Cymoxanil-succinic acid pesticide eutectic crystal and preparation method thereof

Abstract

The invention relates to a cymoxanil-succinic acid pesticide eutectic crystal and a preparation method thereof. In the method, cymoxanil and succinic acid are mixed and weighed according to the molar ratio of 2: 1, and the eutectic is prepared by adopting a solvent evaporation method, a solvent-assisted grinding method and a slurry method. Compared with the technical cymoxanil, the eutectic crystal shows higher chemical stability, so that the use frequency is reduced, and the bioavailability is remarkably improved. The preparation method of the eutectic crystal is simple to operate, high in cost effectiveness and very suitable for commercial large-scale production.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pesticide co-crystals, and particularly relates to a cymoxanil-succinic acid pesticide co-crystal and a preparation method thereof. BACKGROUND

[0002] Cymoxanil (chemical name: 1-(2-cyano-2-methoxyiminoacetyl)-3-ethylurea) is disclosed in US3957847, and has a molecular formula of C7H 10 N4O3, a relative molecular mass of 198.18, and a structural formula as follows:

[0003]

[0004] Cymoxanil is a urea in which two nitrogen atoms are each replaced by an ethyl group and a 2-cyano-2-(methoxyimino) acetyl group. It is a fungicide used to control downy mildew on a range of crops including grapevines, hops, and potatoes. It has the effects of environmental pollutants, exotic organisms, and antifungal pesticides. It is a member of the urea, nitrile, oxime O-ether, and aliphatic nitrogen antifungal agents. Cymoxanil is an effective systemic fungicide for the prevention and treatment of plant diseases caused by fungal infection such as cucumber downy mildew. The main mode of action of cymoxanil is not yet known, and it is currently known to have a strong inhibitory effect on mycelial growth. Although cymoxanil has been used for a long time in the application of controlling downy mildew, cymoxanil technical material has poor stability and is prone to degradation in an alkaline environment and at high temperatures, thereby resulting in the problem of short duration of drug efficacy.

[0005] A study published in the international journal Front. Mol. Biosci. in 2021 prepared a new type of non-phospholipid liposome nanocarrier by using cholesterol and stearylamine, successfully achieving efficient loading (loading efficiency of 92.6%) and sustained release (duration of 3 days) of cymoxanil. This nanocarrier significantly improves the stability and antifungal efficacy of cymoxanil, and provides a new and efficient drug release strategy for agricultural prevention and treatment.

[0006] WO2021250653A1 discloses a stable cymoxanil preparation, which improves the stability of cymoxanil by adjusting the pH value to the range of 2-5. The suspension agent contains cymoxanil and a buffer system with a pH of 2 to 5, and also adds at least one other pesticide, at least one agriculturally acceptable carrier, and other additives to achieve better stability and effect.

[0007] However, the current method for improving the stability of cymoxanil is often too complex, involving multiple additives, which is difficult to directly apply to factory production. Therefore, it is urgent to develop a simple and easy method to solve these problems by directly modifying the cymoxanil technical. SUMMARY

[0008] Technical problem: The present application aims to provide a cymoxanil-succinic acid co-crystal and a preparation method thereof, which can improve the chemical stability of the pesticide cymoxanil, thereby solving the problem of short efficacy and high application frequency.

[0009] Technical solution: The raw material drug cymoxanil used in the present application has a chemical name of 1-(2-cyano-2-methoxy imino acetyl)-3-ethyl urea, an English name of Cymoxanil, a chemical formula of C7H 10 N4O3, a formula weight of 198.18, and a molecular structure as shown in formula (I); the selected succinic acid has a chemical formula of C4H6O4, a formula weight of 118.09, and a molecular structure as shown in formula (II).

[0010]

[0011] The cymoxanil-succinic acid pesticide co-crystal prepared by the present application is a stable solid form, and its crystal structure can be simply summarized as follows: the asymmetric unit of the cymoxanil-succinic acid pesticide co-crystal contains two components of cymoxanil and succinic acid. The cymoxanil-succinic acid pesticide co-crystal belongs to monoclinic system, the space group is P21 / n, the cell parameters are α=90°, β=92.980(3)°, γ=90°, Mr=257.23g / mol, Z=4.

[0012] The cymoxanil-succinic acid co-crystal prepared by the present application is a uniform and stable solid form. The powder X-ray diffraction technology (PXRD) is used to assist in verifying the cymoxanil-succinic acid pesticide co-crystal, and the powder X-ray diffraction technology (PXRD) characteristic diffraction peak appears at 8.86±0.2°, 9.12±0.2°, 13.82±0.2°, 14.50±0.2°, 17.62±0.2°, 20.60±0.2°, 21.42±0.2°, 25.46±0.2°, 26.52±0.2°, 27.35±0.2°, 28.04±0.2°, 29.38±0.2°, 30.46±0.2°, 32.18±0.2°.

[0013] There are three methods for preparing the cymoxanil-succinic acid pesticide co-crystal: solvent evaporation method, solvent-assisted grinding method and slurry method. The solvent evaporation method is to place cymoxanil and succinic acid in a conical flask at a molar ratio of 1:1, dissolve them in a mixed solvent of methanol / dichloromethane (volume ratio: 1:1), the mass ratio of cymoxanil to succinic acid and the volume ratio of organic solvent are 2 mg / ml and 1 mg / ml respectively, and then ultrasonic-assisted dissolution is performed. Then, the solution is filtered into a vial, and colorless flaky crystals are obtained after 25-45 days, which are cymoxanil-succinic acid pesticide co-crystal single crystals. The solvent-assisted grinding method is to place cymoxanil and succinic acid in a mortar at a molar ratio of 2:1, add a small amount of methanol for auxiliary grinding for 2-3 hours. After grinding, vacuum drying is performed. After drying, cymoxanil-succinic acid pesticide co-crystal powder is obtained. The slurry method is to weigh cymoxanil and succinic acid at a molar ratio of 2:1 and place them in a flask, add methanol (an amount that can saturate the system) and stir at 25℃ for 24 hours. After washing and filtering, the filter cake is dried, and the powder is cymoxanil-succinic acid pesticide co-crystal.

[0014] Beneficial effects:

[0015] The cymoxanil-succinic acid pesticide co-crystal prepared by the present application is a uniform and stable solid form. Under the premise of keeping the original cymoxanil unchanged, the chemical stability of cymoxanil under different pH conditions is effectively improved by small molecule succinic acid. This will help the pesticide to maintain effectiveness during the crop growth period, making the pesticide application more accurate and efficient, avoiding repeated application, reducing the amount of pesticide, thereby reducing costs and environmental pressure. Therefore, the cymoxanil-succinic acid pesticide co-crystal prepared by the present application has significant application value, not only improving the economic value of the pesticide and reducing the cost of agricultural production, but also helping to achieve the goal of sustainable agricultural development. BRIEF DESCRIPTION OF DRAWINGS

[0016] Figure 1 is the asymmetric unit graph of the crystal structure of the cymoxanil-succinic acid pesticide co-crystal;

[0017] Figure 2 is the PXRD spectrum of the cymoxanil-succinic acid pesticide co-crystal;

[0018] Figure 3 is the differential scanning calorimetry spectrum of the cymoxanil-succinic acid pesticide co-crystal;

[0019] Figure 4 is the thermogravimetric analysis graph of the cymoxanil-succinic acid pesticide co-crystal;

[0020] Figure 5 is the residual rate column chart of the cymoxanil-succinic acid pesticide co-crystal and the original cymoxanil in pH=5.8 and pH=8.0 buffer salt solution and pure water for 20 days. DETAILED DESCRIPTION

[0021] The above content of the present application will be further described in detail through the specific embodiments in the form of examples, but this should not be understood as the above main scope of the present application being limited to the following examples only.

[0022] The instrument for detecting the structure and performance of the pharmaceutical cocrystal in the present application is as follows:

[0023] The model of the X-ray single crystal diffractometer is Bruker APEX-II CCD, and the light source is Mo target. The data is integrated and reduced by using the SAINT program. The final data is subjected to multiple scan absorption correction by using SADABS. The crystal structure is analyzed by direct method by using SHELXL2014 software, and is refined by full matrix least squares method. Diamond is used for drawing the crystal structure diagram.

[0024] The model of the X-ray powder diffractometer is Rigaku SmartLab X-ray diffractometer (40 kV, 40 mA, Cu Kα ) above. The scanning speed is 10° / min, the step is 0.02°, and the 2θ angle range is 5-60° at room temperature.

[0025] The model of the differential scanning calorimeter is TGA-SDT Q600 V8.2 Build 100. The experiment is carried out in the range of 30-300°C under the inert environment of high-purity nitrogen at a fixed heating rate (10°C / min).

[0026] The model of the thermal gravimetric analyzer is TGA-SDT Q600 V8.2 Build 100. The experiment is carried out in the range of 30-300°C under the inert environment of high-purity nitrogen at a fixed heating rate (10°C / min).

[0027] Example 1: A preparation method of the cymoxanil-succinic acid pharmaceutical cocrystal, the raw drug cymoxanil (39.6 mg) and succinic acid (23.6 mg) are placed in a conical flask in a molar ratio of 1:1 at room temperature, and then ultrasonic dissolution is carried out in 20 ml of a mixed solution of methanol / dichloromethane (volume ratio: 1:1), filtered into a vial, and slowly evaporated at room temperature to obtain colorless flaky crystals, which are cymoxanil-succinic acid pharmaceutical cocrystal.

[0028] Example 2:

[0029] A preparation method of the cymoxanil-succinic acid pesticide co-crystal, cymoxanil (1.19 g) and succinic acid (0.35 g) are weighed according to a molar ratio of 2:1 and placed in a marver, ground for 3 hours, a small amount of methanol (about 1.0 ml) is added multiple times to assist grinding during the grinding process, and then vacuum drying is performed. After drying is completed, the obtained solid powder is the cymoxanil-succinic acid pesticide co-crystal powder.

[0030] Example 3:

[0031] A preparation method of the cymoxanil-succinic acid pesticide co-crystal, 5.0 g of cymoxanil and 1.5 g of succinic acid are weighed according to a molar ratio of 2:1 and placed in a flask, 8 ml of methanol is added, and stirring is performed at 25°C for 24 hours. Then, the obtained filter cake is dried after being washed and filtered with methanol and dichloromethane, 3.0 g is obtained, and the yield is 66.7%. The obtained solid powder is the cymoxanil-succinic acid pesticide co-crystal powder.

[0032] The cymoxanil-succinic acid pesticide co-crystal prepared in the example is characterized by powder X-ray diffraction, differential scanning calorimetry, and thermogravimetric analysis, and the results are consistent with those of the cymoxanil-succinic acid pesticide co-crystal prepared in Example 1.

[0033] Example 4:

[0034] The cymoxanil technical drug and the product obtained in Example 2 are subjected to 20-day chemical stability determination at different pH values.

[0035] Experimental method: Cymoxanil and the product obtained in Example 2 (based on 50 mg of cymoxanil) are weighed into a 50 ml volumetric flask. Then, 10 ml of phosphate buffer solution with different pH values (pH = 5.8 and pH = 8.0) and pure water are added to the flask, and then all are placed in a constant-temperature water bath at 25°C. After 20 days, the volumetric flask is taken out and immediately diluted with acetonitrile to reach the scale mark. The sample is filtered using a 0.22 μm nylon membrane filter for high performance liquid chromatography analysis. The experiment is repeated three times.

[0036] High performance liquid chromatography determination experimental conditions: the instrument is Wufeng LC100, a C-18 (250 x 4.6 mm) chromatographic column is used as a separation column, the column temperature is 25°C. The flow rate of the mobile phase is 1.0 ml / min, the injection amount is 20 μL, the mobile phase is acetonitrile: water = 3:7, and the detection wavelength is 240 nm.

[0037] The experimental results are as follows: Figure 5The results show that after 20 days of the test, the content of the cymoxanil in the cymoxanil-succinic acid pesticide co-crystal is higher than that of the cymoxanil technical under any pH condition. Especially under the conditions of pure water and pH value of 8, the performance of the cymoxanil-succinic acid pesticide co-crystal is more prominent. In pure water, the residual rate of the cymoxanil technical is about 60%, while the residual rate of the cymoxanil in the cymoxanil-succinic acid pesticide co-crystal is as high as about 88%. More significantly, under the condition of pH value of 8, the residual rate of the cymoxanil technical is almost zero after 20 days, while the residual rate of the cymoxanil in the cymoxanil-succinic acid pesticide co-crystal is close to 90%. In addition, under the conditions of pH value of 5.8, pure water and pH value of 8.0, the 20-day pesticide residual rate of the cymoxanil-succinic acid pesticide co-crystal is more than 80%. These data clearly show that the chemical stability of the cymoxanil-succinic acid pesticide co-crystal is significantly improved compared with the cymoxanil technical.

Claims

1. A cymoxanil-succinic acid pesticide eutectic, characterized in that: Cymoxanil and succinic acid were used to obtain a cyclohexanil-succinic acid pesticide eutectic single crystal suitable for single-crystal X-ray diffraction via solvent evaporation. The molecular formula of the cyclohexanil-succinic acid pesticide eutectic is [C7H]. 10 [N4O3·0.5(C4H6O4)], the molar ratio of cymoxanil and succinic acid is 2:1, the cymoxanil-succinic acid pesticide eutectic belongs to the monoclinic crystal system, space group P21 / n, and cell parameters are... α=90°, β=92.980(3)°, γ=90°, Mr=257.23g / mol, Z = 4.

2. The cymoxanil-succinic acid pesticide eutectic according to claim 1, characterized in that, Powder X-ray diffraction (PXRD) was used to assist in the verification of the cymoxanil-succinic acid pesticide eutectic. The characteristic peaks of its PXRD spectrum appeared at: 8.86±0.2°, 9.12±0.2°, 13.82±0.2°, 14.50±0.2°, 17.62±0.2°, 20.60±0.2°, 21.42±0.2°, 25.46±0.2°, 26.52±0.2°, 27.35±0.2°, 28.04±0.2°, 29.38±0.2°, 30.46±0.2°, and 32.18±0.2°.

3. The cymoxanil-succinic acid pesticide eutectic according to claim 1, characterized in that, Cymoxanil-succinic acid pesticide eutectic is a homogeneous and stable solid form in which the asymmetric units in the unit cell contain both cymoxanil and succinic acid components.

4. The method for preparing the cymoxanil-succinic acid pesticide eutectic according to claim 1, characterized in that: The solvent evaporation method includes the following steps: Cymoxanil and succinic acid are placed together in an Erlenmeyer flask at a molar ratio of 1:1 and dissolved together in a solvent composed of a mixture of methanol and dichloromethane (volume ratio 1:1). The mass ratio of cymoxanil to succinic acid to the volume of the organic solvent is 2 mg / ml and 1 mg / ml, respectively. The solution is dissolved by sonication, filtered, and the mixed solution is placed in a suitable environment for slow evaporation. Colorless flaky crystals are obtained after 25-45 days, which are the cymoxanil-succinic acid pesticide cocrystals.

5. The method for preparing the cymoxanil-succinic acid pesticide eutectic according to claim 1, characterized in that: The solvent-assisted grinding method includes the following steps: weigh cymoxanil and succinic acid in a molar ratio of 2:1 and place them in a mortar. Grind for 2-3 hours to ensure thorough grinding, and add a small amount of methanol to assist grinding during the process. Afterward, vacuum dry to obtain a white powder, which is the cymoxanil-succinic acid pesticide eutectic.

6. The method for preparing the cymoxanil-succinic acid pesticide eutectic according to claim 1, characterized in that: The slurry method includes the following steps: Weigh cymoxanil and succinic acid in a molar ratio of 2:1 into a flask, add methanol (the amount is enough to make the system supersaturated), suspend and stir at 25°C for 24 hours, wash and filter to obtain filter cake, and dry to obtain cymoxanil-succinic acid pesticide eutectic.

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