A method for synthesizing fluopyram

Abstract

This invention discloses a method for synthesizing fluopyram. The method involves reacting diethyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)malonate with dihalomethane in the presence of a polar aprotic solvent and an inorganic base to obtain diethyl 2-halomethyl-2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)malonate, followed by condensation with 2-trifluoromethylbenzamide to obtain diethyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-2-((2-(trifluoromethane)benzoylamino)methyl)malonate. After adjusting the pH of the reaction system to 4-5, the temperature is increased to induce a decarboxylation reaction, yielding fluopyram. This invention employs a simple one-pot process, which is convenient to operate, has a high yield, and low cost, making it suitable for industrial production.

Description

Technical Field

[0001] This invention relates to a method for synthesizing fluopyram, belonging to the field of organic synthesis technology. Background Technology

[0002] Fluopyram, chemically named N-(2-(3-chloro-5-(trifluoromethyl)-2-pyridyl)ethyl)-2-trifluoromethylbenzamide, is a novel benzamide fungicide developed by Bayer Crop Science. It inhibits mitochondrial respiration by blocking electron transfer from succinate dehydrogenase in the respiratory chain, thereby suppressing spore germination, germination tube growth, mycelial growth, and spore formation. Fluopyram is mainly used to control gray mold, powdery mildew, late blight, downy mildew, and rice blast caused by fungal pathogens, and has broad application prospects. Molecular formula: C 16 H 11 ClF6N2O, with the following structural formula:

[0003] The main synthetic methods reported so far are as follows: Patents WO2004016088A3 and CN1674784A disclose a method using 2,3-dichloro-5-trifluoromethylpyridine as a raw material, which involves condensation and hydrolysis with ethyl cyanoacetate to obtain 2-cyanomethyl-3-chloro-5-trifluoromethylpyridine, followed by palladium-catalyzed hydrogenation reduction to obtain 2-aminoethyl-3-chloro-5-trifluoromethylpyridine, and finally amide condensation with o-trifluoromethylbenzoyl chloride to obtain fluopyram. This route involves a long reaction process, requires palladium-carbon catalysis for cyano hydrogenation reduction, is complex, has low yield, and relatively high cost. Furthermore, the amino group requires protection and deprotection, making the operation more cumbersome and unsuitable for industrialization.

[0004] The reaction equation is:

[0005] Patents CN109293565B and CN110437139A improved this route by simultaneously reducing the cyano group to an amino group and protecting it with o-trifluoromethylbenzoyl chloride, o-trifluoromethylbenzoic anhydride, or o-trifluoromethylbenzoic acid-pentanoic anhydride to obtain fluopyram. This method simplifies the process, but still requires the use of the precious metal catalyst palladium on carbon, resulting in high production costs. Furthermore, o-trifluoromethylbenzoyl chloride and o-trifluoromethylbenzoic anhydride are highly reactive and prone to side reactions, leading to lower fluopyram content.

[0006] Patents WO2006067103A3 and CN108822024B report a method using o-trifluoromethylbenzoic acid as a raw material, which involves acylation, amidation, hydroxymethylation, and esterification to obtain (2-(trifluoromethyl)benzoamido)methyl acetate. The (2-(trifluoromethyl)benzoamido)methyl acetate then undergoes a condensation reaction with diethyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)malonate, and finally, high-temperature decarboxylation yields fluopyram technical. This method is lengthy, the intermediate product is difficult to separate and purify, and there are many byproducts, making it unsuitable for industrial production. Patent CN116854629A reports a similar method, only replacing the intermediate (2-(trifluoromethyl)phenylamino)methyl acetate with N-(chloromethyl)-2-(trifluoromethyl)benzamide. This method also suffers from unstable intermediate products, difficulty in separation and purification, and many byproducts, making it unsuitable for industrial production. Specific reaction equation:

[0007] Patent CN113429338B discloses a method for obtaining fluopyram from 2-bromoethylamine as a starting material via cyclization, amide condensation, and coupling reactions. This method uses a highly toxic, flammable, and explosive cycloethylamine intermediate, which is unstable and prone to side reactions, resulting in low yield and high cost. Furthermore, this route uses alkyllithium reagents such as n-butyllithium or tert-butyllithium, which are prone to spontaneous combustion upon contact with air, making industrial control difficult and increasing the risk of production safety accidents. The specific reactions are as follows:

[0008] Patent CN113620867B reports a method for obtaining fluopyram using 2,3-dichlorotrifluorotoluene and 2,3-dichloro-5-trifluoromethylpyridine as starting materials, through ten steps including fluorination, cyano substitution, hydrolysis, hydroxymethylation, hydroxyl protection, splicing reaction, catalytic reductive dehalogenation, and decarboxylation. This method involves a long reaction process, making it difficult to separate and purify intermediate products. Furthermore, the fluorination reaction temperature is as high as 220℃, resulting in numerous side reactions and low yields. The catalytic dehalogenation reaction uses the precious metal catalyst palladium on carbon, leading to high production costs. Additionally, this method uses the highly toxic chemical sodium cyanide, posing high safety risks and making safety management difficult for industrial production. The specific reactions are as follows:

[0009] Patent CN114031551B reports a method for obtaining fluopyram from 2-acetonitrile-3-chloro-5-trifluoromethylpyridine as a starting material, via sodium borohydride reduction catalyzed by a nickel-aluminum supported catalyst and an acid-amine condensation reaction. This method uses a nickel-aluminum supported catalyst, which spontaneously combusts upon contact with air, posing a high safety risk and making industrial-scale production difficult using microwave reactors. Furthermore, the acid-amine condensation reaction uses an equimolar amount of potassium trimethylsilanolate catalyst, which is expensive and not commercially available. The specific reaction is as follows:

[0010] Patent CN120623102A describes a method using diethyl malonate as a nucleophile to undergo a substitution reaction with 2,3-dichloro-5-trifluoromethylpyridine to yield diethyl 2-(3-chloro-5-(trifluoromethyl)-2-pyridyl)malonate. This is followed by condensation with N-bromomethylphthalimide, decarboxylation, and then hydrazolysis to obtain 3-chloro-5-(trifluoromethyl)-2-ethylaminopyridine. Finally, an amide condensation reaction with o-trifluoromethylbenzoyl chloride yields fluopyram. While this method involves fewer steps, the reagents are expensive, and the decarboxylation and hydrazolysis reactions generate a large amount of organic waste, violating atom economy principles and resulting in high industrialization costs.

[0011] Patent CN120081783A reports a method for obtaining fluopyram using 2-vinyl-3-chloro-5-trifluoromethylpyridine as a starting material via a Michael reaction and an amide condensation reaction. However, the synthesis of 2-vinyl-3-chloro-5-trifluoromethylpyridine is complex, expensive, and lacks industrial-scale product availability, making industrial production impossible. The specific reaction is as follows: Summary of the Invention

[0012] The purpose of this invention is to overcome the shortcomings of the prior art and provide a method for synthesizing fluopyram. The invention provides the following technical solution: Using diethyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)malonate as a raw material, and one of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, or dimethyl sulfoxide as a reaction solvent, and one of lithium carbonate, sodium carbonate, potassium carbonate, or cesium carbonate as a base, a dihalomethane (one of difluoromethane, dichloromethane, dibromomethane, or diiodomethane) is added at a specific temperature and time to yield diethyl 2-halomethyl-2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)malonate. A sample was analyzed by liquid chromatography, and the 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)malonate content was ≤0.5%. 2-trifluoromethylbenzamide and an equal mass of reaction mixture were then added dropwise. A solvent mixture was added to the reaction system, and condensation yielded diethyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-2-((2-(trifluoromethane)benzoylamino)methyl)malonate. A sample was analyzed by liquid chromatography, and the content of diethyl 2-halomethyl-2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)malonate was ≤0.5%. The reaction was considered complete. The pH of the system was adjusted to 4-5 with hydrochloric acid, and the temperature was raised to a certain level to induce a decarboxylation reaction. A sample was then analyzed by liquid chromatography, and the content of diethyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-2-((2-(trifluoromethane)benzoylamino)methyl)malonate was ≤0.5%. The reaction was stopped, and a certain amount of water was added to the system. The mixture was filtered and dried to obtain fluopyram.

[0013] Preferably, the amount of reaction solvent used in the technical solution is 6 to 8 times the mass of diethyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)malonate.

[0014] Preferably, in the technical solution, the molar ratio of diethyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)malonate to dihalomethane is 1:1.1~1.2.

[0015] Preferably, in the technical solution, the molar ratio of diethyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)malonate to alkali is 1:2.0~2.5.

[0016] Preferably, in the technical solution, the molar ratio of diethyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)malonate to 2-trifluoromethylbenzamide is 1:1.1~1.2.

[0017] Preferably, the reaction temperature of diethyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)malonate with dihalomethane and the condensation reaction temperature of diethyl 2-halomethyl-2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)malonate with 2-trifluoromethylbenzamide are 70~80℃.

[0018] Preferably, the decarboxylation reaction temperature in the technical solution is 150~160℃.

[0019] Preferably, the mass of water added in the technical solution is 3 to 6 times the mass of the reaction solvent.

[0020] Compared with other synthesis methods, the present invention has the following advantages: 1) The one-pot synthesis method for fluopyram is simple, easy to operate, and low in cost; 2) The three-step reaction uses a unified solvent, which simplifies the post-processing and improves production efficiency; 3) This method avoids the use of precious metal palladium catalysts, reduces raw material costs, and simplifies the process; 4) This method avoids the use of highly toxic, flammable and explosive compounds, reducing production safety risks; 5) Product content ≥ 98.5% (external standard method by liquid chromatography), yield ≥ 92.0% based on diethyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)malonate. Detailed Implementation

[0021] The present invention will be further described below in conjunction with the specification and specific preferred embodiments, but this does not limit the scope of protection of the present invention. Example 1

[0022] 200.0g N,N-dimethylformamide, 34.0g diethyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)malonate, and 21.2g sodium carbonate were added sequentially to a 500mL four-necked flask equipped with a mechanical stirrer, a condenser, and a thermometer. Then, 5.7g difluoromethane was introduced into the system. The temperature was raised to 70-72℃, and the reaction was stirred for 2 hours. A sample was taken and analyzed by liquid chromatography (LC) to confirm that diethyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)malonate was ≤0.5%. The temperature was controlled at 70-72℃. Then, a mixed solution of 20.8 g of 2-trifluoromethylbenzamide and 20 g of N,N-dimethylformamide was added dropwise, and the reaction was stirred for 3 hours. A sample was taken and analyzed by LC to confirm that diethyl 2-fluoromethyl-2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)malonate was ≤0.5%. After the reaction was completed, 30% hydrochloric acid was used. The pH of the aqueous solution system was adjusted to 4-5, the temperature was raised to 150℃, and the reaction was maintained for 6 hours. A sample was taken and analyzed by liquid chromatography (LC) to confirm that diethyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-2-((2-(trifluoromethane)benzoylamino)methyl)malonate was ≤0.5%. 600g of water was added with stirring, and the mixture was filtered. The filter cake was washed with 50g of water and dried in a forced-air oven at 80℃ to constant weight, yielding 37.1g of white powdered fluopyram with a purity of 98.5% (LC external standard method) and a yield of 92.0%. Example 2

[0023] 220.0 g of N,N-dimethylacetamide, 34.0 g of diethyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)malonate, 16.3 g of lithium carbonate, and 9.5 g of dichloromethane were sequentially added to a 500 mL four-necked flask equipped with a mechanical stirrer, condenser, and thermometer. The temperature was raised to 72-75 °C, and the reaction was stirred for 2 h. A sample was taken for liquid chromatography analysis, and the diethyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)malonate content was ≤0.5%. The temperature was controlled at 72-75 °C. Then, a mixed solution of 21.2 g of 2-trifluoromethylbenzamide and 21 g of N,N-dimethylacetamide was added dropwise, and the reaction was stirred for 3 h. A sample was taken for liquid chromatography analysis, and the diethyl 2-chloromethyl-2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)malonate content was ≤0.5%. After the reaction was completed, 30% hydrochloric acid was used to treat the reaction. The pH of the aqueous solution system was adjusted to 4-5, the temperature was raised to 153℃, and the reaction was maintained for 7 hours. A sample was taken and analyzed by liquid chromatography (LC) to confirm that diethyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-2-((2-(trifluoromethane)benzoylamino)methyl)malonate was ≤0.5%. 700g of water was added with stirring, and the mixture was filtered. The filter cake was washed with 50g of water and dried in a forced-air oven at 80℃ to constant weight, yielding 37.2g of white powdered fluopyram with a purity of 98.7% (LC external standard method) and a yield of 92.5%. Example 3

[0024] 230.0 g of N-methylpyrrolidone, 34.0 g of diethyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)malonate, 33.1 g of potassium carbonate, and 20.0 g of dibromomethane were sequentially added to a 500 mL four-necked flask equipped with a mechanical stirrer, condenser, and thermometer. The temperature was raised to 75-78 °C, and the reaction was stirred for 2 h. A sample was taken for liquid chromatography analysis, and the diethyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)malonate content was ≤0.5%. The temperature was controlled at 75-78 °C. Then, a mixed solution of 21.7 g of 2-trifluoromethylbenzamide and 21 g of N-methylpyrrolidone was added dropwise, and the reaction was stirred for 3 h. A sample was taken for liquid chromatography analysis, and the diethyl 2-bromomethyl-2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)malonate content was ≤0.5%. After the reaction was completed, 30% hydrochloric acid solution was used to clean the mixture. The pH of the solution system was adjusted to 4-5, the temperature was raised to 156℃, and the reaction was maintained for 8 hours. A sample was taken and analyzed by liquid chromatography (LC) to determine that diethyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-2-((2-(trifluoromethane)benzoylamino)methyl)malonate was ≤0.5%. 800g of water was added with stirring, and the mixture was filtered. The filter cake was washed with 50g of water and dried in a forced-air oven at 80℃ to constant weight, yielding 37.4g of white powdered fluopyram with a purity of 98.6% (LC external standard method) and a yield of 93.0%. Example 4

[0025] 240.0 g of dimethyl sulfoxide, 34.0 g of diethyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)malonate, 81.4 g of cesium carbonate, and 32.1 g of diiodomethane were sequentially added to a 500 mL four-necked flask equipped with a mechanical stirrer, condenser, and thermometer. The temperature was raised to 78-80 °C, and the reaction was stirred for 2 h. A sample was taken for liquid chromatography analysis, and the diethyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)malonate content was ≤0.5%. The temperature was controlled at 78-80 °C. Then, a mixed solution of 22.7 g of 2-trifluoromethylbenzamide and 22 g of dimethyl sulfoxide was added dropwise, and the reaction was stirred for 3 h. A sample was taken for liquid chromatography analysis, and the diethyl 2-iodomethyl-2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)malonate content was ≤0.5%. After the reaction was completed, the solution was adjusted with 30% hydrochloric acid aqueous solution. The system pH was set at 4-5, the temperature was raised to 160℃, and the reaction was maintained for 10 hours. A sample was taken and analyzed by liquid chromatography (LC) to confirm that diethyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-2-((2-(trifluoromethane)benzoylamino)methyl)malonate was ≤0.5%. 1000g of water was added with stirring, and the mixture was filtered. The filter cake was washed with 50g of water and dried in a forced-air oven at 80℃ to constant weight, yielding 37.7g of white powdered fluopyram with a purity of 98.9% (LC external standard method) and a yield of 94.0%.

[0026] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention in any way. Although the present invention has been disclosed above with reference to preferred embodiments, it is not intended to limit the invention. Therefore, any simple modifications, equivalent changes, and alterations made to the above embodiments based on the technical essence of the present invention without departing from the scope of the present invention should fall within the protection scope of the present invention.

Claims

1. A method for synthesizing fluopyram, characterized in that... Using diethyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)malonate as a raw material, and one of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, or dimethyl sulfoxide as a reaction solvent, and one of lithium carbonate, sodium carbonate, potassium carbonate, or cesium carbonate as a base, a dihalomethane of one of difluoromethane, dichloromethane, dibromomethane, or diiodomethane is added at a certain temperature and time to obtain diethyl 2-halomethyl-2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)malonate. After sampling and controlled analysis by liquid chromatography to ensure that the content of diethyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)malonate is ≤0.5%, 2-trifluoromethylbenzamide and an equal mass of reaction solvent are added dropwise. The mixture was added to the reaction system, where condensation yielded diethyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-2-((2-(trifluoromethane)benzoylamino)methyl)malonate. A sample was analyzed by liquid chromatography (LC) to ensure that diethyl 2-halomethyl-2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)malonate was ≤0.5%. The pH of the reaction solution was adjusted to 4-5 with hydrochloric acid, and then the temperature was raised to a certain level to induce a decarboxylation reaction. A sample was then analyzed by LC to ensure that diethyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-2-((2-(trifluoromethane)benzoylamino)methyl)malonate was ≤0.5%. The reaction was stopped, and a certain amount of water was added to the system. The mixture was filtered and dried to obtain fluopyram. The reaction formula is as follows: 。 2. The method for synthesizing fluopyram according to claim 1, characterized in that, The amount of reaction solvent used is 6 to 8 times the mass of diethyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)malonate.

3. The method for synthesizing fluopyram according to claim 1, characterized in that, The molar ratio of 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)malonic acid diethyl ester to dihalomethane is 1:1.1~1.

2.

4. The method for synthesizing fluopyram according to claim 1, characterized in that, The molar ratio of 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)malonic acid diethyl ester to base is 1:2.0~2.

5.

5. The method for synthesizing fluopyram according to claim 1, characterized in that, The molar ratio of diethyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)malonate to 2-trifluoromethylbenzamide is 1:1.1~1.

2.

6. The method for synthesizing fluopyram according to claim 1, characterized in that, The reaction temperature of diethyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)malonate with dihalomethane and the condensation reaction temperature of diethyl 2-halomethyl-2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)malonate with 2-trifluoromethylbenzamide are 70~80℃.

7. The method for synthesizing fluopyram according to claim 1, characterized in that, The decarboxylation reaction temperature is 150~160℃.

8. The method for synthesizing fluopyram according to claim 1, characterized in that, The mass of water added should be 3 to 6 times the mass of the reaction solvent.

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