Crystal form, technical drug, mother drug or preparation of compound and use thereof

Abstract

The present application provides a compound (2R, 3R, 4S) 2-(6-amino-9H-purine-9-yl) 2-(hydroxymethyl) 5-methylenetetrahydrofuran-3,4-diol crystal form, which is selected from one of crystal form A and crystal form B, or a mixture of the two; wherein, crystal form A uses Cu-Kα radiation, and the characteristic diffraction peaks of the X-ray powder diffraction pattern represented by 2θ values ​​± 0.2° include any three or more of 9.55, 13.01, 16.57, and 18.78; crystal form B uses Cu-Kα radiation, and the characteristic diffraction peaks of the X-ray powder diffraction pattern represented by 2θ values ​​± 0.2° include any three or more of 5.00, 5.60, 9.69, and 14.56. The crystal form has good stability, can remain stable under illumination, high temperature, high humidity, and accelerated conditions, and can better meet the requirements of pesticides in production, processing, transportation, and storage.

Description

Technical Field

[0001] This application belongs to the field of agricultural technology, specifically relating to the crystal form, technical material, parent material or formulation of a compound and its uses. Background Technology

[0002] (2R,3R,4S)-2-(6-amino-9H-purine-9-yl)-2-(hydroxymethyl)-5-methylenetetrahydrofuran-3,4-diol is a plant growth regulator produced by Streptomyces. It promotes germination and rooting in rice and also enhances plant stress resistance.

[0003] Currently, there is no research on the crystal form of (2R,3R,4S)-2-(6-amino-9H-purine-9-yl)-2-(hydroxymethyl)-5-methylenetetrahydrofuran-3,4-diol. Since the crystal form of a drug is a key factor in its drug-like properties, it is necessary to fill this gap in research in order to obtain a plant growth regulator with excellent chemical and physical stability. Summary of the Invention

[0004] In view of the above-mentioned problems in the prior art, this application provides a technical solution to solve the above problems.

[0005] According to one aspect of this application, a crystal form of the compound (2R,3R,4S)-2-(6-amino-9H-purin-9-yl)-2-(hydroxymethyl)-5-methylenetetrahydrofuran-3,4-diol is provided, which is selected from one of crystal form A and crystal form B, or a mixture of two; wherein,

[0006] The characteristic diffraction peaks of the X-ray powder diffraction pattern of crystal form A, expressed as 2θ value ± 0.2°, include any three or more of the following: 9.55, 13.01, 16.57, and 18.78.

[0007] Crystal form B, using Cu-Kα radiation, exhibits X-ray powder diffraction patterns with characteristic diffraction peaks expressed as 2θ values ​​± 0.2°, including any three or more of the following: 5.00, 5.60, 9.69, and 14.56.

[0008] Optionally, the characteristic diffraction peaks of the X-ray powder diffraction pattern of crystal form A using Cu-Kα radiation, expressed in 2θ values ​​± 0.2°, also include any one or more of 19.13, 20.12, and 25.39.

[0009] Optionally, for crystal form B, the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, using Cu-Kα radiation, also include any one or more of 4.38, 15.07, and 16.76.

[0010] Optionally, for crystal form B, the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, using Cu-Kα radiation, also include any one or more of 15.34 and 17.58.

[0011] According to another aspect of this application, a technical grade drug or parent drug is provided, said technical grade drug or parent drug containing the crystal form described above.

[0012] Optionally, the crystal form is present in the drug substance or parent drug at a weight percentage of 5-99.9%.

[0013] According to another aspect of this application, a formulation or pesticide composition is provided, the formulation or pesticide composition containing the crystal form described above.

[0014] Optionally, the formulation or pesticide composition contains the crystal form and adjuvants described above.

[0015] Optionally, the crystal form is 0.001-50% by weight in the formulation or pesticide composition.

[0016] Optionally, the dosage form of the formulation is selected from any one of the following: powder, granules, large granules, fine granules, microparticles, microcapsule granules, wettable powder, oil-dispersible powder, water-dispersible granules, emulsion granules, effervescent granules, dispersible tablets, effervescent tablets, sustained-release agents, sustained-release blocks, sustained-release tubes, sustained-release granules, soluble powders, soluble granules, soluble tablets, soluble solutions, aqueous solutions, soluble gels, oils, spreading oils, ultra-low volume liquids, ultra-low volume microcapsule suspensions, emulsifiable concentrates, latexes, dispersible liquids, pastes, concentrated gels, water emulsions, oil emulsions, microemulsions, greases, suspensions, microcapsule suspensions, oil suspensions, suspension emulsions, seed-treated dispersible powders, seed-treated soluble powders, seed-treated liquids, seed-treated emulsions, seed-treated suspensions, suspension seed coating agents, and seed-treated microcapsule suspensions.

[0017] According to another aspect of this application, the use of the crystal form, the technical grade or parent material described above, or the formulation or pesticide composition described above in regulating plant growth is provided.

[0018] According to another aspect of this application, the use of the crystal form, the technical grade or parent material described above, or the formulation or pesticide composition described above in the preparation of plant growth regulators is provided.

[0019] According to another aspect of this application, the use of the crystal form, the technical grade or parent material described above, or the formulation or pesticide composition described above in improving plant stress resistance is provided.

[0020] According to another aspect of this application, the use of the crystal form, the technical grade or parent material described above, or the formulation or pesticide composition described above in the preparation of products that enhance plant stress resistance is provided.

[0021] The positive and progressive effects of this application are as follows:

[0022] The crystal forms provided in this application have good stability, especially crystal form A, which has almost no hygroscopicity. It can remain stable and effectively extend the shelf life of the pesticide under light, high temperature, high humidity and accelerated conditions, and can better meet the requirements of pesticides in production, processing, transportation and storage. Attached Figure Description

[0023] Figure 1 The image shows the XRPD pattern of crystal form B, where the horizontal axis represents 2θ (°) and the vertical axis represents the intensity (count).

[0024] Figure 2 The image shows the XRPD pattern of crystal form A, where the horizontal axis represents 2θ (°) and the vertical axis represents the intensity (count).

[0025] Figure 3 The image shows the XRPD pattern of crystal form I, where the horizontal axis represents 2θ (°) and the vertical axis represents the intensity (count).

[0026] Figure 4 The DSC and TGA spectra are for crystal form A;

[0027] Figure 5 The DSC and TGA spectra are for crystal form B.

[0028] Figure 6 The NMR spectrum is for crystal form A;

[0029] Figure 7 XRPD spectra of crystal form A before and after DVS testing;

[0030] Figure 8 XRPD spectra of crystal form B before and after DVS testing;

[0031] Figure 9 Experimental results on room temperature stability of crystal form I;

[0032] Figure 10 The results are from the stability test of crystal form A;

[0033] Figure 11 The results are from the stability determination of crystal form B. Detailed Implementation

[0034] The term "crystal form" refers to a single or polymorphic form of the compound (2R,3R,4S)-2-(6-amino-9H-purin-9-yl)-2-(hydroxymethyl)-5-methylenetetrahydrofuran-3,4-diol. A polymorphic form is a mixture of two or more crystal forms of the compound (2R,3R,4S)-2-(6-amino-9H-purin-9-yl)-2-(hydroxymethyl)-5-methylenetetrahydrofuran-3,4-diol.

[0035] The term "other crystal forms different from crystal form A" refers to a crystal form of the compound (2R,3R,4S)-2-(6-amino-9H-purine-9-yl)-2-(hydroxymethyl)-5-methylenetetrahydrofuran-3,4-diol described in this application that is different from crystal form A. Other similar expressions have a similar meaning.

[0036] The term "solvent" refers to those crystal forms of the compounds described in this application that coordinate with solvent molecules (such as water, organic solvents such as formic acid, toluene, etc.) to form complexes. Hydrates are a specific form of solvate in which coordination with water occurs. For example, a solvate can be a hydrate.

[0037] The term "raw material" refers to the product obtained during the production process, which consists of active ingredients and related impurities, and may include a small amount of additives if necessary.

[0038] The term "mother drug" refers to the product obtained during the production process, which consists of the active ingredient and related impurities, and may contain small amounts of necessary additives and appropriate diluents.

[0039] The term "formulation" refers to a stable product made from pesticide technical (mother drug) and suitable adjuvants, or processed by methods such as bio-fermentation and plant extraction.

[0040] The term "adjuvant" refers to any single or multiple components, other than the active ingredient, added to a pesticide product that do not possess pesticide activity or the function of the active ingredient, but can or help to improve or enhance the physicochemical properties of the pesticide product.

[0041] The term "plant growth regulator" refers to compounds that regulate the plant's developmental process and cause changes in plant growth and development. Examples include, but are not limited to, promoting or inhibiting germination, rooting, flower bud differentiation, flowering, fruiting, and leaf fall.

[0042] The term "enhancing plant stress resistance" refers to improving a plant's adaptation to stressful environments. Examples of this include, but are not limited to, enhancing a plant's ability to withstand cold, salt, alkali, and drought.

[0043] In one specific embodiment, the compound (2R,3R,4S)-2-(6-amino-9H-purine-9-yl)-2-(hydroxymethyl)-5-methylenetetrahydrofuran-3,4-diol described in this application has a single crystal form, selected from crystal form A or crystal form B.

[0044] In one specific embodiment, the compound (2R,3R,4S)-2-(6-amino-9H-purin-9-yl)-2-(hydroxymethyl)-5-methylenetetrahydrofuran-3,4-diol described in this application is polymorphic, which is a mixture comprising at least crystal form A and / or crystal form B. Optionally, the compound (2R,3R,4S)-2-(6-amino-9H-purin-9-yl)-2-(hydroxymethyl)-5-methylenetetrahydrofuran-3,4-diol described in this application is polymorphic, which is a mixture consisting of crystal form A and optionally one or more other crystal forms different from crystal form A. Alternatively, the compound (2R,3R,4S)-2-(6-amino-9H-purin-9-yl)-2-(hydroxymethyl)-5-methylenetetrahydrofuran-3,4-diol described in this application is polymorphic, which is a mixture of polymorph A and optionally one or more other polymorphs different from polymorph A and polymorph B. Alternatively, the compound (2R,3R,4S)-2-(6-amino-9H-purin-9-yl)-2-(hydroxymethyl)-5-methylenetetrahydrofuran-3,4-diol described in this application is polymorphic, which is a mixture of polymorph B and optionally one or more other polymorphs different from polymorph B. Alternatively, the compound (2R,3R,4S)-2-(6-amino-9H-purin-9-yl)-2-(hydroxymethyl)-5-methylenetetrahydrofuran-3,4-diol described in this application is polymorphic, which is a mixture of crystal form B and optionally one or more other crystal forms different from crystal form A and crystal form B. Alternatively, the compound (2R,3R,4S)-2-(6-amino-9H-purin-9-yl)-2-(hydroxymethyl)-5-methylenetetrahydrofuran-3,4-diol described in this application is polymorphic, which is a mixture of crystal form A, crystal form B, and one or more other crystal forms different from crystal form A and crystal form B.

[0045] In one specific embodiment, the compound (2R,3R,4S)-2-(6-amino-9H-purin-9-yl)-2-(hydroxymethyl)-5-methylenetetrahydrofuran-3,4-diol described in this application may be a solvate, and optionally, a hydrate. Optionally, crystal form A or crystal form B may be a hydrate (e.g., a hemihydrate, monohydrate, dihydrate, etc.).

[0046] In one specific embodiment, the characteristic diffraction peaks of the crystal form A of the compound (2R,3R,4S)-2-(6-amino-9H-purin-9-yl)-2-(hydroxymethyl)-5-methylenetetrahydrofuran-3,4-diol described in this application, expressed as 2θ values ​​± 0.2° using Cu-Kα radiation, include any three or more of 9.55, 13.01, 16.57, and 18.78; optionally, it also includes any one, any two, or any three of 19.13, 20.12, and 25.39; optionally, it also includes any one, any two, or any three of 21.09, 24.32, and 26.93.

[0047] In one specific implementation, the thermogravimetric analysis spectrum of crystal form A shows a weight loss of 5.7% during heating to 140℃±2℃, and decomposition may occur above 180℃.

[0048] In one specific implementation, the differential scanning calorimetry spectrum of crystal form A has an endothermic signal corresponding to the weight loss in the thermogravimetric analysis spectrum at 122℃±2℃, an exothermic peak at 144℃±2℃, and an endothermic peak at 174℃±2℃.

[0049] In one specific embodiment, the characteristic diffraction peaks of crystal form B of the compound (2R,3R,4S)-2-(6-amino-9H-purin-9-yl)-2-(hydroxymethyl)-5-methylenetetrahydrofuran-3,4-diol described in this application, expressed as 2θ values ​​± 0.2° using Cu-Kα radiation, include any three or more of the following peaks: 5.00, 5.60, 9.69, and 14.56. Optionally, it also includes any one or more of the following peaks: 4.38, 15.07, and 16.76. Optionally, it also includes any one or more of the following peaks: 15.34 and 17.58.

[0050] In one specific implementation, the thermogravimetric analysis (TGA) spectrum of crystal form B shows an 8.9% weight loss during heating to 195℃±2℃, and decomposition may occur above 200℃.

[0051] In one specific implementation, the differential scanning calorimetry spectrum of crystal form B has a broad endothermic signal at around 90℃±2℃, and endothermic peaks at around 169℃±2℃ and 189℃±2℃, respectively.

[0052] In one embodiment, crystal form A can be prepared by methods such as evaporation, single solvent room temperature suspension, single solvent high temperature suspension, binary solvent positive drop, single solvent cooling, and binary solvent cooling.

[0053] Optionally, the evaporation method includes the following steps: the sample is completely dissolved in a solvent, left to stand at room temperature, until the solvent is completely evaporated to obtain a solid.

[0054] Optionally, the single-solvent room temperature suspension method includes the following steps: dissolving the sample in a solvent, suspending it at room temperature for 5-8 days, centrifuging, and drying. The solvent can be selected from heptane, cyclohexane, chloroform, etc.

[0055] Optionally, the single-solvent high-temperature suspension method includes the following steps: adding a solvent to the sample to prepare a suspension, suspending and stirring at 30-70℃ for 1-3 days, centrifuging, and drying. The solvent can be acetonitrile, etc.

[0056] Optionally, the binary solvent positive titration method includes: dissolving the sample in a good solvent; adding a poor solvent dropwise until a solid precipitates, followed by centrifugation and drying. The good solvent is selected from dioxane, and the poor solvent is selected from acetonitrile.

[0057] Optionally, the single solvent cooling method includes: dissolving the sample in a solvent at 40-70℃, cooling it to room temperature until solids precipitate, centrifuging, and drying.

[0058] Optionally, the binary solvent cooling method includes: adding a binary solvent to the sample, suspending it at room temperature for 5-8 days until solids precipitate, centrifuging, and drying. The binary solvent is selected from a mixture of water and acetonitrile.

[0059] If no solid precipitates in the above method, placing the sample at 4°C or lower can help the solid precipitate.

[0060] In one specific embodiment, the technical grade or parent drug provided in this application contains the crystal form described in this application, wherein the weight percentage of the crystal form in the technical grade or parent drug is 5-99.9%, preferably 8.0-99.9%. For example, the weight percentage of the crystal form in the technical grade or parent drug is 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 99.9%. Optionally, the weight percentage of the crystal form in the technical grade or parent drug is 8-99.9%. Optionally, the weight percentage of the crystal form in the technical grade or parent drug is 10-99.9%. Optionally, the weight percentage of the crystal form in the technical grade or parent drug is 8-50%.

[0061] In one specific embodiment, the formulation or pesticide composition provided in this application contains the crystal form described in this application. Optionally, the weight percentage of the crystal form in the formulation is 0.001-50.0%, for example, the weight percentage of the crystal form in the formulation is 0.1%, 0.5%, 5%, 10%, 20%, 30%, or 40%. Optionally, the weight percentage of the crystal form in the formulation is 0.1%-0.5%, 0.5-1%, 0.5-10%, or 20-40%. Optionally, the weight percentage of the crystal form in the formulation or pesticide composition is 0.1-20%. Optionally, the weight percentage of the crystal form in the formulation or pesticide composition is 0.1-10%. Optionally, the weight percentage of the crystal form in the formulation or pesticide composition is 0.1-8%. Optionally, the weight percentage of the crystal form in the formulation or pesticide composition is 0.1-5%. Specific implementation examples:

[0063] All commercially available reagents and solvents were not further purified.

[0064] The sample testing in the examples was performed according to the following method.

[0065] 1. X-ray powder diffraction (XRPD)

[0066] The solid samples obtained in the experiment were analyzed using a Bruker D8 Advance X-ray powder diffractometer (Bruker, GER). The 2θ scanning angle ranged from 3° to 45°, the scanning step size was 0.02°, and the exposure time was 0.08 seconds. The testing method was Cu target Kα1 radiation, voltage 40 kV, current 40 mA, and a zero-background sample disk.

[0067] 2. Differential Scanning Calorimetry (DSC)

[0068] The differential scanning calorimeter was a TA Discovery 2500 (TA, US). 1-2 mg of sample was accurately weighed and placed in a perforated DSC Tzero sample pan. The sample was heated to the final temperature at a rate of 10 °C / min, with nitrogen purging at a rate of 50 mL / min.

[0069] 3. Thermogravimetric analysis (TGA)

[0070] The thermogravimetric analyzer was a TA Discovery 55 (TA, US). 2-5 mg of sample was placed in a pre-equilibrated open aluminum sample pan and automatically weighed inside the TGA furnace. The sample was heated to the final temperature at a rate of 10 °C / min, with nitrogen purging at the sample location at 60 mL / min and at the balance at 40 mL / min.

[0071] 4. Nuclear magnetic resonance analysis (1H NMR)

[0072] Several milligrams of solid sample were dissolved in dimethyl sulfoxide-d6 solvent and analyzed by nuclear magnetic resonance on a Bruker AVANCE NEO 400 (Bruker, GER).

[0073] 5. Dynamic moisture adsorption-desorption analysis (DVS)

[0074] Dynamic moisture adsorption-desorption analysis was performed using DVS Intrinsic (SMS, UK). The test employed a gradient mode with humidity variations of 50%-95%-0%-50%. Within the 0% to 90% range, each gradient represented a 10% change in humidity. The gradient endpoint was determined using the dm / dt method, with a dm / dt value less than 0.002% maintained for 10 minutes as the endpoint, or each gradient maintained for a maximum of 180 minutes. After the test, XRPD analysis was performed on the samples to confirm whether the solid form had changed.

[0075] 6. Stability Study

[0076] (1) Influencing Factors Experiment

[0077] Weigh 20 mg of sample into a weighing bottle and place it open under high temperature (60℃), high humidity (25℃ / 92.5%RH) or light (25℃ / 4500Lux) conditions respectively. Take samples at 7 and 15 days to observe the appearance, perform XRPD characterization and HPLC testing, and compare with the original sample.

[0078] (2) Accelerated stability test

[0079] Weigh 20 mg of sample into a weighing bottle, place it open under accelerated conditions (40℃ / 75% RH), and take samples at 7 and 15 days to observe the appearance, perform XRPD characterization and HPLC testing, and compare with the original sample.

[0080] 7. High Performance Liquid Chromatography (HPLC)

[0081] Mobile phase: Acetonitrile / 0.1% phosphoric acid solution (volume ratio 5:95)

[0082] Column: Poroshell 120EC-C18 reversed-phase column

[0083] Detection wavelength: 261nm

[0084] Flow rate: 1.0 mL / min

[0085] Column temperature: 25℃

[0086] Injection volume: 10 μL

[0087] (I) Preparation Examples

[0088] Example 1: Preparation of compound (2R,3R,4S)-2-(6-amino-9H-purin-9-yl)-2-(hydroxymethyl)-5-methylenetetrahydrofuran-3,4-diol sample

[0089] Under aseptic conditions, Streptomyces caniferus NEAU6, which had been activated on Gao's No. 1 agar medium, was scraped and transferred to seed culture medium. The culture was carried out at 30°C and 200 rpm for 2 days. Then, the seed culture was inoculated into fermentation medium at 6% (v / v) and cultured at 30°C and 200 rpm for 5 days.

[0090] The fermentation broth was centrifuged to remove bacterial cells. The supernatant was extracted four times with an equal volume of ethyl acetate, followed by silica gel column chromatography, gel chromatography, and C-18 column chromatography. The chromatography yielded the compound (2R,3R,4S)-2-(6-amino-9H-purine-9-yl)-2-(hydroxymethyl)-5-methylenetetrahydrofuran-3,4-diol. XRPD analysis showed... Figure 1 As shown, it is named crystal form B.

[0091] Example 2: Preparation of crystal form B

[0092] Weigh 90 mg of the compound (2R,3R,4S)-2-(6-amino-9H-purin-9-yl)-2-(hydroxymethyl)-5-methylenetetrahydrofuran-3,4-diol sample prepared in Example 1, dissolve it in 0.90 mL of ethylene glycol methyl ether, take 0.15 mL of the solution, add 1.5 mL of acetone until a solid precipitates, centrifuge, and dry. The XRPD result of the obtained solid is crystal form B.

[0093] Example 3: Preparation of crystal form B

[0094] Weigh 20 mg of the compound (2R,3R,4S)-2-(6-amino-9H-purine-9-yl)-2-(hydroxymethyl)-5-methylenetetrahydrofuran-3,4-diol sample prepared in Example 1, add 5 mL of preheated n-propanol dropwise at 50 °C, let stand at room temperature for 2 h, and then cool further at -15 °C to precipitate a solid. Centrifuge, separate, and dry. The XRPD result of the obtained solid is crystal form B.

[0095] Example 4: Preparation of crystal form A

[0096] Weigh 20 mg of the compound (2R,3R,4S)-2-(6-amino-9H-purin-9-yl)-2-(hydroxymethyl)-5-methylenetetrahydrofuran-3,4-diol sample prepared in Example 1, add 10 mL of n-heptane, suspend and stir at room temperature for 7 days, then centrifuge and dry to obtain solid XRPD as shown in Figure 1. Figure 2 As shown, it is named crystal form A.

[0097] Example 5: Preparation of crystal form A

[0098] Weigh 20 mg of the compound (2R,3R,4S)-2-(6-amino-9H-purine-9-yl)-2-(hydroxymethyl)-5-methylenetetrahydrofuran-3,4-diol sample prepared in Example 1, add 10 mL of cyclohexane, suspend and stir at room temperature for 7 days, then centrifuge and dry. The XRPD result shows crystal form A.

[0099] Example 6: Preparation of crystal form A

[0100] Weigh 120 mg of the compound (2R,3R,4S)-2-(6-amino-9H-purine-9-yl)-2-(hydroxymethyl)-5-methylenetetrahydrofuran-3,4-diol sample prepared in Example 1, dissolve it in 7.0 mL of dioxane, take 0.6 mL of the solution, add 5.4 mL of acetonitrile dropwise until a solid precipitates, centrifuge, dry, and the XRPD result shows crystal form A.

[0101] Example 7: Preparation of Crystal Form I

[0102] Weigh 15 mg of the (2R,3R,4S)-2-(6-amino-9H-purin-9-yl)-2-(hydroxymethyl)-5-methylenetetrahydrofuran-3,4-diol sample prepared in Example 1, add 0.5 mL of ethyl acetate, heat to 50 °C, then add 1.4 mL of preheated tetrahydrofuran until the solution is clear. Cool the solution to room temperature, then place it at -15 °C to precipitate a solid. Centrifuge the system with precipitated solid, then vacuum dry at room temperature. XRPD is as follows: Figure 3 As shown, it is named crystal form I.

[0103] (II) Basic Characterization of Crystal Forms

[0104] (1) XRPD diffraction peak data analysis

[0105] The XRPD diffraction peak data of the compound (2R,3R,4S)-2-(6-amino-9H-purin-9-yl)-2-(hydroxymethyl)-5-methylenetetrahydrofuran-3,4-diol described in this application are shown in Table 1; the XRPD diffraction peak data of the compound B are shown in Table 2; and the XRPD diffraction peak data of the compound I are shown in Table 3.

[0106] Table 1. XRPD diffraction peak data for crystal form A

[0107]

[0108]

[0109] As shown in Table 1, the main characteristic diffraction peaks of the X-ray powder diffraction pattern of crystal form A using Cu-Kα radiation, expressed as 2θ value ± 0.2°, include any three or more of 9.55, 13.01, 16.57, and 18.78; optionally, it also includes any one or more of 19.13, 20.12, and 25.39.

[0110] Table 2 XRPD diffraction peak data for crystal form B

[0111]

[0112]

[0113]

[0114] As shown in Table 2, the main characteristic diffraction peaks of the X-ray powder diffraction pattern of crystal form B using Cu-Kα radiation, expressed as 2θ values ​​± 0.2°, include any three or more of 5.00, 5.60, 9.69, and 14.56. Optionally, it also includes any one or more of 4.38, 15.07, and 16.76. Optionally, it also includes any one or more of 15.34 and 17.58.

[0115] Table 3 XRPD diffraction peak data for crystal form I

[0116]

[0117]

[0118]

[0119] As shown in Table 3, the main characteristic diffraction peaks of the X-ray powder diffraction pattern of crystal form I using Cu-Kα radiation, expressed as 2θ values ​​± 0.2°, include 11.32, 13.07, and 14.21. Optionally, they also include 15.59, 16.97, and 17.27. Optionally, they also include 5.66, 7.14, and 10.70.

[0120] Conclusion: By comparing the XRPD spectra of crystal form A, crystal form B and crystal form I, it can be seen that these three crystal forms have distinct characteristic diffraction peaks and can be identified as three different crystal forms.

[0121] (2) Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA)

[0122] The DSC and TGA spectra of the compound (2R,3R,4S)-2-(6-amino-9H-purin-9-yl)-2-(hydroxymethyl)-5-methylenetetrahydrofuran-3,4-diol crystal form A described in this application are as follows: Figure 4 As shown; the DSC and TGA spectra of crystal form B are as follows. Figure 5 As shown.

[0123] TGA results show that crystal form A loses 5.7% of its weight when heated to 140℃, and may decompose above 180℃. DSC results show that crystal form A has an endothermic signal corresponding to the weight loss in TGA at around 122℃, an exothermic peak at around 144℃, and an endothermic peak at around 174℃.

[0124] TGA results showed that crystal form B lost 8.9% of its weight when heated to 195℃, and may decompose above 200℃. DSC results showed that crystal form B had a broad endothermic signal around 90℃, with endothermic peaks around 169℃ and 189℃, respectively.

[0125] (3) Nuclear magnetic resonance analysis (1H NMR)

[0126] NMR showed that crystal form A had no obvious organic solvent signal peaks (e.g. Figure 6 (As shown).

[0127] NMR showed that crystal form B also had no obvious organic solvent signal peaks.

[0128] Based on the above results, it can be concluded that the compound (2R,3R,4S)-2-(6-amino-9H-purin-9-yl)-2-(hydroxymethyl)-5-methylenetetrahydrofuran-3,4-diol of this application has the following crystal form A: hydrate, which appears off-white. Crystal form B is also a hydrate, appearing colorless and transparent. Crystal form I is a metastable crystal form; no thermal analysis or NMR tests were performed on crystal form I.

[0129] (III) Dynamic moisture adsorption-desorption analysis (DVS)

[0130] DVS results showed that crystal form A gained 0.16% weight at 95% humidity, and during adsorption, it gained 0.04% weight at 80% humidity and lost 0.17% weight at 0% humidity, indicating that crystal form A has almost no hygroscopicity. XRPD results of crystal form A before and after DVS testing (…) Figure 7 The results show that the crystal form of the sample did not change after the DVS test.

[0131] DVS results showed that crystal form B lost 0.13% weight at 80% humidity, 2.33% weight at 95% humidity, and 2.66% weight at 0% humidity during adsorption, indicating that crystal form B is hygroscopic. Furthermore, comparing the XRPD patterns before and after DVS testing... Figure 8 It can be observed that crystal form B transforms into crystal form A under high humidity conditions.

[0132] (iv) Stability determination

[0133] (1) Influencing Factors Experiment

[0134] Preliminary experiments: Preliminary experiments were conducted on crystal forms A, B, and I at room temperature (1 day and 6 days at 25°C). The results showed that crystal form I underwent a crystal transformation after 1 day at room temperature, becoming a mixture of crystal forms A and B (e.g., ...). Figure 9 As shown in the figure, this indicates that crystal form I is a metastable crystal form. Crystal forms A and B, however, do not undergo any crystal form transformation after being placed at 25°C for 6 days.

[0135] Stability studies were conducted on crystal forms A and B under high temperature (60℃), high humidity (25℃ / 92.5% RH), and light exposure (25℃ / 4500 Lux) conditions. Samples were taken at 7 and 15 days, and their appearance was observed, XRPD characterized, and HPLC tested. The results were compared with the original samples, and are shown in Table 3. Figure 10 and Figure 11 As shown in the figure. XRPD results indicate that crystal form A remained stable for 15 days under high temperature, high humidity, and light conditions, with no change in appearance or color compared to the original sample (both being off-white). No crystal form transformation occurred, and the chemical purity showed no significant change. Crystal form B transformed into crystal form A after 7 days under high humidity conditions; under high temperature conditions, no crystal form transformation occurred after 7 and 15 days, but the sample color changed from colorless and transparent to yellow, and the chemical purity decreased significantly. Under light conditions, no crystal form transformation occurred after 15 days, with no change in appearance or chemical purity.

[0136] Table 3. Experimental Results of Influencing Factors

[0137]

[0138] (2) Accelerated stability test

[0139] Stability studies were conducted on crystal forms A and B under accelerated (40℃ / 75% RH) conditions. Samples were taken at 7 and 15 days, and their appearance was observed, XRPD characterized, and HPLC tested. The results were compared with the original samples. The results are shown in Table 4. Figure 10 and Figure 11As shown, crystal form A remained stable for 15 days under accelerated conditions, with no change in appearance, no crystal form transformation, and no significant change in chemical purity; crystal form B transformed into crystal form A within 7 days under accelerated conditions.

[0140] Table 4 Accelerated Stability Experiment

[0141]

[0142]

[0143] Therefore, the compound (2R,3R,4S)-2-(6-amino-9H-purine-9-yl)-2-(hydroxymethyl)-5-methylenetetrahydrofuran-3,4-diol provided in this application has good stability, especially crystal form A, which has excellent stability and can better meet the requirements of pesticides in production, processing, transportation and storage.

[0144] The crystal form provided in this application can be used as an effective ingredient in the original drug or parent drug. The content of the crystal form in the original drug or parent drug can be 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%, etc.

[0145] The crystal form provided in this application can be used in liquid formulations (e.g., aqueous solutions, oils, emulsifiable concentrates, dispersible liquids, etc.) or solid formulations (e.g., powders, granules, large granules, fine granules, etc.). To facilitate better use, film-forming agents (e.g., seaweed powder, sodium carboxymethyl cellulose, chitosan, etc.), thickeners (e.g., xanthan gum, carboxymethyl cellulose, gelatin, seaweed, gypsum, hydroxyethyl cellulose, methyl cellulose, magnesium aluminum silicate, polyvinyl alcohol), and dispersants (e.g., Morwet D-42) can be added. 5. At least one of Terspense-2500, naphthalene sulfonate, lignin sulfonate, polycarboxylate, etc.), wetting agents (e.g., sodium dodecyl sulfate, MorwetEFW, polyoxyethylene alkylphenol ether, polyoxyethylene fatty alcohol ether, polyoxyethylene polyoxypropylene block copolymer, etc.), and surfactants (e.g., sodium dodecylbenzene sulfonate, sodium dodecyl sulfate, sodium hexadecylbenzene sulfonate, sodium hexadecyl sulfate, sodium octadecylbenzene sulfonate, sodium octadecyl sulfate, Tween-80, etc.).

[0146] The specific embodiments described above further illustrate the purpose, technical solution, and beneficial effects of this application. It should be understood that the above descriptions are merely specific embodiments of this application and are not intended to limit the scope of protection of this application. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and intent of this application should be included within the scope of protection of this application.

Claims

1. The crystal form of compound (2R,3R,4S)-2-(6-amino-9H-purin-9-yl)-2-(hydroxymethyl)-5-methylenetetrahydrofuran-3,4-diol, characterized in that, It is selected from crystal form A; among which, The characteristic diffraction peaks of the X-ray powder diffraction pattern of crystal form A, expressed as 2θ values ​​± 0.2°, include 9.55, 13.01, 16.57, and 18.

78.

2. The crystal form according to claim 1, characterized in that, The characteristic diffraction peaks of the X-ray powder diffraction pattern of crystal form A, expressed as 2θ value ± 0.2°, also include any one or more of 19.13, 20.12, and 25.

39.

3. A technical grade drug or parent drug, characterized in that, The active ingredient or parent ingredient contains the crystal form described in any one of claims 1-2.

4. The technical grade drug or parent drug according to claim 3, characterized in that, The crystal form is present in the drug substance or parent drug at a weight percentage of 5-99.9%.

5. A pesticide composition, characterized in that, The pesticide composition contains the crystal form described in any one of claims 1-2.

6. The pesticide composition according to claim 5, characterized in that, The crystal form is present in the pesticide composition at a weight percentage of 0.001-50%.

7. A formulation, characterized in that, The formulation contains the crystal form as described in any one of claims 1-2.

8. The formulation according to claim 7, characterized in that, The crystal form is present in the formulation at a weight percentage of 0.001-50%.

9. The formulation according to claim 7, characterized in that, The dosage form of the preparation is selected from any one of powder, granules, oil, and seed treatment suspension.

10. The formulation according to claim 7, characterized in that, The dosage form of the formulation is selected from sustained-release formulations.

11. The formulation according to claim 7, characterized in that, The dosage form of the preparation is selected from suspensions.

12. The formulation according to claim 7, characterized in that, The formulation is selected from suspension seed coating agents.

13. The formulation according to claim 7, characterized in that, The dosage form of the formulation is selected from any one of seed treatment dispersible powder, seed treatment soluble powder, seed treatment liquid, seed treatment emulsion, and seed treatment microcapsule suspension.

14. The formulation according to claim 7, characterized in that, The dosage form of the formulation is selected from any one of the following: large granules, fine granules, microparticles, microcapsules, wettable powders, oil-dispersible powders, water-dispersible granules, emulsions, effervescent granules, dispersible tablets, effervescent tablets, sustained-release blocks, sustained-release tubes, sustained-release granules, soluble powders, soluble granules, soluble tablets, soluble solutions, aqueous solutions, soluble gels, spreading oils, ultra-low volume liquids, ultra-low volume microcapsule suspensions, emulsions, latexes, dispersible liquids, pastes, concentrated gels, water emulsions, oil emulsions, microemulsions, liposomes, microcapsule suspensions, oil suspensions, and suspension emulsions.

15. The use of the crystal form according to any one of claims 1-2, the technical grade or parent material according to any one of claims 3-4, or the pesticide composition according to any one of claims 5-6, or the formulation according to any one of claims 7-14 in regulating plant growth.

16. The use of the crystal form according to any one of claims 1-2, the technical grade or parent material according to any one of claims 3-4, or the pesticide composition according to any one of claims 5-6, or the formulation according to any one of claims 7-14 in the preparation of plant growth regulators.

17. The use of the crystal form according to any one of claims 1-2, the technical grade or parent material according to any one of claims 3-4, or the pesticide composition according to any one of claims 5-6, or the formulation according to any one of claims 7-14 in improving plant stress resistance.

18. The use of the crystal form according to any one of claims 1-2, the technical grade or parent material according to any one of claims 3-4, or the pesticide composition according to any one of claims 5-6, or the formulation according to any one of claims 7-14 in the preparation of products that enhance plant stress resistance.

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