阅读说明：本技术 3-(二氟甲基)-1-甲基-1h-吡唑-4-羧酸酯类化合物及其制备方法和应用 (3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic ester compound and preparation method and application thereof ) 是由 刘幸海 蔡彭鹏 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3-(二氟甲基)-1-甲基-1<I>H</I>-吡唑-4-羧酸酯类化合物及其制备方法和应用。3-(二氟甲基)-1-甲基-1<I>H</I>-吡唑-4-羧酸酯类化合物,即2-(苯甲酰氧基)乙基3-(二氟甲基)-1-甲基-1<I>H</I>-吡唑-4-羧酸酯类化合物,其结构式如式(Ⅰ)所示：<Image he="185" wi="326" file="DEST_PATH_IMAGE002.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>式(Ⅰ)中：取代基R为苯基或取代苯基,所述取代苯基的苯环上的取代基为卤素或C1-C3烷基。本发明公开的2-(苯甲酰氧基)乙基3-(二氟甲基)-1-甲基-1<I>H</I>-吡唑-4-羧酸酯类化合物为具有杀菌活性的新化合物,其在50ppm浓度下对小麦赤霉病菌有较好的抑制率,为新农药的研发提供了基础。(The invention discloses 3- (difluoromethyl) -1-methyl-1 H -pyrazole-4-carboxylic ester compounds, and preparation methods and applications thereof. 3- (difluoromethyl) -1-methyl-1 H Pyrazole-4-carboxylic acid esters, i.e. 2- (benzoyloxy) ethyl 3- (difluoromethyl) -1-methyl-1 H -pyrazole-4-carboxylic acid esters of formula (i): in formula (I): and the substituent R is phenyl or substituted phenyl, and the substituent on the benzene ring of the substituted phenyl is halogen or C1-C3 alkyl. The invention discloses 2- (benzoyloxy) ethyl 3- (difluoromethyl) -1-methyl-1 H -pyrazole-4-carboxylic acidThe ester compound is a new compound with bactericidal activity, has better inhibition rate on wheat scab germs at the concentration of 50ppm, and provides a foundation for the research and development of new pesticides.)

1. A3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic ester compound, namely a 2- (benzoyloxy) ethyl 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic ester compound, is characterized in that the structural formula is shown as the formula (I):

in formula (I): and the substituent R is phenyl or substituted phenyl, and the substituent on the benzene ring of the substituted phenyl is halogen or C1-C3 alkyl.

2. 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid ester compounds according to claim 1, wherein R in formula (i) is one of the following: 2-tolyl group, 3-fluorophenyl group, phenyl group.

3. The process for producing a 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid ester compound according to claim 1 or 2, which comprises 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, concentrating to remove the solvent after the reaction is finished, stirring the concentrated residue, ethylene glycol and triethylamine in an organic solvent C at room temperature to react, 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 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid 2-hydroxyethyl ester shown in the formula (IV);

4) stirring and mixing the 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid 2-hydroxyethyl ester shown in the formula (IV) obtained in the step 3), an organic solvent D and triethylamine uniformly, then dropwise adding substituted benzoyl chloride, stirring and reacting at room temperature, tracking the reaction process by TLC, removing the solvent by rotary evaporation and concentration after the reaction is finished, and purifying the rotary evaporation and concentration residue by column chromatography separation to obtain the 2- (benzoyloxy) ethyl 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid ester compound shown in the formula (I);

wherein, the substituent on the benzene ring of the substituted benzoyl chloride is H, halogen or C1-C3 alkyl.

4. The process for preparing 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid esters according to claim 3, wherein in step 1), the organic solvent A is acetic anhydride, and the organic solvent B is ethanol; the organic solvent C in the step 3) and the organic solvent D in the step 4) are both dichloromethane.

5. The method for preparing 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid ester compounds according to claim 3, wherein the molar ratio of ethyl difluoroacetoacetate, triethyl orthoformate and methylhydrazine added in step 1) is 1: 1.1-1.5.

6. The method for preparing 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid ester compounds according to claim 3, wherein in step 3), the feeding molar ratio of 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid represented by formula (III) to ethylene glycol is 1: 1.2-2; in the step 4), the feeding molar ratio of the 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid 2-hydroxyethyl ester shown in the formula (IV) to the substituted benzoyl chloride is 1: 1.05-1.3.

7. The method for preparing 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid ester compounds according to claim 3, wherein the molar ratio of the organic solvent A to ethyl difluoroacetoacetate in the step 1) is 2.5-4: 1; the volume usage amount of the organic solvent B in the step 1) is 0.4-0.8 mL/mmol based on the amount of the ethyl difluoroacetoacetate.

8. The method for producing a 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid ester compound according to claim 3, wherein the volume of the organic solvent C used in step 3) is 0.6 to 1.0mL/mmol, based on the amount of the 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid represented by formula (III); the volume usage amount of the organic solvent D in the step 4) is 5-8 mL/mmol based on the amount of the 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid 2-hydroxyethyl ester shown in the formula (IV).

9. The method for preparing 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid ester compounds according to claim 3, wherein eluents for column chromatography separation in step 3) and step 4) are mixed solution of ethyl acetate and petroleum ether in a volume ratio of 1: 0.5-2.

10. Use of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid esters according to claim 1 or 2 for the preparation of fungicides.

Technical Field

The invention relates to a 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic ester compound and a preparation method and application thereof.

Background

Nowadays, pyrazole ester compounds usually have excellent and wide biological activity such as low toxicity, high efficiency and the like due to containing high-activity structural groups such as pyrazole, ester group and the like, and a pyrazole ring is an important member of nitrogen-containing heterocycles, has very unique structural form, and has high biological activity to various microorganisms, pathogenic factors and diseases, so that the pyrazole ester 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. Although the appearance of the bactericide with an ester group structure is relatively late, the bactericide has occupied an extremely important position in the field of the bactericide since the advent, and the methoxy acrylate bactericide is the first of the global sterilization market to surpass triazoles in 2016. 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 diester bactericide 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 a 2- (benzoyloxy) ethyl 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic ester compound and a preparation method and application thereof. The invention designs and synthesizes a series of compounds such as pyrazole diester and the like based on the structure of SDH inhibitors such as fluxapyroxad and the like, introduces extension and substituted benzoyl oxygen and the like by taking a pyrazole ester 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 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic ester compound is a 2- (benzoyloxy) ethyl 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic ester compound, and is characterized in that the structural formula is shown as the formula (I):

in formula (I): and the substituent R is phenyl or substituted phenyl, and the substituent on the benzene ring of the substituted phenyl is halogen or C1-C3 alkyl.

The 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic ester compound is characterized in that R in the formula (I) is one of the following compounds: 2-tolyl group, 3-fluorophenyl group, phenyl group.

The preparation method of the 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic ester compound is characterized by comprising the following 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, concentrating to remove the solvent after the reaction is finished, stirring the concentrated residue, ethylene glycol and triethylamine in an organic solvent C at room temperature to react, 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 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid 2-hydroxyethyl ester shown in the formula (IV);

4) stirring and mixing the 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid 2-hydroxyethyl ester shown in the formula (IV) obtained in the step 3), an organic solvent D and triethylamine uniformly, then dropwise adding substituted benzoyl chloride, stirring and reacting at room temperature, tracking the reaction process by TLC, removing the solvent by rotary evaporation and concentration after the reaction is finished, and purifying the rotary evaporation and concentration residue by column chromatography separation to obtain the 2- (benzoyloxy) ethyl 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid ester compound shown in the formula (I);

wherein, the substituent on the benzene ring of the substituted benzoyl chloride is H, halogen or C1-C3 alkyl.

The preparation method of the 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic ester compound is characterized in that in the step 1), an organic solvent A is acetic anhydride, and an organic solvent B is ethanol; the organic solvent C in the step 3) and the organic solvent D in the step 4) are both dichloromethane.

The preparation method of the 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic ester 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 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic ester 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 ethylene glycol is 1: 1.2-2; in the step 4), the feeding molar ratio of the 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid 2-hydroxyethyl ester shown in the formula (IV) to the substituted benzoyl chloride is 1: 1.05-1.3.

The preparation method of the 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic ester compound is characterized in that the molar ratio of the organic solvent A to the ethyl difluoroacetoacetate in the step 1) is 2.5-4: 1; the volume usage amount of the organic solvent B in the step 1) is 0.4-0.8 mL/mmol based on the amount of the ethyl difluoroacetoacetate.

The preparation method of the 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic ester compound is characterized in that the volume usage of the organic solvent C in the step 3) is 0.6-1.0 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 solvent D in the step 4) is 5-8 mL/mmol based on the amount of the 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid 2-hydroxyethyl ester shown in the formula (IV).

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

The 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic ester compound is applied to the preparation of bactericides.

The synthetic reaction route of the 2- (benzoyloxy) ethyl 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic ester compound is as follows:

compared with the prior art, the invention has the following beneficial effects: the invention provides a 2- (benzoyloxy) ethyl 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic ester compound, a preparation method thereof and application thereof in preparing a bactericide, wherein the preparation method is simple and convenient to operate, and the obtained compound has a good inhibition rate on wheat scab germs at a concentration of 50 ppm. The compound provided by the invention is a new compound with bactericidal activity, and provides a foundation for the research and development of new pesticides.

Detailed Description

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