New crystal form, preparation method and application of isoxazoline urea pyrimidine compound

Abstract

The invention relates to the technical field of C07D413 / 10, in particular to a novel crystal form, a preparation method and application of an isoxazoline urea pyrimidine compound. An X-ray powder diffraction pattern of the novel crystal form of the isoxazoline urea pyrimidine compound has characteristic peaks when the diffraction angle 2 theta 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 and 26.1 + / -0.2. The invention provides a novel crystal form of an isoxazoline urea pyrimidine compound. The novel crystal form solves the problems of pipeline blockage, difficulty in material taking, inaccurate metering and difficulty in storage and split charging in production caused by an oily isoxazoline urea pyrimidine compound in the prior art.

Description

Technical Field

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

[0002] Isoxazoline uracil compounds can remove weeds during the growth of soybeans, cotton, vegetables, corn, peanuts, etc. Currently, the prepared isoxazoline uracil compounds are all oily substances. For example, in Chinese Patent CN201811146442, the reaction of compound II with methyl chloride gives an oily isoxazoline uracil compound, and the last step of obtaining the product is completed by evaporating the solvent. This form has certain difficulties in scale-up, especially in production. In particular, considering that the product is an oily substance, it is difficult to completely evaporate the solvent, and the oily substance cannot be dried, resulting in the content of the product not meeting the requirements. In addition, due to its viscosity, the oily substance may cause low-temperature solidification during production, resulting in blockage of the pipelines of the production equipment, difficult discharging, and a series of problems such as difficult metering, difficult sampling, difficult packaging, difficult transportation, and difficult dissolution of the oily viscous substance. Summary of the Invention

[0003] In view of some problems existing in the prior art, the first aspect of the present invention provides a new crystal form of an isoxazoline uracil compound, and 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, 26.1±0.2.

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

[0005] In one embodiment, 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, 33.2±0.2.

[0006] In one embodiment, the isoxazoline uracil compound has Figure 1 the characteristic diffraction peaks shown in the XRD pattern as shown.

[0007] In the prior art, due to the specific properties of isoxazoline uracil compounds, they are oily viscous substances. However, the oily viscous materials may cause low-temperature solidification of the materials during the production of products, resulting in blockage of pipelines in the production equipment and difficulty in discharging the materials. At the same time, when the oily viscous substance is used as a herbicide, it may be difficult to take the material, accurately measure it, feed it, and it is difficult to evaporate the solvent completely and dry it, and the content of the product cannot meet the requirements. In addition, due to the lack of a fixed form, the oily viscous substance is difficult to be sub-packed during transportation and storage. During use, it is viscous when dissolved in a solvent, easily adheres to the stirring paddle, and has a slow dissolution rate. The applicant unexpectedly discovered a new crystal form of this compound during experiments. It 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 isoxazoline uracil compound in this crystal form is a powdery solid, which solves a series of problems caused by the oily substance due to the crystal form in the prior art.

[0008] In one embodiment, as Figure 2 , the new crystal form is a bundle-like crystal aggregated by rod-like crystals or a massive crystal.

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

[0010] The applicant unexpectedly found that when the crystal form of the isoxazoline uracil compound is a bundle-like crystal aggregated by rod-like crystals or a massive crystal, especially when the length of the rod-like crystals is 100 nm - 10 mm, not only does the isoxazoline uracil compound maintain the form of a powdery solid, but also during the process of making the powdery solid into a preparation, the powdery solid is more easily dispersed and dissolved. The applicant believes that the possible reason is the ordered arrangement of the rod-like crystals between the bundle-like crystals or massive crystals. Under the action of organic or inorganic solvents, it promotes their fluidity. At the same time, the solvent is easily diffused between the rod-like crystals, increasing the dispersion between the rod-like crystals.

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

[0012] Preferably, the new crystal form of the isoxazolinuracil compound has Figure 3 the characteristic diffraction peaks shown in the XRD pattern as shown.

[0013] In one embodiment, its 1H NMR spectrum has the following peaks, 1 H 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).

[0014] In one embodiment, its 13C NMR spectrum has the following peaks, 13 C NMR (101 MHz, CDCl3) δ 171.57 (s), 159.74 (s), 159.33 (s), 156.76 (s), 154.43 (s), 150.52 (s), 141.83 (q, J = 34.7 Hz), 134.74 (d, J = 9.8 Hz), 131.90 (d, J = 1.2 Hz), 125.87 (d, J = 4.0 Hz), 121.40 (d, J = 14.0 Hz), 119.35 (q, J = 276.7 Hz), 119.30 (s), 119.07 (s), 102.98 (q, J = 5.5 Hz), 87.13 (d, J = 1.7 Hz), 62.10 (s), 46.53 (s), 32.69 (q, J = 3.6 Hz), 23.28 (s), 14.06 (s).

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

[0016] Preferably, the new crystal form has Figure 4 the absorption and exothermic peaks shown in the DSC pattern as shown.

[0017] The applicant unexpectedly found that, as in this application Figure 4The absorption and exothermic peaks shown indicate that this new crystal form of the isoxazoline uracil compound endows the isoxazoline uracil compound with good storage stability, representing a significant improvement over the prior art in terms of the advantages of the isoxazoline uracil compound in the form of an oil. This may be because the molecular arrangement of this isoxazoline uracil compound is relatively regular, enhancing its heat resistance. When it is under the action of a certain content of organic solvent or water, the molecules can quickly disperse from each other.

[0018] The test conditions for the XRD pattern of the new crystal form of the isoxazoline uracil compound in this application are as follows: absorption coefficient = 0; activation absorber = 0; α1 = 1.5406; α2 = 1.54439; average α = 1.54184; alpha ratio = 0.5; analyzer = 0; anode = copper; anti-scattering slit = 6.9; beam optical flag = 189; β = 1.39222; β relative intensity = 0; deactivation absorber = 0; detector slit = 12.21; divergence slit = 0.6; goniometer control = 9999; goniometer diameter = 500; goniometer model = 516; goniometer stage = 0; monochromator = 0; near sample slit = 0; main Soller slit = 2.5; sample changer = 0; second Soller slit = 2.5; synchronous axis = 0; film attachment = 0; wave unit = Å; actual λ used = 1.5406; additional detector shield = 257; data record length = 4; delay time = 0; display plane number = 0; estimated scan time = 0; additional parameter mask = 0; generator current = 40; generator voltage = 40; increment = 0.0194797; increment 3 = 0; number of completed data = 2824; count number = 1; number of detectors = 0; number of drivers = 2; number of encoder drivers = 0; number of measured data = 2824; number of variable parameters = 0; range start time = 1088421888; rotation speed = 0; scan mode = 1; scan type = locked coupling; analog Meas condition = 0; slit changer inches = 9999; Smooting width = 0; start = 5; number of steps = 2824; synchronous rotation = 0; time = 19.2.

[0019] The test conditions for the DSC spectrum are as follows: Instrument: NETZSCH STA 449F3; Sample: 1; Sample mass / mg: 8; Material: empty; Reference mass / mg: 0; Crucible type: DSC / TG pan Al2O3; 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 = 8.2 mm, EHT = 5.00 kV, ESB Gridis = 0 V, Signal A = lnLens, Column Mode = Analytic.

[0021] In one embodiment, the preparation method of the new crystal form includes: ethyl 3-(2-chloro-4-fluoro-5-(2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)phenyl)-5-methyl-4,5-dihydroisoxazole-5-carboxylate reacts with methyl chloride in toluene until the reaction is complete, then 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.

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

[0023] The second aspect of the present invention provides a herbicide, which includes the isoxazoline uracil compound of the new crystal form, and also includes one or more pharmaceutically acceptable carriers and / or adjuvants.

[0024] The third aspect of the present invention provides an application of the herbicide in controlling Setaria viridis, Echinochloa crusgalli, Arthraxon hispidus, Cyperus difformis, Digitaria sanguinalis, Cyperus serotinus.

[0025] The present invention has the following beneficial effects compared with the prior art:

[0026] The present invention provides a new crystal form of an isoxazoline uracil compound, which solves the problems of pipeline blockage, difficult material taking, inaccurate metering, difficult storage and sub-packaging in production caused by the oily isoxazoline uracil compound in the prior art. Description of the Drawings

[0027] Figure 1 It is the XRD pattern of the new crystal form of the isoxazoline uracil compound (benzoxacil) of the present invention;

[0028] Figure 2 It is the SEM pattern of the new crystal form of the isoxazoline uracil compound (benzoxacil) of the present invention;

[0029] Figure 3 It is the infrared spectrum of the new crystal form of the isoxazoline uracil compound (benzoxacil) of the present invention;

[0030] Figure 4 It is the DSC pattern of the new crystal form of the isoxazoline uracil compound (benzoxacil) of the present invention;

[0031] Figure 5 It is the 1H NMR spectrum of the new crystal form of the isoxazoline uracil compound (benzoxacil) of the present invention;

[0032] Figure 6 This is the carbon-13 NMR spectrum of the new crystal form of the isoxazolinuracil compound of the present invention, namely benzoxazolinone. Detailed implementation mode

[0033] The present invention will be described below through specific implementation modes, but is not limited to the specific examples given below.

[0034] Example 1

[0035] A new crystal form of an isoxazolinuracil compound (benzoxazolinone, ethyl 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-carboxylate)), as Figure 1 shown, 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, 26.1 ± 0.2, 27.7 ± 0.2, 29.3 ± 0.2, 30.3 ± 0.2, 31.8 ± 0.2, 33.2 ± 0.2. As Figure 2 shown, this new crystal form is a bundle crystal or a massive crystal formed by the aggregation of rod-like crystals, and the length of the rod-like crystals is 100 nm - 10 mm. As Figure 3 shown, in its infrared spectrum, at 458 ± 2 cm -1 、516 ± 2 cm -1 、565 ± 2 cm -1 、603 ± 2 cm -1 、632 ± 2 cm -1 、674 ± 2 cm -1 、715 ± 2 cm -1 、746 ± 2 cm -1 、781 ± 2 cm -1 、985 ± 2 cm -1 、1066 ± 2 cm -1 、1402 ± 2 cm -1 、1629 ± 2 cm -1 、3239 ± 2 cm -1 characteristic absorption peaks are shown at the wavenumbers. As Figure 4 shown, the DSC spectrum has an absorption peak at 360 - 390 °C and an exothermic peak at 60 - 100 °C. As Figure 5 shown, the nuclear magnetic resonance hydrogen spectrum has the following peaks, 11H 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 Figure 6 shown, its carbon nuclear magnetic resonance spectrum has the following peaks: 13 13C NMR (101 MHz, CDCl3) δ 171.57 (s), 159.74 (s), 159.33 (s), 156.76 (s), 154.43 (s), 150.52 (s), 141.83 (q, J = 34.7 Hz), 134.74 (d, J = 9.8 Hz), 131.90 (d, J = 1.2 Hz), 125.87 (d, J = 4.0 Hz), 121.40 (d, J = 14.0 Hz), 119.35 (q, J = 276.7 Hz), 119.30 (s), 119.07 (s), 102.98 (q, J = 5.5 Hz), 87.13 (d, J = 1.7 Hz), 62.10 (s), 46.53 (s), 32.69 (q, J = 3.6 Hz), 23.28 (s), 14.06 (s).

[0036] The preparation method is as follows: Ethyl 3-(2-chloro-4-fluoro-5-(2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)phenyl)-5-methyl-4,5-dihydroisoxazole-5-carboxylate reacts completely with methyl chloride in toluene, then is washed with water, toluene is removed, a solvent is added dropwise to dissolve it, after heating up, it is then cooled for recrystallization to obtain the product.

Claims

1. A new crystal form of an isoxazoline uracil 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, 26.1±0.2; Among them, the isoxazoline uracil compounds are shown by the following formula (1), 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, 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-shaped crystals.

4. The new crystal form of the isoxazoline uracil compound according to claim 3, characterized in that, The length of the rod-shaped 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 isoxazoline uracil 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 reacting completely 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. Use of the herbicide according to claim 9 in controlling Setaria viridis, Echinochloa crusgalli, Arthraxon hispidus, Cyperus difformis, Digitaria sanguinalis, Cyperus serotinus.

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