CN115160226A - A kind of method for preparing bixafen by one-step condensation method - Google Patents

Abstract

The invention discloses a method for preparing bixafen by a one-step condensation method. 1-methyl-3-difluoromethyl-1H-pyrazole-4-formic acid is used as a raw material, in an organic solvent, in an alkali and a Under the action of the catalyst, it reacts with 3',4'-dichloro-5-fluoro-2-benzidine hydrochloride, and condenses in one step to generate bixafen, and after post-processing, the product bixafen is obtained. The present invention uses methylsulfonyl chloride etc. as the condensation catalyst of acid and amine to carry out amidation one-pot reaction, so that the original two-step reaction is combined in one kettle to complete, both the reaction steps and the post-treatment process are greatly simplified, and the technological operation is convenient , high safety, shortens the process cycle; the invention avoids and reduces the production of polluting gases such as sulfur dioxide, hydrogen chloride, etc. and a large number of complicated post-treatment processes in the existing process, effectively reduces the generation of waste acid, waste water, waste gas and other three wastes, production process It is more concise, safe, clean and environmentally friendly, and is more suitable for industrial production.

Description

A kind of method for preparing bixafen by one-step condensation method

technical field

The invention belongs to the technical field of fine chemical synthesis, relates to the synthesis of a pesticide and fungicide, and in particular relates to a method for preparing bixafen by a one-step condensation method.

Background technique

Bixafen is a pyrazole amide fungicide developed by Bayer CropScience and is an important member of the fastest growing succinate dehydrogenase inhibitor (SDHI) class of fungicides. In 2018, the sales of bixafen were US$265 million; in 2019, the sales were US$276 million. Bixafen is a blockbuster fungicide jointly created by Bayer and FMC, and has now become one of the SDHI sterilizers. Among the top four pharmaceutical agents, the annual peak sales of bixafen will exceed 300 million euros. It has good promotion prospects in both wheat and corn in the future.

Synthesis of bixafen with 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid and 3',4'-dichloro-3-fluoro-biphenyl-2-amine Amidation obtained. There is a big defect in the traditional synthesis process. The traditional synthesis method is divided into two-step reactions, using 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid as a raw material to conduct acid chloride with thionyl chloride in a solvent. 1-methyl-3-difluoromethyl-1H-pyrazole-4-formyl chloride is obtained first; then in solvent, alkali, etc. Under the conditions, 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride is reacted with 3′,4′-dichloro-5-fluoro-2-benzidine to generate bixafen, The finished product of bixafen is obtained after hydrolyzing and washing with water, separating liquids, steaming the organic phase under reduced pressure, and crystallizing. The traditional process is a two-step reaction, both the feeding reaction and the post-processing operation are very cumbersome, not only the reaction and post-processing (such as atmospheric and vacuum distillation, etc.) process requires high temperature, but also the reaction produces a large amount of acidic waste gas sulfur dioxide SO ₂ and hydrogen chloride tail gas, the environment is not good. Friendly; in addition, the thionyl chloride used in the reaction is highly corrosive and easy to corrode equipment, which increases the production cost invisibly.

Acylation of 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid with thionyl chloride to form 1-methyl-3-difluoromethyl-1H-pyrazole-4-methyl Acyl chloride, and by-product HCl and sulfur dioxide, its reaction equation is as follows:

1-Methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride reacts with 3′,4′-dichloro-5-fluoro-2-benzidine to generate bixafen and by-product HCl and alkali form salt, and its reaction equation is as follows:

Therefore, there is an urgent need to find a more efficient and simple method to synthesize bixafen, so that the synthesis of bixafen is safer, more concise and environmentally friendly.

SUMMARY OF THE INVENTION

For the deficiencies in the prior art, the object of the present invention is to provide a method for preparing bixafen by a one-step condensation method, the present invention uses methylsulfonyl chloride etc. as the condensation catalyst of acid and amine to carry out amidation one-pot reaction, The original two-step reaction is combined into one kettle to complete, both the reaction steps and the post-treatment process are greatly simplified, the process operation is convenient, the safety is high, and the process cycle is shortened.

The present invention is achieved through the following technical solutions:

A method for preparing bixafen by a one-step condensation method, using 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid as a raw material, in an organic solvent, under the action of a base and a catalyst , reacts with 3',4'-dichloro-5-fluoro-2-benzidine hydrochloride, and condenses in one step to generate bixafen, and after post-processing, the product bixafen is obtained.

The chemical reaction equation is as follows:

The reaction mechanism of the present invention is as follows:

A further improvement scheme of the present invention is:

The catalyst is methylsulfonyl chloride or N,N'-carbonyldiimidazole or a mixture of the two, preferably, the catalyst is methylsulfonyl chloride.

Further, the feeding method of the catalyst is dropwise addition at a uniform speed, batch feeding, or the form of a solution configured with a reaction solvent and then added dropwise to the reaction system. Preferably, the catalyst feeding method is dropwise addition at a uniform speed.

Further, the organic solvent is a mixture of one or more of dichloromethane, dichloroethane, tetrahydrofuran, acetonitrile, toluene, xylene, chlorobenzene or methylcyclohexane.

Further, the 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid, 3',4'-dichloro-5-fluoro-2-benzidine hydrochloride, catalyst and base The molar ratio is 1:(1.00~1.10):(1.15~1.5):(3.00~6.00), and the organic solvent and 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid have a The mass ratio of feeding materials is (2~10): 1; preferably, the 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid, 3′,4′-dichloro-5-fluoro The molar ratio of -2-benzidine hydrochloride, catalyst and base is 1:(1.00~1.005):(1.15~1.30):(3.10~4.00).

Further, the base is one or a mixture of substituted or unsubstituted triethylamine, pyridine and DMAP, preferably, the base is triethylamine.

Further, the base is an inorganic base, and a phase transfer catalyst needs to be added to the reaction system, and the charging mole of the phase transfer catalyst is 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid. 0.30% to 3.00% of the molar amount.

Further, the alkali is one or more mixtures of potassium carbonate, potassium bicarbonate, sodium carbonate or sodium bicarbonate.

Further, the phase transfer catalyst is tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium hydrogen sulfate, benzyltriethylammonium chloride, dodecyltrimethylammonium chloride, One or more mixtures of methyltributylammonium chloride, PEG400, PEG600, PEG1000, polyethylene glycol dialkyl ether, 18-crown-6, 15-crown-5 or cyclodextrin ; Preferably, the phase transfer catalyst is tetrabutylammonium bromide.

Further, during the material mixing process, the temperature of the system is controlled to be 0-30°C, the reaction temperature is controlled to be 10-30°C after the feeding is completed, and the reaction time is 1-6h.

Further, the described post-processing methods are processes such as adding water, washing, standing for stratification, concentrating the organic layer under reduced pressure, adding a crystallization solvent for cooling crystallization, filtration, washing, and vacuum drying, which are well known to those skilled in the art.

Compared with the prior art, the beneficial effects of the present invention are:

1, the present invention uses methanesulfonyl chloride etc. as condensation catalysts to promote acid and amine to carry out amidation one-pot reaction, so that the original two-step reaction is merged in one kettle to complete, no matter reaction step or post-processing process is greatly simplified, The process is easy to operate, has high safety, and shortens the process cycle. The content of the product is over 97%, and the yield can be as high as about 92%, which is a big improvement over the existing large-scale production yield of about 72%;

2. The present invention avoids and reduces the use of acid chloride reagents such as thionyl chloride and other acid chlorination reagents to generate acid chloride intermediates in the existing process, and the acid chlorination process produces polluting gases such as sulfur dioxide, hydrogen chloride, etc. and a large number of complicated post-processing processes such as intermediates. Acyl chloride vacuum distillation concentration, corrosive intermediate acid chloride transfer, etc., effectively reduce the generation of waste acid, waste water, waste gas and other three wastes, the production process is more concise, safe, clean and environmentally friendly, and is more suitable for industrial production.

Detailed ways

Example 1

In a 1000mL reaction flask, a stirring, a thermometer and a condensing reflux tube were installed, 400 g of an organic solvent dichloromethane was added to the reactor, the stirring was turned on, the stirring speed was adjusted, the temperature was cooled to 10 ° C, and the raw material 1-methyl-3- Difluoromethyl-1H-pyrazole-4-carboxylic acid 66g, triethylamine 120g, stir and mix evenly, slowly add 55.0g of condensation catalyst methylsulfonyl chloride into the reactor, control the reaction temperature at 20～25℃, 1.0 h dropwise addition was completed. After the dropwise addition was completed, the temperature was maintained at 20-25°C and the reaction was continued for 1.5h, and 108 g of 3',4'-dichloro-5-fluoro-2-benzidine hydrochloride was added in batches, and the addition was completed at 20-25°C. Incubate the reaction for 2.0h, sample and analyze, after the reaction is qualified, slowly add 100ml of water to the reactor, let stand for stratification, the organic phase is decompressed and desolubilized, add 150ml of crystallization solvent, cool down to 0°C, filter, wash, and vacuum dry The product bixafen 142.37 g was obtained with a content of 98.3% (HPLC) and a yield of 90.1%.

Example 2

In a 1000mL reaction flask, a stirring, a thermometer and a condensing reflux tube were installed, 350 g of organic solvent dichloromethane was added to the reactor, the stirring was turned on, the stirring speed was adjusted, the temperature was cooled to 5°C, and the raw material 1-methyl-3- Difluoromethyl-1H-pyrazole-4-carboxylic acid 66g, triethylamine 125g, stir and mix evenly, slowly add 58.70g of condensation catalyst methylsulfonyl chloride dropwise to the reactor, control the reaction temperature at 10～15℃, 1h The dropwise addition was completed. After the dropwise addition was completed, the temperature was maintained at 20-25 °C and the reaction was continued for 2 h, and 108 g of 3',4'-dichloro-5-fluoro-2-benzidine hydrochloride was added in batches, and the temperature was kept at 20-25 °C after the dropping was completed. The reaction was carried out for 2.5 hours, sampling and analysis. After the reaction was qualified, 100 ml of water was slowly added to the reactor, and the layers were left to stand for decompression. The organic phase was de-dissolved under reduced pressure. The product bixafen was 145.07 g, the content was 98.5% (HPLC), and the yield was 92.0%.

Example 3

In a 1000mL reaction flask, a stirring, a thermometer and a condensation reflux tube were installed, 500 g of organic solvent dichloroethane was added to the reactor, the stirring was turned on, the stirring speed was adjusted, the temperature was cooled to 5°C, and the raw material 1-methyl-3 was added. - Difluoromethyl-1H-pyrazole-4-carboxylic acid 66g, potassium carbonate 185g and phase transfer catalyst tetrabutylammonium bromide 2g, stir and mix well, slowly add condensation catalyst methanesulfonyl chloride 50.0g into the reactor , control the reaction temperature at 25 ~ 30 ℃, 1h dropwise completion. After the dropwise addition was completed, the temperature was maintained at 25-30 °C and the reaction was continued for 1.5 h, and 108 g of 3',4'-dichloro-5-fluoro-2-benzidine hydrochloride was added in batches, and the addition was completed at 20-25 °C. Incubate the reaction for 2 hours, sample and analyze, after the reaction is qualified, slowly add 200 ml of water to the reactor, let stand for stratification, the organic phase is decompressed and desolubilized, add 100 ml of crystallization solvent, cool down to 5 ° C, suction filtration, washing, and vacuum drying to obtain The product bixafen was 137.58 g, the content was 98.0% (HPLC), and the yield was 86.8%.

Claims (10)

1. A method for preparing bixafen by a one-step condensation method is characterized in that 1-methyl-3-difluoromethyl-1H-pyrazole-4-formic acid is used as a raw material and reacts with 3',4' -dichloro-5-fluoro-2-benzidine hydrochloride in an organic solvent under the action of alkali and a catalyst to generate the bixafen by one-step condensation, and the product of the bixafen is obtained by post-treatment.

2. The method for preparing bixafen by a one-step condensation method according to claim 1, characterized in that: the catalyst is methylsulfonyl chloride or N, N' -carbonyldiimidazole or a mixture of the two.

3. The method for preparing bixafen by a one-step condensation process according to any one of claims 1 or 2, characterized in that: the catalyst is added in a constant speed dropwise adding mode, a batch feeding mode or a mode of preparing a solution by using a reaction solvent and then dropwise adding the solution to a reaction system.

4. The method for preparing bixafen by a one-step condensation method according to claim 1, characterized in that: the organic solvent is a mixture of more than two of dichloromethane, dichloroethane, tetrahydrofuran, acetonitrile, toluene, xylene, chlorobenzene or methylcyclohexane.

5. The method for preparing bixafen by the one-step condensation method according to claim 1, characterized by comprising the following steps: the molar ratio of the 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid to the 3',4' -dichloro-5-fluoro-2-benzidine hydrochloride to the catalyst to the base is 1 (1.00 to 1.10) to (1.15 to 1.5) to (3.00 to 6.00); the mass ratio of the organic solvent to the 1-methyl-3-difluoromethyl-1H-pyrazole-4-formic acid is (2 to 10) to 1.

6. The method for preparing bixafen by a one-step condensation method according to claim 1, characterized in that: the alkali is one or more than two of substituted or unsubstituted triethylamine, pyridine and DMAP.

7. The method for preparing bixafen by a one-step condensation method according to claim 1, characterized in that: the alkali is inorganic alkali, a phase transfer catalyst is required to be added into a reaction system, and the feeding mole of the phase transfer catalyst is 0.30-3.00% of the mole amount of 1-methyl-3-difluoromethyl-1H-pyrazole-4-formic acid.

8. The method for preparing bixafen by a one-step condensation method according to claim 7, characterized in that: the alkali is one or more of potassium carbonate, potassium bicarbonate, sodium carbonate or sodium bicarbonate.

9. The method for preparing bixafen by a one-step condensation method according to claim 7, characterized in that: the phase transfer catalyst is one or more of tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium hydrogen sulfate, benzyltriethylammonium chloride, dodecyltrimethylammonium chloride, methyltributylammonium chloride, PEG400, PEG600, PEG1000, polyethylene glycol dialkyl ether, 18-crown-6, 15-crown-5 or cyclodextrin.

10. The method for preparing bixafen by a one-step condensation method according to claim 1, characterized in that: in the process of mixing materials, the temperature of the system is controlled to be 0 to 30 ℃, the reaction temperature is controlled to be 10 to 30 ℃ after the feeding is finished, and the reaction time is 1 to 6 hours.