Crystal form of aromatic vinyl derivative, production method thereof, and use

Abstract

The present invention discloses crystalline forms of aromatic vinyl derivatives and their preparation and use. Specifically, the present invention discloses crystalline forms A, B, and C of the compound represented by Formula I. The crystalline forms of the present invention have good stability, are less likely to absorb moisture, and are easy to prepare, making them of great value in the optimization and development of pharmaceuticals. [Formula 1] TIFF2023518393000029.tif32170

Description

Detailed Description of the Invention

[0001] This application claims the priority of Chinese Patent Application CN2020101855977 with an application date of March 17, 2020. This application incorporates the full text of the Chinese patent application by reference. [Technical Field] The present invention relates to a crystalline form of an aromatic vinyl derivative, a method for producing the same, and uses thereof.

[0002] [Background Art] Human programmed cell death ligand 1 (PD-L1), also known as B7-H1, belongs to the B7 family and is widely distributed in peripheral tissues and hematopoietic cells. The full-length cDNA of PD-L1q is 870 bp and encodes a type I transmembrane protein containing 290 amino acids. PD-L1 is mainly expressed on the membrane surfaces of hematopoietic cells such as mature CD4 T cells, CD8 T cells, B cells, monocytes, dendritic cells (DCs), macrophages, and some non-hematopoietic cells such as endothelial cells, pancreatic islet cells, and mast cells. Among them, PD-L1 is highly expressed in various tumors such as lung cancer, gastric cancer, multiple myeloma, melanoma, and breast cancer. Programmed death protein 1 (PD-1) is the main receptor of PD-L1 and is mainly distributed in immune-related cells such as T cells, B cells, and NK cells, playing an important role in immune response processes such as autoimmune diseases, tumors, infections, organ transplantation, allergies, and immune privilege.

[0003] PD-L1 inhibits T cell activation or induces apoptosis of mature T cells by interacting with its receptor, programmed death protein 1, thereby inhibiting the immune response. During the development of tumors, cancer cells induce apoptosis of T cells by increasing the expression of PD-L1, and the immune system avoids clearance of it. PD-L1-targeted antibody drugs can specifically block the PD-1 / PD-L1 interaction, disrupt tumor immune tolerance, restore the killing function of tumor-specific T cells against tumor cells, and achieve tumor clearance.

[0004] PD-1 / PD-L1 plays a role in negative immune regulation. The PD-1 / PD-L1 signal inhibits the activation and proliferation of T cells and simultaneously reduces the secretion of cytokines interleukin-2 (IL-2), interferon-γ, and IL-10 (Eur. J. Immunol., 2002, 32(3), 634-643.). Also, the immune function of the PD-1 / PD-L1 signal on B cells is similar to that on T cells. After PD-1 crosslinks with the B cell antigen receptor, the cytoplasmic region of PD-1 interacts with tyrosine kinases including the protein tyrosine kinase 2 binding site, ultimately inhibiting the activation of B cells. The role of the immune negative regulatory factor PD-1 / PD-L1 in tumor immune escape has been attracting increasing attention. When the PD-L1 on the surface of tumor cells in the tumor microenvironment increases, it binds to PD-1 on activated T cells at the same time, transmitting a negative regulatory signal, resulting in apoptosis or immune deficiency of tumor antigen-specific T cells, thereby inhibiting the immune response and promoting the escape of tumor cells, which has been proven by many studies.

[0005] Currently, the commercially available PD-1 / PD-L1 antibody inhibitors include Nivolumab (2014) from BMS, Lambrolizumab (2014) from Merck, Toripalimab from Junshi Bio, Sintilimab from Innovent, Atezolizumab from Roche, and Durvalumab from AstraZeneca. Compared with biopolymers, small molecule compounds can pass through cell membranes and act on intracellular targets. After chemical modification, small molecule compounds often have better bioavailability and compliance and effectively avoid the degradation inactivation of enzymes in the digestive tract.

[0006] Currently, there is still no commercially available small molecule PD-1 / PD-L1 inhibitor that is easy to use and orally effective. Patent CN109988144A discloses an aromatic ethylene-based small molecule PD-L1 compound, and the chemical structural formula is

[0007]

Chemical formula

[0008] In addition to excellent inhibitory activity against kinases, the crystal structure of a pharmaceutical active ingredient often affects the chemical stability of the drug, and the crystal structure of a compound may change depending on the crystal form, production method, and storage conditions, and sometimes it may be accompanied by the generation of other crystal forms. Generally, amorphous pharmaceuticals do not have a regular crystal structure and often have disadvantages such as low product stability, fine crystallization, easy caking, and poor fluidity, and these differences often make it difficult to scale up production. Also, the crystal form has a decisive influence on the stability during the production, processing, storage, and transportation of the drug and the bioavailability during treatment. Furthermore, from the perspective of obtaining a commercially viable production method or manufacturing a pharmaceutical composition containing an active compound, the chemical stability, solid stability, and shelf life of the active ingredient are all important factors. Therefore, providing an appropriate form of the drug with desirable properties is very important for the production and storage of the drug.

[0009] [Summary of the Invention] The present invention provides a crystal form of an aromatic vinyl derivative, a method for producing the same, and uses thereof. The crystal form of the present invention has good stability, is difficult to absorb moisture, is easy to manufacture, and has important value for the optimization and development of drugs.

[0010] The present invention provides a Form A crystal of a compound represented by formula I, the powder X-ray diffraction pattern of which represented by 2θ angle has characteristic peaks at 9.923 ± 0.2°, 10.883 ± 0.2°, and 17.357 ± 0.2°.

[0011] Or, it has characteristic peaks at 3.979 ± 0.2°, 9.923 ± 0.2°, 10.883 ± 0.2°, 17.357 ± 0.2°, 18.607 ± 0.2°, and 19.294 ± 0.2°.

[0012] Or, it has characteristic peaks at 3.979 ± 0.2°, 4.991 ± 0.2°, 9.923 ± 0.2°, 10.883 ± 0.2°, 14.251 ± 0.2°, 16.210 ± 0.2°, 17.357 ± 0.2°, 18.607 ± 0.2°, 19.294 ± 0.2°, 19.594 ± 0.2°, and 20.792 ± 0.2°.

[0013] Or, it has characteristic peaks at 3.979 ± 0.2°, 4.991 ± 0.2°, 7.113 ± 0.2°, 8.135 ± 0.2°, 9.923 ± 0.2°, 10.883 ± 0.2°, 11.613 ± 0.2°, 14.251 ± 0.2°, 14.866 ± 0.2°, 16.210 ± 0.2°, 17.357 ± 0.2°, 18.607 ± 0.2°, 19.294 ± 0.2°, 19.594 ± 0.2°, 20.792 ± 0.2°, 21.272 ± 0.2°, 24.437 ± 0.2°, 25.257 ± 0.2°, 26.2295 ± 0.2°, 27.870 ± 0.2°, 28.631 ± 0.2°, 29.126 ± 0.2°, 29.943 ± 0.2°.

[0014]

Chemical formula

[0015] In some preferred embodiments of the present invention, for the A-type crystal, the 2θ values in the powder X-ray diffraction pattern represented by the 2θ angle are as shown in Table 1.

[0016]

Table 1

[0017] In some preferred embodiments of the present invention, in the polarized light microscopic analysis of the A-type crystal, the crystal shape is preferably granular or rod-shaped, the particle size is preferably 10 to 100 μm, and the polarized light microscopic analysis of the A-type crystal can be carried out under the following conditions: the microscope is preferably a 10x objective lens, and the microscope is preferably a crossed polarizer. The polarized light micrograph of the A-type crystal is preferably as shown in FIG. 1.

[0018] In some preferred embodiments of the present invention, in the differential scanning calorimetry analysis of the A-type crystal, it has an endothermic peak at 247 °C, and its heat of fusion is preferably 118.0 J / g. The differential scanning calorimetry analysis of the A-type crystal can be carried out under the following conditions: preferably carried out in an unsealed aluminum tray, preferably carried out under a nitrogen gas flow (for example, a nitrogen gas flow with a flow rate of 50 mL / min), preferably equilibrated at 25 °C, preferably heated at a heating rate of 10 °C / min, and preferably heated from 25 °C to 300 °C. The differential scanning calorimetry (DSC) pattern of the A-type crystal is preferably as shown in FIG. 2.

[0019] In some preferred embodiments of the present invention, in the thermogravimetric analysis of the A-type crystal, the weight loss of the sample from 26.76 °C to 119.97 °C is only 0.1447%, and the “%” is weight percentage. The thermogravimetric analysis of the A-type crystal can be carried out under the following conditions: preferably carried out in a platinum sample pan, preferably carried out in a nitrogen gas flow (for example, a nitrogen gas flow with a flow rate of 60 mL / min), preferably heated at a heating rate of 10 °C / min, and preferably heated from 25 °C to 300 °C. The thermogravimetric analysis (TGA) pattern of the A-type crystal is preferably as shown in FIG. 3.

[0020] In some preferred embodiments of the present invention, in the X-ray diffraction analysis of the Type A crystal, the X-ray diffraction analysis of the Type A crystal can be carried out under the following conditions: preferably performed with a CuK light source, preferably with an X-ray intensity of 40KV / 40mA, preferably with a scan mode of Theta-Theta, preferably with an angle range of 2° to 40° (for example, 4° to 40°), preferably with a step size of 0.05°, and preferably with a scan speed of 0.5 seconds / step. The powder X-ray diffraction pattern (XRPD) of the Type A crystal is preferably as shown in FIG. 4.

[0021] In some preferred embodiments of the present invention, in the dynamic moisture sorption analysis of the Type A crystal, the increase in moisture absorption weight at a humidity of 80% RH is 0.310%, and the increase in moisture absorption weight at a humidity of 95% RH is 0.409%, indicating that the Type A crystal has slight hygroscopicity. The dynamic moisture sorption analysis of the Type A crystal can be carried out under the following conditions: preferably performed at a temperature of 25°C, preferably after being dried at a humidity of 0% RH for 60 minutes. The dynamic moisture sorption analysis pattern (DVS) of the Type A crystal is preferably as shown in FIG. 5.

[0022] The present invention provides a Type B crystal of a compound represented by Formula I having characteristic peaks at 3.424 ± 0.2°, 6.576 ± 0.2° and 19.297 ± 0.2° in the powder X-ray diffraction pattern represented by the 2θ angle.

[0023] Or, it has characteristic peaks at 3.424 ± 0.2°, 6.576 ± 0.2°, 18.217 ± 0.2°, 19.297 ± 0.2°, 20.901 ± 0.2° and 26.379 ± 0.2°.

[0024] Or, it has characteristic peaks at 3.424 ± 0.2°, 6.576 ± 0.2°, 14.467 ± 0.2°, 16.406 ± 0.2°, 17.567 ± 0.2°, 18.217 ± 0.2°, 19.297 ± 0.2°, 20.557 ± 0.2°, 20.901 ± 0.2°, 22.460 ± 0.2°, 25.084 ± 0.2°, 25.878 ± 0.2°, 26.379 ± 0.2°, and 28.983 ± 0.2°.

[0025] Or, it has characteristic peaks at 3.424 ± 0.2°, 6.576 ± 0.2°, 9.732 ± 0.2°, 11.304 ± 0.2°, 12.905 ± 0.2°, 13.918 ± 0.2°, 14.467 ± 0.2°, 16.406 ± 0.2°, 17.567 ± 0.2°, 18.217 ± 0.2°, 19.297 ± 0.2°, 20.557 ± 0.2°, 20.901 ± 0.2°, 22.460 ± 0.2°, 23.872 ± 0.2°, 25.084 ± 0.2°, 25.878 ± 0.2°, 26.379 ± 0.2°, 28.983 ± 0.2°, 29.531 ± 0.2°, 30.459 ± 0.2°, 32.171 ± 0.2°, 34.297 ± 0.2°, 37.676 ± 0.2°, and 38.902 ± 0.2°.

[0026]

Chemical Formula

[0027] In some preferred embodiments of the present invention, for the B-type crystal, the 2θ values in the powder X-ray diffraction pattern represented by the 2θ angle are as shown in Table 2.

[0028]

Table 2

[0029] In some preferred embodiments of the present invention, in the X-ray diffraction analysis of the B-type crystal, the X-ray diffraction analysis of the B-type crystal can be carried out under the following conditions: preferably performed with a CuK light source, preferably with an X-ray intensity of 40 KV / 40 mA, preferably with a scan mode of Theta-Theta, preferably with an angular range of 2° to 40° (for example, 4° to 40°), preferably with a step size of 0.05°, and preferably with a scan speed of 0.5 seconds / step. The powder X-ray diffraction pattern (XRPD) of the B-type crystal is preferably as shown in FIG. 6.

[0030] In some preferred embodiments of the present invention, in the differential scanning calorimetry analysis of the B-type crystal, it has an endothermic peak at 243 °C, and its heat of fusion is preferably 93.73 J / g. The differential scanning calorimetry analysis of the B-type crystal can be carried out under the following conditions: preferably performed in an unsealed aluminum tray, preferably performed under a nitrogen gas flow (for example, a nitrogen gas flow with a flow rate of 50 mL / min), preferably equilibrated at 25 °C, preferably heated at a heating rate of 10 °C / min, and preferably heated from 25 °C to 300 °C. The differential scanning calorimetry pattern (DSC) of the B-type crystal is preferably as shown in FIG. 7.

[0031] In some preferred embodiments of the present invention, in the thermogravimetric analysis of the B-type crystal, when heated from 25.3 °C to 92.5 °C, there is a 5.2% weight loss, where the "%" is weight percentage. The thermogravimetric analysis of the B-type crystal can be carried out under the following conditions: preferably performed in a platinum sample pan, preferably performed in a nitrogen gas flow (for example, a nitrogen gas flow with a flow rate of 60 mL / min), preferably heated at a heating rate of 10 °C / min, and preferably heated from 25 °C to 300 °C. The thermogravimetric analysis (TGA) pattern of the B-type crystal is preferably as shown in FIG. 8.

[0032] In some preferred embodiments of the present invention, in the dynamic moisture sorption analysis of the B-type crystal, the weight increase of the sample from a relative humidity (RH) of 0% to 95% RH is 7.235%, indicating that the B-type crystal has hygroscopicity. The dynamic moisture sorption analysis of the B-type crystal can be carried out under the following conditions: preferably at a temperature of 25 °C, preferably after drying at a humidity of 0% RH for 60 minutes. The dynamic moisture sorption analysis (DVS) of the B-type crystal is preferably as shown in FIG. 9.

[0033] The present invention provides a C-type crystal of a compound represented by formula I, the powder X-ray diffraction pattern of which represented by 2θ angle has characteristic peaks at 6.250 ± 0.2°, 18.458 ± 0.2° and 19.302 ± 0.2°.

[0034] Or, it has characteristic peaks at 6.250 ± 0.2°, 8.779 ± 0.2°, 13.720 ± 0.2°, 18.458 ± 0.2° and 19.302 ± 0.2°. Or, it has characteristic peaks at 6.250 ± 0.2°, 8.779 ± 0.2°, 12.635 ± 0.2°, 13.720 ± 0.2°, 16.525 ± 0.2°, 18.458 ± 0.2° and 19.302 ± 0.2°.

[0035] Or, it has characteristic peaks at 6.250 ± 0.2°, 6.979 ± 0.2°, 8.779 ± 0.2°, 12.635 ± 0.2°, 13.720 ± 0.2°, 16.525 ± 0.2°, 18.458 ± 0.2°, 19.302 ± 0.2°, 20.852 ± 0.2°, 22.345 ± 0.2°, 24.772 ± 0.2°, 25.230 ± 0.2°, 27.285 ± 0.2°.

[0036] Or it has characteristic peaks at 6.250 ± 0.2°, 6.979 ± 0.2°, 8.779 ± 0.2°, 12.635 ± 0.2°, 13.720 ± 0.2°, 15.285 ± 0.2°, 16.525 ± 0.2°, 18.458 ± 0.2°, 19.302 ± 0.2°, 20.852 ± 0.2°, 22.345 ± 0.2°, 24.772 ± 0.2°, 25.230 ± 0.2°, 25.996 ± 0.2°, 27.285 ± 0.2°, 28.303 ± 0.2°, 28.829 ± 0.2°, 29.699 ± 0.2°, 30.703 ± 0.2°, 33.133 ± 0.2°, 34.655 ± 0.2°, 36.829 ± 0.2°, 37.967 ± 0.2°.

[0037]

Chemical formula

[0038] In some preferred embodiments of the present invention, for the C-type crystal, the 2θ values in the powder X-ray diffraction pattern represented by the 2θ angle are as shown in Table 3.

[0039]

Table 3

[0040] In some preferred embodiments of the present invention, in the X-ray diffraction analysis of the C-type crystal, the powder X-ray diffraction pattern (XRPD) of the C-type crystal is preferably as shown in FIG. 10. In some preferred embodiments of the present invention, in the differential scanning calorimetry analysis of the C-type crystal, it has an endothermic peak at 243 °C, and the heat of fusion is preferably 99.33 J / g. The differential scanning calorimetry analysis of the C-type crystal can be carried out under the following conditions: preferably carried out in an unsealed aluminum tray, preferably carried out under a nitrogen gas flow (for example, a nitrogen gas flow with a flow rate of 50 mL / min), preferably equilibrated at 25 °C, preferably heated at a heating rate of 10 °C / min, and preferably heated from 25 °C to 300 °C. The differential scanning calorimetry pattern (DSC) of the C-type crystal is preferably as shown in FIG. 11.

[0041] In some preferred embodiments of the present invention, in the thermogravimetric analysis of the C-type crystal, when heated from 24.0 °C to 58.0 °C, there is a weight loss of 0.62%, and when heated from 58.0 °C to 162.3 °C, there is a weight loss of 2.5%. The “%” is weight percentage. The thermogravimetric analysis of the C-type crystal can be carried out under the following conditions: preferably in a platinum sample pan, preferably in a nitrogen gas stream (for example, a nitrogen gas stream with a flow rate of 60 mL / min), preferably heated at a heating rate of 10 °C / min, and preferably heated from 25 °C to 300 °C. The thermogravimetric analysis (TGA) pattern of the C-type crystal is preferably as shown in FIG. 12.

[0042] In some preferred embodiments of the present invention, in the dynamic moisture sorption analysis of the C-type crystal, the weight increase of the sample from 0% RH to 95% RH is 4.767%, indicating that the C-type crystal has hygroscopicity. The dynamic moisture sorption analysis of the C-type crystal can be carried out under the following conditions: preferably at a temperature of 25 °C, preferably after drying for 60 minutes at a humidity of 0% RH. The dynamic moisture sorption analysis pattern (DVS) of the C-type crystal is preferably as shown in FIG. 13.

[0043] In the present invention, the spectrum used in the powder X-ray diffraction spectrum is the Kα spectrum. In the present invention, the type of the target used in the powder X-ray diffraction spectrum is a Cu target.

[0044] Further, the present invention provides a method for producing the A-type crystal of the compound represented by formula I, including the step of crystallizing the compound represented by formula I in the following solvent. The crystallization method is a suspension equilibrium method, a solution heating-cooling method or an antisolvent method. The solvent is ethanol. When the crystallization method is an antisolvent method, the antisolvent is an alkane-based solvent.

[0045] In the method for producing the A-type crystal, when the crystallization method is the antisolvent method, the alkane solvent may be a normal alkane solvent in the technical field, and the alkane solvent is preferably C 1-10 an alkane solvent, more preferably n-heptane.

[0046] In the method for producing the A-type crystal, the crystallization temperature may be a normal temperature in the technical field, and the crystallization temperature is preferably 20°C to 60°C (for example, room temperature (20°C to 25°C) or 50°C).

[0047] In the method for producing the A-type crystal, the mass-volume ratio of the compound represented by the formula I to the solvent may be a normal ratio in the technical field, and is preferably 5 mg / mL to 20 mg / mL (for example, 7.7 mg / mL to 20 mg / mL).

[0048] In the method for producing the A-type crystal, the crystallization time is not particularly limited as long as crystals can be precipitated, and the crystallization time is preferably 1 h to 20 d (for example, 1 h to 2 h, 5 h to 6 h, or 10 d to 20 d).

[0049] In the method for producing the A-type crystal, when the crystallization method is the antisolvent method, the mass ratio of the antisolvent to the solvent may be a normal ratio in the technical field, and is preferably 5:1 to 8:1 (for example, 6.5:1).

[0050] In the method for producing the A-type crystal, preferably the following steps are included: mixing the solvent and the compound represented by the formula I, and obtaining the target crystal form by ultrasonic treatment, rotation, and centrifugation. The rotation is preferably carried out in the dark. The rotation is preferably carried out at room temperature. The rotation is preferably carried out using a Labquaker rotating device. The rotation is preferably carried out for 10 d to 20 d. After the centrifugation, it is preferably further included an operation of drying. The mass-volume ratio of the compound represented by the formula I to the solvent is preferably 5 mg / mL to 20 mg / mL (for example, 7.7 mg / mL to 20 mg / mL).

[0051] In the method for producing the A-type crystal, preferably the following steps are included: mixing the solvent and the compound represented by the formula I, heating and dissolving it, gradually cooling it to room temperature, and centrifuging to obtain the target crystal form. The temperature of the heating and dissolving is preferably 50 °C to 60 °C. The heating and dissolving is preferably water bath heating. The heating and dissolving preferably includes a stirring operation at the same time, and the stirring speed is preferably 200 rpm. After the heating and dissolving is completed, it is preferably included a heat preservation operation, and the heat preservation time is preferably 15 minutes. After the heating and dissolving is completed, it is preferably further included a hot filtration operation, and the filtration preferably employs a 0.45 μm filter membrane. The rate of gradual cooling is preferably 6 °C / h. After the centrifugation, it is preferably further included an operation of evaporating and drying the solvent. The mass-volume ratio of the compound represented by the formula I to the solvent is preferably 5 mg / mL to 20 mg / mL (for example, 7.7 mg / mL to 20 mg / mL).

[0052] In the method for producing the A-type crystal, preferably the following steps are included: mixing the solvent and the compound represented by the above formula I, heating and dissolving, dropping the anti-solvent, then naturally cooling, and centrifuging to obtain the target crystal form. The temperature of the heating and dissolving is preferably 50°C to 60°C. The heating and dissolving preferably includes a stirring operation at the same time, and the stirring speed is preferably 200 rpm. After the heating and dissolving is completed, it is preferably to include a heat preservation operation, and the heat preservation time is preferably 15 minutes. After the heating and dissolving is completed, it is preferably to further include a hot filtration operation, and preferably a 0.45 μm filter membrane is adopted for the filtration. At the same time as dropping the anti-solvent, it is preferably to include a stirring operation. The volume ratio of the anti-solvent to the solvent is preferably 5:1 to 8:1 (for example, 6.5:1). After the dropping of the anti-solvent is completed, it is preferably to include a heat preservation operation, and the heat preservation time is preferably 10 minutes. After the centrifuging is completed, it is preferably to further include an operation of evaporating and drying the solvent. The mass-volume ratio of the compound represented by the formula I to the solvent is preferably 5 mg / mL to 20 mg / mL (for example, 7.7 mg / mL to 20 mg / mL).

[0053] In addition, the present invention provides a method for producing a B-type crystal of a compound represented by the formula I, which includes the step of crystallizing the compound represented by the formula I in the following solvent, and the crystallization method is a suspension equilibrium method or an anti-solvent method. When the crystallization method is a suspension equilibrium method, the solvent is water, or ethanol and water. When the crystallization method is an anti-solvent method, the solvent is ethanol or tetrahydrofuran, and the anti-solvent is water.

[0054] In the method for producing the B-type crystal, the water may be one or more of distilled water, deionized water, purified water, tap water and mineral water. In the method for producing the B-type crystal, the crystallization temperature may be a normal temperature in the technical field, and the crystallization temperature is preferably 20°C to 60°C (for example, room temperature (20°C to 25°C) or 50°C).

[0055] In the method for producing the B-type crystal, the mass-volume ratio of the compound represented by the formula I to the solvent may be a normal ratio in the technical field, preferably 5 mg / mL to 40 mg / mL (for example, 7.7 mg / mL, 11.1 mg / mL, 20 mg / mL, or 33.3 mg / mL).

[0056] In the method for producing the B-type crystal, when the crystallization method is the suspension equilibrium method and the solvent is ethanol and water, the volume ratio of ethanol to water is preferably 1:3 to 1:5 (for example, 1:4).

[0057] In the method for producing the B-type crystal, when the crystallization method is the anti-solvent method, the volume ratio of the anti-solvent to the solvent is preferably 1:1 to 4:1 (for example, 1:1 or 2.7:1). In the method for producing the B-type crystal, the crystallization time is not particularly limited as long as crystals can be precipitated, and the crystallization time is preferably 1 h to 20 d (for example, 1 h to 2 h, 1 d, or 17 d).

[0058] In the method for producing the B-type crystal, when the crystallization method is the suspension equilibrium method, it preferably includes the following steps: mixing the solvent and the compound represented by the formula I, slurrying, and separating the solid to obtain the target crystal form. The slurrying is preferably carried out at room temperature. The slurrying is preferably carried out with stirring. The stirring is preferably magnetic stirring. The slurrying is preferably carried out for 1 d to 17 d. The separation of the solid is preferably centrifugation or filtration. After the separation of the solid is completed, an operation including drying is preferably further carried out. The drying is preferably carried out at 40 °C, and the drying is preferably carried out for 4 h. The mass-volume ratio of the compound represented by the formula I to the solvent is preferably 5 mg / mL to 40 mg / mL (for example, 7.7 mg / mL, 11.1 mg / mL, 20 mg / mL, or 33.3 mg / mL).

[0059] In the method for producing the B-type crystal, when the crystallization method is the antisolvent method, it preferably includes the following steps: Mix the solvent and the compound represented by Formula I, heat and dissolve them, dropwise add the antisolvent, then cool naturally, and perform centrifugation to obtain the target crystal form. The temperature for heating and dissolving is preferably 50°C to 60°C. The heating and dissolving preferably includes a stirring operation simultaneously, and the stirring speed is preferably 200 rpm. After the heating and dissolving is completed, it preferably includes a heat preservation operation, and the heat preservation time is preferably 15 minutes. After the heating and dissolving is completed, it preferably includes a hot filtration operation, and the filtration preferably employs a 0.45 μm filter membrane. The dropping of the antisolvent is preferably carried out while stirring. After the dropping of the antisolvent is completed, it preferably includes a heat preservation operation, and the heat preservation time is preferably 10 minutes. After the centrifugation is completed, it is preferably further included an operation of evaporating and drying the solvent. The mass-volume ratio of the compound represented by Formula I to the solvent is preferably 5 mg / mL to 40 mg / mL (for example, 7.7 mg / mL, 11.1 mg / mL, 20 mg / mL, or 33.3 mg / mL).

[0060] In addition, the present invention provides a method for producing a C-type crystal of a compound represented by Formula I, which includes the step of crystallizing the compound represented by Formula I by the suspension equilibrium method in the following solvent, and the solvent is isopropanol, N,N-dimethylacetamide, or acetone and water.

[0061] In the method for producing the C-type crystal, when the solvent is acetone and water, the volume ratio of acetone to water is preferably 7:1 to 10:1 (for example, 8:1). In the method for producing the C-type crystal, the water may be one or more of distilled water, deionized water, purified water, tap water, and mineral water.

[0062] In the method for producing the C-type crystal, the crystallization temperature may be a normal temperature in the technical field, and the crystallization temperature is preferably room temperature. In the method for producing the C-type crystal, the mass-volume ratio of the compound represented by the formula I to the solvent may be a normal ratio in the technical field, and the mass-volume ratio of the compound represented by the formula I to the solvent is preferably 10 mg / mL to 50 mg / mL (for example, 20 mg / mL, 40 mg / mL, or 44.4 mg / mL).

[0063] In the method for producing the C-type crystal, the crystallization time is not particularly limited as long as crystals can be precipitated, and the crystallization time is preferably 1 d to 20 d (for example, 1 d, 7 d, 10 d, or 20 d).

[0064] In the method for producing the C-type crystal, preferably, the following steps are included: mixing the solvent and the compound represented by the formula I, slurrying or rotating, and separating the solid to obtain the target crystal form. After the mixing is completed, it is preferably further included ultrasonic operation, and the ultrasonic is preferably performed for 1 minute. When the method for producing the C-type crystal includes slurrying, the slurrying is preferably performed for 1 d, the slurrying is preferably performed under stirring, and the stirring is preferably magnetic stirring. When the method for producing the C-type crystal includes rotation, the rotation is preferably performed for 10 d to 20 d, the rotation is preferably performed with a Labquaker rotating device, and the rotation is preferably performed in the dark. The separation of the solid is preferably centrifugation or filtration. After the separation of the solid is completed, an operation including drying is preferably further performed. The drying is preferably performed at 70 °C, and the drying is preferably performed for 4 h. The mass-volume ratio of the compound represented by the formula I to the solvent is preferably 10 mg / mL to 50 mg / mL (for example, 20 mg / mL, 40 mg / mL, or 44.4 mg / mL).

[0065] Furthermore, the present invention provides the use of the crystalline form of the compound represented by formula I in the manufacture of a drug. The compound is used in the manufacture of a drug for preventing, alleviating and / or treating a related disease caused by cancer, and the cancer is preferably one or more of lung cancer, esophageal cancer, gastric cancer, colorectal cancer, liver cancer, nasopharyngeal cancer, brain tumor, breast cancer, cervical cancer, blood cancer and bone cancer. The drug is preferably the A-type crystal, B-type crystal or C-type crystal of the compound represented by formula I containing a therapeutically effective amount.

[0066] As used herein, the term "d" refers to day, the term "h" refers to hour, and the term "min" refers to minute. Based on the common general knowledge in the art, by arbitrarily combining the above preferred conditions, each preferred example of the present invention can be obtained.

[0067] All the reagents and raw materials used in the present invention can be obtained as commercially available products. The positive progressive effects of the present invention are as follows. 1. The prior art does not describe the crystalline form of the compound represented by formula I, and the present application discovers a plurality of new crystalline forms thereof for the first time. Through extensive experiments and screenings, the A-type crystal, B-type crystal and C-type crystal were selected as candidates.

[0068] 2. The A-type crystal, B-type crystal and C-type crystal produced by the present invention have good stability, are difficult to absorb moisture, are easy to manufacture, can avoid the risk of trans-crystallization during drug development or manufacture, avoid changes in bioavailability and drug efficacy, can be developed into a dosage form suitable for clinical use, and have high economic value.

[0069] 3. The present invention also provides a method for manufacturing a novel crystalline form of the compound represented by formula I, which is simple, easy to operate, highly reproducible, the solvent does not easily remain, is environmentally friendly, and is suitable for manufacture on different scales.

Brief Description of the Drawings

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Figure 25

Mode for Carrying Out the Invention

[0071] [Specific Embodiments] Hereinafter, the present invention will be further described with reference to examples, but the present invention is not limited to the above examples. In the following examples, experimental methods for which specific conditions are not indicated shall follow conventional methods and conditions or be selected according to the trade specifications.

[0072] In the following production methods of crystal forms, the volume (mL) of the solvent to be added = sample mass × volume multiple (mL). For example, the volume of ethanol in Production Method 1 of Example 1 is: 0.02 × 50 mL = 1 mL.

[0073] Production of amorphous Compound I (compound represented by Formula I): At room temperature, acetic acid (32.8 mg, 0.54 mmol) was added to a mixed solution of compound 5-a (the production of compound 5-a was obtained with reference to the method of patent CN109988144A) and (S)-2-methylserine (65 mg, 0.54 mmol) in methanol (10 mL) and dichloromethane (10 mL), and the reaction solution was stirred at room temperature for 1 hour. Next, sodium cyanoborohydride (85.8 mg, 1.36 mmol) was added and stirred for 16 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in ethyl acetate (50 mL), washed with water (20 mL) and saturated brine (20 mL), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated on a silica gel TLC preparative plate using a mobile phase of dichloromethane:methanol = 10:1. The silica gel containing compound I was washed with methanol (20 mL × 3), and the washing solution was concentrated under reduced pressure to obtain amorphous compound I (24 mg, yield 18.7%). LC-MS (ESI): m / z = 468 [M-H] -

[0074] 1 H NMR (500 MHz, CD3OD) δ: 8.17 (s, 1H), 7.81 - 7.79 (d, J = 8.5 Hz, 1H), 7.68 - 7.62 (m, 2H), 7.57 - 7.55 (d, J = 8.0 Hz, 1H), 7.46 - 7.43 (m, 2H), 7.39 - 7.28 (m, 5H), 7.20 - 7.19 (d, J = 7.0 Hz, 1H), 4.36 - 4.28 (q, 2H), 4.03 - 4.00 (d, J = 12.5 Hz, 1H), 3.86 - 3.84 (d, J = 12.5 Hz, 1H), 2.33 (s, 3H), 1.57 (s, 3H) ppm.

[0075] Example 1: Method for producing A-type crystals: Manufacturing Method 1: Weigh 20 mg of the compound represented by Formula I into a 4 mL glass bottle, add 50 volumes of ethanol (EtOH) to the glass bottle, perform ultrasonic treatment for 1 minute to obtain a suspension of the sample, wrap the suspension sample vial with aluminum foil to avoid light, place it on a Labquaker rotating device, start equilibration by rotating 360 degrees at room temperature (about 20 - 25 °C), collect the samples on the 10th day and 20th day respectively, centrifuge them, and after drying, evaluate the characteristics by XRPD. The result of the characteristic evaluation was A-type crystals.

[0076] Manufacturing Method 2: Weigh approximately 20 mg of the compound represented by Formula I into a 10 mL glass vial, add 130 volumes of ethanol (EtOH) to the glass vial, place the sample on a magnetic heating stirrer, with the water bath temperature at about 50 °C and the rotation speed at 200 rpm, promote the dissolution of the sample by heating, keep it warm for 15 minutes, then filter the solution through a 0.45 μm filter while it is hot, transfer the filtrate to a new glass bottle, slowly lower the temperature to room temperature (20 - 25 °C) at a rate of 6 °C / h, centrifuge the solvent system in which the solid has precipitated, take out the solid, evaporate the solvent to dryness, and then evaluate the characteristics by XRPD. The result of the characteristic evaluation was A-type crystals.

[0077] Manufacturing Method 3: (Anti-solvent method): Weigh approximately 80 mg of the compound sample represented by Formula I into a 20 ml glass vial, add 130 volumes of the good solvent ethanol (EtOH) to the vial, place the sample vial on a magnetic heating stirrer, with the water bath temperature at about 50 °C and the rotation speed at 200 rpm, promote the dissolution of the sample by heating, keep it warm for 15 minutes, then filter the solution through a 0.45 μm filter while it is hot, transfer the filtrate to a new glass bottle, slowly add 850 times the anti-solvent n-heptane to each vial while stirring, keep it warm for 10 minutes, then let the temperature drop naturally, next centrifuge the solvent system in which the solid has precipitated to take out the solid, evaporate the solvent to dryness, and then evaluate the characteristics by XRPD. The result of the characteristic evaluation was A-type crystals.

[0078] Example 2: Manufacturing method of B-type crystals: Manufacturing Method 1: Weigh 200 mg of the compound represented by Formula I into a vial, add 10 times the amount of ethanol and 40 times the amount of water to the vial, stir magnetically at room temperature for 1 day to form a slurry, centrifuge the solution, collect the solid, dry it at 40 °C for 4 hours, evaluate the characteristics of the dried solid, and the result of the characteristic evaluation was B-type crystals.

[0079] Manufacturing Method 2: Weigh 100 mg of the compound represented by Formula I into a glass vial, add 30 times the volume of water to the glass vial, stir magnetically at room temperature for 17 days to form a slurry, filter under reduced pressure, dry at 40 °C for 4 hours, evaluate the characteristics by XRPD, and the result of the characteristic evaluation was B-type crystals.

[0080] Manufacturing Method 3 (Anti-solvent Method): Weigh approximately 80 mg of a sample of the compound represented by Formula I into a 20 mL glass vial, add an appropriate volume of a good solvent to the vial according to the following table (see Table 4 for specific volumes), place the sample vial on a magnetic heating stirrer, the water bath temperature is about 50 °C, the rotation speed is 200 rpm, the water bath temperature is maintained to promote the dissolution of the sample, keep warm for 15 minutes, filter each solution through a 0.45 μm filter while it is hot, transfer the filtrate to a new vial, slowly drop different anti-solvents into each vial while stirring, keep warm for 10 minutes, then let the temperature drop naturally, then centrifuge the solvent system in which the solid has precipitated to take out the solid, after the solvent has dried up, evaluate the characteristics by XRPD, and the result of the characteristic evaluation was B-type crystals.

[0081]

Table 4

[0082] Example 3: Manufacturing Method of C-Type Crystals: Manufacturing Method 1: Weigh 200 mg of a sample of the compound represented by Formula I, add 20 times the amount of acetone and 2.5 times the amount of water, stir magnetically at room temperature for 1 day to form a slurry, then centrifuge the solution, collect the solid, dry the collected solid at 70 °C for 4 hours, evaluate the characteristics of the dried solid by XRPD, and the result of the characteristic evaluation was C-type crystals.

[0083] Manufacturing Method 2: 200 mg of the compound represented by Formula I and 25 times the amount of isopropanol (IPA) were magnetically stirred at room temperature for 7 days to form a slurry, filtered under reduced pressure, the solid was dried at 70 °C for 4 hours, the solid sample was characterized by XRPD, and the result of the characterization was that it was a C-type crystal.

[0084] Manufacturing Method 3: 20 mg of the compound represented by Formula I was weighed into a 4 mL glass vial, 50 times the volume of N,N-dimethylacetamide (DMA) was added to the glass vial, sonicated for 1 minute to obtain a suspension of the sample, the suspension sample vial was wrapped with aluminum foil to avoid light, placed in a Labquaker rotating device, and rotation was started at room temperature (about 20 - 25 °C) for 360 degrees. The samples were sampled on the 10th and 20th days respectively, centrifuged, characterized by XRPD after drying, and the result of the characterization was that it was a C-type crystal.

[0085] The structure determination of the A-type crystal, B-type crystal, and C-type crystal of the said compound was carried out by powder X-ray diffraction pattern (XRPD), differential scanning calorimetry (DSC), thermogravimetric loss analyzer (TGA), or dynamic vapor sorption analyzer (DVS), etc., and crystal form research, etc. was carried out.

[0086] Example 4: Polarizing Microscope Characterization of A-Type Crystal (Figure 1) A small amount of the sample of the A-type crystal of the compound represented by Formula I was taken, placed on a graduated glass slide, an appropriate amount of liquid paraffin was added and dispersed, covered with a cover glass, placed under a microscope equipped with a 10x objective lens, the particle morphology, size, and crystal characteristics were observed, the birefringence and crystallinity of the sample were shown with a cross-polarizing microscope, and photographed with a digital camera.

[0087] The results show that there is obvious birefringence in the sample under the polarizing microscope, showing granular and rod-like shapes, and the particle size is 10 - 100 μm. Example 5: Differential Scanning Calorimetry Analysis (DSC) of A-Type Crystal (As Shown in Figure 2) A sample of 3.1820 mg of the A-form crystal of the compound represented by formula I was weighed, placed in an unsealed aluminum tray, and the sample was equilibrated at 25 °C in an atmosphere of a nitrogen gas stream (50 mL / min), and then heated from 25 °C to 300 °C at a heating rate of 10 °C / min. The results are shown in detail in Table 5.

[0088] [Table 5]

[0089] Example 6: Thermogravimetric analysis (TGA) of A-form crystals (Figure 3) A sample of 15.3240 mg of the A-form crystal of the compound represented by formula I was weighed, placed in a platinum sample pan, and heated from 25 °C to 300 °C at a heating rate of 10 °C / min in an atmosphere of a nitrogen gas stream (60 mL / min) for the sample. The weight loss of the sample from 26.76 °C to 119.97 °C was only 0.1447%, indicating that the sample contained little water or solvent. The results are shown in detail in Table 6.

[0090] [Table 6]

[0091] Example 7: Powder X-ray diffraction analysis (XRPD) of A-form crystals (Figure 4) The light source was CuK, the X-ray intensity was 40 KV / 40 mA, the scan mode was Theta-Theta, the scan angle range was 4° to 40°, the step size was 0.05°, the scan speed was 0.5 seconds / step, and the results are shown in detail in Table 7.

[0092] [Table 7]

[0093] Example 8: Dynamic vapor sorption analysis (DVS) of A-form crystals (Figure 5) A sample of the A-type crystal of the compound represented by Formula I in an appropriate amount was weighed and dried for 60 minutes under the conditions of a temperature of 25°C and a humidity of 0%RH. Then, the moisture absorption characteristics of the sample when the humidity changed from 0%RH to 95%RH and the dehumidification characteristics of the sample when the humidity changed from 95%RH to 0%RH were measured. The humidity change in each step was 5%RH, the equilibrium criterion was that the weight change rate within 10 minutes was less than 0.01% / min, the longest equilibrium time was 2 hours, and the test results of DVS showed that the weight increase due to moisture absorption of the A-type crystal at 25°C and 80%RH humidity was 0.310%, and the weight increase due to moisture absorption at 95%RH humidity was 0.409%, indicating that the sample was slightly hygroscopic.

[0094] Example 9: Powder X-ray diffraction analysis (XRPD) of B-type crystal (Figure 6) The light source was CuK, the X-ray intensity was 40KV / 40mA, the scan mode was Theta-Theta, the scan angle range was 4° to 40°, the step size was 0.05°, the scan speed was 0.5 seconds / step, and the results are shown in detail in Table 8.

[0095]

Table 8

[0096] Example 10: Differential scanning calorimetry analysis (DSC) of B-type crystal (Figure 7) 1.5330 mg of a sample of the B-type crystal of the compound represented by Formula I was weighed, placed in an unsealed aluminum tray, and the sample was equilibrated at 25°C in an atmosphere of a nitrogen gas flow (50 mL / min). Then, it was heated from 25°C to 300°C at a heating rate of 10°C / min, and the results are shown in detail in Table 9.

[0097]

Table 9

[0098] Example 11: Thermogravimetric analysis (TGA) of B-type crystal (Figure 8) 1.7310 mg of a sample of the B-type crystal of the compound represented by formula I was weighed, placed in a platinum sample pan, and the sample was heated from 25 °C to 300 °C at a heating rate of 10 °C / min in an atmosphere of a nitrogen gas stream (60 mL / min). When the starting sample was heated from 25.3 °C to 92.5 °C, there was a 5.2% weight loss.

[0099] Example 12: Dynamic Vapor Sorption Analysis (DVS) of B-Type Crystal (Figure 9) An appropriate amount of a sample of the B-type crystal of the compound represented by formula I was weighed, dried for 60 minutes under the conditions of a temperature of 25 °C and a humidity of 0% RH, and then the moisture absorption characteristics of the sample when the humidity changed from 0% RH to 95% RH and the dehumidification characteristics of the sample when the humidity changed from 95% RH to 0% RH were measured. The humidity change at each step was 5% RH, the equilibrium criterion was that the weight change rate within 5 minutes was less than 0.01% / min, the longest equilibrium time was 2 hours, and the results showed that the weight increase of the sample from 0% RH to 95% RH was 7.235%, indicating that the sample had hygroscopicity.

[0100] Example 13: Powder X-ray Diffraction Analysis (XRPD) of C-Type Crystal (Figure 10) The light source was CuK, the X-ray intensity was 40 KV / 40 mA, the scan mode was Theta-Theta, the scan angle range was 4° to 40°, the step size was 0.05°, the scan speed was 0.5 seconds / step, and the results are shown in detail in Table 10.

[0101]

Table 10

[0102] Example 14: Differential Scanning Calorimetry Analysis (DSC) of C-Type Crystal (Figure 11) 1.550 mg of a sample of the C-type crystal of the compound represented by formula I was weighed, placed in an unsealed aluminum tray, and the sample was equilibrated at 25 °C in an atmosphere of a nitrogen gas stream (50 mL / min), and then heated from 25 °C to 300 °C at a heating rate of 10 °C / min. The results are shown in detail in Table 11.

[0103]

Table 11

[0104] Example 15: Thermogravimetric Analysis (TGA) of C-Type Crystals (Figure 12) A sample of 5.3570 mg of the C-type crystals of the compound represented by Formula I was weighed, placed in a platinum sample pan, and the sample was heated from 25 °C to 300 °C at a heating rate of 10 °C / min in an atmosphere of a nitrogen gas stream (60 mL / min). When the sample was heated from 24.0 °C to 58.0 °C, there was a weight loss of 0.62%, and when heated from 58.0 °C to 162.3 °C, there was a weight loss of 2.5%. The sample was heated to 200 °C, and the C-type crystals were converted to A-type crystals, and the results are shown in detail in Table 12.

[0105]

Table 12

[0106] Example 16: Dynamic Vapor Sorption Analysis (DVS) of C-Type Crystals (Figure 13) An appropriate amount of a sample of the C-type crystals of the compound represented by Formula I was weighed and dried for 60 minutes under the conditions of a temperature of 25 °C and a humidity of 0% RH. Then, the moisture absorption characteristics of the sample when the humidity changed from 0% RH to 95% RH and the dehumidification characteristics of the sample when the humidity changed from 95% RH to 0% RH were measured. The humidity change in each step was 5% RH, the equilibrium criterion was that the weight change rate within 5 minutes was less than 0.01% / min, and the longest equilibrium time was 2 hours. The results showed that the weight increase of the sample from 0% RH to 95% RH was 4.767%, indicating that the sample has hygroscopicity.

[0107] Example 17: Comparison of Equilibrium Solubility and Dissolution Rate of A-Type Crystals, B-Type Crystals, and C-Type Crystals To further investigate whether there are differences in the equilibrium solubility and dissolution rate of A-type crystals, B-type crystals, and C-type crystals in pure water and physiological relevant media in vivo, the equilibrium solubility and dissolution rate of four crystal form samples were tested in water, simulated gastric fluid (SGF), simulated fasting intestinal fluid (FaSSIF), and simulated fed intestinal fluid (FeSSIF), respectively. Approximately 20 mg of samples A, B, and C were weighed into 4 mL glass vials, 3 mL of the medium was sequentially added to each, sonicated for 15 seconds, placed in a shaker at 37 °C and a rotation speed of 200 rpm. At 0.5 h, 2 h, and 24 h, approximately 1 mL of the suspension was taken, centrifuged at a rotation speed of 12,000 rpm for 5 minutes. If necessary, the supernatant (diluent: methanol / water = 9 / 1) was diluted at an appropriate ratio, or the concentration of each sample was directly measured by HPLC to calculate the solubility value of each sample. The results of the solubility tests at each time point are as shown in Table 13.

[0108]

Table 13

[0109] Example 18: Solid Stability Experiments of A-Type Crystals, B-Type Crystals, and C-Type Crystals Samples of A-type crystals, B-type crystals, and C-type crystals were weighed into 20 mL colorless transparent glass vials respectively. The sample vials were placed under the corresponding stress factors and accelerated conditions (the vials under humidity conditions were sealed with tin foil with small holes, and the other samples were tightly capped). After being placed for 1 week and 2 weeks respectively, they were taken out. The content and related substances of the samples were detected by HPLC under various conditions. According to the same method as above, the samples were weighed respectively, placed under the corresponding stress factors and accelerated conditions, taken out after being placed for 2 weeks, and the appearance and XRPD characteristics of each sample were observed to investigate the physical stability of each crystal form. The test methods are shown in detail in Tables 14 and 15. At the same time, samples of A-type crystals, B-type crystals, and C-type crystals of the compound represented by Formula I were accurately weighed into two 20 mL colorless transparent glass vials, tightly capped, placed in a -20 °C refrigerator for storage, taken out as standard samples for HPLC analysis at the second week, and the test results are shown in detail in Tables 16 and 17.

[0110]

Table 14

[0111]

Table 15

[0112]

Table 16

[0113]

Table 17

[0114] Conclusion: The appearance of the samples of A-type crystal, B-type crystal, and C-type crystal placed under the four conditions of high temperature, high humidity, light irradiation, and acceleration for two weeks was the same as that of the initial samples, all off-white. There was no significant difference in A-type crystal and C-type crystal compared with the initial samples, and their physical stability was good. However, B-type crystal showed trans-crystallization at high temperature (60 °C), and its physical stability was poor.

[0115] A-type crystal, B-type crystal, and C-type crystal were greatly affected by light irradiation. The total amount of related substances after two weeks increased by 11.18%, 1.28%, and 1.56% respectively, indicating that light irradiation had a significant impact on A-type crystal, B-type crystal, and C-type crystal, and it was necessary to pay attention to storing them away from light.

[0116] Comparative Example 1: Preparation of V-type crystal (suspension equilibrium method) Weighed 100 mg of a sample of the compound represented by Formula I and placed it in a vial, added 20-fold methanol to the vial, magnetically stirred at room temperature for 14 days to form a slurry, centrifuged the solution, collected the solid, dried it at 40 °C for 4 hours, characterized the dried solid, defined the crystal form as Form V, the XRPD pattern of Form V is as shown in Figure 14, the DSC pattern of Form V is as shown in Figure 15, and when Form V crystals were heated to 85 °C, Form V crystals were converted to Form A crystals.

[0117] Figure 16 is a TGA diagram of Form V crystals (as shown in Figure 16, when the sample is heated from 24.8 °C to 82.7 °C, it shows a weight loss of 3.690%). Comparative Example 2: Preparation of Form VII Crystals (Solution Heating - Slow Cooling Method) Weighed 100 mg of a sample of the compound represented by Formula I and placed it in a glass vial, added 100-fold volume of ethyl acetate (EA) and 20-fold volume of methanol (MeOH) to the vial, placed the sample on a magnetic heating stirrer, dissolved it by magnetic stirring at a water bath temperature of 50 °C, filtered it, slowly cooled the filtrate to room temperature at a rate of 6 °C / h, after one night, filtered it under reduced pressure, dried the solid at 70 °C for 4 hours, characterized the dried solid, defined the crystal form as Form VII, the XRPD pattern of Form VII is as shown in Figure 17, the sample was heated to 200 °C and cooled to room temperature, and the XRPD was characterized, and as a result, Form VII crystals were converted to Form A crystals.

[0118] Figure 18 is a DSC diagram of Form VII crystals (as shown in Figure 18, the DSC heat flow curve shows that its initial melting point is 241.9 °C and there are multiple endothermic and exothermic peaks before 200 °C). Figure 19 is a TGA diagram of Form VII crystals (as shown in Figure 19, the sample shows a weight loss of 0.75% from 26.2 °C to 112 °C and a weight loss of 1.69% from 112 °C to 200 °C).

[0119] Comparative Example 3: Preparation of Form VIII Crystals (Suspension Equilibrium Method) Weighed 100 mg of the sample of the compound represented by Formula I and placed it in a vial. Added 30 times the volume of acetonitrile (ACN) (mass of the sample (g) × volume multiple) to the vial, magnetically stirred at room temperature for 2 days to form a slurry, filtered under reduced pressure, collected the solid, dried it at 40 °C for 4 hours, then characterized the dried solid, defined the crystal form as Form VIII crystal, and the XRPD pattern of Form VIII crystal is as shown in Figure 20. When the sample was heated to 180 °C, the Form VIII crystal sample was converted to Form A crystal.

[0120] Figure 21 is the DSC diagram of Form VIII crystal (as shown in Figure 21, the DSC heat flow curve shows that its initial melting point is 239.0 °C and there is an endothermic peak broader than 100 °C). Figure 22 is the TGA diagram of Form VIII crystal (as shown in Figure 22, the sample shows a weight loss of 3.409% from 26.1 °C to 85.2 °C).

[0121] Comparative Example 4: Preparation of Form IX Crystal (Solution Heating - Slow Cooling Method) Weighed 100 mg of the sample of the compound represented by Formula I and placed it in a glass vial. Added 30 times the volume of N,N - dimethylacetamide (DMA) to the vial, placed the sample on a magnetic heating stirrer, dissolved it by magnetic stirring at a water bath temperature of 50 °C, filtered, slowly cooled the filtrate to room temperature at a rate of 6 °C / h, filtered under reduced pressure, dried the solid at 70 °C for 4 hours, characterized the dried solid, defined the crystal form as Form IX, and the XRPD pattern of Form IX crystal is as shown in Figure 23. When the sample was heated to 180 °C, the Form IX crystal sample was converted to Form A crystal.

[0122] Figure 24 is the DSC diagram of Form IX crystal (as shown in Figure 24, the DSC heat flow curve shows that its initial melting point is 241.8 °C and there are multiple endo - and exothermic peaks before 200 °C). Figure 25 is the TGA diagram of Form IX crystal (as shown in Figure 25, the sample shows a slight weight loss of 0.035% from 27.4 °C to 95 °C and a weight loss of 0.841% from 95 °C to 200 °C).

Claims

1. The powder X-ray diffraction pattern represented by the 2θ angle has characteristic peaks at 9.923 ± 0.2°, 10.883 ± 0.2° and 17.357 ± 0.2°, or has characteristic peaks at 3.979 ± 0.2°, 9.923 ± 0.2°, 10.883 ± 0.2°, 17.357 ± 0.2°, 18.607 ± 0.2° and 19.294 ± 0.2°, or has characteristic peaks at 3.979 ± 0.2°, 4.991 ± 0.2°, 9.923 ± 0.2°, 10.883 ± 0.2°, 14.251 ± 0.2°, 16.210 ± 0.2°, 17.357 ± 0.2°, 18.607 ± 0.2°, 19.294 ± 0.2°, 19.594 ± 0.2° and 20.792 ± 0.2°, or has characteristic peaks at 3.979 ± 0.2°, 4.991 ± 0.2°, 7.113 ± 0.2°, 8.135 ± 0.2°, 9.923 ± 0.2°, 10.883 ± 0.2°, 11.613 ± 0.2°, 14.251 ± 0.2°, 14.866 ± 0.2°, 16.210 ± 0.2°, 17.357 ± 0.2°, 18.607 ± 0.2°, 19.294 ± 0.2°, 19.594 ± 0.2°, 20.792 ± 0.2°, 21.272 ± 0.2°, 24.437 ± 0.2°, 25.257 ± 0.2°, 26.2295 ± 0.2°, 27.870 ± 0.2°, 28.631 ± 0.2°, 29.126 ± 0.2°, 29.943 ± 0.2°. The A-type crystal of the compound represented by Formula I is characterized by this. 【Chemical 1】

2. The 2θ values in the powder X-ray diffraction pattern represented by the 2θ angle are as shown in the following table, 【Table 1】 and / or, in the polarized light microscopic analysis of the A-type crystal, the crystal form is granular or rod-shaped, and / or, in the differential scanning calorimetry of the A-type crystal, it has an endothermic peak at 247 °C and its heat of fusion is 118.0 J / g, and / or, in the thermogravimetric analysis of the A-type crystal, the weight loss of the sample from 26.76 °C to 119.97 °C is 0.1447%, and the “%” is weight percentage, and / or, in the dynamic moisture adsorption analysis of the A-type crystal, the moisture absorption weight increase at a relative humidity of 80% is 0.310%, and the moisture absorption weight increase at a relative humidity of 95% is 0.409%. The A-type crystal of the compound represented by Formula I according to Claim 1 is characterized by this.

3. A method for producing A-type crystals of a compound represented by formula I, comprising the step of crystallizing the compound represented by formula I in a solvent, wherein the crystallization method is a suspension equilibrium method, a solution heating-cooling method or an antisolvent method, the solvent is ethanol, and when the crystallization method is an antisolvent method, the antisolvent is an alkane solvent, according to claim 1 or 2.

4. The crystallization temperature is 20°C to 60°C, And / or, when the crystallization method is an anti-solvent method, the alkane-based solvent is C １－１０ an alkane-based solvent, and / or the mass-volume ratio of the compound represented by formula I to the solvent is 5 mg / mL to 20 mg / mL, and / or the crystallization time is 1 h to 20 d, and / or when the crystallization method is an antisolvent method, the mass ratio of the antisolvent to the solvent is 5:1 to 8:1, a method for producing A-type crystals of a compound represented by formula I according to claim 3.

5. The crystallization temperature is room temperature or 50°C, and / or when the crystallization method is an antisolvent method, the alkane solvent is n-heptane, and / or the mass-volume ratio of the compound represented by formula I to the solvent is 7.7 mg / mL to 20 mg / mL d, and / or the crystallization time is 1 h to 2 h, 5 h to 6 h or 10 d to 20 d, and / or when the crystallization method is an antisolvent method, the mass ratio of the antisolvent to the solvent is 6.5:1, a method for producing A-type crystals of a compound represented by formula I according to claim 4.

6. Use of the crystal form according to claim 1 or 2 in the manufacture of a drug, wherein the drug is a drug for the prevention, alleviation and / or treatment of cancer.

7. The cancer is one or more of lung cancer, esophageal cancer, gastric cancer, colorectal cancer, liver cancer, nasopharyngeal cancer, brain tumor, breast cancer, cervical cancer, blood cancer and bone cancer, the use according to claim 6.

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