Preparation method of chlorantraniliprole impurity

Abstract

The invention discloses a preparation method of a chlorantraniliprole impurity, which comprises the following steps: preparing # imgabs 0 # by using 5-bromo-3-chloro-2-hydrazinopyridine as a raw material, preparing # imgabs 2 # by using # imgabs 1 # as a raw material, preparing # imgabs 4 # by using # imgabs 3 # as a raw material, mixing # imgabs 5 # thionyl chloride, an organic solvent and a catalyst, heating in inert gas for reaction, concentrating after reaction to obtain a mixture, and purifying to obtain the chlorantraniliprole impurity. According to the present invention, the chlorantraniliprole impurity # imgabs6 is obtained by mixing the chlorantraniliprole with an organic solvent, 2-amino-5-chloro-N, 3-dimethyl benzamide and an acid-binding agent and then carrying out a reaction at a room temperature, and after-treatment, the impurity is easily generated in the chlorantraniliprole preparation process, is difficult to separate, and has a large influence on the purity, and the preparation method has characteristics of simple process, high product purity, and good industrial application prospect. The conversion rate is high.

Description

Technical Field

[0001] The invention relates to the technical field of chemical synthesis, and in particular to a method for preparing a chlorantraniliprole impurity. Background Art

[0002] Chlorantraniliprole (patent W003015519) is the most widely used insecticide at home and abroad. It is a green chemical insecticide developed by DuPont in the United States. This compound has the characteristics of low dosage, long lasting effect, and little impact on humans, animals and the environment in the control of lepidopteran pests in crops such as grains, cotton, fruits and vegetables. However, impurities will be generated during the preparation of chlorantraniliprole, and some impurities will also participate in subsequent reactions and are difficult to remove, which seriously affects the quality of the product. The impurity named 3-bromo-1-(5-bromo-3-chloropyridin-2-yl)-N-(4-chloro-2-methyl-6-(methylcarbamoyl)phenyl)-1H-pyrazole-5-carboxamide (impurity A) is the impurity most easily generated in the synthesis of chlorantraniliprole, with the molecular formula: C 18 H 13 Br2Cl2N5O2, molecular weight: 562.04, structural formula: It can provide a reference for the quality analysis of chlorantraniliprole products.

[0003] The Chinese patent application document with publication number CN108033944A discloses a process for preparing chlorantraniliprole impurity, wherein the chlorantraniliprole impurity S2 obtained is reacted with compound M3 in the presence of a sulfonyl chloride compound, and after the reaction is completed, chlorantraniliprole impurity S3 is obtained;

[0004]

[0005] The specific steps include: adding 2.0g of chlorfenapyr impurity S2 (0.0052mol), 1.09g M3 (0.0055mol), 15g acetonitrile and 1.24g pyridine (0.016mol) into a 100mL three-necked flask, stirring, cooling, and starting to drop a mixture of 5g acetonitrile and 0.72g methanesulfonyl chloride (0.0063mol) at -5°C, and completing the dropwise addition within 10min, keeping warm and stirring for 2h, a large amount of solid precipitates, naturally heating, adding 7g of water at room temperature, continuing stirring for 1h, filtering, washing the filter cake twice with 2g of 30% acetonitrile aqueous solution, and drying in a vacuum oven at 55°C for 4h to obtain 2.8g of white solid chlorfenapyr impurity S3, with a yield of 95.6%, HPLC: 98.4%; however, it uses methanesulfonyl chloride, which is difficult to obtain. Summary of the invention

[0006] The technical problem to be solved by the present invention is how to prepare chlorantraniliprole impurity

[0007] The present invention solves the above technical problems through the following technical means:

[0008] A method for preparing a chlorantraniliprole impurity, wherein the structural formula of the chlorantraniliprole impurity is The following steps are involved:

[0009] S1. 5-bromo-3-chloro-2-hydrazinepyridine is used as a raw material, mixed with ethanol, sodium ethoxide and a catalyst, and diethyl maleate is added after heating. After the reaction, glacial acetic acid and ice water are added, concentrated, extracted with ethyl acetate and the organic phases are combined, and then concentrated. An organic solvent and phosphorus oxybromide are added, and the mixture is heated to reflux for reaction. After the reaction is completed, 3-bromo-1-(5-bromo-3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid ethyl ester is obtained through post-treatment. Wherein, the organic solvent is a mixture of one or more of acetonitrile, ethyl acetate, chloroform, and dichloromethane;

[0010] S2, As raw material, a mixture of one or more of acetonitrile, toluene, ethyl acetate and tetrahydrofuran is used as solvent, and reacted in the presence of concentrated sulfuric acid and potassium persulfate to obtain

[0011] S3, As raw material, a mixture of one or more of ethanol, methanol, n-pentanol and n-propanol is used as solvent, and reacted in the presence of sodium hydroxide aqueous solution to obtain 3-bromo-1-(5-bromo-3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid

[0012] S4, 3-bromo-1-(5-bromo-3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid Dichlorothionyl, an organic solvent and a catalyst are mixed, heated under an inert gas for reaction, and concentrated to obtain a mixture after the reaction; wherein the organic solvent is a mixture of one or more of dichloromethane, 1,2-dichloroethane, chloroform and toluene;

[0013] S5. Mix the mixture, the organic solvent, 2-amino-5-chloro-N,3-dimethylbenzamide and the acid binding agent, react at room temperature, and perform post-treatment to obtain the chlorantraniliprole impurity.

[0014] Preferably, in S1, the catalyst comprises at least one of bis(triphenylphosphine)nickel dibromide, bis(triphenylphosphine)palladium dichloride, tetrakis(triphenylphosphine)palladium or bis(triphenylphosphine)nickel chloride.

[0015] Preferably, in S1, the molar ratio of the catalyst to 5-bromo-3-chloro-2-hydrazinopyridine is 0.01 to 0.1:1; and the molar ratio of the organic solvent to 5-bromo-3-chloro-2-hydrazinopyridine is 50:1 to 100:1.

[0016] Preferably, in S5, the organic solvent is a mixture of one or more of dichloromethane, 1,2-dichloroethane, chloroform and toluene.

[0017] Preferably, in S4, the usage ratio of the 3-bromo-1-(5-bromo-3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid and thionyl chloride is 0.1 mol:100 mL; the molar ratio of the organic solvent to 3-bromo-1-(5-bromo-3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid is 40:1 to 80:1; the usage ratio of the catalyst to 3-bromo-1-(5-bromo-3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid is 50 mL:0.1 mol.

[0018] Preferably, in S4, the reaction is carried out under a nitrogen atmosphere by heating to reflux, and the reaction time is 3 hours.

[0019] Preferably, in S5, the reaction time is 72 hours.

[0020] Preferably, the molar ratio of 2-amino-5-chloro-N,3-dimethylbenzamide in S5 to 3-bromo-1-(5-bromo-3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid in S4 is 1:1.

[0021] Preferably, in S5, the usage ratio of 2-amino-5-chloro-N,3-dimethylbenzamide and the organic solvent is 0.1 mol:500 mL; and the usage ratio of the 2-amino-5-chloro-N,3-dimethylbenzamide and the acid binding agent is 0.1 mol:100 mL.

[0022] Preferably, in S4, the catalyst is N,N-dimethylformamide; in S5, the acid binding agent is a mixture of one or more of N,N-diisopropylethylamine, N-methylmorpholine, pyridine and triethylamine.

[0023] Preferably, in S5, the post-treatment includes column chromatography, and the column chromatography uses petroleum ether:ethyl acetate volume ratio = 9:1 to 3:1 as the mobile phase.

[0024] Preferably, S3 specifically includes the following steps: using 3-bromo-1-(5-bromo-3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid ethyl ester as a raw material, mixing it with a solvent and an aqueous sodium hydroxide solution, heating to react, and after the reaction is completed, concentrating the mixture, adding water, adding a dilute hydrochloric acid solution, filtering, and drying to obtain the product 3-bromo-1-(5-bromo-3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid.

[0025] Preferably, the molar ratio of the solvent to ethyl 3-bromo-1-(5-bromo-3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylate is 45:1 to 125:1.

[0026] Preferably, S2 specifically includes the following steps: using 3-bromo-1-(5-bromo-3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid ethyl ester as a raw material, mixing it with a solvent, a concentrated sulfuric acid solution, and potassium persulfate, heating it to reflux reaction, and after the reaction is completed, cooling it to 65°C, filtering it while hot, and concentrating the solution; after column chromatography, obtaining the product 3-bromo-1-(5-bromo-3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid ethyl ester.

[0027] Preferably, the molar ratio of the solvent to ethyl 3-bromo-1-(5-bromo-3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate is 40:1 to 100:1.

[0028] Preferably, S1 specifically includes the following steps: using 5-bromo-3-chloro-2-hydrazinepyridine as a raw material, mixing it with anhydrous ethanol solution, sodium ethanol ethanol solution and a catalyst, heating for reaction, then adding diethyl maleate, continuing the reaction, adding glacial acetic acid and ice water after the reaction, concentrating, extracting with ethyl acetate, combining the organic phases, and concentrating the organic phases; adding an organic solvent to the mixture, then adding phosphorus oxybromide, heating to reflux reaction, adding to a saturated sodium bicarbonate aqueous solution after the reaction, extracting with ethyl acetate, combining the organic phases, and obtaining the product 3-bromo-1-(5-bromo-3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid ethyl ester after column chromatography.

[0029] Preferably, the preparation method of 5-bromo-3-chloro-2-hydrazinepyridine comprises the following steps: using 5-bromo-2,3-dichloropyridine as a raw material, mixing it with a hydrazine hydrate solution with a mass fraction of 85% and an organic solvent, heating it to reflux reaction, and after the reaction is completed, cooling it to room temperature, filtering, washing with water, and drying to obtain the product 5-bromo-3-chloro-2-hydrazinepyridine.

[0030] Preferably, the organic solvent comprises at least one of ethanol, methanol, 1,4-dioxane or n-pentanol; and the molar ratio of the organic solvent to 5-bromo-2,3-dichloropyridine is 20:1 to 40:1.

[0031] The advantages of the present invention are:

[0032] (1) The present invention achieves the effect of reducing the generation of by-products by controlling various process conditions, and then prepares high-purity finished product impurities through column chromatography, recrystallization, filtration and other means, and the conversion rate is high.

[0033] (2) The present invention provides a method for preparing chlorantraniliprole impurities, which provides assistance for the quality analysis of chlorantraniliprole. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 is the H NMR spectrum of 5-bromo-3-chloro-2-hydrazinopyridine prepared in Example 1 of the present invention;

[0035] Figure 2 is the C NMR spectrum of 5-bromo-3-chloro-2-hydrazinopyridine prepared in Example 1 of the present invention;

[0036] Figure 3 is the H NMR spectrum of compound 2 prepared in Example 1 of the present invention;

[0037] Figure 4 is the C NMR spectrum of compound 2 prepared in Example 1 of the present invention;

[0038] Figure 5 is the H NMR spectrum of compound 3 prepared in Example 1 of the present invention;

[0039] Figure 6 is the C NMR spectrum of compound 3 prepared in Example 1 of the present invention;

[0040] Figure 7 is the H NMR spectrum of compound 4 prepared in Example 1 of the present invention;

[0041] Figure 8 is the C NMR spectrum of compound 4 prepared in Example 1 of the present invention;

[0042] Fig. 9 is the mass spectrum of impurity A prepared in Example 1 of the present invention;

[0043] Fig.10 is the H NMR spectrum of impurity A prepared in Example 1 of the present invention;

[0044] Fig.11 This is the NMR C spectrum of impurity A prepared in Example 1 of the present invention. DETAILED DESCRIPTION

[0045] In order to make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution in the embodiments of the present invention will be clearly and completely described in combination with the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0046] Unless otherwise specified, the test materials and reagents used in the following examples can be obtained from commercial sources.

[0047] If no specific techniques or conditions are specified in the examples, they can be carried out according to the techniques or conditions described in the literature in the art or according to the product instructions.

[0048] The synthetic route of chlorantraniliprole impurity of the present invention is as follows:

[0049]

[0050] Example 1

[0051] A method for preparing a chlorantraniliprole impurity (3-bromo-1-(5-bromo-3-chloropyridin-2-yl)-N-(4-chloro-2-methyl-6-(methylcarbamoyl)phenyl)-1H-pyrazole-5-carboxamide) comprises the following steps:

[0052] Step 1. Add 5-bromo-2,3-dichloropyridine (22.7 g, 0.1 mol), ethanol solution (140 mL) and 85% hydrazine hydrate solution (50 mL) to a 250 mL four-necked flask equipped with a mechanical stirrer, a thermometer, a reflux condenser and a nitrogen inlet. Heat the mixture to reflux for 20 h, monitor the reaction by TLC, and cool to room temperature after the reaction to precipitate a white solid. Collect the obtained solid by filtration, wash thoroughly with water until neutral, and dry to obtain 20.7 g of compound 1 5-bromo-3-chloro-2-hydrazinepyridine, with a yield of 93.4%. The H NMR spectrum and C NMR spectrum of 5-bromo-3-chloro-2-hydrazinepyridine are as follows: Figure 1 , Figure 2 shown.

[0053] Step 2: Anhydrous ethanol solution (500mL), sodium ethanol ethanol solution (mass fraction 20%, 500mL), 5-bromo-3-chloro-2-hydrazinepyridine (22.3g, 0.1mol) and bis(triphenylphosphine) nickel dibromide (0.75g, 1mmol) were added to a 2L four-necked flask equipped with a mechanical stirrer, a thermometer, a reflux condenser and a nitrogen inlet. The mixture was heated at 40°C for 15min, and then diethyl maleate (20.7g, 0.12mol) was added dropwise, and the reaction was continued for 4h. After the reaction was completed, glacial acetic acid and ice water were added to the reaction solution, and the reactant was concentrated by rotary evaporation, extracted with ethyl acetate, and the organic phase was combined and concentrated for the next step of reaction. The above-mentioned concentrated organic phase was used as the reaction solution, acetonitrile solution (500mL) and phosphorus oxybromide (34.4g, 0.12mol) were added, and the mixture was refluxed at 83°C for 12h, and the reaction was monitored by TLC. After the reaction, the solution was concentrated and added to a saturated sodium bicarbonate solution until the gas was completely released, and then ethyl acetate was added for extraction, and the organic phases were combined; column chromatography was performed, and petroleum ether:ethyl acetate (PE:EA volume ratio = 80:1-20:1) was used as the mobile phase for column chromatography, and rotary evaporation was performed to obtain 37.1 g of compound 2 3-bromo-1-(5-bromo-3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid ethyl ester, with a yield of 90.2%. The NMR H spectrum and NMR C spectrum of compound 2 are as follows: Figure 3 , Figure 4 shown.

[0054] Step 3: Add acetonitrile solution (500 mL), concentrated sulfuric acid solution (50 mL), ethyl 3-bromo-1-(5-bromo-3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate (41.2 g, 0.1 mol) and potassium persulfate (32.4 g, 0.12 mol) into a 2L four-necked flask equipped with a mechanical stirrer, a thermometer, a reflux condenser and a nitrogen inlet. The mixture was refluxed at 83°C for 12 h and the reaction was monitored by TLC. After the reaction, the temperature was lowered to 65°C, filtered while hot, and the solution was concentrated; column chromatography was performed, using petroleum ether: ethyl acetate (PE: EA volume ratio = 80: 1 to 20: 1) as the mobile phase, and rotary evaporation was performed to obtain 34.8 g of compound 3 3-bromo-1-(5-bromo-3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid ethyl ester, with a yield of 85.1%. The NMR H spectrum and NMR C spectrum of the prepared compound 3 are as follows: Figure 5 , Figure 6 shown.

[0055] Step 4. Add ethanol solution (500 mL), 20% sodium hydroxide aqueous solution (200 mL) and 3-bromo-1-(5-bromo-3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid ethyl ester (41.0 g, 0.1 mol) to a 2L four-necked flask equipped with a mechanical stirrer, a thermometer, a reflux condenser and a nitrogen inlet. The mixture was reacted at 30°C for 3 hours and the reaction was monitored by TLC. After the reaction, deionized water was added to the solution after rotary evaporation, and then a dilute hydrochloric acid solution was slowly added dropwise to the aqueous phase to precipitate a solid, which was filtered and dried to obtain 35.7 g of compound 4 3-bromo-1-(5-bromo-3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid with a yield of 93.7%; the NMR H spectrum and NMR C spectrum of the prepared compound 4 are as follows: Figure 7 , Figure 8 shown.

[0056] Step 5: Add 3-bromo-1-(5-bromo-3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid (38.2 g, 0.1 mol), thionyl chloride solution (100 mL), dichloromethane solution (400 mL) to a 1L four-necked flask equipped with a mechanical stirrer, a thermometer, a reflux condenser and a nitrogen inlet, and then add N, N-dimethylformamide solution (50 mL). The mixture was refluxed at 80 ° C for 3 h. After the reaction was completed, the thionyl chloride was removed and directly used as the reaction solution for the next step of the reaction. Dichloromethane solution (500 mL) and 2-amino-5-chloro-N, 3-dimethylbenzamide (19.9 g, 0.1 mol) were added to the above reaction solution, and triethylamine solution (100 mL) was slowly added dropwise to the mixture, and the reaction was carried out at room temperature for 72 h, and the reaction was monitored by TLC. After the reaction, column chromatography was performed, using petroleum ether: ethyl acetate (PE: EA volume ratio = 9: 1 to 3: 1) as the mobile phase, and rotary evaporation was performed to obtain 46.6 g of impurity A 3-bromo-1-(5-bromo-3-chloropyridin-2-yl)-N-(4-chloro-2-methyl-6-(methylcarbamoyl)phenyl)-1H-pyrazole-5-carboxamide, with a yield of 80.3% and a purity of 99.8%. The prepared impurity A The mass spectrum of the product is as follows Fig. 9 As shown, the H NMR spectrum and C spectrum are as follows Fig.10 , Fig.11 shown.

[0057] Example 2

[0058] A method for preparing a chlorantraniliprole impurity (3-bromo-1-(5-bromo-3-chloropyridin-2-yl)-N-(4-chloro-2-methyl-6-(methylcarbamoyl)phenyl)-1H-pyrazole-5-carboxamide) comprises the following steps:

[0059] Step 1. This step is different from step 1 in Example 1 in that: in this step, the solvent is replaced from ethanol to methanol solution (140 mL); after the reaction is completed, it is cooled to room temperature to precipitate a white solid, and the resulting solid is collected by filtration, washed thoroughly with water until neutral, and dried to obtain 20.2 g of 5-bromo-3-chloro-2-hydrazinepyridine with a yield of 91.2%.

[0060] Step 2. The difference between this step and step 2 in Example 1 is that: in this step, the catalyst is replaced by bis(triphenylphosphine)nickel dibromide with bis(triphenylphosphine)palladium dichloride (0.71 g, 1 mmol), and the solvent is replaced by acetonitrile solution with ethyl acetate solution (500 mL); after the reaction is completed, the solution is concentrated, added to a saturated sodium bicarbonate solution until the gas escapes completely, then ethyl acetate is added for extraction, and the organic phases are combined; column chromatography is performed, and petroleum ether: ethyl acetate (PE: EA volume ratio = 80: 1 to 20: 1) is used as the mobile phase for column chromatography, and 3-bromo-1-(5-bromo-3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid ethyl ester 34.8 g is obtained by rotary evaporation, and the yield is 84.7%.

[0061] Step 3. The difference between this step and step 3 in Example 1 is that: in this step, the solvent is replaced from acetonitrile solution to toluene solution (500 mL); after the reaction is completed, the temperature is lowered to 65 ° C., filtered while hot, and the solution is concentrated; column chromatography is performed, and petroleum ether: ethyl acetate (PE: EA volume ratio = 80: 1 to 20: 1) is used as the mobile phase for column chromatography, and 3-bromo-1-(5-bromo-3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid ethyl ester 33.5 g is obtained by rotary evaporation, and the yield is 82.1%.

[0062] Step 4. This step is different from step 4 in Example 1 in that: in this step, the solvent is replaced from ethanol solution to methanol solution (500 mL); after the reaction is completed, deionized water is added after rotary evaporation of the solution, and then a dilute hydrochloric acid solution is slowly added dropwise to the aqueous phase to precipitate a solid, which is filtered off and dried to obtain 35.2 g of 3-bromo-1-(5-bromo-3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid, with a yield of 92.5%.

[0063] Step 5. This step is different from Step 5 in Example 1 in that: in this step, the solvent is replaced from dichloromethane solution (400 mL) to 1,2-dichloroethane solution (400 mL); after the reaction is completed, column chromatography is performed, and petroleum ether: ethyl acetate (PE: EA volume ratio = 9: 1 to 3: 1) is used as the mobile phase for column chromatography, and 3-bromo-1-(5-bromo-3-chloropyridin-2-yl)-N-(4-chloro-2-methyl-6-(methylcarbamoyl)phenyl)-1H-pyrazole-5-carboxamide 45.0 g is obtained by rotary evaporation, with a yield of 77.6% and a purity of 99.7%.

[0064] Example 3

[0065] A method for preparing a chlorantraniliprole impurity (3-bromo-1-(5-bromo-3-chloropyridin-2-yl)-N-(4-chloro-2-methyl-6-(methylcarbamoyl)phenyl)-1H-pyrazole-5-carboxamide) comprises the following steps:

[0066] Step 1. This step is different from step 1 in Example 1 in that: in this step, the solvent is replaced from ethanol solution to 1,4-dioxane solution (140 mL); after the reaction is completed, it is cooled to room temperature to precipitate a white solid, and the resulting solid is collected by filtration, washed thoroughly with water until neutral, and dried to obtain 20.0 g of 5-bromo-3-chloro-2-hydrazinopyridine with a yield of 90.3%.

[0067] Step 2. The difference between this step and step 2 in Example 1 is that: in this step, the catalyst is replaced by tetrakis(triphenylphosphine)palladium (1.16 g, 1 mmol) from bis(triphenylphosphine)nickel dibromide, and the solvent is replaced by chloroform solution (500 mL) from acetonitrile solution; after the reaction is completed, the solution is concentrated, added to a saturated sodium bicarbonate solution until the gas escapes completely, then ethyl acetate is added for extraction, and the organic phases are combined; column chromatography is performed, and petroleum ether: ethyl acetate (PE: EA volume ratio = 80: 1 to 20: 1) is used as the mobile phase for column chromatography, and 35.8 g of 3-bromo-1-(5-bromo-3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid ethyl ester is obtained by rotary evaporation, and the yield is 87.1%.

[0068] Step 3. The difference between this step and step 3 in Example 1 is that: in this step, the solvent is replaced from acetonitrile solution to ethyl acetate solution (500 mL); after the reaction is completed, the temperature is lowered to 65 ° C., filtered while hot, and the solution is concentrated; column chromatography is performed, and petroleum ether: ethyl acetate (PE: EA volume ratio = 80: 1 to 20: 1) is used as the mobile phase for column chromatography, and 30.9 g of 3-bromo-1-(5-bromo-3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid ethyl ester is obtained by rotary evaporation, and the yield is 75.7%.

[0069] Step 4. The difference between this step and step 4 in Example 1 is that in this step, the solvent is replaced from ethanol solution to n-pentanol solution (500 mL); after the reaction is completed, deionized water is added after rotary evaporation of the solution, and a dilute hydrochloric acid solution is slowly added dropwise to the aqueous phase to precipitate a solid, which is filtered and dried to obtain 35.2 g of 3-bromo-1-(5-bromo-3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid with a yield of 92.5%.

[0070] Step 5. This step is different from step 5 in Example 1 in that: in this step, the solvent is replaced from dichloromethane solution (400 mL) to chloroform solution (400 mL); after the reaction is completed, column chromatography is performed, and petroleum ether: ethyl acetate (PE: EA volume ratio = 9: 1 to 3: 1) is used as the mobile phase for column chromatography, and 3-bromo-1-(5-bromo-3-chloropyridin-2-yl)-N-(4-chloro-2-methyl-6-(methylcarbamoyl)phenyl)-1H-pyrazole-5-carboxamide 45.0 g is obtained by rotary evaporation, with a yield of 77.6% and a purity of 99.5%.

[0071] Example 4

[0072] A method for preparing a chlorantraniliprole impurity (3-bromo-1-(5-bromo-3-chloropyridin-2-yl)-N-(4-chloro-2-methyl-6-(methylcarbamoyl)phenyl)-1H-pyrazole-5-carboxamide) comprises the following steps:

[0073] Step 1. This step is different from step 1 in Example 1 in that: in this step, the solvent is replaced from ethanol solution to n-pentanol solution (140 mL); after the reaction is completed, it is cooled to room temperature to precipitate a white solid, and the obtained solid is collected by filtration, washed thoroughly with water until neutral, and dried to obtain 19.7 g of 5-bromo-3-chloro-2-hydrazinopyridine with a yield of 89.4%.

[0074] Step 2. The difference between this step and step 2 in Example 1 is that: in this step, the catalyst is replaced by bis(triphenylphosphine)nickel dibromide with bis(triphenylphosphine)nickel chloride (0.66 g, 1 mmol), and the solvent is replaced by acetonitrile solution with dichloromethane solution (500 mL); after the reaction is completed, the solution is concentrated, added to a saturated sodium bicarbonate solution until the gas escapes completely, and then ethyl acetate is added for extraction, and the organic phases are combined; column chromatography is performed, and petroleum ether: ethyl acetate (PE: EA volume ratio = 80: 1 to 20: 1) is used as the mobile phase for column chromatography, and 3-bromo-1-(5-bromo-3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid ethyl ester 33.7 g is obtained by rotary evaporation, and the yield is 82.0%.

[0075] Step 3. The difference between this step and step 3 in Example 1 is that: in this step, the solvent is replaced from acetonitrile solution to tetrahydrofuran solution (500 mL); after the reaction is completed, the temperature is lowered to 65 ° C, filtered while hot, and the solution is concentrated; column chromatography is performed, and petroleum ether: ethyl acetate (PE: EA volume ratio = 80: 1 to 20: 1) is used as the mobile phase for column chromatography, and 30.4 g of 3-bromo-1-(5-bromo-3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid ethyl ester is obtained by rotary evaporation, and the yield is 74.4%.

[0076] Step 4. The difference between this step and step 4 in Example 1 is that in this step, the solvent is replaced from ethanol solution to n-propanol solution (500 mL); after the reaction is completed, deionized water is added after rotary evaporation of the solution, and a dilute hydrochloric acid solution is slowly added dropwise to the aqueous phase to precipitate a solid, which is filtered off and dried to obtain 34.7 g of 3-bromo-1-(5-bromo-3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid, with a yield of 91.3%.

[0077] Step 5. The difference between this step and step 5 in Example 1 is that: in this step, the solvent is replaced from dichloromethane solution (400 mL) to toluene solution (400 mL); after the reaction is completed, column chromatography is performed, and petroleum ether: ethyl acetate (PE: EA volume ratio = 9: 1 to 3: 1) is used as the mobile phase for column chromatography, and 3-bromo-1-(5-bromo-3-chloropyridin-2-yl)-N-(4-chloro-2-methyl-6-(methylcarbamoyl)phenyl)-1H-pyrazole-5-carboxamide 41.5 g is obtained by rotary evaporation, with a yield of 71.6% and a purity of 99.3%.

[0078] Comparative Example 1

[0079] The solvent of step 1 in Example 1 was replaced from ethanol solution to ethyl acetate solution (140 mL), and the mixture was heated to reflux. The reaction was monitored by TLC, and no intermediate product 5-bromo-3-chloro-2-hydrazinopyridine was generated.

[0080] Comparative Example 2

[0081] Step 1 is the same as Example 1, except that the solvent of step 2 in Example 1 is replaced from acetonitrile solution to acetone solution (500 mL), and the mixture is heated to 83° C. and refluxed. The reaction is monitored by TLC, and no intermediate product 3-bromo-1-(5-bromo-3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid ethyl ester is generated.

[0082] Comparative Example 3

[0083] Step 1 and step 2 are the same as in Example 1, except that the solvent in step 3 in Example 1 is replaced from acetonitrile solution to acetone solution (500 mL), and the mixture is heated to 83 ° C. and refluxed. The reaction is monitored by TLC, and no intermediate product 3-bromo-1-(5-bromo-3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid ethyl ester is generated.

[0084] Comparative Example 4

[0085] Step 1, step 2, and step 3 are the same as in Example 1, except that the solvent in step 4 in Example 1 is replaced with chloroform solution (500 mL) from ethanol solution; after completion of the reaction, the intermediate product 3-bromo-1-(5-bromo-3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid is obtained in a yield of only 61.1%.

[0086] Comparative Example 5

[0087] Step 1, step 2, step 3, and step 4 are the same as in Example 1, except that the solvent in step 5 in Example 1 is replaced with acetonitrile solution (400 mL) from dichloromethane solution (400 mL), and the remaining steps are the same as step 5 in Example 1, and the impurity 3-bromo-1-(5-bromo-3-chloropyridin-2-yl)-N-(4-chloro-2-methyl-6-(methylcarbamoyl)phenyl)-1H-pyrazole-5-carboxamide is not obtained.

[0088] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit the same. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that the technical solutions described in the aforementioned embodiments may still be modified, or some of the technical features may be replaced by equivalents. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing a chlorantraniliprole impurity, wherein the structural formula of the chlorantraniliprole impurity is Features: The following steps are involved: S1. 5-bromo-3-chloro-2-hydrazinepyridine is used as a raw material, mixed with ethanol, sodium ethoxide and a catalyst, and diethyl maleate is added after heating. After the reaction, glacial acetic acid and ice water are added, concentrated, extracted with ethyl acetate and the organic phases are combined, and then concentrated. An organic solvent and phosphorus oxybromide are added, and the mixture is heated to reflux for reaction. After the reaction is completed, 3-bromo-1-(5-bromo-3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid ethyl ester is obtained through post-treatment. Wherein, the organic solvent is a mixture of one or more of acetonitrile, ethyl acetate, chloroform, and dichloromethane; S2, As raw material, a mixture of one or more of acetonitrile, toluene, ethyl acetate and tetrahydrofuran is used as solvent, and reacted in the presence of concentrated sulfuric acid and potassium persulfate to obtain S3, As raw material, a mixture of one or more of ethanol, methanol, n-pentanol and n-propanol is used as solvent, and reacted in the presence of sodium hydroxide aqueous solution to obtain 3-bromo-1-(5-bromo-3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid S4, 3-bromo-1-(5-bromo-3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid Dichlorothionyl, an organic solvent and a catalyst are mixed, heated under an inert gas for reaction, and concentrated to obtain a mixture after the reaction; wherein the organic solvent is a mixture of one or more of dichloromethane, 1,2-dichloroethane, chloroform and toluene; S5. Mix the mixture, the organic solvent, 2-amino-5-chloro-N,3-dimethylbenzamide and the acid binding agent, react at room temperature, and perform post-treatment to obtain the chlorantraniliprole impurity.

2. The method for preparing chlorantraniliprole impurity according to claim 1, wherein: In S1, the catalyst includes at least one of bis(triphenylphosphine)nickel dibromide, bis(triphenylphosphine)palladium dichloride, tetrakis(triphenylphosphine)palladium or bis(triphenylphosphine)nickel chloride.

3. The method for preparing chlorantraniliprole impurity according to claim 1, wherein: In S1, the molar ratio of the catalyst to 5-bromo-3-chloro-2-hydrazinopyridine is 0.01 to 0.1:1; the molar ratio of the organic solvent to 5-bromo-3-chloro-2-hydrazinopyridine is 50:1 to 100:

1.

4. The method for preparing chlorantraniliprole impurity according to claim 1, characterized in that: In S5, the organic solvent is a mixture of one or more of dichloromethane, 1,2-dichloroethane, chloroform, and toluene.

5. The method for preparing chlorantraniliprole impurity according to claim 1, characterized in that: In S4, the usage ratio of 3-bromo-1-(5-bromo-3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid and dichlorothionyl is 0.1 mol:100 mL; the molar ratio of the organic solvent to 3-bromo-1-(5-bromo-3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid is 40:1 to 80:1; the usage ratio of the catalyst to 3-bromo-1-(5-bromo-3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid is 50 mL:0.1 mol.

6. The method for preparing chlorantraniliprole impurity according to claim 1, characterized in that: In S4, the reaction was carried out by heating to reflux under a nitrogen atmosphere for 3 hours.

7. The method for preparing chlorantraniliprole impurities according to claim 1, characterized in that: In S5, the reaction time is 72 hours.

8. The method for preparing chlorantraniliprole impurity according to claim 1, characterized in that: The molar ratio of 2-amino-5-chloro-N,3-dimethylbenzamide in S5 to 3-bromo-1-(5-bromo-3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid in S4 is 1:

1.

9. The method for preparing chlorantraniliprole impurity according to claim 1, characterized in that: In S5, the usage ratio of 2-amino-5-chloro-N,3-dimethylbenzamide and the organic solvent is 0.1 mol:500 mL; the usage ratio of the 2-amino-5-chloro-N,3-dimethylbenzamide and the acid binding agent is 0.1 mol:100 mL.

10. The method for preparing the chlorantraniliprole impurity according to any one of claims 1 to 9, characterized in that: In S4, the catalyst is N,N-dimethylformamide; in S5, the acid binding agent is a mixture of one or more of N,N-diisopropylethylamine, N-methylmorpholine, pyridine and triethylamine.

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