New crystal form of benzamide compound

Abstract

The invention relates to the field of medicinal chemistry, in particular to novel crystal forms alpha and beta of a benzamide compound, a preparation method of the novel crystal forms alpha and beta, a pharmaceutical composition containing the novel crystal forms and medical application of the pharmaceutical composition in prevention and / or treatment of diseases related to cell differentiation and proliferation.

Description

Technical Field

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

[0002] The compound of formula (I) is a histone deacetylase inhibitor of benzamide structure, its chemical name is N-(2-amino-4-fluorophenyl)-4-(N-(3-pyridylacryloyl)aminomethyl)benzamide, and its chemical structure is as follows:

[0003]

[0004] Patent CN110981910B discloses the crystalline form A and crystalline form B of the compound of formula (I).

[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 α 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 α has characteristic diffraction peaks at the following 2θ angles:

[0010] 6.6±0.2°, 18.4±0.2°, 20.0±0.2° or 23.7±0.2°.

[0011] In some embodiments, the X-ray powder diffraction pattern of the crystalline form α has characteristic diffraction peaks at the following 2θ angles:

[0012] 6.6±0.2°, 11.2±0.2°, 18.4±0.2°, 19.3±0.2°, 20.0±0.2°, 23.7±0.2°, 25.5±0.2° or 28.6±0.2°.

[0013] In some embodiments, the X-ray powder diffraction pattern of the crystalline form α has characteristic diffraction peaks at the following 2θ angles:

[0014] 6.6±0.2°, 9.0±0.2°, 11.2±0.2°, 17.3±0.2°, 18.4±0.2°, 19.3±0.2°, 20.0±0.2°, 21.3±0.2°, 22.1±0.2°, 22.6±0.2°, 22.9±0.2°, 23.7±0.2°, 25.2±0.2°, 25.5±0.2°, 25.8±0.2°, 26.8±0.2°, 27.3±0.2°, 28.6±0.2° or 31.3±0.2°.

[0015] In some embodiments, the X-ray powder diffraction pattern of the crystalline form α has a characteristic diffraction peak at the following 2θ angles: 6.6±0.2°, 8.4±0.2°, 9.0±0.2°, 11.2±0.2°, 17.3±0.2°, 18.4±0.2°, 19.3±0.2°, 20.0±0.2°, 21.3±0.2°, 22.1±0.2°, 22.6±0.2°, 22.9±0.2°, 23.7±0.2°, 25.2±0.2°, 25.5±0.2°, 25.8±0.2°, 26.8±0.2°, 27.3±0.2°, 28.6±0.2° or 31.3±0.2°.

[0016] In some embodiments, the X-ray powder diffraction pattern of the crystalline form α is as follows Figure 1 As shown, it has Figure 1 The X-ray powder diffraction pattern shown represents the characteristics of.

[0017] In some embodiments, the differential scanning calorimetry curve of the crystalline form α has an endothermic peak with an onset temperature of 238.65°C.

[0018] In some embodiments, the DSC spectrum of the crystalline form α is as follows Figure 2 As shown, it has Figure 2 The DSC spectrum shown represents the characteristics of.

[0019] In some embodiments, the thermogravimetric analysis curve of the Form α shows no weight loss.

[0020] In some embodiments, the TGA spectrum of the crystalline form α is as follows Figure 3 As shown, it has Figure 3 The TGA spectrum shown represents the characteristics of.

[0021] On the other hand, the present invention also provides a method for preparing the crystalline form α, comprising:

[0022] Solution 1: dissolving the crystalline form A of the compound of formula (I) in dimethyl sulfoxide, and then adding isopropanol to precipitate; or

[0023] Solution 2: The crystalline form A of the compound of formula (I) is added to an organic solvent A for slurrying, wherein the organic solvent A is selected from methanol, ethanol, acetone or 1,4-dioxane.

[0024] In some embodiments, the above preparation method includes a suction filtration and drying step.

[0025] In some embodiments, in Scheme 1 of the above preparation method: the mass volume ratio of the compound of formula (I) and dimethyl sulfoxide is 0.5 g / mL.

[0026] In some embodiments, in Scheme 2 of the above preparation method: the mass volume ratio of the compound of formula (I) and the organic solvent A is 6.7-40 mg / mL.

[0027] On the other hand, the present invention provides a crystalline form β of the compound of formula (I), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 6.6±0.2°, 13.3±0.2°, 19.9±0.2°, 21.0±0.2° or 24.5±0.2°,

[0028] The structure of the compound of formula (I) is:

[0029]

[0030] In some embodiments, the X-ray powder diffraction pattern of the crystalline form β has a characteristic diffraction peak at the following 2θ angles: 6.6±0.2°, 13.3±0.2°, 18.3±0.2°, 19.9±0.2°, 20.3±0.2°, 21.0±0.2°, 21.4±0.2°, 24.5±0.2° or 26.0±0.2°.

[0031] In some embodiments, the X-ray powder diffraction pattern of the crystalline form β has a characteristic diffraction peak at the following 2θ angles: 6.6±0.2°, 10.9±0.2°, 13.3±0.2°, 15.4±0.2°, 18.3±0.2°, 19.4±0.2°, 19.9±0.2°, 20.3±0.2°, 21.0±0.2°, 21.4±0.2°, 24.5±0.2°, 26.0±0.2°, 26.3±0.2° or 27.3±0.2°.

[0032] In some embodiments, the X-ray powder diffraction pattern of the crystalline form β has a characteristic diffraction peak at the following 2θ angles: 6.6±0.2°, 7.7±0.2°, 10.9±0.2°, 13.3±0.2°, 15.4±0.2°, 18.3±0.2°, 19.4±0.2°, 19.9±0.2°, 20.3±0.2°, 21.0±0.2°, 21.4±0.2°, 24.5±0.2°, 26.0±0.2°, 26.3±0.2° or 27.3±0.2°.

[0033] In some embodiments, the X-ray powder diffraction pattern of the crystalline form β is as follows Figure 4 As shown, it has Figure 4 The X-ray powder diffraction pattern shown represents the characteristics of.

[0034] In some embodiments, the differential scanning calorimetry curve of the crystalline form β has two endothermic peaks, and the onset temperatures are 109.41° C. and 235.51° C., respectively.

[0035] In some embodiments, the DSC spectrum of the crystalline form β is as follows Figure 5 As shown, it has Figure 5 The DSC spectrum shown represents the characteristics of.

[0036] In some embodiments, the thermogravimetric analysis curve of the crystalline form β has a weight loss of 17.4-18.0%, preferably 17.691%.

[0037] In some embodiments, the TGA spectrum of the crystalline form β is as follows Figure 6 As shown, it has Figure 6 The TGA spectrum shown represents the characteristics of.

[0038] On the other hand, the present invention also provides a method for preparing the crystalline form β, comprising:

[0039] Solution 1: dissolving the crystalline form A of the compound of formula (I) in acetic acid, and then adding n-heptane to precipitate; or

[0040] Scheme 2: Dissolve the crystalline form A of the compound of formula (I) in acetic acid, and then add purified water to precipitate.

[0041] In some typical embodiments, the above preparation method comprises a suction filtration and drying step.

[0042] In some embodiments, the mass volume ratio of the compound of formula (I) and acetic acid in the above preparation method is 0.5 g / mL.

[0043] On the other hand, the present application also provides a pharmaceutical composition, which is prepared by mixing one or more of the crystalline form α or crystalline form β of the compound represented by formula (I) described above with one or more pharmaceutically acceptable carriers, diluents or excipients.

[0044] In another aspect, the present invention provides use of the crystalline form α or crystalline form or pharmaceutical composition of the compound of formula (I) in the preparation of a medicament for treating diseases associated with cell differentiation and proliferation.

[0045] 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.

[0046] 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.

[0047] As used herein, "XRPD" means X-ray powder diffraction;

[0048] As used herein, "DSC" refers to differential scanning calorimetry;

[0049] As used herein, "TGA" refers to thermogravimetric analysis;

[0050] In the present invention, "h" means hour, "min" means minute, "ml" means milliliter, and "μl" means microliter;

[0051] In the present invention, "room temperature" refers to 25°C;

[0052] In the present invention, "suction filtration" means filtration under reduced pressure.

[0053] In the present invention, the determination method of X-ray powder diffractometer (XRPD) is as follows:

[0054] Instrument model: D8 Advance

[0055] Test conditions:

[0056] X-ray generator: Cu, Kα,

[0057] Tube voltage: 40kV, tube current: 40mA.

[0058] Scattering slit: 0.6mm

[0059] Detector slit: 5mm

[0060] Anti-scattering slit: 0.6mm

[0061] Scanning range: 3-40°

[0062] Step size: 0.02°

[0063] Rate: 0.3S

[0064] 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.

[0065] The differential thermal analysis (also known as "differential scanning calorimetry", Differential Scanning Calorimeter, DSC) method of the present invention is as follows:

[0066] 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.

[0067] 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.

[0068] Thermogravimetric analysis (TGA) method of the present invention

[0069] Instrument model: TGA550

[0070] 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.

[0071] 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.

[0072] The present invention provides new crystalline form α and crystalline form β of the compound of formula (I), which are different from the crystalline forms disclosed in the existing literature. Compared with the crystalline forms disclosed in the prior art, the crystalline form α of the present application is not easy to absorb moisture and has better thermodynamic stability, physical stability, chemical stability and bulk density. BRIEF DESCRIPTION OF THE DRAWINGS

[0073] Figure 1 This is the X-ray powder diffraction pattern of the crystalline form α of the compound of formula (I) prepared in Example 1.

[0074] Figure 2 This is the DSC spectrum of the crystalline form α of the compound of formula (I) prepared in Example 1.

[0075] Figure 3 This is the TGA spectrum of the crystalline form α of the compound of formula (I) prepared in Example 1.

[0076] Figure 4 This is the X-ray powder diffraction pattern of the crystalline form β of the compound of formula (I) prepared in Example 3.

[0077] Figure 5This is the DSC spectrum of the crystalline form β of the compound of formula (I) prepared in Example 3.

[0078] Figure 6 This is the TGA spectrum of the crystalline form β of the compound of formula (I) prepared in Example 3.

[0079] Figure 7 It is the DVS spectrum of Form A of the compound of formula (I).

[0080] Figure 8 It is the DVS spectrum of Form B of the compound of formula (I).

[0081] Fig. 9 This is the DVS spectrum of the crystalline form α of the compound of formula (I) prepared in Example 1. DETAILED DESCRIPTION

[0082] 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.

[0083] Except for the crystal form A in the examples of the present invention which was marked as purchased from Shanghai Hanxiang Biotechnology Co., Ltd., the rest were prepared with reference to the preparation method disclosed in patent CN110981910B, and the crystal form B was prepared with reference to the preparation method disclosed in patent CN110981910B.

[0084] Example 1

[0085] 0.1 g of the compound of formula (I) (purchased from Shanghai Hanxiang Biotechnology Co., Ltd., crystal form A) was dissolved in 2 ml of dimethyl sulfoxide, and 40 ml of isopropanol was slowly added dropwise to the above solution. Solids gradually precipitated during the addition, and the mixture was stirred for 2 h, filtered, and vacuum dried to obtain crystal form α. The X-ray powder diffraction spectrum, DSC spectrum, and TGA spectrum of the crystal form are shown as follows: Figure 1 , Figure 2 and Figure 3 shown.

[0086] Example 2

[0087] Referring to Example 1 in patent CN103833626B, the crystalline form A of the compound of formula (I) was prepared, and 20 mg of the prepared crystalline form A of the compound of formula (I) was slurried in an organic solvent A (see the table below) to prepare crystalline form α. The XRPD spectrum, DSC spectrum, and TGA spectrum were consistent with those in Example 1.

[0088] Organic solvent A Methanol Ethanol acetone 1,4-Dioxane Feeding amount 0.5mL 2mL 3mL 3mL

[0089] Example 3

[0090] 0.1 g of the compound of formula (I) (purchased from Shanghai Hanxiang Biotechnology Co., Ltd., crystal form A) was dissolved in 2 ml of acetic acid, and 40 ml of n-heptane was slowly added dropwise to the above solution. Solids gradually precipitated during the addition, and the mixture was stirred for 2 h, filtered, and dried to obtain 95 mg of crystal form β. The X-ray powder diffraction spectrum, DSC spectrum and TGA spectrum of the crystal form are shown respectively. Figure 4 , Figure 5 and Figure 6 shown.

[0091] Example 4

[0092] 1 g of the compound of formula (I) (purchased from Shanghai Hanxiang Biotechnology Co., Ltd., crystal form A) was dissolved in 20 ml of acetic acid, and 200 ml of purified water was slowly added dropwise to the above solution. Solids gradually precipitated during the addition, and the mixture was stirred for 2 h, filtered, and dried to obtain 0.99 g of crystal form β. The XRPD spectrum, DSC spectrum, and TGA spectrum were consistent with those in Example 3.

[0093] Example 5

[0094] Experimental conditions:

[0095] The moisture absorption capacity was tested by a dynamic moisture sorption instrument (DVS Intrinsic).

[0096] Experimental equipment: DVS Intrinsic

[0097] Experimental method: 10-15 mg of each of the crystalline form A, crystalline form B and crystalline form α of the compound of formula (I) were placed in a DVS sample tray for testing.

[0098] Experimental results: At 80% humidity, the moisture absorption of Form A, Form B and Form α were 0.29%, 0.33% and 0.20% respectively, and the DVS spectra were shown in Table 1. Figure 7 , 8 and 9.

[0099] Example 6

[0100] Take the crystal form α and crystal form B samples, weigh about 10 mg of each sample and add it to a liquid phase vial, add 1 ml of anhydrous ethanol to the liquid phase vial, stir the resulting sample at 20°C, 30°C, 40°C and 50°C for 24 hours, centrifuge, and filter the supernatant using a 0.22um filter head and test the solubility by HPLC. The results are as follows:

[0101]

[0102] Example 7

[0103] To 1.0 mL of ethanol (two portions) and 1.0 mL of 1,4-dioxane (two portions) were added 20 mg of a sample of the compound of formula (I) (purchased from Shanghai Hanxiang Biotechnology Co., Ltd., Form A), the resulting suspension was stirred at 25°C and 50°C for 2 h, and filtered to obtain a saturated solution; 10 mg of Form α and 10 mg of Form B were added to each saturated solution, the resulting samples were stirred at 25°C and 50°C for 24 h, respectively, and the solid was characterized by XRD.

[0104] The results are as follows:

[0105] serial number Solvents temperature Crystal form 1 Ethanol 25℃ Crystal form α 2 1,4-Dioxane 25℃ Crystal form α 3 Ethanol 50℃ Crystal form α 4 1,4-Dioxane 50℃ Crystal form α

[0106] In addition, Form A is slurried in methanol, ethanol, acetone or 1,4-dioxane solution, and gradually transforms into Form α during the process.

[0107] Example 8

[0108] The samples of Form α and Form B were added to open containers respectively, and the samples were spread into a thin layer of ≤5 mm. The container was opened and placed in a high temperature (60°C), high humidity (92.5%±5%) and light (sunlight: 5000±500lux; ultraviolet: 90μW / cm 2 ) for 10 days, and samples were taken to characterize the purity and crystal form of the samples. The results are as follows:

[0109]

[0110] Example 9

[0111] Take a 100ml measuring cylinder and accurately weigh the mass of the measuring cylinder. Take excess crystal form α and crystal form B samples relative to the volume of the measuring cylinder and pass them through a sieve with a pore size of 1.0mm to remove lumps that may have formed during storage. Allow the sample to flow freely into the measuring cylinder until it overflows, carefully scrape the sample on the top of the measuring cylinder, remove the powder attached to the outer wall, accurately weigh the total mass of the measuring cylinder and the sample in the measuring cylinder, and calculate the bulk density as follows:

[0112] ρ 堆 =(m-m0) / v

[0113] where ρ 堆 is the bulk density, g / ml or g / cm 3 ;

[0114] m is the total mass of the measuring cylinder and the sample in the measuring cylinder, g;

[0115] m0 is the mass of the measuring cylinder, g;

[0116] v is the volume of the measuring cylinder, mL.

[0117] The results are as follows:

[0118] Crystal form <![CDATA[Bulk density (mg / cm 3 )]]> Crystal form α 260.65 Form B 88.94

Claims

1. A crystalline form α of a compound of formula (I), characterized in that: The X-ray powder diffraction pattern of the crystalline form α has characteristic diffraction peaks at the following 2θ angles: 6.6±0.2°, 18.4±0.2°, 20.0±0.2° or 23.7±0.2°; Preferably, the X-ray powder diffraction pattern of the crystalline form α has characteristic diffraction peaks at the following 2θ angles: 6.6±0.2°, 11.2±0.2°, 18.4±0.2°, 19.3±0.2°, 20.0±0.2°, 23.7±0.2°, 25.5±0.2° or 28.6±0.2°; Further preferably, the X-ray powder diffraction pattern of the crystalline form α has characteristic diffraction peaks at the following 2θ angles: 6.6±0.2°, 9.0±0.2°, 11.2±0.2°, 17.3±0.2°, 18.4±0.2°, 19.3±0.2°, 20.0±0.2°, 21.3±0.2°, 22.1±0.2°, 22.6±0.2°, 22.9±0.2°, 23.7±0.2°, 25.2±0.2°, 25.5±0.2°, 25.8±0.2°, 26.8±0.2°, 27.3±0.2°, 28.6±0.2° or 31.3±0.2°; More preferably, the X-ray powder diffraction pattern of the crystalline form α has characteristic diffraction peaks at the following 2θ angles: 6.6±0.2°, 8.4±0.2°, 9.0±0.2°, 11.2±0.2°, 17.3±0.2°, 18.4±0.2°, 19.3±0.2°, 20.0±0.2°, 21.3±0.2°, 22.1±0.2°, 22.6±0.2°, 22.9±0.2°, 23.7±0.2°, 25.2±0.2°, 25.5±0.2°, 25.8±0.2°, 26.8±0.2°, 27.3±0.2°, 28.6±0.2° or 31.3±0.2°; Most preferably, the X-ray powder diffraction pattern of the crystalline form α is as shown in FIG1 , that is, it has the characteristics represented by the X-ray powder diffraction pattern shown in FIG1 ; Wherein, the structure of the compound of formula (I) is:

2. The crystalline form α of the compound of formula (I) according to claim 1, characterized in that: The differential scanning calorimetry curve of the crystalline form α has an endothermic peak with an onset temperature of 238.65° C.; preferably, the DSC spectrum of the crystalline form α is as shown in FIG. 2 , that is, it has the characteristics represented by the DSC spectrum shown in FIG. 2 .

3. The crystalline form α of the compound of formula (I) according to claim 1, characterized in that: The thermogravimetric analysis curve of the crystal form α shows no weight loss; preferably, the TGA spectrum of the crystal form α is as shown in FIG3 , that is, it has the characteristics represented by the TGA spectrum shown in FIG3 .

4. A method for preparing the crystalline form α of the compound of formula (I) according to claim 1, comprising: Scheme 1: dissolving the crystalline form A of the compound of formula (I) in dimethyl sulfoxide, and then adding isopropanol to precipitate; or Solution 2: The crystalline form A of the compound of formula (I) is added to an organic solvent A for slurrying, wherein the organic solvent A is selected from methanol, ethanol, acetone or 1,4-dioxane.

5. A crystalline form β of the compound of formula (I), characterized in that: The X-ray powder diffraction pattern of the crystalline form β has characteristic diffraction peaks at the following 2θ angles: 6.6±0.2°, 13.3±0.2°, 19.9±0.2°, 21.0±0.2° or 24.5±0.2°; Preferably, the X-ray powder diffraction pattern of the crystalline form β has characteristic diffraction peaks at the following 2θ angles: 6.6±0.2°, 13.3±0.2°, 18.3±0.2°, 19.9±0.2°, 20.3±0.2°, 21.0±0.2°, 21.4±0.2°, 24.5±0.2° or 26.0±0.2°; Further preferably, the X-ray powder diffraction pattern of the crystalline form β has characteristic diffraction peaks at the following 2θ angles: 6.6±0.2°, 10.9±0.2°, 13.3±0.2°, 15.4±0.2°, 18.3±0.2°, 19.4±0.2°, 19.9±0.2°, 20.3±0.2°, 21.0±0.2°, 21.4±0.2°, 24.5±0.2°, 26.0±0.2°, 26.3±0.2° or 27.3±0.2°; More preferably, the X-ray powder diffraction pattern of the crystalline form β has characteristic diffraction peaks at the following 2θ angles: 6.6±0.2°, 7.7±0.2°, 10.9±0.2°, 13.3±0.2°, 15.4±0.2°, 18.3±0.2°, 19.4±0.2°, 19.9±0.2°, 20.3±0.2°, 21.0±0.2°, 21.4±0.2°, 24.5±0.2°, 26.0±0.2°, 26.3±0.2° or 27.3±0.2°; Most preferably, the X-ray powder diffraction pattern of the crystalline form β is as shown in FIG4 , that is, it has the characteristics represented by the X-ray powder diffraction pattern shown in FIG4 ; The structure of the compound of formula (I) is:

6. The crystalline form β of the compound of formula (I) according to claim 5, characterized in that: The differential scanning calorimetry curve of the crystalline form β has two endothermic peaks, and the starting temperatures are 109.41° C. and 235.51° C., respectively; preferably, the DSC spectrum of the crystalline form β is as shown in FIG. 5 , that is, it has the characteristics represented by the DSC spectrum shown in FIG. 5 .

7. The crystalline form β of the compound of formula (I) according to claim 5, characterized in that: The thermogravimetric analysis curve of the crystal form β shows a weight loss of 17.4-18.0% at ; preferably, the TGA spectrum of the crystal form β is as shown in FIG6 , that is, it has the characteristics represented by the TGA spectrum shown in FIG6 .

8. A method for preparing the crystalline form β of the compound of formula (I) as claimed in claim 5, comprising: Scheme 1: dissolving the crystalline form A of the compound of formula (I) in acetic acid, and then adding n-heptane to precipitate; or Scheme 2: Dissolve the crystalline form A of the compound of formula (I) in acetic acid, and then add purified water to precipitate.

9. A pharmaceutical composition, which is prepared by mixing one or more of the crystalline forms α or crystalline form β of the compound represented by formula (I) according to claims 1 to 8 with one or more pharmaceutically acceptable carriers, diluents or excipients.

10. Use of the crystalline form α, crystalline form β of the compound of formula (I) according to claims 1-8 or the pharmaceutical composition according to claim 9 in the preparation of a drug for treating diseases related to cell differentiation and proliferation.

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