Crystal form A of benzoxazine compound as well as preparation method and application of crystal form A

Abstract

The invention discloses a crystal form A of a benzoxazine compound as well as a preparation method and application of the crystal form A. The crystal form A is the crystal form A of a compound I. The reflection angle 2 theta of an X-ray powder diffraction pattern of the crystal form A has characteristic absorption peaks at 7.0 + / -0.2 degrees, 10.5 + / -0.2 degrees, 12.0 + / -0.2 degrees, 12.6 + / -0.2 degrees, 16.5 + / -0.2 degrees and 20.2 + / -0.2 degrees. The crystal form A of the compound shown in the formula I is a crystal with more stable thermodynamics, can be simply and conveniently stored at room temperature, is easy for industrial large-scale production, and is convenient for further processing and application of products. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the agrochemical field, and particularly relates to a crystalline form A of a benzoxazine compound, a preparation method and an application thereof. Background Art

[0002] The compound 3-(7-fluoro-3-oxo-4-(prop-2-yn-1-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-1-methyl-6-(trifluoromethyl)pyrimidine-2,4(1H,3H)-dione (Formula I), a preparation method thereof and its herbicidal activity have been reported in US Patent US5084084A. Its structure is similar to that of the commercial herbicide flumioxazin, and it belongs to a protoporphyrinogen oxidase inhibitor. By causing the accumulation of protoporphyrin, it enhances the lipid peroxidation of cell membranes, inhibits plant photosynthesis, makes its leaves dry and die quickly, and has the characteristics of high efficiency, low toxicity and broad spectrum. It has the following chemical structural formula:

[0003]

[0004] Whether it is medicine or pesticide, the truly effective substance (collectively referred to as the technical material) plays a role. However, the technical material generally cannot be directly used. A stable and excellent preparation dosage form is the key to exerting the drug effect. For the production of technical materials on an industrial scale and the development of preparations, in many cases, it is necessary to first understand the possible existing states of this technical material, such as: crystalline variants (also called crystal forms) or solvates, which often play a decisive and important role. A technical material can exist in different crystal forms or in an amorphous form, and different existing states may bring different drug effects and functions, such as differences in the following properties: solubility, vapor pressure, dissolution rate, thermal stability, stability during grinding, suspension stability, optical and mechanical properties, hygroscopicity, crystal form and size, fluidity, filterability, density, melting point, decomposition stability, color, chemical reactivity or biological activity.

[0005] Laboratory findings show that the technical material of Formula I prepared according to US Patent US5084084A exists as an oil. The following problems exist in the process of formulation processing: First, the technical material exists in the form of an oil, and its viscosity is relatively high, resulting in difficulty in effectively reducing the particle size by conventional methods during the preparation process, thus affecting the uniformity and effect of the final product. Second, the suspension rate is relatively low: oily technical materials are usually not easily dispersed or suspended in water, which will cause the active ingredient to easily settle during use, reducing the effective concentration during application and affecting the control effect. Third, the dilution stability is unqualified: when the technical material is diluted, phenomena such as stratification and precipitation may occur, which means that in actual applications, the active ingredient of the pesticide may not be evenly distributed in the target area, reducing the activity and use safety of the pesticide. Summary of the Invention

[0006] The object of the present invention is to solve the technical problems that the technical problems of the existing oil-based active ingredient of formula I and the preparation thereof include unstable storage, aggregation after storage, and inability to be formulated into a suitable composition or preparation. On the basis of the prior art, a new crystal form of the compound of formula I, its preparation method and uses are provided.

[0007] After the inventors studied the active ingredient of formula I prepared in Patent US5084084A, they found that there were many technical problems in the subsequent processing, and its physical properties and herbicidal activity were not satisfactory. After a large number of experimental verifications, it was surprisingly found that by a suitable method, while improving the purity of the compound of formula I, a previously unknown crystalline and stable variant could also be obtained, and it did not exhibit the disadvantages of the oil form of formula I. These variants are also described below as crystal form A. The preparation method provided by the present invention has simple process operation, low economic cost, high product purity, good crystal form stability, and is more suitable for large-scale industrial production.

[0008] The object of the present invention can be achieved by the following measures:

[0009] A crystal form of Compound I, which is crystal form A of Compound I, and its X-ray powder diffraction pattern has characteristic absorption peaks at reflection angles 2θ of 7.0±0.2°, 10.5±0.2°, 12.0±0.2°, 12.6±0.2°, 16.5±0.2°, 20.2±0.2°; wherein Compound I has the following chemical structure:

[0010]

[0011] In a preferred embodiment, the X-ray powder diffraction pattern of crystal form A of Compound I further has characteristic absorption peaks at reflection angles 2θ of 14.0±0.2°, 18.1±0.2°, 19.3±0.2°, 21.0±0.2°, 22.5±0.2°, 23.9±0.2°, 25.0±0.2°, 26.6±0.2°, 27.3±0.2°.

[0012] In one embodiment, the X-ray powder diffraction pattern of crystal form A of Compound I has characteristic absorption peaks at reflection angles 2θ of 7.0±0.1°, 10.5±0.1°, 12.0±0.1°, 12.6±0.1°, 16.5±0.1°, 20.2±0.1°, or further, it has characteristic absorption peaks at reflection angles 2θ of 14.0±0.1°, 18.1±0.1°, 19.3±0.1°, 21.0±0.1°, 22.5±0.1°, 23.9±0.1°, 25.0±0.1°, 26.6±0.1°, 27.3±0.1°.

[0013] In a preferred embodiment, the X-ray powder diffraction pattern of Form A of Compound I has characteristic absorption peaks at 2θ (reflection angle) of 7.0, 10.5, 12.0, 12.6, 16.5, 20.2°. Alternatively, further, it has characteristic absorption peaks at 14.0, 18.1, 19.3, 21.0, 22.5, 23.9, 25.0, 26.6, 27.3.

[0014] In a more preferred embodiment, the X-ray powder diffraction pattern of Form A of Compound I has characteristic absorption peaks at 2θ (reflection angle) of 7.020, 10.498, 12.022, 12.637, 14.061, 16.521, 18.103, 19.319, 20.182, 21.082, 22.521, 23.918, 25.058, 26.640, 27.338.

[0015] In a preferred embodiment, the X-ray powder diffraction pattern of Form A of Compound I is substantially as Figure 1 shown.

[0016] In a preferred embodiment, the single crystal cell parameters of Form A of Compound I are: crystal system Monoclinic, space group P21 / n; α = 90°, β = 95.139(2)°, γ = 90°.; volume

[0017] The DSC pattern of Form A of Compound I of the present invention has an endothermic peak at 194 - 208 °C.

[0018] In a preferred embodiment, the DSC pattern of Form A of Compound I of the present invention is as Figure 12 shown, with an endothermic peak at 201.61 °C.

[0019] Form A of Compound I of the present invention has a UV spectrum substantially as Figure 10 shown.

[0020] Form A of Compound I of the present invention has an IR spectrum substantially as Figure 11 shown.

[0021] The single crystal data of the present invention can be collected on a single crystal X-ray diffractometer (Bruker D8 VENTURE) in accordance with the General Rules for the Determination of Crystal and Molecular Structures of Small Molecule Compounds by Four-Circle Single Crystal X-ray Diffractometer JY / T 0588 - 2020.

[0022] The present invention provides a method for preparing Form A of Compound I, which includes the step of treating the crude product of Compound I oil-based drug with various organic solvents.

[0023] The present invention discloses a method for preparing crystalline form A of compound I, which comprises steps S1, S2 or S3:

[0024] S1) Under ultrasonic conditions, a solvent is added dropwise to the crude oil of starting compound I until it becomes clear. With or without filtration, the solution is placed in a stable environment for crystallization. The solvent is selected from methyl tert-butyl ether, acetone, acetonitrile, N,N-dimethylformamide, o-xylene, toluene or a methanol-water mixed solvent;

[0025] S2) The crude oil of starting compound I and a solvent are dissolved until clear under boiling conditions. With or without filtration, crystallization occurs upon cooling. The solvent is selected from methanol, isopropanol, xylene, p-ethylbenzene or ethyl acetate;

[0026] S3) After the crude oil of starting compound I and a good solvent are mixed and dissolved, an anti-solvent is slowly added to precipitate a solid. The solid is collected and dried. The good solvent is selected from 1,2-dichloroethane or toluene, and the anti-solvent is selected from petroleum ether, n-hexane, n-octane, n-pentane or n-heptane.

[0027] The present invention discloses a pesticide formulation, which contains an effective dose of crystalline form A of compound I. Here, the pesticide formulation includes, but is not limited to, solid or liquid formulations such as emulsifiable concentrates, soluble liquid formulations, dispersible liquid formulations, microemulsions, suspoemulsions, emulsifiable concentrates, aqueous suspensions, dispersible oil suspensions, wettable powders, water-dispersible granules, etc. In a preferred embodiment, a suspension concentrate (SC), wettable powder or water-dispersible granule (WG) can be used. Auxiliary materials used in the formulation include, but are not limited to, dispersants, wetting agents, thickeners, antifreezing agents, fillers, dispersion media, etc.

[0028] The crystalline form A of compound I provided by the present invention can be applied in the preparation of pesticide herbicides, or the use of crystalline form A in the preparation of formulations for controlling unwanted plants.

[0029] Advantages of the present invention:

[0030] 1. The crystalline form A of the compound of formula I discovered by the present invention is a thermodynamically more stable crystal, which can be simply and conveniently stored at room temperature, is easy to be industrially produced on a large scale, and is convenient for further processing and application of the product;

[0031] 2. The overall process of the method of the present invention has low energy consumption, the purified mother liquor can be reused multiple times, the production of three wastes is less, and the production cost is low;

[0032] 3. The crystalline form A of Compound I can be prepared into various dosage forms such as a dispersible oil suspension dosage form. When the same particle size target is achieved, compared with the original drug of Formula I prepared according to Patent US5084084A, the grinding time is reduced by 50%, which can greatly save production energy consumption and is more conducive to processing and production. The dispersible oil suspension dosage form prepared using crystalline form A has a low preparation viscosity, good dilution and dispersion in water, no flocculation, and can better exert the drug effect.

[0033] 4. The crystalline form A of Compound I provided by the present invention can be conveniently and directly used in agrochemical preparations, especially more environmentally friendly solid preparations such as suspension concentrates, water dispersible granules, wettable powders, etc., and has a significantly improved herbicidal activity against weeds. Description of the Drawings

[0034] Figure 1 is the X-ray powder diffraction pattern of the crystalline form A of Compound I of the present invention;

[0035] Figure 2 is the XRD pattern of the toluene-volatile crystallization powder of the crystalline form A of Compound I;

[0036] Figure 3 is the XRD pattern of the methanol-water-volatile crystallization powder of the crystalline form A of Compound I;

[0037] Figure 4 is the XRD pattern of the xylene-recrystallized (slow cooling) powder of the crystalline form A of Compound I;

[0038] Figure 5 is the XRD pattern of the ethylbenzene-recrystallized (rapid) powder of the crystalline form A of Compound I;

[0039] Figure 6 is the XRD pattern of the 1,2-dichloroethane anti-solvent n-octane powder of the crystalline form A of Compound I;

[0040] Figure 7 is the XRD pattern of the toluene-n-pentane gas-phase diffusion n-octane powder of the crystalline form A of Compound I;

[0041] Figure 8 is the XRD pattern of the toluene-n-heptane liquid-phase diffusion n-octane powder of the crystalline form A of Compound I;

[0042] Figure 9 is the comparison of the A crystal form diagram of the crystalline form A of Compound I with the test diagrams of various samples;

[0043] Figure 10 is the ultraviolet test diagram of the crystalline form A of Compound I;

[0044] Figure 11 is the infrared test diagram of the crystalline form A of Compound I;

[0045] Figure 12 is the DSC test diagram of the crystalline form A of Compound I;

[0046] Figure 13 It is the single crystal diffraction pattern of polymorph A of Compound I;

[0047] Figure 14 It is the single crystal diffraction pattern of polymorph C of Compound I;

[0048] Figure 15 It is the powder XRD pattern of polymorph C of Compound I. Detailed implementation manners

[0049] According to the following examples, the present invention can be better understood. However, those skilled in the art can easily understand that the content described in the examples is only used to illustrate the present invention and should not and will not limit the present invention described in detail in the claims.

[0050] The compound shown by the formula I structure in the present invention can also be simply referred to as Compound I of formula I or Compound (I).

[0051] Example 1. Preparation of polymorph A of Compound I

[0052] Using the crude drug of Compound I in oil form as the raw material, about 30 mg was weighed, and under the condition of ultrasonic wave, o-xylene as the solvent was added dropwise until it became clear; after filtration, the filtered solution was placed in a stable environment for single crystal cultivation, and after 2 days, the crystal form was sampled for single crystal testing.

[0053] Compound I polymorph A was determined using a diffractometer with Cu-K radiation, and its X-ray powder diffraction pattern is as Figure 1 shown.

[0054] In Figure 1 the specific single crystal data is shown in Table 1.

[0055] Table 1. Figure 1 Powder XRD data of single crystal A in

[0056]

[0057]

[0058] In the XRD data, the following 15 characteristic peaks were selected as the main peaks: 7.020, 10.498, 12.022, 12.637, 14.061, 16.521, 18.103, 19.319, 20.182, 21.082, 22.521, 23.918, 25.058, 26.640, 27.338.

[0059] Single crystal X-ray diffraction measurement was carried out on Compound I polymorph A, and its single crystal diffraction pattern is as Figure 13As shown below. The unit cell parameters of polymorph A are: crystal system Monoclinic, space group P21 / n; α = 90°, β = 95.139(2)°, γ = 90°.; volume

[0060] Table 2, Figure 13 Single crystal data table of polymorph A in

[0061]

[0062] Example 2, XRD of the volatilized and crystallized A polymorph powder

[0063] Using the crude drug of Compound I oil as the raw material and toluene as the solvent, the preparation method is as follows: Weigh about 30 mg of the raw drug sample, under ultrasonic conditions, add 20 ml of the solvent dropwise, and filtration is required. Place the filtered solution in a stable environment for volatilization and crystallization.

[0064] Measure the XRD of the solid powder to obtain the XRD pattern of the toluene-volatile sample powder, and the results are as Figure 2 shown.

[0065] Example 3, XRD of the A polymorph powder crystallized by volatilization of a mixed solvent with water

[0066] When 5% water is added to the solvent methanol and volatilized at room temperature, a sample of polymorph A can be obtained.

[0067] Using the crude drug of Compound I oil as the raw material, the preparation method is as follows: Weigh about 30 mg of the raw drug sample, under ultrasonic conditions, add the mixed solvent (V 甲醇 :V 水 = 95:5) until it becomes clear; alternatively, in the case of slightly soluble, directly perform the filtration operation, and place the filtered solution in a stable environment for volatilization and crystallization.

[0068] Measure the XRD of the solid powder to obtain the XRD pattern of the methanol-water volatile sample powder, and the results are as Figure 3 shown.

[0069] Example 4, XRD of the recrystallized A polymorph powder (slow cooling)

[0070] The solvent p-xylene can obtain a sample of polymorph A under the condition of slow cooling during recrystallization.

[0071] Using the crude drug of Compound I oil as the raw material, the preparation method is as follows: Weigh about 200 mg of the raw drug sample, use p-xylene as the recrystallization solvent, set the temperature 5 °C higher than its boiling point, add the solvent at the set temperature and continuously stir to promote dissolution until it becomes clear. Filtration is not required. Then turn off the heating device and transfer it to a room temperature environment for cooling and crystallization.

[0072] The XRD of the solid powder was measured, and the XRD pattern of the powder obtained by slow cooling of p-xylene recrystallization was obtained. The results are as Figure 4 shown.

[0073] Example 5. XRD of the recrystallized A crystal form powder (rapid cooling)

[0074] Using ethylbenzene as the solvent, crystal form A samples can be obtained under the condition of rapid cooling during recrystallization.

[0075] Using the oily crude drug of Compound I as the raw material, the preparation method is as follows: Weigh about 200 mg of the crude drug sample, use ethylbenzene as the recrystallization solvent, set the temperature 5 °C higher than its boiling point, add the solvent at the set temperature and continuously stir to promote dissolution. After it becomes clear, add 10% more solvent. There is no need to filter. Then turn off the heating device and transfer it to an ice-water bath for cooling and crystallization.

[0076] The XRD of the solid powder was measured, and the XRD pattern of the powder obtained by rapid cooling of ethylbenzene recrystallization was obtained. The results are as Figure 5 shown.

[0077] Example 6. XRD of the A crystal form powder by the antisolvent method

[0078] Using 1,2-dichloroethane as the solvent, crystal form A samples can be obtained under the condition of the antisolvent n-octane.

[0079] Using the oily crude drug of Compound I as the raw material, the preparation method is as follows: Weigh about 50 mg of the crude drug sample, add an appropriate volume of a good solvent (1,2-dichloroethane) to completely dissolve it, and then dropwise add the antisolvent (n-octane) to precipitate enough solids. Stir at room temperature. When solids precipitate, collect the wet solids by centrifugation and further dry them under reduced pressure and vacuum (40 °C) overnight. Then measure the powder XRD of the dried solid.

[0080] The XRD pattern of 1,2-dichloroethane antisolvent n-octane powder was obtained. The results are as Figure 6 shown.

[0081] Example 7. XRD of the A crystal form powder by gas diffusion

[0082] Using toluene as the solvent, crystal form A samples can be obtained under the condition of gas diffusion.

[0083] Using the crude drug of Compound I in oil form as the raw material, the preparation method is as follows: Weigh about 100 mg of the API sample and add an appropriate volume of a good solvent (toluene) to a 4 mL glass vial to completely dissolve it. Add an appropriate amount of anti-solvent (n-pentane) to a 40 mL bottle. Place the open 4 mL glass vial containing the clear solution into the 40 mL bottle, seal the 40 mL bottle with a lid, and place it in a fume hood. After solids precipitate, collect the solids and dry them under reduced pressure in a vacuum (40 °C) overnight, and then measure the powder XRD of the dried solids.

[0084] The toluene - vapor diffusion - n-pentane powder XRD pattern was obtained, and the results are as Figure 7 shown.

[0085] Example 8. Powder XRD of polymorph A by liquid diffusion

[0086] Using toluene as the solvent, polymorph A samples can be obtained under liquid diffusion conditions.

[0087] Using the crude drug of Compound I in oil form as the raw material, the preparation method is as follows: Take an appropriate amount of the API sample, prepare 3.0 mL of a saturated solution of toluene. Take 2.5 mL of the saturated solution and add it to a long test tube. Dilute the remaining 0.5 mL with solvent to 1 mL as a buffer solution, and add it along the wall of the test tube. Then slowly add 8 mL of a poor solvent (n-heptane), seal it, and store it in a stable environment to wait for diffusion and crystallization.

[0088] Measure the solid powder XRD to obtain the toluene - liquid diffusion - n-heptane powder XRD pattern, and the results are as Figure 8 shown.

[0089] Example 9. Comparison of powder XRD overlay diagrams

[0090] Compare the powder XRD patterns in Examples 2 - 8 above with Figure 1 to determine that each crystallization belongs to polymorph A.

[0091] The results are as Figure 9 shown.

[0092] Example 10. Ultraviolet UV

[0093] Perform ultraviolet UV testing on polymorph A of the compound of formula I obtained in Example 1, and the results are as Figure 10 shown.

[0094] Table 3. Ultraviolet data table of polymorph A

[0095] Serial number Peak / Trough Wavelength (nm) Abs 1 Peak 265.20 0.2689 2 Peak 208.70 0.9484 3 Trough 234.80 0.1679

[0096] Example 11. Infrared IR

[0097] Perform infrared IR testing on polymorph A of the compound of formula I obtained in Example 1, and the results are asFigure 11 as shown

[0098] Example 12, Differential Scanning Calorimeter DSC

[0099] The DSC test was carried out on the crystalline form A of the compound I obtained in Example 1, and the results are as Figure 12 shown

[0100] For the DSC test of the crystalline form A sample, the temperature range was 50 - 250 °C, and the highest temperature change point was 201.61 °C.

[0101] Example 13, Preparation and XRD of Crystalline Form C

[0102] Weigh about 30 mg of the oily raw material sample of Compound I. Under ultrasonic conditions, add the solvent 1,4 - dioxane dropwise until it becomes clear. Filtration is required. Place the filtered solution in a stable environment for volatilization crystallization to obtain the 1,4 - dioxane solvate, named Crystalline Form C.

[0103] After performing single - crystal diffraction test on this Crystalline Form C sample, its unit cell parameters were obtained: Crystal system Monoclinic, Space group P21 / c; α = 90°, β = 95.239(2)°, γ = 90°. Volume Its single - crystal diffraction pattern is as Figure 14 shown

[0104] Table 4, Single - crystal data table of Crystalline Form C

[0105]

[0106] The X - ray powder diffraction pattern of this Crystalline Form C was measured using a diffractometer with Cu - K radiation, and it is as Figure 15 shown

[0107] Example 14, Stability of Crystalline Form C

[0108] The crystalline form C sample of the compound has a good crystallization state.

[0109] In the stability experiment, under the conditions of 45 °C and 75% RH, the XRD data results of the crystalline form C powder showed that there was a phenomenon of crystal transformation in Crystalline Form C. At the same time, when measuring the melting point of Crystalline Form C by differential scanning calorimetry, the results showed that there was an obvious crystal transformation peak, approximately at a temperature near 161 °C.

[0110] In addition, in the preliminary list of carcinogens published by the International Agency for Research on Cancer of the World Health Organization, 1,4 - dioxane is included in the list of Group 2B carcinogens.

[0111] Example 15, 5% aqueous suspension

[0112] A 5% aqueous suspension was prepared using the oily drug substance of the compound of formula I and crystalline form A of the compound of formula I prepared by the method of Example 1. The specific preparation method is as follows:

[0113] Weigh each raw material according to the following formula. Place the raw materials except xanthan gum in a feed tank and shear for 2 minutes using a shearing machine. After the drug substance and additives are fully mixed and homogenized, use a vertical sand mill to grind at 1800 revolutions per minute until the particle size D90 < 1 μm. Then add a 2% xanthan gum solution and stir at high speed for 10 minutes until the xanthan gum is fully mixed and swollen to obtain a 5% aqueous suspension.

[0114] Table 5. Formulation of 5% aqueous suspension of the compound of formula I

[0115]

[0116] Table 6. Comparison of particle sizes at different grinding times

[0117]

[0118] Note: The value of D50 represents that 50% of the suspension particle size is smaller than this value; similarly, D90 and D98 respectively represent that 90% and 98% of the suspension particle size is smaller than this value.

[0119] In the table, one-way ANOVA was performed using Duncan's new multiple range method in SPSS software. Lowercase letters indicate significant differences in the same column of data (P < 0.05), and uppercase letters indicate extremely significant differences in the same column of data (P < 0.01).

[0120] From the test results of the laser particle size analyzer, at the same grinding time, the particle size of crystalline form A is always smaller. The grinding efficiency of crystalline form A is better than that of the oily drug substance. For example, when grinding for 2 hours, the D90 of the suspension prepared from crystalline form A reached 1.8973 μm, meeting the product index requirements; while for the suspension prepared from the drug substance, D90 reached 2.7087 μm only when grinding for 4 hours to meet the product index requirements. This shows that under the same grinding conditions, crystalline form A is easier to grind and has a higher grinding efficiency. And crystalline form A is more sensitive to the grinding time. Especially after long-term (4h) grinding, there are significant differences in its D50, D90, and D98.

[0121] In the actual large-scale production process, improving the grinding efficiency can achieve energy conservation and consumption reduction, thereby reducing production costs. This shows that crystalline form A has higher market value.

[0122] The stability test results of different forms of the compound of formula I and the preparation after storage at 40 °C, 54 °C, and 70 °C for two weeks are shown in Table 7:

[0123] Table 7. Stability of different forms of the compound of formula I and the preparation under different temperature conditions

[0124]

[0125] As can be seen from the above table, there is no significant difference in the thermal storage decomposition rate at 40 °C between the A crystal form of the compound of formula I and the technical material in the form of an oil. However, differences in the decomposition rate between the A crystal form and the technical material in the form of an oil occurred during thermal storage at 54 °C and 70 °C. In particular, the difference in the decomposition rate during thermal storage at 70 °C was extremely significant. The thermal storage results of the suspending agents prepared from the compound of formula I in two forms under different temperature conditions also showed significant differences, and the differences became more obvious as the temperature increased.

[0126] In the industry, thermal storage at 54 °C for two weeks usually represents the data of storage at room temperature for two years. Therefore, as can be seen from the above table, the stability of the A crystal form is significantly improved compared with the technical material in the form of an oil. The purpose of the experiment at 70 °C was to simulate the stability of the goods when passing through the equator in a container. The data shows that the higher the temperature, the higher the decomposition rate of the technical material in the form of an oil. The A crystal form is more stable, has a longer shelf life, and has good application prospects.

[0127] Example 16. Dispersible oil-based suspension concentrate

[0128] A dispersible oil-based suspension concentrate was prepared using the technical material in the form of an oil of the compound of formula I and the A crystal form of the compound of formula I prepared by the method of Example 1, respectively.

[0129] Table 8. Formulation of 5% dispersible oil-based suspension concentrate of the compound of formula I

[0130]

[0131]

[0132] Specific preparation method: Weigh each raw material according to the formula and place it in a feed tank. Stir with a high-shear dispersion emulsifier for 3 minutes. After the technical material, additives and solvent are fully mixed evenly, use a vertical sand mill to grind at 1800 rpm until the particle size D90 < 3 μm to obtain a 5% dispersible oil-based suspension concentrate.

[0133] Table 9. Comparison of particle sizes at different grinding times

[0134]

[0135] The comparison results of the grinding efficiency of the dispersible oil-based suspension concentrates of the compound of formula I in different forms showed that significant differences in D50, D90 and D98 occurred for the suspension concentrates prepared from the compound of formula I in different forms; compared with the grinding particle size of the water-based suspension concentrate, the oil-based suspension concentrate was more difficult to grind, but the A crystal form still showed certain grinding advantages compared with the technical material in the form of an oil.

[0136] Example 17. Wettable powder

[0137] Prepare wettable powders using the oily original drug of the compound of formula I and crystalline form A of the compound of formula I prepared by the method of Example 1 respectively.

[0138] Table 10, Formulation of 10% Wettable Powder of Compound of Formula I

[0139] Raw material Mass fraction Remarks 98% technical material 10.00％ Technical material in the form of an oil or crystal form A Sodium dodecylbenzenesulfonate 2.00％ Wetting agent Sodium lignosulfonate 5.00％ Dispersant Naphthalene sulfonic acid formaldehyde condensate (NNO) 4.00％ Dispersant Silica white 10.00％ Filler Kaolin Make up Filler

[0140] Specific preparation method: Weigh each raw material according to the formulation and place it in a jet mill. After pulverization, a 10% wettable powder is obtained.

[0141] Table 11, Test Results of Product Indexes of 10% Wettable Powder

[0142]

[0143] It can be seen from the above table that under the same auxiliary agent system, the suspension rate of the wettable powder prepared from crystalline form A is 95.6%, and it is 95.4% after two weeks of heat storage at 54 °C; while the suspension rate of the wettable powder prepared from the oily original drug is 89.4%, and it is 87.8% after heat storage. The suspension rate of the wettable powder prepared from crystalline form A is higher, indicating that crystalline form A is easier to pulverize, thus increasing the suspension rate, and energy conservation and consumption reduction can also be achieved during large-scale production.

[0144] Example 18, Water Dispersible Granules

[0145] Prepare water dispersible granules using the oily original drug of the compound of formula I and crystalline form A of the compound of formula I prepared by the method of Example 1 respectively.

[0146] Table 12, Formulation of 10% Water Dispersible Granules of Compound of Formula I

[0147] Raw material Mass fraction Remarks 98% technical material 10.00％ Technical material in the form of an oil or crystal form A Sodium dodecylbenzenesulfonate 2.00％ Wetting agent Copolymer of acrylic acid and maleic anhydride 5.00％ Dispersant Naphthalene sulfonic acid formaldehyde condensate 2.00％ Dispersant Sodium sulfate 1.50％ Disintegrant Silica white 10.00％ Filler Kaolin Make up Filler

[0148] Specific preparation method: Weigh each raw material according to the formulation and place it in a jet mill. After pulverization, carry out water kneading, extrusion granulation, drying, and sieving in sequence to obtain 10% water dispersible granules.

[0149] Table 13, Test Results of Product Indexes of 10% Water Dispersible Granules

[0150]

[0151] It can be seen from the above table that under the same auxiliary agent system, the suspension rate of the water dispersible granules prepared from crystalline form A is 97.5%, and it is 97.3% after two weeks of heat storage at 54 °C; while the suspension rate of the water dispersible granules prepared from the oily original drug is 89.3%, and it is 89.1% after heat storage. The suspension rate of the water dispersible granules prepared from crystalline form A is higher, indicating that crystalline form A is easier to pulverize, thus increasing the suspension rate, and energy conservation and consumption reduction can also be achieved during large-scale production.

[0152] Example 19, Biological Assay

[0153] Test weeds: Eleusine indica and Digitaria sanguinalis

[0154] Test agents: The following agent formulations (D90 < 3) were prepared respectively according to the methods of Examples 16 and 17: 5% crystalline form A dispersible oil suspension, 5% oil dispersible oil suspension, 10% crystalline form A wettable powder, and 10% oil wettable powder

[0155] Test method: Stem and leaf spraying method (NY / T 1155.4 - 2006): Fill a pot with a height of 11 cm and a diameter of 9 cm with a certain amount of soil to 3 / 4 of the pot, sow the test targets (Eleusine indica and Digitaria sanguinalis) on the surface of the pot soil, cover with about 1 cm of fine soil, and place in a greenhouse for cultivation. When the weeds grow to the 4 - 5 leaf stage, conduct stem and leaf spraying treatment. Set different agent dose gradients, application dose: The four agents were applied at 30 g.a.i / ha, 22.5 g.a.i / ha, 15 g.a.i / ha, 11.25 g.a.i / ha, 7.5 g.a.i / ha, and 3.75 g.a.i / ha of the active ingredient respectively. Each treatment was replicated 4 times, and a treatment without the agent was set as the control. After treatment, the test materials were placed in the greenhouse for cultivation, and the growth of the weeds was observed regularly

[0156] Investigation method: Visually observe the damage symptoms and growth inhibition of the target in the test treatment. Weigh the fresh weight of the above - ground part 21 days after application, and calculate the fresh weight inhibition rate

[0157] Fresh weight inhibition rate (%) = (control fresh weight - treated fresh weight) / control fresh weight × 100%

[0158] Data analysis: Use DPS statistical software to analyze the data according to the agent dose and the fresh weight inhibition rate of the weeds, obtain the linear regression equation, correlation coefficient, and GR50 and GR95 values. The results are shown in Table 14

[0159] Table 14. Control efficacy results of crystalline form A and oil compounds against Eleusine indica and Digitaria sanguinalis

[0160]

[0161] As shown in Table 14, the results of regression analysis for all dosage forms showed that there was a significant linear correlation between the dosage of the agent and the weed growth inhibition rate (correlation coefficient ≥ 0.96), indicating that the experimental data of this test had good reliability. It is worth noting that the GR50 and GR95 values of the 5% crystalline form A oil suspension for Eleusine indica and Digitaria sanguinalis were the lowest, significantly superior to other dosage forms, indicating that it had the highest herbicidal activity. In contrast, the GR50 and GR95 values of the oil-based dosage forms (5% oil-based oil suspension and 10% oil-based wettable powder) were significantly higher than those of the crystalline form dosage forms, indicating that their control effects on Eleusine indica and Digitaria sanguinalis were significantly reduced. Therefore, the experimental data of this example clearly confirmed that the crystalline form A dosage form of the compound of formula I had a significant advantage over the oil-based dosage form in terms of herbicidal activity.

[0162] The above embodiments are only used to illustrate the technical solutions of the present invention, not to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that: they may still modify the technical solutions recorded in the foregoing embodiments, or perform equivalent replacements for some of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the various embodiments of the present invention.

Claims

1. A crystal form of Compound I, characterized in that It is polymorph A of Compound I, and the reflection angle 2θ of its X-ray powder diffraction pattern has characteristic absorption peaks at 7.0±0.2°, 10.5±0.2°, 12.0±0.2°, 12.6±0.2°, 16.5±0.2°, 20.2±0.2°; Compound I has the following chemical structure:

2. The crystalline form according to claim 1, wherein The reflection angle 2θ of its X-ray powder diffraction pattern has characteristic absorption peaks at 14.0±0.2°, 18.1±0.2°, 19.3±0.2°, 21.0±0.2°, 22.5±0.2°, 23.9±0.2°, 25.0±0.2°, 26.6±0.2°, 27.3±0.2°.

3. The crystalline form according to claim 1, wherein The reflection angle 2θ of its X-ray powder diffraction pattern has characteristic absorption peaks at 7.020, 10.498, 12.022, 12.637, 14.061, 16.521, 18.103, 19.319, 20.182, 21.082, 22.521, 23.918, 25.058, 26.640, 27.

338.

4. The crystalline form according to claim 1, characterized in that Its X-ray powder diffraction pattern is basically as shown in Figure 1.

5. The crystalline form according to claim 1, characterized in that The unit cell parameters of its single crystal are: crystal system Monoclinic, space group P21 / n; α = 90°, β = 95.139(2)°, γ = 90°; Volume 6. The crystalline form according to claim 1, wherein The DSC pattern of this polymorph A has an endothermic peak at 194-208°C.

7. The crystalline form according to claim 5, wherein The DSC pattern of this polymorph A is as shown in Figure 12 and has an endothermic peak at 201.61°C.

8. The crystalline form according to claim 1, characterized in that This polymorph A has an ultraviolet spectrum basically as shown in Figure 10 or an infrared spectrum basically as shown in Figure 11.

9. A method for preparing the crystal form according to claim 1, characterized in that Including steps S1, S2 or S3: S1) Under ultrasonic conditions, add a solvent dropwise to the oily crude drug of raw material Compound I until it becomes clear. With or without filtration, place the solution in a stable environment for crystallization. The solvent is selected from methyl tert-butyl ether, acetone, acetonitrile, N,N-dimethylformamide, o-xylene, toluene or a methanol-water mixed solvent; S2) Dissolve the oily crude drug of raw material Compound I and the solvent until clear under boiling conditions. With or without filtration, cool and crystallize; the solvent is selected from methanol, isopropanol, xylene, p-ethylbenzene or ethyl acetate; S3) After mixing and dissolving the oily crude drug of raw material Compound I with a good solvent, slowly add an anti-solvent to precipitate a solid. Collect the solid and dry it; the good solvent is selected from 1,2-dichloroethane or toluene, and the anti-solvent is selected from petroleum ether, n-hexane, n-octane, n-pentane or n-heptane.

10. A pesticide formulation, characterized in that It contains an effective dose of polymorph A of Compound I.

11. The pesticide formulation according to claim 10, characterized in that The preparation includes a water suspension concentrate, a dispersible oil suspension concentrate, a wettable powder or a water dispersible granule.

12. Use of polymorph A of Compound I as claimed in claim 1 in the preparation of a preparation for controlling unwanted plants.

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