A method for preparing fluopyram

Abstract

The application provides a preparation method of fluopyram, comprising the following steps: step 1: amine ethyl trimethylsilane and 2-trifluoromethyl benzoyl chloride are added into a solvent, a first alkaline substance is added dropwise after cooling, and after the reaction of 2-trifluoromethyl benzoyl chloride is completed, an intermediate N-(trimethylsilylethyl)-2-trifluoromethyl benzamide is obtained; then the reaction liquid is cooled to-5 DEG C, stirred, filtered, and a filtrate is obtained; step 2: 2-halo-3-chloro-5-trifluoromethyl pyridine, a second alkaline substance and a catalyst are added into the filtrate obtained in step 1, and the reaction is continued; after the reaction of the intermediate N-(trimethylsilylethyl)-2-trifluoromethyl benzamide is completed, part of the solvent is recovered under reduced pressure, cooled, and filtered to obtain fluopyram. The fluopyram is prepared from amine ethyl trimethylsilane and 2-trifluoromethyl benzoyl chloride through two-step reactions, the reaction yield is high, the product purity is high, the solvent can be recycled and reused, no special dangerous reaction is involved, and the method can be popularized in industrialization.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pesticides and organic synthesis, and particularly relates to a preparation method of fluopyram. BACKGROUND

[0002] Fluopyram is a unique succinate dehydrogenase inhibitor (SDI) developed by Bayer, which disrupts the function of complex II in the electron transport of respiration. It can be used for preventing and treating various diseases of crops such as grape trees, table grapes, pome fruits, stone fruits, vegetables and field crops, including gray mold, powdery mildew, scab and brown rot.

[0003] The existing technology mainly has the following methods for synthesizing fluopyram:

[0004] The old method basically uses 2,3-dichloro-5-trifluoromethylpyridine and ethyl cyanoacetate as starting materials, and an intermediate 2-ethylamino-3-chloro-5-trifluoromethylpyridine hydrochloride is prepared by reduction reaction, and then reacted with o-trifluoromethyl benzoyl chloride to obtain the product. For example, patents WO2004016088, CN101080390B and CN115215793A. Such reaction route is long, and the reduction and hydrolysis of cyano group is not complete, which is easy to produce impurities and difficult to remove, resulting in product quality below 95%.

[0005] Patent CN114805188A discloses a new method, which uses 2-trifluoromethylbenzoic acid as raw material, and then is subjected to sulfoxide chlorination and reaction with N-vinyl formamide, and finally is subjected to chemical selective intermolecular coupling reaction by pyridyl halide radical reduction under photocatalysis to obtain fluopyram. Although the yield of this method is high, photocatalysis is suitable for laboratory research.

[0006] Patents CN110437138A and W02006067103 both adopt a route passing through 2-(3-chloro-5-trifluoromethyl-2-pyridyl)-2-[(2-trifluoromethylbenzoyl) aminomethyl]-1,3-propanediol diester step, and the former improves the route and increases the yield to 96%. SUMMARY

[0007] Therefore, the present application aims to provide a preparation method of fluopyram, which has simple preparation process, high reaction yield and high product purity.

[0008] To achieve the above-mentioned purpose, the technical scheme of the present application is as follows:

[0009] A preparation method of fluopyram, comprising the following steps:

[0010] Step 1: amine ethyl trimethylsilane and 2-trifluoromethyl benzoyl chloride are added into a solvent, after cooling, a first basic substance is added dropwise, after the reaction of 2-trifluoromethyl benzoyl chloride is completed, an intermediate N-(trimethylsilylethyl)-2-trifluoromethyl benzamide is obtained, then the reaction solution is cooled to -5℃, stirring, filtration, and a filtrate is obtained;

[0011] Step 2: 2-halo-3-chloro-5-trifluoromethyl pyridine, a second basic substance, a catalyst are added into the filtrate of step 1, and the reaction is continued, after the reaction of the intermediate N-(trimethylsilylethyl)-2-trifluoromethyl benzamide is completed, part of the solvent is recovered under reduced pressure, cooling, and filtration to obtain fluopicolide.

[0012] The solvent in step 2 can be repeatedly used.

[0013] The reaction formula of the above two steps is as follows:

[0014]

[0015] Further, the molar ratio of 2-trifluoromethyl benzoyl chloride, amine ethyl trimethylsilane, the first basic substance, and the solvent in step 1 is 1: (1-1.5): (1-2): (10-40).

[0016] Further, the first basic substance in step 1 is an organic base or an inorganic base.

[0017] The organic base is one of methylamine solution, tetramethyl diethylamine, tris (2-amine ethyl) amine, methyldiethylamine, trimethylamine, triethylamine, dimethylamine, tripropylamine, tri-n-propylamine, cyclohexanediamine, pyridine, vinylpyridine resin, guanidine, tetramethyl guanidine, trimethyl guanidine, piperidine, morpholine, N, N-diisopropyl ethylamine, methyl morpholine, and quinoline.

[0018] The inorganic base is one of potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, and ammonia.

[0019] Further, the reaction temperature of step 1 is 0-40℃, preferably 5℃.

[0020] Further, the molar ratio of N-(trimethylsilylethyl)-2-trifluoromethyl benzamide, 2-halo-3-chloro-5-trifluoromethyl pyridine, the second basic substance, and the catalyst in step 2 is 1: (1-1.1): (1-2): (0.01-0.06).

[0021] Further, the second basic substance in step 2 is an organic base or an inorganic base.

[0022] The organic base is one of methylamine solution, tetramethylammonium diethylamine, tris (2-amine ethyl) amine, methyldiethylamine, trimethylamine, triethylamine, dimethylamine, tripropylamine, tri-n-propylamine, cyclohexanediamine, pyridine, vinylpyridine resin, guanidine, tetramethylguanidine, trimethylguanidine, piperidine, morpholine, N, N-diisopropylethylamine, methylmorpholine, quinoline;

[0023] The inorganic base is one of potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, ammonia.

[0024] Further, the 2-halo-3-chloro-5-trifluoromethylpyridine in step 2 is 2-fluoro-3-chloro-5-trifluoromethylpyridine, 2-bromo-3-chloro-5-trifluoromethylpyridine or 2-chloro-3-chloro-5-trifluoromethylpyridine.

[0025] Further, the catalyst in step 2 is one of ferric chloride, palladium acetate, palladium sulfate, palladium chloride, cobalt chloride, nickel chloride, copper bromide.

[0026] Further, the reaction temperature of step 2 is 50-90℃.

[0027] Further, the solvent in step 1 and step 2 is one or more of diethyl ether, tetrahydrofuran, dichloromethane, chloroform, 1, 2-dichloroethane, toluene, chlorobenzene, dioxane, acetonitrile, dimethyl sulfoxide, N, N-dimethylacetamide, water.

[0028] Compared with the prior art, the preparation method of fluopyram provided by the application has the following advantages: the application provides a new method for synthesizing fluopyram, which uses amine ethyl trimethyl silane and 2-trifluoromethyl benzoyl chloride as raw materials, and is prepared through two-step reaction, so that the reaction route is short, the reaction yield is high, the product purity is high, the solvent can be recycled and reused, no special dangerous reaction is involved, and the method can be popularized in industry. BRIEF DESCRIPTION OF DRAWINGS

[0029] The accompanying drawings, which form a part of the present application, are used to provide further understanding of the present application, and serve as an explanation of the illustrative embodiments of the present application, and do not constitute improper limitations of the present application. In the drawings:

[0030] Figure 1 The HPLC chart of fluopyram described in example 5 of the application. DETAILED DESCRIPTION

[0031] It should be noted that the examples in the application and the features in the examples can be combined with each other without conflict.

[0032] The application will be described in detail below with reference to the accompanying drawings and in combination with the examples.

[0033] Example 1

[0034] Into a reaction flask, 13.6 g of amine ethyl trimethyl silane, 20.8 g of 2- trifluoromethylbenzoyl chloride, 100 g of 1,2-dichloroethane were added, the reaction solution was cooled to 5°C, 19.5 g of N,N-diisopropylethylamine and 50 g of 1,2-dichloroethane were added dropwise, the reaction temperature was kept below 20°C during the dropwise addition, after the dropwise addition was completed, the reaction solution was cooled to -5°C and stirred for 1 hour, then filtered, the filter cake was washed with 100 ml of cold 1,2-dichloroethane, 26 g of 2-bromo-3-chloro-5-trifluoromethylpyridine, 19.5 g of N,N-diisopropylethylamine, 1 g of palladium acetate were added to the filtrate, and the reaction was slowly warmed to 70°C, after the intermediate N-(trimethylsilylethyl)-2-trifluoromethylbenzamide was completely reacted, part of the solvent was recovered under reduced pressure, then cooled and filtered, and vacuum dried to obtain fludioxonil 37.4 g, white powder, yield 94.44%, liquid phase content 99.43%.

[0035] Example 2

[0036] Into a reaction flask, 13.6 g of amine ethyl trimethyl silane, 20.8 g of 2- trifluoromethylbenzoyl chloride, 120 g of toluene were added, the reaction solution was cooled to 5°C, 19.5 g of N,N-diisopropylethylamine and 50 g of 1,2-dichloroethane were added dropwise, the reaction temperature was kept below 20°C during the dropwise addition, after the dropwise addition was completed, the reaction solution was cooled to -5°C and stirred for 1 hour, then filtered, the filter cake was washed with 100 ml of cold toluene, 26 g of 2-bromo-3-chloro-5-trifluoromethylpyridine, 19.5 g of N,N-diisopropylethylamine, 1 g of palladium acetate were added to the filtrate, and the reaction was slowly warmed to 70°C, after the intermediate N-(trimethylsilylethyl)-2-trifluoromethylbenzamide was completely reacted, part of the solvent was recovered under reduced pressure, then cooled and filtered, and vacuum dried to obtain fludioxonil 35.9 g, white powder, yield 90.65%, liquid phase content 99.12%.

[0037] Example 3

[0038] To the reaction flask was added 13.6 g of amine ethyl trimethyl silane, 20.8 g of 2-trifluoromethyl benzoyl chloride, 120 g of chloroform, the reaction solution was cooled to 5 °C, and a mixture of 13.1 g of methyldiethylamine and 50 g of chloroform was added dropwise while maintaining the reaction temperature at no more than 20 °C. After the dropwise addition was complete, the reaction solution was cooled to -5 °C and stirred for 1 hour. The reaction solution was filtered, the filter cake was rinsed with 100 ml of cold chloroform, and 26 g of 2-bromo-3-chloro-5-trifluoromethylpyridine, 13.1 g of methyldiethylamine, and 1.6 g of cobalt chloride were added to the filtrate. The reaction was slowly warmed to 60 °C, and after the intermediate N-(trimethylsilylethyl)-2-trifluoromethylbenzamide was completely reacted, the solvent was recovered under reduced pressure, and the reaction solution was filtered and dried under vacuum to obtain fludioxonil 29.8 g as a light yellow powder at a yield of 75.25% and a liquid-phase content of 98.29%.

[0039] Example 4

[0040] To the reaction flask was added 13.6 g of amine ethyl trimethyl silane, 20.8 g of 2-trifluoromethyl benzoyl chloride, 120 g of chloroform, the reaction solution was cooled to 5 °C, and a mixture of 13.1 g of methyldiethylamine and 50 g of chloroform was added dropwise while maintaining the reaction temperature at no more than 20 °C. After the dropwise addition was complete, the reaction solution was cooled to -5 °C and stirred for 1 hour. The reaction solution was filtered, the filter cake was rinsed with 100 ml of cold chloroform, and 26 g of 2-bromo-3-chloro-5-trifluoromethylpyridine, 13.1 g of methyldiethylamine, and 1.6 g of cobalt chloride were added to the filtrate. The reaction was slowly warmed to 60 °C, and after the intermediate N-(trimethylsilylethyl)-2-trifluoromethylbenzamide was completely reacted, the solvent was recovered under reduced pressure, and the reaction solution was filtered and dried under vacuum to obtain fludioxonil 29.8 g as a light yellow powder at a yield of 75.25% and a liquid-phase content of 98.29%.

[0041] Example 5

[0042] To the reaction flask was added 13.6 g of amine ethyl trimethyl silane, 20.8 g of 2-trifluoromethylbenzoyl chloride, 100 g of 1,2-dichloroethane, the reaction solution was cooled to 5 °C, 19.5 g of N,N-diisopropylethylamine and 50 g of 1,2-dichloroethane were added dropwise, the reaction temperature was maintained at no more than 20 °C during the dropwise addition, after the dropwise addition was completed, the reaction solution was cooled to -5 °C and stirred for 1 hour, filtered, the filter cake was washed with 100 ml of cold 1,2-dichloroethane, 20 g of 2-fluoro-3-chloro-5-trifluoromethylpyridine, 19.5 g of N,N-diisopropylethylamine, 1 g of palladium acetate were added to the filtrate, and the temperature was slowly increased to 70 °C for reaction, after the intermediate N-(trimethylsilylethyl)-2-trifluoromethylbenzamide was completely reacted, part of the solvent was recovered under reduced pressure, then cooled and filtered, and vacuum dried to obtain flupyradifuram 38.9 g, white powder, yield 98.23%, liquid phase content 99.85%.

[0043] Example 6

[0044] To the reaction flask was added 13.6 g of amine ethyl trimethyl silane, 20.8 g of 2-trifluoromethylbenzoyl chloride, 100 g of 1,2-dichloroethane, the reaction solution was cooled to 5 °C, 19.5 g of N,N-diisopropylethylamine and 50 g of 1,2-dichloroethane were added dropwise, the reaction temperature was maintained at no more than 20 °C during the dropwise addition, after the dropwise addition was completed, the reaction solution was cooled to -5 °C and stirred for 1 hour, filtered, the filter cake was washed with 100 ml of cold 1,2-dichloroethane, 20 g of 2-fluoro-3-chloro-5-trifluoromethylpyridine, 19.5 g of N,N-diisopropylethylamine, 1 g of palladium acetate were added to the filtrate, and the temperature was slowly increased to 70 °C for reaction, after the intermediate N-(trimethylsilylethyl)-2-trifluoromethylbenzamide was completely reacted, part of the solvent was recovered under reduced pressure, then cooled and filtered, and vacuum dried to obtain flupyradifuram 38.9 g, white powder, yield 98.23%, liquid phase content 99.85%.

[0045] Example 7

[0046] Into a reaction flask, 13.6 g of amine ethyl trimethyl silane, 20.8 g of 2-trifluoromethyl benzoyl chloride, 130 g of toluene were added, the reaction solution was cooled to 5°C, 21.5 g of tri-n-propyl amine and 80 g of toluene were added dropwise, the temperature was kept below 20°C during the dropwise addition, after the dropwise addition was completed, the reaction solution was cooled to -5°C and stirred for 1 hour, then filtered, the filter cake was washed with 100 ml of cold toluene, 20 g of 2-fluoro-3-chloro-5-trifluoromethyl pyridine, 21.5 g of tri-n-propyl amine, 1.6 g of ferric chloride were added to the filtrate, and the temperature was slowly increased to 90°C for reaction, after the intermediate N-(trimethyl silane ethyl)-2-trifluoromethyl benzamide was completely reacted, part of the solvent was recovered under reduced pressure, then cooled and filtered, and vacuum dried to obtain fludioxonil 31.5 g, white powder, yield 79.55%, liquid phase content 98.59%.

[0047] The above description is merely preferred embodiments of the present application, but not to limit the present application, any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A process for the preparation of fluopyram characterized in that: Comprise the following steps: Step 1: amine ethyl trimethylsilane and 2-trifluoromethyl benzoyl chloride are added to a solvent, after cooling, drop the first alkaline material, after the reaction of 2-trifluoromethyl benzoyl chloride is complete, the intermediate N-(trimethylsilylethyl)-2-trifluoromethyl benzamide is obtained, then the reaction liquid is cooled to-5 DEG C, stirring, filtering, and the filtrate is obtained; Step 2: 2-halo-3-chloro-5-trifluoromethyl pyridine, a second alkaline material, a catalyst are added to the filtrate of step 1, and the reaction is continued, after the reaction of the intermediate N-(trimethylsilylethyl)-2-trifluoromethyl benzamide is complete, part of the solvent is recovered under reduced pressure, cooled, and filtered to obtain fluopicolide; The reaction formula of the above two steps is: ； The second alkaline material in step 2 is an organic base or an inorganic base; The organic base is one of tetramethyl diethylamine, methyldiethylamine, trimethylamine, triethylamine, tripropylamine, pyridine, N,N-diisopropyl ethylamine; The inorganic base is one of potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate; The 2-halo-3-chloro-5-trifluoromethyl pyridine in step 2 is 2-fluoro-3-chloro-5-trifluoromethyl pyridine or 2-bromo-3-chloro-5-trifluoromethyl pyridine; The catalyst in step 2 is one of ferric chloride, palladium acetate, palladium chloride, cobalt chloride, nickel chloride.

2. A process for the preparation of fluopyram as claimed in claim 1, wherein: The molar ratio of 2-trifluoromethyl benzoyl chloride, amine ethyl trimethylsilane, the first alkaline material, the solvent in step 1 is 1:(1-1.5):(1-2):(10-40).

3. The method for preparing fluopyram according to claim 1, characterized in that: The first alkaline material in step 1 is an organic base or an inorganic base; The organic base is one of tetramethyl diethylamine, methyldiethylamine, trimethylamine, triethylamine, tripropylamine, pyridine, N,N-diisopropyl ethylamine; The inorganic base is one of potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate.

4. The method for preparing fluopyram according to claim 1, characterized in that: The reaction temperature of step 1 is 0-40 DEG C.

5. The process for the preparation of fluopyram as claimed in claim 4, wherein: The reaction temperature of step 1 is 5 DEG C.

6. The method for preparing fluopyram according to claim 1, characterized in that: The molar ratio of N-(trimethylsilylethyl)-2-trifluoromethyl benzamide, 2-halo-3-chloro-5-trifluoromethyl pyridine, the second alkaline material, the catalyst in step 2 is 1:(1-1.1):(1-2):(0.01-0.06).

7. The method for preparing fluopyram according to claim 1, characterized in that: The reaction temperature of step 2 is 50-90 DEG C.

8. The method for preparing fluopyram according to claim 1, characterized in that: The solvent in step 1 and step 2 is one or more of diethyl ether, tetrahydrofuran, dichloromethane, chloroform, 1,2-dichloroethane, toluene, chlorobenzene, dioxane, acetonitrile, dimethyl sulfoxide, N,N-dimethylacetamide.

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