7.60(m,1H,Ar-H),7.02-6.96(m,2H,Ar-H),4.25-4.12(m,1H, COCHCO),3.83-3.80(m,4H,OCH3,NCH2),3.35(s,1H,CONCH2),3.03-2.97(m,1H,CONCH),2.85-2.73(m,2H,CONCH2,NCH2),2.18-1.81(m,7H),1.61-1.37(m,10H).HRMS (ESI)calcd for C24H32N4O3[M+H]十425.2547,found 425.2554.
化合物4
黄色固体0.42g,收率70%.Mp 187-188℃。1H NMR(400MHz,DMSO-d6)δ11.46(s,0.21H,CONH),11.44(s,0.19H,CONH),11.38(s,0.19H,CONH),11.29(s,0.27H,CONH),8.19(s, 0.15H,N=CH),8.16(s,0.22H,N=CH),7.99(s,0.19H,N=CH),7.93(s,0.28H,N=CH),7.85-7.83 (m,0.30H,Ar-H),7.60-7.53(m,1.8H,Ar-H),7.30-7.21(m,2H,Ar-H),4.20-4.13(m,1H, COCHCO),3.84-3.52(m,3H,CONCH2,CONCH),3.16-3.12(m,0.36H,NCH2),3.02-2.96(m, 0.9H,NCH2),2.79-2.73(m,2H,NCH2),2.36-2.18(m,3H),2.18-1.22(m,17H).HRMS(ESI) calcd for C24H32N4O2[M+H]+409.2598,found 409.2605.
化合物5
黄色固体0.26g,收率75%。Mp 163-164℃。1H NMR(400MHz,DMSO-d6)δ11.26(s,0.22H,CONH),11.24(s,0.16H,CONH),11.14(s,0.16H,CONH),11.04(s,0.22H,CONH),8.07(s,0.18H,CH=N),8.04(s,0.19H,CH=N),7.88(s,0.16H,CH=N),7.81(s,0.22H,CH=N),7.50-7.45(m,2H),6.74-6.68(m,2H),4.18-4.11(m,1H,CONCH2),3.88-3.73(s,1H,CONCH2),3.29-3.27(m,0.39H,COCHCO),3.20-3.05(m,0.59H,COCHCO),2.96(s,N(CH3)2,6H), 2.83-2.75(m,2H,CONCH,NCH2),2.18-1.86(m,7H),1.57-1.16(m,11H).HRMS(ESI)calcd forC25H35N5O2[M+H]+438.2864,found 438.2864.
化合物6
淡黄色固体0.52g,收率69%,Mp 190-191℃。1H NMR(400MHz,DMSO-d6)δ11.58(s,0.17H,CONH),11.56(s,0.15H,CONH),11.50(s,0.26H,CONH),11.42(s,0.27H,CONH),8.28(s,0.17H,C=NH),8.25(s,0.18H,CH=N),8.09-7.98(m,1H,CH=N),7.93(s,0.24H,CH=N),7.91 (s,0.23H,CH=N),7.79-7.67(m,5H,Ar-H),7.54-7.45(m,2H,Ar-H),7.41-7.37(m,1H,Ar-H), 4.25-4.14(m,1H,CONCH2),3.94-3.82(m,1H,CONCH),3.39-3.15(m,2H,CONCH2), 3.01-2.95(m,1H,CONCH),2.85-2.71(m,2H,NCH2),2.23-1.12(m,16H).HRMS(ESI)calcd for C29H34N4O2[M+H]+471.2755,found 471.2759.
化合物7
淡黄色固体0.6g,收率为65%,Mp 169-170℃。1H NMR(400MHz,DMSO-d6)δ11.77(s,1H,CONH),11.37(s,0.13H,CONH),11.37(s,0.17H,CONH),11.37(s,0.31H,CONH),11.37(s,0.20H,CONH),8.42-8.24(m,1H,CH=N),7.64-7.50(m,1H,Ar-H),7.30-7.21(m,1H,Ar-H),6.93-6.81(m,2H,Ar-H),4.20-4.12(m,1H,CONCH2),3.83-3.81(m,1H,CONCH2),3.31-3.25(m,0.4H,COCHCO),3.17-3.13(m,0.5H,COCHCO)3.02-2.95(m,1H,CONHCH),2.82-2.67 (m,2H,NCH2),2.22-1.75(m,7H),1.66-1.16(m,10H).HRMS(ESI)calcd for C23H31N4O3 [M+H]+411.2391,found 411.2395.
化合物8
淡黄色固体0.29g,收率66%,Mp 167-168℃。1H NMR(400MHz,DMSO-d6)δ11.51(s,0.21H,CONH),11.49(s,0.14H,CONH),11.39(s,0.15H,CONH),11.30(s,0.23H,CONH),8.13(s,0.16H,CH=N),8.10(s,0.22H,CH=N),7.92(s,0.15H,CH=N),7.87(s,0.23H,CH=N),7.25-6.81(m,4H,Ar-H),4.17(s,1H,CONCH2),3.96-3.79(m,1H,CONCH2),3.37(s,2H,CONCH,NCH2),3.05-2.96(m,1H,NCH2),2.83-2.68(m,1H,NCH2),2.18-1.79(m,6H), 1.64-1.12(m,11H).HRMS(ESI)calcd for C23H31N4O3[M+H]+411.2391,found 411.2390.
化合物9
淡黄色固体0.38g,收率为57%,Mp 177-178℃。1H NMR(400MHz,DMSO-d6)δ11.50(s,0.20H,CONH),11.48(s,0.19H,CONH),11.40(s,0.14H,CONH),11.31(s,0.15H,CONH),8.62(s,0.03H,CH=N),8.29(s,0.04H,CH=N),8.15(d,J=12.0Hz,0.81H,CH=N),8.07(s,0.15H, Ph-H),8.03(s,0.25H,Ph-H),7.95(s,0.17H,Ph-H),7.90(s,0.26H,Ph-H),7.84-7.78(m,1H, Ph-H),7.15-7.05(m,1H,Ph-H),4.22-4.14(m,2H,CONCH,CONCH2),4.04(dd,J=12.0,8.0 Hz,0.6H,CONCH2),3.88-3.76(m,1.44H,CONCH2,COCHCO),3.61(s,0.3H,NCH2),3.17(s, 1H,NCH2),3.00-2.84(m,1H,NCH2),2.87-2.81(m,2H,NCH2),2.31-2.18(m,1H,NCH2), 2.05-1.80(m,4H,CH2),1.62-1.36(m,9H,CH2),1.23-1.17(m,1H,CH2).HRMS(ESI)calcd for C23H30N5O5[M+H]+456.2241,found 456.2242.
化合物10
淡黄色固体0.98g,收率80%,Mp 170-171℃。1H NMR(400MHz,DMSO-d6)δ11.42(s,0.22H,CONH),11.40(s,0.15H,CONH),11.31(s,0.22H,CONH),11.22(s,0.26H,CONH),10.81(br,1H,OH),8.08-8.03(m,1H,CH=N),7.88-7.07(m,2H,Ar-H),7.54-7.44(m,1H,Ar-H),7.10-6.97(m,1H,Ar-H),4.16(m,1H,CONCH2),3.85-3.78(m,1H,CONCH2,COCHCO), 3.17-3.06(m,1H,NCH2),3.03-2.95(m,1H,NCH2),2.87-2.70(m,2H,NCH2),2.19-1.77(m,7H),1.44(m,10H).HRMS(ESI)calcd for C23H29BrN4O3[M+H]+489.1496,found 489.1504and491.1527.
化合物11
淡黄色固体0.38g,收率为54.3%,Mp 168-169℃。1H NMR(400MHz,DMSO-d6)δ13.16(s,0.17H,CONH),12.31(s,0.61H,CONH),11.46(s,0.13H,CONH),11.29(s,0.14H,CONH),8.64(s,0.70H,CH=N),7.64(s,0.39H,CH=N),7.17-7.10(s,1H,Ph-H),6.98-6.88(m,1H,Ph-H), 4.21-4.18(m,1H,CONCH),3.72-3.71(m,1H,CONCH2),3.55-3.31(m,3H,CONCH2,NCH2), 2.96-2.88(m,1H,COCHCO),2.75(s,2H,NCH2,CH2),2.22-1.87(m,7H,CH3,CH2),1.70-1.16 (m,13H,CH2),0.86(s,1H,CH2).HRMS(ESI)calcd for C25H34N4O3[M+H]+439.2704,found 439.2710.
化合物12
淡黄色固体0.78g,收率为60%,Mp 169-170℃。1H NMR(400MHz,DMSO-d6)δ11.55(s,0.19H,CONH),11.53(s,0.25H,CONH),11.50(s,0.22H,CONH),11.41(s,0.21H,CONH),8.22(s,0.23H,CH=N),8.19(s,0.19H,CH=N),8.00(s,0.24H,CH=N),7.95(s,0.29H,CH=N),7.74-7.68(m,2H,Ar-H),7.53-7.45(m,2H,Ar-H),4.22-4.16(m,1H,COCHCO),3.96-3.76(m, 1H,CONCH),3.39-3.30(m,1H,CONCH2),3.03-2.96(m,1H,CONCH2),2.83-2.72(m,2H,NCH2),2.19-1.80(m,7H),1.60-1.24(m,10H).HRMS(ESI)calcd for C23H29ClN4O2[M+H]+429.2052,found 429.2048.
化合物13
淡黄色固体0.52g,收率69%,Mp 161-162℃。1H NMR(400MHz,DMSO-d6)δ11.60(s,0.14H,CONH),11.58(s,0.15H,CONH),11.51(s,0.29H,CONH),11.43(m,0.21H,CONH),8.21(m,0.12H,CH=N),8.18(m,0.19H,CH=N)7.99(m,0.20H,CH=N),7.96(s,0.34H,CH=N)7.85-7.84(m,1H,Ar-H),7.75-7.64(m,3H,Ar-H),4.23-4.12(m,1H,CONCH),3.84-3.82(m,1H, CONCH),3.46-3.29(m,1H,COHCO),2.98-2.96(m,1H,CONCH),2.86-2.75(m,2H,NCH2),2.20-1.86(m,7H),1.56-1.15(m,10H).HRMS(ESI)calcd for C23H29BrN4O2[M+H]+473.1547,found 473.1552and 475.1535.
化合物14
淡黄色固体0.42g,收率55%,Mp 176-177℃。1H NMR(400MHz,DMSO-d6)δ11.60(s,0.32H,CONH),11.53(s,0.26H,CONH),11.43(s,0.23H,CONH),8.25(d,J=2.4Hz,0.27H, CH=N),8.09-7.97(m,0.84H,CH=N),7.84-7.76(m,2H,Ar-H),7.46-7.37(m,2H,Ar-H),4.21-4.11(m,1H,CONCH2),3.94-3.76(m,1H,CONCH2),3.56-3.14(m,2H,COCHCO), 3.04-2.91(m,1H,NCH2),2.89-2.73(m,2H,NCH2),2.21-0.84(m,16H).HRMS(ESI)calcd forC24H29F3N4O3[M+H]+479.2265,found 479.2260.
化合物15
黄色固体0.28g,收率67%,Mp 184-185℃。1H NMR(400MHz,DMSO-d6)δ11.78(s,0.37H,CONH),11.72(s,0.08H,CONH),11.69(s,0.14H,CONH),11.59(s,0.22H,CONH),8.54(s,0.42H,CH=N),8.52(s,0.42H,CH=N),8.44(s,0.42H,CH=N),8.41(s,0.42H,CH=N),8.34- 8.04(m,3H,Ar-H),7.76-7.57(m,1H,Ar-H),4.24-4.13(m,1H,CONCH2),3.89-3.78(m,1H, CONCH2),3.38(s,2H,COCHCO),3.02-2.91(m,1H,CONCH),2.75(s,1H,NCH2),2.20-1.23(m, 17H).HRMS(ESI)calcd for C23H29N5O4[M+H]+440.2292,found 440.2300
化合物16
淡黄色固体0.54g,收率为75%,Mp 168-169℃。1H NMR(400MHz,DMSO-d6)δ10.91(s,0.19H,CONH),10.88(s,0.33H,CONH),10.83(s,0.22H,CONH),10.81(s,0.22H,CONH),8.27(dd,J=8.0,4.0Hz,1H,Ph-H),8.24(s,0.25H,Ph-H),8.20(s,0.11H,Ph-H),8.17(s,0.26H, Ph-H),8.15(s,0.32H,Ph-H),8.06-8.02(m,1H,Ph-H),7.99(d,J=4.0Hz,0.52H,Ph-H),7.96(s, 0.31H,Ph-H),7.86(s,0.21H,Ph-H)7.84(s,0.20H,Ph-H),4.30-4.05(m,1H,CONCH),3.82(s, 1H,CONCH2),3.64(t,J=4.0Hz,0.29H,CONCH2),3.50(t,J=8.0Hz,0.22H,CONCH2), 3.04-2.94(m,0.55H,CONCH2),2.85-2.68(m,2H,COCHCO,NCH2),2.38-2.19(m,4H,NCH2, CH2),2.07-1.85(m,7H,CH2),1.68-1.23(m,10H,CH2,CH3).HRMS(ESI)calcdfor C24H31N5O4 [M+H]+454.2356,found,454.2355.
化合物17
淡黄色固体0.38g,收率为58%,Mp 177-178℃。1H NMR(400MHz,DMSO-d6)δ11.71(s,0.17H,CONH),11.70(s,0.26H,CONH),11.62(s,0.27H,CONH),11.54(s,0.28H,CONH),8.78(s,0.09H,CH=N),8.31(s,0.12H,CH=N),8.26(s,0.26H,CH=N),8.23(s,0.31H,CH=N), 8.10-8.03(m,1H,Ph-H),8.05-7.08(m,1H,Ph-H),7.87(t,J=8.0Hz,1H,Ph-H),7.75(t,J=8.0 Hz,0.21H,Ph-H),7.77-7.50(m,0.82H,Ph-H),4.26(s,0.20H,CONCH),4.16(s,1H,CONCH2), 3.98(s,0.2H,CONCH2),3.83(s,1H,CONCH2),3.16(t,J=8.0Hz,0.25H,CONCH2),3.03-2.95 (m,1H,CONCH2),2.82-2.71(m,2H,NCH2),2.17(s,1H,NCH2),2.09-1.87(m,7H,NCH2,CH2), 1.68-1.34(m,10H,CH2).HRMS(ESI)calcd for C24H29N5O2[M+H]+420.2394,found 420.2402.
化合物18
黄色固体0.18g,收率64%,Mp 180-181℃。1H NMR(400MHz,DMSO-d6)δ11.76(s,0.17H,CONH),11.74(s,0.16H,CONH),11.70(s,0.17H,CONH),11.62(s,0.22H,CONH),8.28(s,0.16H,CH=N),8.25(s,0.18H,CH=N),8.05s,0.21H,CH=N),8.01s,0.27H,CH=N),7.91-7.82 (m,4H,Ar-H),4.26-4.12(m,1H,CONCH2),4.01-3.75(m,1H,CONCH2),3.35(s,1H,COCHCO),3.18-2.02(m,1H,CONCH),2.76(s,2H,NCH2),2.18-1.12(m,17H).HRMS(ESI)calcd for C24H29N5O3[M+H]+420.2394,found 420.2402.
化合物19
淡黄色固体0.46g,收率为65%。Mp 148-149℃。1H NMR(400MHz,DMSO-d6)δ 11.58-11.36(m,1H,CONH),8.37-8.11(m,2H,N=CH,Ph-H),8.06-7.85(m,4H,Ph-H),7.56-7.46(m,2H,Ph-H),4.31-4.16(m,1H,CONCH),3.96-3.81(m,1H,CONCH2),3.33(d,J=8.0Hz,1H,CONCH2),3.18-2.71(m,3H,NCH2),2.25-1.34(m,17H,NCH2,NCH,CH,CH2).HRMS(ESI) calcdfor C27H32N4O2[M+H]+445.2598,found 445.2603.
化合物20
淡黄色固体0.39g,收率68%,Mp 144-145℃。1H NMR(400MHz,DMSO-d6)δ11.03(s,0.19H,CONH),11.01(s,0.15H,CONH),10.91(s,0.18H,CONH),10.88(s,0.17H,CONH),7.89(d,J=8.0Hz,0.19H,CH=N),7.49-7.44(m,0.34H,CH=N),7.27(t,J=4.0Hz,0.34H,CH=N), 7.02(d,J=12.0Hz,0.19H,CH=N),4.20-4.12(m,1H),3.82-3.69(m,2H),3.00-2.91(m,1H), 2.75(s,2H),2.19-2.14(m,3H),2.01-1.85(m,6H),1.59-1.47(m,12H),0.92-0.86(m,3H). HRMS(ESI)calcd for C20H32N4O2[M+H]+361.2598,found 361.2604.
化合物21
淡黄色固体0.39g,收率为67%,Mp 136-137℃。1H NMR(400MHz,DMSO-d6)δ10.16(s,0.22H,CONH),10.11(s,0.22H,CONH),10.09(s,0.22H,CONH),9.97(s,0.21H,CONH),4.20-4.13(m,1H,CONCH),4.07(s,0.27H,CONCH),3.76-3.71(m,1H,CONCH2),3.45(t,J=4.0Hz,0.25H,CONCH2),3.34(s,0.83H,CONCH2),2.99-2.92(m,1H,COCHCO),2.74(t,J=12.0Hz,2H,NCH2),2.16-2.01(m,2H,NCH2),1.92-1.78(m,8H,CH2),1.62-1.35(m,10H,CH2),1.11-1.04(m,9H,CH2,CH3).HRMS(ESI)calcd for C22H36N4O2[M+H]+389.2911,found389.2918.
化合物22
淡黄色固体0.50g,收率75%,Mp 121-122℃。1H NMR(400MHz,DMSO-d6)δ11.13-11.00(m,0.35H,CONH),10.95-10.77(m,0.41H,CONH),7.25(t,J=8.0Hz,0.50H,Ph-H),7.18-7.12(m,0.66H,Ph-H),4.17-4.15(m,1H,CONCH),3.82-3.74(m,1H,CONCH2),3.73-3.50 (m,1H,CONCH2),3.00-2.91(m,1H,COCHCO),2.75-2.74(m,2H,NCH2),2.30(s,1H,NCH2), 2.20-2.10(m,2H,NCH2,CH2),1.99(s,1H,CH2),1.92-1.77(m,4H,CH3),1.58-1.44(m,6H, CH2),1.35(s,4H,CH2),1.25-1.16(m,14H,CH2).HRMS(ESI)calcd for C24H40N4O2[M+H]+417.3224,found 417.3228.
化合物23
淡黄色固体0.35g,收率55%,Mp 142-143℃。1H NMR(400MHz,DMSO-d6)δ10.97(s,0.31H,CONCH),10.89(s,0.25H,CONCH),10.82(s,0.17H,CONCH),10.79(s,0.11H,CONCH),7.65(d,J=8.0Hz,0.09,CH=N),7.39-7.35(m,0.40,CH=N),7.17(s,0.50,CH=N),4.20-4.09(m, 1H,CONCH),3.80-3.69(m,1H,CONCH2),2.99-2.91(m,1H,CONCH2),2.77-2.70(m,2H, COCHCO,NCH2),2.17-2.07(m,3H,NCH2),1.92-1,82(m,6H,CH2),1.77-1.67(m,5H,CH2),1.63-1.51(m,6H,CH2),1.35-1.14(m,9H,CH2).HRMS(ESI)calcd for C23H36N4O2[M+H]+401.2918,found 401.2915.
化合物24
淡黄色固体0.40g,收率为64%,Mp 183-184℃。1H NMR(400MHz,DMSO-d6)δ 11.66-11.44(m,1H,CONH),8.84-8.77(m,1H,N=CH),8.60-8.24(m,1H,Ph-H),8.26(d,J=12.0Hz,0.5H,Ph-H),8.09-7.99(m,1.5H,Ph-H),7.49-7.44(m,1H,Ph-H),4.24-4.10(m,1H,CONCH),3.82(s,1H,CONCH2),3.36(s,3H,CONCH2,NCH2),3.17(d,J=8.0Hz,0.5H,NCH2),3.00-2.97(m,1H,NCH2),2.78-2.71(m,1.5H,NCH2,COCH2CO),2.23-1.20(m,15H,CH, CH2).HRMS(ESI)calcd for C22H28N5O2[M+H]+396.2394,found 396.2398.
化合物25
淡黄色固体0.48g,收率为73%,Mp 193-194℃。1H NMR(400MHz,DMSO-d6)δ11.38(s,0.25H,CONH),11.37(m,0.17H,CONH),11.31(m,0.16H,CONH),11.19(m,0.26H,CONH),9.81(s,0.12H,CH=N),8.71(s,0.12H,CH=N),8.40-8.28(m,0.47H,CH=N),8.22-8.00(m,0.62H, CH=N),7.48-7.15(m,1H,Ar-H),6.93-6.77(m,1H,Ar-H),4.22-3.99(m,1H,CONCH2), 4.01-3.89(m,0.4H,CONCH2),3.85-3.73(m,0.69H,CONCH2),3.64-3.57(m,0.50H,COCHCO), 3.28-3.23(s,0.44H,COCHCO),3.16-3.07(s,0.58H,CONCH),3.02-2.95(m,0.53H,CONCH), 2.82-2.71(m,2H,NCH2),2.55-2.42(m,4H),2.18-2.09(m,1H),2.02-1.79(m,5H),1.63-1.36 (m,10H).HRMS(ESI)calcd for C22H30N4O2S[M+H]+415.2162,found415.2162.
实施例3 11-酰腙苦参碱衍生物中化合物26的合成
N-苄基苦参酸苄酯(TM-1)合成参考文献(赵秀梅,张娜,张桂贤,等.苦参碱-美法仑复合物MAT-MEL的合成及其体内外抗肿瘤活性的研究[J].华西药学杂志,2016,31(4):339-341.)方法:mp 73.2~73.8℃
N-苄基苦参酰肼
于100mL干燥的圆底烧瓶中加入N-苄基苦参酸苄酯(2.20g,5.90mmol),水合肼(3mL, 48.0mmol),回流,TLC监测反应完全,脱溶后,加入5.00-10.00mL乙醇,减压蒸馏除去水合肼,重复进行三次,得橙黄色油状液体1.85g,收率为100%。1H NMR(400MHz,DMSO-d6)δ8.95(s,1H,CONH),7.32-7.22(m,5H,Ph-H),4.49(s,2H,NCH2Ph),4.49-3.96(m,2H,NCH,NCH2),3.36(s,1H,NCH2),3.09(s,1H,NCH2),2.87-1.65(m,3H,NCH2),2.22(d,J=8.0Hz,1H,NCH2),2.03(s,2H,COCH2),1.85-1.25(m,14H,CH,CH2).HRMS(ESI)calcd forC22H34N4O[M+H]+371.2805,found 371.2806.
化合物26
取100mL圆底烧瓶,依次加入N-苄基苦参酰肼(0.50g,1.40mmol),2,4-二甲氧基苯甲醛(0.46mL,2.80mmol),和30mL甲苯,回流5h。TLC检测反应完成,脱溶,硅胶柱层析分离(DCM∶MeOH=20∶1),得到淡黄色固体0.39g,收率为66%,Mp 139-140℃。1H NMR (400MHz,DMSO-d6)δ11.45-11.03(m,1H,CONH),8.47-8.40(m,0.5H,N=CH),8.24-8.19(m, 0.5H,N=CH),7.70-7.63(m,1H,Ph-H),7.46(s,1H,PH-H),7.32-7.29(m,4H,Ph-H),6.61-6.50 (m,2H,Ph-H),4.22-4.00(m,1H,NCH2Ph),3.83(d,J=4.0Hz,3H,OCH3),3.80(d,J=8.0Hz,3H,OCH3),3.25-2.57(m,6H,NCH2Ph,NCH2,NCH),2.33-1.23(m,19H,NCH2,CH,CH2).HRMS (ESI)calcd for C31H42N4O3[M+H]+519.3330,found 519.3334.
实施例4 11-酰腙苦参碱衍生物中化合物27-45参照实施例3中化合物26的方法的合成 (结构式见附图4)
化合物27
淡黄色固体0.45g,收率为63%,Mp 147-148℃。1H NMR(400MHz,DMSO-d6)δ11.55(s,0.3H,CONH),11.24(s,0.2H,CONH),11.11(s,0.4H,CONH),8.19(s,0.2H,N=CH), 7.94-7.89(s,0.4H,N=CH),7.64(d,0.4H,N-CH),7.48-7.25(m,7H,Ph-H),7.01-6.92(m,1H, Ph-H),4.19-3.91(m,1H,NCH2Ph),3.82-3.76(m,6H,OCH3),3.25-3.16(m,2H,NCH2Ph,NCH2),2.95-2.51(m,4H,NCH,NCH2),2.34-1.23(m,19H,NCH2,CH,CH2).HRMS(ESI)calcd forC31H42N4O3[M+H]+519.3330,found 519.3338.
化合物28
淡黄色固体0.40g,收率为62%,Mp 149-150℃。1H NMR(400MHz,DMSO)δ11.45(s,0.3H,CONH),11.37(s,0.2H,CONH),11.10(s,0.2H,CONH),10.97(s,0.3H,CONH),8.72(s,0.5H,Ph-OH),8.68(s,0.4H,Ph-OH),8.10(s,0.3H,N=CH),8.01(s,0.2H,N=CH),7.83(d,J= 12.0Hz,0.5H,N=CH),7.65(s,1H,Ph-H),7.45(s,1H,Ph-H),7.32-7.20(m,5H,Ph-H),4.19-3.90 (m,1H,NCH2Ph),3.22-2.60(m,7H,NCH2Ph,NCH2,NCH),2.33-1.13(m,24H,NCH2,CH,CH2). HRMS(ESI)calcd for C31H42N4O2[M+H]+503.3381,found 503.3387.
化合物29
淡黄色固体0.28g,收率为43%,Mp 146-147℃。1H NMR(400MHz,DMSO-d6)δ11.93(s,0.3H,CONH),11.88(s,0.2H,CONH),11.32(s,0.1H,CONH),11.20(s,0.5H,CONH),11.16(s,0.1H,CONH),10.18(d,J=12.0Hz,0.5H,Ph-OH),9.85-9.67(m,0.5H,Ph-OH)8.49(s,0.4H, N=CH),8.41(s,0.2H,N=CH),8.29(s,0.2H,N=CH),8.25(s,0.2H,N=CH),7.63-7.33(m,3H, Ph-H),7.29-7.22(m,4H,Ph-H),6.92-6.81(m,2H,Ph-H),4.19-3.92(m,1H,NCH2Ph),3.60-3.20 (m,5H,NCH2Ph,NCH2),3.05-2.59(m,4H,NCH,NCH2),2.41-1.34(m,16H,NCH2,CH2,CH). HRMS(ESI)calcd for C29H38N4O2[M+H]+475.3068,found 475.3073.
化合物30
淡黄色固体0.32g,收率为49%,Mp 129-130℃。1H NMR(400MHz,DMSO-d6)δ11.62(s,0.3H,CONH),11.29(s,0.2H,CONH),11.16(s,0.3H,CONH),9.64(d,J=8.0Hz,1H,Ph-OH), 8.19(s,0.3H,N=CH),8.11(s,0.1,N=CH),7.90(s,0.1H,N=CH),7.88(s,0.3,N=CH),7.65-7.01 (m,8H,Ph-H),6.82-6.80(m,1H,Ph-H),4.19-3.91(m,1H,NCH2Ph),3.37-2.62(m,7H,NCH2Ph, NCH,NCH2),2.33-1.23(m,18H,NCH2,CH,CH2).HRMS(ESI)calcd forC29H38N4O2[M+H]+ 475.3068,found 475.3075.
化合物31
淡黄色固体0.40,收率为51%,Mp 126-127℃。1H NMR(400MHz,DMSO-d6)δ11.78(s,0.5H,CONH),11.26(s,0.4H,CONH),11.20(s,0.5H,Ph-OH),10.44(s,0.4H,Ph-OH),8.35(s,0.5H,N=CH),8.21(s,0.5H,N=CH),7.76-7.72(m,2H,Ph-H),7.41-7.32(m,6H,Ph-H),6.88(d,J =12.0Hz,1H,Ph-H),4.22-3.98(m,1H,NCH2Ph),3.31-2.60(m,6H,NCH2Ph,NCH,NCH2),2.28(s,1H,NCH2),2.01-1.23(m,18H,NCH2,CH,CH2).HRMS(ESI)calcd for C29H37BrN4O2 [M+H]+553.2173,found 553.2188and 555.2188.
化合物32
淡黄色固体0.45g,收率为65%,Mp 131-132℃。1H NMR(400MHz,DMSO-d6)δ11.71(s,0.3H,CONH),11.30(s,0.5H,CONH),8.24(s,0.3H,N=CH),7.94(d,J=8.0Hz,0.8H,N=CH), 7.69-6.73(m,9H,Ph-H),4.23-3.84(m,1H,NCH2Ph),3.22-2.65(m,6H,NCH2Ph,NCH),2.33(s, 1H,NCH2,NCH),2.16-1.16(m,18H,NCH2,CH,CH2).HRMS(ESI)calcd for C29H37ClN4O[M+H]+493.2729,found 493.2736.
化合物33
淡黄色固体0.40g,收率为55%,Mp 120-121℃。1H NMR(400MHz,DMSO-d6)δ11.80(s,0.3H,CONH),11.38(s,0.5H,CONH),8.14(s,0.3H,N=CH),7.93(s,0.4H,N=CH),7.88(d,J =12.0Hz,1H,Ph-H),7.68-7.62(m,2H,Ph-H),7.47-7.23(m,5H,Ph-H),4.13-4.02(m,1H, NCH2Ph),3.18-3.07(m,2H,NCH2Ph,NCH),2.87-2.63(m,4H,NCH2,NCH).2.32-1.23(m,19H, NCH2,CH,CH2).HRMS(ESI)calcd for C29H32Cl2N4O[M+H]+527.2339,found 527.2346.
化合物34
棕色固体0.28g,收率为37%,Mp 140-141℃.1H NMR(400MHz,DMSO-d6)δ11.67(s,0.2H,CONH),11.54(s,0.2H,CONH),11.36(s,0.2H,CONH),11.25(s,0.2H,CONH),8.20(s,0.1H,N=CH),8.16(s,0.1H,N=CH),8.04(s,0.8H,N=CH),7.95-7.92(m,1H,Ph-H),7.87-7.80(m, 1H,Ph-H),7.66-7.56(m,1H,Ph-H),7.48-7.22(m,6H,Ph-H),4.24-4.15(m,1H,NCH2Ph), 3.36-2.26(m,9H,NCH2Ph,NCH2,NCH),2.33-1.23(m,16H,CH,CH2).HRMS(ESI)calcd for C29H37BrN4O[M+H]+537.2224,found 537.2227and 539.2224.
化合物35
淡黄色固体0.31g,收率为47%,Mp 134-135℃.1H NMR(400MHz,DMSO-d6)δ11.81(s,0.3H),11.42(s,0.6H),10.20(s,0.2H),9.79(s,0.3H),8.23(s,0.4H),8.07-7.96(s,3H),7.85(dd, J=8.0,4.0Hz,1H),7.66-7.17(m,6H),4.22-3.96(m,1H,NCH),3.27-3.09(m,2H,NCH2), 2.87-2.66(m,4H,NCH2),2.33-1.23(m,19H,NCH2,COCH2,CH2,CH).HRMS(ESI)calcd for C30H37N5O[M+H]+484.3071,found 484.3076.
化合物36
淡黄色固体0.44g,收率为60%,Mp 144-145℃.1H NMR(400MHz,DMSO-d6)δ11.88(s, 0.4H,CONH),11.51(s,0.6H,CONH),8.57(s,0.4H,N=CH),8.33(s,0.6H,N=CH),8.13(d,J= 8.0Hz,1H,Ph-H),7.84-7.52(m,4H,Ph-H),7.37-7.24(m,5H,Ph-H),4.20-3.97(m,1H, NCH2Ph),2.90-2.82(m,3H,NCH2Ph,NCH2),2.68(s,2H,NCH2,NCH),2.30(s,2H,NCH2),1.93-1.23(m,18H,NCH2,CH,CH2).HRMS(ESI)calcd for C30H37F3N4O[M+H]+527.2992, found527.3001.
化合物37
淡黄色固体0.41g,收率为57%,Mp 187-188℃.1H NMR(400MHz,DMSO-d6)δ11.88(s, 0.2H,CONH),11.66(s,0.2H,CONH),11.46(s,0.4H,CONH),8.48(s,0.5H,N=CH),8.41(s,0.5H, N=CH),8.25-8.08(m,3H,Ph-H),7.74-7.15(m,6H,Ph-H),4.22-3.98(m,1H,NCH2Ph), 3.28-3.20(m,1H,NCH),3.09-2.64(m,5H,NCH2),2.33-1.26(m,19H,NCH2,CH,CH2).HRMS (ESI)calcd for C29H37N5O3[M+H]+504.2969,found 504.2975.
化合物38
淡黄色固体0.52g,收率为73%,Mp 125-126℃。1H NMR(400MHz,DMSO-d6)δ11.69(s,0.3H,CONH),11.35(s,0.5H,CONH),8.15(s,0.5H,N=CH),8.09(s,0.5H,N=CH),8.04-7.91 (m,5H,Ph-H),7.55(d,J=4.0Hz,2H,Ph-H),7.34-7.20(m,5H,Ph-H),4.14-4.01(m,1H, NCH2Ph),3.38(s,4H,NCH2Ph,NCH),2.89-2.51(m,4H,NCH2,NCH),2.30(s,2H,NCH2),1.96 -1.22(m,15H,NCH2,CH2,CH).HRMS(ESI)calcd for C33H40N4O[M+H]+509.3275,found509.3285.
化合物39
淡黄色固体0.40g,收率为55%,Mp 119-120℃。1H NMR(400MHz,DMSO-d6)δ11.70(s,0.2H,CONH),11.63(s,0.1H,CONH),11.34(s,0.2H,CONH),11.21(s,0.3H,CONH),10.35(s, 0.2H,Ph-OH),10.18(s,0.1H,Ph-OH),10.04(s,0.7H,Ph-OH),8.83(s,0.2H,N=CH),8.30(s, 0.1H,N=CH),8.21(s,0.1H,N=CH),8.08(s,0.4H,N=CH),8.00-7.67(m,5H,Ph-H),7.45-7.12 (m,6H,Ph-H),4.15-3.91(m,1H,NCH2Ph),3.38-2.67(m,7H,NCH2Ph,NCH,NCH2),2.34-1.16 (m,18H,NCH2,CH,CH2).HRMS(ESI)calcd for C33H40N4O2[M+H]+525.3224,found 525.3233.
化合物40
淡黄色固体0.40g,收率为62%,Mp 178-179℃。1H NMR(400MHz,DMSO-d6)δ11.68(s,0.3H,NHCO),11.26(d,J=41.6Hz,0.4H,NHCO),10.39(s,0.1H,NHCO),9.89(s,0.3H,NHCO),8.49(s,0.5H,N=CH),8.16(s,0.5H,N=CH),7.63-7.10(m,8H,Ph-H),4.16-3.93(m,1H, NCH2Ph),4.35-3.14(m,5H,NCH2Ph,NCH),2.21-1.70(m,3H,NCH2,NCH),2.31-1.23(m,17H, NCH2,CH,CH2).HRMS(ESI)calcd for C27H36N4OS[M+H]+465.2683,found 465.2688.
化合物41
淡黄色固体0.48,收率为75%,Mp 170-171℃。1H NMR(400MHz,DMSO-d6)δ11.76(s,0.3H,CONH),11.42(s,0.5H,CONH),9.07(s,0.1H,N=CH),8.79(s,0.9H,N=CH),8.58-8.55(m, 1H,Ph-H),8.27-8.01(m,2H,Ph-H),7.50-7.27(m,5H,Py-H,Ph-H),4.14(s,1H,NCH2Ph), 3.34-2.67(m,9H,NCH,NCH2),2.29(s,2H,CH2),1.93-1.23(m,14H,CH,CH2).HRMS(ESI) calcd for C28H37N5O[M+H]+460.3071,found 460.3075.
化合物42
淡黄色固体0.48,收率为65%,Mp 143-144℃。1H NMR(400MHz,DMSO-d6)δ11.79(s,0.2H,NHCO),11.75(s,0.4H,NHCO),10.97(s,0.4H,NHCO),8.35(s,1H,Ph-H),8.27(s,0.5H,N=CH),8.13(s,0.5H,N=CH),7.83-7.80(m,1H,Ph-H),7.50-7.24(m,7H,Ph-H),4.03-3.88(m, 1H,NCH2Ph),3.17(d,J=4.0Hz,3H,NCH2Ph,NCH),2.89-2.68(m,4H,NCH2),2.32-1.23(m, 18H,NCH2,CH,CH2).HRMS(ESI)calcd for C31H36BrN5O[M+H]+576.2332,found576.2366and 578.2367.
化合物43
淡黄色油状液体0.34g,收率为52%,1H NMR(400MHz,DMSO)δ11.18(s,0.4H,CONH), 10.87(s,0.2H,CONH),10.77(s,0.2H,CONH),8.00(s,0.2H,N=CH),7.65(s,0.5H,N=CH), 7.49-7.32(m,5H,Ph-H),4.17-3.82(m,1H,NCH2Ph,NCH2),3.17-2.73(m,6H,NCH,NCH2), 2.27-1.25(m,31H,NCH2,CH,CH2),0.85(t,J=8.0Hz,3H,CH3).HRMS(ESI)calcd forC28H44N4O[M+H]+481.3906,found 481.3910.
化合物44
淡黄色油状液体0.19g,收率为31%。1H NMR(400MHz,DMSO-d6)δ11.20(d,J=28.0Hz,0.3H,CONH),10.86(s,0.3H,CONH),10.72(s,0.4H,CONH),7.66-7.62(m,0.4H,N=CH),7.52-7.43(m,0.6H,N=CH),7.41-7.19(m,5H,Ph-H),4.19-4.02(m,1H,NCH2Ph),3.24-3.16(m, 1H,NCH2Ph),3.03-2.68(m,4H,NCH2,NCH),2.33-1.55(m,17H,NCH2,CH,CH3),1.35-1.23(m,3H,CH3),1.11(s,2H,CH3),1.01(d,J=8.0Hz,7H,CH3).HRMS(ESI)calcd for C27H42N4O[M+H]+439.3431,found 439.3437.
化合物45
淡黄色固体0.35g,收率为54%,Mp 108-109℃。1H NMR(400MHz,DMSO-d6)δ9.77(s,1H,CONH),7.47-7.23(m,5H,Ph-H),4.17-4.02(m,1H,NCH2Ph),3.24-2.65(m,5H,NCH2,NCH),2.37-2.23(m,6H,NCH2,CH,CH2),1.97-1.23(m,24H,CH,CH2).HRMS(ESI)calcd forC28H42N4O[M+H]+465.3588,found 465.3592.
实施例5:14-及11-酰腙苦参碱化合物抗烟草花叶病毒、杀虫与杀菌的活性测试方法
抗病毒测试方法:
(1)病毒提纯及浓度测定:病毒提纯及浓度测定参照南开大学元素所生测室编制烟草花叶病毒SOP规范执行。将病毒粗提取液经过二次聚乙二醇离心处理后测定浓度,于4℃冷藏备用。
(2)化合物溶液配制:化合物称量后,原药用DMF溶解,制得1×105μg/mL的母液,后用含1‰吐温80(聚山梨酯-80)水溶液稀释至所需浓度。
(3)离体活性:摩擦接种珊西烟适龄叶片,并用流水冲洗。病毒浓度为10μg/mL。收干后剪下,沿叶中脉对剖,左右半叶分别浸于1‰吐温水及药剂中,30min之后取出,于适宜光照及温度下保湿培养,每3片叶为1次重复,重复3次。3d后,记录病斑数,计算防效。
(4)活体保护作用:
选长势均匀一致的3-5叶期珊西烟,全株喷雾施药,每处理3次重复,并设1‰吐温80 水溶液对照。24h后,叶面撒布金刚砂(500目),用毛笔蘸取病毒液,在全叶面沿支脉方向轻擦2次,叶片下方用手掌支撑,病毒浓度10μg/mL,接种后用流水冲洗。3d后记录病斑数,计算防效。
(5)活体治疗作用:
选长势均匀一致的3-5叶期珊西烟,用毛笔全叶接种病毒,病毒浓度为10μg/mL,接种后用流水冲洗。叶面收干后,全株喷雾施药,每处理3次重复,并设1‰吐温80水溶液对照。3d后记录病斑数,计算防效。
(6)活体钝化作用:
选长势均匀一致的3-5叶期珊西烟,将药剂与等体积的病毒汁液混合钝化30min后,摩擦接种,病毒浓度20μg/mL,接种后即用流水冲洗,重复3次,设1‰吐温80水溶液对照。3d后数病斑数,计算防效。
抑制率(%)=[(对照枯斑数-处理枯斑数)/对照枯斑数]×100%
杀虫活性测试方法:
棉铃虫:饲料混药法,从事先配置好的所需浓度的溶液中移取3mL加入约27g的刚配置好的饲料中,从而得到稀释十倍的所需浓度。药剂混匀后均匀地倒入干净的24孔板中,晾凉后接入24头3龄棉铃虫幼虫,观察3-4天后检查结果。
玉米螟、小菜蛾幼虫、粘虫:与棉铃虫同法。
蚜虫:试虫为蚜虫(Aphis laburni Kaltenbach),实验室蚕豆叶饲养的正常群体。称取药品,加1mL DMF溶解,加两滴吐温-20乳化剂,加入一定量的蒸馏水,搅拌均匀,配成所需浓度的药液。将带蚜虫(约60只)蚕豆叶片浸入药剂中5秒钟,拿出轻轻甩干,用滤纸吸干多余药剂,然后将蚕豆枝插入吸水海绵中,并用玻璃罩罩住枝条,用纱布封口,96小时检查结果,每个化合物重复3次。对照只向蒸馏水中加入乳化剂和溶剂,搅拌均匀。
朱砂叶螨成螨:供试验用的矮生菜豆长至两片真叶时,选择长势比较整齐、叶面积4-5 平方厘米、株高10厘米左右的植株接虫,每株虫量控制在60-100头左右。接虫24小时后,进行药剂处理。药剂处理采用植株浸渍法,浸渍时间5秒钟。植株从药液中取出后,轻轻抖动,甩掉多余药液,然后移入水培缸中,放置在室温下。处理后24小时在双目镜下检查结果。 (做三次平行试验取平均值)
蚊幼虫:尖音库蚊淡色亚种,室内饲养的正常群体。称取供试化合物约5mg于盘尼西林药瓶中,加5mL丙酮(或适宜溶剂),振荡溶解,即为1000μg/mL母液。移取1.0mL母液,加入盛有89.0mL水的100mL烧杯中,选取10头4龄初蚊子幼虫,连同10mL饲养液一并倒入烧杯中,其药液的浓度即为10μg/mL。放入标准处理室内,24小时检查结果。以含有1.0 mL试验溶剂的水溶液为空白对照。同理配制5,2,1μg/mL化合物溶液测试。
杀菌活性测试方法
离体杀菌测试,菌体生长速率测定法(平皿法):将一定量药剂溶解在适量丙酮内,然后用含有200μg/mL乳化剂水溶液稀释至所需浓度,然后各吸取1mL药液注入培养皿内,再分别加入9mL培养基,摇匀后制成50μg/mL的含药平板,以添加1mL灭菌水的平板做空白对照。用直径4mm的打孔器沿菌丝外缘切取菌盘,移至含药平板上。每处理重复三次。将培养皿放在24±1℃恒温培养箱内培养。48小时后调查各处理菌盘扩展直径,求平均值,与空白对照比较计算相对抑菌率。
实施例6:14-及11-酰腙苦参碱衍生物的抗烟草花叶病毒病、杀虫与杀菌活性测试结果化合物1-25抗烟草花叶病毒:
表1 化合物1-25抗烟草花叶病毒(TMV)活性测试数据
由表1我们可以得出以下构效关系:
1.一半以上化合物的活性离体高于商品化病毒唑(40.9%,500μg/mL)与苦参碱(29.8%,500μg/mL),少数化合物离体活性与宁南霉素(55.4%,500μg/mL)相近。例如,14-(3- 硝基-4-羟基苯甲醛)苦参碱甲酰腙(9)(49.6%,500μg/mL)与14-(3,5-二甲基-4-羟基苯甲醛苦参碱甲酰腙)(11)(51.3%,500μg/mL)有较高的离体活性。
2.带吸电子基团的苯甲醛类苦参碱酰腙化合物活体活性>苯环上带给电子基团的苯甲醛类苦参碱酰腙化合物>病毒唑>苦参碱,例如,14-(4-三氟甲氧基苯甲醛)苦参碱甲酰腙(14)的活体活性为(53.3±2.9,49.6±1.4,50±0.8%,500μg/mL)高于14-(4-二甲氨基苯甲醛)苦参碱甲酰腙(5)(48.5±3.1,45±0.8,50.6±2.0%,500μg/mL)和14-(3-羟基苯甲醛)苦参碱甲酰腙(8) (42.1±1.7,45.5±3.8,48.3±1.0%,500μg/mL)。
当苯甲醛上连有羟基时,2-羟基与3-羟基苯甲醛苦参酰腙的活性均大于苦参碱,但两者活性几乎相同,说明羟基位置不影响活性,即14-(3-羟基苯甲醛)苦参碱甲酰腙(8)(42.1±1.7, 45.5±3.8,48.3±1.0%,500μg/mL)≈14-(2-羟基苯甲醛)苦参碱甲酰腙(7)(42.4±3.6,46±1.3, 39±2.2%,500μg/mL)。
3.烷基醛类苦参碱酰腙化合物的活体活性总体高于苦参碱(39±2.8,33.4±3.1,40.3±1.5%,500μg/mL)与病毒唑(36.5±0.9,38.0±1.6,35.1±2.2%,500μg/mL),而且支链醛类苦参碱酰腙化合物的活体活性与环状醛类苦参碱酰腙化合物的活性相当。例如,14-特戊醛苦参碱甲酰腙(21)(46.5±0.4,49±0.6,42±3.6%,500μg/mL)≈14-环己醛苦参碱甲酰腙(23) (43.1±4.0,48.2±2.8,39.7±0.5%,500μg/mL)。
4.对于杂环类醛的苦参碱化合物,噻吩类苦参碱酰腙的活体活性低于吡啶类苦参碱酰腙,即14-(3-吡啶甲醛)苦参碱甲酰腙(24)(51.9±1.6,47.1±2.7,53.5±4.0%,500μg/mL)>14-(5- 甲基噻吩甲醛)苦参碱甲酰腙)(25)(44.6±2.7,49.8±3.3,40.2±3.9%,500μg/mL)。
化合物1-25杀虫活性
表2 化合物1-25杀虫活性测试数据
表3 化合物1-25杀虫活性测试数据
由表2和3我们可以得出以下构效关系:
1.几乎所有衍生物对玉米螟、棉铃虫、成螨和蚜虫无活性。
2.所有衍生物抑制蚊幼虫活性较好,有很好选择性。在10μg/mL的浓度下,有一半以上化合物活性达100%,14-(3-硝基-4-羟基苯甲基)苦参碱甲酰腙(9)和14-(3-硝基苯甲醛)苦参碱甲酰腙(15)在2μg/mL的浓度下,杀虫活性仍能到达45%。
3.所有衍生物抑制小菜蛾活性较好。在600μg/mL的浓度下,所有化合物致死率可达到 60%以上,在200μg/mL的浓度下,一半以上化合物致死率达到100%。14-(3-硝基-4-羟基苯甲醛)苦参碱甲酰腙)(9)、14-(3,5-二甲基-4-羟基苯甲基)苦参碱甲酰腙(I1)、14-(4-氯苯甲基) 苦参碱甲酰腙(12)、14-(4-三氟甲氧基苯甲醛)苦参碱甲酰腙(14)、14-(叔丁基乙酮)苦参碱甲酰腙(20)在50μg/mL的浓度下仍表现出一定的杀虫活性,抑制率分别是30%,30%,20%, 20%,25%。
4.总的来看,当苯环上为吸电子基团时,有利于活性提高,当为脂肪链或者给电子基团时,活性较低。
化合物1-25杀菌活性
表4 化合物1-25杀菌活性测试数据
由表4我们可以得出以下构效关系:
1.大多数衍生物均有杀菌活性,说明苦参碱衍生物具有广谱杀菌活性,但是活性与对照物商品化杀菌剂多菌灵和百菌清还有差距。
2.较多化合物具有抑制小麦纹枯病菌活性。其中14-(4-对甲氧基苯甲基)苦参碱甲酰腙 (3)、14-(4-甲基苯甲基)苦参碱甲酰腙(4)、14-(3-溴-4-羟基苯甲醛)苦参碱甲酰腙(10)、14-(3- 硝基苯甲醛)苦参碱甲酰腙(15)、14-(对硝基苯乙酮)苦参碱甲酰腙(16)、14-特戊醛苦参碱甲酰腙(21)对小麦纹枯的离体杀菌活性较好,在50mg/kg的浓度下,抑制活性分别为74.1%, 77.8%,70.4%,80.2%,81.5%,74.1%。
3. 14-(3-硝基苯甲醛)苦参碱甲酰腙(15)与14-(5-甲基噻吩甲醛)苦参碱甲酰腙(25)在 50mg/kg的浓度下苹果轮纹的离体杀菌活性分别为66.1%,87.5%。14-(3-羟基苯甲醛)苦参碱甲酰腙(8)和14-(3-硝基苯甲醛)苦参碱甲酰腙(15)在50mg/kg的浓度下辣椒疫霉的离体杀菌活性分别为60.7%,64.3%。
总的来说,整体杀菌活性较好,有进一步研究价值。
化合物26-45抗烟草花叶病毒活性
表5 11-苦参碱酰腙衍生物的抗烟草花叶病毒活性测试数据
由表5我们可以得出以下构效关系:
1.几乎所有化合物离体活性均高于苦参碱(29.8%,500μg/mL)与商品化病毒唑(40.9%,500μg/mL),且近似于宁南霉素(55.1%,500μg/mL)。尤其N-苄基-11-(3,4-二氯苯甲醛)苦参碱酰腙(33)(61.4%,500μg/mL),N-苄基-11-(4-溴-3-吲哚甲醛)苦参碱酰腙(42) (65.8%,500μg/mL)和N-苄基-11-正辛醛苦参酰腙(43)(63.1%,500μg/mL)离体活性高于宁南霉素。
2.在取代苯甲醛类苦参酰腙化合物活体活性结果中,苯环上带吸电子基团的苦参酰腙化合物活性高于苯环上带吸电子基团的苦参酰腙化合物活性。例如,N-苄基-11-(3-三氟甲基苯甲醛)苦参酰腙(36)(62.5±3.2,64.7±1.5,56.2±3.6%,500μg/mL)好于N-苄基-11-(3,4-二甲氧基苯甲醛)苦参酰腙(27)(57.2±2.1,53.1±4.3,58.9±1.5%,500μg/mL),也好于N-苄基-11-(2,4- 二甲氧基苯甲醛)苦参酰腙(26)(46.2±1.5,40.4±2.8,38.9±1.0%,500μg/mL)。
取代苯甲醛上的羟基在苯环的邻位时,其活体活性好于羟基在间位,例如N-苄基-11-(2- 羟基苯甲醛)苦参酰腙(29)(53.5±2.0,50.8±0.4,47.9±3.6%,500μg/mL)好于N-苄基-11-(3- 羟基苯甲醛)苦参酰腙(30)(45.2±2.8,39.6±0.3,41.5±2.5%,500μg/mL)。
3.在烷基类醛苦参碱酰腙类化合物中,活体活性结果表明,直链醛活体活性好于环状醛与支链醛,例如,N-苄基-11-正辛醛苦参酰腙(43)(52.4±4.4,55.7±1.6,60.8±2.0%,500 μg/mL)>N-苄基-11-环己基甲醛苦参酰腙(45)(51.7±2.7,53.1±3.9,48.4±1.1,500μg/mL)>N- 苄基-11-特戊醛苦参酰腙(44)(30.5±1.3,38.2±2.7,36.1±0.4%,500μg/mL)。
4.在杂环类醛苦参酰腙化合物中,活体活性结果表明,N-苄基-11-(4-溴-3-吲哚甲醛)苦参酰腙(42)(71.8±2.8,66.8±1.3,69.5±3.1%,500μg/mL)的活体活性最好,接近于NK-007 (67.8±1.0,66.9±0.6,70.2±0.7%,500μg/mL),而N-苄基-11-(噻吩-3-甲醛)苦参碱酰腙(40) (60.1±3.4,55.8±2.6,63.9±1.8%,500μg/mL)活性相近于宁南霉素(57.8±1.4,55.3±0.5, 60.3±1.2%,500μg/mL)。
总的来说,此类化合物具有优良的抗烟草花叶病毒活性,值得进一步研究。
化合物26-45杀虫活性
表6 14-酰腙苦参碱酰腙衍生物的杀虫活性测试数据
表7 11-苦参碱酰腙衍生物的活性测试数据)(续)
由表6和7我们可以看出:
1.大多数化合物在600μg/mL的浓度下,对小菜蛾抑制率大于70%。N-苄基-11-特戊醛苦参酰腙(44)对小菜蛾抑制率最高为100%,有待进一步筛选。
2.N-苄基-11-(2,4-二甲氧基苯甲醛)苦参酰腙(26)对蚊幼虫活性较好,在5μg/mL的浓度下,能达到20%的抑制率,有进一步研究价值。
化合物26-45杀菌活性
表8 11-苦参碱酰腙衍生物的离体杀菌活性测试数据
由表8我们可以得出以下构效关系:
1.N-苄基-11-(3,4-二氯苯甲醛)苦参酰腙(33)、N-苄基-11-(3-溴苯甲醛)苦参酰腙(34)、N- 苄基-11-(3-三氟甲基苯甲醛)苦参酰腙(36)、N-苄基-11-(3-硝基苯甲醛)苦参酰腙(37)和N-苄基 -11-正辛醛苦参酰腙(43)对辣椒疫霉有较好的杀菌活性,在50mg/kg浓度下,分别为75.0%、75.0%、81.3%、62.5%以及62.5%。
2.N-苄基-11-(3-羟基苯甲醛)苦参酰腙(30)、N-苄基-11-(噻吩-3-甲醛)苦参碱酰腙(40)在 50mg/kg浓度下对苹果轮纹的离体杀菌活性分别为62.2%和94.6%。N-苄基-11-(3-三氟甲基苯甲醛)苦参酰腙(36)和N-苄基-11-(1-萘甲醛)苦参酰腙(38)在50mg/kg浓度下水稻纹枯的离体杀菌活性分别为69.4%和61.2%。N-苄基-11-(噻吩-3-甲醛)苦参碱酰腙(40)在50mg/kg浓度下,小麦纹枯的离体杀菌活性81.4%。
3.所有化合物都有一定程度的杀菌活性,具备进一步研究的价值。
Claims (6)
4.权利要求1所述的14-及11-酰腙苦参碱衍生物在抑制烟草花叶病毒方面的应用。
5.权利要求1所述的14-及11-酰腙苦参碱衍生物在杀虫方面的应用。
6.权利要求1所述的14-及11-酰腙苦参碱衍生物在杀菌方面的应用。
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