1, 2, 4-oxadiazole compound as well as preparation method and application thereof

Abstract

The invention discloses a 1, 2, 4-oxadiazole compound and a preparation method and application thereof.The preparation method comprises the steps that 1, 2, 4-oxadiazole serves as a parent nucleus structure and reacts with aromatic amine intermediates containing different substituent groups, structures such as alkyl, halogen, alkoxy and trifluoromethyl are introduced, oxalyl chloride serves as an acylating agent, a condensation reaction is conducted in THF and other solvents, and the 1, 2, 4-oxadiazole compound is obtained; a series of target compounds are synthesized. The structure of the obtained compound is confirmed by NMR, the compound has clear and controllable hydrogen spectrum and fluorine spectrum signals, the synthesis process is simple, the raw materials are easy to obtain, the reaction condition is mild, the yield is good (most yield is more than 65%), and the developed 1, 2, 4-oxadiazole compound not only has clear structure and stable physicochemical properties, but also has wide application prospects. Good sterilization performance and structure regulation and control space are also shown, and high further research and development value is achieved.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of drug synthesis, and particularly relates to 1,2,4-oxadiazole compounds and a preparation method and application thereof. BACKGROUND

[0002] In recent years, with the continuous improvement of agricultural intensification and high efficiency, the situation of plant diseases, insect pests and weeds is becoming increasingly severe, which seriously threatens crop yield and quality. According to national statistical data, in 2023, the area of crops affected by disasters in China reached 10.54 million hectares, directly affecting agricultural production safety. As an indispensable input in modern agriculture, chemical pesticides still play an important role in the comprehensive management of crop pests due to their fast-acting, wide application range, and convenient use.

[0003] Although chemical pesticides have made important contributions to food security, long-term and large-scale use has also brought a series of problems such as environmental pollution, increased target resistance, and increased risk to non-target organisms, which has restricted the sustainable development of agriculture. Therefore, developing new pesticides with low toxicity, high efficiency, environmental friendliness, and strong sustainability has become an important direction in the field of pesticide creation.

[0004] Heterocyclic compounds play an increasingly important role in the design of new pesticide molecules due to their excellent physicochemical properties and diverse structural modification space. In particular, compounds containing 1,2,4-oxadiazole structures have attracted widespread attention in recent years due to their excellent performance in molecular recognition, target binding, and metabolic stability. These compounds have shown promising activity in insecticidal, fungicidal, herbicidal, and miticidal applications. 1,2,4-oxadiazole derivatives not only have good biological activity but also have the potential for further structural optimization and functional expansion, making them one of the important molecular scaffolds for green pesticide creation.

[0005] Previous studies have shown that some 1,2,4-oxadiazole compounds exhibit good inhibitory effects on plant parasitic nematodes. Compounds represented by clothianidin have been applied to control various soil-borne nematodes, but there are still deficiencies in the current market in terms of activity intensity, suitable crops, safety, and environmental degradation. Therefore, derivative innovation and screening around this structure to explore new varieties with better control performance have clear practical value and promotion prospects.

[0006] To meet the needs of green agriculture and sustainable development, exploring the application of 1,2,4-oxadiazole compounds in the field of nematode control and developing new structures with high activity, low toxicity, and low residue is an important research direction in the field of pesticides. SUMMARY

[0007] In view of the problems existing in the prior art, the purpose of the present application is to provide 1,2,4-oxadiazole compounds and a preparation method and application thereof, the synthesis method is simple in process, raw materials are easy to obtain, and the yield is high, and the prepared compounds are clear in structure and stable in performance.

[0008] To achieve the above-mentioned purpose, the technical scheme of the present application is as follows:

[0009] 1,2,4-oxadiazole compounds, the structural formula is as shown in formula (I):

[0010]

[0011] In formula (I), the substituent group R is alkyl, nitro, acetyl, halogen, alkoxy or halogenated alkyl.

[0012] Further, the substituent group R is 2-fluoro, 3-fluoro, 4-fluoro, 2-chloro, 4-chloro, 3-nitro, 4-nitro, 2-methyl, 3-methyl, 4-methyl, 2-methoxy, 3-methoxy, 4-methoxy, 4-acetyl, 2-trifluoromethyl, 4-trifluoromethyl, 2,3-dichloro, 2,4-dichloro or 2-chloro-4-trifluoromethyl.

[0013] The present application provides a preparation method of the 1,2,4-oxadiazole compound, comprising the following steps:

[0014] 1) oxalyl chloride is reacted with a compound as shown in formula (II) to generate a compound as shown in formula (III) by taking EDC as a solvent;

[0015] 2) the compound as shown in formula (III) obtained in step 1) is reacted with N-hydroxy-N-(2,4-dichlorophenyl) methylamine to generate a compound as shown in formula (I) by taking THF as a solvent and TEA as an acid binding agent;

[0016] The reaction process is as follows:

[0017]

[0018] The substituent group R is alkyl, nitro, acetyl, halogen, alkoxy or halogenated alkyl.

[0019] Further, in the synthesis of the compound as shown in formula (III) in step 1), the molar ratio of formula (II) to oxalyl chloride is 1:1.5-3.

[0020] Further, in the synthesis of the compound as shown in formula (I) in step 2), the molar ratio of the compound as shown in formula (III) to N-hydroxy-N-(2,4-dichlorophenyl) methylamine is 1:1-1.5.

[0021] The application further provides application of the 1,2,4-oxadiazole compound prepared by the method as a fungicide.

[0022] Compared with the prior art, the application has the following beneficial effects:

[0023] 1) The application first takes 1,2,4-oxadiazole as a mother nucleus structure, introduces alkyl, halogen, alkoxy, trifluoromethyl and the like structures by reacting with an aromatic amine intermediate containing different substituents, adopts oxalyl chloride as an acylating agent, and performs condensation reaction in a THF solvent or the like to synthesize a series of target compounds. The structure of the obtained compound is confirmed by NMR, and the compound has clear hydrogen spectrum and fluorine spectrum signals, indicating that the structure is clear and controllable.

[0024] 2) The bactericidal activity test on 20 target products (I1-I20) synthesized shows that a plurality of compounds exhibit good activity on cucumber downy mildew, corn rust and cucumber powdery mildew at a concentration of 200 mg / L (i.e. 200 ppm). Among them, I10 has a prevention effect on the three kinds of pathogenic bacteria of more than 90%; I4, I5 and I7 and the like have an inhibition rate of 100% on cucumber downy mildew; I13 has an inhibition rate of 90% on corn rust; and I20 has an inhibition rate of 70% on corn rust and cucumber powdery mildew, respectively.

[0025] 3) Some compounds of the application exhibit broad-spectrum and high-efficiency biological activity characteristics, for example, I9 has an average prevention effect of 90% on the three kinds of tested diseases, and shows multi-target inhibition ability on downy mildew, rust and powdery mildew, and has potential as a broad-spectrum fungicide.

[0026] 4) The synthesis process of the application is simple, raw materials are easy to obtain, the reaction condition is mild, and the yield is good (more than 65% in most cases). The developed 1,2,4-oxadiazole derivatives not only have clear structure and stable physicochemical properties, but also exhibit good fungicidal performance and structure regulation space, and have high further research and development value. DETAILED DESCRIPTION

[0027] The application will be further described below in combination with specific examples, but the protection scope of the application is not limited thereto.

[0028] Preparation of the compound as shown in formula (III) in Example 1

[0029] In a 100 mL round-bottom flask, the compound as shown in formula (II) (0.6 g, 5.88 mmol) was dissolved in EDC (3 mL), oxalyl chloride (1.40 g, 11.03 mmol) was added, 1 drop of DMF was added dropwise as a catalyst, and after refluxing for 3 h, the solvent was dried to obtain the compound as shown in formula (III). Without purification, it was ready for use. The substituent R is alkyl, nitro, acetyl, halogen, alkoxy or halogenated alkyl.

[0030] Preparation of the compound of formula (I) according to Example 2

[0031] Example 2 Preparation of the compound of formula (I) according to Example 2

[0032] Table 1 Physico-chemical data of the compounds of formula (I)

[0033]

[0034]

[0035] Table 2 Hydrogen and fluorine spectrum data of the compounds of formula (I)

[0036]

[0037]

[0038]

[0039] Example 3 Test of fungicidal activity

[0040] (1) Test method of cucumber powdery mildew

[0041] The biological activity of the agent was determined by spore suspension spray inoculation. A true leaf stage cucumber seedling with uniform growth was selected, and the test agent was prepared into a 500 mg / L solution for spray treatment, with 4 repeats (4 pots of cucumber seedlings) per treatment. After 24 hours, the cucumber leaves covered with powdery mildew were inoculated with the spore suspension by spraying (pressure 0.1 MPa). The spore suspension was prepared by gently washing the fresh conidiospores on the surface of the cucumber leaves with sterile water, filtering with double gauze, and preparing a conidiospore suspension with a concentration of 1 x 105 / mL. After inoculation, the test materials were naturally air-dried for half an hour, then moved to a greenhouse with a temperature of 23-25°C, a relative humidity of 60-70%, and a light / dark cycle of 14 / 10 h for cultivation. After one week, the incidence of the blank control was observed and graded according to the "Standard for Evaluation of Biological Activity of Pesticides", and the control effect was calculated according to the disease index. The test was repeated 3 times.

[0042] (2) Cucumber downy mildew test method

[0043] The biological activity of the agent was determined by spore suspension spray inoculation. Two-leaf stage (growing point removed), uniform growth pot-grown cucumber seedlings were selected, two plants per pot, and a YW 5.2-A type micro-sprayer with a pressure of 0.1 MPa was used to uniformly spray the sample liquid with a concentration of 500 mg / L on the surface of the cucumber leaves. Five replicates (5 pots of cucumber seedlings) were set up for each concentration, with thifluzamide as the control, and the sprayed plants were naturally air-dried. After 24 hours of agent treatment, a spore suspension (spore suspension preparation: fresh cucumber downy mildew diseased leaves were collected, and the downy mildew-like substance on the back of the diseased leaves was washed off with a sterile water-dipped brush to prepare a spore suspension with a concentration of 2x105-3x105 spores / mL for use.) was uniformly sprayed on the cucumber leaves using an inoculation sprayer (pressure 0.1 MPa), and then the inoculated cucumber seedlings were moved to a greenhouse with a relative humidity of 100% and a temperature of 20°C, with a light-dark cycle of 14 / 10 h. After 5 days, the disease severity was investigated and the control effect was calculated according to the disease index. The test was repeated 3 times.

[0044] (3) Corn rust test method

[0045] Leaf inoculation method was used. Two pots of uniform growth true leaf stage pot-grown corn seedlings were selected, the sample was dissolved in an appropriate amount of DMF solvent to prepare a 500 mg / L concentration of liquid, which was sprayed on the leaf surface. After the agent was sprayed and dried, the bacteria cake was inoculated on the leaves. After 24-26°C dark light and 24 hours of moisture preservation, natural light was restored and the culture was maintained for about 3 days. After the control was fully diseased, the diameter of each inoculation spot was measured with a caliper, and the control effect was calculated.

[0046] The disease incidence and mycelial growth of the leaves and plants were observed and recorded after the test treatment, and the relative control effect was calculated according to the disease index and mycelial diameter, according to the "SOP for the creation of pesticide biological activity evaluation" fungicide volume, according to the disease index.

[0047] (4) Fungicide efficacy calculation formula

[0048] Disease index:

[0049]

[0050] Control effect:

[0051]

[0052] Fungicidal activity grade standard: A level control effect (inhibition rate) ≥ 90%, 70% ≤ B level control effect (inhibition rate) < 90%, 50% ≤ C level control effect (inhibition rate) < 70%, D level control effect (inhibition rate) < 50%.

[0053] The activity test results are shown in Table 3:

[0054]

[0055]

[0056] The 20 synthesized compounds were tested for cucumber powdery mildew, corn rust and cucumber downy mildew in vivo. The control effects of compound I9 on powdery mildew, rust and downy mildew were 80%, 100% and 90% respectively, and it had strong broad-spectrum activity. The control effects of compound I8 on the three diseases were 90%, 100% and 30% respectively, and it had obvious inhibitory effect on powdery mildew and rust.

[0057] Compounds I4 and I5 had 100% control effect on cucumber downy mildew, showing strong activity. The control effects of compound I7 on rust and downy mildew were 70% and 90% respectively. The control effects of compound I6 on the three diseases were 50%, 40% and 50% respectively, and it had certain broad-spectrum activity.

[0058] In addition, some compounds showed outstanding performance on specific diseases. For example, I13 had 90% control effect on corn rust; I14 had 60% control effect on powdery mildew; I10 had 60% control effect on downy mildew; and I5 had significant inhibitory activity on powdery mildew and downy mildew.

[0059] In summary, compounds I9, I8 and I6 showed good fungicidal activity in the tested diseases, and had the potential to be used as candidate fungicide structures.

[0060] Example 4 Nematicidal experimental method

[0061] 1. Sample dissolution: after assisted dissolution with solvent, dilute to the concentration to be tested.

[0062] 2. In vitro test: use a pipette to take 50 μL of the drug solution and 50 μL of the J2 suspension and place them in a 96-well plate in a 25°C constant temperature incubator, and continuously check the number of J2 deaths for 24-72 h.

[0063] In vitro test results of compound lethality (200 mg / L)

[0064] Treatment 24 hour mortality 48 hour mortality 72 hour mortality I1 1.4 2.4 2.8 I2 2.3 3.2 3.6 I10 1.4 2.3 2.8 I11 2.2 3.0 5.2 I12 89.5 100.0 100.0 I20 2.3 23.7 65.1

[0065] In summary, compound I12 showed good activity in the in vitro nematode test, and had the potential to be used as a candidate nematicidal agent structure.

Claims

1. A 1,2,4-oxadiazole compound characterized in that The structural formula is shown as formula (I): In formula (I), the substituent R is alkyl, nitro, acetyl, halogen, alkoxy or halogenated alkyl.

2. The 1,2,4-oxadiazole compound according to claim 1, wherein The substituent R is 2-fluoro, 3-fluoro, 4-fluoro, 2-chloro, 4-chloro, 3-nitro, 4-nitro, 2-methyl, 3-methyl, 4-methyl, 2-methoxy, 3-methoxy, 4-methoxy, 4-acetyl, 2-trifluoromethyl, 4-trifluoromethyl, 2,3-dichloro, 2,4-dichloro or 2-chloro-4-trifluoromethyl.

3. A process for the preparation of a 1,2,4-oxadiazole compound according to any one of claims 1 -2, characterized in that The method comprises the following steps: 1) reacting oxalyl chloride with a compound shown as formula (II) to generate a compound shown as formula (III) in EDC as solvent; 2) reacting the compound shown as formula (III) obtained in step 1) with N-hydroxy-N-(2,4-dichlorophenyl) methylamine in THF as solvent and TEA as acid binding agent to generate a compound shown as formula (I); The reaction process is as follows: The substituent R is alkyl, nitro, acetyl, halogen, alkoxy or halogenated alkyl.

4. The method of claim 3, wherein the 1,2,4-oxadiazole compound is prepared by the reaction of the compound of formula (2) with the compound of formula (3) in the presence of a base. In the synthesis of the compound shown as formula (III) in step 1), the molar ratio of formula (II) to oxalyl chloride is 1:1.5-3.

5. The method for preparing 1,2,4-oxadiazole compounds according to claim 3, characterized in that... In the synthesis of the compound shown as formula (I) in step 2), the molar ratio of the compound shown as formula (III) to N-hydroxy-N-(2,4-dichlorophenyl) methylamine is 1:1-1.

5.

6. The use of the 1,2,4-oxadiazole compound prepared by the method according to any one of claims 3-5 as a fungicide.

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