Isoxazoline uracil compound crystallization method and application thereof

Abstract

Disclosed in the present invention is an isoxazoline uracil compound crystallization method, comprising the following steps: preparing an isoxazoline uracil compound, washing an organic layer with water, and performing filtering; evaporating part of an organic solvent A and adding a solvent B; after heating, performing thorough mixing, cooling, and crystallization to obtain a slurry, performing solid-liquid separation, and performing drying to obtain a powdery solid. The present invention optimizes the amount of organic solvent A removed so that the mass ratio of the isoxazoline uracil compound to the organic solvent A in the remaining solution is 5:1-1:5, reducing the content of the solvent in an oily product, increasing the saturation of a target product in the solution, and facilitating further crystallization and purification. Further, the crystal form of the isoxazoline-containing uracil compound can be transformed, so that the isoxazoline-containing uracil compound transforms from an oily substance into a bundle-shaped crystal form or a crystal block, and changes from an oily state to a powdery state, improving transport and material storage during production of the isoxazoline-containing uracil compound and the product usability thereof, and expanding the application range of the product.

Description

A crystallization method of isoxazoline uracil compounds and its application Technical Field

[0001] The present invention relates to a crystallization method of an isoxazoline uracil compound, relates to C07D, and particularly relates to the field of preparation of heterocyclic compounds. Background Art

[0002] Isoxazoline-uracil compounds are excellent herbicides with highly effective herbicidal activity, particularly against glyphosate-resistant weeds such as goosegrass. However, the isoxazoline-uracil compounds described in current patents are in the form of oils. During actual scale-up production, the oils tend to condense at low temperatures, causing blockages in the production pipelines and making it difficult to discharge the material. During storage, the compounds tend to form amorphous amber-like solid blocks, making them difficult to access and measure accurately when preparing formulations. Furthermore, the amber-like compounds cannot be bottled. Even if the amber-like solids are crushed, they will aggregate during storage and transportation, returning to their amber-like state. These properties of the compounds cause various inconveniences during production, filling, storage, transfer, and use.

[0003] Chinese invention patent 201811146442.1 discloses a method for preparing isoxazoline-containing uracil 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 oil at a slightly high temperature above 25°C. After being placed at a low temperature, it becomes an amber-like solid. After the solid is crushed, it will aggregate again during storage, causing great inconvenience in production, filling, storage, transfer, and use. Summary of the Invention

[0004] In order to improve the existence state of isoxazoline uracil compounds and solve the defects in their production, filling, storage, transfer and use, the first aspect of the present application provides a crystallization method of isoxazoline uracil compounds, which comprises the following steps:

[0005] (1) preparing an isoxazoline uracil compound, washing the organic layer with water and filtering;

[0006] (2) distilling off the organic solvent A and adding solvent B;

[0007] (3) After heating to a certain temperature, fully mixing, cooling and crystallizing to obtain slurry, solid-liquid separation, and drying to obtain a powdered solid.

[0008] As a preferred embodiment, step 2 further comprises adding a certain amount of solvent C to dissolve it and then adding solvent B; or after distilling off the organic solvent A, adding a mixed solution of solvent B and solvent C.

[0009] As a preferred embodiment, the structural formula of the isoxazoline uracil compound is In the formula, R1 is fluorine, R2 is chlorine, R3 and R4 are hydrogen, R5 is CO2C2H5, and R6 is methyl.

[0010] As a preferred embodiment, the preparation method of the isoxazoline uracil compound is based on invention patent 201811146442.1, and the organic solvent A is the organic solvent in patent 201811146442.1, and the preferred organic solvent A is toluene.

[0011] As a preferred embodiment, the polarity of the solvent B is lower than that of the organic solvent A and the solvent C. Preferably, the solvent B is selected from one or a combination of ethers, aliphatic hydrocarbons, carbon tetrachloride, carbon disulfide, and alkanes.

[0012] As a preferred embodiment, the solvent B is selected from one or a combination of petroleum ether, ethyl ether, propylene oxide, n-pentane, cyclopentane, hexane, octane, cyclohexane, n-heptane, isooctane, carbon tetrachloride, and carbon disulfide.

[0013] As a preferred embodiment, the solvent B is one of petroleum ether, n-heptane, n-pentane or cyclopentane.

[0014] During the experiment, the applicant found that when the isoxazoline-containing uracil compound containing an organic solvent was directly distilled and dried, the solvent was not completely evaporated, the oily substance could not be dried, and the product purity was low. The applicant used one of petroleum ether, n-heptane, n-pentane or cyclopentane as solvent B. After adding it to the organic solvent A, the oily substance was converted into a crystalline substance, and after solid-liquid separation, it was converted into a powdered solid, greatly improving the practicality of the product. The possible reason is speculated to be: the isoxazoline-uracil compound is in an oily state in the organic solvent A due to its special crystal structure. When one of petroleum ether, n-heptane, n-pentane or cyclopentane with low polarity is introduced, the one of petroleum ether, n-heptane, n-pentane or cyclopentane is mixed with the organic solvent at a specific temperature, so that the isoxazoline-uracil compound enters the one of petroleum ether, n-heptane, n-pentane or cyclopentane, and the crystals of the isoxazoline-uracil compound are arranged in an orderly manner. The solvent slowly diffuses between the crystals, causing the crystal form of the isoxazoline-uracil compound to change, presenting aggregated bundled crystals or block crystals. After recrystallization, solid-liquid separation is achieved, and the compound becomes a powdery solid. The applicant further discovered that when solvent B is one of petroleum ether, n-heptane, n-pentane or cyclopentane, the amount of product obtained is large and the quantitative content is high. The reason may be that the polarity of organic solvent A is significantly different from that of petroleum ether, n-heptane, n-pentane or cyclopentane, and the proportion of crystal transformation is high, so a solid powder with a higher yield content can be obtained.

[0015] As a preferred embodiment, after the organic solvent A is distilled, the mass ratio of the isoxazoline uracil compound to the organic solvent A in the remaining solution is (1-5):(0-5).

[0016] As a preferred embodiment, after the organic solvent A is distilled, the mass ratio of the isoxazoline uracil compound to the organic solvent A in the remaining solution is (1-4): (0-4).

[0017] As a preferred embodiment, after the organic solvent A is distilled, the mass ratio of the isoxazoline uracil compound to the organic solvent A in the remaining solution is 1:1.

[0018] As a preferred embodiment, after the organic solvent A is distilled, the mass ratio of the isoxazoline uracil compound to the organic solvent A in the remaining solution is 1:0.

[0019] During the experiment, the applicant discovered that the isoxazoline-containing uracil compound is an oily substance. In actual production and use, the oily viscous substance easily solidifies at low temperatures, clogging the material pipeline, making it difficult to discharge the material, and affecting the production of scale-up experiments. The applicant found that after washing and filtering the organic layer containing the oily product, a portion of the organic solvent was distilled off at atmospheric pressure to achieve a mass ratio of the target product to the organic solvent in the remaining solution of 5:1 to 1:5. This can increase the saturation of the target product in the solution and allow the target product to be concentrated in a smaller volume. When solvent B is introduced into the solution, the target product can be transferred into solvent B with organic solvent A, forming a system in which solvent B is the continuous phase and organic solvent A is the dispersed phase, which is conducive to the mutual solubility transfer in subsequent steps. The applicant also found that when the mass ratio of the target product to the organic solvent is 5:1 to 1:5, atmospheric distillation is less difficult and the organic solvent A can be removed through a simple process. When the mass ratio exceeds the preferred ratio, the difficulty of removing the organic solvent A increases sharply. It is speculated that the possible reason is that the oily product has good solubility in the organic solvent A. As the organic solvent A is removed, the proportion of the oily substance in the solution gradually increases, and the oily substance excessively affects the boiling point of the solution, causing distillation difficulties.

[0020] As a preferred embodiment, the mass ratio of the added amount of the solvent B to the organic solvent A in the remaining solution or the newly added solvent C is 1:10-10:1.

[0021] As a preferred embodiment, the mass ratio of the added amount of the solvent B to the organic solvent A in the remaining solution or the newly added solvent C is 1:5-5:1.

[0022] As a preferred embodiment, the mass ratio of the added amount of the solvent B to the organic solvent A in the remaining solution or the newly added solvent C is 4.3:1.

[0023] During experiments, the applicant discovered that isoxazoline-containing uracil compounds can undergo a crystal transformation in a mixed solvent with a mass ratio of 1:10 to 10:1, transforming from an oily form to a rod-shaped crystal aggregate. This facilitates solid-liquid separation and produces a powdered solid. The applicant speculates that this may be due to the fact that in a mixed solvent of organic solvent A and solvent B with a mass ratio of 1:10 to 10:1, the isoxazoline-containing uracil compounds tend to form ordered crystals, forming rod-shaped crystals. This increases the regularity of the arrangement of the isoxazoline-containing uracil compounds and reduces the number of randomly arranged crystals, thereby transforming the oily form into a rod-shaped crystal aggregate. Within the preferred weight ratio range, the number of ordered crystals is the highest, resulting in a higher yield of the solid powder obtained after solid-liquid separation. Furthermore, the high crystal transformation rate significantly increases the content of the target substance, thereby increasing the quantitative content of the target substance.

[0024] As a preferred embodiment, the heating temperature in step 3 does not exceed the boiling point of the mixed solution of organic solvent A and solvent B. Preferably, the heating temperature is 30-95°C.

[0025] As a preferred embodiment, the heating temperature in step 3 does not exceed the boiling point of the mixed solution of organic solvent A and solvent B. Preferably, the heating temperature is 35-60°C.

[0026] As a preferred embodiment, the heating temperature in step 3 does not exceed the boiling point of the mixed solution of organic solvent A and solvent B. Preferably, the heating temperature is 40°C.

[0027] During the experiment, the applicant discovered that the solubility of the isoxazoline-containing uracil compound in solvent B was low. The applicant discovered that the solubility of the isoxazoline-containing uracil compound in solvent B could be increased by increasing the temperature. When the temperature reached 40-70°C, the solution reached a homogeneous state, achieving complete miscibility. The isoxazoline-containing uracil compound containing an organic solvent could be completely dissolved and dispersed in solvent B, achieving a crystal form transition. It is speculated that the possible reason is that the oily isoxazoline-containing uracil compound has poor dispersibility in the low-polarity solvent B. By increasing the temperature, the intermolecular mobility increases, the molecular distance increases, and the crystal form transition occurs. Solvent B penetrates into the interstitial spaces of the isoxazoline-containing uracil compound, increasing the solubility of the isoxazoline-containing uracil compound in a mixture of solvent A and one of petroleum ether, n-heptane, n-pentane, or cyclopentane, and increasing the rate of crystal form change. The applicant further discovered that when the temperature is increased above the preferred temperature, boiling occurs easily between the solvents, increasing the volatility of one of petroleum ether, n-heptane, n-pentane or cyclopentane. As the volatility of one of petroleum ether, n-heptane, n-pentane or cyclopentane increases, the amount of crystal transformation of the isoxazoline-containing uracil compound decreases, resulting in a decrease in the quantitative content of the final product and a decrease in the final yield of the target product.

[0028] As a preferred embodiment, in step 3, the method of cooling and crystallizing is: cooling to 0-10°C within 2-5 hours, and keeping the temperature for crystallization for 1-6 hours.

[0029] As a preferred embodiment, in step 3, the method of cooling and crystallizing is: cooling to 5°C within 2-4 hours, and keeping the temperature for crystallization for 4-5 hours.

[0030] As a preferred embodiment, in step 3, the method of cooling and crystallizing is: cooling to 5°C within 3 hours, and keeping the temperature for crystallization for 5 hours.

[0031] As a preferred embodiment, the solvent C is selected from one or a combination of aromatic hydrocarbons, alicyclic hydrocarbons, esters, ketones, and halogenated hydrocarbon organic solvents.

[0032] As a preferred embodiment, the solvent C is selected from one or a combination of 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, ethyl bromide, chloropropane, and methyl oleate.

[0033] As a preferred embodiment, the solvent C is ethyl acetate.

[0034] The second aspect of the present invention provides an application of a crystallization method of an isoxazoline-uracil compound, which is applied to the crystallization preparation of an isoxazoline-uracil compound.

[0035] Compared with the prior art, the present invention has the following beneficial effects:

[0036] (1) The crystallization method of the isoxazoline-uracil compound of the present invention can reduce the content of the solvent in the oily product and increase the saturation of the target product in the solution by optimizing the removal amount of the organic solvent A so that the mass ratio of the isoxazoline-uracil compound to the organic solvent A in the remaining solution is 5:1-1:5, which is conducive to further crystallization and purification.

[0037] (2) The crystallization method of the isoxazoline-uracil compound of the present invention uses one of petroleum ether, n-heptane, n-pentane or cyclopentane with a polarity lower than that of the organic solvent A as solvent B, which can transform the crystal form of the isoxazoline-uracil compound from an oily substance into a bundle-like crystal form or a crystal block, and can be transformed into a powdery solid after solid-liquid separation.

[0038] (3) The crystallization method of the isoxazoline-uracil compound of the present invention adopts a heating temperature that does not exceed the boiling point of the mixed solvent, which can increase the solubility of the isoxazoline-uracil compound in one of petroleum ether, n-heptane, n-pentane or cyclopentane, improve the crystal form conversion rate, reduce the volatilization of the solvent, and avoid the influence of the solvent reduction on recrystallization.

[0039] (4) In the crystallization method of the isoxazoline uracil compound of the present invention, the mass ratio of the added amount of solvent B to the organic solvent A in the remaining solution is 1:10-10:1, which can increase the yield of the final product solid powder and increase the quantitative content of the target compound in the solid powder.

[0040] (5) The crystallization method of the isoxazoline-uracil compound of the present invention improves the storage and usability of the isoxazoline-uracil compound by converting the isoxazoline-uracil compound from an oily substance into a powdery solid, thereby expanding the application range of the product. DETAILED DESCRIPTION

[0041] The present invention is described in detail below by way of examples. It is necessary to point out that the following examples are only used to further illustrate the present invention and are not to be construed as limiting the scope of protection of the present invention. Any non-essential improvements and adjustments made by professionals in this field based on the above-mentioned contents of the present invention still fall within the scope of protection of the present invention.

[0042] In addition, unless otherwise stated, except for the isoxazoline uracil compounds, all other raw materials used were commercially available.

[0043] Example 1

[0044] A method for crystallizing an isoxazoline uracil compound comprises the following steps:

[0045] (1) preparing an isoxazoline uracil compound, washing the organic layer with water and filtering;

[0046] (2) distilling off part of the organic solvent A and adding solvent B;

[0047] (3) After heating to a certain temperature, fully mixing, cooling and crystallizing to obtain slurry, solid-liquid separation, and drying to obtain a powdered solid.

[0048] The preparation method of the isoxazoline uracil compound is based on invention patent 201811146442.1, which is to react 464g of ethyl 3-(2-chloro-5-(2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)-4-fluorophenyl)-5-methyl-4,5-dihydroisoxazole-5-carboxylate with 46.6g of monochloromethane in 2000g of toluene, and then wash with water to obtain a toluene layer, which is then divided into four equal parts.

[0049] S1: Take one portion of the product and distill it under normal pressure to remove 384g of organic solvent A, toluene. Then, add 498g of solvent B, petroleum ether, dropwise to the toluene solution of the product while stirring. After the addition, heat it to 60°C and keep it for 30 minutes. Then, cool it to 0°C within 3 hours, keep it warm for 5 hours for crystallization, separate the solid and liquid, and dry the solid to obtain the product.

[0050] S2 takes the second portion and removes 384g of organic solvent A, toluene, by distillation at normal pressure. 498g of solvent B, cyclopentane, is added dropwise to the toluene solution of the product under stirring. After the addition, the temperature is raised to 60°C and kept warm for 30 minutes. The temperature is then lowered to 0°C within 3 hours, and the temperature is kept warm for 5 hours for crystallization. The solid-liquid separation is performed, and the solid is dried to obtain the product.

[0051] S3: Take the third portion and remove 384 g of organic solvent A, toluene, by distillation at normal pressure. Then, add 498 g of solvent B, n-pentane, dropwise to the toluene solution of the product under stirring. After the addition, heat to 60°C and keep warm for 30 minutes. Then, cool to 0°C within 3 hours, keep warm and crystallize for 5 hours, separate the solid and liquid, and dry the solid to obtain the product.

[0052] S4: Take the fourth portion and remove 384 g of organic solvent A, toluene, by distillation at normal pressure. Add 498 g of solvent B, n-heptane, dropwise to the toluene solution of the product under stirring. After the addition, heat to 60°C and keep warm for 30 minutes. Cool to 0°C within 3 hours, keep warm for 5 hours for crystallization, separate the solid and liquid, and dry the solid to obtain the product.

[0053] Example 2

[0054] A method for crystallizing an isoxazoline uracil compound, wherein the specific steps are the same as those in Example 1, except that the organic solvent A is ethyl acetate. Example 3

[0055] A method for crystallizing an isoxazoline uracil compound comprises the following steps:

[0056] (1) preparing an isoxazoline uracil compound, washing the organic layer with water and filtering;

[0057] (2) Add a certain amount of solvent C to dissolve, then add solvent B;

[0058] (3) After heating to a certain temperature, fully mixing, cooling and crystallizing to obtain slurry, solid-liquid separation, and drying to obtain a powdered solid.

[0059] The preparation method of the isoxazoline uracil compound is based on invention patent 201811146442.1, which is to react 464g of ethyl 3-(2-chloro-5-(2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)-4-fluorophenyl)-5-methyl-4,5-dihydroisoxazole-5-carboxylate with 46.6g of monochloromethane, and evaporate all the organic solvent A toluene to prepare 484g of an oily substance with a quantitative content of 92.8%, which is divided into four equal parts.

[0060] Take one portion of the oil in S1 and dissolve it with 133.1g of solvent C, ethyl acetate, to form a homogeneous solution. Then add 266.2g of solvent B, petroleum ether, and heat to 50°C and keep warm for 30 minutes to form a homogeneous solution. Then cool to 0°C within 3 hours, keep warm for 5 hours to crystallize, separate the solid and liquid, and dry the solid to obtain the product.

[0061] S2: Take the second portion of the oil, dissolve it with 133.1g of solvent C, ethyl acetate, to form a homogeneous solution, add 266.2g of solvent B, cyclopentane, and heat to 50°C for 30 minutes to form a homogeneous solution. Cool to 0°C within 3 hours, heat and crystallize for 5 hours, separate the solid and liquid, and dry the solid to obtain the product;

[0062] S3: The third portion of the oil was dissolved in 133.1 g of solvent C, ethyl acetate, to form a homogeneous solution. 266.2 g of solvent B, n-pentane, was added dropwise, and the temperature was raised to 50°C and kept for 30 minutes to form a homogeneous solution. The temperature was then lowered to 0°C within 3 hours, kept for 5 hours to crystallize, and the solid-liquid separation was performed. The solid was dried to obtain the product.

[0063] S4: Take the fourth portion of the oily substance, dissolve it with 133.1 g of solvent C, ethyl acetate, to form a homogeneous solution, add 266.2 g of solvent B, n-heptane, and heat to 50°C and keep warm for 30 minutes to form a homogeneous solution. Cool to 0°C within 3 hours, keep warm for 5 hours to crystallize, separate the solid and liquid, and dry the solid to obtain the product.

[0064] Performance Testing

[0065] The solids prepared in Examples 1-3 were weighed, and then the quantitative content of the target substance was determined by HPLC. Examples 1-3 correspond to Tables 1-3, respectively.

[0066] Table 1

[0067] Table 2

[0068] Table 3

Claims

1. A crystallization method for isoxazoline uracil compounds, characterized in that, It includes the following steps: (1) Prepare isoxazoline uracil compounds. Wash the organic layer with water and filter. (2) Distill off organic solvent A and add solvent B. (3) After heating to a certain temperature, mix well, cool and crystallize to obtain a slurry. Separate the solid from the liquid and dry to obtain a powdery solid.

2. The crystallization method of the isoxazoline uracil compound according to claim 1, characterized in that, In step 2, it also includes adding a certain amount of solvent C to dissolve and then adding solvent B; or after distilling off organic solvent A, adding a mixed solution of solvent B and solvent C.

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

4. The crystallization method of the isoxazolinyluracil compound according to claim 2, characterized in that, The polarity of solvent B is lower than that of organic solvent A and solvent C. Preferably, solvent B is selected from one or a combination of ethers, aliphatic hydrocarbons, carbon tetrachloride, carbon disulfide, etc.

5. The crystallization method of the isoxazoline uracil compound according to claim 2, characterized in that, After distilling organic solvent A, the mass ratio of isoxazoline uracil compounds to organic solvent A in the remaining solution is (1 - 5):(0 - 5).

6. The crystallization method of the isoxazolinyluracil compound according to claim 2, characterized in that, The addition amount of solvent B to the mass of organic solvent A in the remaining solution or newly added solvent C is 1:10 - 10:

1.

7. The crystallization method of the isoxazoline uracil compound according to claim 2, characterized in that, In step 3, the heating temperature does not exceed the boiling point of the mixture of organic solvent A and solvent B. Preferably, the heating temperature is 30 - 95 °C.

8. The crystallization method of the isoxazolinyluracil compound according to claim 1, characterized in that, In step 3, the method of cooling and crystallizing is: cool to 0 - 10 °C within 2 - 5 h and keep the temperature for crystallization for 1 - 6 h.

9. The crystallization method of the isoxazolinyluracil compound according to claim 2, characterized in that, Solvent C is selected from one or a combination of aromatic hydrocarbons, alicyclic hydrocarbons, esters, ketones, halogenated hydrocarbon organic solvents, etc.

10. Use of a crystallization method for an isoxazolinyluracil compound according to any one of claims 2-9, characterized in that, It is applied to the crystallization preparation of isoxazoline uracil compounds.

Images