Fluopyram compounds and preparation methods thereof

Abstract

The present 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 of the present invention comprises: 1) in the presence of a first organic solvent and a first base, subjecting a compound having a structure represented by formula (1) to a nucleophilic substitution reaction with a compound having a structure represented by formula (2); 2) in the presence of a first solvent and a first acid, subjecting the nucleophilic substitution reaction product obtained in step 1) to a decarboxylation reaction; 3) in the presence of a second solvent and a second acid, subjecting the decarboxylation reaction product obtained in step 2) to a decyanation reaction to obtain a fluopyram compound, wherein X represents a halogen, and R1 represents -COOC 1‑6 Alkyl; in formula (2), R2 represents an alkyl group having 1-6 carbon atoms. The method for preparing fluopyram compounds according to the present invention has a higher yield and is more convenient to operate. #imgabs0# Formula (1) #imgabs1# Formula (2)

Description

Technical Field

[0001] The present invention relates to the technical field of pesticides, and in particular 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 enzyme of pathogens, inhibiting their respiration. They disrupt the mitochondrial tricarboxylic acid cycle and respiratory chain within plant cells, thereby inhibiting respiration. These fungicides are highly specific, potent, long-lasting, and significantly increase yields.

[0003] Fluopyram, developed by Bayer CropScience, is a representative SDHIs fungicide. In addition to being used to prevent and control leaf spot, leaf spot, gray mold, powdery mildew, sclerotinia, early blight, etc. on vegetables and field crops such as grapes, pear trees, bananas, apples, cucumbers, tomatoes, etc., it can also be used to prevent and control various nematodes. It is a highly effective, 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] There are mainly two reported synthetic routes for fluopyram. One is obtained by the reaction of 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)ethanamine and 2-trifluoromethylbenzoyl chloride; the other is obtained by the nucleophilic reaction of dimethyl 2-(3-chloro-5-(trifluoromethyl)-2-pyridinyl)-1,3-malonate with N-((acetoxy)methyl)-2-trifluoromethylbenzamide, followed by hydrolysis and decarboxylation.

[0006] Regarding Route 1, 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)ethanamine is a key intermediate in the synthesis of fluopyram. Most reported synthetic routes for 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)ethanamine use 2-cyanomethyl-3-chloro-5-trifluoromethylpyridine as a raw material and are prepared by high-pressure hydrogenation reduction using precious metal catalysts, yielding approximately 80%. However, the reaction conditions are harsh, the operation is cumbersome, and industrial production costs are prohibitive.

[0007] Regarding route 2, WO2006067103A2 proposes a reaction route starting from 2,3-dichloro-5-trifluoromethylpyridine and reacting it with a malonate to synthesize the key intermediate 3-chloro-5-trifluoromethyl-2-pyridyl malonate. However, the reaction separation yield is only 82-88%, which is low and affects the overall reaction yield. Summary of the Invention

[0008] The purpose of the present invention is to overcome the problem of low total yield in the prior art and to provide a method for preparing a fluopyram compound with higher yield and more convenient operation and the fluopyram compound prepared therefrom.

[0009] In order to achieve the above object, the first aspect of the present invention provides a method for preparing a fluopyram compound, wherein the method comprises the following steps:

[0010] 1) in the presence of a first organic solvent and a first base, subjecting the compound represented by formula (1) and the compound represented by formula (2) to a nucleophilic substitution reaction to obtain a nucleophilic substitution reaction product containing a compound represented by formula (3);

[0011] 2) in the presence of a first solvent and a first acid, subjecting the nucleophilic substitution reaction product obtained in step 1) to a decarboxylation reaction to obtain a decarboxylation reaction product of a compound having a structure represented by formula (4);

[0012] 3) in the presence of a second solvent and a second acid, subjecting the decarboxylation reaction product obtained in step 2) to a decyanation reaction to obtain a fluopyram compound having a structure represented by formula (5);

[0013] Formula (1) Formula (2)

[0014] Formula (3) Formula (4)

[0015] Formula (5)

[0016] In formula (1) and formula (3)-(5), X represents halogen; in formula (1) and formula (3), R1 represents -COOC 1-6 Alkyl group; in formula (2), R2 represents an alkyl group having 1 to 6 carbon atoms.

[0017] Preferably, in formula (1) and formula (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 The alkyl group is preferably -COOCH3, -COOCH2CH3 or -COOCCH2CH2CH3, more preferably -COOCH3 or -COOCH2CH3.

[0018] Preferably, in formula (2), R2 represents an alkyl group having 1 to 3 carbon atoms, preferably a methyl group, an ethyl group or a propyl group, more preferably a methyl group.

[0019] Preferably, in step 1), the molar ratio of the compound having the structure represented by formula (1) to the compound having the structure represented by formula (2) is 1:0.9-1.5, preferably 1:1-1.5, and more preferably 1:1-1.2.

[0020] Preferably, in step 1), the molar ratio of the compound having the structure represented by formula (1) to the first base is 1:1-2, preferably 1:1-1.5, and more preferably 1:1-1.3.

[0021] Preferably, in step 1), the weight ratio of the compound having the structure represented by formula (1) to the first organic solvent is 1:1-10, preferably 1:1-3.

[0022] 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.

[0023] 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.

[0024] Preferably, the temperature of the nucleophilic substitution reaction is 20-100°C, preferably 30-70°C.

[0025] Preferably, in step 1), the nucleophilic substitution reaction product is obtained by extracting and desolvating the reactants.

[0026] Preferably, in step 2), the molar ratio of the nucleophilic substitution reaction product, calculated as the compound having the structure represented by formula (3), to the first acid is 1:1-4, preferably 1:1-2, and more preferably 1:1-1.3.

[0027] Preferably, in step 2), the weight ratio of the nucleophilic substitution reaction product, calculated as the compound having the structure represented by formula (3), to the first solvent is 1:1-10, preferably 1:1-3.

[0028] 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.

[0029] 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.

[0030] Preferably, in step 2), the temperature of the decarboxylation reaction is 50-140°C, preferably 100-120°C.

[0031] Preferably, in step 2), the decarboxylation reaction product is obtained by extracting and desolvating the reactants.

[0032] Preferably, in step 3), the molar ratio of the decarboxylation reaction product, calculated as the compound having the structure represented by formula (4), to the second acid is 1:1-5, preferably 1:1.5-4, more preferably 1:2-3.

[0033] Preferably, the molar ratio of the decarboxylation reaction product calculated as the compound of the structure represented by formula (4) to the second solvent is 1:1-5, preferably 1:1-3, more preferably 1:1-2.

[0034] 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.

[0035] 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.

[0036] Preferably, the temperature of the decyanation reaction is 50-140°C, preferably 50-100°C.

[0037] Preferably, in step 3), the reactants are extracted and desolvated to obtain a fluopyram compound having a structure represented by formula (5).

[0038] According to a second aspect of the present invention, there is provided a fluopyram compound prepared by the method for preparing the fluopyram compound according to the first aspect of the present invention.

[0039] Through the above technical solution, the present invention can provide a method for preparing fluopyram compounds with higher yield and more convenient operation, and the fluopyram compounds prepared therefrom. DETAILED DESCRIPTION

[0040] The endpoints of the ranges and any values disclosed herein are not limited to the precise ranges or values, and these ranges or values should be understood to include values close to these ranges or values. For numerical ranges, the endpoints of each range, the endpoints of each range and individual point values, and the individual point values can be combined with each other to obtain one or more new numerical ranges, which should be considered to be specifically disclosed herein.

[0041] The first aspect of the present invention provides a method for preparing a fluopyram compound, wherein the method comprises the following steps:

[0042] 1) in the presence of a first organic solvent and a first base, subjecting the compound represented by formula (1) and the compound represented by formula (2) to a nucleophilic substitution reaction to obtain a nucleophilic substitution reaction product containing a compound represented by formula (3);

[0043] 2) in the presence of a first solvent and a first acid, subjecting the nucleophilic substitution reaction product obtained in step 1) to a decarboxylation reaction to obtain a decarboxylation reaction product of a compound having a structure represented by formula (4);

[0044] 3) in the presence of a second solvent and a second acid, subjecting the decarboxylation reaction product obtained in step 2) to a decyanation reaction to obtain a fluopyram compound having a structure represented by formula (5);

[0045] Formula (1) Formula (2)

[0046] Formula (3) Formula (4)

[0047] Formula (5)

[0048] In formula (1) and formula (3)-(5), X represents halogen, and R1 represents -COOC 1-6 Alkyl group; in formula (2), R2 represents an alkyl group having 1 to 6 carbon atoms.

[0049] In the present invention, "alkyl group having 1 to 6 carbon atoms" and "C 1-6 The term "alkyl" refers to a linear or branched alkyl group having 1 to 6 carbon atoms, and examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, and n-hexyl. Among these, an alkyl group having 1 to 3 carbon atoms is preferred, and a methyl, ethyl, or n-propyl group is more preferred.

[0050] In the present invention, as "C 1-6 "Alkyl" includes, for example, -COOCH3, -COOCH2CH3, -COOCH2CH2CH3, -COOCH2CH2CH2CH3, -COOCH2CH2CH2CH2CH3, or -COOCH2CH2CH2CH2CH2CH3.

[0051] In the present invention, in formula (1) and formula (3) to (5), X represents a halogen, for example, F, Cl, Br, I, etc. Preferably, X represents F, Cl or B; more preferably, X represents F or Cl; particularly preferably, X is Cl.

[0052] In the present invention, in formula (1) and formula (3), R1 represents -COOC 1-6 Alkyl; preferably, R1 represents -COOC 1-3 Alkyl; more preferably, R1 is -COOCH3, -COOCH2CH3 or -COOCCH2CH2CH3; particularly preferably, R1 is -COOCH3 or -COOCH2CH3.

[0053] In the present invention, the compound represented by formula (1) is preferably one or more compounds represented by the following formulas:

[0054] Formula (1-A), Formula (1-B), Formula (1-C),

[0055] In formula (1-A) to formula (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.

[0056] In the present invention, in formula (2), R2 represents an alkyl group having 1 to 6 carbon atoms; preferably, R2 represents an alkyl group having 1 to 3 carbon atoms; more preferably, R2 is a methyl group, an ethyl group or a propyl group; particularly preferably, R2 is a methyl group.

[0057] In the present invention, the compound represented by formula (2) is preferably one or more compounds represented by the following formulas:

[0058] Formula (2-A), Formula (2-B), Formula (2-C).

[0059] The preparation method of the fluopyram compound of the present invention is described in steps below.

[0060] Step 1): Nucleophilic substitution reaction

[0061] According to the method of the present invention, in step 1), in the presence of a first organic solvent and a first base, a compound having a structure represented by formula (1) and a compound having a structure represented by formula (2) undergo a nucleophilic substitution reaction to obtain a nucleophilic substitution reaction product containing a compound having a structure represented by formula (3).

[0062] According to the method of the present invention, in step 1), the amount of the compound of the structure represented by formula (2) can be selected based on the amount of the compound of the structure represented by formula (1). Preferably, in step 1), the molar ratio of the compound of the structure represented by formula (1) to the compound of the structure represented by formula (2) is 1:0.9-1.5; more preferably, in step 1), the molar ratio of the compound of the structure represented by formula (1) to the compound of the structure represented by formula (2) is 1:1-1.5; further preferably, in step 1), the molar ratio of the compound of the structure represented by formula (1) to the compound of the structure represented by formula (2) is 1:1-1.2.

[0063] In the present invention, specific examples of the molar ratio of the compound represented by formula (1) to the compound represented by formula (2) include: 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, etc., as well as ranges consisting of any two of the above and all values within the range.

[0064] According to the method of the present invention, in step 1), the amount of the first base can also be selected based on the amount of the compound of formula (1). Preferably, in step 1), the molar ratio of the compound of formula (1) to the first base is 1:1-2; more preferably, in step 1), the molar ratio of the compound of formula (1) to the first base is 1:1-1.5; further preferably, in step 1), the molar ratio of the compound of formula (1) to the first base is 1:1-1.3.

[0065] In the present invention, specific examples of the molar ratio of the compound represented by formula (1) to the first base 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, etc., as well as ranges consisting of any two of the above ratios and all values within the range.

[0066] 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 well dissolve the reaction raw materials 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.

[0067] According to the method of the present invention, the amount of the first organic solvent can be selected based on the reaction raw materials, as long as it can effectively dissolve the reaction raw materials. Preferably, in step 1), the weight ratio of the compound of formula (1) to the first organic solvent is 1:1-10; more preferably, in step 1), the weight ratio of the compound of formula (1) to the first organic solvent is 1:1-3.

[0068] In the present invention, specific examples of the weight ratio of the compound represented by formula (1) to the first organic solvent include: 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 range formed by any two of the above ratios and all values within the range.

[0069] According to the method of the present invention, the first base can be selected from an inorganic base or an organic base. 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.

[0070] In a preferred embodiment of the present invention, the first base is triethylamine, which can significantly improve the overall yield of the present invention.

[0071] In a particularly preferred embodiment of the present invention, the first organic solvent is toluene, and the first base is triethylamine, thereby being able to further significantly improve the total yield of the present invention.

[0072] 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.

[0073] In addition, the time of the nucleophilic substitution reaction can be as long as it can ensure that the compound of the structure represented by formula (1) is fully reacted to obtain the compound of the structure represented by formula (3). For example, the time of the nucleophilic substitution reaction can be 6-12 hours, preferably 6-8 hours.

[0074] According to the method of the present invention, in step 1), there is no particular limitation on the order of adding the raw materials. The first organic solvent may be added first, and then the other raw materials may be added together or in steps to the first organic solvent to start the reaction. Alternatively, the other raw materials may be added together or in steps to the reaction vessel first, and then added to the first organic solvent to start the reaction.

[0075] In a preferred embodiment of the present invention, after the first base is added to the first organic solvent, the compound represented by formula (1) and the compound represented by formula (2) are added to react. This can further improve the yield.

[0076] According to the method of the present invention, in step 1), after the nucleophilic substitution reaction is completed, the post-treatment thereof is very simple, and there is no need to purify the reactants to obtain the compound having the structure represented by formula (3) before proceeding to the next reaction. Instead, it is only necessary to extract and desolvate the reactants to obtain the nucleophilic substitution reaction product, and use the nucleophilic substitution reaction product to directly proceed to the next decarboxylation reaction. Thus, the post-treatment of step 1) is extremely simple and there is no loss of the target product caused by purification, thereby simplifying the steps and further improving the total yield.

[0077] The extraction method is not particularly limited. For example, the reactants may be mixed with water and then an extraction solvent may be added to perform extraction.

[0078] The amount of water used can be, for example, 1-20 times, preferably 1-10 times, and more preferably 5-10 times the volume of the reactants.

[0079] The extraction solvent used in the extraction process may be, for example, an ester organic solvent and / or a halogenated alkane organic solvent. Preferably, the extraction solvent is selected from one or more of methyl acetate, ethyl acetate, and dichloromethane. The volume ratio of the extraction solvent to the water is 0.1-1:1, preferably 0.1-0.5:1, and more preferably 0.1-0.2:1.

[0080] In the above extraction process, the organic phase separated after extraction is preferably dried using a desiccant before solid-liquid separation and desolventization.

[0081] As the desiccant, for example, various desiccants commonly used in the art can be used, for example, anhydrous sodium sulfate can be used.

[0082] The method for the solid-liquid separation is not limited, and can be carried out, for example, by filtration, centrifugation, or the like.

[0083] According to the method of the present invention, preferably, the compound of the structure represented by formula (1) is obtained by subjecting the compound of the structure represented by formula (1-1) to a nucleophilic substitution reaction with the compound of the structure represented by formula (1-2) in the presence of a second organic solvent and a second base.

[0084] Formula (1-1) Formula (1-2)

[0085] In formula (1-1), X represents a halogen; in formula (1-2), R1 represents an alkyl group having 1 to 6 carbon atoms.

[0086] Here, X in formula (1-1) and R1 in formula (1-2) are the same as X and R1 in formula (1).

[0087] In the above-mentioned preferred method for preparing the compound of the structure represented by formula (1), preferably, the molar ratio of the compound of the structure represented by formula (1-1) to the compound of the structure represented by formula (1-2) is 1:1-1.5; more preferably, the molar ratio of the compound of the structure represented by formula (1-1) to the compound of the structure represented by formula (1-2) is 1:1-1.5; further preferably, the molar ratio of the compound of the structure represented by formula (1-1) to the compound of the structure represented by formula (1-2) is 1:1-1.2.

[0088] In the present invention, specific examples of the molar ratio of the compound represented by formula (1-1) to the compound represented by formula (1-2) include: 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, etc., as well as the range formed by any two of the above and all values within the range.

[0089] In the above-mentioned preferred method for preparing the compound of the structure represented by formula (1), preferably, the molar ratio of the compound of the structure represented by formula (1-1) to the second base is 1:1-2; more preferably, the molar ratio of the compound of the structure represented by formula (1-1) to the second base is 1:1-1.5; further preferably, the molar ratio of the compound of the structure represented by formula (1-1) to the second base is 1:1-1.3.

[0090] In the present invention, specific examples of the molar ratio of the compound represented by formula (1-1) to the second base 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, etc., as well as ranges consisting of any two of the above and all values within the range.

[0091] In the preferred method for preparing the compound of formula (1), the amount of the second organic solvent can be selected based on the reaction raw materials, as long as it can effectively dissolve the reaction raw materials. Preferably, the weight ratio of the compound of formula (1-1) to the second organic solvent is 1:1-10; more preferably, the weight ratio of the compound of formula (1-1) to the second organic solvent is 1:1-3.

[0092] In the present invention, specific examples of the weight ratio of the compound represented by formula (1-1) to the second organic solvent include: 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 range formed by any two of the above and all values within the range.

[0093] In the preferred method for preparing the compound of formula (1), the second base can be selected from an inorganic base or an organic base. 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.

[0094] In the present invention, the first base and the second base may be the same or different.

[0095] In the preferred method for preparing the compound of formula (1), the second organic solvent is used to dissolve the reaction raw materials to promote the reaction. Therefore, any organic solvent that is inert to the reaction raw materials and can well dissolve the reaction raw materials can be used in 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.

[0096] In the present invention, the first organic solvent and the second organic solvent may be the same or different.

[0097] In the above-mentioned preferred method for preparing the compound of the structure represented by formula (1), the temperature of the nucleophilic substitution reaction is preferably 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 can be sufficient as long as the compound of the structure represented by formula (1) is fully reacted to obtain the compound of the structure represented by formula (3). For example, the time of the nucleophilic substitution reaction can be 2-10 hours, preferably 2-4 hours.

[0098] In the preferred method for preparing the compound of formula (1), there is no particular limitation on the order of adding the raw materials. The second organic solvent may be added first, and then the other raw materials may be added together or in steps to the second organic solvent to start the reaction. Alternatively, the other raw materials may be added together or in steps to the reaction vessel first, and then the second organic solvent may be added to start the reaction.

[0099] In the preferred method for preparing the compound of formula (1), preferably, after adding the second base to the second organic solvent, the compound of formula (1-1) and the compound of formula (1-2) are added to react. This can further improve the yield.

[0100] In the above-mentioned preferred method for preparing the compound of the structure represented by formula (1), after the nucleophilic substitution reaction is completed, the post-treatment is very simple. For example, it is only necessary to cool the reaction mixture to room temperature after the nucleophilic substitution reaction is completed, and then add the reactants to an acid solution with a pH value of 2-3 (preferably dropwise to an acid solution with a pH value of 2-3, more preferably dropwise to a hydrochloric acid solution with a pH value of 2-3) for precipitation, thereby obtaining the compound of the structure represented by formula (1) with high purity and high yield.

[0101] Step 2): Decarboxylation reaction

[0102] According to the method of the present invention, in step 2), the nucleophilic substitution reaction product obtained in step 1) is subjected to a decarboxylation reaction in the presence of a first solvent and a first acid to obtain a decarboxylation reaction product of a compound having a structure represented by formula (4).

[0103] According to the method of the present invention, in step 2), the amount of the first acid can be selected based on the amount of the nucleophilic substitution reaction product calculated as the compound of the structure represented by formula (3). Preferably, in step 2), the molar ratio of the nucleophilic substitution reaction product calculated as the compound of the structure represented by formula (3) to the first acid is 1:1-4; more preferably, in step 2), the molar ratio of the nucleophilic substitution reaction product calculated as the compound of the structure represented by formula (3) to the first acid is 1:1-2; further preferably, in step 2), the molar ratio of the nucleophilic substitution reaction product calculated as the compound of the structure represented by formula (3) to the first acid is 1:1-1.3.

[0104] In the present invention, specific examples of the molar ratio of the nucleophilic substitution reaction product to the first acid based on the compound of the structure represented by formula (3) 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 ranges consisting of any two of the above and all values within the range.

[0105] 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.

[0106] According to the method of the present invention, the amount of the first solvent used can also be selected based on the reaction raw materials, as long as it can effectively dissolve the reaction raw materials. Preferably, in step 2), the weight ratio of the nucleophilic substitution reaction product, calculated as the compound of the structure represented by formula (3), to the first solvent is 1:1-10; more preferably, in step 2), the weight ratio of the nucleophilic substitution reaction product, calculated as the compound of the structure represented by formula (3), to the first solvent is 1:1-3.

[0107] In the present invention, specific examples of the weight ratio of the nucleophilic substitution reaction product to the first solvent, calculated as the compound of the structure represented by formula (3), include: 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, etc., as well as ranges consisting of any two of the above ratios and all values within the range.

[0108] According to the method of the present invention, the first acid can be selected from an inorganic acid or an organic acid. 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.

[0109] 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.

[0110] In addition, the decarboxylation reaction time can be any time as long as it can ensure sufficient reaction and obtain the compound represented by formula (4). For example, the decarboxylation reaction time can be 2-10 h, preferably 2-4 h.

[0111] According to the method of the present invention, in step 2), there is no particular limitation on the order of adding the raw materials. The first solvent can be added first, and then the other raw materials can be added to the first solvent together or in steps to start the reaction. Alternatively, the other raw materials can be added to the reaction vessel together or in steps first, and then added to the first solvent to start the decarboxylation reaction.

[0112] In a preferred embodiment of the present invention, the nucleophilic substitution reaction product is dissolved in the first solvent, and then the first acid is added dropwise to carry out the reaction, thereby further improving the yield.

[0113] According to the method of the present invention, in step 2), after the decarboxylation reaction is completed, the post-processing thereof is very simple, and there is no need to purify the reactant to obtain the compound of the structure represented by formula (4) before proceeding to the next reaction. Instead, it is only necessary to extract and desolventize the reactant to obtain the decarboxylation reaction product, and use the decarboxylation reaction product to directly proceed to the next decyanation reaction. As a result, the post-processing of step 2) is extremely simple and there is no loss of the target product caused by purification, thereby simplifying the steps and further improving the total yield.

[0114] The extraction method is not particularly limited. For example, the reactants may be mixed with water and then an extraction solvent may be added to perform extraction.

[0115] The amount of water used can be, for example, 1-20 times the volume of the reactants, preferably 10-20 times, more preferably 10-15 times.

[0116] The extraction solvent can be an ester organic solvent and / or a halogenated alkane organic solvent. Preferably, the extraction solvent is selected from one or more of methyl acetate, ethyl acetate, and dichloromethane. The volume ratio of the extraction solvent to the water is 0.1-1:1, preferably 0.1-0.5:1, and more preferably 0.1-0.2:1.

[0117] In the above extraction process, the organic phase separated after extraction is preferably dried using a desiccant before solid-liquid separation and desolventization.

[0118] As the desiccant, for example, various desiccants commonly used in the art can be used, for example, anhydrous sodium sulfate can be used.

[0119] The method for the solid-liquid separation is not limited, and can be carried out, for example, by filtration, centrifugation, or the like.

[0120] Step 3): Decyanation reaction

[0121] According to the method of the present invention, in step 3), the decarboxylation reaction product obtained in step 2) is subjected to a decyanation reaction in the presence of a second solvent and a second acid to obtain a fluopyram compound having a structure represented by formula (5).

[0122] According to the method of the present invention, in step 3), the amount of the second acid can be selected based on the amount of the decarboxylation reaction product calculated as the compound of the structure represented by formula (4). Preferably, in step 3), the molar ratio of the decarboxylation reaction product calculated as the compound of the structure represented by formula (4) to the second acid is 1:1-5; more preferably, in step 3), the molar ratio of the decarboxylation reaction product calculated as the compound of the structure represented by formula (4) to the second acid is 1:1.5-4; further preferably, in step 3), the molar ratio of the decarboxylation reaction product calculated as the compound of the structure represented by formula (4) to the second acid is 1:2-3.

[0123] In the present invention, specific examples of the molar ratio of the decarboxylation reaction product to the second acid based on the compound of the structure represented by formula (4) 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 ranges consisting of any two of the above numbers and all values within the range.

[0124] According to the method of the present invention, the second acid can be selected from either an inorganic acid or an organic acid. 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.

[0125] 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.

[0126] According to the method of the present invention, preferably, the molar ratio of the decarboxylation reaction product calculated as the compound of the structure represented by formula (4) to the second solvent is 1:1-5; more preferably, the molar ratio of the decarboxylation reaction product calculated as the compound of the structure represented by formula (4) to the second solvent is 1:1-3; further preferably, the molar ratio of the decarboxylation reaction product calculated as the compound of the structure represented by formula (4) to the second solvent is 1:1-2.

[0127] Specific examples of the molar ratio of the decarboxylation reaction product to the second solvent based on the compound of the structure represented by formula (4) 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, 1:4.2, 1:4.5, 1:4.8, 1:5, etc., as well as ranges consisting of any two of the above and all values within the range.

[0128] 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.

[0129] In addition, the decyanation reaction time can be any time required to ensure sufficient reaction and obtain the compound represented by formula (5). For example, the decyanation reaction time can be 6-12 h, preferably 6-8 h.

[0130] According to the method of the present invention, in step 3), there is no particular limitation on the order of adding the raw materials. The second solvent can be added first, and then the other raw materials can be added to the second solvent together or in steps to start the reaction. Alternatively, the other raw materials can be added to the reaction vessel together or in steps, and then added to the second solvent to start the decyanation reaction.

[0131] In a preferred embodiment of the present invention, the decyanation reaction is carried out by mixing the decarboxylation reaction product, the second acid, and the second solvent, thereby further improving the yield.

[0132] According to the method of the present invention, in step 3), after the decyanation reaction is completed, the subsequent treatment is very simple, and the fluopyram compound having the structure shown in formula (5) can be obtained by simply extracting and desolvating the reactants.

[0133] There are no particular limitations on the extraction method. For example, the reactants can be mixed with water and then an extraction solvent can be added for extraction. If the solvent for the decyanation reaction is water, the extraction solvent can be added directly for extraction, or water can be added or partially removed as needed before adding the extraction solvent for extraction.

[0134] The amount of water used during extraction can be, for example, 1-10 times, preferably 5-10 times, and more preferably 5-6 times the volume of the reactants.

[0135] The extraction solvent can be an ester organic solvent and / or a halogenated alkane organic solvent. Preferably, the extraction solvent is selected from one or more of methyl acetate, ethyl acetate, and dichloromethane. The volume ratio of the extraction solvent to the water is 0.1-1:1, preferably 0.1-0.5:1, and more preferably 0.1-0.2:1.

[0136] In the above extraction process, the organic phase separated after extraction is preferably dried using a desiccant before solid-liquid separation and desolventization.

[0137] As the desiccant, for example, various desiccants commonly used in the art can be used, for example, anhydrous sodium sulfate can be used.

[0138] The method for the solid-liquid separation is not limited, and can be carried out, for example, by filtration, centrifugation, or the like.

[0139] According to the method of the present invention, in step 1), after the nucleophilic substitution reaction is completed, it is only necessary to cool the reaction mixture to room temperature after the nucleophilic substitution reaction is completed, and then add the reactants to an acid solution with a pH value of 2-3 for precipitation, so as to obtain the compound of the structure shown in formula (1) with high purity and high yield; and in step 2), after the decarboxylation reaction is completed, it is not necessary to purify the reactants to obtain the compound of the structure shown in formula (4) before proceeding to the next reaction, but it is only necessary to extract and desolventize the reactants to obtain the decarboxylation reaction product, and use the decarboxylation reaction product to directly proceed to the next decyanation reaction; in step 3), it is only necessary to extract and desolventize the reactants to obtain the fluopyram compound of the structure shown in formula (5). Therefore, 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 purification, and can significantly improve the total yield while simplifying the steps.

[0140] According to a second aspect of the present invention, there is provided a fluopyram compound prepared by the method for preparing the fluopyram compound according to the first aspect of the present invention.

[0141] Through the above technical solution, the present invention can provide a method for preparing fluopyram compounds with higher yield and more convenient operation, and the fluopyram compounds prepared therefrom.

[0142] The present invention will be described in detail below through examples, but the present invention is not limited to the following examples.

[0143] Unless otherwise specified, the raw materials used in the following examples 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.

[0144] In the following examples, the compounds synthesized 1 H NMR ( 1 H-NMR) was performed on a Bruker AVANCE III-500 MHz spectrometer using DMSO- d 6 is the solvent and the reaction is carried out at 25°C.

[0145] Preparation Example 1

[0146] To a 250 mL four-necked flask equipped with a thermometer, mechanical stirring paddle, and reflux line, 50.4 g of N,N-dimethylacetamide, 16.8 g of potassium carbonate, and 1.0 g of tetrabutylammonium bromide were added sequentially. The temperature was then raised to 75°C. Once heated, 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 mixture over an hour. The reaction was then incubated for 2 hours. HPLC results indicated a 2,3-dichloro-5-trifluoromethylpyridine content of less than 0.05%. After the reaction mixture cooled to room temperature, it was added dropwise to a hydrochloric acid solution at a pH of 1-2, resulting in the precipitation of a solid. The filter cake was filtered, washed with water, and dried to yield a yellow solid, the intermediate methyl 3-chloro-5-trifluoromethyl-2-pyridyl-2-cyanoacetate, in a yield of 96.2% and a purity of 98.9% by weight.

[0147] 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).

[0148] Preparation Example 2

[0149] To a 250 mL four-necked flask equipped with a thermometer, mechanical stirring paddle, and reflux line, 50.4 g of N,N-dimethylacetamide, 16.8 g of potassium carbonate, and 1.0 g of tetrabutylammonium bromide were added sequentially. The temperature was then raised to 75°C. Once the temperature was reached, 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 mixture over an hour. The reaction was then incubated for 2 hours. HPLC results indicated a 2,3-dichloro-5-trifluoromethylpyridine content of less than 0.05%. After the reaction mixture cooled to room temperature, it was added dropwise to a hydrochloric acid solution at a pH of 1-2, resulting in the precipitation of a solid. The filter cake was filtered, washed with water, and dried to yield a yellow solid, the intermediate ethyl 3-chloro-5-trifluoromethyl-2-pyridyl-2-cyanoacetate, in a yield of 90.4% and a purity of 98.5% by weight.

[0150] NMR data: 1 H (DMSO- d6, 500 MHz): 1.22 (t, 3H); 4.23 (q, 2H); 8.34 (s, 1H); 8.54 (s, 1H); 14.56 (s, 1H).

[0151] Example 1

[0152] 1) To a 100 mL four-necked flask equipped with a thermometer, mechanical stirrer, and reflux line, 13.9 g of methyl 3-chloro-5-trifluoromethyl-2-pyridinyl-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 sequentially. The temperature was then raised to 30°C and the reaction was maintained for 6 h. HPLC results indicated that the content of methyl 3-chloro-5-trifluoromethyl-2-pyridinyl-2-cyanoacetate was less than 0.05%. After the reaction mixture cooled to room temperature, 500 mL of water was added and extracted with ethyl acetate. The organic phase was washed with water, dried, filtered, and desolvated to yield a yellow solid, crude methyl 2-(3-chloro-5-trifluoromethylpyridin-2-yl)-2-cyano-3-(2-trifluoromethylbenzamido)propanoate. This was used directly in the next step without purification.

[0153] 2) To a 100 mL four-necked flask equipped with a thermometer, mechanical stirring paddle, and reflux tube, crude methyl 2-(3-chloro-5-trifluoromethylpyridin-2-yl)-2-cyano-3-(2-trifluoromethylbenzamido)propanoate (24.0 g, calculated as methyl 2-(3-chloro-5-trifluoromethylpyridin-2-yl)-2-cyano-3-(2-trifluoromethylbenzamido)propanoate), 50.0 g of N,N-dimethylacetamide, and 6.1 g of concentrated hydrochloric acid (37 wt %, the same applies hereinafter) were added sequentially. The temperature was then raised to 120°C and the reaction was maintained for 6 hours. HPLC results indicated that the content of methyl 3-chloro-5-trifluoromethyl-2-pyridinyl-2-cyano-acetate was less than 0.05%. After the reaction mixture cooled to room temperature, 500 ml of water was added and extracted with ethyl acetate. The organic phase was washed with water, dried, filtered, and desolventized to obtain a yellow solid, which was crude N-(2-(3-chloro-5-trifluoromethylpyridin-2-yl)-2-cyanoethyl)-2-trifluoromethylbenzamide. This was used directly in the next step without purification.

[0154] 3) In a 100 mL four-necked flask equipped with a thermometer, mechanical stirring paddle, and reflux tube, crude N-(2-(3-chloro-5-trifluoromethylpyridin-2-yl)-2-cyanoethyl)-2-trifluoromethylbenzamide (21.0 g, calculated as 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 (98% by weight, the same applies hereinafter), and 0.9 g of water were added. The temperature was then raised to 100°C and the reaction was maintained. HPLC results indicated that the N-(2-(3-chloro-5-trifluoromethylpyridin-2-yl)-2-cyanoethyl)-2-trifluoromethylbenzamide content was less than 0.05%. The reaction solution was cooled to room temperature, desolventized, washed with water, extracted with ethyl acetate, dried, and desolventized again to obtain a yellow solid. The yellow solid was placed in a mixed solvent of methanol: water = 1:3 (v / v), stirred at 25°C for 30 minutes, and then filtered under reduced pressure to obtain a solid product. The filter cake was washed with a mixed solvent of methanol: water = 1:3 (v / v) and dried to obtain 18.3 g of the product fluopyram with a purity of 96.0% by weight. The total yield of the three steps was 88.5%.

[0155] 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).

[0156] In addition, in order to confirm the structure of the compound obtained in step 1) and step 2), another preparation was carried out according to the same method as step 1) and step 2). A small amount of the yellow solid in step 1) and step 2) was purified and then subjected to NMR identification. The results are as follows:

[0157] Step 1) NMR data: 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).

[0158] Step 2) NMR data: 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).

[0159] Example 2

[0160] 1) To a 100 mL four-necked flask equipped with a thermometer, mechanical stirrer, and reflux tube, 14.6 g of ethyl 3-chloro-5-trifluoromethyl-2-pyridinyl-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 sequentially. The temperature was then raised to 30°C and the reaction was maintained for 6 hours. HPLC results indicated that the content of methyl 3-chloro-5-trifluoromethyl-2-pyridinyl-2-cyanoacetate was less than 0.05%. After the reaction mixture cooled to room temperature, 500 mL of water was added and extracted with ethyl acetate. The organic phase was washed with water, dried, filtered, and desolvated to yield a yellow solid, crude ethyl 2-(3-chloro-5-trifluoromethylpyridin-2-yl)-2-cyano-3-(2-trifluoromethylbenzamido)propionate. This was used directly in the next step without purification.

[0161] 2) To a 100 mL four-necked flask equipped with a thermometer, mechanical stirring paddle, and reflux tube, crude methyl 2-(3-chloro-5-trifluoromethylpyridin-2-yl)-2-cyano-3-(2-trifluoromethylbenzamido)propanoate (24.7 g of ethyl 2-(3-chloro-5-trifluoromethylpyridin-2-yl)-2-cyano-3-(2-trifluoromethylbenzamido)propanoate), 50.0 g of N,N-dimethylacetamide, and 6.1 g of concentrated hydrochloric acid were added sequentially. The temperature was then raised to 120°C and the reaction was maintained for 6 hours. HPLC results indicated that the content of methyl 3-chloro-5-trifluoromethyl-2-pyridinyl-2-cyano-acetate was less than 0.05%. After the reaction mixture cooled to room temperature, 500 ml of water was added and extracted with ethyl acetate. The organic phase was washed with water, dried, filtered, and desolventized to obtain a yellow solid, which was crude N-(2-(3-chloro-5-trifluoromethylpyridin-2-yl)-2-cyanoethyl)-2-trifluoromethylbenzamide. This was used directly in the next step without purification.

[0162] 3) In a 100 mL four-necked flask equipped with a thermometer, mechanical stirring paddle, and reflux tube, crude N-(2-(3-chloro-5-trifluoromethylpyridin-2-yl)-2-cyanoethyl)-2-trifluoromethylbenzamide (21.0 g, calculated as N-(2-(3-chloro-5-trifluoromethylpyridin-2-yl)-2-cyanoethyl)-2-trifluoromethylbenzamide), 40.0 g glacial acetic acid, 5.0 g concentrated sulfuric acid, and 0.9 g water were added. The temperature was then raised to 100°C and the reaction was maintained. HPLC results indicated that the N-(2-(3-chloro-5-trifluoromethylpyridin-2-yl)-2-cyanoethyl)-2-trifluoromethylbenzamide content was less than 0.05%. The reaction solution was cooled to room temperature, desolventized, washed with water, extracted with ethyl acetate, dried, and desolventized again to obtain a yellow solid. The yellow solid was placed in a mixed solvent of methanol: water = 1:3 (v / v), stirred at 25°C for 30 minutes, and then filtered under reduced pressure to obtain a solid product. The filter cake was washed with a mixed solvent of methanol: water = 1:3 (v / v) and dried to obtain 18.0 g of the product fluopyram with a purity of 95.5% by weight. The total yield of the three steps was 87.0%.

[0163] 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).

[0164] Example 3

[0165] 1) To a 100 mL four-necked flask equipped with a thermometer, mechanical stirrer, and reflux line, add 13.9 g of methyl 3-chloro-5-trifluoromethyl-2-pyridinyl-2-cyanoacetate, 13.1 g of N-acetoxymethyl-2-trifluoromethylbenzamide, 9.0 g of a 30 wt% sodium methoxide solution in methanol, and 50.0 g of N,N-dimethylacetamide. The mixture was then heated to 30°C and allowed to react for 6 hours. HPLC results indicated a methyl 3-chloro-5-trifluoromethyl-2-pyridinyl-2-cyanoacetate content of less than 0.05%. After the reaction mixture cooled to room temperature, 500 ml of water was added and extracted with ethyl acetate. The organic phase was washed with water, dried, filtered, and desolvated to yield a yellow solid, crude methyl 2-(3-chloro-5-trifluoromethylpyridin-2-yl)-2-cyano-3-(2-trifluoromethylbenzamide)propanoate. This was used directly in the next step without purification.

[0166] 2) To a 100 mL four-necked flask equipped with a thermometer, mechanical stirring paddle, and reflux line, crude methyl 2-(3-chloro-5-trifluoromethylpyridin-2-yl)-2-cyano-3-(2-trifluoromethylbenzamido)propanoate (24.0 g, calculated as methyl 2-(3-chloro-5-trifluoromethylpyridin-2-yl)-2-cyano-3-(2-trifluoromethylbenzamido)propanoate), 50.0 g of N,N-dimethylacetamide, and 6.1 g of concentrated hydrochloric acid were added sequentially. The temperature was then raised to 120°C and the reaction was maintained for 6 hours. HPLC results indicated that the content of methyl 3-chloro-5-trifluoromethyl-2-pyridinyl-2-cyano-acetate was less than 0.05%. After the reaction mixture cooled to room temperature, 500 ml of water was added and extracted with ethyl acetate. The organic phase was washed with water, dried, filtered, and desolventized to obtain a yellow solid, which was crude N-(2-(3-chloro-5-trifluoromethylpyridin-2-yl)-2-cyanoethyl)-2-trifluoromethylbenzamide. This was used directly in the next step without purification.

[0167] 3) In a 100 mL four-necked flask equipped with a thermometer, mechanical stirring paddle, and reflux tube, crude N-(2-(3-chloro-5-trifluoromethylpyridin-2-yl)-2-cyanoethyl)-2-trifluoromethylbenzamide (21.0 g, calculated as N-(2-(3-chloro-5-trifluoromethylpyridin-2-yl)-2-cyanoethyl)-2-trifluoromethylbenzamide), 40.0 g glacial acetic acid, 5.0 g concentrated sulfuric acid, and 0.9 g water were added. The temperature was then raised to 100°C and the reaction was maintained. HPLC results indicated that the N-(2-(3-chloro-5-trifluoromethylpyridin-2-yl)-2-cyanoethyl)-2-trifluoromethylbenzamide content was less than 0.05%. The reaction solution was cooled to room temperature, desolventized, washed with water, extracted with ethyl acetate, dried, and desolventized again to obtain a yellow solid. The yellow solid was placed in a mixed solvent of methanol: water = 1:3 (v / v), stirred at 25°C for 30 minutes, and then filtered under reduced pressure to obtain a solid product. The filter cake was washed with a mixed solvent of methanol: water = 1:3 (v / v) and dried to obtain 18.8 g of the product fluopyram with a purity of 96.2% by weight. The total yield of the three steps was 91.3%.

[0168] Example 4

[0169] The method of Example 1 was followed, except that the reaction temperature was 40° C. and the reaction time was 6 h. Other steps were performed identically to obtain 16.71 g of fluopyram with a purity of 95.7% by weight. The total yield of the three steps was 80.8%.

[0170] Example 5

[0171] The method of Example 1 was followed, except that the reaction temperature was 60° C. and the reaction time was 2 h. The other steps were performed identically, and the residue was slurried to obtain 16.52 g of fluopyram with a purity of 96.3% by weight. The total yield of the three steps was 80.3%.

[0172] Example 6

[0173] The method of Example 1 was followed, except that potassium carbonate was replaced with the same molar amount of triethylamine. The other steps were carried out identically, and the residue was slurried to obtain 18.59 g of fluopyram with a purity of 98.5% by weight. The total yield of the three steps was 92.5%.

[0174] Example 7

[0175] The method of Example 1 was followed, except that potassium carbonate was replaced with the same molar amount of triethylamine, and the solvent N,N-dimethylacetamide was replaced with the same mass of toluene. The other steps were performed identically, and the residue was slurried to obtain 18.64 g of fluopyram with a purity of 99.0% by weight. The total yield of the three steps was 93.2%.

[0176] Example 8

[0177] 1) To a 100 mL four-necked flask equipped with a thermometer, mechanical stirrer, and reflux tube, 13.9 g of methyl 3-chloro-5-trifluoromethyl-2-pyridinyl-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 sequentially. The temperature was then raised to 80°C and the reaction was maintained for 6 h. HPLC results indicated that the content of methyl 3-chloro-5-trifluoromethyl-2-pyridinyl-2-cyanoacetate was less than 0.05%. After the reaction mixture cooled to room temperature, 500 mL of water was added and extracted with ethyl acetate. The organic phase was washed with water, dried, filtered, and desolvated to yield a yellow solid, crude methyl 2-(3-chloro-5-trifluoromethylpyridin-2-yl)-2-cyano-3-(2-trifluoromethylbenzamido)propanoate. This was used directly in the next step without purification.

[0178] 2) To a 100 mL four-necked flask equipped with a thermometer, mechanical stirring paddle, and reflux line, crude methyl 2-(3-chloro-5-trifluoromethylpyridin-2-yl)-2-cyano-3-(2-trifluoromethylbenzamido)propanoate (24.0 g, calculated as methyl 2-(3-chloro-5-trifluoromethylpyridin-2-yl)-2-cyano-3-(2-trifluoromethylbenzamido)propanoate), 50.0 g of N,N-dimethylacetamide, and 6.1 g of concentrated hydrochloric acid were added sequentially. The temperature was then raised to 120°C and the reaction was maintained for 6 hours. HPLC results indicated that the content of methyl 3-chloro-5-trifluoromethyl-2-pyridinyl-2-cyano-acetate was less than 0.05%. After the reaction mixture cooled to room temperature, 500 ml of water was added and extracted with ethyl acetate. The organic phase was washed with water, dried, filtered, and desolventized to obtain a yellow solid, which was crude N-(2-(3-chloro-5-trifluoromethylpyridin-2-yl)-2-cyanoethyl)-2-trifluoromethylbenzamide. This was used directly in the next step without purification.

[0179] 3) In a 100 mL four-necked flask equipped with a thermometer, mechanical stirring paddle, and reflux tube, crude N-(2-(3-chloro-5-trifluoromethylpyridin-2-yl)-2-cyanoethyl)-2-trifluoromethylbenzamide (21.0 g, calculated as N-(2-(3-chloro-5-trifluoromethylpyridin-2-yl)-2-cyanoethyl)-2-trifluoromethylbenzamide), 40.0 g glacial acetic acid, 5.0 g concentrated sulfuric acid, and 0.9 g water were added. The temperature was then raised to 100°C and the reaction was maintained. HPLC results indicated that the N-(2-(3-chloro-5-trifluoromethylpyridin-2-yl)-2-cyanoethyl)-2-trifluoromethylbenzamide content was less than 0.05%. The reaction solution was cooled to room temperature, desolventized, washed with water, extracted with ethyl acetate, dried, and desolventized again to obtain a yellow solid. The yellow solid was placed in a mixed solvent of methanol: water = 1:3 (v / v), stirred at 25°C for 30 minutes, and then filtered under reduced pressure to obtain a solid product. The filter cake was washed with a mixed solvent of methanol: water = 1:3 (v / v) and dried to obtain 12.9 g of the product fluopyram with a purity of 96.1% by weight. The total yield of the three steps was 62.4%.

[0180] Example 9

[0181] 1) To a 100 mL four-necked flask equipped with a thermometer, mechanical stirrer, and reflux tube, 13.9 g of methyl 3-chloro-5-trifluoromethyl-2-pyridinyl-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 sequentially. The mixture was then heated to 30°C and allowed to react for 12 hours. HPLC results indicated that the content of methyl 3-chloro-5-trifluoromethyl-2-pyridinyl-2-cyanoacetate was less than 0.05%. After the reaction mixture cooled to room temperature, 500 mL of water was added and extracted with ethyl acetate. The organic phase was washed with water, dried, filtered, and desolvated to yield a yellow solid, crude methyl 2-(3-chloro-5-trifluoromethylpyridin-2-yl)-2-cyano-3-(2-trifluoromethylbenzamido)propanoate. This was used directly in the next step without purification.

[0182] 2) To a 100 mL four-necked flask equipped with a thermometer, mechanical stirring paddle, and reflux line, crude methyl 2-(3-chloro-5-trifluoromethylpyridin-2-yl)-2-cyano-3-(2-trifluoromethylbenzamido)propanoate (24.0 g, calculated as methyl 2-(3-chloro-5-trifluoromethylpyridin-2-yl)-2-cyano-3-(2-trifluoromethylbenzamido)propanoate), 50.0 g of N,N-dimethylacetamide, and 6.1 g of concentrated hydrochloric acid were added sequentially. The temperature was then raised to 120°C and the reaction was maintained for 6 hours. HPLC results indicated that the content of methyl 3-chloro-5-trifluoromethyl-2-pyridinyl-2-cyano-acetate was less than 0.05%. After the reaction mixture cooled to room temperature, 500 ml of water was added and extracted with ethyl acetate. The organic phase was washed with water, dried, filtered, and desolventized to obtain a yellow solid, which was crude N-(2-(3-chloro-5-trifluoromethylpyridin-2-yl)-2-cyanoethyl)-2-trifluoromethylbenzamide. This was used directly in the next step without purification.

[0183] 3) In a 100 mL four-necked flask equipped with a thermometer, mechanical stirring paddle, and reflux tube, crude N-(2-(3-chloro-5-trifluoromethylpyridin-2-yl)-2-cyanoethyl)-2-trifluoromethylbenzamide (21.0 g, calculated as N-(2-(3-chloro-5-trifluoromethylpyridin-2-yl)-2-cyanoethyl)-2-trifluoromethylbenzamide), 40.0 g glacial acetic acid, 5.0 g concentrated sulfuric acid, and 0.9 g water were added. The temperature was then raised to 100°C and the reaction was maintained. HPLC results indicated that the N-(2-(3-chloro-5-trifluoromethylpyridin-2-yl)-2-cyanoethyl)-2-trifluoromethylbenzamide content was less than 0.05%. The reaction solution was cooled to room temperature, desolvated, washed with water, extracted with ethyl acetate, dried, and desolvated again to obtain a yellow solid. The yellow solid was placed in a mixed solvent of methanol: water = 1:3 (v / v), stirred at 25°C for 30 minutes, and then filtered under reduced pressure to obtain a solid product. The filter cake was washed with a mixed solvent of methanol: water = 1:3 (v / v) and dried to obtain 15.3 g of the product fluopyram with a purity of 96.8% by weight. The total yield of the three steps was 74.9%.

[0184] The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited thereto. Within the technical concept of the present invention, various simple variations of the technical solution of the present invention may be made, including combining the various technical features in any other appropriate manner. These simple variations and combinations should also be regarded as disclosed in the present invention and fall within the scope of protection of the present invention.

Claims

1. A method for preparing a fluopyram compound, characterized in that: The method The following steps are included: 1) in the presence of a first organic solvent and a first base, subjecting the compound represented by formula (1) and the compound represented by formula (2) to a nucleophilic substitution reaction to obtain a nucleophilic substitution reaction product containing a compound represented by formula (3); 2) in the presence of a first solvent and a first acid, subjecting the nucleophilic substitution reaction product obtained in step 1) to a decarboxylation reaction to obtain a decarboxylation reaction product of a compound having a structure represented by formula (4); 3) in the presence of a second solvent and a second acid, subjecting the decarboxylation product obtained in step 2) to a decyanation reaction to obtain a fluopyram compound having a structure represented by formula (5); Formula (1) Formula (2) Formula (3) Formula (4) Formula (5) In formula (1) and formula (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, The first base is triethylamine, the first organic solvent is toluene, The temperature of the nucleophilic substitution reaction is 30-70°C.

2. The method according to claim 1, wherein In formula (1) and formula (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 formula (3)-(5), X is F or Cl; In formula (1) and formula (3), R1 is -COOCH3, -COOCH2CH3 or -COOCH2CH2CH3; In formula (2), R2 is a methyl group, an ethyl group or a propyl group.

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

5. The method according to claim 1, wherein In step 1), the molar ratio of the compound represented by formula (1) to the compound represented by 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 represented by formula (1) to the compound represented by 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 represented by 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 represented by 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 represented by formula (1) to the first organic solvent is 1:1-10.

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

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

12. The method according to claim 11, wherein In step 2), the molar ratio of the nucleophilic substitution reaction product, calculated as the compound having the structure represented by formula (3), to the first acid is 1:1-1.

3.

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

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

15. The method according to any one of claims 1 to 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.

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

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

18. The method according to any one of claims 1 to 9, wherein: In step 3), the molar ratio of the decarboxylation reaction product, calculated as the compound having the structure represented by formula (4), to the second acid is 1:1-5.

19. The method according to claim 18, wherein In step 3), the molar ratio of the decarboxylation reaction product, calculated as the compound having the structure represented by formula (4), to the second acid is 1:2-3.

20. The method according to any one of claims 1 to 9, wherein: The weight ratio of the decarboxylation reaction product calculated as the compound of the structure represented by formula (4) to the second solvent is 1:1-5.

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

22. The method according to any one of claims 1 to 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.

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

24. The method according to any one of claims 1 to 9, wherein: In step 3), the reactants are extracted and desolvated to obtain a fluopyram compound having a structure shown in formula (5).

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