Novel crystalline forms, manufacturing methods, and herbicides / uses of isoxazoline uracil compounds

Abstract

The present invention relates to the technical field of C07D413 / 10, and more specifically to a novel crystalline form of isoxazoline uracil compounds, a method of production, and herbicides and their uses. The novel crystalline form of isoxazoline uracil compounds exhibits 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 in the X-ray powder diffraction spectrum. The present invention provides a novel crystalline form of isoxazoline uracil compounds, which solves the problems of the prior art in which oily isoxazoline uracil compounds clog piping during production, making material discharge difficult, resulting in inaccurate measurement and difficulties in storage and individual packaging.

Description

[Technical Field]

[0001] The present invention relates to the technical field of C07D413 / 10, and more specifically to novel crystalline forms, methods for production, and herbicides and uses of isoxazoline uracil compounds. [Background technology]

[0002] Isoxazoline uracil compounds are useful for weed control during the growing season of soybeans, cotton, vegetables, corn, peanuts, and other crops. Currently, all isoxazoline uracil compounds produced are oily. For example, in Chinese patent CN201811146442, compound II is reacted with methyl chloride to obtain an oily isoxazoline uracil compound. The final step to obtain the product is to evaporate and remove the solvent. This method can present certain difficulties in scale-up, especially in production. In particular, because the product is oily, it is difficult to completely evaporate the solvent, and it is also impossible to dry the oily substance, resulting in the product content not meeting requirements. Furthermore, because the oily substance is viscous, it can solidify at low temperatures during production, potentially clogging the piping of production equipment and making material discharge difficult. The oily viscosity also causes a series of problems, such as difficulties in weighing, material discharge, individual packaging, transportation, and dissolution. [Overview of the project]

[0003] In response to several problems in the prior art, the first aspect of the present invention provides a characteristic peak in the X-ray powder diffraction spectrum 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 provides a novel crystalline form of the isoxazoline uracil compound represented by the following formula (1). [ka] (R1 is fluorine, R2 is chlorine, R3 and R4 are hydrogen, R5 is CO2C2H5, and R6 is methyl.)

[0004] In one embodiment, characteristic peaks are also present in the X-ray powder diffraction spectrum 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.

[0005] In one embodiment, the isoxazoline uracil compound has characteristic diffraction peaks as shown in the XRD spectrum in Figure 1.

[0006] In the prior art, isoxazoline uracil compounds, due to their specific properties, become oily viscous substances. However, when producing the product, this oily viscous substance can solidify at low temperatures, potentially clogging the piping of production equipment or making material discharge difficult. Furthermore, when using this oily viscous substance as a herbicide, material discharge, accurate measurement, and input are difficult, evaporation of the solvent to dryness is difficult, drying is not possible, and the product content may not meet the requirements. In addition, because the oily viscous substance does not have a fixed shape, individual packaging during transport and storage is difficult, and when used, it becomes viscous when dissolved in a solvent, tends to adhere to stirring paddles, and the dissolution rate is slow. The applicant unexpectedly discovered a novel crystalline form of the compound during experiments. This crystalline form exhibits 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 crystalline form of isoxazoline uracil compounds realizes a powdery solid form and solves a series of problems caused by the oily nature of conventional crystalline forms.

[0007] In one embodiment, as shown in Figure 2, the novel crystal form is a bundle of rod-shaped crystals or a massive crystal.

[0008] Preferably, the length of the rod-shaped crystals is 100 nm to 10 mm.

[0009] When the crystal form of the isoxazoline uracil-based compound is a bundle-like crystal or a massive crystal formed by aggregation of rod-shaped crystals, particularly when the length of the rod-shaped crystals is 100 nm to 10 mm, the applicant unexpectedly found that not only does the isoxazoline uracil-based compound maintain a powdery solid form, but the powdery solid is more easily dispersed and dissolved during the process of formulating the powdery solid. The applicant believes that the reason is that the rod-shaped crystals between the bundle-like crystals or massive crystals are regularly arranged, so the fluidity is promoted by the action of an organic solvent or an inorganic solvent, and the solvent easily diffuses between the rod-shaped crystals, enhancing the dispersibility between the rod-shaped crystals.

[0010] In one embodiment, in its infrared spectrum, 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.

[0011] Preferably, the novel crystal form of the isoxazoline uracil-based compound has characteristic diffraction peaks shown in the XRD spectrum shown in FIG. 3.

[0012] In one embodiment, in its 1H NMR spectrum, the following peaks exist. 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)

[0013] In one embodiment, in its 13C NMR spectrum, the following peaks are present. 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)

[0014] In one embodiment, in its DSC spectrum, an endothermic peak exists at 360 - 390 °C and an exothermic peak exists at 60 - 100 °C.

[0015] Preferably, the novel crystal form has an endothermic peak and an exothermic peak shown in the DSC spectrum shown in FIG. 4.

[0016] As shown by the endothermic peak and exothermic peak shown in FIG. 4 of the present application, the applicant unexpectedly discovered that due to the novel crystal form of the isoxazoline uracil-based compound, the isoxazoline uracil-based compound has relatively good storage stability and has a remarkable improvement in the advantages over the isoxazoline uracil-based compound which is an oily substance in the prior art. Since the molecular arrangement of this isoxazoline uracil-based compound is relatively regular, its heat resistance is improved, and it is considered that the molecules are rapidly dispersed under the action of a certain amount of organic solvent or water.

[0017] In the present application, the test conditions of the XRD spectrum of the novel crystal form of the isoxazoline uracil-based compound: absorption coefficient = 0; absorber activation = 0; α1 = 1.5406; α2 = 1.54439; α average value = 1.54184; alpha ratio = 0.5; analyzer = 0; anode = copper; anti-scattering slit = 6.9; beam optical mark = 189; β = 1.39222; β relative intensity = 0; inactivated absorber = 0; detector slit = 12.21; divergence slit = 0.6; goniometer control = 9999; diameter of goniometer = 500; angle meter model = 516; goniometer grade = 0; monochromator = 0; slit near sample = 0; main solar slit = 2.5; sample converter = 0; second solar slit = 2.5; synchronous axis = 0; thin film deposition = 0; wave unit = A; actually used λ = 1.5406; additional detector shield = 257; data recording 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; amount of completed data = 2824; counted number = 1; number of detectors = 0; number of drives = 2; number of encoder drivers = 0; amount of measured data = 2824; number of variable parameters = 0; range start time = 1088421888; rotation number = 0; scan mode = 1; scan type = lock coupling; simulate Meas conditions = 0; slit switcher inch = 9999; Smooting width = 0; start = 5; number of steps = 2824; synchronous rotation = 0; time = 19.2.

[0018] DSC spectrum test conditions: Apparatus: 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; Code modification: 20; EXO: 1; Range: 30 / 15.0 (K / min) / 500; Segment: S1 / 1.

[0019] SEM test conditions: Gemini SEM 300, Mag=1.00KX, WD=8.2mm, EHT=5.00kV, ESB Grid is=0V, Signal A=lnLens, Column Mode=Analytic.

[0020] In one embodiment, the method for producing the novel crystalline form includes completely reacting 3-(2-chloro-4-fluoro-5-(2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidine-1(2H)-yl)phenyl)-5-methyl-4,5-dihydroisoxazole-5-ethylcarboxylate with methyl chloride in toluene, washing with water to remove toluene, dissolving by adding a solvent dropwise, raising the temperature, and then lowering the temperature to recrystallize, thereby obtaining the novel crystalline form.

[0021] Those skilled in the art can obtain the novel crystal form in this application by the manufacturing method of the novel crystal form in this application through ordinary selection.

[0022] A second aspect of the present invention provides a herbicide comprising the novel crystalline isoxazoline uracil compound, further comprising one or more pharmaceutically acceptable carriers and / or auxiliary agents.

[0023] A third aspect of the present invention provides the use of the herbicide in the control of foxtail grass, barnyard grass, knotweed, sedge, crabgrass, and water sedge. [Effects of the Invention]

[0024] Compared to the prior art, the present invention has the following beneficial effects.

[0025] This invention provides a novel crystalline form of isoxazoline uracil compounds, which solves the problems of the prior art in which oily isoxazoline uracil compounds clog piping during production, making material discharge difficult, resulting in inaccurate measurement and difficulties in storage and individual packaging. [Brief explanation of the drawing]

[0026] [Figure 1] This is the XRD spectrum of a novel crystalline form of isosaphenacil, an isoxazoline uracil compound of the present invention. [Figure 2] This is the SEM spectrum of a novel crystalline form of isosaphenacil, an isoxazoline uracil compound of the present invention. [Figure 3] This is the infrared spectrum of a novel crystalline form of isosaphenacil, an isoxazoline uracil compound of the present invention. [Figure 4] This is the DSC spectrum of a novel crystalline form of isosaphenacil, an isoxazoline uracil compound of the present invention. [Figure 5] This is the 1H NMR spectrum of a novel crystalline form of isosaphenacil, an isoxazoline uracil compound of the present invention. [Figure 6] This is the 1C NMR spectrum of a novel crystalline form of isosaphenacil, an isoxazoline uracil compound of the present invention. [Modes for carrying out the invention]

[0027] The present invention will be described below with reference to specific embodiments, but is not limited to the specific embodiments shown below. Example 1

[0028] The novel crystalline form of the isoxazoline uracil compound (isoxafenacil, (3-(2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidine-1(2H)-yl)phenyl)-5-methyl-4,5-dihydroisoxazole-5-ethylcarboxylate)) is shown in Figure 1, and its X-ray powder In the diffraction spectrum, characteristic peaks exist at diffraction angles 2θ at 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. As shown in Figure 2, the novel crystal form is a bundle crystal or massive crystal composed of rod-shaped crystals, with the length of the rod-shaped crystals ranging from 100 nm to 10 mm. As shown in Figure 3, in its infrared spectrum, 458±2 cm⁻¹ is observed. -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 Characteristic absorption peaks are shown at the wavenumber. As shown in Figure 4, in the DSC spectrum, there are endothermic peaks at 360-390°C and exothermic peaks at 60-100°C. As shown in Figure 5, the following peaks are present in the H NMR spectrum. 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 shown in Figure 6, the following peaks are present in its ¹³C NMR spectrum. 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 = 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). The manufacturing method is as follows: 3-(2-chloro-4-fluoro-5-(2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidine-1(2H)-yl)phenyl)-5-methyl-4,5-dihydroisoxazole-5-ethylcarboxylate is completely reacted with methyl chloride in toluene, then washed with water to remove toluene, dissolved by adding a solvent dropwise, heated, and then cooled to recrystallize, thereby obtaining a new crystalline form.

Claims

1. A novel crystalline form of isoxazoline uracil compounds, characterized by the presence of 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 in the X-ray powder diffraction spectrum. The isoxazoline uracil compound is characterized by being represented by the following formula (1), and is a novel crystalline form of an isoxazoline uracil compound. 【Chemistry 1】 (R １ is fluorine, R ２ is chlorine, R ３ , R ４ is hydrogen, R ５ is CO ２ C ２ H ５ and R ６ is methyl.)

2. A novel crystalline form of the isoxazoline uracil compound according to claim 1, characterized in that characteristic peaks are also present 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 in the X-ray powder diffraction spectrum.

3. The novel crystalline form of the isoxazoline uracil compound according to claim 1 is characterized in that the novel crystalline form is a bundle of rod-shaped crystals or a massive crystal.

4. A novel crystalline form of the isoxazoline uracil compound according to claim 3, characterized in that the length of the rod-shaped crystal is 100 nm to 10 mm.

5. A novel crystalline form of the isoxazoline uracil compound according to any one of claims 1 to 4, characterized in that the following peaks are present in the 1C NMR spectrum. １３ | ３ ) δ pi (1), [#]. pi pi. (), ( ), ( ) , # , , )

6. A novel crystalline form of the isoxazoline uracil compound according to claim 5, characterized in that the following peaks are present in its 1H NMR spectrum. １ H NMR (400 MHz, CDCl ３ ) 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. A novel crystalline form of the isoxazoline uracil compound according to claim 1, characterized in that the DSC spectrum has an endothermic peak at 360-390°C and an exothermic peak at 60-100°C.

8. A method for producing a novel crystalline form of an isoxazoline uracil compound according to any one of claims 1 to 7, comprising: completely reacting 3-(2-chloro-4-fluoro-5-(2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidine-1(2H)-yl)phenyl)-5-methyl-4,5-dihydroisoxazole-5-ethylcarboxylate with methyl chloride in toluene, washing with water to remove toluene, dissolving by adding a solvent dropwise, raising the temperature, and then lowering the temperature to recrystallize, thereby obtaining a novel crystalline form.

9. A herbicide comprising a novel crystalline isoxazoline uracil compound as described in any one of claims 1 to 7, and further comprising one or more pharmaceutically acceptable carriers and / or auxiliary agents.

10. Use of the herbicide according to claim 9 for the control of foxtail grass, barnyard grass, knotweed, sedge, crabgrass, and water sedge.

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