New crystal form of isoxazoline uracil compound, preparation method, and herbicide and use

Abstract

A new crystal form of an isoxazoline uracil compound represented by formula (1), a preparation method, and an herbicide containing the new crystal form of an isoxazoline uracil compound and the use thereof. An X-ray powder diffraction pattern of the new crystal form has characteristic peaks at diffraction angles 2θ of 6.3 ± 0.2, 7.2 ± 0.2, 11.2 ± 0.2, 14.3 ± 0.2, 17.3 ± 0.2, 19.6 ± 0.2, 20.7 ± 0.2, 24.3 ± 0.2, 25.2 ± 0.2 and 26.1 ± 0.2. The new crystal form solves the problems of pipeline blockage during production, difficulty in acquiring materials, inaccurate metering, and difficulty in storage and sub-packaging caused by oily isoxazoline uracil compounds in the prior art. In formula (1), R1 is fluorine, R2 is chlorine, R3 and R4 are hydrogen, R5 is CO2C2H5, and R6 is methyl.

Description

New crystal form, preparation method, herbicide and application of isoxazoline uracil compounds Technical Field

[0001] The present invention relates to the technical field of C07D413 / 10, and more specifically, to a new crystal form of an isoxazoline uracil compound, a preparation method, a herbicide, and applications thereof. Background Art

[0002] Isoxazoline-uracil compounds can remove weeds during the growth of soybeans, cotton, vegetables, corn, peanuts, etc. The isoxazoline-uracil compounds currently prepared are all oily substances. For example, Chinese patent CN201811146442 reacts compound II with chloroform to obtain an oily isoxazoline-uracil compound, and the last step to obtain the product is to evaporate the solvent. This method will be difficult to scale up, especially in production, especially when the product is an oily substance. The solvent is difficult to evaporate completely, and the oily substance cannot be dried, so that the content of the product cannot meet the requirements. In addition, due to its viscosity, the oily substance may cause low-temperature solidification during production, causing blockage of the production equipment pipeline and difficulty in discharging. The oily viscous substance also causes a series of problems such as difficulty in metering, material collection, packaging, transportation, and dissolution. Summary of the Invention

[0003] In response to some problems existing in the prior art, the first aspect of the present invention provides a new crystal form of an isoxazoline uracil compound, whose X-ray powder diffraction pattern has characteristic peaks at diffraction angles 2θ of 6.3±0.2, 7.2±0.2, 11.2±0.2, 14.3±0.2, 17.3±0.2, 19.6±0.2, 20.7±0.2, 24.3±0.2, 25.2±0.2, and 26.1±0.2.

[0004] Among them, the isoxazoline uracil compound is shown in the following formula (1): In formula (1), R1 is fluorine, R2 is chlorine, R3 and R4 are hydrogen, R5 is CO2C2H5, and R6 is methyl.

[0005] In one embodiment, the X-ray powder diffraction pattern thereof further has characteristic peaks at diffraction angles 2θ of 27.7±0.2, 29.3±0.2, 30.3±0.2, 31.8±0.2, and 33.2±0.2.

[0006] In one embodiment, the isoxazoline uracil compound has the characteristic diffraction peak shown in the XRD pattern shown in FIG1 .

[0007] The specific properties of isoxazoline-uracil compounds in the prior art result in them being oily and viscous. However, this oily and viscous material may cause low-temperature solidification of the material during product production, resulting in blockage of pipelines in the production equipment and difficulty in material discharge. Furthermore, when used as a herbicide, this oily and viscous material may be difficult to access, accurately measure, and feed, and the solvent may be difficult to evaporate and dry, resulting in product content that does not meet requirements. Furthermore, the oily and viscous material has no fixed form during transportation and storage, making it difficult to package. During use, when dissolved in a solvent, it becomes viscous and easily adheres to the stirring paddle, resulting in a slow dissolution rate. The applicant unexpectedly discovered a new crystal form of the compound during the experiment, which has characteristic peaks at diffraction angles 2θ of 6.3±0.2, 7.2±0.2, 11.2±0.2, 14.3±0.2, 17.3±0.2, 19.6±0.2, 20.7±0.2, 24.3±0.2, 25.2±0.2, and 26.1±0.2. This crystal form of the isoxazoline uracil compound makes it a powdery solid form, solving a series of problems caused by the oily substance caused by the crystal form in the prior art.

[0008] In one embodiment, as shown in FIG2 , the new crystal form is a bundle of rod-shaped crystals or a block of crystals.

[0009] Preferably, the length of the rod-shaped crystals is 100 nm to 10 mm.

[0010] The applicant unexpectedly discovered that when the crystalline form of the isoxazoline-uracil compound is a bundle of crystals or block crystals aggregated from rod-shaped crystals, especially when the length of the rod-shaped crystals is 100 nm to 10 mm, not only does the isoxazoline-uracil compound maintain a powdered solid form, but the powdered solid is also more easily dispersed and dissolved during the process of preparing the powdered solid into a formulation. The applicant believes that the possible reason is that the orderly arrangement of the rod-shaped crystals between the bundles or block crystals promotes their fluidity under the action of organic or inorganic solvents. At the same time, the solvent easily diffuses between the rod-shaped crystals, increasing the dispersion between the rod-shaped crystals.

[0011] In one embodiment, its infrared spectrum, at 458±2cm -1 、516±2cm -1 、565±2cm -1 、603±2cm -1 、632±2cm -1 、674±2cm -1 、715±2cm -1 、746±2cm -1 、781±2cm -1 、985±2cm -1 、1066±2cm -1、1402±2cm -1 、1629±2cm -1 、3239±2cm -1 The characteristic absorption peak is shown at the wave number of .

[0012] Preferably, the new crystal form of the isoxazoline uracil compound has the characteristic diffraction peaks shown in the XRD diagram shown in FIG3 .

[0013] In one embodiment, its proton nuclear magnetic resonance spectrum has the following peaks, 1 H NMR (400MHz, CDCl3) δ7.67(d,J=7.6Hz,1H),7.35(d,J=9.0Hz,1H),6.35(s,1H),4.26(q,J=7.1Hz,2H),4.00 (t,J=16.8Hz,1H),3.54(s,3H),3.39(dd,J=17.4,13.9Hz,1H),1.70(d,J=1.4Hz,3H),1.32(t,J=7.1Hz,3H).

[0014] In one embodiment, its carbon NMR spectrum has the following peaks, 13 C NMR(101MHz, CDCl3)δ171.57(s),159.74(s),159.33(s),156.76(s),154.43(s),150.52 (s),141.83(q,J=34.7Hz),134.74(d,J=9.8Hz),131.90(d,J=1.2Hz),125.87(d,J=4.0Hz ),121.40(d,J=14.0Hz),119.35(q,J=276.7Hz),119.30(s),119.07(s),102.98(q,J=5. 5Hz), 87.13 (d, J = 1.7Hz), 62.10 (s), 46.53 (s), 32.69 (q, J = 3.6Hz), 23.28 (s), 14.06 (s).

[0015] In one embodiment, the DSC spectrum thereof has an absorption peak at 360-390°C and an exothermic peak at 60-100°C.

[0016] Preferably, the new crystal form has an absorption exothermic peak as shown in the DSC diagram shown in FIG4 .

[0017] The applicant unexpectedly discovered that, as shown in the absorption and exothermic peaks in Figure 4 of the present application, the new crystal form of the isoxazoline-uracil compound enables the isoxazoline-uracil compound to have better storage stability, which is significantly improved compared to the oily isoxazoline-uracil compounds in the prior art. This may be because the molecular arrangement of this isoxazoline-uracil compound is relatively regular, which improves its heat resistance, and when it is exposed to a certain amount of organic solvent or water, the molecules can be quickly dispersed.

[0018] The test conditions of the XRD pattern of the novel crystalline isoxazoline uracil compound in the present application are as follows: absorption coefficient = 0; activated absorber = 0; α1 = 1.5406; α2 = 1.54439; α average = 1.54184; alpha ratio = 0.5; analyzer = 0; anode = copper; anti-scattering slit = 6.9; beam optical index = 189; β = 1.39222; β relative intensity = 0; deactivated absorber = 0; detector slit = 12.21; divergence slit = 0.6; goniometer control = 9999; goniometer diameter = 500; goniometer model = 516; goniometer level = 0; monochromator = 0; near sample slit = 0; primary Soller slit = 2.5; sample converter = 0; secondary Soller slit = 2.5; synchronization axis = 0; film attachment = 0; wave unit = A; the actual used λ = 1.5406; Additional Detector Mask = 257; Data Record Length = 4; Delay Time = 0; Display Plane Number = 0; Estimated Sweep Time = 0; Additional Parameter Mask = 0; Generator Current = 40; Generator Voltage = 40; Increment = 0.0194797; Increment by 3 = 0; Number of Completed Data = 2824; Number of Counts = 1; Number of Detectors = 0; Number of Drives = 2; Number of Encoder Drives = 0; Number of Measurement Data = 2824; Number of Variable Parameters = 0; Range Start Time = 1088421888; Speed ​​= 0; Sweep Mode = 1; Sweep Type = Locked Coupling; Simulate Meas Condition = 0; Seam Changer Inches = 9999; Smooting Width = 0; Starts = 5; Number of Steps = 2824; Synchronous Rotation = 0; Time = 19.2

[0019] DSC spectrum test conditions: instrument: NETZSCH STA449F3; sample: 1; sample mass / mg: 8; material: empty; reference mass / mg: 0; crucible type: DSC / TGpanAl2O3; sample crucible mass / mg: 0; reference crucible mass / mg: 0; correction code: 20; EXO: 1; range: 30 / 15.0 (K / min) / 500; segment: S1 / 1.

[0020] SEM test conditions: Gemini SEM 300, Mag = 1.00KX, WD = 8.2mm, EHT = 5.00kV, ESB Grid is = 0V, Signal A = lnLens, Column Mode = Analytical.

[0021] In one embodiment, the preparation method of the new crystal form includes: 3-(2-chloro-4-fluoro-5-(2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)phenyl)-5-methyl-4,5-dihydroisoxazole-5-carboxylic acid ethyl ester is completely reacted with monochloromethane in toluene, washed with water, toluene is removed, a solvent is added dropwise to dissolve, the temperature is increased, and then the temperature is reduced for recrystallization to obtain the crystal form.

[0022] Those skilled in the art can obtain the new crystal form in the present application by conventional selection according to the preparation method of the new crystal form in the present application.

[0023] The second aspect of the present invention provides a herbicide comprising the novel crystalline isoxazoline-uracil compound and one or more pharmaceutically acceptable carriers and / or adjuvants.

[0024] The third aspect of the present invention provides a use of the herbicide in controlling foxtail grass, barnyard grass, sedge grass, sedge grass, crabgrass, and water sedge.

[0025] Compared with the prior art, the present invention has the following beneficial effects:

[0026] The present invention provides a new crystal form of an isoxazoline-uracil compound, which solves the problems of oily isoxazoline-uracil compounds in the prior art, such as pipeline blockage, difficulty in material collection, inaccurate metering, and difficulty in storage and packaging during production. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] FIG1 is an XRD pattern of a new crystalline form of an isoxazoline uracil compound, namely, benzylpyrimidine, according to the present invention;

[0028] FIG2 is an SEM image of a new crystal form of the isoxazoline uracil compound of the present invention, namely, benzylpyrimidine;

[0029] FIG3 is an infrared spectrum of the isoxazoline uracil compound of the present invention, namely, a new crystal form of benzylpyrimidine;

[0030] FIG4 is a DSC spectrum of the isoxazoline uracil compound of the present invention, namely, a new crystal form of benzylpyrimidine;

[0031] FIG5 is a hydrogen NMR spectrum of the isoxazoline uracil compound of the present invention, namely, a new crystal form of benzylpyrimidine;

[0032] FIG6 is a carbon NMR spectrum of the isoxazoline uracil compound of the present invention, namely, a new crystal form of benzylpyrimidine. DETAILED DESCRIPTION

[0033] The present invention is described below by way of specific embodiments, but is not limited to the specific embodiments given below.

[0034] Example 1

[0035] A new crystalline form of an isoxazoline uracil compound (benzacloazole, (3-(2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)phenyl)-5-methyl-4,5-dihydroisoxazole-5-carboxylic acid ethyl ester)) is shown in FIG1 . The X-ray powder diffraction pattern thereof is shown in FIG1 . The diffraction angle 2θ is 6.3±0.2 , 7.2±0.2, 11.2±0.2, 14.3±0.2, 17.3±0.2, 19.6±0.2, 20.7±0.2, 24.3±0.2, 25.2±0.2, 26.1±0.2, 27.7±0.2, 29.3±0.2, 30.3±0.2, 31.8±0.2, and 33.2±0.2 have characteristic peaks. As shown in Figure 2, the new crystal form is a bundle of rod-shaped crystals or block crystals, and the length of the rod-shaped crystals is 100nm-10mm. As shown in Figure 3, in its infrared spectrum, at 458±2cm -1 、516±2cm -1 、565±2cm -1 、603±2cm -1 、632±2cm -1 、674±2cm -1 、715±2cm -1 、746±2cm -1 、781±2cm -1 、985±2cm -1 、1066±2cm -1 、1402±2cm -1 、1629±2cm -1 、3239±2cm -1 The characteristic absorption peak is shown at the wave number of . As shown in Figure 4, the DSC spectrum has an absorption peak at 360-390℃ and an exothermic peak at 60-100℃. As shown in Figure 5, the nuclear magnetic resonance hydrogen spectrum has the following peaks, 1H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 7.6 Hz, 1H), 7.35 (d, J = 9.0 Hz, 1H), 6.35 (s, 1H), 4.26 (q, J = 7.1 Hz, 2H), 4.00 (t, J = 16.8 Hz, 1H), 3.54 (s, 3H), 3.39 (dd, J = 17.4, 13.9 Hz, 1H), 1.70 (d, J = 1.4 Hz, 3H), 1.32 (t, J = 7.1 Hz, 3H). As shown in Figure 6, its carbon NMR spectrum has the following peaks: 13 C NMR(101MHz, CDCl3)δ171.57(s),159.74(s),159.33(s),156.76(s),154.43(s),150.52 (s),141.83(q,J=34.7Hz),134.74(d,J=9.8Hz),131.90(d,J=1.2Hz),125.87(d,J=4.0Hz ),121.40(d,J=14.0Hz),119.35(q,J=276.7Hz),119.30(s),119.07(s),102.98(q,J=5. 5Hz), 87.13 (d, J = 1.7Hz), 62.10 (s), 46.53 (s), 32.69 (q, J = 3.6Hz), 23.28 (s), 14.06 (s).

[0036] The preparation method is as follows: 3-(2-chloro-4-fluoro-5-(2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)phenyl)-5-methyl-4,5-dihydroisoxazole-5-carboxylic acid ethyl ester is completely reacted with chloromethane in toluene, washed with water, toluene is removed, a solvent is added dropwise to dissolve, the temperature is raised, and then the temperature is lowered for recrystallization to obtain the product.

Claims

1. A new crystal form of an isoxazolinyluracil compound, characterized in that, Its X-ray powder diffraction pattern has characteristic peaks at diffraction angles 2θ of 6.3±0.2, 7.2±0.2, 11.2±0.2, 14.3±0.2, 17.3±0.2, 19.6±0.2, 20.7±0.2, 24.3±0.2, 25.2±0.2, and 26.1±0.2; Among them, the isoxazoline uracil compounds are shown by the following formula (1), In formula (1), R1 is fluorine, R2 is chlorine, R3 and R4 are hydrogen, R5 is CO2C2H5, and R6 is methyl.

2. The new crystal form of the isoxazolinyluracil compound according to claim 1, characterized in that, Its X-ray powder diffraction pattern also has characteristic peaks at diffraction angles 2θ of 27.7±0.2, 29.3±0.2, 30.3±0.2, 31.8±0.2, and 33.2±0.

2.

3. The new crystal form of the isoxazoline uracil compound according to claim 1, characterized in that, The new crystal form is a bundle crystal or a massive crystal aggregated by rod-like crystals.

4. The new crystal form of the isoxazolinyluracil compound according to claim 3, characterized in that, The length of the rod-like crystal is 100 nm - 10 mm.

5. The new crystal form of the isoxazoline uracil compound according to any one of claims 1-4, characterized in that, Its carbon-13 NMR spectrum has the following peaks, 13 C NMR(101MHz,CDCl3)δ171.57(s),159.74(s),159.33(s),156.76(s),154.43(s),150.52(s),141.83(q,J=34.7Hz),134.74(d,J=9.8Hz),131.90(d,J=1.2Hz),125.87(d,J=4.0Hz),121.40(d,J=14.0Hz),119.35(q,J=276.7Hz),119.30(s),119.07(s),102.98(q,J=5.5Hz),87.13(d,J=1.7Hz),62.10(s),46.53(s),32.69(q,J=3.6Hz),23.28(s),14.06(s).

6. The new crystal form of the isoxazolinyluracil compound according to claim 5, characterized in that, Its 1H NMR spectrum has the following peaks, 1 1H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 7.6 Hz, 1H), 7.35 (d, J = 9.0 Hz, 1H), 6.35 (s, 1H), 4.26 (q, J = 7.1 Hz, 2H), 4.00 (t, J = 16.8 Hz, 1H), 3.54 (s, 3H), 3.39 (dd, J = 17.4, 13.9 Hz, 1H), 1.70 (d, J = 1.4 Hz, 3H), 1.32 (t, J = 7.1 Hz, 3H).

7. The new crystal form of the isoxazoline uracil compound according to claim 1, characterized in that, Its DSC pattern has an absorption peak at 360 - 390 °C and an exothermic peak at 60 - 100 °C.

8. A method for preparing a new crystal form of the isoxazoline uracil compound according to any one of claims 1-7, characterized in that, Comprising: 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 is obtained by completely reacting with chloromethane in toluene, washing with water, removing toluene, adding a solvent dropwise to dissolve, heating, and then cooling for recrystallization.

9. A herbicide, characterized in that, An isoxazolineuracil compound comprising the new crystal form according to any one of claims 1 - 7, further comprising one or more pharmaceutically acceptable carriers and / or adjuvants.

10. An application of the herbicide according to claim 9 in controlling Setaria viridis, Echinochloa crusgalli, Arthraxon hispidus, Cyperus difformis, Digitaria sanguinalis, and Cyperus serotinus.

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