A process for the preparation of a 3-bromo-1-(3-chloro-2-pyridinyl)-1-H-pyrazole-5-carboxylic acid compound

Abstract

The present application relates to the technical field of organic chemical synthesis, and discloses a preparation method of 3-bromo-1-(3-chloro-2-pyridyl)-1-H-pyrazole-5-carboxylic acid compound, which takes 3-halogenated-1-(3-chloropyridine-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid ethyl ester compound as raw material, takes palladium-carbon as catalyst, adds solvent and co-catalyst into the raw material, seals the reaction in the atmosphere of mixed gas, recovers the catalyst after the reaction is completed, and obtains the target product after the filtrate is neutralized, extracted, distilled and recrystallized. The present application solves the technical problem of the existing preparation method of 3-bromo-1-(3-chloro-2-pyridyl)-1-H-pyrazole-5-carboxylic acid compound, i.e. large consumption of oxidant, which cannot be recycled, thus resulting in high production cost.

Description

Technical Field

[0001] This invention relates to the field of organic chemical synthesis technology, specifically to a method for preparing 3-bromo-1-(3-chloro-2-pyridyl)-1-H-pyrazole-5-carboxylic acid compounds. Background Technology

[0002] Chlorantraniliprole is a novel, highly effective, and low-toxicity o-formamidobenzamide insecticide developed by DuPont. Its Chinese alternative name is 3-bromo-N-[4-chloro-2-methyl-6-[(methylcarbamoyl)benzene]-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide. Chlorantraniliprole possesses broad-spectrum insecticidal properties and is primarily used to control lepidopteran pests on various crops. It also shows good control efficacy against other pests, thus possessing broad market prospects.

[0003] 3-Bromo-1-(3-chloropyridin-2-pyridinyl)-1H-pyridin-5-carboxylic acid is a key intermediate in the synthesis of chlorantraniliprole. Currently, its mainstream synthesis process mostly uses strong oxidizing agents such as persulfate to react with ethyl 3-halo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid via an oxidative dehydrogenation reaction. For example, Chinese Patent CN115557931A provides an efficient synthesis method for 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid. Using ethyl 2-(3-chloropyridin-2-yl)-5-hydroxypyrazole-3-carboxylate as a raw material, the method first undergoes a bromination reaction, then an oxidation reaction with sulfuric acid and potassium persulfate, and finally separates and recovers 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid salt. This method is simple, requires only one solvent, simplifies the solvent recovery process, and is environmentally friendly.

[0004] However, the existing technologies mentioned above still have the following problems: 1. Persulfate, as an oxidant, is a hazardous chemical, and there are significant risks in its transportation, storage and reaction processes. At the same time, persulfate is also a high pollutant, and the wastewater and waste salt produced by its reaction are large and difficult to treat, which increases the difficulty and cost of industrial production; 2. Persulfate is a consumable as an oxidant, which increases production costs. Summary of the Invention

[0005] The present invention aims to provide a method for preparing 3-bromo-1-(3-chloro-2-pyridyl)-1-H-pyrazole-5-carboxylic acid compounds, in order to solve the technical problems of high oxidant consumption and inability to recover oxidants in existing methods for preparing 3-bromo-1-(3-chloro-2-pyridyl)-1-H-pyrazole-5-carboxylic acid compounds, which result in high production costs.

[0006] To achieve the above objectives, the present invention adopts the following technical solution: a method for preparing 3-bromo-1-(3-chloro-2-pyridyl)-1-H-pyrazole-5-carboxylic acid compounds, using compound I as raw material, adding solvent, co-catalyst and palladium on carbon, and sealing the reaction under a mixed gas atmosphere, after the reaction is completed, filtering to recover the catalyst palladium on carbon, and the filtrate is neutralized, extracted, distilled and recrystallized to obtain the product;

[0007] The structural formula of compound I is shown below:

[0008]

[0009] The principles and advantages of this scheme are:

[0010] In this application, palladium is supported on activated carbon to form palladium on carbon, which serves as a catalyst. Compared to the existing technology that uses persulfate as a catalyst for oxidative dehydrogenation, palladium on carbon can be recycled and reused, significantly reducing production costs. Furthermore, using palladium on carbon as a catalyst eliminates the generation of highly polluting wastewater and waste salts during the reaction, making it cleaner, more environmentally friendly, and simplifying post-processing steps, thus increasing its value for large-scale application. Finally, using palladium on carbon as a catalyst allows for milder and more controllable reaction conditions, avoiding the violent exothermic reactions that occur in oxidation reactions, thereby reducing the risks associated with production.

[0011] Preferably, as an improvement, in compound I, R1 is H or an alkyl group, and the carbon chain length of the alkyl group is 1 to 5; R2 is H or any halogen element; and R3 and R4 are any halogen elements.

[0012] The preparation method provided in this application is applicable to the preparation and production of various 3-bromo-1-(3-chloro-2-pyridyl)-1-H-pyrazole-5-carboxylic acid compounds.

[0013] Preferably, as an improvement, the mass ratio of metallic palladium to the raw material in the palladium on carbon is 1% to 4%.

[0014] In this application, the mass ratio of catalyst to raw materials directly affects the reaction rate and product purity. The aforementioned mass ratio represents a preferred range. Insufficient catalyst will lead to a reduced reaction rate and excessively long reaction preparation time. Conversely, excessive catalyst, such as a mass ratio greater than 4% to raw materials, will not significantly increase the reaction rate, resulting in raw material waste.

[0015] Preferably, as an improvement, the co-catalyst is one or more of sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, sodium carbonate, potassium carbonate, ammonium carbonate, cesium carbonate, sodium hydroxide, and potassium hydroxide, and the amount of the co-catalyst added is 10% to 15% of the raw material mass.

[0016] In this application, the co-catalyst can accelerate the reaction rate. The co-catalysts selected in this scheme are all common inorganic salts, with widely available and inexpensive raw materials, making them more suitable for industrial applications.

[0017] Preferably, as an improvement, the solvent is one or more of N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, acetone, methanol, and ethanol, and the amount of solvent added is 4 to 10 times the mass of the raw material.

[0018] In this application, using a common polar solution as the solvent in the reaction and controlling the amount of solvent added can ensure that the raw materials are fully dissolved, so that the raw materials can fully contact and react with the catalyst and co-catalyst, thereby improving the reaction rate and efficiency.

[0019] Preferably, as an improvement, the water content in the reaction system is less than 10%, and the oxygen content is less than or equal to 0.2%.

[0020] In this application, the presence of moisture in the reaction system will affect the selectivity and rate of the reaction, reducing the conversion rate of the reaction product. The difference between this technical solution and existing technologies lies in the stringent requirements for the oxygen content in the reaction system, as oxygen can severely affect the selectivity of the reaction, preventing the formation of the target product.

[0021] Preferably, as an improvement, the mixed gas includes hydrogen and an inert gas, wherein the inert gas includes one or more of nitrogen, argon, or carbon dioxide; and the volume ratio of hydrogen to inert gas is 0-10:90-100.

[0022] In this application, the inert gas in the mixed gas is used to ensure that the reaction raw materials are not affected by the reaction environment. Adding hydrogen to the mixed gas can accelerate the reaction rate. However, if too much hydrogen is added, it will lead to an increase in side reactions, the production of hydrogenation products, and a reduction in the purity of the reactants.

[0023] Preferably, as an improvement, the sealing reaction temperature is 100–160°C and the reaction time is 15–25 h.

[0024] In this application, the sealing reaction temperature affects the reaction process. The reaction temperature in this application needs to take into account both the reaction rate and the boiling point of the solvent. If the temperature is too high, the solvent will evaporate, or if the temperature is too low, the reaction rate will be affected.

[0025] Preferably, as an improvement, the specific steps of filtration, neutralization, extraction, distillation and recrystallization are as follows: after the reaction is completed, the reaction solution is cooled to room temperature, the reaction solution is filtered to obtain filtrate and catalyst, and the catalyst is recovered and reused; water and acid are added to the filtrate to neutralize the filtrate, and then an extractant is added to the filtrate for extraction to obtain an extracted organic phase and a raffinate aqueous phase. The raffinate aqueous phase is treated as wastewater, the extracted organic phase is distilled under reduced pressure to obtain a crude product, and an ethanol & water mixed solution is added to the crude product for recrystallization to finally obtain the target product.

[0026] In this application, catalysts and other components can be recovered and reused, and the purity of the target product can be improved, through steps of filtration, neutralization, extraction, distillation, and recrystallization. The purity of the refined target product can reach 98-99%, and it can be used directly as an intermediate for chlorantraniliprole without further processing.

[0027] Preferably, as an improvement, the pH of the neutralized filtrate is 3 to 4, and the acid includes any one or a combination of sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, formic acid, acetic acid, and oxalic acid.

[0028] In this application, adjusting the pH of the solution to acidic after filtration can better extract the target product and ensure that the purity of the extracted product remains at a high level. Detailed implementation method:

[0029] The following detailed description illustrates the specific implementation method:

[0030] Example 1

[0031] A method for preparing 3-bromo-1-(3-chloro-2-pyridinyl)-1-H-pyrazole-5-carboxylic acid compounds. The target product of this embodiment is 3-bromo-1-(3-chloro-2-pyridinyl)-1-H-pyrazole-5-carboxylic acid. The structural formula of its raw materials is shown below, which is equivalent to R1 and R2 being H, R3 being Cl, and R4 being Br in compound I.

[0032]

[0033] The specific reaction steps are as follows: Take 10g of 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid as the starting material, 100g of N,N-dimethylacetamide as the solvent, 1.25g of potassium carbonate as the co-catalyst, and 3.5g of palladium on carbon (5% wt. Pd) as the catalyst. Add the above substances to a flask equipped with a stirrer. It should be noted that the solvents in this scheme need to be purified by reflux and distillation before use to ensure that the reaction system does not contain water. Then, first, purge the flask with nitrogen gas for 15 minutes to ensure that the air in the flask is expelled, then purge it with hydrogen gas to replace part of the nitrogen gas, and finally ensure that the mixed gas in the flask contains 5% by volume H2 and 95% by volume N2. After sealing the flask, heat it to 100°C and stir the reaction until the reaction is complete.

[0034] After the reaction is complete and the reaction solution is cooled to room temperature, the reaction solution is filtered to obtain the filtrate and catalyst. The catalyst is recovered for future use. 200g of water is added to the filtrate, followed by sulfuric acid to neutralize the pH to 3. In this invention, a pH of 3-4 after neutralization is sufficient to meet the preparation requirements. In addition to sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, or oxalic acid, or a mixture thereof, can also be added to neutralize the filtrate. After thorough mixing, 300g of ethyl acetate is added to the filtrate for extraction, and the extraction is repeated three times. In this embodiment, chloroform or dichloromethane can also be used as the extractant. During extraction, the volume ratio of extractant to filtrate should be maintained between 1:1 and 3 to ensure that the organic phase in the filtrate is extracted, thereby improving the product yield. The organic phases obtained from multiple extractions were combined, and the extractant and product were separated by vacuum distillation. The extractant was recovered and reused. 25% ethanol / water solution was added to the product, and the mixture was stirred to dissolve and recrystallize to obtain the final product 3-bromo-1-(3-chloro-2-pyridyl)-1-H-pyrazole-5-carboxylic acid.

[0035] Example 2

[0036] The difference between this embodiment and Example 1 lies in the different raw materials and target product. Specifically, the target product in this embodiment is ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylate, and the raw material is ethyl 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate. The structural formula of the raw material is shown below, which is equivalent to R1 being ethyl, R2 being H, R3 being Cl, and R4 being Br in compound I.

[0037]

[0038] The specific reaction steps are as follows: Take 10g of ethyl 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate as the starting material, 100g of N,N-dimethylacetamide as the solvent, 1.25g of potassium carbonate as the co-catalyst, and 3.5g of palladium on carbon (5% wt. Pd) as the catalyst (where the amount of palladium added is 1.75% of the starting material). Add the above substances to a flask equipped with a stirrer. First, purge the flask with nitrogen gas for 15 minutes to ensure that the air in the flask is purged. Then, purge the flask with hydrogen gas to replace part of the nitrogen gas. Finally, ensure that the mixed gas in the flask contains 5% by volume H2 and 95% by volume N2. After sealing the flask, heat it to 100℃ and stir the reaction until the reaction is complete.

[0039] After the reaction is complete, the reaction solution is cooled to room temperature. The reaction solution is then filtered to obtain the filtrate and catalyst, which is recovered for future use. 200g of water is added to the filtrate, followed by the addition of an appropriate amount of sulfuric acid to neutralize the pH to 3. After thorough mixing, 300g of ethyl acetate is added to the filtrate for extraction. This extraction is repeated three times. The extracted organic phases are combined, and the extractant and product are separated by vacuum distillation. The extractant is recovered and reused. A 25% ethanol / water solution is added to the product, and the mixture is stirred to dissolve and recrystallize to obtain the final product, ethyl 3-bromo-1-(3-chloro-2-pyridyl)-1-H-pyrazole-5-carboxylate.

[0040] Example 3

[0041] The difference between this embodiment and Embodiment 1 lies in the proportion of components in the mixed gas. Specifically, in this embodiment, the mixed gas comprises 10% by volume H2 and 90% by volume N2.

[0042] Example 4

[0043] The difference between this embodiment and Embodiment 1 is the reaction temperature. Specifically, the reaction temperature in this embodiment is 160°C.

[0044] Example 5

[0045] The difference between this embodiment and Example 1 lies in the amount of catalyst added. Specifically, in this embodiment, the amount of palladium added is 3.25% of the raw material mass.

[0046] Example 6

[0047] The difference between this embodiment and Embodiment 1 lies in the reaction gas atmosphere. Specifically, in this embodiment, the reaction gas atmosphere is 100% nitrogen.

[0048] Comparative Example 1

[0049] The difference between this comparative example and Example 1 is that the component ratios of the mixed gas are different. Specifically, the mixed gas in this comparative example includes 20% by volume H2 and 80% by volume N2.

[0050] Comparative Example 2

[0051] The difference between this comparative example and Example 1 is the reaction gas atmosphere. Specifically, the reaction gas atmosphere in this comparative example is 100% hydrogen.

[0052] Comparative Example 3

[0053] The difference between this comparative example and Example 6 is that the reaction solvent was not purified by reflux and distillation. The solvent N,N-dimethylacetamide in this comparative example contains approximately 10% water.

[0054] Comparative Example 4

[0055] The difference between this comparative example and Example 1 is the reaction gas atmosphere. Specifically, the reaction gas atmosphere in this comparative example is 100% oxygen.

[0056] Comparative Example 5

[0057] The difference between this comparative example and Example 1 is the reaction temperature. Specifically, the reaction temperature in this comparative example is 60°C.

[0058] Comparative Example 6

[0059] The difference between this comparative example and Example 1 lies in the amount of catalyst added. Specifically, in this comparative example, the amount of palladium added is 0.35% of the raw material mass.

[0060] The experimental conditions and results of the above embodiments and comparative examples are recorded in Table 1 below, where the amount of palladium added is the ratio of its amount to the amount of raw materials added:

[0061] Table 1: Experimental Conditions and Results Recording Table for Examples & Comparative Examples

[0062]

[0063] Analysis of experimental results:

[0064] According to the embodiments of the technical solution of the present invention, after about 20 hours of reaction, the conversion rate of raw materials can reach more than 98%, and the selectivity of the reaction can reach more than 70%, and can reach up to 85%.

[0065] A comparison of the experimental data from Example 6 and Example 1 shows that adding an appropriate amount of hydrogen to the reaction system can effectively accelerate the reaction rate and improve the selectivity of the reaction.

[0066] A comparison of the experimental data from Comparative Example 1 and the Examples shows that when the amount of hydrogen added is slightly excessive, the reaction rate still increases, but the selectivity of the reaction decreases, indicating that when hydrogen is excessive, the hydrogenation byproducts increase.

[0067] A comparison of the experimental data from Comparative Example 2 and the Examples shows that when hydrogen is added in excessive amounts, it not only fails to accelerate the reaction rate and improve the selectivity, but also negatively impacts both the selectivity and the reaction rate. When the reaction atmosphere is entirely hydrogen, the selectivity of the reaction is significantly affected, and the amount of by-products increases.

[0068] The comparison between the experimental data of Comparative Example 3 and the Example shows that when the reaction system contains water, the reaction process and selectivity are greatly affected.

[0069] The comparison between the experimental data of Comparative Example 4 and the Example shows that the presence of oxygen in the reaction system has a significant impact on the selectivity of the reaction.

[0070] A comparison of the experimental data from Comparative Examples 5 and 6 with those from the Example shows that the reaction rate decreases significantly when the reaction temperature is lowered or the amount of catalyst used is reduced.

[0071] The above descriptions are merely embodiments of the present invention, and common knowledge such as specific technical solutions and / or characteristics are not described in detail here. It should be noted that those skilled in the art can make various modifications and improvements without departing from the technical solutions of the present invention, and these should also be considered within the scope of protection of the present invention. These modifications and improvements will not affect the effectiveness of the implementation of the present invention or the practicality of the patent. The scope of protection claimed in this application should be determined by the content of its claims, and the specific embodiments described in the specification can be used to interpret the content of the claims.

Claims

1. A method for preparing a 3-bromo-1-(3-chloro-2-pyridyl)-1-H-pyrazole-5-carboxylic acid compound, characterized in that: Using compound I as a raw material, a solvent, a co-catalyst, and palladium on carbon were added to it. The reaction was carried out in a sealed environment under a mixed gas atmosphere. After the reaction was completed, the catalyst palladium on carbon was recovered by filtration. The filtrate was neutralized, extracted, distilled, and recrystallized to obtain the product. The co-catalyst is one or more of sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, sodium carbonate, potassium carbonate, ammonium carbonate, cesium carbonate, sodium hydroxide, and potassium hydroxide, and the amount of the co-catalyst added is 10% to 15% of the mass of the raw material; The mixed gas consists of hydrogen and a protective gas, wherein the protective gas includes one or more of nitrogen, argon, or carbon dioxide; the volume ratio of hydrogen to the protective gas is 0–10:90–100, but the volume ratio of hydrogen in the mixed gas is not 0%. The structural formula of compound I is shown below: ； In compound I, R1 is H or an alkyl group, and the carbon chain length of the alkyl group is 1 to 5; R2 is H or any halogen element; R3 and R4 are any halogen elements.

2. The method for preparing a 3-bromo-1-(3-chloro-2-pyridyl)-1-H-pyrazole-5-carboxylic acid compound according to claim 1, characterized in that: The mass ratio of metallic palladium to raw materials in the palladium on carbon is 1% to 4%.

3. The method for preparing a 3-bromo-1-(3-chloro-2-pyridyl)-1-H-pyrazole-5-carboxylic acid compound according to claim 2, characterized in that: The solvent is one or more of N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, acetone, methanol, and ethanol, and the amount of solvent added is 4 to 10 times the mass of the raw material.

4. The method for preparing a 3-bromo-1-(3-chloro-2-pyridyl)-1-H-pyrazole-5-carboxylic acid compound according to claim 1, characterized in that: The reaction system contains less than 10% water and less than or equal to 0.2% oxygen.

5. The method for preparing a 3-bromo-1-(3-chloro-2-pyridyl)-1-H-pyrazole-5-carboxylic acid compound according to claim 1, characterized in that: The temperature of the sealing reaction is 100–160°C, and the reaction time is 15–25 h.

6. The method for preparing a 3-bromo-1-(3-chloro-2-pyridyl)-1-H-pyrazole-5-carboxylic acid compound according to claim 1, characterized in that: The specific steps of filtration, neutralization, extraction, distillation and recrystallization are as follows: After the reaction is completed, the reaction solution is cooled to room temperature, the reaction solution is filtered to obtain filtrate and catalyst, and the catalyst is recovered and reused; water and acid are added to the filtrate to neutralize the filtrate, and then an extractant is added to the filtrate for extraction to obtain an extractable organic phase and a raffinate aqueous phase. The raffinate aqueous phase is treated as wastewater, and the extractable organic phase is distilled under reduced pressure to obtain a crude product. An ethanol & water mixed solution is added to the crude product for recrystallization to finally obtain the target product.

7. The method for preparing a 3-bromo-1-(3-chloro-2-pyridyl)-1-H-pyrazole-5-carboxylic acid compound according to claim 6, characterized in that: The pH of the neutralized filtrate is 3 to 4, and the acid includes any one or a combination of sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, formic acid, acetic acid, and oxalic acid.

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