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 crystal form D and crystal form E; wherein the characteristic diffraction peak of the X-ray powder diffraction pattern of the crystal form D using Cu-K alpha radiation, expressed by a 2 theta value ± 0.2°, includes 5.16, 7.26, 14.53 and 17.52; the characteristic diffraction peak of the X-ray powder diffraction pattern of the crystal form E using Cu-K alpha radiation, expressed by a 2 theta value ± 0.2°, includes 5.06, 7.18, 13.59 and 14.45. The crystal form has good stability and can maintain stability 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 at present, 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 existing 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 a 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 D, crystal form E, or a mixture of the two; wherein,

[0006] The characteristic diffraction peak of the X-ray powder diffraction pattern of crystal form D using Cu-Kα radiation includes 5.16, 7.26, 14.53, 17.52, expressed in 2θ value ± 0.2°;

[0007] The characteristic diffraction peak of the X-ray powder diffraction pattern of crystal form E using Cu-Kα radiation includes 5.06, 7.18, 13.59, 14.45, expressed in 2θ value ± 0.2°.

[0008] Alternatively, the characteristic diffraction peak of the X-ray powder diffraction pattern of crystal form D using Cu-Kα radiation further includes any one or more of 15.44, 15.63, expressed in 2θ value ± 0.2°;

[0009] The characteristic diffraction peak of the X-ray powder diffraction pattern of crystal form E using Cu-Kα radiation further includes any one or more of 15.32, 15.57, expressed in 2θ value ± 0.2°.

[0010] Alternatively, the characteristic diffraction peak of the X-ray powder diffraction pattern of crystal form D using Cu-Kα radiation further includes any one or more of 17.34, 17.99, expressed in 2θ value ± 0.2°.

[0011] The characteristic diffraction peaks of the X-ray powder diffraction pattern of Form E expressed as 2θ values ​​±0.2° using Cu-Kα radiation also include any one or more of 17.27 and 17.89.

[0012] Optionally, Form D and / or Form E is a solvate.

[0013] According to another aspect of the present application, a raw material or a mother drug is provided, wherein the raw material or the mother drug contains the above-mentioned crystal form.

[0014] Optionally, the weight percentage of the crystal form in the original drug or mother drug is 5-99.9%.

[0015] According to another aspect of the present application, a preparation or pesticide composition is provided, wherein the preparation or pesticide composition contains the above-mentioned crystal form.

[0016] Optionally, the weight percentage of the crystal form in the formulation or pesticide composition is 0.001-50%.

[0017] Optionally, the formulation or pesticide composition contains the above-mentioned crystal form and adjuvant.

[0018] 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, emulsifiable granules, 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, latexes, 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, seed treatment liquids, seed treatment emulsions, seed treatment suspensions, suspended seed coatings, and microcapsule suspensions for seed treatment.

[0019] According to another aspect of the present application, there is provided the use of the aforementioned crystal form, the aforementioned technical or parent drug, or the aforementioned preparation or pesticide composition in regulating plant growth.

[0020] According to another aspect of the present application, there is provided the use of the aforementioned crystal form, the aforementioned technical or parent drug, or the aforementioned preparation or pesticide composition in the preparation of a plant growth regulator.

[0021] According to another aspect of the present application, there is provided the use of the aforementioned crystal form, the aforementioned technical or mother drug, or the aforementioned preparation or pesticide composition in improving plant stress resistance.

[0022] According to another aspect of the present application, there is provided use of the crystal form, the prodrug or the drug as described above, or the preparation or the pesticide composition as described above in the preparation of a product for improving plant stress resistance.

[0023] The positive progress effect of the present application is that:

[0024] The crystal form D and the crystal form E provided by the present application have 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

[0025] Figure 1 The XRPD pattern of the crystal form B, wherein the abscissa is 2θ (°) and the ordinate is intensity (counts);

[0026] Figure 2 The XRPD pattern of the crystal form I, wherein the abscissa is 2θ (°) and the ordinate is intensity (counts);

[0027] Figure 3 The XRPD pattern of the crystal form E, wherein the abscissa is 2θ (°) and the ordinate is intensity (counts);

[0028] Figure 4 The XRPD pattern of the crystal form D, wherein the abscissa is 2θ (°) and the ordinate is intensity (counts);

[0029] Figure 5 The DSC spectrum and the TGA spectrum of the crystal form B;

[0030] Figure 6 The DSC spectrum and the TGA spectrum of the crystal form E;

[0031] Figure 7 The DSC spectrum and the TGA spectrum of the crystal form D;

[0032] Figure 8 The NMR spectrum of the crystal form E;

[0033] Figure 9 The NMR spectrum of the crystal form D;

[0034] Figure 10 The XRPD patterns of the crystal form B before and after DVS test;

[0035] Figure 11 The XRPD patterns of the crystal form E before and after DVS test;

[0036] Figure 12 The results of the room temperature stability test of the crystal form I;

[0037] Figure 13Stability test results for Form B

[0038] Figure 14 Stability test results for Form E. DETAILED DESCRIPTION

[0039] The term "crystalline form" refers to a single crystalline 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 crystalline forms of (2R,3R,4S)-2-(6-amino-9H-purin-9-yl)-2-(hydroxymethyl)-5- methylenetetrahydrofuran-3,4-diol.

[0040] The term "other crystalline form different from Form D" refers to a crystalline form of (2R,3R,4S)-2-(6-amino-9H-purin-9-yl)-2-(hydroxymethyl)-5-methylenetetrahydrofuran- 3,4-diol described herein that is different from Form D. Other similar expressions have similar meanings.

[0041] The term "solvate" refers to those forms of the crystalline form of the compound described herein that form a complex with a molecule of a solvent (such as water, an organic solvent such as methanol, ethanol, formic acid, toluene, etc.) through coordination. Hydrates are a specific form of solvates in which coordination occurs with water. For example, a solvate can be a hydrate, an alcohol solvate, etc.

[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 "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.

[0044] 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.

[0045] The term "C1-C6alkyl alcohol" refers to a straight-chain or branched alkyl alcohol having 1-6 carbon atoms, i.e., a C1-C6alkyl group having a hydroxyl (OH) group. Examples thereof include, but are not limited to, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, n-pentanol, 2-pentanol, 3-pentanol, n-hexanol, etc.

[0046] The term "adjuvant" refers to a single component or a plurality of components that are added to a pesticide product in addition to the active ingredient, which do not have a pesticidal activity and a function of the active ingredient themselves, but can or help to improve the physicochemical properties of the pesticide product.

[0047] The term "plant growth regulator" refers to a compound that has the action of regulating the developmental program of a plant, causing changes in the growth and development of the plant. Examples include, but are not limited to, compounds that promote or inhibit germination, rooting, flower bud differentiation, flowering, fruiting, leaf abscission, and the like.

[0048] The term "improving plant stress tolerance" refers to improving the adaptation of a plant to a stressful environment. Examples include, but are not limited to, improving the ability of a plant to withstand cold, salt, alkaline, and drought stress, and the like.

[0049] 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 D or Form E.

[0050] 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 D and / or Form E. 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 D, Form E and optionally one or more other crystalline forms different from Form D, Form E. 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 D, Form E and optionally one or more other crystalline forms different from Form D, Form E 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 D, Form E and one or more other crystalline forms different from Form E, Form B and Form I. 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 D, Form E 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 D, Form E, Form B and one or more other crystalline forms different from Form D, Form E 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 D, Form E, Form B and one or more other crystalline forms different from Form D, Form E, Form B and Form I. 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 D, Form E, Form B and Form I and one or more other crystalline forms different from Form D, Form E, Form B and Form I.

[0051] In one embodiment, the crystalline Form D or Form E of (2R, 3R, 4S)-2-(6-amino-9H-purin-9-yl)-2-(hydroxymethyl)-5-methylenetetrahydrofuran-3,4-diol described herein can be a hydrate or an alcohol solvate. Preferably, the crystalline Form D or Form E can be a Ci-C6alkyl alcohol solvate. Preferably, the crystalline Form D is a methanol solvate and the crystalline Form E is an ethanol solvate.

[0052] In one embodiment, the crystalline Form B of (2R, 3R, 4S)-2-(6-amino-9H-purin-9-yl)-2-(hydroxymethyl)-5-methylenetetrahydrofuran-3,4-diol described herein has an X-ray powder diffraction pattern, expressed in terms of 2-theta values ± 0.2°, comprising any three or more of 5.00, 5.60, 9.69, 14.56 using Cu-Ka radiation. Preferably, it further comprises any one or more of 4.38, 15.07, 16.76. Preferably, it further comprises any one or more of 15.34, 17.58, 17.58, 17.58.

[0053] In one embodiment, the thermogravimetric analysis pattern of the crystalline Form B has a weight loss of 8.9% during heating to 195°C ± 2°C, and decomposition can occur above 200°C.

[0054] In one embodiment, the differential scanning calorimetry pattern of the crystalline Form B has a broad endothermic signal around 90°C ± 2°C, and endothermic peaks at around 169°C ± 2°C and 189°C ± 2°C.

[0055] In one embodiment, the crystalline Form I of (2R, 3R, 4S)-2-(6-amino-9H-purin-9-yl)-2-(hydroxymethyl)-5-methylenetetrahydrofuran-3,4-diol described herein has an X-ray powder diffraction pattern, expressed in terms of 2-theta values ± 0.2°, comprising 11.32, 13.07, 14.21 using Cu-Ka radiation. Preferably, it further comprises 15.59, 16.97, 17.27. Preferably, it further comprises 5.66, 7.14, 10.70.

[0056] In one embodiment, the crystalline Form D of (2R, 3R, 4S)-2-(6-amino-9H-purin-9-yl)-2- (hydroxymethyl)-5-methylenetetrahydrofuran-3,4-diol described herein has an X-ray powder diffraction pattern, expressed in terms of 2-theta values ± 0.2°, using Cu-Ka radiation, comprising the following main characteristic diffraction peaks: 5.16, 7.26, 14.53, 17.52. Preferably, it further comprises any one or more of 15.44, 15.63. Preferably, it further comprises any one or more of 17.34, 17.99. Preferably, it further comprises any one or more of 16.1, 17.03. Preferably, it further comprises any one or more of 13.92, 18.18.

[0057] In one embodiment, the crystalline Form E of (2R, 3R, 4S)-2-(6-amino-9H-purin-9-yl)-2- (hydroxymethyl)-5-methylenetetrahydrofuran-3,4-diol described herein has an X-ray powder diffraction pattern, expressed in terms of 2-theta values ± 0.2°, using Cu-Ka radiation, comprising the following main characteristic diffraction peaks: 5.06, 7.18, 13.59, 14.45. Preferably, it further comprises any one or more of 15.32, 15.57. Preferably, it further comprises any one or more of 17.27, 17.89. Preferably, it further comprises any one or more of 15.98, 17.11. Preferably, it further comprises any one or more of 16.84, 20.82.

[0058] In one embodiment, the thermal gravimetric analysis profile of the crystalline Form D has no weight loss up to 110°C, 4.6% weight loss between 110°C and 195°C, and possible decomposition above 200°C.

[0059] In one embodiment, the differential scanning calorimetry profile of the crystalline Form D has an endothermic peak around 193°C.

[0060] In one embodiment, the thermal gravimetric analysis profile of the crystalline Form E has 1.1% weight loss up to 100°C, 5.3% weight loss between 100 and 185°C, and possible decomposition above 190°C.

[0061] In one embodiment, the differential scanning calorimetry profile of the crystalline Form E has an endothermic peak around 180°C and an exothermic peak around 189°C.

[0062] In one embodiment, the crystalline Form D or Form E provided herein can be prepared by using a solvent room temperature suspension method or a solvent cooling method.

[0063] Preferably, the single solvent room temperature suspension method comprises:

[0064] The sample is added to the solvent and left to suspend at room temperature for 5-8 days, centrifuged, and vacuumed. The solvent can be selected from at least one of methanol, ethanol.

[0065] Preferably, the solvent cooling method comprises:

[0066] The sample is added to the solvent which has been pre-heated (e.g. 40-70 °C) and quickly transferred to room temperature to cool to solid precipitation, centrifuged, and dried. The solvent can be selected from at least one of methanol, ethanol.

[0067] In one embodiment, the present application provides a formulation or a pesticide composition containing the crystal form described in the present application, preferably, the weight percentage of the crystal form in the formulation is 0.1-50.0%, for example, the weight percentage of the crystal form in the formulation is 0.1%, 0.5%, 5%, 10%, 20%, 30% or 40%. Preferably, the weight percentage of the crystal form in the formulation is 0.1%-0.5%, 0.5-1%, 0.5-10% or 20-40%. Preferably, the weight percentage of the crystal form in the formulation or pesticide composition is 0.1-20%. Preferably, the weight percentage of the crystal form in the formulation or pesticide composition is 0.1-10%. Preferably, the weight percentage of the crystal form in the formulation or pesticide composition is 0.1-8%. Preferably, the weight percentage of the crystal form in the formulation or pesticide composition is 0.1-5%.

[0068] In one embodiment, the present application provides a formulation or a pesticide composition containing the crystal form described in the present application, preferably, the weight percentage of the crystal form in the formulation is 0.1-50.0%, for example, the weight percentage of the crystal form in the formulation is 0.1%, 0.5%, 5%, 10%, 20%, 30% or 40%. Preferably, the weight percentage of the crystal form in the formulation is 0.1%-0.5%, 0.5-1%, 0.5-10% or 20-40%. Preferably, the weight percentage of the crystal form in the formulation or pesticide composition is 0.1-20%. Preferably, the weight percentage of the crystal form in the formulation or pesticide composition is 0.1-10%. Preferably, the weight percentage of the crystal form in the formulation or pesticide composition is 0.1-8%. Preferably, the weight percentage of the crystal form in the formulation or pesticide composition is 0.1-5%. Specific embodiments:

[0070] All commercially available reagents and solvents were used without further purification.

[0071] The sample in the examples was detected according to the following method.

[0072] 1. X-ray powder diffraction (XRPD)

[0073] 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.

[0074] 2. Differential scanning calorimetry analysis (DSC)

[0075] The differential scanning calorimetry analyzer was a TA Discovery 2500 (TA, US). After 1-2 mg of the sample was accurately weighed, it was placed in a perforated DSC Tzero sample disc and heated to the final temperature at a rate of 10 °C / min, with a nitrogen purge speed of 50 mL / min in the furnace.

[0076] 3. Thermogravimetric analysis (TGA)

[0077] The thermogravimetric analyzer was a TA Discovery 55 (TA, US). 2-5 mg of the sample was placed in an open aluminum sample disc that had been equilibrated and was automatically weighed in the TGA heating furnace. The sample was heated to the final temperature at a rate of 10 °C / min, with a nitrogen purge speed of 60 mL / min at the sample and a nitrogen purge speed of 40 mL / min at the balance.

[0078] 4. Nuclear magnetic resonance analysis (1H NMR)

[0079] Several milligrams of the solid sample were dissolved in dimethyl sulfoxide-d6 solvent, and nuclear magnetic resonance analysis was performed on a Bruker AVANCE NEO 400 (Bruker, GER).

[0080] 5. Dynamic vapor sorption analysis (DVS)

[0081] The 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 point of the gradient was determined using the 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.

[0082] 6. Stability study

[0083] (1) Influencing factor experiment

[0084] Take 20 mg of sample into a weighing bottle, and place it in an open state under high temperature (60℃), high humidity (25℃ / 92.5% RH) or light (25℃ / 4500 Lux), respectively. Take samples at 7 days and 15 days, observe the appearance, perform XRPD characterization and HPLC test, and compare with the original sample.

[0085] (2) Accelerated stability experiment

[0086] Take 20 mg of sample into a weighing bottle, and place it in an open state under high temperature (60℃), high humidity (25℃ / 92.5% RH) or light (25℃ / 4500 Lux), respectively. Take samples at 7 days and 15 days, observe the appearance, perform XRPD characterization and HPLC test, and compare with the original sample.

[0087] 7. High performance liquid chromatography (HPLC)

[0088] Mobile phase: acetonitrile / 0.1% phosphoric acid water (volume ratio 5:95)

[0089] Chromatographic column: Poroshell 120 EC-C18 reversed-phase chromatographic column

[0090] Detection wavelength: 261 nm

[0091] Flow rate: 1.0 mL / min

[0092] Column temperature: 25℃

[0093] Injection volume: 10 μL

[0094] (I) Preparation Example

[0095] Example 1: Preparation of (2R, 3R, 4S)-2-(6-amino-9H-purin-9-yl)-2- (hydroxymethyl)-5-methylenetetrahydrofuran-3, 4-diol sample

[0096] Under sterile conditions, the Streptomyces caniferus NEAU6, which has been activated on Gause I agar medium, was scraped and transferred to seed medium, and cultured at 30℃, 200 rpm for 2 days. Then the seed liquid was inoculated into fermentation medium at 6% (v / v), and cultured at 30℃, 200 rpm for 5 days.

[0097] The fermentation broth was centrifuged to remove the bacterial cells, and the supernatant was extracted with an equal volume of ethyl acetate four times, and then subjected to silica gel column chromatography, gel chromatography and C-18 column chromatography in turn. After chromatography, the (2R, 3R, 4S)-2-(6-amino-9H-purin-9-yl)-2-(hydroxymethyl)-5-methylenetetrahydrofuran-3, 4-diol sample was obtained, and the XRPD was as shown in Figure 1 , which was named as crystal form B.

[0098] Example 2: Preparation of Form I

[0099] A sample of (2R,3R,4S)-2-(6-amino-9H-purin-9-yl)-2-(hydroxymethyl)-5- methylenetetrahydrofuran-3,4-diol prepared in Example 1 was weighed out at 15 mg, and after addition of 0.5 mL of ethyl acetate was heated to 50°C, and 1.4 mL of preheated tetrahydrofuran was added dropwise until the solution was clear. The solution was left to cool at room temperature, and then was placed at -15°C to precipitate the solid. The system with the solid precipitated was centrifuged, and the solid was dried at room temperature under vacuum. The XRPD, as shown in Figure 2 , was assigned to Form I.

[0100] Example 3: Preparation of Form E

[0101] A sample of (2R,3R,4S)-2-(6-amino-9H-purin-9-yl)-2-(hydroxymethyl)-5- methylenetetrahydrofuran-3,4-diol prepared in Example 1 was weighed out at 15 mg, and a suspension was prepared by addition of 0.8 mL of ethanol, and was stirred at 50°C for 24 h. The supernatant was removed by centrifugation, and the solid was dried at room temperature under vacuum. The XRPD, as shown in Figure 3 , was assigned to Form E.

[0102] Example 4: Preparation of Form D

[0103] A sample of (2R,3R,4S)-2-(6-amino-9H-purin-9-yl)-2-(hydroxymethyl)-5- methylenetetrahydrofuran-3,4-diol prepared in Example 1 was weighed out at 20 mg, and 1.7 mL of preheated methanol was added dropwise at 50°C. After complete dissolution of the solid, the solution was cooled at room temperature, left to stand for 2 h, and was centrifuged and dried under vacuum. The XRPD, as shown in Figure 4 , was assigned to Form D.

[0104] (B) Basic characterization of the forms

[0105] (1) Analysis of the XRPD diffraction peak data

[0106] The XRPD diffraction peak data of Form B are shown in Table 1; the XRPD diffraction peak data of Form I are shown in Table 2; the XRPD diffraction peak data of Form E are shown in Table 3, and the XRPD diffraction peak data of Form D are shown in Table 4.

[0107] Table 1 XRPD diffraction peak data of Form B

[0108]

[0109]

[0110]

[0111] As can be seen from Table 1, the main characteristic peaks of the X-ray powder diffraction pattern of Form B using Cu-Ka radiation expressed in terms of 2-theta values ± 0.2° include any three or more of 5.00, 5.60, 9.69, 14.56. Preferably, any one or more of 4.38, 15.07, 16.76 are also included. Preferably, any one or more of 15.34, 17.58 are also included.

[0112] Table 2 XRPD diffraction peak data for Form I

[0113]

[0114]

[0115] As can be seen from Table 2, the main characteristic 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, 15.59, 16.97, 17.27 are also included. Preferably, 5.66, 7.14, 10.70 are also included.

[0116] Table 3 XRPD diffraction peak data for Form E

[0117]

[0118]

[0119] As can be seen from Table 3, the main characteristic peaks of the X-ray powder diffraction pattern of Form E using Cu-Ka radiation expressed in terms of 2-theta values ± 0.2° include 5.06, 7.18, 13.59, 14.45. Preferably, any one or more of 15.32, 15.57 are also included. Preferably, any one or more of 17.27, 17.89 are also included. Preferably, any one or more of 15.98, 17.11 are also included. Preferably, any one or more of 16.84, 20.82 are also included.

[0120] Table 4 XRPD diffraction peak data for Form D

[0121]

[0122]

[0123]

[0124] As shown in Table 4, the main characteristic diffraction peaks of the X-ray powder diffraction pattern of crystalline Form D using Cu-Ka radiation expressed in terms of 2 theta values ± 0.2° include 5.16, 7.26, 14.53, 17.52. Preferably, any one or more of 15.44, 15.63 are also included. Preferably, any one or more of 17.34, 17.99 are also included. Preferably, any one or more of 16.1, 17.03 are also included. Preferably, any one or more of 13.92, 18.18 are also included.

[0125] (2) Differential scanning calorimetry analysis (DSC) and thermogravimetric analysis (TGA)

[0126] The DSC pattern and TGA pattern of (2R, 3R, 4S)-2-(6-amino-9H-purin-9-yl)-2- (hydroxymethyl)-5-methylene tetrahydrofuran-3, 4-diol crystalline Form B described in the present application are as shown in Figure 5 The DSC pattern and TGA pattern of (2R, 3R, 4S)-2-(6-amino-9H-purin-9-yl)-2- (hydroxymethyl)-5-methylene tetrahydrofuran-3, 4-diol crystalline Form B described in the present application are as shown in Figure 6 The DSC pattern and TGA pattern of (2R, 3R, 4S)-2-(6-amino-9H-purin-9-yl)-2- (hydroxymethyl)-5-methylene tetrahydrofuran-3, 4-diol crystalline Form B described in the present application are as shown in Figure 7 The DSC pattern and TGA pattern of (2R, 3R, 4S)-2-(6-amino-9H-purin-9-yl)-2- (hydroxymethyl)-5-methylene tetrahydrofuran-3, 4-diol crystalline Form B described in the present application are as shown in

[0127] The TGA result shows that crystalline Form B has a weight loss of 8.9% during heating to 195°C, and possible decomposition above 200°C. The DSC result shows that crystalline Form B has a broad endothermic signal around 90°C, and endothermic peaks at around 169°C and 189°C.

[0128] The TGA result shows that crystalline Form E has a weight loss of 1.1% during heating to 100°C, a weight loss of 5.3% during heating from 100 to 185°C, and possible decomposition above 190°C. The DSC result shows that crystalline Form E has an endothermic peak at around 180°C, and an exothermic peak at around 189°C.

[0129] The TGA result shows that crystalline Form D has no weight loss during heating to 110°C, a weight loss of 4.6% during heating from 110 to 195°C, and possible decomposition above 200°C. The DSC result shows that crystalline Form D has an endothermic peak at around 193°C.

[0130] (3) Nuclear magnetic resonance analysis (1H NMR)

[0131] NMR shows that crystalline Form B has no obvious organic solvent signal peak.

[0132] NMR result (as shown in Figure 8The NMR result (as shown) shows that the crystalline form E has signal peaks of ethanol at 4.35 ppm, 3.44 ppm and 1.05 ppm. According to the integral result, the ratio of (2R, 3R, 4S)-2-(6-amino-9H-purin-9-yl)-2-(hydroxymethyl)-5-methylenetetrahydrofuran-3,4-diol to ethanol is 1:0.3, and the estimated mass ratio is 4.7%, which is close to the weight loss of TGA.

[0133] The NMR result (as shown) shows that the crystalline form D has signal peaks of methanol at 4.10 ppm and 3.17 ppm. According to the integral result, the ratio of (2R, 3R, 4S)-2-(6-amino-9H-purin-9-yl)-2-(hydroxymethyl)-5-methylenetetrahydrofuran-3,4-diol to methanol is 1:0.4, and the estimated mass ratio is about 4.4%, which is close to the weight loss of TGA. Figure 9 Based on the above results, it can be concluded that:

[0134] 1) The crystalline form B is a hydrate, which is colorless and transparent;

[0135] 2) The crystalline form I is a metastable form, and no thermal analysis and NMR test are performed on the crystalline form I;

[0136] 3) The crystalline form E is an ethanol solvate, which is white;

[0137] 4) The crystalline form D is a methanol solvate, which is white.

[0138] (III) Dynamic water adsorption and desorption analysis (DVS)

[0139] 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 (as shown) before and after the DVS test, it can be found that the crystalline form B undergoes a crystal transformation under high humidity conditions.

[0140] Figure 10 The DVS result shows that the crystalline form E has a weight gain of 1.22% at 95% humidity, a weight gain of 0.41% at 80% humidity, and a weight loss of 1.42% at 0% humidity during the adsorption process, indicating that the crystalline form E has slight hygroscopicity.

[0141] The XRPD result (as shown) shows that the crystalline form E sample after the DVS test does not undergo a crystal change. Figure 11 The DVS result shows that the crystalline form D is similar to the crystalline form E, which has slight hygroscopicity, and the crystal form does not change before and after the DVS test.

[0142] (IV) Stability determination

[0143] ​​

[0144] (1) Influence factor experiment

[0145] Pre-experiment: The pre-experiment (25℃ for 1 day and 6 days) of Form B, Form I, Form E and Form D showed that Form I was transformed into another crystal form at room temperature for 1 day (as shown in Figure 12 ), indicating that Form I was a metastable crystal form. While Form B, Form E and Form D were not transformed into another crystal form at 25℃ for 6 days.

[0146] The stability of Form B and Form E under high temperature (60℃), high humidity (25℃ / 92.5% RH) and light (25℃ / 4500 Lux) conditions was studied, and samples were taken at 7 days and 15 days for XRPD characterization and HPLC testing, respectively. The results are shown in Table 5, Figure 13 and Figure 14 .

[0147] The XRPD results showed that Form B was transformed into another crystal form under high humidity conditions for 7 days; under high temperature conditions for 7 days and 15 days, no crystal transformation occurred, but the appearance of the sample changed from colorless and transparent to yellow, and the chemical purity was significantly reduced.

[0148] The XRPD results showed that Form E was stable under high temperature, high humidity and light conditions for 15 days, without crystal transformation, no significant change in chemical purity, and no change in appearance, still maintaining the original white color.

[0149] The XRPD results showed that Form D was similar to Form E, stable under high temperature, high humidity and light conditions for 15 days, without crystal transformation, no significant change in chemical purity, and no change in appearance, still maintaining the original white color.

[0150] Table 5 Results of influence factor experiment

[0151]

[0152] (2) Accelerated stability experiment

[0153] The stability of Form B and Form E under accelerated (40℃ / 75% RH) conditions was studied, 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 Table 6, Figure 13 and Figure 14 , indicating that Form B was transformed into another crystal form under accelerated conditions for 7 days, Form E was stable under accelerated conditions for 15 days without crystal transformation, and the chemical purity did not change significantly.

[0154] The accelerated stability experiment results show that the crystal form D is similar to the crystal form E, and no crystal form conversion occurs and no significant change in chemical purity occurs under the accelerated condition for 15 days.

[0155] Table 6 Accelerated stability experiment results

[0156]

[0157] It can be seen that the crystal form D and the crystal form E of (2R, 3R, 4S)-2-(6-amino-9H-purin-9-yl)-2-(hydroxymethyl)-5-methylenetetrahydrofuran-3, 4-diol provided in the present application have more excellent stability compared with the crystal form B and the crystal form I, and can be well maintained under the conditions of light, high temperature, high humidity and acceleration, and can better meet the requirements of pesticides in production, processing, transportation and storage.

[0158] The crystal form provided in the present application can be used as an effective component 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.

[0159] In order to facilitate better use, at least one of a film forming agent (for example, algin powder, sodium hydroxymethyl cellulose, chitin, 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 thickening agent (for example, xanthan gum, hydroxymethyl cellulose, gelatin, seaweed, gypsum, hydroxyethyl cellulose, methyl cellulose, magnesium aluminum silicate, polyvinyl alcohol), a surfactant (for example, sodium dodecylbenzenesulfonate, sodium dodecylsulfonate, sodium dodecyl sulfate, sodium hexadecylbenzenesulfonate, sodium hexadecylsulfonate, sodium hexadecyl sulfate, sodium octadecylbenzenesulfonate, sodium octadecylsulfonate, Tween-80, etc.), a dispersing agent (for example, Morwet D-425, Terspense-2500, naphthalene sulfonate, lignin sulfonate, polycarboxylate, etc.) can be added to the crystal form, so as to be made into or solid formulations (for example, powder, granules, large granules, fine granules, etc.) or liquid formulations (for example, water, oil, emulsion, dispersible liquid, etc.).

[0160] The above specific embodiments further illustrate the purpose, technical solutions and advantages of the present application, and it should be understood that the above description is only for specific embodiments of the present application, and is not used to limit the protection scope of the present application, and any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application should be included in the protection scope of the present 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: It is selected from one of crystal form D and crystal form E, or a mixture of the two; wherein, The characteristic diffraction peaks of the X-ray powder diffraction pattern of Form D using Cu-Kα radiation expressed as 2θ values ​​±0.2° include 5.16, 7.26, 14.53, and 17.52; The X-ray powder diffraction pattern of Form E using Cu-Kα radiation, expressed as 2θ values ​​±0.2°, has characteristic diffraction peaks including 5.06, 7.18, 13.59, 14.45, and 15.

98.

2. The crystal form according to claim 1, characterized in that The characteristic diffraction peaks of the X-ray powder diffraction pattern of Form D using Cu-Kα radiation expressed as 2θ values ​​±0.2° also include any one or more of 15.44 and 15.63; The characteristic diffraction peaks of the X-ray powder diffraction pattern of Form E expressed as 2θ values ​​±0.2° using Cu-Kα radiation also include any one or more of 15.32 and 15.

57.

3. The crystal form according to claim 1, characterized in that The characteristic diffraction peaks of the X-ray powder diffraction pattern of Form D using Cu-Kα radiation expressed as 2θ values ​​±0.2° also include any one or more of 17.34 and 17.99; The characteristic diffraction peaks of the X-ray powder diffraction pattern of Form E expressed as 2θ values ​​±0.2° using Cu-Kα radiation also include any one or more of 17.27 and 17.

89.

4. The crystal form according to claim 1, characterized in that Crystalline Form D and / or Crystalline Form E is a solvate.

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.

Images