Crystalline forms, technical or pharmaceutical preparations of compounds and their use

Abstract

The application provides a crystal form of a compound (2R, 3R, 4S)-2-(6-amino-9H-purin-9-yl)-2-(hydroxymethyl)-5-methylenetetrahydrofuran-3, 4-diol, which is selected from the crystal form F; wherein the crystal form F has characteristic diffraction peaks of an X-ray powder diffraction pattern expressed by 2θ values ± 0.2° using Cu-Kα radiation, and the characteristic diffraction peaks include 7.43, 13.07 and 13.69. The crystal form has good stability, can be kept stable under light, high temperature, high humidity and acceleration conditions, and can better meet the requirements of pesticides in production, processing, transportation and storage.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of agricultural technology, and particularly relates to a crystal form of a compound, a technical material, a mother drug or a preparation and use thereof. BACKGROUND

[0002] (2R, 3R, 4S)-2-(6-amino-9H-purin-9-yl)-2-(hydroxymethyl)-5-methylenetetrahydrofuran-3, 4-diol is a plant growth regulator produced by Streptomyces, which has the effects of promoting germination and rooting of rice and improving plant stress resistance.

[0003] However, there is no research on the crystal form of (2R, 3R, 4S)-2-(6-amino-9H-purin-9-yl)-2-(hydroxymethyl)-5-methylenetetrahydrofuran-3, 4-diol, and it is necessary to fill this gap and obtain a crystal form with good chemical and physical stability. SUMMARY

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

[0005] According to one aspect of the present 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 the crystal form F; wherein,

[0006] The characteristic diffraction peak of the X-ray powder diffraction pattern of the crystal form F using Cu-Ka radiation expressed in 2θ value ± 0.2° includes 7.43, 13.07, 13.69.

[0007] Alternatively, the characteristic diffraction peak of the X-ray powder diffraction pattern of the crystal form F using Cu-Ka radiation expressed in 2θ value ± 0.2° further includes any one or more of 14.97, 17.38.

[0008] Alternatively, the characteristic diffraction peak of the X-ray powder diffraction pattern of the crystal form F using Cu-Ka radiation expressed in 2θ value ± 0.2° further includes any one or more of 15.26, 15.89.

[0009] Alternatively, the crystal form F is an anhydrous substance.

[0010] According to another aspect of the present application, a technical material or a mother drug is provided, which contains the above-mentioned crystal form.

[0011] Alternatively, the weight percentage of the crystal form in the technical material or the mother drug is 5-99.9%.

[0012] According to another aspect of the present application, there is provided a formulation or a pesticidal composition comprising the crystal form described above.

[0013] Optionally, the crystal form is present in the formulation or the pesticidal composition in a weight percentage of 0.001-50%.

[0014] Optionally, the formulation or the pesticidal composition comprises the crystal form described above and an adjuvant.

[0015] Optionally, the dosage form of the formulation is selected from any one of a powder, a granule, a macrogranule, a fine granule, a microgranule, a microencapsulated granule, a wettable powder, an oil dispersible powder, a water dispersible granule, a milk granule, an effervescent granule, a dispersible tablet, an effervescent tablet, a sustained release agent, a sustained release block, a sustained release tube, a sustained release granule, a soluble powder, a soluble granule, a soluble tablet, a soluble solution, an aqueous agent, a soluble gel agent, an oil agent, a spreadable oil agent, an ultra-low volume liquid agent, an ultra-low volume microcapsule suspension agent, a cream, a latex, a dispersible liquid agent, a paste, a thick gel agent, an aqueous emulsion, an oil emulsion, a microemulsion, a grease, a suspension agent, a microcapsule suspension agent, an oil suspension agent, a suspoemulsion, a seed treatment dispersible powder, a seed treatment soluble powder, a seed treatment liquid agent, a seed treatment emulsion, a seed treatment suspension agent, a flowable concentrate, and a seed treatment microcapsule suspension agent.

[0016] According to another aspect of the present application, there is provided a use of the crystal form described above, the technical-grade or technical product described above, or the formulation or the pesticidal composition described above in regulating the growth of plants.

[0017] According to another aspect of the present application, there is provided a use of the crystal form described above, the technical-grade or technical product described above, or the formulation or the pesticidal composition described above in preparing a plant growth regulator.

[0018] According to another aspect of the present application, there is provided a use of the crystal form described above, the technical-grade or technical product described above, or the formulation or the pesticidal composition described above in improving the stress resistance of plants.

[0019] According to another aspect of the present application, there is provided a use of the crystal form described above, the technical-grade or technical product described above, or the formulation or the pesticidal composition described above in preparing a product for improving the stress resistance of plants.

[0020] The positive progress effect of the present application is that:

[0021] The crystal form F provided in the present application has good stability and can remain stable under light, high temperature, high humidity, and acceleration conditions, and can better meet the requirements of pesticides in production, processing, transportation, and storage. BRIEF DESCRIPTION OF DRAWINGS

[0022] Figure 1XRPD pattern of Form B, wherein the abscissa is 2 theta (°) and the ordinate is intensity (counts);

[0023] Figure 2 XRPD pattern of Form C, wherein the abscissa is 2 theta (°) and the ordinate is intensity (counts);

[0024] Figure 3 XRPD pattern of Form I, wherein the abscissa is 2 theta (°) and the ordinate is intensity (counts);

[0025] Figure 4 XRPD pattern of Form F, wherein the abscissa is 2 theta (°) and the ordinate is intensity (counts);

[0026] Figure 5 DSC pattern and TGA pattern of Form B;

[0027] Figure 6 DSC pattern and TGA pattern of Form C;

[0028] Figure 7 NMR pattern of Form C;

[0029] Figure 8 DSC pattern and TGA pattern of Form F;

[0030] Figure 9 NMR pattern of Form F;

[0031] Figure 10 XRPD patterns of Form B before and after DVS test;

[0032] Figure 11 XRPD patterns of Form F before and after DVS test;

[0033] Figure 12 Thermal conversion experiment results of Form C;

[0034] Figure 13 Room temperature stability determination results of Form C;

[0035] Figure 14 Room temperature stability experiment results of Form I;

[0036] Figure 15 Stability determination results of Form B;

[0037] Figure 16 Stability determination results of Form F. DETAILED DESCRIPTION

[0038] The term "crystal form" refers to a single crystal form or a polymorph of the compound (2R,3R,4S)-2-(6-amino-9H-purin-9-yl)-2-(hydroxymethyl)-5-methylenetetrahydrofuran-3,4-diol, and a polymorph refers to a mixture of two or more crystal forms of (2R,3R,4S)-2-(6-amino-9H-purin-9-yl)-2-(hydroxymethyl)-5-methylenetetrahydrofuran-3,4-diol.

[0039] The term "other crystal form(s) different from crystal form F" refers to crystal forms of (2R,3R,4S)-2-(6-amino-9H-purin-9-yl)-2-(hydroxymethyl)-5-methylenetetrahydrofuran-3,4-diol described herein that are different from crystal form F. Other similar expressions have similar meanings.

[0040] The term "solvate" refers to those forms of the crystal form of the compound described herein that form a complex with a molecule of a solvent (such as water, an organic solvent such as formic acid, toluene, etc.) through coordination. Hydrates are a specific form of solvates in which coordination occurs with water. For example, solvates can be hydrates, alcohol solvates, etc.

[0041] The term "technical material" refers to a product obtained during production, consisting of the active ingredient and related impurities, to which a small amount of additives can be added, if necessary.

[0042] The term "technical material" refers to a product obtained during production, consisting of the active ingredient and related impurities, to which a small amount of additives can be added, if necessary.

[0043] The term "formulation" refers to a product that is stable in its state, which is processed from a pesticide technical material (technical material) and a suitable adjuvant, or processed by methods such as biological fermentation, plant extraction, etc.

[0044] The term "adjuvant" refers to any single component or multiple components of substances added in a pesticide product in addition to the active ingredient, which do not have pesticide activity and active ingredient function by themselves, but can or help to improve the physicochemical properties of the pesticide product.

[0045] The term "plant growth regulator" refers to a compound that has the function of regulating the development program of plants and can cause changes in plant growth and development. Examples thereof include, but are not limited to, promoting or inhibiting germination, rooting, flower bud differentiation, flowering, fruiting, leaf fall, etc.

[0046] The term "improving plant stress resistance" refers to improving the adaptation of plants to stressful environments, examples of which include, but are not limited to, improving the ability of plants to resist cold, salt, alkali, drought, etc.

[0047] In one embodiment, the crystalline form of (2R,3R,4S)-2-(6-amino-9H-purin-9-yl)-2- (hydroxymethyl)-5-methylenetetrahydrofuran-3,4-diol described herein is a single crystalline form selected from Form F.

[0048] In one embodiment, the crystalline form of (2R,3R,4S)-2-(6-amino-9H-purin-9-yl)-2- (hydroxymethyl)-5-methylenetetrahydrofuran-3,4-diol described herein is a polymorph which is a mixture comprising at least Form F. Preferably, the crystalline form of (2R,3R,4S)-2-(6-amino-9H-purin-9-yl)-2-(hydroxymethyl)-5-methylenetetrahydrofuran-3,4-diol described herein is a polymorph which is a mixture consisting of Form F and optionally one or more other crystalline forms different from Form F. Or preferably, the crystalline form of (2R,3R,4S)-2-(6-amino-9H-purin-9-yl)-2-(hydroxymethyl)-5-methylenetetrahydrofuran-3,4-diol described herein is a polymorph which is a mixture consisting of Form F and optionally one or more other crystalline forms different from Form F and Form B. Or preferably, the crystalline form of (2R,3R,4S)-2-(6-amino-9H-purin-9-yl)-2-(hydroxymethyl)-5-methylenetetrahydrofuran-3,4-diol described herein is a polymorph which is a mixture consisting of Form F and one or more other crystalline forms different from Form F, Form B and Form C. Or preferably, the crystalline form of (2R,3R,4S)-2-(6-amino-9H-purin-9-yl)-2-(hydroxymethyl)-5-methylenetetrahydrofuran-3,4-diol described herein is a polymorph which is a mixture consisting of Form F and Form B. Or preferably, the crystalline form of (2R,3R,4S)-2-(6-amino-9H-purin-9-yl)-2-(hydroxymethyl)-5-methylenetetrahydrofuran-3,4-diol described herein is a polymorph which is a mixture consisting of Form F, Form B and one or more other crystalline forms different from Form F and Form B. Or preferably, the crystalline form of (2R,3R,4S)-2-(6-amino-9H-purin-9-yl)-2-(hydroxymethyl)-5-methylenetetrahydrofuran-3,4-diol described herein is a polymorph which is a mixture consisting of Form F, Form B and one or more other crystalline forms different from Form F, Form B and Form C. Or preferably, the crystalline form of (2R,3R,4S)-2-(6-amino-9H-purin-9-yl)-2-(hydroxymethyl)-5-methylenetetrahydrofuran-3,4-diol described herein is a polymorph which is a mixture consisting of Form F, Form B and Form C and one or more other crystalline forms different from Form F, Form B and Form C. Or preferably, the crystalline form of (2R,3R,4S)-2-(6-amino-9H-purin-9-yl)-2-(hydroxymethyl)-5-methylenetetrahydrofuran-3,4-diol described herein is a polymorph which contains Form F and one or both of Form B and Form C, for example, Form F and Form B, or Form F and Form C, or Form F, Form B and Form C

[0049] In one embodiment, the crystalline form of (2R, 3R, 4S)-2-(6-amino-9H-purin-9-yl)-2- (hydroxymethyl)-5-methylene tetrahydrofuran-3,4-diol described herein can be a hydrate, a solvate or an anhydrate. Alternatively, the crystalline form B can be a hydrate (e.g. hemihydrate, monohydrate, dihydrate, etc.), the crystalline form C can be a dimethylformamide solvate, and the crystalline form F can be an anhydrate.

[0050] In one embodiment, the crystalline form F has characteristic peaks in the X-ray powder diffraction pattern, expressed in values of 2-theta ± 0.2°, including 7.43, 13.07, 13.69. Alternatively, it can further include any one or more of 14.97, 17.38. Alternatively, it can further include any one or more of 15.26, 15.89. Alternatively, it can further include any one or more of 4.96, 18.08.

[0051] In one embodiment, the crystalline form described herein is contained in a prodrug or a parent drug, and the weight percentage of the crystalline form in the prodrug or the parent drug is 5-99.9%, preferably 8.0-99.9%. For example, the weight percentage of the crystalline form in the prodrug or the parent drug is 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 99.9%. Preferably, the weight percentage of the crystalline form in the prodrug or the parent drug is 8-90%. Preferably, the weight percentage of the crystalline form in the prodrug or the parent drug is 8-70%. Preferably, the weight percentage of the crystalline form in the prodrug or the parent drug is 8-50%.

[0052] In one embodiment, the crystalline form described herein is contained in a formulation or a pesticide composition, and the weight percentage of the crystalline form in the formulation is 0.1-50.0%, for example, the weight percentage of the crystalline form in the formulation is 0.1%, 0.5%, 5%, 10%, 20%, 30% or 40%. Preferably, the weight percentage of the crystalline form in the formulation is 0.1%-0.5%, 0.1-20%, 0.1-10%, 0.1-8%, 0.1-5%, 0.5-1%, 0.5-10% or 20-40%. Specific embodiments:

[0054] All commercially available reagents and solvents were used without further purification.

[0055] The sample in the examples was detected according to the following method:

[0056] 1. X-ray powder diffraction (XRPD)

[0057] The solid samples obtained from the experiments were analyzed using an X-ray powder diffractometer, Bruker D8 Advance (Bruker, GER). The 2 theta scan angle was from 3° to 45°, with a scan step of 0.02° and an exposure time of 0.08 seconds. The testing method was Cu target K alpha 1 ray, voltage 40 kV, current 40 mA, and the sample disc was a zero background sample disc.

[0058] 2. Thermogravimetric analysis (TGA)

[0059] The thermogravimetric analyzer was model TA Discovery 55 (TA, US). 2-5 mg of sample was placed in an open aluminum sample pan, which was automatically weighed in the TGA furnace. The sample was heated at a rate of 10 °C / min to the final temperature, with a nitrogen purge rate of 60 mL / min at the sample and 40 mL / min at the balance.

[0060] 3. Differential scanning calorimetry analysis (DSC)

[0061] The differential scanning calorimetry analyzer was model TA Discovery 2500 (TA, US). 1-2 mg of sample was accurately weighed and placed in a pierced DSC Tzero sample pan, which was heated at a rate of 10 °C / min to the final temperature, with a nitrogen purge rate of 50 mL / min in the furnace.

[0062] 4. Nuclear magnetic resonance analysis (1H NMR)

[0063] Several milligrams of solid sample were dissolved in dimethyl sulfoxide-d6 solvent, and nuclear magnetic resonance analysis was performed on a Bruker AVANCE NEO 400 (Bruker, GER).

[0064] 5. Dynamic vapor sorption analysis (DVS)

[0065] Dynamic vapor sorption analysis was determined using a DVS Intrinsic (SMS, UK). The test used a gradient mode, with a humidity change of 50%-95%-0%-50%, and a humidity change of 10% in the range of 0% to 90% for each gradient. The end of the gradient was determined using a dm / dt method, with dm / dt less than 0.002% for 10 minutes, or a maximum of 180 minutes for each gradient. After the test was completed, the sample was analyzed by XRPD to confirm whether the solid form had changed.

[0066] 6. Thermal conversion experiment

[0067] Thermal recrystallization was performed using Instec HCS424GXY hot stage (Instec Inc., US) with 6-8 mg sample placed on a glass slide on the hot stage, heated to the target temperature at a rate of 10 °C / min, and kept at the target temperature for 10 min, then cooled to room temperature naturally, and the solid was obtained for XRPD test.

[0068] 7. Stability study

[0069] (1) Influencing factor experiment

[0070] 20 mg sample was weighed into a weighing bottle and placed in high temperature (60 °C), high humidity (25 °C / 92.5% RH), light (25 °C / 4500 Lux) respectively, and samples were taken at 7 days and 15 days, the appearance was observed, XRPD characterization and HPLC test were performed, and compared with the original sample.

[0071] (2) Accelerated stability experiment

[0072] 20 mg sample was weighed into a weighing bottle and placed in high temperature (60 °C), high humidity (25 °C / 92.5% RH), light (25 °C / 4500 Lux), acceleration (40 °C / 75% RH) respectively, and samples were taken at 7 days and 15 days, the appearance was observed, XRPD characterization and HPLC test were performed, and compared with the original sample.

[0073] 8. High performance liquid chromatography (HPLC)

[0074] Mobile phase: acetonitrile / 0.1% phosphoric acid water (volume ratio 5:95)

[0075] Chromatographic column: Poroshell 120 EC-C18 reversed-phase chromatographic column

[0076] Detection wavelength: 261 nm

[0077] Flow rate: 1.0 mL / min

[0078] Column temperature: 25 °C

[0079] Injection volume: 10 μL

[0080] (I) Preparation example

[0081] Example 1: Preparation of (2R, 3R, 4S)-2-(6-amino-9H-purin-9-yl)-2- (hydroxymethyl)-5-methylenetetrahydrofuran-3, 4-diol sample

[0082] Under sterile conditions, Streptomyces caniferus NEAU6 activated on Gao's agar medium was scraped and transferred to the seed medium, cultured at 30°C, 200 rpm for 2 days, and then the seed liquid was inoculated into the fermentation medium at 6% (v / v) and cultured at 30°C, 200 rpm for 5 days.

[0083] The fermentation broth was centrifuged to remove the bacteria, and the supernatant was extracted four times with an equal volume of ethyl acetate and then subjected to silica gel column chromatography, gel chromatography, and C-18 column chromatography in sequence. After chromatography, a (2R,3R,4S)-2-(6-amino-9H-purin-9-yl)-2-(hydroxymethyl)-5-methylenetetrahydrofuran-3,4-diol sample was obtained. XRPD was as follows Figure 1 As shown, it is named as Form B.

[0084] Example 2: Preparation of Form C

[0085] 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 1 mL of ethyl acetate, and heat to 50°C. Then, add 0.2 mL of preheated dimethylformamide dropwise until the solution is clear. The solution is allowed to cool at room temperature. Place at 4°C to precipitate a solid, centrifuge, and dry in vacuo at room temperature. XRPD is as follows: Figure 2 As shown, it is named as Form C.

[0086] Example 3: Preparation of Form I

[0087] 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 and heat to 50°C. Then, add 1.4 mL of preheated tetrahydrofuran dropwise until the solution is clear. The solution is allowed to cool at room temperature and then placed at -15°C to precipitate a solid. The system with the precipitated solid is centrifuged and dried under vacuum at room temperature. XRPD is as follows: Figure 3 As shown, it is named as Form I.

[0088] Example 4: Preparation of Form F

[0089] 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 into a glass bottle, add 1.5 mL of ethylene glycol dimethyl ether to prepare a suspension, and stir at 50°C for 24 hours. Centrifuge to remove the supernatant, and dry the solid under vacuum at room temperature. XRPD detection is as follows: Figure 4 As shown, it is named as Form F.

[0090] Example 5: Preparation of Form F

[0091] 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 was weighed into a glass bottle, 1.5 mL of dioxane / acetone (v / v, 1:2) was added to prepare a suspension, and the suspension was stirred at room temperature for 7 days. The supernatant was removed by centrifugation, and the solid was vacuum dried at room temperature. The XRPD test results showed that the crystal form F

[0092] (II) Basic characterization of crystal form

[0093] (1) Basic characterization of Form B

[0094] (1.1) XRPD diffraction peak data analysis

[0095] The XRPD diffraction peak data of Form B are shown in Table 1.

[0096] Table 1 XRPD diffraction peak data of Form B

[0097]

[0098]

[0099]

[0100] As shown in Table 1, the main characteristic diffraction peaks of the X-ray powder diffraction pattern of 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. Preferably, it also includes any one or more of 4.38, 15.07, and 16.76. Preferably, it also includes any one or more of 15.34 and 17.58.

[0101] (1.2) Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA)

[0102] The DSC spectrum and TGA graph of Form B are as follows Figure 5 shown.

[0103] TGA results showed that Form B lost 8.9% of its weight when heated to 195°C, and decomposition may occur above 200°C. DSC results showed that Form B had a broad endothermic signal around 90°C, with endothermic peaks at around 169°C and 189°C, respectively.

[0104] (1.3) Nuclear magnetic resonance analysis (1H NMR)

[0105] NMR results showed that Form B had no obvious organic solvent peak signal.

[0106] (2) Basic characterization of Form C

[0107] (2.1) XRPD diffraction peak data analysis

[0108] The XRPD diffraction peak data of Form C are shown in Table 2.

[0109] Table 2 XRPD diffraction peak data of Form C

[0110]

[0111]

[0112]

[0113] As shown in Table 2, the X-ray powder diffraction pattern of Form C using Cu-Kα radiation, expressed as 2θ values ​​±0.2°, has main characteristic diffraction peaks including 5.49, 9.57, and 13.05, preferably also including 14.33, 15.38, and 16.59.

[0114] (2.2) Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA)

[0115] The DSC and TGA spectra of Form C are as follows: Figure 6 shown.

[0116] TGA results showed that Form C experienced a 10.2% weight loss upon heating to 175°C, and decomposition may occur above 185°C. DSC results showed that Form C exhibited an endothermic signal corresponding to the TGA weight loss at approximately 113°C, an exothermic peak at approximately 121°C, and an endothermic peak at approximately 173°C.

[0117] (2.3) Nuclear magnetic resonance analysis (1H NMR)

[0118] The NMR of (2R,3R,4S)-2-(6-amino-9H-purin-9-yl)-2-(hydroxymethyl)-5-methylenetetrahydrofuran-3,4-diol Form C described in this application is as follows Figure 7 shown.

[0119] The NMR results showed that signal peaks of dimethylformamide were visible at 7.95ppm, 2.89ppm and 2.73ppm. According to the integration results, the ratio of the compound to dimethylformamide was 1:0.35, and the rough estimated mass share was about 8.4%, which was close to the TGA weight loss.

[0120] (3) Basic characterization of Form I

[0121] (3.1) XRPD Diffraction Peak Data Analysis

[0122] The XRPD diffraction peak data of Form I is shown in Table 3.

[0123] Table 3 XRPD Diffraction Peak Data of Form I

[0124]

[0125]

[0126]

[0127] As can be seen from Table 3, the main characteristic diffraction peaks of the X-ray powder diffraction pattern of Form I using Cu-Ka radiation expressed in terms of 2-theta values ± 0.2° include 11.32, 13.07, 14.21. Preferably, it also includes 15.59, 16.97, 17.27. Preferably, it also includes 5.66, 7.14, 10.70.

[0128] Form I undergoes a crystal transformation when left at room temperature for 1 day, so no thermal analysis and NMR tests were performed.

[0129] (4) Basic Characterization of Form F

[0130] (4.1) XRPD Diffraction Peak Data Analysis

[0131] The XRPD diffraction peak data of Form F of (2R,3R,4S)-2-(6-amino-9H-purin-9-yl)-2- (hydroxymethyl)-5-methylenetetrahydrofuran-3,4-diol described herein is shown in Table 4.

[0132] Table 4 XRPD Diffraction Peak Data of Form F

[0133]

[0134]

[0135]

[0136] As can be seen from Table 4, the main characteristic diffraction peaks of the X-ray powder diffraction pattern of Form F using Cu-Ka radiation expressed in terms of 2-theta values ± 0.2° include 7.43, 13.07, 13.69. Optionally, it also includes any one or more of 14.97, 17.38. Optionally, it also includes any one or more of 15.26, 15.89. Optionally, it also includes any one or more of 4.96, 18.08.

[0137] (4.2) Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA)

[0138] The DSC and TGA patterns of the crystalline form F of (2R, 3R, 4S)-2-(6-amino-9H-purin-9-yl)-2-(hydroxymethyl)-5-methylene tetrahydrofuran-3,4-diol described in the present application are shown in Figure 8 .

[0139] The TGA result shows that the crystalline form F has a weight loss of 0.6% during heating to 100°C, and possible decomposition above 195°C. The DSC result shows that the crystalline form F has an endothermic peak at about 185°C.

[0140] (4.3) Nuclear magnetic analysis (1H NMR)

[0141] The NMR of the crystalline form F is shown in Figure 9 .

[0142] The NMR result shows that the sample has no obvious solvent signal peak.

[0143] Based on the above results, it can be concluded that the crystalline form B of (2R, 3R, 4S)-2-(6-amino-9H-purin-9-yl)-2-(hydroxymethyl)-5-methylene tetrahydrofuran-3,4-diol in the present application is a hydrate, and its appearance is colorless and transparent. The crystalline form C is a dimethylformamide solvate. The crystalline form I is a metastable crystalline form, and no thermal analysis and NMR test are performed on the crystalline form I. The crystalline form F is an anhydrate, and its appearance is white.

[0144] (III) Dynamic water adsorption and desorption analysis (DVS)

[0145] The DVS result shows that the crystalline form B has a weight loss of 0.13% at 80% humidity, a weight loss of 2.33% at 95% humidity, and a weight loss of 2.66% at 0% humidity during the adsorption process, indicating that the crystalline form B has hygroscopicity. By comparing the XRPD patterns before and after the DVS test Figure 10 , it can be found that the crystalline form B has a crystalline form transition under high humidity conditions.

[0146] The DVS result shows that the crystalline form F has a weight gain of 2.01% at 95% humidity, a weight gain of 1.69% at 80% humidity, and a weight loss of 0.90% at 0% humidity during the adsorption process, indicating that the crystalline form F has slight hygroscopicity. By comparing the XRPD patterns before and after the DVS test Figure 11 , it can be found that the crystalline form F has no change in crystalline form after the DVS test.

[0147] (IV) Thermal transition experiment

[0148] The thermal transition experiment is performed on the crystalline form C, and the result is shown in Figure 12 , indicating that the crystalline form C is converted into the crystalline form F with poor crystallinity after being heated to 150°C and then cooled to room temperature.

[0149] (V) Stability Experiments

[0150] (1) Influence Factor Experiments

[0151] Pre-experiment: The pre-experiment of Form B, Form C, Form I and Form F at room temperature (25 °C for 1 day and 6 days) showed that Form C did not change in crystal form after 1 day at room temperature, but changed in crystal form after 6 days (as shown in Figure 13 ). Form I changed in crystal form after 1 day at room temperature (as shown in Figure 14 ), indicating that Form I is a metastable crystal form. Form B and Form F did not change in crystal form after 6 days at 25 °C.

[0152] Stability studies of Form B and Form F were carried out under high temperature (60 °C), high humidity (25 °C / 92.5% RH) and light (25 °C / 4500 Lux) conditions, and samples were taken at 7 days and 15 days, respectively, to observe the appearance, perform XRPD characterization and HPLC testing, and compare with the original sample. The results are shown in Tables 5, Figure 15 and Figure 16 . The results showed that Form B changed in crystal form under high humidity conditions for 7 days; under high temperature conditions for 7 days and 15 days, no crystal form change occurred, but the appearance of the sample changed from colorless and transparent to yellow, and the chemical purity was significantly reduced. The XRPD results showed that Form F was stable under high temperature, high humidity and light conditions for 15 days, without crystal form change, no change in appearance, color consistent with the original sample, and no significant change in chemical purity.

[0153] Table 5 Results of Influence Factor Experiments

[0154]

[0155]

[0156] (2) Accelerated Stability Experiments

[0157] Stability studies of Form B and Form F were carried out under accelerated (40 °C / 75% RH) conditions, and samples were taken at 7 days and 15 days, respectively, to observe the appearance, perform XRPD characterization and HPLC testing, and compare with the original sample. The results are shown in Tables 6, Figure 15 and Figure 16 , indicating that Form B changed in crystal form under accelerated conditions for 7 days, while Form F was stable under accelerated conditions for 15 days without crystal form change, and there was no significant change in appearance and chemical purity.

[0158] Table 6 Results of Accelerated Stability Experiments

[0159]

[0160] From the above experimental results, it can be concluded that, compared with crystal form B, crystal form C and crystal form I, the crystal form F of (2R, 3R, 4S)-2-(6-amino-9H-purin-9-yl)-2-(hydroxymethyl)-5-methylenetetrahydrofuran-3, 4-diol provided in the application has better stability, can remain stable under light, high temperature, high humidity and acceleration conditions, and can better meet the requirements of pesticides in production, processing, transportation and storage.

[0161] The crystal form provided in the application can be used as an effective ingredient in a prodrug or a parent drug, and the content of the crystal form in the prodrug or the parent drug can be 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 95%, etc.

[0162] The crystal form provided in the application can be used in liquid formulations (for example, water agent, oil agent, emulsion, dispersible liquid, etc.) or solid formulations (for example, powder, granule, large particle, fine particle, etc.) in specific use. In order to facilitate better use, at least one of a film-forming agent (for example, algin powder, sodium hydroxymethyl cellulose, chitin, etc.), a thickening agent (for example, xanthan gum, hydroxymethyl cellulose, gelatin, algin, gypsum, hydroxyethyl cellulose, methyl cellulose, magnesium aluminum silicate, polyvinyl alcohol), a dispersing agent (for example, Morwet D-425, Terspense-2500, naphthalene sulfonate, lignin sulfonate, polycarboxylate, etc.), a wetting agent (for example, sodium dodecyl sulfate, Morwet EFW, polyoxyethylene alkyl phenol ether, polyoxyethylene fatty alcohol ether, polyoxyethylene polyoxypropylene block copolymer, etc.), a surfactant (for example, sodium dodecyl benzene sulfonate, sodium dodecyl sulfonate, sodium dodecyl sulfate, sodium hexadecyl benzene sulfonate, sodium hexadecyl sulfonate, sodium hexadecyl sulfate, sodium octadecyl benzene sulfonate, sodium octadecyl sulfonate, Tween-80, etc.) can be added.

[0163] The above specific embodiments further illustrate the purpose, technical solutions and beneficial effects of the application, and it should be understood that the above description is only for specific embodiments of the application and is not used to limit the protection scope of the application. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the application should be included in the protection scope of the application.

Claims

1. A crystalline form of the compound (2R,3R,4S)-2-(6-amino-9H-purin-9-yl)-2-(hydroxymethyl)-5-methylenetetrahydrofuran-3,4-diol, characterized in that: Selected from Form F; wherein, The X-ray powder diffraction pattern of Form F using Cu-Kα radiation, expressed as 2θ values ​​±0.2°, has characteristic diffraction peaks including 7.43, 13.07, 13.69, and 14.

97.

2. The crystal form according to claim 1, characterized in that The X-ray powder diffraction pattern of Form F using Cu-Kα radiation, expressed as a 2θ value ±0.2°, also includes a characteristic diffraction peak at 17.

38.

3. The crystal form according to claim 1, characterized in that The characteristic diffraction peaks of the X-ray powder diffraction pattern of Form F expressed as 2θ values ​​±0.2° using Cu-Kα radiation also include any one or more of 15.26 and 15.

89.

4. The crystal form according to claim 1, characterized in that Form F is an anhydrate.

5. A technical drug or a parent drug, characterized in that: The original drug or mother drug contains the crystal form according to any one of claims 1 to 4.

6. The original drug or parent drug according to claim 5, characterized in that The weight percentage of the crystal form in the original drug or mother drug is 5-99.9%.

7. A pesticide composition, characterized in that The pesticide composition contains the crystal form according to any one of claims 1 to 4.

8. The pesticide composition according to claim 7, characterized in that The weight percentage of the crystal form in the pesticide composition is 0.001-50%.

9. A preparation, characterized in that The preparation contains the crystal form according to any one of claims 1 to 4.

10. The preparation according to claim 9, characterized in that The weight percentage of the crystal form in the preparation is 0.001-50%.

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

12. The preparation according to claim 9, characterized in that The dosage form of the preparation is selected from a sustained-release preparation.

13. The preparation according to claim 9, characterized in that The dosage form of the preparation is selected from a suspension.

14. The preparation according to claim 9, characterized in that The dosage form of the preparation is selected from a suspension seed coating agent.

15. The preparation according to claim 9, characterized in that The dosage form of the preparation 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.

16. The preparation according to claim 9, characterized in that The dosage form of the preparation is selected from any one of large granules, fine granules, microgranules, microcapsule granules, wettable powders, oil-dispersible powders, water-dispersible granules, emulsifiable granules, 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, film-spreading oils, ultra-low volume liquids, ultra-low volume microcapsule suspensions, emulsifiable concentrates, latexes, dispersible liquids, pastes, concentrated gels, aqueous emulsions, oil emulsions, microemulsions, ointments, microcapsule suspensions, oil suspensions, and suspoemulsions.

17. Use of the crystal form according to any one of claims 1 to 4, the technical or bulk drug according to any one of claims 5 to 6, the pesticide composition according to any one of claims 7 to 8, or the formulation according to any one of claims 9 to 16 in regulating plant growth.

18. Use of the crystal form according to any one of claims 1 to 4, the technical or bulk drug according to any one of claims 5 to 6, the pesticide composition according to any one of claims 7 to 8, or the formulation according to any one of claims 9 to 16 in the preparation of a plant growth regulator.

19. Use of the crystal form according to any one of claims 1 to 4, the technical or bulk drug according to any one of claims 5 to 6, the pesticide composition according to any one of claims 7 to 8, or the formulation according to any one of claims 9 to 16 in improving plant stress resistance.

20. Use of the crystal form according to any one of claims 1 to 4, the technical or bulk drug according to any one of claims 5 to 6, the pesticide composition according to any one of claims 7 to 8, or the formulation according to any one of claims 9 to 16 in the preparation of a product for improving plant stress resistance.

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