CN111848441B - 一种n-取代苯甲酰腙类化合物及其制备方法与应用 - Google Patents

一种n-取代苯甲酰腙类化合物及其制备方法与应用 Download PDF

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CN111848441B
CN111848441B CN202010740125.3A CN202010740125A CN111848441B CN 111848441 B CN111848441 B CN 111848441B CN 202010740125 A CN202010740125 A CN 202010740125A CN 111848441 B CN111848441 B CN 111848441B
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朱翠萍
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Shandong Zhongxin Kenong Biological Technology Co ltd
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Abstract

本发明提供一种N‑取代苯甲酰腙类化合物及其制备方法，该类化合物是由酰腙化合物与二芳基丙烯醇在氧化剂的作用下反应制得的，反应氧化剂为二叔丁基过氧化物，溶剂均为无水1、4‑二氧六环，该反应条件简单，有较好的底物普适性，产率高；本发明制备的N‑取代苯甲酰腙类化合物具有良好的生物活性，对麦蚜、棉铃虫、红蜘蛛、白粉虱具有优良的杀虫活性，对人体正常细胞低毒，且酰腙基团容易降解，残留时间短，代谢产物低毒或无毒，危害较小，可应用于新农药的制备中。

Description

一种N-取代苯甲酰腙类化合物及其制备方法与应用
技术领域
本发明属于农药技术领域，尤其涉及一种N-取代苯甲酰腙类化合物及其制备方法与应用。
背景技术
苯甲酰肼可用于农药生产、染料生产及香料等方面，也是有机合成的重要中间体，主要用于医药中间体、有机合成、有机溶剂。农药对农业的发展有着巨大的作用，随着农业的发展，农药大量使用，增产增收的同时带来了严重的环境和社会问题，如水资源污染、大气污染、生物种群灭绝、人类疾病增加等等，所以随着人类对环境保护意识的进一步增强，人们对农药的观念也发生了改变，即在强调其高生物活性的同时更加注重其对人类、环境和非靶标生物的安全性。
酰肼类昆虫生长调节剂是近年来陆续开发的一类高效、选择性强、对环境友好的昆虫生长调节剂，其通过诱导昆虫提前蜕皮，但是又使得其蜕皮过程无法完全进行而杀死害虫。而酰腙类化合物农药与其前体酰肼化合物相比，-NH2基消失，毒性较小，很符合现代农药所要求的低毒高效。
酰腙化合物分子中由于同时含有氧原子与氮原子，因而可以参与生物体中氢键的形成，增加与受体之间亲和力，进而影响生物体内的正常生化反应过程。酰腙基团的代谢产物低毒或无毒，危害较小，且酰腙基团容易降解，残留时间短，所以通过引入腙类基团来改进农药、降低毒性、提高选择性是新的也更加方便安全的方法。
发明内容
本发明的目的在于提供一种N-取代苯甲酰腙类化合物及其制备方法与在抑制害虫中的应用。
本发明的N-取代苯甲酰腙类化合物，具有以下结构通式：
Figure BDA0002606456720000011
其中，R1＝H、4-F、4-Cl、4-Br、4-Me、4-OMe、3-CF3、3,4-2Me；R2＝H、4-F、4-Cl、4-Br、4-Me、4-OMe、3-CF3；R3＝4-Me、4-OMe、4-Cl、2-OH；R4＝4-Me、4-OMe、4-tBu、4-N(CH3)2、4-F、4-Cl、2-OMe、2-OH；或者ArR4＝呋喃、噻吩、吡啶、萘、吲哚。
本发明的N-取代苯甲酰腙类化合物，可以通过以下方法得到产物：
由苯甲酰肼化合物与苯甲醛反应制得酰腙化合物，之后使酰腙化合物与二芳基丙烯醇在氧化剂的作用下反应生成N-取代苯甲酰腙类化合物。
优选地，所述二芳基烯丙醇为1,1-二苯基丙烯醇，1,1-二(4-氟苯基)-丙烯醇，1,1-二(4-氯苯基)-丙烯醇，1,1-二(4-溴苯基)-丙烯醇，1,1-二(4-甲基苯基)-丙烯醇，1,1-二(4-甲氧基苯基)-丙烯醇，1,1-二(3-三氟甲基苯基)-丙烯醇，1-苯基-1-(4-氟苯基)-丙烯醇，1-苯基-1-(4-氯苯基)-丙烯醇，1-苯基-1-(3,4-二甲基苯基)-丙烯醇；
优选地，所述制得的酰腙化合物为N’-苯亚甲基苯并酰肼，N’-苯亚甲基-4-甲基苯并酰肼，N’-苯亚甲基-4-甲氧基苯并酰肼，N’-苯亚甲基-4-氯苯并酰肼，N’-苯亚甲基-2-羟基苯并酰肼，N’-(4-甲基苯亚甲基)苯并酰肼，N’-(2-甲氧基苯亚甲基)苯并酰肼，N’-(4-甲氧基苯亚甲基)苯并酰肼，N’-(4-叔丁基苯亚甲基)苯并酰肼，N’-(4-(二甲基氨基)苯亚甲基)苯并酰肼，N’-(4-氟苯亚甲基)苯并酰肼，N’-(4-氯苯亚甲基)苯并酰肼，N’-(2-羟基苯亚甲基)苯并酰肼，N’-(呋喃-2-亚甲基)苯并酰肼，N’-(噻吩-2-亚甲基)苯并酰肼，N’-(萘-1-亚甲基)苯并酰肼，N’-(1H-吲哚-3-亚甲基)苯并酰肼。
所述N-取代苯甲酰腙类化合物的制备方法，包括以下步骤：
一、将二芳基丙烯醇化合物、酰腙化合物及氧化剂添加于反应管中，惰性气体保护下加入溶剂，然后于100℃下加热反应8h，得到反应混合液；
二、将步骤一所得反应混合液进行分离提纯，得到N-取代苯甲酰腙类化合物。
优选地，所述二芳基丙烯醇化合物、酰腙化合物及氧化剂的摩尔质量比为1:1.1-1.3:1.2-1.5；
优选地，所述溶剂均为无水1,4-二氧六环；
优选地，所述氧化剂为二叔丁基过氧化物；
优选地，步骤二中所述分离提纯的具体为柱色谱提纯法，所用的展开剂为乙酸乙酯：石油醚体积比＝1:6-1:8；
本发明的N-取代苯甲酰腙类化合物的合成反应的通式如下：
Figure BDA0002606456720000031
本发明N-取代苯甲酰腙类化合物是由苯甲酰肼化合物与苯甲醛制备的酰腙化合物在氧化剂作用下生成酰腙的氮中心自由基，之后自由基进攻二芳基丙烯醇的双键得到碳中心自由基中间体，随后中间体在经过分子内成环及芳基迁移后又被氧化、去质子化即得目标产物。
本发明N-取代苯甲酰腙类化合物对麦蚜、棉铃虫、红蜘蛛、白粉虱具有良好的杀虫活性，可应用于农药的制备中。
与现有技术相比，本发明具有如下有益效果：
1.本发明制备的N-取代苯甲酰腙类化合物具有良好的生物活性，对麦蚜、棉铃虫、红蜘蛛、白粉虱具有优良的杀虫活性，且对人体正常细胞低毒。
2.本发明的N-取代苯甲酰腙类化合物的制备方法简单，底物普适性好，且克级反应的产率也达到88％，具有良好的应用前景。
附图说明
图1是本发明N-取代苯甲酰腙类化合物对HEK293细胞的抗增殖活性。
具体实施方式
下面结合具体实施例及附图对本发明技术方案作进一步的详细描述，以使本领域的技术人员可以更好的理解本发明并能予以实施，但所举实施例不作为对本发明的限定。
本发明所述的一种N-取代苯甲酰腙类化合物，该类化合物的结构式为：
Figure BDA0002606456720000041
a 化合物与其异构体的比例
原料酰腙化合物的制备方法参考文献(Vantomme G,Jiang S M,Lehn JM.Adaptation in Constitutional Dynamic Libraries and Networks,Switchingbetween Orthogonal Metalloselection and Photoselection Processes[J].J.Am.Chem.Soc.,2014,136(26):9509-9518)：称取一定量的苯甲酰肼溶于乙醇中，然后加入苯甲醛，升温回流，搅拌过夜，TLC检测反应完全，将反应液冷却至室温，有固体析出，过滤分离，固体用乙醇重结晶并用乙醚洗涤，即得纯品苯并酰肼化合物。
实施例1
化合物3aa的制备：
称取2mmol的1,1-二苯基丙烯醇、2.4mmol的N’-苯亚甲基苯并酰肼以及2.4mmol二叔丁基过氧化物于反应瓶中，加入磁力搅拌子，氮气保护下加入10mL无水1,4-二氧六环，然后于100℃下加热搅拌反应，TLC检测反应，8h后反应完全，反应液用乙酸乙酯萃取，200-300目的硅胶柱色谱分离，展开剂采用乙酸乙酯：石油醚(1:8)，反应得到目标化合物的结构式与表征如下：
Figure BDA0002606456720000051
N'-苯亚甲基-N-(3-氧代-2,3-二苯丙基)苯并酰肼；1H NMR(400MHz,CDCl3)δ8.03(s,1H),7.81(ddd,J＝13.3,7.1,1.4Hz,4H),7.52–7.23(m,16H),5.22-5.12(m,1H),4.74–4.62(m,1H),4.37–4.26(m,1H).13C NMR(101MHz,CDCl3)δ196.20,168.13,149.89,137.45,136.94,134.86,133.34,132.82,132.12,130.25,129.86,129.51,129.22,129.06,128.91,128.68,128.45,127.93,54.96,49.54.HRMS(ESI):calcd for C29H25N2O2[M+H]+433.1911,found 433.1913.
实施例2
化合物3ba的制备：
称取2mmol的1,1-二(4-氟苯基)-丙烯醇、2.4mmol的N’-苯亚甲基苯并酰肼以及2.4mmol二叔丁基过氧化物于反应瓶中，加入磁力搅拌子，氮气保护下加入10mL无水1,4-二氧六环，然后于100℃下加热搅拌反应，TLC检测反应，8h后反应完全，反应液用乙酸乙酯萃取，200-300目的硅胶柱色谱分离，展开剂采用乙酸乙酯：石油醚(1:8)，反应得到目标化合物的结构式与表征如下：
Figure BDA0002606456720000061
N'-苯亚甲基-N-(2,3-二(4-氟苯基)3-氧丙基)苯并酰肼；1H NMR(400MHz,CDCl3)δ8.01(s,1H),7.91–7.83(m,2H),7.78–7.69(m,2H),7.51–7.41(m,3H),7.40–7.27(m,5H),7.09–6.96(m,4H),6.78–6.68(m,2H),5.13–5.04(m,1H),4.69–4.60(m,1H),4.45–4.36(m,1H).13C NMR(101MHz,CDCl3)δ196.09,167.83,167.71,165.61,162.84,160.75,149.59,134.56,134.15,134.12,133.59,133.55,133.04,131.82,131.33,131.27,130.95,130.89,129.56,129.21,128.92,128.61,127.63,115.43,115.21,115.06,114.84,54.66,49.24.HRMS(ESI):calcd for C29H23F2N2O2[M+H]+469.1722,found 469.1720.
实施例3
化合物3ea的制备：
称取2mmol的1,1-二(4-甲基苯基)-丙烯醇、2.4mmol的N’-苯亚甲基苯并酰肼以及2.4mmol二叔丁基过氧化物于反应瓶中，加入磁力搅拌子，氮气保护下加入10mL无水1,4-二氧六环，然后于100℃下加热搅拌反应，TLC检测反应，8h后反应完全，反应液用乙酸乙酯萃取，200-300目的硅胶柱色谱分离，展开剂采用乙酸乙酯：石油醚(1:8)，反应得到目标化合物的结构式与表征如下：
Figure BDA0002606456720000062
N'-苯亚甲基-N-(3-氧代-2,3-二-对甲苯基丙基)苯并酰肼；1H NMR(400MHz,CDCl3)δ8.03(s,1H),7.91–7.81(m,2H),7.72(d,J＝7.3Hz,2H),7.44(dd,J＝5.9,2.6Hz,3H),7.38–7.28(m,5H),7.18(dd,J＝15.4,7.5Hz,4H),7.04–6.97(m,2H),5.18–5.04(m,1H),4.67–4.49(m,1H),4.27–4.13(m,1H),2.38(s,3H),2.33(s,3H).13C NMR(101MHz,CDCl3)δ196.08,168.02,149.78,144.25,137.96,136.02,135.50,134.75,133.23,132.01,131.55,129.75,129.70,129.40,129.10,128.93,128.80,128.42,127.81,54.84,49.43,21.41.HRMS(ESI):calcd for C31H29N2O2[M+H]+461.2224,found 461.2220.
实施例4
化合物3ja的制备：
称取2mmol的1-苯基-1-(3,4-二甲基苯基)-丙烯醇、2.4mmol的N’-苯亚甲基苯并酰肼以及2.6mmol二叔丁基过氧化物于反应瓶中，加入磁力搅拌子，氮气保护下加入10mL无水1,4-二氧六环，然后于100℃下加热搅拌反应，TLC检测反应，8h后反应完全，反应液用乙酸乙酯萃取，200-300目的硅胶柱色谱分离，展开剂采用乙酸乙酯：石油醚(1:6)，反应得到目标化合物的结构式与表征如下：3ja和它的同分异构体3ja’
Figure BDA0002606456720000071
N'-苯亚甲基-N-(3-(3,4-二甲基苯基)-3-氧代-2-苯丙基)苯并酰肼(3ja)与N'-苯亚甲基-N-(2-(3,4-二甲基苯基)-3-氧代-3-苯基丙基)苯并酰肼(3ja’)；1H NMR(400MHz,CDCl3)3ja:δ7.93(s,1H),7.84(dd,J＝7.3,1.3Hz,2H),7.58(d,J＝1.4Hz,1H),7.56–7.33(m,11H),7.29(dd,J＝6.1,2.7Hz,3H),7.14(d,J＝7.5Hz,1H),5.14–5.01(m,1H),4.32–4.17(m,1H),3.98–3.81(m,1H),2.34(d,J＝5.1Hz,6H).3ja’:δ7.88(s,1H),7.86–7.82(m,2H),7.69(dd,J＝7.5,1.5Hz,2H),7.55–7.28(m,12H),7.23(dd,J＝7.5,1.4Hz,1H),7.11(d,J＝7.5Hz,1H),5.03–4.95(m,1H),4.25–4.17(m,1H),3.92–3.84(m,1H),2.34(s,6H).13C NMR(101MHz,CDCl3)3ja and3ja’:δ196.33(d,J＝7.2Hz),195.80(d,J＝6.8Hz),167.73(d,J＝6.8Hz),149.49(d,J＝9.0Hz),141.18,137.05,136.81,136.54,135.59,135.35,135.20,134.68,134.46(d,J＝4.2Hz),132.94(d,J＝3.2Hz),132.91,132.42,131.72(d,J＝9.6Hz),131.09,129.85,129.73,129.46(d,J＝3.8Hz),129.11(d,J＝2.7Hz),128.82(d,J＝12.6Hz),128.66,128.51(d,J＝10.4Hz),128.36,128.28,128.05,127.53(d,J＝14.0Hz),125.82,54.56,53.98,49.14(d,J＝10.6Hz),20.37,20.14,19.44,19.24.HRMS(ESI):calcd for C31H29N2O2[M+H]+461.2224,found 461.2222
实施例5
化合物3ab的制备：
称取2mmol的1,1-二苯基丙烯醇、2.4mmol的N’-苯亚甲基-4-甲基苯并酰肼以及2.4mmol二叔丁基过氧化物于反应瓶中，加入磁力搅拌子，氮气保护下加入10mL无水1,4-二氧六环，然后于100℃下加热搅拌反应，TLC检测反应，8h后反应完全，反应液用乙酸乙酯萃取，200-300目的硅胶柱色谱分离，展开剂采用乙酸乙酯：石油醚(1:6)，反应得到目标化合物的结构式与表征如下：
Figure BDA0002606456720000081
N'-苯亚甲基-4-甲基-N-(3-氧代-2,3-二苯丙基)苯并酰肼；1H NMR(400MHz,CDCl3)δ8.28(s,1H),7.75(dd,J＝9.6,4.3Hz,4H),7.46–7.32(m,8H),7.32–7.21(m,7H),5.03–4.95(m,1H),4.20–4.14(m,1H),3.92–3.83(m,1H),2.30(s,3H).13C NMR(101MHz,CDCl3)δ195.91,167.84,149.60,141.95,137.16,136.65,134.57,132.53,132.28,129.96,129.57,129.25,129.22,128.91,128.77,128.61,128.39,128.16,127.64,54.67,49.25,21.23.HRMS(ESI):calcd for C30H27N2O2[M+Na]+447.2067,found 447.2068.
实施例6
化合物3ad的制备：
称取2mmol的1,1-二苯基丙烯醇、2.4mmol的N’-苯亚甲基-4-氯苯并酰肼以及2.4mmol二叔丁基过氧化物于反应瓶中，加入磁力搅拌子，氮气保护下加入10mL无水1,4-二氧六环，然后于100℃下加热搅拌反应，TLC检测反应，8h后反应完全，反应液用乙酸乙酯萃取，200-300目的硅胶柱色谱分离，展开剂采用乙酸乙酯：石油醚(1:6)，反应得到目标化合物的结构式与表征如下：
Figure BDA0002606456720000082
N'-苯亚甲基-4-氯-N-(3-氧代-2,3-二苯丙基)苯并酰肼；1H NMR(400MHz,CDCl3)δ8.27(s,1H),7.78–7.69(m,4H),7.45–7.21(m,15H),5.00-4.91(m,1H),4.19–4.13(m,1H),3.87–3.81(m,1H).13C NMR(101MHz,CDCl3)δ195.80,167.73,149.49,139.46,137.05,136.54,134.46,132.99,132.42,129.85,129.46,129.32,129.12,128.66,128.50,128.28,128.05,127.53,54.56,49.14.HRMS(ESI):calcd for C29H24ClN2O2[M+H]+467.1521,found467.1523.
实施例7
化合物3ag的制备：
称取2mmol的1,1-二苯基丙烯醇、2.4mmol的N’-(4-甲氧基苯亚甲基)苯并酰肼以及2.4mmol二叔丁基过氧化物于反应瓶中，加入磁力搅拌子，氮气保护下加入10mL无水1,4-二氧六环，然后于100℃下加热搅拌反应，TLC检测反应，8h后反应完全，反应液用乙酸乙酯萃取，200-300目的硅胶柱色谱分离，展开剂采用乙酸乙酯：石油醚(1:6)，反应得到目标化合物的结构式与表征如下：
Figure BDA0002606456720000091
N'-(4-甲氧基苯亚甲基)-N-(3-氧代-2,3-二苯丙基)苯并酰肼；1H NMR(400MHz,CDCl3)δ8.03(s,1H),7.91–7.82(m,2H),7.73(dd,J＝7.5,1.2Hz,2H),7.45(dd,J＝6.0,2.5Hz,3H),7.40–7.35(m,3H),7.35–7.23(m,5H),6.98(d,J＝7.5Hz,2H),6.83(d,J＝7.5Hz,2H),4.80–4.72(m,1H),4.53–4.41(m,1H),4.24–4.17(m,1H),3.81(s,3H).13C NMR(101MHz,CDCl3)δ195.66,167.73,161.12,149.49,137.05,136.54,132.94,132.42,131.72,129.85,129.62,128.82,128.66,128.51,128.28,128.05,127.11,114.51,56.03,54.56,49.14.HRMS(ESI):calcd for C30H27N2O3[M+H]+463.2016,found 463.2015.
实施例8
化合物3ai的制备：
称取2mmol的1,1-二苯基丙烯醇、2.6mmol的N’-(4-(二甲基氨基)苯亚甲基)苯并酰肼以及2.6mmol二叔丁基过氧化物于反应瓶中，加入磁力搅拌子，氮气保护下加入10mL无水1,4-二氧六环，然后于100℃下加热搅拌反应，TLC检测反应，8h后反应完全，反应液用乙酸乙酯萃取，200-300目的硅胶柱色谱分离，展开剂采用乙酸乙酯：石油醚(1:6)，反应得到目标化合物的结构式与表征如下：
Figure BDA0002606456720000101
N'-(4-(二甲基氨基)苯亚甲基)-N-(3-氧代-2,3-二苯丙基)苯并酰肼；1H NMR(400MHz,CDCl3)δ8.27(s,1H),7.92–7.82(m,2H),7.72(dd,J＝7.4,1.4Hz,2H),7.50–7.20(m,11H),6.51(d,J＝7.5Hz,2H),6.23(d,J＝7.5Hz,2H),4.89–4.79(m,1H),4.46–4.40(m,1H),4.24–4.17(m,1H),2.93(s,6H).13C NMR(101MHz,CDCl3)δ195.60,167.77,154.45,149.49,137.05,136.54,132.94,132.42,131.72,129.85,128.93,128.82,128.66,128.51,128.28,128.05,121.43,111.28,54.56,49.14,41.90.HRMS(ESI):calcd for C31H30N3O2[M+H]+476.2333,found476.2337.
实施例9
化合物3ak的制备：
称取2mmol的1,1-二苯基丙烯醇、2.4mmol的N’-(4-氯苯亚甲基)苯并酰肼以及2.4mmol二叔丁基过氧化物于反应瓶中，加入磁力搅拌子，氮气保护下加入10mL无水1,4-二氧六环，然后于100℃下加热搅拌反应，TLC检测反应，8h后反应完全，反应液用乙酸乙酯萃取，200-300目的硅胶柱色谱分离，展开剂采用乙酸乙酯：石油醚(1:6)，反应得到目标化合物的结构式与表征如下：
Figure BDA0002606456720000102
N'-(4-氯亚苄基)-N-(3-氧代-2,3-二苯丙基)苯并酰肼；1H NMR(400MHz,CDCl3)δ8.15(s,1H),7.87–7.79(m,4H),7.50–7.37(m,8H),7.37–7.26(m,5H),7.20(d,J＝7.5Hz,2H),5.04–4.96(m,1H),4.52–4.44(m,1H),4.20–4.13(m,1H).13C NMR(101MHz,CDCl3)δ195.71,167.65,149.49,137.05,136.54,135.95,133.88,132.94,132.42,131.72,129.85,129.69,129.37,128.82,128.66,128.51,128.28,128.05,54.56,49.14.HRMS(ESI):calcdfor C29H24ClN2O2[M+H]+467.1521,found 467.1523.
实施例10
化合物3an的制备：
称取2mmol的1,1-二苯基丙烯醇、2.4mmol的N’-(呋喃-2-亚甲基)苯并酰肼以及2.4mmol二叔丁基过氧化物于反应瓶中，加入磁力搅拌子，氮气保护下加入10mL无水1,4-二氧六环，然后于100℃下加热搅拌反应，TLC检测反应，8h后反应完全，反应液用乙酸乙酯萃取，200-300目的硅胶柱色谱分离，展开剂采用乙酸乙酯：石油醚(1:6)，反应得到目标化合物的结构式与表征如下：
Figure BDA0002606456720000111
N'-(呋喃-2-基亚甲基)-N-(3-氧代-2,3-二苯丙基)苯并酰肼；1H NMR(400MHz,CDCl3)δ8.14(s,1H),7.83–7.78(m,4H),7.68(dd,J＝6.6,2.4Hz,1H),7.49–7.24(m,11H),6.41–6.35(m,2H),4.95–4.96(m,1H),4.24–4.17(m,1H),4.08–3.97(m,1H).13C NMR(101MHz,CDCl3)δ194.90,167.53,148.94,144.95,137.05,136.54,132.94,132.42,131.72,130.72,129.85,128.82,128.66,128.51,128.28,128.05,118.62,112.85,54.56,49.14.HRMS(ESI):calcd for C27H23N2O3[M+H]+423.1703,found 423.1708.
实施例11
化合物3aq的制备：
称取2mmol的1,1-二苯基丙烯醇、2.4mmol的N’-(萘-1-亚甲基)苯并酰肼以及2.4mmol二叔丁基过氧化物于反应瓶中，加入磁力搅拌子，氮气保护下加入10mL无水1,4-二氧六环，然后于100℃下加热搅拌反应，TLC检测反应，8h后反应完全，反应液用乙酸乙酯萃取，200-300目的硅胶柱色谱分离，展开剂采用乙酸乙酯：石油醚(1:6)，反应得到目标化合物的结构式与表征如下：
Figure BDA0002606456720000112
N'-(萘-1-基亚甲基)-N-(3-氧代-2,3-二苯丙基)苯并酰肼；1H NMR(400MHz,CDCl3)δ8.32(s,1H),7.90(dt,J＝6.9,1.6Hz,1H),7.86–7.66(m,6H),7.59–7.49(m,2H),7.49–7.30(m,8H),7.28–7.15(m,5H),4.88–4.81(m,1H),4.49–4.39(m,1H),4.23–4.15(m,1H).13C NMR(101MHz,CDCl3)δ196.30,167.95,140.82,137.05,136.54,133.27,132.94,132.42,131.72,131.26,130.24,129.85,129.15,128.82,128.66,128.56,128.51,128.28,128.05,127.53,127.34,126.55,124.27,122.40,54.56,49.14.HRMS(ESI):calcd forC33H27N2O2[M+H]+483.2067,found483.2068.
实施例12
化合物3ar的制备：
称取2mmol的1,1-二苯基丙烯醇、2.4mmol的N’-(1H-吲哚-3-亚甲基)苯并酰肼以及2.8mmol二叔丁基过氧化物于反应瓶中，加入磁力搅拌子，氮气保护下加入10mL无水1,4-二氧六环，然后于100℃下加热搅拌反应，TLC检测反应，8h后反应完全，反应液用乙酸乙酯萃取，200-300目的硅胶柱色谱分离，展开剂采用乙酸乙酯：石油醚(1:6)，反应得到目标化合物的结构式与表征如下：(二叔丁基过氧化物的量由2.4mmol增至2.8mmol，产率提高了11％)
Figure BDA0002606456720000121
N'-((1H-吲哚-3-基)亚甲基)-N-(3-氧代-2,3-二苯丙基)苯并酰肼；1H NMR(400MHz,CDCl3)δ8.35(s,1H),7.82(dd,J＝7.4,1.3Hz,2H),7.73(dd,J＝7.4,1.3Hz,2H),7.65(dd,J＝7.2,1.9Hz,1H),7.59(s,1H),7.49–7.18(m,15H),5.03–4.92(m,1H),4.36–4.38(m,1H),4.12–4.06(m,1H).13C NMR(101MHz,CDCl3)δ196.80,167.91,137.05,136.54,135.70,134.90,134.81,132.94,132.42,131.72,129.85,128.82,128.66,128.51,128.28,128.05,127.11,121.32,120.74,118.38,113.20,105.61,54.56,49.14.HRMS(ESI):calcdfor C31H26N3O2[M+H]+472.2020,found 472.2024.
实施例13
化合物3aa的克级反应：
与实施例1相比，1,1-二苯基丙烯醇的量为10mmol，N’-苯亚甲基苯并酰肼为12mmol，二叔丁基过氧化物为12mmol，溶剂50mL，其余条件不变。反应得到目标化合物的产率为88％，说明了该反应在克级规模以上时仍具有较高的产率。
对比例1
与实施例1相比，将反应体系中的二叔丁基过氧化物DTBP改变为TBPB，TBHP，DCP，K2S2O8，PhI(OAc)2，AgOAc，Cu(OAc)2中的一种，其余反应条件不变。(结果详见表1)
表1
氧化剂 产率(％)
实施例1 DTBP 92
对比例11 TBPB 35
对比例12 TBHP 16
对比例13 DCP 68
对比例14 K<sub>2</sub>S<sub>2</sub>O<sub>8</sub> 10
对比例15 PhI(OAc)<sub>2</sub> 12
对比例16 AgOAc 10％产物4
对比例17 Cu(OAc)<sub>2</sub> 41％产物4
由表1数据可知，二叔丁基过氧化物对本发明反应具有更好的催化作用，当使用金属氧化剂AgOAc、Cu(OAc)2时没有得到本发明N-取代苯甲酰腙类化合物结构的产物，但是核磁检测发现有其他新化合物生成，结构式与表征如下：
Figure BDA0002606456720000131
1-苯甲酰-5-(羟基二苯基甲基)-3-苯基吡唑啉；产率41％。1H NMR(400MHz,CDCl3)δ7.74(m,2H),7.49-7.42(m,3H),7.38–7.16(m,15H),5.38(s,1H),4.67(s,1H),4.28(t,J＝9.8Hz,1H),3.93(t,J＝8.3Hz,1H),2.54(dt,J＝16.4,9.6Hz,1H),2.35(m,1H).13C NMR(101MHz,CDCl3)δ167.64,143.06,139.45,135.32,132.95,129.53,129.35,129.29,129.16,128.68,128.65,128.11,127.56,81.41,70.29,65.36,34.57.HRMS(ESI):calcdfor C29H27N2O2[M+H]+435.2067,found 435.2064.
对比例2
与实施例1相比，将反应体系中的溶剂1,4-二氧六环改变为甲苯，二氯甲烷，四氢呋喃，N,N-二甲基甲酰胺中的一种(以上溶剂均为无水溶剂)，其余反应条件不变。(结果详见表2)表2
溶剂 产率(％)
实施例1 1,4-Dioxane 92
对比例21 Toluene 20
对比例22 CH<sub>2</sub>Cl<sub>2</sub> —
对比例23 THF —
对比例24 DMF 34
由表2数据可知，当溶剂为二氯甲烷或四氢呋喃时，反应不能发生，当溶剂为甲苯或N,N-二甲基甲酰胺，反应产率较低，均在40％以下，1,4-二氧六环为最佳溶剂。
对比例3
与实施例1相比，将反应体系中1,1-二苯基丙烯醇、N’-苯亚甲基苯并酰肼及叔丁基过氧化物的摩尔质量比变为1:1.1:1.2，1:1.3:1.2，1:1.5:1.2，1:1.2:1.0，1:1.2:1.5，1:1.2:1.7，其余反应条件不变。(结果详见表3)
表3
组分摩尔比 产率(％)
实施例1 1:1.2:1.2 92
对比例31 1:1.1:1.2 88
对比例32 1:1.3:1.2 92
对比例33 1:1.5:1.2 92
对比例34 1:1.2:1.0 84
对比例35 1:1.2:1.5 90
对比例36 1:1.2:1.7 90
由表3数据可知，固定氧化剂的量为1.2当量，当1,1-二苯基丙烯醇、N’-苯亚甲基苯并酰肼的比例由1:1.1增至1:1.5时，反应产率先由88％增至92％，之后不变。固定1,1-二苯基丙烯醇、N’-苯亚甲基苯并酰肼的比例为1:1.2，增加氧化剂的量，发现氧化剂为1.2当量时，产率最高92％。
生物活性测试：
对本发明N-取代苯甲酰腙类化合物3aa-3ja及3ab-3ar的生物活性进行测试：
药液的配制：称取10mg的化合物，溶于2mLDMSO/甲醇(1:9)的混合溶剂中，并加入48mL含有0.02％曲拉通X-100的水溶液，充分混合均匀，即得待测药液。
实验对象：麦蚜、棉铃虫、红蜘蛛、白粉虱。采取生理状况相似的幼龄麦蚜、红蜘蛛、白粉虱以及2龄棉铃虫各40只，并分别转接于浸泡过配制药液的小麦叶、豌豆叶、枣叶及黄瓜叶上，之后放入含有保湿滤纸的培养皿中，设置空白组，空白组的叶片只浸泡相同的溶剂，叶片在溶液中的浸泡时间均为5秒钟，同样条件室温光照培养3天，观察结果；对照组采用氯虫酰胺原药、哒螨灵原药以及市售的1％苦参·印楝素乳油，稀释800倍配成药液，实验方法同各实验组。死亡率＝(实验组死亡只数-空白组死亡只数)/(40-空白组死亡只数)×100％，空白组死亡只数大于等于8只即为无效实验。(结果详见表4)：
细胞毒性测试：
以HEK293细胞为正常细胞模型，研究本发明N-取代苯甲酰腙类化合物3aa-3ja及3ab-3ar对人体正常细胞的毒性及抗增殖活性。将HEK293细胞接种于96孔板中，每孔接种5×10 4个细胞，每个化合物设置3个复孔，接种培养24h让细胞贴壁和生长，之后换为含有N-取代苯甲酰腙类化合物的培养基，浓度分别为10、20、40、80、150、300、600、1000μM，培养24h后进行MTT测试，计算各浓度N-取代苯甲酰腙类化合物对HEK细胞的抑制率。
(图1)
由图1数据可以看出，各N-取代苯甲酰腙类化合物对HEK293细胞的抑制有一定的差距，但是均随着浓度的增大对细胞的抑制率增加，IC50在80μM至100μM之间，且浓度达1000μM时，抑制率也均小于90％，说明各N-取代苯甲酰腙类化合物对HEK293细胞的毒性不大。
表4各个化合物药液对麦蚜、棉铃虫、红蜘蛛、白粉虱的杀虫活性
Figure BDA0002606456720000151
Figure BDA0002606456720000161
从表中数据可以看出，由本发明方法制备的N-取代苯甲酰腙类化合物制成的药液对麦蚜、棉铃虫、红蜘蛛、白粉虱具有良好的杀虫活性，对照组的氯虫酰胺对麦蚜有100％的杀虫活性，但是对棉铃虫、红蜘蛛、白粉虱的杀虫活性较低；哒螨灵对红蜘蛛的杀虫活性为100％，但是对麦蚜、棉铃虫不具有杀虫活性。本发明化合物3ba，3da，3ga，3aj，3ao，3ap对麦蚜的杀死率达80％以上；3ia，3ad，3aj，3am，3ao，3ap对棉铃虫的杀死率也达80％以上，其中3ap对棉铃虫的杀死率达100％；3ba，3ga，3ad，3ae，3ai，3am，3an，3ao，3ap对红蜘蛛的杀死率达80％以上，3ga对红蜘蛛的杀死率为100％；3ca，3ga，3ia，3ae，3ai，3ak，3am，3an，3ap，3aq，3ar对白粉虱的杀死率也达80％以上，这表明本发明得到的N-取代苯甲酰腙类化合物在农药的应用方面具有良好的应用前景。
以上仅为本发明的优选实施例，并非因此限制本发明的专利范围，凡是利用本发明说明书内容所作的等效结构或等效流程变换，或直接或间接运用在其他相关的技术领域，均同理包括在本发明的专利保护范围内。

Claims (8)

1.一种N-取代苯甲酰腙类化合物，其特征在于，该N-取代苯甲酰腙类化合物的结构通式为：
Figure FDA0003877864350000011
其中，R1＝H、4-F、4-Cl、4-Br、4-Me、4-OMe、3-CF3、3,4-二甲基；R2＝H、4-F、4-Cl、4-Br、4-Me、4-OMe、3-CF3；R3＝4-Me、4-OMe、4-Cl、2-OH；R4＝4-Me、4-OMe、4-tBu、4-N(CH3)2、4-F、4-Cl、2-OMe、2-OH。
2.根据权利要求1所述的N-取代苯甲酰腙类化合物的制备方法，其特征在于，所述方法包括步骤：由苯甲酰肼类化合物与苯甲醛类化合物反应制得酰腙类化合物，之后使酰腙类化合物与二芳基丙烯醇类化合物在氧化剂的作用下反应生成N-取代苯甲酰腙类化合物。
3.根据权利要求2所述的制备方法，其特征在于，所述二芳基烯丙醇为1,1-二苯基丙烯醇，1,1-二(4-氟苯基)-丙烯醇，1,1-二(4-氯苯基)-丙烯醇，1,1-二(4-溴苯基)-丙烯醇，1,1-二(4-甲基苯基)-丙烯醇，1,1-二(4-甲氧基苯基)-丙烯醇，1,1-二(3-三氟甲基苯基)-丙烯醇，1-苯基-1-(4-氟苯基)-丙烯醇，1-苯基-1-(4-氯苯基)-丙烯醇，1-苯基-1-(3,4-二甲基苯基)-丙烯醇。
4.根据权利要求2或3所述的制备方法，其特征在于，包括以下反应通式和反应步骤：
Figure FDA0003877864350000021
其中，R1＝H、4-F、4-Cl、4-Br、4-Me、4-OMe、3-CF3、3,4-二甲基；R2＝H、4-F、4-Cl、4-Br、4-Me、4-OMe、3-CF3；R3＝4-Me、4-OMe、4-Cl、2-OH；R4＝4-Me、4-OMe、4-tBu、4-N(CH3)2、4-F、4-Cl、2-OMe、2-OH，
一、将二芳基丙烯醇类化合物、酰腙类化合物及氧化剂添加于反应管中，惰性气体保护下加入溶剂，然后于100℃下加热反应8h，得到反应混合液；
二、将步骤一所得反应混合液进行分离提纯，得到N-取代苯甲酰腙类化合物。
5.根据权利要求4所述的N-取代苯甲酰腙类化合物的制备方法的制备方法，其特征在于，所述二芳基丙烯醇类化合物、酰腙类化合物及氧化剂的摩尔质量比为1:1.1-1.3:1.2-1.5。
6.根据权利要求4所述的N-取代苯甲酰腙类化合物的制备方法的制备方法，其特征在于，所述溶剂均为无水1,4-二氧六环，所述氧化剂为二叔丁基过氧化物。
7.根据权利要求4所述的N-取代苯甲酰腙类化合物的制备方法，其特征在于，步骤二中所述分离提纯的具体为柱色谱提纯法，所用的展开剂为乙酸乙酯：石油醚体积比＝1:6-1:8。
8.权利要求1所述的N-取代苯甲酰腙类化合物或根据权利要求2-7中任一项所述的制备方法获得的N-取代苯甲酰腙类化合物在制备抑制麦蚜、棉铃虫、红蜘蛛、白粉虱的农药中的应用。
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