New crystal form of hexaflumuron and its preparation method and application

Abstract

The present application relates to the technical field of pharmaceutical chemistry, and particularly relates to a new crystal form of flutriarol, a preparation method and application thereof. The new crystal form of flutriarol comprises crystal form I and crystal form II. The present application realizes the purpose of improving the insecticidal activity of flutriarol by changing the crystal form without changing the chemical structure of flutriarol and introducing other insecticidal active ingredients, which is an effective new way to realize the synergistic application of flutriarol. Meanwhile, the change of the crystal form also improves the solubility, dispersibility, suspension stability, storage stability, crystal form stability and preparation processing adaptability of flutriarol, which helps to improve the utilization efficiency of flutriarol as an effective ingredient and provides a basis for developing high-efficiency low-dose insecticide preparations.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, and in particular to a novel crystalline form of flufenoxuron, its preparation method, and its applications. Background Technology

[0002] Hexaflumuron is a benzoylurea insect growth regulator that primarily exerts its insecticidal effect by interfering with insect chitin synthesis, thus hindering normal molting, metamorphosis, and epidermal formation in larvae. Compared to traditional neurotoxic insecticides such as organophosphates, carbamates, and pyrethroids, hexaflumuron has a different mechanism of action and exhibits control activity against a variety of Lepidoptera, Coleoptera, Diptera, and Homoptera pests. It can also be used for the management of resistant pests and for pesticide rotation. Therefore, hexaflumuron has significant application value in agricultural pest control.

[0003]

[0004] Although flufenoxuron possesses good insecticidal activity, it has low water solubility and strong hydrophobicity. In common pesticide formulations such as aqueous suspensions, wettable powders, and water-dispersible granules, flufenoxuron is usually not present in a completely dissolved state, but rather mainly dispersed in the formulation system or application solution as technical grade solid particles. After application, the effectiveness of its active ingredient is closely related to the deposition, attachment, contact, and transfer of solid particles on leaf surfaces, insect body surfaces, feeding sites, or other target interfaces, which significantly affects its insecticidal efficacy.

[0005] Existing technologies generally improve the insecticidal efficacy of flufenoxuron through methods such as compounding, synergistic effects using synergists or adjuvants, and formulation optimization. However, existing compounding or adjuvant-based synergistic solutions still have certain limitations. Compounding solutions typically require the introduction of a second insecticidal active ingredient, potentially increasing formulation complexity, compatibility evaluation, residue control, toxicological and environmental risk assessment, and registration management difficulties. Synergistic or adjuvant solutions rely on exogenous formulation components, and their synergistic effect is easily affected by the type and proportion of synergist, the solvent system, formulation stability, processing conditions, and application environment. While formulation optimization can improve deposition, wetting, or penetration properties, its core remains the regulation of the external formulation system and does not address the issue of flufenoxuron itself, which still has room for improvement in its activity efficiency.

[0006] With the increasing demands for pesticide reduction and efficiency enhancement, green prevention and control, and resistance management in agricultural production, simply increasing the application dosage or the amount of adjuvants to improve efficacy is no longer sufficient to meet the needs for efficient, safe, and sustainable application. Summary of the Invention

[0007] In view of this, the technical problem to be solved by the present invention is to provide a new crystal form of flufenoxuron, its preparation method and application, wherein the new crystal form of flufenoxuron provided by the present invention has higher insecticidal activity.

[0008] The first aspect of the present invention provides a crystal form I of flufenoxuron, wherein the X-ray powder diffraction pattern of the crystal form I, expressed as a diffraction angle 2θ, has diffraction peaks at 17.477°±0.2°, 20.823°±0.2°, and 24.414°±0.2°.

[0009] Preferably, the X-ray powder diffraction pattern of crystal form I, expressed in terms of diffraction angle 2θ, has diffraction peaks at 8.702°±0.2°, 17.477°±0.2°, 20.823°±0.2°, 21.654°±0.2°, 24.414°±0.2°, 25.346°±0.2°, and 27.905°±0.2°.

[0010] In some specific embodiments, the X-ray powder diffraction pattern of crystal form I, expressed as a diffraction angle 2θ, shows diffraction peaks at 5.905°±0.2°, 8.702°±0.2°, 16.657°±0.2°, 17.477°±0.2°, 19.929°±0.2°, 20.823°±0.2°, 21.654°±0.2°, 24.414°±0.2°, 25.346°±0.2°, 26.266°±0.2°, 27.905°±0.2°, 28.213°±0.2°, 28.721°±0.2°, 30.647°±0.2°, and 36.289°±0.2°.

[0011] In some specific embodiments, the X-ray powder diffraction pattern of crystal form I, expressed in terms of a diffraction angle of 2θ, is... Figure 1 They are essentially the same.

[0012] In some specific implementations, the specific diffraction angle data corresponding to the X-ray powder diffraction pattern of crystal form I, expressed in terms of diffraction angle 2θ, are basically as shown in Table 1.

[0013] Preferably, the differential scanning calorimetry (DSC) curve of crystal form I includes an endothermic peak at an initial temperature of 203℃±3℃, which corresponds to the melting process of crystal form I. Its enthalpy of fusion is 68.44 J / g. No crystal transformation peak was observed, indicating that the prepared crystal form I is thermodynamically stable. Single-crystal X-ray diffraction characterization shows that it belongs to the triclinic crystal system.

[0014] In some specific implementations, the differential scanning calorimetry curve of crystal form I is compared with... Figure 2 They are essentially the same.

[0015] A second aspect of the present invention provides a method for preparing crystal form I of the above-mentioned flufenoxuron, comprising the following steps: Flufenoxuron is dissolved in a first solvent to obtain a flufenoxuron solution; The flufenoxuron solution was allowed to evaporate under unsealed conditions, precipitating a solid and yielding flufenoxuron crystal form I. The first solvent includes one or more of the following: acetone, methanol, acetonitrile, ethyl acetate, ethyl formate, and tetrahydrofuran.

[0016] The preferred mass-volume ratio of flufenoxuron to the first solvent is 50 mg: (6~10) mL. For example, it can be 50 mg: 6 mL, 50 mg: 7 mL, 50 mg: 8 mL, 50 mg: 9 mL, or 50 mg: 10 mL, with 50 mg: 8 mL being particularly preferred.

[0017] In some specific embodiments, the preparation method includes the following steps: Flufenoxuron was mixed with a first solvent and then sonicated to fully dissolve the flufenoxuron, resulting in a clear solution.

[0018] Then, preferably, the solution is filtered, preferably using a 0.22μm microporous membrane filter head.

[0019] The filtered solution is then placed in a well-ventilated environment, preferably with a wind speed of 0.5 m / s, to allow the solvent to evaporate slowly. After the solvent has completely evaporated, the precipitated solid is collected, yielding flufenoxuron crystal form I.

[0020] In addition, the crystal form I can also be prepared by slurry conversion, seed induction, and other methods.

[0021] The third aspect of the present invention provides a crystal form II of flufenoxuron, wherein the X-ray powder diffraction pattern of the crystal form II, expressed as a diffraction angle 2θ, has diffraction peaks at 6.168°±0.2°, 23.726°±0.2°, and 25.739°±0.2°.

[0022] Preferably, the X-ray powder diffraction pattern of crystal form II, expressed in terms of diffraction angle 2θ, has diffraction peaks at 6.168°±0.2°, 12.052°±0.2°, 12.679°±0.2°, 14.733°±0.2°, 20.171°±0.2°, 20.601°±0.2°, 23.726°±0.2°, 24.885°±0.2°, 25.739°±0.2°, and 33.208°±0.2°.

[0023] In some specific embodiments, the X-ray powder diffraction pattern of crystal form II, expressed as a diffraction angle 2θ, is at 6.168°±0.2°, 12.052°±0.2°, 12.679°±0.2°, 14.733°±0.2°, 15.321°±0.2°, 19.196°±0.2°, 19.787°±0.2°, 20.171°±0.2°, and 20.601°±0.2°. Diffraction peaks are observed at 2°, 22.368°±0.2°, 23.726°±0.2°, 24.538°±0.2°, 24.885°±0.2°, 25.739°±0.2°, 26.889°±0.2°, 27.197°±0.2°, 28.092°±0.2°, 30.078°±0.2°, 32.415°±0.2°, and 33.208°±0.2°.

[0024] In some specific embodiments, the X-ray powder diffraction pattern of crystal form II, expressed in terms of a diffraction angle of 2θ, is consistent with... Figure 4 They are essentially the same.

[0025] In some specific implementations, the specific diffraction angle data corresponding to the X-ray powder diffraction pattern of crystal form II expressed in terms of diffraction angle 2θ are basically as shown in Table 3.

[0026] Preferably, the differential scanning calorimetry (DSC) curve of crystal form II includes endothermic peaks at initial temperatures of 134℃±3℃ and 211℃±3℃. The endothermic peak at 134.35℃ corresponds to the crystal transformation process of crystal form II, and the peak at 211.11℃ corresponds to the melting behavior, with a melting enthalpy of -95.49 J / g, indicating that the flufenoxuron crystal form II provided by this invention is a thermodynamically metastable crystal form. Single-crystal X-ray diffraction characterization shows that it belongs to the monoclinic crystal system.

[0027] In some specific implementations, the differential scanning calorimetry curve of crystal form II is compared with... Figure 5 They are essentially the same.

[0028] The fourth aspect of this invention provides a method for preparing the crystal form II of the above-mentioned flufenoxuron, comprising the following steps: Flufenoxuron is dissolved in a second solvent to obtain a flufenoxuron solution; Flufenoxuron solution was allowed to evaporate under unsealed conditions, precipitating a solid and yielding flufenoxuron crystal form II. The second solvent includes one or more of diethyl ether, methyl tert-butyl ether, and isobutyl acetate, or a mixed solvent selected from diethyl ether and ethanol, or a mixed solvent selected from n-propyl acetate and acetone.

[0029] In the mixed solvent of diethyl ether and ethanol, the volume ratio of diethyl ether to ethanol is preferably (0.5~2):1. For example, it can be 0.5:1, 1:1, 1.5:1, 2:1, and especially preferably 1:1.

[0030] In the mixed solvent of n-propyl acetate and acetone, the volume ratio of n-propyl acetate to acetone is preferably (0.5~2):1, and can be 0.5:1, 1:1, 1.5:1, 2:1, and is particularly preferred to be 1:1.

[0031] The preferred mass-volume ratio of flufenoxuron to the second solvent is 50 mg: (4~12) mL. For example, it can be 50 mg: 4 mL, 50 mg: 5 mL, 50 mg: 6 mL, 50 mg: 7 mL, 50 mg: 8 mL, 50 mg: 9 mL, 50 mg: 10 mL, 50 mg: 11 mL, or 50 mg: 12 mL.

[0032] In some specific embodiments, the preparation method includes the following steps: Flufenoxuron was mixed with a second solvent and then sonicated to fully dissolve the flufenoxuron, resulting in a clear solution.

[0033] Then, preferably, the solution is filtered, preferably using a 0.22μm microporous membrane filter head.

[0034] The filtered solution is then placed in a well-ventilated environment, preferably with a wind speed of 0.5 m / s, to allow the solvent to evaporate slowly. After the solvent has completely evaporated, the precipitated solid is collected, yielding flufenoxuron crystal form II.

[0035] And / or, the preparation method includes the following steps: Flufenoxuron was dissolved in a good solvent to obtain a flufenoxuron solution. Then, the flufenoxuron solution was mixed with a poor solvent to precipitate a solid, thus obtaining flufenoxuron crystal form II. The preferred solvent includes one or more of acetone, n-pentanol, and ethylene glycol dimethyl ether. The preferred solvent is water.

[0036] The preferred mass-volume ratio of flufenoxuron to the good solvent is 100 mg: (5~10) mL. For example, it can be 100 mg: 5 mL, 100 mg: 6 mL, 100 mg: 7 mL, 100 mg: 8 mL, 100 mg: 9 mL, or 100 mg: 10 mL.

[0037] The volume ratio of the good solvent to the bad solvent is preferably 1:(0.5~2), and for example, it can be 1:0.5, 1:0.6, 1:0.7, 1:1, 1:1.5, or 1:2.

[0038] In some specific embodiments, the preparation method includes the following steps: Flufenoxuron is dissolved in a good solvent to obtain a flufenoxuron solution. Preferably, the flufenoxuron solution is ultrasonically treated to ensure more complete dissolution. Then, preferably, the flufenoxuron solution is filtered to remove impurities, preferably using a 0.22 μm microporous membrane filter. The filtered solution is then mixed with a poor solvent. Preferably, the poor solvent is added to the flufenoxuron solution. Preferably, the system is gently shaken or stirred during mixing to ensure more uniform mixing. With the addition of the poor solvent, the supersaturation in the system increases, and a solid precipitate gradually forms, which is flufenoxuron crystal form II. Preferably, the obtained solid is dried. The drying can be done by a method well known to those skilled in the art, preferably vacuum drying. The vacuum drying temperature is preferably 40~60℃, and for example, 40, 50, or 60℃. The vacuum drying time is preferably 12~36 hours, and for example, 12, 24, or 36 hours.

[0039] And / or, the preparation method includes the following steps: Flufenoxuron was dissolved in a third solvent until it was supersaturated. The system was then heated and slowly cooled to allow the solid to precipitate, yielding crystalline form II of flufenoxuron. The third solvent includes one or more of chloroform and sec-butanol.

[0040] The system is preferably heated to 70~90℃, for example, it can be 70, 80, or 90℃.

[0041] Preferably, the solution is kept at the above temperature for 40 to 80 minutes to allow it to become fully clear. For example, the solution can be kept at 40, 50, 60, 70, or 80 minutes.

[0042] The slow cooling is preferably such that the system is cooled to 1~5℃ within 72 hours. For example, it can be cooled to 1, 2, 3, 4 or 5℃. Preferably, the system is cooled to 4℃ within 72 hours.

[0043] In some specific embodiments, the preparation method includes the following steps: Flufenoxuron is added to the third solvent until it becomes supersaturated. Preferably, the supersaturated solution is ultrasonically treated to ensure more complete dissolution of flufenoxuron or to form a homogeneous supersaturated solution. Preferably, the supersaturated solution system is kept in a water bath at 75-85°C for 20-40 minutes, maintaining the system in a supersaturated state during the heating process. Preferably, the system is filtered to remove impurities, preferably using a 0.22 μm microporous membrane filter head. Then, the system is heated to 70-90°C and held for 40-80 minutes, preferably to 80°C and held for 60 minutes, to ensure the solution becomes fully clear. Subsequently, the system is slowly cooled, preferably from 80°C to 4°C within 72 hours, during which a solid precipitate gradually forms, which is flufenoxuron crystal form II. Preferably, the obtained solid is dried, and the drying can be a drying method well known to those skilled in the art, preferably vacuum drying. The vacuum drying temperature is preferably 40~60℃, and for example, it can be 40, 50, or 60℃. The vacuum drying time is preferably 12~36h, and for example, it can be 12, 24, or 36h.

[0044] And / or, the preparation method includes the following steps: Flufenoxuron and a fourth solvent were mixed and ground to obtain crystalline form II of flufenoxuron; The fourth solvent is selected from sec-butanol.

[0045] The preferred mass-to-volume ratio of flufenoxuron to the fourth solvent is 100 mg: (0.1~0.3) mL. For example, it can be 100 mg: 0.1 mL, 100 mg: 0.2 mL, or 100 mg: 0.3 mL, with 100 mg: 0.2 mL being particularly preferred.

[0046] The grinding power is preferably 30~80Hz, and for example, it can be 30, 40, 50, 60, 70, or 80Hz.

[0047] The grinding time is preferably 0.2 to 1 hour, and for example, it can be 0.2, 0.5, 0.8, or 1 hour.

[0048] After grinding, preferably, the obtained powder is dried. The drying can be a drying method known to those skilled in the art, preferably vacuum drying. The vacuum drying temperature is preferably 40~60℃, for example, 40, 50, or 60℃. The vacuum drying time is preferably 12~36h, for example, 12, 24, or 36h.

[0049] The physical stability test results show that neither crystal form I nor crystal form II of the flufenoxuron provided by the present invention underwent crystal form transformation in the deionized water suspension system, and both exhibit good physical stability in the aqueous medium.

[0050] A fifth aspect of the present invention provides a pesticide composition comprising crystal form I of the above-mentioned flufenoxuron and / or crystal form II of the above-mentioned flufenoxuron, and an adjuvant.

[0051] The present invention does not impose any particular limitation on the formulation of the pesticide composition, and can be any agriculturally acceptable formulation, including but not limited to powder, wettable powder, granules, emulsifiable concentrate, suspension emulsion, aqueous solution, water-dispersible granules, water-in-oil emulsion, microemulsion, seed treatment agent, etc., with water suspension being particularly preferred.

[0052] The present invention does not impose any special limitation on the excipients, and can use any applicable excipients known to those skilled in the art. Those skilled in the art can select the appropriate excipients according to the dosage form.

[0053] In some specific embodiments, the present invention provides an aqueous suspension containing flufenoxuron, comprising: crystal form I of the above-mentioned flufenoxuron, and / or crystal form II of the above-mentioned flufenoxuron, and an excipient.

[0054] Preferably, the excipients include: dispersion medium, wetting agent, dispersant, thickener, filler, antifreeze agent, and defoamer.

[0055] The dispersion medium is preferably water.

[0056] The wetting and dispersing agents include, but are not limited to, sodium lignosulfonate.

[0057] The thickeners include, but are not limited to, xanthan gum.

[0058] The experimental results show that the crystal forms I and II of flufenoxuron provided by the present invention can maintain their original crystal form characteristics after being formulated into an aqueous suspension. No crystal form transformation was observed after 14 days of heat storage, indicating that the crystal forms I and II of flufenoxuron have good physical stability in the aqueous suspension system.

[0059] The sixth aspect of the present invention provides the use of the crystal form I of the above-mentioned flufenoxuron, and / or the crystal form II of the above-mentioned flufenoxuron, and / or the pesticide composition described above in the preparation of insecticides.

[0060] In some specific implementation schemes, the insecticide is used to control one or more of the following: diamondback moth, beet armyworm, cotton bollworm, tobacco budworm, cabbage worm, armyworm, rice leaf roller, rice stem borer, corn borer, bean borer, melon leaf roller, leafroller, golden leafminer, peach fruit moth, and pear fruit moth.

[0061] In some specific implementations, the insecticide can be applied to the roots, stems, leaves, etc. of plants.

[0062] The plant is selected from one or more of the following: cruciferous vegetables, solanaceous vegetables, cucurbitaceous crops, legumes, grasses, cotton, tea trees, and fruit trees; preferably, the plant is selected from one or more of the following: Chinese cabbage, kale, cauliflower, broccoli, rapeseed, radish, tomato, pepper, eggplant, cucumber, pumpkin, soybean, cowpea, rice, corn, wheat, cotton, tea trees, apple trees, pear trees, and peach trees.

[0063] Compared with existing commercially available crystalline forms, the novel crystalline form provided by this invention exhibits higher insecticidal activity or lower LC50 at the same amount of active ingredient. 50 Higher mortality rate. Activity assay results show that both crystalline forms I and II of flufenoxuron provided by this invention have high insecticidal activity. Crystalline form II exhibits 5.92 times the insecticidal activity against diamondback moth compared to crystalline form I. Under the same active ingredient concentration conditions, crystalline form II demonstrates superior insecticidal effect compared to crystalline form I, and thus has application value for further development into a highly effective insecticide formulation.

[0064] The present invention also provides a method for controlling a target pest, the method comprising applying the crystal form I of flufenoxuron and / or the crystal form II of flufenoxuron and / or the pesticide composition thereof to the target pest and / or to the environment of the target pest.

[0065] The application methods include, but are not limited to: spraying, spreading, and root irrigation.

[0066] The preferred concentration of the applied concentration of the crystalline form I of flufenoxuron, and / or the crystalline form II of flufenoxuron, and / or the pesticide composition is 0.0625~4 mg / L, more preferably 0.125~4 mg / L, even more preferably 0.25~4 mg / L, further preferably 0.5~4 mg / L, and most preferably 1~4 mg / L.

[0067] In this invention, the crystal form I and / or crystal form II of flufenoxuron can be used alone as active ingredients, or they can be combined with agriculturally acceptable carriers or adjuvants to form a formulation system, or used in combination with other pesticide active ingredients, as needed. Preferably, the crystal form I and / or crystal form II of flufenoxuron are used as the sole insecticidal active ingredient, which does not depend on other insecticidal active ingredients and achieves enhanced activity solely through the regulation of the insecticide's own crystal form.

[0068] Compared with the prior art, the present invention provides new crystal forms of flufenoxuron, including crystal form I and crystal form II.

[0069] This invention achieves enhanced insecticidal activity of flufenoxuron solely through alteration of its crystal form, without changing its chemical structure or introducing other insecticidal active ingredients. This represents a novel and effective method for synergistic effects of flufenoxuron. Furthermore, the change in crystal form improves flufenoxuron's solubility, dispersibility, suspension stability, storage stability, crystal form stability, and formulation processing adaptability, thus enhancing its utilization efficiency as an active ingredient and providing a foundation for developing highly effective, low-dosage insecticide formulations. Attached Figure Description

[0070] Figure 1 The PXRD pattern of flufenoxuron crystal form I; Figure 2 Differential scanning calorimetry (DSC) curves for flufenoxuron crystal form I; Figure 3 The single-crystal X-ray diffraction (SCXRD) structure diagram of flufenoxuron crystal form I is shown. Figure 4 The PXRD pattern of flufenoxuron crystal form II; Figure 5 Differential scanning calorimetry (DSC) curves for flufenoxuron crystal form II; Figure 6 This is the single-crystal X-ray diffraction (SCXRD) structure of flufenoxuron crystal form II. Detailed Implementation

[0071] To further illustrate the present invention, a detailed description is provided below with reference to embodiments. However, it should be understood that these descriptions are merely for further illustrating the features and advantages of the present invention, and not for limiting the scope of the claims.

[0072] In the following examples and comparative examples, the raw materials, reagents and other experimental materials used, unless otherwise specified, are all materials that are conventionally available in the art, can be purchased through commercial channels, or can be prepared according to methods disclosed in the prior art.

[0073] The testing method is as follows: Powder X-ray diffraction (XRD) method: A Bruker D8 ADVANCE powder XRD spectrometer was used with a Cu-Kα radiation source (λ = 1.54178 Å), an operating voltage of 40 kV, an operating current of 40 mA, and an EIGER2R detector. The tests were conducted at room temperature, with a scanning range of 2θ = 3°–40° and a scanning speed of 10° / min. The obtained powder XRD patterns were used to characterize the crystal structure of the samples.

[0074] It should be noted that powder X-ray diffraction (PXRD) results can vary due to various factors, such as differences in sample loading height during sample preparation, instrument errors, instrument calibration discrepancies, operator errors during peak position reading, and preferred orientations caused by the sample's inherent properties. Instrument calibration errors and sample height differences typically cause diffraction peaks to shift in the same direction. For flat sample holders, even small changes in sample height can cause significant 2θ peak shifts. Studies have shown that a sample height difference of approximately 1 mm can result in a 2θ peak shift of up to approximately 1°. Such systematic shifts can usually be identified through powder X-ray diffraction patterns and can be corrected by using a uniform calibration factor or by recalibrating the instrument. Therefore, when comparing PXRD results between different instruments or different batches of samples, calibration or peak position correction can improve the consistency of peak position data.

[0075] Differential scanning calorimetry (DSC) method: A Mettler Toledo DSC 1 / 500 DSC was used for testing in a nitrogen atmosphere at a heating rate of 10 °C / min. The sample was placed in an aluminum crucible, and a temperature scan was performed within the set temperature range. The heat flow changes during the heating process were recorded to analyze the sample's melting behavior, crystal transformation behavior, or other thermal characteristics.

[0076] Example 1: Preparation of Flufenoxuron Crystal Form I

[0077] Accurately weigh 50 mg of flufenoxuron technical grade and place it in a 15 mL centrifuge tube. Add 8 mL of acetone as a crystallization solvent. Sonicate the mixture for 5 min to fully dissolve the flufenoxuron, obtaining a clear solution. Then, filter the solution using a 0.22 μm microporous membrane filter and collect the filtrate in a new, clean centrifuge tube. Place the centrifuge tube containing the filtrate in a well-ventilated environment to allow the solvent to slowly evaporate at a wind speed of 0.5 m / s. After complete solvent evaporation, collect the precipitated solid, which is flufenoxuron crystal form I.

[0078] The prepared flufenoxuron crystal form I was subjected to PXRD testing, and the results are as follows: Figure 1 As shown in Table 1, the specific diffraction angle data corresponding to the obtained PXRD pattern of crystal form I are basically as follows: Table 1 Summary of PXRD data for flufenoxuron crystal form I

[0079] The prepared crystal form I was subjected to DSC testing, and the results are as follows: Figure 2 As shown.

[0080] Figure 2In the figure, the endothermic peak corresponds to the melting process of crystal form I, with a peak value of 203.95 °C and a melting enthalpy of 68.44 J / g. No crystal transformation peak was found, indicating that the prepared crystal form I is a thermodynamically stable crystal form.

[0081] In addition, the single-crystal X-ray diffraction (SCXRD) structure of crystal form I was also obtained (e.g. Figure 3 As shown in Table 2, its parameters are as follows: Table 2. X-ray diffraction parameters of single crystal I

[0082] Example 2: Preparation of Flufenoxuron Crystal Form I

[0083] The only difference from Example 1 is that acetone is replaced with methanol, acetonitrile, ethyl acetate, ethyl formate or tetrahydrofuran. Under the same or similar volatilization crystallization conditions, a solid is obtained. It is found to be the same as the flufenoxuron crystal form I prepared in Example 1, and has similar XRD patterns, DSC curves and X-ray diffraction parameters as the flufenoxuron crystal form I prepared in Example 1.

[0084] Example 3: Preparation of Flufenoxuron Crystal Form II

[0085] Weigh 50 mg of flufenoxuron technical grade and place it in a 15 mL centrifuge tube. Add 4 mL of diethyl ether as a crystallization solvent. Sonicate the resulting mixture for 5 min to fully dissolve the flufenoxuron, obtaining a clear solution. Then, filter the solution using a 0.22 μm microporous membrane filter and transfer the filtrate to a new clean centrifuge tube. Place the centrifuge tube containing the filtrate in a well-ventilated environment and allow the solvent to evaporate at an air velocity of 0.5 m / s. After complete solvent evaporation, collect the precipitated solid, which is flufenoxuron crystal form II.

[0086] The prepared flufenoxuron crystal form I was subjected to PXRD testing, and the results are as follows: Figure 4 As shown in Table 3, the specific diffraction angle data corresponding to the obtained PXRD pattern of crystal form II are basically as follows: Table 3 Summary of PXRD data for flufenoxuron crystal form II

[0087] The prepared crystal form I was subjected to DSC testing, and the results are as follows: Figure 5 As shown. Figure 5 In the study, the endothermic peak at 134.35 °C corresponds to the crystal transformation process of crystal form II, and the peak at 211.11 °C corresponds to the melting behavior. The enthalpy of melting is -95.49 J / g, indicating that the prepared crystal form II is a thermodynamically metastable crystal form.

[0088] In addition, single-crystal X-ray diffraction (SCXRD) structures of crystal form II were also obtained (e.g. Figure 6 As shown in Table 4, its parameters are as follows: Table 4. X-ray diffraction parameters of single crystals of crystal form II

[0089] Example 4: Preparation of Flufenoxuron Crystal Form II

[0090] Weigh 50 mg of flufenoxuron technical grade and place it in a 15 mL centrifuge tube. Add 8 mL of methyl tert-butyl ether as a crystallization solvent. Sonicate the mixture for 5 min to ensure complete dissolution of the flufenoxuron. Filter the resulting solution through a 0.22 μm microporous membrane filter and collect the filtrate into a new clean centrifuge tube. Place the filtrate in a well-ventilated environment and allow it to naturally evaporate and crystallize at an air velocity of 0.5 m / s. After complete solvent evaporation, collect the solid and XRD analysis confirms it is flufenoxuron crystal form II.

[0091] Example 5: Preparation of Flufenoxuron Crystal Form II

[0092] Accurately weigh 50 mg of flufenoxuron technical grade and add it to a 15 mL centrifuge tube, followed by 4 mL of isobutyl acetate as a crystallization solvent. Sonicate the mixture for 5 min to fully dissolve the flufenoxuron, obtaining a clear solution. Filter the resulting solution through a 0.22 μm microporous membrane filter and transfer the filtrate to a new centrifuge tube. Place the centrifuge tube containing the filtrate in a well-ventilated environment to evaporate the solvent at an air velocity of 0.5 m / s. After complete solvent evaporation, collect the precipitated crystals, which, according to XRD analysis, are flufenoxuron crystal form II.

[0093] Example 6: Preparation of Flufenoxuron Crystal Form II

[0094] Accurately weigh 50 mg of flufenoxuron technical grade and place it in a 15 mL centrifuge tube. Add 12 mL of a mixed solvent consisting of diethyl ether and ethanol (volume ratio 1:1). Sonicate the resulting system for 5 min to ensure complete dissolution of the flufenoxuron. Then, filter the solution using a 0.22 μm microporous membrane filter and collect the filtrate into a new, clean centrifuge tube. Place the centrifuge tube containing the filtrate in a well-ventilated environment and allow the solvent to evaporate at an air velocity of 0.5 m / s. After complete evaporation of the mixed solvent, collect the resulting solid. XRD analysis confirmed that it was flufenoxuron crystal form II.

[0095] Example 7: Preparation of Flufenoxuron Crystal Form II

[0096] Accurately weigh 50 mg of flufenoxuron technical grade and add it to a 15 mL centrifuge tube. Then add 12 mL of a mixed solvent consisting of propyl acetate and acetone (volume ratio 1:1). Sonicate the mixture for 5 min to fully dissolve the flufenoxuron, obtaining a clear solution. Filter the resulting solution through a 0.22 μm microporous membrane and transfer it to a new clean centrifuge tube. Place the filtrate in a ventilated environment and allow it to evaporate and crystallize at an air velocity of 0.9 m / s. After complete solvent evaporation, collect the precipitated solid and analyze it by XRD; it is confirmed to be flufenoxuron crystal form II.

[0097] Example 8: Preparation of Flufenoxuron Crystal Form II

[0098] Accurately weigh 100 mg of flufenoxuron technical grade and place it in a 15 mL centrifuge tube. Add 5 mL of acetone as a good solvent. Sonicate the resulting mixture for 5 min to fully dissolve the flufenoxuron, obtaining a clear solution. Then, filter the solution using a 0.22 μm microporous membrane filter and collect the filtrate in a new clean centrifuge tube. Add 5 mL of pure water as a countersolvent to the filtrate using a pipette, gently shaking or stirring during the addition process to ensure thorough mixing. With the addition of pure water, the supersaturation in the system increases, and a solid precipitate gradually forms. After complete precipitation, filter the resulting suspension and collect the solid precipitate. Place the collected precipitate in a vacuum drying oven and dry it at 50 ℃ for 24 h to obtain a dried solid. XRD analysis confirmed it to be flufenoxuron crystal form II.

[0099] Example 9: Preparation of Flufenoxuron Crystal Form II

[0100] Accurately weigh 100 mg of flufenoxuron technical grade and place it in a 15 mL centrifuge tube. Add 7 mL of n-pentanol as a solvent. Sonicate the system for 5 min to ensure complete dissolution of flufenoxuron or to form a homogeneous solution. Then, filter the solution using a 0.22 μm microporous membrane filter to remove any insoluble impurities and transfer the filtrate to a new, clean centrifuge tube. Add 5 mL of pure water as a countersolvent to the filtrate using a pipette. Upon addition of pure water, flufenoxuron gradually precipitates from the solution. After complete precipitation, filter the resulting suspension and collect the solid precipitate. Place the precipitate in a vacuum drying oven and dry it at 50 °C for 24 h to obtain a dried solid. XRD analysis confirmed that the solid was flufenoxuron crystal form II.

[0101] Example 10: Preparation of Flufenoxuron Crystal Form II

[0102] Accurately weigh 100 mg of flufenoxuron technical grade and place it in a 15 mL centrifuge tube. Add 5 mL of ethylene glycol dimethyl ether as a solvent. Sonicate the resulting mixture for 5 min to fully dissolve the flufenoxuron, obtaining a clear or homogeneous solution. Then, filter the solution using a 0.22 μm microporous membrane filter and transfer the filtrate to a new clean centrifuge tube. Add 5 mL of pure water as a countersolvent to the filtrate using a pipette. As pure water is added, flufenoxuron gradually precipitates to form a solid precipitate. After complete precipitation, filter the resulting suspension and collect the precipitate. Place the precipitate in a vacuum drying oven and dry it at 50 °C for 24 h to obtain a dried solid. XRD analysis confirmed it to be flufenoxuron crystal form II.

[0103] Example 11: Preparation of Flufenoxuron Crystal Form II

[0104] Add 5 mL of chloroform as a crystallization solvent to a 15 mL centrifuge tube, then add flufenoxuron technical grade until the system reaches supersaturation. Sonicate the resulting supersaturated system for 10 min to fully dissolve the flufenoxuron or form a homogeneous supersaturated solution. Place the centrifuge tube in an 80 °C water bath for 30 min, maintaining the system in a supersaturated state during this process. Then, filter the resulting solution using a 0.22 μm microporous membrane filter and transfer the filtrate to a 10 mL clean glass bottle. Place the glass bottle containing the filtrate in a crystallizer, heat the crystallizer to 80 °C and maintain the temperature for 60 min to allow the solution to become fully clear. Subsequently, allow the system to cool from 80 °C to 4 °C over 72 h, during which a solid precipitate gradually forms. After complete precipitation, filter the resulting suspension and collect the solid precipitate. Place the precipitate in a vacuum drying oven at 50 °C for 24 h to obtain a dried solid, which, according to XRD analysis, is flufenoxuron crystal form II.

[0105] Example 12: Preparation of Flufenoxuron Crystal Form II

[0106] Add 5 mL of sec-butanol as a crystallization solvent to a 15 mL centrifuge tube, then add flufenoxuron technical grade to the solvent until a supersaturated system is formed. Sonicate the resulting system for 10 min to fully dissolve the flufenoxuron or form a homogeneous supersaturated solution. Place the centrifuge tube in an 80 °C water bath for 30 min, maintaining the system in a supersaturated state during the incubation. After incubation, filter the solution using a 0.22 μm microporous membrane filter, collecting the filtrate in a 10 mL clean glass bottle. Place the bottle containing the filtrate in a crystallizer, heating the crystallizer to 80 °C and maintaining the temperature for 60 min to clarify the solution. Then, slowly cool the crystallizer from 80 °C to 4 °C over 72 h, allowing the flufenoxuron to gradually precipitate during the cooling process. After complete precipitation, filter the resulting suspension, and dry the precipitate in a vacuum drying oven at 50 °C for 24 h to obtain a dried solid. XRD analysis confirmed it to be flufenoxuron crystal form II.

[0107] Example 13: Preparation of Flufenoxuron Crystal Form II

[0108] Take 100 mg of flufenoxuron technical grade, add 0.2 mL of sec-butanol and place it in a ball mill jar. Grind it in a ball mill at 50 Hz for 0.5 hours. Place the resulting powder in a vacuum drying oven at 50 ℃ for 24 h to obtain a solid. XRD analysis showed that it was flufenoxuron crystal form II.

[0109] Physical stability experiment 1: 100 mg each of the crystal form I powder prepared in Example 1 and the crystal form II powder prepared in Example 3 were weighed and added to 20 mL of deionized water to form a suspension system under stirring conditions of 54 °C and 400 rpm. Samples were taken on days 7 and 14, 4 mL each time. After filtering to remove the dispersion medium, the resulting solids were dried in a vacuum drying oven and subjected to PXRD testing. The test results showed that neither crystal form I nor crystal form II underwent a crystal form transformation in the deionized water suspension system, indicating that both have good physical stability in aqueous media. Since it is necessary to maintain the original crystal form of flufenoxuron solid during subsequent property evaluation and formulation development, deionized water can be used as the preferred dispersion medium for flufenoxuron crystal form II, and suspension concentrate (SC) can be considered a suitable direction for its formulation development.

[0110] Physical stability experiment 2: Flufenoxuron crystal form I powder prepared in Example 1 and flufenoxuron crystal form II powder prepared in Example 3 were used as active ingredients and formulated into aqueous suspensions with an effective ingredient concentration of 10000 mg / L using deionized water as the dispersion medium. In the aqueous suspensions, sodium lignosulfonate was used as the wetting and dispersing agent at a concentration of 1000 mg / L, and xanthan gum was used as the thickener at a concentration of 200 mg / L. During the preparation process, the system was ultrasonically treated to ensure that the flufenoxuron powder was fully wetted and uniformly dispersed in the aqueous phase, resulting in flufenoxuron crystal form I and flufenoxuron crystal form II aqueous suspensions, respectively. The above aqueous suspensions were placed in a 54 ℃ oven for thermal storage stability testing for 14 days. Samples were taken on days 3, 7, and 14, with 6 mL samples taken each time. After sampling, the suspensions were centrifuged, the supernatant was discarded, and the resulting solid was washed with deionized water. The solid was then thoroughly dried and subjected to PXRD testing. Test results show that both flufenoxuron crystal form I and crystal form II maintain their original crystal characteristics in the above-mentioned aqueous suspension system, and no crystal form transformation was observed after 14 days of heat storage. This result indicates that flufenoxuron crystal form II has good physical stability in the aqueous suspension system, and the suspension formulation can be used for subsequent insecticidal activity evaluation and related formulation performance studies.

[0111] Indoor bioactivity assay of insecticides: Leaf dipping method: The ground mother liquor was diluted with distilled water to 4 mg / L, and then diluted again with distilled water to the test concentration. The target insect was the diamondback moth larva. A suitable amount of cabbage leaves were thoroughly soaked in the prepared solution, then placed in a petri dish lined with filter paper and allowed to air dry naturally. Thirty mid-second instar diamondback moth larvae were then inoculated per dish and cultured in an observation room at 25±1℃. Results were assessed after 96 hours. Individuals unable to coordinate their movements when touched with a brush were considered dead. The test concentrations were 4, 2, 1, 0.5, 0.25, 0.125, and 0.0625 mg / L.

[0112] The results of the insecticidal activity tests of crystal form I and crystal form II are shown in Table 5-6. The results show that after leaf immersion treatment, at 2 mg / L, the mortality rates of diamondback moths treated with crystal form I and crystal form II were 89.17% and 100%, respectively. It is also worth mentioning that the insecticidal activity of crystal form II against diamondback moth is 5.92 times that of crystal form I.

[0113] Table 5. Comparison of insecticidal activity of flufenoxuron crystal form I and crystal form II at 96 h.

[0114] Table 6. Comparison of insecticidal activities of flufenoxuron crystal form I and crystal form II at different concentrations.

[0115] As shown in the table above, under the same effective ingredient concentration, the insecticidal effect of flufenoxuron crystal form II prepared in this invention on the tested pests is better than that of flufenoxuron crystal form I. This indicates that crystal form II can improve the biological activity efficiency of flufenoxuron and has application value for further development into a highly efficient insecticide formulation.

[0116] The above description of the embodiments is only for the purpose of helping to understand the method and core ideas of the present invention. It should be noted that those skilled in the art can make several improvements and modifications to the present invention without departing from the principles of the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention.

Claims

1. A crystalline form I of flufenoxuron, characterized in that, The X-ray powder diffraction pattern of crystal form I, expressed as a diffraction angle 2θ, shows diffraction peaks at 17.477°±0.2°, 20.823°±0.2°, and 24.414°±0.2°.

2. The crystal form I of flufenoxuron according to claim 1, characterized in that, The X-ray powder diffraction pattern of crystal form I, expressed in terms of diffraction angle 2θ, shows diffraction peaks at 8.702°±0.2°, 17.477°±0.2°, 20.823°±0.2°, 21.654°±0.2°, 24.414°±0.2°, 25.346°±0.2°, and 27.905°±0.2°.

3. The crystal form I of flufenoxuron according to claim 1, characterized in that, The X-ray powder diffraction pattern of crystal form I, expressed in terms of diffraction angle 2θ, is shown in Figure 1. The differential scanning calorimetry curve of crystal form I includes an endothermic peak with an initial temperature of 203℃ ± 3℃.

4. The method for preparing crystal form I of flufenoxuron according to any one of claims 1 to 3, characterized in that, Includes the following steps: Flufenoxuron is dissolved in a first solvent to obtain a flufenoxuron solution; Flufenoxuron solution was allowed to evaporate under unsealed conditions, precipitating a solid and yielding flufenoxuron crystal form I. The first solvent includes one or more of the following: acetone, methanol, acetonitrile, ethyl acetate, ethyl formate, and tetrahydrofuran.

5. A crystalline form II of flufenoxuron, characterized in that, The X-ray powder diffraction pattern of crystal form II, expressed in terms of diffraction angle 2θ, shows diffraction peaks at 6.168°±0.2°, 23.726°±0.2°, and 25.739°±0.2°.

6. The crystalline form II of flufenoxuron according to claim 5, characterized in that, The X-ray powder diffraction pattern of crystal form II, expressed in terms of diffraction angle 2θ, shows diffraction peaks at 6.168°±0.2°, 12.052°±0.2°, 12.679°±0.2°, 14.733°±0.2°, 20.171°±0.2°, 20.601°±0.2°, 23.726°±0.2°, 24.885°±0.2°, 25.739°±0.2°, and 33.208°±0.2°.

7. The crystalline form II of flufenoxuron according to claim 5, characterized in that, The X-ray powder diffraction pattern of crystal form II, expressed in terms of diffraction angle 2θ, is shown in Figure 4. The differential scanning calorimetry curve of crystal form II includes endothermic peaks at starting temperatures of 134℃±3℃ and 211℃±3℃.

8. The method for preparing crystalline form II of flufenoxuron according to any one of claims 5 to 7, characterized in that, Includes the following steps: Flufenoxuron is dissolved in a second solvent to obtain a flufenoxuron solution; Flufenoxuron solution was allowed to evaporate under unsealed conditions, precipitating a solid and yielding flufenoxuron crystal form II. The second solvent includes one or more of diethyl ether, methyl tert-butyl ether, and isobutyl acetate, or a mixed solvent selected from diethyl ether and ethanol, or a mixed solvent selected from n-propyl acetate and acetone. And / or, including the following steps: Flufenoxuron was dissolved in a good solvent to obtain a flufenoxuron solution. Then, the flufenoxuron solution was mixed with a poor solvent to precipitate a solid, thus obtaining flufenoxuron crystal form II. The good solvent includes one or more of acetone, n-pentanol, and ethylene glycol dimethyl ether; The unsuitable solvent is selected from water; And / or, including the following steps: Flufenoxuron was dissolved in a third solvent until it was supersaturated. The system was then heated and slowly cooled to allow the solid to precipitate, yielding crystalline form II of flufenoxuron. The third solvent includes one or more of chloroform and sec-butanol; And / or, including the following steps: Flufenoxuron and the fourth solvent were mixed and ground to obtain crystalline form II of flufenoxuron; The fourth solvent is selected from sec-butanol; The mass-to-volume ratio of flufenoxuron to the fourth solvent is 100 mg: (0.1~0.3) mL.

9. A pesticide composition, characterized in that, It includes crystal form I of flufenoxuron as described in any one of claims 1 to 3, and / or crystal form II of flufenoxuron as described in any one of claims 5 to 7, as well as excipients.

10. The use of the crystal form I of flufenoxuron according to any one of claims 1 to 3, and / or the crystal form II of flufenoxuron according to any one of claims 5 to 7, and / or the use of the pesticide composition according to claim 9 in the preparation of an insecticide.

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