New crystal form of quinazoline compound

Abstract

According to the novel crystal form of the quinazoline compound and the preparation method of the novel crystal form, by means of the preparation method, the dissolution limit of a product meets the requirement, the dissolution rate and the dissolution amount of the obtained product are high, and the novel crystal form is suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry, and in particular to new crystal forms A, B and C of quinazoline compounds and a preparation method thereof. Background Art

[0002] The compound of formula (I) is a VEGFR inhibitor of quinazoline structure, its chemical name is 6-(6,7-dimethoxyquinazoline-4-oxo)-N,2-dimethylbenzofuran-3-carboxamide, and its chemical structure is as follows:

[0003]

[0004] Patent CN110981910B applied for by Hutchison Whampoa Pharmaceuticals discloses the crystalline forms I, II, III, IV, VII and VIII of the compound of formula (I), wherein the crystalline forms II, IV and VIII are all solvate crystalline forms, and the crystalline forms I, III and VII are anhydrous crystals.

[0005] Compounds can exist in a variety of crystal forms. The crystal structure of compounds that are active ingredients often affects the chemical and physical stability of the drug. Different crystal forms, preparation methods, and storage conditions may lead to changes in the crystal structure of the compound, and sometimes other forms of crystals may be produced. The physical and chemical properties of different crystal forms are slightly different, which will also affect the efficacy and stability of the final drug. Therefore, it is necessary to improve the properties of the compound in all aspects, and in-depth research is needed to find new crystal forms with good physical and chemical stability. Summary of the invention

[0006] In one aspect, the present invention provides a crystalline form A of a compound of formula (I),

[0007] The structure of the compound of formula (I) is:

[0008]

[0009] The X-ray powder diffraction pattern of the crystalline form A has characteristic diffraction peaks at the following 2θ angles: 10.7±0.2°, 11.8±0.2°, 13.1±0.2° or 14.5±0.2°.

[0010] In some embodiments, the X-ray powder diffraction pattern of the crystalline form A has characteristic diffraction peaks at the following 2θ angles: 9.9±0.2°, 10.7±0.2°, 11.8±0.2°, 13.1±0.2°, 14.5±0.2°, 18.4±0.2°, 18.7±0.2°, 19.2±0.2° or 22.6±0.2°.

[0011] In some embodiments, the X-ray powder diffraction pattern of the crystalline form A has characteristic diffraction peaks at the following 2θ angles: 9.9±0.2°, 10.7±0.2°, 11.8±0.2°, 13.1±0.2°, 14.5±0.2°, 18.4±0.2°, 18.7±0.2°, 19.2±0.2°, 22.6±0.2°, 23.8±0.2°, 25.5±0.2° or 26.5±0.2°.

[0012] In some embodiments, the X-ray powder diffraction pattern of the crystalline form A has characteristic diffraction peaks at the following 2θ angles: 9.9±0.2°, 10.7±0.2°, 11.8±0.2°, 13.1±0.2°, 14.5±0.2°, 15.0±0.2°, 18.4±0.2°, 18.7±0.2°, 19.2±0.2°, 21.5±0.2°, 22.6±0.2°, 22.9±0.2°, 23.8±0.2°, 25.5±0.2° or 26.5±0.2°.

[0013] In some embodiments, the X-ray powder diffraction pattern of the crystalline form A has characteristic diffraction peaks at the following 2θ angles: 3.7±0.2°, 9.3±0.2°, 9.9±0.2°, 10.7±0.2°, 11.8±0.2°, 13.1±0.2°, 14.5±0.2°, 15.0±0.2°, 18.4±0.2°, 18.7±0.2°, 19.2±0.2°, 21.5±0.2°, 22.6±0.2°, 22.9±0.2°, 23.8±0.2°, 25.5±0.2° or 26.5±0.2°.

[0014] In some embodiments, the X-ray powder diffraction pattern of Form A is as follows Figure 1 As shown, it has Figure 1 The features represented by the X-ray powder diffraction pattern shown. Despite the existence of experimental errors, instrument errors and orientation preferences, a person skilled in the art can still obtain sufficient information for identifying the crystalline form A and other crystalline forms of the compound of formula (I) from the XRPD data provided in this patent.

[0015] In some embodiments, the DSC spectrum of the crystalline form A is as follows Figure 2 As shown, it has Figure 2 The DSC spectra shown represent the characteristics.

[0016] In some embodiments, the crystalline form A of the compound of formula (I) is substantially free of other crystalline forms described herein. For example, the weight content of the crystalline form A of the compound of formula (I) is at least 99%, at least 95%, at least 90%, or lower to 80%. Alternatively, the weight content of the crystalline form A of the compound of formula (I) is at least 70%, or at least 60%. Or further, the weight content of the crystalline form A of the compound of formula (I) is at least 50%.

[0017] In another aspect, the present invention also provides a method for preparing the crystalline form A, comprising: grinding or pulverizing the compound of formula (I) after recrystallization.

[0018] In some embodiments, in the method for preparing the above-mentioned crystalline form A, the recrystallization step is to dissolve the compound of formula (I) in a dissolving solvent, filter, and then add the filtrate to an anti-dissolving solvent to precipitate a solid.

[0019] In some embodiments, in the method for preparing the above-mentioned crystal form A, the filtration step uses a filter membrane for filtration.

[0020] In some embodiments, in the method for preparing the above-mentioned crystal form A, the dissolving solvent is selected from a mixed solvent of methanol and dichloromethane, dichloromethane or chloroform.

[0021] In some embodiments, in the preparation method of the above-mentioned crystalline form A, the volume mass ratio of the compound of formula (I) and the dissolving solvent is selected from 30 to 70 mL / g; in some typical embodiments, the volume mass ratio of the compound of formula (I) and the dissolving solvent is selected from 30 mL / g or 60 to 70 mL / g.

[0022] In some embodiments, in the method for preparing the above-mentioned crystalline form A, the anti-dissolving solvent is selected from methyl tert-butyl ether or cyclohexane.

[0023] In some embodiments, in the method for preparing the above-mentioned crystal form A, the volume ratio of the anti-dissolving solvent to the dissolving solvent is selected from 2 to 6: 1. In some typical embodiments, in the method for preparing the above-mentioned crystal form A, the volume ratio of the anti-dissolving solvent to the dissolving solvent is selected from 3 to 6: 1.

[0024] In some embodiments, in the method for preparing the above-mentioned crystal form A, the filtrate is added to the anti-dissolution solvent at a temperature below zero. In some typical embodiments, in the method for preparing the above-mentioned crystal form A, the filtrate is added to the anti-dissolution solvent at a temperature of less than or equal to -10°C.

[0025] In some embodiments, the method for preparing the above-mentioned crystal form A further comprises a step of stirring after recrystallization.

[0026] In some embodiments, the method for preparing the above-mentioned crystal form A further comprises the step of stirring for 0.5 to 3 hours after recrystallization. In some typical embodiments, the method further comprises the step of stirring for 0.5 to 2 hours after recrystallization.

[0027] In some embodiments, the method for preparing the above-mentioned crystal form A further comprises the steps of stirring and filtering after recrystallization.

[0028] In some embodiments, the method for preparing the above-mentioned crystal form A further comprises the steps of stirring, filtering and drying after recrystallization.

[0029] In some embodiments, in the method for preparing the above-mentioned crystal form A, the grinding step uses a mortar.

[0030] In some embodiments, the grinding step of the preparation method of the above-mentioned crystal form A needs to be ground for 15-60 minutes. In some typical embodiments, the grinding step of the preparation method of the above-mentioned crystal form A needs to be ground for 15-30 minutes.

[0031] In some embodiments, in the method for preparing the above-mentioned crystal form A, a pulverizer is used in the pulverizing step. In some typical embodiments, in the method for preparing the above-mentioned crystal form A, a multi-functional pulverizer or a hammer mill is used in the pulverizing step.

[0032] In some embodiments, in the method for preparing the above-mentioned crystal form A, the pulverizing step needs to be pulverized for 2-15 minutes. In some typical embodiments, in the method for preparing the above-mentioned crystal form A, the pulverizing step needs to be pulverized for 2-5 minutes.

[0033] In another aspect, the present invention provides a method for preparing the crystalline form A of the compound of formula (I), comprising: dissolving the compound of formula (I) in a dissolving solvent, filtering, and then adding the filtrate to an anti-dissolving solvent to precipitate a solid and then grinding or crushing it, wherein the dissolving solvent is selected from a mixed solvent of methanol and dichloromethane, dichloromethane or chloroform, and the anti-dissolving solvent is selected from methyl tert-butyl ether or cyclohexane; the X-ray powder diffraction pattern of the crystalline form A has characteristic diffraction peaks at the following 2θ angles: 10.7±0.2°, 11.8±0.2°, 13.1±0.2° or 14.5±0.2°.

[0034] In some embodiments, the filtrate is added to the anti-solvent at a temperature below zero. In some typical embodiments, the filtrate is added to the anti-solvent at a temperature of -10°C or less.

[0035] In another aspect, the present invention provides a crystalline form B of the compound of formula (I), wherein the X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 11.8±0.2°, 13.0±0.2°, 14.4±0.2°, 14.9±0.2° or 22.5±0.2°,

[0036] The structure of the compound of formula (I) is:

[0037]

[0038] In some embodiments, the X-ray powder diffraction pattern of the crystalline Form B has characteristic diffraction peaks at the following 2θ angles: 5.2±0.2°, 7.2±0.2°, 10.6±0.2°, 11.8±0.2°, 13.0±0.2°, 13.8±0.2°, 14.4±0.2°, 14.9±0.2° or 22.5±0.2°.

[0039] In some embodiments, the X-ray powder diffraction pattern of the crystalline Form B has characteristic diffraction peaks at the following 2θ angles: 5.2±0.2°, 7.2±0.2°, 10.6±0.2°, 11.1±0.2°, 11.8±0.2°, 13.0±0.2°, 13.8±0.2°, 14.4±0.2°, 14.9±0.2°, 18.7±0.2°, 22.5±0.2° or 26.1±0.2°.

[0040] In some embodiments, the X-ray powder diffraction pattern of Form B is as follows Figure 3 As shown, it has Figure 3 The features represented by the X-ray powder diffraction pattern shown.

[0041] In some embodiments, the differential scanning calorimetry curve of the crystalline form B has one endothermic peak with an onset temperature of 245.0-246.0°C.

[0042] In some embodiments, the DSC spectrum of the crystalline form B is as follows Figure 4 As shown, it has Figure 4 The DSC spectra shown represent the characteristics.

[0043] In some embodiments, the crystalline form B of the compound of formula (I) is substantially free of other crystalline forms described herein. For example, the weight content of the crystalline form B of the compound of formula (I) is at least 99%, at least 95%, at least 90%, or lower to 80%. Alternatively, the weight content of the crystalline form B of the compound of formula (I) is at least 70%, or at least 60%. Or further, the weight content of the crystalline form B of the compound of formula (I) is at least 50%.

[0044] On the other hand, the present invention also provides a method for preparing the crystalline form B, comprising:

[0045] The compound of formula (I) is dissolved in a dissolving solvent, filtered through a filter membrane, added into an anti-dissolving solvent to precipitate a solid, stirred, filtered and dried.

[0046] In some embodiments, in the preparation method of the above-mentioned crystal form B, the dissolving solvent is selected from methanol, ethanol, isopropanol, acetone, dichloromethane, chloroform, dimethyl sulfoxide and N,N-dimethylformamide. In some typical embodiments, the dissolving solvent is chloroform.

[0047] In some embodiments, in the preparation method of the above-mentioned crystal form B, the anti-dissolving solvent is selected from C 2-5 Ether or C 5-8 Branched or straight chain alkanes. In some typical embodiments, the anti-solvent is selected from methyl tert-butyl ether, n-hexane, cyclohexane or n-heptane. In some more typical embodiments, the anti-solvent is selected from methyl tert-butyl ether or n-hexane.

[0048] In some embodiments, in the preparation method of the above-mentioned crystal form B, the mass volume ratio of the compound of formula (I) to the dissolving solvent is selected from 60 to 70 mg / mL. In some typical embodiments, the mass volume ratio of the crystal form I to the dissolving solvent is 60 mg / mL.

[0049] In some embodiments, in the method for preparing the above-mentioned crystal form B, the volume ratio of the anti-dissolving solvent to the dissolving solvent is selected from 3 to 4: 1. In some typical embodiments, in the method for preparing the above-mentioned crystal form B, the volume ratio of the anti-dissolving solvent to the dissolving solvent is 3.6:1.

[0050] In another aspect, the present invention provides a crystalline form C of the compound of formula (I), wherein the X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 5.2±0.2°, 10.6±0.2°, 13.8±0.2°, 14.5±0.2° or 19.8±0.2°,

[0051] The structure of the compound of formula (I) is:

[0052]

[0053] In some embodiments, the X-ray powder diffraction pattern of the crystalline Form C has characteristic diffraction peaks at the following 2θ angles: 5.2±0.2°, 6.4±0.2°, 7.2±0.2°, 10.6±0.2°, 13.8±0.2°, 14.5±0.2°, 16.2±0.2° or 19.8±0.2°.

[0054] In some embodiments, the X-ray powder diffraction pattern of the crystalline Form C has characteristic diffraction peaks at the following 2θ angles: 5.2±0.2°, 6.4±0.2°, 7.2±0.2°, 10.6±0.2°, 13.8±0.2°, 14.5±0.2°, 16.2±0.2°, 19.8±0.2°, 21.1±0.2° or 21.3±0.2°.

[0055] In some embodiments, the X-ray powder diffraction pattern of the crystalline form C has characteristic diffraction peaks at the following 2θ angles: 5.2±0.2°, 6.4±0.2°, 7.2±0.2°, 8.6±0.2°, 10.6±0.2°, 13.8±0.2°, 14.5±0.2°, 16.2±0.2°, 19.8±0.2°, 21.1±0.2° or 21.3±0.2°.

[0056] In some embodiments, the X-ray powder diffraction pattern of Form C is as follows Figure 5 As shown, it has Figure 5 The features represented by the X-ray powder diffraction pattern shown.

[0057] In some embodiments, the differential scanning calorimetry curve of the crystalline form C has one endothermic peak with an onset temperature of 245.0-246.0°C.

[0058] In some embodiments, the DSC spectrum of the crystalline form C is as follows Figure 6 As shown, it has Figure 6 The DSC spectra shown represent the characteristics.

[0059] In some embodiments, the crystalline form C of the compound of formula (I) is substantially free of other crystalline forms described herein. For example, the weight content of the crystalline form C of the compound of formula (I) is at least 99%, at least 95%, at least 90%, or lower to 80%. Alternatively, the weight content of the crystalline form C of the compound of formula (I) is at least 70%, or at least 60%. Or further, the weight content of the crystalline form C of the compound of formula (I) is at least 50%.

[0060] On the other hand, the present invention also provides a method for preparing the crystalline form C, comprising:

[0061] 1) adding the compound of formula (I) to a mixed solvent of tetrahydrofuran and water, heating to dissolve and filtering, cooling, filtering and drying;

[0062] 2) taking the sample of step 1) and placing it in a forced air drying oven, and rapidly heating it to 150° C.; after keeping it at 150° C. for 10 minutes, collecting it to obtain the crystalline form C of the compound of formula (I).

[0063] On the other hand, the present application also provides a pharmaceutical composition, which is prepared by mixing one or more of the crystalline forms A, B or C of the compound represented by formula (I) described above with one or more pharmaceutically acceptable carriers, diluents or excipients.

[0064] In another aspect, the present invention provides use of the crystalline form A, crystalline form B or crystalline form C of the compound of formula (I) or a pharmaceutical composition thereof in the preparation of a medicament for treating diseases associated with abnormal angiogenesis.

[0065] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular phrase or term should not be considered ambiguous or unclear without special definition, but should be understood according to the ordinary meaning.

[0066] In the present invention, when referring to a spectrum and / or data in a graph, the term "diffraction peak" refers to a characteristic peak that a person skilled in the art would not attribute to background noise.

[0067] As used herein, "XRPD" means X-ray powder diffraction;

[0068] In the present invention, "DCM" refers to dichloromethane;

[0069] As used herein, "DSC" refers to differential scanning calorimetry;

[0070] As used herein, "TGA" refers to thermogravimetric analysis;

[0071] In the present invention, "h" means hour, "min" means minute, "ml" means milliliter, and "μl" means microliter;

[0072] In the present invention, "room temperature" refers to 25°C;

[0073] In the present invention, "suction filtration" means filtration under reduced pressure.

[0074] In the present invention, "dissolving solvent" refers to any appropriate organic solvent that can partially or completely dissolve the solute under appropriate conditions, such as appropriate amount, appropriate temperature, such as room temperature or elevated temperature.

[0075] In the present invention, "anti-solvent" refers to any appropriate organic solvent in which the solubility of a substance is lower than that of a substance in a solvent.

[0076] As described herein, the crystal forms of the present invention can be identified by one or more solid-state analysis methods. For example, the crystal forms of the present invention can be identified by one or more methods, such as powder X-ray diffraction, lattice parameters of single crystals, Fourier transform infrared spectroscopy, differential scanning calorimetry analysis data and / or thermogravimetric curves. And if the identification analysis results of one of the methods are consistent with the crystal forms of the present invention, it does not mean that the identification results of any other method are inconsistent with the crystal forms of the present invention.

[0077] In the present invention, the determination method of X-ray powder diffractometer (XRPD) is as follows:

[0078] Instrument model: D8 Advance

[0079] Test conditions:

[0080] X-ray generator: Cu, Kα,

[0081] Tube voltage: 40kV, tube current: 40mA.

[0082] Scattering slit: 0.6mm

[0083] Detector slit: 5mm

[0084] Anti-scattering slit: 0.6mm

[0085] Scanning range: 3-40°

[0086] Step size: 0.02°

[0087] Rate: 0.3S

[0088] It should be noted that in the X-ray powder diffraction pattern (XRPD), the diffraction pattern obtained by the crystalline compound is often characteristic for a specific crystal, wherein the relative intensity of the band (especially at low angles) may vary due to the difference in crystallization conditions, particle size and other measurement conditions resulting from the dominant orientation effect. Therefore, the relative intensity of the diffraction peak is not characteristic for the crystal targeted, and when judging whether it is the same as a known crystal, more attention should be paid to the relative position of the peak rather than their relative intensity. In addition, for any given crystal, the position of the peak may have a slight error, which is also well known in the field of crystallography. For example, due to changes in temperature, sample movement, or calibration of the instrument when analyzing the sample, the position of the peak may move, and the measurement error of the 2θ value is sometimes about ± 0.5°, preferably about ± 0.3°, and more preferably about ± 0.2°. Therefore, when determining each crystalline structure, this error should be taken into account, and the 2θ value within the error also belongs to the scope of the present invention. In XRPD spectra, the peak position is usually represented by the 2θ angle or the interplanar distance d, and there is a simple conversion relationship between the two: d = λ / 2sinθ, where d represents the interplanar distance (also known as "interplanar spacing"), λ represents the wavelength of the incident X-ray, and θ is the diffraction angle. For the same type of crystals of the same compound, the peak positions of their XRPD spectra are similar overall, and the relative intensity errors may be large. It should also be pointed out that in the identification of mixtures, some diffraction lines may be missing due to factors such as decreased content. At this time, there is no need to rely on all the bands observed in high-purity samples, and even one band may be characteristic for a given crystal.

[0089] The differential thermal analysis (also known as "differential scanning calorimetry", Differential Scanning Calorimeter, DSC) method of the present invention is as follows:

[0090] Test method: Take a sample (1-10 mg) and place it in a DSC aluminum pan for testing. The method is: starting temperature ~40°C, heating rate is 10°C / min.

[0091] DSC measures the transition temperature when a crystal absorbs or releases heat due to a change in its crystalline structure or melting of the crystal. For the same crystal of the same compound, the error of thermal transition temperature and melting point is typically within about 5°C, usually within about 3°C ​​in consecutive analyses. When we say that a compound has a given DSC peak or melting point, this refers to the DSC peak or melting point ±5°C. DSC provides an auxiliary method for distinguishing different crystals. Different crystalline forms can be identified by their different transition temperature characteristics. It should be pointed out that for mixtures, their DSC peaks or melting points may vary over a larger range. In addition, since decomposition is accompanied by the melting of the substance, the melting temperature is related to the heating rate.

[0092] Thermogravimetric analysis (TGA) method of the present invention

[0093] Instrument model: TGA550

[0094] Test conditions: Take a sample (1-10 mg) and place it in a TGA platinum pan for testing. The method is: starting temperature ~30°C, heating rate is 10°C / min.

[0095] In the present invention, when referring to, for example, an XRPD pattern, a DSC pattern or a TGA pattern, the term "as shown by..." includes patterns that are not necessarily the same as those depicted herein but fall within the limits of experimental error when considered by those skilled in the art.

[0096] The present invention provides novel crystalline forms A, B and C of the compound of formula (I), which are different from the crystalline forms disclosed in the prior art. The preparation method of the crystalline form A disclosed in the present application enables the residual solubility limit of the product to meet the requirements, and the obtained product has high dissolution rate and dissolution amount, which is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0097] Figure 1 This is the X-ray powder diffraction pattern of Form A of the compound of formula (I) prepared in Scheme 1 of Example 1.

[0098] Figure 2 This is the DSC spectrum of Form A of the compound of formula (I) prepared in Scheme 1 of Example 1.

[0099] Figure 3 This is the X-ray powder diffraction pattern of Form B of the compound of formula (I) prepared in Example 2.

[0100] Figure 4 This is the DSC spectrum of Form B of the compound of formula (I) prepared in Example 2.

[0101] Figure 5 This is the X-ray powder diffraction pattern of Form C of the compound of formula (I) prepared in Example 3.

[0102] Figure 6 This is the DSC spectrum of Form C of the compound of formula (I) prepared in Example 3. DETAILED DESCRIPTION

[0103] The embodiments of the present invention disclose the crystalline form of the compound of formula (I), its preparation method and application. Those skilled in the art can refer to the contents of this article and appropriately improve the process parameters to achieve. It is particularly important to point out that all similar substitutions and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention. The method of the present invention has been described by preferred embodiments, and relevant personnel can obviously modify or appropriately change and combine the methods described herein without departing from the content, spirit and scope of the present invention to implement and apply the technology of the present invention.

[0104] The crystalline form I of the compound of formula (I) used in the embodiment of the present invention was purchased from Beijing Coupling Technology Co., Ltd., and can also be prepared by referring to the preparation method disclosed in patent CN110981910B. Other compounds or reagents used in the specific embodiments of the present invention can be purchased from commercial sources or prepared by conventional methods known to those skilled in the art. The residual solvent used in the embodiment of the present invention is detected by gas chromatography, wherein the detection method of the residual dichloromethane solvent is as follows:

[0105]

[0106]

[0107] The specific detection method of chloroform is as follows:

[0108]

[0109] Example 1 Preparation method of crystal form A

[0110] Scheme 1: Form I is dissolved in 60-70 times (volume mass ratio mL / g relative to Form I) of DCM and filtered; at -10--20°C or lower, the filtrate is added to 200 times (volume mass ratio mL / g relative to Form I) of tertiary methyl ether to precipitate a large amount of white precipitate; -20°C is kept warm and stirred for 2 hours; 0.22 μm filter membrane is filtered, the filter cake is rinsed with acetone, and air-dried at 60°C for 2 hours. The residual dichloromethane solvent is 1.7% (the limit is 0.06%). After grinding the crystalline product for 15-30 minutes or crushing for 2-5 minutes, the residual dichloromethane solvent is 0.01%. The X-ray powder diffraction spectrum and DSC spectrum of the obtained sample of Form A of the compound of formula (I) are as follows: Figure 1 and Figure 2 shown.

[0111] Scheme 2: Form I is dissolved in 30 times (volume mass ratio mL / g relative to Form I) MeOH / DCM (1:1, v:v), filtered with a 0.22 μm filter membrane; at -10 to -20°C or lower, the filtrate is added to 100 times (volume mass ratio mL / g relative to Form I) tertiary methyl ether, and a large amount of white precipitate is precipitated; stirred at -20°C for 2 hours; filtered, the filter cake is rinsed with methanol, and dried at 60°C for 2 hours, the residual dichloromethane solvent is 0.86% (the limit is 0.06%), and the crystalline product is ground for 15-30min or crushed for 2-5min, and the residual dichloromethane solvent is 0.003%. The X-ray powder diffraction pattern of the sample obtained by this method is consistent with the Form A sample of the compound of formula (I) obtained in Scheme 1 of Example 1.

[0112] Scheme 3: 300 mg of Form I was dissolved in 5 mL of chloroform, filtered with a 0.22 μm filter membrane; the filtrate was added to 30 mL of tertiary methyl ether at room temperature, and a large amount of white precipitate was precipitated; stirred at room temperature for 0.5 hours; filtered with suction, the filter cake was rinsed twice with acetone, dried under reduced pressure at 45°C for 3 hours, and 200 mg of product was collected. The residual chloroform solvent was 0.15% (the limit was 0.006%). After grinding the crystalline product for 15-30 minutes or crushing for 2-5 minutes, the residual chloroform solvent was not detected. The X-ray powder diffraction pattern of the sample obtained by this method was consistent with the Form A sample of the compound of formula (I) obtained in Scheme 1 of Example 1.

[0113] Scheme 4: 200 mg of Form I was dissolved in 3.3 mL of chloroform, filtered with a 0.22 μm filter membrane; the filtrate was added to 12 mL of cyclohexane at room temperature, and a large amount of white precipitate was precipitated; stirred at room temperature for 0.5 hours; filtered with suction, the filter cake was rinsed twice with acetone, dried under reduced pressure at 45°C for 3 hours, and 191 mg of product was collected, the chloroform solvent residue was 0.27% (the limit was 0.006%), and the crystalline product was ground for 15-30 minutes or crushed for 2-5 minutes, and the chloroform solvent residue was 0.002%. The X-ray powder diffraction pattern of the sample obtained by this method was consistent with the Form A sample of the compound of formula (I) obtained in Scheme 1 of Example 1.

[0114] Example 2 Preparation method of crystal form B

[0115] 300 mg of the crystalline form I of the compound of formula (I) was dissolved in 5.0 mL of chloroform and filtered through a 0.22 μm filter membrane; the filtrate was added to 18 mL of methyl tert-butyl ether (or n-hexane) to precipitate a large amount of white precipitate; the mixture was stirred at room temperature for 0.5 hour; the mixture was filtered with suction, the filter cake was rinsed twice with acetone, and dried under reduced pressure at 45° C. for 3 hours to obtain 285.0 mg of the crystalline form B of the compound of formula (I), the X-ray powder diffraction spectrum and DSC spectrum of the crystalline form were as follows: Figure 3 and Figure 4 shown.

[0116] Example 3 Preparation method of crystal form C

[0117] Step 1: Add 500 mg of Form I of the compound of formula (I) into a 100 mL glass bottle, add 20 mL of tetrahydrofuran / water (3:1, v:v), heat to 70°C until the solid dissolves, filter while hot, and slowly cool the filtrate; filter with suction; and air-dry the filter cake.

[0118] Step 2: Place the sample obtained in step 1 in a forced air drying oven and quickly heat it to 150°C; after keeping it at 150°C for 10 minutes, collect and obtain a sample of the crystal form C of the compound of formula (I). The X-ray powder diffraction spectrum and DSC spectrum of the crystal form are as follows: Figure 5 and Figure 6 shown.

[0119] The crystal forms A, B and C prepared by the present invention are anhydrous crystal forms as tested by TGA.

[0120] Example 4 Solubility Experiment

[0121] 1. Weigh 10 mg of the crystalline form I or crystalline form A of the compound of formula (I) into a HPLC vial, add 1.0 mL of acetone, place the resulting suspension under magnetic stirring (1000 rpm) at 40°C for 24 hours, centrifuge (10000 rpm, 2 min), filter the supernatant using a 0.22 μm PTFE filter membrane (discard the first two drops), determine the HPLC concentration of the filtrate, and confirm the crystalline form of the remaining solid using powder X-ray diffraction. Compared with crystalline form I, the solubility of crystalline form A in acetone is increased by 37%.

[0122] 2. Weigh 10 mg of the crystalline form I or crystalline form A of the compound of formula (I) into a HPLC vial, add 1.0 mL of water, and place the resulting suspension under room temperature conditions for oscillation (400 rpm) for 24 hours. Centrifuge (10000 rpm, 2 min) and filter the supernatant using a 0.22 μm PTFE filter membrane (discard the first two drops). Determine the HPLC concentration of the filtrate, and confirm the crystalline form of the remaining solid using powder X-ray diffraction. Compared with crystalline form I, the solubility of crystalline form A in water is increased by 26%.

[0123] Example 5: Confirmation of stable form at room temperature

[0124] Weigh an equal mass (about 10 mg) of the crystalline form A, crystalline form B or one or more of the crystalline forms of the compound of formula (I) into a HPLC vial, add 1.0 mL of a solvent pre-saturated with the crystalline form I at a corresponding temperature, and stir the resulting suspension at a corresponding temperature (1000 rpm). Take samples at 1 hour, 6 hours, 1 day and 3 days, collect the solid by centrifugation and perform XRD analysis.

[0125] The experimental results are shown in Table 1

[0126] Table 1. Results of the stable morphology confirmation experiment of Forms A, B and C at room temperature

[0127]

[0128] Note: RT stands for room temperature, "--" stands for unmeasured

[0129] Example 6: Stability under conditions of high temperature, high humidity, light, etc.

[0130] The crystal form A sample (purity 99.79%) was placed under high temperature 60°C, high humidity 92.5%RH, light, long-term (25°C / 60%RH) and accelerated (40°C / 75%RH) conditions, and the physical and chemical stability of the sample was investigated by XRD and HPLC. The experimental results are shown in Table 2.

[0131] Table 2. Experimental results of factors affecting crystal form

[0132]

[0133]

[0134] Example 7 Dissolution Test

[0135] The dissolution method adopts the first dissolution method of the Chinese Pharmacopoeia, the basket method, with 0.1 mol / L hydrochloric acid as the dissolution medium, the rotation speed is 100 rpm, sampling is performed at appropriate time intervals, and the same volume of dissolution medium is added. Filter membrane filtration, high performance liquid chromatography determination of content and calculation of dissolution rate.

Claims

1. A crystalline form A of a compound of formula (I), The structure of the compound of formula (I) is: The X-ray powder diffraction pattern of the crystalline form A has characteristic diffraction peaks at the following 2θ angles: 10.7±0.2°, 11.8±0.2°, 13.1±0.2° or 14.5±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form A has characteristic diffraction peaks at the following 2θ angles: 9.9±0.2°, 10.7±0.2°, 11.8±0.2°, 13.1±0.2°, 14.5±0.2°, 18.4±0.2°, 18.7±0.2°, 19.2±0.2° or 22.6±0 .2°; preferably, the X-ray powder diffraction pattern of the crystalline form A has characteristic diffraction peaks at the following 2θ angles: 9.9±0.2°, 10.7±0.2°, 11.8±0.2°, 13.1±0.2°, 14.5±0.2°, 18.4±0.2°, 18.7±0.2°, 19.2±0.2°, 22.6±0.2°, 23.8±0.2°, 25.5±0.2° or 26.5±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form A has characteristic diffraction peaks at the following 2θ angles Peak: 9.9±0.2°, 10.7±0.2°, 11.8±0.2°, 13.1±0.2°, 14.5±0.2°, 15.0±0.2°, 18.4±0.2°, 18.7±0.2°, 19.2±0.2°, 21.5±0.2°, 22.6±0.2°, 22.9±0.2°, 23.8±0.2°, 25.5±0.2° or 26.5±0.2°; Preferably, the X-ray powder diffraction pattern of the crystalline form A has characteristic diffraction peaks at the following 2θ angles: 3.7 ±0.2°, 9.3±0.2°, 9.9±0.2°, 10.7±0.2°, 11.8±0.2°, 13.1±0.2°, 14.5±0.2°, 15.0±0.2°, 18.4±0.2°, 18.7±0.2°, 19.2±0.2°, 21.5±0.2°, 22.6±0.2°, 22.9±0.2°, 23.8±0.2°, 25.5±0.2° or 26.5±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form A is shown in Figure 1.

2. The crystalline form A according to claim 1, Features: The crystal form A has a DSC spectrum as shown in FIG2 .

3. The method for preparing the crystalline form A according to any one of claims 1 to 2, include: The compound of formula (I) is recrystallized and then ground or pulverized.

4. The preparation method according to claim 3, Features: The recrystallization step is to dissolve the compound of formula (I) in a dissolving solvent, filter, and then add the filtrate to an anti-dissolving solvent to precipitate a solid.

5. The preparation method according to claim 4, Features: The dissolving solvent is selected from a mixed solvent of methanol and dichloromethane, dichloromethane or chloroform.

6. The preparation method according to claim 4, Features: The anti-solvent is selected from methyl tert-butyl ether or cyclohexane.

7. The preparation method according to claim 4, Features: The filtrate is added to the anti-dissolution solvent at a sub-zero temperature; preferably, the filtrate is added to the anti-dissolution solvent at a temperature of -10°C or less.

8. A method for preparing the crystalline form A of the compound of formula (I), include: The compound of formula (I) is dissolved in a dissolving solvent, filtered, and the filtrate is added to an anti-dissolving solvent to precipitate a solid, which is then ground or crushed, wherein the dissolving solvent is selected from a mixed solvent of methanol and dichloromethane, dichloromethane or chloroform, and the anti-dissolving solvent is selected from methyl tert-butyl ether or cyclohexane. The X-ray powder diffraction pattern of the crystalline form A has characteristic diffraction peaks at the following 2θ angles: 10.7±0.2°, 11.8±0.2°, 13.1±0.2° or 14.5±0.2°, and the structure of the compound of formula (I) is:

9. A crystalline form B of a compound of formula (I), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 11.8±0.2°, 13.0±0.2°, 14.4±0.2°, 14.9±0.2° or 22.5±0.2°, or The crystalline form C of the compound of formula (I) has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ angles: 5.2±0.2°, 10.6±0.2°, 13.8±0.2°, 14.5±0.2° or 19.8±0.2°, The structure of the compound of formula (I) is:

10. A pharmaceutical composition, prepared by mixing the crystalline form A, crystalline form B or crystalline form C of the compound of formula (I) with one or more pharmaceutically acceptable carriers, diluents or excipients.

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