Compound hydrochloride crystal form and application thereof

Abstract

The invention relates to a crystal form I of an agricultural antibiotic 5-amino-2-methyl-6-(2, 3, 4, 5, 6-hydroxycyclohexyl oxo) pyran-3-ylamino-alpha-imino acetic acid hydrochloride and a preparation method thereof, the crystal form I shows good stability in a high-temperature and high-humidity illumination environment, and can better meet the requirements of pesticides in production, processing, transportation and storage, and the crystal form I can be used for preparing the agricultural antibiotic 5-amino-2-methyl-6-(2, 3, 4, 5, 6-hydroxycyclohexyl oxo) pyran-3-ylamino-alpha-imino acetic acid hydrochloride. And the composition has excellent effects in the aspects of preparation processing and preparation stability, and can better meet the requirements of mixed agent processing and stable shelf life. Meanwhile, the amorphous substance of the 5-amino-2-methyl-6-(2, 3, 4, 5, 6-hydroxycyclohexyl oxo) pyran-3-ylamino-alpha-imino acetic acid hydrochloride has an unexpected effect in the aspect of the prevention and treatment effect of plant diseases. The invention further discloses a preparation method of the amorphous substance of the 5-amino-2-methyl-6-(2, 3, 4, 5, 6-hydroxycyclohexyl oxo) pyran-3-ylamino-alpha-imino acetic acid hydrochloride.

Description

Technical Field

[0001] The invention belongs to the field of agricultural technology, and specifically relates to a crystal form and a preparation method of 5-amino-2-methyl-6-(2,3,4,5,6-hydroxycyclohexyloxy)pyran-3-ylamino-α-imidoacetic acid hydrochloride. Background Art

[0002] 5-Amino-2-methyl-6-(2,3,4,5,6-hydroxycyclohexyloxy)pyran-3-ylamino-α-imidoacetic acid (CAS 6980-18-3) belongs to the aminoglycoside antibiotics. Since its discovery in the 1960s and 1970s, 5-amino-2-methyl-6-(2,3,4,5,6-hydroxycyclohexyloxy)pyran-3-ylamino-α-imidoacetic acid has been widely used in the prevention and control of various diseases of various crops including rice, potatoes, cabbage, melon, etc. Due to its excellent prevention and control effect and environmentally friendly characteristics, 5-amino-2-methyl-6-(2,3,4,5,6-hydroxycyclohexyloxy)pyran-3-ylamino-α-imidoacetic acid is currently the main biological pesticide product for the prevention and control of crop diseases. 5-Amino-2-methyl-6-(2,3,4,5,6-hydroxycyclohexyloxy)pyran-3-ylamino-α-imidoacetic acid is extremely unstable in an alkaline environment, and 5-amino-2-methyl-6-(2,3,4,5,6-hydroxycyclohexyloxy)pyran-3-ylamino-α-imidoacetic acid is a hygroscopic compound. Considering transportation, storage and quality control, more stable and less hygroscopic 5-amino-2-methyl-6-(2,3,4,5,6-hydroxycyclohexyloxy)pyran-3-ylamino-α-imidoacetic acid salt products are desired by production and processing companies.

[0003] At the beginning of the discovery of 5-amino-2-methyl-6-(2,3,4,5,6-hydroxycyclohexyloxy)pyran-3-ylamino-α-imidoacetic acid, Ikekawa T et al. briefly investigated the crystalline structure of 5-amino-2-methyl-6-(2,3,4,5,6-hydroxycyclohexyloxy)pyran-3-ylamino-α-imidoacetic acid hydrobromide (The Journal of Antibiotics, 01Jan 1966, 19(1):49-50). CN115925475A reported the use of 5-amino-2-methyl-6-(2,3,4,5,6-hydroxycyclohexyloxy)pyran-3-ylamino-α-imidoacetic acid phosphate to supplement phosphorus while preventing and controlling pathogens. CN108822167A reported 5-amino-2-methyl-6-(2,3,4,5,6-hydroxycyclohexyloxy)pyran-3-ylamino-α-imidoacetic acid hydrochloride and its white needle-shaped or flaky crystals. CN106083951B and CN109666051B reported the extraction of 5-amino-2-methyl-6-(2,3,4,5,6-hydroxycyclohexyloxy)pyran-3-ylamino-α-imidoacetic acid hydrochloride by adding acetone, methanol, ethanol and other solvents to water for crystallization.

[0004] Although the prior art has disclosed a method for preparing high-purity 5-amino-2-methyl-6-(2,3,4,5,6-hydroxycyclohexyloxy)pyran-3-ylamino-α-imidoacetic acid hydrochloride, the crystalline products prepared by different crystallization methods are often different, and their physical and chemical properties are also quite different, and the performance of the corresponding crystalline products in formulation processing is also different. Therefore, a stable crystalline product of 5-amino-2-methyl-6-(2,3,4,5,6-hydroxycyclohexyloxy)pyran-3-ylamino-α-imidoacetic acid salt that is conducive to formulation processing and storage is the goal pursued by biopesticide companies. Summary of the invention

[0005] In view of the above problems existing in the prior art, the present invention provides a technical solution to the above problems.

[0006] According to one aspect of the present invention, a crystalline form I of an agricultural antibiotic 5-amino-2-methyl-6-(2,3,4,5,6-hydroxycyclohexyloxy)pyran-3-ylamino-α-imidoacetic acid hydrochloride is provided, wherein the crystalline form I uses Cu-Kα radiation, and the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed as 2θ values ​​±0.2° include 8.66, 10.11, 11.05 and 13.3.

[0007] Optionally, the crystal form I uses Cu-Kα radiation, and the characteristic diffraction peaks of the X-ray powder diffraction pattern represented by 2θ values ​​±0.2° also include one or two of 13.92 and 15.56, preferably also include one or two of 16.47 and 17.29.

[0008] Optionally, the particle size D of Form I 90 It is 10 μm-200 μm, preferably 15 μm-150 μm, and more preferably 20 μm-120 μm.

[0009] Optionally, the crystal form I is in the form of particles or rods.

[0010] Differential scanning calorimetry (DSC) analysis showed that the 5-amino-2-methyl-6-(2,3,4,5,6-hydroxycyclohexyloxy)pyran-3-ylamino-α-imidoacetic acid hydrochloride Form I had a continuous endothermic signal in the range of 110±2°C to 210±2°C, and an endothermic signal at 226±2°C; compared with the height of the endothermic peak (or peak valley), Form I had a strong endothermic process at 226±2°C, and a weak endothermic process in the range of 110±2°C to 210±2°C.

[0011] Thermogravimetric analysis (TGA) shows that the crystalline form I has a weight loss of less than 5% when heated from 100±2°C to 220±2°C, and a weight loss of less than 15.5% when heated from 220±2°C to 255±2°C.

[0012] According to another aspect of the present invention, the present invention provides a 5-amino-2-methyl-6-(2,3,4,5,6-hydroxycyclohexyloxy)pyran-3-ylamino-α-imidoacetic acid hydrochloride amorphous substance.

[0013] Optionally, the amorphous substance has Figure 6 X-ray powder diffraction peaks are shown.

[0014] DSC showed that the amorphous substance had endothermic signals at 73±2°C and 187±2°C;

[0015] TGA results show that the amorphous material has a weight loss of less than 9% when heated to 175±2°C, and has a weight loss of less than 15% when heated from 175±2°C to 255±2°C.

[0016] Optionally, the 5-amino-2-methyl-6-(2,3,4,5,6-hydroxycyclohexyloxy)pyran-3-ylamino-α-imidoacetic acid hydrochloride amorphous substance is a sheet-like structure.

[0017] Optionally, the amorphous substance D 90It is 10 μm-200 μm, preferably 15 μm-150 μm, and more preferably 20 μm-120 μm.

[0018] According to another aspect of the present invention, a technical or a parent drug is provided, wherein the technical or the parent drug contains the above-mentioned crystal form I and / or amorphous material.

[0019] Based on the total mass, the content of Form I and / or amorphous matter in the original drug is not less than 65%, such as not less than 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79% or 80%; preferably, not less than 85% or 90% or 95%.

[0020] Based on the total mass, the content of Form I and / or amorphous matter in the mother drug is not less than 5% or 10%, such as not less than 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79% or 80%; preferably not less than 85% or 90% or 95%.

[0021] According to another aspect of the present invention, a formulation or pesticide composition is provided, wherein the formulation or pesticide composition contains the above-mentioned crystal form I and / or amorphous material and an adjuvant.

[0022] Optionally, the weight percentage of the crystalline form I and / or the amorphous substance in the formulation or the pesticide composition is at least 0.001%.

[0023] Optionally, the dosage form of the preparation is selected from any one of powder, granules, large granules, fine granules, microgranules, microcapsule granules, wettable powder, oil-dispersible powder, water-dispersible granules, emulsions, effervescent granules, dispersible tablets, effervescent tablets, sustained-release agents, sustained-release blocks, sustained-release tubes, sustained-release particles, soluble powders, soluble granules, soluble tablets, soluble solutions, aqueous solutions, soluble gels, oils, film-spreading oils, ultra-low volume liquids, ultra-low volume microcapsule suspensions, emulsifiable concentrates, latex, dispersible liquids, pastes, concentrated gels, emulsions in water, oil emulsions, microemulsions, ointments, suspensions, microcapsule suspensions, oil suspensions, suspoemulsions, dispersible powders for seed treatment, soluble powders for seed treatment, liquid solutions for seed treatment, emulsions for seed treatment, suspensions for seed treatment, suspended seed coatings, and microcapsule suspensions for seed treatment. Preferably, the crystal form I or amorphous solid of the present invention exhibits excellent processability and solid application control effect in pesticide solid formulations. Specifically, the crystal form I or amorphous solid of the present invention is used in wettable powders or dusts; wherein the particle size D of the crystal form I and / or amorphous solid in the dust or wettable powder is90 The preferred particle size D is 5 μm-80 μm. 90 It is 10μm-50μm, or 15μm-45μm, or 20μm, 30μm, 40μm, 60μm and 70μm.

[0024] According to another aspect of the present invention, there is provided the use of the above-mentioned Form I, the amorphous material, the technical or parent drug, or the preparation or pesticide composition in the process of plant disease prevention and control.

[0025] According to another aspect of the present application, there is provided the use of the above-mentioned Form I, the amorphous material, the technical drug or the mother drug, or the preparation or the pesticide composition in the preparation of a plant disease control preparation.

[0026] The positive and progressive effects of the present invention are:

[0027] The applicant believes that the crystal form I provided in this application has good stability, almost no hygroscopicity, and can remain stable under light, high temperature, high humidity, and accelerated conditions, effectively extending the shelf life of the drug storage, and can better meet the requirements of pesticides in production, processing, transportation, and storage. At the same time, the crystal form I has also achieved good technical effects in plant disease prevention and control. Unexpectedly, the amorphous material has shown the best effect in plant disease prevention and control, and the agricultural terminal application effect is more prominent. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 This is the hydrogen nuclear magnetic analysis (1H-NMR) spectrum of compound crystal form I;

[0029] Figure 2 is an X-ray powder diffraction (XRPD) pattern of Form I, wherein the abscissa is 2θ (°) and the ordinate is intensity (counts);

[0030] Figure 3 This is the hydrogen nuclear magnetic analysis (1H-NMR) spectrum of compound crystal form II;

[0031] Figure 4 is the X-ray powder diffraction (XRPD) spectrum of Form II, wherein the abscissa is 2θ (°) and the ordinate is intensity (counts);

[0032] Figure 5 It is the hydrogen nuclear magnetic analysis (1H-NMR) spectrum of amorphous substance;

[0033] Figure 6 is the X-ray powder diffraction (XRPD) spectrum of amorphous material, where the abscissa is 2θ (°) and the ordinate is intensity (counts);

[0034] Figure 7The differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) patterns of Form I are shown in FIG.

[0035] Figure 8 The differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) patterns of Form II;

[0036] Fig. 9 The differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) spectra of the amorphous substance;

[0037] Fig.10 is the polarizing light microscope analysis (PLM) spectrum of Form I;

[0038] Fig.11 This is a polarizing light microscope analysis (PLM) image of Form II;

[0039] Fig.12 This is a polarizing light microscopy (PLM) image of an amorphous substance;

[0040] Fig.13 This is the particle size distribution measurement (PSD) image of Form I;

[0041] Fig.14 This is the particle size distribution measurement (PSD) image of Form II;

[0042] Fig.15 It is the dynamic moisture adsorption and desorption analysis test (DVS) spectrum of Form I;

[0043] Fig.16 The stability test results of Form I are shown in FIG.

[0044] Fig.17 The results of the potted antibacterial experiment, where a-1 is the front view of the blank control leaf, a-2 is the back view of the blank control leaf, b-1 is the front view of the crystal form II powder experiment leaf, b-2 is the back view of the crystal form II powder experiment leaf, c-1 is the front view of the crystal form I powder experiment leaf, c-2 is the back view of the crystal form I powder experiment leaf, Fig.17 d-1 is the front view of the leaves in the amorphous powder experiment, and d-2 is the back view of the leaves in the amorphous powder experiment. DETAILED DESCRIPTION

[0045] The term "solvate" refers to those forms of the crystalline forms of the compounds described herein that are used to form complexes with molecules of solvents (e.g., water, organic solvents such as formic acid, toluene, etc.) by coordination. Hydrates are a specific form of solvates in which coordination is performed with water. For example, the solvate may be a hydrate.

[0046] The term "technical product" refers to the product obtained during the production process consisting of active ingredients and related impurities, and a small amount of additives may be added if necessary.

[0047] The term "mother drug" refers to the product obtained during the production process consisting of active ingredients and related impurities, and may contain small amounts of necessary additives and appropriate diluents.

[0048] The term "formulation" refers to a stable product made from the original pesticide (mother pesticide) and suitable adjuvants, or processed by biological fermentation, plant extraction and other methods.

[0049] The term "adjuvant" refers to any single component or multiple components added to pesticide products, in addition to the active ingredient, which does not have pesticide activity and active ingredient function itself, but can or helps to enhance or improve the physical and chemical properties of the pesticide product.

[0050] The term "plant disease" refers to the phenomenon that during the growth and development of plants, due to infection by other organisms and the influence of adverse abiotic factors, the growth and development of plants are significantly hindered, and pathological changes occur in the physiology and tissue structure inside and outside the plants, resulting in morbidity or even death, resulting in reduced yield and deterioration of quality. The "plant disease" of this application specifically refers to the disease caused by the infection of plants by other organisms, including but not limited to fungi (such as cucumber downy mildew caused by Pseudomonas aeruginosa), or bacteria (such as bacterial angular leaf spot of cucurbits), etc.

[0051] The terms “around”, “about” and “substantially” refer to numerical variations within the normal experimental or measurement error range, such as “substantially” represents an error of no more than 15%, preferably no more than 10%.

[0052] In a specific embodiment, in a specific embodiment, the 5-amino-2-methyl-6-(2,3,4,5,6-hydroxycyclohexyloxy)pyran-3-ylamino-α-imidoacetic acid hydrochloride crystal form I described in the present application is a hydrate.

[0053] In a specific embodiment, the 5-amino-2-methyl-6-(2,3,4,5,6-hydroxycyclohexyloxy)pyran-3-ylamino-α-imidoacetic acid hydrochloride form I described in the present application uses Cu-Kα radiation, and the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed by 2θ values ​​± 0.2° include 8.66, 10.11, 11.05 and 13.3, preferably, the crystal form I uses Cu-Kα radiation, and the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed by 2θ values ​​± 0.2° include 8.66, 10.11, 11.05, 13.3, 13.92 and 15.56; preferably, the X-ray powder diffraction pattern expressed by 2θ values ​​± 0.2° includes 8.66, 10.11, 11.05, 13.3, 13.92 and 15.56; preferably, the X-ray powder diffraction pattern expressed by 2θ values ​​± 0.2° includes 8.66, 10.11, 11.05, 13.3, 13.92 and 15.56. The characteristic diffraction peaks of the X-ray powder diffraction pattern include 8.66, 10.11, 11.05, 13.3, 13.92, 15.56, 16.47 and 17.29; more preferably, the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed as 2θ values ​​± 0.2° include 8.66, 10.11, 11.05, 13.3, 13.92, 15.56, 16.47, 17.29, 18.59, 19.25, or include 8.66, 10.11, 11.05, 13.3, 13.92, 15.56, 16.47, 17.29, 18.59, 19.25, 20.41 and 20.78.

[0054] In a specific embodiment, the crystalline form I of the compound 5-amino-2-methyl-6-(2,3,4,5,6-hydroxycyclohexyloxy)pyran-3-ylamino-α-imidoacetic acid hydrochloride described in the present application is granular or rod-shaped. In order to meet the actual production, facilitate solid-liquid filtration and facilitate the processing of subsequent pesticide solid preparations, the particle size D of the crystalline form I is 90 Preferably, the particle size D of Form I is 10 μm to 200 μm. 90 15 μm-150 μm, 20 μm-120 μm, for example, the particle size D of the crystal form I 90 It can also be 10, 15, 25, 35, 45, 55, 65, 75, 85, 95, 100, 110, 130, 140, 150, 160, 170, 180, 190 or 200 μm.

[0055] In a specific embodiment, differential scanning calorimetry (DSC) shows that the 5-amino-2-methyl-6-(2,3,4,5,6-hydroxycyclohexyloxy)pyran-3-ylamino-α-imidoacetic acid hydrochloride Form I has a continuous endothermic signal in the range of 110±2°C to 210±2°C, and an endothermic signal at 226±2°C; compared with the height (or peak valley) of the endothermic peak, Form I has a strong endothermic process at 226±2°C, and a weak endothermic process in the range of 110±2°C to 210±2°C.

[0056] Thermogravimetric analysis (TGA) shows that the crystalline form I has a weight loss of less than 5% when heated from 100±2°C to 220±2°C, and a weight loss of less than 15.5% when heated from 220±2°C to 255±2°C.

[0057] In a specific embodiment, the 5-amino-2-methyl-6-(2,3,4,5,6-hydroxycyclohexyloxy)pyran-3-ylamino-α-imidoacetic acid hydrochloride prepared in the present application is an amorphous substance having the following properties: Figure 6 XRPD diffraction peak spectrum shown.

[0058] DSC showed that the amorphous substance had endothermic signals at 73±2°C and 187±2°C.

[0059] TGA showed that the amorphous material had a weight loss of less than 9% during heating to 175±2°C and a weight loss of less than 15% during heating from 175±2°C to 255±2°C.

[0060] Optionally, the 5-amino-2-methyl-6-(2,3,4,5,6-hydroxycyclohexyloxy)pyran-3-ylamino-α-imidoacetic acid hydrochloride amorphous substance is a sheet-like structure.

[0061] Optionally, the amorphous particle size D 90 Preferably, the particle size D of Form I is 10 μm to 200 μm. 90 15 μm-150 μm, 20 μm-120 μm, for example, the particle size D of the crystal form I 90 It can also be 10, 15, 25, 35, 45, 55, 65, 75, 85, 95, 100, 110, 130, 140, 150, 160, 170, 180, 190 or 200 μm.

[0062] In one embodiment, the crystalline solid can be prepared by dissolution back drop method, liquid vapor diffusion method, single solvent room temperature suspension method, single solvent high temperature suspension method, binary solvent forward drop method, single solvent cooling method, binary solvent cooling method and the like.

[0063] Preferably, Form I is prepared by a dissolution back-titration method, a liquid vapor diffusion method, and the like. It is not limited by the examples of the preparation examples of the present application. The 5-amino-2-methyl-6-(2,3,4,5,6-hydroxycyclohexyloxy)pyran-3-ylamino-α-imidoacetic acid hydrochloride Form I described in the present invention is prepared by other crystallization methods such as a single solvent room temperature suspension method, a single solvent high temperature suspension method, a binary solvent positive drop method, a single solvent cooling method, and a binary solvent cooling method. It also falls within the scope of protection of the present invention.

[0064] Preferably, the amorphous material is prepared by freeze drying, and the freeze drying can be selected from circulating freezer drying or medium freeze drying (such as dry ice freeze drying or nitrogen freeze drying).

[0065] Preferably, the elution back-titration method comprises the following steps: dropping an aqueous solution containing 5-amino-2-methyl-6-(2,3,4,5,6-hydroxycyclohexyloxy)pyran-3-ylamino-α-imidoacetic acid hydrochloride into a poor solvent, suspending for 10-120 minutes after precipitation, and filtering to obtain a solid. The dropping process may be stirred or not stirred, and the stirring rate is 20-120 rpm; the poor solvent is dioxane or ethylene glycol dimethyl ether.

[0066] Preferably, the liquid vapor diffusion method comprises the following steps: weighing a certain amount of 5-amino-2-methyl-6-(2,3,4,5,6-hydroxycyclohexyloxy)pyran-3-ylamino-α-imidoacetic acid hydrochloride solution dissolved in a good solvent, placing the clear solution in a poor solvent atmosphere, standing at room temperature until solids precipitate and then filtering. The good solvent is water or formamide, and the poor solvent is trifluoroethanol.

[0067] In a specific embodiment, the technical or mother drug provided by the present application contains the crystalline form I or the amorphous material described in the present application, and the content of the crystalline form I in the technical is not less than 65% by total mass, such as not less than 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79% or 80%; preferably, not less than 85% or 90% or 95%.

[0068] Based on the total mass, the content of Form I and / or amorphous matter in the mother drug is not less than 5% or 10%, such as not less than 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79% or 80%; preferably not less than 85% or 90% or 95%.

[0069] In a specific embodiment, the formulation or pesticide composition provided herein contains the crystalline form I and / or amorphous substance described herein, preferably, the weight percentage of the crystalline form I and / or amorphous substance in the formulation is at least 0.001%, for example, the weight percentage of the crystalline form I and / or amorphous substance in the formulation is at least 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9% or 10%. Preferably, the weight percentage of the crystalline form I and / or amorphous substance in the formulation is 0.1%-10%, 0.5-7%, or 1-5%.

[0070] In another embodiment, there is provided a use of the above-mentioned Form I, the above-mentioned amorphous material, the above-mentioned technical or mother drug, or the above-mentioned preparation or pesticide composition in the preparation of a plant disease control agent. Specific embodiment:

[0072] All commercial reagents and solvents were used without further purification.

[0073] The sample testing in the examples was carried out according to the following method.

[0074] 1. X-ray powder diffraction (XRPD)

[0075] The solid samples obtained in the experiment were analyzed by X-ray powder diffractometer Bruker D8 Advance (Bruker, GER). The 2θ scanning angle was from 3° to 45°, the scanning step was 0.02°, and the exposure time was 0.08 seconds. The test method was Cu target Kα1 radiation, voltage 40kV, current 40mA, and the sample pan was a zero background sample pan.

[0076] 2. Differential Scanning Calorimetry (DSC)

[0077] The model of the differential scanning calorimeter was TA Discovery 2500 (TA, US). 1-2 mg of sample was accurately weighed and placed in a DSC Tzero sample pan with holes, and heated to the final temperature at a rate of 10°C / min, with a nitrogen purge rate of 50 mL / min in the furnace.

[0078] 3. Thermogravimetric analysis (TGA)

[0079] The model of the thermogravimetric analyzer is TADiscovery 55 (TA, US). 2-5 mg of sample was placed in a balanced open aluminum sample pan and automatically weighed in the TGA heating furnace. The sample was heated to the final temperature at a rate of 10 °C / min, and the nitrogen purge rate at the sample was 60 mL / min and the nitrogen purge rate at the balance was 40 mL / min.

[0080] 4. Nuclear magnetic analysis (1H NMR)

[0081] Several milligrams of solid sample were dissolved in dimethyl sulfoxide-d6 solvent and subjected to NMR analysis on Bruker AVANCE NEO 400 (Bruker, GER).

[0082] 5. Polarized light microscopy (PLM)

[0083] The polarizing microscope model is Nikon Ci-POL (Nikon, JP). Place a small amount of sample on a glass slide and select a suitable lens to observe the sample morphology.

[0084] 6. Particle size distribution determination (PSD)

[0085] The laser particle size analyzer model is Mastersizer 3000 (Malvern Panalytical, UK). Take 20 mg of sample and disperse it in 8 mL of dispersant, add sample dispersion unit until the shading degree is 10-20% and start measurement, stirring speed is 2000 rpm, duration is 10 s, dispersant is ethanol, scattering model is Mie, and analysis model is universal.

[0086] 7. Dynamic moisture adsorption and desorption analysis (DVS)

[0087] Dynamic moisture adsorption and desorption analysis was performed using DVS Intrinsic (SMS, UK). The test used a gradient mode, with humidity changes of 50%-95%-0%-50%, and the humidity change of each gradient in the range of 0% to 90% was 10%. The gradient end point was determined using the dm / dt method, with dm / dt less than 0.002% and maintained for 10 minutes as the gradient end point, or each gradient was maintained for a maximum of 180 minutes. After the test was completed, the sample was analyzed by XRPD to confirm whether the solid morphology had changed.

[0088] 8. Stability study

[0089] (1) Experiment on influencing factors

[0090] Weigh 20 mg of sample and place it in a weighing bottle. Leave it open at high temperature (60°C), high humidity (25°C / 92.5% RH) or light (25°C / 4500Lux). Take samples on 7 days and 15 days, observe the appearance, perform XRPD characterization and high performance liquid chromatography (HPLC) test, and compare the results with those on day 0.

[0091] (2) Accelerated stability test

[0092] Weigh 20 mg of sample into a weighing bottle, place it open under accelerated conditions (40°C / 75% RH), take samples on 7 days and 15 days, observe the appearance, perform XRPD characterization and HPLC test, and compare with the result on day 0.

[0093] 9. HPLC

[0094] The high performance liquid chromatography model was ACQUITY ARC-2489 (Waters, US);

[0095] Mobile phase: acetonitrile: sodium dodecyl sulfate solution = 1:4, v / v (pH adjusted to 2.5 with phosphoric acid). Preparation of sodium dodecyl sulfate solution: 0.8 g sodium dodecyl sulfate solid was dissolved in 400 ml ultrapure water;

[0096] Chromatographic column: CORTECS C18 4.6×150mm, 2.7μm

[0097] Detection wavelength: 210nm

[0098] Flow rate: 1.2mL / min

[0099] Column temperature: 30°C

[0100] Injection volume: 5 μL

[0101] (I) Preparation Example

[0102] Comparative Example 1: Preparation of 5-amino-2-methyl-6-(2,3,4,5,6-hydroxycyclohexyloxy)pyran-3-ylamino-α-imidoacetic acid hydrochloride crystal form II

[0103] A fermentation broth containing 5-amino-2-methyl-6-(2,3,4,5,6-hydroxycyclohexyloxy)pyran-3-ylamino-α-imidoacetic acid is provided, specifically: using Streptomyces aureus as a producing bacterium, and obtaining the fermentation broth through multi-stage fermentation in a culture medium containing low-temperature soybean cake powder, soybean oil, yeast powder, liquid sugar and other raw materials. According to the purification and crystallization method described in the embodiment of CN106083951B, the fermentation broth is pretreated, filtered by a ceramic membrane, decolorized by a macroporous resin, and concentrated by nanofiltration for purification. In the crystallization process, organic solvents such as acetone, methanol, ethanol, propanol or isopropanol are added for crystallization to prepare 5 solid crystalline products;

[0104] The solid crystalline products were vacuum dried and then subjected to NMR and XRPD measurements. NMR showed that the solid crystalline products were all 5-amino-2-methyl-6-(2,3,4,5,6-hydroxycyclohexyloxy)pyran-3-ylamino-α-imidoacetic acid hydrochloride. The NMR spectrum of the solid crystalline products obtained by crystallization with organic solvent methanol is as follows: Figure 3The XRPD results show that the solid crystalline product is a crystalline form, called crystalline form II, wherein the XRPD pattern of the solid crystalline product crystallized by organic solvent acetone is as follows Figure 4 shown.

[0105] Comparative Example 2: Preparation of 5-amino-2-methyl-6-(2,3,4,5,6-hydroxycyclohexyloxy)pyran-3-ylamino-α-imidoacetic acid hydrochloride crystal form II

[0106] Streptomyces aureus was used as the producing bacteria, and fermentation liquid was obtained by multi-stage fermentation in a culture medium containing low-temperature soybean cake powder, soybean oil, yeast powder, liquid sugar and other raw materials. Purification and crystallization were carried out according to the method described in the embodiment of CN109666051B, and the crystallization method adopted cooling crystallization or adding organic solvent acetone or ethanol crystallization to prepare three kinds of solid crystalline products respectively; the above solid crystalline products were vacuum dried at room temperature and then subjected to NMR and XRPD determination respectively, and NMR showed that the above solid crystalline products were all 5-amino-2-methyl-6-(2,3,4,5,6-hydroxycyclohexyloxy)pyran-3-ylamino-α-imidoacetic acid hydrochloride, and XRPD showed that the above solid crystalline products were the same as the crystal form obtained in Comparative Example 1, all of which were crystal form II.

[0107] Example 1: Preparation of 5-amino-2-methyl-6-(2,3,4,5,6-hydroxycyclohexyloxy)pyran-3-ylamino-α-imidoacetic acid hydrochloride Form I

[0108] a) acidifying a fermentation broth containing 5-amino-2-methyl-6-(2,3,4,5,6-hydroxycyclohexyloxy)pyran-3-ylamino-α-imidoacetic acid with oxalic acid and filtering the resulting broth;

[0109] b) collecting the filtrate, adsorbing it with a strong acidic cation exchange resin and then analyzing it;

[0110] c) the ammonium chloride solution is concentrated by nanofiltration membrane and further decolorized by activated carbon;

[0111] d) filtering the decolorized liquid and concentrating it in vacuum to obtain a vacuum concentrated liquid;

[0112] e) taking 10 ml of the vacuum concentrate prepared in step d, adding the concentrate dropwise to 20 times the volume of dioxane (poor solvent) at room temperature, stirring at 60 rpm, suspending for 30-40 min, and filtering to obtain a precipitate;

[0113] f) drying the obtained precipitate at room temperature to obtain a high-purity solid crystalline product, and performing NMR and XRPD analysis on the solid crystalline product; after analysis, the NMR of the solid crystalline product is as follows: Figure 1As shown, it is 5-amino-2-methyl-6-(2,3,4,5,6-hydroxycyclohexyloxy)pyran-3-ylamino-α-imidoacetic acid hydrochloride. XRPD is as follows Figure 2 As shown, it is called Form I.

[0114] Example 2: Preparation of 5-amino-2-methyl-6-(2,3,4,5,6-hydroxycyclohexyloxy)pyran-3-ylamino-α-imidoacetic acid hydrochloride crystal form I

[0115] A high-purity solid crystalline product was prepared according to steps af of Example 1, except that the poor solvent was replaced with ethylene glycol dimethyl ether. The solid crystalline product was identified by NMR and XRPD to be 5-amino-2-methyl-6-(2,3,4,5,6-hydroxycyclohexyloxy)pyran-3-ylamino-α-imidoacetic acid hydrochloride Form I.

[0116] Example 3: Preparation of 5-amino-2-methyl-6-(2,3,4,5,6-hydroxycyclohexyloxy)pyran-3-ylamino-α-imidoacetic acid hydrochloride crystal form I

[0117] a) taking 250 mg of the dried solid crystalline product of Example 1;

[0118] b) dissolving the solid crystalline product in 4 ml of water;

[0119] c) taking 1 ml of the solution in step b, placing the concentrated solution in an atmosphere of trifluoroethanol, and standing at room temperature until solid precipitates;

[0120] d) removing the solution in the system with solid precipitation with a syringe, and performing NMR and XRPD tests on the solid sample. The results showed that the solid sample was Form I of 5-amino-2-methyl-6-(2,3,4,5,6-hydroxycyclohexyloxy)pyran-3-ylamino-α-imidoacetic acid hydrochloride.

[0121] Example 4: Preparation of 5-amino-2-methyl-6-(2,3,4,5,6-hydroxycyclohexyloxy)pyran-3-ylamino-α-imidoacetic acid hydrochloride amorphous

[0122] a) taking 100 mg of the dried solid crystalline product of Example 1;

[0123] b) dissolving the solid crystalline product in 2 ml of water;

[0124] c) freezing the solution in step b using dry ice and freeze drying it in a freeze dryer for 1 day;

[0125] d) The freeze-dried product was subjected to NMR and XRPD measurements, and the NMR results showed that it was 5-amino-2-methyl-6-(2,3,4,5,6-hydroxycyclohexyloxy)pyran-3-ylamino-α-imidoacetic acid hydrochloride (eg Figure 5 The XRPD results showed that it was an amorphous substance without obvious characteristic peaks (as shown in Figure 6 shown).

[0126] Example 5: Preparation of powder

[0127] According to the methods of Comparative Example 1, Example 1 and Example 4, about 70 g of three kinds of dry solids, namely, Form II, Form I and amorphous material, were prepared respectively, with contents of 98.1%, 98.7% and 96.3%, respectively, for use as technical / mother drug of the preparation.

[0128] Use small vertical sand mill and zirconium beads ( Zhimo (Shanghai) New Material Technology Co., Ltd.) crushed the above-mentioned technical / concentrated drug respectively, wherein the amount of zirconium beads was 40g, the speed of the sand mill was 1500r / min, the grinding time was 30min, and the zirconium beads and fine powder were separated after the grinding.

[0129] PSD analysis showed that the particle size D90 of the three technical / concentrated drug fine powders was 36.6μm-40.2μm.

[0130] 4 g of each of the three technical / mother drug fine powders were taken, and the three fine powders were sieved with 96 g of diatomaceous earth through 200 meshes and then fully mixed to prepare three powders.

[0131] Example 6: Preparation of wettable powder

[0132] The dosage of each component of wettable powder is shown in the following table:

[0133]

[0134] The wettable powder is prepared by the following steps:

[0135] 1) According to the above table, the crystal form I and amorphous original drug / mother drug fine powder prepared in Example 5 are respectively taken and set aside;

[0136] 2) fully mixing copper oxychloride, sodium lauryl sulfate, sodium lignin sulfonate, white carbon black and diatomaceous earth, and grinding them by an ultra-fine grinder to obtain an additive powder;

[0137] 3) The fine powder of the original drug / concentrated drug is fully mixed with the auxiliary agent powder prepared in step 2) to obtain a wettable powder.

[0138] (II) Basic characterization of crystal form

[0139] (1) 1H NMR analysis

[0140] NMR showed Form I ( Figure 1 As shown), Form II (as Figure 3 shown) and amorphous (as Figure 5 ) are all 5-amino-2-methyl-6-(2,3,4,5,6-hydroxycyclohexyloxy)pyran-3-ylamino-α-imidoacetic acid hydrochloride compounds.

[0141] (2) XRPD diffraction peak data analysis

[0142] The XRPD diffraction peak data of the compound 5-amino-2-methyl-6-(2,3,4,5,6-hydroxycyclohexyloxy)pyran-3-ylamino-α-imidoacetic acid hydrochloride form I described in the present application are shown in Table 1; the XRPD diffraction peak data of the form II are shown in Table 2.

[0143] Table 1 XRPD diffraction peak data of Form I

[0144]

[0145]

[0146] As can be seen from Table 1, the main characteristic diffraction peaks of the X-ray powder diffraction pattern of Form I using Cu-Kα radiation, represented by 2θ values ​​±0.2°, include 8.66, 10.11, 11.05 and 13.3, and also include any one or more characteristic diffraction peaks of 13.92, 15.56, 16.47 and 17.29, specifically including 8.66, 10.11, 11.05, 13.3, 13.92 and 15.56; or including 8.66, 10.11, 11.05, 13.3, 16.47 and 17.29; or including 8.66, 10.11, 11.05, 13.3, 13.92, 15.56, 16.47 and 17.29.

[0147] Table 2 XRPD diffraction peak data of Form II

[0148]

[0149] As can be seen from Table 2, the main characteristic diffraction peaks of the X-ray powder diffraction pattern of Form II using Cu-Kα radiation and represented by 2θ values ​​±0.2° include 8.91, 10.03, 10.51, 12.12, 15.01, 16.40, 17.14 and 26.68; compared with Form I, the characteristic diffraction peaks of Form II do not contain characteristic diffraction peaks such as 8.66, 11.05 and 13.30, but contain characteristic diffraction peaks such as 8.91, 10.51 and 12.12.

[0150] according to Figure 6 It was found that an amorphous substance without a significant diffraction peak was obtained by freeze-drying.

[0151] In summary, three solid products are prepared by the preparation method of the present invention, namely, Form I, Form II and amorphous matter. By comparing the XRPD spectra and diffraction peak data of Form I and Form II, it can be seen that the two belong to different crystal forms.

[0152] (3)DSC and TGA analysis

[0153] The DSC spectrum and TGA spectrum of the crystal form I described in this application are as follows Figure 7 As shown; the DSC spectrum and TGA spectrum of Form II are as shown Figure 8 shown.

[0154] DSC shows that the crystal form I has a continuous endothermic signal in the range of 110±2°C to 210±2°C, and an endothermic signal at 226±2°C; compared with the height of the endothermic peak (or peak and valley), the crystal form I has a strong endothermic process at 226±2°C, and the endothermic process in the range is a weak endothermic process.

[0155] TGA shows that the crystalline form I has a weight loss of about 0.2% when heated to 100±2°C, a weight loss of less than 5% when heated from 100±2°C to 220±2°C, and a weight loss of less than 15.5% when heated from 220±2°C to 255C±2°C.

[0156] DSC shows that the crystal form II has a weak endothermic signal at 147±2°C and a strong endothermic signal at 215±2°C; compared with the height of the endothermic peak (or peak valley), the crystal form I has a strong endothermic process at 215±2°C and a weak endothermic process at 147±2°C.

[0157] TGA shows that the crystalline form II has a weight loss of less than 6% when heated to 195±2°C, and has a weight loss of less than 15% when heated from 220±2°C to 250±2°C.

[0158] DSC showed that the amorphous substance had endothermic signals at 73±2°C and 187±2°C;

[0159] TGA results show that the amorphous phase has a weight loss of less than 9% when heated to 175±2°C, and a weight loss of substantially less than 15% when heated from 175±2°C to 255±2°C.

[0160] (4)PLM and PSD analysis

[0161] PLM images show that Form I is mainly granular (e.g. Fig.10 Particle size distribution analysis shows that the particle size D of Form I 5064.2μm, D 90 119 μm (such as Fig.13 shown).

[0162] PLM images show that Form II is mainly needle-shaped (e.g. Fig.11 Particle size distribution analysis shows that the particle size of Form II is D 50 24.7μm, D 90 70.1 μm (such as Fig.14 shown).

[0163] PLM images show that amorphous materials are flake-like (e.g. Fig.12 As shown), particle size D 50 It is 30.2μm.

[0164] (III) Powder fluidity

[0165] In order to verify the processing properties of different solid products, the fluidity of the three fine powders prepared in Example 5 was tested, and the fluidity of the fine powder was measured according to the "angle of repose" method in the "Guidelines for Determination of Powder Flowability" issued by the National Pharmacopoeia Commission on December 19, 2022. Among them, the test was carried out in a fixed funnel height mode (10 cm), the experimental temperature was room temperature, the humidity was about 5%, and the experimental fine powder dosage was 60 g. The experimental results are shown in Table 3.

[0166] Table 3 Powder fluidity evaluation

[0167] Fine powder information Angle of repose(°) Liquidity Evaluation Crystal form I fine powder 29 very good Crystalline Form II fine powder 41 generally Amorphous fine powder 39 better

[0168] As can be seen from Table 3, the crystalline form I and the amorphous material after crushing under the same conditions have better powder fluidity than the crystalline form II, indicating that the 5-amino-2-methyl-6-(2,3,4,5,6-hydroxycyclohexyloxy)pyran-3-ylamino-α-imidoacetic acid hydrochloride in the form of crystalline form I and amorphous material is more conducive to the processing and utilization of subsequent mixtures and preparations, among which 5-amino-2-methyl-6-(2,3,4,5,6-hydroxycyclohexyloxy)pyran-3-ylamino-α-imidoacetic acid hydrochloride in the crystalline form I structure shows the best effect in processing. The hygroscopicity and stability of crystalline form I, crystalline form II and amorphous material will be further investigated in the future.

[0169] (IV) DVS analysis

[0170] like Fig.15 As shown, Form I only gained 1.57% weight at 95% humidity, gained 0.40% weight at 80% humidity, and lost 1.02% weight at 0% humidity, indicating that Form I has basically no hygroscopicity, indicating that Form I is also a stable solid product in a high humidity environment.

[0171] In comparison, Form II gained 2.2% weight by absorbing moisture under 95% high humidity and 0.74% weight by 80% humidity, showing weak hygroscopicity under high humidity; the amorphous material showed the common hygroscopic characteristics of amorphous materials.

[0172] (V) Stability determination

[0173] The stability of Form I and Form II was studied under high temperature (60°C), high humidity (25°C / 92.5% RH), light (25°C / 4500Lux) and accelerated (40°C / 75% RH) conditions. Samples were taken at 7 days and 15 days, respectively, and the appearance, XRPD characterization and HPLC test were observed, and the results were compared with the original sample. The results showed that Form I remained stable under high temperature, high humidity, light and accelerated stability conditions, specifically: the appearance remained unchanged, no crystal form transformation occurred, and the chemical purity did not change significantly (as shown in Table 4, Fig.16 ), indicating that Form I is a stable solid crystalline product.

[0174] The stability results of Form II showed that the appearance of Form II remained stable under 15 days of high temperature and high humidity test conditions. After 7 days of light exposure test, the appearance changed from white to yellow, and after 15 days, the color changed to light brown, indicating that Form II was less stable under continuous light exposure.

[0175] Table 4 Experimental results of different environmental factors affecting Form I

[0176]

[0177] (VI) Antibacterial effect of potted plants

[0178] 1. Preparation of cucumber downy mildew spore suspension

[0179] Cucumber downy mildew was collected from naturally diseased leaves in Weinan Ecological Agriculture Demonstration Park. The mold layer on the back of the leaf spots was removed with a brush dipped in distilled water. The leaves were placed in an artificial climate box at 25°C and 80% relative humidity for 16 hours in the dark to produce fresh sporangia. The fresh sporangia were then brushed into a culture dish filled with distilled water with a brush and filtered twice to prepare a spore suspension (concentration of 2×10 5 -4×10 5 / mL) for later use.

[0180] 2. Cucumber indoor cultivation

[0181] Cucumbers (Xinnong 58, 20 pots in total, 1 plant / pot) were planted in plastic pots with a diameter of 5 cm. The plants were cultured at a temperature of 20°C-28°C (day and night), a relative humidity of (90±5)%, and a fluorescent light for 12 h until they were about 1 meter tall. Twelve cucumber seedlings with similar growth potential were selected as samples for subsequent experiments.

[0182] 3. Preventive foliar application

[0183] Two leaves with a height equivalent to that of the 12 cucumber seedlings (calculated from the soil surface) and a leaf width of about 5-8 cm were selected from each plant. The three mixed powders prepared in Example 5 were respectively loaded in the same specification powder spraying bottles, and preventive application was carried out according to the powder pesticide application method: two powder sprays were carried out at a height of about 40 cm from the leaf surface, and three plants and 6 leaves were sprayed with each powder as a parallel experiment, and the blank group was only sprayed with diatomaceous earth powder. The leaves were marked and recorded accordingly (Group A was a blank group, Group B was a group containing crystalline II powder, Group C was a group containing crystalline I powder, and Group D was a group containing amorphous powder), and cucumber downy mildew inoculation was carried out after continuing to cultivate for 48 hours according to the previous planting conditions.

[0184] 4. Cucumber downy mildew inoculation and therapeutic application

[0185] The prepared spore suspension was poured into a watering can, sprayed twice on the leaves from a height of about 20 cm from the selected leaves, and immediately covered with a transparent plastic bag and fastened with the bag buckle after spraying, so as to complete the downy mildew inoculation of 24 leaves on 12 cucumber seedlings. After inoculation, the transparent plastic bag was removed at 2h, 6h and 10h respectively, the inoculated leaves were moistened with pure water by spraying, and then the bagging process was continued. 24h after the completion of inoculation, the preventive application method was used for therapeutic application (Group A was sprayed with diatomaceous earth powder, Group B was sprayed with powder containing crystal form II, Group C was sprayed with powder containing crystal form I, and Group D was sprayed with powder containing amorphous substance), and the leaves were cleaned 15 days after the therapeutic application, and the experimental leaf surface conditions were observed and recorded, and statistical analysis was performed.

[0186] The disease is graded according to the area of ​​the lesions. The grading standards are:

[0187] Level 0: no lesions on leaves;

[0188] Level 1: The lesion area accounts for less than 5% of the entire leaf area;

[0189] Level 3: The lesion area accounts for 6-10% of the entire leaf area;

[0190] Level 5: The lesion area accounts for 11-25% of the entire leaf area;

[0191] Level 7: The lesion area accounts for 26-50% of the entire leaf area;

[0192] Level 9: The lesion area accounts for more than 50% of the entire leaf area;

[0193] Disease index = {[∑(number of diseased leaves at each level of each treatment × corresponding level value)] / total number of leaves investigated × 9} × 100;

[0194] Control effect (%) = [(blank control disease index - drug treatment disease index) / blank control disease index] × 100;

[0195] The results of the four groups of experiments are shown in Table 5. Some of the results are shown in Fig.17 shown.

[0196] Table 5 Foliar control effect

[0197] Group Disease index Control effect (%) A 96.30 -- B 48.15 50.00 C 22.22 79.63 D 11.11 88.46

[0198] According to the plant disease index and control effect, surprisingly, there are significant differences in the plant disease control effect between crystal form I, crystal form II and amorphous, among which the plant disease control effect of the powder containing amorphous is the best, followed by the powder containing crystal form I. This shows that different crystal forms and amorphous forms of 5-amino-2-methyl-6-(2,3,4,5,6-hydroxycyclohexyloxy)pyran-3-ylamino-α-imidoacetic acid hydrochloride may have differences in drug release, plant absorption and antibacterial ability, and the plant disease control effect of the amorphous form and crystal form I of 5-amino-2-methyl-6-(2,3,4,5,6-hydroxycyclohexyloxy)pyran-3-ylamino-α-imidoacetic acid hydrochloride is better than that of crystal form II.

[0199] The specific embodiments described above further illustrate the objectives, technical solutions and beneficial effects of the present invention in detail. It should be understood that the above are only specific embodiments of the present invention and are not intended to limit the scope of protection of the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and purpose of the present invention should be included in the scope of protection of the present invention.

Claims

1. An agricultural antibiotic 5-amino-2-methyl-6-(2,3,4,5,6-hydroxycyclohexyloxy)pyran-3-ylamino-α-imidoacetic acid hydrochloride crystal form I, characterized in that: The crystal form I uses Cu-Kα radiation, and the characteristic diffraction peaks of the X-ray powder diffraction pattern represented by 2θ values ​​±0.2° include 8.66, 10.11, 11.05, 13.30, and any one or more characteristic diffraction peaks selected from the following: 13.92, 15.56, 16.47 and 17.

29.

2. The crystalline form I according to claim 1, characterized in that The crystal form I uses Cu-Kα radiation, and the characteristic diffraction peaks of the X-ray powder diffraction pattern represented by 2θ values ​​±0.2° include 8.66, 10.11, 11.05, 13.30 and 13.

92.

3. The crystalline form I according to claim 1, characterized in that The crystal form I uses Cu-Kα radiation, and the characteristic diffraction peaks of the X-ray powder diffraction pattern represented by 2θ values ​​±0.2° include 8.66, 10.11, 11.05, 13.30 and 15.

56.

4. The crystalline form I according to claim 1, characterized in that The crystal form I uses Cu-Kα radiation, and the characteristic diffraction peaks of the X-ray powder diffraction pattern represented by 2θ values ​​±0.2° include 8.66, 10.11, 11.05, 13.30 and 16.

47.

5. The crystalline form I according to claim 1, characterized in that The crystal form I uses Cu-Kα radiation, and the characteristic diffraction peaks of the X-ray powder diffraction pattern represented by 2θ values ​​±0.2° include 8.66, 10.11, 11.05, 13.30 and 17.

29.

6. The crystalline form I according to any one of claims 1 to 5, characterized in that: The crystal form I uses Cu-Kα radiation, and the characteristic diffraction peaks of the X-ray powder diffraction pattern represented by 2θ values ​​±0.2° also include any one or more characteristic diffraction peaks of 9.59, 18.59, 19.25 and 19.

99.

7. The crystalline form I according to any one of claims 1 to 6, characterized in that: Differential scanning calorimetry analysis shows that the crystalline form I has a continuous endothermic signal in the range of 110±2°C to 210±2°C. Preferably, differential scanning calorimetry analysis shows that the crystalline form I also has an endothermic signal at 226±2°C.

8. The crystalline form I according to any one of claims 1 to 7, characterized in that: Thermogravimetric analysis shows that the Form I has a weight loss of less than 5% when heated from 100±2°C to 220±2°C, and a weight loss of less than 15.5% when heated from 220±2°C to 255C±2°C.

9. The crystalline form I according to any one of claims 1 to 8, characterized in that: The X-ray powder diffraction pattern of the crystalline form I is shown in FIG2 .

10. A method for preparing the crystalline form I according to any one of claims 1 to 9, characterized in that: The method comprises: 1) precipitating a crystalline solid; and 2) filtering the crystalline solid.

11. The method according to claim 10, characterized in that: The method for precipitating the crystalline solid is a dissolution back-drip method, a liquid gas phase diffusion method, a single solvent room temperature suspension method, a single solvent high temperature suspension method, a binary solvent forward drip method, a single solvent cooling method or a binary solvent cooling method; preferably any one of the dissolution back-drip method, the liquid gas phase diffusion method or the single solvent cooling method.

12. An agricultural antibiotic 5-amino-2-methyl-6-(2,3,4,5,6-hydroxycyclohexyloxy)pyran-3-ylamino-α-imidoacetic acid hydrochloride crystal form I, characterized in that: The invention is prepared by the preparation method according to any one of claims 10 to 11.

13. An amorphous form of 5-amino-2-methyl-6-(2,3,4,5,6-hydroxycyclohexyloxy)pyran-3-ylamino-α-imidoacetic acid hydrochloride.

14. The amorphous material according to claim 13, characterized in that: The amorphous material has no obvious X-ray powder diffraction peak.

15. The amorphous material according to claim 13 or 14, characterized in that: The differential scanning calorimetry analysis of the amorphous material shows endothermic signals at 73±2°C and 187±2°C; preferably, the thermogravimetric analysis results show that the amorphous material has a weight loss of less than 9% when heated to 175±2°C, and a weight loss of less than 15% when heated from 175±2°C to 255±2°C.

16. The amorphous material according to any one of claims 13 to 15, characterized in that: The amorphous material is a sheet-like structure; preferably, the amorphous material D 90 10μm-200μm.

17. A technical drug or a parent drug, characterized in that: The technical or mother drug contains the crystalline form I described in any one of claims 1-9 and claim 12 and / or the amorphous material described in any one of claims 13-16.

18. A preparation or pesticide composition, characterized in that The preparation or pesticide composition contains the crystalline form I according to any one of claims 1 to 9 and claim 12 and / or the amorphous material according to any one of claims 13 to 16.

19. Use of the crystalline form I according to any one of claims 1 to 9 and claim 12, the amorphous material according to any one of claims 13 to 16, the technical or bulk drug according to claim 17, or the preparation or pesticide composition according to claim 18 in plant disease control.

20. Use of the crystalline form I according to any one of claims 1 to 9 and claim 12, the amorphous material according to any one of claims 13 to 16, the technical or parent drug according to claim 17, or the preparation or pesticide composition according to claim 18 in the preparation of a plant disease control preparation.

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