CN116425696A - 氧杂二唑硝基苯胍基脲化合物及其制备方法与应用 - Google Patents
氧杂二唑硝基苯胍基脲化合物及其制备方法与应用 Download PDFInfo
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- A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
- A01N47/40—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having a double or triple bond to nitrogen, e.g. cyanates, cyanamides
- A01N47/42—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having a double or triple bond to nitrogen, e.g. cyanates, cyanamides containing —N=CX2 groups, e.g. isothiourea
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
本发明公开了一种氧杂二唑硝基苯胍基脲化合物及其制备与应用。该类化合物的结构式如式Ⅰ所示。本发明基于酶催化机理的活性亚结构构建方法,设计并合成了一类新颖的含N‑(7‑硝基苯‑2‑氧杂‑1,3‑二唑)的胍基脲化合物。活性测定结果表明这些化合物具有几丁质酶的抑制活性,同时对小菜蛾、亚洲玉米螟等昆虫具有高效的生长调节杀虫活性,对农业上的病虫害防治具有重要的意义。
Description
技术领域
本发明涉及一类氧杂二唑硝基苯胍基脲化合物及其制备方法与应用,属于农药化合物制备领域。
背景技术
几丁质是一种结构特殊、广泛存在于自然界中的多糖,存在于昆虫的外表皮、真菌和细菌的细胞壁中。GH18家族的几丁质酶Of ChtI和GH20家族的β-N-乙酰氨基葡萄糖苷酶Of Hex1在昆虫幼虫生长发育过程中的作用。几丁质酶Of ChtI将几丁质水解为短链几丁质,随后β-N-乙酰氨基葡萄糖苷酶Of Hex1继续将短链几丁质水解为单糖,这一过程提供了昆虫生长发育所需的能量和营养,同时也导致昆虫表皮老化脱落。由于这两个酶在昆虫的生长发育中起着关键作用,因此近年来它们已成为新型杀虫剂开发的热门靶标酶。
几丁质酶的抑制剂可以抑制几丁质酶的活性,从而在农业上具有广泛的应用前景,可以用于控制病虫害等问题。目前的几丁质酶抑制剂天然产物Argifin和Argadin(J.Antibiot.53,603–606和Chem.Pharm.Bull.48,1442–1446.)以及假三糖类的Allosamidin(Tetrahedron Lett.27,2475-2478.)具有对几丁质酶的抑制活性较好,但合成困难,获取成本高,因此不能够大规模的应用。通过对Argifin和Argadin的构效关系分析,研究人员发现,二甲基胍基脲片段是这些化合物的共同药效团结构。而近年来,研究者们也开始尝试通过化学合成的方法来开发几丁质酶抑制剂。例如,基于Argifin的Dimethylguanylurea活性片段结构和红霉素的大环内酯设计合成的新型几丁质酶抑制剂对来自沙雷氏菌的几丁质酶抑制活性达到了0.036μM,其抑制活性已经超过了天然产物。尽管这类抑制剂的几丁质酶抑制剂的活性很高,但是其大环结构复杂,成本高,不能大量合成。因此,开发结构简单且容易得到的几丁质酶抑制剂是非常有必要的。
发明内容
本发明的目的是提供一种新颖高效的几丁质酶抑制剂,其具有结构简单、易于合成等优点。
本发明的技术方案具体介绍如下:
根据本发明的第一方面,提供一种氧杂二唑硝基苯胍基脲化合物,其结构如式Ⅰ所示:
其中:n=1或2,
R选自:
根据本发明的第二方面,提供上述氧杂二唑硝基苯胍基脲化合物的制备方法,包括以下步骤:
(1)4-氯-7-硝基-2,1,3-苯并氧杂噁二唑在催化剂条件下与伯胺发生取代反应得到化合物式Ⅳ;
(2)半硫酸异甲基硫脲式Ⅴ与二碳酸二叔丁酯式Ⅵ反应得到单Boc保护的异甲基硫脲式Ⅶ;
(3)单Boc保护的异甲基硫脲式Ⅶ与酰氯式Ⅷ反应得到式Ⅸ;
(4)式Ⅳ和式Ⅸ反应得到式Ⅰ;
进一步地,步骤(1)中,反应溶剂为二氯甲烷,反应温度为0-30℃,反应所用的催化剂是三乙胺、4-DMAP或者DIPEA中的任意一种。步骤(1)中,反应结束后需要用碳酸氢钠水溶液对反应液进行萃取。
进一步地,步骤(2)中,所用溶剂为两种溶剂按体积比为1:1~5:1的混合,两种溶剂是二氧六环/水、四氢呋喃/水或丙酮/水;所用的碱是碳酸氢钠、碳酸钠、碳酸钾或者氢氧化钠中的任意一种。
进一步地,步骤(3)中,反应温度为0℃-25℃,所用的溶剂是二氯甲烷、甲苯、DMF或者丙酮;所用的碱是三乙胺、4-DMAP或者碳酸钾中的任意一种。
进一步地,步骤(4)中,所用的溶剂为DMF、二氧六环或者四氢呋喃,反应温度为25℃-70℃。
根据本发明的第三方面,提供第一方面所述的氧杂二唑硝基苯胍基脲化合物在昆虫几丁质酶抑制剂或防治农业有害生物中的应用。
具体情况下,当用于昆虫几丁质酶抑制剂时,其几丁质酶来源于亚洲玉米螟。
具体情况下,当用于防治农业有害生物中的应用时,所述有害生物包括鳞翅目、鞘翅目、直翅目、等翅目、半翅目、膜翅目、双翅目、缨翅目;或所述有害生物包括线虫,所述线虫包括下述属的线虫:胞囊线虫属、球异皮线虫属、根结线虫属、穿孔线虫属、短体线虫属、小垫刃线虫属、长针线虫属、毛刺线虫属、剑线虫属、茎线虫属、滑刃线虫属和鳗线虫属。
氧杂二唑硝基苯是一种结构简单并且易于获得的芳香结构,能够代替大环结构实现与二甲基胍基脲片段的结构拼接。本发明基于酶催化机理的活性亚结构构建方法,设计并合成了一类新颖的含N-(7-硝基苯-2-氧杂-1,3-二唑)的胍基脲化合物。活性测定结果表明这些化合物具有几丁质酶的抑制活性,同时对小菜蛾、亚洲玉米螟等昆虫具有高效的生长调节杀虫活性。对农业上的病虫害防治具有重要的意义,可以为农业生产提供一种新的、高效的控制手段。
附图说明
图1为化合物A1的核磁氢谱。
图2为化合物A1的核磁碳谱。
图3为化合物A1的IC50抑制曲线。
具体实施方式
下面结合实施实例对本明的技术方案进行详细阐述。
下述实施例中所使用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材料、试剂等,如无特殊说明,均可从商业途径得到。一、通式为式Ⅰ的化合物的制备及结构表征
实施例1、化合物A1的制备过程
(a)将式Ⅲ溶于二氯甲烷中,室温下缓慢滴加式Ⅱ的二氯甲烷溶液,室温下继续搅拌反应3小时,反应结束后用碳酸氢钠水溶液洗涤,进行萃取,收集有机相,无水硫酸钠干燥,浓缩溶剂后过柱,使用石油醚/乙酸乙酯=3:1(体积比,下同)的洗脱剂收集橙色固体产物。
(b)在收集到的产物中加入三氟乙酸,室温搅拌30分钟,反应结束后浓缩三氟乙酸,用饱和碳酸氢钠水溶液中和剩余的三氟乙酸,用二氯甲烷对反应物进行萃取,无水硫酸钠干燥,浓缩溶剂,抽干产物,产率为85%。
将式Ⅴ所示的半硫酸异甲基硫脲0.15mol与0.15mol的碳酸氢钠溶于40ml溶剂四氢呋喃/水(V:V=1:1)中,冰水浴并且搅拌条件下缓慢滴加0.1mol的式ⅥBoc酸酐,20min滴加完毕,室温继续搅拌反应1小时,反应结束后浓缩除去四氢呋喃,用二氯甲烷对剩余物进行萃取,收集二氯甲烷相,无水硫酸钠干燥,浓缩溶剂,得到白色固体产物Ⅶ,产率为89%。
结构确证数据如下:
1H NMR(500MHz,CDCl3)δ12.44(s,1H),2.39(s,3H),2.22(s,3H),1.52(s,9H)。
13C NMR(125MHz,CDCl3)δ171.19,168.32,160.89,81.21,27.97,24.53,14.41。
将0.1mol的单Boc酸酐保护的异甲基硫脲式Ⅶ与0.2mol的三乙胺溶于40ml的二氯甲烷中,冰浴搅拌条件下,缓慢滴加0.2mol的甲氨基甲酰氯-二氯甲烷溶液于反应瓶中,滴加完毕后继续搅拌过夜,反应结束后加入水对反应液进行萃取,收集二氯甲烷相,无水硫酸钠干燥,浓缩溶剂过柱,使用石油醚/乙酸乙酯=10:1的洗脱剂收集白色固体产物,产率为95%。
结构确证数据如下:
1H NMR(500MHz,CDCl3)δ12.30(s,1H),5.57(s,1H),2.84(d,J=5.1Hz,3H),2.29(s,3H),1.48(s,9H)。
13C NMR(126MHz,CDCl3)δ167.16,162.55,151.12,82.53,28.01,26.70,14.21。
(a)将1mmol的NBD中间体式Ⅳ与甲基胍基脲中间体式Ⅸ溶于溶剂THF中,升温至50℃,搅拌反应24小时,浓缩溶剂过柱,使用石油醚/乙酸乙酯=3:2的洗脱剂收集橙色固体产物。
(b)在收集到的产物中加入三氟乙酸中,室温搅拌30分钟,反应结束后浓缩三氟乙酸,用饱和碳酸氢钠水溶液中和剩余的三氟乙酸,用二氯甲烷对反应物进行萃取,无水硫酸钠干燥,浓缩溶剂,抽干产物,产率为83%。
结构确证数据如下:
1H NMR(500MHz,DMSO-d6)δ10.47(s,1H),9.51(s,1H),9.13(s,1H),8.51(d,J=7.5Hz,3H),7.34(s,1H),6.43(d,J=8.9Hz,1H),3.53(t,J=6.5Hz,2H),3.37(q,J=6.8Hz,2H),2.63(d,J=4.5Hz,3H),1.94(p,J=6.8Hz,2H)。
13C NMR(126MHz,DMSO-d6)δ160.05,159.79,159.52,159.26,154.25,153.93,145.12,144.49,144.11,137.84,120.89,117.90,115.54,99.16,40.65,38.55,26.48,26.03。
其他通式为式Ⅰ的系列化合物均可按照上述方法制备得到。部分化合物编号、结构、理化数据见表1,结构鉴定的核磁共振氢谱、质谱数据见表2。
表1.部分化合物的结构及其理化性质
表2.部分化合物的核磁表征和高分辨数据
二、通式为式Ⅰ的化合物酶抑制活性测定
酶活性测定方法:测Of ChtI的抑制活性时以4-甲基伞形酮基N,N'-二乙酰基-β-D-壳二糖苷(4-MethyluMbelliferyl N,N-diacetyl-β-D-chitobioside)为测试底物;测OfHex1的抑制活性时以4-甲基伞形酮基N-乙酰基-β-D-葡萄糖(4-MU-GlcNAc)为测试底物。将酶与缓冲溶液(20mM NaH2PO4,pH6.0)在96孔板内混合至终体积为90μL,加入10μL40μM底物pNP-β-GlcNAc开始反应,25℃温育5min,加入100μL 0.5M碳酸钠终止反应,于405nm测定吸收值。当荧光强度约为8000-12000(a.u.)之间时,可以用于抑制剂活性测定。
化合物抑制活性测定方法:将样品用DMSO溶解且稀释为多个不同的浓度梯度,范围在0.001-100μM之间。在96孔板上,每孔分别加入抑制剂2μL,酶液88μL,底物10μL,使得每孔的溶液总体积为100μL。在30℃条件下震荡孵育20min,然后在酶标板的每孔加入100μL的终止液,使用酶标仪测定荧光强度。测试过程设置激发波长为350nm,发射波长为450nm,测定荧光强度,计算每个样品浓度的抑制率,使用软件GraphPad Prism拟合IC50值,部分化合物的几丁质酶抑制活性如表3所示。
表3.部分化合物的几丁质酶半数有效抑制浓度(IC50)
化合物 | Of ChtⅠ(μM) | OfHex1(μM) |
A1 | 0.0126 | 1.77 |
A2 | 0.036 | 3.14 |
A3 | 2.87 | 1.78 |
A4 | 0.36 | 2.87 |
A5 | >50 | 25.95 |
A6 | >50 | 19.36 |
A7 | 19.65 | 23.91 |
A8 | 31.67 | 35.54 |
A9 | 20.65 | 26.28 |
A10 | 45.23 | 39.98 |
三、通式为式Ⅰ的化合物的杀虫活性测定
测定方法:测定方法:采用点滴法处理待测昆虫,测试化合物的浓度为200mg/L。在昆虫的化蛹期计算其校正死亡率(%),不能成功羽化的昆虫为死亡的昆虫。与对照药除虫脲比对,判断药剂毒性大小。部分化合物的杀虫活性数据见表4。
下述供试靶标:小菜蛾(Plutella xylostella Linnaeus),亚洲玉米螟(Ostriniafurnacalis),斜纹夜蛾,甜菜夜蛾,玉米粘虫都从商业途径购买得到。在室内用用相应的饲料进行喂养,饲养条件为室温(27±1)℃,湿度为40%,光照强度为2000lux,光照时间为每天12h。在室内饲养条件下,用虫龄、体重及生理状况一致的3龄幼虫进行药剂活性筛选试验。所有测试组的昆虫都需要喂养至化蛹期,根据羽化的情况记录化合物对昆虫的致死情况。
表4.部分化合物的杀虫活性(500mg/L,200mg/L,50mg/L).
以上实施例的说明只是用于帮助理解本发明的方法及其核心思想。应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以对本发明进行若干改进和修饰,这些改进和修饰也落入本发明权利要求的保护范围内。
Claims (10)
3.根据权利要求2所述的制备方法,其特征在于,步骤(1)中,反应溶剂为二氯甲烷,反应温度为0-30℃,反应所用的催化剂是三乙胺、4-DMAP或者DIPEA中的任意一种。
4.根据权利要求2所示的制备方法,其特征在于,步骤(2)中,所用溶剂为两种溶剂按体积比为1:1~5:1的混合,两种溶剂是二氧六环/水、四氢呋喃/水或丙酮/水;所用的碱是碳酸氢钠、碳酸钠、碳酸钾或者氢氧化钠中的任意一种。
5.根据权利要求2所示的制备方法,其特征在于,步骤(3)中,反应温度为0℃-25℃,所用的溶剂是二氯甲烷、甲苯、DMF或者丙酮;所用的碱是三乙胺、4-DMAP或者碳酸钾中的任意一种。
6.根据权利要求2所示的制备方法,其特征在于,步骤(4)中,所用的溶剂为DMF、二氧六环或者四氢呋喃,反应温度为25℃-70℃。
7.根据权利要求1所述的氧杂二唑硝基苯胍基脲化合物在昆虫几丁质酶抑制剂或防治农业有害生物中的应用。
8.根据权利要求7所述的应用,当用于昆虫几丁质酶抑制剂时,其几丁质酶来源于亚洲玉米螟。
9.根据权利要求7所述的应用,当用于防治农业有害生物中的应用时,所述有害生物包括鳞翅目、鞘翅目、直翅目、等翅目、半翅目、膜翅目、双翅目、缨翅目。
10.根据权利要求7所述的应用,当用于防治农业有害生物中的应用时,所述有害生物包括线虫,所述线虫包括下述属的线虫:胞囊线虫属、球异皮线虫属、根结线虫属、穿孔线虫属、短体线虫属、小垫刃线虫属、长针线虫属、毛刺线虫属、剑线虫属、茎线虫属、滑刃线虫属和鳗线虫属。
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