CN-121342751-B - Difluoromethylpyrazole formylbiphenyl amine compound as well as synthesis method and application thereof

CN121342751BCN 121342751 BCN121342751 BCN 121342751BCN-121342751-B

Abstract

The invention belongs to the technical field of pesticide synthesis, and particularly relates to a difluoromethyl pyrazole formylbiphenyl amine compound, a synthesis method and application thereof. According to the invention, firstly, 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid (DFPA for short) is used for preparing DFPA acyl chloride, then the obtained DFPA acyl chloride is in butt joint with benzidine with different substituents, the difluoromethyl pyrazole carboxamide compound is synthesized, and the difluoromethyl pyrazole carboxamide compound is determined to have excellent activity in terms of antipathogen. The compound can be used for preparing anti-pathogenic bacteria pharmaceutical preparations.

Inventors

YANG FUWEI
XUE DONG
WANG CUIPING
XUAN GUANGSHAN
LIU WEIJIE
SUN CHAO

Assignees

山东绿德地药物研发有限公司
济南绿德地生物科技有限公司
山东绿德地生物科技有限公司

Dates

Publication Date: 20260508
Application Date: 20251218

Claims (9)

1. A difluoromethyl pyrazole carboxanilide compound, which is characterized in that the structural formula of the compound is selected from any one of the following formulas: Or (b) 。
2. A process for the preparation of difluoromethyl pyrazole carboxamides according to claim 1, comprising the steps of: (1) Synthesis of intermediate compound a: Firstly, adding substituted o-bromoaniline and substituted phenylboronic acid into ethanol water solution, wherein the molar ratio of the substituted o-bromoaniline to the substituted phenylboronic acid is 1 (1.0-3.0); The structural formula of the substituted o-bromoaniline is as follows: wherein R 1 =H,R 2 = F; The structural formula of the substituted phenylboronic acid is as follows: Wherein R 3 = Cl or CF 3 ,R 4 =CF 3 ; Then adding sodium carbonate and a catalyst, heating to 60-80 ℃ and reacting for 1-5h, wherein the catalyst is palladium acetate or bis (triphenylphosphine) palladium dichloride; finally, cooling to room temperature, filtering, concentrating and extracting the reaction liquid, evaporating the obtained extract liquid to dryness to obtain an intermediate compound A for later use; The structural formula of the intermediate compound A is as follows: wherein R 1 =H,R 2 =F,R 3 = Cl or CF 3 ,R 4 =CF 3 ; (2) Synthesis DFPA: firstly, dropwise adding N, N-dimethylformamide dimethyl acetal into 4, 4-difluoroacetoacetic acid ethyl ester by taking toluene as a solvent, and carrying out reflux reaction for 1-5h at 60-80 ℃, wherein the molar ratio of the 4, 4-difluoroacetoacetic acid ethyl ester to the N, N-dimethylformamide dimethyl acetal is 1 (1-3); Then cooling to-10 to-5 ℃ after the reaction is finished, dropwise adding methyl hydrazine in methanol solution to react for 1-2 hours, heating to room temperature of 20-25 ℃ and continuing to react for 1-2 hours, and removing the solvent by rotary evaporation to obtain an intermediate product for later use; Wherein, the molar ratio of methyl hydrazine to 4, 4-difluoro acetoacetic acid ethyl ester is (1-2): 1; Finally, adding sodium hydroxide solution into the obtained intermediate product, heating to 50-55 ℃ and reacting for 1-2h; Cooling to 5-10 ℃ after the reaction is finished, adding toluene solvent, dropwise adding hydrochloric acid solution, adjusting the pH value of the reaction solution to 1-2, carrying out suction filtration, and drying to obtain DFPA; (3) Synthesis DFPA of acid chloride: adding DFPA and 2-3 equivalents of thionyl chloride obtained in the step (2) into toluene solvent, and reacting for 1-2h at 70-80 ℃ with DMF as a catalyst to obtain DFPA acyl chloride; (4) Synthesizing a difluoromethyl pyrazole formylbiphenyl amine compound: acetonitrile, triethylamine and DFPA acyl chloride are added into the intermediate compound A obtained in the step (1), the temperature is raised to 70-75 ℃, and the temperature is kept for 1-2h; wherein the molar ratio of the intermediate compound A to the triethylamine is 1 (1-2); DFPA the molar ratio of acyl chloride to intermediate compound A is (1.1-1.3) 1; After the reaction is finished, cooling to room temperature, filtering, concentrating, washing and evaporating to dryness to obtain the difluoromethyl pyrazole formylbiphenyl amine compound.
3. The method for preparing difluoromethyl pyrazole formylbiphenyl amine compound according to claim 2, wherein the molar ratio of substituted o-bromoaniline to substituted phenylboronic acid in the step (1) is 1 (1.0-1.3); the mass ratio of ethanol to water in the ethanol water solution is (3-5): 1.
4. The method for producing a difluoromethyl pyrazole formylbiphenyl amine compound according to claim 2, wherein the mass ratio of sodium carbonate to substituted phenylboronic acid in the step (1) is (1-5) 1; the addition amount of the catalyst is 1% -2% of the mass of the substituted o-bromoaniline.
5. The process for producing difluoromethyl pyrazole carboxamides according to claim 2, wherein the molar ratio of ethyl 4, 4-difluoroacetoacetate to N, N-dimethylformamide dimethyl acetal in step (2) is 1:1.5; the molar ratio of the methyl hydrazine to the ethyl 4, 4-difluoroacetoacetate is (1-1.2) 1.
6. The method for producing a difluoromethyl pyrazole formylbiphenyl amine compound according to claim 2, wherein the mass fraction of the sodium hydroxide solution in the step (2) is 10% to 20%; the mass ratio of the sodium hydroxide to the intermediate product is (2-3) 1.
7. Use of a difluoromethyl pyrazole carboxanilide compound according to claim 1 for the preparation of succinate dehydrogenase inhibitors.
8. The use of a difluoromethyl pyrazole formylbiphenyl amine compound according to claim 1 in the preparation of an antipathogenic medicament, wherein the pathogenic bacterium is rhizoctonia solani, botrytis cinerea or phytophthora.
9. A bactericidal composition characterized in that the active ingredient is the difluoromethyl pyrazole formylbiphenyl amine compound of claim 1.

Description

Difluoromethylpyrazole formylbiphenyl amine compound as well as synthesis method and application thereof Technical Field The invention belongs to the technical field of pesticide synthesis, and particularly relates to a difluoromethyl pyrazole formylbiphenyl amine compound, a synthesis method and application thereof. Background The succinic acid dehydrogenase inhibitor (SDHI) bactericide has the characteristics of high activity, good selectivity, broad bactericidal spectrum, low toxicity, high efficiency and the like, can improve the quality and the yield of crops, and has wider prospect in the bactericide market. The difluoromethyl pyrazole carboxamide compound belongs to an important member of SDHI bactericides, and as the difluoromethyl substituent can remarkably improve the biological activity of the organic compound compared with the trifluoromethyl substituent, the difluoromethyl substituent can not only show the simulation effect, the electronic effect, the permeation effect and the blocking effect of fluorine atoms, but also show that hydrogen atoms can form intermolecular hydrogen bonds to further enhance the drug effect. The currently marketed difluoromethyl pyrazole carboxamides SDHI bactericides include isopyrazam, sedaxane, benzovindiflupyr (benzovindiflupyr), fluxapyroxad (pydiflumetofen), fluxapyroxad (fluxapyroxad), bixafen (bixafen), penflufen (fluindapyr), inpyrfluxam, and fluoxastrobin (flubeneteram). However, these SDHI bactericides have a high risk of resistance due to the single site of action, and tend to be resistant. Therefore, in practical application, the compound preparation needs to be formed by combining other bactericides with different action mechanisms (such as prothioconazole, tebuconazole, spiroxamine, fluoxastrobin and the like) so as to overcome the generation of resistance. Disclosure of Invention The invention aims to provide a difluoromethyl pyrazole formylbiphenyl amine compound, a synthesis method and application thereof, aiming at the defects, wherein the compound has excellent activity on resisting pathogenic bacteria and can be used for preparing an anti-pathogenic bacteria pharmaceutical preparation. According to the invention, firstly, 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid (DFPA for short) is used for preparing DFPA acyl chloride, then the obtained DFPA acyl chloride is in butt joint with benzidine with different substituents, the difluoromethyl pyrazole carboxamide compound is synthesized, and the difluoromethyl pyrazole carboxamide compound is determined to have excellent activity in terms of antipathogen. The technical scheme of the invention is as follows: A difluoromethyl pyrazole carboxanilide compound, the structural formula of which is selected from any one of the following formulas: Or (b) 。 The synthesis method of the difluoromethyl pyrazole formylbiphenyl amine compound comprises the following steps: (1) Synthesis of intermediate compound a: Firstly, adding substituted o-bromoaniline and substituted phenylboronic acid into ethanol water solution, wherein the molar ratio of the substituted o-bromoaniline to the substituted phenylboronic acid is 1 (1.0-3.0). Preferably, the molar ratio of the substituted o-bromoaniline to the substituted phenylboronic acid is 1 (1.0-1.3). The mass ratio of ethanol to water in the ethanol water solution is (3-5): 1. The structural formula of the substituted o-bromoaniline is as follows: Wherein R 1=H,R2 = F. The structural formula of the substituted phenylboronic acid is as follows: where R 3 = Cl or CF 3,R4=CF3. Then adding sodium carbonate and catalyst, heating to 60-80 ℃ and reacting for 1-5h. Wherein the catalyst is palladium acetate or bis (triphenylphosphine) palladium dichloride. The mass ratio of the sodium carbonate to the substituted phenylboronic acid is (1-5) to 1. Preferably, the mass ratio of the sodium carbonate to the substituted phenylboronic acid is (2-3) 1. The addition amount of the catalyst is 1% -2% of the mass of the substituted o-bromoaniline. Finally, cooling to room temperature, filtering, concentrating the filtrate, removing ethanol, adding ethyl acetate for extraction for 2 times, combining the ethyl acetate, and evaporating to dryness to obtain an intermediate compound A for later use. The structural formula of the intermediate compound A is as follows: Where R 1=H,R2=F,R3 = Cl or CF 3,R4=CF3. (2) Synthesis DFPA (3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid): Firstly, dropwise adding N, N-dimethylformamide dimethyl acetal (DMF-DMA) into 4, 4-difluoroacetic acid ethyl ester by taking toluene as a solvent, and carrying out reflux reaction for 1-5h at 60-80 ℃, wherein the molar ratio of the 4, 4-difluoroacetic acid ethyl ester to the DMF-DMA is 1 (1-3). Preferably, the mole ratio of the 4, 4-difluoroacetic acid ethyl ester to the DMF-DMA is 1:1.5. Then cooling to-10 to-5 ℃ after the reaction is finished, dropwise adding methyl hydrazine in methanol solution to react