A method for purifying 4-h isomer of difenoconazole

Abstract

The present application provides a kind of refining method of difenoconazole 4-H isomer, the refining method of the present application is after difenoconazole 4-H isomer containing difenoconazole crude product is treated by 5-30% acid, and water phase is obtained by layering, the water phase is neutralized and extracted, and the organic phase is obtained by layering after extraction, the organic phase is concentrated to obtain difenoconazole 4-H isomer crude product, in the presence of crystallization solvent, the difenoconazole 4-H isomer crude product is crystallized at-5-30 ℃ to obtain the difenoconazole 4-H isomer, and the difenoconazole 4-H isomer prepared by the refining method of the present application is high in content.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and specifically to a method for purifying the 4-H isomer of phenylethyl benzoate. Background Technology

[0002] Difenoconazole is a broad-spectrum and highly effective fungicide that can control various diseases on crops caused by fungi, deuteromycetes, and other pathogens, including black spot, powdery mildew, leaf spot, rust, and anthracnose. A single application of difenoconazole can control multiple diseases and exhibits good systemic, bidirectional translocation, and penetrability, with a residual effect lasting 3-5 weeks. It is mainly used on fruit trees, vegetables, wheat, potatoes, beans, and melons, providing excellent protection and treatment against various fungal diseases in vegetables and fruits. Furthermore, it is environmentally friendly, does not contaminate agricultural products, and does not harm beneficial organisms, making it an ideal fungicide for controlling diseases such as citrus scab and leaf spot in crops in my country and worldwide.

[0003] The difenoconazole synthesized using existing techniques contains 10-25 wt% of the 4-H isomer. Crude difenoconazole is separated from the 4-H isomer through distillation or product salt formation to obtain a higher purity difenoconazole. However, the 4-H isomer lacks the aforementioned protective and preventative effects, and the separated isomer is disposed of as solid waste, causing environmental pollution. Currently, some researchers have discovered that the 4-H isomer can be used as a raw material in compound reactions, which not only solves the solid waste problem but also has economic benefits. However, the purification technology for the 4-H isomer has not yet attracted sufficient attention and research, hindering its rapid development. The 4-H isomer is a byproduct in the synthesis process, present in low concentrations, and is difficult to effectively enrich and purify using conventional methods. Summary of the Invention

[0004] The purpose of this invention is to provide a purification method for obtaining high-purity difenoconazole 4-H isomers.

[0005] To solve the above problems, the present invention adopts the following technical solution:

[0006] This invention provides a method for purifying the 4-H isomer of difenoconazole. The method involves treating crude difenoconazole containing the 4-H isomer with acid to obtain an aqueous phase, extracting the aqueous phase, and then separating the extract to obtain an organic phase. The organic phase is then concentrated to obtain a crude difenoconazole 4-H isomer. The crude difenoconazole 4-H isomer is then crystallized in the presence of a crystallization solvent to obtain the difenoconazole 4-H isomer.

[0007] The mass concentration of the acid is 5-30%; the crystallization temperature is controlled to be -5-30℃.

[0008] The structural formula of the difenoconazole is:

[0009]

[0010] The structural formula of the 4-H isomer of difenoconazole is:

[0011]

[0012] Preferably, the mass concentration of the acid is 10-15%, for example 11%, 11.5%, 12%, 12.5%, 13%, 13.5%, 14%, 14.5%, etc.

[0013] More preferably, the mass concentration of the acid is 10-13%.

[0014] Preferably, the acid is selected from one or more of hydrochloric acid, sulfuric acid, nitric acid, and acetic acid.

[0015] More preferably, the acid is selected from hydrochloric acid and / or sulfuric acid.

[0016] Preferably, the mass ratio of the acid to the crude difenoconazole is (0.1-0.5):1, for example, 0.2:1, 0.3:1, 0.4:1, etc.

[0017] More preferably, the mass ratio of the acid to the crude difenoconazole is (0.15-0.35):1.

[0018] Preferably, the crystallization temperature is controlled to be 10-30°C, for example, 11°C, 12°C, 13°C, 14°C, 15°C, 20°C, 22°C, 24°C, 26°C, 28°C, etc.

[0019] More preferably, the crystallization temperature is controlled to be 15–30°C.

[0020] Preferably, the crude 4-H isomer of difenoconazole is mixed with the crystallization solvent, and the mixture is heated to 40-110°C (e.g., 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, 100°C, 110°C, 120°C, 130°C, etc.) before crystallization.

[0021] More preferably, the crude 4-H isomer of difenoconazole is mixed with the crystallization solvent, and the mixture is heated to 40-80°C before crystallization.

[0022] More preferably, the crude 4-H isomer of difenoconazole is mixed with the crystallization solvent, and the mixture is heated to 40-60°C before crystallization.

[0023] Preferably, the specific steps of the crystallization are as follows: first, the system is cooled to 25-30°C, seed crystals are added, and then the temperature is further cooled to 10-20°C.

[0024] More preferably, the specific steps of the crystallization are as follows: first, the system is cooled to 25-30°C, seed crystals are added, and the system is kept at this temperature for 2-10 hours (e.g., 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, etc.), and then the temperature is further cooled to 10-20°C.

[0025] More preferably, the specific steps of the crystallization are as follows: first, the system is cooled to 25-30°C, seed crystals are added, and the system is kept at this temperature for 2-5 hours, and then the temperature is further cooled to 10-20°C.

[0026] Preferably, the crystallization solvent is selected from one or more of methanol, ethanol, isopropanol, toluene, methylcyclohexane, cyclohexane, heptane, petroleum ether, dichloromethane, dichloroethane, and N,N-dimethylformamide.

[0027] More preferably, the crystallization solvent is selected from one or more of cyclohexane, methylcyclohexane, isopropanol, and toluene.

[0028] Preferably, the mass ratio of the crystallization solvent to the crude 4-H isomer of phenyl ether tebuconazole is (0.5-2):1, for example, 0.6:1, 0.8:1, 1:1, 1.2:1, 1.4:1, 1.6:1, 1.8:1, etc.

[0029] More preferably, the mass ratio of the crystallization solvent to the crude 4-H isomer of phenyl ether tebuconazole is (0.8-1.5):1.

[0030] Preferably, before the acid treatment, the crude difenoconazole is dissolved in a dissolving solvent selected from one or more of benzene, toluene, cyclohexane, methylcyclohexane, dichloromethane, chlorobenzene and ethyl acetate, and the mass ratio of the dissolving solvent to the crude difenoconazole is (2-7):1.

[0031] More preferably, the dissolving solvent is selected from one or more of toluene, cyclohexane, methylcyclohexane, and chlorobenzene.

[0032] More preferably, the mass ratio of the dissolving solvent to the crude difenoconazole is (4-7):1, for example, 4.5:1, 5:1, 5.5:1, 6:1, 6.5:1, etc.

[0033] Preferably, the extraction is carried out in the presence of an alkali and an extraction solvent, wherein the alkali is selected from one or more of sodium hydroxide, sodium carbonate, potassium hydroxide, and sodium bicarbonate, and the extraction solvent is selected from one or more of toluene, methylcyclohexane, cyclohexane, xylene, chlorobenzene, and dichloromethane.

[0034] More preferably, the pH of the extraction system is 7 to 9, such as 7.5, 8, 8.5, etc.

[0035] Preferably, the crude difenoconazole contains 10-25 wt% of the difenoconazole 4-H isomer.

[0036] More preferably, the crude difenoconazole contains 10-20 wt% of the difenoconazole 4-H isomer.

[0037] Preferably, the crude product of the difenoconazole 4-H isomer contains 55-95 wt% of the difenoconazole 4-H isomer.

[0038] More preferably, the crude product of the difenoconazole 4-H isomer contains 80-95 wt% of the difenoconazole 4-H isomer.

[0039] More preferably, the crude product of the difenoconazole 4-H isomer contains 82-93 wt% of the difenoconazole 4-H isomer.

[0040] Preferably, the purification method further includes a post-processing step, wherein the post-processing step is to filter the product obtained by the crystallization and dry the filtered solid, which is the 4-H isomer of fenether tebuconazole.

[0041] Due to the application of the above-mentioned technical solution, the present invention has the following advantages compared with the prior art:

[0042] The purification method of the present invention utilizes a 5-30% (w / w) acid solution to treat crude difenoconazole containing the 4-H isomer. Subsequently, the aqueous phase obtained by separation is extracted, and the extracted organic phase is concentrated to obtain crude difenoconazole 4-H isomer. This crude product is then mixed with the extraction solvent and crystallized at a temperature of -5 to 30°C to obtain the difenoconazole 4-H isomer. The difenoconazole 4-H isomer obtained by the above method has a high content. Detailed Implementation

[0043] The present invention will be further described in detail below with reference to specific embodiments. It should be understood that these embodiments are used to illustrate the basic principles, main features and advantages of the present invention, and the present invention is not limited to the following embodiments. The implementation conditions used in the embodiments can be further adjusted according to specific requirements, and the implementation conditions not specified are generally the conditions in conventional experiments.

[0044] Currently, some domestic manufacturers of difenoconazole are optimizing their processes towards the transposition of the 4-H isomer. For example, CN111393418A discloses a method for converting the 4-H difenoconazole isomer to the 1-H difenoconazole isomer. This undoubtedly alleviates the environmental pollution caused by the 4-H difenoconazole isomer and brings economic benefits to enterprises. However, the purification technology of the 4-H difenoconazole isomer has not yet attracted much attention and research. In the purification methods of difenoconazole, the existing technology involves forming a salt (solid) of difenoconazole under strong acid conditions, thereby initially separating difenoconazole and the 4-H difenoconazole isomer. Through long-term research and extensive practice, the inventors discovered that difenoconazole and its 4-H isomer have different solubilities in organic solvents under low-concentration acid conditions. Therefore, it is possible to initially separate difenoconazole and its 4-H isomer without converting difenoconazole into a salt (solid). This led to the technical solution proposed in this invention.

[0045] This invention provides a method for purifying the 4-H isomer of difenoconazole, wherein crude difenoconazole containing the 4-H isomer is dissolved in a dissolving solvent, and treated with 5-30 wt% acid, allowed to stand and separate into layers, and the acid-aqueous phase is collected;

[0046] Extraction solvent and liquid alkali were added to the acidic aqueous phase, and the mixture was allowed to stand and separate into layers to obtain the organic phase. The organic phase was then concentrated to obtain the crude product of the 4-H isomer of difenoconazole.

[0047] The crude 4-H isomer of difenoconazole obtained above was dissolved in an extraction solvent and heated to 40-140°C. Then the system was cooled to 25-30°C, seed crystals were added, and the mixture was kept at this temperature for 2-10 hours. After cooling to 10-20°C, the mixture was filtered and dried to obtain the 4-H isomer of difenoconazole.

[0048] The 4-H isomer of difenoconazole prepared by this invention has a high content and can be used as a raw material for other reactions. It effectively solves the solid waste problem of the 4-H isomer of difenoconazole, realizes waste recycling, is environmentally friendly, and brings economic benefits to enterprises. After adding 5-30 wt% acid, difenoconazole dissolves in the organic phase. If further purification is required, it can be carried out using existing technologies, simplifying the purification operation steps.

[0049] The present invention will be described in detail below with reference to embodiments. Unless otherwise specified, "%" represents a mass percentage. In the following embodiments, unless otherwise specified, the raw materials, reagents, etc. used are all conventional commercially available products, and the method parameters, etc., are all conventional methods in the art.

[0050] Example 1

[0051] 1000g of crude difenoconazole (15% difenoconazole 4-H isomer) was added to a four-necked flask, followed by 5000g of toluene. The mixture was heated to 50°C, and 300g of 12.5% ​​dilute sulfuric acid was added dropwise while stirring for 0.5h. The mixture was then allowed to stand and separate into layers. 250g of toluene was added to the acidic aqueous phase, and 30% liquid alkali was added dropwise to adjust the pH to 8. The mixture was allowed to stand and separate into layers. The organic phase was concentrated to obtain 145g of difenoconazole 4-H isomer (90% purity). 145g of cyclohexane was added, and the mixture was heated to 60°C and held at this temperature for 0.5h. The temperature was then slowly lowered. When the temperature dropped to 25°C, seed crystals were added, and the mixture was kept at this temperature for 2 hours. The difenoconazole 4-H isomer solid slowly precipitated. The temperature was further lowered to 15-20°C, and the solid was filtered to obtain a pale yellow solid. This solid was dried at 40°C to obtain 125g of difenoconazole 4-H isomer (98% purity, 81.7% yield).

[0052] Example 2

[0053] 1000g of crude difenoconazole (4-H isomer content 15%) was added to a four-necked flask, along with 5000g of methylcyclohexane. The mixture was heated to 50°C, and 300g of 10% dilute hydrochloric acid was added dropwise while stirring for 0.5h. The mixture was then allowed to stand and separate into layers. 150g of methylcyclohexane was added to the acidic aqueous phase, and 30% liquid alkali was added dropwise to adjust the pH to 8. The mixture was allowed to stand and separate into layers. The organic phase was concentrated to obtain 140g of difenoconazole 4-H isomer (91% purity). 140g of methylcyclohexane was added, the temperature was raised to 60℃, and after holding at this temperature for 0.5h, the temperature was slowly lowered. When the temperature dropped to 30℃, seed crystals were added, and the temperature was held for 2 hours. The solid 4-H isomer of difenoconazole slowly precipitated out. The temperature was further lowered to 15-20℃, and the solid was filtered to obtain a pale yellow solid. The solid was dried at 40℃ to obtain 126g of difenoconazole 4-H isomer with a purity of 98% and a yield of 82.3%.

[0054] Example 3

[0055] 1000g of crude difenoconazole (15% difenoconazole 4-H isomer) was added to a four-necked flask, along with 6000g of cyclohexane. The mixture was heated to 50°C, and 200g of 25% dilute sulfuric acid was added dropwise while stirring for 0.5h. The mixture was then allowed to stand and separate into layers. 250g of cyclohexane was added to the acidic aqueous phase, and 30% liquid alkali was added dropwise to adjust the pH to 8. The mixture was allowed to stand and separate into layers. The organic phase was concentrated to obtain 140g of difenoconazole 4-H isomer (85% difenoconazole). 140g of methylcyclohexane was added, and the mixture was heated to 60°C. After holding at this temperature for 0.5h, the temperature was slowly lowered. When the temperature reached 25°C, seed crystals were added, and the mixture was kept at this temperature for 2 hours. The difenoconazole 4-H isomer solid slowly precipitated. The temperature was further lowered to 15-20°C, and the solid was filtered to obtain a pale yellow solid. This solid was dried at 40°C to obtain 125g of difenoconazole 4-H isomer (94% difenoconazole, 78.3% yield).

[0056] Example 4

[0057] 1000g of crude difenoconazole (4-H isomer content 15%) was added to a four-necked flask, along with 5000g of methylcyclohexane. The mixture was heated to 50°C, and 300g of 10% dilute hydrochloric acid was added dropwise while stirring for 0.5h. The mixture was then allowed to stand and separate into layers. 150g of methylcyclohexane was added to the acidic aqueous phase, and 30% liquid alkali was added dropwise to adjust the pH to 8. The mixture was allowed to stand and separate into layers. The organic phase was concentrated to obtain 140g of difenoconazole 4-H isomer (91% purity). 140g of methylcyclohexane was added, the temperature was raised to 60℃, and after holding at this temperature for 0.5h, the temperature was slowly lowered. When the temperature dropped to 30℃, seed crystals were added, and the temperature was held for 2 hours. The solid 4-H isomer of difenoconazole slowly precipitated out. The temperature was further lowered to 25℃, and the solid was filtered to obtain a pale yellow solid. The solid was dried at 40℃ to obtain 105g of difenoconazole 4-H isomer with a purity of 98.5% and a yield of 68.9%.

[0058] Example 5

[0059] 1000g of crude difenoconazole (4-H isomer content 15%) was added to a four-necked flask, along with 5000g of methylcyclohexane. The mixture was heated to 50°C, and 300g of 10% dilute hydrochloric acid was added dropwise while stirring for 0.5h. The mixture was then allowed to stand for separation. 150g of methylcyclohexane was added to the acidic aqueous phase, and 30% liquid alkali was added dropwise to adjust the pH to 8. The mixture was allowed to stand for separation, and the organic phase was concentrated to obtain 140g of difenoconazole 4-H isomer (91% purity). 140g of methylcyclohexane was added, and the mixture was heated to 60°C. After maintaining this temperature for 0.5h, the temperature was slowly lowered to 15-20°C within 2h. The mixture was filtered to obtain a pale yellow solid, which was dried at 40°C to obtain 85g of difenoconazole 4-H isomer (98.3% purity, yield 55.7%).

[0060] Example 6

[0061] 1000g of crude difenoconazole (4-H isomer content 15%) was added to a four-necked flask, along with 5000g of methylcyclohexane. The mixture was heated to 50℃, and 100g of 30% dilute hydrochloric acid was added dropwise while stirring for 0.5h. The mixture was then allowed to stand and separate into layers. 150g of methylcyclohexane was added to the acidic aqueous phase, and 30% liquid alkali was added dropwise to adjust the pH to 8. The mixture was allowed to stand and separate into layers. The organic phase was concentrated to obtain 210g of difenoconazole 4-H isomer (56% purity). 210g of methylcyclohexane was added, the temperature was raised to 60℃, and after holding at this temperature for 0.5h, the temperature was slowly lowered. When the temperature dropped to 30℃, seed crystals were added, and the temperature was held for 2 hours. The solid 4-H isomer of difenoconazole slowly precipitated out. The temperature was further lowered to 15-20℃, and the solid was filtered to obtain a pale yellow solid. The solid was dried at 40℃ to obtain 95g of difenoconazole 4-H isomer with a purity of 85.2% and a yield of 53.9%.

[0062] Example 7

[0063] 1000g of crude difenoconazole (15% purity of the 4-H isomer) was added to a four-necked flask, along with 5000g of methylcyclohexane. The mixture was heated to 50°C, and 300g of 10% dilute hydrochloric acid was added dropwise while stirring for 0.5 hours. The mixture was then allowed to stand and separate into layers. 150g of methylcyclohexane was added to the acidic aqueous phase, and 30% liquid alkali was added dropwise to adjust the pH to 8. The mixture was allowed to stand and separate into layers. The organic phase was concentrated to obtain 140g of difenoconazole 4-H isomer (91% purity). 140g of methylcyclohexane was added, and the mixture was heated to 60°C. Seed crystals were added, and the temperature was lowered to 15-20°C within 2 hours. The mixture was filtered to obtain a pale yellow solid, which was dried at 40°C to obtain 59g of difenoconazole 4-H isomer (97.5% purity, yield 38.3%).

[0064] As can be seen from the above embodiments, the purification method provided by this invention yields a high content of difenoconazole isomers. In particular, the technical solutions of Examples 1 and 2 of this application produce a high content of difenoconazole 4-H isomers while maintaining a good yield. The difenoconazole 4-H isomers obtained by this invention can be used as raw materials for other reactions, effectively solving the solid waste problem of difenoconazole 4-H isomers, realizing waste recycling, which is not only beneficial to environmental protection but also brings economic benefits to enterprises.

[0065] The present invention has been described in detail above, with the aim of enabling those skilled in the art to understand and implement the invention. However, this description should not be construed as limiting the scope of protection of the invention. All equivalent changes or modifications made in accordance with the spirit and essence of the invention should be included within the scope of protection of the invention.

Claims

1. A method for purifying the 4-H isomer of difenoconazole, characterized in that, The acid treatment of the diafenthiuron crude product containing the 4-H isomer of diafenthiuron is followed by layer separation to obtain an aqueous phase, and before the acid treatment, the diafenthiuron crude product is dissolved in a dissolving solvent; the aqueous phase is extracted, and after the extraction, layer separation is performed to obtain an organic phase, and the organic phase is concentrated to obtain a diafenthiuron 4-H isomer crude product, and in the presence of a crystallization solvent, the diafenthiuron 4-H isomer crude product is crystallized to obtain the diafenthiuron 4-H isomer; wherein the diafenthiuron crude product contains 10-25 wt% of the diafenthiuron 4-H isomer; the diafenthiuron 4-H isomer crude product contains 55-95 wt% of the diafenthiuron 4-H isomer; wherein the mass concentration of the acid is 5-30%; the temperature of the crystallization is controlled to be -5-30 °C; the acid is selected from hydrochloric acid and / or sulfuric acid; the mass ratio of the acid to the diafenthiuron crude product is (0.1-0.5):

1.

2. The refining method according to claim 1, characterized by, The mass concentration of the acid is 10-15%.

3. The refining method according to claim 1, characterized by, The temperature of the crystallization is controlled to be 10-30 °C.

4. The refining method according to claim 1, characterized by, The diafenthiuron 4-H isomer crude product is mixed with the crystallization solvent, and after the mixing, the temperature is first raised to 40-110 °C, and then the crystallization is performed.

5. The refining method according to any one of claims 1 to 4, characterized in that, The specific steps of the crystallization are: first, the system is cooled to 25-30 °C, seed crystals are added, and then the temperature is further lowered to 10-20 °C.

6. The method of claim 1, wherein The crystallization solvent is selected from methylcyclohexane and / or cyclohexane; and / or, the mass ratio of the crystallization solvent to the diafenthiuron 4-H isomer crude product is (0.5-2):

1.

7. The method of claim 1, wherein the refining is performed by a method comprising: The mass ratio of the crystallization solvent to the diafenthiuron 4-H isomer crude product is (0.8-1.5):

1.

8. The method of claim 1, wherein, The dissolving solvent is selected from one or more of benzene, toluene, cyclohexane, methylcyclohexane, dichloromethane, chlorobenzene, and ethyl acetate, and the mass ratio of the dissolving solvent to the diafenthiuron crude product is (2-7):

1.

9. The method of claim 1, wherein The extraction is performed in the presence of a base and an extraction solvent, the base is selected from one or more of sodium hydroxide, sodium carbonate, potassium hydroxide, and sodium bicarbonate, and the extraction solvent is selected from one or more of toluene, methylcyclohexane, cyclohexane, xylene, chlorobenzene, and dichloromethane.

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