Pyridazinone derivative as well as preparation method and application thereof

Abstract

The invention relates to the field of compound synthesis technologies and pesticides, in particular to a pyridazinone derivative and a preparation method and application thereof.The pyridazinone derivative has effective pre-emergence and post-emergence herbicidal activity and can be applied as a herbicide; the derivative is simple in structure and preparation process, low in production cost and wide in application prospect.

Description

Technical Field

[0001] This invention belongs to the fields of compound synthesis technology and pesticides, specifically relating to a pyridazinone derivative and its preparation method and application. Background Technology

[0002] With global population growth, food security is becoming increasingly important, and ensuring stable and increased grain production has become a core objective of agricultural development. Herbicides, as an important means of improving agricultural production efficiency, reducing labor costs, and protecting the environment, are being used more and more frequently. However, the extensive use of herbicides has also led to problems such as increased weed resistance and environmental pollution. With rising environmental protection requirements and demands for a higher quality of life, the development of new, highly efficient, low-toxicity, and environmentally friendly herbicides has become an urgent need for agricultural production.

[0003] Pyridazinone compounds are widely used in pharmaceuticals, pesticides, and other fields. In pesticide applications, herbicides based on pyridazinones, such as fluroxypyr and flupyridaben, are already on the market. However, existing pyridazinone herbicides still suffer from problems such as high cost, large dosage, and the development of resistance, making it difficult to meet the demands of modern agriculture for highly efficient, safe, and environmentally friendly herbicides. Therefore, developing herbicides with novel mechanisms of action that are highly efficient, low in toxicity, and economical has become a current research focus.

[0004] Patent CN116262743B discloses a pyridazinone compound containing aromatic bicyclic substitution, its preparation method, and its uses. It discloses the fungicidal and insecticidal activity of the pyridazinone structure to address agricultural pest and disease control. Patent CN119039233A discloses a pyridazinone herbicide and pyridazinone intermediates for preparing the herbicide. The compound is specifically designed for selective control of weeds in crops (such as wheat, barley, corn, soybean, sunflower, cotton, rapeseed, and rice) and specialty crops (such as sugarcane, citrus, fruits, and nut crops). Although existing technologies disclose pyridazinone compounds as potential structures, further optimization is needed to address weed resistance and environmental challenges, particularly regarding crop safety, tolerance, application rates, and costs. In the future, innovative research and development will drive the development of herbicides towards high efficiency, safety, and environmental friendliness, providing crucial support for sustainable agricultural development. Summary of the Invention

[0005] This invention addresses the limited variety and lack of diversity among existing pyridazinone herbicides by proposing a pyridazinone derivative, its preparation method, and its applications.

[0006] Specifically, this is achieved through the following technical solutions:

[0007] One pyridazinone derivative is a pyridazinone derivative containing an N-substituted aryl group;

[0008] A pyridazinone derivative has the general structural formula as shown in formula (A):

[0009]

[0010] In formula (A): R is any one of substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthiol, or substituted or unsubstituted carbonyl; X is a substituted electron-withdrawing group.

[0011] Further, X is selected from one or more of hydrogen, tritium, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, trifluoromethyl, trifluoromethoxy, nitro, and halogen; R is any one of substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkylmeritol, and substituted or unsubstituted C1-C6 carbonyl; substitution refers to substitution by one or more of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylmeritol, hydroxyl, and halogen.

[0012] Furthermore, the substituted C1-C6 alkyl group is any one of alkoxymethylene and alkoxymerylmethylene.

[0013] Furthermore, R is any one of methyl, ethyl, formaldehyde, acetyl, methoxymethylene, ethoxymethylene, propoxymethylene, butoxymethylene, pentooxymethylene, isopropoxymethylene, isobutoxymethylene, (2-methoxyethoxy)methylene, (2-isopropoxyethoxy)methylene, (eththio)methylene, (propthio)methylene, and hydroxymethyl; X is one or more of trifluoromethyl, fluorine, chlorine, nitro, trifluoromethoxy, hydrogen, and tritium.

[0014] The pyridazinone derivatives include the following compounds:

[0015]

[0016]

[0017] Another object of the present invention is to provide a method for preparing the said pyridazinone derivative.

[0018] The preparation method of the pyridazinone derivative includes the following steps:

[0019] (1) Preparation of intermediate 2:

[0020] Compound 1 was dissolved in ethanol, 1.2 eq of hydrazine hydrate was added, and the mixture was heated to reflux. After the reaction of compound 1 was completed, the mixture was cooled and a large amount of ethanol was removed under reduced pressure. A large amount of white solid precipitated out and was filtered to obtain intermediate 2.

[0021] (2) Preparation of intermediates 3a-3b:

[0022] Intermediate 2 was dissolved in anhydrous tetrahydrofuran, cooled to 0°C, and then 3 eq of Grignard reagent was slowly added dropwise. After the addition was complete, the mixture was reacted at 0°C for 1 h, then naturally heated to room temperature for 2 h, and then cooled to -5°C. The reaction was quenched by adding saturated ammonium chloride aqueous solution while stirring. The mixture was filtered, the organic layer was extracted with ethyl acetate, washed with saturated sodium chloride, dried, and then subjected to column chromatography to obtain intermediates 3a-3b.

[0023] (3) Preparation of intermediates 4a-4d and 12a-12g:

[0024] Take intermediate 3a or 3b in dichloromethane, add 2 eq of copper acetate, add 2 eq of pyridine while stirring, stir at room temperature for 6-12 h, after the reaction is complete, add 1M HCl until the solid is completely dissolved, extract with dichloromethane, wash with saturated sodium chloride, dry and then column chromatography to obtain intermediates 4a-4d and 12a-12g.

[0025] (4) Preparation of intermediates 6a-6b and 13a-13h:

[0026] Take intermediate 4a-4d or 12a-12g in carbon tetrachloride, then add 0.1 eq of AIBN and 1.5 eq of NBS, heat under reflux for 6-12h, extract with dichloromethane, wash with saturated sodium chloride, dry and then column chromatography to obtain intermediate 6a-6b, 13a-13h.

[0027] (5) Preparation of intermediates 7a-7b:

[0028] Intermediates 6a-6b were placed in dimethyl sulfoxide, a small amount of water was added, and the mixture was heated to 80°C. After the reactants had reacted completely, the mixture was cooled to room temperature, extracted with ethyl acetate, washed with saturated sodium chloride, dried, and then subjected to column chromatography to obtain intermediates 7a-7b.

[0029] (6) Preparation of intermediates 8a-8b:

[0030] Intermediates 7a-7b were placed in dichloromethane, 10 eq of manganese dioxide was added, and the mixture was heated to reflux. After the reactants had reacted completely, the mixture was cooled to room temperature, extracted with dichloromethane, washed with saturated sodium chloride, dried, and then subjected to column chromatography to obtain intermediates 8a-8b.

[0031] (7) Preparation of intermediates 10a-10k, 14a-14h and 15a-15h:

[0032] Take intermediate 6a or 13a-13h in a reaction flask, use the starting alcohol as solvent, heat to 120℃, and after the starting material has reacted completely, cool, extract with ethyl acetate, wash with saturated sodium chloride, dry and then column chromatography to obtain intermediates 10a-10k, 14a-14h and 15a-15h.

[0033] (8) Preparation of target products 9a-9b, 5a-5d, 11a-11l, 16a-16h and 17a-17h:

[0034] Intermediate 4a-4d, 8a-8b, 7a, 10a-10k, 14a-14h, or 15a-15h was placed in dimethyl sulfoxide, and 0.1 eq of CuI, 2 eq of K3PO4, and 1.2 eq of methylamine hydrochloride were added. The mixture was heated to 80°C under nitrogen protection until the reactants were completely reacted. After cooling, the mixture was extracted with ethyl acetate, washed with saturated sodium chloride, dried, and then subjected to column chromatography to obtain the target product.

[0035]

[0036] Another object of the present invention is the use of the pyridazine derivative in the preparation of herbicidal pesticides.

[0037] Specifically, the weeds are barnyard grass, barnyard grass, velvetleaf, amaranth retroflexus, lambsquarters, ryegrass, purslane, bermudagrass, rapeseed, speedwell, amaranth, black nightshade, sow thistle, dandelion, sage, clover, chickweed, goosegrass, goosegrass, and foxtail grass.

[0038] Beneficial effects:

[0039] This invention is based on the pyridazinone structure. By introducing an electron-withdrawing phenyl group at the 2-position of the pyridazinone, an alkyl group, an alkoxy group, an alkoxymethylene group, an alkimidyl group, an alkimidylmethylene group, a carbonyl group, etc., at the 4-position, and a methylamino group at the 5-position, a small molecule of pyridazinone herbicide pesticide with relatively stable physicochemical properties and excellent drug-like properties is created. This type of derivative has a particularly significant pre-emergence and early post-emergence inhibition effect on monocotyledonous and dicotyledonous weeds.

[0040] Pre- and post-emergence herbicidal activity was assessed. At a concentration of 300 g ai / ha, most compounds exhibited both pre- and post-emergence herbicidal activity. Compounds 11b, 11c, and 16c showed pre-emergence herbicidal activity comparable to the positive control fluroxypyr. Compound 16c, in particular, showed higher activity against *Amaranthus tricuspidata* and *Amaranthus retroflexus* at 150 g ai / ha than the positive control fluroxypyr. Furthermore, the compounds demonstrated low toxicity in crop safety assessments.

[0041] This invention relates to pyridazine derivatives with simple structure, simple preparation process, low production cost, high yield, low toxicity, easy degradation, good environmental compatibility, high safety in use, and non-toxic and harmless preparation process. Detailed Implementation

[0042] The specific embodiments of the present invention will be described in further detail below, but the present invention is not limited to these embodiments. Any improvements or substitutions based on these embodiments shall still fall within the scope of protection claimed by the claims of the present invention.

[0043] Example 1: Synthesis of compound 9a, comprising the following steps:

[0044] (1) Preparation of intermediate 2:

[0045] Compound 1 (1.68 g, 10 mmol) was dissolved in ethanol, 500 mg of hydrazine hydrate was added, and then the mixture was heated to reflux. After the reaction of compound 1 was completed, the mixture was cooled and a large amount of ethanol was removed under reduced pressure. A large amount of white solid precipitated out and was filtered to obtain intermediate 2.

[0046] (2) Preparation of intermediates 3a-3b:

[0047] Intermediate 2 (1.68 g, 10 mmol) was dissolved in anhydrous tetrahydrofuran, cooled to 0 °C, and then 30 mL of methyl magnesium bromide with a concentration of 1 mol / L was slowly added dropwise. After the addition was complete, the mixture was reacted at 0 °C for 1 h, then naturally heated to room temperature for 2 h, and then cooled to -5 °C. The reaction was quenched by adding saturated ammonium chloride aqueous solution dropwise with stirring. The mixture was filtered, the organic layer was extracted with ethyl acetate, washed with saturated sodium chloride, dried, and then subjected to column chromatography to obtain intermediate 3a.

[0048] (3) Preparation of intermediate 4a:

[0049] Intermediate 3a (1.44 g, 10 mmol) and 3-trifluoromethylphenylboronic acid (2.28 g, 12 mmol) were placed in dichloromethane, and copper acetate (3.62 g, 20 mmol) was added. Pyridine (1.6 g, 20 mmol) was added while stirring and the mixture was stirred at room temperature for 12 h. After the reaction was complete, 1 M HCl was added until the solid was completely dissolved and the green color disappeared. The mixture was extracted with dichloromethane, washed with saturated sodium chloride, dried, and then subjected to column chromatography to obtain intermediate 4a.

[0050] (4) Preparation of intermediate 6a:

[0051] Intermediate 4a (2.88 g, 10 mmol) was placed in carbon tetrachloride, and then 0.1 eq of AIBN (164 mmol) was added.

[0052] The intermediate 6a was obtained by heating and refluxing for 12 h with 1.5 eq of NBS (2.67 g) and extracting with dichloromethane, washing with saturated sodium chloride, drying and column chromatography.

[0053] (5) Preparation of intermediate 7a:

[0054] Take intermediate 6a (3.66 g, 10 mmol) in 30 mL of dimethyl sulfoxide, add 1 mL of water, heat to 80 °C, wait for the starting material to react completely, cool to room temperature, extract with ethyl acetate, wash with saturated sodium chloride, dry and then column chromatography to obtain intermediate 7a.

[0055] (6) Preparation of intermediate 8a:

[0056] Intermediate 7a (3.04 g, 10 mmol) was placed in dichloromethane, and 10 eq of manganese dioxide (8.6 g) was added. The mixture was heated to reflux until the reactants were completely reacted. The mixture was then cooled to room temperature, extracted with dichloromethane, washed with saturated sodium chloride, dried, and then subjected to column chromatography to obtain intermediate 8a.

[0057] (7) Preparation of target compound 9a:

[0058] Take intermediate 8a (3.03 g, 10 mmol) in a reaction flask, add 0.1 eq CuI, 2 eq K3PO4 and 1.2 eq methylamine hydrochloride, heat to 80 °C under nitrogen protection, and after the reactants have reacted completely, cool, extract with ethyl acetate, wash with saturated sodium chloride, dry and then column chromatography to obtain the target product 9a.

[0059] Example 2: Synthesis of compound 11b

[0060] (1) The synthesis of intermediate 6a is carried out according to the method of Example 1:

[0061] (2) Preparation of intermediate 10b:

[0062] Take intermediate 6a (3.67 g, 10 mmol) in a reaction flask, add ethanol, and then heat to 120 °C. After 6a has reacted completely, cool to room temperature, extract with ethyl acetate, wash with saturated sodium chloride, dry and then column chromatography to obtain intermediate 10b.

[0063] (3) Preparation of target 11b:

[0064] Take intermediate 10b (3.03 g, 10 mmol) in a reaction flask, add 0.1 eq CuI, 2 eq K3PO4 and 1.2 eq methylamine hydrochloride, heat to 80 °C under nitrogen protection, and after the reactants have reacted completely, cool, extract with ethyl acetate, wash with saturated sodium chloride, dry and then column chromatography to obtain the target product 11b.

[0065] The physicochemical data of the target compounds prepared in the above examples are shown below:

[0066]

[0067]

[0068]

[0069]

[0070]

[0071]

[0072]

[0073]

[0074]

[0075] Pre-seeding activity assay of target compounds:

[0076] This experiment employed a closed-system method, using various weeds as test subjects. Weed seeds were evenly scattered in 10×10cm plastic flowerpots filled two-thirds full with organic substrate soil, then covered with 1cm of organic substrate soil and watered thoroughly. After 24 hours, the substrate soil surface was sprayed with herbicides. The herbicide solution was prepared by dissolving the compound in 100μL DMF and diluting it with 0.1% Tween-80 to a dosage of 300 and 150 g ai / ha. Fluroxypyr was used as a positive control. After 21 days in a greenhouse, the herbicidal activity was evaluated visually, comparing to the control group (CK). Pre-emergence herbicidal activity data are shown in Table 1.

[0077] Table 1. Pre-emergence herbicidal activity test of target compounds.

[0078]

[0079]

[0080] Post-seeding activity test of target compound:

[0081] This experiment used a spraying method with various weeds as test subjects. Weed seeds were evenly scattered in 10×10cm plastic pots filled two-thirds full with organic substrate, then covered with 1cm of organic substrate, and watered thoroughly. The pots were then placed in a greenhouse for growth. Both grass and broadleaf weeds were ready for testing when they reached the 1-2 leaf stage. The compounds were dissolved in 100μL DMF and diluted with 0.1% Tween-80 to doses of 300 and 150g ai / ha. Commercial flufenoxuron was used as a positive control and target compound for spraying all weeds. After 21 days in the greenhouse, the treated weeds were visually inspected against the control (CK) group to evaluate their herbicidal activity. The crop safety test was also conducted using this method. Results are shown in Table 2.

[0082] Table 2. Post-emergence herbicidal activity test of target compounds

[0083]

[0084]

[0085] The methods for evaluating crop safety before and after emergence are the same as those for weed control before and after emergence. The results are shown in Tables 3 and 4. From the tables, it can be seen that compounds 11b, 11c, and 16c have low toxicity to crops.

[0086] Table 3. Post-emergence crop selectivity (200g ai / ha)

[0087]

[0088]

[0089] Table 4. Pre-emergence crop selectivity (200g ai / ha)

[0090]

[0091] In summary, this series of pyridazine derivatives exhibits excellent herbicidal and inhibitory activity. Therefore, this series of compounds can be further developed as novel pre- and post-emergence herbicides for application in a wider range of farmlands.

[0092] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Any simple modifications, equivalent changes, and alterations made to the above embodiments without departing from the technical essence of the present invention shall still fall within the scope of the present invention.

Claims

1. A pyridazinone derivative, characterized in that, The structure of the pyridazinone derivative is shown in formula (A): In formula (A): R is any one of substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxy-mercapto, or substituted or unsubstituted carbonyl; X is a substituted electron-withdrawing group.

2. The pyridazinone derivative as described in claim 1, characterized in that, X is selected from one or more of hydrogen, tritium, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, nitro, and halogen; R is any one of substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkylmeritol, and substituted or unsubstituted C1-C6 carbonyl; substitution refers to being substituted by one or more of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylmeritol, hydroxyl, and halogen.

3. The pyridazinone derivative as described in claim 2, characterized in that, The substituted C1-C6 alkyl group is any one of alkoxymethylene and alkoxymerylmethylene.

4. The pyridazinone derivative as described in claim 1, characterized in that, R is any one of methyl, ethyl, formaldehyde, acetyl, methoxymethylene, ethoxymethylene, propoxymethylene, butoxymethylene, pentooxymethylene, isopropoxymethylene, isobutoxymethylene, (2-methoxyethoxy)methylene, (2-isopropoxyethoxy)methylene, (eththio)methylene, (propthio)methylene, and hydroxymethyl; X is one or more of trifluoromethyl, fluorine, chlorine, nitro, trifluoromethoxy, hydrogen, and tritium.

5. The pyridazine derivative as described in claim 1, characterized in that, Including the following compounds:

6. The pyridazine derivative as described in claim 1, characterized in that, The pyridazinone derivatives are 3,4-disubstituted and N-substituted aryl pyridazinone derivatives.

7. The method for preparing the pyridazinone derivative according to any one of claims 1-6, characterized in that, The synthesis route and steps are as follows: (1) Preparation of intermediate 2: Compound 1 was dissolved in ethanol, hydrazine hydrate was added, and the mixture was heated under reflux. After the reaction of compound 1 was completed, the temperature was lowered and a large amount of ethanol was removed under reduced pressure, resulting in the precipitation of a white solid. The solid was then filtered to obtain intermediate 2. (2) Preparation of intermediates 3a-3b: Intermediate 2 was dissolved in anhydrous tetrahydrofuran, cooled to 0°C, and then Grignard reagent was slowly added dropwise. After the addition was complete, the mixture was reacted at 0°C for 1 hour, then naturally heated to room temperature for 2 hours. The mixture was then cooled to -5°C, and the reaction was quenched by adding saturated ammonium chloride aqueous solution while stirring. The mixture was filtered, the organic layer was extracted with ethyl acetate, washed with saturated sodium chloride, dried, and then subjected to column chromatography to obtain intermediates 3a-3b. (3) Preparation of intermediates 4a-4d and 12a-12g: Take intermediate 3a or 3b in dichloromethane, add copper acetate, add pyridine while stirring, stir at room temperature for 6-12 h, after the reaction is complete, add HCl until the solid is completely dissolved, extract with dichloromethane, wash with saturated sodium chloride, dry and then column chromatography to obtain intermediates 4a-4d and 12a-12g. (4) Preparation of compounds 6a-6b and 13a-13h: Dissolve compounds 4a-4d or 12a-12g in an organic solvent, add AIBN and NBS, heat to reflux, and after the reactants have reacted, add water, extract with ethyl acetate, dry and column chromatography to obtain solids, which are intermediates 6a-6b and 13a-13h. (5) Preparation of compounds 7a-7b: Compounds 6a-6b were placed in dimethyl sulfoxide, a small amount of water was added, and the mixture was heated to 80°C and stirred until the reactants were completely reacted. After cooling to room temperature, water was added, and the mixture was extracted with ethyl acetate. After washing with saturated sodium chloride and drying, the intermediates 7a-7b were obtained by column chromatography. (6) Preparation of compounds 8a-8b: Intermediates 7a-7b were placed in dichloromethane, MnO2 was added, and the mixture was heated under reflux. After the reaction of the raw materials was completed, the mixture was extracted with dichloromethane, washed with saturated sodium chloride, dried, and then subjected to column chromatography to obtain intermediates 8a-8b. (7) Preparation of compounds 10a-10k, 14a-14h and 15a-15h: Take intermediate 6a or 13a-13h in a reaction flask, use the starting alcohol as solvent, heat to 120℃, wait for the starting material to react completely, cool, extract with ethyl acetate, wash with saturated sodium chloride, dry and then column chromatography to obtain intermediates 10a-10k, 14a-14h and 15a-15h. (8) Preparation of target products 5a-5d, 9a-9b, 11a-11l, 16a-16h and 17a-17h: Compounds 4a-4d, 8a-8b, 7a, 10a-10k, 14a-14h, or 15a-15h were reacted in dimethyl sulfoxide with CuI, K3PO4, and methylamine hydrochloride. The mixture was heated to 80°C under nitrogen protection. After the reactants had reacted completely, the mixture was cooled, extracted with ethyl acetate, washed with saturated sodium chloride, dried, and then subjected to column chromatography to obtain the target product.

8. The use of the pyridazinone derivative as described in any one of claims 1-6 in the preparation of herbicides.

9. The use of the pyridazine derivative as described in claim 8 in the preparation of herbicides, characterized in that, The weeds targeted are barnyard grass, velvetleaf, amaranth, lambsquarters, ryegrass, purslane, bermudagrass, rapeseed, speedwell, amaranth, black nightshade, sow thistle, dandelion, sage, clover, chickweed, goosegrass, and foxtail.

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