CN113173890B - 一种含异噁唑二苯乙烯杀菌剂的制备方法及应用 - Google Patents
一种含异噁唑二苯乙烯杀菌剂的制备方法及应用 Download PDFInfo
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Abstract
本发明属于农药学领域,公开了一种含异噁唑二苯乙烯杀菌剂的制备方法及应用,该杀菌剂具有式I所示的化学结构,其制备方法依次经环合反应、NBS溴代反应、Arbuzov反应及Wittig‑Horner反应。本发明的杀菌剂对灰霉菌有良好的防治效果,与多菌灵相当。
Description
技术领域
本发明公开了一种含异噁唑二苯乙烯杀菌剂的制备方法及应用,属于农药学领域。
背景技术
灰霉菌是一种宿主广泛的死体营养型植物致病真菌,可以感染包括几乎所有蔬菜和水果作物在内的200多种植物。在作物种植期间和蔬果贮藏期间造成重大经济损失,每年达数百亿乃至千亿美元。即便是在低温贮藏条件下,灰霉菌仍然可以在果实上生长并扩散,其引发的灰霉病被视为造成贮藏果实品质恶化腐烂的第二大真菌病害。化学杀菌剂目前是治理灰霉菌的首选工具,然而由于长期或不合理的使用导致了严重的病原菌抗性问题和环境污染问题。
天然产物作为具有新颖作用方式和适度降解性质的活性物质的丰富来源,一直以来都是药物研发的重要领域之一。植物次级代谢产物天然二苯乙烯类化合物具有易于合成的结构单元及多样的生物活性。最广为人知的当属白藜芦醇,因其作为植保素保护植物免受病原微生物的侵入而引起研究者的兴趣。杂环化合物具有高效低毒、选择性好等优点,在药物研发中被普遍用于先导化合物的结构优化。异噁唑是含有相邻氮氧原子的五元芳香杂环,是许多生物活性分子的重要结构单元。异噁唑类化合物具有广谱而优良的生物活性,包括抗菌、抗寄生虫、除草、抗神经痛、杀虫等,然而其合成却存在着原料结构复杂或价格昂贵、反应条件严苛、区域选择性不易控制等难点。对天然产物的结构骨架进行改造,有望开发出结构新颖、作用机制独特的化合物,从而减缓病原菌耐药性的产生。
发明内容
本发明的目的在于提供一种含异噁唑二苯乙烯化合物,可作为防治灰霉菌的高效杀菌剂。
本发明的又一目的在于提供上述化合物的制备方法。
本发明的另一目的在于提供上述化合物的应用。
本发明通过以下技术方案实现:
一种含异噁唑二苯乙烯杀菌剂,化学结构式如下:
杀菌剂的制备方法,以(E)-1-(4-甲基苯基)-3-(3,4-二氯苯基)-2-丙烯-1-酮为原料,经环合反应、NBS溴代反应、Arbuzov反应及Wittig-Horner反应制得含异噁唑二苯乙烯化合物,步骤如下:
杀菌剂在制备防治灰霉菌的农药中的应用。
相比于现有技术,本发明具有如下优点和有益效果:
1.本发明以方便易得的原料,通过条件温和、后处理简便的反应路线,合成了一种含异噁唑二苯乙烯化合物。
2.本发明含异噁唑二苯乙烯化合物对灰霉菌具有良好的抗菌活性,可用作新型高效杀菌剂。
附图说明
图1-4为含异噁唑二苯乙烯化合物(I-IV)的核磁共振谱图,其中(a)氢谱,(b)碳谱。
图5-8为含异噁唑二苯乙烯化合物(I-IV)的高分辨质谱图。
图9为含异噁唑二苯乙烯化合物I对灰霉菌的体内防治效果,其中(A)空白对照;(B)多菌灵;(C)化合物I。
具体实施方式
下面结合具体实施例对本发明作进一步具体详细描述,但本发明的实施方式不限于此,对于未特别注明的工艺参数,可参照常规技术进行。
实施例1
5-(4-甲基苯基)-3-(3,4-二氯苯基)异噁唑的制备
2.91g(10.0mmol)(E)-1-(4-甲基苯基)-3-(3,4-二氯苯基)-2-丙烯-1-酮搅拌溶解于45mL四氢呋喃和30mL甲醇,滴加10mL碳酸钾溶液(8M),逐滴滴加60mLN-对甲基苯磺酰基羟胺的甲醇溶液(1.25M),室温搅拌反应过夜。加入5.53g(40.0mmol)碳酸钾,并升温至60℃,反应10h后,旋蒸除去有机溶剂,加水使产物析出并溶解析出的盐,抽滤,滤饼用水洗涤后红外干燥,粗产物用无水乙醇重结晶,得到白色固体5-(4-甲基苯基)-3-(3,4-二氯苯基)异噁唑,反应收率77.6%。
实施例2
5-(4-(溴甲基)苯基)-3-(3,4-二氯苯基)异噁唑的制备
取1.52g(5.0mmol)5-(4-甲基苯基)-3-(3,4-二氯苯基)异噁唑加入40mL四氯化碳,搅拌升温至50℃,加入0.03g(0.1mmol)过氧化二苯甲酰,继续升温至85℃,分批加入1.16g(6.5mmol)N-溴代琥珀酰亚胺,TLC监测反应,待5-(4-甲基苯基)-3-(3,4-二氯苯基)异噁唑完全转化后,停止加热。冷却至室温后,旋蒸除去四氯化碳,加水分散固体并抽滤。滤饼依次用饱和NaHCO3溶液和水洗涤,干燥后,用四氢呋喃/甲醇的混合溶剂重结晶。得到白色固体5-(4-(溴甲基)苯基)-3-(3,4-二氯苯基)异噁唑,收率为74.3%。
实施例3
(4-(3-(3,4-二氯苯基)-异噁唑-5-基)苄基)膦酸二乙酯的制备
取1.15g(3mmol)5-(4-(溴甲基)苯基)-3-(3,4-二氯苯基)异噁唑及8.1mL亚磷酸三乙酯置于50mL烧瓶中,搅拌升温至130℃,反应8h后,停止加热。待温度降至80℃时,减压蒸馏(温度逐渐升至130℃)除去过量的亚磷酸三乙酯。蒸馏后待体系降温至60℃,加入适量正己烷使产物析出,冷却至室温后抽滤,干燥,粗产物用四氢呋喃和正己烷的混合溶剂重结晶提纯,得白色固体(4-(3-(3,4-二氯苯基)-异噁唑-5-基)苄基)膦酸二乙酯,收率75.0%。
实施例4
(E)-5-(4-(2-氯苯乙烯基)苯基)-3-(3,4-二氯苯基)-异噁唑(I)的制备
取0.22g(0.5mmol)(4-(3-(3,4-二氯苯基)-异噁唑-5-基)苄基)膦酸二乙酯搅拌溶于10mL四氢呋喃中,再加入1.05当量的邻氯苯甲醛(0.52mmol),混合均匀后,逐滴滴加1.4mL的叔丁醇钾的乙醇溶液(0.75M),室温搅拌过夜。加入10mL无水乙醇,搅拌使固体充分析出后抽滤,滤饼依次用水和无水乙醇洗涤,室温干燥。粗产物用二甲基亚砜/乙醇重结晶纯化,得白色固体(E)-5-(4-(2-氯苯乙烯基)苯基)-3-(3,4-二氯苯基)-异噁唑,收率66.9%。1HNMR(500MHz,DMSO-d6)δ8.18(d,J=1.8Hz,1H,C6H3,2-H),7.95–7.89(m,4H,C6H3,6-H,C6H4,2,6-H,C6H4,6-H),7.84(dd,J=8.3,2.0Hz,3H,C6H3,5-H,C6H4,2,5-H),7.75(s,1H,isoxazole-H),7.59(d,J=16.3Hz,1H,CH=CH),7.51(d,J=7.3Hz,1H,C6H4,3-H),7.43–7.37(m,2H,CH=CH,C6H4,5-H),7.35(td,J=7.6Hz,1.4Hz,1H,C6H4,4-H);13CNMR(126MHz,DMSO-d6)δ170.36,161.35,139.27,134.93,133.45,132.92,132.57,132.00,131.25,130.25,130.04,129.59,128.94,128.14,128.05,127.55,127.07,126.52,126.43,125.85,99.46;HRMS(ESI),calcdforC23H14Cl3NO[M+H]+426.0214,found:426.0214。
另外,实施例4所制备的含异噁唑二苯乙烯化合物(I)的核磁谱图如图1,高分辨质谱如图5。
实施例5
(E)-5-(4-(2-溴苯乙烯基)苯基)-3-(3,4-二氯苯基)-异噁唑(II)的制备
取0.22g(0.5mmol)(4-(3-(3,4-二氯苯基)-异噁唑-5-基)苄基)膦酸二乙酯搅拌溶于10mL四氢呋喃中,再加入1.05当量的邻溴苯甲醛(0.52mmol),混合均匀后,逐滴滴加1.4mL的叔丁醇钾的乙醇溶液(0.75M),室温搅拌过夜。加入10mL无水乙醇,搅拌使固体充分析出后抽滤,滤饼依次用水和无水乙醇洗涤,室温干燥。粗产物用二甲基亚砜/乙醇重结晶纯化,得黄绿色固体(E)-5-(4-(2-溴苯乙烯基)苯基)-3-(3,4-二氯苯基)-异噁唑,收率73.1%。1HNMR(500MHz,DMSO-d6)δ8.19(d,J=1.4Hz,1H,C6H3,2-H),7.97–7.91(m,3H,C6H3,6-H,C6H4,2,6-H),7.90(d,J=8.0Hz,1H,C6H4,3-H),7.87–7.81(m,3H,C6H3,5-H,C6H4,2,5-H),7.76(s,1H,isoxazole-H),7.69(d,J=8.0Hz,1H,C6H4,6-H),7.54(d,J=16.3Hz,1H,CH=CH),7.45(t,J=7.5Hz,1H,C6H4,5-H),7.36(d,J=16.3Hz,1H,CH=CH),7.27(t,1H,C6H4,4-H);13CNMR(126MHz,DMSO-d6)δ170.37,161.36,139.24,136.60,133.48,133.46,132.57,132.01,131.37,130.32,129.59,128.95,128.63,128.57,128.11,127.78,127.08,126.57,126.44,123.93,99.47;HRMS(ESI),calcd for C23H14BrCl2NO[M+H]+469.9709,found:469.9716。
另外,实施例5所制备的含异噁唑二苯乙烯化合物(II)的核磁谱图如图2,高分辨质谱如图6。
实施例6
(E)-5-(4-(4-氟苯乙烯基)苯基)-3-(3,4-二氯苯基)-异噁唑(III)的制备
取0.22g(0.5mmol)(4-(3-(3,4-二氯苯基)-异噁唑-5-基)苄基)膦酸二乙酯搅拌溶于10mL四氢呋喃中,再加入1.05当量的4-氟苯甲醛(0.52mmol),混合均匀后,逐滴滴加1.4mL的叔丁醇钾的乙醇溶液(0.75M),室温搅拌过夜。加入10mL无水乙醇,搅拌使固体充分析出后抽滤,滤饼依次用水和无水乙醇洗涤,室温干燥。粗产物用二甲基亚砜/乙醇重结晶纯化,得白色固体(E)-5-(4-(4-氟苯乙烯基)苯基)-3-(3,4-二氯苯基)-异噁唑,收率65.0%。1HNMR(500MHz,DMSO-d6)δ8.17(d,J=2.0Hz,1H,C6H3,2-H),7.96–7.88(m,3H,C6H3,6-H,C6H4,2,6-H),7.84(d,J=8.4Hz,1H,C6H3,5-H),7.80(d,J=8.3Hz,2H,C6H4,3,5-H),7.71(dd,J=8.6,5.7Hz,2H,C6H4,2,6-H),7.68(s,1H,isoxazole-H),7.42(d,J=16.5Hz,1H,CH=CH),7.29(d,J=16.5Hz,1H,CH=CH),7.24(t,J=8.9Hz,2H,C6H4,3,5-H);13CNMR(126MHz,DMSO-d6)δ170.50,162.38(d,J=245.8Hz),161.32,139.79,133.84(d,J=3.2Hz),133.44,132.56,132.01,129.63,129.61,129.18,129.12,128.92,127.80,127.78,127.73,127.06,126.43,125.85,116.25,116.08,99.23;HRMS(ESI),calcd forC23H14Cl2FNO[M+H]+410.0509,found:410.0516。
另外,实施例6所制备的含异噁唑二苯乙烯化合物(III)的核磁谱图如图3,高分辨质谱如图7。
实施例7
(E)-5-(4-(2,4-二氟苯乙烯基)苯基)-3-(3,4-二氯苯基)-异噁唑(IV)的制备
取0.22g(0.5mmol)(4-(3-(3,4-二氯苯基)-异噁唑-5-基)苄基)膦酸二乙酯搅拌溶于10mL四氢呋喃中,再加入1.05当量的2,4-二氟苯甲醛(0.52mmol),混合均匀后,逐滴滴加1.4mL的叔丁醇钾的乙醇溶液(0.75M),室温搅拌过夜。加入10mL无水乙醇,搅拌使固体充分析出后抽滤,滤饼依次用水和无水乙醇洗涤,室温干燥。粗产物用二甲基亚砜/乙醇重结晶纯化,得浅绿色固体(E)-5-(4-(2,4-二氟苯乙烯基)苯基)-3-(3,4-二氯苯基)-异噁唑,收率88.8%。1HNMR(500MHz,DMSO-d6)δ8.16(s,1H,C6H3,2-H),7.94–7.85(m,4H,C6H3,6-H,C6H4,2,6-H,C6H3,6-H),7.85–7.79(m,3H,C6H3,5-H,C6H4,3,5-H),7.73(s,1H,isoxazole-H),7.38(d,J=17Hz,1H,CH=CH),7.37(d,1H,J=17Hz,CH=CH),7.33–7.26(m,1H,C6H4,5-H),7.16(t,J=8.3Hz,1H,C6H4,3-H);13CNMR(126MHz,DMSO-d6)δ170.38,162.28(dd,J=247.3,12.2Hz),161.31,158.28(d,J=245.4Hz),139.39,133.43,132.55,131.98,130.43,130.41,130.39,129.67,129.56,129.44(q,J=9.5,4.8Hz),128.89,127.95,127.04,126.44,126.24,126.11,121.59(dd,J=12.3,3.7Hz),112.63(dd,J=21.4,3.4Hz),104.80(t,J=26.1Hz),99.34;HRMS(ESI),calcd for C23H13Cl2F2NO[M+H]+428.0415,found:428.0426。
另外,实施例7所制备的含异噁唑二苯乙烯化合物(IV)的核磁谱图如图4,高分辨质谱如图8。
实施例8
本测试例采用菌丝生长速率法测定本发明实施例4至实施例7所制备的含异噁唑二苯乙烯化合物(I-IV)和对照药剂(多菌灵)对灰霉菌的体外抑制活性。
实验方法:将本发明化合物(I-IV)和多菌灵用DMSO(终浓度为0.5%,v/v)溶解并用0.1%吐温水稀释配制成4mg/mL母液。取1mL上述母液与9mL熔融PDA培养基混合均匀,并转移至无菌培养皿中,制得含药固体平板培养基。从在PDA上培养一周的灰霉菌的菌落边缘打取菌饼,然后以菌丝面朝下接种于各含药培养基中央。培养皿密封后倒置于恒温培养箱中,25℃、避光条件下培养4天。测量菌落直径并计算各处理对灰霉菌的抑制率。
表1
序号 | 灰霉菌抑制率(%,400μg/mL) |
I | 36.85 |
II | 23.28 |
III | 10.99 |
IV | 15.37 |
多菌灵 | 40.58 |
由表1数据可知,本发明化合物I对灰霉菌具有与对照药剂多菌灵相当的杀菌活性。
实施例9
本测试例采用番茄活体转接实验测试本发明实施例4至实施例7所制备的含异噁唑二苯乙烯化合物(I-IV)和对照药剂(多菌灵)对灰霉菌的体内抑菌活性。
实验方法:按照《农药生物活性测定标准操作规范(SOP)》,将本发明化合物(I-IV)和多菌灵溶解于DMSO中,再用0.2%Triton-100的无菌水稀释至600μg/mL。选取大小、成熟度较为均一的健康番茄果实作为试验材料,果实表面用75%酒精消毒后,用流动的清水洗净,并自然晾干。在果实赤道处用无菌针头等距离刺破表皮,形成三处直径均为5mm的圆形伤口。从已活化的灰霉菌PDA培养基上的菌落边缘用已灭菌处理的打孔器打孔,随后将菌丝块以菌丝面朝下的方式接种于番茄伤口处。处理后的果实在25℃,90-95%相对湿度条件下培养4天。通过十字交叉法测量的菌丝生长直径确定各处理对番茄灰霉病的防治效果。
表2
序号 | 对灰霉菌的防治效果(%,600μg/mL) |
I | 45.00 |
II | 37.50 |
III | 17.57 |
IV | 23.40 |
多菌灵 | 49.21 |
实验结果见图9,结合图9和表2可知,本发明化合物I对灰霉菌的体内防治效果与商品化药剂多菌灵相当,体现了该杀菌剂较强的实用性。
本发明合成的含异噁唑二苯乙烯杀菌剂对严重危害农业生产的灰霉菌具有良好的防治效果,对于灰霉菌新型防控杀菌剂的研发具有重要意义。更重要地是,本发明化合物异噁唑环具有不对称性及更多的修饰位点,从而有利于化合物结构的衍生化与多样化,并且其制备反应属于“一锅法”合成,简化了反应步骤,使其更适于生产应用。
上述实施例为本发明较佳的实施方式,但本发明的实施方式并不受上述实施例的限制,其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化,均应为等效的置换方式,都包含在本发明的保护范围之内。
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