Triazole compounds, processes for their preparation and use, and fungicides

Abstract

The application relates to the technical field of bactericides, and discloses a triazole compound, a preparation method and application thereof, and a bactericide, the compound has a structure shown in formula (I), wherein R1, R2 and R3 are each independently selected from H, halogen, C1-C6 alkyl or C1-C6 halogenated alkyl; R4, R5, R6 and R7 are each independently selected from H, halogen, -NO2, -NH2, -OH, -CN, C1-C6 alkyl, C1-C6 alkoxy or C1-C6 halogenated alkyl; and L is absent or L is a small-molecule compound developed by the application and taking a triazole ring as a central skeleton, the small-molecule compound can be used as a broad-spectrum bactericide, the problem of fungus resistance to existing bactericides is improved, and good bactericidal activity is shown in in-vitro and in-vivo tests.

Description

Technical Field

[0001] This invention relates to the field of bactericide technology, specifically to a triazole compound, its preparation method and application, and a bactericide. Background Technology

[0002] Plant diseases caused by plant viruses and fungal pathogens severely impact crop yield and quality, posing a significant threat to global food security. Chemical pesticides, due to their ease of use and economic advantages, are crucial strategic resources for agricultural development; their rational use can effectively reduce economic losses caused by pests, diseases, and weeds. However, with the continued application of existing pesticide inhibitors, the problem of plant and fungal resistance has become increasingly prominent. Therefore, developing pesticide inhibitors with novel structures and high activity is of paramount importance. Summary of the Invention

[0003] This invention develops a novel triazole skeleton fungicide to combat fungal resistance, and provides a triazole compound, its preparation method and application, as well as a fungicide.

[0004] To achieve the above objectives, a first aspect of the present invention provides a triazole compound having the structure shown in formula (I).

[0005]

[0006] R1, R2, and R3 are each independently selected from H, halogens, C1-C6 alkyl groups, or C1-C6 haloalkyl groups;

[0007] R4, R5, R6, and R7 are each independently selected from H, halogens, -NO2, -NH2, -OH, -CN, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 haloalkyl.

[0008] L is non-existent or L is

[0009] A second aspect of the present invention provides a method for preparing triazole compounds, the method comprising the following steps:

[0010] (1) In the presence of a first solvent, the compound shown in formula (II) is brought into a first contact with the compound shown in formula (III) to obtain the compound shown in formula (IV);

[0011] (2) In the presence of an inorganic base and a second solvent, the compound shown in formula (Ⅳ) is subjected to a second contact with the compound shown in formula (Ⅴ);

[0012]

[0013] In Equations (II), (III), (IV), and (V), R1, R2, R3, R4, R5, R6, and R7 are defined in the same way as those in the first aspect.

[0014] The third aspect of this invention provides the application of the triazole compounds described in the first aspect in inhibiting plant pathogens.

[0015] A fourth aspect of the present invention provides a bactericide containing the triazole compound and excipients described in the first aspect.

[0016] Through the above technical solution, the present invention achieves the following beneficial effects:

[0017] (1) The small molecule compound with triazole ring as the central skeleton developed in this invention can be used as a broad-spectrum fungicide to improve the problem of fungal resistance to existing fungicides. It shows good fungicidal activity in both in vitro and in vivo tests.

[0018] (2) The compounds of the present invention can effectively inhibit the biosynthesis of sterols in fungi. Sterol metabolites are the main components of fungal cell membranes. The inhibition of sterol synthesis will lead to damage and collapse of hyphae, and ultimately the death of the colony.

[0019] Other features and advantages of the present invention will be described in detail in the following specific embodiments. Detailed Implementation

[0020] The endpoints and any values ​​of the ranges disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein.

[0021] The first aspect of this invention provides a triazole compound having the structure shown in formula (I).

[0022]

[0023] R1, R2, and R3 are each independently selected from H, halogens, C1-C6 alkyl groups, or C1-C6 haloalkyl groups;

[0024] R4, R5, R6, and R7 are each independently selected from H, halogens, -NO2, -NH2, -OH, -CN, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 haloalkyl.

[0025] L is non-existent or L is

[0026] In this invention, the alkyl, alkoxy, haloalkyl, and other groups are not limited to straight-chain or branched chains. The terminology used in this invention can be interpreted in a manner conventional in the art.

[0027] In this invention, the halogen can be F, Cl, Br, or I; the C1-C6 alkyl group can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, etc.; and the C1-C6 alkoxy group can be methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, etc.

[0028] In this invention, the number of halogen atoms in the C1-C6 haloalkyl group is not limited, that is, the hydrogen atoms in the alkyl group are partially or completely replaced by halogen atoms. In the preferred case, all the hydrogen atoms in the alkyl group are replaced by halogen atoms.

[0029] According to the present invention, preferably, R1 is selected from halogens or C1-C3 haloalkyl groups; more preferably, R1 is Cl or CF3.

[0030] According to the present invention, preferably, R2, R3, R4, R6, and R7 are each independently selected from H or halogens; more preferably, R2 is H or Cl, R3 is H, and R4, R6, and R7 are each independently selected from H or halogens.

[0031] According to the present invention, preferably, R5 is selected from H, halogen, -NO2, -OH, C1-C3 alkyl, C1-C3 alkoxy or C1-C3 haloalkyl; more preferably, R5 is selected from H, halogen, -NO2, C1-C3 alkyl or C1-C3 haloalkyl.

[0032] The substituents listed in Table 1 can be combined in the manner listed in Table 1 or in other ways. That is, R1, R2, R3, R4, R5, R6, and R7 in the triazole compounds with the structure shown in formula (I) of the present invention can be independently selected from the substituents listed in Table 1, or they can be combined in the manner listed in Table 1 to form triazole compounds with the structure shown in formula (I) (such as a1, a2, a3, a4, a5, etc.). The triazole compounds with the structure shown in formula (I) of the present invention can be described by the specific compounds listed in Table 1, but the present invention is not limited to these compounds.

[0033] Table 1

[0034]

[0035]

[0036] A second aspect of the present invention provides a method for preparing triazole compounds, the method comprising the following steps:

[0037] (1) In the presence of a first solvent, the compound shown in formula (II) is brought into a first contact with the compound shown in formula (III) to obtain the compound shown in formula (IV);

[0038] (2) In the presence of an inorganic base and a second solvent, the compound shown in formula (Ⅳ) is subjected to a second contact with the compound shown in formula (Ⅴ);

[0039]

[0040] In equations (II), (III), (IV), and (V), R1, R2, R3, R4, R5, R6, and R7 are defined in the same way as those described in the first aspect above. Further details will not be provided here.

[0041] According to the present invention, preferably, the conditions for the first contact include: a temperature of 75-85°C, a time of 2-3 hours, and a molar ratio of the compound represented by formula (II) to the compound represented by formula (III) of 1-1.1:1 (e.g., 1:1, 1.02:1, 1.05:1, 1.08:1, 1.1:1, and any two of the above); the first solvent is selected from C1-C3 monohydric alcohols.

[0042] According to the present invention, preferably, the amount of the first solvent is 4-6 mL relative to 1 mmol of the compound represented by formula (II). More preferably, the first solvent is ethanol.

[0043] According to the present invention, preferably, the conditions for the second contact include: a temperature of 55-65°C, a time of 2-3 hours, and a molar ratio of the compound represented by formula (Ⅳ) to the compound represented by formula (Ⅴ) of 0.8-0.9:1 (e.g., 0.8:1, 0.82:1, 0.85:1, 0.87:1, 0.9:1, and any two of the above); the inorganic base is selected from cesium carbonate and / or potassium carbonate, and the second solvent is selected from acetone and / or toluene.

[0044] According to the present invention, preferably, the amount of the second solvent is 20-50 mL (e.g., 20 mL, 30 mL, 40 mL, 50 mL and any two of the above) relative to 1 mmol of the compound represented by formula (Ⅳ).

[0045] According to the present invention, preferably, the preparation method of the compound represented by formula (II) includes a third contact of thioaminourea and benzyl bromo in the presence of a third solvent, wherein the conditions of the third contact include: a temperature of 75-85°C, a time of 2-3 h, and a molar ratio of thioaminourea to benzyl bromo of 0.8-0.9:1; the third solvent is selected from C1-C3 monohydric alcohols. The structural formula of thioaminourea is...

[0046] In this invention, the post-processing of the products from the first, second, and third contacts can refer to commonly used purification methods in the art, such as recrystallization and column chromatography. Specifically, the product from the first contact, after solvent removal, yields a white solid powder, which is then recrystallized from ethanol to obtain the compound shown in formula (Ⅳ). The product from the third contact, after partial solvent removal, is then recrystallized under ice bath conditions to obtain thioaminourea.

[0047] According to the present invention, preferably, the contact product obtained in step (2) is eluent with a mixture of dichloromethane and methanol (dichloromethane:methanol = 30-60:1), and silica gel (e.g., 400 mesh silica gel) is used as the chromatographic column packing material. After separation, the compound shown in formula (I) is obtained.

[0048] The present invention does not impose any particular limitation on the reaction conditions involved in the above preparation process. Those skilled in the art can obtain suitable reaction conditions based on common knowledge in the field of organic synthesis and the specific examples provided in the embodiments of the present invention.

[0049] The third aspect of this invention provides the application of the triazole compounds described in the first aspect in inhibiting plant pathogens.

[0050] According to the present invention, the plant pathogens can be common plant pathogens. Preferably, the plant pathogens include at least one of the following: rice sheath blight pathogen, wheat scab pathogen, apple ring rot pathogen, cucumber gray mold pathogen, tomato early blight pathogen, rapeseed sclerotinia rot pathogen, and peanut brown spot pathogen. The triazole compounds of the present invention can effectively inhibit the above-mentioned plant pathogens, but are not limited to them, and also have good inhibitory effects on other common plant pathogens in the art.

[0051] In this invention, the plant can be an agricultural crop, such as rice, wheat, apple, pear, cucumber, tomato, rapeseed, and peanut.

[0052] A fourth aspect of the present invention provides a bactericide containing the triazole compound and excipients described in the first aspect.

[0053] In this invention, the excipients can be additives commonly used in the art. Preferably, the excipients include surfactants, organic solvents, and water. The surfactant can be a nonionic surfactant, such as Tween 80, and the organic solvent can be N,N-dimethylformamide (DMF). More preferably, the content of organic solvent in the bactericide is less than 1% by weight, and the content of surfactant is 0.1-0.2% by weight.

[0054] According to the present invention, preferably, the content of triazole compounds in the bactericide is 10 mg / L-50 g / L.

[0055] The present invention will be described in detail below through examples. In the following examples, unless otherwise specified, all raw materials used are commercially available and of analytical purity. The target fungus was obtained from the Nankai University Student Bioassay Center.

[0056] Example

[0057] The compounds listed in Table 2 of this invention are reacted according to the following route:

[0058]

[0059] (1) Dissolve 4 g (43.9 mmol) of thioaminourea (compound 1) in 25 mL of anhydrous ethanol, stir at room temperature for 5 min, then add 1 equivalent of benzyl bromide to the system, heat to 80 °C and reflux for 3 hours, monitor the reaction progress by TLC, and after the reaction is complete, remove 15 mL of solvent by vortexing, and precipitate the solid in an ice bath to obtain S-benzyl isothioaminourea (compound 3), with a yield of 90%.

[0060] (2) Dissolve 446 mg (2.46 mmol) of S-phenylmethylisothiocyanate (compound 3) in 10 mL of anhydrous ethanol, and add 1 equivalent of polysubstituted phenyl isothiocyanate (compound 4) to it. Heat to 80 °C and reflux for 3 h. Monitor the reaction progress by TLC. After the reaction is complete, cool to 0 °C to precipitate a white powdery solid. Filter the solid, dry it, and recrystallize it with 20 mL of ethanol to obtain compound 5 with a yield of 85%.

[0061] (3) Dissolve 150 mg (0.55 mmol) of the triazole ring intermediate (compound 5) in 25 mL of acetone, add 1.5 equivalents of cesium carbonate, add 1.2 equivalents of polysubstituted benzyl bromide (compound 6-1) while stirring at room temperature, heat to 60 °C and reflux for 2 h, monitor the reaction progress by TLC, after the reaction is completed, directly evaporate to dryness and remove solvent, and then separate by column chromatography (dichloromethane:methanol = 50:1) to obtain the final compounds a / b, with a yield of 75%.

[0062] The NMR data of the above-obtained compounds were tested respectively, and the results are recorded in Table 2.

[0063] Table 2

[0064]

[0065]

[0066]

[0067]

[0068]

[0069] Test Example 1

[0070] In vitro antibacterial activity test: The compound was dissolved in DMF to prepare a 20 mg / mL stock solution, which was then added to potato dextrose agar (PDA) medium to prepare a 50 mg / L drug-containing medium. In vitro antibacterial activity experiments against seven fungi were conducted using the mycelial growth inhibition method at a compound concentration of 50 mg / L. The target fungi were placed on potato dextrose agar plates and pre-cultured at 25 ± 1 °C for 5 days. Then, under sterile conditions, a 4 mm diameter fungal pad was inoculated into the center of a PDA plate containing the experimental compound using an inoculation needle. Each experiment was repeated three times. Cultured for 3-5 days depending on the growth rate of different fungi. The average growth diameter was obtained by calculating the average of the three replicates. The growth inhibition rate (%) was then calculated using the formula: [(CK0-PT1) / (CK0-4)] × 100%; CK0 represents the average growth diameter of the mycelial disc cultured on a PDA plate without fungicide, and PT1 represents the average growth diameter of the mycelial disc cultured on a PDA plate with fungicide. The results of the in vitro antibacterial test are shown in Table 3.

[0071] Comparison Test 1

[0072] The test was conducted according to the method in Test Example 1, except that the compound was replaced with I-A4 from 202111415539.X. The results of the in vitro antibacterial test are shown in Table 3.

[0073] Table 3

[0074]

[0075] As can be seen from Table 3, the series of compounds prepared in this invention all showed inhibitory activity against seven plant pathogens, especially against cucumber gray mold and peanut brown spot. Most compounds showed an inhibitory effect of more than 50% against cucumber gray mold and more than 40% against peanut brown spot.

[0076] More preferably, compounds a4, a11, a12, b5, b9, and b12 exhibit better antibacterial effects and broad-spectrum activity (inhibiting multiple plant pathogens). In particular, compound a11 generally achieves inhibition of over 50% against seven plant pathogens, compound a12 generally achieves inhibition of over 50% against apple ring rot, cucumber gray mold, tomato early blight, rapeseed sclerotinia stem rot, and peanut brown spot, and compound b12 generally achieves inhibition of over 50% against rice sheath blight, wheat scab, apple ring rot, cucumber gray mold, rapeseed sclerotinia stem rot, and peanut brown spot.

[0077] More preferably, chlorothalonil has an antibacterial effect of only 20% when used to treat wheat scab, while the compounds of this application generally have an antibacterial effect of more than 20% when used to treat wheat scab. Therefore, the compounds of this invention can better inhibit wheat scab.

[0078] Test Example 2

[0079] In vivo antibacterial activity test:

[0080] (1) Preparation of bactericide: The compound is dissolved in DMF and the concentration of the compound is diluted to 100 mg / L with an aqueous solution of 0.1% Tween 80 to obtain a bactericide, wherein the content of organic solvent (DMF) in the bactericide does not exceed 1% by weight.

[0081] (2) Spraying fungicide: Spray evenly on plant material at the 2-4 true leaf stage, with 3 replicates per group. After the fungicide solution is naturally air-dried, spray with a suspension of spores to inoculate the fungus. After inoculation, transfer to a humidification chamber (relative humidity above 95%, temperature 20℃~22℃) and culture in the dark for 24 hours. Then, culture for 7 days at 20℃~25℃, with 12 hours of alternating light and dark (light intensity 5000Lux~10000Lux) and relative humidity 80%~90%. When the diseased leaf rate of the blank control reaches more than 50%, grade and investigate the disease status of each treatment. At least 30 leaves are investigated for each treatment. The grading method is: Grade 0: No disease spots;

[0082] Grade 1: Lesions cover less than 5% of the total leaf area;

[0083] Grade 3: Lesions cover 5% to 15% of the total leaf area;

[0084] Level 5: Lesions cover 15%–25% of the total leaf area;

[0085] Level 7: Lesions cover 25%–50% of the total leaf area;

[0086] Level 9: Lesions cover more than 50% of the total leaf area.

[0087] Calculate according to formula (1), and keep the result to two decimal places.

[0088]

[0089] In the formula:

[0090] X --- Disease index;

[0091] N i ---Number of diseased leaves at each level;

[0092] i --- Relative numerical value;

[0093] N---Total number of leaves surveyed.

[0094] Calculate according to formula (2), and keep the result to two decimal places.

[0095]

[0096] In the formula:

[0097] P---Prevention and control effect, expressed as a percentage (%);

[0098] CK---Blank control disease index;

[0099] PT---Drug treatment severity index.

[0100] Based on the in vitro antibacterial test results of Test Example 1, this invention further tested the in vivo antibacterial effects (control effects) of six compounds with high activity, namely a4, a11, a12, b5, b9, and b12, at an application rate of 200 μg / mL against rapeseed sclerotium, cucumber gray enzyme, and rice sheath blight pathogens. The test results are shown in Table 4.

[0101] Table 4

[0102] a4 200 44.6％ 53.6％ 29.8％ a11 200 54.4％ 69.3％ 44.3％ a12 200 64.3％ 63.6％ 18.4％ b5 200 49.4％ 55.6％ 34.6％ b9 200 28.5％ 50.9％ 38.2％ b12 200 34.3％ 55.3％ 31.6％ Chlorothalonil 200 68.2％ 67.3％ 35％

[0103] The preferred embodiments of the present invention have been described in detail above; however, the present invention is not limited thereto. Within the scope of the inventive concept, various simple modifications can be made to the technical solutions of the present invention, including combinations of various technical features in any other suitable manner. These simple modifications and combinations should also be considered as the content disclosed in the present invention and are all within the protection scope of the present invention.

Claims

1. A triazole compound, characterized in that, The compound has the structure shown in formula (I). （I）， R1, R2, and R3 are each independently selected from H, halogens, C1-C6 alkyl groups, or C1-C6 haloalkyl groups; R4, R5, R6, and R7 are each independently selected from H, halogens, -NO2, -NH2, -OH, -CN, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 haloalkyl. L is .

2. The compound according to claim 1, wherein, R1 is selected from halogens or C1-C3 haloalkyl groups; R2, R3, R4, R6, and R7 are each independently selected from H or halogens; R5 is selected from H, halogen, -NO2, -OH, C1-C3 alkyl, C1-C3 alkoxy, or C1-C3 haloalkyl.

3. The compound according to claim 1 or 2, wherein, R1 is either Cl or CF3; R2 is H or Cl; R3 is H; R4, R6, and R7 are each independently selected from H or halogens; R5 is selected from H, halogen, -NO2, C1-C3 alkyl or C1-C3 haloalkyl.

4. A method for preparing triazole compounds, characterized in that, The method includes the following steps: (1) In the presence of a first solvent, the compound shown in formula (II) is brought into a first contact with the compound shown in formula (III) to obtain the compound shown in formula (IV); (2) In the presence of an inorganic base and a second solvent, the compound shown in formula (Ⅳ) is subjected to a second contact with the compound shown in formula (Ⅴ) to obtain the compound shown in formula (I); （I） (II) (III) （Ⅳ） （Ⅴ） In formulas (I), (II), (III), (IV), and (V), R1, R2, and R3 are each independently selected from H, halogens, C1-C6 alkyl groups, or C1-C6 haloalkyl groups. R4, R5, R6, and R7 are each independently selected from H, halogens, -NO2, -NH2, -OH, -CN, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 haloalkyl. L is .

5. The method according to claim 4, wherein, R1 is selected from halogens or C1-C3 haloalkyl groups; R2, R3, R4, R6, and R7 are each independently selected from H or halogens; R5 is selected from H, halogen, -NO2, -OH, C1-C3 alkyl, C1-C3 alkoxy, or C1-C3 haloalkyl.

6. The method according to claim 4 or 5, wherein, R1 is either Cl or CF3; R2 is H or Cl; R3 is H; R4, R6, and R7 are each independently selected from H or halogens; R5 is selected from H, halogen, -NO2, C1-C3 alkyl or C1-C3 haloalkyl.

7. The method according to claim 4, wherein, The conditions for the first contact include: a temperature of 75-85℃, a time of 2-3h, a molar ratio of the compound shown in formula (II) to the compound shown in formula (III) of 1-1.1:1; and the first solvent being selected from C1-C3 monohydric alcohols.

8. The method according to claim 4, wherein, The conditions for the second contact include: a temperature of 55-65℃, a time of 2-3h, a molar ratio of the compound shown in formula (Ⅳ) to the compound shown in formula (Ⅴ) of 0.8-0.9:1; an inorganic base selected from cesium carbonate and / or potassium carbonate, and a second solvent selected from acetone and / or toluene.

9. The application of a triazole compound in inhibiting plant pathogens, characterized in that, The compound has the structure shown in formula (I). （I）， R1, R2, and R3 are each independently selected from H, halogens, C1-C6 alkyl groups, or C1-C6 haloalkyl groups; R4, R5, R6, and R7 are each independently selected from H, halogens, -NO2, -NH2, -OH, -CN, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 haloalkyl. L does not exist or L is ; The plant pathogens are selected from at least one of the following: rice sheath blight pathogens, wheat scab pathogens, apple ring rot pathogens, cucumber gray mold pathogens, tomato early blight pathogens, rapeseed sclerotinia rot pathogens, and peanut brown spot pathogens.

10. A bactericide comprising a triazole compound as described in any one of claims 1-3 or a triazole compound prepared by the method described in any one of claims 4-8, and excipients.

11. The bactericide according to claim 10, wherein the content of triazole compounds in the bactericide is 10 mg / L-50 g / L.

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