WO2021147484A1 - 一种用于小麦全蚀病病菌抑制的2-(1，2，4-三氮唑)苯甲酰芳胺类活性化合物 - Google Patents

一种用于小麦全蚀病病菌抑制的2-(1，2，4-三氮唑)苯甲酰芳胺类活性化合物 Download PDF

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WO2021147484A1
WO2021147484A1 PCT/CN2020/129000 CN2020129000W WO2021147484A1 WO 2021147484 A1 WO2021147484 A1 WO 2021147484A1 CN 2020129000 W CN2020129000 W CN 2020129000W WO 2021147484 A1 WO2021147484 A1 WO 2021147484A1
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active compound
triazole
arylamine
benzoyl
rot disease
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PCT/CN2020/129000
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French (fr)
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程绎南
李洪连
郭线茹
蒋振华
苏子洋
张蒙萌
孙连省
申国富
马艺超
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河南农业大学
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Priority to AU2020424232A priority Critical patent/AU2020424232B2/en
Priority to US17/629,254 priority patent/US20220348550A1/en
Publication of WO2021147484A1 publication Critical patent/WO2021147484A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/64—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with three nitrogen atoms as the only ring hetero atoms
    • A01N43/647—Triazoles; Hydrogenated triazoles
    • A01N43/653—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
    • A01P3/00—Fungicides

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  • the invention relates to the field of compounds for the prevention and control of crop diseases and insect pests, in particular to a new 2-(1,2,4-triazole) benzoyl arylamine compound for sterilization and a preparation method thereof, and a composition containing these compounds Used to prevent and control wheat rot disease.
  • US Patent Nos. US005482974A, US006028101A, US005994270A and World Patent WO9307751A1 disclose a series of active compounds for wheat rot disease, but only the silityamid compounds disclosed in US patent US005486621A are commercially available, and are used for the prevention and control of wheat rot disease.
  • some agents including silthiazamide have even developed resistance.
  • the present invention provides an excellent inhibitory effect on wheat rot disease, the synthesis of raw materials is cheap and easy to obtain, does not involve air-sensitive compounds, the synthesis process is smooth, simple, and safe, and the product easily purified 2-(1,2,4-triazole) benzoyl arylamine bactericidal active compound and its preparation method.
  • a 2-(1,2,4-triazole) benzoyl arylamine active compound for inhibiting wheat rot disease characterized in that it has the structure shown in formula I:
  • R 1 , R 2 , R 3 , and R 4 are -H, -F, -Cl, -Br, -I, -CN, -NO 2 , -CF 3 , -CHO, -C 1 -C 4 Alkyl group or -C 1 -C 4 haloalkyl group or -OR 5 .
  • X and Y are -H, -F, -Cl, -Br, -I, -CN, -NO 2 , -CF 3 or -COOR 6 .
  • R 5 is -C 1 -C 4 alkyl or -C 1 -C 4 haloalkyl or aryl.
  • R 6 is -C 1 -C 4 alkyl or -C 1 -C 4 haloalkyl or aryl.
  • a preparation method of 2-(1,2,4-triazole) benzoyl arylamine active compound for inhibiting wheat rot disease characterized in that:
  • the active compound is synthesized in the following way:
  • the compound I can be obtained by condensation of intermediate II and substituted aniline III under set reaction conditions A, as shown in reaction formula 1:
  • the reaction condition A is: Intermediate II in the presence of a chlorinating agent including SOCl 2 , PCl 3 , POCl 3 , PCl or oxalyl chloride, in the presence of toluene, N,N-dimethylformamide, ethyl acetate , THF or acetonitrile solvent, it is converted into the corresponding acid chloride in the range of -10°C to reflux temperature, and then includes triethylamine, pyridine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate or potassium acetate Under the catalysis of a catalyst, react with substituted aniline III at room temperature to reflux temperature for 0.5-10 hours;
  • a chlorinating agent including SOCl 2 , PCl 3 , POCl 3 , PCl or oxalyl chloride
  • the molar ratio of II to III and the condensing agent is 1:0.8-5:0.8-4, and the amount of the catalyst relative to the intermediate II is 0-200% by mole;
  • the intermediate II can be formed by the hydrolysis of intermediate IV under the set reaction conditions B, as shown in reaction formula 2:
  • the said reaction condition B is: Intermediate IV uses water as a solvent under the action of a set ratio of sulfuric acid and nitrous acid to react at a temperature of -10 to 20°C for 1 to 12 hours, and then react at reflux temperature. 1 to 8 hours.
  • the intermediate IV is obtained by hydrolysis of the intermediate V under the set conditions C, as shown in reaction formula 3:
  • reaction condition C is: Intermediate V is reacted in an aqueous solution of sulfuric acid with a predetermined concentration at 50° C. to reflux temperature at atmospheric pressure for 5-25 hours;
  • the mass concentration of sulfuric acid is 50-85%; the molar ratio of intermediate V to sulfuric acid is 1:5-10.
  • the compound V is obtained by catalytic coupling of raw material VI and 1,2,4-triazole under set conditions D, as shown in reaction formula 4;
  • the reaction condition D is: raw material VI and 1,2,4-triazole in a solvent including toluene, dimethyl sulfoxide (DMSO) or N,N-dimethylformamide (DMF), with a ratio of 1 to 3 molar equivalents of alkali metal carbonates including sodium carbonate, potassium carbonate or cesium carbonate are bases, under the catalysis of 1-10% molar equivalents of CuI and 8-hydroxyquinoline-N-oxide, at 50°C ⁇ React for 5-18 hours in the temperature range of 130°C.
  • DMSO dimethyl sulfoxide
  • DMF N,N-dimethylformamide
  • composition containing the compound I is applied to the prevention and control of crop diseases.
  • the compound of the present invention has an excellent inhibitory effect on wheat rot disease, and its activity on the tested disease bacterium significantly exceeds the activity of the specific agent silitianil for the prevention and control of wheat rot disease. It can be used for Effectively control wheat rot disease and ensure the safety of wheat production; provide alternative methods, measures and options for the prevention and control of wheat rot disease;
  • the synthetic materials of the compound of the present invention are cheap and easy to obtain, and do not involve air-sensitive compounds. The process is smooth, simple and safe, the product is easy to purify, and the product cost is significantly lower than that of silitianil, which is easy to promote and apply.
  • Figure 1 is a characterization data table of the structure and physical and chemical parameters of the compound of Example 2-23;
  • Figure 2 is a data table showing the structure and physical and chemical parameters of the compounds of Examples 24-25;
  • Figure 3 is a table showing the inhibitory activity of Example Compounds 1-25 against wheat rot disease
  • Figure 4 is a characterization data table of the structure and physicochemical parameters of the compounds of Examples 24-25.
  • Step 1 Combine 0.17g (1mmol) 2,6-dichlorobenzonitrile, 0.09g (1.3mmol) technical grade 1,2,4-triazole, 0.43g (1.3mmol) anhydrous cesium carbonate and 9.5mg ( 0.05mmol) CuI and 8.1mg (0.05mmol) of 8-hydroxyquinoline-N-oxide ligand were added to a 20mL small reaction flask, and then 3mL of N,N-dimethylformamide was measured and added to the reaction Place the bottle in an oil bath at 85°C, stir and heat to react for 12 hours.
  • Step 2 Add 6.1g (30mmol) of 2-chloro-6-(1H-1,2,4-triazol-1-yl)benzonitrile into a three-necked flask, and then add 30g of 80% sulfuric acid (0.24mol) The aqueous solution was heated to 100°C and refluxed for 18 hours. The reaction was a dark red homogeneous solution. TLC detected that the reaction was complete. Add water to adjust the pH to neutral, extract and dry with ethyl acetate, and evaporate the solvent under reduced pressure to obtain the crude product as a gray solid. Chromatographic separation yielded 5.3 g of pure 2-chloro-6-(1H-1,2,4-triazol-1-yl)benzamide.
  • Step 3 Add 14.3g (0.064mol) of 2-chloro-6-(1H-1,2,4-triazol-1-yl)benzamide into a 100mL three-necked reaction flask, and place the three-necked flask in an ice bath In the temperature range of 0°C ⁇ 10°C, slowly add 79g 80% sulfuric acid (0.64mol) aqueous solution, after dripping, start to add dropwise 22.1g (0.32mol) sodium nitrite which has been cooled to 0°C ⁇ 10°C. The reaction is always maintained between 0°C ⁇ 10°C. After the dripping is completed, the reaction is kept for 1h. Then it is reacted at 100°C for 2h.
  • Step 4 Put 1.4g (6.3mmol) of 2-chloro-6-(1H-1,2,4-triazol-1-yl)benzoic acid into a 50mL three-port reaction containing 20mL of toluene with reflux and gas absorption device Into the flask, slowly add 1.5g (12.6mmol) of thionyl chloride at 80°C, and continue the reaction for 2h after the addition.
  • Example 1 It was synthesized in the same way as in Example 1. Using the intermediate 2-chloro-6-(1H-1,2,4-triazol-1-yl)benzoic acid synthesized in Example 1 as a raw material, it was synthesized by reaction with different substituted anilines and separated. The structure, some physical and chemical parameters and characterization data of the compound are shown in Figure 1.
  • the biological activity of the compound was tested by the mycelial growth rate method.
  • the tested pathogen was wheat rot disease, which was isolated and purified from Zhumadian, Henan province. First, weigh 200g of peeled fresh potatoes, boil them with 1L of distilled water for 20 minutes, filter out the uncooked potatoes with gauze, add 20g of glucose and 15g of agar to the filtrate, stir well until it is completely dissolved, and then distilled water to make the volume. To 1L. Then, it was sterilized by moist heat at 120°C for 20 minutes, and cooled to prepare a PDA medium.
  • test samples of appropriate concentration with dimethyl sulfoxide (DMSO) as the solvent, and add appropriate amount of surfactant Tween for use.
  • Pipette 1 mL of the test sample solution of appropriate concentration and 9 mL of PDA medium melted and cooled to 50°C and mix thoroughly, then pour it into a sterile petri dish and cool to room temperature.
  • the medium is the control.
  • the data in Figure 3 shows that the compound of the invention has high virulence to the pathogen of wheat rot disease, and the EC50 value is significantly better than that of the control silthiosam; the EC50 value of some compounds is close to or lower than the newly registered fungicide C in my country
  • the EC50 value of thioconazole shows excellent inhibitory activity against wheat rot disease.
  • the compound of the present invention has two advantages: (1) It has an excellent inhibitory effect on wheat rot disease, and its activity on the tested pathogens significantly exceeds the activity of the specific agent silitianil for the prevention and control of wheat rot disease.
  • the prevention and control of wheat rot disease provides alternative methods, measures and options;
  • the synthetic materials of the compound of the present invention are cheap and easy to obtain, do not involve air-sensitive compounds, the synthesis process is smooth, simple, and safe, the product is easy to purify, and the product cost is relatively low.
  • Sithiazamide has a relatively large reduction and is easy to popularize and apply.

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Abstract

本发明公开了一种用于小麦全蚀病病菌抑制的2-(1，2，4-三氮唑)苯甲酰芳胺类活性化合物及其制备方法，其特征在于：活性化合物具有式I所示结构。所述R 1、R 3、R 4为-H，-F，-Cl，-Br，-I，-CN，-NO 2，-CF 3，-CHO，-C 1-C 4的烷基或-C 1-C 4的卤代烷基或-O-R 5；所述R 2为-H，-F，-Cl，-Br，-I，-CN，-CF 3，-CHO，-C 1-C 4的烷基或-C 1-C 4的卤代烷基或-O-R 5；X为-F、-Cl、-Br、-I、-CN、-NO 2、-CF 3或-COOR 6；Y为-H、-F、-Cl、-Br、-I、-CN、-NO 2、-CF 3或-COOR 6；R 5为-C 1-C 4的烷基或-C 1-C 4的卤代烷基；R 6为-C 1-C 4的烷基或-C 1-C 4的卤代烷基；所述化合物I对小麦全蚀病病菌具有优异的抑制效果，可应用于小麦全蚀病的防治；所述化合物I的合成反应过程简单、流畅、安全，产品易于纯化，适于规模合成与开发。

Description

一种用于小麦全蚀病病菌抑制的2-(1，2，4-三氮唑)苯甲酰芳胺类活性化合物 技术领域
本发明涉及防治农作物病虫害化合物领域，具体为一种用于杀菌的新的2-(1，2，4-三氮唑)苯甲酰芳胺类化合物及其制备方法，含有这些化合物的组合物用于防治小麦全蚀病。
背景技术
随着社会的发展，尤其是科学技术的不断进步，大大促进了社会生产力的发展；人们的生活水平也得到了很大的改善与提高，尤其是工业化进程带动的新型农业的发展，使得我国农业更加现代化，农业耕作模式也在发生着巨大变化。
秸秆还田已成为农业的主要作业模式。由于植物秸秆本身具有滋生和携带病原菌的特点，秸秆还田某种程度上会加大农作物病害发生的风险和发生的成度。因此农作物病害的防治、以及农作物病害新防治药剂的开发在农业现代化的进程中就变得非常重要。文献《农药》，2008，47(1)，6-7，20报道了酰胺类化合物在农业领域的应用；文献J.Mol.Biol.，2010，397，1067-1078报道了三唑类化合物不同活性应用领域，以上文献所公开的化合物一定程度上能够满足农业领域特定作物及特定病害的防治要求。然而，对于小麦全蚀病的防治由于防治效果有限，现有可供选择的品种很少。美国专利US005482974A、US006028101A、US005994270A和世界专利WO9307751A1公开了一系列的小麦全蚀病活性化合物，但商品化的只有美国专利US005486621A公开的硅噻菌胺化合物，并用于小麦全蚀病的防治。然而，随着农作物病害抗性水平的不断发展，包括硅噻菌胺在内的一些药剂甚至已经产生了抗性。
因此提供一种新型小麦全蚀病防治活性化合物及开发新型杀菌剂就变得尤为必要。
发明内容
为了解决上述现有技术中存在的不足，本发明提供了一种对小麦全蚀病病菌具有优异的抑制效果，合成原料便宜易得，不涉及空气敏感化合物，合成过程流畅、简单、安全，产品易于纯化的2-(1，2，4-三氮唑)苯甲酰芳胺类杀菌活性化合物及其制备方法。
本发明的目的这样实现的：
一种用于小麦全蚀病病菌抑制的2-(1，2，4-三氮唑)苯甲酰芳胺类活性化合物，其特征在于，具有式I所示结构：
Figure PCTCN2020129000-appb-000001
其中：R 1、R 2、R 3、R 4为-H，-F，-Cl，-Br，-I，-CN，-NO 2，-CF 3，-CHO，-C 1-C 4的烷基或-C 1-C 4的卤代烷基或-O-R 5。
X、Y为-H、-F、-Cl、-Br、-I、-CN、-NO 2、-CF 3或-COOR 6。
R 5为-C 1-C 4的烷基或-C 1-C 4的卤代烷基或芳基。
R 6为-C 1-C 4的烷基或-C 1-C 4的卤代烷基或芳基。
一种用于小麦全蚀病病菌抑制的2-(1，2，4-三氮唑)苯甲酰芳胺类活性化合物的制备方法，其特征在于：
所述活性化合物通过以下方式合成：
Figure PCTCN2020129000-appb-000002
所述化合物I可通过中间体II和取代的苯胺III在设定的反应条件A下缩合而得，具体如反应式1所示：
Figure PCTCN2020129000-appb-000003
反应式1
所述的反应条件A为：中间体II在包括SOCl 2、PCl 3、POCl 3、PCl或草酰氯的氯化剂存在下，在包括甲苯、N，N-二甲基甲酰胺、乙酸乙酯、THF或乙腈溶剂中，在-10℃到回流温度范围内转化为相应的酰氯，再在包括三乙胺、吡啶、氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、乙酸钠或乙酸钾催化剂的催化下，与取代的苯胺III在室温至回流温度下反应0.5～10小时；
或中间体II和取代的苯胺III在包括甲苯、N，N-二甲基甲酰胺、乙酸乙酯、THF或乙腈的溶剂中，在包括二环己基碳二亚胺(DCC)、二异丙基碳二亚胺(DIC)或1-(3-二甲胺基丙基)-3-乙基碳二亚胺(EDCI)缩合剂的存在下，在或者不在包括1-羟基苯并三唑(HOBt)、4-二甲氨基吡啶的(DMAP)、N-羟基-7-氮杂苯并三氮唑(HOAt)催化剂的催化下，在-10℃到回流温度下反应1～15小时而得。
所述的反应式1反应中，II对III及缩合剂的投料摩尔比为1∶0.8～5∶0.8～4，催化剂相对于中间体II的用量为0-200％摩尔；
所述中间体II可由中间体IV在设定的反应条件B下水解而成，具体如反应式2所示：
Figure PCTCN2020129000-appb-000004
反应式2
所述的反应条件B为：中间体IV以水为溶剂在设定比例的硫酸和亚硝酸的作用下，在-10～20℃温度范围内，反应1～12小时，再在回流温度下反应1～8小时。
所述的反应式2反应中，中间体IV对硫酸和亚硝酸投料摩尔比为1∶5～15∶2～8。
所述中间体IV由中间体V在设定条件C下通过水解而得，具体如反应式3所示：
Figure PCTCN2020129000-appb-000005
反应式3
所述的反应条件C为：中间体V在设定浓度硫酸的水溶液中，在50℃到回流温度下，常压反应5～25小时；
所述的反应式3反应中，硫酸的质量浓度为50～85％；中间体V对硫酸的摩尔比为1∶5～10。
所述化合物V由原料VI和1，2，4-三氮唑在设定的条件D下通过催化偶联而得，具体如反应式4所示；
Figure PCTCN2020129000-appb-000006
反应式4
所述反应条件D为：原料VI和1，2，4-三氮唑在包括甲苯、二甲亚砜(DMSO)或N，N-二甲基甲酰胺(DMF)的溶剂中，以1～3摩尔当量的包括碳酸钠、碳酸钾或碳酸铯的碱金属碳酸盐为碱，在1～10％摩尔当量的CuI和8-羟基喹啉-N-氧化物的催化下，在50℃～130℃温度范围内，反应5～18小时。
所述的反应式4中，原料VI和1，2，4-三氮唑的投料摩尔比为1∶0.8～3。
包含所述化合物I的组合物，应用于农作物病害的防治。
积极有益效果：(1)本发明化合物对小麦全蚀病病菌具有优异的抑制效果，对供试病菌，其活性显著超过了防治小麦全蚀病的特效药剂硅噻菌胺的活性，可以用来有效地防治小麦全蚀病，保障小麦生产安全；为小麦全蚀病的防治提供了可替代的方法、措施及选择；(2)本发明化合物合成原料便宜易得，不涉及空气敏感化合物，合成过程流畅、简单、安全，产品易于纯化，产品成本较硅噻菌胺具有较大幅度的降低，易于推广应用。
附图说明：
图1为实施例2-23化合物结构及物化参数表征数据表；
图2为实施例24-25化合物结构及物化参数表征数据表；
图3为实施例化合物1～25对小麦全蚀病病菌的抑制活性表；
图4为实施例24-25化合物结构及物化参数表征数据表。
具体实施方式
下面结合具体例，对本发明做进一步的说明：
实施例1
2-氯-N-(4-氯苯基)-6-(1H-1，2，4-三氮唑-1-基)苯甲酰胺
2-chloro-N-(4-chlorophenyl)-6-(1H-1，2，4-triazol-1-yl)benzamide
Figure PCTCN2020129000-appb-000007
步骤1 将0.17g(1mmol)2，6-二氯苯甲腈，0.09g(1.3mmol)工业级1，2，4-三氮唑，0.43g(1.3mmol)无水碳酸铯和9.5mg(0.05mmol)CuI及8.1mg(0.05mmol)8-羟基喹啉-N-氧化物配体加入到20mL的小反应瓶中，然后量取3mL的N，N-二甲 基甲酰胺，加入到反应瓶中，放置在85℃的油浴中，搅拌加热反应12h。TLC检测反应完全后，减压过滤碳酸钾以及未反应的三氮唑，滤液水洗萃取后浓缩，用薄层色谱分离得到亚白色固体133mg。2-氯-6-(1H-1，2，4-三唑-1-基)苯甲腈，亚白色固体，熔点：170℃-172℃收率：65％. 1H NMR(400MHz，CDCl 3)δ：8.79(s，1H)，8.20(s，1H)，7.72-7.70(dd，J＝4Hz，2H)，7.64-7.62(m，1H). 13C NMR(100MHz，CDCl 3)δ：153.3，143.3，140.3，139.2，134.5，129.8，123.1，113.3，107.7.
步骤2 将2-氯-6-(1H-1，2，4-三唑-1-基)苯甲腈6.1g(30mmol)加入到三口烧瓶中，然后加入30g 80％的硫酸(0.24mol)水溶液，加热到100℃回流反应18h，反应呈暗红色均相溶液，TLC检测反应完全，加水调节pH至中性，用乙酸乙酯萃取干燥，减压蒸出溶剂得到粗品为灰色固体，经过柱色谱分离得到纯品2-氯-6-(1H-1，2，4-三唑-1-基)苯甲酰胺5.3g。2-氯-6-(1H-1，2，4-三唑-1-基)苯甲酰胺，灰色固体，熔点：128℃-130℃收率：79％. 1H NMR(400MHz，CDCl 3)δ：8.52(s，1H)，8.11(s，1H)，7.58-7.56(m，1H)，7.53-7.49(m，2H)，5.86(brs，2H). 13C NMR(100MHz，CDCl 3)δ：165.7，152.7，144.2，135.2，132.1，131.5，131.1，130.5，124.0.
步骤3 将2-氯-6-(1H-1，2，4-三唑-1-基)苯甲酰胺14.3g(0.064mol)加入到100mL的三口反应瓶中，将三口烧瓶置于冰浴中，在0℃～10℃范围内，慢慢加入79g80％的硫酸(0.64mol)水溶液，滴完后开始滴加已降温至0℃～10℃的22.1g(0.32mol)亚硝酸钠配制成的水溶液，使反应始终维持在0℃～10℃之间，滴加完毕后保温反应1h后.然后再在100℃下反应2h，TLC检测反应完全为止.反应液用乙酸乙酯萃取、干燥、减压蒸出溶剂后得到淡黄色2-氯-6-(1H-1，2，4-三唑-1-基)苯甲酸固体12g。2-氯-6-(1H-1，2，4-三唑-1-基)苯甲酸，黄色固体，熔点：122℃-124℃.收率：84％. 1H NMR(400MHz，CDCl 3)δ：9.03(s，1H)，8.26(s，1H)，7.74-7.64(m，3H). 13C NMR(100MHz，CDCl 3)δ：165.7，152.9，144.9，135.0，131.7，131.2，130.4，130.3，123.6.
步骤4 将1.4g(6.3mmol)2-氯-6-(1H-1，2，4-三唑-1-基)苯甲酸投入盛有20mL甲苯的带有回流和气体吸收装置的50mL三口反应瓶中，在80℃条件下缓慢加入1.5g(12.6mmol)的氯化亚砜，加完后继续反应2h.负压脱出溶剂和过量的氯化亚砜后，向反应瓶中补加10mL新鲜甲苯，接着向反应瓶中滴加含有2.4g(18.9mmol)对氯苯胺和0.64g(6.3mmol)三乙胺的10mL甲苯溶液，在85℃温度下反应2h。加入饱和食盐水洗涤，静置分层，有机相用温水洗涤三次(每次5mL)，干燥剂后过滤，滤液负压蒸出溶剂，用色谱柱或重结晶分离得到2-氯-N-(4-氯苯基)-6-(1H-1，2，4-三唑-1-基)苯甲酰胺化合物，浅黄色固体。熔点：136.4℃-137.9℃收率63％. 1H NMR(400Hz，DMSO-d)δ(ppm)：10.79(s，1H)，8.93(s，1H)，8.16(s，1H)，7.77～7.68(m，3H)，7.58～7.56(d，J＝8.8Hz，2H)，7.39～7.37(d，J＝8.8Hz，2H)。
实施例2～23
按照实施例1相同的方法合成。以实施例1合成得到的中间体2-氯-6-(1H-1，2，4-三唑-1-基)苯甲酸为原料，与不同的取代苯胺反应合成并分离。化合物的结构、部分物化参数及表征数据如图1所示。
实施例24～25
分别以2-氯苯腈、2，3-二氯苯腈为原料，按照实施例1步骤1相同的方法分别合成相应的2-(1H-1，2，4-三唑-1-基)苯腈和3-氯-2-(1H-1，2，4-三唑-1-基)苯腈；再分别以相应的2-(1H-1，2，4-三唑-1-基)苯腈和3-氯-2-(1H-1，2，4-三唑-1-基)苯腈为中间体，按照与实施例1步骤2，3相同的方法，将取代的氰水解分别得到2-(1H-1，2，4-三唑-1-基)苯甲酸和3-氯-2-(1H-1，2，4-三唑-1-基)苯甲酸；再按照与实施例1步骤4相同的方法，把得到的酸分别与4-胺基苯甲酸异丙酯缩合得到目标化合物。化合物的结构、部分物化参数及表征数据如图2所示。
实施例1～25化合物的活性测试
化合物的生物活性采用菌丝生长速率法测试。供试病原菌为小麦全蚀病病菌，分别分离纯化自河南省驻马店地区。首先，称取200g去皮后的新鲜土豆，用1L蒸馏水加热煮沸20min，用纱布滤出未煮烂的土豆，向滤液中加入葡萄糖20g和琼脂15g，充分搅拌待其完全溶解后用蒸馏水定容到1L。接着在120℃下湿热灭菌20分钟，冷却制得PDA培养基。
然后，以二甲亚砜(DMSO)为溶剂配制适当浓度的供试样品，并加入适当数量的表面活性剂吐温备用。移取适当浓度的供试样品溶液1mL和熔化并冷却至50℃的PDA培养基9mL充分混合，然后倒入无菌培养皿中冷却至室温。把在PDA平板上培养7天的小麦全蚀病病原菌用直径5mm的打孔器制作成菌饼，然后将菌饼以倒扣的方式接种在含药的PDA平板中央，以不含药的平板培养基为对照。每个药剂设置100、50、10、1、0.1、0.01μg/mL六个浓度，每个浓度设3个重复，在25℃培养箱中避光培养6天，调查菌落直径，计算各浓度相对抑制率[相对抑制率＝(空白对照菌落生长直径-药剂处理菌落生长直径)/空白对照菌落生长直径×100％]，以浓度的对数值与相对抑制率的机率值拟合回归毒力方程，进而求出EC 50值。实施例化合物通过活性测试计算出的EC 50值如图3所示。
图3中数据显示，该发明化合物对小麦全蚀病病原菌具有较高的毒力，EC50值均明显优于对照药剂硅噻菌胺；部分化合物EC50值接近或低于我国新登记的杀菌剂丙硫菌唑的EC50值，对小麦全蚀病病菌表现出优异的抑制活性。
对比实施例1～3
作为对比，如果该发明化合物酰胺的氮原子取代基不是芳香取代基，酰胺氮原子被1或2个饱和碳原子取代基取代，其对小麦全蚀病病菌活性较差，在测试浓度下几乎没有表现出活性。对比实施例化合物的结构、部分物性参数及EC50值如图4所示：
本发明化合物具有两方面的优点：(1)对小麦全蚀病病菌具有优异的抑制效果，对供试病原菌，其活性显著超过了防治小麦全蚀病的特效药剂硅噻菌胺的活性，为小麦全蚀病的防治提供了可替代的方法、措施及选择；(2)本发明化合物合成原料便宜易得，不涉及空气敏感化合物，合成过程流畅、简单、安全，产品易于纯化，产品成本较硅噻菌胺具有较大幅度的降低，易于推广应用。

Claims (9)

  1. 一种用于小麦全蚀病病菌抑制的2-(1，2，4-三氮唑)苯甲酰芳胺类活性化合物，其特征在于：具有式I所示结构：
    Figure PCTCN2020129000-appb-100001
    所述R 1、R 3、R 4为-H，-F，-Cl，-Br，-I，-CN，-NO 2，-CF 3，-CHO，-C 1-C 4的烷基或-C 1-C 4的卤代烷基或-O-R 5；
    所述R 2为-H，-F，-Cl，-Br，-I，-CN，-CF 3，-CHO，-C 1-C 4的烷基或-C 1-C 4的卤代烷基或-O-R 5；
    X为-F、-Cl、-Br、-I、-CN、-NO 2、-CF 3或-COOR 6；Y为-H、-F、-Cl、-Br、-I、-CN、-NO 2、-CF 3或-COOR 6；
    R 5为-C 1-C 4的烷基或-C 1-C 4的卤代烷基；
    R 6为-C 1-C 4的烷基或-C 1-C 4的卤代烷基。
  2. 一种如权利要求1用于小麦全蚀病病菌抑制的2-(1，2，4-三氮唑)苯甲酰芳胺类活性化合物的制备方法，其特征在于：
    所述活性化合物通过以下方式合成：
    Figure PCTCN2020129000-appb-100002
  3. 根据权利要求2所述的一种用于小麦全蚀病病菌抑制的2-(1，2，4-三氮唑)苯甲酰芳胺类活性化合物的制备方法，其特征在于：所述条件D为原料VI和1，2，4-三氮唑在甲苯、二甲亚砜(DMSO)、N，N-二甲基甲酰胺(DMF)的溶剂中，以1～3摩尔当量的碳酸盐为碱，在1～10％摩尔当量的CuI和8-羟基喹啉-N-氧化物的催化下，在50℃～130℃温度范围内，反应 5～18小时；原料VI和1，2，4-三氮唑的投料摩尔比为1∶0.8～3。
  4. 根据权利要求3所述的一种用于小麦全蚀病病菌抑制的2-(1，2，4-三氮唑)苯甲酰芳胺类活性化合物的制备方法，其特征在于：所述的碳酸盐为碳酸钠、碳酸钾或碳酸铯碱金属。
  5. 根据权利要求2所述的一种用于小麦全蚀病病菌抑制的2-(1，2，4-三氮唑)苯甲酰芳胺类活性化合物的制备方法，其特征在于：所述条件C为中间体V在设定浓度硫酸的水溶液中，在50℃到回流温度下，常压反应5～25小时；硫酸的质量浓度为50～85％；中间体V对硫酸的摩尔比为1∶5～10。
  6. 根据权利要求2所述的一种用于小麦全蚀病病菌抑制的2-(1，2，4-三氮唑)苯甲酰芳胺类活性化合物的制备方法，其特征在于：所述条件B中间体IV以水为溶剂在设定比例的硫酸和亚硝酸的作用下，在-10℃到20℃温度范围内，反应1～12小时，再在回流温度下反应1～8小时；中间体IV对硫酸和亚硝酸投料摩尔比为1∶5～15∶2～8。
  7. 据权利要求2所述的一种用于小麦全蚀病病菌抑制的2-(1，2，4-三氮唑)苯甲酰芳胺类活性化合物的制备方法，其特征在于：所述条件A：(1)中间体II在SOCl 2、PCl 3、POCl 3、PCl或草酰氯氯化剂的存在下，在甲苯、N，N-二甲基甲酰胺、乙酸乙酯、THF或乙腈溶剂中，在-10℃到回流温度下转化为相应的酰氯，再在三乙胺、吡啶、氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、乙酸钠或乙酸钾的催化剂的催化下，与取代的苯胺III在室温至回流温度下反应；(2)中间体II和取代的苯胺III在甲苯、N，N-二甲基甲酰胺、乙酸乙酯、THF或乙腈溶剂中，在二环己基碳二亚胺(DCC)、二异丙基碳二亚胺(DIC)或1-(3-二甲胺基丙基)-3-乙基碳二亚胺(EDCI)缩合剂的存在下，在或者不在1-羟基苯并三唑(HOBt)、4-二甲氨基吡啶的(DMAP)催化剂的催化下，在-10℃到回流温度下直接缩合。
  8. 一种如权利要求1所述的杀菌活性化合物的应用，其特征在于：包含所述活性化合物的组合物应用于小麦全蚀病的农作物病害的防治。
  9. 一种如权利要求1所述的杀菌活性化合物，其特征在于：所述活性化合物组分与农学上能够接受的载体形成的杀菌剂或所述活性化合物组分与其它杀菌活性组分及农学上能够接受的载体复合形成的杀菌剂，可应用于农作物病害的防治。
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