Fluorine-containing nitrogen heterocyclic compound and bactericidal application thereof

Abstract

The invention relates to a fluorine-containing nitrogen heterocyclic compound, which is a series of compounds with a structure as shown in a formula I: # imgabs0 #. The novel series of fluorine-containing nitrogen heterocyclic compounds provided by the invention have excellent biological activity on various plant pathogenic fungi. The bactericidal composition has excellent prevention and treatment effects on diseases caused by botrytis cinerea, rhizoctonia solani, wheat stem rot, physalospora piricola, pyricularia grisea, sigatoka and the like, is safe to crops, and has great popularization and application values.

Description

Technical Field

[0001] The invention relates to the field of agricultural science, in particular to a class of fluorine-containing nitrogen heterocyclic compounds and uses thereof. Background Art

[0002] Plant diseases cause a large amount of crop losses every year, posing a serious threat to global food security and sustainable agricultural development. The main means of protecting crops from pathogens is the application of fungicides. At present, quinone exogenous inhibitors (QoIs), β-tubulin inhibitors (MBCs), sterol 14α-demethylase inhibitors (DMIs) and succinate dehydrogenase inhibitors (SDHIs) have become the most competitive fungicides due to their wide antimicrobial spectrum and efficient disease control effects. However, irrational use and long-term overuse increase the risk of pathogen resistance to single target-site or even multiple target-site fungicides. For example, 19 pathogens have been reported to be resistant to DMIs at home and abroad, involving multiple resistance mechanisms such as target CYP51 gene mutations, target site overexpression, efflux pump activity changes, metabolic avoidance and metabolic detoxification; 22 pathogens have developed resistance to SDHIs, which is related to 83 mutations in the target sdh gene. In addition, the large-scale use of these fungicides has had a profound impact on the environment, especially the emergence of pesticide metabolites as major pollutants in aquatic ecosystems, which has attracted worldwide attention. With the continuous development of agricultural production, the increase in the types of diseases, the increase in the demand for disease prevention and control, and the continuous improvement of people's pursuit of high-quality agricultural products and food safety, traditional fungicides can no longer meet the needs of modern agricultural production. Therefore, the innovative research and development of new fungicides is particularly important to meet the needs of modern agricultural production for more efficient, safer and more environmentally friendly fungicide products.

[0003] In view of this, the present invention discloses a class of fluorine-containing nitrogen heterocyclic compounds, which have a novel chemical structure, a broad spectrum and high efficiency fungicidal activity, and can be used to prevent and treat plant diseases. In addition, the compounds are safe for crops, have no phytotoxicity, and can be further developed into new agricultural fungicides. Summary of the invention

[0004] One of the purposes of the present invention is to provide a class of fluorine-containing nitrogen heterocyclic compounds or their stereoisomers, or their salts or solvates.

[0005] Another object of the present invention is to provide a composition containing the above-mentioned fluorine-containing nitrogen heterocyclic compound or its stereoisomer, or its salt or solvate.

[0006] Another object of the present invention is to provide the use of the above-mentioned fluorine-containing nitrogen heterocyclic compound or its stereoisomer, or its salt or solvate, or the composition.

[0007] Another object of the present invention is to provide a method for controlling agricultural, forestry, horticultural and sanitary pests using the above-mentioned fluorine-containing nitrogen heterocyclic compound or its stereoisomer, or its salt or solvate, or the composition.

[0008] To achieve the above object, the present invention adopts the following technical solutions:

[0009] A fluorine-containing nitrogen heterocyclic compound or a stereoisomer thereof, or a salt thereof or a solvate thereof, characterized in that the compound has a structure shown in the following general formula I:

[0010]

[0011] in:

[0012] X is selected from Any one of;

[0013] R 1 is selected from any one of alkyl, alkenyl, alkynyl, substituted and unsubstituted aryl and heteroaryl (including thiophene, furan, pyridine, pyrrole, pyrazole, pyrimidine, pyrazine, pyridazine, thiazole), or R 1 is any one of haloalkyl, cycloalkyl, alkoxy, haloalkoxy, halogen, alkoxyalkyl, haloalkoxyalkyl, aryloxyalkyl, thioalkyl, halothioalkyl, hydroxy, cyano, nitro, thiocyanate, amino, cycloamino (including pyrrolidinyl, piperidinyl, N-alkylpiperidinyl, morpholino), or R 1 C(=O)CF, S(O) 2 R 4 、C(=O)OR 4 、C(=O)NR 4 、NHC(=O)CF、OCFC(=O)OR 4 Any of the following:

[0014] R 2 is selected from nitrogen heterocyclic rings, and is any one of substituted or unsubstituted triazolyl, tetrazolyl, pyrazolyl, pyridyl, pyrimidinyl, or R 2 It is any one of a substituted or unsubstituted five-membered ring group, six-membered ring group, or polycyclic ring group containing 1 to 4 nitrogen atoms;

[0015] R 3 is selected from halogen, hydrogen, cyano, nitro, alkyl, haloalkyl, haloalkoxy, or substituted and unsubstituted amino, substituted and unsubstituted aryl, substituted and unsubstituted nitrogen heterocyclic group;

[0016] R 4 Selected from haloalkyl;

[0017] Preferably, R 1 Selected from substituted and unsubstituted aryl and heteroaryl groups, wherein the substituted aryl and heteroaryl groups are halogenated or trifluoromethyl-substituted aryl and heteroaryl groups;

[0018] Preferably, R 2 is selected from substituted and unsubstituted five-membered cyclic groups, wherein the substituted and unsubstituted five-membered cyclic groups are substituted and unsubstituted five-membered cyclic groups containing three nitrogen atoms;

[0019] Preferably, R 3 is selected from substituted and unsubstituted nitrogen heterocyclic groups, wherein the substituted and unsubstituted nitrogen heterocyclic groups are substituted and unsubstituted R-containing 2 Nitrogen heterocycles;

[0020] Most preferably, the compound is selected from the following specific compounds:

[0021]

[0022] 2. An intermediate compound for preparing the compound according to claim 1 or its stereoisomer, or its salt or solvate, characterized in that the compound contains the structure shown in general formula I.

[0023] 3. A composition, characterized in that it is a composition of the compound according to claim 1 or its stereoisomer, or its salt or solvate, preferably, the target compound generates a composition of the compound represented by general formula I in the presence of a fluorinated substance.

[0024] Preferably, the compound and composition can be used as fungicides, insecticides or herbicides or adjuvants in agriculture, forestry, horticulture and sanitation; more preferably, the composition is used in agriculture, forestry, horticulture and sanitation in any dosage form such as emulsifiable concentrates, powders, aqueous solutions, wettable powders, granules, suspensions, microcapsules, aqueous emulsions, water-dispersible granules, etc.

[0025] Preferably, the compounds and compositions are used in any dosage form processing.

[0026] Preferably, the compounds and compositions are used for controlling agricultural, forestry, horticultural and sanitary pests. More preferably, the agricultural, forestry, horticultural and sanitary pests are plant fungi or bacteria; more preferably, the agricultural, forestry, horticultural and sanitary pests are rice blast, rice sheath blight, wheat stem rot, corn leaf blight, tomato gray mold, tomato early blight, tomato corynepora leaf spot, apple ring rot, apple leaf spot, banana leaf spot, grape anthracnose, Candida albicans, or a combination thereof.

[0027] A method for preventing and controlling plant diseases, pests and weeds, comprising applying the compound or its stereoisomer, or its salt or solvate, or the composition to a harmful substance or its living environment; preferably, the plant diseases, pests and weeds are plant fungal or bacterial diseases; more preferably, the plant diseases, pests and weeds are wheat stem base rot, apple ring rot, banana leaf spot, banana wilt, rice blast, rice sheath blight, corn leaf spot, grape anthracnose, tomato gray mold, tomato early blight, tomato coryneporium leaf spot, apple leaf spot, citrus anthracnose, citrus scab, citrus fruit pythium, watermelon anthracnose, cucumber wilt, grape anthracnose, peanut white rot, potato late blight, and rapeseed sclerotinia.

[0028] The invention relates to a method for protecting plants from agricultural pests and diseases, comprising a method and steps of contacting the compound or its stereoisomer, or its salt or solvate, or the composition with the plant.

[0029] By adopting the above technical scheme, the present invention uses fluorine-containing nitrogen heterocyclic compounds as the basis, and applies the compounds or their compositions to the prevention and treatment of agricultural, forestry, horticultural and sanitary harmful substances, and has good bactericidal effects on pathogenic fungi and bacteria [such as rice blast fungus (Magnaporthe oryzae), rice sheath blight fungus (Rhizoctonia solani), banana leaf spot fungus (Exserohilum rostratum), etc.], and can be further developed into a new agricultural fungicide to provide a basis.

[0030] Compared with the prior art, the present invention has the following beneficial effects:

[0031] 1. The fluorinated nitrogen heterocyclic compounds in the present invention can be developed into new fungicides with excellent cost performance, short synthesis route, high yield, cheap and easy-to-obtain raw materials, and meet the needs of modern industrial production. In addition, the compounds in the present invention can be synthesized according to the method in our published literature (He et al. Org. Lett. 2022, 24: 2299-2304), and the synthesis process of the compounds is simple, low cost, and simple and novel in structure.

[0032] 2. The present invention tests the fungicidal activity of fluorine-containing nitrogen heterocyclic compounds and confirms that the compounds have excellent fungicidal activity against a variety of pathogens. In particular, the compounds numbered 0292A, 0303B, and 0311C (the structural formulas of these compounds are as follows) have fungicidal activities against pathogens such as rice sheath blight, banana leaf spot, and rice blast that are equal to or even better than existing commercial fungicides.

[0033]

[0034] 3. The fluorine-containing nitrogen heterocyclic compounds in the present invention have high biological safety and low toxicity to humans and animals. When used in field applications to achieve better protective effects, the concentration used is more diluted than the control agent, the dosage is lower, and it is safer for crops and the environment.

[0035] 4. When the fluorine-containing nitrogen heterocyclic compound of the present invention is used as a fungicide, it can be mixed with a carrier or diluent permitted in water to be formulated into various commonly used dosage forms, such as emulsions, hydrates, flowable agents, aqueous solvents, suspensions, etc., for use in preventing and controlling plant diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 The pot experiment shows the effect of compound 0303B in controlling rice blast, where A is the control group and B is the compound 0303B treatment group. DETAILED DESCRIPTION

[0037] The technical solutions in the embodiments of the present invention will be described clearly and completely below in conjunction with the embodiments of the present invention. It should be understood that the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0038] The present invention is described using compounds 0292A, 0303B, and 0311C as representatives, and the embodiments of the present invention are used to illustrate the technical solutions of the present invention, but the contents of the embodiments are not limited thereto.

[0039] Example 1 Fungicidal activity of the compounds against E. rostratum

[0040] The compound was dissolved in DMSO and prepared into a mother solution of 10000 μg / mL. The corresponding mother solution was added to the melted PDA medium to make the final concentration of the compound in the medium 0.05, 0.1, 0.2, 0.4, 0.8, 1.6, 3.2 μg / mL. After the medium solidified, the banana leaf spot pathogen was inoculated with a bacterial plate (with a diameter of 5 mm). Each treatment was repeated 3 times and cultured at 25°C for 48h and 96h. The colony diameter was measured by the cross method and the inhibition rate was calculated. The calculation formula is: Inhibition rate (%) = (CT) / (C-5) × 100%. Among them, C represents the colony diameter of the control group without the drug, and T represents the colony diameter of the drug-treated group. The experimental results of the target compound are shown in Table 1.

[0041] Table 1 Fungicidal activity of compounds 0292A, 0303B and 0311C against banana leaf spot pathogen (%)

[0042]

[0043] Example 2 Fungicidal activity of the compounds against R. solani

[0044] The compound was dissolved in DMSO and prepared into a 10000 μg / mL mother solution. The corresponding mother solution was added to the melted PDA medium to make the final concentration of the compound in the medium 0.05, 0.1, 0.2, 0.4, 0.8, 1.6, 3.2, 6.25, 12.5, 25, 50 μg / mL. After the medium solidified, the rice sheath blight fungus plate (diameter 5 mm) was inoculated. Each treatment was repeated 3 times and cultured at 25°C for 48h and 96h. The colony diameter was measured by the cross method and the inhibition rate was calculated. The calculation formula is: Inhibition rate (%) = (CT) / (C-5) × 100%. Among them, C represents the colony diameter of the control group without the drug, and T represents the colony diameter of the drug-treated group. The experimental results of the target compound are shown in Table 2.

[0045] Table 2 Fungicidal activity of compounds 0292A, 0303B and 0311C against Rhizoctonia solani (%)

[0046]

[0047] Example 3 Fungicide activity of compounds against rice blast fungus (M.oryzae)

[0048] The compound was dissolved in DMSO and prepared into a 10000 μg / mL mother solution. The corresponding mother solution was added to the melted PDA medium to make the final concentration of the compound in the medium 0.2, 0.4, 0.8, 1.6, 3.2, 6.4, 12.5, 25, 50 μg / mL. After the medium solidified, the rice blast fungus plate (diameter 5 mm) was inoculated. Each treatment was repeated 3 times and cultured at 25°C for 48h and 96h. The colony diameter was measured by the cross method and the inhibition rate was calculated. The calculation formula is: Inhibition rate (%) = (CT) / (C-5) × 100%. Among them, C represents the colony diameter of the control group without the drug, and T represents the colony diameter of the drug-treated group. The experimental results of the target compound are shown in Table 3.

[0049] Table 3 Fungicidal activity of compounds 0292A, 0303B and 0311C against rice blast fungus (%)

[0050]

[0051]

[0052] Example 4 Compounds against banana leaf spot pathogen, rice sheath blight pathogen, rice blast pathogen EC 50 Determination

[0053] Dissolve the compound in DMSO and prepare a 10000μg / mL stock solution. Take the corresponding stock solution and add it to the melted PDA medium to make the final concentration of the compound in the medium 0.05, 0.1, 0.2, 0.4, 0.8, 1.6, 3.2, 6.4, 12.8, 25, 50μg / mL. After the medium solidifies, inoculate the rice blast fungus plate (diameter 5mm). Each treatment is repeated 3 times and placed at 25℃ for 36h and 96h. The colony diameter is measured by the cross method and the inhibition rate is calculated. According to the logarithmic value of each agent concentration and the probability value of mycelial growth inhibition rate, regression analysis is performed to calculate the EC of the compound. 50 The experimental results of the target compounds are shown in Table 4.

[0054] Table 4 EC values ​​of compounds 0292A, 0303B and 0311C against Psoralea corylifolia, Psoralea solani and Pyricularia oryzae 50 value

[0055]

[0056] Example 5 Effects of Compounds on Different Plant Pathogens EC 50 Determination of

[0057] In order to illustrate the broad-spectrum fungicidal activity of trifluoromethyl nitrogen heterocyclic compounds, compound 0292A was subjected to EC 50 As shown in Table 5, compound 0292A has good inhibitory activity against a variety of different plant pathogenic fungi, especially against rice sheath blight, rice blast, apple ring rot, corn leaf blight and citrus phytopathogenes, EC 50 The value is less than 1.0 μg / mL, which has a strong inhibitory effect on pathogenic fungi.

[0058] Table 5 EC values ​​of compound 0292A against various plant pathogenic fungi 50 Value (μg / mL)

[0059]

[0060]

[0061] Example 6 Effect of the combination of compounds 0292A, 0303B and 0311C on different plant pathogens EC 50 Determination of

[0062] The compound was dissolved in DMSO and prepared into a mother solution of 10000 μg / mL. The mother solution of the compound was combined in a 1:1 ratio to form 0292A / 0303B, 0292A / 0311C, and 0303B / 0311C compositions. The composition solution was then added to the melted PDA medium to make the final concentration of the compound in the medium 3.0 μg / mL. After the medium solidified, banana leaf spot pathogen, rice sheath blight pathogen, and rice blast pathogen were inoculated with fungal discs (with a diameter of 5 mm) respectively. Each treatment was repeated 3 times and cultured at a constant temperature of 25°C for 72 hours. The colony diameter was measured by the cross method and the inhibition rate (%) was calculated. The experimental results of the target compound are shown in Table 6.

[0063] Table 6 Fungicidal activity of the combination of compounds 0292A / 0303B, 0292A / 0311C and 0303B / 0311C against banana leaf spot pathogen, rice sheath blight pathogen and rice blast pathogen (%)

[0064] Pathogens 0292A / 0303B 0292A / 0311C 0303B / 0311C Banana leaf spot 88.34±0.21 87.32±0.64 90.06±0.39 Rhizoctonia solani 83.42±0.38 85.67±0.56 87.18±0.43 Rice blast fungus 80.87±0.32 83.53±0.86 87.33±0.58

[0065] Example 7 Control Effects of Compounds 0292A, 0303B and 0311C on Plant Diseases

[0066] The tomato gray mold test was designed in accordance with Part 28 of the "Standards for Field Efficacy Tests of Pesticides (I)"; the wheat scab test was designed in accordance with Part 15 of the "Standards for Agricultural Industry of the People's Republic of China" NY / T 1464.15-2007; the rice blast test was designed in accordance with GB / T 17980.19-2000 "Standards for Field Efficacy Tests of Pesticides (I)" - Fungicides for Control of Rice Leaf Diseases; the rice sheath blight test was designed in accordance with GB / T 17980.20-2000 "Standards for Field Efficacy Tests of Pesticides (I)" - Fungicides for Control of Rice Sheath Blight. The target compounds were all formulated into 5% aqueous emulsions, and the control effects on tomato gray mold, wheat scab, rice blast, and rice sheath blight are shown in Table 7. Among them, the pot test effect of compound 0303B for controlling rice blast is shown in the attached figure of the specification. It can be seen from the data in the table that compounds 0292A, 0303B and 0311C have good control effects on the four diseases under field conditions. At the same time, compounds 0292A, 0303B and 0311C are safe for crops such as tomatoes, wheat, and rice, and no phytotoxicity is observed.

[0067] Table 7 Control effects of target compounds on tomato gray mold, wheat head blight, rice blast and rice sheath blight.

[0068]

[0069] Example 8 Animal Safety Test of Compounds 0292A, 0303B and 0311C

[0070] In the safety test, the acute oral toxicity test design is designed in accordance with Part 3 of GB / T15670 "Toxicological Test Methods for Pesticide Registration"; the skin irritation test design is designed in accordance with Part 7 of GB / T15670 "Toxicological Test Methods for Pesticide Registration"; the acute eye irritation test design is designed in accordance with Part 8 of GB / T15670 "Toxicological Test Methods for Pesticide Registration".

[0071] The results showed that the representative compounds 0292A, 0303B and 0311C had acute oral toxicity in rats: ♂>5000 mg / kg, ♀>5000 mg / kg; acute dermal toxicity in rats: ♂>5000 mg / kg, ♀>5000 mg / kg; the rabbit eye irritation score was 0 (1h), and after 48h, it was diluted to 0 (1:100), and it was non-irritating to the eyes; the skin irritation score was 0 (4h), and it was non-irritating to the skin.

[0072] The above embodiments are only used to illustrate the technical solutions of the present invention rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, a person skilled in the art should understand that the technical solutions described in the aforementioned embodiments may still be modified, or some of the technical features may be replaced by equivalents, and these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A fluorinated nitrogen heterocyclic compound or a stereoisomer thereof, or a salt thereof or a solvate thereof, characterized in that: The compound has the structure shown in the following general formula I: in: X is selected from Any one of; R 1 is selected from any one of alkyl, alkenyl, alkynyl, substituted and unsubstituted aryl and heteroaryl (including thiophene, furan, pyridine, pyrrole, pyrazole, pyrimidine, pyrazine, pyridazine, thiazole), or R 1 is any one of haloalkyl, cycloalkyl, alkoxy, haloalkoxy, halogen, alkoxyalkyl, haloalkoxyalkyl, aryloxyalkyl, thioalkyl, halothioalkyl, hydroxy, cyano, nitro, thiocyanate, amino, cycloamino (including pyrrolidinyl, piperidinyl, N-alkylpiperidinyl, morpholino), or R 1 is C(=O)CF, S(O)2R 4 、C(=O)OR 4 、C(=O)NR 4 、NHC(=O)CF、OCFC(=O)OR 4 Any of the following: R 2 is selected from nitrogen heterocyclic rings, and is any one of substituted or unsubstituted triazolyl, tetrazolyl, pyrazolyl, pyridyl, pyrimidinyl, or R 2 It is any one of a substituted or unsubstituted five-membered ring group, six-membered ring group, or polycyclic ring group containing 1 to 4 nitrogen atoms; R 3 is selected from halogen, hydrogen, cyano, nitro, alkyl, haloalkyl, haloalkoxy, or substituted and unsubstituted amino, substituted and unsubstituted aryl, substituted and unsubstituted nitrogen heterocyclic group; R 4 Selected from haloalkyl; Preferably, R 1 Selected from substituted and unsubstituted aryl and heteroaryl groups, wherein the substituted aryl and heteroaryl groups are halogenated or trifluoromethyl-substituted aryl and heteroaryl groups; Preferably, R 2 is selected from substituted and unsubstituted five-membered cyclic groups, wherein the substituted and unsubstituted five-membered cyclic groups are substituted and unsubstituted five-membered cyclic groups containing three nitrogen atoms; Preferably, R 3 is selected from substituted and unsubstituted nitrogen heterocyclic groups, wherein the substituted and unsubstituted nitrogen heterocyclic groups are substituted and unsubstituted R-containing 2 Nitrogen heterocycles; Most preferably, the compound is selected from the following specific compounds:

2. An intermediate compound for preparing the compound according to claim 1 or its stereoisomer, or its salt or solvate, characterized in that: The compound has a structure shown in general formula I.

3. A composition, characterized in that The composition of the compound or its stereoisomer, or its salt or solvate according to claim 1, preferably, the target compound generates a composition of the compound represented by general formula I in the presence of a fluorinated substance.

4. The compound according to claim 1, or its stereoisomer, or its salt or solvate, wherein: The composition can be used as a fungicide, insecticide or herbicide or adjuvant in agriculture, forestry, gardening and sanitation; preferably, the composition is used in the fields of agriculture, forestry, gardening and sanitation in any dosage form such as emulsifiable concentrate, powder, aqueous solution, wettable powder, granule, suspension, microcapsule, aqueous emulsion, water-dispersible granule, etc.

5. The compound according to claim 1, or its stereoisomer, or its salt or solvate, wherein: The compound or stereoisomer thereof, or salt or solvate thereof according to claim 1, for use in any dosage form processing.

6. Use of the compound or its stereoisomer, or its salt or solvate according to claim 1, or the composition according to claim 3 for controlling agricultural, forestry, horticultural or sanitary pests, preferably, the agricultural, forestry, horticultural or sanitary pests are plant fungi or bacteria; more preferably, the agricultural, forestry, horticultural or sanitary pests are rice blast, rice sheath blight, wheat stem rot, corn leaf blight, tomato gray mold, tomato early blight, tomato corynespora leaf spot, apple ring rot, apple leaf spot, banana leaf spot, grape anthracnose, Candida albicans, or a combination thereof.

7. A method for preventing and controlling plant diseases, insect pests and weeds, characterized in that: The compound or stereoisomer thereof, or salt or solvate thereof according to claim 1, or the composition according to claim 3 is applied to a harmful substance or its living environment; preferably, the plant diseases, insects and weeds are plant fungal or bacterial diseases; more preferably, the plant diseases, insects and weeds are wheat stem base rot, apple ring rot, banana leaf spot, banana wilt, rice blast, rice sheath blight, corn leaf spot, grape anthracnose, tomato gray mold, tomato early blight, tomato coryneform leaf spot, apple leaf spot, citrus anthracnose, citrus scab, citrus fruit rot, watermelon anthracnose, cucumber wilt, grape anthracnose, peanut white rot, potato late blight, and rapeseed sclerotinia.

8. A method for protecting plants from agricultural pests and diseases, characterized in that A method and step for contacting a compound according to claim 1 or a stereoisomer thereof, or a salt or a solvate thereof, or a composition according to claim 3 with a plant.

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