CN103833734B - 一种n-氨乙基萜品烯马来酰亚胺基咪唑衍生物的合成方法 - Google Patents

一种n-氨乙基萜品烯马来酰亚胺基咪唑衍生物的合成方法 Download PDF

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CN103833734B
CN103833734B CN201410088268.5A CN201410088268A CN103833734B CN 103833734 B CN103833734 B CN 103833734B CN 201410088268 A CN201410088268 A CN 201410088268A CN 103833734 B CN103833734 B CN 103833734B
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aminoethyl
dimaleoyl imino
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CN103833734A (zh
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段文贵
蔺志铎
岑波
林桂汕
刘陆智
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Guangxi University
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
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Abstract

一种N-氨乙基萜品烯马来酰亚胺基咪唑衍生物的合成方法，包括以下步骤：以α-蒎烯为原料，先将α-蒎烯转化为α-萜品烯马来酸酐加成物(简称TMA)，然后将α-萜品烯马来酸酐加成物与乙二胺反应制备得到中间体N-氨乙基萜品烯马来酰亚胺(简称ATM)，然后通过N-氨乙基萜品烯马来酰亚胺中氨基的改性反应，合成具有潜在生物活性的N-氨乙基萜品烯马来酰亚胺基咪唑衍生物。本发明首次实现了将N原子引入到α-萜品烯马来酸酐结构中，合成一种含咪唑环的重要的有机化合物。N-氨乙基萜品烯马来酰亚胺基咪唑化合物具有多种生物活性，特别是杀菌活性，扩大了α-蒎烯的应用范围，为天然有机绿色资源—松节油的深度开发利用提供新的途径。

Description

一种N-氨乙基萜品烯马来酰亚胺基咪唑衍生物的合成方法
技术领域
本发明涉及有机合成技术领域，特别是一种N-氨乙基萜品烯马来酰亚胺基咪唑衍生物的合成方法。
背景技术
咪唑类化合物作为许多天然酶和生物系统的活性中心功能基，在医药和农药领域都发挥重要用途。在医药领域，部分咪唑类化合物具有抗菌、抗癌、抗炎、镇痛、抗过敏等药物活性。在农药领域，许多含有咪唑基的化合物可以作为杀菌剂、酶抑制剂、杀虫剂、植物生长调节剂和除草剂等。咪唑类化合物具有高效、低毒、不易产生抗药性和环境友好的特点而倍受许多科学家关注。近年来,咪唑类衍生物成为了国内外含氮新型杂环化合物合成与应用的研究热点。
松节油是我国的再生性天然优势资源，主要成分是α-蒎烯。松节油有独特香气，无毒，廉价易得，很早就被广泛应用于香料、医药、油漆溶剂和清洁剂。目前世界上对松节油的利用已从直接利用松节油初产品向深入开发松节油衍生物转变。α-蒎烯为双环单萜，其分子中的主要官能团是双键和四元环，其分子本身及其亚结构单元是良好的活性基团，易于进行改性。基于双键的改性主要有氧化、加成、酯化、成环和聚合等多种反应，其被氧化生成蒎烷、α-蒎烯臭氧化物、蒎酮、紫苏醛、蒎酮酸和高聚物等。基于四元环的改性主要是利用四元环内张力较大，经催化发生瓦格纳-迈尔外因重排，可以异构化为龙脑、β-蒎烯、莰烯、小茴香烯和双戊烯等多种重要的化合物。α-萜品烯马来酸酐加成物是松节油改性产品之一，是α-蒎烯经瓦格纳-迈尔外因重排之后，再与马来酸酐发生狄尔斯-阿尔德环加成反应的产物，再将其他基团引入α-萜品烯马来酸酐骨架中。目前，已在杀菌、杀虫、和除草等方面得到应用。
本发明N-氨乙基萜品烯马来酰亚胺基咪唑衍生物是一种新型的功能性衍生物，该物质及其合成方法到目前为止未见有国内外报道。
发明内容
本发明的目的是提供一种N-氨乙基萜品烯马来酰亚胺基咪唑衍生物的合成方法，所得产物成本低，制备方法简单。
本发明采用以下技术方案达到上述目的：
一种N-氨乙基萜品烯马来酰亚胺基咪唑衍生物，其特征在于，所述化合物的结构通式为：
其中R为氢、对氟、邻氟、对氯、邻氯、对溴、邻溴、邻硝基、邻甲氧基中的任意一种。
一种制备所述的N-氨乙基萜品烯马来酰亚胺基咪唑衍生物的方法，按下式反应：
其中R为氢、对氟、邻氟、对氯、邻氯、对溴、邻溴、邻硝基、邻甲氧基中的任意一种，所述TMA是将α-蒎烯转化为α-萜品烯马来酸酐加成物，简称TMA。
一种制备所述的N-氨乙基萜品烯马来酰亚胺基咪唑衍生物的方法，包括以下步骤：
(1)中间体ATM的制备
在三口瓶中，先加入2.7gTMA和20ml无水乙醇，搅拌、加热升温至80℃，开始向烧瓶中滴加3.0ml乙二胺的无水乙醇20ml溶液，10min滴完，回流反应4h，用TLC和水合茚三酮跟踪反应至终点，减压旋蒸除去溶剂，用硅胶柱层析纯化，洗脱剂按体积比为甲醇:二氯甲烷=1:5，真空干燥，得到黄色粘性液体ATM，所述ATM是将α-萜品烯马来酸酐加成物与乙二胺反应制备得到中间体N-氨乙基萜品烯马来酰亚胺，简称ATM。
(2)合成N-氨乙基萜品烯马来酰亚胺基咪唑衍生物
以氧化锌作为反应的催化剂，按质量比为：ATM：苯偶酰：取代苯甲醛：乙酸铵＝1:1:1.2:10反应。
所述的取代苯甲酸为苯甲醛、对氟基苯甲醛、邻氟基苯甲醛、对氯苯甲醛、邻氯基苯甲醛、对溴苯甲醛、邻溴苯甲醛、邻硝基苯甲醛、邻甲氧基苯甲醛中的任意一种。
本发明的有益效果：
以我国天然再生性优势资源松节油的主要成分—α-蒎烯为原料，将其经瓦格纳-迈尔外因重排得α-萜品烯，再与马来酸酐发生狄尔斯-阿尔德环加成反应得到TMA，然后将α-萜品烯马来酸酐加成物与乙二胺反应制备得到中间体ATM，最后通过ATM中氨基的改性反应，制备得到N-氨乙基萜品烯马来酰亚胺基咪唑衍生物。从而提高了松节油的附加值，为天然有机绿色资源—松节油的深度开发利用提供新的途径。
具体实施方式
以下通过具体实施例对本发明的技术方案作进一步说明。
实施例1
化合物a的制备：
向三口瓶中加入0.6gATM，0.4g苯偶酰，0.26g苯甲醛，1.5gNH4OAc，0.032gZnO和5ml甲苯，搅拌回流2h，用TLC和水合茚三酮检测无ATM时结束反应，蒸出溶剂，粗产品用硅胶柱纯化，洗脱剂为石油醚/乙酸乙酯：10/1,5/1,3/1梯度洗脱，再用二氯甲烷和石油醚混合溶液重结晶得到目标产物a。白色晶体，m.p.187～188℃。IR(KBr,cm-1)ν:3030(Ar-H),2958,2869(C-H),1771,1700(C=O),1601(Ar-C=C),1502(C=N),1125(C-N)。1HNMR(600MHz,CDCl3)δ/ppm:7.73～7.71(m,2H,C19-H,C23-H),7.52～7.49(m,5H,Cb1-H,Cc1-H,Cd1-H,Ce1-H,Cf1-H),7.49～7.46(m,4H,C20-H,C22-H,Cb-H,Cf-H),7.45(t,J=7.4Hz,1H,C21-H),7.19(t,J=7.5Hz,2H,Cc-H,Ce-H),7.13(t,J=7.3Hz,1H,Cd-H),5.74(d,J=8.4Hz,1H,C8-H),5.66(d,J=8.4Hz,1H,C7-H),4.21(m,1H,C16-Ha),4.08(m,1H,C15-Ha),3.32(dt,J=13.6,6.8Hz,1H,C16-Hb),3.22(dt,J=13.6,5.7Hz,1H,C15-Hb),2.43(d,J=7.8Hz,1H,C2-H),2.42～2.38(m,1H,C11-H),2.17(d,J=7.9Hz,1H,C5-H),1.40～1.35(m,1H,C9-Ha),1.34(s,3H,C14-H),1.31～1.26(m,1H,C10-Ha),1.22(td,J=12.0,3.8Hz,1H,C9-Hb),1.15(td,J=11.7,4.5Hz,1H,C10-Hb),0.96(d,J=6.8Hz,3H,C13-H),0.89(d,J=7.0Hz,3H,C12-H)。13CNMR(150MHz,CDCl3)δ/ppm:176.57(C-4),176.34(C-3),147.50(C-17),138.50(C-25),136.17(C-7),135.54(C-8),134.56(C-a),131.29(C-20,C-22),131.05(C-a1),131.02(C-21),129.77(C-18),129.34(C-c1,C-e1),129.25(C-c,C-e),129.00(C-24),128.96(C-d1),128.87(C-19,C-23),128.09(C-b1,C-f1),127.06(C-b,C-f),126.42(C-d),50.08(C-5),46.21(C-2),43.40(C-1),41.77(C-15),38.18(C-16),36.74(C-6),34.41(C-10),29.46(C-11),22.82(C-9),22.64(C-14),18.38(C-13),16.85(C-12)。ESI-MSm/z:556([M+H]+)。
实施例2
化合物b的制备：
向三口瓶中加入0.6gATM，0.4g苯偶酰，0.3g对氟苯甲醛，1.5gNH4OAc，0.032gZnO和5ml甲苯，搅拌回流2h，用TLC和水合茚三酮检测无ATM时结束反应，蒸出溶剂，粗产品用硅胶柱纯化，洗脱剂为石油醚/乙酸乙酯：10/1,5/1,3/1梯度洗脱，再用二氯甲烷和石油醚混合溶液重结晶得到目标产物b。淡黄色粉末,m.p.212～214℃。IR(KBr,cm-1)ν:3030(Ar-H),2958,2869(C-H),1771,1700(C=O),1601(Ar-C=C),1529(C=N),1107(C-N)。1HNMR(600MHz,CDCl3)δ/ppm:7.73(m,2H,C19-H,C23-H),7.50(m,5H,Cb1-H,Cc1-H,Cd1-H,Ce1-H,Cf1-H),7.47～7.44(m,2H,Cb-H,Cf-H),7.21(m,2H,C20-H,C22-H),7.19(m,2H,Cc-H,Ce-H),7.13(t,J=7.3Hz,1H,Cd-H),5.76(d,J=8.4Hz,1H,C8-H),5.67(d,J=8.4Hz,1H,C7-H),4.13(dt,J=14.0,6.8Hz,1H,C16-Ha),4.02(dt,J=12.2,6.4Hz,1H,C15-Ha),3.33(dt,J=13.6,6.8Hz,1H,C16-Hb),3.26～3.21(m,1H,C15-Hb),2.53(d,J=7.9Hz,1H,C2-H),2.43(dt,J=13.7,6.8Hz,1H,C11-H),2.24(d,J=7.9Hz,1H,C5-H),1.41～1.36(m,1H,C9-Ha),1.36(s,3H,C14-H),1.31(dd,J=11.1,6.7Hz,1H,C10-Ha),1.22(dd,J=12.2,3.7Hz,1H,C9-Hb),1.17(td,J=11.8,4.5Hz,1H,C10-Hb),0.98(d,J=6.8Hz,3H,C13-H),0.91(d,J=7.0Hz,3H,C12-H)。13CNMR(150MHz,CDCl3)δ/ppm:176.61(C-4),176.34(C-3),164.14(C-21),162.48(C-17),146.68(C-25),138.47(C-a),136.22(C-7),135.59(C-8),134.43(C-a1),131.31(C-23),131.25(C-19),131.23(C-c1,C-e1),130.86(C-24),129.81(C-d1),129.41(C-c,C-e),129.07(C-d),128.18(C-b1,C-f1),127.09(C-b,C-f),126.57(C-18),116.07(C-22),115.92(C-20),50.13(C-5),46.29(C-2),43.51(C-1),41.81(C-15),38.07(C-16),36.84(C-6),34.41(C-10),29.52(C-11),22.87(C-9),22.66(C-14),18.41(C-13),16.82(C-12)。ESI-MSm/z:574([M+H]+)。
实施例3
化合物c的制备：
向三口瓶中加入0.6gATM，0.4g苯偶酰，0.26g邻氟苯甲醛，1.5gNH4OAc，0.032gZnO和5ml甲苯，搅拌回流2h，用TLC和水合茚三酮检测无ATM时结束反应，蒸出溶剂，粗产品用硅胶柱纯化，洗脱剂为石油醚/乙酸乙酯：10/1,7/1,5/1,3/1,2/1梯度洗脱，再用二氯甲烷和石油醚混合溶液重结晶得到目标产物c。淡黄色粉末,m.p.65～68℃。IR(KBr,cm-1)ν:3039(Ar-H),2958,2869(C-H),1771,1700(C=O),1601(Ar-C=C),1580(C=N),1017(C-N)。1HNMR(600MHz,CDCl3)δ/ppm:7.71(td,J=7.5,1.7Hz,1H,C23-H),7.51(dd,J=7.3,6.0Hz,5H,Cb1-H,Cc1-H,Cd1-H,Ce1-H,Cf1-H),7.49～7.48(m,2H,Cb-H,Cf-H),7.47(m,1H,C21-H),7.31(td,J=7.5,0.9Hz,1H,C20-H),7.21(m,1H,C22-H),7.18(d,J=7.7Hz,2H,Cc-H,Ce-H),7.13(t,J=7.3Hz,1H,Cd-H),5.75(d,J=8.4Hz,1H,C8-H),5.66(d,J=8.4Hz,1H,C7-H),4.09(m,1H,C16-Ha),3.98(dt,J=15.0,5.6Hz,1H,C15-Ha),3.28(m,1H,C16-Hb),3.16(dt,J=13.6,5.5Hz,1H,C15-Hb),2.50(d,J=7.9Hz,1H,C2-H),2.40(dt,J=13.8,6.9Hz,1H,C11-H),2.22(d,J=7.9Hz,1H,C5-H),1.41～1.36(m,1H,C9-Ha),1.33(s,3H,C14-H),1.31(dd,J=12.3,4.5Hz,1H,C10-Ha),1.22(td,J=12.0,3.7Hz,1H,C9-Hb),1.15(td,J=11.8,4.4Hz,1H,C10-Hb),0.95(d,J=6.8Hz,3H,C13-H),0.89(d,J=7.0Hz,3H,C12-H)。13CNMR(150MHz,CDCl3)δ/ppm:176.59(C-4),176.33(C-3),160.81(C-19),159.16(C-17),142.68(C-25),139.02(C-a),136.22(C-7),135.58(C-8),134.49(C-a1),132.81(d,J=2.1Hz,C-21),131.28(C-c1,C-e1),130.85(C-24),129.91(C-23),129.37(C-c,C-e),129.01(C-d1),128.15(C-b1,C-f1),127.11(C-b,C-f),126.54(C-d),124.86(d,J=3.4HzC-22),116.40(C-18),116.26(C-22),50.09(C-5),46.26(C-2),43.48(C-1),41.78(C-15),38.22(C-16),36.81(C-6),34.44(C-10),29.49(C-11),22.89(C-9),22.67(C-14),18.42(C-13),16.88(C-12)。ESI-MSm/z:574([M+H]+)。
实施例4
化合物d的制备：
向三口瓶中加入0.6gATM，0.4g苯偶酰，0.34g对氯苯甲醛，1.5gNH4OAc，0.032gZnO和5ml甲苯，搅拌回流2h，用TLC和水合茚三酮检测无ATM时结束反应，蒸出溶剂，粗产品用硅胶柱纯化，洗脱剂为石油醚/乙酸乙酯：10/1,5/1,4/1梯度洗脱，再用二氯甲烷和石油醚混合溶液重结晶得到目标产物d。淡黄色粉末,m.p.207～209℃。IR(KBr,cm-1)ν:3039(Ar-H),2958,2869(C-H),1771,1700(C=O),1601(Ar-C=C),1502(C=N),1090(C-N)。1HNMR(600MHz,CDCl3)δ/ppm:7.70(d,J=8.5Hz,2H,C19-H,C23-H),7.52～7.49(m,5H,Cb1-H,Cc1-H,Cd1-H,Ce1-H,Cf1-H),7.48(dd,J=4.0,2.1Hz,2H,C20-H,C22-H),7.46～7.44(m,2H,Cb-H,Cf-H),7.19(dd,J=8.1,6.8Hz,2H,Cc-H,Ce-H),7.14(t,J=7.3Hz,1H,Cd-H),5.76(d,J=8.4Hz,1H,C8-H),5.68(d,J=8.4Hz,1H,C7-H),4.19～4.14(m,1H,C16-Ha),4.06–4.01(m,1H,C15-Ha),3.34(dt,J=13.6,6.8Hz,1H,C16-Hb),3.23(dt,J=13.5,5.9Hz,1H,C15-Hb),2.49(d,J=7.9Hz,1H,C2-H),2.43(dt,J=13.7,6.9Hz,1H,C11-H),2.21(d,J=7.9Hz,1H,C5-H),1.42～1.37(m,1H,C9-Ha),1.36(s,3H,C14-H),1.34～1.29(m,1H,C10-Ha),1.25～1.21(m,1H,C9-Hb),1.17(td,J=11.8,4.4Hz,1H,C10-Hb),0.99(d,J=6.8Hz,3H,C13-H),0.91(d,J=6.9Hz,3H,C12-H)。13CNMR(150MHz,CDCl3)δ/ppm:176.56(C-4),176.35(C-3),146.36(C-17),138.67(C-25),136.19(C-7),135.57(C-8),135.18(C-a),134.36(C-21),131.21(C-20,C-22),130.77(C-a1),130.53(C-c1,C-e1),130.09(C-24),129.47(C-d1),129.41(C-c,C-e),129.13(C-19,C-23),129.11(C-d),128.16(C-b1,C-f1),127.05(C-b,C-f),126.58(C-18),50.13(C-5),46.26(C-2),43.48(C-1),41.83(C-15),38.10(C-16),36.80(C-6),34.40(C-10),29.50(C-11),22.86(C-9),22.64(C-14),18.39(C-13),16.81(C-12)。ESI-MSm/z:590([M+H]+)。
实施例5
化合物e的制备：
向三口瓶中加入0.6gATM，0.4g苯偶酰，0.34g邻氯苯甲醛，1.5gNH4OAc，0.032gZnO和5ml甲苯，搅拌回流2h，用TLC和水合茚三酮检测无ATM时结束反应，蒸出溶剂，粗产品用硅胶柱纯化，洗脱剂为石油醚/乙酸乙酯：10/1,5/1,3/1梯度洗脱，再用二氯甲烷和石油醚混合溶液重结晶得到目标产物e。白色粉末,m.p.172～175℃。IR(KBr,cm-1)ν:3057(Ar-H),2958,2869(C-H),1771,1700(C=O),1601(Ar-C=C),1502(C=N),1125(C-N)。1HNMR(600MHz,CDCl3)δ/ppm:7.68(dd,J=7.0,2.1Hz,1H,C23-H),7.53～7.48(m,5H,Cb1-H,Cc1-H,Cd1-H,Ce1-H,Cf1-H),7.47(d,J=5.3Hz,2H,Cb-H,Cf-H),7.46(s,1H,C20-H),7.43(dt,J=10.3,4.7Hz,2H,C21-H,C22-H),7.19(t,J=7.6Hz,2H,Cc-H,Ce-H),7.13(t,J=7.3Hz,1H,Cd-H),5.74(d,J=8.4Hz,1H,C8-H),5.65(d,J=8.4Hz,1H,C7-H),4.02～3.97(m,1H,C16-Ha),3.90(dt,J=14.8,5.7Hz,1H,C15-Ha),3.27(dt,J=13.4,6.6Hz,1H,C16-Hb),3.19～3.13(m,1H,C15-Hb),2.58(d,J=7.9Hz,1H,C2-H),2.40(dt,J=13.7,6.9Hz,1H,C11-H),2.27(d,J=7.9Hz,1H,C5-H),1.41～1.36(m,1H,C9-Ha),1.33(s,3H,C14-H),1.32～1.28(m,1H,C10-Ha),1.22(td,J=12.0,3.7Hz,1H,C9-Hb),1.16(td,J=11.8,4.4Hz,1H,C10-Hb),0.96(d,J=6.7Hz,3H,C13-H),0.89(d,J=7.0Hz,3H,C12-H)。13CNMR(150MHz,CDCl3)δ/ppm:176.55(C-4),176.23(C-3),145.03(C-17),138.30(C-25),136.20(C-7),135.56(C-8),134.50(C-18),133.07(C-a),131.19(C-c1,C-e1),131.05(C-a1),130.80(C-19),130.58(C-21),130.00(C-24),129.36(C-c,C-e),129.15(C-20),128.93(C-23),128.12(C-b1,C-f1),127.23(C-d1),127.10(C-b,C-f),126.48(C-d),117.11(C-22),50.11(C-5),46.31(C-2),43.48(C-1),41.70(C-15),38.23(C-16),36.81(C-6),34.39(sC-10),29.45(C-11),22.87(C-9),22.64(C-14),18.40(C-13),16.86(C-12)。MS(ESI)m/z:590([M+H]+)。
实施例6
化合物f的制备：
向三口瓶中加入0.6gATM，0.4g苯偶酰，0.45g对溴苯甲醛，1.5gNH4OAc，0.032gZnO和5ml甲苯，搅拌回流2h，用TLC和水合茚三酮检测无ATM时结束反应，蒸出溶剂，粗产品用硅胶柱纯化，洗脱剂为石油醚/乙酸乙酯：10/1,7/1,3/1梯度洗脱，再用二氯甲烷和石油醚混合溶液重结晶得到目标产物f。白色晶体,m.p.211～213℃。IR(KBr,cm-1)ν:3039(Ar-H),2958,2869(C-H),1771,1700(C=O),1601(Ar-C=C),1502(C=N),1125(C-N)。1HNMR(600MHz,CDCl3)δ/ppm:7.64(s,4H,C19-H,C20-H,C22-H,C23-H),7.52～7.47(m,5H,Cb1-H,Cc1-H,Cd1-H,Ce1-H,Cf1-H),7.46～7.44(m,2H,Cb-H,Cf-H),7.19(t,J=7.5Hz,2H,Cc-H,Ce-H),7.13(t,J=7.3Hz,1H,Cd-H),5.76(d,J=8.4Hz,1H,C8-H),5.68(d,J=8.4Hz,1H,C7-H),4.20～4.14(m,1H,C16-Ha),4.04(m,1H,C15-Ha),3.34(dt,J=13.5,6.8Hz,1H,C16-Hb),3.23(dt,J=13.5,5.8Hz,1H,C15-Hb),2.48(d,J=7.9Hz,1H,C2-H),2.45～2.39(m,1H,C11-H),2.20(d,J=7.9Hz,1H,C2-H),1.42～1.37(m,1H,C9-Ha),1.36(s,3H,C14-H),1.34～1.28(m,1H,C10-Ha),1.23(td,J=12.0,3.7Hz,1H,C9-Hb),1.17(td,J=11.8,4.4Hz,1H,C10-Hb),1.00(d,J=6.8Hz,3H,C13-H),0.91(d,J=7.0Hz,3H,C12-H)。13CNMR(150MHz,CDCl3)δ/ppm:176.57(C-4),176.36(C-3),146.34(C-17),138.71(C-25),136.18(C-7),135.56(C-8),135.54(C-a),134.34(C-a1),132.07(C-20,C-22),131.20(C-19,C-23),130.75(C-c1,C-e1),130.14(C-18),129.92(C-24),129.41(C-c,C-e),129.11(C-d1),128.16(C-b1,C-f1),127.03(C-b,C-f),126.59(C-d),123.40(C-21),50.14(C-5),46.26(C-2),43.48(C-1),41.83(C-15),38.12(C-16),36.79(C-6),34.39(C-10),29.51(C-11),22.86(C-9),22.64(C-14),18.40(C-13),16.86(C-12)。ESI-MSm/z:634([M+H]+)。
实施例7
化合物g的制备：
向三口瓶中加入0.6gATM，0.4g苯偶酰，0.45g邻溴苯甲醛，1.5gNH4OAc，0.032gZnO和5ml甲苯，搅拌回流2h，用TLC和水合茚三酮检测无ATM时结束反应，蒸出溶剂，粗产品用硅胶柱纯化，洗脱剂为石油醚/乙酸乙酯：10/1,7/1,3/1梯度洗脱，再用二氯甲烷和石油醚混合溶液重结晶得到目标产物g。白色粉末,m.p.96～98℃。IR(KBr,cm-1)ν:3039(Ar-H),2958,2869(C-H),1771,1700(C=O),1601(Ar-C=C),1502(C=N),1152(C-N)。1HNMR(600MHz,CDCl3)δ/ppm:7.69(d,J=7.6Hz,1H,C23-H),7.67(dd,J=7.6,1.6Hz,1H,C20-H),7.52～7.47(m,5H,Cb1-H,Cc1-H,Cd1-H,Ce1-H,Cf1-H),7.46(t,J=3.7Hz,2H,Cb-H,Cf-H),7.44(d,J=1.3Hz,1H,C22-H),7.36(td,J=7.8,1.7Hz,1H,C21-H),7.19(t,J=7.6Hz,2H,Cc-H,Ce-H),7.13(t,J=7.3Hz,1H,Cd-H),5.74(d,J=8.4Hz,1H,C8-H),5.65(d,J=8.4Hz,1H,C7-H),3.97(dt,J=13.7,6.7Hz,1H,C16-Ha),3.87(dt,J=14.8,5.8Hz,1H,C15-Ha),3.27(dt,J=13.5,6.7Hz,1H,C16-Hb),3.17(dt,J=13.5,5.8Hz,1H,C15-Hb),2.60(d,J=7.9Hz,1H,C2-H),2.39(dt,J=13.7,6.9Hz,1H,C11-H),2.28(d,J=7.9Hz,1H,C2-H),1.41～1.36(m,1H,C9-Ha),1.33(s,3H,C14-H),1.32～1.28(m,1H,C10-Ha),1.23(td,J=12.0,3.7Hz,1H,C9-Hb),1.16(td,J=11.8,4.4Hz,1H,C10-Hb),0.96(d,J=6.8Hz,3H,C13-H),0.89(d,J=7.0Hz,3H,C12-H)。13CNMR(150MHz,CDCl3)δ/ppm:176.58(C-4),176.23(C-3),146.26(C-17),138.08(C-25),136.23(C-7),135.59(C-8),134.52(C-18),133.19(C-a),133.12(C-a1),132.66(C-20),131.25(C-21),131.23(C-c1,C-e1),130.82(C-23),129.38(C-c,C-e),129.00(C-24),128.94(C-d1),128.14(C-b1,C-f1),127.77(C-22),127.12(C-b,C-f),126.49(C-d),124.61(C-19),50.14(C-5),46.35(C-2),43.51(C-1),41.81(C-15),38.23(C-16),36.84(C-6),34.41(C-10),29.47(C-11),27.06(C-9),22.89(C-14),18.41(C-13),16.88(C-12)。ESI-MSm/z:634([M+H]+)。
实施例8
化合物h的制备：
向三口瓶中加入0.6gATM，0.4g苯偶酰，0.36g邻硝基苯甲醛，1.5gNH4OAc，0.032gZnO和5ml甲苯，搅拌回流2h，用TLC和水合茚三酮检测无ATM时结束反应，蒸出溶剂，粗产品用硅胶柱纯化，洗脱剂为石油醚/乙酸乙酯：14/1,5/1,3/1,1/1梯度洗脱，再用二氯甲烷和石油醚混合溶液重结晶得到目标产物h。黄色粉末,m.p.232～234℃。IR(KBr,cm-1)ν:3048(Ar-H),2958,2869(C-H),1771,1700(C=O),1601(Ar-C=C),1529(C=N),1197(C-N)702(NO2)。1HNMR(600MHz,CDCl3)δ/ppm:8.19(d,J=8.4Hz,1H,C23-H),7.79(d,J=3.5Hz,2H,C20-H,C22-H),7.69(m,1H,C21-H),7.53～7.47(m,5H,Cb1-H,Cc1-H,Cd1-H,Ce1-H,Cf1-H),7.46(d,J=7.3Hz,2H,Cb-H,Cf-H),7.18(t,J=7.5Hz,2H,Cc-H,Ce-H),7.12(t,J=7.3Hz,1H,Cd-H),5.74(d,J=8.4Hz,1H,C8-H),5.65(d,J=8.4Hz,1H,C7-H),3.88(m,1H,C16-Ha),3.81～3.75(m,1H,C15-Ha),3.32(dt,J=14.2,7.1Hz,1H,C16-Hb),3.24(m,1H,C15-Hb),2.61(d,J=7.9Hz,1H,C2-H),2.38(dt,J=13.7,6.8Hz,1H,C11-H),2.29(d,J=7.9Hz,1H,C5-H),1.40～1.35(m,1H,C9-Ha),1.33(s,3H,C14-H),1.29(dd,J=10.1,4.0Hz,1H,C10-Ha),1.22(td,J=12.1,3.6Hz,1H,C9-Hb),1.15(td,J=11.8,4.3Hz,1H,C10-Hb),0.95(d,J=6.8Hz,3H,C-13),0.89(d,J=7.0Hz,3H,C-12)。13CNMR(150MHz,CDCl3)δ/ppm:176.67(C-4),176.26(C-3),149.20(C-17),143.04(C-19),138.58(C-25),136.23(C-7),135.56(C-8),134.28(C-a),133.52(C-22),131.21(C-c1,C-e1),131.14(C-23),130.79(C-a1),130.49(C-24),129.51(C-21),129.44(C-c,C-e),129.16(C-d1),128.18(C-b1,C-f1),127.05(C-b,C-f),126.61(C-d),126.43(C-18),125.16(C-20),50.09(C-5),46.28(C-2),43.53(C-1),41.64(C-15),37.85(C-16),36.83(C-6),34.34(C-10),29.47(C-11),22.88(C-9),22.64(C-14),18.42(C-13),16.88(C-12)。ESI-MSm/z:601([M+H]+)。
实施例9
化合物i的制备：
向三口瓶中加入0.6gATM，0.4g苯偶酰，0.33g邻甲氧基苯甲醛，1.5gNH4OAc，0.032gZnO和5ml甲苯，搅拌回流2h，用TLC和水合茚三酮检测无ATM时结束反应，蒸出溶剂，粗产品用硅胶柱纯化，洗脱剂为石油醚/乙酸乙酯：7/1,5/1,3/1,2/1梯度洗脱，再用二氯甲烷和石油醚混合溶液重结晶得到目标产物i。淡黄色粉末,m.p.101～103℃。IR(KBr,cm-1)ν:3030(Ar-H),2958,2869(C-H),1763,1700(C=O),1601(Ar-C=C),1583(C=N),1242(C-O),1017(C-N)。1HNMR(600MHz,CDCl3)δ/ppm:7.61(dd,J=7.5,1.8Hz,1H,C23-H),7.51(t,J=1.6Hz,1H,C21-H),7.51～7.48(m,5H,Cb1-H,Cc1-H,Cd1-H,Ce1-H,Cf1-H),7.46(m,2H,Cb-H,Cf-H),7.17(t,J=7.5Hz,2H,Cc-H,Ce-H),7.09(m,2H,C20-H,C22-H),7.00(d,J=8.1Hz,1H,Cd-H),5.73(d,J=8.4Hz,1H,C8-H),5.65(d,J=8.4Hz,1H,C7-H),4.08～4.02(m,1H,C16-Ha),3.93(dt,J=14.9,5.5Hz,1H,C15-Ha),3.86(s,3H,C26-H),3.28(m,1H,C16-Hb),3.16(dt,J=13.6,5.5Hz,1H,C15-Hb),2.45(d,J=7.9Hz,1H,C2-H),2.40(dt,J=13.7,6.9Hz,1H,C11-H),2.18(d,J=7.9Hz,1H,C5-H),1.40～1.34(m,1H,C9-Ha),1.33(s,3H,C14-H),1.29(dd,J=12.2,4.5Hz,1H,C10-Ha),1.21(td,J=12.0,3.8Hz,1H,C9-Hb),1.14(td,J=11.8,4.5Hz,1H,C10-Hb),0.96(d,J=6.8Hz,3H,C-13),0.89(d,J=7.0Hz,3H,C-12)。13CNMR(150MHz,CDCl3)δ/ppm:176.68(C-4),176.42(C-3),157.15(C-19),145.31(C-17),138.38(C-25),136.18(C-7),135.55(C-8),134.80(C-a),132.86(C-a1),131.35(C-c1,C-e1),131.31(C-23),131.13(C-21),129.30(C-24),129.24(C-c,C-e),128.76(C-d1),128.01(C-b1,C-f1),127.06(C-b,C-f),126.21(C-d),121.13(C-22),120.52(C-18),111.45(C-20),55.73(C-26),50.08(C-5),46.22(C-2),43.41(C-1),41.67(C-15),38.34(C-16),36.76(C-6),34.46(C-10),29.48(C-11),27.04(C-9),22.67(C-14),18.39(C-13),16.88(C-12)。ESI-MSm/z:586([M+H]+)。
将实施例1－9所制备得的N-氨乙基萜品烯马来酰亚胺基咪唑衍生物进行杀菌活性测试，测试方法及结果如下：
（1）杀菌活性测试方法：
离体法(琼脂稀释法):①先将样品溶解在丙酮中，然后把200ppm的sorporl-144乳化剂稀释成500ppm药液。②取1ml药液注入培养皿中，然后加9ml的PSA培养基，配制成最终浓度为50ppm的含药平板。③用打孔器打取直径5mm培养好的供试菌饼，放在含药平板内，每皿3块呈等边三角形摆放，以不加任何药剂作空白照。④在培养箱内温度为24±1℃下培养48h。⑤计量各处理过菌丝扩展直径，并空白对照的菌丝做比较来计算相对抑菌率(w%)。
杀菌活性指标：A级w≥90%，B级70%≤w＜90%，C级50%≤w＜70%，D级w＜50%。
（2）杀菌活性测试结果：
N-氨乙基萜品烯马来酰亚胺基咪唑衍生物的杀菌活性
活性分级指标：A级w≥90%；B级70%≤w＜90%；C级50%≤w＜70%；D级w＜50%。
由表可知，样品浓度在50μg·ml-1下，目标化合物a～i对黄瓜枯萎、苹果轮纹、番茄早疫、花生褐斑和小麦赤霉5种病菌表现出不同程度的杀菌活性。尤其对苹果轮纹病菌的抑制活性较突出，有6个目标合物的抑制率达到或超过60%，其中化合物d(R=4-Cl)、a(R=H)、f(R=4-Br)和i(R=2-OCH3)的抑制率分别为69.1%、66.8%、64.5%和64.5%；化合物i对花生褐斑病菌的抑制效果最好，抑制率为68.8%；化合物i对番茄早疫病菌的抑制效果最好，抑制率为68.3%；化合物h(R=2-NO2)对小麦赤霉病菌的抑制效果最好，抑制率均为50.6%；目标化合物对黄瓜枯萎病菌的抑制活性较弱。显然，化合物i(R=2-OCH3)对黄瓜枯萎、花生褐斑和番茄早疫等三种病菌均有最好的抑制活性，且对苹果轮纹也有相对较好的活性(64.5%)，故该化合物是值得进一步研究的先导化合物。

Claims (5)

1.一种N-氨乙基萜品烯马来酰亚胺基咪唑衍生物，其特征在于，结构通式如下：
其中R为氢、对氟、邻氟、对氯、邻氯、对溴、邻溴、邻硝基、邻甲氧基中的任意一种。
2.权利要求1所述N-氨乙基萜品烯马来酰亚胺基咪唑衍生物的合成方法，其特征在于，按下式反应：
其中R为氢、对氟、邻氟、对氯、邻氯、对溴、邻溴、邻硝基、邻甲氧基中的任意一种，所述TMA是将α-蒎烯转化为α-萜品烯马来酸酐加成物，简称TMA，所述ATM是将α-萜品烯马来酸酐加成物与乙二胺反应制备得到中间体N-氨乙基萜品烯马来酰亚胺，简称ATM。
3.如权利要求2所述N-氨乙基萜品烯马来酰亚胺基咪唑衍生物的合成方法，其特征在于，包括以下步骤：
(1)中间体ATM的制备
在三口瓶中，先加入2.7gTMA和20ml无水乙醇，搅拌、加热升温至80℃，开始向烧瓶中滴加3.0ml乙二胺的无水乙醇20ml溶液，10min滴完，回流反应4h，用TLC和水合茚三酮跟踪反应至终点，减压旋蒸除去溶剂，用硅胶柱层析纯化，洗脱剂按体积比为甲醇:二氯甲烷＝1:5，真空干燥，得到黄色粘性液体ATM，所述ATM是将α-萜品烯马来酸酐加成物与乙二胺反应制备得到中间体N-氨乙基萜品烯马来酰亚胺，简称ATM，
(2)合成N-氨乙基萜品烯马来酰亚胺基咪唑衍生物
以氧化锌作为反应的催化剂，按质量比为：ATM：苯偶酰：取代苯甲醛：乙酸铵＝1:1:1.2:10反应。
4.如权利要求2或3所述N-氨乙基萜品烯马来酰亚胺基咪唑衍生物的合成方法，其特征在于，所述的取代苯甲醛为苯甲醛、对氟基苯甲醛、邻氟基苯甲醛、对氯苯甲醛、邻氯苯甲醛、对溴苯甲醛、邻溴苯甲醛、邻硝基苯甲醛、邻甲氧基苯甲醛中的任意一种。
5.权利要求1所述N-氨乙基萜品烯马来酰亚胺基咪唑衍生物在制备杀菌剂中的应用。
CN201410088268.5A 2013-10-09 2014-03-11 一种n-氨乙基萜品烯马来酰亚胺基咪唑衍生物的合成方法 Expired - Fee Related CN103833734B (zh)

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