A method for purifying difenoconazole
By using copper chloride, liquid alkali, and dilute hydrochloric acid, copper salt of difenoconazole was prepared, reduced, and recrystallized. This solved the problems of strong acid corrosion and incomplete impurity removal in existing technologies, enabling the preparation of high-purity difenoconazole and reducing costs and environmental risks.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- SHANDONG WEIFANG SHUANGXING PESTICIDES CO LTD
- Filing Date
- 2026-05-14
- Publication Date
- 2026-06-16
AI Technical Summary
Existing methods for preparing difenoconazole suffer from problems such as high corrosiveness of strong acids, difficulty in recovering metal salts, and incomplete removal of impurities, resulting in high equipment costs and difficulty in improving purity.
By using conventional reagents such as copper chloride, liquid alkali, and dilute hydrochloric acid, and through the steps of preparing fenether tebuconazole copper salt, reduction reaction, and recrystallization, copper recycling and effective removal of impurities are achieved, thereby improving purity.
It enables safe operation in ordinary equipment, reduces equipment investment and maintenance costs, improves product purity, meets green chemistry requirements, and the recycling of copper salts reduces the pressure of waste liquid treatment.
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Abstract
Description
Technical Field
[0001] This invention relates to the field of pesticide technical preparation technology, and in particular to a purification method for difenoconazole. Background Technology
[0002] Difenoconazole is a highly effective, low-toxicity, broad-spectrum triazole fungicide with strong systemic conductivity, broad fungicidal spectrum, resistance to rain washout, and low toxicity. It is widely used in agriculture to control various crop diseases, including fruit trees (apple scab, citrus scab, grape anthracnose, etc.), staple crops (wheat loose smut, rice sheath blight, etc.), and vegetable and cash crops (tomato early blight, watermelon anthracnose, etc.).
[0003] Currently, most synthetic routes for preparing difenoconazole contain 13%-15% isomers, with crude product content ranging from 80%-85%. Common purification methods are as follows: Application CN113248479B discloses a concentrated nitric acid salt formation method: crude difenoconazole is dissolved in toluene solution, and excess concentrated nitric acid is added dropwise with stirring at room temperature. Recrystallization yields pure difenoconazole with a purity of 95.7%. The concentrated nitric acid used in this method is highly corrosive and can easily corrode equipment, posing a hazard. The reaction equation is as follows: .
[0004] Application CN110204534B discloses a concentrated hydrochloric acid salt formation method: crude difenoconazole is dissolved in toluene solution, concentrated hydrochloric acid is added dropwise with stirring at room temperature, and recrystallization yields pure difenoconazole with a purity of 95.5%. This method uses highly corrosive concentrated hydrochloric acid and requires sophisticated equipment. The reaction equation is as follows: .
[0005] Furthermore, application CN105884749A proposes a method for purifying zinc chloride, which can achieve a purity of over 97%. However, the wastewater treatment, evaporation concentration, and chemical conversion costs required for the recovery of the zinc chloride used are higher than the cost of directly purchasing new zinc salts, and a large amount of byproducts are generated that are difficult to recycle. Summary of the Invention
[0006] To address the aforementioned shortcomings, this invention provides a purification method for difenoconazole, which overcomes the deficiencies of existing technologies such as strong acid corrosion, difficulty in recovering metal salts, and incomplete removal of impurities, and achieves higher purity.
[0007] To achieve the above objectives, the present invention provides the following technical solution: a method for purifying difenoconazole, comprising: Step 1: Preparation of copper salt of difenoconazole: Crude difenoconazole containing the isomer is dissolved in a first organic solvent and heated until the solution is clear. Then, copper chloride methanol solution is added to react and generate copper salt of difenoconazole. The salt formation reaction equation is as follows:
[0008] Step 2, Preparation of difenoconazole semi-finished product: The copper salt of difenoconazole obtained in Step 1 is reduced in a second organic solvent using liquid alkali. The pH value is adjusted to 8, and then the difenoconazole oil and filter cake are separated. The separated filter cake is adjusted to pH 6 with dilute hydrochloric acid to obtain copper chloride. The reduction reaction equation is as follows:
[0009] Step 3: Preparation of pure difenoconazole: Dissolve the difenoconazole oil obtained in step 2 in a polar solvent, then add n-hexane, n-heptane, or methyl tert-butyl ether dropwise, and recrystallize to obtain pure difenoconazole solid.
[0010] As a further improvement of the present invention, the first step is specifically as follows: by weight, 60 parts of crude difenoconazole are mixed with 150 parts of toluene solvent and heated to 40°C to dissolve the solution. The added copper chloride methanol solution is prepared by dissolving 9.93 parts of copper chloride in 100 parts of methanol.
[0011] As a further improvement of the present invention, after adding copper chloride methanol solution in the first step, the temperature needs to be raised to 68-75°C and the reaction time is 3-5 hours; after the reaction is completed, the methanol is distilled off, and then the temperature is lowered to 18-22°C and kept at that temperature for 1-1.5 hours. After the solid is precipitated, it is filtered to obtain copper difenoconazole salt.
[0012] As a further improvement of the present invention, in the second step, the second organic solvent is 50 parts by weight of toluene solution.
[0013] As a further improvement of the present invention, the separation of difenoconazole oil and filter cake in the second step specifically involves dehydrating the oil by refluxing it through a water separator until the moisture content is less than 0.2%, and then filtering out the insoluble matter.
[0014] As a further improvement of the present invention, in the third step, the polar solvent is 58-62 parts by weight of isopropanol or methanol.
[0015] As a further improvement of the present invention, the specific steps of the third step are as follows: dissolve the fenofibrate oil in a polar solvent, heat to 60-62°C until it is completely dissolved, then cool to 38-40°C, and add 88-92 parts by weight of n-hexane, n-heptane, or methyl tert-butyl ether to precipitate a solid.
[0016] As a further improvement of the present invention, after the solid is precipitated in the third step, it is necessary to cool it to -2 to 0°C and stir it for 1 hour, and then filter and dry it to obtain pure difenoconazole.
[0017] The beneficial effects of this invention are: 1. This invention uses only conventional reagents such as copper chloride, liquid alkali, and dilute hydrochloric acid throughout the entire process, without the involvement of highly corrosive acids. It can be safely implemented in ordinary stainless steel or glass reactors, significantly reducing equipment investment and maintenance costs. The conditions in each step are mild, and the solvents are easily recovered through distillation. No special equipment or stringent anhydrous and oxygen-free operations are required, facilitating the transition from laboratory to industrial production. Furthermore, the filter cake obtained in the second step of this invention, after adjusting the pH to 6 with dilute hydrochloric acid, can regenerate a copper chloride solution, which can be directly reused in the next batch of salt formation reactions. The entire process achieves copper recycling, generates almost no difficult-to-treat waste liquid containing heavy metals, reduces raw material costs, and meets the requirements of green chemistry.
[0018] 2. In the second step of copper ion removal, liquid alkali is added to adjust the pH to 8 to generate copper hydroxide. This substance not only achieves the dissociation of copper salt and the recovery of copper, but also has a flocculation effect, adsorbing trace pigments, suspended particles, and other organic impurities in the reaction system, which are then removed during filtration of insoluble matter. This additional adsorption step further improves the purity of the semi-finished product, resulting in a higher purity of the final recrystallized product compared to other methods for refining difenoconazole. Detailed Implementation
[0019] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.
[0020] This invention provides a method for purifying difenoconazole, comprising: Step 1: Preparation of copper salt of difenoconazole: Difenoconazole crude product containing isomers is prepared into copper salt of difenoconazole in toluene using copper chloride. The salt formation reaction equation is as follows:
[0021] The preparation of copper salt of difenoconazole is as follows: In a reaction flask, 60 parts by weight of crude difenoconazole are added, and the solution is heated to 40°C in 150 parts of toluene solvent until it dissolves completely. After dissolution, a copper chloride methanol solution is slowly added dropwise. The added copper chloride methanol solution is prepared by dissolving 9.93 parts of copper chloride in 100 parts of methanol.
[0022] Heat to 68-75℃ and react for 3.5-4.5 hours to distill off 100g of methanol. Then cool to 18-22℃ and keep warm for 1-1.5 hours. After the warming period, filter to obtain white copper difenoconazole.
[0023] As a further explanation of this embodiment, the nitrogen atom on the triazole ring in the difenoconazole molecule has a lone pair of electrons, which can form a stable coordinate bond with Cu ions to generate difenoconazole copper salt. This copper salt has low solubility in a mixed solvent of toluene and methanol and precipitates as a white solid. The ineffective isomer, due to steric hindrance or electronic effects, cannot effectively coordinate with Cu ions to form a salt and remains dissolved in the mother liquor. The use of copper chloride and copper sulfate is primarily for recycling purposes.
[0024] Step 2: Preparation of difenoconazole semi-finished product: Difenoconazole copper salt is converted into difenoconazole in toluene solvent using liquid alkali.
[0025] The preparation of the difenoconazole semi-finished product is as follows: By weight, 50 parts of toluene were added to the copper salt of difenoconazole obtained by vacuum filtration. Liquid alkali was slowly added to adjust the pH to 8. The mixture was then dehydrated by reflux using a water separator until the water content was less than 0.2%. The insoluble matter was then filtered off, and the filtrate was dehydrated under reduced pressure to remove the toluene solvent, yielding an oily difenoconazole product. The filtered cake was adjusted to pH 6 with dilute hydrochloric acid to obtain copper chloride, which can be reused in the next batch of reaction. The reaction equation is as follows:
[0026] As a further explanation of this embodiment, during the copper ion removal process, copper hydroxide is generated by adjusting the alkali. Copper hydroxide has a certain flocculation effect and adsorbs impurities. To overcome the difficulty in filtering copper hydroxide after alkali adjustment, toluene dehydration is used to filter copper hydroxide through toluene.
[0027] The third step is the preparation of pure difenoconazole. Difenoconazole is recrystallized in a polar solvent to obtain pure difenoconazole solid.
[0028] The preparation of pure difenoconazole is as follows: by weight, add 58-62 parts of isopropanol or methanol and heat to 60-62℃ to dissolve. Then, cool to 38-40℃ and slowly add 88-92 parts of n-hexane, n-heptane, or methyl tert-butyl ether. During the addition, solids will precipitate. Finally, cool to -2-0℃ and stir for 1 hour. Filter to obtain wet pure difenoconazole. After drying, obtain pure difenoconazole.
[0029] Example 1: Step 1: In a 500ml reaction flask, add 60g of crude difenoconazole, add 150g of toluene, and heat to 40℃ until dissolved. After dissolution, slowly add copper chloride methanol solution (prepared by mixing 9.93g of copper chloride and 100g of methanol). Heat to 70℃ and react for 4 hours, distilling off 100g of methanol. Then cool to 20℃ and maintain the temperature for 1.5 hours. After the temperature maintenance is completed, filter to obtain 70g of white difenoconazole copper salt.
[0030] Step 2: Add 50g of toluene, slowly add liquid alkali to adjust the pH to 8, reflux and dehydrate using a water separator until the water content is less than 0.2%, then filter out the insoluble matter, remove the toluene solvent from the filtrate under reduced pressure to obtain difenoconazole oil, and adjust the pH of the filter cake to 6 with dilute hydrochloric acid to obtain copper chloride.
[0031] Step 3: Add 60g of isopropanol and heat to 60℃ to dissolve. After cooling to 40℃, slowly add 90g of n-hexane. During the addition, solid precipitates out. Cool to 0℃ and stir for 1 hour. Filter to obtain pure wet product of difenoconazole. After drying, 49.5g of pure difenoconazole is obtained. HPLC analysis shows that the content is 98.3%.
[0032] Example 2 Step 1: In a 500ml reaction flask, add 60g of crude difenoconazole, add 150g of toluene, and heat to 40℃ until dissolved. After dissolution, slowly add copper chloride methanol solution (the copper chloride methanol solution is prepared by mixing 9.93g of copper chloride and 100g of methanol, and the copper chloride used includes the copper chloride obtained in step 2 of Example 1 and new copper chloride). Heat to 68℃ and react for 3.5 hours, distill off 100g of methanol, then cool to 18℃ and keep warm for 1 hour. After the warming is completed, filter to obtain 71g of white difenoconazole copper salt.
[0033] Step 2: Add 50g of toluene, slowly add liquid alkali to adjust the pH to 8, reflux and dehydrate using a water separator until the water content is less than 0.2%, then filter out the insoluble matter, remove the toluene solvent from the filtrate under reduced pressure to obtain difenoconazole oil, and adjust the pH of the filter cake to 6 with dilute hydrochloric acid to obtain copper chloride.
[0034] Step 3: Add 58g of isopropanol and heat to 61℃ to dissolve. Cool to 39℃ and slowly add 88g of n-heptane. During the addition, solid precipitates out. Cool to -2℃ and stir for 1 hour. Filter to obtain pure wet product of difenoconazole. After drying, 48.7g of pure difenoconazole is obtained. HPLC analysis shows that the content is 98.1%.
[0035] Example 3 First, in a 500ml reaction flask, 60g of crude difenoconazole was added, followed by 150g of toluene. The mixture was heated to 40℃ until dissolved. After dissolution, a copper chloride methanol solution was slowly added dropwise (the copper chloride methanol solution was prepared by mixing 9.93g of copper chloride and 100g of methanol, and the copper chloride used included the copper chloride obtained in the second step of Example 2 and the new copper chloride). The mixture was heated to 75℃ and reacted for 4.5 hours. 100g of methanol was distilled off, and then the temperature was lowered to 22℃ and maintained for 1.3 hours. After the temperature maintenance was completed, 70g of white difenoconazole copper salt was obtained by suction filtration.
[0036] Step 2: Add 50g of toluene, slowly add liquid alkali to adjust the pH to 8, reflux and dehydrate using a water separator until the water content is less than 0.2%, then filter out the insoluble matter, remove the toluene solvent from the filtrate under reduced pressure to obtain difenoconazole oil, and adjust the pH of the filter cake to 6 with dilute hydrochloric acid to obtain copper chloride.
[0037] Step 3: Add 60g of methanol and heat to 61℃ to dissolve. Cool to 40℃ and slowly add 90g of n-hexane. During the addition, solid precipitates out. Cool to -2℃ and stir for 1 hour. Filter to obtain pure wet product of difenoconazole. After drying, 48.7g of pure difenoconazole is obtained. HPLC analysis shows that the content is 98.1%.
[0038] Example 4 Step 1: In a 500mL reaction flask, add 60g of crude difenoconazole, add 150g of toluene, and heat to 40℃ until dissolved. After dissolution, slowly add copper chloride methanol solution (the copper chloride methanol solution is prepared by mixing 9.93g of copper chloride and 100g of methanol, and the copper chloride used includes the copper chloride obtained in step 2 of Example 3 and new copper chloride). Heat to 75℃ and react for 4.5 hours, distill off 100g of methanol, then cool to 22℃ and keep warm for 1 hour. After the warming is completed, filter to obtain 70g of white difenoconazole copper salt.
[0039] Step 2: Add 50g of toluene, slowly add liquid alkali to adjust the pH to 8, reflux and dehydrate using a water separator until the water content is less than 0.2%, then filter out the insoluble matter, remove the toluene solvent from the filtrate under reduced pressure to obtain difenoconazole oil, and adjust the pH of the filter cake to 6 with dilute hydrochloric acid to obtain copper chloride.
[0040] Step 3: Add 60g of isopropanol and heat to 60℃ to dissolve. Cool to 40℃ and slowly add 90g of methyl tert-butyl ether. During the addition, solid precipitates out. Cool to 0℃ and stir for 1 hour. Filter to obtain pure wet product of difenoconazole. After drying, 49.5g of pure difenoconazole is obtained. HPLC analysis shows that the content is 98.1%.
[0041] The above are merely preferred embodiments of the present invention. The scope of protection of the present invention is not limited to the above-described embodiments. All technical solutions falling within the scope of the present invention's concept are within the scope of protection of the present invention. It should be noted that for those skilled in the art, any improvements and modifications made without departing from the principles of the present invention should also be considered within the scope of protection of the present invention.
Claims
1. A method for purifying difenoconazole, characterized in that, include: Step 1: Preparation of copper salt of difenoconazole: Crude difenoconazole containing the isomer is dissolved in a first organic solvent and heated until the solution is clear. Then, copper chloride methanol solution is added to react and generate copper salt of difenoconazole. The salt formation reaction equation is as follows: Step 2, Preparation of difenoconazole semi-finished product: The copper salt of difenoconazole obtained in Step 1 is reduced in a second organic solvent using liquid alkali. The pH value is adjusted to 8, and then the difenoconazole oil and filter cake are separated. The separated filter cake is adjusted to pH 6 with dilute hydrochloric acid to obtain copper chloride. The reduction reaction equation is as follows: Step 3: Preparation of pure difenoconazole: Dissolve the difenoconazole oil obtained in step 2 in a polar solvent, then add n-hexane, n-heptane, or methyl tert-butyl ether dropwise, and recrystallize to obtain pure difenoconazole solid.
2. The purification method of difenoconazole according to claim 1, characterized in that, The first step specifically involves mixing 60 parts by weight of crude difenoconazole with 150 parts by weight of toluene solvent and heating the mixture to 40°C until it dissolves. The added copper chloride methanol solution is prepared by dissolving 9.93 parts by weight of copper chloride in 100 parts by weight of methanol.
3. The method for purifying difenoconazole according to claim 2, characterized in that, In the first step, after adding the copper chloride methanol solution, the temperature needs to be raised to 68-75℃ and the reaction time is 3-5 hours. After the reaction is completed, the methanol is distilled off, and then the temperature is lowered to 18-22℃ and kept at that temperature for 1-1.5 hours. After the solid is precipitated, it is filtered to obtain the copper salt of difenoconazole.
4. The method for purifying difenoconazole according to claim 1, characterized in that, In the second step, the second organic solvent is 50 parts by weight of toluene solution.
5. The method for purifying difenoconazole according to claim 1, characterized in that, In the second step, the separation of the difenoconazole oil and filter cake specifically involves dehydrating the filter cake by reflux through a water separator until the moisture content is less than 0.2%, followed by filtering out the insoluble matter.
6. The method for purifying difenoconazole according to claim 1, characterized in that, In the third step, the polar solvent is 58-62 parts by weight of isopropanol or methanol.
7. The method for purifying difenoconazole according to claim 6, characterized in that, The specific steps of the third step are as follows: dissolve the fenofibrate oil in a polar solvent, heat to 60-62°C until it is completely dissolved, then cool to 38-40°C, and add 88-92 parts by weight of n-hexane, n-heptane, or methyl tert-butyl ether to precipitate the solid.
8. The method for purifying difenoconazole according to claim 7, characterized in that, After the solid precipitates in the third step, the temperature needs to be lowered to -2 to 0°C and stirred for 1 hour, then filtered and dried to obtain pure difenoconazole.