Azoxystrobin channel type solvate, co-crystal and preparation method thereof

Abstract

The present invention provides azoxystrobin channel-type solvate, cocrystal and preparation method thereof. Specifically, the present invention relates to (E)-2-{2-[6-(2-cyanophenoxy)pyrimidin-4-yloxy]phenyl}-3-methoxy acrylate channel-type solvate, cocrystal and preparation method and use thereof.

Description

Technical Field

[0001] The present invention belongs to the field of pesticide chemistry, and in particular relates to azoxystrobin channel-type solvate, co-crystal, and application and preparation method thereof. Background Art

[0002]

[0003] Azoxystrobin (compound of formula I), chemical name (E)-2-{2-[6-(2-cyanophenoxy)pyrimidin-4-yloxy]phenyl}-3-methoxyacrylate, its common name is known as azoxystrobin, this compound is a β-methoxyacrylate fungicide, as a systemic broad-spectrum fungicide, it can inhibit the mitochondrial respiration of pathogenic fungi, destroy the energy synthesis of pathogens, and has the triple effects of protection, treatment and eradication. It has good preventive effect on four major plant pathogenic fungi, namely, ascomycetes (such as powdery mildew), basidiomycetes (such as rust), deuteromycetes (such as rice blast) and oomycetes (such as downy mildew).

[0004] The same compound may have different solubility, stability, fluidity, compressibility and bioavailability in different crystal forms. These physical and chemical properties will have a certain impact on the application of the compound. According to the preparation method in the original compound patent CN101522639A, the prepared crystal form is named Crystal Form I, which has low solubility and instability.

[0005] Therefore, there is an urgent need in the art to develop other crystalline forms of the compound of formula I, which require simple preparation methods, good light and heat stability, low hygroscopicity, high solubility, and scalable production. Summary of the invention

[0006] The object of the present invention is to provide a polymorph or co-crystal of azoxystrobin solvate and a preparation method thereof.

[0007] In the first aspect of the present invention, there is provided a solvate of a compound of formula I,

[0008]

[0009] The solvent in the solvate is selected from the group consisting of dimethyl succinate, thiophene, ethylene glycol diethyl ether, or a combination thereof.

[0010] In another preferred embodiment, the solvate is a channel-type solvate.

[0011] In another preferred embodiment, the molecular volume of the solvent suitable for this channel is between 90 and 109 cm 3 / mol or between 40 and 64 cm 3 / mol.

[0012] In another preferred embodiment, the solvate is a solvate formed by the compound of formula I and dimethyl succinate, and in the solvate, the molar ratio of the compound of formula I to the dimethyl succinate solvent is (1.8-2.2):1, preferably 2:1.

[0013] In another preferred embodiment, the solvate is a solvate formed by the compound of formula I and thiophene, and in the solvate, the molar ratio of the compound of formula I to the thiophene solvent is (0.8-1.2):1, preferably 1:1.

[0014] In another preferred embodiment, the solvate is a solvate formed by the compound of formula I and ethylene glycol diethyl ether, and in the solvate, the molar ratio of the compound of formula I to the ethylene glycol diethyl ether solvent is (1.8-2.2):1, preferably 2:1.

[0015] In another preferred embodiment, the solvate is crystalline or amorphous, preferably crystalline.

[0016] In another preferred embodiment, the solvate is selected from the following group: Form III, Form IV, Form V, or a combination thereof.

[0017] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form III includes 3 or more 2θ values ​​selected from the following group: 7.7±0.2°, 8.4±0.2°, 14.2±0.2°, 18.3±0.2°, 18.9±0.2°, 20.4±0.2°, 21.4±0.2° and 22.0±0.2°.

[0018] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form III includes 3 or more 2θ values ​​selected from the following group: 7.4±0.2°, 7.7±0.2°, 8.4±0.2°, 12.0±0.2°, 13.4±0.2°, 14.2±0.2°, 14.9±0.2°, 15.7±0.2°, 16.8±0.2°, 18.3±0.2°, 18.9±0.2°, 20.4±0.2°, 21.4±0.2°, 2 2.0±0.2°, 23.0±0.2°, 23.4±0.2°, 23.8±0.2°, 23.9±0.2°, 24.7±0.2°, 25.4±0.2°, 26.7±0.2°, 27.0±0.2°, 27.5±0.2°, 28.6±0.2°, 31.3±0.2°, 31.7±0.2°, 35.8±0.2°, 37.3±0.2°, 39.6±0.2° and 40.7±0.2°.

[0019] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form III includes 5 or more 2θ values ​​selected from the following group: 7.4±0.2°, 7.7±0.2°, 8.4±0.2°, 12.0±0.2°, 13.4±0.2°, 14.2±0.2°, 14.9±0.2°, 15.7±0.2°, 16.8±0.2°, 18.3±0.2°, 18.9±0.2°, 20.4±0.2°, 21.4±0.2°, 2 2.0±0.2°, 23.0±0.2°, 23.4±0.2°, 23.8±0.2°, 23.9±0.2°, 24.7±0.2°, 25.4±0.2°, 26.7±0.2°, 27.0±0.2°, 27.5±0.2°, 28.6±0.2°, 31.3±0.2°, 31.7±0.2°, 35.8±0.2°, 37.3±0.2°, 39.6±0.2° and 40.7±0.2°.

[0020] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form III includes 10 or more 2θ values ​​selected from the following group: 7.4±0.2°, 7.7±0.2°, 8.4±0.2°, 12.0±0.2°, 13.4±0.2°, 14.2±0.2°, 14.9±0.2°, 15.7±0.2°, 16.8±0.2°, 18.3±0.2°, 18.9±0.2°, 20.4±0.2°, 21.4±0.2°, 22.0±0.2°, 23.0±0.2°, 23.4±0.2°, 23.8±0.2°, 23.9±0.2°, 24.7±0.2°, 25.4±0.2°, 26.7±0.2°, 27.0±0.2°, 27.5±0.2°, 28.6±0.2°, 31.3±0.2°, 31.7±0.2°, 35.8±0.2°, 37.3±0.2°, 39.6±0.2° and 40.7±0.2°.

[0021] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form III may further include one or more 2θ values ​​selected from the following group: 12.4±0.2°, 13.8±0.2°, 14.7±0.2°, 18.5±0.2°, 19.3±0.2°, 26.1±0.2°, 37.7±0.2°, 38.8±0.2°, 42.7±0.2° and 43.6±0.2°.

[0022] In another preferred embodiment, the crystalline form III has a 2θ (°) value selected from those shown in Table 1.

[0023] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form III is substantially as follows Figure 1 Characterized by.

[0024] In another preferred embodiment, the TGA diagram of the crystalline form III is substantially as follows Figure 3 Characterized by.

[0025] In another preferred embodiment, the DSC graph of the crystalline form III has endothermic peaks in the ranges of 62-88°C and 100-125°C.

[0026] In another preferred embodiment, the DSC diagram of the crystalline form III is substantially as follows Figure 2 Characterized by.

[0027] In another preferred embodiment, the purity of the crystal form III is greater than 95%.

[0028] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form IV includes 3 or more 2θ values ​​selected from the following group: 7.6±0.2°, 8.7±0.2°, 18.3±0.2°, 20.6±0.2°, 21.7±0.2°, 22.5±0.2°, 24.0±0.2°, and 26.6±0.2°.

[0029] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form IV includes 3 or more 2θ values ​​selected from the following group: 7.6±0.2°, 8.7±0.2°, 13.4±0.2°, 14.6±0.2°, 15.5±0.2°, 16.4±0.2°, 17.4±0.2°, 18.3±0.2°, 18.7±0.2°, 19.3±0.2°, 20.6±0.2°, 21.7±0.2°, 22.5±0.2°, 24.0±0.2°, 24.4±0.2°, 26.6±0.2°, 28.4±0.2°, 29.0±0.2°, 30.5±0.2°, 33.9±0.2°, 36.9±0.2° and 38.2±0.2°.

[0030] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form IV includes 5 or more 2θ values ​​selected from the following group: 7.6±0.2°, 8.7±0.2°, 13.4±0.2°, 14.6±0.2°, 15.5±0.2°, 16.4±0.2°, 17.4±0.2°, 18.3±0.2°, 18.7±0.2°, 19.3±0.2°, 20.6±0.2°, 21.7±0.2°, 22.5±0.2°, 24.0±0.2°, 24.4±0.2°, 26.6±0.2°, 28.4±0.2°, 29.0±0.2°, 30.5±0.2°, 33.9±0.2°, 36.9±0.2° and 38.2±0.2°.

[0031] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form IV includes 10 or more 2θ values ​​selected from the following group: 7.6±0.2°, 8.7±0.2°, 13.4±0.2°, 14.6±0.2°, 15.5±0.2°, 16.4±0.2°, 17.4±0.2°, 18.3±0.2°, 18.7±0.2° , 19.3±0.2°, 20.6±0.2°, 21.7±0.2°, 22.5±0.2°, 24.0±0.2°, 24.4±0.2°, 26.6±0.2°, 28.4±0.2°, 29.0±0.2°, 30.5±0.2°, 33.9±0.2°, 36.9±0.2° and 38.2±0.2°.

[0032] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form IV may further include one or more 2θ values ​​selected from the following group: 11.8±0.2°, 22.9±0.2°, 23.7±0.2°, 25.4±0.2°, 27.5±0.2°, 29.4±0.2°, 31.1±0.2°, 32.2±0.2°, 40.75±0.2°, 41.4±0.2° and 43.9±0.2°.

[0033] In another preferred embodiment, the crystalline form IV has a 2θ (°) value selected from those shown in Table 4.

[0034] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form IV is substantially as follows Fig.10 Characterized by.

[0035] In another preferred embodiment, the TGA diagram of the crystalline form IV is substantially as follows Fig.12 Characterized by.

[0036] In another preferred embodiment, the DSC graph of the crystalline form IV has endothermic peaks in the ranges of 77-100°C and 106-123°C.

[0037] In another preferred embodiment, the DSC diagram of the crystalline form IV is substantially as follows Fig.11 Characterized by.

[0038] In another preferred embodiment, the purity of the crystalline form IV is greater than 95%.

[0039] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form V includes 3 or more 2θ values ​​selected from the following group: 7.7±0.2°, 8.5±0.2°, 14.5±0.2°, 21.5±0.2°, 22.5±0.2°, 23.0±0.2°, 24.5±0.2° and 29.0±0.2°.

[0040] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form V includes 3 or more 2θ values ​​selected from the following group: 7.7±0.2°, 8.5±0.2°, 13.9±0.2°, 14.5±0.2°, 17.8±0.2°, 18.3±0.2°, 19.1±0.2°, 20.5±0.2°, 21.5±0.2°, 22.5±0.2°, 23.0±0.2°, 24.5±0.2°, 26.4±0.2°, 27.0±0.2°, 29.0±0.2°, 30.8±0.2°, 36.3±0.2° and 38.7±0.2°.

[0041] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form V includes 5 or more 2θ values ​​selected from the following group: 7.7±0.2°, 8.5±0.2°, 13.9±0.2°, 14.5±0.2°, 17.8±0.2°, 18.3±0.2°, 19.1±0.2°, 20.5±0.2°, 21.5±0.2°, 22.5±0.2°, 23.0±0.2°, 24.5±0.2°, 26.4±0.2°, 27.0±0.2°, 29.0±0.2°, 30.8±0.2°, 36.3±0.2° and 38.7±0.2°.

[0042] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form V includes 10 or more 2θ values ​​selected from the following group: 7.7±0.2°, 8.5±0.2°, 13.9±0.2°, 14.5±0.2°, 17.8±0.2°, 18.3±0.2°, 19.1±0.2°, 20.5±0.2°, 21.5±0.2°, 22.5±0.2°, 23.0±0.2°, 24.5±0.2°, 26.4±0.2°, 27.0±0.2°, 29.0±0.2°, 30.8±0.2°, 36.3±0.2° and 38.7±0.2°.

[0043] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form V may further include one or more 2θ values ​​selected from the following group: 10.9±0.2°, 13.4±0.2°, 15.3±0.2°, 15.9±0.2°, 17.1±0.2°, 24.0±0.2°, 28.1±0.2°, 31.3±0.2°, 41.4±0.2° and 41.9±0.2°.

[0044] In another preferred embodiment, the crystalline form V has a 2θ (°) value selected from those shown in Table 5.

[0045] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form V is substantially as follows Fig.13Characterized by.

[0046] In another preferred embodiment, the TGA diagram of the crystalline form V is substantially as follows Fig.15 Characterized by.

[0047] In another preferred embodiment, the DSC graph of the crystalline form V has an endothermic peak in the range of 106 to 127°C.

[0048] In another preferred embodiment, the DSC graph of the crystalline form V is substantially as follows Fig.14 Characterized by.

[0049] In another preferred embodiment, the purity of the crystalline form V is greater than 95%.

[0050] The second aspect of the present invention provides a co-crystal of a compound of formula I and succinimide,

[0051]

[0052] In another preferred embodiment, the co-crystal is a co-crystal formed by the compound of formula I and succinimide in a molar ratio of 1:0.8-1.2 (preferably 1:1).

[0053] In another preferred embodiment, the cocrystal is Form IX.

[0054] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form IX includes 3 or more 2θ values ​​selected from the following group: 14.1±0.2°, 15.7±0.2°, 16.6±0.2°, 17.1±0.2°, 20.3±0.2°, 21.8±0.2°, 23.6±0.2° and 29.0±0.2°.

[0055] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form IX includes 3 or more 2θ values ​​selected from the following group: 7.4±0.2°, 10.2±0.2°, 10.7±0.2°, 11.7±0.2°, 13.1±0.2°, 14.1±0.2°, 15.7±0.2°, 16.6±0.2°, 17.1±0.2°, 17.4±0.2°, 18.4±0.2°, 19.6±0.2°, 20. 0.2°, 20.3±0.2°, 21.2±0.2°, 21.8±0.2°, 23.6±0.2°, 24.3±0.2°, 24.9±0.2°, 25.8±0.2°, 26.3±0.2°, 26.7±0.2°, 27.2±0.2°, 28.0±0.2°, 29.0±0.2°, 31.0±0.2°, 36.8±0.2° and 37.4±0.2°.

[0056] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form IX includes 5 or more 2θ values ​​selected from the following group: 7.4±0.2°, 10.2±0.2°, 10.7±0.2°, 11.7±0.2°, 13.1±0.2°, 14.1±0.2°, 15.7±0.2°, 16.6±0.2°, 17.1±0.2°, 17.4±0.2°, 18.4±0.2°, 19.6±0.2°, 20.8±0.2°, 21.3±0.2°, 22.1±0.2°, 23.9±0.2°, 24.8±0.2°, 25.9±0.2°, 26.7±0.2°, 27.8±0.2°, 28.9±0.2°, 29.0±0.2°, 30.1±0.2°, 31. 0.2°, 20.3±0.2°, 21.2±0.2°, 21.8±0.2°, 23.6±0.2°, 24.3±0.2°, 24.9±0.2°, 25.8±0.2°, 26.3±0.2°, 26.7±0.2°, 27.2±0.2°, 28.0±0.2°, 29.0±0.2°, 31.0±0.2°, 36.8±0.2° and 37.4±0.2°.

[0057] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form IX includes 10 or more 2θ values ​​selected from the following group: 7.4±0.2°, 10.2±0.2°, 10.7±0.2°, 11.7±0.2°, 13.1±0.2°, 14.1±0.2°, 15.7±0.2°, 16.6±0.2°, 17.1±0.2°, 17.4±0.2°, 18.4±0.2°, 19.6 ±0.2°, 20.3±0.2°, 21.2±0.2°, 21.8±0.2°, 23.6±0.2°, 24.3±0.2°, 24.9±0.2°, 25.8±0.2°, 26.3±0.2°, 26.7±0.2°, 27.2±0.2°, 28.0±0.2°, 29.0±0.2°, 31.0±0.2°, 36.8±0.2° and 37.4±0.2°.

[0058] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form IX may further include one or more 2θ values ​​selected from the following group: 10.7±0.2°, 14.9±0.2°, 15.3±0.2°, 23.9±0.2°, 25.4±0.2°, 30.3±0.2°, 31.3±0.2°, 34.1±0.2°, 38.4±0.2°, 38.8±0.2° and 41.5±0.2°.

[0059] In another preferred embodiment, the crystalline form IX has a 2θ (°) value selected from those shown in Table 6.

[0060] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form IX is substantially as follows Fig.16 Characterized by.

[0061] In another preferred embodiment, the TGA diagram of the crystalline form IX is substantially as follows Fig.18 Characterized by.

[0062] In another preferred embodiment, the DSC graph of the crystalline form IX has an endothermic peak in the range of 79 to 113°C.

[0063] In another preferred embodiment, the DSC diagram of the crystalline form IX is substantially as follows Fig.17 Characterized by.

[0064] In another preferred embodiment, the purity of the crystalline form IX is greater than 95%.

[0065] The third aspect of the present invention provides a pesticide composition, which comprises: (a) the solvate as described in the first aspect of the present invention and / or the co-crystal as described in the second aspect of the present invention, and (b) an pesticide-acceptable carrier.

[0066] In a fourth aspect, the present invention provides a method for preparing the crystalline form III described in the first aspect of the present invention, comprising the steps of:

[0067] (i) providing a first solution of a compound of formula I in dimethyl succinate;

[0068] (ii) volatilizing the first solution, or mixing with an anti-solvent and crystallizing to obtain the crystal form III.

[0069] In another preferred embodiment, the anti-solvent is selected from the following group: n-hexane, cyclohexane, n-heptane, water, or a combination thereof.

[0070] In another preferred embodiment, the method comprises the steps of:

[0071] (i) providing a first solution of a compound of formula I dissolved in dimethyl succinate;

[0072] (ii) volatilizing the first solution to obtain the crystalline form III described in the first aspect of the present invention.

[0073] In another preferred embodiment, the method comprises the steps of:

[0074] (i) providing a first solution of a compound of formula I dissolved in dimethyl succinate;

[0075] (ii) adding n-hexane to the first solution to form a second solution, and subjecting the second solution to crystallization to obtain the crystal form III according to the first aspect of the present invention.

[0076] In a fifth aspect, the present invention provides a method for preparing the crystalline form IV described in the first aspect of the present invention, comprising the steps of:

[0077] (i) providing a first solution of a compound of formula I in thiophene;

[0078] (ii) volatilizing the first solution, or mixing with an anti-solvent and crystallizing to obtain the crystal form IV.

[0079] In another preferred embodiment, the anti-solvent is selected from the following group: n-hexane, cyclohexane, n-heptane, water, or a combination thereof.

[0080] In another preferred embodiment, the method comprises the steps of:

[0081] (i) providing a first solution of a compound of formula (I) in a thiophene solvent;

[0082] (ii) volatilizing the first solution to obtain the crystalline form IV described in the first aspect of the present invention.

[0083] In another preferred embodiment, the method comprises the steps of:

[0084] (i) providing a first solution of a compound of formula (I) in a thiophene solvent;

[0085] (ii) adding n-hexane to the first solution to form a second solution, and subjecting the second solution to crystallization to obtain the crystalline form IV according to the first aspect of the present invention.

[0086] In a sixth aspect of the present invention, a method for preparing the crystal form VIII of the first aspect of the present invention comprises the steps of:

[0087] (i) providing a first solution of a compound of formula (I) in ethylene glycol diethyl ether;

[0088] (ii) mixing the first solution with an anti-solvent to form a second solution, and subjecting the second solution to crystallization to obtain the crystalline form V described in the first aspect of the present invention.

[0089] In another preferred embodiment, the anti-solvent is selected from the following group: n-hexane, cyclohexane, n-heptane, water, or a combination thereof.

[0090] In another preferred embodiment, the method comprises the steps of:

[0091] (i) providing a first solution of a compound of formula (I) dissolved in ethylene glycol diethyl ether;

[0092] (ii) adding n-hexane to the first solution to form a second solution, and subjecting the second solution to crystallization to obtain the crystalline form V according to the first aspect of the present invention.

[0093] In a seventh aspect of the present invention, a method for preparing the crystal form IX according to the second aspect of the present invention comprises the steps of:

[0094] (i) providing a first solution of a compound of formula (I) and succinimide dissolved in dichloromethane;

[0095] (ii) subjecting the first solution to rapid rotary evaporation to obtain the crystal form IX described in the second aspect of the present invention.

[0096] In another preferred embodiment, the rapid rotary evaporation treatment includes rotating at a speed of 120 to 140 rpm and a water bath temperature of 10±5° C., and rotary evaporation is performed to obtain the crystal form IX described in the second aspect of the present invention.

[0097] In an eighth aspect, the present invention provides a use of the solvate described in the first aspect of the present invention and the co-crystal described in the second aspect of the present invention or the pesticide composition described in the third aspect of the present invention for preventing or controlling diseases; or for inhibiting harmful microorganisms in agriculture, forestry or horticulture.

[0098] In another preferred embodiment, the prevention or control is the prevention or control of diseases in agriculture, forestry or horticulture.

[0099] In another preferred embodiment, the disease is selected from the following group of plant diseases: downy mildew, powdery mildew, anthracnose, leaf spot, or a combination thereof.

[0100] In another preferred embodiment, the harmful microorganisms are selected from the following groups: Ascomycetes, Basidiomycetes, Deuteromycetes and Oomycetes, or a combination thereof.

[0101] In another preferred embodiment, the prevention, control or inhibition is in vitro prevention, control or inhibition.

[0102] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. BRIEF DESCRIPTION OF THE DRAWINGS

[0103] Figure 1 The XRPD pattern of azoxystrobin Form III is shown.

[0104] Figure 2 The DSC graph of azoxystrobin Form III is shown.

[0105] Figure 3 The TGA graph of azoxystrobin Form III is shown.

[0106] Figure 4 The projection diagram of the three-dimensional structure of the crystal form III molecule is shown.

[0107] Figure 5 The crystal cell stacking projection of Form III is shown.

[0108] Figure 6 The five-day high humidity stability XRPD pattern of Form III is shown.

[0109] Figure 7The XRPD spectrum of Form III's ten-day high humidity stability is shown.

[0110] Figure 8 The five-day light stability XRPD spectrum of Form III is shown.

[0111] Fig. 9 The XRPD spectrum of Form III's ten-day light stability is shown.

[0112] Fig.10 The XRPD pattern of azoxystrobin Form IV is shown.

[0113] Fig.11 The DSC graph of azoxystrobin Form IV is shown.

[0114] Fig.12 The TGA graph of azoxystrobin Form IV is shown.

[0115] Fig.13 The XRPD pattern of azoxystrobin Form V is shown.

[0116] Fig.14 The DSC graph of azoxystrobin Form V is shown.

[0117] Fig.15 The TGA graph of azoxystrobin Form V is shown.

[0118] Fig.16 The XRPD pattern of azoxystrobin Form IX is shown.

[0119] Fig.17 The DSC graph of azoxystrobin Form IX is shown.

[0120] Fig.18 The TGA graph of azoxystrobin Form IX is shown.

[0121] Fig.19 The XRPD pattern of Form IX showing five-day high temperature stability.

[0122] Fig. 20 The XRPD spectrum of Form IX showing its ten-day high temperature stability.

[0123] Fig.21 The five-day high humidity stability XRPD pattern of Form IX is shown.

[0124] Fig. 22 The XRPD pattern of Form IX's ten-day high humidity stability is shown.

[0125] Fig.23 The five-day light stability XRPD pattern of Form IX is shown.

[0126] Fig.24 The XRPD pattern of Form IX for ten days of light stability is shown. DETAILED DESCRIPTION

[0127] Through extensive and in-depth research, the inventors unexpectedly discovered new solvates and cocrystals of azoxystrobin and their preparation methods for the first time. The three solvates (crystal forms III-V) and cocrystals (crystal form IX) described in the present invention are of high purity, have good thermal stability and non-hygroscopicity, and are superior to existing azoxystrobin in terms of solubility. They are suitable for preparing pesticide compositions that inhibit harmful microorganisms, thereby having better preventive effects on most diseases such as downy mildew, powdery mildew, anthracnose, leaf spot, etc. caused by four major categories of pathogenic fungi, namely, ascomycetes, basidiomycetes, deuteromycetes and oomycetes. In addition, the preparation method of the solvate of the present invention is simple and suitable for large-scale industrial production. On this basis, the inventors completed the present invention.

[0128] Terminology

[0129] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0130] As used herein, when used in reference to a specific recited numerical value, the term "about" means that the value may vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes all values ​​between 99 and 101 (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0131] As used herein, the term "comprising" or "including (comprising)" may be open, semi-closed and closed. In other words, the term also includes "consisting essentially of" or "consisting of".

[0132] As used herein, the term "n or more 2θ values ​​selected from the following group" refers to any positive integer (e.g., n, n+1, ...) including n and greater than n, wherein the upper limit Nup is the number of all 2θ peaks in the group. For example, "1 or more" includes not only 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, ... each positive integer of the upper limit Nup, but also includes "2 or more", "3 or more", "4 or more", "5 or more", "6 or more", "7 or more", "8 or more", "9 or more", "10 or more", etc. ranges. For example, "3 or more" not only includes 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, ... the upper limit Nup, each positive integer, but also includes "4 or more", "5 or more", "6 or more", "7 or more", "8 or more", "9 or more", "10 or more", and other ranges.

[0133] Compounds of formula I

[0134]

[0135] Azoxystrobin (compound of formula I), chemical name is (E)-2-{2-[6-(2-cyanophenoxy)pyrimidin-4-yloxy]phenyl}-3-methoxyacrylate methyl ester. This compound is a brand-new β-methoxyacrylate fungicide, which can inhibit the mitochondrial respiration of pathogenic fungi and destroy the energy synthesis of pathogens, and has the triple effects of protection, treatment and eradication. It has a good preventive effect on most diseases caused by four major categories of pathogenic fungi, namely, ascomycetes, basidiomycetes, deuteromycetes and oomycetes, such as downy mildew, powdery mildew, anthracnose, leaf spot, etc.

[0136] Polymorph

[0137] Solids exist in either amorphous or crystalline form. In the case of crystalline form, the molecules are positioned in a three-dimensional lattice. When a compound crystallizes from a solution or slurry, it can crystallize in different spatial lattice arrangements (a property known as "polymorphism"), forming crystals with different crystalline forms, which are known as "polymorphs". Different polymorphs of a given substance may differ from one another in one or more physical properties, such as solubility and dissolution rate, true specific gravity, crystal shape, packing mode, fluidity and / or solid state stability.

[0138] crystallization

[0139] The solubility limit of the compound of interest can be exceeded by operating the solution, thereby completing production-scale crystallization. This can be accomplished by a variety of methods, for example, dissolving the compound at a relatively high temperature and then cooling the solution to below the saturation limit. Alternatively, the liquid volume can be reduced by boiling, atmospheric evaporation, vacuum drying or by some other methods. The solubility of the compound of interest can be reduced by adding an antisolvent or a solvent in which the compound has a low solubility or a mixture of such solvents. Another alternative method is to adjust the pH value to reduce solubility. For a detailed description of the crystallization, see Crystallization, the third edition, JW Mullens, Butterworth-Heineman Ltd., 1993, ISBN0750611294.

[0140] If it is desired that salt formation and crystallization occur simultaneously, the addition of an appropriate acid or base may result in direct crystallization of the desired salt if the salt is less soluble in the reaction medium than the starting materials. Likewise, completion of the synthesis reaction in a medium in which the final desired form is less soluble than the reactants may result in direct crystallization of the final product.

[0141] Optimization of crystallization can include seeding the crystallization medium with crystals of the desired form. In addition, many crystallization methods use a combination of the above strategies. One embodiment is to dissolve the compound of interest in a solvent at an elevated temperature, followed by the addition of an appropriate volume of anti-solvent in a controlled manner to bring the system just below the saturation level. At this point, seeds of the desired form can be added (while maintaining the integrity of the seeds), and the system is cooled to complete crystallization.

[0142] Solvate

[0143] During the contact between compound or drug molecules and solvent molecules, it is inevitable that the solvent molecules and compound molecules form a eutectic and remain in the solid material due to external and internal conditions. The substance formed after the compound and solvent crystallize is called a solvate. The types of solvents that easily form solvates with organic compounds are water, methanol, benzene, ethanol, ether, aromatic hydrocarbons, heterocyclic aromatic hydrocarbons, etc.

[0144] Hydrate is a special solvate. In the pharmaceutical industry, whether in the synthesis of raw materials, drug preparation, drug storage and drug activity evaluation, hydrate is worth discussing separately because of its special characteristics.

[0145] In the present invention, the crystalline form III-V of the compound represented by formula I is a channel-type solvate.

[0146] In another preferred embodiment, the solvent in the solvate is selected from the following group: dimethyl succinate, thiophene, ethylene glycol diethyl ether, or a combination thereof.

[0147] Cocrystal

[0148] The so-called pharmaceutical cocrystal refers to a crystal formed by the active pharmaceutical ingredient (API) and the cocrystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, in which the pure state of API and CCF are solid at room temperature. The CCF in the pharmaceutical cocrystal can include physiologically acceptable acids, bases, salts and non-ionized molecules, such as food additives, preservatives, pharmaceutical excipients, vitamins, minerals, amino acids and other active molecules, and even other APIs, which can be connected to the API in the same crystal lattice by hydrogen bonds, π-π stacking, van der Waals forces and other non-covalent bonds. From a chemical point of view, the API molecule itself has not changed, so it still maintains its original efficacy, while the solubility, bioavailability, stability and other aspects of the cocrystal drug will be greatly improved, especially for the development of some oral drug preparations. It has a very positive effect.

[0149] As used herein, "co-crystal", "co-crystal form" and "co-crystal" are used interchangeably and all refer to the co-crystal Form IX formed by (E)-2-{2-[6-(2-cyanophenoxy)pyrimidin-4-yloxy]phenyl}-3-methoxyacrylate and succinimide as described in the second aspect of the present invention.

[0150] Pesticide composition

[0151] The "active ingredient" or "active compound" in the pesticide composition of the present invention refers to the compound of formula I of the present invention, especially the compound of formula I in the crystalline form of the present invention.

[0152] The "active ingredients" or "active compounds" and pesticide compositions described in the present invention can be used to prevent or control diseases; or to inhibit harmful microorganisms in agriculture, forestry or horticulture.

[0153] Differential Scanning Calorimetry

[0154] Also known as "Differential Scanning Calorimetry" (DSC), it is a technique that measures the relationship between the energy difference between the substance being tested and the reference substance and the temperature during the heating process. The peak position, shape and number of peaks on the DSC spectrum are related to the properties of the substance, so it can be used to qualitatively identify the substance. This method is commonly used in this field to detect various parameters such as the phase transition temperature, glass transition temperature, reaction heat, etc. of the substance.

[0155] Preparation method

[0156] When preparing the azoxystrobin crystal form V, the present invention uses a dissolution method that is easy to quickly and mass industrially produce; the method for preparing the azoxystrobin crystal forms III and IV uses a volatilization or dissolution method, both of which are simple and easy to perform and easy to industrially produce.

[0157] use

[0158] The present invention provides a solvate of azoxystrobin and uses of a pesticide composition thereof. The solvate is highly effective and broad-spectrum, and has good preventive effects on most diseases such as downy mildew, powdery mildew, anthracnose, leaf spot, etc. caused by four major categories of pathogenic fungi, namely, ascomycetes, basidiomycetes, deuteromycetes and oomycetes.

[0159] Main advantages of the present invention

[0160] (1) The solvate and co-crystal of the compound of formula I of the present invention have good thermal stability and non-hygroscopicity, and are superior to the existing azoxystrobin original drug crystal form I in terms of solubility, can greatly improve bioavailability, and are very suitable for drug formulation.

[0161] (2) The method for preparing the solvate and co-crystal of the compound of formula I of the present invention is simple and easy to operate, has low cost, prepares crystals with high purity and little solvent residue, and is suitable for application in drug research and development and large-scale industrial production.

[0162] (3) The solvates and co-crystals of the compounds of formula I of the present invention can be used to prevent or control diseases; or to inhibit harmful microorganisms in agriculture, forestry or horticulture.

[0163] The present invention is further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples that do not specify specific conditions are usually carried out under conventional conditions or under conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are calculated by weight. The experimental materials and reagents used in the following examples can be obtained from commercial channels unless otherwise specified. Normal temperature or room temperature refers to 4°C-25°C, preferably 15-25°C.

[0164] Test method:

[0165] XRD (X-ray powder diffraction) method: Instrument: Rigaku Ultima IV powder diffractometer, target: Cu-Kα (40 kV, 40 mA), D / tex Ultra detector at room temperature. The scanning range is from 3° to 45° in the 2θ interval, and the scanning speed is 20° / min.

[0166] The measurement differences associated with such X-ray powder diffraction analysis results are caused by a variety of factors including: (a) errors in sample preparation (e.g., sample height), (b) instrument errors, (c) calibration differences, (d) operator errors (including errors in determining peak positions), and (e) the nature of the material (e.g., preferred orientation errors). Calibration errors and sample height errors often result in displacements of all peaks in the same direction. When a flat support is used, small differences in sample height will result in large displacements of XRD peak positions. Systematic studies have shown that sample height differences of 1 mm can result in peak displacements of up to 1° of 2θ. These displacements can be identified from the X-ray diffraction pattern and can be eliminated by compensating for the displacements (applying the system calibration factor to all peak position values) or recalibrating the instrument. As described above, by applying the system calibration factor to make the peak positions consistent, measurement errors from different instruments can be corrected.

[0167] TGA (thermogravimetric analysis) method: Instrument model: TA Q500 thermogravimetric analyzer, using N2 atmosphere, heating rate of 10°C / min.

[0168] DSC (Differential Scanning Calorimetry) Method: Instrument model: TA Q2000 differential scanning calorimeter, using N2 atmosphere, heating rate of 10°C / min.

[0169] Example 1. Preparation of Form I

[0170] The preparation method of Form I refers to the preparation method in patent CN101522639A.

[0171] Example 2. Preparation of Crystalline Form III Azoxystrobin

[0172] Weigh 50 mg of the raw material into a container, add 0.5 ml of dimethyl succinate to dissolve, evaporate at room temperature, and vacuum dry the solid to obtain azoxystrobin Form III (yield 97%).

[0173] Weigh 50 mg of the raw material into a container, add 0.5 ml of dimethyl succinate to dissolve, then add 2.5 ml of cyclohexane, filter, and vacuum dry the solid to obtain azoxystrobin Form III (yield 95%).

[0174] Weigh 50 mg of the raw material into a container, add 0.5 ml of dimethyl succinate to dissolve, then add 2.5 ml of n-hexane, filter, and vacuum dry the solid to obtain azoxystrobin Form III (yield 95%).

[0175] Weigh 50 mg of the raw material into a container, add 0.5 ml of dimethyl succinate to dissolve, then add 2.5 ml of n-heptane, filter, and vacuum dry the solid to obtain azoxystrobin Form III (yield 95%).

[0176] Weigh 50 mg of the raw material into a container, add 0.5 ml of dimethyl succinate to dissolve, then add 2.5 ml of water, filter, and vacuum dry the solid to obtain azoxystrobin Form III (yield 95%).

[0177] The obtained crystal form III azoxystrobin has an XRD pattern substantially as shown in Figure 1 As shown, the diffraction angle data is basically as shown in Table 1 below.

[0178] Table 1 XRD data of Form III

[0179]

[0180]

[0181] The DSC diagram of Form III is shown in Figure 2 As shown, the endothermic peak corresponds to the desolvation process, and has an endothermic peak in the range of 90 to 110°C.

[0182] The TGA diagram of Form III is as follows Figure 3 As shown, it can be seen from the figure that there is basically no weight loss before decomposition.

[0183] In addition, the single crystal X-ray diffraction (SXRD) structure of Form III in Example 2 was obtained, as shown in FIG. Figure 4 , Figure 5 Its parameters are shown in Table 2 below.

[0184] Table 2 Single crystal X-ray diffraction parameters of Form III

[0185]

[0186] Example 3. Study on the stability of crystal form III azoxystrobin

[0187] The crystal form III azoxystrobin sample in Example 2 was placed under high humidity (RH92.5%) and light (4500lx±500lx) conditions, and the sample was taken out for XRPD testing after 5 and 10 days to examine the stability of the crystal form III. Figure 6 , Figure 7 , Figure 8 and Fig. 9 As shown, the results show that the Form III sample is stable under this condition.

[0188] Example 4. Comparison of solubility of Form I and Form III

[0189] Excessive amounts of Form I and Form III were weighed and suspended in ethanol. After shaking for 24 hours, the solubility was tested using UPLC. The test results are shown in Table 3 below:

[0190] Table 3 Solubility of Form III and Form I

[0191] Crystal form Solubility (mg / ml) Crystal form I 14.18 Crystal form III 18.33

[0192] It can be seen from Table 3 that the solubility of Form III in ethanol is greater than that of Form I, which is about 1.3 times that of Form I.

[0193] Example 5. Preparation of Crystalline Form IV Azoxystrobin

[0194] Weigh 50 mg of the raw material into a container, add 0.5 ml of thiophene solution, evaporate at room temperature, and vacuum dry the solid to obtain azoxystrobin crystal form IV (yield 97%).

[0195] Weigh 50 mg of the raw material into a container, add 0.5 ml of thiophene solution, then add 2.5 ml of cyclohexane, filter, and vacuum dry the solid to obtain azoxystrobin crystal form IV (yield 93%).

[0196] Weigh 50 mg of the raw material into a container, add 0.5 ml of thiophene solution, then add 2.5 ml of n-hexane, filter, and vacuum dry the solid to obtain azoxystrobin Form IV (yield 93%).

[0197] Weigh 50 mg of the raw material into a container, add 0.5 ml of thiophene solution, then add 2.5 ml of n-heptane, filter, and vacuum dry the solid to obtain azoxystrobin Form IV (yield 93%).

[0198] The obtained crystal form IV azoxystrobin has an XRD pattern substantially as shown in Fig.10 As shown, the diffraction angle data is basically as shown in Table 4 below.

[0199] Table 4 XRD data of Form IV

[0200]

[0201]

[0202] The DSC diagram of Form IV is shown in Fig.11 As shown, the endothermic peak corresponds to the desolvation process, and has an endothermic peak in the range of 106 to 123°C.

[0203] The TGA diagram of Form IV is shown in Fig.12 As shown, it can be seen from the figure that there is basically no weight loss before decomposition.

[0204] The stability and solubility of the prepared crystalline form IV were investigated, and the results showed that the crystalline form IV had good stability and solubility, lower hygroscopicity, and high bioavailability.

[0205] Example 6. Preparation of Crystalline Form V Azoxystrobin

[0206] Weigh 50 mg of the raw material into a container, add 1.75 ml of ethylene glycol diethyl ether to dissolve, then add 9 ml of n-hexane, filter, and vacuum dry the solid to obtain azoxystrobin Form V (yield 82%).

[0207] The obtained crystal form V azoxystrobin has an XRD pattern substantially as shown in Fig.13 As shown, the diffraction angle data is basically as shown in Table 5 below.

[0208] Table 5 XRD data of Form V

[0209]

[0210]

[0211] The DSC diagram of Form V is shown in Fig.14 As shown, the first endothermic peak corresponds to the desolvation process, and the second endothermic peak corresponds to the melting decomposition process, with endothermic peaks in the range of 109 to 125°C.

[0212] The TGA diagram of Form V is shown in Fig.15 As shown, it can be seen from the figure that there is basically no weight loss before decomposition.

[0213] The stability and solubility of the prepared crystalline form V were investigated, and the results showed that the crystalline form V had good stability and solubility, lower hygroscopicity, and high bioavailability.

[0214] Example 7. Preparation of Form IX Azoxystrobin

[0215] Weigh 80.6 mg of the raw material and 19.8 mg of succinimide into a container, add an appropriate amount of dichloromethane to dissolve, then quickly rotary evaporate, and vacuum dry the solid to obtain azoxystrobin Form IX (yield 97%).

[0216] The obtained crystal form IX azoxystrobin has an XRD pattern substantially as shown in Fig.16 As shown, the diffraction angle data is basically as shown in Table 6 below.

[0217] Table 6 XRD data of Form IX

[0218]

[0219]

[0220] The DSC diagram of Form IX is shown in Fig.17 As shown, the endothermic peak corresponds to the melting decomposition process, and has an endothermic peak in the range of 79 to 113°C.

[0221] The TGA diagram of Form IX is shown in Fig.18 As shown, it can be seen from the figure that there is basically no weight loss before decomposition.

[0222] Example 8. Study on the stability of crystal form IX azoxystrobin

[0223] The crystal form IX azoxystrobin sample in Example 11 was placed under high temperature (60±2°C), high humidity (RH92.5%), and light (4500lx±500lx) conditions, and the sample was taken out for XRPD testing after 5 and 10 days to examine the crystal stability of the sample to temperature, humidity, and light. Fig.19 , Fig. 20 , Fig.21 , Fig. 22 , Fig.23 and Fig.24 As shown, the results show that the Form IX sample is stable under the conditions of high temperature, high humidity and light.

[0224] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A solvate or co-crystal of a compound of formula I, characterized in that The solvent in the solvate is dimethyl succinate; The co-crystal is a co-crystal formed by the compound of formula I and succinimide, And the solvate or co-crystal is selected from the following group: The solvate is Form III, and the X-ray powder diffraction pattern of Form III includes the following 2θ values: 7.7±0.2°, 8.4±0.2°, 14.2±0.2°, 18.3±0.2°, 18.9±0.2°, 20.4±0.2°, 21.4±0.2°, 22.0±0.2°, 12.4±0.2°, 13.8±0.2°, 14.7±0.2°, 18.5±0.2°, 19.3±0.2°, 26.1±0.2°, 37.7±0.2°, 38.8±0.2°, 42.7±0.2° and 43.6±0.2°; The cocrystal is Form IX, and the X-ray powder diffraction pattern of Form IX includes the following 2θ values: 14.1±0.2°, 15.7±0.2°, 16.6±0.2°, 17.1±0.2°, 20.3±0.2°, 21.8±0.2°, 23.6±0.2°, 29.0±0.2°, 10.7±0.2°, 14.9±0.2°, 15.3±0.2°, 23.9±0.2°, 25.4±0.2°, 30.3±0.2°, 31.3±0.2°, 34.1±0.2°, 38.4±0.2°, 38.8±0.2° and 41.5±0.2°.

2. The solvate or co-crystal according to claim 1, characterized in that The solvate is a channel type solvate, and the volume of the solvent molecule is 90 to 109 cm 3 / mol.

3. The solvate or co-crystal according to claim 1, characterized in that The solvate is a solvate formed by the compound of formula I and dimethyl succinate, and in the solvate, the molar ratio of the compound of formula I to the dimethyl succinate solvent is 2:

1.

4. The solvate or co-crystal according to claim 1, characterized in that The TGA graph of the Form III is substantially as shown in FIG3 .

5. The solvate or co-crystal according to claim 1, characterized in that The DSC graph of the crystalline form III is basically represented as shown in FIG2 .

6. The solvate or co-crystal according to claim 1, characterized in that The Form III has the following 2θ values: 7.363, 7.717, 8.441, 11.984, 12.438, 13.421, 13.758, 14.179, 14.662, 14.92, 15.74, 16.802, 18.34, 18.54, 18.901, 19.337, 20.398, 21.38, 22.04, 23.022, 23.442, 23.883, 24. 278, 24.721, 25.359, 26.117, 26.681, 27.021, 27.46, 28.62, 29.8, 30.28, 30.82, 31.282, 31.74, 32.077, 33, 34.419, 34.806, 35.837, 37.32, 37.758, 38.78, 39.639, 40.72, 42.681, 43.017, 43.

617.

7. The solvate or co-crystal according to claim 1, characterized in that The solvate is a crystalline form III, and the crystalline form III has one or more characteristics selected from the following group: (1) The X-ray powder diffraction pattern of the crystalline form III includes the following 2θ values: 7.4±0.2°, 7.7±0.2°, 8.4±0.2°, 12.0±0.2°, 13.4±0.2°, 14.2±0.2°, 14.9±0.2°, 15.7±0.2°, 16.8±0.2°, 18.3±0.2°, 18.9±0.2°, 20.4±0.2°, 21.4±0.2°, 22.0±0.2° , 23.0±0.2°, 23.4±0.2°, 23.8±0.2°, 23.9±0.2°, 24.7±0.2°, 25.4±0.2°, 26.7±0.2°, 27.0±0.2°, 27.5±0.2°, 28.6±0.2°, 31.3±0.2°, 31.7±0.2°, 35.8±0.2°, 37.3±0.2°, 39.6±0.2°, 40.7±0.2°; and / or (2) the TGA graph of the Form III is substantially as shown in FIG3 ; and / or (3) the DSC graph of the crystal form III has an endothermic peak in the range of 90 to 110°C; and / or (4) The purity of the crystal form III is greater than 95%.

8. The solvate or co-crystal according to claim 1, characterized in that The solvate is a crystalline form III, and the crystalline form III has one or two characteristics selected from the following group: (1) the X-ray powder diffraction pattern of the crystalline form III is substantially as shown in FIG1 ; and / or (2) The DSC graph of the crystal form III is basically as shown in FIG2 .

9. The solvate or co-crystal according to claim 1, characterized in that The TGA graph of the crystalline form IX is basically represented as shown in Figure 18.

10. The solvate or co-crystal according to claim 1, characterized in that The DSC graph of the crystalline form IX is basically represented as shown in Figure 17.

11. The solvate or co-crystal according to claim 1, characterized in that The co-crystal is a co-crystal formed by the compound of formula I and succinimide in a molar ratio of 1:

1.

12. The solvate or co-crystal according to claim 1, characterized in that The co-crystal is Form IX, and the Form IX has a feature selected from the group consisting of: (1) The X-ray powder diffraction pattern of Form IX includes the following 2θ values: 7.4±0.2°, 10.2±0.2°, 10.7±0.2°, 13.1±0.2°, 14.1±0.2°, 15.7±0.2°, 16.6±0.2°, 17.1±0.2°, 17.4±0.2°, 18.4±0.2°, 19.6±0.2°, 20. 3±0.2°, 21.2±0.2°, 21.8±0.2°, 23.6±0.2°, 23.9±0.2°, 24.9±0.2°, 25.4±0.2°, 25.8±0.2°, 26.3±0.2°, 26.7±0.2°, 27.2±0.2°, 28.0±0.2°, 36.8±0.2°, 37.4±0.2°; and / or (2) the TGA graph of Form IX is substantially as shown in FIG18 ; and / or (3) the DSC graph of the crystalline form IX has an endothermic peak in the range of 79 to 113° C.; and / or (4) The purity of the crystalline form IX is greater than 95%.

13. The solvate or co-crystal according to claim 1, characterized in that The co-crystal is Form IX, and the Form IX has a feature selected from the group consisting of: (1) the X-ray powder diffraction pattern of Form IX is substantially as shown in FIG16 ; and / or (2) The DSC graph of the crystal form IX is basically as shown in FIG17 .

14. A pesticide composition, characterized in that: The composition comprises: (a) a solvate or co-crystal according to any one of claims 1 to 13, and (b) an agrochemically acceptable carrier.

15. A method for preparing the solvate according to claim 1, characterized in that: The solvate is a crystalline form III, comprising the steps of: (i) providing a first solution of a compound of formula I in dimethyl succinate; and (ii) volatilizing the first solution, or mixing with an anti-solvent and crystallizing to obtain the crystal form III.

16. The method according to claim 15, characterized in that The anti-solvent is selected from the group consisting of n-hexane, cyclohexane, n-heptane, water, or a combination thereof.

17. A method for preparing the eutectic according to claim 1, characterized in that: Includes steps: (i) providing a first solution of a compound of formula I and succinimide in dichloromethane; and (ii) subjecting the above solution to rapid rotary evaporation to obtain the co-crystal according to claim 1, i.e., Form IX.

18. The method according to claim 17, characterized in that The rapid rotary evaporation treatment is carried out at a rotation speed of 120 to 140 rpm and a water bath temperature of 10±5° C., and the crystal form IX is obtained after rotary evaporation.

19. Use of the solvate or co-crystal according to any one of claims 1 to 13 or the pesticide composition according to claim 14, characterized in that: Used to prevent or control diseases.

20. The use according to claim 19, characterized in that Used to inhibit harmful microorganisms in agriculture, forestry or horticulture.

21. The use according to claim 19, characterized in that The prevention or control mentioned above refers to the prevention or control of diseases in agriculture, forestry or horticulture.

22. The use according to claim 19, characterized in that The disease is selected from the group consisting of plant diseases: downy mildew, powdery mildew, anthracnose, leaf spot, or a combination thereof.

23. The use according to claim 19, characterized in that The harmful microorganisms are selected from the following groups: Ascomycetes, Basidiomycetes, Deuteromycetes, Oomycetes, or a combination thereof.

24. The use according to claim 19, characterized in that The prevention, control or inhibition is in vitro prevention, control or inhibition.

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