Thiophanate-methyl and fludioxonil eutectic crystal and preparation method thereof

Abstract

The invention relates to a thiophanate-methyl and fludioxonil eutectic crystal and a preparation method thereof. Both the thiophanate-methyl and the fludioxonil are active ingredients of a bactericide, and co-crystals are formed through intermolecular interaction such as hydrogen bonds and the like. A liquid-assisted grinding method and a solvent evaporation method are respectively adopted for preparation. In the co-crystal, the water solubility of the thiophanate-methyl is reduced, the threat of leaching and runoff of the thiophanate-methyl to aquatic ecology is reduced, the water solubility of the fludioxonil is improved, and the bioavailability of the fludioxonil is improved. Under the condition that the synergistic effect of the two bactericides is reserved, the environment friendliness and bioavailability of the pesticide are improved, the lasting period of the pesticide is prolonged, the process is simple, and practical application and production are facilitated.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of pesticide co-crystals, and particularly relates to a thiophanate-methyl and fludioxonil co-crystal and a preparation method thereof. BACKGROUND

[0002] Thiophanate-methyl has the following structural formula:

[0003]

[0004] Thiophanate-methyl is an internal systemic fungicide, belongs to the benzimidazole class, and has protective and curative effects, and is widely used in the prevention and treatment of diseases because of its broad-spectrum fungicidal activity. After being absorbed by plants, thiophanate-methyl is metabolically degraded into carbendazim, interferes with the formation of spindles in mitosis of fungi, and affects cell division, thereby playing a fungicidal effect. Thiophanate-methyl is usually prepared into a suspension or a wettable powder for use. However, thiophanate-methyl is prone to resistance when used alone for a long time and has cross-resistance with benzimidazole fungicides, and needs to be used with other pesticides in rotation. In addition, thiophanate-methyl is easily transferred to an aquatic environment through leaching and runoff, has a short persistence, and its decomposition products are often detected in rivers, which poses a great threat to the survival of fish, amphibians, crustaceans and algae. Therefore, it is necessary to reduce its water solubility to reduce its mobility in soil, reduce the risk of leaching and runoff, and improve its environmental friendliness.

[0005] Fludioxonil has the following structural formula:

[0006]

[0007] Fludioxonil is a non-systemic broad-spectrum fungicide, belongs to the phenylpyrrole class, and the effect of fludioxonil is to inhibit spore germination, germ tube elongation and mycelial growth of pathogenic fungi. Fludioxonil is used for seed treatment, has fast film formation and does not fall off, and has the characteristics of low water solubility, and the active ingredient does not move in the soil, and the drug effect is stable and persistent. It is not only widely used for seed treatment, but also can be used for foliar spraying to prevent diseases on fruits and leaves of various crops. In addition, fludioxonil has a unique action mechanism and no cross-resistance with existing fungicides, and is often used as a compounding agent. CN102258042A discloses a fungicidal composition taking fludioxonil and thiophanate-methyl as main active components, the action mechanisms of the two are different, and mutual mixing will not produce mutual resistance. It is proved by tests that the fungicidal composition can synergistically increase efficiency, reduce cost, is easy to transport and use, causes less environmental pollution, and is not prone to cause pesticide damage. However, the essence of the fungicidal composition is a compounded pesticide obtained by physically mixing thiophanate-methyl, fludioxonil, adjuvants, carriers and the like. The problem that thiophanate-methyl has a short persistence and is easily transferred to an aquatic environment is not solved.

[0008] In recent years, co-crystal technology has been successfully applied to solve the problems encountered in the development of pesticide products. Its essence is that two or more discrete neutral molecules are combined by non-covalent interactions (such as hydrogen bonds, van der Waals forces and π···π interactions) in stoichiometric ratio. The preparation of co-crystals can change the solubility, dissolution rate, bioavailability, hygroscopicity, melting point, stability and other properties of the pesticide while retaining the pharmacological activity of the pesticide itself. By introducing low water-soluble components through co-crystal technology, the purpose of reducing water solubility can usually be achieved.

[0009] Both thiophanate-methyl and fludioxonil have good hydrogen bond acceptors and donors, and can form thiophanate-methyl and fludioxonil co-crystals through hydrogen bonds and other non-covalent interactions. The thiophanate-methyl and fludioxonil co-crystals retain the synergistic effect of the two fungicides while reducing the water solubility of thiophanate-methyl, reducing the risk of leaching and runoff to aquatic ecology, improving the environmental friendliness, increasing the water solubility of fludioxonil, and improving the bioavailability. SUMMARY

[0010] Technical problem: The purpose of the present application is to reduce the solubility of thiophanate-methyl while retaining the synergistic effect of thiophanate-methyl and fludioxonil after compounding.

[0011] Technical solution: In order to achieve the above purpose, the present application provides the following technical solution:

[0012] A thiophanate-methyl and fludioxonil co-crystal, the molar ratio of thiophanate-methyl to fludioxonil in the co-crystal is 2:1, and the fludioxonil molecules are orientationally disordered with an occupancy of 0.5:0.5.

[0013] The thiophanate-methyl and fludioxonil co-crystal belongs to triclinic system, and the space group is Axial length: Angle: α / °=71.115(2), β / °=84.505(2), γ / °=70.307(2), Z=2.

[0014] The powder X-ray diffraction characteristic peaks of the thiophanate-methyl and fludioxonil co-crystal appear at 2θ=6.2°, 10.06°, 12.5°, 13.3°, 15.5°, 15.7°, 17.8°, 18.3°, 18.7°, 20.0°, 22.7°, 23.9°, 24.9°, 25.7°, 26.5°, 27.3°, 28.9°, 29.9°, 30.3°, 30.7°, 31.6° and 33.0°.

[0015] The application also provides a preparation method of the thiophanate-methyl and fludioxonil co-crystal.

[0016] The preparation method of the thiophanate-methyl and fludioxonil co-crystal, wherein the liquid-assisted grinding method is as follows: weighing thiophanate-methyl and fludioxonil in a molar ratio of 2:1, placing them in a marbled mortar, adding a small amount of methanol solution, grinding for 3 hours, and drying in a vacuum drying box to obtain the thiophanate-methyl and fludioxonil co-crystal.

[0017] The preparation method of the thiophanate-methyl and fludioxonil co-crystal, wherein the solvent evaporation method is as follows: dissolving thiophanate-methyl and fludioxonil in a mixed solvent in a molar ratio of 2:1, filtering the solution, and evaporating at room temperature until crystals are precipitated.

[0018] Advantages:

[0019] (1) In the application, thiophanate-methyl and fludioxonil form a co-crystal, in which the water solubility of thiophanate-methyl is reduced, reducing the risk of leaching and runoff, and the water solubility of fludioxonil is increased, improving its bioavailability. The application is beneficial to improving the bioavailability of pesticides, prolonging the efficacy of pesticides, and enhancing the environmental friendliness of pesticides.

[0020] (2) The preparation method of the thiophanate-methyl and fludioxonil co-crystal provided by the application is simple, low in cost, and beneficial to practical application and production.

[0021] (3) The thiophanate-methyl and fludioxonil co-crystal of the application is composed of two fungicide active ingredients, has a dual action mechanism, can synergize, and delays the development of resistance of pathogens. BRIEF DESCRIPTION OF DRAWINGS

[0022] Figure 1 PXRD patterns of thiophanate-methyl, fludioxonil, and the thiophanate-methyl and fludioxonil co-crystal;

[0023] Figure 2 The minimum unit of the structure of the thiophanate-methyl and fludioxonil co-crystal;

[0024] Figure 3 DSC curves of thiophanate-methyl, fludioxonil, and the thiophanate-methyl and fludioxonil co-crystal;

[0025] Figure 4 Solubility of thiophanate-methyl, fludioxonil, and the thiophanate-methyl and fludioxonil co-crystal in pure water at 25℃. DETAILED DESCRIPTION

[0026] For the convenience of those skilled in the art to understand the present application, the present application will be further described in detail below in conjunction with specific examples.

[0027] Example 1:

[0028] 0.7 g thiophanate-methyl and 0.254 g fludioxonil were weighed in a molar ratio of 2:1 in a marcasite mortar, a small amount of methanol was added as an auxiliary solvent, and grinding was carried out for 3 h. The product was then placed in a vacuum drying oven at 40°C and dried for 12 h to obtain a eutectic crystal of thiophanate-methyl and fludioxonil. The PXRD pattern of the product is shown in Figure 1 , and the characteristic peaks are located at 2θ = 6.2°, 10.06°, 12.5°, 13.3°, 15.5°, 15.7°, 17.8°, 18.3°, 18.7°, 20.0°, 22.7°, 23.9°, 24.9°, 25.7°, 26.5°, 27.3°, 28.9°, 29.9°, 30.3°, 30.7°, 31.6° and 33.0°.

[0029] Example 2:

[0030] 0.05 g thiophanate-methyl and 0.0181 g fludioxonil were weighed in a molar ratio of 2:1 and dissolved in a mixed solvent of 16 ml methanol and 4 ml cyclohexane. The solution was filtered and evaporated to obtain a eutectic crystal of thiophanate-methyl and fludioxonil in the form of colorless transparent square plates. The obtained eutectic crystal of thiophanate-methyl and fludioxonil was characterized by SCXRD, and the crystal structure is shown in Figure 2 , which belongs to the triclinic system with a space group of Axis length: Angle: α / ° = 71.115(2), β / ° = 84.505(2), γ / ° = 70.307(2), Z = 2. The PXRD pattern of the product is similar to that of Example 1. The DSC pattern of the product is shown in Figure 3 , and the melting peak is at 195.13°C.

[0031] Example 3:

[0032] 0.07 g of the eutectic crystal of thiophanate-methyl and fludioxonil obtained in Example 1 was weighed and dissolved in a mixed solvent of 16 ml acetone and 4 ml cyclohexane. The solution was filtered and evaporated to obtain a eutectic crystal of thiophanate-methyl and fludioxonil in the form of colorless transparent square plates. The PXRD pattern and DSC pattern of the product are similar to those of Example 2.

[0033] Example 4:

[0034] 0.07 g of the methyl thiophanate and fludioxonil co-crystal powder obtained in Example 1 was weighed and dissolved in a mixed solvent of 16 ml acetonitrile and 4 ml cyclohexane. The solution was filtered and then evaporated until crystals precipitated. The resulting methyl thiophanate and fludioxonil co-crystal was a colorless, transparent, square plate-like substance. The PXRD and DSC spectra of this product were similar to those of Example 2.

[0035] Example 5:

[0036] Excess amounts of thiophanate-methyl, fludioxonil, and 3 mg of the thiophanate-methyl and fludioxonil co-crystal powder prepared in Example 1 were weighed and added to 20 ml of pure water, respectively, to investigate their solubility at 25 °C. The results are as follows: Figure 4 As shown, the water solubility of thiophanate-methyl in the cocrystal is significantly reduced, while the solubility of fludioxonil in the cocrystal is increased.

[0037] This invention is not limited to the embodiments described above. Any variations thereof without departing from the principles of this invention should also be considered within the scope of this invention.

Claims

1. A methyl thiophanate and fludioxonil co-crystal, characterized in that... It contains two fungicide active ingredients, thiophanate-methyl and fludioxonil, which form a eutectic through intermolecular hydrogen bonds.

2. The eutectic according to claim 1, characterized in that... Thiophanate-methyl and fludioxonil form a eutectic in a molar ratio of 2:

1. The fludioxonil molecules are orientationally disordered, with a occupancy ratio of 0.5:0.

5. The eutectic belongs to the triclinic crystal system, space group [missing information]. Axis length: Angle: α / °=71.115(2), β / °=84.505(2), γ / °=70.307(2), Z = 2.

3. The eutectic according to claim 1, characterized in that, The powder X-ray diffraction characteristic peaks of the methyl thiophanate and fludioxonil cocrystal appear at 2θ = 6.2°, 10.06°, 12.5°, 13.3°, 15.5°, 15.7°, 17.8°, 18.3°, 18.7°, 20.0°, 22.7°, 23.9°, 24.9°, 25.7°, 26.5°, 27.3°, 28.9°, 29.9°, 30.3°, 30.7°, 31.6°, and 33.0°.

4. The method for preparing the methyl thiophanate and fludioxonil co-crystal according to claim 1, characterized in that, The co-crystal of thiophanate-methyl and fludioxonil can be obtained by using liquid-assisted grinding and solvent evaporation methods.

5. The method according to claim 4, characterized in that, The liquid-assisted grinding method involves weighing thiophanate-methyl and fludioxonil in a molar ratio of 2:1, adding a small amount of methanol, grinding for 3 hours, and then drying under vacuum to obtain a eutectic of thiophanate-methyl and fludioxonil.

6. The method according to claim 4, characterized in that, The solvent evaporation method involves dissolving thiophanate-methyl and fludioxonil in a mixed solvent at a molar ratio of 2:1, filtering the solution, and then evaporating it at room temperature until crystals precipitate.

7. The method according to claim 6, characterized in that, The mixed solvent is one of cyclohexane and methanol, acetone or acetonitrile, in a volume ratio of 1:4.

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