A kind of synthetic method of fluopyrabamide

Abstract

The present invention provides a kind of synthetic method of fluopyrabamide, belongs to the field of chemical product synthesis technology, comprises the following steps: nickel chloride hexahydrate, tetraethyl orthosilicate and potassium hydrogen oxalate are mixed in water, high temperature treatment, cooling, separation, drying obtain nickel-based silicate carrier, aluminum chloride and ferric citrate are loaded on nickel-based silicate carrier to obtain composite catalyst;3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid, thionyl chloride, N, N-dimethylformamide, composite catalyst are mixed, heating and stirring, cooling separation, vacuum distillation obtain mixed solution;3', 4', 5'-trifluorobiphenyl-2-amine, toluene, composite catalyst, mixed solution are mixed, heating and stirring, cooling separation, vacuum distillation, stirring beating, centrifugal washing and drying obtain fluopyrabamide. Fluopyrabamide prepared by the present invention is not only higher in purity and yield, but also preparation process does not need the addition of additional acid binding agent, reduces the impact brought by-products, and has good industrial application prospects.

Description

Technical Field

[0001] The invention relates to the technical field of chemical product synthesis, and in particular to a method for synthesizing fluopyrabendazim. Background Art

[0002] Fluopyrab is a broad-spectrum, highly effective fungicide belonging to the pyrazole class of compounds, mainly used to control fungal diseases on fruit trees, vegetables and other crops, such as root rot, downy mildew and powdery mildew. Its chemical structure features fluoromethyl and trifluorobiphenyl, which inhibit the electron transport chain of fungal mitochondria, interfere with its energy metabolism, and cause fungal death. Fluopyrab has a long lasting effect and low toxicity, and is less harmful to humans, animals and the environment. It is often used by spraying or root irrigation, and has a good control effect.

[0003] At present, the commonly used synthesis steps of fluopyrabamide are to react 3-difluoromethyl-1-methyl-1-piperazole-4-yl chloride with 2-(3,4,5-trifluorophenyl)aniline to obtain the product. Although the method has simple steps, the reaction time is long, and in order to neutralize the acidic by-products generated in the reaction and maintain the pH of the reaction system, it is usually necessary to use excessive amounts of acid-binding agents such as pyridine and triethylamine. The generated materials such as pyridine hydrochloride and triethylamine hydrochloride require a large amount of liquid alkali for neutralization, resulting in a large amount of wastewater; and then the energy consumption of distillation to recover anhydrous pyridine and anhydrous triethylamine is large. In addition, the by-products generated in the reaction will not overflow completely at high temperatures, and some will remain in the system, affecting the purity of the target product.

[0004] The article entitled Synthesis Research of New Fungicides Fluopyram and Bixafen published in the Modern Pesticides Journal used 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid, thionyl chloride and N,N-dimethylformamide to obtain 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride by heating to reflux and then distilling under reduced pressure; then 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride, 3,4,5-trifluoro-2'-aminobiphenyl and toluene were heated to reflux in the presence of triethylamine, extracted, washed with water and dried to obtain fluopyram with a yield of 82.3%. This solution has a simple and economical process, mild conditions, and a high yield of fluopyrabamide. However, although the addition of N,N-dimethylformamide in the above reaction can stabilize the reaction intermediates and increase the reaction rate, it is difficult to remove, and the energy consumption of distilling and removing triethylamine is large. The influence of the residual by-products in the reaction system on the purity of the target product or the harm of directly discharging the by-products is not conducive to further improving the yield of the target product.

[0005] Therefore, it is urgent to develop a method that does not require the addition of components with high recovery energy consumption, can accelerate the reaction process, and improve the purity of the target product, so as to solve the problems existing in the above-mentioned prior art. Summary of the invention

[0006] In view of this, the present invention provides a method for synthesizing fluopyram. The fluopyram prepared by the present invention not only has higher purity and yield, but also does not require the addition of additional acid-binding agents during the preparation process, thereby reducing the impact of by-products and having good industrial application prospects.

[0007] To achieve the above object, the present invention provides a method for synthesizing fluopyrabendazim, comprising the following steps:

[0008] S1, nickel chloride hexahydrate, ethyl orthosilicate and potassium hydrogen oxalate are mixed in deionized water, subjected to high temperature treatment, cooled, separated, solids are washed and dried to obtain a nickel-based silicate carrier, and then aluminum chloride and ferric citrate are loaded on the nickel-based silicate carrier to obtain a composite catalyst;

[0009] S2, 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid and thionyl chloride are mixed and stirred, N,N-dimethylformamide is added dropwise and a composite catalyst is added during the mixture, and the mixture is heated and stirred, cooled, separated, and distilled under reduced pressure to obtain a mixed solution containing 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride;

[0010] S3, mixing 3',4',5'-trifluorobiphenyl-2-amine and toluene, adding a composite catalyst, dropping the mixed solution, heating and stirring, cooling, separating, distilling under reduced pressure, stirring and beating, centrifuging to obtain a solid, washing and drying to obtain pentopyroxamidine.

[0011] The present invention prepares a nickel-based silicate carrier loaded with aluminum chloride and ferric citrate to obtain a composite catalyst. Wherein, an acidic environment is generated when potassium hydrogen oxalate is hydrolyzed in water to promote the hydrolysis of tetraethyl orthosilicate, thereby accelerating the formation of silicate, and potassium hydrogen oxalate generates gas at high temperature, so that the nickel-based silicate carrier forms a rough structure, and its rough surface structure helps to take away the residual by-products in the system during the subsequent solid-liquid separation through adsorption and embedding of small molecule by-products. Nickel ions are combined with silicate ions of tetraethyl orthosilicate to form a coordination compound, which helps to stabilize the structure of the carrier and give the carrier a certain acidity. In addition, nickel ions, as active centers, can play a certain catalytic role. In the composite catalyst, since aluminum ions have a higher positive charge and a smaller ionic radius, it is easier to form acidic sites relative to other metal sources. These acidic sites play a role in promoting the reaction in acyl chloride reaction and amidation reaction, and ferric citrate further enhances the surface acidic environment. The synergistic effect of aluminum ions and ferric citrate in the catalyst further improves the catalytic activity of the catalyst. In addition, the multi-component composite catalyst is also conducive to improving the performance of single component easy agglomeration.

[0012] In the process of the acyl chloride reaction, the acidic sites of aluminum ions in the composite catalyst are used to interact with chloride or other polar molecules in the acyl chloride reaction to help reactants enter the reaction active sites. N, N-dimethylformamide is added to the composite catalyst to catalyze the acyl chloride reaction, shortening the reaction time and improving the reaction efficiency. The rough surface structure of the composite catalyst is used to adsorb trace amounts of N, N-dimethylformamide with a basic small molecule structure in the system. The composite catalyst is then recovered by solid-liquid separation while N, N-dimethylformamide in the system is also removed. Subsequently, the thionyl chloride that does not participate in the reaction is distilled out by reduced pressure distillation. The structural diagram of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride is shown in Figure 1 Chinese style (Ⅰ).

[0013] The present invention activates the amino group of 3',4',5'-trifluoro-[1,1'-biphenyl]-2-amine by impregnating the transition metal salt ferric citrate, thereby promoting the rapid progress of the amidation reaction. The citric acid in the ferric citrate can form a strong chemical bond with the hydroxyl group on the surface of the nickel-based silicate carrier through coordination, thereby enhancing the interaction between the iron ion and the nickel-based silicate carrier, making the composite catalyst more stable, and avoiding the problem that the commonly used inorganic iron salt may cause uneven or unstable loading due to mutual repulsion of charges or weak surface binding, thereby reducing the side reaction caused by excessive local acidity, and at the same time, the acid gas that is not completely released due to the acyl chloride reaction and the amidation reaction in the system can be adsorbed, thereby avoiding the by-products caused by the additional use of an acid binding agent, and improving the purity of the target product. The adsorbed acidic substance also helps to improve the acidity of the surface of the composite catalyst, thereby providing positive feedback for the adsorption of the acidic substance, thereby enhancing the adsorption effect.

[0014] Optionally, in step S1, ethyl orthosilicate and potassium hydrogen oxalate are added and stirred at 300-400 r / min for 20-30 min, subjected to high temperature treatment, cooled to room temperature, solid-liquid separation, the solid is washed with deionized water, and dried at 70-80° C. for 12-14 h to obtain a nickel-based silicate carrier.

[0015] Optionally, the temperature of the high temperature treatment in step S1 is 170-220° C., and the time is 11-13 hours.

[0016] Optionally, the composite catalyst is prepared by mixing aluminum chloride hexahydrate and a nickel-based silicate carrier in a closed container, heating the mixture to 180-200°C and keeping the mixture warm for 1-2 hours, then cooling the mixture to room temperature, adding ferric citrate and deionized water, stirring the mixture at a rate of 300-400 r / min for 1-2 hours, centrifuging the mixture at 5000-6000 rpm for 8-10 minutes, washing the mixture with deionized water for 5-7 times, and drying the mixture at 170-190°C for 6-8 hours.

[0017] The present invention introduces aluminum chloride on the surface of a nickel-based silicate carrier by vapor deposition at high temperature, which can activate the carboxylic acid group in 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid to improve the catalytic efficiency and enhance the stability of the catalyst system under high temperature.

[0018] Optionally, in step S2, toluene is added at the same time as 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid and thionyl chloride.

[0019] The thionyl chloride used in step S2 of the present invention has a low boiling point and is volatile. In order to improve its utilization rate, the thionyl chloride is stabilized in a toluene system. Toluene is used as a solvent to dilute the concentration of the thionyl chloride so that it will not accumulate to an excessively high concentration in a local area, provide a certain spatial isolation effect for the thionyl chloride molecules, slow down the interaction between the thionyl chloride molecules, and reduce the occurrence of byproducts such as sulfur dichloride generated by dimerization reaction of excessive thionyl chloride.

[0020] Optionally, in step S2, 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid, thionyl chloride and toluene are stirred at 300-400 r / min for 0.5-1.5 h, during which N,N-dimethylformamide is added dropwise, and a composite catalyst is added and stirred at a rate of 300-400 r / min at 70-80° C. for 2-3 h, the gas generated in the reaction is collected by an absorption tower, and then the temperature is reduced to 40-50° C., solid-liquid separation is performed, and reduced pressure distillation is performed until no significant organic matter is distilled out to obtain 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride, and 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride is mixed with toluene to obtain a mixed solution.

[0021] Optionally, in step S2, the heating and stirring temperature is 70-80°C, the rotation speed is 300 r / min, and the time is 2-3 h.

[0022] Optionally, in step S3, 3',4',5'-trifluorobiphenyl-2-amine and toluene are stirred at 110-120°C and 300-400 r / min for 1-1.5 h, a composite catalyst is added, the mixed solution is added dropwise, and the temperature is maintained at 110-120°C and stirred at 300-400 r / min for 2-4 h, the gas generated in the reaction is collected by an absorption tower, and then the temperature is reduced to 40-60°C, purified water is added, the solid-liquid separation is carried out, the composite catalyst is recovered, and the organic phase is distilled under reduced pressure until no fraction is dropped, a sodium hydroxide solution is added to adjust the pH of the system, the mixture is stirred and slurried, the solid is centrifuged, and the solid is washed with purified water and dried to obtain fluopyrabamide.

[0023] The present invention adopts heating and stirring in the amidation reaction process in order to make the acidic byproducts generated by the amidation reaction in the system escape at high temperature, thereby eliminating the addition and post-treatment of acid binding agents. At the same time, the gas generated in the reaction is collected by an absorption tower to prevent direct emission from causing harm to the atmospheric environment and simplify the process. Figure 1 Chinese style (Ⅱ).

[0024] Optionally, the mixed solution in step S3 is added dropwise within 1 to 1.5 hours.

[0025] Optionally, the mass concentration of the sodium hydroxide solution is 3%.

[0026] Optionally, in step S3, after solid-liquid separation and recovery of the composite catalyst, and reduced pressure distillation until no fraction drips out of the organic phase, sodium hydroxide solution is added to adjust the pH of the system to 8-9, and the stirring and beating temperature is 20-30°C and the time is 20-40 min.

[0027] The above technical solution of the present invention includes at least the following beneficial effects:

[0028] 1. The present invention prepares a nickel-based silicate carrier to load aluminum chloride and ferric citrate to prepare a composite catalyst. The rough structure of the composite catalyst helps to remove the residual byproducts in the system during the subsequent solid-liquid separation through physical adsorption and embedding of small molecular byproducts. Aluminum ions in the composite catalyst form acidic sites, and the addition of ferric citrate further enhances the surface acidity. The synergistic effect of aluminum ions and ferric citrate in the catalyst further improves the catalytic activity of the catalyst.

[0029] 2. In the process of acyl chlorination reaction, the present invention utilizes the interaction between the acidic sites of aluminum ions in the composite catalyst and the chloride or other polar molecules in the acyl chlorination reaction to help the reactants enter the reaction active sites, and N,N-dimethylformamide is added together with the composite catalyst to catalyze the acyl chlorination reaction, thereby shortening the reaction time and improving the reaction efficiency.

[0030] 3. The present invention activates the amino group of 3',4',5'-trifluoro-[1,1'-biphenyl]-2-amine by impregnating ferric citrate, thereby promoting the rapid progress of the amidation reaction. The citric acid in the ferric citrate can form a strong chemical bond with the hydroxyl group on the surface of the nickel-based silicate carrier, thereby improving the stability of the composite catalyst. It also avoids the problem that the commonly used inorganic iron salts may cause uneven or unstable loading, thereby reducing side reactions caused by excessive local acidity. At the same time, the adsorption effect between acidic substances is utilized to adsorb the acidic gas that is not completely released in the system due to the acyl chloride reaction and the amidation reaction, thereby improving the purity of the target product. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 The present invention is a structural diagram of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride (intermediate) and fluopyrabendazole; wherein formula (I) is 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride, and formula (II) is fluopyrabendazole.

[0032] Figure 2 The purity test chromatogram of the intermediate prepared in Example 1 of the present invention is shown in FIG.

[0033] Figure 3 This is a purity detection chromatogram of fluopyraclostrobin prepared in Example 1 of the present invention.

[0034] Figure 4 This is a purity detection chromatogram of fluopyraclostrobin prepared in Example 5 of the present invention. DETAILED DESCRIPTION

[0035] In order to make the purpose, technical solution and advantages of the embodiment of the present invention clearer, the technical solution of the embodiment of the present invention will be clearly and completely described in combination with the embodiment of the present invention. Obviously, the described embodiment is a part of the embodiment of the present invention, not all the embodiments. Based on the described embodiment of the present invention, all other embodiments obtained by ordinary technicians in this field belong to the scope of protection of the present invention.

[0036] The sodium hydroxide solution used in the following examples is a sodium hydroxide solution with a mass concentration of 3%, which was purchased from Shanghai Yien Chemical Technology Co., Ltd. Among them, the structure diagrams of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride and fluopyraclostrobin are shown in Figure 1 , wherein formula (I) is 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride and formula (II) is fluopyrabdo.

[0037] Example 1

[0038] 1.56g nickel chloride hexahydrate was mixed evenly in 500mL deionized water, 7.32mL ethyl orthosilicate and 10g potassium hydrogen oxalate were added and stirred at 300r / min for 30min, then treated in an autoclave at 220℃ for 12h, cooled to room temperature, solid-liquid separation was performed, the solid was washed with deionized water, and then dried at 75℃ for 12h to obtain a nickel-based silicate carrier. 0.1g aluminum chloride hexahydrate was mixed with 1g nickel-based silicate carrier in a sealed container, heated to 190℃ and kept warm for 1h, cooled to room temperature, 0.15g ferric citrate and 50mL deionized water were added, stirred at 300r / min for 1h, centrifuged at 5000rpm for 10min, the precipitate was washed with deionized water 5 times, and then dried at 190℃ for 6h to obtain a composite catalyst.

[0039] 50 g of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid, 40.4 mL of thionyl chloride and 461.5 mL of toluene were stirred at 300 r / min for 1 h, during which 0.22 mL of N,N-dimethylformamide was added dropwise, and 5 g of the composite catalyst was added, followed by stirring at 300 r / min for 2 h at 75° C. The gas generated in the reaction was collected by an absorption tower, and then the temperature was lowered to 40° C., the solid-liquid separation was performed, and the composite catalyst was recovered, and then the separated solution was distilled under reduced pressure until no significant organic matter was distilled out to obtain 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride. 50 g of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride was mixed with 600 mL of toluene to obtain a mixed solution.

[0040] 52 g of 3',4',5'-trifluoro-[1,1'-biphenyl]-2-amine and 472 mL of toluene were stirred at 300 r / min at 110° C. for 1 h, 7 g of the composite catalyst was added, 530 mL of the mixed solution was added dropwise, the addition was completed in 1 h, the temperature was maintained at 110° C. and the stirring was 300 r / min for 3 h, the gas generated in the reaction was collected by an absorption tower, the temperature was lowered to 40° C., purified water was added, the solid-liquid separation was carried out, and the composite catalyst was recovered, and then the separated solution was distilled under reduced pressure until no fraction was dropped from the organic phase, sodium hydroxide solution was added to adjust the pH of the system to 8.5, and after stirring and beating at 25° C. for 20 min, the solid was centrifuged, washed with purified water and dried to obtain fluopyraclostrobin.

[0041] Example 2

[0042] 1.5g nickel chloride hexahydrate was mixed evenly in 500mL deionized water, 6.7mL ethyl orthosilicate and 9.2g potassium hydrogen oxalate were added and stirred at 300r / min for 20min, then treated in an autoclave at 220℃ for 11.5h, cooled to room temperature, solid-liquid separation was performed, the solid was washed with deionized water, and then dried at 80℃ for 12h to obtain a nickel-based silicate carrier. 0.15g aluminum chloride hexahydrate was mixed with 1g nickel-based silicate carrier in a sealed container, heated to 220℃ and kept warm for 2h, cooled to room temperature, 0.15g ferric citrate and 50mL deionized water were added, stirred at 400r / min for 1h, centrifuged at 6000rpm for 8min, the precipitate was washed 7 times with deionized water, and then dried at 170℃ for 8h to obtain a composite catalyst.

[0043] 48 g of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid, 38.8 mL of thionyl chloride and 443.1 mL of toluene were mixed and stirred at 300 r / min for 0.5 h, during which 0.21 mL of N,N-dimethylformamide was added dropwise, and 10 g of the composite catalyst was added. The mixture was then stirred at 400 r / min for 3 h at 70° C., and the gas generated in the reaction was collected by an absorption tower. The mixture was then cooled to 60° C., solid-liquid separation was performed, and the composite catalyst was recovered. The separated solution was then distilled under reduced pressure until no significant organic matter was distilled out to obtain 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride. 50 g of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride was mixed with 600 mL of toluene to obtain a mixed solution.

[0044] 50 g of 3',4',5'-trifluoro-[1,1'-biphenyl]-2-amine and 453 mL of toluene were stirred at 400 r / min at 115° C. for 1.5 h, 15 g of the composite catalyst was added, 510 mL of the mixed solution was added dropwise, the addition was completed within 1.5 h, the temperature was maintained at 115° C. and the stirring was performed at 400 r / min for 2 h, the gas generated in the reaction was collected by an absorption tower, the temperature was lowered to 45° C., purified water was added, the solid-liquid separation was performed, and the composite catalyst was recovered, and then the separated solution was distilled under reduced pressure until no fraction was dropped from the organic phase, sodium hydroxide solution was added to adjust the pH of the system to 8, and the system was stirred and slurried at 20° C. for 20 min, and then the solid was centrifuged, washed with purified water and dried to obtain fluopyraclostrobin.

[0045] Example 3

[0046] 1.45g nickel chloride hexahydrate was mixed evenly in 500mL deionized water, 6.3mL ethyl orthosilicate and 8.6g potassium hydrogen oxalate were added and stirred at 400r / min for 25min, then treated in an autoclave at 170°C for 13h, cooled to room temperature, solid-liquid separation was performed, the solid was washed with deionized water, and then dried at 70°C for 14h to obtain a nickel-based silicate carrier. 0.1g aluminum chloride hexahydrate and 1g nickel-based silicate carrier were heated to 195°C in a sealed container and kept warm for 1.5h, then cooled to room temperature, 0.1g ferric citrate and 50mL deionized water were added, stirred at 300r / min for 1.5h, centrifuged at 6000rpm for 8min, the precipitate was washed with deionized water 6 times, and then dried at 190°C for 7h to obtain a composite catalyst.

[0047] 52 g of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid and 42 mL of thionyl chloride were stirred at 400 r / min for 1 h, during which 0.23 mL of N,N-dimethylformamide was added dropwise, and 7 g of the composite catalyst was added. The mixture was then stirred at 400 r / min for 2 h at 80° C., and the gas generated in the reaction was collected by an absorption tower. The mixture was then cooled to 55° C., solid-liquid separation was performed, and the composite catalyst was recovered. The separated solution was then distilled under reduced pressure until no significant organic matter was distilled out to obtain 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride. 50 g of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride was mixed with 600 mL of toluene to obtain a mixed solution.

[0048] 53 g of 3',4',5'-trifluoro-[1,1'-biphenyl]-2-amine and 481 mL of toluene were stirred at 400 r / min at 110° C. for 1.5 h, 12 g of the composite catalyst was added, 540 mL of the mixed solution was added dropwise, the addition was completed in 1.5 h, the temperature was maintained at 110° C. and the stirring was performed at 400 r / min for 4 h, the gas generated in the reaction was collected by an absorption tower, the temperature was lowered to 50° C., purified water was added, the solid-liquid separation was performed, and the composite catalyst was recovered, and then the separated solution was distilled under reduced pressure until no fraction was dropped from the organic phase, sodium hydroxide solution was added to adjust the pH of the system to 9, and after stirring and beating at 30° C. for 20 min, the solid was centrifuged, washed with purified water and dried to obtain fluopyraclostrobin.

[0049] Example 4

[0050] 1.6g nickel chloride hexahydrate was mixed evenly in 500mL deionized water, 7.1mL ethyl orthosilicate and 9.7g potassium hydrogen oxalate were added and stirred at 400r / min for 20min, then treated in an autoclave at 175°C for 12.5h, cooled to room temperature, solid-liquid separation was performed, the solid was washed with deionized water, and then dried at 75°C for 13h to obtain a nickel-based silicate carrier. 0.2g aluminum chloride hexahydrate was mixed with 1g nickel-based silicate carrier in a sealed container, heated to 200°C and kept warm for 1h, cooled to room temperature, 0.2g ferric citrate and 50mL deionized water were added, stirred at 400r / min for 1.5h, centrifuged at 5000rpm for 10min, the precipitate was washed with deionized water 7 times, and then dried at 170°C for 8h to obtain a composite catalyst.

[0051] 53 g of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid, 42.8 mL of thionyl chloride and 453 mL of toluene were stirred at 400 r / min for 0.5 h, during which 0.23 g of N,N-dimethylformamide was added dropwise, and 8 g of the composite catalyst was added. The mixture was then stirred at 300 r / min for 3 h at 70° C., and the gas generated in the reaction was collected by an absorption tower. The mixture was then cooled to 45° C., the solid-liquid separation was performed, and the composite catalyst was recovered. The separated solution was then distilled under reduced pressure until no significant organic matter was distilled out to obtain 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride. 50 g of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride was mixed with 600 mL of toluene to obtain a mixed solution.

[0052] 55 g of 3',4',5'-trifluoro-[1,1'-biphenyl]-2-amine and 499 mL of toluene were stirred at 300 r / min at 120° C. for 1 h, 13 g of the composite catalyst was added, 560 mL of the mixed solution was added dropwise, the addition was completed in 1 h, the temperature was maintained at 120° C. and the stirring was 300 r / min for 2.5 h, the gas generated in the reaction was collected by an absorption tower, the temperature was lowered to 55° C., purified water was added, the solid-liquid separation was carried out, and the composite catalyst was recovered, and then the separated solution was distilled under reduced pressure until no fraction was dropped from the organic phase, sodium hydroxide solution was added to adjust the pH of the system to 8.5, and after stirring and beating at 20° C. for 20 min, the solid was centrifuged, washed with purified water and dried to obtain fluopyraclostrobin.

[0053] Example 5

[0054] 1.5g nickel chloride hexahydrate was mixed evenly in 500mL deionized water, 7.1mL ethyl orthosilicate and 9.7g potassium hydrogen oxalate were added and stirred at 400r / min for 25min, then treated in an autoclave at 170°C for 13h, cooled to room temperature, solid-liquid separation was performed, the solid was washed with deionized water, and then dried at 70°C for 13.5h to obtain a nickel-based silicate carrier. 0.15g aluminum chloride hexahydrate was mixed with 1g nickel-based silicate carrier in a sealed container, heated to 220°C and kept warm for 2h, cooled to room temperature, 0.2g ferric citrate and 50mL deionized water were added, stirred at 300r / min for 2h, centrifuged at 5000rpm for 8min, the precipitate was washed with deionized water several times, and then dried at 190°C for 6h to obtain a composite catalyst.

[0055] 46 g of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid, 37.2 mL of thionyl chloride and 521 mL of toluene were stirred at 300 r / min for 1.5 h, during which 0.2 mL of N,N-dimethylformamide was added dropwise, and 6 g of the composite catalyst was added, followed by stirring at 300 r / min for 2.5 h at 75° C., and the gas generated in the reaction was collected by an absorption tower, and then the temperature was lowered to 50° C., the solid-liquid separation was performed, and the composite catalyst was recovered, and then the separated solution was distilled under reduced pressure until no significant organic matter was distilled out to obtain 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride, and 50 g of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride was mixed with 600 mL of toluene to obtain a mixed solution.

[0056] 51 g of 3',4',5'-trifluoro-[1,1'-biphenyl]-2-amine and 463 mL of toluene were stirred at 300 r / min at 110° C. for 1 h, 10 g of the composite catalyst was added, 520 mL of the mixed solution was added dropwise, the addition was completed in 1.5 h, the temperature was maintained at 110° C. and the stirring was 300 r / min for 3.5 h, the gas generated in the reaction was collected by an absorption tower, the temperature was lowered to 60° C., purified water was added, the solid-liquid separation was carried out, and the composite catalyst was recovered, and then the separated solution was distilled under reduced pressure until no fraction was dropped from the organic phase, sodium hydroxide solution was added to adjust the pH of the system to 8, and after stirring and beating at 30° C. for 20 min, the solid was centrifuged, washed with purified water and dried to obtain fluopyraclostrobin.

[0057] Example 6

[0058] 1.45g nickel chloride hexahydrate was mixed evenly in 500mL deionized water, 6.3mL ethyl orthosilicate and 9.2g potassium hydrogen oxalate were added and stirred at 300r / min for 20min, then treated in an autoclave at 220℃ for 11h, cooled to room temperature, separated solid and liquid, washed with deionized water, and then dried at 80℃ for 12.5h to obtain a nickel-based silicate carrier. 0.1g aluminum chloride hexahydrate and 1g nickel-based silicate carrier were heated to 185℃ and kept warm for 1.5h in a closed container, then cooled to room temperature, 0.15g ferric citrate and 50mL deionized water were added, stirred at 400r / min for 1.5h, centrifuged at 6000rpm for 8min, the precipitate was washed with deionized water several times, and then dried at 220℃ for 6h to obtain a composite catalyst.

[0059] 52 g of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid, 42 mL of thionyl chloride and 480 mL of toluene were stirred at 400 r / min for 0.5 h, during which 0.21 mL of N,N-dimethylformamide was added dropwise, and 9 g of the composite catalyst was added. The mixture was then stirred at 400 r / min for 2 h at 80° C., and the gas generated in the reaction was collected by an absorption tower. The mixture was then cooled to 50° C., solid-liquid separation was performed, and the composite catalyst was recovered. The separated solution was then distilled under reduced pressure until no significant organic matter was distilled out to obtain 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride. 50 g of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride was mixed with 600 mL of toluene to obtain a mixed solution.

[0060] 50 g of 3',4',5'-trifluoro-[1,1'-biphenyl]-2-amine and 453 mL of toluene were stirred at 400 r / min at 120° C. for 1.5 h, 8 g of the composite catalyst was added, 520 mL of the mixed solution was added dropwise, the addition was completed in 1 h, the temperature was maintained at 120° C. and the stirring was 400 r / min for 2.5 h, the gas generated in the reaction was collected by an absorption tower, the temperature was lowered to 50° C., purified water was added, the solid-liquid separation was carried out, and the composite catalyst was recovered, and then the separated solution was distilled under reduced pressure until no fraction was dropped from the organic phase, sodium hydroxide solution was added to adjust the pH of the system to 9, and after stirring and beating at 25° C. for 20 min, the solid was centrifuged, washed with purified water and dried to obtain fluopyraclostrobin.

[0061] The present invention also provides comparative examples and related tests.

[0062] Comparative Example 1

[0063] Compared with Example 1, the difference is that no composite catalyst is prepared, and triethylamine is added as an acid binding agent to absorb acidic gas during the preparation of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride and fluopyraclostrobin, and other reaction conditions, components, steps and other operations remain unchanged.

[0064] Comparative Example 2

[0065] Compared with Example 1, the difference is that aluminum chloride is not loaded during the preparation of the composite catalyst, and other reaction conditions, components, steps and other operations remain unchanged.

[0066] Comparative Example 3

[0067] Compared with Example 1, the difference is that ferric citrate is not loaded during the preparation of the composite catalyst, and other reaction conditions, components, steps and other operations remain unchanged.

[0068] In the test process of the above Examples 1 to 6 and Comparative Examples 1 to 3, the obtained 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride is recorded as an intermediate, and the structure is shown in Figure 1 The structure of the finally prepared fluopyraclostrobin is shown in Figure 1 Chinese formula (II), and the content and purity of the intermediate and flupyraclostrobin were tested. The test methods and related results are as follows:

[0069] 1. Purity detection method of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride:

[0070] Instrument: Agilent 1260 high performance liquid chromatograph;

[0071] Mobile phase: (1000ml water + 1ml acetic acid): (1000ml methanol + 1ml acetic acid) = 70:30

[0072] Flow rate: 1.0 mL / min;

[0073] Chromatographic column: ZORBAXSB-C18 5µm; 4.6×150mm;

[0074] Column temperature: 40°C;

[0075] Wavelength: 230nm.

[0076] 2. Fluopyraclostrobin purity detection method:

[0077] Instrument: Agilent 1260 high performance liquid chromatograph;

[0078] Mobile phase: (1000ml water + 1ml acetic acid): (1000ml methanol + 1ml acetic acid) = 38:62;

[0079] Flow rate: 1.0 mL / min;

[0080] Chromatographic column: ZORBAXSB-C18 5µm; 4.6×150mm;

[0081] Column temperature: 40°C;

[0082] Wavelength: 225nm.

[0083] Solution preparation:

[0084] (1) Accurately weigh 50.00 mg of the intermediate standard sample and place it in a 100 ml volumetric flask. Add methanol to fully dissolve it, then dilute it to the scale with methanol and shake well to obtain the standard solution.

[0085] (2) Accurately weigh 50.00 mg of the fluopicolide sample and place it in a 100 ml volumetric flask. Add methanol to fully dissolve it, then dilute it to the mark with methanol and shake well to obtain a crude sample solution.

[0086] Molar yield = ;

[0087] MR: relative molecular mass of raw materials, mR: input mass of raw materials;

[0088] mP: actual output mass of the product, Mp: relative molecular mass of the product;

[0089] Content calculation:

[0090] External standard method; Standard product: Manufacturer: Shenyang Chemical Research Institute, content 98.50%;

[0091] Sample content = ;

[0092] Wherein, A: detection peak area, C: concentration.

[0093] After the contents of the intermediates and fluopyrab in Examples 1 to 6 and Comparative Examples 1 to 3 were detected by high performance liquid chromatography, the data were collated and the contents of the intermediates and fluopyrab were recorded in Table 1.

[0094] Table 1

[0095]

[0096] As shown in Table 1, the contents of the intermediate and fluopyram prepared in Examples 1 to 6 are all greater than 93%, and the test results are significantly better than the fluopyram prepared in Comparative Examples 1 to 5, and the performance of Example 1 is the best, which is the best solution of the present invention. In Example 3, due to the fact that toluene is not added to mix with thionyl chloride during the preparation of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride, the purity of the intermediate prepared is affected, and the purity of the intermediate is lower than that of other embodiments. Comparative Example 1 does not prepare a composite catalyst, so that the content of intermediate and fluopyram is significantly reduced, and Comparative Example 2 does not load aluminum chloride, which has a relatively low impact on chlorination reaction and causes the content of intermediate to be relatively low, and Comparative Example 3 does not load ferric citrate, which has a slightly larger impact on amidation reaction, resulting in a significant reduction in the content of fluopyram at last.

[0097] The intermediates and fluopyrabendazole prepared in Examples 1 to 6 and Comparative Examples 1 to 3 were tested for purity by high performance liquid chromatography. The results showed that the intermediates and fluopyrabendazole in the reaction processes of Examples 1 to 2 and Examples 4 to 6 had high purity and no impurities. A partial liquid phase detection chromatogram is attached, as shown in FIG. Figure 2 The intermediate obtained in Example 1, Figure 3This is a liquid phase detection chromatogram of fluopyraclostrobin obtained in Example 1, Figure 4 This is the liquid phase detection chromatogram of fluopyraclostrobin obtained in Example 5, Figure 2~Figure 4 The peak information results corresponding to the liquid phase detection chromatograms are shown in Tables 2 to 4 below, wherein Table 2 is a peak information result table of the intermediate prepared in Example 1, Table 3 is a peak information result table of fluopyram prepared in Example 1, and Table 4 is a peak information result table of fluopyram prepared in Example 5.

[0098] Table 2

[0099]

[0100] Table 3

[0101]

[0102] Table 4

[0103]

[0104] Combination Figure 2 From Table 2, it can be seen that the main peak appears at 4.75 min, the ultraviolet absorption peak is very significant, and no impurity peak appears, indicating that the intermediate prepared in Example 1 has high purity. Figure 3 Table 3 shows the liquid chromatography test results of fluopyraclostrobin obtained in Example 1. Figure 4 Table 4 shows the liquid chromatography detection results of fluopyrabamide prepared in Example 5. It can be seen that the main peak of fluopyrabamide appears at 6.59-6.60 min at an ultraviolet absorption wavelength of 225 nm, and it can be seen from the figure that the main peak is obvious and there are no excessive peaks, that is, the reaction is sufficient and the purity is high.

[0105] The above are preferred embodiments of the present invention. It should be pointed out that, for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as within the scope of protection of the present invention.

Claims

1. A method for synthesizing fluopyrabendazim, characterized in that: The following steps are involved: S1, nickel chloride hexahydrate, ethyl orthosilicate and potassium hydrogen oxalate are mixed in deionized water, subjected to high temperature treatment, cooled, separated, solids are washed and dried to obtain a nickel-based silicate carrier, and then aluminum chloride and ferric citrate are loaded on the nickel-based silicate carrier to obtain a composite catalyst; S2, 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid and thionyl chloride are mixed and stirred, N,N-dimethylformamide is added dropwise and a composite catalyst is added during the mixture, and the mixture is heated and stirred, cooled, separated, and distilled under reduced pressure to obtain a mixed solution containing 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride; S3, 3',4',5'-trifluorobiphenyl-2-amine and toluene are mixed and stirred, a composite catalyst is added, and the mixed solution containing 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride obtained in step S2 is added dropwise, heated and stirred, cooled, separated, distilled under reduced pressure, stirred and slurried, centrifuged to obtain a solid, washed and dried to obtain fluopyraclostrobin.

2. The method for synthesizing fluopyrabdo according to claim 1, characterized in that: In the step S1, ethyl orthosilicate and potassium hydrogen oxalate are added and stirred at 300-400 r / min for 20-30 min, subjected to high temperature treatment, cooled to room temperature, solid-liquid separation, solids are washed with deionized water, and dried at 70-80° C. for 12-14 h to obtain a nickel-based silicate carrier.

3. The method for synthesizing fluopyrabdo according to claim 1, characterized in that: The temperature of the high temperature treatment in step S1 is 170-220° C. and the time is 11-13 hours.

4. The method for synthesizing fluopyrabdo according to claim 1, characterized in that: The composite catalyst is prepared by mixing aluminum chloride hexahydrate and a nickel-based silicate carrier in a closed container, heating the mixture to 180-200° C. and keeping the temperature for 1-2 hours, then cooling the mixture to room temperature so that the aluminum chloride is loaded on the nickel-based silicate carrier, adding ferric citrate and deionized water, stirring the mixture at a rate of 300-400 r / min for 1-2 hours, centrifuging the mixture at 5000-6000 rpm for 8-10 minutes, washing the mixture with deionized water for 5-7 times, and drying the mixture at 170-190° C. for 6-8 hours.

5. The method for synthesizing fluopyrabdo according to claim 1, characterized in that: In the step S2, toluene is added at the same time as 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid and thionyl chloride.

6. The method for synthesizing fluopyrabdo according to claim 5, characterized in that: In the step S2, 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid, thionyl chloride and toluene are stirred at 300-400 r / min for 0.5-1.5 h, during which N,N-dimethylformamide is added dropwise, and a composite catalyst is added and stirred at a rate of 300-400 r / min at 70-80° C. for 2-3 h, and the gas generated in the reaction is collected by an absorption tower, and then the temperature is lowered to 40-50° C., solid-liquid separation is performed, and reduced pressure distillation is performed until no significant organic matter is distilled out to obtain 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride, and 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride is mixed with toluene to obtain a mixed solution.

7. The method for synthesizing fluopyrabdo according to claim 1, characterized in that: In the step S3, 3',4',5'-trifluorobiphenyl-2-amine and toluene are stirred at 110-120°C and 300-400 r / min for 1-1.5 hours, a composite catalyst is added, a mixed solution is added dropwise, and the mixture is kept at 110-120°C and stirred at 300-400 r / min for 2-4 hours, a gas generated in the reaction is collected by an absorption tower, and then the temperature is reduced to 40-60°C, purified water is added, solid-liquid separation is performed, the composite catalyst is recovered, and distillation is performed under reduced pressure until no fraction is dropped from the organic phase, a sodium hydroxide solution is added to adjust the pH of the system, stirring and slurrying are performed, a solid is obtained by centrifugation, and the solid is washed with purified water and dried to obtain fluopyraclostrobin.

8. The method for synthesizing fluopyrabdo according to claim 1, characterized in that: The mixed solution in step S3 is added dropwise within 1 to 1.5 hours.

9. The method for synthesizing fluopyrabdo according to claim 7, characterized in that: The mass concentration of the sodium hydroxide solution is 3%.

10. The method for synthesizing fluopyrabdo according to claim 7, characterized in that: In step S3, after solid-liquid separation and recovery of the composite catalyst, and reduced pressure distillation until no fraction drips out of the organic phase, sodium hydroxide solution is added to adjust the pH of the system to 8-9, and the stirring and beating temperature is 20-30° C. and the time is 20-40 min.

Images