CN119977940A - A preparation method of chlorantraniliprole impurity - Google Patents
A preparation method of chlorantraniliprole impurity Download PDFInfo
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Abstract
本发明公开了一种氯虫苯甲酰胺杂质的制备方法，包括：以5‑溴‑3‑氯‑2‑肼基吡啶为原料制备得到以为原料制备得到以为原料制备得到将二氯亚砜、有机溶剂与催化剂混合，在惰性气体下加热进行反应，反应后浓缩得到混合物，与有机溶剂、2‑氨基‑5‑氯‑N,3‑二甲基苯甲酰胺、缚酸剂混合后室温下进行反应，后处理得到所述氯虫苯甲酰胺杂质本发明杂质在氯虫苯甲酰胺制备过程中容易产生，分离困难，对纯度有较大影响，本发明的制备方法过程简单，产品纯度高，转化率高。
The invention discloses a method for preparing chlorantraniliprole impurity, comprising: using 5-bromo-3-chloro-2-hydrazinylpyridine as a raw material to prepare by Prepared from raw materials by Prepared from raw materials Will Dithionyl chloride, an organic solvent and a catalyst are mixed, heated under an inert gas for reaction, concentrated after the reaction to obtain a mixture, mixed with an organic solvent, 2-amino-5-chloro-N,3-dimethylbenzamide and an acid binding agent, and reacted at room temperature, and post-treated to obtain the chlorantraniliprole impurity The impurities of the invention are easily generated during the preparation process of chlorantraniliprole, are difficult to separate, and have a great influence on the purity. The preparation method of the invention has a simple process, high product purity and high conversion rate.
Description
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to a preparation method of chlorantraniliprole impurities.
Background
The chlorantraniliprole (patent W003015519) is a pesticide which is the most widely used at home and abroad at present, is a green chemical pesticide developed by DuPont company in U.S.A., and has the characteristics of small dosage, long lasting period, small influence on human, livestock and environment and the like in the aspect of controlling lepidoptera pests of crops such as grains, cottons, fruits and vegetables. However, impurities are generated in the preparation process of chlorantraniliprole, and some impurities also participate in subsequent reactions and are difficult to remove, so that the quality of the product is seriously affected. 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 most easily produced impurity during the synthesis of chlorantraniliprole, and has the formula C 18H13Br2Cl2N5O2, molecular weight 562.04, structural formulaWhich can provide a reference for the mass analysis of chlorantraniliprole products.
The Chinese patent application publication No. CN108033944A discloses a chlorantraniliprole impurity preparation process, wherein the obtained chlorantraniliprole impurity S2 is reacted with a compound M3 in the presence of sulfonyl chloride compounds, and the chlorantraniliprole impurity S3 is obtained after the reaction is finished;
specifically, 2.0g of chlorantraniliprole impurity S2 (0.0052 mol), 1.0 g of M3 (0.0055 mol), 15g of acetonitrile and 1.24g of pyridine (0.016 mol) are added into a 100mL three-port bottle, stirring and cooling are carried out, a mixture of 5g of acetonitrile and 0.72g of methanesulfonyl chloride (0.0063 mol) is dropwise added at-5 ℃ and is completed within 10min, stirring is carried out for 2h under heat preservation, a large amount of solids are separated out, water is naturally heated, 7g of water is added at room temperature, stirring is continued for 1h, filtering is carried out, a filter cake is washed twice by using 2g of 30% acetonitrile water solution, a 55 ℃ vacuum oven is dried for 4h, 2.8g of white solid chlorantraniliprole impurity S3 is obtained, the yield is 95.6%, and HPLC is 98.4%, but the acquisition of methanesulfonyl chloride is difficult.
Disclosure of Invention
The technical problem to be solved by the invention is how to prepare chlorantraniliprole impurity
The invention solves the technical problems by the following technical means:
a preparation method of chlorantraniliprole impurities comprises the following steps of The method comprises the following steps:
S1, mixing 5-bromo-3-chloro-2-hydrazinopyridine serving as a raw material with ethanol, sodium ethoxide and a catalyst, heating, adding diethyl maleate, reacting, adding glacial acetic acid and ice water, concentrating, extracting ethyl acetate, combining organic phases, concentrating, adding an organic solvent and phosphorus tribromoxide, heating to reflux reaction, and performing aftertreatment after the reaction is finished to obtain 3-bromo-1- (5-bromo-3-chloropyridin-2-yl) -4, 5-dihydro-1H-pyrazole-5-ethyl formate Wherein the organic solvent is one or a mixture of acetonitrile, ethyl acetate, chloroform and dichloromethane;
S2, by The preparation method comprises the steps of taking one or more of acetonitrile, toluene, ethyl acetate and tetrahydrofuran as a solvent, and reacting in the presence of concentrated sulfuric acid and potassium persulfate to obtain the product
S3, byTaking one or a mixture of ethanol, methanol, n-amyl alcohol and n-propanol as a solvent, and reacting 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, reacting 3-bromo-1- (5-bromo-3-chloropyridin-2-yl) -1H-pyrazole-5-carboxylic acidMixing thionyl chloride, an organic solvent and a catalyst, heating under inert gas for reaction, and concentrating after the reaction to obtain a mixture, wherein the organic solvent is one or more of dichloromethane, 1, 2-dichloroethane, chloroform and toluene;
S5, mixing the mixture, an organic solvent, 2-amino-5-chloro-N, 3-dimethylbenzamide and an acid binding agent, reacting at room temperature, and performing post-treatment to obtain the chlorantraniliprole impurity.
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.
Preferably, in S1, the molar ratio of the catalyst to the 5-bromo-3-chloro-2-hydrazinopyridine is 0.01-0.1:1, and the molar ratio of the organic solvent to the 5-bromo-3-chloro-2-hydrazinopyridine is 50:1-100:1.
Preferably, in S5, the organic solvent is a mixture of one or more of dichloromethane, 1, 2-dichloroethane, chloroform, toluene.
Preferably, in S4, the dosage ratio of the 3-bromo-1- (5-bromo-3-chloropyridin-2-yl) -1H-pyrazole-5-carboxylic acid to thionyl chloride is 0.1mol:100mL, the molar ratio of the organic solvent to the 3-bromo-1- (5-bromo-3-chloropyridin-2-yl) -1H-pyrazole-5-carboxylic acid is 40:1-80:1, and the dosage ratio of the catalyst to the 3-bromo-1- (5-bromo-3-chloropyridin-2-yl) -1H-pyrazole-5-carboxylic acid is 50mL:0.1mol.
Preferably, in S4, the reaction is performed after heating to reflux under nitrogen atmosphere for 3 hours.
Preferably, in S5, the reaction time is 72 hours.
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.
Preferably, in S5, the dosage ratio of the 2-amino-5-chloro-N, 3-dimethylbenzamide to the organic solvent is 0.1mol:500mL, and the dosage ratio of the 2-amino-5-chloro-N, 3-dimethylbenzamide to the acid-binding agent is 0.1mol:100mL.
Preferably, in S4, the catalyst is N, N-dimethylformamide, and in S5, the acid-binding agent is one or more of N, N-diisopropylethylamine, N-methylmorpholine, pyridine and triethylamine.
Preferably, in S5, the post-treatment includes column chromatography, and the column chromatography uses petroleum ether to ethyl acetate volume ratio=9:1 to 3:1 as mobile phase.
Preferably, the S3 specifically comprises the following steps of taking 3-bromo-1- (5-bromo-3-chloropyridin-2-yl) -1H-pyrazole-5-carboxylic acid ethyl ester as a raw material, mixing with a solvent and an aqueous solution of sodium hydroxide, heating for reaction, concentrating the mixture after the reaction is finished, 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.
Preferably, the molar ratio of the solvent to the 3-bromo-1- (5-bromo-3-chloropyridin-2-yl) -1H-pyrazole-5-carboxylic acid ethyl ester is 45:1-125:1.
Preferably, the S2 specifically comprises the steps of taking 3-bromo-1- (5-bromo-3-chloropyridin-2-yl) -4, 5-dihydro-1H-pyrazole-5-carboxylic acid ethyl ester as a raw material, mixing with a solvent, a concentrated sulfuric acid solution and potassium persulfate, heating to reflux reaction, cooling to 65 ℃ after the reaction is finished, filtering while the solution is hot, 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.
Preferably, the molar ratio of the solvent to the ethyl 3-bromo-1- (5-bromo-3-chloropyridin-2-yl) -4, 5-dihydro-1H-pyrazole-5-carboxylate is 40:1 to 100:1.
Preferably, the S1 specifically comprises the steps of taking 5-bromo-3-chloro-2-hydrazinopyridine as a raw material, mixing the raw material with an absolute ethanol solution, a sodium ethoxide 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 is finished, concentrating, extracting ethyl acetate, merging organic phases, concentrating the organic phases, adding the mixture into an organic solvent, adding phosphorus tribromoxide, heating to reflux reaction, adding the mixture into a saturated sodium bicarbonate aqueous solution after the reaction is finished, extracting with ethyl acetate, merging 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.
Preferably, the preparation method of the 5-bromo-3-chloro-2-hydrazinopyridine comprises the following steps of taking 5-bromo-2, 3-dichloropyridine as a raw material, mixing with a hydrazine hydrate solution with the mass fraction of 85% and an organic solvent, heating to reflux reaction, cooling to room temperature after the reaction is finished, filtering, washing with water, and drying to obtain the product 5-bromo-3-chloro-2-hydrazinopyridine.
Preferably, the organic solvent comprises at least one of ethanol, methanol, 1, 4-dioxane or n-amyl alcohol, and the molar ratio of the organic solvent to the 5-bromo-2, 3-dichloropyridine is 20:1-40:1.
The invention has the advantages that:
(1) The invention achieves the effect of reducing the generation of byproducts by controlling the process conditions, and prepares finished impurities with high purity and higher conversion rate by means of column chromatography, recrystallization, filtration and the like.
(2) The invention provides a preparation method of chlorantraniliprole impurities, which provides assistance for mass analysis of chlorantraniliprole.
Drawings
FIG. 1 is a nuclear magnetic H-spectrum of 5-bromo-3-chloro-2-hydrazinopyridine prepared in example 1 of the present invention;
FIG. 2 is a nuclear magnetic C-spectrum of 5-bromo-3-chloro-2-hydrazinopyridine prepared in example 1 of the present invention;
FIG. 3 is a nuclear magnetic H-pattern of Compound 2 prepared in example 1 of the present invention;
FIG. 4 is a nuclear magnetic C-profile of compound 2 prepared in example 1 of the present invention;
FIG. 5 is a nuclear magnetic H-pattern of Compound 3 prepared in example 1 of the present invention;
FIG. 6 is a nuclear magnetic C-profile of Compound 3 prepared in example 1 of the present invention;
FIG. 7 is a nuclear magnetic H-pattern of Compound 4 prepared in example 1 of the present invention;
FIG. 8 is a nuclear magnetic C-spectrum of compound 4 prepared in example 1 of the present invention;
FIG. 9 is a mass spectrum of impurity A prepared in example 1 of the present invention;
FIG. 10 is a nuclear magnetic H spectrum of impurity A prepared in example 1 of the present invention;
FIG. 11 is a nuclear magnetic C-spectrum of impurity A prepared in example 1 of the present invention.
Detailed Description
For the purpose of making the objects, technical solutions and advantages of the embodiments of the present invention more apparent, the technical solutions in the embodiments of the present invention will be clearly and completely described in the following in conjunction with the embodiments of the present invention, and it is apparent that the described embodiments are some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The test materials, reagents and the like used in the examples described below are commercially available unless otherwise specified.
Those of skill in the art, without any particular mention of the techniques or conditions, may follow the techniques or conditions described in the literature in this field or follow the product specifications.
The synthetic route of the chlorantraniliprole impurity is shown as follows:
Example 1
A method for preparing chlorantraniliprole impurity (3-bromo-1- (5-bromo-3-chloropyridin-2-yl) -N- (4-chloro-2-methyl-6- (methylcarbamoyl) phenyl) -1H-pyrazole-5-carboxamide), comprising the following steps:
Step one 5-bromo-2, 3-dichloropyridine (22.7 g,0.1 mol), ethanol solution (140 mL), and 85% strength by mass hydrazine hydrate solution (50 mL) were charged to a 250mL four-necked flask equipped with a mechanical stirrer, thermometer, reflux condenser, and nitrogen inlet. The mixture is heated to reflux reaction for 20H, TLC monitors the reaction, after the reaction is finished, the reaction is cooled to room temperature, white solid is separated out, the obtained solid is collected by filtration, and is thoroughly washed to be neutral by water, and 20.7g of compound 1 5-bromo-3-chloro-2-hydrazinopyridine is obtained after drying, the yield is 93.4%, and the nuclear magnetic H spectrum and the nuclear magnetic C spectrum of the 5-bromo-3-chloro-2-hydrazinopyridine are shown in figure 1 and figure 2.
Step two, an absolute ethanol solution (500 mL), a sodium ethoxide ethanol solution (mass fraction 20%,500 mL), 5-bromo-3-chloro-2-hydrazinopyridine (22.3 g,0.1 mol) and bis (triphenylphosphine) nickel dibromide (0.75 g,1 mmol) were charged into 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℃for 15min, diethyl maleate (20.7 g,0.12 mol) was added dropwise and the reaction was continued for 4h. After the reaction, glacial acetic acid and ice water are added into the reaction liquid, the reactant is concentrated by rotary evaporation, ethyl acetate is used for extraction, the organic phases are combined, and the organic phases are concentrated for the next reaction. The concentrated organic phase was used as a reaction solution, acetonitrile solution (500 mL), phosphorus oxybromide (34.4 g,0.12 mol) was added, the mixture was refluxed at 83℃for 12h, and the reaction was monitored by TLC. Concentrating the solution after the reaction, adding saturated sodium bicarbonate solution until the gas escapes completely, adding ethyl acetate for extraction, and combining organic phases, performing column chromatography by using petroleum ether and ethyl acetate (PE: EA volume ratio=80:1-20:1) as mobile phases, and performing rotary evaporation to obtain 37.1g of compound 2 3-bromo-1- (5-bromo-3-chloropyridin-2-yl) -4, 5-dihydro-1H-pyrazole-5-ethyl formate, wherein the yield is 90.2%, and the nuclear magnetic H spectrum and the nuclear magnetic C spectrum of compound 2 are shown in fig. 3 and 4.
Step three, an acetonitrile solution (500 mL), a 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) were charged to 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 ℃ for 12h and the reaction monitored by tlc. After the reaction is finished, the temperature is reduced to 65 ℃, the solution is filtered while the reaction is still hot, the solution is concentrated, column chromatography is carried out, petroleum ether is adopted as a mobile phase by the column chromatography, ethyl acetate (PE: EA volume ratio=80:1-20:1), 34.8g of compound 3 3-bromo-1- (5-bromo-3-chloropyridin-2-yl) -1H-pyrazole-5-ethyl formate is obtained by rotary evaporation, the yield is 85.1%, and the nuclear magnetic H spectrum and the nuclear magnetic C spectrum of the prepared compound 3 are shown in fig. 5 and 6.
Step four, an ethanol solution (500 mL) was added to a 2L four-necked flask equipped with a mechanical stirrer, a thermometer, a reflux condenser and a nitrogen inlet, and the mass fraction was 20% aqueous sodium hydroxide solution (200 mL), ethyl 3-bromo-1- (5-bromo-3-chloropyridin-2-yl) -1H-pyrazole-5-carboxylate (41.0 g,0.1 mol). The mixture was reacted at 30℃for 3h, and the reaction was monitored by TLC. After the reaction is finished, adding deionized water after rotary evaporation, slowly dripping dilute hydrochloric acid solution into a water phase, precipitating solid, carrying out suction filtration and drying to obtain 35.7g of compound 4 3-bromo-1- (5-bromo-3-chloropyridin-2-yl) -1H-pyrazole-5-carboxylic acid, and obtaining 93.7% of yield, wherein the nuclear magnetic H spectrum and the nuclear magnetic C spectrum of the prepared compound 4 are shown in figure 7 and figure 8.
Step five 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) and then N, N-dimethylformamide solution (50 mL) were charged to a 1L four-necked flask equipped with a mechanical stirrer, thermometer, reflux condenser and nitrogen inlet. The mixture was reacted at 80 ℃ under reflux for 3h. After the reaction is finished, the thionyl chloride is dehydrated, and the thionyl chloride is directly used as a reaction liquid for the next reaction. To the above reaction solution was added a dichloromethane solution (500 mL), 2-amino-5-chloro-N, 3-dimethylbenzamide (19.9 g,0.1 mol), and to the mixture was slowly added a triethylamine solution (100 mL) dropwise, and the reaction was carried out at room temperature for 72h, followed by TLC monitoring. After the reaction, column chromatography is carried out, petroleum ether and ethyl acetate (PE: EA volume ratio=9:1-3:1) are used as mobile phases, and the impurity A3-bromo-1- (5-bromo-3-chloropyridin-2-yl) -N- (4-chloro-2-methyl-6- (methylcarbamoyl) phenyl) -1H-pyrazole-5-carboxamide is obtained by rotary evaporation, wherein 46.6g of the impurity A3-bromo-1- (5-bromo-3-chloropyridin-2-yl) -N- (4-chloro-2-methyl-6- (methylcarbamoyl) phenyl) -1H-pyrazole-5-carboxamide is obtained, and the yield is 80.3% and the purity is 99.8%. Prepared impurity AThe mass spectrum of the finished product is shown in figure 9, and the nuclear magnetism H spectrum and the nuclear magnetism C spectrum are shown in figure 10 and figure 11.
Example 2
A method for preparing chlorantraniliprole impurity (3-bromo-1- (5-bromo-3-chloropyridin-2-yl) -N- (4-chloro-2-methyl-6- (methylcarbamoyl) phenyl) -1H-pyrazole-5-carboxamide), comprising the following steps:
Step one, this step was different from step one in example 1 in that in this step, the solvent was changed from ethanol to a methanol solution (140 mL), and after the completion of the reaction, the reaction was cooled to room temperature, a white solid was precipitated, the obtained solid was collected by filtration, thoroughly washed with water to neutrality, and dried to obtain 20.2g of 5-bromo-3-chloro-2-hydrazinopyridine in 91.2% yield.
Step two, the difference with step two in example 1 is that in the step, the catalyst is changed from bis (triphenylphosphine) nickel dibromide into bis (triphenylphosphine) palladium dichloride (0.71 g,1 mmol), the solvent is changed into ethyl acetate solution (500 mL) from acetonitrile solution, after the reaction is finished, the solution is concentrated, the solution is added into saturated sodium bicarbonate solution until the gas is completely escaped, then ethyl acetate is added for extraction, the organic phase is combined, column chromatography is carried out, petroleum ether and ethyl acetate (PE: volume ratio of EA=80:1-20:1) are used as mobile phase, and the 3-bromo-1- (5-bromo-3-chloropyridin-2-yl) -4, 5-dihydro-1H-pyrazole-5-ethyl formate is obtained by rotary evaporation, and the yield is 84.7%.
Step three, the difference with the step three in example 1 is that in the step, the solvent is changed into toluene solution (500 mL) from acetonitrile solution, after the reaction is finished, the temperature is reduced to 65 ℃, the solution is filtered while the solution is hot, the solution is concentrated, column chromatography is carried out, petroleum ether and ethyl acetate (PE: EA volume ratio=80:1-20:1) are used as mobile phases for column chromatography, and 33.5g 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 82.1%.
Step four, the difference with step four in example 1 is that in the step, the solvent is changed into methanol solution (500 mL) from ethanol solution, deionized water is added after the reaction is finished, dilute hydrochloric acid solution is slowly added into aqueous phase, solid is separated out, suction filtration and drying are carried out, and 35.2g of 3-bromo-1- (5-bromo-3-chloropyridin-2-yl) -1H-pyrazole-5-carboxylic acid is obtained, and the yield is 92.5%.
Step five, this step is different from step five in example 1 in that in this step, the solvent is changed from dichloromethane solution (400 mL) to 1, 2-dichloroethane 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 mobile phase, and rotary evaporation is performed to obtain 45.0g of 3-bromo-1- (5-bromo-3-chloropyridin-2-yl) -N- (4-chloro-2-methyl-6- (methylcarbamoyl) phenyl) -1H-pyrazole-5-carboxamide, yield 77.6%, purity 99.7%.
Example 3
A method for preparing chlorantraniliprole impurity (3-bromo-1- (5-bromo-3-chloropyridin-2-yl) -N- (4-chloro-2-methyl-6- (methylcarbamoyl) phenyl) -1H-pyrazole-5-carboxamide), comprising the following steps:
Step one, this step was different from step one in example 1 in that in this step, the solvent was changed from an ethanol solution to a1, 4-dioxane solution (140 mL), and after the completion of the reaction, the reaction was cooled to room temperature, a white solid was precipitated, the obtained solid was collected by filtration, thoroughly washed with water to neutrality, and dried to obtain 20.0g of 5-bromo-3-chloro-2-hydrazinopyridine in a yield of 90.3%.
Step two, the difference with step two in example 1 is that in the step, the catalyst is changed from bis (triphenylphosphine) nickel dibromide to tetra (triphenylphosphine) palladium (1.16 g,1 mmol), the solvent is changed from acetonitrile solution to chloroform solution (500 mL), after the reaction is finished, the concentrated solution is added into saturated sodium bicarbonate solution until the gas is completely escaped, ethyl acetate is added for extraction, the organic phase is combined, column chromatography is carried out, petroleum ether and ethyl acetate (PE: EA volume ratio=80:1-20:1) are used as mobile phase, and the 3-bromo-1- (5-bromo-3-chloropyridin-2-yl) -4, 5-dihydro-1H-pyrazole-5-ethyl formate is obtained by rotary evaporation, wherein the yield is 87.1%.
Step three, the difference with the step three in example 1 is that in the step, the solvent is changed into ethyl acetate solution (500 mL) from acetonitrile solution, after the reaction is finished, the temperature is reduced to 65 ℃, the solution is filtered while the solution is hot, the solution is concentrated, column chromatography is carried out, petroleum ether and ethyl acetate (PE: EA volume ratio=80:1-20:1) are used as mobile phases, and 30.9g 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%.
Step four, the difference with the step four in the example 1 is that in the step, the solvent is changed into n-amyl alcohol solution (500 mL) from ethanol solution, deionized water is added after the reaction is finished, dilute hydrochloric acid solution is slowly added into water phase in a dropwise manner after the solution is distilled, solid is separated out, pumping filtration and drying are carried out, and 35.2g of 3-bromo-1- (5-bromo-3-chloropyridin-2-yl) -1H-pyrazole-5-carboxylic acid is obtained, and the yield is 92.5%.
Step five, this step is different from step five in example 1 in that in this step, the solvent is changed 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 a mobile phase, and the 3-bromo-1- (5-bromo-3-chloropyridin-2-yl) -N- (4-chloro-2-methyl-6- (methylcarbamoyl) phenyl) -1H-pyrazole-5-carboxamide is obtained by rotary evaporation in a yield of 77.6% and a purity of 99.5%.
Example 4
A method for preparing chlorantraniliprole impurity (3-bromo-1- (5-bromo-3-chloropyridin-2-yl) -N- (4-chloro-2-methyl-6- (methylcarbamoyl) phenyl) -1H-pyrazole-5-carboxamide), comprising the following steps:
Step one, this step is different from step one in example 1 in that in this step, the solvent is changed from ethanol solution to n-pentanol solution (140 mL), after the reaction is completed, the reaction is cooled to room temperature, a white solid is precipitated, the obtained solid is collected by filtration, thoroughly washed with water to neutrality, and after drying, 19.7g of 5-bromo-3-chloro-2-hydrazinopyridine is obtained in 89.4% yield.
Step two, this step is different from step two in example 1 in that in this step, the catalyst is changed from bis (triphenylphosphine) nickel dibromide to bis (triphenylphosphine) nickel chloride (0.66 g,1 mmol), the solvent is changed from acetonitrile solution to dichloromethane solution (500 mL), after the reaction is finished, the solution is concentrated, added into saturated sodium bicarbonate solution until the gas escapes completely, then ethyl acetate is added for extraction, the organic phase is combined, column chromatography is performed, petroleum ether and ethyl acetate (PE: volume ratio of EA=80:1-20:1) are used as mobile phase, and rotary evaporation is performed to obtain 33.7g of 3-bromo-1- (5-bromo-3-chloropyridin-2-yl) -4, 5-dihydro-1H-pyrazole-5-carboxylic acid ethyl ester, and the yield is 82.0%.
Step three, the difference with the step three in example 1 is that in the step, the solvent is changed into tetrahydrofuran solution (500 mL) from acetonitrile solution, after the reaction is finished, the temperature is reduced to 65 ℃, the solution is filtered while the reaction is hot, the solution is concentrated, column chromatography is carried out, petroleum ether and ethyl acetate (PE: EA volume ratio=80:1-20:1) are used as mobile phases for column chromatography, and 30.4g 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%.
Step four, the difference with the step four in the example 1 is that in the step, the solvent is changed into normal propyl alcohol solution (500 mL) from ethanol solution, deionized water is added after the reaction is finished, dilute hydrochloric acid solution is slowly added into water phase in a dropwise manner after the solution is distilled, solid is separated out, pumping filtration and drying are carried out, and 34.7g of 3-bromo-1- (5-bromo-3-chloropyridin-2-yl) -1H-pyrazole-5-carboxylic acid is obtained, and the yield is 91.3%.
Step five, this step is different from step five in example 1 in that in this step, the solvent is changed from methylene chloride 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 a mobile phase, and the 3-bromo-1- (5-bromo-3-chloropyridin-2-yl) -N- (4-chloro-2-methyl-6- (methylcarbamoyl) phenyl) -1H-pyrazole-5-carboxamide is obtained by rotary evaporation in a yield of 71.6% and a purity of 99.3%.
Comparative example 1
The solvent of step one of example 1 was changed from ethanol to ethyl acetate (140 mL) and the mixture was heated to reflux and TLC monitored the reaction without formation of the intermediate product 5-bromo-3-chloro-2-hydrazinopyridine.
Comparative example 2
Step one the same as in example 1, the solvent of step two of example 1 was changed from acetonitrile to acetone (500 mL), the mixture was heated to 83 ℃ reflux, TLC monitored the reaction, and no intermediate product, ethyl 3-bromo-1- (5-bromo-3-chloropyridin-2-yl) -4, 5-dihydro-1H-pyrazole-5-carboxylate, was formed.
Comparative example 3
Step one, step two were identical to example 1, the solvent of step three of example 1 was changed from acetonitrile to acetone (500 mL), the mixture was heated to 83 ℃ reflux, TLC monitored the reaction, and no intermediate 3-bromo-1- (5-bromo-3-chloropyridin-2-yl) -1H-pyrazole-5-carboxylic acid ethyl ester was formed.
Comparative example 4
Step one, step two and step three were the same as in example 1, and the solvent of step four in example 1 was changed from ethanol solution to chloroform solution (500 mL), and after the reaction was completed, 3-bromo-1- (5-bromo-3-chloropyridin-2-yl) -1H-pyrazole-5-carboxylic acid was obtained as an intermediate product in a yield of only 61.1%.
Comparative example 5
Step one, step two, step three and step four were the same as in example 1, the solvent of step five in example 1 was changed from dichloromethane solution (400 mL) to acetonitrile solution (400 mL), and the remaining steps were the same as in step five of example 1, and no impurity 3-bromo-1- (5-bromo-3-chloropyridin-2-yl) -N- (4-chloro-2-methyl-6- (methylcarbamoyl) phenyl) -1H-pyrazole-5-carboxamide was obtained.
The foregoing embodiments are merely for illustrating the technical solution of the present invention, but not for limiting the same, and although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those skilled in the art that modifications may be made to the technical solution described in the foregoing embodiments or equivalents may be substituted for parts of the technical features thereof, and that such modifications or substitutions do not depart from the spirit and scope of the technical solution of the embodiments of the present invention in essence.
Claims (10)
1. A preparation method of chlorantraniliprole impurities comprises the following steps ofThe method is characterized by comprising the following steps of:
S1, mixing 5-bromo-3-chloro-2-hydrazinopyridine serving as a raw material with ethanol, sodium ethoxide and a catalyst, heating, adding diethyl maleate, reacting, adding glacial acetic acid and ice water, concentrating, extracting ethyl acetate, combining organic phases, concentrating, adding an organic solvent and phosphorus tribromoxide, heating to reflux reaction, and performing aftertreatment after the reaction is finished to obtain 3-bromo-1- (5-bromo-3-chloropyridin-2-yl) -4, 5-dihydro-1H-pyrazole-5-ethyl formate Wherein the organic solvent is one or a mixture of acetonitrile, ethyl acetate, chloroform and dichloromethane;
S2, by The preparation method comprises the steps of taking one or more of acetonitrile, toluene, ethyl acetate and tetrahydrofuran as a solvent, and reacting in the presence of concentrated sulfuric acid and potassium persulfate to obtain the product
S3, byTaking one or a mixture of ethanol, methanol, n-amyl alcohol and n-propanol as a solvent, and reacting 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, reacting 3-bromo-1- (5-bromo-3-chloropyridin-2-yl) -1H-pyrazole-5-carboxylic acidMixing thionyl chloride, an organic solvent and a catalyst, heating under inert gas for reaction, and concentrating after the reaction to obtain a mixture, wherein the organic solvent is one or more of dichloromethane, 1, 2-dichloroethane, chloroform and toluene;
S5, mixing the mixture, an organic solvent, 2-amino-5-chloro-N, 3-dimethylbenzamide and an acid binding agent, reacting at room temperature, and performing post-treatment to obtain the chlorantraniliprole impurity.
2. The method for preparing chlorantraniliprole impurity according to claim 1, wherein 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.
3. The method for preparing chlorantraniliprole impurities according to claim 1, wherein in S1, the molar ratio of the catalyst to the 5-bromo-3-chloro-2-hydrazinopyridine is 0.01-0.1:1, and the molar ratio of the organic solvent to the 5-bromo-3-chloro-2-hydrazinopyridine is 50:1-100:1.
4. The method for preparing chlorantraniliprole impurity according to claim 1, wherein in S5, the organic solvent is one or more of dichloromethane, 1, 2-dichloroethane, chloroform and toluene.
5. The preparation method of the chlorantraniliprole impurity according to claim 1, wherein in S4, the dosage ratio of 3-bromo-1- (5-bromo-3-chloropyridin-2-yl) -1H-pyrazole-5-carboxylic acid and thionyl chloride is 0.1mol:100mL, the molar ratio of the organic solvent to 3-bromo-1- (5-bromo-3-chloropyridin-2-yl) -1H-pyrazole-5-carboxylic acid is 40:1-80:1, and the dosage ratio of the catalyst to 3-bromo-1- (5-bromo-3-chloropyridin-2-yl) -1H-pyrazole-5-carboxylic acid is 50mL:0.1mol.
6. The method for preparing chlorantraniliprole impurity as claimed in claim 1, wherein in S4, the reaction is carried out after heating to reflux under nitrogen atmosphere for 3 hours.
7. The method for preparing a chlorantraniliprole impurity according to claim 1, wherein the reaction time is 72 hours in S5.
8. The method for preparing chlorantraniliprole impurity 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.
9. The method for preparing the chlorantraniliprole impurity according to claim 1, wherein in S5, the dosage ratio of the 2-amino-5-chloro-N, 3-dimethylbenzamide to the organic solvent is 0.1mol:500mL, and the dosage ratio of the 2-amino-5-chloro-N, 3-dimethylbenzamide to the acid-binding agent is 0.1mol:100mL.
10. The method for preparing chlorantraniliprole impurity according to any one of claims 1 to 9, wherein in S4, the catalyst is N, N-dimethylformamide, and in S5, the acid-binding agent is one or more of N, N-diisopropylethylamine, N-methylmorpholine, pyridine and triethylamine.
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| CN1713819A (en) * | 2001-09-21 | 2005-12-28 | 杜邦公司 | Anthranilamide arthropodicide treatment |
| CN108033944A (en) * | 2017-12-28 | 2018-05-15 | 利尔化学股份有限公司 | Rynaxypyr impurity preparation process |
| WO2019207595A1 (en) * | 2018-04-23 | 2019-10-31 | Natco Pharma Limited | An improved process for the preparation of anthranilamide derivatives |
| WO2021033172A1 (en) * | 2019-08-20 | 2021-02-25 | Eurofins Advinus Limited | Process for the preparation of chlorantraniliprole |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1713819A (en) * | 2001-09-21 | 2005-12-28 | 杜邦公司 | Anthranilamide arthropodicide treatment |
| CN108033944A (en) * | 2017-12-28 | 2018-05-15 | 利尔化学股份有限公司 | Rynaxypyr impurity preparation process |
| WO2019207595A1 (en) * | 2018-04-23 | 2019-10-31 | Natco Pharma Limited | An improved process for the preparation of anthranilamide derivatives |
| WO2021033172A1 (en) * | 2019-08-20 | 2021-02-25 | Eurofins Advinus Limited | Process for the preparation of chlorantraniliprole |
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| HUIBIN YANG ET AL.: "Anthranilic diamide compounds: Discovery of tetrachlorantraniliprole", 《ADVANCED AGROCHEM》, vol. 2, 14 October 2023 (2023-10-14), pages 371 - 375 * |
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