Method for crystallizing isoxazoline uracil compounds and their use
Patent Information
- Authority / Receiving Office
- JP · JP
- Patent Type
- Applications
- Current Assignee / Owner
- NANTONG JIANGSHAN AGROCHEMICAL & CHEMICALS CO LTD
- Filing Date
- 2024-12-04
- Publication Date
- 2026-06-05
Smart Images
Figure 2026518372000001 
Figure 2026518372000002 
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Abstract
Description
Technical Field
[0001] The present invention relates to a crystallization method of an isoxazoline uracil-based compound, relates to C07D, and specifically relates to the field of production of heterocyclic compounds.
Background Art
[0002] Isoxazoline uracil-based compounds are herbicides with excellent properties, particularly having high herbicidal activity and showing excellent control effects against glyphosate-resistant weeds such as barnyard grass. However, the isoxazoline uracil-based compounds in conventional patents are oily substances. In actual scale-up, oily substances are likely to condense at low temperatures, resulting in clogging of pipes in the production equipment and difficulty in discharging materials. The compound is likely to form an amorphous amber-like massive solid during storage, which is difficult to handle during formulation, difficult to weigh, and difficult to accurately weigh. Also, the amber-like compound cannot be filled into cans. The amber-like solid, even if pulverized, aggregates into one body during storage and transportation and returns to the original amber-like state. These properties of the compound cause various inconveniences in the processes of production, filling, storage, transportation, and use.
[0003] Chinese Invention Patent 201811146442.1 discloses a method for producing an isoxazoline-containing uracil-based compound by methylation. The last step for obtaining the product is carried out by removing the solvent under reduced pressure. However, the product produced by this method is a viscous amorphous oily substance at a slightly high temperature of 25 °C or higher and changes to an amber-like solid when placed at low temperature. This solid, even if pulverized, aggregates again during storage, resulting in great inconveniences in production, filling, storage, transportation, and use.
Summary of the Invention
[0004] In order to improve the existence state of the isoxazoline uracil-based compound and solve the defects in its production, filling, storage, transportation, and use, the first aspect of the present application is Step (1) involves preparing an isoxazoline uracil compound, washing the organic layer with water, and filtering it. Step (2) involves evaporating organic solvent A and adding solvent B, The present invention provides a method for crystallizing an isoxazoline uracil compound, comprising the steps of (3) raising the temperature to a predetermined temperature, thoroughly mixing, lowering the temperature to crystallize, obtaining a slurry, separating the solid and liquid, drying, and obtaining a powdered solid.
[0005] In a preferred embodiment, step 2 further includes adding a predetermined amount of solvent C to dissolve it, then adding solvent B, or evaporating organic solvent A, and then adding a mixed solution of solvent B and solvent C.
[0006] As a preferred embodiment, the structural formula of the isoxazoline uracil compound is shown below. [ka] (In the formula, R1 is fluorine, R2 is chlorine, R3 and R4 are hydrogen, R5 is CO2C2H5, and R6 is methyl.) In a preferred embodiment, the method for producing the isoxazoline uracil compound is in accordance with the invention patent 201811146442.1, where the organic solvent A is the organic solvent described in patent 201811146442.1, and preferably, the organic solvent A is toluene.
[0007] In a preferred embodiment, the polarity of solvent B is lower than that of organic solvent A and solvent C, and preferably, solvent B is one or more selected from ethers, aliphatic hydrocarbons, carbon tetrachloride, carbon disulfide, and alkanes.
[0008] In a preferred embodiment, solvent B is one or more selected from petroleum ether, ethyl ether, propylene oxide, n-pentane, cyclopentane, hexane, octane, cyclohexane, n-heptane, isooctane, carbon tetrachloride, and carbon disulfide.
[0009] In a preferred embodiment, solvent B is one of petroleum ether, n-heptane, n-pentane, or cyclopentane.
[0010] The applicant discovered during experiments that when isoxazoline-containing uracil compounds containing organic solvents were directly distilled and dried, the solvent did not completely evaporate, preventing the drying of the oily substance and resulting in low purity of the product. The applicant found that by using one of petroleum ether, n-heptane, n-pentane, or cyclopentane as solvent B and adding it to organic solvent A, the oily substance could be converted into a crystalline substance, which could then be separated into solid and liquid to convert it into a powdered solid, thereby significantly improving the practicality of the product. The reason for this is thought to be that the isoxazoline-containing uracil compound has a special crystal structure, so it is oily in organic solvent A. However, when one of the low-polarity petroleum ether, n-heptane, n-pentane, or cyclopentane is introduced, the petroleum ether, n-heptane, n-pentane, or cyclopentane mixes and melts with the organic solvent at a specific temperature, and the isoxazoline-containing uracil compound enters the petroleum ether, n-heptane, n-pentane, or cyclopentane. The crystals of the isoxazoline-containing uracil compound are arranged regularly, and as the solvent slowly diffuses between the crystals, the crystal form of the isoxazoline-containing uracil compound changes, becoming aggregated bundle crystals or massive crystals. After recrystallization, solid-liquid separation occurs, resulting in a powdery solid. The applicant further discovered that when solvent B is one of the petroleum ether, n-heptane, n-pentane, or cyclopentane, the amount of product obtained is large and the quantitative content is high. The reason for this is thought to be that the polarity of organic solvent A is significantly different from that of petroleum ether, n-heptane, n-pentane, or cyclopentane, resulting in a high crystal form conversion rate and thus a high yield of solid powder.
[0011] In a preferred embodiment, the mass ratio of the isoxazoline uracil compound to the organic solvent A in the solution remaining after distillation of the organic solvent A is (1-5):(0-5).
[0012] In a preferred embodiment, the mass ratio of the isoxazoline uracil compound to the organic solvent A in the solution remaining after distillation of the organic solvent A is (1-4):(0-4).
[0013] In a preferred embodiment, the mass ratio of the isoxazoline uracil compound to the organic solvent A in the solution remaining after distillation of the organic solvent A is 1:1.
[0014] In a preferred embodiment, the mass ratio of the isoxazoline uracil compound to the organic solvent A in the solution remaining after distillation of the organic solvent A is 1:0.
[0015] The applicant discovered during experiments that isoxazoline-containing uracil compounds are oily substances, and in actual production and use, this oily viscosity tends to solidify at low temperatures, causing the material to clog pipes and making material discharge difficult, thus affecting production in scale-up experiments. The applicant found that by washing and filtering the organic layer containing the oily product with water, and then distilling off a portion of the organic solvent under atmospheric pressure, the mass ratio of the target product to the organic solvent in the residual solution can be set to 5:1 to 1:5, thereby increasing the saturation of the target product in the solution and concentrating the target product to a smaller volume. When solvent B is introduced into the solution, the target product migrates to solvent B along with organic solvent A, forming a system where solvent B is the continuous phase and organic solvent A is the dispersed phase, which is favorable for migration by mutual dissolution in subsequent steps. The applicant also discovered that when the mass ratio of the target product to the organic solvent is 5:1 to 1:5, the difficulty of atmospheric distillation is relatively low, and organic solvent A can be removed in a simple process. When the mass ratio exceeds the preferred ratio, the difficulty of removing organic solvent A increases sharply. The reason for this is thought to be that the oily product dissolves well in organic solvent A, but as organic solvent A is removed, the proportion of oily substances in the solution gradually increases, and these oily substances excessively affect the boiling point of the solution, making distillation difficult.
[0016] In a preferred embodiment, the mass ratio of the amount of solvent B added to the organic solvent A in the residual solution or the newly added solvent C is 1:10 to 10:1.
[0017] In a preferred embodiment, the mass ratio of the amount of solvent B added to the organic solvent A in the residual solution or the newly added solvent C is 1:5 to 5:1.
[0018] In a preferred embodiment, the mass ratio of the amount of solvent B added to the organic solvent A in the residual solution or the newly added solvent C is 4.3:1.
[0019] The applicant discovered during experiments that isoxazoline-containing uracil compounds undergo a crystal transformation from an oily crystalline form to a crystalline form composed of rod-shaped crystals in a mixed solvent with a mass ratio of 1:10 to 10:1, facilitating solid-liquid separation and enabling the preparation of a powdered solid. The reason for this is thought to be that in a mixed solvent of organic solvent A and solvent B with a mass ratio of 1:10 to 10:1, isoxazoline-containing uracil compounds are arranged regularly, making it easier to form rod-shaped crystals. This improves the regularity of the arrangement among the isoxazoline-containing uracil compounds, reducing the number of randomly arranged crystals, and thereby converting the oily substance into a rod-shaped crystal aggregate. Within the preferred weight ratio range, the number of regularly arranged crystals is greatest, improving the yield of solid powder after solid-liquid separation. Furthermore, the high crystal transformation rate significantly increases the content of the target substance, improving the quantitative content of the target substance.
[0020] In one preferred embodiment, in step 3, the heating temperature is below the boiling point of the mixture of organic solvent A and solvent B, and preferably, the heating temperature is 30 to 95°C.
[0021] In one preferred embodiment, in step 3, the heating temperature is below the boiling point of the mixture of organic solvent A and solvent B, and preferably, the heating temperature is 35 to 60°C.
[0022] As a preferred embodiment, in the step 3, the temperature rising temperature is below the boiling point of the mixed solution of organic solvent A and solvent B, and preferably, the temperature rising temperature is 40°C.
[0023] The applicant discovered during the experiment that the solubility of the isoxazoline-containing uracil compound in solvent B is relatively low. The applicant discovered that by raising the temperature, the solubility of the isoxazoline-containing uracil compound in solvent B can be increased. When the temperature reached 40-70°C, the solution reached a homogeneous state and could be completely miscible. The isoxazoline-containing uracil compound containing an organic solvent could be completely dissolved and dispersed in solvent B to achieve crystal form conversion. The reason is that the oily isoxazoline-containing uracil compound has poor dispersibility in the low-polarity solvent B. Therefore, as the temperature rises, the molecular mobility increases, the intermolecular distance expands, crystal form conversion occurs, and solvent B penetrates into the crystal gaps of the isoxazoline-containing uracil compound, increasing the solubility of the isoxazoline-containing uracil compound in the mixed solution of one of petroleum ether, n-heptane, n-pentane, or cyclopentane and solvent A and increasing the crystal form change rate. The applicant further found that when the temperature is raised beyond the preferred temperature, boiling occurs between the solvents, the volatilization amount of one of petroleum ether, n-heptane, n-pentane, or cyclopentane increases, and as the volatilization amount of one of petroleum ether, n-heptane, n-pentane, or cyclopentane increases, the crystal form conversion amount of the isoxazoline-containing uracil compound decreases, the quantitative content of the final product decreases, and the final yield of the target product decreases.
[0024] As a preferred embodiment, in the step 3, the cooling crystallization method is to cool down to 0-10°C within 2-5 h and keep warm for 1-6 h for crystallization.
[0025] As a preferred embodiment, in the step 3, the cooling crystallization method is to cool down to 5°C within 2-4 h and keep warm for 4-5 h for crystallization.
[0026] As a preferred embodiment, in the step 3, the cooling crystallization method is to cool down to 5°C within 3 hours and keep the temperature at 5°C for 5 hours for crystallization.
[0027] As a preferred embodiment, the solvent C is one or a combination of more than one selected from organic solvents such as aromatic hydrocarbons, alicyclic hydrocarbons, esters, ketones, and halogenated hydrocarbons.
[0028] As a preferred embodiment, the solvent C is one or a combination of more than one selected from 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.
[0029] As a preferred embodiment, the solvent C is ethyl acetate.
[0030] The second aspect of the present invention provides the use of a crystallization method of an isoxazoline-uracil-based compound for the crystallization production of an isoxazoline-containing uracil-based compound.
Advantages of the Invention
[0031] Compared with the prior art, the present invention has the following beneficial effects.
[0032] (1) The crystallization method of the isoxazoline-uracil-based compound described in the present invention optimizes the removal amount of the organic solvent A so that the mass ratio of the isoxazoline-uracil-based compound to the organic solvent A in the residual solution is 5:1 to 1:5, thereby reducing the solvent content in the oily product and increasing the saturation of the target product in the solution, contributing to further crystallization and purification.
[0033] (2) The crystallization method for isoxazoline uracil compounds described in the present invention uses one of petroleum ether, n-heptane, n-pentane, or cyclopentane as solvent B, which has lower polarity than organic solvent A, thereby converting the crystalline form of the isoxazoline-containing uracil compound from an oily substance to bundled crystals or massive crystals, and converting it to a powdered solid after solid-liquid separation.
[0034] (3) The crystallization method of isoxazoline uracil compounds described in the present invention employs a heating temperature below the boiling point of the mixed solvent, thereby increasing the solubility of the isoxazoline-containing uracil compound in one of petroleum ether, n-heptane, n-pentane, or cyclopentane, improving the crystal form conversion rate, reducing solvent volatilization, and avoiding the effect of solvent reduction on recrystallization.
[0035] (4) In the crystallization method of isoxazoline uracil compounds described in the present invention, the mass ratio of the amount of solvent B added to the organic solvent A in the residual solution is 1:10 to 10:1, which increases the yield of the final product solid powder and increases the quantitative content of the target substance in the solid powder.
[0036] (5) The crystallization method for isoxazoline uracil compounds described in the present invention improves the storage and usability of isoxazoline-containing uracil compounds and expands the range of applications of the product by converting the isoxazoline uracil compounds from an oily substance to a powdered solid. [Modes for carrying out the invention]
[0037] The present invention will be described in detail below with reference to examples. The following examples are merely for illustrative purposes and should not be understood as limiting the scope of protection of the present invention. Non-essential improvements and modifications made by those skilled in the art based on the above-described aspects of the present invention are still within the scope of protection of the present invention. Furthermore, unless otherwise specified, all other raw materials used, with the exception of isoxazoline uracil compounds, were commercially available. [Examples]
[0038] The crystallization method for isoxazoline uracil compounds includes the following steps. (1) An isoxazoline uracil compound was prepared, the organic layer was washed with water, and the mixture was filtered. (2) A portion of the organic solvent A was evaporated, and solvent B was added. (3) After raising the temperature to a predetermined level, the mixture was thoroughly mixed, cooled to crystallize, and a slurry was obtained. The slurry was then separated into solid and liquid forms and dried to obtain a powdered solid. The method for producing the isoxazoline uracil compound described above is as follows, in accordance with the invention patent 201811146442.1: 464 g of 3-(2-chloro-5-(2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidine-1(2H)-yl)-4-fluorophenyl)-5-methyl-4,5-dihydroisoxazole-5-ethylcarboxylate is reacted with 46.6 g of methyl chloride in 2000 g of toluene, then washed with water to obtain a toluene layer, which is then divided into four equal parts. S1: One portion of the mixture was distilled under atmospheric pressure to remove 384g of organic solvent A, toluene. While stirring, 498g of solvent B, petroleum ether, was added dropwise to the toluene solution of the product. After the addition was complete, the temperature was raised to 60°C and maintained for 30 minutes. Within 3 hours, the temperature was lowered to 0°C and maintained for 5 hours to crystallize. Solid-liquid separation was performed, and the solid was dried. S2: The other portion was distilled under atmospheric pressure to remove 384 g of organic solvent A, toluene. 498 g of solvent B, cyclopentane, was added dropwise to the toluene solution of the product while stirring. After the addition was complete, the temperature was raised to 60°C and maintained for 30 minutes. Within 3 hours, the temperature was lowered to 0°C and maintained for 5 hours to crystallize. Solid-liquid separation was performed, and the solid was dried. S3: The third portion was distilled under atmospheric pressure to remove 384 g of organic solvent A, toluene. While stirring, 498 g of solvent B, n-pentane, was added dropwise to the toluene solution of the product. After the addition was complete, the temperature was raised to 60°C and maintained for 30 minutes. Within 3 hours, the temperature was lowered to 0°C and maintained for 5 hours to crystallize. Solid-liquid separation was performed, and the solid was dried. S4: The fourth portion was distilled at atmospheric pressure to remove 384g of organic solvent A, toluene. While stirring, 498g of solvent B, n-heptane, was added dropwise to the toluene solution of the product. After the addition was complete, the temperature was raised to 60°C and maintained for 30 minutes. Within 3 hours, the temperature was lowered to 0°C and maintained for 5 hours to crystallize. Solid-liquid separation was performed, and the solid was dried. [Examples]
[0039] The crystallization method for the isoxazoline uracil compound was similar in specific steps to that of Example 1, but differed in that the organic solvent A was ethyl acetate. [Examples]
[0040] The crystallization method for isoxazoline uracil compounds includes the following steps. (1) An isoxazoline uracil compound was prepared, the organic layer was washed with water, and the mixture was filtered. (2) After dissolving with a predetermined amount of solvent C, solvent B was added. (3) After raising the temperature to a predetermined level, the mixture was thoroughly mixed, cooled to crystallize, and a slurry was obtained. The slurry was then separated into solid and liquid forms and dried to obtain a powdered solid. The method for producing the isoxazoline uracil compound described above is as follows, in accordance with the invention patent 201811146442.1: 464 g of 3-(2-chloro-5-(2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidine-1(2H)-yl)-4-fluorophenyl)-5-methyl-4,5-dihydroisoxazole-5-ethyl carboxylate is reacted with 46.6 g of methyl chloride, and all of the organic solvent A, toluene, is removed by evaporation to produce 484 g of an oily substance with a quantitative content of 92.8%, which is then divided into four equal parts. S1: A portion of the oily substance was dissolved in 133.1 g of ethyl acetate, solvent C, to form a homogeneous solution. 266.2 g of petroleum ether, solvent B, was added dropwise, and the temperature was raised to 50°C and maintained for 30 minutes to form a homogeneous solution. The temperature was then lowered to 0°C within 3 hours and maintained for 5 hours to crystallize. Solid-liquid separation was performed, and the solid was dried. S2: The other portion of the oily substance was dissolved in 133.1 g of ethyl acetate, solvent C, to form a homogeneous solution. 266.2 g of cyclopentane, solvent B, was added dropwise, and the temperature was raised to 50°C and maintained for 30 minutes to form a homogeneous solution. The temperature was then lowered to 0°C within 3 hours and maintained for 5 hours to crystallize. Solid-liquid separation was performed, and the solid was dried. S3: The third portion of the oily substance was dissolved in 133.1 g of ethyl acetate, solvent C, to form a homogeneous solution. 266.2 g of n-pentane, solvent B, was added dropwise, and the temperature was raised to 50°C and maintained for 30 minutes to form a homogeneous solution. The temperature was then lowered to 0°C within 3 hours and maintained for 5 hours to crystallize. Solid-liquid separation was performed, and the solid was dried. S4: The fourth portion of the oily substance was dissolved in 133.1 g of ethyl acetate, solvent C, to form a homogeneous solution. 266.2 g of n-heptane, solvent B, was added dropwise, and the temperature was raised to 50°C and maintained for 30 minutes to form a homogeneous solution. The temperature was then lowered to 0°C within 3 hours and maintained for 5 hours to crystallize. Solid-liquid separation was performed, and the solid was dried. Performance testing
[0041] The solids prepared in Examples 1-3 were weighed, and the quantitative content of the target substance was measured by HPLC. Examples 1-3 correspond to Tables 1-3, respectively.
[0042] [Table 1]
[0043] [Table 2]
[0044] [Table 3]
Claims
1. A method for crystallizing isoxazoline uracil compounds, Step (1) involves preparing an isoxazoline uracil compound, washing the organic layer with water, and filtering it. Step (2) involves evaporating organic solvent A and adding solvent B, A method for crystallizing an isoxazoline uracil compound, characterized by comprising the steps of: (3) raising the temperature to a predetermined temperature, thoroughly mixing, lowering the temperature to crystallize, obtaining a slurry, separating the solid and liquid, drying, and obtaining a powdered solid.
2. The method for crystallizing an isoxazoline uracil compound according to claim 1, characterized in that step 2 further comprises adding a predetermined amount of solvent C to dissolve the compound, then adding solvent B, or evaporating organic solvent A and then adding a mixed solution of solvent B and solvent C.
3. The method for crystallizing an isoxazoline uracil compound according to claim 1, characterized in that the structural formula of the isoxazoline uracil compound is shown below. 【Chemistry 1】 (where R １ is fluorine, R ２ is chlorine, R ３ , R ４ is hydrogen, R ５ is CO ２ C ２ H ５ and R ６ is methyl.)
4. The method for crystallizing an isoxazoline uracil compound according to claim 2, characterized in that the polarity of solvent B is lower than that of organic solvent A and solvent C, and preferably, solvent B is one or more selected from ethers, aliphatic hydrocarbons, carbon tetrachloride, and carbon disulfide.
5. The method for crystallizing an isoxazoline uracil compound according to claim 2, characterized in that the mass ratio of the isoxazoline uracil compound to the organic solvent A in the solution remaining after evaporation of the organic solvent A is (1-5):(0-5).
6. The method for crystallizing an isoxazoline uracil compound according to claim 2, characterized in that the mass ratio of the amount of solvent B added to the organic solvent A in the residual solution or the newly added solvent C is 1:10 to 10:
1.
7. The method for crystallizing an isoxazoline uracil compound according to claim 2, characterized in that, in step 3, the heating temperature is below the boiling point of the mixture of organic solvent A and solvent B, and preferably the heating temperature is 30 to 95°C.
8. The method for crystallizing an isoxazoline uracil compound according to claim 1, characterized in that, in step 3, the cooling crystallization method involves cooling the temperature to 0 to 10°C within 2 to 5 hours and then maintaining the temperature for 1 to 6 hours to crystallize.
9. The method for crystallizing an isoxazoline uracil compound according to claim 2, characterized in that the solvent C is one or a combination of several organic solvents selected from aromatic hydrocarbons, alicyclic hydrocarbons, esters, ketones, and halogenated hydrocarbons.
10. A use of the crystallization method for isoxazoline uracil compounds according to any one of claims 2 to 9, characterized in that it is used for the crystallization and production of isoxazoline-containing uracil compounds.