Crystallization method of isoxazoline uracil compound and application thereof

Abstract

This invention discloses a method for crystallizing isoxazoline uracil compounds, comprising the following steps: preparing isoxazoline uracil compounds; washing the organic layer with water and filtering; distilling off a portion of organic solvent A; adding solvent B; heating and mixing thoroughly; cooling and crystallizing to obtain a slurry; separating the solid and liquid phases; and drying to obtain a powdered solid. This invention optimizes the removal of organic solvent A, ensuring that the mass ratio of isoxazoline uracil compounds to organic solvent A in the remaining solution is 5:1 to 1:5. This reduces the solvent content in the oily product, increases the saturation of the target product in the solution, and facilitates further crystallization and purification. Furthermore, it can transform the crystal form of isoxazoline uracil compounds, changing them from an oily substance to a bundled crystal form or crystal blocks, and from an oily state to a powder state. This improves the transfer, material storage, and usability of the production process for isoxazoline uracil compounds, expanding the product's application range.

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:

[0005] (1) Prepare isoxazoline urea pyrimidine compounds, wash the organic layer with water and filter;

[0006] (2) Evaporate organic solvent A, then add solvent B;

[0007] (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.

[0008] In a preferred embodiment, step 2 may further include adding a certain amount of solvent C to dissolve the solvent, and then adding solvent B; or evaporating organic solvent A and then adding a mixed solution of solvent B and solvent C.

[0009] 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.

[0010] In a preferred embodiment, the method for preparing the isoxazoline ureapyridine compound is based on invention patent 201811146442.1, wherein the organic solvent A is the organic solvent in patent 201811146442.1, and preferably the organic solvent A is toluene.

[0011] In a preferred embodiment, 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 several of ethers, aliphatic hydrocarbons, carbon tetrachloride, carbon disulfide, and alkanes.

[0012] 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.

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

[0014] 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 A, 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 A 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 compounds to enter the mixture. The crystals of the isoxazoline urea pyrimidine compounds then arrange themselves in an orderly manner, and the solvent slowly diffuses between the crystals, causing the crystal structure of the isoxazoline urea pyrimidine compounds to change, resulting in aggregated bundles of crystals or blocky crystals. After recrystallization, solid-liquid separation is achieved, resulting in 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 greater and the quantitative content is higher. The reason may be that the polarity of organic solvent A 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.

[0015] In a preferred embodiment, after distillation, the mass ratio of isoxazoline ureapyridine compounds to organic solvent A in the remaining solution is (1-5):(0-5).

[0016] In a preferred embodiment, after distillation, the mass ratio of isoxazoline ureapyridine compounds to organic solvent A in the remaining solution is (1-4):(0-4).

[0017] In a preferred embodiment, after distillation, the mass ratio of isoxazoline ureapyridine compounds to organic solvent A in the remaining solution is 1:1.

[0018] In a preferred embodiment, after distillation, the mass ratio of isoxazoline ureapyridine compounds to organic solvent A in the remaining solution is 1:0.

[0019] During the experiment, the applicant discovered that compounds containing isoxazoline ureapyridines 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 A to solvent B, forming a system where solvent B is the continuous phase and organic solvent A 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 organic solvent A can be removed through a simple process. However, when the mass ratio exceeds the preferred ratio, the difficulty of removing organic solvent A increases sharply. The possible reason is that the oily product has good solubility in organic solvent A. As organic solvent A 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.

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

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

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

[0023] 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 A and solvent B with a mass ratio of 1:10 to 10:1, isoxazoline uracil compounds readily align in an ordered manner, 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.

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

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

[0026] In a preferred embodiment, the heating temperature in step 3 does not exceed the boiling point of the mixture of organic solvent A and solvent B; preferably, the heating temperature is 40°C.

[0027] 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 reaches 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. Increasing the temperature increases intermolecular activity and widens the intermolecular distance, leading to a crystal form transformation. 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 A, 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.

[0028] 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.

[0029] 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.

[0030] In a preferred embodiment, the cooling crystallization method in step 3 is as follows: cool down to 5°C within 3 hours and maintain the temperature for crystallization for 5 hours.

[0031] 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.

[0032] In a preferred embodiment, the solvent C is selected from one or a combination of several 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, bromoethane, chloropropane, and methyl oleate.

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

[0034] 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.

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

[0036] (1) The crystallization method of isoxazoline uridine compounds of the present invention, by optimizing the amount of organic solvent A removed, so that the mass ratio of isoxazoline uridine compounds to organic solvent A in the remaining solution is 5:1-1:5, 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.

[0037] (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 A, as solvent B. This 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, it can be transformed into a powdery solid.

[0038] (3) The crystallization method of isoxazoline urea pyrimidine compounds of the present invention uses a heating temperature not exceeding the boiling point of the mixed solvent, which can increase the solubility of isoxazoline urea pyrimidine compounds 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.

[0039] (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 organic solvent A in the remaining solution, which can increase the yield of the final product solid powder and increase the quantitative content of the target substance in the solid powder.

[0040] (5) The crystallization method of isoxazoline uridine compounds described in this invention improves the storage and usability of isoxazoline uridine compounds by transforming the isoxazoline uridine compounds from an oily substance into a powdery solid, thereby expanding the application range of the product. Detailed Implementation

[0041] 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.

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

[0043] Example 1

[0044] A method for crystallizing isoxazoline ureapyridine compounds, comprising the following steps:

[0045] (1) Prepare isoxazoline urea pyrimidine compounds, wash the organic layer with water and filter;

[0046] (2) Evaporate part of the organic solvent A, and add solvent B;

[0047] (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.

[0048] 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-carboxylate in 2000g of toluene with 46.6g of chloromethane. After the reaction is complete, the mixture is washed with water to obtain a toluene layer, which is then divided into four equal portions.

[0049] S1 Take one portion and remove 384g of organic solvent A (toluene) by atmospheric distillation. Add 498g of solvent B (petroleum ether) dropwise to the toluene solution of the product under stirring. After the addition is complete, heat to 60℃ and keep warm for 30 minutes. Cool down to 0℃ within 3 hours and keep warm to crystallize for 5 hours. Separate the solid and liquid and dry the solid to obtain the product.

[0050] S2. Take the second portion of the product and remove 384g of organic solvent A (toluene) by atmospheric distillation. Add 498g of solvent B (cyclopentane) dropwise to the toluene solution of the product while stirring. After the addition is complete, heat the product to 60℃ and keep it at that temperature for 30 minutes. Then, cool the product to 0℃ within 3 hours and keep it at that temperature for 5 hours to crystallize. Separate the solid and liquid, and dry the solid to obtain the final product.

[0051] S3. Take the third part and remove 384g of organic solvent A toluene by atmospheric distillation. Add 498g of solvent B n-pentane to the toluene solution of the product by stirring. After the addition is complete, heat to 60℃ and keep warm for 30 minutes. Cool down to 0℃ within 3 hours and keep warm for crystallization for 5 hours. Separate the solid and liquid and dry the solid to obtain the product.

[0052] S4. Take the fourth portion and remove 384g of organic solvent A (toluene) by atmospheric distillation. Add 498g of solvent B (n-heptane) dropwise to the toluene solution of the product while stirring. After the addition is complete, heat to 60℃ and keep warm for 30 minutes. Cool down to 0℃ within 3 hours and keep warm for crystallization for 5 hours. Separate the solid and liquid, and dry the solid to obtain the final product.

[0053] Example 2

[0054] A method for crystallizing isoxazoline ureapyridine compounds, the specific steps of which are the same as in Example 1, except that the organic solvent A is ethyl acetate. Example 3

[0055] A method for crystallizing isoxazoline ureapyridine compounds, comprising the following steps:

[0056] (1) Prepare isoxazoline urea pyrimidine compounds, wash the organic layer with water and filter;

[0057] (2) After dissolving in a certain amount of solvent C, solvent B is added;

[0058] (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.

[0059] 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.

[0060] 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;

[0061] 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;

[0062] 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;

[0063] 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.

[0064] Performance testing

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

[0066] Table 1

[0067] S1 S2 S3 S4 mass / g 109.95 111.20 110.80 112.30 Quantitative content / % 98.12 97.95 98.02 98.02

[0068] Table 2

[0069] S1 S2 S3 S4 mass / g 110.32 110.35 111.20 111.65 Quantitative content / % 98.10 98.08 97.90 97.96

[0070] Table 3

[0071] S1 S2 S3 S4 mass / g 107.15 107.46 107.25 108.20 Quantitative content / % 98.51 98.23 98.41 97.56

Claims

1. A crystallization method of an isoxazoline uracil compound, characterized by, The method comprises the following steps: (1) preparing isoxazoline uracil compound, washing the organic layer with water, and filtering; (2) evaporating part of the organic solvent A and adding solvent B; (3) after being heated to a certain temperature, being fully mixed, being cooled to crystallize, obtaining slurry, being separated into solid and liquid, and being dried to obtain powder solid; The organic solvent A is one of toluene or ethyl acetate; The solvent B is one of petroleum ether, n-heptane, n-pentane or cyclopentane; The isoxazoline uracil compound has a structural formula as shown in the following formula (I) , wherein R1 is fluorine, R2 is chlorine, R3 and R4 are hydrogen, R5 is CO2C2H5, and R6 is methyl. After distillation of the organic solvent A, the mass ratio of isoxazoline uracil compound to the organic solvent A in the remaining solution is 5:1-1:

5.

2. The crystallization method of the isoxazoline uracil compound according to claim 1, characterized by, In step 3, the heating temperature is not higher than the boiling point of the mixed solution of the organic solvent A and the solvent B, and the heating temperature is 30-95 DEG C.

3. The crystallization method of the isoxazoline uracil compound according to claim 1, characterized by, In step 3, the method for cooling to crystallize is cooling to 0-10 DEG C within 2-5 h and crystallizing for 1-6 h.

Images