A method of post-treating a pyrazole ring
By optimizing the crystallization system of pyrazole rings, adding adsorbents, and controlling the stirring speed and cooling rate, the problems of low purity and unsatisfactory yield in the preparation of pyrazole rings were solved, achieving the production of high-purity and high-yield pyrazole rings, which is suitable for large-scale industrial production.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- SYNWILL YICHANG CHEM CO LTD
- Filing Date
- 2024-12-06
- Publication Date
- 2026-06-09
AI Technical Summary
The existing technology for preparing pyrazole rings suffers from problems such as agglomeration, impurity contamination, low product purity, and unsatisfactory yield. In particular, due to the influence of tar and moisture, it is difficult to achieve high-quality and high-yield industrial production.
By optimizing the crystallization system, adding an appropriate amount of adsorbent to treat the cyclized crude product, removing moisture and tar by combining distillation, controlling the stirring speed and cooling rate, and adopting a three-in-one closed-bottle heating and drying method, the crystallization habit of the pyrazole ring is optimized, thereby improving the purity and particle size of the product.
This enables the production of pyrazole rings with high purity and high yield, reduces production costs, and facilitates large-scale industrial production.
Abstract
Description
Technical Field
[0001] This invention relates to the field of organic chemical post-processing technology, specifically to a method for post-processing pyrazole rings. Background Technology
[0002] The pyrazole ring, officially named 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole-3-nitrile, is a key intermediate in fipronil and fenproxetine.
[0003] Existing technologies CN1213366A, CN111018786A, and CN110240566A typically use 2,6-dichloro-4-trifluoromethylaniline and ethyl 2,3-dicyanopropionate as starting materials, undergoing diazotization and cyclization reactions to obtain 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole-3-nitrile. After removing the reaction solvent, an organic solvent is added, followed by dissolution in water, and then crystallization and drying to obtain a solid pyrazole ring. However, the product obtained by this method has the problem of agglomeration and precipitation during the drying process, and the product quality needs to be further improved.
[0004] Therefore, this invention proposes a pyrazole ring post-treatment method, which can optimize the crystallization system, thereby improving the reaction yield, improving product quality, reducing production costs, and facilitating large-scale industrial production. Summary of the Invention
[0005] This invention proposes a post-processing method for the pyrazole ring, which can improve the reaction yield, product quality, and reduce production costs by controlling the crystallization habit of the product and optimizing the crystallization system, thereby facilitating large-scale industrial production.
[0006] Specifically, it includes the following steps:
[0007] Organic solvent and water were added to the crude pyrazole ring, and the mixture was allowed to stand and separate into layers. Adsorbent was added to the organic layer, and the mixture was thoroughly mixed and filtered. The filtrate was crystallized by stirring and gradually cooling. After stirring for 3-6 hours, part of the mother liquor was separated by pressure filtration, and the remaining mother liquor was dried by heating. Crystals precipitated from the solvent were obtained, which is the high-purity pyrazole ring.
[0008] The organic solvent is selected from one or more of toluene and dichloroethane.
[0009] The adsorbent is selected from one or more of diatomaceous earth, activated alumina, alkaline clay, silica gel, and activated carbon.
[0010] The weight ratio of crude pyrazole ring to adsorbent is 1:0.001–0.3, preferably 1:0.01–0.1. The adsorption time between the organic layer and the adsorbent is 0.1–1 h, preferably 0.5–1 h. In principle, the adsorbent does not react with any substance in the system.
[0011] Furthermore, prior to the adsorption operation, the organic layer is distilled to remove residual moisture from the system. Preferably, toluene is added to remove moisture from the system via azeotropic distillation.
[0012] Furthermore, after the adsorption operation is completed, the adsorbent can be removed by simple filtration, and the filtrate can be used for the next step.
[0013] During the crystallization process of the filtrate, the temperature is gradually reduced to 0-10℃ while stirring. Preferably, the present invention adopts a cooling method of slow first and then fast, for example, cooling at a rate of 8-10℃ / h first, and then cooling at a rate of 15-20℃ / h.
[0014] Furthermore, to ensure sufficient crystallization of the product in the filtrate, the stirring speed of the filtrate is maintained at 50-200 rpm. Preferably, the present invention employs a stirring method that starts slowly and then increases in speed. For example, a stirring rate of 50 rpm is used initially, followed by a stirring rate of 200 rpm.
[0015] Furthermore, different stirring speeds and system temperatures have different effects on the crystallization of the filtrate. The preferred method of stirring and gradient cooling in this invention is to first stir at a stirring speed of 50-100 rpm for 2-4 hours while cooling at a rate of 8-10℃ / h, and then stir at a stirring speed of 150-200 rpm for 1-2 hours while cooling at a rate of 15-20℃ / h.
[0016] Furthermore, after the crystallization stirring operation is completed, some of the mother liquor is removed by pressure filtration, and the product is dried by heating in a three-in-one closed-chamber process, which can yield a product with larger particle size and higher bulk density.
[0017] The temperature for heating and drying is 40–70℃, preferably 50–60℃. The drying time is 3–20 hours, preferably 8–16 hours.
[0018] Specifically, the crude pyrazole ring in this application can be prepared with reference to existing technologies CN1213366A, CN111018786A or CN110240566A. It is prepared by using 2,6-dichloro-4-trifluoromethylaniline and ethyl 2,3-dicyanopropionate as starting materials, carrying out diazotization and cyclization reactions, and removing the reaction solvent to obtain 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole-3-nitrile, which is simply referred to as the pyrazole ring.
[0019] Specifically, the operation steps are as follows:
[0020] After the cyclization reaction of 2,6-dichloro-4-trifluoromethylaniline and ethyl 2,3-dicyanopropionate, the solvent was removed to obtain crude pyrazole rings. Toluene and water were added for washing. After washing, the mixture was allowed to stand and separate into layers. The system was heated and toluene was distilled to remove water. An adsorbent was added to the organic layer, and the mixture was thoroughly stirred and filtered. The filtrate was then gradually cooled to 0°C while stirring. After this process, the crystallization solution was transferred to a three-in-one container, and some of the toluene mother liquor was removed by pressure filtration. The solvent was dried by heating, and the material was dried to obtain high-purity pyrazole rings.
[0021] The applicant's research has revealed that existing cyclization reactions for preparing pyrazole rings involve side reactions and impurities. Particularly during the ring closure process, the diazonium salt decomposes upon dropwise addition. During the reaction, some of the decomposed diazonium salt undergoes cyclization or fails, generating a large amount of byproducts. These impurities severely affect product quality. Furthermore, the complex composition of the system leads to the formation of a large amount of tar after the reaction. Simple crystallization cannot completely remove the tar; the residual tar makes it difficult to thoroughly dry and remove moisture. Consequently, the product cannot fully crystallize in organic solvents, resulting in only fine crystals, thus affecting yield and quality. Moreover, when using toluene for direct crystallization, residual tar causes adhesion during crystallization, leading to agglomeration of the final product. Impurities are mixed or encapsulated within the product, making separation difficult. This inevitably results in the loss of the pyrazole ring during further purification. All these factors contribute to low product purity and unsatisfactory reaction yields.
[0022] Through numerous experiments and studies, the applicant has discovered that impurities and moisture are key factors affecting product purity in cyclization reaction systems. These factors influence the crystallization habit of the pyrazole ring, thereby affecting product purity. This application addresses this issue by adding an appropriate amount of adsorbent to treat the crude cyclized product, effectively removing moisture, tar, and other byproducts from the cyclization system. This optimizes the crystallization habit of the pyrazole ring, thus improving product purity. Furthermore, distilling the organic layer before adsorption removes residual moisture more thoroughly, simplifying and shortening subsequent drying operations and improving reaction efficiency. Further research reveals that the stirring speed and system temperature during crystallization also affect the crystallization habit of the product, thus influencing the total amount of product precipitated. In the early stages of crystallization, slow stirring and cooling rates promote sufficient product aggregation in the system. In the later stages of crystallization, faster stirring and cooling rates facilitate complete product precipitation. Additionally, combining a three-in-one closed-boiler heating method for drying the product yields products with larger particle sizes and higher bulk density. In summary, the post-processing method described in this application can comprehensively optimize the crystallization habit of the pyrazole ring and improve product quality.
[0023] This application has the following beneficial effects:
[0024] 1. This application improves product quality and reaction yield and reduces production costs by controlling impurities and moisture content, optimizing the crystallization system, and regulating the crystallization behavior of the product.
[0025] 2. This application is simple to operate and can efficiently remove residual moisture, tar and by-products in the reaction system, which is conducive to improving the reaction yield and product quality, and thus helps to realize large-scale industrial production.
[0026] 3. Compared to the traditional three-in-one process of drying the mother liquor and then baking it, this application transforms the process by filtering out half of the mother liquor in the three-in-one process, and then dissolving the product using the remaining mother liquor. This avoids excessively rapid cooling that could lead to crystal transformation, and is more conducive to crystal precipitation. The crystalline material obtained by this application is more stable and has a higher bulk density. At the same time, pressing and filtering at a slightly higher temperature is more conducive to the solvent removing impurities. Finally, crystal transformation is carried out using the remaining mother liquor, resulting in a purer product and a higher product yield. Detailed Implementation
[0027] Example 1
[0028] After the cyclization reaction of 850 kg of 2,6-dichloro-4-trifluoromethylaniline and 580 kg of ethyl 2,3-dicyanopropionate was completed, the solvent was removed to obtain 1180 kg of crude pyrazole ring (purity 90.1%). The mixture was cooled to about 85°C, and 3000 kg of toluene and 3000 kg of water were added for washing, while maintaining the temperature at 60-70°C. After washing, the mixture was allowed to stand and separate into layers. The organic layer was heated to 80-100°C, and the toluene was distilled to remove the water.
[0029] Add 45 kg of diatomaceous earth to the organic layer, stir thoroughly for 30 min, and filter. The filtrate is then gradually cooled to 0°C while stirring. First, stir at 60-80 rpm for 4 h while cooling at a rate of 8°C / h, then stir at 150-180 rpm for 2 h while cooling at a rate of 18°C / h. After this, transfer the crystallization solution to a three-in-one container, filter to remove half of the toluene mother liquor, heat to 40-50°C, dry the solvent under vacuum, and continue heating to 50-60°C for further drying. Once drying is complete, 1153.8 kg of pyrazole rings are obtained, with a product purity of 99.5% and a bulk density of 0.68. The reaction yield, based on aniline, is 96.6%.
[0030] Example 2
[0031] After the cyclization reaction of 850 kg of 2,6-dichloro-4-trifluoromethylaniline and 580 kg of ethyl 2,3-dicyanopropionate was completed, the solvent was removed to obtain 1170 kg of crude pyrazole ring (purity 91.0%). The mixture was cooled to about 85°C, and 3000 kg of toluene and 3000 kg of water were added for washing, while maintaining the temperature at 60-70°C. After washing, the mixture was allowed to stand and separate into layers. The organic layer was heated to 80-100°C, and the toluene was distilled to remove the water.
[0032] Add 50 kg of activated carbon to the organic layer, stir thoroughly for 30 min, and filter. The filtrate is then gradually cooled to 0 °C while stirring. First, stir at 60-80 rpm for 3 h while cooling at a rate of 10 °C / h, then stir at 150-180 rpm for 2 h while cooling at a rate of 18 °C / h. After this, transfer the crystallization solution to a three-in-one container, filter to remove half of the toluene mother liquor, heat to 40-50 °C, dry the solvent under vacuum, and continue heating to 50-60 °C for further drying. After drying, 1146.2 kg of pyrazole rings are obtained, with a product purity of 99.5% and a bulk density of 0.68. The reaction yield is 96.0% based on aniline.
[0033] Example 3
[0034] After the cyclization reaction of 850 kg of 2,6-dichloro-4-trifluoromethylaniline and 580 kg of ethyl 2,3-dicyanopropionate was completed, the solvent was removed to obtain 1180 kg of crude pyrazole ring (purity 90.5%). The mixture was cooled to about 85°C, and 3000 kg of toluene and 3000 kg of water were added for washing, while maintaining the temperature at 60-70°C. After washing, the mixture was allowed to stand and separate into layers. The organic layer was heated to 80-100°C, and the toluene was distilled to remove the water.
[0035] Add 45 kg of diatomaceous earth to the organic layer, stir thoroughly for 30 min, and filter. The filtrate is then gradually cooled to 0°C while stirring. First, stir at 80-100 rpm for 3 h while cooling at a rate of 10°C / h, then stir at 180-200 rpm for 1.5 h while cooling at a rate of 20°C / h. After this, transfer the crystallization solution to a three-in-one container, filter to remove half of the toluene mother liquor, heat to 40-50°C, dry the solvent under vacuum, and continue heating to 50-60°C for further drying. After drying, 1142.5 kg of pyrazole rings are obtained, with a product purity of 99.0% and a bulk density of 0.68. The reaction yield is 95.2% based on aniline.
[0036] Example 4
[0037] After the cyclization reaction of 850 kg of 2,6-dichloro-4-trifluoromethylaniline and 580 kg of ethyl 2,3-dicyanopropionate was completed, the solvent was removed to obtain 1180 kg of crude pyrazole ring (purity 90.1%). The mixture was cooled to about 85°C, and 3000 kg of toluene and 3000 kg of water were added for washing, while maintaining the temperature at 60-70°C. After washing, the mixture was allowed to stand and separate into layers. The organic layer was heated to 80-100°C, and the toluene was distilled to remove the water.
[0038] Add 45 kg of diatomaceous earth to the organic layer, stir thoroughly for 30 min, and filter. The filtrate is then gradually cooled to 0°C while stirring. First, stir at 50-60 rpm for 4 h while cooling at a rate of 8°C / h, then stir at 150-160 rpm for 2 h while cooling at a rate of 15°C / h. After this, transfer the crystallization solution to a three-in-one container, filter to remove half of the toluene mother liquor, heat to 40-50°C, dry the solvent under vacuum, and continue heating to 50-60°C for further drying. After drying, 1139.4 kg of pyrazole rings are obtained, with a product purity of 99.0% and a bulk density of 0.68. The reaction yield is 94.9% based on aniline.
[0039] Comparative Example 1
[0040] Refer to CN110240566A without adsorbent
[0041] After the cyclization reaction of 850g of 2,6-dichloro-4-trifluoromethylaniline and 580g of ethyl 2,3-dicyanopropionate was completed, the solvent was removed to obtain 1180g of crude pyrazole ring (purity 90.0%). The mixture was cooled to about 85℃, and 3000g of toluene and 3000g of water were added for washing, while maintaining the temperature at 60-70℃. After washing, the mixture was allowed to stand and separate into layers. The organic layer was frozen to crystallize, filtered, and dried to obtain 1090.1g of solid pyrazole ring. The product purity was 96.1%, the reaction yield was 88.6%, and the bulk density was 0.75.
[0042] Comparative Example 2
[0043] After the cyclization reaction of 850 kg of 2,6-dichloro-4-trifluoromethylaniline and 580 kg of ethyl 2,3-dicyanopropionate was completed, the solvent was removed to obtain 1180 kg of crude pyrazole ring (purity 90.1%). The mixture was cooled to about 85°C, and 3000 kg of toluene and 3000 kg of water were added for washing, while maintaining the temperature at 60-70°C. After washing, the mixture was allowed to stand and separate into layers. The organic layer was heated, and the toluene was distilled to remove water.
[0044] Add 45 kg of diatomaceous earth to the organic layer, stir thoroughly for 30 min, and filter. The filtrate is cooled to 0 °C at a rate of 15 °C / h while stirring at 120-150 rpm for 5 h. After completion, transfer the crystallization liquid to a three-in-one container, filter to remove half of the toluene mother liquor, heat to 40-50 °C, dry the solvent under vacuum, and continue to heat to 50-60 °C to dry. After drying, 1066.6 kg of pyrazole rings are obtained with a product purity of 96.5% and a bulk density of 0.68. The reaction yield is 86.6% based on aniline.
[0045] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.
Claims
1. A method for post-treatment of the pyrazole ring, characterized in that, Includes the following steps: Organic solvent and water were added to the crude pyrazole ring, and the mixture was allowed to stand and separate into layers. Adsorbent was added to the organic layer, and the mixture was thoroughly mixed and filtered. The filtrate was crystallized by stirring and gradually cooling. After stirring for 3-6 hours, part of the mother liquor was separated by pressure filtration, and the remaining mother liquor was dried by heating. Crystals precipitated from the solvent were obtained, which is the high-purity pyrazole ring.
2. The post-processing method according to claim 1, characterized in that, The organic solvent is selected from one or more of toluene and dichloroethane.
3. The post-processing method according to claim 1, characterized in that, The adsorbent is selected from one or more of diatomaceous earth, activated alumina, alkaline clay, silica gel, and activated carbon.
4. The post-processing method according to claim 1, characterized in that, The weight ratio of the crude pyrazole ring to the adsorbent is 1:0.001 to 0.3, preferably 1:0.01 to 0.1; the adsorption time between the organic layer and the adsorbent is 0.1-1 h, preferably 0.5-1 h.
5. The post-processing method according to claim 1, characterized in that, During the crystallization process, the temperature is gradually reduced to 0-10℃ while stirring, and the stirring speed is maintained at 50-200 rpm.
6. The post-processing method according to claim 5, characterized in that, The stirring rate and cooling rate are both slow at first and then fast. First, stir at a stirring rate of 50-100 rpm for 2-4 hours, while cooling at a rate of 8-10℃ / h. Then, stir at a stirring rate of 150-200 rpm for 1-2 hours, while cooling at a rate of 15-20℃ / h.
7. The post-processing method according to claim 1, characterized in that, The drying temperature is 40–70°C, preferably 50–60°C; The drying time is 3-20 hours, preferably 8-16 hours.
8. The post-processing method according to claim 1, characterized in that, After the crystallization stirring operation is completed, part of the mother liquor is removed by pressure filtration, and the product is dried by heating in a three-in-one closed-chamber process.