Crystallization method of isoxazoline uracil compound and application thereof

Abstract

The application discloses a crystallization method of an isoxazoline uracil compound, which comprises the following steps: preparing the isoxazoline uracil compound, washing an organic layer with water, and filtering; adding a certain amount of a solvent C to dissolve, and then adding a solvent B; fully mixing after heating, and crystallizing after cooling to obtain slurry, and then performing solid-liquid separation and drying to obtain a powdery solid. The application is characterized in that the mass ratio of the amount of the solvent B to the amount of the solvent C is 5:1-1:5 by optimizing the amount of the solvent C, the content of the solvent in the oily product is reduced, the saturation of the target product in the solution is improved, and the further crystallization and purification are facilitated. Moreover, the crystal form of the isoxazoline uracil compound can be changed, the isoxazoline uracil compound is changed from an oily substance into a bundle-shaped crystal form or a crystal block, and the isoxazoline uracil compound is changed from an oily substance into a powdery substance, the transfer of the production process of the isoxazoline uracil compound, the storage of the material and the usability of the product are improved, and the application range of the product is expanded.

Description

Technical Field

[0001] This invention relates to a method for crystallizing isoxazoline ureapyridine compounds, specifically to CO7D, and more particularly to the field of preparation of heterocyclic compounds. Background Technology

[0002] Isoxazoline uracil compounds are high-performance herbicides with excellent herbicidal activity, especially effective against glyphosate-resistant weeds such as goosegrass. However, the isoxazoline uracil compounds in the current patent are oily substances. In actual large-scale production, these oily substances are prone to solidification at low temperatures, causing pipe blockages in the production equipment and making material discharge difficult. During storage, the compound easily forms amorphous amber-like lumps, making it difficult to handle and accurately measure when preparing formulations. Furthermore, the amber-like compound cannot be packaged. Even if the amber-like solid is crushed, it will agglomerate again during storage and transportation, reverting to its amber state. These properties of the compound cause various inconveniences in its production, packaging, storage, transfer, and use.

[0003] Chinese invention patent 201811146442.1 discloses a method for preparing isoxazoline urea pyrimidine compounds by methylation. The final step of obtaining the product is achieved by removing the solvent under reduced pressure. However, the product prepared by this method is a viscous, amorphous, oily substance at slightly higher temperatures above 25°C. After being placed at low temperatures, it becomes an amber-like solid. This solid will also re-aggregate during storage after being crushed, causing great inconvenience in the production, filling, storage, transfer, and use processes. Summary of the Invention

[0004] To improve the state of isoxazoline ureapyridine compounds and overcome their defects in production, filling, storage, transfer, and use, the first aspect of this application provides a method for crystallizing isoxazoline ureapyridine compounds, comprising the following steps: (1) Preparation of isoxazoline ureapyridine compounds: the organic layer is washed with water and filtered; (2) After evaporating all organic solvent A, add a certain amount of solvent C to dissolve it, and then add solvent B; (3) After heating to a certain temperature, mix thoroughly, cool down to crystallize, obtain slurry, separate solid and liquid, and dry to obtain powdered solid.

[0005] In a preferred embodiment, the mass ratio of solvent B to solvent C is 1:10-10:1.

[0006] As a preferred embodiment, the structural formula of the isoxazoline uracil compound is as follows: In the formula, R1 is fluorine, R2 is chlorine, R3 and R4 are hydrogen, R5 is CO2C2H5, and R6 is methyl.

[0007] As a preferred embodiment, the preparation method of the isoxazoline ureapyridine compound is based on invention patent 201811146442.1.

[0008] In a preferred embodiment, the polarity of solvent B is lower than that of solvent C. Preferably, solvent B is selected from one or a combination of several of ethers, aliphatic hydrocarbons, carbon tetrachloride, carbon disulfide, and alkanes.

[0009] In a preferred embodiment, the solvent B is selected from one or a combination of several of petroleum ether, diethyl ether, propylene oxide, n-pentane, cyclopentane, hexane, octane, cyclohexane, n-heptane, isooctane, carbon tetrachloride, and carbon disulfide.

[0010] In a preferred embodiment, solvent B is one of petroleum ether, n-heptane, n-pentane, or cyclopentane.

[0011] During the experiment, the applicant discovered that directly distilling and drying isoxazoline ureapyridine compounds containing organic solvents resulted in incomplete solvent evaporation, making it impossible to dry the oily substance and leading to low product purity. The applicant used one of petroleum ether, n-heptane, n-pentane, or cyclopentane as solvent B, which, when added to organic solvent C, could transform the oily substance into a crystalline substance. After solid-liquid separation, it was transformed into a powdery solid, greatly improving the practicality of the product. The possible reason is that isoxazoline urea pyrimidine compounds exhibit an oily state in organic solvent C due to their special crystal structure. When one of the less polar petroleum ether, n-heptane, n-pentane, or cyclopentane is introduced, the mixture of petroleum ether, n-heptane, n-pentane, or cyclopentane with the organic solvent at a specific temperature allows the isoxazoline urea pyrimidine compound to enter the mixture. The crystals of the isoxazoline urea pyrimidine compound then arrange themselves in an orderly manner, and the solvent slowly diffuses between the crystals, causing the crystal structure of the isoxazoline urea pyrimidine compound to change, resulting in aggregated bundles or blocky crystals. After recrystallization, solid-liquid separation is achieved, resulting in a powdery solid. The applicant further discovered that when solvent C is one of petroleum ether, n-heptane, n-pentane, or cyclopentane, the amount of product obtained is greater and the quantitative content is higher. The reason may be that the polarity of organic solvent C is much different from that of petroleum ether, n-heptane, n-pentane, or cyclopentane, resulting in a higher proportion of crystal transformation, thus yielding a solid powder with a higher yield.

[0012] During the experiment, the applicant discovered that compounds containing isoxazoline ureapyrimidines are oily substances. In actual production, these oily, viscous substances easily solidify at low temperatures, clogging material pipelines, making discharge difficult, and affecting scale-up production. The applicant found that washing and filtering the organic layer containing the oily product with water, followed by atmospheric distillation to remove part of the organic solvent, resulting in a target product to organic solvent mass ratio of 5:1 to 1:5 in the remaining solution, can increase the saturation of the target product in the solution, allowing it to concentrate in a smaller volume. When solvent B is introduced into the solution, the target product can carry organic solvent C to solvent B, forming a system where solvent B is the continuous phase and organic solvent C is the dispersed phase, which is beneficial for the miscibility and transfer in subsequent steps. Furthermore, the applicant discovered that when the mass ratio of the target product to the organic solvent is 5:1 to 1:5, atmospheric distillation is relatively easy, and the removal of organic solvent C can be achieved through a simple process. However, when the mass ratio exceeds the preferred ratio, the difficulty of removing organic solvent C increases sharply. The possible reason is that the oily product has good solubility in the original solvent toluene. As organic solvent C is removed, the proportion of oily product in the solution gradually increases, and the oily product excessively affects the boiling point of the solution, making distillation difficult.

[0013] In a preferred embodiment, the mass ratio of solvent B to solvent C is 1:10-10:1.

[0014] In a preferred embodiment, the mass ratio of solvent B to solvent C is 1:5 to 5:1.

[0015] In a preferred embodiment, the mass ratio of solvent B to solvent C is 4.3:1.

[0016] During the experiment, the applicant discovered that isoxazoline uracil compounds can undergo a crystal transformation in a mixed solvent with a mass ratio of 1:10 to 10:1, changing from an oily crystal form to a rod-shaped aggregate of crystals. This facilitates solid-liquid separation, yielding a powdered solid. The applicant hypothesizes that this transformation is likely due to the fact that in a mixed solvent of organic solvent C and solvent B with a mass ratio of 1:10 to 10:1, isoxazoline uracil compounds readily undergo ordered arrangement, forming rod-shaped crystals. This increases the regularity of the arrangement among the isoxazoline uracil compounds and reduces the number of randomly arranged crystals, thus transforming the oily substance into a rod-shaped crystal aggregate. Within the preferred weight ratio range, the number of ordered crystals is highest, resulting in a higher yield of solid powder after solid-liquid separation. Furthermore, the high crystal transformation rate significantly increases the content of the target compound, improving its quantitative content.

[0017] In a preferred embodiment, the heating temperature in step 3 does not exceed the boiling point of the mixture of organic solvent C and solvent B. Preferably, the heating temperature is 30-95℃.

[0018] In a preferred embodiment, the heating temperature in step 3 does not exceed the boiling point of the mixture of organic solvent C and solvent B. Preferably, the heating temperature is 35-60°C.

[0019] In a preferred embodiment, the heating temperature in step 3 does not exceed the boiling point of the mixture of organic solvent C and solvent B; preferably, the heating temperature is 40°C.

[0020] During the experiment, the applicant discovered that isoxazoline uracil compounds have low solubility in solvent B. The applicant found that increasing the temperature can increase the solubility of isoxazoline uracil compounds in solvent B. When the temperature reaches 40-70℃, the solution can reach a homogeneous state, achieving complete miscibility. Isoxazoline uracil compounds containing organic solvents can be completely dissolved and dispersed in solvent B, achieving a crystal form transformation. The applicant speculates that the possible reason is that oily isoxazoline uracil compounds have poor dispersibility in the low-polarity solvent B. By increasing the temperature, the intermolecular mobility increases, the intermolecular distance widens, and a crystal form transformation occurs. Solvent B penetrates into the intercrystalline spaces of the isoxazoline uracil compounds, increasing the solubility of the isoxazoline uracil compounds in a mixture of petroleum ether, n-heptane, n-pentane, or cyclopentane with solvent C, thus increasing the rate of crystal form change. The applicant further discovered that when the temperature rises above the preferred temperature, boiling easily occurs between the solvents, increasing the volatilization of one of petroleum ether, n-heptane, n-pentane, or cyclopentane. As the volatilization of one of petroleum ether, n-heptane, n-pentane, or cyclopentane increases, the amount of isoxazoline ureapyridine compounds undergoing crystal form transformation decreases, leading to a decrease in the quantitative content of the final product and reducing the final yield of the target product.

[0021] In a preferred embodiment, the cooling crystallization method in step 3 is as follows: cooling to 0-10℃ within 2-5 hours, and then maintaining the temperature for crystallization for 1-6 hours.

[0022] In a preferred embodiment, the cooling crystallization method in step 3 is as follows: cooling to 5°C within 2-4 hours and maintaining the temperature for crystallization for 4-5 hours.

[0023] In a preferred embodiment, the cooling crystallization method in step 3 is as follows: cooling down to 5°C within 3 hours and maintaining the temperature for crystallization for 5 hours.

[0024] In a preferred embodiment, the solvent C is selected from one or a combination of several of the following organic solvents: aromatic hydrocarbons, alicyclic hydrocarbons, esters, ketones, and halogenated hydrocarbons.

[0025] In a preferred embodiment, the solvent C is selected from one or a combination of several of the following: benzene, toluene, xylene, chlorobenzene, dichlorobenzene, ethyl acetate, ethyl oleate, propyl acetate, isopropyl acetate, methyl acetate, acetone, methyl butyl ketone, methyl isobutyl ketone, methyl ethyl ketone, dichloromethane, 1,2-dichloroethane, chloroform, bromoethane, chloropropane, and methyl oleate.

[0026] In a preferred embodiment, the solvent C is ethyl acetate.

[0027] A second aspect of the present invention provides an application of a crystallization method for isoxazoline ureapyridine compounds, which is used in the crystallization preparation of isoxazoline ureapyridine compounds.

[0028] Compared with the prior art, the present invention has the following beneficial effects: (1) The crystallization method of isoxazoline ureapyridine compounds of the present invention makes the mass ratio of the amount of solvent B added to the amount of solvent C added 5:1-1:5, which can reduce the content of solvent in the oily product, increase the saturation of the target product in the solution, and facilitate further crystallization and purification.

[0029] (2) The crystallization method of the isoxazoline urea pyrimidine compound of the present invention uses one of petroleum ether, n-heptane, n-pentane or cyclopentane, which has a lower polarity than organic solvent C, as solvent B. This method can transform the crystal form of the isoxazoline urea pyrimidine compound from an oily substance to a bundled crystal form or a block of crystals. After solid-liquid separation, the compound can be transformed into a powdery solid.

[0030] (3) The crystallization method of the isoxazoline urea pyrimidine compound of the present invention uses a heating temperature not exceeding the boiling point of the mixed solvent, which can increase the solubility of the isoxazoline urea pyrimidine compound in one of petroleum ether, n-heptane, n-pentane or cyclopentane, improve the crystal form transformation rate, reduce solvent volatilization, and avoid the impact of solvent reduction on recrystallization.

[0031] (4) In the crystallization method of isoxazoline ureapyridine compounds of the present invention, the amount of solvent B added is in a mass ratio of 1:10 to 10:1 with the amount of solvent C added, which can increase the yield of the final product solid powder and increase the quantitative content of the target substance in the solid powder.

[0032] (5) The crystallization method of isoxazoline uridine compounds described in this invention improves the storage and usability of isoxazoline uridine compounds by converting them from oily substances into powdery solids, thereby expanding the application range of the products. Detailed Implementation

[0033] The present invention will now be described in detail through embodiments. It should be noted that the following embodiments are only for further illustration of the present invention and should not be construed as limiting the scope of protection of the present invention. Non-essential improvements and adjustments made by those skilled in the art based on the above description of the present invention still fall within the scope of protection of the present invention.

[0034] In addition, unless otherwise stated, all raw materials used, except for isoxazoline ureapyridine compounds, are commercially available.

[0035] Example 1 A method for crystallizing isoxazoline ureapyridine compounds, comprising the following steps: (1) Preparation of isoxazoline ureapyridine compounds: the organic layer is washed with water and filtered; (2) After dissolving in a certain amount of solvent C, solvent B is added; (3) After heating to a certain temperature, mix thoroughly, cool down to crystallize, obtain slurry, separate solid and liquid, and dry to obtain powdered solid.

[0036] The preparation method of the isoxazoline uracil compound is based on invention patent 201811146442.1, which involves reacting 464g of ethyl 3-(2-chloro-5-(2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)-4-fluorophenyl)-5-methyl-4,5-dihydroisooxazo-5-carboxylic acid with 46.6g of chloromethane, removing all organic solvent A (toluene) by evaporation, and obtaining 484g of an oily substance with a quantitative content of 92.8%, which is then divided into four equal portions.

[0037] S1 Take one portion of the oily substance, dissolve it with 133.1g of solvent C ethyl acetate to form a homogeneous solution, add 266.2g of solvent B petroleum ether dropwise, heat to 50℃ and keep warm for 30 minutes to form a homogeneous solution, cool down to 0℃ within 3 hours, keep warm to crystallize for 5 hours, separate the solid and liquid, and dry the solid to obtain the product; S2 Take the second part of the oily substance, dissolve it with 133.1g of solvent C ethyl acetate to form a homogeneous solution, add 266.2g of solvent B cyclopentane dropwise, heat to 50℃ and keep warm for 30 minutes to form a homogeneous solution, cool down to 0℃ within 3 hours, keep warm to crystallize for 5 hours, separate the solid and liquid, and dry the solid to obtain the product; S3 Take the third part of the oily substance, dissolve it with 133.1g of solvent C ethyl acetate to form a homogeneous solution, add 266.2g of solvent B n-pentane dropwise, heat to 50℃ and keep warm for 30 minutes to form a homogeneous solution, cool down to 0℃ within 3 hours, keep warm to crystallize for 5 hours, separate the solid and liquid, and dry the solid to obtain the product; S4 Take the fourth part of the oily substance, dissolve it with 133.1g of solvent C ethyl acetate to form a homogeneous solution, add 266.2g of solvent B n-heptane dropwise, heat to 50℃ and keep warm for 30 minutes to form a homogeneous solution, cool down to 0℃ within 3 hours, keep warm to crystallize for 5 hours, separate the solid and liquid, and dry the solid to obtain the product.

[0038] Performance testing The solid obtained in Example 1 was weighed, and then the quantitative content of the target analyte was determined by HPLC. Example 1 corresponds to Table 1.

[0039] Table 1

Claims

1. A method for crystallizing isoxazoline uracil compounds, characterized in that, Includes the following steps: (1) Preparation of isoxazoline ureapyridine compounds: the organic layer is washed with water and filtered; (2) After evaporating all organic solvent A, add a certain amount of solvent C to dissolve it, and then add solvent B; (3) After heating to a certain temperature, mix thoroughly, cool down to crystallize, obtain a slurry, separate the solid and liquid, and dry to obtain a powdered solid; The mass ratio of solvent B to solvent C is 1:10-10:

1.

2. The crystallization method of the isoxazoline uracil compound according to claim 1, characterized in that, The structural formula of the isoxazoline uracil compound is as follows: In the formula, R1 is fluorine, R2 is chlorine, R3 and R4 are hydrogen, R5 is CO2C2H5, and R6 is methyl.

3. The crystallization method of the isoxazoline uracil compound according to claim 1, characterized in that, The polarity of solvent B is lower than that of solvent C. Preferably, solvent B is selected from one or a combination of several of ethers, aliphatic hydrocarbons, carbon tetrachloride, and carbon disulfide.

4. The crystallization method of the isoxazoline uracil compound according to claim 1, characterized in that, In step 3, the heating temperature should not exceed the boiling point of solvent B mixture, preferably 30-95℃.

5. The crystallization method of the isoxazoline uracil compound according to claim 1, characterized in that, In step 3, the cooling crystallization method is as follows: cool down to 0-10℃ within 2-5 hours, and maintain the temperature for crystallization for 1-6 hours.

6. The crystallization method of the isoxazoline uracil compound according to claim 1, characterized in that, The solvent C is selected from one or a combination of several of the following organic solvents: aromatic hydrocarbons, alicyclic hydrocarbons, esters, ketones, and halogenated hydrocarbons.

7. The application of a method for crystallizing isoxazoline uracil compounds according to any one of claims 1-6, characterized in that, It is used in the crystallization preparation of compounds containing isoxazoline ureapyridine.

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