Crystallization method and application of isoxazoline urea pyrimidine compound

Abstract

The invention discloses a crystallization method of an isoxazoline urea pyrimidine compound, which comprises the following steps: preparing the isoxazoline urea pyrimidine compound, washing an organic layer with water, and filtering; evaporating out part of the organic solvent A, and adding a solvent B; and heating, fully mixing, cooling and crystallizing to obtain slurry, carrying out solid-liquid separation, and drying to obtain a powdery solid. By optimizing the removal amount of the organic solvent A, the mass ratio of the isoxazoline urea pyrimidine compound to the organic solvent A in the residual solution is (5: 1)-(1: 5), the content of the solvent in an oily product is reduced, the saturation degree of a target product in the solution is improved, and further crystallization and purification are facilitated. The isoxazoline-containing urea pyrimidine compound can be converted into a crystal form, so that the isoxazoline-containing urea pyrimidine compound is converted into a bunchy crystal form or a crystal block from an oily substance and is converted into powder from the oily substance, the transfer of the production process of the isoxazoline-containing urea pyrimidine compound, the material storage and the usability of the product are improved, and the application range of the product is expanded.

Description

Technical Field

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

[0002] Isoxazoline uracil compounds are herbicides with excellent properties and high herbicidal activity. They have excellent control effects especially on glyphosate-resistant weeds such as Eleusine indica. However, the isoxazoline uracil compounds in current patents are oily substances. During actual large-scale production, the oily substances are prone to condense at low temperatures, causing blockages in pipelines in the production equipment and difficulty in discharging materials. When stored, this compound is prone to form amorphous amber-like solid blocks, which are difficult to take during the preparation of formulated products, inconvenient to measure and difficult to accurately take; moreover, the amber-like compound cannot be filled. Even if the amber-like solid is crushed, it will agglomerate into one body during storage and transportation and return to the amber-like state. These properties of this compound bring various inconveniences during production, filling, storage, transfer, and use.

[0003] Chinese Patent Invention 201811146442.1 discloses a method for preparing isoxazoline uracil compounds by methylation. The last 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 and becomes an amber-like solid after being placed at low temperatures. After being crushed, this solid will also aggregate again during storage, causing great inconvenience during production, filling, storage, transfer, and use. Summary of the Invention

[0004] In order to improve the existing state of isoxazoline uracil compounds and solve the defects existing during production, filling, storage, transfer, and use. The first aspect of this application provides a crystallization method of isoxazoline uracil compounds, which includes the following steps:

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

[0006] (2) Distill off organic solvent A and add solvent B;

[0007] (3) After heating to a certain temperature, mix well, cool and crystallize to obtain a slurry, separate the solid and liquid, and obtain a powdery solid after drying.

[0008] As a preferred embodiment, 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.

[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 the invention patent 201811146442.1, and the organic solvent A is the organic solvent in the patent 201811146442.1. Preferably, the 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 several 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 several of petroleum ether, diethyl 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] The applicant found during the experiment that when directly distilling and drying the isoxazoline uracil compound containing an organic solvent, the solvent evaporation is incomplete, the oily substance cannot be dried, and the product purity is low. When the applicant uses one of petroleum ether, n-heptane, n-pentane, or cyclopentane as the solvent B and adds it to the organic solvent A, the oily substance can be transformed into a crystalline substance. After solid-liquid separation, it is transformed into a powdery solid, greatly improving the practicality of the product. It is speculated that the possible reason is that the isoxazoline uracil compound presents 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, one of petroleum ether, n-heptane, n-pentane, or cyclopentane is miscible with the organic solvent at a specific temperature, enabling the isoxazoline uracil compound to enter one of petroleum ether, n-heptane, n-pentane, or cyclopentane. The crystals of the isoxazoline uracil compound are arranged in an orderly manner, and the solvent slowly diffuses between the crystals, causing the crystal form of the isoxazoline uracil compound to change, presenting aggregated bundle-shaped crystals or massive crystals. After recrystallization, solid-liquid separation is achieved, resulting in a powdery solid. The applicant further found that when the solvent B is one of petroleum ether, n-heptane, n-pentane, or cyclopentane, the amount of the obtained product is relatively large and the quantitative content is relatively high. The reason may be that the polarity difference between the organic solvent A and petroleum ether, n-heptane, n-pentane, or cyclopentane is relatively large, and the proportion of crystal form transformation is relatively high. Therefore, a solid powder with a relatively high 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] The applicant found during the experiment that the isoxazoline uracil compound-containing product is an oily substance. In actual production and use, the oily viscous substance is prone to solidification at low temperatures, blocking the material pipeline, making it difficult to discharge the material, and affecting the production of the scale-up experiment. The applicant found that after the organic layer containing the oily product is washed and filtered with water, a part of the organic solvent is distilled off at normal pressure, so that the mass ratio of the target product to the organic solvent in the remaining solution is 5:1 to 1:5, which can increase the saturation of the target product in the solution, enabling the target product to be concentrated in a smaller volume. When solvent B is introduced into the solution, the target product can carry the organic solvent A and transfer to solvent B, forming a system with solvent B as the continuous phase and organic solvent A as the dispersed phase, which is conducive to the mutual dissolution and transfer in the subsequent steps. And the applicant found that when the mass ratio of the target product to the organic solvent is 5:1 to 1:5, the difficulty of distillation at normal pressure is relatively small, and the removal of organic solvent A can be achieved through a simple process. Beyond the preferred mass ratio, the difficulty of removing organic solvent A increases sharply. It is speculated that the possible reason is that the oily product has good solubility in organic solvent A. As organic solvent A is removed, the proportion of the oily substance in the solution gradually increases, and the oily substance overly affects the boiling point of the solution, resulting in difficult distillation.

[0020] As a preferred embodiment, the addition amount of the solvent B to the mass of 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 addition amount of the solvent B to the mass of 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 addition amount of the solvent B to the mass of the organic solvent A in the remaining solution or the newly added solvent C is 4.3:1.

[0023] During the experiment, the applicant found that the isoxazoline uracil compounds can achieve crystal form transformation in a mixed solvent with a mass ratio of 1:10 to 10:1, changing from the crystal form of an oil-like substance to the crystal form of aggregated rod-like crystals, which makes it easy to achieve solid-liquid separation and obtain a powdery solid. It is speculated that the possible reason is that in the mixed solvent of organic solvent A and solvent B with a mass ratio of 1:10 to 10:1, the isoxazoline uracil compounds are prone to orderly arrangement, forming rod-like crystals, improving the arrangement regularity among the isoxazoline uracil compounds, reducing the number of randomly arranged crystals, and thus transforming the oil-like substance into an aggregate of rod-like crystals. Within the preferred weight ratio range, the number of orderly arranged crystals is the highest. Therefore, after solid-liquid separation, the yield of the obtained solid powder is higher. Moreover, the high crystal form transformation rate also significantly increases the content of the target substance, improving the quantitative content of the target substance.

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

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

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

[0027] During the experiment, the applicant found that the solubility of isoxazoline uracil compounds in solvent B was relatively low. The applicant discovered that by increasing the temperature, the solubility of isoxazoline uracil compounds in solvent B could be increased. When the temperature reached 40 - 70 °C, the solution could reach a homogeneous state and achieve complete miscibility. The isoxazoline uracil compounds containing organic solvents could be completely dissolved and dispersed in solvent B, realizing the transformation of crystal form. It is speculated that the possible reason is that the isoxazoline uracil compounds in the form of an oil have poor dispersibility in the low-polarity solvent B. By increasing the temperature, the molecular mobility increases, the molecular distance expands, and the crystal form transforms. Solvent B penetrates into the crystal gaps of the isoxazoline uracil compounds, improving the solubility of the isoxazoline uracil compounds in a mixed solution of one of petroleum ether, n-heptane, n-pentane or cyclopentane and solvent A, and increasing the change rate of crystal form change. The applicant further found that when the increased temperature exceeded the preferred temperature, boiling was likely to occur between the solvents, increasing the volatilization amount of one of petroleum ether, n-heptane, n-pentane or cyclopentane. As the volatilization amount of one of petroleum ether, n-heptane, n-pentane or cyclopentane increased, the amount of crystal form transformation of the isoxazoline uracil compounds decreased, resulting in a decrease in the quantitative content of the final product and a reduction in the final yield of the target product.

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

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

[0030] As a preferred embodiment, in step 3, the method of cooling crystallization is: cool down to 5 °C within 3 h and keep the temperature for crystallization for 5 h.

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

[0032] As a preferred embodiment, 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] As a preferred embodiment, solvent C is ethyl acetate.

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

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

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

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

[0038] (3) In the crystallization method of the isoxazoline uracil compounds of the present invention, by using a heating temperature not exceeding the boiling point of the mixed solvent, the solubility of the isoxazoline uracil compounds in one of petroleum ether, n-heptane, n-pentane or cyclopentane can be increased, the crystal form transformation rate can be improved, the volatilization of the solvent can be reduced, and the influence on recrystallization caused by the reduction of the solvent can be avoided.

[0039] (4) In the crystallization method of the isoxazoline uracil compounds of the present invention, when the addition amount of solvent B and organic solvent A in the remaining solution is in a mass ratio of 1:10 - 10:1, the yield of the final product solid powder can be increased, and the quantitative content of the target substance in the solid powder can be increased.

[0040] (5) In the crystallization method of the isoxazoline uracil compounds of the present invention, by transforming the isoxazoline uracil compounds from an oily substance to a powdery solid, the storage and usability of the isoxazoline uracil compounds are improved, and the application range of the product is expanded. Specific Embodiments

[0041] The present invention will be specifically described below by way of examples. It is necessary to point out here that the following examples are only used to further illustrate the present invention and should not be construed as limiting the protection scope of the present invention. Some non-essential improvements and adjustments made by those skilled in the art based on the above content of the present invention still fall within the protection scope of the present invention.

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

[0043] Example 1

[0044] A crystallization method for isoxazoline uracil compounds, which comprises the following steps:

[0045] (1) Prepare isoxazoline uracil compounds. The organic layer is washed with water and filtered;

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

[0047] (3) After heating to a certain temperature, mix well, cool down for crystallization to obtain a slurry, separate the solid from the liquid, and obtain a powdery solid after drying.

[0048] The preparation method of the isoxazoline uracil compound is based on the invention patent 201811146442.1. After reacting 464 g of ethyl 3-(2-chloro-5-(2,6-dioxo-4-(trifluoromethyl)-3,6-dihydro-1(2H)-pyrimidinyl)-4-fluorophenyl)-5-methyl-4,5-dihydroisoxazole-5-carboxylate with 46.6 g of chloromethane in 2000 g of toluene, the toluene layer is obtained after washing with water, and the toluene layer is evenly divided into four parts.

[0049] S1 Take one of them and distill off 384 g of the organic solvent A toluene at normal pressure. While stirring, add 498 g of the solvent B petroleum ether dropwise to the toluene solution of the product. After adding, heat up to 60 °C and keep warm for 30 minutes, cool down to 0 °C within 3 hours, keep warm for crystallization for 5 hours, separate the solid from the liquid, and obtain it after drying the solid;

[0050] S2 Take the second part and distill off 384 g of the organic solvent A toluene at normal pressure. While stirring, add 498 g of the solvent B cyclopentane dropwise to the toluene solution of the product. After adding, heat up to 60 °C and keep warm for 30 minutes, cool down to 0 °C within 3 hours, keep warm for crystallization for 5 hours, separate the solid from the liquid, and obtain it after drying the solid;

[0051] S3 Take the third part and distill off 384 g of the organic solvent A toluene at normal pressure. While stirring, add 498 g of the solvent B n-pentane dropwise to the toluene solution of the product. After adding, heat up to 60 °C and keep warm for 30 minutes, cool down to 0 °C within 3 hours, keep warm for crystallization for 5 hours, separate the solid from the liquid, and obtain it after drying the solid;

[0052] S4 Take the fourth part and distill off 384 g of the organic solvent A toluene at normal pressure. While stirring, add 498 g of the solvent B n-heptane dropwise to the toluene solution of the product. After adding, heat up to 60 °C and keep warm for 30 minutes, cool down to 0 °C within 3 hours, keep warm for crystallization for 5 hours, separate the solid from the liquid, and obtain it after drying the solid.

[0053] Example 2

[0054] A crystallization method for isoxazolinouracil compounds, the specific steps are the same as those in Example 1, except that the organic solvent A is ethyl acetate. Example 3

[0055] A crystallization method for isoxazolinouracil compounds, which comprises the following steps:

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

[0057] (2) After dissolving with a certain amount of solvent C, add solvent B;

[0058] (3) After heating to a certain temperature, mix well, cool and crystallize to obtain a slurry, separate the solid and liquid, and obtain a powdery solid after drying.

[0059] The preparation method of the isoxazolinouracil compounds is based on the invention patent 201811146442.1. 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 (464 g) is reacted with chloromethane (46.6 g), and all the organic solvent A, toluene, is distilled off to prepare 484 g of an oily substance with a quantitative content of 92.8%, which is evenly divided into four parts.

[0060] S1 Take one part 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, petroleum ether, and then heat to 50 °C and keep warm for 30 minutes to form a homogeneous solution. Cool to 0 °C within 3 hours and keep warm for crystallization for 5 hours. Separate the solid and liquid, and obtain the product after drying the solid;

[0061] S2 Take the second part 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, cyclopentane, and then heat to 50 °C and keep warm for 30 minutes to form a homogeneous solution. Cool to 0 °C within 3 hours and keep warm for crystallization for 5 hours. Separate the solid and liquid, and obtain the product after drying the solid;

[0062] S3 Take the third part 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-pentane, and then heat to 50 °C and keep warm for 30 minutes to form a homogeneous solution. Cool to 0 °C within 3 hours and keep warm for crystallization for 5 hours. Separate the solid and liquid, and obtain the product after drying the solid;

[0063] S4 Take the fourth part 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 then heat to 50 °C and keep warm for 30 minutes to form a homogeneous solution. Cool to 0 °C within 3 hours and keep warm for crystallization for 5 hours. Separate the solid and liquid, and obtain the product after drying the solid.

[0064] Performance test

[0065] Weigh the solids prepared in Examples 1-3, and then use HPLC to determine the quantitative content of the target substance. 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 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 isoxazolinyluracil 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 isoxazolinyluracil compound according to claim 1, wherein 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, wherein, 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, and carbon disulfide.

5. The crystallization method of the isoxazolinyluracil 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, wherein, In step 3, the method of cooling and crystallization 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 isoxazoline uracil compound according to claim 2, wherein, Solvent C is selected from one or a combination of several of aromatic hydrocarbons, alicyclic hydrocarbons, esters, ketones, and halogenated hydrocarbon organic solvents.

10. Use of a crystallization method of 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.

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