阅读说明：本技术 一种n-(2-苯甲酰胺)-1h-吡唑-4-甲酰胺类化合物及其制备方法和应用 (N- (2-benzamide) -1H-pyrazole-4-formamide compound and preparation method and application thereof ) 是由 刘幸海 余玮 金涛 谭成侠 翁建全 武宏科 于 2019-10-25 设计创作，主要内容包括：本发明公开了一种N-(2-苯甲酰胺)-1<I>H</I>-吡唑-4-甲酰胺类化合物及其制备方法和应用。N-(2-苯甲酰胺)-1<I>H</I>-吡唑-4-甲酰胺类化合物,即N-(2-苯甲酰胺)-3-(二氟甲基)-1-甲基-1<I>H</I>-吡唑-4-甲酰胺类化合物,其结构式如式(Ⅰ)所示：<Image he="199" wi="334" file="DEST_PATH_IMAGE002.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>式(Ⅰ)中：R为苯基或取代苯基,所述取代苯基的苯环上的取代基数量为一个或多个,各个取代基各自独立地选自卤素、C1-C3烷基或C1-C3烷氧基。本发明公开的N-(2-苯甲酰胺)-3-(二氟甲基)-1-甲基-1<I>H</I>-吡唑-4-甲酰胺类化合物为具有杀菌活性的新化合物,其在50ppm浓度下对水稻纹枯病菌有较好的抑制率,为新农药的研发提供了基础。(The invention discloses N- (2-benzamide) -1 H -pyrazole-4-carboxamides, processes for their preparation and their use. N- (2-benzamide) -1 H Pyrazole-4-carboxamides, i.e. N- (2-benzamide) -3- (difluoromethyl) -1-methyl-1 H -pyrazole-4-carboxamides of formula (i): in formula (I): r is phenyl or substituted phenyl, the number of the substituent groups on the benzene ring of the substituted phenyl is one or more, and each substituent group is independently selected from halogen, C1-C3 alkyl or C1-C3 alkoxy. The invention discloses N- (2-benzamide) -3- (difluoro)Methyl) -1-methyl-1 H The-pyrazole-4-formamide compound is a new compound with bactericidal activity, has a better inhibition rate on rhizoctonia solani at a concentration of 50ppm, and provides a foundation for the research and development of new pesticides.)

1. An N- (2-benzamide) -1H-pyrazole-4-carboxamide compound, namely an N- (2-benzamide) -3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxamide compound, is characterized in that the structural formula is shown as the formula (I):

in formula (I): r is phenyl or substituted phenyl, the number of the substituent groups on the benzene ring of the substituted phenyl is one or more, and each substituent group is independently selected from halogen, C1-C3 alkyl or C1-C3 alkoxy.

2. A N- (2-benzamide) -1H-pyrazole-4-carboxamide according to claim 1, characterized in that in formula (i) R is one of the following: 2-methylphenyl, 2, 6-dichlorophenyl, 2, 3-dichlorophenyl, 4-methoxyphenyl, 2, 4-dichlorophenyl and phenyl.

3. A process for the preparation of N- (2-benzamide) -1H-pyrazole-4-carboxamides according to claim 1 or 2, characterized by comprising the steps of:

1) heating ethyl difluoroacetoacetate and triethyl orthoformate in an organic solvent A to reflux reaction, concentrating to remove the solvent after the reaction is finished, adding the concentrated residue into a mixed solution of a methylhydrazine aqueous solution and an organic solvent B, stirring and reacting at the temperature of 45-60 ℃, and tracking the reaction process by TLC; after the reaction is finished, carrying out post-treatment on the reaction solution to obtain 1-methyl-3-difluoromethyl-1H-pyrazole-4-ethyl formate shown in a formula (II);

2) adding the 1-methyl-3-difluoromethyl-1H-pyrazole-4-ethyl formate shown in the formula (II) obtained in the step 1) into a NaOH aqueous solution with the mass concentration of 8-12%, stirring and reacting at the temperature of 55-70 ℃ until a reaction liquid system is transparent, naturally cooling to room temperature, adding acid to adjust the pH of the reaction liquid to 1.5-3.0, separating out a solid, performing suction filtration, and drying filter residues to obtain 1-methyl-3-difluoromethyl-1H-pyrazole-4-formic acid shown in the formula (III);

3) heating the 1-methyl-3-difluoromethyl-1H-pyrazole-4-formic acid shown in the formula (III) obtained in the step 2) in thionyl chloride to reflux reaction, concentrating to remove excessive thionyl chloride after the reaction is finished, stirring and reacting the concentrated residue with N-Boc-ethylenediamine and triethylamine in an organic solvent C at room temperature, tracking the reaction process by TLC, distilling and concentrating to remove the solvent after the reaction is finished, and separating the distilled and concentrated residue by column chromatography to obtain (2- (3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxamido) ethyl) carbamic acid tert-butyl ester shown in the formula (IV);

4) heating the tert-butyl (2- (3- (difluoromethyl) -1-methyl-1H-pyrazole-4-formamido) ethyl) carbamate obtained in the step 3) and trifluoromethyl acetic acid in an organic solvent D to reflux reaction, tracking the reaction process by TLC, distilling and concentrating to remove the solvent after the reaction is finished, and separating the distilled concentrate by column chromatography to obtain the N- (2-aminoethyl) -3- (difluoromethyl) -1-methyl-1H-pyrazole-4-formamide shown in the formula (V);

5) uniformly stirring and mixing the N- (2-aminoethyl) -3- (difluoromethyl) -1-methyl-1H-pyrazole-4-formamide shown in the formula (V) obtained in the step 4), an organic solvent E and triethylamine, then dropwise adding substituted benzoyl chloride, stirring and reacting at room temperature, tracking the reaction process by TLC, performing rotary evaporation and concentration after the reaction is finished to remove the solvent, and performing column chromatography separation and purification on the rotary evaporation and concentration residue to obtain the N- (2-benzamide) -3- (difluoromethyl) -1-methyl-1H-pyrazole-4-formamide shown in the formula (I);

wherein the number of the substituent groups on the benzene ring of the substituted benzoyl chloride is one or more, and each substituent group is independently selected from H, halogen, C1-C3 alkyl or C1-C3 alkoxy.

4. The process for preparing N- (2-benzamide) -1H-pyrazole-4-carboxamide compound according to claim 3, wherein the organic solvent A in step 1) is acetic anhydride and the organic solvent B is ethanol; the organic solvent C in the step 3), the organic solvent D in the step 4) and the organic solvent E in the step 5) are all dichloromethane.

5. The method for preparing N- (2-benzamide) -1H-pyrazole-4-carboxamide compound according to claim 3, wherein in step 1), the molar ratio of ethyl difluoroacetoacetate, triethyl orthoformate and methylhydrazine is 1: 1.1-1.5.

6. The method for preparing an N- (2-benzamide) -1H-pyrazole-4-carboxamide compound according to claim 3, wherein in step 3), the charging molar ratio of 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid represented by formula (III) to N-Boc-ethylenediamine is 1: 1.1-1.5; in the step 4), the feeding molar ratio of the tert-butyl (2- (3- (difluoromethyl) -1-methyl-1H-pyrazole-4-formamido) ethyl) carbamate shown in the formula (IV) to the trifluoromethyl acetic acid is 1: 1.05-1.2.

7. The method for preparing an N- (2-benzamide) -1H-pyrazole-4-carboxamide according to claim 3, wherein in step 5), the molar ratio of N- (2-aminoethyl) -3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxamide represented by formula (v) to the substituted benzoyl chloride is 1:1.05 to 1.2.

8. The process for preparing N- (2-benzamide) -1H-pyrazole-4-carboxamide compound according to claim 3, wherein the molar ratio of organic solvent A to ethyl difluoroacetoacetate in step 1) is 2-4: 1, the volume of organic solvent B is 0.3-0.8 ml/mmol based on the amount of ethyl difluoroacetoacetate; the volume dosage of the organic reagent C in the step 3) is 0.5-1.0 ml/mmol based on the amount of the 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid shown in the formula (III); the volume usage amount of the organic reagent D in the step 4) is 5-8 ml/mmol based on the substance amount of (2- (3- (difluoromethyl) -1-methyl-1H-pyrazole-4-formamido) ethyl) carbamic acid tert-butyl ester shown in a formula (IV); the volume usage amount of the organic reagent E in the step 5) is 5-8 ml/mmol based on the amount of the N- (2-aminoethyl) -3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxamide shown in the formula (V).

9. The method for preparing N- (2-benzamide) -1H-pyrazole-4-carboxamide compound according to claim 3, wherein the eluents for column chromatography in step 3), step 4) and step 5) are mixed solution of ethyl acetate and petroleum ether in a volume ratio of 1: 0.5-2.

10. Use of an N- (2-benzamide) -1H-pyrazole-4-carboxamide compound as claimed in claim 1 or 2 for the preparation of fungicides.

Technical Field

The invention relates to an N- (2-benzamide) -1H-pyrazole-4-formamide compound and a preparation method and application thereof.

Background

Nowadays, pyrazole amide compounds usually have excellent and wide biological activity such as low toxicity, high efficiency and the like because of containing high-activity structural groups such as pyrazole, amide and the like, and a pyrazole ring is an important member of nitrogen-containing heterocycles, has a very unique structural form, and has high biological activity to various microorganisms, pathogenic factors and diseases, so that the pyrazole amide compounds are not only used in the fields of sterilization, disinsection and acaricidal action, but also widely applied in the field of weeding, and even applied in the field of anticancer in medicine. In recent years, some overseas pesticides have been interested in the development of bisamide pesticides, and chlorantraniliprole and cyantraniliprole developed by DuPont and flubendiamide developed by Bayer and Japanese pesticide Kabushiki Kaisha are on the market. There are developed Tetraniliprol of Bayer, Bromocha fluorobenzenediamide developed by Pasv and Mitsui chemistry, and the like. The compound has the advantages of low residue on plants, small phytotoxicity, low acute toxicity on mammals and the like.

The design and synthesis of the novel pyrazole diacyl fungicide have important significance for developing novel pesticides with high efficiency, low toxicity and low residue.

Disclosure of Invention

Aiming at the technical problems in the prior art, the invention aims to provide an N- (2-benzamide) -3- (difluoromethyl) -1-methyl-1H-pyrazole-4-formamide compound and a preparation method and application thereof. The invention designs and synthesizes a series of compounds such as pyrazole diacyl and the like based on the structure of SDH inhibitors such as fluxapyroxad and the like, introduces modes such as extension and substituted benzamide and the like by taking a pyrazole amide structure as a matrix, and introduces difluoromethyl at the 3-position of a pyrazole ring to investigate the influence on the biological activity of the compounds.

The N- (2-benzamide) -1H-pyrazole-4-formamide compound, namely the N- (2-benzamide) -3- (difluoromethyl) -1-methyl-1H-pyrazole-4-formamide compound, is characterized in that the structural formula is shown as the formula (I):

in formula (I): r is phenyl or substituted phenyl, the number of the substituent groups on the benzene ring of the substituted phenyl is one or more, and each substituent group is independently selected from halogen, C1-C3 alkyl or C1-C3 alkoxy.

The N- (2-benzamide) -1H-pyrazole-4-formamide compound is characterized in that R in the formula (I) is one of the following compounds: 2-methylphenyl, 2, 6-dichlorophenyl, 2, 3-dichlorophenyl, 4-methoxyphenyl, 2, 4-dichlorophenyl and phenyl.

The preparation method of the N- (2-benzamide) -1H-pyrazole-4-formamide compound is characterized by comprising the following steps:

1) heating ethyl difluoroacetoacetate and triethyl orthoformate in an organic solvent A to reflux reaction, concentrating to remove the solvent after the reaction is finished, adding the concentrated residue into a mixed solution of a methylhydrazine aqueous solution and an organic solvent B, stirring and reacting at the temperature of 45-60 ℃, and tracking the reaction process by TLC; after the reaction is finished, carrying out post-treatment on the reaction solution to obtain 1-methyl-3-difluoromethyl-1H-pyrazole-4-ethyl formate shown in a formula (II);

2) adding the 1-methyl-3-difluoromethyl-1H-pyrazole-4-ethyl formate shown in the formula (II) obtained in the step 1) into a NaOH aqueous solution with the mass concentration of 8-12%, stirring and reacting at the temperature of 55-70 ℃ until a reaction liquid system is transparent, naturally cooling to room temperature, adding acid to adjust the pH of the reaction liquid to 1.5-3.0, separating out a solid, performing suction filtration, and drying filter residues to obtain 1-methyl-3-difluoromethyl-1H-pyrazole-4-formic acid shown in the formula (III);

3) heating the 1-methyl-3-difluoromethyl-1H-pyrazole-4-formic acid shown in the formula (III) obtained in the step 2) in thionyl chloride to reflux reaction, concentrating to remove excessive thionyl chloride after the reaction is finished, stirring and reacting the concentrated residue with N-Boc-ethylenediamine and triethylamine in an organic solvent C at room temperature, tracking the reaction process by TLC, distilling and concentrating to remove the solvent after the reaction is finished, and separating the distilled and concentrated residue by column chromatography to obtain (2- (3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxamido) ethyl) carbamic acid tert-butyl ester shown in the formula (IV);

4) heating the tert-butyl (2- (3- (difluoromethyl) -1-methyl-1H-pyrazole-4-formamido) ethyl) carbamate obtained in the step 3) and trifluoromethyl acetic acid in an organic solvent D to reflux reaction, tracking the reaction process by TLC, distilling and concentrating to remove the solvent after the reaction is finished, and separating the distilled concentrate by column chromatography to obtain the N- (2-aminoethyl) -3- (difluoromethyl) -1-methyl-1H-pyrazole-4-formamide shown in the formula (V);

5) uniformly stirring and mixing the N- (2-aminoethyl) -3- (difluoromethyl) -1-methyl-1H-pyrazole-4-formamide shown in the formula (V) obtained in the step 4), an organic solvent E and triethylamine, then dropwise adding substituted benzoyl chloride, stirring and reacting at room temperature, tracking the reaction process by TLC, performing rotary evaporation and concentration after the reaction is finished to remove the solvent, and performing column chromatography separation and purification on the rotary evaporation and concentration residue to obtain the N- (2-benzamide) -3- (difluoromethyl) -1-methyl-1H-pyrazole-4-formamide shown in the formula (I);

wherein the number of the substituent groups on the benzene ring of the substituted benzoyl chloride is one or more, and each substituent group is independently selected from H, halogen, C1-C3 alkyl or C1-C3 alkoxy.

The preparation method of the N- (2-benzamide) -1H-pyrazole-4-formamide compound is characterized in that the organic solvent A in the step 1) is acetic anhydride, and the organic solvent B is ethanol; the organic solvent C in the step 3), the organic solvent D in the step 4) and the organic solvent E in the step 5) are all dichloromethane.

The preparation method of the N- (2-benzamide) -1H-pyrazole-4-formamide compound is characterized in that in the step 1), the feeding molar ratio of ethyl difluoroacetoacetate, triethyl orthoformate and methylhydrazine is 1: 1.1-1.5.

The preparation method of the N- (2-benzamide) -1H-pyrazole-4-formamide compound is characterized in that in the step 3), the feeding molar ratio of 1-methyl-3-difluoromethyl-1H-pyrazole-4-formic acid shown in the formula (III) to N-Boc-ethylenediamine is 1: 1.1-1.5; in the step 4), the feeding molar ratio of the tert-butyl (2- (3- (difluoromethyl) -1-methyl-1H-pyrazole-4-formamido) ethyl) carbamate shown in the formula (IV) to the trifluoromethyl acetic acid is 1: 1.05-1.2.

The preparation method of the N- (2-benzamide) -1H-pyrazole-4-formamide compound is characterized in that in the step 5), the feeding molar ratio of the N- (2-aminoethyl) -3- (difluoromethyl) -1-methyl-1H-pyrazole-4-formamide shown in the formula (V) to the substituted benzoyl chloride is 1: 1.05-1.2.

The preparation method of the N- (2-benzamide) -1H-pyrazole-4-formamide compound is characterized in that the molar ratio of the organic solvent A to the ethyl difluoroacetoacetate in the step 1) is 2-4: 1, and the volume usage of the organic solvent B is 0.3-0.8 ml/mmol based on the mass of the ethyl difluoroacetoacetate; the volume dosage of the organic reagent C in the step 3) is 0.5-1.0 ml/mmol based on the amount of the 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid shown in the formula (III); the volume usage amount of the organic reagent D in the step 4) is 5-8 ml/mmol based on the substance amount of (2- (3- (difluoromethyl) -1-methyl-1H-pyrazole-4-formamido) ethyl) carbamic acid tert-butyl ester shown in a formula (IV); the volume usage amount of the organic reagent E in the step 5) is 5-8 ml/mmol based on the amount of the N- (2-aminoethyl) -3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxamide shown in the formula (V).

The preparation method of the N- (2-benzamide) -1H-pyrazole-4-formamide compound is characterized in that eluents for column chromatography separation in the steps 3), 4) and 5) are mixed liquid of ethyl acetate and petroleum ether in a volume ratio of 1: 0.5-2.

The N- (2-benzamide) -1H-pyrazole-4-formamide compound is applied to preparation of a bactericide.

The synthetic process route of the N- (2-benzamide) -3- (difluoromethyl) -1-methyl-1H-pyrazole-4-formamide compound is as follows:

compared with the prior art, the invention has the following beneficial effects: the invention provides an N- (2-benzamide) -3- (difluoromethyl) -1-methyl-1H-pyrazole-4-formamide compound, a preparation method thereof and application thereof in preparing a bactericide, the preparation method is simple, the operation is convenient, the obtained compound has the best inhibition activity on rhizoctonia solani under the concentration of 50ppm, and the inhibition rate reaches 54.3%.

Detailed Description

The present invention is further illustrated by the following examples, which should not be construed as limiting the scope of the invention.