New crystal form of isoxazoline uracil compound, preparation method and application thereof

Abstract

The present application relates to the technical fields of C07D413 / 10, and more particularly, it relates to a new crystal form of isoxazoline uracil compound, a preparation method and an application.A new crystal form of isoxazoline uracil compound has a characteristic peak at a diffraction angle 2 theta 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 an X-ray powder diffraction pattern.The present application provides a new crystal form of isoxazoline uracil compound, which solves the problems of pipeline blockage, difficult material taking, inaccurate metering, difficult storage and sub-packaging caused by the oil-like isoxazoline uracil compound in the prior art.

Description

Technical Field

[0001] This invention relates to the field of C07D413 / 10 technology, and more specifically, to novel crystal forms, preparation methods and applications of isoxazoline uridine compounds. Background Technology

[0002] Isoxazoline uracil compounds can remove weeds during the growth of soybeans, cotton, vegetables, corn, peanuts, and other crops. Currently, the prepared isoxazoline uracil compounds are all oily. For example, Chinese patent CN201811146442 describes the reaction of compound II with chloromethane to obtain an oily isoxazoline uracil compound. The final step in obtaining the product involves solvent evaporation. This method presents challenges for scale-up, especially in production, particularly since the product is oily, making complete solvent evaporation difficult and preventing the oil from drying completely, thus failing to meet the required content. Furthermore, the viscosity of the oily substance can lead to low-temperature solidification during production, causing blockages in the production equipment's pipelines and difficulties in discharging. The oily and viscous nature also presents challenges in metering, sampling, packaging, transportation, and dissolving. Summary of the Invention

[0003] To address some problems existing in the prior art, the first aspect of this invention provides a novel crystal form of isoxazoline uracil compounds, whose X-ray powder diffraction pattern 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.

[0004] Among them, isoxazoline uracil compounds are shown in formula (1) below. 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, its X-ray powder diffraction pattern has characteristic peaks at diffraction angles 2θ at 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 ureapyridine compound has Figure 1 The characteristic diffraction peaks shown in the XRD pattern are illustrated.

[0007] Existing isoxazoline uracil compounds, due to their specific properties, are oily and viscous. However, these oily and viscous materials may cause low-temperature solidification during production, leading to blockages in pipelines and difficulties in material discharge. Furthermore, when used as herbicides, these oily and viscous materials may be difficult to handle, accurately measured, and dispensed, and the solvent may be difficult to evaporate completely, resulting in insufficient product content. In addition, the lack of a fixed form during transportation and storage makes them difficult to package; during use, they dissolve in solvents in a viscous state, easily adhering to the stirring paddle and dissolving slowly. The applicant unexpectedly discovered a new crystal form of the compound during experiments, 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 isoxazoline uracil compound makes it a powdery solid, solving a series of problems caused by the oily substance resulting from the crystal form in the prior art.

[0008] In one implementation, such as Figure 2 The new crystal form is a bundle of rod-shaped crystals or a bulk crystal.

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

[0010] The applicant unexpectedly discovered that when the isoxazoline uridine compound has the crystal form of a bundle of rod-shaped crystals or a block of crystals, especially when the length of the rod-shaped crystals is 100 nm-10 mm, not only does the isoxazoline uridine compound maintain a powder solid form, but the powder solid is also easier to disperse and dissolve during the formulation process. The applicant believes that the possible reason is that the orderly arrangement of the rod-shaped crystals between the bundled or blocky crystals promotes its 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 is at 458±2 cm⁻¹. -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 displayed at the wavenumber.

[0012] Preferably, the novel crystal form of the isoxazoline uracil compound has Figure 3 The characteristic diffraction peaks shown in the XRD pattern are illustrated.

[0013] In one embodiment, its proton nuclear magnetic resonance spectrum has the following peaks: 1 H NMR (400 MHz, CDCl3) δ7.67 (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, 13.9Hz, 1H), 1.70 (d, J = 1.4 Hz, 3H), 1.32 (t, J = 7.1 Hz, 3H).

[0014] In one embodiment, its carbon NMR spectrum has the following peaks. 13 C NMR (101 MHz, CDCl3) δ171.57 (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 spectrum has an absorption peak at 360-390℃ and an exothermic peak at 60-100℃.

[0016] Preferably, the new crystal form has Figure 4 The absorption and exothermic peaks shown in the DSC diagram are illustrated.

[0017] An unexpected discovery by the applicant, as in this application Figure 4 The absorption and exothermic peak shown indicates that the new crystal form of this isoxazoline uridine compound gives it better storage stability, which is significantly improved compared to the oily isoxazoline uridine compounds in the prior art. This may be because the molecular arrangement of this isoxazoline uridine compound is relatively regular, which improves its heat resistance, and when it is in the presence of a certain amount of organic solvent or water, the molecules can be rapidly dispersed.

[0018] The XRD patterns of the novel isoxazoline uridine compounds in this application were tested under the following conditions: absorption coefficient = 0; activated absorber = 0; α1 = 1.5406; α2 = 1.54439; average α value = 1.54184; alpha ratio = 0.5; analyzer = 0; anode = copper; antiscattering slit = 6.9; beam optical mark = 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; angle meter model = 516; goniometer grade = 0; monochromator = 0; near-sample slit = 0; main Soler slit = 2.5; sample converter = 0; second Soler slit = 2.5; synchro axis = 0; thin film adhesion = 0; wave unit = Å; actual usage λ=1.5406; Additional detector shielding=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; Number of completed data=2824; Number of counts=1; Number of detectors=0; Number of drivers=2; Number of encoder drivers=0; Number of measurement data=2824; Number of variable parameters=0; Range start time=1088421888; Rotation speed=0; Scan mode=1; Scan type=locked coupling; Simulated Meas condition=0; Slot changer inch=9999; Smooting width=0; Start=5; Number of steps=2824; Synchronous rotation=0; Time=19.2.

[0019] DSC spectral testing conditions: 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=8.2mm, EHT=5.00kV, ESBGrid is=0V, Signal A=lnLens, Column Mode=Analytic.

[0021] In one embodiment, the method for preparing the new crystal form includes: reacting 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-carboxylic acid in toluene until completely reacted with chloromethane, washing with water to remove toluene, dissolving in a solvent, heating, and then cooling and recrystallizing to obtain the crystal form.

[0022] Those skilled in the art can conventionally select and obtain the new crystal form in this application based on the preparation method of the new crystal form in this application.

[0023] A second aspect of the present invention provides a herbicide comprising the novel crystalline form of an isoxazoline pyrimidine compound, and further comprising one or more pharmaceutically acceptable carriers and / or adjuvants.

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

[0025] Compared with the prior art, the present invention has the following advantages: This invention provides a novel crystal form of isoxazoline ureapyridine compounds, which solves the problems of pipeline blockage, difficulty in material handling, inaccurate metering, and difficulty in storage and packaging caused by oily isoxazoline ureapyridine compounds in the prior art. Attached Figure Description

[0026] Figure 1 The XRD pattern of the new crystal form of the isoxazoline uridine compound of this invention, namely bensulfuron-methyl; Figure 2 This is the SEM image of the new crystal form of the isoxazoline uridine compound, namely bensulfuron, of this invention; Figure 3 The infrared spectrum of the isoxazoline uridine compound of this invention, namely the new crystal form of pyrimethanil; Figure 4 This is the DSC spectrum of the new crystal form of the isoxazoline uridine compound, namely bensulfuron, of this invention; Figure 5 This is the 1H NMR spectrum of the isoxazoline uridine compound of the present invention, namely the new crystal form of pyrimethanil; Figure 6 This is the carbon NMR spectrum of the isoxazoline uridine compound of the present invention, namely the new crystal form of bensulfuron. Detailed Implementation

[0027] The present invention will be described below through specific embodiments, but is not limited to the specific embodiments given below.

[0028] Example 1 New crystal forms of isoxazoline uracil compounds (pyrimiazole, (3-(2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)phenyl)-5-methyl-4,5-dihydroisooxazo-5-carboxylic acid ethyl ester)) such as Figure 1 As shown, its X-ray powder diffraction pattern 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, 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. Figure 2 As shown, this new crystal form is a bundle of rod-shaped crystals or a bulk crystal, with the length of the rod-shaped crystals ranging from 100 nm to 10 mm. Figure 3 As shown, 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 -1It shows a characteristic absorption peak at the wavenumber. For example... Figure 4 As shown, the DSC spectrum exhibits absorption peaks at 360-390℃ and exothermic peaks at 60-100℃. Figure 5 As shown, the proton 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). For example... Figure 6 As shown, its carbon 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 = 1.7Hz), 62.10 (s), 46.53 (s), 32.69 (q, J = 3.6 Hz), 23.28 (s), 14.06 (s).

[0029] 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-carboxylic acid is reacted completely with chloromethane in toluene, washed with water to remove toluene, dissolved by adding solvent dropwise, heated, and then cooled and recrystallized to obtain the final product.

Claims

1. A novel crystalline form of an isoxazoline uridine compound, characterized in that, Its X-ray powder diffraction pattern shows 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, isoxazoline uracil compounds are shown in formula (1) below. Formula (1), R1 is fluorine, R2 is chlorine, R3 and R4 are hydrogen, R5 is CO2C2H5, and R6 is methyl; Its carbon 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 = 34.7Hz), 134.74 (d, J = 9.8 Hz), 131.90 (d, J = 1.2 Hz), 125.87 (d, J = 4.0Hz), 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); Its proton 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).

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

2.

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

4. The novel crystal 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. The novel crystal form of the isoxazoline uracil compound according to claim 1, characterized in that, Its DSC spectrum shows an absorption peak at 360-390℃ and an exothermic peak at 60-100℃.

6. A method for preparing a novel crystal form of the isoxazoline uracil compound according to any one of claims 1-5, characterized in that, include: Ethyl 3-(2-chloro-5-(2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)-4-fluorophenyl)-5-methyl-4,5-dihydroisoxazole-5-carboxylic acid was reacted completely with chloromethane in toluene, washed with water to remove toluene, dissolved dropwise with solvent, heated, and then cooled and recrystallized to obtain the final product.

7. A herbicide, characterized in that, The compound includes the isoxazoline uridine compound of any of the novel crystal forms of claims 1-5, and further includes one or more pharmaceutically acceptable carriers and / or adjuvants.

8. The application of the herbicide according to claim 7 in controlling foxtail grass, barnyard grass, sedge, sedge, crabgrass, and water sedge.

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