A method for preparing a chlorantraniliprole impurity

Abstract

The application discloses a preparation method of chlorantraniliprole impurity, which comprises the following steps: 5-bromo-3-chloro-2-hydrazinylpyridine is used as raw material to prepare 2-amino-5-chloro-N,3-dimethylbenzamide, dichlorosulfoxide, an organic solvent and a catalyst are mixed, and the mixture is heated to react under inert gas; after the reaction, the mixture is concentrated to obtain a mixture; the mixture is mixed with the organic solvent, the 2-amino-5-chloro-N,3-dimethylbenzamide and an acid binding agent, and the mixture is reacted at room temperature; and the chlorantraniliprole impurity is obtained through post-treatment. The chlorantraniliprole impurity is easy to be generated in the preparation process of chlorantraniliprole, is difficult to separate, and has a great influence on purity. The preparation method is simple, the product has high purity, and the conversion rate is high.

Description

Technical Field

[0001] The present 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 currently 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. 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. 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] Chinese patent application publication number CN108033944A discloses a process for preparing a chlorantraniliprole impurity, wherein the chlorantraniliprole impurity S2 is reacted with a compound M3 in the presence of a sulfonyl chloride compound, and the reaction is completed to obtain a chlorantraniliprole impurity S3.

[0004]

[0005] The specific steps are as follows: 2.0 g of chlorantraniliprole impurity S2 (0.0052 mol), 1.09 g M3 (0.0055 mol), 15 g acetonitrile and 1.24 g pyridine (0.016 mol) were added to a 100 mL three-necked flask, stirred, cooled, and a mixture of 5 g acetonitrile and 0.72 g methanesulfonyl chloride (0.0063 mol) was added dropwise at -5°C. The addition was completed within 10 minutes. The mixture was kept warm and stirred for 2 hours. A large amount of solid precipitated. The temperature was naturally raised. 7 g of water was added at room temperature. Stirring was continued for 1 hour. The filter cake was washed twice with 2 g of 30% acetonitrile aqueous solution and dried in a vacuum oven at 55°C for 4 hours to obtain 2.8 g of white solid chlorantraniliprole impurity S3 with a yield of 95.6% and an HPLC index of 98.4%. However, methanesulfonyl chloride is used, 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-hydrazinylpyridine is used as a raw material, mixed with ethanol, sodium ethoxide and a catalyst, heated and added with diethyl maleate, and after the reaction, glacial acetic acid and ice water are added, concentrated, extracted with ethyl acetate and the organic phases are combined, concentrated and added with an organic solvent and phosphorus oxybromide, heated to reflux for reaction, and after the reaction is completed, post-processed to obtain 3-bromo-1-(5-bromo-3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid ethyl ester. Wherein, the organic solvent is a mixture of one or more of acetonitrile, ethyl acetate, chloroform, and dichloromethane;

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

[0011] S3, As raw materials, a mixture of one or more of ethanol, methanol, n-pentanol and n-propanol is used as solvent, and a sodium hydroxide aqueous solution is used to react 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 Thionyl chloride, 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, an organic solvent, 2-amino-5-chloro-N,3-dimethylbenzamide, and an 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; and 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 after heating to reflux under a nitrogen atmosphere, 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 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 a sodium hydroxide aqueous 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; and obtaining the product 3-bromo-1-(5-bromo-3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid ethyl ester after column chromatography.

[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-hydrazinylpyridine as a raw material, mixing it with an anhydrous ethanol solution, a sodium ethanol ethanol solution and a catalyst, heating to react, then adding diethyl maleate, continuing the reaction, adding glacial acetic acid and ice water after the reaction is completed, 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, 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-hydrazinylpyridine comprises the following steps: using 5-bromo-2,3-dichloropyridine as a raw material, mixing it with a hydrazine hydrate solution having a mass fraction of 85% and an organic solvent, heating it to reflux for reaction, cooling it to room temperature after the reaction is completed, filtering, washing with water, and drying to obtain the product 5-bromo-3-chloro-2-hydrazinylpyridine.

[0030] Preferably, the organic solvent includes 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 reduces the generation of by-products by controlling various process conditions, and then produces high-purity finished product impurities through column chromatography, recrystallization, filtration, etc., with a high conversion rate.

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

[0035] Figure 2 This 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] Figure 9 This is the mass spectrum of impurity A prepared in Example 1 of the present invention;

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

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

[0045] To make the objectives, technical solutions, and advantages of the embodiments of the present invention more clear, the technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only 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 making creative efforts shall fall 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 field or according to the product instructions.

[0048] The synthetic route of the 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 hours and monitor the reaction by TLC. After the reaction is completed, cool to room temperature to precipitate a white solid. The resulting solid is collected by filtration, washed thoroughly with water until neutral, and dried to obtain 20.7 g of compound 1 5-bromo-3-chloro-2-hydrazinylpyridine with a yield of 93.4%. The H NMR spectrum and C NMR spectrum of 5-bromo-3-chloro-2-hydrazinylpyridine are as follows: Figure 1 , Figure 2 shown.

[0053] Step 2: Anhydrous ethanol solution (500 mL), sodium ethanolate ethanol solution (mass fraction 20%, 500 mL), 5-bromo-3-chloro-2-hydrazinepyridine (22.3 g, 0.1 mol) and bis(triphenylphosphine) nickel dibromide (0.75 g, 1 mmol) 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 15 min, and then diethyl maleate (20.7 g, 0.12 mol) was added dropwise and the reaction was continued for 4 h. After the reaction was completed, glacial acetic acid and ice water were added to the reaction solution, and the reactants were concentrated by rotary evaporation. Ethyl acetate was used for extraction, and the organic phases were combined and concentrated for the next step of the reaction. The above-mentioned concentrated organic phase was used as the reaction solution, acetonitrile solution (500 mL) and phosphorus oxybromide (34.4 g, 0.12 mol) were added, and the mixture was refluxed at 83 ° C for 12 h, 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 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 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 H NMR spectrum and C NMR 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) to a 2L four-necked flask equipped with a mechanical stirrer, thermometer, reflux condenser, and 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 H NMR spectrum and C NMR spectrum of the prepared compound 3 are as follows: Figure 5 , Figure 6 shown.

[0055] Step 4. Ethanol solution (500 mL), 20% sodium hydroxide aqueous solution (200 mL) and ethyl 3-bromo-1-(5-bromo-3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylate (41.0 g, 0.1 mol) 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 reacted at 30 ° C for 3 h 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, filter it with suction, and dry it to obtain compound 4 3-bromo-1-(5-bromo-3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid 35.7 g with a yield of 93.7%; the nuclear magnetic H spectrum and nuclear magnetic 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, thermometer, reflux condenser, and nitrogen inlet. Then, add N,N-dimethylformamide solution (50 mL). The mixture was refluxed at 80°C for 3 h. After the reaction, the thionyl chloride was removed and used directly as the reaction solution for the next step. To the above reaction solution, dichloromethane solution (500 mL) and 2-amino-5-chloro-N,3-dimethylbenzamide (19.9 g, 0.1 mol) were added. Triethylamine solution (100 mL) was slowly added dropwise to the mixture. The mixture was reacted 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 Figure 9 As shown, the H and C NMR spectra are as follows Figure 10 , Figure 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 differs 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-hydrazinopyridine in 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 to bis(triphenylphosphine)palladium dichloride (0.71 g, 1 mmol), and the solvent is replaced by acetonitrile solution to ethyl acetate solution (500 mL); after completion of the reaction, the solution is concentrated and added to a saturated sodium bicarbonate solution until the gas is completely evolved, and then ethyl acetate is added for extraction, and the organic phases are combined; column chromatography is performed using petroleum ether: ethyl acetate (PE: EA volume ratio = 80: 1 to 20: 1) as the mobile phase, and rotary evaporation gives 34.8 g of ethyl 3-bromo-1-(5-bromo-3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate in a yield of 84.7%.

[0061] Step 3. This step is different from step 3 in Example 1 in 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 using petroleum ether: ethyl acetate (PE: EA volume ratio = 80: 1 to 20: 1) as the mobile phase, and rotary evaporation is performed to obtain 33.5 g of ethyl 3-bromo-1-(5-bromo-3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylate with a yield of 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 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%.

[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 column chromatography uses petroleum ether: ethyl acetate (PE: EA volume ratio = 9: 1 to 3: 1) as the mobile phase, and rotary evaporation gives 3-bromo-1-(5-bromo-3-chloropyridin-2-yl)-N-(4-chloro-2-methyl-6-(methylcarbamoyl)phenyl)-1H-pyrazole-5-carboxamide 45.0 g, 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 give 20.0 g of 5-bromo-3-chloro-2-hydrazinopyridine in 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 bis(triphenylphosphine)nickel dibromide to tetrakis(triphenylphosphine)palladium (1.16 g, 1 mmol), and the solvent is replaced by acetonitrile solution to chloroform solution (500 mL); after the reaction is completed, the solution is concentrated and added to a saturated sodium bicarbonate solution until the gas is completely evolved, and then ethyl acetate is added for extraction, and the organic phases are combined; column chromatography is performed using petroleum ether: ethyl acetate (PE: EA volume ratio = 80: 1 to 20: 1) as the mobile phase, and rotary evaporation gives 35.8 g of ethyl 3-bromo-1-(5-bromo-3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate in a yield of 87.1%.

[0068] Step 3. This step is different from step 3 in Example 1 in 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 using petroleum ether: ethyl acetate (PE: EA volume ratio = 80: 1 to 20: 1) as the mobile phase, and rotary evaporation is performed to obtain 30.9 g of ethyl 3-bromo-1-(5-bromo-3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylate with a yield of 75.7%.

[0069] 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 n-pentanol solution (500 mL); after the reaction is completed, deionized water is added after rotary evaporation of the solution, and 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 using petroleum ether: ethyl acetate (PE: EA volume ratio = 9: 1 to 3: 1) as the mobile phase, and rotary evaporation gives 45.0 g of 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 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 differs 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, the solution is cooled to room temperature to precipitate a white solid, which is collected by filtration and thoroughly washed with water until neutral. After drying, 19.7 g of 5-bromo-3-chloro-2-hydrazinopyridine is obtained with a yield of 89.4%.

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

[0075] Step 3. This step is different from step 3 in Example 1 in 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 using petroleum ether: ethyl acetate (PE: EA volume ratio = 80: 1 to 20: 1) as the mobile phase, and rotary evaporation is performed to obtain 30.4 g of ethyl 3-bromo-1-(5-bromo-3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylate with a yield of 74.4%.

[0076] 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 n-propanol solution (500 mL); after the reaction is completed, deionized water is added after rotary evaporation of the solution, and dilute hydrochloric acid solution is slowly added dropwise to the aqueous phase to precipitate a solid, which is filtered 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. 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 toluene solution (400 mL); after completion of the reaction, column chromatography is performed using petroleum ether: ethyl acetate (PE: EA volume ratio = 9: 1 to 3: 1) as the mobile phase, and rotary evaporation gives 41.5 g of 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 71.6% and a purity of 99.3%.

[0078] Comparative Example 1

[0079] The solvent in step 1 of 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 was the same as in Example 1, except that the solvent in Step 2 in Example 1 was replaced from acetonitrile solution to acetone solution (500 mL). The mixture was heated to 83 ° C. and refluxed. The reaction was monitored by TLC. No intermediate product, ethyl 3-bromo-1-(5-bromo-3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate, was produced.

[0082] Comparative Example 3

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

[0084] Comparative Example 4

[0085] Step 1, step 2, and step 3 were the same as in Example 1, except that the solvent in step 4 in Example 1 was replaced with a chloroform solution (500 mL) from an ethanol solution; after completion of the reaction, the intermediate product 3-bromo-1-(5-bromo-3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid was 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 from dichloromethane solution (400 mL) to acetonitrile solution (400 mL). 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 they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein. 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 various embodiments of the present invention.

Claims

1. A method for preparing a chlorantraniliprole impurity, wherein the structural formula of the chlorantraniliprole impurity is Its characteristics are: The following steps are involved: S1. 5-bromo-3-chloro-2-hydrazinylpyridine is used as a raw material, mixed with ethanol, sodium ethoxide and a catalyst, heated and added with diethyl maleate, and after the reaction, glacial acetic acid and ice water are added, concentrated, extracted with ethyl acetate and the organic phases are combined, concentrated and added with an organic solvent and phosphorus oxybromide, heated to reflux for reaction, and after the reaction is completed, post-processed to obtain 3-bromo-1-(5-bromo-3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid ethyl ester. wherein the organic solvent is a mixture of one or more of acetonitrile, ethyl acetate, chloroform, and dichloromethane; the catalyst comprises at least one of bis(triphenylphosphine)nickel dibromide, bis(triphenylphosphine)palladium dichloride, tetrakis(triphenylphosphine)palladium, or bis(triphenylphosphine)nickel chloride; S2, As raw materials, a mixture of one or more of acetonitrile, toluene, ethyl acetate and tetrahydrofuran is used as solvent, and the reaction is carried out in the presence of concentrated sulfuric acid and potassium persulfate to obtain S3, As raw materials, a mixture of one or more of ethanol, methanol, n-pentanol and n-propanol is used as solvent, and a sodium hydroxide aqueous solution is used to react 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 Thionyl chloride, an organic solvent and a catalyst are mixed, heated under an inert gas for reaction, and concentrated after the reaction to obtain a mixture; wherein the organic solvent is a mixture of one or more of dichloromethane, 1,2-dichloroethane, chloroform and toluene; and the catalyst is N,N-dimethylformamide; S5. Mix the mixture, an organic solvent, 2-amino-5-chloro-N,3-dimethylbenzamide, and an acid binding agent, react at room temperature, and post-treat to obtain the chlorantraniliprole impurity; the organic solvent is a mixture of one or more of dichloromethane, 1,2-dichloroethane, chloroform, and toluene; and the acid binding agent is a mixture of one or more of N,N-diisopropylethylamine, N-methylmorpholine, pyridine, and triethylamine.

2. The method for preparing chlorantraniliprole impurities 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; and the molar ratio of the organic solvent to 5-bromo-3-chloro-2-hydrazinopyridine is 50:1 to 100:

1.

3. The method for preparing chlorantraniliprole impurities according to claim 1, wherein: In S4, the usage ratio of 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; and 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.

4. The method for preparing chlorantraniliprole impurities according to claim 1, wherein: In S4, the reaction was carried out by heating to reflux under a nitrogen atmosphere for 3 h.

5. The method for preparing chlorantraniliprole impurities according to claim 1, wherein: In S5, the reaction time is 72 h.

6. The method for preparing chlorantraniliprole impurities according to claim 1, wherein: 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.

7. The method for preparing chlorantraniliprole impurities according to claim 1, wherein: 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.

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