A method for producing diamide compounds

Abstract

This invention provides a method for producing diamide compounds, comprising the following steps: A) acylation reaction of substituted pyrazolamide carboxylic acid and an acyl chloride reagent in a first dynamic tubular reactor to obtain substituted pyrazolamide carboxyl chloride; B) condensation reaction of the substituted pyrazolamide carboxyl chloride obtained in step A) and o-aminobenzamide in a second dynamic tubular reactor to obtain diamide compounds. This invention avoids the use of dehydrating coupling agents such as methanesulfonyl chloride, thus avoiding the difficult-to-treat and costly problems caused by the use of methanesulfonyl chloride. It not only achieves continuous reaction but also reduces the amount of acyl chloride reagent used in the acylation reaction stage, avoids side reactions between the acyl chloride reagent and o-aminobenzamide, and allows the obtained acylation reaction solution to be directly fed into the condensation reactor for continuous condensation reaction, avoiding intermediate treatment of the acylation reaction solution and hydrolysis caused by temporary storage of substituted pyrazolamide carboxyl chloride, simplifying the production process and improving production efficiency.

Description

Technical Field

[0001] This invention relates to the field of pesticide production technology, and more particularly to a method for producing diamide compounds. Background Technology

[0002] Bisamide compounds such as chlorantraniliprole, bromocyanamide, tetrachlorantraniliprole, cyclobromocyanamide, and flufenoxuron are a class of low-toxicity, highly effective new insecticides that have good control effects on Lepidoptera moths such as Noctuidae, Pyralidae, Fruit Boreridae, Leaf Rolleridae, Pyralidae, and Gramineae.

[0003] Currently, numerous literatures have reported methods for synthesizing diamide compounds. For example, patent CN101072767B discloses a method for preparing diamide compounds using 3-halo-1-(3-chloro-2-pyridyl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid and substituted o-aminobenzamide as raw materials under the action of methanesulfonyl chloride and an acid-binding agent. This method produces a dehydration cyclization byproduct, iminobenzoxazine. To reduce product loss, the reaction mixture needs to be treated with an aqueous acid during the production process to convert the byproduct into the product, thereby generating a large amount of mixed salt wastewater containing pyridine, sodium chloride, and sodium methanesulfonate, which is complex and costly to treat.

[0004]

[0005] Patent CN101945861B discloses the preparation of 3-halo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid as a raw material via acyl halogenation and simultaneous oxidation to obtain 3-halo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid halide. This substituted pyrazole carboxylic acid halide is then reacted with substituted aniline to produce a diamide compound without the aid of an acid-binding agent. This replaces the traditional oxidation reaction using an oxidizing agent, avoids the use of methanesulfonyl chloride, simplifies the reaction steps, and improves the reaction yield. However, after the acyl halogenation and simultaneous oxidation reaction, the solvent needs to be evaporated to dryness. This operation not only leads to the generation of impurities but also poses safety hazards, hindering stable operation in industrial production. Furthermore, the reduction products generated by the acyl halogenation reagent during the acyl halogenation and simultaneous oxidation process are difficult to detect in the liquid phase and are not easily separated from the final product. To obtain high-quality products, a complex purification process is required during production.

[0006]

[0007] Patent CN113896714A discloses a method for preparing 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid by acylation, followed by the preparation of chlorantraniliprole with 2-amino-5-chloro-N,3-dimethylbenzamide under reflux conditions. This method avoids the waste salt problem caused by the use of methanesulfonyl chloride and the impact of the reduction products of the acylation reagent on product quality. However, in order to improve the conversion rate of substituted pyrazole carboxylic acid, this method uses an excessive amount of acylation reagent in the acylation reaction stage. Furthermore, the acylation solution obtained by the acylation reaction is directly added to 2-amino-5-chloro-N,3-dimethylbenzamide for reflux reaction without separation. This causes the unreacted acylation reagent to compete with 2-amino-5-chloro-N,3-dimethylbenzamide for side reactions, thereby affecting the yield and content of the product.

[0008]

[0009] Currently, it is particularly important to find a preparation method that can be applied to industrial production and achieve continuous, safe and stable production, and can directly obtain high-purity products based on a simplified process. Summary of the Invention

[0010] In view of this, the technical problem to be solved by the present invention is to provide a method for producing diamide compounds, which simplifies the operation and has high yield and purity.

[0011] To achieve the above objectives, the present invention provides a method for producing diamide compounds, comprising the following steps:

[0012] A) Acidification reaction of substituted pyrazol carboxylic acid and acyl chloride reagent is carried out in a first dynamic tubular reactor to obtain substituted pyrazol carboxylic chloride;

[0013] B) The substituted pyrazolamide chloride obtained in step A) and o-aminobenzamide are subjected to a condensation reaction in a second dynamic tubular reactor to obtain a diamide compound.

[0014] Preferably, the production method includes the following steps:

[0015] S1) The mixture of substituted pyrazole carboxylic acid and solvent and the acyl chloride reagent or the mixture of acyl chloride reagent and solvent are respectively fed into the first dynamic tubular reactor by a feed pump to carry out the acylation reaction to obtain an acylation reaction solution containing substituted pyrazole carboxylic acid chloride.

[0016] S2) The mixture of o-aminobenzamide and solvent and the acylation reaction solution containing substituted pyrazole carboxyl chloride obtained in step S1) are respectively fed to the second dynamic tubular reactor for condensation reaction to obtain a condensation reaction solution containing diamide compounds.

[0017] S3) The condensation reaction solution obtained in step S2) is concentrated by distillation, and after distilling off part of the solvent, a concentrated reaction solution is obtained.

[0018] S4) The reaction concentrate is mixed with washing reagent and washed, then solid-liquid separation and drying are performed to obtain the product diamide compound.

[0019] The preferred temperature for the above acylation reaction is 40–100°C, more preferably 50–90°C, and the preferred reaction time is 2–30 min.

[0020] The preferred temperature for the condensation reaction is 30–100°C, more preferably 40–90°C, and the preferred reaction time is 2–30 min.

[0021] Preferably, the substituted pyrazolic acid is one of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-carboxylic acid and 3-bromo-1-(3,5-dichloro-2-pyridinyl)-1H-pyrazol-5-carboxylic acid.

[0022] Preferably, the o-aminobenzamide is one of 2-amino-5-chloro-N,3-dimethylbenzamide, 2-amino-5-cyano-N,3-dimethylbenzamide, 2-amino-3,5-dichloro-N-methylbenzamide, and 2-amino-3-bromo-5-chloro-N-(1-cyclopropylethyl)benzamide.

[0023] In the reaction to prepare substituted pyrazolamide chloride from substituted pyrazolamide, the high material cost of substituted pyrazolamide and the resulting substituted pyrazolamide chloride are difficult to separate from the substituted pyrazolamide. The conventional choice in this field is to use an excess of acyl chloride reagent to improve the conversion rate of substituted pyrazolamide. However, the use of excess acyl chloride reagent will result in the presence of unreacted acyl chloride reagent in the acylation reaction solution. Studies have found that directly using this reaction solution for the condensation reaction will cause side reactions such as acylation and cyclization between the acyl chloride reagent and o-aminobenzamide, introducing sulfur-containing impurities, reducing the utilization rate of o-aminobenzamide, and affecting the yield and purity of the final product. To avoid the side reactions between the acyl chloride reagent and o-aminobenzamide, the acyl chloride reagent in the acylation reaction solution needs to be removed by distillation, which will cause additional operations and increase costs.

[0024] The present invention has found that using a dynamic tubular reactor for the acylation reaction of substituted pyrazolamide in step A or S1, and controlling the reaction temperature at 40-100℃, preferably 50-90℃, not only improves the reaction efficiency, but also effectively reduces the use of acyl chloride reagents while ensuring the conversion rate of substituted pyrazolamide. This results in a lower residual acyl chloride reagent in the final acylation reaction solution, which can be directly used for the next condensation reaction. This not only simplifies the process and saves intermediate distillation equipment, but also effectively avoids the occurrence of side reactions.

[0025] The present invention has found that by directly feeding the acylation reaction liquid flowing out of the first dynamic tubular reactor in step A or S1 into the second dynamic tubular reactor, and simultaneously feeding in a mixture of o-aminobenzamide and solvent, and controlling the temperature at 30-100°C, preferably at 40-90°C, the acylation reaction liquid and o-aminobenzamide can be continuously reacted. This not only improves the reaction efficiency but also avoids the hydrolysis of pyrazolyl chloride caused by the acylation reaction liquid being left to stand.

[0026] The residence time of materials in the dynamic tubular reactor during the acylation and condensation reaction stages is related to the reaction temperature. In the acylation reaction stage, when the reaction temperature is 40–100℃, a residence time of 2–30 min is sufficient to obtain an acylation reaction solution containing substituted pyrazole carboxylic acid chloride. In the condensation reaction stage, when the reaction temperature is 30–100℃, a residence time of 2–30 min is sufficient to obtain a condensation reaction solution containing a diamide compound, wherein the conversion rate of substituted pyrazole carboxylic acid can reach over 99%.

[0027] Conventional production methods obtain the product by direct cooling, filtration, and drying after the condensation reaction. However, because a small amount of product is dissolved in the mother liquor, to improve the product yield and reduce the burden of organic wastewater treatment, the mother liquor is distilled to recover the solvent and heavy components. The heavy components are then washed and separated multiple times before the product is recovered. However, the product obtained by this method often contains a lot of impurities and has a low content, requiring further purification by recrystallization. This invention has discovered that by utilizing the different solubilities of the product, raw materials, and impurities in the solvent, a distillation and concentration of the condensation reaction solution is added at the end of step S2. This reduces the amount of solvent in the reaction solution, causing the less soluble product to precipitate out, while the more soluble raw materials and impurities remain dissolved in the solvent. Solid-liquid separation is then performed to increase the degree of separation between impurities and product and reduce product loss, thereby increasing both the yield and the product content. The distillation and concentration are preferably carried out in a distillation kettle.

[0028] In this invention, the dynamic tubular reactor described in step A or S1 and step B or S2 is a plug flow reactor, having a reaction chamber and a heat exchange chamber, with a stirring shaft inside the reaction chamber. The reaction chamber of the dynamic tubular reactor provides the site for the material reaction, and the central stirring shaft inside the reaction chamber has a stirring paddle or stirring fins, which, through rotation, achieve a stirring and mixing effect. The effective liquid holdup in the reaction chamber is 1-200 L. The heat exchange chamber uses a circulating heat exchange medium for heat exchange within the reaction chamber. Studies have shown that, compared to a reaction vessel, the dynamic tubular reactor used in this invention not only enables continuous production but also increases the reaction rate and reduces the amount of acyl chloride reagent used. Compared to a static tubular reactor without a stirring shaft in the reaction chamber, under the same temperature and residence time conditions, it can improve reaction efficiency and thus achieve a higher yield.

[0029] Since gas is generated during the acylation reaction, the generated gas will occupy the space of the reaction chamber of the dynamic tubular reactor and affect the reactor's processing capacity. Timely discharge of gas can promote the acylation reaction. As a preferred technical solution of the present invention, the selected first dynamic tubular reactor also has an exhaust port, which is connected to the inlet of the gas-liquid separator condenser. The gas-liquid separator condenser also has a gas outlet and a condensate outlet, which are used to separate the gas generated during the acylation reaction and recover the solvent and acylation reagent.

[0030] To achieve effective utilization of materials, reduce waste, and lower material costs, as a more preferred technical solution of the present invention, the first dynamic tubular reactor also has a condensate inlet, which is connected to the condensate outlet of the gas-liquid separator condenser, for returning the recovered solvent and acylation reagent to the acylation reaction stage of the first dynamic tubular reactor.

[0031] To ensure the conversion rate of substituted pyrazolonic acid in the acylation reaction stage, as a preferred technical solution of the present invention, the acyl chloride reagent used in step A or S1 is selected from one or more of thionyl chloride, oxalyl chloride, and triphosgene. When the acyl chloride reagent is thionyl chloride or oxalyl chloride, the molar ratio of substituted pyrazolonic acid to acyl chloride reagent is 1:1 to 1.3. When the acyl chloride reagent is triphosgene, the molar ratio of substituted pyrazolonic acid to acyl chloride reagent is 1:0.34 to 0.43.

[0032] To improve material solubility and facilitate post-processing, as a preferred technical solution of the present invention, the solvent used in step A or S1 and step B or S2 is selected from one or more of dichloromethane, dichloropropane, dichloroethane, acetonitrile, and toluene, preferably dichloroethane, acetonitrile, or toluene. The mass ratio of the solvent to the substituted pyrazolium carboxylic acid is preferably 1.5-8:1. When the boiling point of the solvent is lower than the reaction temperature, back pressure can be applied to the reaction system to avoid severe solvent vaporization due to excessively high reaction temperature, which would affect the reactor's processing capacity and the stability of the reaction process. The magnitude of the back pressure can be calculated in advance based on the saturated vapor pressure of the solvent at different temperatures.

[0033] In order to balance the relationship between product yield, purity and production efficiency, as a preferred technical solution of the present invention, the total amount of solvent in step B or S2 is 3 to 20 times the mass of substituted pyrazole carboxylic acid, preferably 4 to 16 times. When the condensation reaction solution is concentrated by distillation in step S3, the amount of solvent distilled off accounts for 50% to 90% of the total amount of solvent in the condensation reaction stage.

[0034] In the condensation reaction stage, insufficient solvent usage will affect the mixing effect and heat transfer efficiency of the reaction process, which is detrimental to industrial production. Furthermore, when a small amount of acylation reagent remains in the acylation reaction solution, insufficient solvent usage will increase the risk of side reactions between the acylation reagent and o-aminobenzamide. Excessive solvent usage will reduce equipment production efficiency and increase equipment and operating costs. If too little solvent is distilled off after the condensation reaction, a small amount of product will still be dissolved in the concentrated condensation reaction solution. Failure to recover the product from the solvent will result in product loss, while recovery requires a series of product refining equipment, which is costly. Conversely, if too much solvent is distilled off after the two reaction stages, the bottom liquid is prone to coking, generating high-boiling-point impurities, and this can easily lead to safety accidents.

[0035] Because the synthesis process of the raw material substituted pyrazolamide is longer and the material cost is higher than that of the raw material o-aminobenzamide, in order to reduce the material cost, as a preferred technical solution of the present invention, the molar ratio of the substituted pyrazolamide chloride to o-aminobenzamide in step S2 is 1:1 to 1.2, preferably 1:1.03 to 1.15.

[0036] To improve the reaction rate of the acylation reaction in step A or S1, as a preferred embodiment of the present invention, DMF is added during the acylation reaction. Preferably, in step S1, the catalyst DMF is added to the mixture of substituted pyrazolonic acid and solvent, and the molar ratio of DMF to substituted pyrazolonic acid is preferably 0.01 to 0.15:1.

[0037] In step S2, hydrogen chloride is generated during the condensation reaction of pyrazolyl chloride and o-aminobenzamide. To avoid the hydrogen chloride gas affecting the reactor's processing capacity, a dynamic tubular reactor with an exhaust port can be selected to promptly discharge the hydrogen chloride generated during the reaction. Alternatively, an acid-binding agent can be added to the mixture of o-aminobenzamide and solvent. The acid-binding agent is preferably one or more of 3-methylpyridine, pyridine, 2-methylpyridine, and triethylamine.

[0038] To achieve effective utilization of materials, reduce waste, and lower material costs, as a preferred technical solution of this invention, the solvent distilled in step S3 is reused in either the acylation reaction stage in step S1 or the condensation reaction stage in step S2. When an acid-binding agent is added in the condensation reaction stage, the solvent distilled in step S3 can be directly reused in the condensation reaction stage or in the acylation reaction stage in step S1. When no acid-binding agent is added in the condensation reaction stage, the solvent distilled in step S3 contains a small amount of hydrogen chloride gas, which can be reused in the condensation reaction stage after dehydrochlorination treatment, or it can be directly reused in the condensation reaction stage.

[0039] In step S3, during the concentration process of the condensation reaction solution containing the product diamide compound, a small amount of impurities will precipitate out along with the product and adhere to its surface. To improve the purity of the product, the concentrated reaction solution obtained after distillation and concentration is mixed with a washing reagent before solid-liquid separation. This carries the impurities adhering to the product surface into the liquid phase, and then the product is separated from the impurities through solid-liquid separation. As a preferred technical solution of the present invention, the washing reagent in step S4 is selected from one or more of water, sodium carbonate solution, sodium bicarbonate solution, sodium hydroxide solution, methanol, ethanol, ethyl acetate, and acetonitrile.

[0040] In step S4, the reaction concentrate is mixed with a washing reagent and then subjected to solid-liquid separation. The separated wet product is dried to obtain the product diamide. To further improve the purity of the product and reduce the impurity content, as a preferred technical solution of the present invention, in step S4, a second washing reagent is used to wash and separate the solid crude product during the solid-liquid separation process. The separated wet product is dried to obtain the product diamide. The second washing reagent is preferably one or more of water, methanol, ethanol, and acetonitrile.

[0041] In one specific embodiment of the present invention, a mixture of substituted pyrazolamide and solvent and an acyl chloride reagent or a mixture of acyl chloride reagent and solvent are fed into a first dynamic tubular reactor by a feed pump for acylation reaction at 40-100°C. After a residence time of 2-30 minutes, the acylation reaction liquid flowing out of the first dynamic tubular reactor enters a second dynamic tubular reactor. At the same time, a mixture of o-aminobenzamide and solvent is introduced. After a residence time of 2-30 minutes at 30-100°C, wherein the total solvent volume is 3-20 times the mass of substituted pyrazolamide, the liquid flows out of the dynamic tubular reactor into a distillation kettle to distill off 50%-90% of the solvent. Then, a washing reagent is added to the distillation kettle to wash the reaction concentrate, and then the product diamide is obtained by solid-liquid separation and drying.

[0042] In one specific embodiment of the present invention, a mixture of substituted pyrazolamide, solvent, and DMF, and a mixture of acyl chloride reagent or acyl chloride reagent and solvent are fed into a first dynamic tubular reactor by a feed pump for acylation reaction at 40–100°C. After a residence time of 2–30 min, the acylation reaction liquid flowing out of the first dynamic tubular reactor enters a second dynamic tubular reactor. At the same time, a mixture of o-aminobenzamide, acid binder, and solvent is introduced. After a residence time of 2–30 min at 30–100°C, wherein the total solvent volume is 3–20 times the mass of substituted pyrazolamide, the liquid flows out of the dynamic tubular reactor into a distillation kettle to distill off 50%–90% of the solvent. Then, a washing reagent is added to the distillation kettle to wash the reaction concentrate. After solid-liquid separation, washing separation, and drying, the product diamide is obtained.

[0043] Compared with existing technologies, this invention provides a method for producing diamide compounds, comprising the following steps: A) acylation reaction of substituted pyrazolamide carboxylic acid and an acyl chloride reagent in a first dynamic tubular reactor to obtain substituted pyrazolamide carboxylic acid chloride; B) condensation reaction of the substituted pyrazolamide carboxylic acid chloride obtained in step A) and o-aminobenzamide in a second dynamic tubular reactor to obtain diamide compounds. This invention avoids the use of dehydrating coupling agents such as methanesulfonyl chloride, thus avoiding the difficult waste treatment and cost problems caused by the use of methanesulfonyl chloride.

[0044] The method for producing diamide compounds provided by this invention employs a dynamic tubular reactor in both the acylation and condensation reaction stages. By controlling suitable reaction conditions, not only is continuous reaction achieved, but the amount of acyl chloride reagent used in the acylation stage is also reduced, avoiding side reactions between the acyl chloride reagent and o-aminobenzamide. The obtained acylation reaction solution can be directly fed into the condensation reactor for continuous condensation reaction, avoiding intermediate treatment of the acylation reaction solution and hydrolysis caused by temporary storage of substituted pyrazole carboxyl chloride. This simplifies the production process and improves production efficiency. Furthermore, concentrating the condensation reaction solution after the condensation reaction increases the product precipitation rate and reduces product loss. This eliminates the need for multi-stage washing and recrystallization purification processes and equipment required for recovering and separating products from the mother liquor, simplifying the process and improving product yield and purity. Detailed Implementation

[0045] To further illustrate the present invention, the production method of the diamide compounds provided by the present invention will be described in detail below with reference to the embodiments.

[0046] Example 1

[0047] Mixture A was prepared by premixing 8582g of 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid with dichloromethane at a mass ratio of 1:1.5. 3545g of thionyl chloride was also prepared. Mixture B was prepared by premixing 5545g of 2-amino-5-chloro-N,3-dimethylbenzamide with dichloromethane at a mass ratio of 1:2.3.

[0048] Mixture A and thionyl chloride were fed into the first dynamic tubular reactor at 358 g / min and 59 g / min, respectively, using feed pumps. After being held at 40°C for 30 min, the acylation reaction solution flowed out from the reactor outlet and directly entered the second dynamic tubular reactor. Simultaneously, mixture B was pumped into the second dynamic tubular reactor at 308 g / min, with the reaction temperature controlled at 30°C. After being held for 30 min, the condensation reaction solution flowed out from the reactor outlet and was collected in a distillation vessel for 10 min. Then, 2.18 kg of dichloromethane was distilled off by heating. A 2% sodium hydroxide solution was then added to the reaction vessel to wash the concentrated reaction solution. Subsequently, solid-liquid separation was performed, followed by washing and separation of the crude solid product with water. Finally, the product chlorantraniliprole was dried to obtain 2189 g, with a yield of 94.1% and a liquid phase detection purity of 98.2%.

[0049] Example 2

[0050] 3441g of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid was premixed with dichloropropane and DMF to obtain mixture A, wherein the mass ratio of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid to dichloropropane was 1:2, and the amount of DMF was 1% of the molar amount of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid. 1660g of oxalyl chloride was prepared, and 2135g of 2-amino-5-cyano-N,3-dimethylbenzamide was premixed with dichloropropane and pyridine in a mass ratio of 1:3.1:0.4 to obtain mixture B.

[0051] Mixture A and oxalyl chloride were fed into the first dynamic tubular reactor at 235 g / min and 38 g / min respectively using feed pumps. After being held at 50°C for 22 min, the acylation reaction solution flowed out from the reactor outlet and directly entered the second dynamic tubular reactor. Simultaneously, mixture B was pumped into the second dynamic tubular reactor at 227 g / min, and the reaction temperature was controlled at 50°C. After being held at 21 min, the condensation reaction solution flowed out from the reactor outlet and was collected in a distillation vessel for 10 min. Then, 1.92 kg of dichloropropane was distilled off. Water was then added to the reaction vessel to wash the concentrated reaction solution. After solid-liquid separation, the crude solid product was washed and separated again with water. Finally, the product bromocyanamide was dried to obtain 1177 g, with a yield of 94.5% and a liquid phase detection content of 98.3%.

[0052] Example 3

[0053] 1194g of 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid was premixed with dichloroethane and DMF to obtain mixture A, wherein the mass ratio of 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid to dichloroethane was 1:3.5, and the DMF was 3% of the molar amount of 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid. 611g of thionyl chloride was prepared. 683g of 2-amino-5-chloro-N,3-dimethylbenzamide was premixed with dichloroethane and 3-methylpyridine in a mass ratio of 1:6.5:0.44 to obtain mixture B.

[0054] Mixture A and thionyl chloride were fed into the first dynamic tubular reactor at 150 g / min and 17 g / min respectively using feed pumps. After being held at 60°C for 18 min, the acylation reaction solution flowed out from the reactor outlet and directly entered the second dynamic tubular reactor. Simultaneously, mixture B was pumped into the second dynamic tubular reactor at 182 g / min, and the reaction temperature was controlled at 60°C. After being held at 15 min, the condensation reaction solution flowed out from the reactor outlet and was collected in a distillation vessel for 10 min. Then, 2.16 kg of dichloroethane was distilled off by heating. Methanol and water were then added to the reaction vessel to wash the concentrated reaction solution. After solid-liquid separation, the crude solid product was washed and separated again with water. Finally, the product chlorantraniliprole was dried to obtain 509 g, with a yield of 95.5% and a liquid phase detection content of 99.3%.

[0055] Example 4

[0056] 488g of 3-bromo-1-(3,5-dichloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid was premixed with acetonitrile and DMF to obtain mixture A, wherein the mass ratio of 3-bromo-1-(3,5-dichloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid to acetonitrile was 1:5, and the DMF was 6% of the molar amount of 3-bromo-1-(3,5-dichloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid. 60g of thionyl chloride was prepared. 241g of 2-amino-3,5-dichloro-N-methylbenzamide was premixed with acetonitrile and 2-methylpyridine in a mass ratio of 1:7:0.39 to obtain mixture B.

[0057] Mixture A and thionyl chloride were fed into the first dynamic tubular reactor at 98 g / min and 2 g / min, respectively, using feed pumps. After residence at 70°C for 15 min, the acylation reaction solution flowed out from the reactor outlet and directly entered the second dynamic tubular reactor. Simultaneously, mixture B was pumped into the second dynamic tubular reactor at 97 g / min, and the reaction temperature was controlled at 70°C. After residence at 10.4 min, the condensation reaction solution flowed out from the reactor outlet and was collected in a distillation vessel for 10 min. Then, 1.12 kg of acetonitrile was distilled off. Methanol and water were then added to the reaction vessel to wash the concentrated reaction solution. Subsequently, solid-liquid separation was performed, followed by washing and separation of the crude solid product with water. Finally, the product tetrachlorantraniliprole was dried to obtain 250 g, with a yield of 95.1% and a liquid phase detection purity of 98.6%.

[0058] Example 5

[0059] Mixture A was prepared by premixing 350g of 3-bromo-1-(3,5-dichloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid with toluene and DMF, wherein the mass ratio of 3-bromo-1-(3,5-dichloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid to toluene was 1:4, and the DMF was 9% of the molar amount of 3-bromo-1-(3,5-dichloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid. Mixture B was prepared by premixing 269g of 2-amino-3-bromo-5-chloro-N-(1-cyclopropylethyl)benzamide with toluene and triethylamine in a mass ratio of 1:6:0.3. Mixture C was prepared by premixing 138g of triphosgene with toluene in a mass ratio of 1:5.1.

[0060] Mixtures A and C were fed into the first dynamic tubular reactor at 68 g / min and 3.2 g / min respectively using feed pumps. After being held at 90°C for 8 min, the acylation reaction solution flowed out of the reactor outlet and directly entered the second dynamic tubular reactor. Simultaneously, mixture C was pumped into the second dynamic tubular reactor at 98 g / min, and the reaction temperature was controlled at 90°C. After being held at 90°C for 5 min, the condensation reaction solution flowed out of the reactor outlet and was collected in a distillation vessel for 10 min. Then, 1.14 kg of toluene was distilled off by heating. Methanol and water were then added to the reaction vessel to wash the concentrated reaction solution. After solid-liquid separation, the crude solid product was washed and separated again with methanol. Finally, the product cyclochlorfenapyr was dried to obtain 244 g of product, with a yield of 94.8% and a liquid phase detection of 99%.

[0061] Example 6

[0062] 2733g of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid was premixed with dichloroethane and DMF to obtain mixture A, wherein the mass ratio of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid to dichloroethane was 1:7, and the DMF was 12% of the molar amount of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid. 645g of thionyl chloride was prepared, and 1298g of 2-amino-5-cyano-N,3-dimethylbenzamide was premixed with dichloroethane and pyridine in a mass ratio of 1:13.3:0.39 to obtain mixture B.

[0063] Mixture A and thionyl chloride were fed into the first dynamic tubular reactor at 650 g / min and 19 g / min, respectively, using feed pumps. After being held at 80°C for 12 min, the acylation reaction solution flowed out from the reactor outlet and directly entered the second dynamic tubular reactor. Simultaneously, mixture B was pumped into the second dynamic tubular reactor at 799 g / min, with the reaction temperature controlled at 80°C. After being held for 7 min, the condensation reaction solution flowed out from the reactor outlet and was collected in a distillation vessel for 10 min. Then, 7.7 kg of dichloroethane was distilled off by heating. Water was then added to the reaction vessel to wash the concentrated reaction solution. Subsequently, solid-liquid separation was performed, followed by washing and separation of the crude solid product with ethanol. Finally, the product bromocyanamide was dried to obtain 1208 g, with a yield of 94.6% and a liquid phase detection purity of 99.1%.

[0064] Example 7

[0065] 725g of 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid was premixed with toluene and DMF to obtain mixture A, wherein the mass ratio of 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid to toluene was 1:8, and the DMF was 15% of the molar amount of 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid. 428g of thionyl chloride was prepared. 553g of 2-amino-5-chloro-N,3-dimethylbenzamide was premixed with toluene and 3-methylpyridine in a mass ratio of 1:15.9:0.4 to obtain mixture B.

[0066] Mixture A and thionyl chloride were fed into the first dynamic tubular reactor at 469 g / min and 31 g / min, respectively, using feed pumps. After being held at 100°C for 2 min, the acylation reaction solution flowed out from the reactor outlet and directly entered the second dynamic tubular reactor. Simultaneously, mixture B was pumped into the second dynamic tubular reactor at 676 g / min, with the reaction temperature controlled at 100°C. After being held for 2 min, the condensation reaction solution flowed out from the reactor outlet and was collected in a distillation vessel for 10 min. Then, 9.4 kg of toluene was distilled off by heating. Water was then added to the reaction vessel to wash the concentrated reaction solution. Subsequently, solid-liquid separation was performed, followed by washing and separation of the crude solid product with methanol and water. Finally, the product chlorantraniliprole was dried to obtain 806 g, with a yield of 95.6% and a liquid phase detection purity of 98.5%.

[0067] Example 8

[0068] 1752g of 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid was premixed with dichloroethane and DMF to obtain mixture A, wherein the mass ratio of 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid to dichloroethane was 1:4.5, and the DMF was 5% of the molar amount of 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid. 1323g of oxalyl chloride was prepared. 1369g of 2-amino-5-chloro-N,3-dimethylbenzamide was premixed with dichloroethane and 3-methylpyridine in a mass ratio of 1:5.7:0.39 to obtain mixture B.

[0069] Mixture A and thionyl chloride were fed into the first dynamic tubular reactor at 302 g / min and 41 kg / min, respectively, using feed pumps. After being held at 70°C for 16 min, the acylation reaction solution flowed out from the reactor outlet and directly entered the second dynamic tubular reactor. Simultaneously, mixture B was pumped into the second dynamic tubular reactor at 306 g / min, with the reaction temperature controlled at 60°C. After being held for 16 min, the condensation reaction solution flowed out from the reactor outlet and was collected in a distillation vessel for 10 min. Then, 4.1 kg of dichloroethane was distilled off by heating. Water was then added to the reaction vessel to wash the concentrated reaction solution. Subsequently, solid-liquid separation was performed, followed by washing and separation of the crude solid product with methanol and water. Finally, the product chlorantraniliprole was dried to obtain 843 g, with a yield of 95.4% and a liquid phase detection purity of 98.8%.

[0070] Comparative Example 1

[0071] 1194g of 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid was premixed with dichloroethane and DMF to obtain mixture A, wherein the mass ratio of 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid to dichloroethane was 1:3.5, and the DMF was 3% of the molar amount of 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid. 611g of thionyl chloride was prepared. 683g of 2-amino-5-chloro-N,3-dimethylbenzamide was premixed with dichloroethane and 3-methylpyridine in a mass ratio of 1:6.5:0.44 to obtain mixture B.

[0072] Mixture A and thionyl chloride were fed into the first static tubular reactor at 150 g / min and 17 g / min respectively using feed pumps. After being held at 60°C for 18 min, the acylation reaction solution flowed out from the reactor outlet and directly entered the second static tubular reactor. Simultaneously, mixture B was pumped into the second static tubular reactor at 182 g / min, and the reaction temperature was controlled at 60°C. After being held at 15 min, the condensation reaction solution flowed out from the reactor outlet and was collected in a distillation vessel for 10 min. Then, 2.16 kg of dichloroethane was distilled off by heating. Methanol and water were then added to the reaction vessel to wash the concentrated reaction solution. After solid-liquid separation, the crude solid product was washed and separated again with water. Finally, the product chlorantraniliprole was dried to obtain 468 g, with a yield of 82.4% and a liquid phase detection content of 93.1%.

[0073] The comparative example used a static tubular reactor. The experimental results showed that its mixing effect was worse than that of the dynamic tubular reactor, the reaction was incomplete, the conversion rate of pyrazolium carboxylic acid was low, and the acylation reagent and the raw material amine underwent side reactions, resulting in low reaction yield and reduced product purity.

[0074] Comparative Example 2

[0075] 1194g of 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid was premixed with dichloroethane and DMF to obtain mixture A, wherein the mass ratio of 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid to dichloroethane was 1:3.5, and the DMF was 3% of the molar amount of 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid. 611g of thionyl chloride was prepared. 683g of 2-amino-5-chloro-N,3-dimethylbenzamide was premixed with dichloroethane and 3-methylpyridine in a mass ratio of 1:6.5:0.44 to obtain mixture B.

[0076] Mixture A and thionyl chloride were fed into the first reactor at 150 g / min and 17 g / min respectively using feed pumps. After 10 min of feeding, the feeding was stopped, and the reaction was continued at 60°C for 1 h with stirring. The acylation reaction solution was then discharged and directly transferred to the second reactor. Simultaneously, mixture B was pumped into the second reactor at 182 g / min using feed pumps. After 10 min of feeding, the feeding was stopped, and the reaction temperature was controlled at 60°C. After 1 h of stirring, the condensation reaction solution flowed out from the reactor outlet. After solid-liquid separation, water washing, and drying, 457 g of chlorantraniliprole was obtained, with a yield of 79.5% and a liquid phase detection content of 92.1%.

[0077] The comparative example used a batch reaction in a reactor, which extended the reaction time, but due to insufficient reaction, the conversion rate of pyrazolic acid was low, and the acylation reagent and the raw material amine underwent side reactions, resulting in a low final reaction yield and decreased product purity.

[0078] Comparative Example 3

[0079] 1194g of 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid was premixed with dichloroethane and DMF to obtain mixture A, wherein the mass ratio of 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid to dichloroethane was 1:3.5, and the DMF was 3% of the molar amount of 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid. 1175g of thionyl chloride was prepared. 683g of 2-amino-5-chloro-N,3-dimethylbenzamide was premixed with dichloroethane and 3-methylpyridine in a mass ratio of 1:6.5:0.44 to obtain mixture B.

[0080] Mixture A and thionyl chloride were fed into the first reactor at 150 g / min and 32.7 g / min respectively using feed pumps. After 10 min of feeding, the feeding was stopped, and the reaction was continued at 60°C for 2 h with stirring. The acylation reaction solution was then discharged, and the solution was placed in a distillation vessel to distill off the solvent dichloroethane. Fresh dichloroethane was then added to prepare an acyl chloride solution, which was then transferred to the second reactor. Simultaneously, mixture B was pumped into the second reactor at 182 g / min using a feed pump. After 10 min of feeding, the feeding was stopped, and the reaction temperature was controlled at 60°C. After 1 h of stirring, the condensation reaction solution flowed out from the reactor outlet. After solid-liquid separation, washing with water, and drying, 512 g of chlorantraniliprole was obtained, with a yield of 91.6% and a liquid phase detection content of 94.8%.

[0081] Compared with Example 3, this comparative example increased the amount of acylation reagent, used a reaction vessel as the reactor, had a longer reaction time, and underwent a solvent removal process after the acylation reaction. After the condensation reaction, solid-liquid separation was performed directly without concentration, resulting in a decrease in both the final reaction yield and product purity.

[0082] The above description of the embodiments is only for the purpose of helping to understand the method and core ideas of the present invention. It should be noted that those skilled in the art can make several improvements and modifications to the present invention without departing from the principles of the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention.

Claims

1. A method for producing a diamide compound, characterized in that, Includes the following steps: S1) The mixture of substituted pyrazole carboxylic acid and solvent and the acyl chloride reagent or the mixture of acyl chloride reagent and solvent are respectively fed into the first dynamic tubular reactor by a feed pump to carry out the acylation reaction to obtain an acylation reaction solution containing substituted pyrazole carboxylic acid chloride. S2) The mixture of o-aminobenzamide and solvent and the acylation reaction solution containing substituted pyrazole carboxyl chloride obtained in step S1) are respectively fed to the second dynamic tubular reactor for condensation reaction to obtain a condensation reaction solution containing diamide compounds. S3) The condensation reaction solution obtained in step S2) is concentrated by distillation, and after distilling off part of the solvent, a concentrated reaction solution is obtained. S4) The reaction concentrate is mixed with washing reagent, washed, and then subjected to solid-liquid separation and drying to obtain the product diamide compound; The acylation reaction is carried out at a temperature of 40~100℃ for a time of 2~30 min; The condensation reaction is carried out at a temperature of 30~100℃ for 2~30 min. The molar ratio of the substituted pyrazolyl chloride to o-aminobenzamide is 1:1 to 1.2; The substituted pyrazolic acid is one of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-carboxylic acid and 3-bromo-1-(3,5-dichloro-2-pyridinyl)-1H-pyrazol-5-carboxylic acid.

2. A method for producing a diamide compound, characterized in that, Includes the following steps: S1) The mixture of substituted pyrazole carboxylic acid and solvent and the acyl chloride reagent or the mixture of acyl chloride reagent and solvent are respectively fed into the first dynamic tubular reactor by a feed pump to carry out the acylation reaction to obtain an acylation reaction solution containing substituted pyrazole carboxylic acid chloride. S2) A mixture of one of 2-amino-5-chloro-N,3-dimethylbenzamide, 2-amino-5-cyano-N,3-dimethylbenzamide, 2-amino-3,5-dichloro-N-methylbenzamide, and 2-amino-3-bromo-5-chloro-N-(1-cyclopropylethyl)benzamide with a solvent and the acylation reaction solution containing substituted pyrazole carboxyl chloride obtained in step S1) are respectively fed to a second dynamic tubular reactor for condensation reaction to obtain a condensation reaction solution containing a diamide compound; S3) The condensation reaction solution obtained in step S2) is concentrated by distillation, and after distilling off part of the solvent, a concentrated reaction solution is obtained. S4) The reaction concentrate is mixed with washing reagent, washed, and then subjected to solid-liquid separation and drying to obtain the product diamide compound; The acylation reaction is carried out at a temperature of 40~100℃ for a time of 2~30 min; The condensation reaction is carried out at a temperature of 30~100℃ for 2~30 min. The molar ratio of the substituted pyrazolyl chloride to o-aminobenzamide is 1:1 to 1.2; The substituted pyrazolic acid is one of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-carboxylic acid and 3-bromo-1-(3,5-dichloro-2-pyridinyl)-1H-pyrazol-5-carboxylic acid.

3. The production method according to claim 1 or 2, characterized in that, The first dynamic tubular reactor has an exhaust port, which is connected to a gas-liquid separator condenser.

4. The production method according to claim 1 or 2, characterized in that, The acyl chloride reagent is selected from one or more of thionyl chloride, oxalyl chloride, and triphosgene; When the acyl chloride reagent is thionyl chloride or oxalyl chloride, the molar ratio of substituted pyrazolium carboxylic acid to the acyl chloride reagent is 1:1~1.3; when the acyl chloride reagent is triphosgene, the molar ratio of substituted pyrazolium carboxylic acid to the acyl chloride reagent is 1:0.34~0.

43.

5. The production method according to claim 1 or 2, characterized in that, The solvents used in steps S1 and S2 are independently selected from one or more of dichloromethane, dichloropropane, dichloroethane, acetonitrile, and toluene.

6. The production method according to claim 1 or 2, characterized in that, DMF was added during the acylation reaction; The molar ratio of DMF to substituted pyrazole carboxylic acid is 0.01~0.15:

1.

7. The production method according to claim 5, characterized in that, DMF was added during the acylation reaction; The molar ratio of DMF to substituted pyrazole carboxylic acid is 0.01~0.15:

1.

8. The production method according to claim 1 or 2, characterized in that, In step S2, the total amount of solvent is 3 to 20 times the mass of substituted pyrazole carboxylic acid; In step S3, the portion of solvent distilled off accounts for 50% to 90% of the total solvent volume in the condensation reaction stage.

9. The production method according to claim 1 or 2, characterized in that, The washing reagent in step S4 is selected from one or more of water, sodium carbonate solution, sodium bicarbonate solution, sodium hydroxide solution, methanol, ethanol, ethyl acetate, and acetonitrile. The solid-liquid separation in step S4 further includes: adding a second washing reagent to wash the crude solid product; The second washing reagent is one or more of water, methanol, ethanol, and acetonitrile.

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