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

Abstract

The invention discloses a crystal form B of a benzoxazine compound as well as a preparation method and application of the crystal form B. The crystal form B is the crystal form B of a compound I. The reflection angle 2 theta of an X-ray powder diffraction pattern of the crystal form B has characteristic absorption peaks at 5.6 + / -0.2 degrees, 8.9 + / -0.2 degrees, 12.8 + / -0.2 degrees, 13.8 + / -0.2 degrees, 14.5 + / -0.2 degrees and 17.6 + / -0.2 degrees. The crystal form B 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 crystal form B 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 (i.e., the following formula I) 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 is the active ingredient therein (collectively referred to as the technical material), and the technical material generally cannot be used directly. 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 existence states of this technical material, such as: crystal polymorphs (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 existence 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 compound of formula I provided in Patent US5084084A exists in the form of an oil, and it has various problems such as low grinding efficiency, low suspension rate, and unqualified dilution stability. In particular, oily pesticides usually have high volatility and persistence, increasing the risk to non-target organisms and the potential for pollution to the environment, especially groundwater. In terms of use, oily pesticides may require additional equipment for application, and may become viscous and difficult to operate at low temperatures, causing inconvenience during the processing. Moreover, various challenges may be encountered during the preparation of preparations. First of all, such substances often have low solubility in water, resulting in limited application in water-based preparations; secondly, it may affect the physical stability of the preparations, such as stratification or precipitation, especially more obvious when the temperature changes. Summary of the Invention

[0006] The object of the present invention is to solve the technical problems that the original drug of formula I and the preparation thereof in the existing oily substances have unstable storage and aggregation after storage, and cannot be prepared into a suitable composition or preparation. On the basis of the existing technology, a new crystal form of the compound of formula I, its preparation method and uses are provided.

[0007] After the inventors studied the original drug of formula I prepared in Patent US5084084A, it was found that there were many technical problems in the later 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 oily substance of formula I. These variants are also described below as crystal form B. The preparation method of crystal form B provided by the present invention has simple process operation, low economic cost, high product purity, good crystal form stability, and is easy to be industrialized and mass-produced.

[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 B of compound I, and has characteristic absorption peaks at reflection angles 2θ of 5.6±0.2°, 8.9±0.2°, 12.8±0.2°, 13.8±0.2°, 14.5±0.2°, 17.6±0.2° in its X-ray powder diffraction pattern; wherein compound I has the following chemical structure:

[0010]

[0011] In one embodiment, crystal form B of compound I of the present invention has the following single crystal cell parameters: crystal system Monoclinic, space group P21 / c; α = 90°, β = 101.573(10)°, γ = 90°.; volume

[0012] In a preferred embodiment, the reflection angles 2θ of the X-ray powder diffraction pattern of crystal form B of compound I of the present invention further have characteristic absorption peaks at 11.3±0.2°, 13.3±0.2°, 15.4±0.2°, 17.9±0.2°, 18.2±0.2°, 19.4±0.2°, 19.5±0.2°, 21.6±0.2°, 22.7±0.2°, 24.1±0.2°, 25.0±0.2°.

[0013] In a preferred embodiment, the X-ray powder diffraction pattern of Form B of Compound I of the present invention has characteristic absorption peaks at reflection angles 2θ of 5.6±0.1°, 8.9±0.1°, 11.3±0.1°, 12.8±0.1°, 13.3±0.1°, 13.8±0.1°, 14.5±0.1°, 15.4±0.1°, 17.6±0.1°, 17.9±0.1°, 18.2±0.1°, 19.4±0.1°, 19.5±0.1°, 21.6±0.1°, 22.7±0.1°, 24.1±0.1°, 25.0±0.1°.

[0014] In a preferred embodiment, the X-ray powder diffraction pattern of Form B of Compound I of the present invention has characteristic absorption peaks at reflection angles 2θ of 5.6, 8.9, 11.3, 12.8, 13.3, 13.8, 14.5, 15.4, 17.6, 17.9, 18.2, 19.4, 19.5, 20.8, 21.6, 22.7, 23.7, 24.1, 25.0, 25.8, 26.7, 27.0.

[0015] In a preferred embodiment, Form B of Compound I of the present invention shows the following reflections in the X-ray powder diffraction pattern at 25 °C and Cu-K radiation, 2-Theta values 5.6, 8.9, 11.3, 12.8, 13.3, 13.8, 14.5, 14.9, 15.4, 17.6, 17.9, 18.2, 19.4, 19.5, 20.4, 20.8, 21.6, 21.8, 22.7, 23.3, 23.5, 23.7, 24.1, 24.8, 25.0, 25.8, 26.7, 27.0, 27.7, 27.9, 28.5, 29.2, 29.6, 29.8, 30.2, 30.8, 31.0, 31.9, 32.7, 32.8, 33.4, 33.9, 34.0, 34.9, 35.1, 35.4, 35.6, 36.6, 37.9, 39.1, 39.6, 40.2, 41.1, 41.6, 42.1, 42.4, 43.0, 43.5, 44.2, 44.4.

[0016] In a preferred embodiment, the X-ray powder diffraction pattern of Form B of Compound I of the present invention is substantially as Figure 1 shown.

[0017] In a preferred embodiment, the DSC pattern of Form B of Compound I of the present invention has an endothermic peak at 194-210 °C.

[0018] In a preferred embodiment, the DSC pattern of Form B of Compound I of the present invention is as Figure 3 shown, having an endothermic peak at 202.67 °C.

[0019] In a preferred embodiment, polymorph B of compound I of the present invention has an ultraviolet spectrum substantially as Figure 4 shown.

[0020] In one embodiment, the infrared spectrum of polymorph B of compound I of the present invention shows at least the following bands (peak maxima recorded in cm -1 ): 3313.8, 3064.5, 1700.8, 1517.4, 1380.3, 1166.0, 1035.5. In a preferred embodiment, polymorph B has an infrared spectrum substantially as Figure 5 shown.

[0021] The single crystal data of the present invention can be collected on a single crystal X-ray diffractometer (Bruker D8 VENTURE) according to the general rules for the determination of crystal and molecular structures of small molecule compounds by four-circle single crystal X-ray diffractometer in JY / T 0588-2020.

[0022] The present invention provides a method for preparing polymorph B of compound I, which comprises steps S1, S2 or S3:

[0023] S1) Under ultrasonic conditions, a solvent is added dropwise to the oily crude drug of raw material 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 acetate, propylene oxide or a mixed solvent of propylene oxide and water;

[0024] S2) The oily crude drug of raw material compound I and the solvent are dissolved until clear under boiling conditions. With or without filtration, crystallization is carried out by cooling; the solvent is selected from propylene oxide, methyl acetate, 2-butanone or acetone;

[0025] S3) After the oily crude drug of raw material compound I is mixed and dissolved with a good solvent, an anti-solvent is slowly added to precipitate a solid, and the solid is collected and dried; the good solvent is selected from methyl acetate or tetrahydrofuran, and the anti-solvent is selected from petroleum ether, n-hexane, n-octane or n-heptane.

[0026] The present invention discloses a pesticide formulation, which contains an effective dose of polymorph B of compound I. Here, the pesticide formulation includes but is not limited to solid or liquid formulations such as emulsifiable concentrate, soluble liquid, dispersible liquid, microemulsion, suspo-emulsion, emulsion in water, water suspension, dispersible oil suspension, wettable powder, water dispersible granule, etc. In a preferred embodiment, a suspension concentrate (SC), wettable powder or water dispersible granule (WG) can be used. The excipients used in the formulation include but are not limited to dispersants, wetting agents, thickeners, antifreezing agents, fillers, dispersion media, etc.

[0027] Polymorph B of compound I provided by the present invention can be used in the preparation of agricultural herbicides, or the use of polymorph B in the preparation of preparations for controlling unwanted plants.

[0028] Advantages of the present invention:

[0029] 1. Polymorph B of compound I discovered in the present invention is a thermodynamically more stable crystal. It can be simply and conveniently stored at room temperature, is easy to industrialize and mass-produce, and is convenient for further processing and application of products;

[0030] 2. The overall process of the method of the present invention has low energy consumption, the mother liquor after purification can be reused multiple times, the generation of three wastes is small, and the production cost is low;

[0031] 3. Polymorph B of compound I can be prepared into various dosage forms such as dispersible oil suspensions. When the same particle size target is reached, compared with the original drug of formula I prepared according to US5084084A, the grinding time can be 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 with polymorph B has a small viscosity of the preparation, good water dispersion after dilution, no flocculation, and can better exert the drug effect.

[0032] 4. Polymorph B 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 suspensions, water-dispersible granules, wettable powders, etc., and the herbicidal activity against weeds is significantly improved. Description of the Drawings

[0033] Figure 1 is the X-ray powder diffraction pattern of polymorph B of compound I of the present invention;

[0034] Figure 2 is the single crystal diffraction pattern of polymorph B of compound I of the present invention;

[0035] Figure 3 is the DSC pattern of polymorph B of compound I of the present invention;

[0036] Figure 4 is the ultraviolet spectrum of polymorph B of compound I of the present invention;

[0037] Figure 5 is the infrared spectrum of polymorph B of compound I of the present invention;

[0038] Figure 6 is the XRD spectrum of the propylene oxide volatile crystallization powder of polymorph B of compound I of the present invention;

[0039] Figure 7 is the XRD spectrum of the propylene oxide-water volatile crystallization powder of polymorph B of compound I of the present invention;

[0040] Figure 8It is the powder XRD pattern of Form B of Compound I of the present invention by recrystallization from acetone (rapid cooling);

[0041] Figure 9 It is the powder XRD pattern of Form B of Compound I of the present invention with methyl acetate - antisolvent n - octane;

[0042] Figure 10 It is the powder XRD pattern of Form B of Compound I of the present invention by liquid - phase diffusion of tetrahydrofuran into n - heptane;

[0043] Figure 11 It is the comparison chart of Form B of Compound I of the present invention with various samples tested.

[0044] Figure 12 It is the single - crystal diffraction pattern of Form C of Compound I;

[0045] Figure 13 It is the powder XRD pattern of Form C of Compound I. Detailed Description of the Invention

[0046] 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.

[0047] The compound shown by the formula I structure in the present invention can also be abbreviated as Compound I of formula I, Compound I or Compound (I).

[0048] Example 1: Preparation of Form B of Compound I

[0049] Preparation of single crystal of Form B of Compound I: Using the crude drug of Compound I in oily form as raw material, about 30 mg was weighed. Under ultrasonic conditions, methyl acetate was added dropwise until it reached a clear solution state and then filtered. The filtered solution was placed in a stable environment for single - crystal cultivation of the crystal form. After 7 days, a sample of the single crystal of the crystal form was taken for testing.

[0050] The X - ray powder diffraction pattern of the single crystal of Form B of Compound I is as Figure 1 shown, and the single - crystal diffraction pattern of Form B is as Figure 2 shown. In Figure 1 , the specific single - crystal data are shown in Table 1.

[0051] Table 1 - Powder XRD data of single - crystal sample of Form B

[0052]

[0053]

[0054] The X-ray powder diffraction pattern at 25 °C and Cu-K radiation shows at least the following reflections, denoted as 2-Theta values: 5.6 ± 0.2 °, 8.9 ± 0.2 °, 12.8 ± 0.2 °, 13.8 ± 0.2 °, 14.5 ± 0.2 °, 17.6 ± 0.2 °.

[0055] More specifically, the B crystal form of Compound I shows the following reflections in the X-ray powder diffraction pattern at 25 °C and Cu-K radiation, with 2-Theta values of 5.6, 8.9, 11.3, 12.8, 13.3, 13.8, 14.5, 14.9, 15.4, 17.6, 17.9, 18.2, 19.4, 19.5, 20.4, 20.8, 21.6, 21.8, 22.7, 23.3, 23.5, 23.7, 24.1, 24.8, 25.0, 25.8, 26.7, 27.0, 27.7, 27.9, 28.5, 29.2, 29.6, 29.8, 30.2, 30.8, 31.0, 31.9, 32.7, 32.8, 33.4, 33.9, 34.0, 34.9, 35.1, 35.4, 35.6, 36.6, 37.9, 39.1, 39.6, 40.2, 41.1, 41.6, 42.1, 42.4, 43.0, 43.5, 44.2, 44.4.

[0056] Table 2, Figure 2 Single crystal data table of crystal form B in

[0057]

[0058] Example 2. Volatile crystallization of B crystal form powder XRD

[0059] Using the crude drug of Compound I in oil form as the raw material, the preparation method is as follows: Weigh about 30 mg of the crude drug sample, and under ultrasonic conditions, add dropwise the solvent (propylene oxide) until it becomes clear. For slightly soluble cases, it can be added up to 10 ml, and in principle, not exceeding 20 ml, and a filtration operation is required. Place the filtered solution in a stable environment for volatile crystallization. The XRD spectrum of the volatile sample powder of propylene oxide is as Figure 6 shown.

[0060] Example 3. Volatile crystallization of A crystal form powder XRD with a mixed solvent of water

[0061] Using the crude drug of Compound I in oil form as the raw material, the preparation method is as follows: Weigh about 30 mg of the crude drug sample, and under ultrasonic conditions, add dropwise the mixed solvent (V 环氧丙烷 : V 水= 95:5) until a clear solution state is reached; it is also possible to directly perform a filtration operation in a slightly soluble situation, and place the filtered solution in a stable environment for volatilization crystallization. The XRD spectra of the propylene oxide and water volatilization sample powders are as follows Figure 7 as shown.

[0062] Example 4. XRD of recrystallized B crystal form powder (slow cooling)

[0063] Using the crude drug of Compound I in oil form as the raw material, the preparation method is as follows: Weigh approximately 200 mg of the raw drug sample, use acetone 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 a clear solution is obtained. There is no need for filtration. Then, turn off the heating device and transfer it to a normal temperature environment for cooling and crystallization

[0064] The XRD spectra of the acetone recrystallized slow cooling powder are as follows Figure 8 as shown.

[0065] Example 5. XRD of B crystal form powder by anti-solvent method

[0066] Using methyl acetate as the solvent, crystal form B samples can be obtained under the condition of anti-solvent n-octane.

[0067] Using the crude drug of Compound I in oil form as the raw material, the preparation method is as follows: Weigh approximately 50 mg of the raw drug sample, add an appropriate volume of good solvent (methyl acetate) to completely dissolve it, and then dropwise add the anti-solvent (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 solids.

[0068] The XRD spectra of methyl acetate - anti-solvent n-octane powder are as follows Figure 9 as shown.

[0069] Example 6. XRD of A crystal form powder by liquid phase diffusion

[0070] Using toluene as the solvent, crystal form A samples can be obtained under the condition of liquid phase diffusion.

[0071] 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 raw drug sample, prepare 3.0 ml of a saturated solution of tetrahydrofuran. Take 2.5 ml of the saturated solution and add it to a long test tube. Dilute the remaining 0.5 ml with the solvent to 1 ml as the buffer solution, and add it along the wall of the test tube. Then, slowly add 8 ml of the poor solvent (n-heptane), seal it and store it in a stable environment, waiting for diffusion crystallization.

[0072] The XRD spectra of tetrahydrofuran - liquid phase diffusion - n-heptane powder are as follows Figure 10 as shown.

[0073] Example 7, Comparison of Powder XRD Overlay Plots

[0074] The powder XRD spectra in Examples 2 - 6 above were compared with Figure 1 to determine that each crystallization belonged to Form B.

[0075] The results are as Figure 11 shown.

[0076] Example 8, Ultraviolet (UV)

[0077] The Form B of the compound of Formula I obtained in Example 1 was tested by ultraviolet (UV), and the results are as Figure 4 shown.

[0078] Table 3, Ultraviolet Data Table of Form B

[0079]

[0080] Example 9, Infrared (IR)

[0081] The Form B of the compound of Formula I obtained in Example 1 was tested by infrared (IR), and the results are as Figure 5 shown.

[0082] The infrared spectrum of Form B showed the following bands (peak maxima in cm -1 ): 441.6, 477.5, 497.4, 528.3, 549.1, 565.1, 584.6, 612.0, 633.7, 659.4, 687.4, 709.6, 736.1, 759.1, 786.5, 828.5, 880.2, 911.3, 930.7, 1008.8, 1035.5, 1064.5, 1083.2, 1166.0, 1220.3, 1273.3, 1295.4, 1380.3, 1406.0, 1422.1, 1457.6, 1517.4, 1615.6, 1700.8, 1728.6, 2978.5, 3064.5, 3079.8, 3313.8, 3409.0.

[0083] The infrared spectrum of Form B showed at least the following bands (peak maxima in cm -1 ): 3313.8, 3064.5, 1700.8, 1517.4, 1380.3, 1166.0, 1035.5.

[0084] Example 10, Differential Scanning Calorimetry (DSC)

[0085] The Form B of the compound of Formula I obtained in Example 1 was tested by DSC, and the results are as Figure 3 shown.

[0086] For the DSC test of the polymorph B sample, the temperature range is 50 - 250 °C, the melting point is 194 - 210 °C, and the highest temperature of change is 202.67 °C.

[0087] Example 11. Preparation and XRD of Polymorph C

[0088] Weigh approximately 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 evaporation crystallization to obtain the 1,4 - dioxane solvate, named polymorph C.

[0089] After performing single - crystal diffraction testing on this polymorph C sample, its unit cell parameters are 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 12 shown.

[0090] Table 4. Single - crystal data table of polymorph C

[0091]

[0092] For this polymorph C, it is measured using a diffractometer with Cu - K radiation. Its X - ray powder diffraction pattern is as Figure 13 shown.

[0093] Example 12. Stability of Polymorph C

[0094] The polymorph C sample of the compound has a good crystalline state.

[0095] In the stability experiment, under the conditions of 45 °C and 75% RH, the XRD data results of the polymorph C powder show that there is a phenomenon of crystal transformation in polymorph C, and it will gradually transform into polymorph B. At the same time, when measuring the melting point of polymorph C using differential scanning calorimetry, the results show that there is an obvious crystal transformation peak, approximately around 161 °C.

[0096] In addition, according to the preliminary compilation reference of the carcinogen list published by the International Agency for Research on Cancer of the World Health Organization, 1,4 - dioxane is in the 2B category of carcinogen list.

[0097] Example 13. 5% Aqueous Suspension Concentrate

[0098] Prepare 5% aqueous suspension concentrate using the oily raw drug of Compound I and polymorph B of Compound I prepared by the method of Example 1 respectively; specific preparation method:

[0099] Weigh each raw material according to the formula. Place the raw materials except xanthan gum in the feed tank and shear them with a shear machine for 2 minutes. Wait until the technical material and the additives are fully and evenly mixed. Then, use a vertical sand mill to grind them at 1800 revolutions per minute until the particle size D90 < 1 μm. Add 2% xanthan gum solution and stir at high speed for 10 minutes until the xanthan gum is fully mixed and swollen, obtaining a 5% aqueous suspension concentrate.

[0100] Table 5. Formulation of 5% aqueous suspension concentrate of compound (I)

[0101]

[0102] Table 6. Comparison of particle sizes at different grinding times

[0103]

[0104] Note: The value of D50 indicates that 50% of the particle size of the aqueous suspension concentrate is smaller than this value; similarly, D90 and D98 respectively indicate that 90% and 98% of the particle size of the aqueous suspension concentrate is smaller than this value.

[0105] 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).

[0106] From the detection results of the laser particle size analyzer, at the same grinding time, the particle size of crystal form B is always smaller. The grinding efficiency of crystal form B is better than that of the oily technical material. For example, when grinding for 2 hours, the D90 of the aqueous suspension concentrate prepared from crystal form B reached 2.1134 μm, meeting the product index requirements; while for the aqueous suspension concentrate prepared from the technical material, the 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, crystal form B is easier to grind and has a higher grinding efficiency. And crystal form B is more sensitive to grinding time. Especially after long-term (4h) grinding, there are significant differences in its D50, D90, and D98. 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 crystal form B has higher market value.

[0107] The technical materials and preparations of different crystal forms were respectively stored at 40 °C, 54 °C, and 70 °C for two weeks, and the stability test results are shown in Table 7.

[0108] Table 7. Stability of technical materials and preparations of different crystal forms under different temperature conditions

[0109]

[0110] As can be seen from the above table, there is no difference in the decomposition rate of the B crystal form of the compound of formula I and the original drug during heat storage at 40 °C. However, differences in the decomposition rate between the B crystal form and the original drug occur during heat storage at 54 °C and 70 °C, especially a highly significant difference in the decomposition rate during heat storage at 70 °C. The heat storage results of the suspending agents prepared with the two original drugs under different temperature conditions also show significant differences, and the differences become more obvious with the increase in temperature. In the industry, heat storage at 54 °C for two weeks usually represents the data of normal temperature storage for two years. Therefore, as can be seen from the above table, the stability of the B crystal form is significantly improved compared to the original drug. The purpose of the experiment at 70 °C is to simulate the stability of the goods when passing through the equator in the container. The data shows that the higher the temperature, the higher the decomposition rate of the original drug. The B crystal form is more stable, has a longer shelf life, and has good application prospects.

[0111] Example 14. Dispersible oil-based suspension concentrate

[0112] The dispersible oil-based suspension concentrate was prepared using the oily original drug of the compound of formula I and the crystal form B of the compound of formula I prepared by the method of Example 1, respectively.

[0113] Table 8. Formulation of 5% dispersible oil-based suspension concentrate of the compound of formula (I)

[0114] Raw material Mass fraction Remarks 98% technical material 5.00％ Technical material and polymorph B Calcium dodecylbenzenesulfonate 5.00％ Emulsifying and dispersing agent Fatty alcohol polyoxyethylene ether 8.00％ Emulsifying and dispersing agent Castor oil polyoxyethylene ether 1.00％ Emulsifying and dispersing agent Organic bentonite 1.00％ Thickening agent Methyl oleate Make up Dispersion medium

[0115] Specific preparation method: Weigh each raw material according to the formula and place it in the feed tank. Stir with a high-shear dispersion emulsifier for 3 minutes. After the original drug, auxiliary agents, and solvents are fully mixed evenly, use a vertical sand mill to grind at 1800 revolutions per minute until the particle size D90 < 3 μm to obtain a 5% dispersible oil-based suspension concentrate.

[0116] Table 9. Comparison of particle sizes at different grinding times

[0117]

[0118] Comparison of grinding efficiency of dispersible oil-based suspension concentrates of different forms of the compound of formula I: Significant differences in D50, D90, and D98 of the suspension concentrates prepared from different forms of the compound of formula I occur; compared with the grinding particle size of the water-based suspension concentrate, the oil-based suspension concentrate is more difficult to grind, but the B crystal form still shows certain grinding advantages compared to the original drug.

[0119] Example 15. Wettable powder

[0120] The wettable powder was prepared using the oily original drug of the compound of formula I and the crystal form B of the compound of formula I prepared by the method of Example 1, respectively.

[0121] Table 10. Formulation of 10% wettable powder of the compound of formula I

[0122] Raw material Mass fraction Remarks 98% technical material 10.00％ Technical material and polymorph B Sodium dodecylbenzenesulfonate 2.00％ Wetting agent Sodium lignosulfonate 5.00％ Dispersing agent Naphthalene sulfonic acid formaldehyde condensate (NNO) 4.00％ Dispersing agent Silica white 10.00％ Filler Kaolin Make up Filler

[0123] Specific preparation method: Weigh each raw material according to the formula and place it in an air-flow pulverizer. After pulverization, a 10% wettable powder is obtained.

[0124] Table 11. Detection results of product indicators of 10% wettable powder

[0125]

[0126]

[0127] It can be seen from the above table that under the same adjuvant system, the suspension rate of the wettable powder prepared from crystal form B is 94.3%, and it is 94.1% after two weeks of heat storage at 54°C; while the suspension rate of the wettable powder prepared from the technical material is 89.4%, and it is 87.8% after heat storage. The suspension rate of the wettable powder prepared from crystal form B is higher, indicating that crystal form B is easier to pulverize, thus increasing the suspension rate, and energy conservation and consumption reduction can also be achieved during large-scale production.

[0128] Example 16. Water dispersible granules

[0129] Use the oily technical material of the compound of formula I and crystal form B of the compound of formula I prepared by the method of Example 1 to prepare wettable powders respectively.

[0130] Table 12. Formulation of 10% water dispersible granules of the compound of formula I

[0131] Raw material Mass fraction Remarks 98% technical material 10.00％ Technical material in the form of an oil or polymorph B Sodium dodecylbenzenesulfonate 2.00％ Wetting agent Copolymer of acrylic acid and maleic anhydride 5.00％ Dispersing agent Naphthalene sulfonic acid formaldehyde condensate 2.00％ Dispersing agent Sodium sulfate 1.50％ Disintegrant Silica white 10.00％ Filler Kaolin Make up Filler

[0132] Specific preparation method: Weigh each raw material according to the formula and place it in an air-flow pulverizer. After pulverization, carry out water addition and kneading, extrusion granulation, drying, and sieving in sequence to obtain 10% water dispersible granules.

[0133] Table 13. Detection results of product indicators of 10% water dispersible granules

[0134]

[0135] It can be seen from the above table that under the same adjuvant system, the suspension rate of the water dispersible granules prepared from crystal form B is 96.4%, and it is 96.3% after two weeks of heat storage at 54°C; while the suspension rate of the water dispersible granules prepared from the technical material is 89.3%, and it is 89.1% after heat storage. The suspension rate of the water dispersible granules prepared from crystal form B is higher, indicating that crystal form B is easier to pulverize, thus increasing the suspension rate, and energy conservation and consumption reduction can also be achieved during large-scale production.

[0136] Example 17. Biological assay

[0137] Test weeds: Eleusine indica, Digitaria sanguinalis.

[0138] Test agents: The following dosage forms (D90 < 3) were prepared according to the methods of Examples 14 and 15: 5% crystalline form B dispersible oil suspension, 5% oil dispersible oil suspension, 10% crystalline form B wettable powder, and 10% oil wettable powder.

[0139] Test method: The stem and leaf spraying method (NY / T 1155.4 - 2006) was used. Quantitative soil was filled to 3 / 4 of a pot with a height of 11 cm and a diameter of 9 cm. The test targets (goosegrass, crabgrass) were sown on the surface of the pot soil, covered with about 1 cm of fine soil, and then placed in a greenhouse for cultivation. When the weeds grew to the 4 - 5 leaf stage, stem and leaf spraying treatment was carried out. Different dosage gradients of the agents were set, and the application doses were as follows: the four agents were applied at the active ingredient doses of 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 respectively. Each treatment had 4 replicates, and a treatment without the agent was set as a control. After treatment, the test materials were placed in the greenhouse for cultivation, and the growth of the weeds was observed regularly.

[0140] Investigation method: The test treatments visually observed the damage symptoms and growth inhibition of the targets. 21 days after spraying, the fresh weight of the above - ground parts was weighed, and the fresh weight inhibition rate was calculated.

[0141] Fresh weight inhibition rate (%) = (control fresh weight - treated fresh weight) / control fresh weight × 100%

[0142] Data analysis: The logarithm of the agent dosage and the probit value of the weed fresh weight inhibition rate were regressed using DPS statistical software, and the correlation coefficient, GR50, and GR95 were calculated. The results are listed in Table 14 respectively.

[0143] Table 14. Control efficacy results of crystalline form B and oil compounds against goosegrass and crabgrass

[0144]

[0145] As shown in Table 14, the regression analysis results of all dosage forms showed that there was a significant linear correlation between the agent dosage 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 B oil suspension against goosegrass and crabgrass were the lowest, significantly better than other dosage forms, indicating that it had the highest herbicidal activity. In contrast, the GR50 and GR95 values of the oil dosage forms (5% oil dispersible oil suspension and 10% oil wettable powder) were significantly higher than those of the crystalline form B dosage form, indicating that their control effects on goosegrass and crabgrass were significantly reduced. Therefore, the experimental data of this example clearly confirmed that the crystalline form B dosage form of the compound of formula I had a significant advantage over the oil dosage form in terms of herbicidal activity.

[0146] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit them; 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: it is still possible to modify the technical solutions described in the foregoing embodiments, or perform equivalent replacements for some of the technical features; and these modifications or replacements do not cause the essence of the corresponding technical solutions to 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 B of Compound I, and its X-ray powder diffraction pattern has characteristic absorption peaks at reflection angles 2θ of 5.6±0.2°, 8.9±0.2°, 12.8±0.2°, 13.8±0.2°, 14.5±0.2°, and 17.6±0.2°; Compound I has the following chemical structure:

2. The crystalline form according to claim 1, wherein The unit cell parameters of single crystal of polymorph B are: crystal system Monoclinic, space group P21 / c; α = 90°, β = 101.573(10)°, γ = 90°.; volume 3. The crystalline form according to claim 1, wherein Its X-ray powder diffraction pattern has characteristic absorption peaks at reflection angles 2θ of 11.3±0.2°, 13.3±0.2°, 15.4±0.2°, 17.9±0.2°, 18.2±0.2°, 19.4±0.2°, 19.5±0.2°, 21.6±0.2°, 22.7±0.2°, 24.1±0.2°, and 25.0±0.2°.

4. The crystalline form according to claim 1, characterized in that Its X-ray powder diffraction pattern has characteristic absorption peaks at reflection angles 2θ of 5.6, 8.9, 11.3, 12.8, 13.3, 13.8, 14.5, 15.4, 17.6, 17.9, 18.2, 19.4, 19.5, 20.8, 21.6, 22.7, 23.7, 24.1, 25.0, 25.8, 26.7, and 27.

0.

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

6. The crystalline form according to claim 1, wherein The DSC spectrum of polymorph B has an endothermic peak at 194-210 °C; the infrared spectrum of polymorph B shows at least the following bands (in cm -1 recorded peak maxima): 3313.8, 3064.5, 1700.8, 1517.4, 1380.3, 1166.0, 1035.

5.

7. The crystalline form according to claim 6, characterized in that The DSC pattern of this polymorph B is as shown in Figure 3, with an endothermic peak at 202.67 °C, or this polymorph B has an ultraviolet spectrum basically as shown in Figure 4, or this polymorph B has an infrared spectrum basically as shown in Figure 5.

8. A method for preparing the crystal form according to claim 1, characterized in that It includes 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, and under the condition of filtering or not filtering, place the solution in a stable environment for crystallization; the solvent is selected from methyl acetate, propylene oxide, or a propylene oxide-water mixed solvent; S2) Dissolve the oily crude drug of raw material Compound I and the solvent until clear under boiling conditions, and under the condition of filtering or not filtering, cool and crystallize; the solvent is selected from propylene oxide, methyl acetate, 2-butanone, or acetone; 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 methyl acetate or tetrahydrofuran, and the anti-solvent is selected from petroleum ether, n-hexane, n-octane, or n-heptane.

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

10. The pesticide formulation according to claim 9, characterized in that The preparation includes a water suspension, a dispersible oil suspension, a wettable powder, or a water dispersible granule.

11. Use of the polymorph B of Compound I according to claim 1 in the preparation of a preparation for controlling unwanted plants.

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