CN113912541A - Preparation method of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid - Google Patents
Preparation method of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid Download PDFInfo
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- CN113912541A CN113912541A CN202111271056.7A CN202111271056A CN113912541A CN 113912541 A CN113912541 A CN 113912541A CN 202111271056 A CN202111271056 A CN 202111271056A CN 113912541 A CN113912541 A CN 113912541A
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- methyl
- carboxylic acid
- pyrazole
- difluoromethyl
- difluoroacetyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
Abstract
The invention discloses a preparation method of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid, which comprises the following steps of synthesizing 2-difluoroacetyl-3- (dimethylamino) ethyl acrylate; step two, synthesizing 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid. The product of the invention is mainly used for synthesizing the fluorine-containing pyrazole amide bactericide, difluoroacetyl chloride is used as a raw material, the obtained yield is relatively high, and the total yield is more than 85%. The methyl hydrazine can be used for closing the ring, and the methyl on dimethyl carbonate can be used for closing the ring by using hydrazine hydrate.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a preparation method of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid.
Background
The fluorine-containing pyrazole amide bactericides contain acylamino in the aspect of chemical structures, the newly developed bactericides are derived by carrying out group substitution on the basis of the existing bactericides, nearly 20 varieties of the developed bactericides exist, for example, products mainly taking carboxin, flutolanil, fluopyram, thifluzamide and the like as effective components, the bactericides are used for fungal diseases on a plurality of crops, and the bactericides become important bactericide varieties in production. However, in recent years, the problem of fungicide resistance has been increasingly highlighted due to the long-term use of conventional fungicides, and therefore, it is very important to find a new mechanism of action to develop the existing fungicides to solve the existing problems.
Disclosure of Invention
The purpose of the invention is as follows: in order to solve the defects of the prior art, the invention provides a preparation method of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid.
The technical scheme is as follows: a preparation method of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid comprises the following steps:
step one, synthesis of 2-difluoroacetyl-3- (dimethylamino) ethyl acrylate: putting N, N-dimethylamino ethyl acrylate, triethylamine and toluene into a reaction kettle, controlling the temperature to be-5 ℃, dropwise adding difluoroacetyl chloride, stirring for 3 hours at room temperature, washing, layering and distilling under reduced pressure after the detection raw materials react to obtain 2-difluoroacetyl-3- (dimethylamino) ethyl acrylate;
step two, synthesis of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid: putting methyl hydrazine and water into a reaction kettle, controlling the temperature to be-5 ℃, dropwise adding 2-difluoroacetyl-3- (dimethylamino) ethyl acrylate, after the reaction is finished, extracting with toluene, and distilling under reduced pressure to obtain difluoropyrazole carboxylic acid ethyl ester; and adding sodium hydroxide for hydrolysis, acidifying with hydrochloric acid, cooling to 0 ℃, stirring for 1 hour, carrying out suction filtration, washing the obtained solid with ice water, and drying to obtain the product 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid.
As an optimization: in the first step, no distillation is needed, and the organic phase obtained by layering is directly subjected to ring closing by using methylhydrazine.
As an optimization: and in the second step, sodium iodide or potassium iodide is selected as the catalyst.
As an optimization: the alcohol solvent in the second step is selected from methanol, ethanol or isopropanol.
Has the advantages that: the product of the invention is mainly used for synthesizing fluorine-containing pyrazole amide bactericides, such as: the method is characterized in that the pyrazolonaphthoramide, bixafen, fluxapyroxad and cyprodinil (epoxiconazole) are used as raw materials, difluoroacetyl chloride is used as the raw material, the yield is high, and the total yield is over 85 percent. The methyl hydrazine can be used for closing the ring, and the methyl on dimethyl carbonate can be used for closing the ring by using hydrazine hydrate. The raw material cost is estimated to be 26 million (difluoroacetyl chloride at 25 million/ton).
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below so that those skilled in the art can better understand the advantages and features of the present invention, and thus the scope of the present invention will be more clearly defined. The embodiments described herein are only a few embodiments of the present invention, rather than all embodiments, and all other embodiments that can be derived by one of ordinary skill in the art without inventive faculty based on the embodiments described herein are intended to fall within the scope of the present invention.
Examples
A preparation method of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid comprises the following steps:
step one, synthesis of 2-difluoroacetyl-3- (dimethylamino) ethyl acrylate: putting N, N-dimethylamino ethyl acrylate, triethylamine and toluene into a reaction kettle, controlling the temperature to be-5 ℃, dropwise adding difluoroacetyl chloride, stirring for 3 hours at room temperature, washing, layering and distilling under reduced pressure after the detection raw materials react to obtain 2-difluoroacetyl-3- (dimethylamino) ethyl acrylate; or, in the first step, the organic phase obtained by layering is directly closed by methyl hydrazine without distillation.
Step two, synthesis of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid: putting methyl hydrazine and water into a reaction kettle, controlling the temperature to be-5 ℃, dropwise adding 2-difluoroacetyl-3- (dimethylamino) ethyl acrylate, after the reaction is finished, extracting with toluene, and distilling under reduced pressure to obtain difluoropyrazole carboxylic acid ethyl ester; and adding sodium hydroxide for hydrolysis, acidifying with hydrochloric acid, cooling to 0 ℃, stirring for 1 hour, carrying out suction filtration, washing the obtained solid with ice water, and drying to obtain the product 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid. Wherein, the catalyst is selected from sodium iodide or potassium iodide. The alcohol solvent is selected from methanol, ethanol or isopropanol.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
A preparation method of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid comprises the following steps:
step one, synthesis of 2-difluoroacetyl-3- (dimethylamino) ethyl acrylate: adding N, N-dimethylamino ethyl acrylate, triethylamine and toluene into a reaction kettle, wherein the molar ratio of the N, N-dimethylamino ethyl acrylate to the triethylamine is 1: 1.2, controlling the temperature to be-5-0 ℃, dropwise adding difluoroacetyl chloride, stirring for 3 hours at room temperature, washing for 3 times by using water after the detection raw materials react, standing for layering, and carrying out reduced pressure distillation on an organic phase to obtain 2-difluoroacetyl-3- (dimethylamino) ethyl acrylate;
or, in the first step, distillation is not needed, and the organic phase obtained by layering is directly subjected to ring closing by using methylhydrazine;
step two, synthesis of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid: putting methyl hydrazine and water into a reaction kettle, controlling the temperature to be-5 ℃, dropwise adding 2-difluoroacetyl-3- (dimethylamino) ethyl acrylate, after the reaction is finished, extracting with toluene, and distilling under reduced pressure to obtain difluoropyrazole carboxylic acid ethyl ester; and adding 1000g of 10% sodium hydroxide for hydrolysis, adding dichloromethane for extracting impurities, standing for layering, adjusting the pH value to 1-2 by using hydrochloric acid, cooling to 0 ℃, stirring for 1 hour, performing suction filtration, washing the obtained solid by using ice water, and drying to obtain the product 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid. The reaction yield was 72%.
Specifically, the chemical formula of the invention is as follows:
the product of the invention is mainly used for synthesizing fluorine-containing pyrazole amide bactericides, such as: the method is characterized in that the pyrazolonaphthoramide, bixafen, fluxapyroxad and cyprodinil (epoxiconazole) are used as raw materials, difluoroacetyl chloride is used as the raw material, the yield is high, and the total yield is over 85 percent. The methyl hydrazine can be used for closing the ring, and the methyl on dimethyl carbonate can be used for closing the ring by using hydrazine hydrate. The raw material cost is estimated to be 26 million (difluoroacetyl chloride at 25 million/ton).
Claims (4)
1. A preparation method of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid is characterized in that: the method comprises the following steps:
step one, synthesis of 2-difluoroacetyl-3- (dimethylamino) ethyl acrylate: putting N, N-dimethylamino ethyl acrylate, triethylamine and toluene into a reaction kettle, controlling the temperature to be-5 ℃, dropwise adding difluoroacetyl chloride, stirring for 3 hours at room temperature, washing, layering and distilling under reduced pressure after the detection raw materials react to obtain 2-difluoroacetyl-3- (dimethylamino) ethyl acrylate;
step two, synthesis of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid: putting methyl hydrazine and water into a reaction kettle, controlling the temperature to be-5 ℃, dropwise adding 2-difluoroacetyl-3- (dimethylamino) ethyl acrylate, after the reaction is finished, extracting with toluene, and distilling under reduced pressure to obtain difluoropyrazole carboxylic acid ethyl ester; and adding sodium hydroxide for hydrolysis, acidifying with hydrochloric acid, cooling to 0 ℃, stirring for 1 hour, carrying out suction filtration, washing the obtained solid with ice water, and drying to obtain the product 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid.
2. The process for the preparation of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid according to claim 1, characterized in that: in the first step, no distillation is needed, and the organic phase obtained by layering is directly subjected to ring closing by using methylhydrazine.
3. The process for the preparation of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid according to claim 1, characterized in that: the alkali used for water washing hydrolysis is selected from sodium hydroxide and potassium hydroxide.
4. The process for the preparation of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid according to claim 1, characterized in that: the molar ratio of the catalyst to the methylhydrazine is 1: 0.1 to 1.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117384096A (en) * | 2023-12-13 | 2024-01-12 | 山东国邦药业有限公司 | Preparation method of difluoro pyrazole acid |
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| CN1871204A (en) * | 2003-10-23 | 2006-11-29 | 拜尔农作物科学股份公司 | Method for producing 2-dihaloacyl-3-amino-acrylic acid esters and 3-dihalomethyl-pyrazole-4-carboxylic acid esters |
| CN102731402A (en) * | 2012-06-29 | 2012-10-17 | 上海康鹏化学有限公司 | Preparation method of 3-trifluoromethylpyrazole-4-carboxylic acid and 3-difluoromethylpyrazole-4-carboxylic acid |
| CN107987021A (en) * | 2017-11-24 | 2018-05-04 | 上海应用技术大学 | A kind of preparation method of 3- difluoromethyls -1- methyl isophthalic acids H- pyrazoles -4- carboxylic acids |
| CN108368055A (en) * | 2015-09-28 | 2018-08-03 | 苏威氟有限公司 | The preparation method of 3- fluoro-alkyl -1- methylpyrazole -4- carboxylic acids |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1871204A (en) * | 2003-10-23 | 2006-11-29 | 拜尔农作物科学股份公司 | Method for producing 2-dihaloacyl-3-amino-acrylic acid esters and 3-dihalomethyl-pyrazole-4-carboxylic acid esters |
| CN102731402A (en) * | 2012-06-29 | 2012-10-17 | 上海康鹏化学有限公司 | Preparation method of 3-trifluoromethylpyrazole-4-carboxylic acid and 3-difluoromethylpyrazole-4-carboxylic acid |
| CN108368055A (en) * | 2015-09-28 | 2018-08-03 | 苏威氟有限公司 | The preparation method of 3- fluoro-alkyl -1- methylpyrazole -4- carboxylic acids |
| CN107987021A (en) * | 2017-11-24 | 2018-05-04 | 上海应用技术大学 | A kind of preparation method of 3- difluoromethyls -1- methyl isophthalic acids H- pyrazoles -4- carboxylic acids |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117384096A (en) * | 2023-12-13 | 2024-01-12 | 山东国邦药业有限公司 | Preparation method of difluoro pyrazole acid |
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