Compound containing 2-chloro-4-trifluoromethylpyridine structure as well as preparation method and application thereof

Abstract

The invention provides a compound containing a 2-chloro-4-trifluoromethylpyridine structure as well as a preparation method and application of the compound. The structural formula of the compound is shown as a formula (I). The compound disclosed by the invention has a good prevention and control effect on soil-borne diseases caused by Meloidogyne incognita, Botrytis cinerea Pers, Sclerotinia sclerotiorum, Fusarium graminearum and / or Ralstinia solanacearum, and is safe to crops, and the compound disclosed by the invention can be used for preventing and controlling the soil-borne diseases caused by the Meloidogyne incognita, the Botrytis cinerea Pers, the Sclerotinia sclerotiorum, the Fusarium graminearum and / or the Ralstinia solanacearum.

Description

Technical Field

[0001] This invention belongs to the field of agricultural chemicals technology, specifically relating to compounds containing a 2-chloro-4-trifluoromethylpyridine structure, their preparation methods, and applications. Background Technology

[0002] Soil-borne diseases are diseases caused by pathogens (fungi, bacteria, nematodes, and viruses, etc.) that exist part or most of their life cycle in the soil, infecting the roots or stems of plants under suitable conditions. In recent years, intensive production and continuous cropping have led to an increase in the accumulation of pathogens in the soil, and soil-borne diseases have become increasingly severe year by year, thus becoming an important factor limiting crop yield and quality, and seriously hindering the sustainable development of agriculture. For a long time, fumigants such as calcium cyanamide, dazomet, sulfuryl fluoride, 1,3-dichloropropene, dimethyl disulfide, methyl methacrylate, and methyl bromide have achieved good results in controlling soil-borne diseases. However, these traditional fumigants have various limitations, such as high toxicity to humans and animals, large dosage, high cost, increased resistance of pests, damage to the ecological environment, unstable activity in soil, susceptibility of activity to environmental conditions, and harm to the planting of crops in the lower strata. They cannot meet the needs of modern agricultural production. Developing efficient, safe, green, and low-cost alternative technologies and products to traditional soil fumigants is an urgent need in the current prevention and control of soil-borne diseases.

[0003] Trifluoromethylpyridine compounds generally possess advantages such as novel structure, low toxicity, and high efficiency, and are widely used in pesticide structural units, endowing pesticide molecules with significant biological activity, metabolic stability, and good lipid solubility. In the field of herbicides, derivatives of the trifluoromethylpyridine structure can effectively inhibit weed growth; for example, some arylpyridine carboxylate herbicides have shown excellent control efficacy against various herbicide-resistant weeds. In fungicides, the trifluoromethylpyridine structure is often used in succinate dehydrogenase inhibitor pesticides, achieving a fungicidal effect by interfering with the respiratory chain of pathogens and inhibiting mitochondrial energy production. Maleic anhydride is an important pesticide intermediate, such as diethyl maleate, an intermediate in the synthesis of the organophosphorus insecticide malathion, and 1-phenyl-3,6-dihydroxypyridazine, an intermediate in pyridazine phosmet. However, the application of compounds involving trifluoromethylpyridine and maleic anhydride derivatives as controls for soil-borne diseases in agricultural production has not yet been reported. Summary of the Invention

[0004] To overcome the shortcomings of existing technologies, this invention designs and synthesizes a series of compounds containing 2-chloro-4-trifluoromethylpyridine structures based on the principle of active substructure superposition. Indoor bioactivity tests and pot experiments show that these compounds have high bioactivity against soil-borne diseases and can be used for the prevention and control of soil-borne plant diseases, providing material support for safe crop production.

[0005] This invention provides compounds containing a 2-chloro-4-trifluoromethylpyridine structure, the structural formula of which is shown in formula (I):

[0006]

[0007] In formula (Ⅰ), R is a substituted or unsubstituted C1-C8 straight-chain or branched alkylamino group, a substituted or unsubstituted C3-C8 cycloalkylamino group, or a substituted or unsubstituted C6-C8 cycloalkylamino group. 30 Aromatic amino groups (such as aniline), acylhydrazide groups (R1CONH-NH-), R2-NH-NH-, and substituted or unsubstituted C3-C groups containing at least one heteroatom of O, S, or N. 30 heteroaryl amino groups, R3-NH-C(=NH)-NH-, amino(thio)urea groups (NH2-C(=S)-NH-NH-), substituted or unsubstituted C6-C 30 One of the following: aryloxy group (such as phenoxy group), substituted or unsubstituted C1-C8 straight-chain or branched alkoxy group, and C3-C8 cycloalkoxy group;

[0008] The substituents in the substituted C1-C8 straight-chain or branched alkylamino groups and the substituted C3-C8 cycloalkylamino groups are each independently selected from: hydroxyl, halogen, cyano, C1-C6 alkyl-OC(=O)-, five- or six-membered rings containing at least one heteroatom of O, S, or N, and C3-C6 cycloalkylamino groups containing at least one heteroatom of O, S, or N. 30 heteroaryl, C1-C6 alkyl-substituted imino, amino, NH2-C(=NH)-NH-;

[0009] The substituted C6-C 30 The substituent in the aromatic amino group can be at least one of C1-C6 alkyl, halogen, C1-C6 alkoxy, nitro, cyano, halogen-substituted C1-C6 alkyl, and halogen-substituted C1-C6 alkoxy.

[0010] In the R1CONH-NH-, R1 can be selected from: C1-C6 alkyl, -CH=CH-COOH, -CH=CH-COOC1-C6 alkyl, substituted or unsubstituted benzene ring, wherein the substituent can be at least one of -OH, C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 alkoxy, nitro, cyano;

[0011] In the R2-NH-NH-, R2 can be selected from: a substituted or unsubstituted benzene ring, wherein the substituent can be at least one of -OH, C1-C6 alkyl, halogen, C1-C6 alkoxy, nitro, and cyano;

[0012] The substituted C3-C 30The substituents in the heteroarylamine group can be at least one of C1-C6 alkyl, C1-C6 alkoxy, halogen, nitro, cyano, halogen-substituted C1-C6 alkyl, and halogen-substituted C1-C6 alkoxy.

[0013] In the R3-NH-C(=NH)-NH-, R3 is a substituted or unsubstituted C1-C8 straight-chain or branched alkyl group, and the substituent in the substituted alkyl group is at least one of amino and C1-C6 alkyl-OC(=O)-.

[0014] The substituted C6-C 30 The substituent in the aryloxy group can be at least one of C1-C6 alkyl, C1-C6 alkoxy, halogen, nitro, cyano, halogen-substituted C1-C6 alkyl, and halogen-substituted C1-C6 alkoxy.

[0015] The substituents in the substituted C1-C8 straight-chain or branched alkoxy groups may be halogens.

[0016] The present invention also provides a method for preparing the compound containing the 2-chloro-4-trifluoromethylpyridine structure shown in formula (Ⅰ).

[0017] The method for preparing the compound containing the 2-chloro-4-trifluoromethylpyridine structure shown in formula (Ⅰ) provided by the present invention includes the following steps:

[0018] 1) In an organic solvent, 2-amino-3-chloro-5-trifluoromethylpyridine is reacted with maleic anhydride to give a solution of the intermediate product shown in formula (III);

[0019]

[0020] 2) Add thionyl chloride to the system containing the intermediate shown in formula (III), and react to obtain the intermediate acyl chloride shown in formula (II);

[0021]

[0022] 3) In an organic solvent, in the presence of an acid-binding agent, the intermediate acyl chloride shown in formula (II) reacts with reactant RH to give the compound shown in formula (I) containing the 2-chloro-4-trifluoromethylpyridine structure.

[0023] In RH, the definition of R is the same as the definition of R in equation (Ⅰ).

[0024] Specifically, the reactant RH can be selected from: methylamine, ethylamine, n-propylamine, isopropylamine, n-butylamine, sec-butylamine, isobutylamine, tert-butylamine, n-pentylamine, 3-aminopentane, isopentylamine, n-hexylamine, 1,3-dimethylbutylamine, isohexylamine, n-heptylamine, 2-heptylamine, 1,3-dimethylpentylamine, n-octylamine, isooctylamine, 2-ethylheptylamine, tert-octylamine, cyclopropylamine, cyclobutylamine, cyclopentylamine, cyclohexylamine, cycloheptylamine, cyclooctylamine, ethanolamine, 2-chloroethylamine, 2-bromoethylamine, 2-fluoroethylamine, 3-chloropropylamine, 2-chloropropane-1-amine, 3-bromopropylamine, 2-bromopropane-1-amine, 3-fluoropropylamine, 2-fluoropropane-1-amine, 4-chloro-1-butylamine, 4 -Bromo-1-butylamine, 4-fluoro-1-butylamine, 5-chloro-1-pentylamine, 5-bromo-1-pentylamine, 5-fluoro-1-pentylamine, 3-aminopropionitrile, 4-aminobutyrone, 3-amino-2-methylpropionitrile, 5-aminopentylamine, 3-amino-3-methylbutyrone, glycine methyl ester, alanine methyl ester, dimethyl glutamate, lysine methyl ester, arginine methyl ester, aniline, p-methylaniline, p-ethylaniline, p-isopropylaniline, p-chloroaniline, m-chloroaniline, o-chloroaniline, 2,4-dichloroaniline, 2,6-dichloroaniline, 3,4-dichloroaniline, 3,5-dichloroaniline, 2,5-dichloroaniline, 2,4,5-trichloroaniline, 2,4,6-trichloroaniline Aniline, 3,4,5-trichloroaniline, 2,3,4-trichloroaniline, p-bromoaniline, m-bromoaniline, o-bromoaniline, 2,4-dibromoaniline, 2,6-dibromoaniline, 3,4-dibromoaniline, 3,5-dibromoaniline, 2,5-dibromoaniline, 2,4,5-tribromoaniline, 2,4,6-tribromoaniline, 3,4,5-tribromoaniline, 2,3,4-tribromoaniline, p-fluoroaniline, m-fluoroaniline, o-fluoroaniline, 2,4-difluoroaniline, 2,6-difluoroaniline, 3,4-difluoroaniline, 3,5-difluoroaniline, 2,5-difluoroaniline, 2,4,5-trifluoroaniline, 2,4,6-trifluoroaniline, 3,4,5-trifluoroaniline Amines, 2,3,4-trifluoroaniline, p-trifluoromethylaniline, p-methoxyaniline, p-nitroaniline, m-nitroaniline, o-nitroaniline, 2,4-dinitroaniline, 2-bromo-3-nitroaniline, 2-chloro-5-nitroaniline, 2-chloro-4,6-dinitroaniline, 2,6-dichloro-4-nitroaniline, p-cyanoaniline, 4-bromo-3,5-dichloroaniline, 2-fluoro-3-chloroaniline, 2-nitro-4-methoxy-5-methylaniline, 5-chloro-4-fluoro-2-methylaniline, 2-chloro-4-fluoro-6-nitroaniline, 2,6-difluoro-4-nitroaniline, 3-fluoro-4,5-dichloroaniline, maleic hydrazide, salicylhydrazide, 2,4-Dinitrophenylhydrazine, acetylhydrazine, octanoylhydrazine, furfurylamine, tetrahydrofurfurylamine, 2-thiophene methylamine, 2-aminothiazole, 2-aminobenzothiazole, 4-aminopyridine, 2-aminopyridine, 2-amino-4-trifluoromethylpyridine, 2-amino-5-chloropyridine, 2-amino-3-chloro-5-trifluoromethylpyridine, 2-amino-5-methylpyridine, 2-amino-6-methylpyridine, 5-chloro-2-pyridineamine, 2-chloro-4-aminopyridine, 2-amino-6-chloro-pyridine, 2-amino-5-nitropyridine, 2-amino-5-cyanopyridine, aminourea, aminothiourea, phenol, p-chlorophenol The following are included: at least one of the following: m-chlorophenol, o-chlorophenol, p-bromophenol, m-bromophenol, o-bromophenol, p-fluorophenol, m-fluorophenol, o-fluorophenol, p-methylphenol, p-nitrophenol, 2-bromo-5-chlorophenol, 4-bromo-5-chloro-2-methylphenol, 2-chloro-4-nitrophenol, 6-bromo-3-chloro-2-fluorophenol, 3-bromo-5-trifluoromethylphenol, methanol, ethanol, n-propanol, isopropanol, cyclopropanol, n-butanol, isobutanol, tert-butanol, n-pentanol, isopentanol, tert-pentanol, 3-hydroxypentane, 2-chloroethanol, 3-chloropropanol, 3-chloro-1-butanol, and 2-chlorobutane-1-ol.

[0025] In step 1) of the above method, the molar ratio of 2-amino-3-chloro-5-trifluoromethylpyridine to maleic anhydride can be 1.0:1.0 to 2.0.

[0026] The reaction temperature can be 25–85°C, and the time can be 3–24 hours.

[0027] The organic solvent may be one or more of acetonitrile, acetone, dichloromethane, chloroform, tetrahydrofuran, ethyl acetate, n-hexane, cyclohexane, and cyclohexanone.

[0028] In step 2) of the above method, the molar ratio of the intermediate product shown in formula (III) to thionyl chloride can be 1.0:1.2-2.0;

[0029] The reaction time can be 2-6 hours.

[0030] In step 3) of the above method, the molar ratio of the intermediate acyl chloride shown in formula (II) to the reactant RH can be 1.0:1.0~1.5;

[0031] The reaction temperature can be 0–50°C, and the time can be 0.5–12 h;

[0032] The organic solvent is one or more of dichloromethane, chloroform, ethyl acetate, n-hexane, cyclohexane, and cyclohexanone;

[0033] The acid-binding agent may be one or more of triethylamine, pyridine, and N,N-diisopropylethylamine.

[0034] The application of the compound shown in formula (I) above in the prevention and control of soil-borne plant diseases or in the preparation of products for the prevention and control of soil-borne diseases is also within the scope of protection of this invention.

[0035] The soil-borne plant diseases mentioned are caused by plant pathogenic fungi, bacteria, and nematodes.

[0036] The compounds containing the 2-chloro-4-trifluoromethylpyridine structure provided by this invention have high activity against plant pathogenic fungi, bacteria, and nematodes.

[0037] In the above applications, the soil-borne diseases can specifically be soil-borne diseases caused by southern root-knot nematodes (Meloidogyne incognita), Botrytis cinera Pers, Sclerotinia sclerotiorum, Fusarium graminearum, and / or Ralstonia solanacearum.

[0038] The beneficial effects of this invention are as follows:

[0039] 1. The preparation conditions provided by this invention are mild and the method is conventional;

[0040] 2. The product obtained by this invention has good environmental compatibility, good control effect on soil-borne plant diseases, and is safe for crops. Attached Figure Description

[0041] Figure 1 This is a synthetic route diagram for the compound represented by formula (Ⅰ) of this invention. Detailed Implementation

[0042] The present invention will now be described in further detail with reference to specific embodiments. The given embodiments are merely illustrative of the invention and not intended to limit its scope. The embodiments provided below can serve as a guide for further improvements by those skilled in the art and do not constitute a limitation on the invention in any way.

[0043] Unless otherwise specified, the experimental methods used in the following examples are conventional methods, performed according to the techniques or conditions described in the literature in this field or according to the product instructions. Unless otherwise specified, the materials and reagents used in the following examples are commercially available.

[0044] Example 1

[0045] Add 4.9 g (25.0 mmol) of 2-amino-3-chloro-5-trifluoromethylpyridine and 40 mL of ethyl acetate to a 100 mL three-necked flask and stir to dissolve. Then add 4.9 g (50.0 mmol) of maleic anhydride to the system and continue stirring at room temperature (25 °C) for 24 h. The reaction progress was monitored by thin-layer chromatography. After the reaction was complete, a solution of intermediate (III) was obtained.

[0046] 3.6 g (30.0 mmol) of thionyl chloride was added dropwise to the above solution containing intermediate (III). After reacting for 6 h, the remaining thionyl chloride and ethyl acetate were removed by rotary evaporation. After washing with ice water and drying, intermediate acyl chloride (II) was obtained. Then, it was dissolved in 40 mL of dichloromethane, and 5 mL of a dichloromethane solution containing 1.5 g (25.0 mmol) of isopropylamine and 2.5 g (25.0 mmol) of triethylamine was slowly added dropwise to the system. After stirring at 35 °C for 2 h, it was washed with acid water, and the oil layer was separated. After solvent removal, the product was obtained with a yield of 85.88%. The structural formula of the product is (I-4).

[0047]

[0048] Example 2

[0049] Add 4.9 g (25.0 mmol) of 2-amino-3-chloro-5-trifluoromethylpyridine and 40 mL of dichloromethane to a 100 mL three-necked flask and stir to dissolve. Then add 2.5 g (25.0 mmol) of maleic anhydride to the system and continue stirring at 85 °C for 6 h. The reaction progress was monitored by thin-layer chromatography. After the reaction was complete, a solution of intermediate (III) was obtained.

[0050] 4.8 g (40.0 mmol) of thionyl chloride was added dropwise to the above solution containing intermediate (III). After reacting for 4.5 h, the remaining thionyl chloride and dichloromethane were removed by rotary evaporation. After washing with ice water and drying, intermediate acyl chloride (II) was obtained. Then, it was dissolved in 40 mL of n-hexane, and 5 mL of n-hexane solution containing 1.4 g (25.0 mmol) cyclopropylamine and 2.5 g (25.0 mmol) triethylamine was slowly added dropwise to the system. After stirring at 50 °C for 2 h, the mixture was washed with acid water, and the oil layer was separated. After solvent removal, the product was obtained with a yield of 86.13%. The structural formula of the product is (I-22).

[0051]

[0052] Example 3

[0053] Add 4.9 g (25.0 mmol) of 2-amino-3-chloro-5-trifluoromethylpyridine and 40 mL of cyclohexane to a 100 mL three-necked flask and stir to dissolve. Then add 2.5 g (25.0 mmol) of maleic anhydride to the system and continue stirring at 85 °C for 6 h. The reaction progress was monitored by thin-layer chromatography. After the reaction was complete, a solution of intermediate (III) was obtained.

[0054] 3.6 g (30.0 mmol) of thionyl chloride was added dropwise to the above solution containing intermediate (III). After reacting for 6 h, the remaining thionyl chloride and cyclohexane were removed by rotary evaporation. After washing with ice water and drying, intermediate acyl chloride (II) was obtained. Then, it was dissolved in 40 mL of dichloromethane, and 5 mL of a dichloromethane solution containing 1.8 g (30.0 mmol) of ethanolamine and 2.0 g (20.0 mmol) of triethylamine was slowly added dropwise to the system. After stirring at 0 °C for 0.5 h, the mixture was washed with acid water, and the oil layer was separated. After solvent removal, the product was obtained with a yield of 90.13%. The structural formula of the product is (I-28).

[0055]

[0056] Example 4

[0057] Add 4.9 g (25.0 mmol) of 2-amino-3-chloro-5-trifluoromethylpyridine and 30 mL of acetonitrile to a 100 mL three-necked flask and stir to dissolve. Then add 3.9 g (40.0 mmol) of maleic anhydride to the system and continue stirring at 45 °C for 5.5 h. The reaction progress was monitored by thin-layer chromatography. After the reaction was complete, a solution of intermediate (III) was obtained.

[0058] 6.0 g (50.0 mmol) of thionyl chloride was added dropwise to the above solution containing intermediate (III). After reacting for 2 h, the remaining thionyl chloride and acetonitrile were removed by rotary evaporation. After washing with ice water and drying, intermediate acyl chloride (II) was obtained. Then, it was dissolved in 40 mL of chloroform, and 5 mL of chloroform solution containing 2.8 g (30.0 mmol) of 3-chloropropylamine and 2.5 g (25.0 mmol) of triethylamine was slowly added dropwise to the system. After stirring at 25 °C for 2.5 h, the mixture was washed with acid water, and the oil layer was separated. After solvent removal, the product was obtained with a yield of 79.35%. The structural formula of the product is (I-32).

[0059]

[0060] Example 5

[0061] Add 4.9 g (25.0 mmol) of 2-amino-3-chloro-5-trifluoromethylpyridine and 30 mL of acetonitrile to a 100 mL three-necked flask and stir to dissolve. Then add 2.5 g (25.0 mmol) of maleic anhydride to the system and continue stirring at room temperature (25 °C) for 12 h. The reaction progress was monitored by thin-layer chromatography. After the reaction was complete, a solution of intermediate (III) was obtained.

[0062] 5.4 g (45.0 mmol) of thionyl chloride was added dropwise to the above solution containing intermediate (III). After reacting for 3 h, the remaining thionyl chloride and acetonitrile were removed by rotary evaporation. After washing with ice water and drying, intermediate acyl chloride (II) was obtained. Then, it was dissolved in 40 mL of dichloromethane, and 5 mL of a dichloromethane solution containing 2.3 g (25.0 mmol) of 2-chloropropane-1-amine and 2.5 g (25.0 mmol) of triethylamine was slowly added dropwise to the system. After stirring at 45 °C for 6 h, the mixture was washed with acid water, and the oil layer was separated. After solvent removal, the product was obtained with a yield of 72.68%. The structural formula of the product is (I-33).

[0063]

[0064] Example 6

[0065] Add 4.9 g (25.0 mmol) of 2-amino-3-chloro-5-trifluoromethylpyridine and 40 mL of acetone to a 100 mL three-necked flask and stir to dissolve. Then add 2.5 g (25.0 mmol) of maleic anhydride to the system and continue stirring at room temperature (25 °C) for 24 h. The reaction progress was monitored by thin-layer chromatography. After the reaction was complete, a solution of intermediate (III) was obtained.

[0066] 3.6 g (30.0 mmol) of thionyl chloride was added dropwise to the above solution containing intermediate (III). After reacting for 6 h, the remaining thionyl chloride and acetone were removed by rotary evaporation. After washing with ice water and drying, intermediate acyl chloride (II) was obtained. Then, it was dissolved in 40 mL of ethyl acetate, and 8 mL of ethyl acetate solution containing 2.5 g (30.0 mmol) of 3-aminobutyronitrile and 2.0 g (25.0 mmol) of pyridine was slowly added dropwise to the system. After stirring at 25 °C for 6 h, the mixture was washed with acid water, and the oil layer was separated. After solvent removal, the product was obtained with a yield of 82.57%. The structural formula of the product is (I-44).

[0067]

[0068] Example 7

[0069] Add 4.9 g (25.0 mmol) of 2-amino-3-chloro-5-trifluoromethylpyridine and 40 mL of chloroform to a 100 mL three-necked flask and stir to dissolve. Then add 2.5 g (25.0 mmol) of maleic anhydride to the system and continue stirring at room temperature (25 °C) for 24 h. The reaction progress was monitored by thin-layer chromatography. After the reaction was complete, a solution of intermediate (III) was obtained.

[0070] 6.0 g (50.0 mmol) of thionyl chloride was added dropwise to the above solution containing intermediate (III). After reacting for 2 h, the remaining thionyl chloride and chloroform were removed by rotary evaporation. After washing with ice water and drying, intermediate acyl chloride (II) was obtained. Then, it was dissolved in 40 mL of dichloromethane, and 10 mL of a dichloromethane solution containing 2.7 g (25.0 mmol) of p-methylaniline and 2.5 g (25.0 mmol) of triethylamine was slowly added dropwise to the system. After stirring at 25 °C for 6 h, the mixture was washed with acid water, and the oil layer was separated. After solvent removal, the product was obtained with a yield of 84.53%. The structural formula of the product is (I-55).

[0071]

[0072] Example 8

[0073] Add 4.9 g (25.0 mmol) of 2-amino-3-chloro-5-trifluoromethylpyridine and 40 mL of dichloromethane to a 100 mL three-necked flask and stir to dissolve. Then add 2.5 g (25.0 mmol) of maleic anhydride to the system and continue stirring at 85 °C for 6 h. The reaction progress was monitored by thin-layer chromatography. After the reaction was complete, a solution of intermediate (III) was obtained.

[0074] 6.0 g (50.0 mmol) of thionyl chloride was added dropwise to the above solution containing intermediate (III). After reacting for 2 h, the remaining thionyl chloride and dichloromethane were removed by rotary evaporation. After washing with ice water and drying, intermediate acyl chloride (II) was obtained. Then, it was dissolved in 40 mL of ethyl acetate, and 5 mL of ethyl acetate solution containing 3.6 g (30.0 mmol) of p-ethylaniline and 3.2 g (25.0 mmol) of N,N-diisopropylethylamine was slowly added dropwise to the system. After stirring at 25 °C for 8 h, the mixture was washed with acid water, and the oil layer was separated. After solvent removal, the product was obtained with a yield of 86.28%. The structural formula of the product is (I-56).

[0075]

[0076] Example 9

[0077] Add 3.9 g (20.0 mmol) of 2-amino-3-chloro-5-trifluoromethylpyridine and 30 mL of dichloromethaneamine to a 100 mL three-necked flask and stir to dissolve. Then add 2.5 g (25.0 mmol) of maleic anhydride to the system and continue stirring at room temperature (25 °C) for 18 h. The reaction progress was monitored by thin-layer chromatography. After the reaction was complete, a solution of intermediate (III) was obtained.

[0078] 4.2 g (35.0 mmol) of thionyl chloride was added dropwise to the above solution containing intermediate (III). After reacting for 5 h, the remaining thionyl chloride and dichloromethane were removed by rotary evaporation. After washing with ice water and drying, intermediate acyl chloride (II) was obtained. Then, it was dissolved in 30 mL of ethyl acetate, and 5 mL of ethyl acetate solution containing 3.2 g (25.0 mmol) of p-chloroaniline and 2.0 g (20.0 mmol) of triethylamine was slowly added dropwise to the system. After stirring at 15 °C for 8 h, the mixture was washed with acid water, and the oil layer was separated. After solvent removal, the product was obtained with a yield of 81.25%. The structural formula of the product is (I-58).

[0079]

[0080] Example 10

[0081] Add 4.9 g (25.0 mmol) of 2-amino-3-chloro-5-trifluoromethylpyridine and 50 mL of n-hexane to a 100 mL three-necked flask and stir to dissolve. Then add 4.9 g (50.0 mmol) of maleic anhydride to the system and continue stirring at 75 °C for 4 h. The reaction progress was monitored by thin-layer chromatography. After the reaction was complete, a solution of intermediate (III) was obtained.

[0082] 5.4 g (45.0 mmol) of thionyl chloride was added dropwise to the above solution containing intermediate (III). After reacting for 3 h, the remaining thionyl chloride and n-hexane were removed by rotary evaporation. After washing with ice water and drying, intermediate acyl chloride (II) was obtained. Then, it was dissolved in 40 mL of dichloromethane, and 12 mL of a dichloromethane solution containing 4.9 g (30.0 mmol) of 2,4-dichloroaniline and 2.5 g (25.0 mmol) of triethylamine was slowly added dropwise to the system. After stirring at 25 °C for 10 h, the mixture was washed with acid water, and the oil layer was separated. After solvent removal, the product was obtained with a yield of 83.18%. The structural formula of the product is (I-61).

[0083]

[0084] Example 11

[0085] Add 4.9 g (25.0 mmol) of 2-amino-3-chloro-5-trifluoromethylpyridine and 40 mL of tetrahydrofuran to a 100 mL three-necked flask and stir to dissolve. Then add 4.9 g (50.0 mmol) of maleic anhydride to the system and continue stirring at 45 °C for 15 h. The reaction progress was monitored by thin-layer chromatography. After the reaction was complete, a solution of intermediate (III) was obtained.

[0086] 3.6 g (30.0 mmol) of thionyl chloride was added dropwise to the above solution containing intermediate (III). After reacting for 6 h, the remaining thionyl chloride and tetrahydrofuran were removed by rotary evaporation. After washing with ice water and drying, intermediate acyl chloride (II) was obtained. Then, it was dissolved in 30 mL of dichloromethane, and 20 mL of a dichloromethane solution containing 4.9 g (25.0 mmol) of 2,4,6-trichloroaniline and 2.5 g (25.0 mmol) of triethylamine was slowly added dropwise to the system. After stirring at 45 °C for 12 h, the mixture was washed with acid water, and the oil layer was separated. After solvent removal, the product was obtained with a yield of 71.63%. The structural formula of the product is (I-67).

[0087]

[0088] Example 12

[0089] Add 4.9 g (25.0 mmol) of 2-amino-3-chloro-5-trifluoromethylpyridine and 40 mL of dichloromethane to a 100 mL three-necked flask and stir to dissolve. Then add 2.5 g (25.0 mmol) of maleic anhydride to the system and continue stirring at 85 °C for 6 h. The reaction progress was monitored by thin-layer chromatography. After the reaction was complete, a solution of intermediate (III) was obtained.

[0090] 4.8 g (40.0 mmol) of thionyl chloride was added dropwise to the above solution containing intermediate (III). After reacting for 4.5 h, the remaining thionyl chloride and dichloromethane were removed by rotary evaporation. After washing with ice water and drying, intermediate acyl chloride (II) was obtained. Then, it was dissolved in 30 mL of dichloromethane, and 10 mL of a dichloromethane solution containing 4.3 g (25.0 mmol) of p-bromoaniline and 3.2 g (25.0 mmol) of N,N-diisopropylethylamine was slowly added dropwise to the system. After stirring at 25 °C for 6 h, the mixture was washed with acid water, and the oil layer was separated. After solvent removal, the product was obtained with a yield of 79.92%. The structural formula of the product is (I-70).

[0091]

[0092] Example 13

[0093] Add 4.9 g (25.0 mmol) of 2-amino-3-chloro-5-trifluoromethylpyridine and 50 mL of cyclohexane to a 100 mL three-necked flask and stir to dissolve. Then add 2.5 g (25.0 mmol) of maleic anhydride to the system and continue stirring at 85 °C for 6 h. The reaction progress was monitored by thin-layer chromatography. After the reaction was complete, a solution of intermediate (III) was obtained.

[0094] 5.4 g (45.0 mmol) of thionyl chloride was added dropwise to the above solution containing intermediate (III). After reacting for 3 h, the remaining thionyl chloride and cyclohexane were removed by rotary evaporation. After washing with ice water and drying, intermediate acyl chloride (II) was obtained. Then, it was dissolved in 40 mL of cyclohexanone, and 8 mL of cyclohexanone solution containing 2.8 g (25.0 mmol) of p-fluoroaniline and 2.5 g (25.0 mmol) of triethylamine was slowly added dropwise to the system. After stirring at 25 °C for 6 h, the mixture was washed with acid water, and the oil layer was separated. After solvent removal, the product was obtained with a yield of 88.38%. The structural formula of the product is (I-82).

[0095]

[0096] Example 14

[0097] Add 4.9 g (25.0 mmol) of 2-amino-3-chloro-5-trifluoromethylpyridine and 40 mL of ethyl acetate to a 100 mL three-necked flask and stir to dissolve. Then add 2.5 g (25.0 mmol) of maleic anhydride to the system and continue stirring at room temperature (25 °C) for 24 h. The reaction progress was monitored by thin-layer chromatography. After the reaction was complete, a solution of intermediate (III) was obtained.

[0098] 3.6 g (30.0 mmol) of thionyl chloride was added dropwise to the above solution containing intermediate (III). After reacting for 6 h, the remaining thionyl chloride and ethyl acetate were removed by rotary evaporation. After washing with ice water and drying, intermediate acyl chloride (II) was obtained. Then, it was dissolved in 40 mL of chloroform, and 10 mL of chloroform solution containing 3.1 g (25.0 mmol) of p-methoxyaniline and 2.5 g (25.0 mmol) of triethylamine was slowly added dropwise to the system. After stirring at 30 °C for 8 h, the mixture was washed with acid water, and the oil layer was separated. After solvent removal, the product was obtained with a yield of 81.25%. The structural formula of the product is (I-95).

[0099]

[0100] Example 15

[0101] Add 4.9 g (25.0 mmol) of 2-amino-3-chloro-5-trifluoromethylpyridine and 40 mL of ethyl acetate to a 100 mL three-necked flask and stir to dissolve. Then add 2.5 g (25.0 mmol) of maleic anhydride to the system and continue stirring at room temperature (25 °C) for 24 h. The reaction progress was monitored by thin-layer chromatography. After the reaction was complete, a solution of intermediate (III) was obtained.

[0102] 6.0 g (50.0 mmol) of thionyl chloride was added dropwise to the above solution containing intermediate (III). After reacting for 2 h, the remaining thionyl chloride and ethyl acetate were removed by rotary evaporation. After washing with ice water and drying, intermediate acyl chloride (II) was obtained. Then, it was dissolved in 30 mL of dichloromethane, and 10 mL of a dichloromethane solution containing 4.1 g (30.0 mmol) of p-nitroaniline and 2.5 g (25.0 mmol) of triethylamine was slowly added dropwise to the system. After stirring at 40 °C for 8 h, the mixture was washed with acid water, and the oil layer was separated. After solvent removal, the product was obtained with a yield of 75.78%. The structural formula of the product is (I-96).

[0103]

[0104] Example 16

[0105] Add 3.9 g (20.0 mmol) of 2-amino-3-chloro-5-trifluoromethylpyridine and 30 mL of n-hexane to a 100 mL three-necked flask and stir to dissolve. Then add 3.9 g (40.0 mmol) of maleic anhydride to the system and continue stirring at 55 °C for 10 h. The reaction progress was monitored by thin-layer chromatography. After the reaction was complete, a solution of intermediate (III) was obtained.

[0106] 6.0 g (50.0 mmol) of thionyl chloride was added dropwise to the above solution containing intermediate (III). After reacting for 2 h, the remaining thionyl chloride and n-hexane were removed by rotary evaporation. After washing with ice water and drying, intermediate acyl chloride (II) was obtained. Then, it was dissolved in 40 mL of ethyl acetate, and 10 mL of ethyl acetate solution containing 4.4 g (30.0 mmol) of 2-fluoro-3-chloroaniline and 2.0 g (20.0 mmol) of triethylamine was slowly added dropwise to the system. After stirring at 45 °C for 9 h, the mixture was washed with acid water, and the oil layer was separated. After solvent removal, the product was obtained with a yield of 83.94%. The structural formula of the product is (I-106).

[0107]

[0108] Example 17

[0109] 4.9 g (25.0 mmol) of 2-amino-3-chloro-5-trifluoromethylpyridine and 40 mL of ethyl acetate were added to a 100 mL three-necked flask and stirred until dissolved. Then, 2.9 g (30.0 mmol) of maleic anhydride was added to the system and stirred for 24 h at room temperature (25 °C). The reaction progress was monitored by thin-layer chromatography. After the reaction was complete, a solution of intermediate (III) was obtained.

[0110] 5.4 g (45.0 mmol) of thionyl chloride was added dropwise to the above solution containing intermediate (III). After reacting for 3 h, the remaining thionyl chloride and ethyl acetate were removed by rotary evaporation. After washing with ice water and drying, intermediate acyl chloride (II) was obtained. Then, it was dissolved in 40 mL of ethyl acetate, and 10 mL of ethyl acetate solution containing 4.0 g (25.0 mmol) of 5-chloro-4-fluoro-2-methylaniline and 2.0 g (25.0 mmol) of pyridine was slowly added dropwise to the system. After stirring at 50 °C for 12 h, the mixture was washed with acid water, and the oil layer was separated. After solvent removal, the product was obtained with a yield of 69.42%. The structural formula of the product is (I-108).

[0111]

[0112] Example 18

[0113] Add 4.9 g (25.0 mmol) of 2-amino-3-chloro-5-trifluoromethylpyridine and 40 mL of acetone to a 100 mL three-necked flask and stir to dissolve. Then add 2.5 g (25.0 mmol) of maleic anhydride to the system and continue stirring at 85 °C for 6 h. The reaction progress was monitored by thin-layer chromatography. After the reaction was complete, a solution of intermediate (III) was obtained.

[0114] 4.8 g (40.0 mmol) of thionyl chloride was added dropwise to the above solution containing intermediate (III). After reacting for 4.5 h, the remaining thionyl chloride and acetone were removed by rotary evaporation. After washing with ice water and drying, intermediate acyl chloride (II) was obtained. Then, it was dissolved in 30 mL of ethyl acetate, and 20 mL of ethyl acetate solution containing 2.8 g (25.0 mmol) maleic hydrazide and 2.5 g (25.0 mmol) triethylamine was slowly added dropwise to the system. After stirring at 25 °C for 8 h, the mixture was washed with acid water, and the oil layer was separated. After solvent removal, the product was obtained with a yield of 76.95%. The structural formula of the product is (I-112).

[0115]

[0116] Example 19

[0117] Add 4.9 g (25.0 mmol) of 2-amino-3-chloro-5-trifluoromethylpyridine and 40 mL of dichloromethane to a 100 mL three-necked flask and stir to dissolve. Then add 2.5 g (25.0 mmol) of maleic anhydride to the system and continue stirring at 85 °C for 6 h. The reaction progress was monitored by thin-layer chromatography. After the reaction was complete, a solution of intermediate (III) was obtained.

[0118] 3.6 g (30.0 mmol) of thionyl chloride was added dropwise to the above solution containing intermediate (III). After reacting for 6 h, the remaining thionyl chloride and dichloromethane were removed by rotary evaporation. After washing with ice water and drying, intermediate acyl chloride (II) was obtained. Then, it was dissolved in 40 mL of dichloromethane, and 15 mL of a dichloromethane solution containing 1.9 g (25.0 mmol) of acetylhydrazine and 2.5 g (25.0 mmol) of triethylamine was slowly added dropwise to the system. After stirring at 25 °C for 8 h, the mixture was washed with acid water, and the oil layer was separated. After solvent removal, the product was obtained with a yield of 87.06%. The structural formula of the product is (I-115).

[0119]

[0120] Example 20

[0121] Add 4.9 g (25.0 mmol) of 2-amino-3-chloro-5-trifluoromethylpyridine and 40 mL of ethyl acetate to a 100 mL three-necked flask and stir to dissolve. Then add 2.5 g (25.0 mmol) of maleic anhydride to the system and continue stirring at room temperature (25 °C) for 24 h. The reaction progress was monitored by thin-layer chromatography. After the reaction was complete, a solution of intermediate (III) was obtained.

[0122] 4.2 g (35.0 mmol) of thionyl chloride was added dropwise to the above solution containing intermediate (III). After reacting for 5 h, the remaining thionyl chloride and ethyl acetate were removed by rotary evaporation. After washing with ice water and drying, intermediate acyl chloride (II) was obtained. Then, it was dissolved in 30 mL of ethyl acetate, and 5 mL of ethyl acetate solution containing 2.4 g (25.0 mmol) of furfurylamine and 2.5 g (25.0 mmol) of triethylamine was slowly added dropwise to the system. After stirring at 25 °C for 4 h, the mixture was washed with acid water, and the oil layer was separated. After solvent removal, the product was obtained with a yield of 82.69%. The structural formula of the product is (I-117).

[0123]

[0124] Example 21

[0125] Add 4.9 g (25.0 mmol) of 2-amino-3-chloro-5-trifluoromethylpyridine and 30 mL of tetrahydrofuran to a 100 mL three-necked flask and stir to dissolve. Then add 3.9 g (40.0 mmol) of maleic anhydride to the system and continue stirring at 55 °C for 10 h. The reaction progress was monitored by thin-layer chromatography. After the reaction was complete, a solution of intermediate (III) was obtained.

[0126] 4.8 g (40.0 mmol) of thionyl chloride was added dropwise to the above solution containing intermediate (III). After reacting for 4.5 h, the remaining thionyl chloride and tetrahydrofuran were removed by rotary evaporation. After washing with ice water and drying, intermediate acyl chloride (II) was obtained. Then, it was dissolved in 40 mL of ethyl acetate, and 8 mL of ethyl acetate solution containing 2.4 g (25.0 mmol) of 4-aminopyridine and 2.0 g (20.0 mmol) of triethylamine was slowly added dropwise to the system. After stirring at 25 °C for 9 h, the mixture was washed with acid water, and the oil layer was separated. After solvent removal, the product was obtained with a yield of 78.97%. The structural formula of the product is (I-122).

[0127]

[0128] Example 22

[0129] Add 4.9 g (25.0 mmol) of 2-amino-3-chloro-5-trifluoromethylpyridine and 40 mL of ethyl acetate to a 100 mL three-necked flask and stir to dissolve. Then add 2.5 g (25.0 mmol) of maleic anhydride to the system and continue stirring at room temperature (25 °C) for 24 h. The reaction progress was monitored by thin-layer chromatography. After the reaction was complete, a solution of intermediate (III) was obtained.

[0130] 3.6 g (30.0 mmol) of thionyl chloride was added dropwise to the above solution containing intermediate (III). After reacting for 6 h, the remaining thionyl chloride and ethyl acetate were removed by rotary evaporation. After washing with ice water and drying, intermediate acyl chloride (II) was obtained. Then, it was dissolved in 30 mL of ethyl acetate, and 10 mL of ethyl acetate solution containing 4.9 g (25.0 mmol) of 2-amino-3-chloro-5-trifluoromethylpyridine and 2.5 g (25.0 mmol) of triethylamine was slowly added dropwise to the system. After stirring at 35 °C for 10 h, the mixture was washed with acid water, and the oil layer was separated. After solvent removal, the product was obtained with a yield of 79.46%. The structural formula of the product is (I-126).

[0131]

[0132] Example 23

[0133] Add 4.9 g (25.0 mmol) of 2-amino-3-chloro-5-trifluoromethylpyridine and 40 mL of dichloromethane to a 100 mL three-necked flask and stir to dissolve. Then add 2.5 g (25.0 mmol) of maleic anhydride to the system and continue stirring at room temperature (25 °C) for 24 h. The reaction progress was monitored by thin-layer chromatography. After the reaction was complete, a solution of intermediate (III) was obtained.

[0134] 3.6 g (30.0 mmol) of thionyl chloride was added dropwise to the above solution containing intermediate (III). After reacting for 6 h, the remaining thionyl chloride and dichloromethane were removed by rotary evaporation. After washing with ice water and drying, intermediate acyl chloride (II) was obtained. Then, it was dissolved in 30 mL of dichloromethane, and 15 mL of a dichloromethane solution containing 3.2 g (25.0 mmol) of 2-amino-6-chloropyridine and 2.5 g (25.0 mmol) of triethylamine was slowly added dropwise to the system. After stirring at 25 °C for 8 h, the mixture was washed with acid water, and the oil layer was separated. After solvent removal, the product was obtained with a yield of 81.95%. The structural formula of the product is (I-130).

[0135]

[0136] Example 24

[0137] Add 4.9 g (25.0 mmol) of 2-amino-3-chloro-5-trifluoromethylpyridine and 40 mL of ethyl acetate to a 100 mL three-necked flask and stir to dissolve. Then add 2.9 g (30.0 mmol) of maleic anhydride to the system and continue stirring at 65 °C for 8 h. The reaction progress was monitored by thin-layer chromatography. After the reaction was complete, a solution of intermediate (III) was obtained.

[0138] 4.2 g (35.0 mmol) of thionyl chloride was added dropwise to the above solution containing intermediate (III). After reacting for 5 h, the remaining thionyl chloride and ethyl acetate were removed by rotary evaporation. After washing with ice water and drying, intermediate acyl chloride (II) was obtained. Then, it was dissolved in 40 mL of ethyl acetate, and 6 mL of ethyl acetate solution containing 2.3 g (25.0 mmol) aminothiourea and 2.5 g (25.0 mmol) triethylamine was slowly added dropwise to the system. After stirring at 25 °C for 4 h, the mixture was washed with acid water, and the oil layer was separated. After solvent removal, the product was obtained with a yield of 87.06%. The structural formula of the product is (I-134).

[0139]

[0140] Example 25

[0141] Add 4.9 g (25.0 mmol) of 2-amino-3-chloro-5-trifluoromethylpyridine and 40 mL of cyclohexanone to a 100 mL three-necked flask and stir to dissolve. Then add 2.5 g (25.0 mmol) of maleic anhydride to the system and continue stirring at room temperature (25 °C) for 24 h. The reaction progress was monitored by thin-layer chromatography. After the reaction was complete, a solution of intermediate (III) was obtained.

[0142] 4.2 g (35.0 mmol) of thionyl chloride was added dropwise to the above solution containing intermediate (III). After reacting for 5 h, the remaining thionyl chloride and cyclohexanone were removed by rotary evaporation. After washing with ice water and drying, intermediate acyl chloride (II) was obtained. Then, it was dissolved in 30 mL of ethyl acetate, and 5 mL of ethyl acetate solution containing 2.8 g (30.0 mmol) of phenol and 2.0 g (25.0 mmol) of pyridine was slowly added dropwise to the system. After stirring at 35 °C for 6 h, the mixture was washed with alkaline water, and the oil layer was separated. After solvent removal, the product was obtained with a yield of 87.08%. The structural formula of the product is (I-135).

[0143]

[0144] Example 26

[0145] Add 4.9 g (25.0 mmol) of 2-amino-3-chloro-5-trifluoromethylpyridine and 40 mL of ethyl acetate to a 100 mL three-necked flask and stir to dissolve. Then add 2.5 g (25.0 mmol) of maleic anhydride to the system and continue stirring at 85 °C for 8 h. The reaction progress was monitored by thin-layer chromatography. After the reaction was complete, a solution of intermediate (III) was obtained.

[0146] 4.8 g (40.0 mmol) of thionyl chloride was added dropwise to the above solution containing intermediate (III). After reacting for 4.5 h, the remaining thionyl chloride and ethyl acetate were removed by rotary evaporation. After washing with ice water and drying, intermediate acyl chloride (II) was obtained. Then, it was dissolved in 30 mL of ethyl acetate, and 10 mL of ethyl acetate solution containing 3.2 g (25.0 mmol) of p-chlorophenol and 2.5 g (25.0 mmol) of triethylamine was slowly added dropwise to the system. After stirring at 45 °C for 8 h, the mixture was washed with alkaline water, and the oil layer was separated. After solvent removal, the product was obtained with a yield of 82.69%. The structural formula of the product is (I-136).

[0147]

[0148] Example 27

[0149] Add 4.9 g (25.0 mmol) of 2-amino-3-chloro-5-trifluoromethylpyridine and 40 mL of dichloromethane to a 100 mL three-necked flask and stir to dissolve. Then add 2.5 g (25.0 mmol) of maleic anhydride to the system and continue stirring at room temperature (25 °C) for 24 h. The reaction progress was monitored by thin-layer chromatography. After the reaction was complete, a solution of intermediate (III) was obtained.

[0150] 4.8 g (40.0 mmol) of thionyl chloride was added dropwise to the above solution containing intermediate (III). After reacting for 4.5 h, the remaining thionyl chloride and dichloromethane were removed by rotary evaporation. After washing with ice water and drying, intermediate acyl chloride (II) was obtained. Then, it was dissolved in 30 mL of dichloromethane, and 10 mL of a dichloromethane solution containing 3.5 g (25.0 mmol) of p-nitrophenol and 2.5 g (25.0 mmol) of triethylamine was slowly added dropwise to the system. After stirring at 45 °C for 8 h, the mixture was washed with alkaline water, and the oil layer was separated. After solvent removal, the product was obtained with a yield of 70.27%. The structural formula of the product is (I-146).

[0151]

[0152] Example 28

[0153] Add 4.9 g (25.0 mmol) of 2-amino-3-chloro-5-trifluoromethylpyridine and 40 mL of dichloromethane to a 100 mL three-necked flask and stir to dissolve. Then add 2.5 g (25.0 mmol) of maleic anhydride to the system and continue stirring at room temperature (25 °C) for 24 h. The reaction progress was monitored by thin-layer chromatography. After the reaction was complete, a solution of intermediate (III) was obtained.

[0154] 3.6 g (30.0 mmol) of thionyl chloride was added dropwise to the above solution containing intermediate (III). After reacting for 6 h, the remaining thionyl chloride and dichloromethane were removed by rotary evaporation. After washing with ice water and drying, intermediate acyl chloride (II) was obtained. Then, it was dissolved in 40 mL of dichloromethane, and 10 mL of a dichloromethane solution containing 4.3 g (25.0 mmol) of 2-chloro-4-nitrophenol and 3.2 g (25.0 mmol) of N,N-diisopropylethylamine was slowly added dropwise to the system. After stirring at 45 °C for 9 h, the mixture was washed with alkaline water, and the oil layer was separated. After solvent removal, the product was obtained with a yield of 68.15%. The structural formula of the product is (I-149).

[0155]

[0156] Example 29

[0157] Add 4.9 g (25.0 mmol) of 2-amino-3-chloro-5-trifluoromethylpyridine and 30 mL of acetonitrile to a 100 mL three-necked flask and stir to dissolve. Then add 3.9 g (40.0 mmol) of maleic anhydride to the system and continue stirring at 45 °C for 5.5 h. The reaction progress was monitored by thin-layer chromatography. After the reaction was complete, a solution of intermediate (III) was obtained.

[0158] 6.0 g (50.0 mmol) of thionyl chloride was added dropwise to the above solution containing intermediate (III). After reacting for 2 h, the remaining thionyl chloride and acetonitrile were removed by rotary evaporation. After washing with ice water and drying, intermediate acyl chloride (II) was obtained. Then, it was dissolved in 40 mL of cyclohexane, and 5 mL of a cyclohexane solution containing 1.8 g (30.0 mmol) isopropanol and 2.0 g (25.0 mmol) pyridine was slowly added dropwise to the system. After stirring at 35 °C for 6 h, the mixture was washed with alkaline water, and the oil layer was separated. After solvent removal, the product was obtained with a yield of 72.19%. The structural formula of the product is (I-155).

[0159]

[0160] Example 30

[0161] Add 4.9 g (25.0 mmol) of 2-amino-3-chloro-5-trifluoromethylpyridine and 40 mL of dichloromethane to a 100 mL three-necked flask and stir to dissolve. Then add 2.5 g (25.0 mmol) of maleic anhydride to the system and continue stirring at room temperature (25 °C) for 24 h. The reaction progress was monitored by thin-layer chromatography. After the reaction was complete, a solution of intermediate (III) was obtained.

[0162] 6.0 g (50.0 mmol) of thionyl chloride was added dropwise to the above solution containing intermediate (III). After reacting for 2 h, the remaining thionyl chloride and dichloromethane were removed by rotary evaporation. After washing with ice water and drying, intermediate acyl chloride (II) was obtained. Then, it was dissolved in 50 mL of cyclohexanone, and 5 mL of cyclohexanone solution containing 2.2 g (30.0 mmol) of n-butanol and 2.5 g (25.0 mmol) of triethylamine was slowly added dropwise to the system. After stirring at 25 °C for 8 h, the mixture was washed with alkaline water, and the oil layer was separated. After solvent removal, the product was obtained with a yield of 88.71%. The structural formula of the product is (I-157).

[0163]

[0164] The structural formula of the reactant RH involved in the above examples and the appearance and yield of the compound of formula (Ⅰ) obtained are shown in Table 1:

[0165] Table 1. Reaction RH structural formula and appearance and yield of the compound shown in formula (I)

[0166]

[0167]

[0168]

[0169]

[0170]

[0171]

[0172]

[0173]

[0174]

[0175] Example 31

[0176] The bioactivity of the compound obtained in this invention against the southern root-knot nematode (Meloidogyne incognita) was tested using the second-instar larval immersion method. The compound was dissolved in an organic solvent and diluted to 100, 200, and 400 mg / L with 0.1% Triton aqueous solution, respectively. 100 μL of the solution and 100 μL of nematode solution (approximately 50 second-instar larvae) were mixed in a 96-well plate, with each treatment repeated three times. A Triton aqueous solution containing only the solvent served as a blank control. After incubating the 96-well plate at 25°C for 24 and 48 hours, mortality was examined under a stereomicroscope, and the nematode mortality rate was calculated using the following formula:

[0177] Mortality rate (%) = Number of dead nematodes / Total number of tested nematodes × 100% (1)

[0178] The results of the indoor toxicity of the compounds described in this invention against southern root-knot nematode (Meloidogyne incognita) are shown in Table 2.

[0179] Table 2 shows the results of the indoor toxicity of the compounds against the southern root-knot nematode (Meloidogyne incognita).

[0180]

[0181]

[0182] The indoor toxicity results of the compounds described in this invention against *Meloidogyne incognita* showed that the compounds of this invention have good control effects against *Meloidogyne incognita*. Specifically, compounds I-58, I-61, I-67, I-82, I-96, I-106, I-108, and I-112 achieved inhibition rates of over 85% against *Meloidogyne incognita* at a concentration of 200 mg / L. In particular, compound I-67 achieved an inhibition rate of 80.42% against *Meloidogyne incognita* at a concentration of 50 mg / L.

[0183] Example 32

[0184] The inhibitory effect of the compound described in this invention on Botrytis cinera Pers was tested using the mycelial growth rate method.

[0185] The compound described in this invention was dissolved in a solvent and prepared as a stock solution using a 0.1% Triton aqueous solution. The stock solution was mixed with PDA medium and poured into a culture medium to prepare a drug-containing medium. 5mm bacterial discs were inoculated, and each treatment was repeated three times. When the colony diameter of the blank control reached approximately 8cm, the colony diameter was measured using the cross-sectional method. The EC50 of each compound against the pathogen was calculated according to formula (2). 50 value.

[0186] Inhibition rate (%) = (Coronary diameter of control group (mm) - Colony diameter of treatment group (mm)) / (Coronary diameter of control group (mm) - 5mm) × 100% (2)

[0187] The results of the indoor toxicity of the compounds described in this invention against Botrytis cinera Pers are shown in Table 3.

[0188] Table 3. Results of indoor toxicity assays of the compounds against Botrytis cinera Pers.

[0189]

[0190] The indoor toxicity results of the compounds described in this invention against *Botrytis cinera* Pers. show that the compounds of this invention have good control effects against *Botrytis cinera*. In particular, compounds I-67 and I-108 exhibited good EC50 activity against *Botrytis cinera*. 50 The values ​​can reach 14.34 mg / L and 14.92 mg / L, respectively.

[0191] Example 33

[0192] The inhibitory effect of the compound described in this invention on Sclerotinia sclerotiorum was tested using the mycelial growth rate method.

[0193] The compound described in this invention was dissolved in a solvent and prepared as a stock solution using a 0.1% Triton aqueous solution. The stock solution was mixed with PDA medium and poured into a culture medium to prepare a drug-containing medium. 5mm bacterial discs were inoculated, and each treatment was repeated three times. When the colony diameter of the blank control reached approximately 8cm, the colony diameter was measured using the cross-sectional method. The EC50 of each compound against the pathogen was calculated according to formula (2). 50 value.

[0194] The results of the indoor toxicity of the compounds described in this invention against Sclerotinia sclerotiorum are shown in Table 4.

[0195] Table 4. Results of indoor toxicity assays of the compounds against *Sclerotinia sclerotiorum*.

[0196]

[0197] The indoor toxicity results of the compounds described in this invention against *Sclerotinia sclerotiorum* showed that the compounds of this invention have good control effects against *Sclerotinia sclerotiorum*. Specifically, compounds I-44, I-56, I-58, I-61, I-67, I-70, I-96, and I-106 exhibited EC50-95% activity against *Sclerotinia sclerotiorum*. 50 The values ​​were all below 10 mg / L. Compound I-61, in particular, showed significant EC50 activity against Sclerotinia sclerotiorum. 50 The value can reach 6.30 mg / L.

[0198] Example 34

[0199] The inhibitory effect of the compound described in this invention on Fusarium graminearum was tested using the mycelial growth rate method.

[0200] The compound described in this invention was dissolved in a solvent and prepared as a stock solution using a 0.1% Triton aqueous solution. The stock solution was mixed with PDA medium and poured into a culture medium to prepare a drug-containing medium. 5mm bacterial discs were inoculated, and each treatment was repeated three times. When the colony diameter of the blank control reached approximately 8cm, the colony diameter was measured using the cross-sectional method. The EC50 of each compound against the pathogen was calculated according to formula (2). 50 value.

[0201] The results of the indoor toxicity of the compounds described in this invention against Fusarium graminearum are shown in Table 5.

[0202] Table 5. Results of indoor toxicity assays of the compounds against Fusarium graminearum.

[0203]

[0204]

[0205] The indoor toxicity results of the compounds described in this invention against *Fusarium graminearum* showed that the compounds of this invention have good control effects against *Fusarium graminearum*. Specifically, compounds I-55, I-58, I-61, I-67, I-82, I-106, I-108, and I-134 showed EC50 activity against *Sclerotinia sclerotiorum*. 50 The values ​​were all below 10 mg / L. Compounds I-67 and I-108, in particular, showed significant EC50 activity against *Sclerotinia sclerotiorum*. 50 The values ​​can reach 8.73 mg / L and 8.18 mg / L, respectively.

[0206] Example 35

[0207] The inhibitory effect of the compound of this invention on Ralstonia solanacearum was tested using the shake-flask method. Specifically, the compound of this invention was dissolved in DMF containing 6% Tween 80 and diluted with deionized water to prepare a series of concentration gradient solutions. The drug solution was then mixed evenly with liquid LB medium in an Erlenmeyer flask to prepare a drug-containing medium. 1 mL (10⁸ CFU) of bacterial suspension was added to the above LB medium, and the Erlenmeyer flask was placed in a shaker at 28-30°C and 150 rpm for 1 minute. -1 Cultured, each treatment was repeated three times. After 24 hours, 200 μL of culture medium was collected and the absorbance (OD) at 600 nm was measured. 600 The EC50 of each compound was calculated using the DPS data processing system. 50 value.

[0208] The results of the indoor toxicity of the compounds described in this invention against Ralstonia solanacearum are shown in Table 6.

[0209] Table 6. Results of indoor toxicity assays of the compounds against Ralstonia solanacearum (Solanaceae).

[0210]

[0211]

[0212] The indoor toxicity results of the compounds described in this invention against *Ralstonia solanacearum* showed that the compounds of this invention have good control effects against *Ralstonia solanacearum*. Specifically, compounds I-61, I-67, I-82, I-106, and I-108 exhibited EC50-95% activity against *Ralstonia solanacearum*. 50 The values ​​were all below 100 mg / L. Compound I-108, in particular, showed significant EC50 activity against *Sclerotinia sclerotiorum*. 50 The value can reach 76.92 mg / L.

[0213] Based on Tables 2-6, the compounds of this invention exhibit good control effects against soil-borne diseases such as *Meloidogyne incognita*, *Botrytis cinera Pers*, *Sclerotinia sclerotiorum*, *Fusarium graminearum*, and *Ralstonia solanacearum*. Compound I-67, in particular, demonstrates excellent biological activity against all of these soil-borne diseases.

[0214] Example 36

[0215] The soil column method was used to test the control effect of the compound described in this invention on southern nematodes in soil.

[0216] Soil samples containing southern root-knot nematodes were collected from a greenhouse at China Agricultural University. After drying, the soil samples were sieved and mixed thoroughly. 180g samples were weighed and placed in medium-sized PVA tubes. The compound was dissolved in an organic solvent and then diluted with 0.1% Triton's aqueous solution to concentrations of 500 and 200 mg / L, respectively. 100mL of the solution was applied to each treatment, with each treatment repeated three times. Triton's aqueous solution containing only the solvent served as a blank control. The control agent was 90% thiazophos technical. After 14 days, 100g of soil from the bottom was weighed, and nematodes were extracted using a modified Bearmann funnel method. The nematode count was observed under a stereomicroscope, and the control efficacy was calculated. The calculation formula is:

[0217] Control efficacy (%) = (Total number of nematodes in the control group - Total number of nematodes in the treatment group) / Total number of nematodes in the control group × 100% (3)

[0218] The control effects of the compound described in this invention on southern root-knot nematodes in soil are shown in Table 7.

[0219] Table 7 shows the control efficacy of the compounds against southern root-knot nematodes (Meloidogyne incognita) in soil.

[0220]

[0221]

[0222] In summary, the compounds described in this invention have shown excellent control effects against soil-borne plant diseases such as southern root-knot nematode (Meloidogyne incognita), Botrytis cinera Pers, Sclerotinia sclerotiorum, Fusarium graminearum, and Ralstonia solanacearum.

[0223] The present invention has been described in detail above. Those skilled in the art will recognize that the invention can be practiced in a wide range of ways with equivalent parameters, concentrations, and conditions without departing from its spirit and scope, and without requiring unnecessary experiments. While specific embodiments have been provided, it should be understood that further modifications can be made to the invention. In summary, according to the principles of the invention, this application is intended to include any changes, uses, or improvements to the invention, including changes made using conventional techniques known in the art that depart from the scope disclosed herein.

Claims

1. The compound shown in formula (Ⅰ): In formula (Ⅰ), R is a substituted or unsubstituted C1-C8 straight-chain or branched alkylamino group, a substituted or unsubstituted C3-C8 cycloalkylamino group, or a substituted or unsubstituted C6-C8 cycloalkylamino group. 30 Aromatic amino groups, hydrazide groups (R1CONH-NH-), R2-NH-NH-, and substituted or unsubstituted C3-C groups containing at least one heteroatom of O, S, or N. 30 heteroaryl amino groups, R3-NH-C(=NH)-NH-, amino(thio)urea groups (NH2-C(=S)-NH-NH-), substituted or unsubstituted C6-C 30 One of the following: aryloxy group, substituted or unsubstituted C1-C8 straight-chain or branched alkoxy group, and C3-C8 cycloalkoxy group.

2. The compound according to claim 1, characterized in that, The substituents in the substituted C1-C8 straight-chain or branched alkylamino groups and the substituted C3-C8 cycloalkylamino groups are each independently selected from: hydroxyl, halogen, cyano, C1-C6 alkyl-OC(=O)-, five- or six-membered rings containing at least one heteroatom of O, S, or N, and C3-C6 cycloalkylamino groups containing at least one heteroatom of O, S, or N. 30 heteroaryl, C1-C6 alkyl-substituted imino, amino, NH2-C(=NH)-NH-; The substituted C6-C 30 The substituent in the aromatic amino group is at least one of C1-C6 alkyl, halogen, C1-C6 alkoxy, nitro, cyano, halogen-substituted C1-C6 alkyl, and halogen-substituted C1-C6 alkoxy. In the R1CONH-NH-, R1 is selected from: C1-C6 alkyl, -CH=CH-COOH, -CH=CH-COOC1-C6 alkyl, substituted or unsubstituted benzene ring, wherein the substituent can be at least one of -OH, C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 alkoxy, nitro, cyano; In the R2-NH-NH-, R2 is selected from: substituted or unsubstituted benzene rings, wherein the substituent can be at least one of -OH, C1-C6 alkyl, halogen, C1-C6 alkoxy, nitro, and cyano; The substituted C3-C 30 The substituent in the heteroarylamine is at least one of C1-C6 alkyl, C1-C6 alkoxy, halogen, nitro, cyano, halogen-substituted C1-C6 alkyl, and halogen-substituted C1-C6 alkoxy. In the R3-NH-C(=NH)-NH-, R3 is a substituted or unsubstituted C1-C8 straight-chain or branched alkyl group, and the substituent in the substituted alkyl group is at least one of amino and C1-C6 alkyl-OC(=O)-. The substituted C6-C 30 The substituent in the aryloxy group is at least one of C1-C6 alkyl, C1-C6 alkoxy, halogen, nitro, cyano, halogen-substituted C1-C6 alkyl, and halogen-substituted C1-C6 alkoxy.

3. A method for preparing the compound of claim 1 or 2, comprising the following steps: 1) In an organic solvent, 2-amino-3-chloro-5-trifluoromethylpyridine is reacted with maleic anhydride to give a solution of the intermediate product shown in formula (III); 2) Add thionyl chloride to the system containing the intermediate shown in formula (III), and react to obtain the intermediate acyl chloride shown in formula (II); 3) In an organic solvent, in the presence of an acid-binding agent, the intermediate acyl chloride shown in formula (II) reacts with reactant RH to give the compound shown in formula (I) containing the 2-chloro-4-trifluoromethylpyridine structure. In RH, the definition of R is the same as the definition of R in equation (Ⅰ).

4. The method according to claim 3, characterized in that, The reactant RH is selected from: methylamine, ethylamine, n-propylamine, isopropylamine, n-butylamine, sec-butylamine, isobutylamine, tert-butylamine, n-pentylamine, 3-aminopentane, isopentylamine, n-hexylamine, 1,3-dimethylbutylamine, isohexylamine, n-heptylamine, 2-heptylamine, 1,3-dimethylpentylamine, n-octylamine, isooctylamine, 2-ethylheptylamine, tert-octylamine, cyclopropylamine, cyclobutylamine, cyclopentylamine, cyclohexylamine, cycloheptylamine, cyclooctylamine, ethanolamine, 2-chloroethylamine, 2-bromoethylamine, 2-fluoroethylamine, 3-chloropropylamine, 2-chloropropane-1-amine, 3-bromopropylamine, 2-bromopropane-1-amine, 3-fluoropropylamine, 2-fluoropropane-1-amine, 4-chloro-1-butylamine, 4-bromo-1-butylamine, 4-bromo-1-butylamine, 4-bromo-1-butylamine, 2-chloro-1-butylamine, 2 ...bromo-1-butylamine, 2-chloro-1-butylamine, 2-bromo-1-butylamine, 2-bromo-1-butylamine, 2-bromo-1-butylamine 3-Butylamine, 4-fluoro-1-butylamine, 5-chloro-1-pentylamine, 5-bromo-1-pentylamine, 5-fluoro-1-pentylamine, 3-aminopropionitrile, 4-aminobutyrile, 3-amino-2-methylpropionitrile, 5-aminopentylamine, 3-amino-3-methylbutyrile, glycine methyl ester, alanine methyl ester, dimethyl glutamate, lysine methyl ester, arginine methyl ester, aniline, p-methylaniline, p-ethylaniline, p-isopropylaniline, p-chloroaniline, m-chloroaniline, o-chloroaniline, 2,4-dichloroaniline, 2,6-dichloroaniline, 3,4-dichloroaniline, 3,5-dichloroaniline, 2,5-dichloroaniline, 2,4,5-trichloroaniline, 2,4,6-trichloroaniline 3,4,5-Trichloroaniline, 2,3,4-Trichloroaniline, p-Bromoaniline, m-Bromoaniline, o-Bromoaniline, 2,4-Dibromoaniline, 2,6-Dibromoaniline, 3,4-Dibromoaniline, 3,5-Dibromoaniline, 2,5-Dibromoaniline, 2,4,5-Tribromoaniline, 2,4,6-Tribromoaniline, 3,4,5-Tribromoaniline, 2,3,4-Tribromoaniline, p-Fluoroaniline, m-Fluoroaniline, o-Fluoroaniline, 2,4-Difluoroaniline, 2,6-Difluoroaniline, 3,4-Difluoroaniline, 3,5-Difluoroaniline, 2,5-Difluoroaniline, 2,4,5-Trifluoroaniline, 2,4,6-Trifluoroaniline, 3,4,5-Trifluoroaniline 2,3,4-Trifluoroaniline, p-Trifluoromethylaniline, p-Methoxyaniline, p-Nitroaniline, m-Nitroaniline, o-Nitroaniline, 2,4-Dinitroaniline, 2-Bromo-3-Nitroaniline, 2-Chloro-5-Nitroaniline, 2-Chloro-4,6-Dinitroaniline, 2,6-Dichloro-4-Nitroaniline, p-Cyanoaniline, 4-Bromo-3,5-Dichloroaniline, 2-Fluoro-3-Chloroaniline, 2-Nitro-4-Methoxy-5-Methylaniline, 5-Chloro-4-Fluoro-2-Methylaniline, 2-Chloro-4-Fluoro-6-Nitroaniline, 2,6-Difluoro-4-Nitroaniline, 3-Fluoro-4,5-Dichloroaniline, Maleic hydrazide, Salicylic hydrazide, 2,4-Dinitrophenylhydrazine, acetylhydrazine, octanoylhydrazine, furfurylamine, tetrahydrofurfurylamine, 2-thiophene methylamine, 2-aminothiazole, 2-aminobenzothiazole, 4-aminopyridine, 2-aminopyridine, 2-amino-4-trifluoromethylpyridine, 2-amino-5-chloropyridine, 2-amino-3-chloro-5-trifluoromethylpyridine, 2-amino-5-methylpyridine, 2-amino-6-methylpyridine, 5-chloro-2-pyridineamine, 2-chloro-4-aminopyridine, 2-amino-6-chloro-pyridine, 2-amino-5-nitropyridine, 2-amino-5-cyanopyridine, aminourea, aminothiourea, phenol, p-chlorophenol The following are included: at least one of the following: m-chlorophenol, o-chlorophenol, p-bromophenol, m-bromophenol, o-bromophenol, p-fluorophenol, m-fluorophenol, o-fluorophenol, p-methylphenol, p-nitrophenol, 2-bromo-5-chlorophenol, 4-bromo-5-chloro-2-methylphenol, 2-chloro-4-nitrophenol, 6-bromo-3-chloro-2-fluorophenol, 3-bromo-5-trifluoromethylphenol, methanol, ethanol, n-propanol, isopropanol, cyclopropanol, n-butanol, isobutanol, tert-butanol, n-pentanol, isopentanol, tert-pentanol, 3-hydroxypentane, 2-chloroethanol, 3-chloropropanol, 3-chloro-1-butanol, and 2-chlorobutane-1-ol.

5. The method according to claim 3, characterized in that, In step 1), the molar ratio of 2-amino-3-chloro-5-trifluoromethylpyridine to maleic anhydride is 1.0:1.0–2.

0. The reaction is carried out at a temperature of 25–85°C for 3–24 hours.

6. The method according to claim 3, characterized in that, In step 2), the molar ratio of the intermediate product shown in formula (Ⅲ) to thionyl chloride is 1.0:1.2-2.0; The reaction time is 2-6 hours.

7. The method according to claim 3, characterized in that, In step 3), the molar ratio of the intermediate acyl chloride shown in formula (II) to the reactant RH is 1.0:1.0~1.5; The reaction is carried out at a temperature of 0–50°C for a duration of 0.5–12 h. The acid-binding agent is one or more of triethylamine, pyridine, and N,N-diisopropylethylamine.

8. The use of the compound of claim 1 or 2 in the prevention and control of soil-borne plant diseases or in the preparation of products for the prevention and control of soil-borne diseases.

9. The application according to claim 8, characterized in that, The soil-borne plant diseases mentioned are caused by plant pathogenic fungi, bacteria, and nematodes.

10. The application according to claim 9, characterized in that, The soil-borne diseases mentioned are those caused by southern root-knot nematodes (Meloidogyne incognita), Botrytis cinera Pers, Sclerotinias clerotiorum, Fusarium graminearum, and / or Ralstonia solanacearum.

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