Fluopyram compound and preparation method thereof

Abstract

The invention relates to the technical field of pesticides, and discloses a fluopyram compound and a preparation method thereof. The preparation method of the fluopyram compound comprises the following steps: 1) in the presence of a first organic solvent and first alkali, carrying out nucleophilic substitution reaction on a compound with a structure as shown in a formula (1) and a compound with a structure as shown in a formula (2); 2) carrying out a decarboxylation reaction on the nucleophilic substitution reaction product obtained in the step 1) in the presence of a first solvent and a first acid; 3) in the presence of a second solvent and a second acid, the decarboxylation reaction product obtained in the step 2) is subjected to a decyanation reaction to obtain the fluopyram compound, in the formula (1), X represents halogen, and R1 represents-COOC1-6 alkyl; in formula (2), R2 represents an alkyl group having 1-6 carbon atoms. According to the preparation method of the fluopyram compound, the yield is higher, and the operation is more convenient. # imgabs 0 # formula (1) # imgabs 1 # formula (2).

Description

Technical Field

[0001] The present invention relates to the technical field of pesticides, and particularly relates to a fluopyram compound and a preparation method thereof. Background Art

[0002] Succinate dehydrogenase inhibitors (SDHIs) are a class of fungicides that act on the succinate dehydrogenase of pathogenic bacteria to inhibit their respiration. They disrupt the tricarboxylic acid cycle and respiratory chain in plant cells, thereby inhibiting their respiration. This class of fungicides has specific action, strong efficacy, long-lasting effect, and significant yield increase effect.

[0003] Fluopyram developed by Bayer CropScience is one of the representatives of SDHIs fungicides. In addition to being used for the prevention and control of spot defoliation, leaf spot, gray mold, powdery mildew, sclerotinia, early blight, etc. on vegetables such as grapes, pears, bananas, apples, cucumbers, tomatoes and field crops, it can also be used to control various nematodes and is an efficient, green and low-toxic nematicide.

[0004] Fluopyram, molecular formula: C 16 H 11 CIF6N 20 , chemical name: N-(2-[3-chloro-5-(trifluoromethyl)-2-pyridyl]ethyl)-a,a,a-o-trifluoromethylbenzamide.

[0005] The reports on the synthesis of fluopyram mainly include two synthetic routes. One is obtained by the reaction of 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)ethylamine and 2-trifluoromethylbenzoyl chloride; the other is obtained by the nucleophilic reaction of 2-(3-chloro-5-(trifluoromethyl)-2-pyridyl)-1,3-dimethyl malonate with N-((acetoxy)methyl)-2-trifluoromethylbenzamide, followed by hydrolysis and decarboxylation.

[0006] For Route 1, 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)ethylamine is the key intermediate for the synthesis of fluopyram. Most of the reported synthetic routes for 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)ethylamine use 2-cyanomethyl-3-chloro-5-trifluoromethylpyridine as the raw material and are prepared by high-pressure hydrogenation reduction using precious metal catalysts, with a yield of about 80%. The reaction conditions are harsh, the operation is cumbersome, and the industrial production cost is too high.

[0007] For Route 2, WO2006067103A2 proposed a reaction route for synthesizing the key intermediate 3-chloro-5-trifluoromethyl-2-pyridyl malonate from 2,3-dichloro-5-trifluoromethylpyridine and malonic ester, but its reaction separation yield is only 82-88%, and the yield is low, affecting the total reaction yield. Summary of the Invention

[0008] The object of the present invention is to overcome the problem of low overall yield existing in the prior art, and to provide a method for preparing fludioxonil compounds with higher yield and more convenient operation, and the fludioxonil compounds prepared thereby.

[0009] To achieve the above object, in the first aspect of the present invention, a method for preparing fludioxonil compounds is provided, wherein the method comprises the following steps: 1) A step of carrying out a nucleophilic substitution reaction between a compound having the structure shown in formula (1) and a compound having the structure shown in formula (2) in the presence of a first organic solvent and a first base to obtain a nucleophilic substitution reaction product containing a compound having the structure shown in formula (3); 2) A step of carrying out a decarboxylation reaction on the nucleophilic substitution reaction product obtained in step 1) in the presence of a first solvent and a first acid to obtain a decarboxylation reaction product containing a compound having the structure shown in formula (4); 3) A step of carrying out a de-cyanation reaction on the decarboxylation reaction product obtained in step 2) in the presence of a second solvent and a second acid to obtain a fludioxonil compound having the structure shown in formula (5). Formula (1) Formula (2) Formula (3) Formula (4) Formula (5) In formula (1) and formulas (3)-(5), X represents a halogen; in formula (1) and formula (3), R1 represents -COOC 1-6 alkyl; in formula (2), R2 represents an alkyl group having 1 to 6 carbon atoms.

[0010] Preferably, in formula (1) and formulas (3)-(5), X represents F, Cl or Br, preferably F or Cl, more preferably Cl; in formula (1) and formula (3), R1 represents -COOC 1-3 alkyl, preferably -COOCH3, -COOCH2CH3 or -COOCCH2CH2CH3, more preferably -COOCH3 or -COOCH2CH3.

[0011] Preferably, in formula (2), R2 represents an alkyl group having 1 to 3 carbon atoms, preferably methyl, ethyl or propyl, more preferably methyl.

[0012] Preferably, in step 1), the molar ratio of the compound having the structure shown in formula (1) to the compound having the structure shown in formula (2) is 1:0.9-1.5, preferably 1:1-1.5, more preferably 1:1-1.2.

[0013] Preferably, in step 1), the molar ratio of the compound of the structure shown in formula (1) to the first base is 1:1 - 2, preferably 1:1 - 1.5, more preferably 1:1 - 1.3.

[0014] Preferably, in step 1), the weight ratio of the compound of the structure shown in formula (1) to the first organic solvent is 1:1 - 10, preferably 1:1 - 3.

[0015] Preferably, the first organic solvent is selected from one or more of dimethyl sulfoxide, N,N - dimethylformamide, N,N - dimethylacetamide, N - methylpyrrolidone, tetrahydrofuran, acetonitrile, dichloromethane, 1,2 - dichloroethane, tert - butanol, benzene, toluene, and xylene, more preferably toluene and / or N,N - dimethylacetamide.

[0016] Preferably, the first base is selected from one or more of potassium hydroxide, sodium hydroxide, sodium methoxide, potassium tert - butoxide, sodium tert - butoxide, sodium hydride, potassium carbonate, sodium carbonate, triethylamine, N,N - diisopropylethylamine, and N,N - dimethylcyclohexylamine; more preferably, the first base is potassium carbonate and / or triethylamine.

[0017] Preferably, the temperature of the nucleophilic substitution reaction is 20 - 100 °C, preferably 30 - 70 °C.

[0018] Preferably, in step 1), the nucleophilic substitution reaction product is obtained by extracting and desolvating the reactants.

[0019] Preferably, in step 2), the molar ratio of the nucleophilic substitution reaction product based on the compound of the structure shown in formula (3) to the first acid is 1:1 - 4, preferably 1:1 - 2, more preferably 1:1 - 1.3.

[0020] Preferably, in step 2), the weight ratio of the nucleophilic substitution reaction product based on the compound of the structure shown in formula (3) to the first solvent is 1:1 - 10, preferably 1:1 - 3.

[0021] Preferably, in step 2), the first acid is selected from one or more of hydrochloric acid, sulfuric acid, phosphoric acid, and acetic acid, preferably hydrochloric acid and / or sulfuric acid.

[0022] Preferably, the first solvent is selected from one or more of dimethyl sulfoxide, N,N - dimethylformamide, N,N - dimethylacetamide, methanol, ethanol, tert - butanol, and water, preferably dimethyl sulfoxide and / or N,N - dimethylacetamide.

[0023] Preferably, in step 2), the temperature of the decarboxylation reaction is 50 - 140 °C, preferably 100 - 120 °C.

[0024] Preferably, in step 2), the decarboxylation reaction product is obtained by extracting and desolvating the reactants.

[0025] Preferably, in step 3), the molar ratio of the decarboxylation reaction product based on the compound of the structure shown in formula (4) to the second acid is 1:1 - 5, preferably 1:1.5 - 4, more preferably 1:2 - 3.

[0026] Preferably, the molar ratio of the decarboxylation reaction product based on the compound of the structure shown in formula (4) to the second solvent is 1:1 - 5, preferably 1:1 - 3, more preferably 1:1 - 2.

[0027] Preferably, in step 3), the second acid is selected from one or more of hydrochloric acid, sulfuric acid, phosphoric acid, and acetic acid, preferably hydrochloric acid and / or sulfuric acid.

[0028] Preferably, the second solvent is selected from one or more of dimethyl sulfoxide, N,N - dimethylformamide, N,N - dimethylacetamide, water, methanol, and acetic acid, preferably water and / or acetic acid.

[0029] Preferably, the temperature of the decyanation reaction is 50 - 140 °C, preferably 50 - 100 °C.

[0030] Preferably, in step 3), the fludioxonil - type compound of the structure shown in formula (5) is obtained by extracting and desolvating the reactants.

[0031] According to the second aspect of the present invention, there is provided a fludioxonil - type compound prepared by the preparation method of the fludioxonil - type compound described in the first aspect of the present invention.

[0032] By the above technical solution, the present invention can provide a preparation method of a fludioxonil - type compound with higher yield and more convenient operation, and the fludioxonil - type compound prepared thereby. Detailed Embodiments

[0033] In the ranges disclosed herein, the endpoints and any values are not limited to the exact ranges or values, and these ranges or values should be understood to include values close to these ranges or values. For numerical ranges, between the endpoint values of each range, between the endpoint values of each range and individual point values, and between individual point values, they can be combined with each other to obtain one or more new numerical ranges, and these numerical ranges should be regarded as specifically disclosed herein.

[0034] The first aspect of the present invention provides a preparation method of a fludioxonil - type compound, wherein the method comprises the following steps. 1) A step of subjecting a compound having the structure shown in formula (1) and a compound having the structure shown in formula (2) to a nucleophilic substitution reaction in the presence of a first organic solvent and a first base to obtain a nucleophilic substitution reaction product containing a compound having the structure shown in formula (3); 2) A step of subjecting the nucleophilic substitution reaction product obtained in step 1) to a decarboxylation reaction in the presence of a first solvent and a first acid to obtain a decarboxylation reaction product containing a compound having the structure shown in formula (4); 3) A step of subjecting the decarboxylation reaction product obtained in step 2) to a de-cyanation reaction in the presence of a second solvent and a second acid to obtain a fluxapyroxad compound having the structure shown in formula (5), Formula (1) Formula (2) Formula (3) Formula (4) Formula (5) In formula (1) and formula (3)-(5), X represents a halogen, and R1 represents -COOC 1-6 alkyl; in formula (2), R2 represents an alkyl having 1 to 6 carbon atoms.

[0035] In the present invention, "alkyl having 1 to 6 carbon atoms" and "C 1-6 alkyl" refer to a linear or branched alkyl having 1 to 6 carbon atoms. For example, it may include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, etc. Among them, an alkyl having 1 to 3 carbon atoms is preferred, and methyl, ethyl or n-propyl is more preferred.

[0036] In the present invention, as "C 1-6 alkyl", for example, it may include: -COOCH3, -COOCH2CH3, -COOCH2CH2CH3, -COOCH2CH2CH2CH3, -COOCH2CH2CH2CH2CH3 or -COOCH2CH2CH2CH2CH2CH3.

[0037] In the present invention, in formula (1) and formula (3)-(5), X represents a halogen. For example, it may include: F, Cl, Br, I, etc. Preferably, X represents F, Cl or B; more preferably, X represents F or Cl; particularly preferably, X is Cl.

[0038] In the present invention, in formula (1) and formula (3), R1 represents -COOC 1-6 alkyl; preferably, R1 represents -COOC 1-3alkyl; more preferably, R1 is -COOCH3, -COOCH2CH3 or -COOCCH2CH2CH3; particularly preferably, R1 is -COOCH3 or -COOCH2CH3.

[0039] In the present invention, the compound of the structure shown in formula (1) is preferably one or more of the compounds of the structures shown in the following formulas, formula (1-A), formula (1-B), formula (1-C), In formulas (1-A)-(1-C), X represents a halogen; preferably, X represents F, Cl or B; more preferably, X represents F or Cl; particularly preferably, X is Cl.

[0040] In the present invention, in formula (2), R2 represents an alkyl group having 1-6 carbon atoms; preferably, R2 represents an alkyl group having 1-3 carbon atoms; more preferably, R2 is methyl, ethyl or propyl; particularly preferably, R2 is methyl.

[0041] In the present invention, the compound of the structure shown in formula (2) is preferably one or more of the compounds of the structures shown in the following formulas, formula (2-A), formula (2-B), formula (2-C).

[0042] The preparation method of the fluopyram compounds of the present invention will be described step by step below.

[0043] Step 1): Nucleophilic substitution reaction According to the method of the present invention, in step 1), in the presence of a first organic solvent and a first base, the compound of the structure shown in formula (1) is subjected to a nucleophilic substitution reaction with the compound of the structure shown in formula (2) to obtain a nucleophilic substitution reaction product containing the compound of the structure shown in formula (3).

[0044] According to the method of the present invention, in step 1), the amount of the compound of the structure shown in formula (2) can be selected according to the amount of the compound of the structure shown in formula (1). Preferably, in step 1), the molar ratio of the compound of the structure shown in formula (1) to the compound of the structure shown in formula (2) is 1:0.9-1.5; more preferably, in step 1), the molar ratio of the compound of the structure shown in formula (1) to the compound of the structure shown in formula (2) is 1:1-1.5; further preferably, in step 1), the molar ratio of the compound of the structure shown in formula (1) to the compound of the structure shown in formula (2) is 1:1-1.2.

[0045] In the present invention, as specific examples of the molar ratio of the compound represented by the formula (1) to the compound represented by the formula (2), for example, the following can be cited: 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, etc., as well as the ranges formed by any two of the above and all values within these ranges.

[0046] According to the method of the present invention, in step 1), the amount of the first base can also be selected according to the amount of the compound represented by the formula (1). Preferably, in step 1), the molar ratio of the compound represented by the formula (1) to the first base is 1:1 - 2; more preferably, in step 1), the molar ratio of the compound represented by the formula (1) to the first base is 1:1 - 1.5; further preferably, in step 1), the molar ratio of the compound represented by the formula (1) to the first base is 1:1 - 1.3.

[0047] In the present invention, as specific examples of the molar ratio of the compound represented by the formula (1) to the first base, for example, the following can be cited: 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, etc., as well as the ranges formed by any two of the above and all values within these ranges.

[0048] According to the method of the present invention, the first organic solvent is used to dissolve the reaction raw materials to promote the reaction. In the present invention, an organic solvent that is inert to the reaction raw materials and can dissolve the reaction raw materials well can be used for the nucleophilic substitution reaction of the present invention. Preferably, the first organic solvent is selected from one or more of dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, acetonitrile, dichloromethane, 1,2-dichloroethane, tert-butanol, benzene, toluene, and xylene; more preferably, the first organic solvent is toluene and / or N,N-dimethylacetamide.

[0049] According to the method of the present invention, the amount of the first organic solvent can also be selected according to the reaction raw materials as long as it can dissolve the reaction raw materials well. Preferably, in step 1), the weight ratio of the compound represented by the formula (1) to the first organic solvent is 1:1 - 10; more preferably, in step 1), the weight ratio of the compound represented by the formula (1) to the first organic solvent is 1:1 - 3.

[0050] In the present invention, as specific examples of the weight ratio of the compound represented by the formula (1) to the first organic solvent, for example, the following can be cited: 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, etc., as well as the ranges formed by any two of the above and all values within these ranges.

[0051] According to the method of the present invention, the first base may be selected from inorganic bases or organic bases. Preferably, the first base is selected from one or more of potassium hydroxide, sodium hydroxide, sodium methoxide, potassium tert-butoxide, sodium tert-butoxide, sodium hydride, potassium carbonate, sodium carbonate, triethylamine, N,N-diisopropylethylamine, and N,N-dimethylcyclohexylamine; more preferably, the first base is sodium methoxide and / or triethylamine; particularly preferably, the first base is triethylamine.

[0052] In a preferred embodiment of the present invention, the first base is triethylamine, whereby the total yield of the present invention can be significantly improved.

[0053] In a particularly preferred embodiment of the present invention, the first organic solvent is toluene and the first base is triethylamine, whereby the total yield of the present invention can be further significantly improved.

[0054] According to the method of the present invention, preferably, the temperature of the nucleophilic substitution reaction is 20-100 °C; more preferably, the temperature of the nucleophilic substitution reaction is 30-70 °C.

[0055] In addition, the time of the nucleophilic substitution reaction only needs to ensure that the compound of the structure shown in formula (1) reacts sufficiently and the compound of the structure shown in formula (3) is obtained. For example, the time of the nucleophilic substitution reaction can be 6-12 h, preferably 6-8 h.

[0056] According to the method of the present invention, in step 1), there is no particular limitation on the feeding order of each raw material. The first organic solvent can be added first, and then other raw materials can be added together or step by step to the first organic solvent and then the reaction is started. Or the above other raw materials can be added together or step by step to the reaction vessel first, and then the first organic solvent is added to start the reaction.

[0057] In a preferred embodiment of the present invention, after adding the first base to the first organic solvent, the compound of the structure shown in formula (1) and the compound of the structure shown in formula (2) are added for reaction. Thereby, the yield can be further improved.

[0058] According to the method of the present invention, in step 1), after the nucleophilic substitution reaction is completed, the post-treatment is very simple. Moreover, it is not necessary to refine the reactants to obtain the compound of the structure shown in formula (3) and then carry out the next reaction. Only by extracting and desolvating the reactants to obtain the nucleophilic substitution reaction product, and directly using this nucleophilic substitution reaction product to carry out the next decarboxylation reaction. Thereby, the post-treatment of step 1) is extremely simple and there is no loss of the target product caused by refining, and the total yield can be further improved while simplifying the steps.

[0059] There is no particular limitation on the above extraction method. For example, after mixing the reactants with water, an extraction solvent can be added for extraction.

[0060] The amount of water used above, for example, can be 1 to 20 times the volume of the reactants, preferably 1 to 10 times, more preferably 5 to 10 times.

[0061] As the extraction solvent for the above extraction, for example, ester organic solvents and / or halogenated alkane organic solvents can be used. Preferably, the extraction solvent for the above extraction is selected from one or more of methyl acetate, ethyl acetate, and dichloromethane. The volume ratio of the extraction solvent to the above water is 0.1 - 1:1, preferably 0.1 - 0.5:1, and more preferably 0.1 - 0.2:1.

[0062] In the above extraction process, preferably, the organic phase separated after extraction is dried with a desiccant and then subjected to solid-liquid separation and solvent removal.

[0063] As the above desiccant, for example, various desiccants commonly used in the art can be used. For example, anhydrous sodium sulfate can be used.

[0064] There is no limitation on the above solid-liquid separation method. For example, it can be carried out by filtration, centrifugation, etc.

[0065] According to the method of the present invention, preferably, the compound of the structure shown in formula (1) is obtained by subjecting the compound of the structure shown in formula (1-1) and the compound of the structure shown in formula (1-2) to a nucleophilic substitution reaction in the presence of a second organic solvent and a second base. Formula (1-1) Formula (1-2) In formula (1-1), X represents a halogen; in formula (1-2), R1 represents an alkyl group having 1 to 6 carbon atoms.

[0066] Here, X in formula (1-1) and R1 in formula (1-2) are the same as X and R1 in formula (1).

[0067] In the above-preferred method for preparing the compound of the structure shown in formula (1), preferably, the molar ratio of the compound of the structure shown in formula (1-1) to the compound of the structure shown in formula (1-2) is 1:1 - 1.5; more preferably, the molar ratio of the compound of the structure shown in formula (1-1) to the compound of the structure shown in formula (1-2) is 1:1 - 1.5; further preferably, the molar ratio of the compound of the structure shown in formula (1-1) to the compound of the structure shown in formula (1-2) is 1:1 - 1.2.

[0068] In the present invention, as specific examples of the molar ratio of the compound represented by the structure of formula (1-1) to the compound represented by the structure of formula (1-2), for example, the following can be cited: 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, etc., as well as the ranges formed by any two of the above and all values within these ranges.

[0069] In the preparation method of the compound represented by the preferred formula (1) as described above, preferably, the molar ratio of the compound represented by the structure of formula (1-1) to the second base is 1:1 - 2; more preferably, the molar ratio of the compound represented by the structure of formula (1-1) to the second base is 1:1 - 1.5; further preferably, the molar ratio of the compound represented by the structure of formula (1-1) to the second base is 1:1 - 1.3.

[0070] In the present invention, as specific examples of the molar ratio of the compound represented by the structure of formula (1-1) to the second base, for example, the following can be cited: 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, etc., as well as the ranges formed by any two of the above and all values within these ranges.

[0071] In the preparation method of the compound represented by the preferred formula (1) as described above, the amount of the second organic solvent can also be selected according to the reaction raw materials, as long as it can dissolve the reaction raw materials well. Preferably, the weight ratio of the compound represented by the structure of formula (1-1) to the second organic solvent is 1:1 - 10; more preferably, the weight ratio of the compound represented by the structure of formula (1-1) to the second organic solvent is 1:1 - 3.

[0072] In the present invention, as specific examples of the weight ratio of the compound represented by the structure of formula (1-1) to the second organic solvent, for example, the following can be cited: 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, etc., as well as the ranges formed by any two of the above and all values within these ranges.

[0073] In the preparation method of the compound represented by the preferred formula (1) as described above, the second base can be selected from inorganic bases or organic bases. Preferably, the second base is selected from one or more of potassium hydroxide, sodium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium hydride, potassium carbonate, sodium carbonate, triethylamine, N,N-diisopropylethylamine, and N,N-dimethylcyclohexylamine; more preferably, the second base is sodium hydroxide and / or potassium carbonate.

[0074] In the present invention, the first base and the second base can be the same or different.

[0075] In the preparation method of the compound with the structure shown in the above-preferred formula (1), the second organic solvent is used to dissolve the reaction raw materials to promote the reaction. Therefore, an organic solvent that is inert to the reaction raw materials and can dissolve the reaction raw materials well can be used for the nucleophilic substitution reaction of the present invention. Preferably, the second organic solvent is selected from one or more of dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, acetonitrile, dichloromethane, 1,2-dichloroethane, tert-butanol, benzene, toluene, and xylene; more preferably, the second organic solvent is dimethyl sulfoxide and / or N,N-dimethylacetamide.

[0076] In the present invention, the first organic solvent and the second organic solvent may be the same or different.

[0077] In the preparation method of the compound with the structure shown in the above-preferred formula (1), preferably, the temperature of the nucleophilic substitution reaction is 30-140 °C; more preferably, the temperature of the nucleophilic substitution reaction is 70-100 °C. In addition, the time of the nucleophilic substitution reaction only needs to ensure that the compound with the structure shown in formula (1) reacts sufficiently to obtain the compound with the structure shown in formula (3). For example, the time of the nucleophilic substitution reaction can be 2-10 h, preferably 2-4 h.

[0078] In the preparation method of the compound with the structure shown in the above-preferred formula (1), there is no particular limitation on the feeding order of each raw material. The second organic solvent can be added first, and then other raw materials can be added together or step by step to the second organic solvent to start the reaction. Or the above other raw materials can be added together or step by step to the reaction vessel first, and then the second organic solvent can be added to start the reaction.

[0079] In the preparation method of the compound with the structure shown in the above-preferred formula (1), preferably, after adding the second base to the second organic solvent, the compound with the structure shown in formula (1-1) and the compound with the structure shown in formula (1-2) are added for reaction. Thereby, the yield can be further improved.

[0080] In the preparation method of the compound with the structure shown in the above-preferred formula (1), after the nucleophilic substitution reaction is completed, the post-treatment is very simple. For example, it only needs to be cooled to room temperature after the nucleophilic substitution reaction is completed, and then the reactant is added to an acid solution with a pH value of 2-3 (preferably dropped into an acid solution with a pH value of 2-3, more preferably dropped into a hydrochloric acid solution with a pH value of 2-3) for precipitation, and the compound with the structure shown in formula (1) can be obtained with high purity and high yield.

[0081] Step 2): Decarboxylation reaction According to the method of the present invention, in step 2), in the presence of a first solvent and a first acid, the nucleophilic substitution reaction product obtained in step 1) is subjected to a decarboxylation reaction to obtain a decarboxylation reaction product containing the compound having the structure shown in formula (4).

[0082] According to the method of the present invention, in step 2), the amount of the first acid can be selected according to the amount of the nucleophilic substitution reaction product based on the compound having the structure shown in formula (3). Preferably, in step 2), the molar ratio of the nucleophilic substitution reaction product based on the compound having the structure shown in formula (3) to the first acid is 1:1 - 4; more preferably, in step 2), the molar ratio of the nucleophilic substitution reaction product based on the compound having the structure shown in formula (3) to the first acid is 1:1 - 2; further preferably, in step 2), the molar ratio of the nucleophilic substitution reaction product based on the compound having the structure shown in formula (3) to the first acid is 1:1 - 1.3.

[0083] In the present invention, as specific examples of the molar ratio of the nucleophilic substitution reaction product based on the compound having the structure shown in formula (3) to the first acid, for example, the following can be cited: 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9, 1:3, 1:3.1, 1:3.2, 1:3.3, 1:3.4, 1:3.5, 1:3.6, 1:3.7, 1:3.8, 1:3.9, 1:4, etc., as well as the ranges formed by any two of the above and all values within the range.

[0084] According to the method of the present invention, the first solvent is used to dissolve the reaction raw materials to promote the reaction. Preferably, the first solvent is selected from one or more of dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, methanol, ethanol, tert-butanol, and water; more preferably, the first solvent is selected from dimethyl sulfoxide and / or N,N-dimethylacetamide.

[0085] According to the method of the present invention, the amount of the first solvent can also be selected according to the reaction raw materials as long as the reaction raw materials can be well dissolved. Preferably, in step 2), the weight ratio of the nucleophilic substitution reaction product based on the compound having the structure shown in formula (3) to the first solvent is 1:1 - 10; more preferably, in step 2), the weight ratio of the nucleophilic substitution reaction product based on the compound having the structure shown in formula (3) to the first solvent is 1:1 - 3.

[0086] In the present invention, specific examples of the weight ratio of the nucleophilic substitution reaction product based on the compound of the structure shown in formula (3) to the first solvent include, for example: 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, etc., as well as the ranges formed by any two of the above and all values within the ranges.

[0087] According to the method of the present invention, the first acid can be selected from inorganic acids or organic acids. Preferably, in step 2), the first acid is selected from one or more of hydrochloric acid, sulfuric acid, phosphoric acid, and acetic acid; more preferably, in step 2), the first acid is hydrochloric acid and / or sulfuric acid.

[0088] According to the method of the present invention, preferably, the temperature of the decarboxylation reaction is 50 - 140 °C; more preferably, the temperature of the decarboxylation reaction is 100 - 120 °C.

[0089] In addition, the time of the decarboxylation reaction only needs to ensure sufficient reaction and obtain the compound of the structure shown in formula (4). For example, the time of the decarboxylation reaction can be 2 - 10 h, preferably 2 - 4 h.

[0090] According to the method of the present invention, in step 2), there is no particular limitation on the feeding order of each raw material. The first solvent can be added first, and then other raw materials can be added together or step by step to the first solvent to start the reaction. Or the above other raw materials can be added together or step by step to the reaction vessel first, and then the first solvent is added to start the decarboxylation reaction.

[0091] In a preferred embodiment of the present invention, after dissolving the nucleophilic substitution reaction product in the first solvent, the first acid is added dropwise to carry out the reaction. Thereby, the yield can be further improved.

[0092] According to the method of the present invention, in step 2), after the decarboxylation reaction is completed, the post-treatment is very simple. Moreover, it is not necessary to refine the reactants to obtain the compound of the structure shown in formula (4) and then carry out the next reaction. Only by extracting and removing the solvent from the reactants to obtain the decarboxylation reaction product, and directly using this decarboxylation reaction product to carry out the next de-cyanation reaction. Thereby, the post-treatment of step 2) is extremely simple and there is no loss of the target product caused by refining. While simplifying the steps, the total yield can be further improved.

[0093] There is no particular limitation on the above extraction method. For example, the reactants can be mixed with water and then an extraction solvent is added for extraction.

[0094] The amount of the above water, for example, can be 1 - 20 times the volume of the reactants, preferably 10 - 20 times, more preferably 10 - 15 times.

[0095] As the extraction solvent for the above extraction, ester organic solvents and / or halogenated alkane organic solvents can be used. Preferably, the above extraction solvent is selected from one or more of methyl acetate, ethyl acetate, and dichloromethane. The volume ratio of the extraction solvent to the above water is 0.1 - 1:1, preferably 0.1 - 0.5:1, and more preferably 0.1 - 0.2:1.

[0096] In the above extraction process, it is preferred that the organic phase separated after extraction is dried using a desiccant and then subjected to solid-liquid separation and solvent removal.

[0097] As the above desiccant, for example, various desiccants commonly used in the art can be used. For example, anhydrous sodium sulfate can be used.

[0098] There is no limitation on the method of the above solid-liquid separation. For example, it can be carried out by filtration, centrifugation, etc.

[0099] Step 3): De-cyanation reaction According to the method of the present invention, in step 3), in the presence of a second solvent and a second acid, the decarboxylation reaction product obtained in step 2) is subjected to a de-cyanation reaction to obtain a fluxapyroxad compound having the structure shown in formula (5).

[0100] According to the method of the present invention, in step 3), the amount of the second acid can be selected according to the amount of the decarboxylation reaction product based on the compound having the structure shown in formula (4). Preferably, in step 3), the molar ratio of the decarboxylation reaction product based on the compound having the structure shown in formula (4) to the second acid is 1:1 - 5; more preferably, in step 3), the molar ratio of the decarboxylation reaction product based on the compound having the structure shown in formula (4) to the second acid is 1:1.5 - 4; further preferably, in step 3), the molar ratio of the decarboxylation reaction product based on the compound having the structure shown in formula (4) to the second acid is 1:2 - 3.

[0101] In the present invention, specific examples of the molar ratio of the decarboxylation reaction product based on the compound having the structure shown in formula (4) to the second acid, for example, can include: 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9, 1:3, 1:3.1, 1:3.2, 1:3.3, 1:3.4, 1:3.5, 1:3.6, 1:3.7, 1:3.8, 1:3.9, 1:4, etc., as well as the ranges formed by any two of the above and all values within the range.

[0102] According to the method of the present invention, the second acid may be selected from inorganic acids or organic acids. Preferably, in step 3), the second acid is selected from one or more of hydrochloric acid, sulfuric acid, phosphoric acid, and acetic acid; more preferably, in step 3), the second acid is hydrochloric acid and / or sulfuric acid.

[0103] According to the method of the present invention, the second solution is used to dissolve the reaction raw materials to promote the reaction. Preferably, the second solvent is selected from one or more of dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, water, methanol, and acetic acid; more preferably, the second solvent is selected from water and / or acetic acid.

[0104] According to the method of the present invention, preferably, the molar ratio of the decarboxylation reaction product based on the compound of the structure shown in formula (4) to the second solvent is 1:1-5; more preferably, the molar ratio of the decarboxylation reaction product based on the compound of the structure shown in formula (4) to the second solvent is 1:1-3; further preferably, the molar ratio of the decarboxylation reaction product based on the compound of the structure shown in formula (4) to the second solvent is 1:1-2.

[0105] As specific examples of the molar ratio of the decarboxylation reaction product based on the compound of the structure shown in formula (4) to the second solvent, for example, the following can be cited: 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9, 1:3, 1:3.1, 1:3.2, 1:3.3, 1:3.4, 1:3.5, 1:3.6, 1:3.7, 1:3.8, 1:3.9, 1:4, 1:4.2, 1:4.5, 1:4.8, 1:5, etc., as well as the ranges formed by any two of the above and all values within the range.

[0106] According to the method of the present invention, preferably, the temperature of the decyanation reaction is 50-140 °C; more preferably, the temperature of the decyanation reaction is 50-100 °C.

[0107] In addition, the time of the decyanation reaction only needs to ensure sufficient reaction and obtain the compound of the structure shown in formula (5). For example, the time of the decyanation reaction can be 6-12 h, preferably 6-8 h.

[0108] According to the method of the present invention, in step 3), there is no particular limitation on the feeding order of each raw material. The second solvent can be added first, and then the other raw materials can be added together or step by step to the second solvent and then the reaction is started. Alternatively, the above other raw materials can be added together or step by step to the reaction vessel first, and then the second solvent is added to start the decyanation reaction.

[0109] In a preferred embodiment of the present invention, the decarboxylation reaction product, the second acid and the second solvent are mixed to carry out the decyanation reaction. Thereby, the yield can be further improved.

[0110] According to the method of the present invention, in step 3), after the decyanation reaction is completed, the post-treatment is very simple. Only by extracting and desolvating the reactants, the fluxapyroxad compound shown in formula (5) can be obtained.

[0111] There is no particular limitation on the above extraction method. For example, the reactants can be mixed with water and then an extraction solvent is added for extraction. When the solvent for the decyanation reaction is water, the extraction solvent can be directly added for extraction, or water can be added or part of the water can be removed as needed and then the extraction solvent is added for extraction.

[0112] The amount of water used during extraction can be, for example, 1 - 10 times the volume of the reactants, preferably 5 - 10 times, more preferably 5 - 6 times.

[0113] As the extraction solvent for the above extraction, ester organic solvents and / or halogenated alkane organic solvents can be used. Preferably, the extraction solvent for the above extraction is selected from one or more of methyl acetate, ethyl acetate and dichloromethane. The volume ratio of the extraction solvent to the above water is 0.1 - 1:1, preferably 0.1 - 0.5:1, preferably 0.1 - 0.2:1.

[0114] During the above extraction process, it is preferred that the organic phase separated after extraction is dried using a desiccant and then solid-liquid separation and desolvation are carried out.

[0115] As the above desiccant, for example, various desiccants commonly used in the art can be used. For example, anhydrous sodium sulfate can be used.

[0116] There is no limitation on the above solid-liquid separation method. For example, it can be carried out by filtration, centrifugation, etc.

[0117] According to the method of the present invention, in step 1), after the nucleophilic substitution reaction is completed, it is only necessary to cool to room temperature after the nucleophilic substitution reaction, and then add the reactant to an acid solution with a pH value of 2-3 for precipitation, and the compound of the structure shown in formula (1) can be obtained with high purity and high yield; moreover, in step 2), after the decarboxylation reaction is completed, it is not necessary to refine the reactant to obtain the compound of the structure shown in formula (4) and then carry out the next reaction. It is only necessary to extract and desolvate the reactant to obtain the decarboxylation reaction product, and use this decarboxylation reaction product to directly carry out the next de-cyanation reaction; in step 3), it is only necessary to extract and desolvate the reactant to obtain the fluopyram compound of the structure shown in formula (5). Thus, the post-treatment of each step of the method of the present invention is extremely simple, which can avoid the loss of the target product caused by refining, and can significantly improve the total yield while simplifying the steps.

[0118] According to the second aspect of the present invention, there is provided a fluopyram compound prepared by the preparation method of the fluopyram compound described in the first aspect of the present invention.

[0119] Through the above technical solutions, the present invention can provide a preparation method of a fluopyram compound with higher yield and more convenient operation and the fluopyram compound prepared thereby.

[0120] The present invention will be described in detail below through examples, but the present invention is not limited to the following examples.

[0121] The raw materials used in the following examples, if not specifically limited, are all disclosed in the prior art, for example, they can be directly purchased or prepared according to the preparation methods disclosed in the prior art.

[0122] In the following examples, the 1 1H nuclear magnetic resonance ( 1 1H-NMR) was carried out on a Bruker AVANCEIII-500 MHz spectrometer, using DMSO- d d6 as the solvent, and carried out at 25 °C.

[0123] Preparation Example 1 In a 250 mL four-necked flask equipped with a thermometer, a mechanical stirring paddle and a reflux pipe, 50.4 g of N,N-dimethylacetamide, 16.8 g of potassium carbonate and 1.0 g of tetrabutylammonium bromide were successively added. Subsequently, the temperature was raised to 75 °C. After reaching the temperature, a mixed solution of 21.6 g of 2,3-dichloro-5-trifluoromethylpyridine and 12.0 g of methyl cyanoacetate was added dropwise to the reaction solution, and the addition was completed within 1 hour. After the addition was completed, the reaction was carried out under insulation for 2 h. According to the HPLC results, the content of 2,3-dichloro-5-trifluoromethylpyridine was observed to be less than 0.05%. After the reaction solution was cooled to room temperature, the reaction solution was added dropwise to an aqueous hydrochloric acid solution with a pH of 1-2, and a solid was precipitated. The solid was filtered, washed with water, and dried to obtain a yellow solid, which was methyl 3-chloro-5-trifluoromethyl-2-pyridyl-2-cyanoacetate, with a yield of 96.2% and a purity of 98.9% by weight.

[0124] NMR data: 1 H (DMSO- d 6, 500 MHz): 3.77 (s, 3H); 8.34 (s, 1H); 8.54 (s,1H); 14.56 (s, 1H).

[0125] Preparation Example 2 In a 250 mL four-necked flask equipped with a thermometer, a mechanical stirring paddle and a reflux pipe, 50.4 g of N,N-dimethylacetamide, 16.8 g of potassium carbonate and 1.0 g of tetrabutylammonium bromide were successively added. Subsequently, the temperature was raised to 75 °C. After reaching the temperature, a mixed solution of 21.6 g of 2,3-dichloro-5-trifluoromethylpyridine and 13.6 g of ethyl cyanoacetate was added dropwise to the reaction solution, and the addition was completed within 1 hour. After the addition was completed, the reaction was carried out under insulation for 2 h. According to the HPLC results, the content of 2,3-dichloro-5-trifluoromethylpyridine was observed to be less than 0.05%. After the reaction solution was cooled to room temperature, the reaction solution was added dropwise to an aqueous hydrochloric acid solution with a pH of 1-2, and a solid was precipitated. The solid was filtered, washed with water, and dried to obtain a yellow solid, which was ethyl 3-chloro-5-trifluoromethyl-2-pyridyl-2-cyanoacetate, with a yield of 90.4% and a purity of 98.5% by weight.

[0126] NMR data: 1 H (DMSO- d 6, 500 MHz): 1.22 (t, 3H); 4.23 (q, 2H); 8.34 (s,1H); 8.54 (s, 1H); 14.56 (s, 1H).

[0127] Example 1 1) In a 100 mL four-necked flask equipped with a thermometer, a mechanical stirrer paddle and a reflux tube, 13.9 g of methyl 3-chloro-5-trifluoromethyl-2-pyridyl-2-cyanoacetate, 13.1 g of N-acetoxymethyl-2-trifluoromethylbenzamide, 6.9 g of potassium carbonate and 50.0 g of N,N-dimethylacetamide were added in sequence. Subsequently, the temperature was raised to 30 °C and the reaction was carried out under insulation for 6 h. According to the HPLC results, the content of methyl 3-chloro-5-trifluoromethyl-2-pyridyl-2-cyanoacetate was observed to be less than 0.05%. After the reaction solution was cooled to room temperature, 500 ml of water was added, and extraction was carried out with ethyl acetate. The organic phase was washed with water, dried, filtered and concentrated to obtain a yellow solid, which was the crude product of methyl 2-(3-chloro-5-trifluoromethylpyridin-2-yl)-2-cyano-3-(2-trifluoromethylbenzamido)propionate. It was directly used in the next step of the reaction without purification.

[0128] 2) In a 100 mL four-necked flask equipped with a thermometer, a mechanical stirrer paddle and a reflux tube, the crude product of methyl 2-(3-chloro-5-trifluoromethylpyridin-2-yl)-2-cyano-3-(2-trifluoromethylbenzamido)propionate (24.0 g calculated as methyl 2-(3-chloro-5-trifluoromethylpyridin-2-yl)-2-cyano-3-(2-trifluoromethylbenzamido)propionate), 50.0 g of N,N-dimethylacetamide and 6.1 g of concentrated hydrochloric acid (concentration: 37 wt%, the same below) were added in sequence. Subsequently, the temperature was raised to 120 °C and the reaction was carried out under insulation for 6 h. According to the HPLC results, the content of methyl 3-chloro-5-trifluoromethyl-2-pyridyl-2-cyanoacetate was observed to be less than 0.05%. After the reaction solution was cooled to room temperature, 500 ml of water was added, and extraction was carried out with ethyl acetate. The organic phase was washed with water, dried, filtered and concentrated to obtain a yellow solid, which was the crude product of N-(2-(3-chloro-5-trifluoromethylpyridin-2-yl)-2-cyanoethyl)-2-trifluoromethylbenzamide. It was directly used in the next step of the reaction without purification.

[0129] 3) Add the crude product of N-(2-(3-chloro-5-trifluoromethylpyridin-2-yl)-2-cyanoethyl)-2-trifluoromethylbenzamide (21.0 g based on N-(2-(3-chloro-5-trifluoromethylpyridin-2-yl)-2-cyanoethyl)-2-trifluoromethylbenzamide), 40.0 g of glacial acetic acid, 5.0 g of concentrated sulfuric acid (concentration 98 wt%, the same below), and 0.9 g of water into a 100 mL four-necked flask equipped with a thermometer, a mechanical stirrer paddle, and a reflux pipe. Then, heat up to 100 °C and keep the reaction at this temperature. According to the HPLC results, the content of N-(2-(3-chloro-5-trifluoromethylpyridin-2-yl)-2-cyanoethyl)-2-trifluoromethylbenzamide was observed to be less than 0.05%. Wait for the reaction solution to cool to room temperature, remove the solvent, wash with water, extract with ethyl acetate, dry, and then remove the solvent again to obtain a yellow solid. Place the yellow solid in a mixed solvent of methanol:water = 1:3 (v / v), stir at 25 °C for 30 minutes, then obtain the solid product by vacuum filtration, and wash and dry the filter cake with a mixed solvent of methanol:water = 1:3 (v / v) to obtain 18.3 g of the product fluopyram, with a purity of 96.0 wt% and a total yield of three steps of 88.5%.

[0130] NMR data: 1 H (DMSO- d 6, 400 MHz): 3.25 - 3.30 (m, 2H); 3.65 - 3.70 (m, 2H); 7.42 - 7.55 (m, 1H); 7.55 - 7.68 (m, 1H); 7.68 - 7.85 (m, 2H); 8.42 (s, 1H); 8.53 - 8.71 (m, 1H); 8.90 (s, 1H).

[0131] In addition, in order to confirm the structures of the compounds obtained in steps 1) and 2), preparations were carried out in the same manner as in steps 1) and 2), and a small amount of the yellow solid was taken for purification and NMR identification in steps 1) and 2) respectively. The results are as follows: NMR data for step 1): 1 H (DMSO- d 6, 500 MHz): 3.93 (s, 3H); 4.56 - 4.64 (q, 1H); 4.66 - 4.75 (q, 1H); 6.76 (s, 1H); 7.48 - 7.69 (m, 4H); 8.09 (s, 1H); 8.77 (s, 1H).

[0132] NMR data for step 2): 1 H (DMSO- d6,500 MHz): 3.78 - 3.97 (m, 2H); 5.11 (t, 1H); 7.47 - 7.85 (m, 4H); 8.62 (s, 1H); 9.00 - 9.10 (m, 2H).

[0133] Example 2 1) In a 100 mL four-necked flask equipped with a thermometer, a mechanical stirrer paddle, and a reflux tube, 14.6 g of ethyl 3-chloro-5-(trifluoromethyl)-2-pyridyl-2-cyanoacetate, 13.1 g of N-acetoxymethyl-2-(trifluoromethyl)benzamide, 6.9 g of potassium carbonate, and 50.0 g of N,N-dimethylacetamide were successively added. Subsequently, the temperature was raised to 30 °C and the reaction was carried out under insulation for 6 h. According to the HPLC results, the content of methyl 3-chloro-5-(trifluoromethyl)-2-pyridyl-2-cyanoacetate was observed to be less than 0.05%. After the reaction solution was cooled to room temperature, 500 ml of water was added, and extraction was carried out with ethyl acetate. The organic phase was washed with water, dried, filtered, and the solvent was removed to obtain a yellow solid, which was the crude product of ethyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-2-cyano-3-(2-(trifluoromethyl)benzamido)propionate. It was directly used in the next step without purification.

[0134] 2) In a 100 mL four-necked flask equipped with a thermometer, a mechanical stirrer paddle, and a reflux tube, the crude product of methyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-2-cyano-3-(2-(trifluoromethyl)benzamido)propionate (24.7 g calculated as ethyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-2-cyano-3-(2-(trifluoromethyl)benzamido)propionate), 50.0 g of N,N-dimethylacetamide, and 6.1 g of concentrated hydrochloric acid were successively added. Subsequently, the temperature was raised to 120 °C and the reaction was carried out under insulation for 6 h. According to the HPLC results, the content of methyl 3-chloro-5-(trifluoromethyl)-2-pyridyl-2-cyanoacetate was observed to be less than 0.05%. After the reaction solution was cooled to room temperature, 500 ml of water was added, and extraction was carried out with ethyl acetate. The organic phase was washed with water, dried, filtered, and the solvent was removed to obtain a yellow solid, which was the crude product of N-(2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-2-cyanoethyl)-2-(trifluoromethyl)benzamide. It was directly used in the next step without purification.

[0135] 3) In a 100 mL four-necked flask equipped with a thermometer, a mechanical stirrer paddle, and a reflux pipe, add the crude product of N-(2-(3-chloro-5-trifluoromethylpyridin-2-yl)-2-cyanoethyl)-2-trifluoromethylbenzamide (21.0 g based on N-(2-(3-chloro-5-trifluoromethylpyridin-2-yl)-2-cyanoethyl)-2-trifluoromethylbenzamide), 40.0 g of glacial acetic acid, 5.0 g of concentrated sulfuric acid, and 0.9 g of water. Subsequently, heat up to 100 °C and hold the reaction. According to the HPLC results, the content of N-(2-(3-chloro-5-trifluoromethylpyridin-2-yl)-2-cyanoethyl)-2-trifluoromethylbenzamide was observed to be less than 0.05%. After the reaction solution was cooled to room temperature, it was desolvated, washed with water, extracted with ethyl acetate, dried, and then desolvated again to obtain a yellow solid. The yellow solid was placed in a mixed solvent of methanol:water = 1:3 (v / v). After stirring at 25 °C for 30 minutes, the solid product was obtained by vacuum filtration, and the filter cake was washed and dried with a mixed solvent of methanol:water = 1:3 (v / v) to obtain 18.0 g of the product fluxapyroxad, with a purity of 95.5% by weight and a total yield of three steps of 87.0%.

[0136] NMR data: 1 H (DMSO- d 6, 500 MHz): 3.26 - 3.51 (m, 2H); 3.62 - 3.75 (m, 2H); 7.41 - 7.56 (m, 1H); 7.58 - 7.62 (m, 1H); 7.63 - 7.86 (m, 2H); 8.41 (s, 1H); 8.50 - 9.71 (m, 1H); 8.90 (s, 1H).

[0137] Example 3 1) In a 100 mL four-necked flask equipped with a thermometer, a mechanical stirrer paddle, and a reflux pipe, sequentially add 13.9 g of methyl 3-chloro-5-trifluoromethyl-2-pyridyl-2-cyanoacetate, 13.1 g of N-acetoxymethyl-2-trifluoromethylbenzamide, 9.0 g of a 30 wt% methanol solution of sodium methoxide, and 50.0 g of N,N-dimethylacetamide. Subsequently, heat up to 30 °C and hold the reaction for 6 h. According to the HPLC results, the content of methyl 3-chloro-5-trifluoromethyl-2-pyridyl-2-cyanoacetate was observed to be less than 0.05%. After the reaction solution was cooled to room temperature, 500 ml of water was added, and it was extracted with ethyl acetate. The organic phase was washed with water, dried, filtered, and desolvated to obtain a yellow solid, which was the crude product of methyl 2-(3-chloro-5-trifluoromethylpyridin-2-yl)-2-cyano-3-(2-trifluoromethylbenzamide)propionate. It was directly used in the next step without purification.

[0138] 2) In a 100 mL four-necked flask equipped with a thermometer, a mechanical stirrer paddle, and a reflux pipe, successively add the crude product of methyl 2-(3-chloro-5-trifluoromethylpyridin-2-yl)-2-cyano-3-(2-trifluoromethylbenzamide)propionate (24.0 g based on methyl 2-(3-chloro-5-trifluoromethylpyridin-2-yl)-2-cyano-3-(2-trifluoromethylbenzamide)propionate), 50.0 g of N,N-dimethylacetamide, and 6.1 g of concentrated hydrochloric acid. Subsequently, heat up to 120 °C and keep the reaction for 6 h. According to the HPLC results, it was observed that the content of methyl 3-chloro-5-trifluoromethyl-2-pyridyl-2-cyanoacetate was less than 0.05%. After the reaction solution cooled to room temperature, add 500 ml of water, extract with ethyl acetate, wash the organic phase, dry, filter, and remove the solvent to obtain a yellow solid, which is the crude product of N-(2-(3-chloro-5-trifluoromethylpyridin-2-yl)-2-cyanoethyl)-2-trifluoromethylbenzamide. It was directly used in the next step without purification.

[0139] 3) In a 100 mL four-necked flask equipped with a thermometer, a mechanical stirrer paddle, and a reflux pipe, add the crude product of N-(2-(3-chloro-5-trifluoromethylpyridin-2-yl)-2-cyanoethyl)-2-trifluoromethylbenzamide (21.0 g based on N-(2-(3-chloro-5-trifluoromethylpyridin-2-yl)-2-cyanoethyl)-2-trifluoromethylbenzamide), 40.0 g of glacial acetic acid, 5.0 g of concentrated sulfuric acid, and 0.9 g of water. Subsequently, heat up to 100 °C and keep the reaction. According to the HPLC results, it was observed that the content of N-(2-(3-chloro-5-trifluoromethylpyridin-2-yl)-2-cyanoethyl)-2-trifluoromethylbenzamide was less than 0.05%. After the reaction solution cooled to room temperature, remove the solvent, wash with water, extract with ethyl acetate, dry, and then remove the solvent to obtain a yellow solid. Place the yellow solid in a mixed solvent of methanol:water = 1:3 (v / v), stir at 25 °C for 30 minutes, and then obtain the solid product by vacuum filtration. Wash the filter cake with a mixed solvent of methanol:water = 1:3 (v / v) and dry to obtain 18.8 g of the product fluxapyroxad, with a purity of 96.2% by weight and a total three-step yield of 91.3%.

[0140] Example 4 Carry out according to the method of Example 1, except that the reaction temperature is 40 °C and the reaction time is 6 h. The other steps are carried out in the same way to obtain 16.71 g of fluxapyroxad, with a purity of 95.7% by weight and a total three-step yield of 80.8%.

[0141] Example 5 Carry out according to the method of Example 1, except that the reaction temperature is 60 °C and the reaction time is 2 h. The other steps are carried out in the same way. Pulp the residue to obtain 16.52 g of fluxapyroxad, with a purity of 96.3% by weight and a total three-step yield of 80.3%.

[0142] Example 6 It was carried out according to the method of Example 1, except that potassium carbonate was replaced with triethylamine in the same molar amount, and other steps were carried out in the same manner. The residue was slurried to obtain 18.59 g of fluxapyroxad with a purity of 98.5% by weight, and the total yield of the three steps was 92.5%.

[0143] Example 7 It was carried out according to the method of Example 1, except that potassium carbonate was replaced with triethylamine in the same molar amount, and the solvent N,N-dimethylacetamide was replaced with toluene in the same mass, and other steps were carried out in the same manner. The residue was slurried to obtain 18.64 g of fluxapyroxad with a purity of 99.0% by weight, and the total yield of the three steps was 93.2%.

[0144] Example 8 1) 13.9 g of methyl 3-chloro-5-(trifluoromethyl)-2-pyridyl-2-cyanoacetate, 13.1 g of N-acetoxymethyl-2-(trifluoromethyl)benzamide, 6.9 g of potassium carbonate and 50.0 g of N,N-dimethylacetamide were successively added to a 100 mL four-necked flask equipped with a thermometer, a mechanical stirrer paddle and a reflux tube. Subsequently, the temperature was raised to 80 °C and the reaction was carried out under heat preservation for 6 h. According to the HPLC results, the content of methyl 3-chloro-5-(trifluoromethyl)-2-pyridyl-2-cyanoacetate was observed to be less than 0.05%. After the reaction solution was cooled to room temperature, 500 ml of water was added, and extraction was carried out with ethyl acetate. The organic phase was washed with water, dried, filtered, and the solvent was removed to obtain a yellow solid, which was the crude product of methyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-2-cyano-3-(2-(trifluoromethyl)benzamido)propionate. It was directly used in the next step of the reaction without purification.

[0145] 2) The crude product of methyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-2-cyano-3-(2-(trifluoromethyl)benzamido)propionate (24.0 g based on methyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-2-cyano-3-(2-(trifluoromethyl)benzamido)propionate), 50.0 g of N,N-dimethylacetamide and 6.1 g of concentrated hydrochloric acid were successively added to a 100 mL four-necked flask equipped with a thermometer, a mechanical stirrer paddle and a reflux tube. Subsequently, the temperature was raised to 120 °C and the reaction was carried out under heat preservation for 6 h. According to the HPLC results, the content of methyl 3-chloro-5-(trifluoromethyl)-2-pyridyl-2-cyanoacetate was observed to be less than 0.05%. After the reaction solution was cooled to room temperature, 500 ml of water was added, and extraction was carried out with ethyl acetate. The organic phase was washed with water, dried, filtered, and the solvent was removed to obtain a yellow solid, which was the crude product of N-(2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-2-cyanoethyl)-2-(trifluoromethyl)benzamide. It was directly used in the next step of the reaction without purification.

[0146] 3) In a 100 mL four-necked flask equipped with a thermometer, a mechanical stirrer paddle, and a reflux tube, add the crude product of N-(2-(3-chloro-5-trifluoromethylpyridin-2-yl)-2-cyanoethyl)-2-trifluoromethylbenzamide (21.0 g based on N-(2-(3-chloro-5-trifluoromethylpyridin-2-yl)-2-cyanoethyl)-2-trifluoromethylbenzamide), 40.0 g of glacial acetic acid, 5.0 g of concentrated sulfuric acid, and 0.9 g of water. Subsequently, heat up to 100 °C and hold for the reaction. According to the HPLC results, it was observed that the content of N-(2-(3-chloro-5-trifluoromethylpyridin-2-yl)-2-cyanoethyl)-2-trifluoromethylbenzamide was less than 0.05%. After the reaction solution was cooled to room temperature, remove the solvent, wash with water, extract with ethyl acetate, dry, and then remove the solvent again to obtain a yellow solid. Place the yellow solid in a mixed solvent of methanol:water = 1:3 (v / v). After stirring at 25 °C for 30 minutes, obtain the solid product by vacuum filtration, and wash and dry the filter cake with a mixed solvent of methanol:water = 1:3 (v / v) to obtain 12.9 g of the product fluopyram, with a purity of 96.1% by weight and a total yield of three steps of 62.4%.

[0147] Example 9 1) In a 100 mL four-necked flask equipped with a thermometer, a mechanical stirrer paddle, and a reflux tube, successively add 13.9 g of methyl 3-chloro-5-trifluoromethyl-2-pyridyl-2-cyanoacetate, 13.1 g of N-acetoxymethyl-2-trifluoromethylbenzamide, 6.9 g of potassium carbonate, and 50.0 g of N,N-dimethylacetamide. Subsequently, heat up to 30 °C and hold for the reaction for 12 h. According to the HPLC results, it was observed that the content of methyl 3-chloro-5-trifluoromethyl-2-pyridyl-2-cyanoacetate was less than 0.05%. After the reaction solution was cooled to room temperature, add 500 ml of water, extract with ethyl acetate, wash the organic phase with water, dry, filter, and remove the solvent to obtain a yellow solid, which is the crude product of methyl 2-(3-chloro-5-trifluoromethylpyridin-2-yl)-2-cyano-3-(2-trifluoromethylbenzamide)propionate. It was directly used in the next step without purification.

[0148] 2) In a 100 mL four-necked flask equipped with a thermometer, a mechanical stirrer paddle and a reflux pipe, successively add the crude product of methyl 2-(3-chloro-5-trifluoromethylpyridin-2-yl)-2-cyano-3-(2-trifluoromethylbenzamide)propionate (24.0 g based on methyl 2-(3-chloro-5-trifluoromethylpyridin-2-yl)-2-cyano-3-(2-trifluoromethylbenzamide)propionate), 50.0 g of N,N-dimethylacetamide, and 6.1 g of concentrated hydrochloric acid. Subsequently, heat up to 120 °C and keep the reaction for 6 h. According to the HPLC results, it is observed that the content of methyl 3-chloro-5-trifluoromethyl-2-pyridyl-2-cyanoacetate is less than 0.05%. Wait for the reaction solution to cool to room temperature, add 500 ml of water, extract with ethyl acetate, wash the organic phase, dry, filter, and remove the solvent to obtain a yellow solid, which is the crude product of N-(2-(3-chloro-5-trifluoromethylpyridin-2-yl)-2-cyanoethyl)-2-trifluoromethylbenzamide. It is directly used in the next reaction without purification.

[0149] 3) In a 100 mL four-necked flask equipped with a thermometer, a mechanical stirrer paddle and a reflux pipe, add the crude product of N-(2-(3-chloro-5-trifluoromethylpyridin-2-yl)-2-cyanoethyl)-2-trifluoromethylbenzamide (21.0 g based on N-(2-(3-chloro-5-trifluoromethylpyridin-2-yl)-2-cyanoethyl)-2-trifluoromethylbenzamide), 40.0 g of glacial acetic acid, 5.0 g of concentrated sulfuric acid, and 0.9 g of water. Subsequently, heat up to 100 °C and keep the reaction. According to the HPLC results, it is observed that the content of N-(2-(3-chloro-5-trifluoromethylpyridin-2-yl)-2-cyanoethyl)-2-trifluoromethylbenzamide is less than 0.05%. Wait for the reaction solution to cool to room temperature, remove the solvent, wash with water, extract with ethyl acetate, dry, and then remove the solvent to obtain a yellow solid. Place the yellow solid in a mixed solvent of methanol:water = 1:3 (v / v), stir at 25 °C for 30 minutes, then obtain the solid product by vacuum filtration, and wash and dry the filter cake with a mixed solvent of methanol:water = 1:3 (v / v) to obtain 15.3 g of the product fluopyram, with a purity of 96.8% by weight, and the total yield of the three steps is 74.9%.

[0150] The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited thereto. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solutions of the present invention, including any other suitable combination of each technical feature. These simple modifications and combinations should also be regarded as the content disclosed by the present invention and fall within the protection scope of the present invention.

Claims

1. A method for preparing a fluxapyroxad compound, characterized in that, The method comprises the following steps: 1) A step of performing a nucleophilic substitution reaction between a compound having the structure shown in formula (1) and a compound having the structure shown in formula (2) in the presence of a first organic solvent and a first base to obtain a nucleophilic substitution reaction product containing a compound having the structure shown in formula (3); 2) A step of performing a decarboxylation reaction on the nucleophilic substitution reaction product obtained in step 1) in the presence of a first solvent and a first acid to obtain a decarboxylation reaction product containing a compound having the structure shown in formula (4); 3) A step of performing a de-cyanation reaction on the decarboxylation reaction product obtained in step 2) in the presence of a second solvent and a second acid to obtain a fluxapyroxad compound having the structure shown in formula (5), Formula (1) Formula (2) Equation (3) Equation (4) Formula (5) In formula (1) and formulae (3)-(5), X represents a halogen; In formula (1) and formula (3), R1 represents -COOC 1-6 alkyl; In formula (2), R2 represents an alkyl group having 1 to 6 carbon atoms.

2. The method according to claim 1, wherein In formula (1) and formulae (3)-(5), X represents F, Cl or Br; In formula (1) and formula (3), R1 represents -COOC 1-3 alkyl; In formula (2), R2 represents an alkyl group having 1 to 3 carbon atoms.

3. The method according to claim 2, wherein In formula (1) and formulae (3)-(5), X is F or Cl; In formula (1) and formula (3), R1 is -COOCH3, -COOCH2CH3 or -COOCCH2CH2CH3; In formula (2), R2 is methyl, ethyl or propyl.

4. The method according to claim 3, wherein, In formula (1) and formulae (3)-(5), X is Cl; In formula (1) and formula (3), R1 is -COOCH3 or -COOCH2CH3; In formula (2), R2 is methyl.

5. The method according to claim 1, wherein In step 1), the molar ratio of the compound having the structure shown in formula (1) to the compound having the structure shown in formula (2) is 1:0.9 - 1.

5.

6. The method according to claim 5, wherein, In step 1), the molar ratio of the compound having the structure shown in formula (1) to the compound having the structure shown in formula (2) is 1:1 - 1.

2.

7. The method according to claim 1, wherein In step 1), the molar ratio of the compound having the structure shown in formula (1) to the first base is 1:1 - 2.

8. The method according to claim 7, wherein, In step 1), the molar ratio of the compound having the structure shown in formula (1) to the first base is 1:1 - 1.

3.

9. The method according to claim 1, wherein In step 1), the weight ratio of the compound having the structure shown in formula (1) to the first organic solvent is 1:1 - 10.

10. The method according to any one of claims 1-9, wherein The first organic solvent is selected from one or more of dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, acetonitrile, dichloromethane, 1,2-dichloroethane, tert-butanol, benzene, toluene and xylene.

11. The method according to any one of claims 1-9, wherein, The first organic solvent is toluene and / or N,N-dimethylacetamide.

12. The method according to any one of claims 1-9, wherein, The first base is selected from one or more of potassium hydroxide, sodium hydroxide, sodium methoxide, potassium tert-butoxide, sodium tert-butoxide, sodium hydride, potassium carbonate, sodium carbonate, triethylamine, N,N-diisopropylethylamine and N,N-dimethylcyclohexylamine.

13. The method according to claim 12, wherein, The first base is potassium carbonate and / or triethylamine.

14. The method according to any one of claims 1-9, wherein, The first organic solvent is toluene and the first base is triethylamine.

15. The method according to any one of claims 1-9, wherein The temperature of the nucleophilic substitution reaction is 20 - 100 °C.

16. The method according to any one of claims 1-9, wherein, In step 1), the nucleophilic substitution reaction product is obtained by extracting and desolvating the reactants.

17. The method according to any one of claims 1-9, wherein In step 2), the molar ratio of the nucleophilic substitution reaction product calculated based on the compound having the structure shown in formula (3) to the first acid is 1:1 - 4.

18. The method according to claim 17, wherein, In step 2), the molar ratio of the nucleophilic substitution reaction product based on the compound having the structure shown in formula (3) to the first acid is 1:1 - 1.

3.

19. The method according to any one of claims 1-9, wherein, In step 2), the weight ratio of the nucleophilic substitution reaction product based on the compound having the structure shown in formula (3) to the first solvent is 1:1 - 10.

20. The method according to any one of claims 1-9, wherein In step 2), the first acid is selected from one or more of hydrochloric acid, sulfuric acid, phosphoric acid, and acetic acid.

21. The method according to any one of claims 1-9, wherein, The first solvent is selected from one or more of dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, methanol, ethanol, tert-butanol, and water.

22. The method according to any one of claims 1-9, wherein, In step 2), the temperature of the decarboxylation reaction is 50 - 140 °C.

23. The method according to any one of claims 1-9, wherein, In step 2), the decarboxylation reaction product is obtained by extracting and desolvating the reactants.

24. The method according to any one of claims 1-9, wherein, In step 3), the molar ratio of the decarboxylation reaction product based on the compound having the structure shown in formula (4) to the second acid is 1:1 - 5.

25. The method according to claim 24, wherein, In step 3), the molar ratio of the decarboxylation reaction product based on the compound having the structure shown in formula (4) to the second acid is 1:2 - 3.

26. The method according to any one of claims 1-9, wherein The weight ratio of the decarboxylation reaction product based on the compound having the structure shown in formula (4) to the second solvent is 1:1 - 5.

27. The method according to any one of claims 1-9, wherein, In step 3), the second acid is selected from one or more of hydrochloric acid, sulfuric acid, phosphoric acid, and acetic acid.

28. The method according to any one of claims 1-9, wherein, The second solvent is selected from one or more of dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, water, methanol, and acetic acid.

29. The method according to any one of claims 1-9, wherein, In step 3), the temperature of the decyanation reaction is 50 - 140 °C.

30. The method according to any one of claims 1-9, wherein, In step 3), the fluopyram compound having the structure shown in formula (5) is obtained by extracting and desolvating the reactants.

31. A fluopyram compound prepared by the method for preparing a fluopyram compound according to any one of claims 1 - 30.

Images