Crystalline polymorph of kinase inhibitor compound, pharmaceutical composition containing same, and method for producing same and application thereof

Abstract

To provide a polymorphic form of a kinase inhibitor compound, a pharmaceutical composition containing the same, and a preparation method therefor.SOLUTION: A compound according to the present invention is as shown in formula I, of which the crystalline form can be crystalline form 1, crystalline form 2, crystalline form 3, crystalline form 5, crystalline form 6, or crystalline form 7. All the crystalline forms of the compound of formula I in the present invention have good crystalline stability and chemical stability, and a decrease in the purity of their main ingredients on chemical stability is less than 2%. Preparation methods of the present invention can prepare the various crystalline forms of the compound of formula I with high purity and are suitable for large scale production.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to the crystalline form of a drug, and more particularly to a crystalline polymorph of a kinase inhibitor compound, a pharmaceutical composition containing the same, and a method for preparing and applying the same.

[0002] Sunitinib is a potent multi-target kinase inhibitor that has demonstrated remarkable therapeutic efficacy against cancer, particularly renal cell carcinoma (RCC) and gastrointestinal stromal tumor (GIST). However, its use is limited by its adverse effects. The most common severe adverse effects observed in clinical trials include neutropenia and fatigue toxicity. These adverse effects significantly limit its use alone or in combination with other treatments. For example, in a phase 1 clinical trial of sunitinib and everolimus in patients with metastatic renal cell carcinoma, daily dosing was poorly tolerated, necessitating a change to weekly everolimus dosing (2011 Genitourinary Cancer Symposium, abst #311). However, a dosing regimen of 4 weeks of sunitinib onset followed by 2 weeks off, followed by 5 weeks of everolimus onset followed by 1 week off improved tolerance, but did not achieve the expected therapeutic benefit. (2014 Genitourinary cancer symposium, abst #438).

[0003] WO2008033562A2 and CN101553482A disclose sunitinib derivatives in which the diethylaminoethyl side chain of sunitinib is replaced by a cyclic side chain, such as 5-[5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ((S)-1-dimethylcarbamoyl-pyrrolidine)-3-group)-amide shown in formula I (molecular weight 439.48, molecular formula C 23 H 26 FN5O3), which reduces the inhibitory activity of AMPK, thereby alleviating the side effects of sunitinib, such as fatigue toxicity.

[0004] [ka]

[0005] In this compound, the alkaline diethylaminoethyl side chain in the sunitinib structure is replaced with a neutral dimethylcarbamyl-pyrrolidine-3- group. While the alkaline side chain is beneficial for sunitinib's solubility, it leads to widespread accumulation of the drug in human tissues, thereby increasing its toxicity. Replacing the alkaline side chain with a neutral group reduced its tissue accumulation and toxicity, but also significantly reduced its water solubility, posing an unavoidable challenge in drug development. Furthermore, current manufacturing methods do not yet meet the requirements for scalable production. Therefore, research and development of compound forms with favorable pharmaceutical properties, such as solubility, stability, bioavailability, or drug metabolism, as well as their formulations and methods suitable for scalable production, are expected to achieve better efficacy.

[0006] [Contents of invention] To overcome the above-mentioned problems of the prior art, the present invention provides a crystalline form of the compound of formula I.

[0007] [ka]

[0008] The crystalline form is crystalline form 1, crystalline form 2, crystalline form 3, crystalline form 5, crystalline form 6, crystalline form 7, or a mixture of any two or more thereof.

[0009] The above-mentioned crystalline form 1 has characteristic peaks at diffraction angles 2θ of 4.3±0.2°, 8.6±0.2°, and 12.9±0.2° in the powder X-ray diffraction pattern.

[0010] The powder X-ray diffraction pattern of the crystalline form 2 has characteristic peaks at diffraction angles 2θ of 8.8±0.2°, 10.1±0.2°, 23.8±0.2° and 26.7±0.2°.

[0011] The above crystalline form 3 has a characteristic peak at a diffraction angle 2θ of 7.8±0.2° in the powder X-ray diffraction pattern.

[0012] The above-mentioned crystalline form 5 has characteristic peaks at diffraction angles 2θ of 8.7±0.2°, 17.0±0.2°, and 17.4±0.2° in the powder X-ray diffraction pattern.

[0013] The above-mentioned crystalline form 6 has characteristic peaks at diffraction angles 2θ of 7.9±0.2°, 9.0±0.2°, and 17.7±0.2° in the powder X-ray diffraction pattern.

[0014] The above crystalline form 7 has characteristic peaks at diffraction angles 2θ of 9.5±0.2°, 10.6±0.2°, and 16.0±0.2° in the powder X-ray diffraction pattern.

[0015] All of the above powder X-ray diffraction patterns were measured using Kα radiation from a Cu target.

[0016] Preferably, the crystalline form 1 has characteristic peaks at diffraction angles 2θ of 4.3±0.2°, 8.6±0.2°, 12.9±0.2°, and 18.3±0.2° in the powder X-ray diffraction pattern.

[0017] Preferably, the crystalline form 1 has characteristic peaks at diffraction angles 2θ of 4.3±0.2°, 7.6±0.2°, 8.6±0.2°, 12.9±0.2° and 18.3±0.2° in the powder X-ray diffraction pattern.

[0018] Preferably, the crystalline form 1 has characteristic peaks at diffraction angles 2θ of 4.3±0.2°, 7.6±0.2°, 8.6±0.2°, 12.9±0.2°, 17.2±0.2° and 18.3±0.2° in the powder X-ray diffraction pattern.

[0019] More preferably, the crystalline form 1 has characteristic peaks at diffraction angles 2θ of 4.3±0.2°, 7.6±0.2°, 8.6±0.2°, 9.0±0.2°, 12.4±0.2°, 12.9±0.2°, 17.2±0.2° and 18.3±0.2° in the powder X-ray diffraction pattern.

[0020] For example, the above-mentioned crystalline form 1 has a powder X-ray diffraction pattern with diffraction angles 2θ of 4.3±0.2°, 6.7±0.2°, 7.6±0.2°, 8.6±0.2°, 9.0±0.2°, 12.4±0.2°, 12.9±0.2°, 14.3±0.2°, 15.5±0.2°, 16.7±0.2°, 17.2±0.2°, 18.3±0.2°, 19.6±0.2°, 20.0±0.2°, 21.0±0.2°, 22.0±0.2°, 23.0±0.2°, 24.0±0.2°, 25.0±0.2°, 26.0±0.2°, 27.0±0.2°, 28.0±0.2°, 29.0±0.2°, 30.0±0.2°, 31.0±0.2°, 32.0±0.2°, 33.0±0.2°, 34.0±0.2°, 35.0±0.2°, 36.0±0.2°, 37.0±0.2°, 38.0±0.2°, 39.0±0.2°, 40.0±0.2°, 41.0±0.2°, 42.0±0.2°, 43.0±0.2°, 44.0±0.2°, 45.0±0.2°, 46.0±0.2°, 47.0±0.2°, 48.0±0.2°, 49.0±0.2°, 50.0±0.2°, 51.0 Characteristic peaks are found at angles selected from 0.3±0.2°, 21.2±0.2°, 21.5±0.2°, 22.4±0.2°, 23.1±0.2°, 24.2±0.2°, 25.1±0.2°, 25.9±0.2°, 27.0±0.2°, 27.4±0.2°, 28.8±0.2°, 30.8±0.2°, 33.4±0.2°, and 39.2±0.2°.

[0021] For example, the above-mentioned crystalline form 1 has a powder X-ray diffraction pattern with diffraction angles 2θ of 4.3±0.2°, 6.7±0.2°, 7.6±0.2°, 8.6±0.2°, 9.0±0.2°, 10.1±0.2°, 12.4±0.2°, 12.9±0.2°, 14.3±0.2°, 15.5±0.2°, 16.7±0.2°, 17.2±0.2°, 18.3±0.2°, 19.6±0.2°, 20.3±0.2°, and 21.5±0.2°. Characteristic peaks are found at angles selected from 1.2±0.2°, 21.5±0.2°, 22.4±0.2°, 23.1±0.2°, 24.2±0.2°, 25.1±0.2°, 25.9±0.2°, 27.0±0.2°, 27.4±0.2°, 28.8±0.2°, 30.8±0.2°, 32.9±0.2°, 33.4±0.2°, 35.0±0.2°, 37.5±0.2°, and 39.2±0.2°.

[0022] Most preferably, the powder X-ray diffraction pattern data of the crystalline form 1 is as shown in Table 1:

[0023] [Table 1]

[0024] Without limitation, a typical example of crystalline Form 1 has a powder X-ray diffraction pattern essentially as shown in FIG.

[0025] Furthermore, the polarized light microscope (PLM) photograph of the above-mentioned crystalline form 1 is shown in Figure 2. Among them, crystalline form 1 is a long, rod-like crystal.

[0026] The solubilities of the above crystalline form 1 in commonly used solvents at 25°C are as follows: 5-12.5 mg / mL in methanol; 1-2.5 mg / mL in ethanol; <1 mg / mL in water; 1-2.5 mg / mL in acetone; <1 mg / mL in ethyl acetate; <1 mg / mL in methyl tert-butyl ether; 1-2.5 mg / mL in tetrahydrofuran; <1 mg / mL in acetonitrile; <1 mg / mL in toluene; and <1 mg / mL in n-heptane.

[0027] Furthermore, the thermogravimetric analysis (TGA) diagram of the crystalline form 1 is essentially as shown in Figure 3. The crystalline form 1 exhibits a weight loss of about 2.6% before 170°C, and is an anhydrous form with a decomposition temperature of about 320°C.

[0028] Furthermore, the crystalline form 1 has a differential scanning calorimetry (DSC) diagram basically as shown in Figure 4. The crystalline form 1 has one exothermic peak at 150-170°C, which is confirmed to be an exothermic crystal transformation peak, and the crystalline form after crystal transformation is the crystalline form 3, and the melting point of the crystalline form 1 is about 260°C.

[0029] Furthermore, the crystalline form 1 has a dynamic moisture sorption diagram (DVS) essentially as shown in Figure 5. The weight change of the crystalline form 1 within the range of 0% RH to 80% RH is about 2.8%.

[0030] Preferably, the crystalline form 2 has characteristic peaks at diffraction angles 2θ of 8.8±0.2°, 10.1±0.2°, 17.7±0.2°, 19.9±0.2°, 20.5±0.2°, 23.8±0.2° and 26.7±0.2° in the powder X-ray diffraction pattern.

[0031] More preferably, the crystalline form 2 has characteristic peaks at diffraction angles 2θ of 5.1±0.2°, 8.8±0.2°, 10.1±0.2°, 11.6±0.2°, 14.6±0.2°, 15.2±0.2°, 16.5±0.2°, 17.3±0.2°, 17.7±0.2°, 18.8±0.2°, 19.9±0.2°, 20.5±0.2°, 21.7±0.2°, 23.2±0.2°, 23.8±0.2° and 26.7±0.2° in the powder X-ray diffraction pattern.

[0032] For example, the above-mentioned crystalline form 2 has a powder X-ray diffraction pattern with diffraction angles 2θ of 5.1±0.2°, 7.8±0.2°, 8.4±0.2°, 8.8±0.2°, 10.1±0.2°, 11.6±0.2°, 14.6±0.2°, 15.2±0.2°, 15.5±0.2°, 16.1±0.2°, 16.5±0.2°, 17.3±0.2°, 17.7±0.2°, 18.8±0.2°, 19.0±0.2°, 19.4±0.2°, and 19.9±0.2°. There are characteristic peaks at angles selected from 20.2°, 20.5±0.2°, 21.7±0.2°, 22.1±0.2°, 23.2±0.2°, 23.8±0.2°, 24.7±0.2°, 25.9±0.2°, 26.7±0.2°, 27.5±0.2°, 28.7±0.2°, 29.7±0.2°, 30.3±0.2°, 31.6±0.2°, 32.5±0.2°, 33.1±0.2°, 36.8±0.2° and 38.9±0.2°.

[0033] Most preferably, the powder X-ray diffraction pattern data of the crystalline form 2 is as shown in Table 2:

[0034] [Table 2]

[0035] Without limitation, a typical example of crystalline form 2 has a powder X-ray diffraction pattern essentially as shown in FIG.

[0036] Furthermore, the polarized light microscope (PLM) photograph of the above-mentioned crystalline form 2 is shown in Figure 8. Among them, crystalline form 2 is a thin needle-like crystal.

[0037] Furthermore, the thermogravimetric analysis (TGA) diagram of the crystalline form 2 is essentially as shown in Figure 9. The crystalline form 2 exhibits a weight loss of about 0.3% before 200°C, and is an anhydrous form with a decomposition temperature of about 320°C. Furthermore, the crystalline form 2 has a differential scanning calorimetry (DSC) diagram essentially as shown in Figure 10. The melting point of the crystalline form 2 is about 258°C.

[0038] Furthermore, the crystalline form 2 has a dynamic moisture sorption diagram (DVS) essentially as shown in Figure 11. The weight change of the crystalline form 2 within the range of 0% RH to 80% RH is about 0.05%.

[0039] Preferably, the crystalline form 3 has characteristic peaks at diffraction angles 2θ of 7.8±0.2°, 9.3±0.2°, 13.7±0.2°, and 16.0±0.2° in the powder X-ray diffraction pattern.

[0040] More preferably, the crystalline form 3 has characteristic peaks at diffraction angles 2θ of 3.9±0.2°, 7.8±0.2°, 9.3±0.2°, 13.7±0.2°, 16.0±0.2°, 18.2±0.2° and 27.2±0.2° in the powder X-ray diffraction pattern.

[0041] For example, the diffraction angle 2θ of the powder X-ray diffraction pattern of the above crystalline form 3 is as shown in Table 3.

[0042] Most preferably, the powder X-ray diffraction pattern data of the crystalline form 3 is as shown in Table 3:

[0043] [Table 3]

[0044] Without limitation, a typical example of crystalline form 3 has a powder X-ray diffraction pattern essentially as shown in FIG.

[0045] Furthermore, the polarized light microscope (PLM) photograph of the crystalline form 3 is shown in Figure 13. Among them, the crystalline form 3 is composed of small particles with partial aggregation.

[0046] Furthermore, the thermogravimetric analysis (TGA) diagram of the crystalline form 3 is essentially as shown in Figure 14. The crystalline form 3 exhibits a weight loss of about 0.2% before 200°C, and is an anhydrous form with a decomposition temperature of about 320°C. Furthermore, the crystalline form 3 has a differential scanning calorimetry (DSC) diagram essentially as shown in Figure 15. The melting point of the crystalline form 3 is about 261°C.

[0047] Furthermore, the crystalline form 3 has a dynamic moisture sorption diagram (DVS) essentially as shown in Figure 16. The weight change of the crystalline form 3 within the range of 0% RH to 80% RH is about 0.08%.

[0048] Preferably, the crystalline form 5 has characteristic peaks at diffraction angles 2θ of 8.3±0.2°, 8.7±0.2°, 9.4±0.2°, 17.0±0.2°, 17.4±0.2°, and 18.1±0.2° in the powder X-ray diffraction pattern.

[0049] More preferably, the crystalline form 5 has characteristic peaks at diffraction angles 2θ of 4.1±0.2°, 8.3±0.2°, 8.7±0.2°, 9.4±0.2°, 10.5±0.2°, 13.4±0.2°, 17.0±0.2°, 17.4±0.2°, and 18.1±0.2° in the powder X-ray diffraction pattern.

[0050] For example, the diffraction angle 2θ of the powder X-ray diffraction pattern of the above crystalline form 5 is shown in Table 4.

[0051] Most preferably, the powder X-ray diffraction pattern data of the crystalline form 5 is as shown in Table 4:

[0052] [Table 4]

[0053] Without limitation, a typical example of crystalline form 5 has a powder X-ray diffraction pattern essentially as shown in FIG.

[0054] Furthermore, the polarized light microscope (PLM) photograph of the crystalline form 5 is shown in Figure 18. Among them, the crystalline form 5 is composed of small particles with partial aggregation.

[0055] Furthermore, the crystalline form 5 has a thermogravimetric analysis (TGA) diagram essentially as shown in Figure 19. The crystalline form 5 exhibits a weight loss of about 1.2% before 200°C, and is an anhydrous form with a decomposition temperature of about 319°C. Furthermore, the crystalline form 5 has a differential scanning calorimetry (DSC) diagram essentially as shown in Figure 20. The melting point of the crystalline form 5 is about 258°C, and the broad endothermic peak before 100°C is due to the removal of the surface solvent.

[0056] Furthermore, the crystalline form 5 has a dynamic moisture sorption diagram (DVS) essentially as shown in Figure 21. The weight change of the crystalline form 5 within the range of 0% RH to 80% RH is about 2.5%.

[0057] Preferably, the crystalline form 6 has characteristic peaks at diffraction angles 2θ of 7.9±0.2°, 9.1±0.2°, 9.6±0.2°, 16.4±0.2°, 17.7±0.2°, and 18.0±0.2° in the powder X-ray diffraction pattern.

[0058] More preferably, the crystalline form 6 has characteristic peaks at diffraction angles 2θ of 3.9±0.2°, 7.9±0.2°, 9.1±0.2°, 9.6±0.2°, 13.2±0.2°, 16.4±0.2°, 17.7±0.2°, and 18.0±0.2° in the powder X-ray diffraction pattern.

[0059] For example, the diffraction angle 2θ of the powder X-ray diffraction pattern of the above crystalline form 6 is shown in Table 5.

[0060] Most preferably, the powder X-ray diffraction pattern data of the crystalline form 6 is as shown in Table 5:

[0061] [Table 5]

[0062] Without limitation, a typical example of crystalline form 6 has a powder X-ray diffraction pattern essentially as shown in FIG.

[0063] Furthermore, the polarized light microscope (PLM) photograph of the crystalline form 6 is shown in Figure 23. Among them, the crystalline form 6 is composed of small particles with partial aggregation.

[0064] Furthermore, the crystalline form 6 has a thermogravimetric analysis (TGA) diagram essentially as shown in Figure 24. The crystalline form 6 has a weight loss of about 0.7% before 200°C, is an anhydrous form, and has a decomposition temperature of about 320°C. Furthermore, the crystalline form 6 has a differential scanning calorimetry (DSC) diagram essentially as shown in Figure 25. The melting point of the crystalline form 6 is about 259°C.

[0065] Furthermore, the crystalline form 6 has a dynamic moisture sorption diagram (DVS) as shown in Figure 26. The weight change of the crystalline form 6 within the range of 0% RH to 80% RH is about 0.26%.

[0066] Preferably, the crystalline form 7 has characteristic peaks at diffraction angles 2θ of 9.5±0.2°, 10.6±0.2°, 13.8±0.2°, 14.3±0.2°, 16.0±0.2°, 18.2±0.2°, and 25.1±0.2° in the powder X-ray diffraction pattern.

[0067] More preferably, the crystalline form 7 has characteristic peaks at diffraction angles 2θ of 4.8±0.2°, 9.5±0.2°, 10.6±0.2°, 13.8±0.2°, 14.3±0.2°, 16.0±0.2°, 18.2±0.2°, 25.1±0.2°, 27.8±0.2°, and 28.9±0.2° in the powder X-ray diffraction pattern.

[0068] For example, the diffraction angle 2θ of the powder X-ray diffraction pattern of the above crystalline form 7 is shown in Table 6.

[0069] Most preferably, the powder X-ray diffraction pattern data of the crystalline form 7 is as shown in Table 6:

[0070] [Table 6]

[0071] Without limitation, a typical example of crystalline form 7 has a powder X-ray diffraction pattern essentially as shown in FIG.

[0072] Furthermore, the polarized light microscope (PLM) photograph of the crystalline form 7 is shown in Figure 28. Among them, the crystalline form 7 is composed of small particles and has partial agglomerations.

[0073] Furthermore, the crystalline form 7 has a thermogravimetric analysis (TGA) diagram essentially as shown in Figure 29. The crystalline form 7 has a weight loss of about 0.5% before 200°C, is an anhydrous form, and has a decomposition temperature of about 320°C. Furthermore, the crystalline form 7 has a differential scanning calorimetry (DSC) diagram essentially as shown in Figure 30. The melting point of the crystalline form 7 is about 259°C.

[0074] Furthermore, the crystalline form 7 has a dynamic moisture sorption (DVS) diagram essentially as shown in Figure 31. The weight change of the crystalline form 7 within the range of 0% RH to 80% RH is about 0.27%.

[0075] According to the present invention, the purity of the above-mentioned Crystalline Form 1, Crystalline Form 2, Crystalline Form 3, Crystalline Form 5, Crystalline Form 6, and Crystalline Form 7 is preferably more than 50%, for example, 80% or more, 85% or more, 90% or more, 95% or more, 99% or more, 99.5% or more, or 99.9% or more.

[0076] The present invention further provides methods for preparing the above crystalline forms, including one or more of the following methods.

[0077] (1) Method 1 for preparing the above crystalline form 1, which includes the following steps: the compound of formula I is mixed with a solvent to obtain a clear solution, and the solvent is evaporated; the solvent is methanol, a mixture of methanol and acetone, or an aqueous methanol solution.

[0078] Method 2 for preparing crystalline form 1 includes the following steps: the compound of formula I is mixed with methanol to obtain a clear solution, and a solvent is added to the solution with stirring to precipitate a solid, where the solvent is acetone, ethyl acetate, methyl tert-butyl ether, or acetonitrile.

[0079] Method 3 for preparing crystalline form 1 includes the following steps: the compound of formula I is mixed with methanol to obtain a clear solution, and the solution is added to a solvent, such as water or methyl tert-butyl ether, with stirring to precipitate a solid.

[0080] Method 4 for preparing crystalline form 1 includes the following steps: the compound of formula I is mixed with a solvent to obtain a clear solution, which can be cooled and stirred for crystallization, where the solvent is methanol, aqueous methanol, a mixture of methanol and ethyl acetate, a mixture of methanol and methyl tert-butyl ether, or a mixture of methanol and acetonitrile.

[0081] In the method for preparing Crystalline Form 1, the temperature of the volatile solvent is preferably 10-40°C. The mass / volume ratio of the compound of Formula I to the solvent is preferably 10 mg / (0.5-2.2 mL), for example, 10 mg / (0.5-2 mL), such as 5 mg / 1.0 mL, 10 mg / 0.6 mL, or 10 mg / 1.2 mL. When the solvent is a mixture of methanol and acetone, the volume ratio of methanol to acetone is preferably 1:1.5-2.5, for example, 1:2; when the solvent is an aqueous methanol solution, the volume ratio of methanol to water is preferably 6:0.5-1.5, for example, 6:1.

[0082] In the method 2 for producing Crystalline Form 1, the mixing may be performed under heating conditions to promote dissolution of the compound of Formula I. The mixing temperature is preferably 45-55°C, for example, 50°C. Based on common knowledge in the art, to ensure a transparent solution, hot filtration may be performed after the compound of Formula I is fully dissolved. The mass / volume ratio of the compound of Formula I to methanol is preferably 20 mg / 1.2-1.6 mL, for example, 20 mg / 1.4 mL. The mass / volume ratio of the compound of Formula I to the solvent is preferably 20 mg / 2-4 mL, for example, 20 mg / 3 mL.

[0083] In Production Method 3 for Crystalline Form 1, the mixing may be performed under heated conditions to promote dissolution of the compound of Formula I. The mixing temperature is preferably 45 to 55°C, for example, 50°C. Based on common knowledge in the art, to ensure a transparent solution, hot filtration may be performed after the compound of Formula I is fully dissolved. The mass / volume ratio of the compound of Formula I to methanol is preferably 20 mg / 1.2 to 20 mg / 1.6 mL, for example, 20 mg / 1.4 mL. The mass / volume ratio of the compound of Formula I to the solvent is preferably 20 mg / 2.0 to 15 mL, for example, 20 mg / 2.5 to 12.0 mL, for example, 20 mg / 3.0 mL, 20 mg / 5.2 mL, or 20 mg / 11.2 mL.

[0084] In Method 4 for Preparing Crystalline Form 1, the mixing may be performed under heated conditions to promote dissolution of the compound of Formula I, and generally, a water bath heating method is adopted; the mixing temperature is preferably 45-70°C, for example, 50°C or reflux temperature. According to common knowledge in the art, to ensure a clear solution, hot filtration may be performed after the compound of Formula I is fully dissolved. Preferably, the compound of Formula I is mixed with a solvent and heated under reflux until a clear solution is obtained.

[0085] Preferably, the above preparation method 4 includes the following steps: mixing the compound of formula I with methanol, heating under reflux until a clear solution is obtained, cooling, stirring to crystallize, filtering, washing and drying.

[0086] Optionally, the above preparation method 4 further comprises a concentration step: for example, after a clear solution is obtained, some of the solvent is concentrated off.

[0087] Preferably, the concentration is carried out under reduced pressure conditions, and the degree of vacuum under the reduced pressure conditions is, for example, 200 to 1500 Pa, for example, 500 to 1000 Pa.

[0088] The concentration temperature may be 20 to 35°C.

[0089] Preferably, the reflux time is less than 4 hours, for example not more than 2 hours; Preferably, the water content of said methanol does not exceed 10%, such as not exceed 6%, such as not exceed 5%, preferably not exceed 1%, eg anhydrous methanol.

[0090] The target temperature for the cooling may be 1 to 50°C, for example 4 to 50°C, for example 5 to 35°C or 10 to 20°C.

[0091] The temperature for the stirring crystallization may be 1 to 50°C, for example, 4 to 50°C, for example, 5 to 35°C or 10 to 20°C.

[0092] The solvent used for the washing is selected from methanol, aqueous methanol solution, a mixture of methanol and ethyl acetate, a mixture of methanol and methyl tert-butyl ether, or a mixture of methanol and acetonitrile to produce the transparent solution, preferably methanol.

[0093] The mass / volume ratio of the compound of formula I to the solvent is preferably 20 mg / (0.5 to 2.2 mL), for example, 20 mg / 0.8 mL, 20 mg / 1.0 mL, 20 mg / 1.2 mL, 20 mg / 1.4 mL, 20 mg / 1.8 mL, or 20 mg / 2.2 mL. When the solvent is methanol, the water content is preferably ≦10%; when the solvent is an aqueous methanol solution, the volume ratio of methanol to water is preferably 7:1.5-2.5, for example, 7:2; when the solvent is a mixture of methanol and ethyl acetate, the volume ratio of methanol to ethyl acetate is preferably 1:1.5-2.5, for example, 1:2; when the solvent is a mixture of methanol and methyl tert-butyl ether, the volume ratio of methanol to methyl tert-butyl ether is preferably 4:6-8, for example, 4:7; when the solvent is a mixture of methanol and acetonitrile, the volume ratio of methanol to acetonitrile is preferably 1:0.5-1.5, for example, 1:1. (2) A method for preparing the above Crystalline Form 2, which comprises the steps of mixing and stirring the compound of Formula I with a solvent for 2-6 days, separating the resulting crystalline slurry into solid and liquid, and then drying the resulting crystalline form; the solvent is water, ethyl acetate, toluene, an aqueous acetone solution, an aqueous acetonitrile solution, a mixture of ethanol and toluene, or an aqueous methanol solution.

[0094] In the method for preparing Crystalline Form 2, the compound of Formula I may be in Crystalline Form 1 and / or Crystalline Form 6. The stirring temperature is preferably 4 to 50°C. The temperature of the mixture may be adjusted during stirring according to common knowledge in the art. For example, the mixture may be stirred at 50°C for 2 hours and then at room temperature for 2 days. The mass / volume ratio of the compound of Formula I to the solvent is preferably (12.5 to 40.0 mg) / mL, such as 10 mg / 0.5 mL, 10 mg / 0.6 mL, 10 mg / 0.8 mL, or 199 mg / 5 mL. When the solvent is an acetone aqueous solution, the volume ratio of acetone to water is preferably 2:1; when the solvent is an acetonitrile aqueous solution, the volume ratio of acetonitrile to water is preferably 2:1 to 5:1; when the solvent is a mixture of ethanol and toluene, the volume ratio of ethanol to toluene is preferably 1:1; and when the solvent is a methanol aqueous solution, the volume ratio of methanol to water is preferably 1:1. The solid-liquid separation method and conditions may be those conventional in the art. Generally, filtration or centrifugation followed by filtration is used. When solid-liquid separation is performed by filtration alone, the filtration is generally suction filtration. The drying method and conditions may be those conventional in the art, but vacuum drying is preferred, and vacuum drying at room temperature for 10 to 16 hours is more preferred. (3) Method 1 for preparing the above crystalline form 3, which includes the following steps: mixing the compound of formula I with tetrahydrofuran to obtain a clear solution, and then evaporating the solvent; Method 2 for preparing the above crystalline form 3, which includes the following steps: the compound of formula I is mixed with ethanol to obtain a clear solution, and the solvent is evaporated at room temperature; Method 3 for preparing the above crystalline form 3, which includes the following steps: the compound of formula I is mixed with aqueous ethanol to obtain a clear solution, and the solvent is evaporated at 60°C; Method 4 for preparing the crystalline form 3 includes the following steps: mixing and stirring the compound of formula I with a solvent, and then subjecting the resulting crystalline slurry to solid-liquid separation and drying; the solvent is ethanol, acetone, or tetrahydrofuran aqueous solution; Method 5 for preparing the crystalline form 3, which includes the following steps: mixing the compound of formula I with a solvent to obtain a clear solution, which can be prepared by cooling and stirring to crystallize; the solvent is tetrahydrofuran or a mixture of methanol and tetrahydrofuran; Method 6 for producing the above crystalline form 3, which includes the following steps: crystalline form 1 can be produced by heating it to 180-190°C and cooling it to room temperature; or crystalline form 7 can be produced by heating it to 258°C and cooling it to room temperature.

[0095] In the method 1 for producing the crystalline form 3, the evaporation temperature of the solvent is preferably 10-40° C. The mass / volume ratio of the compound of formula I to tetrahydrofuran is preferably 1 mg / 0.5-1.5 mL, for example, 1:1 mL.

[0096] In the production method 2 for the crystalline form 3, the mass / volume ratio of the compound of formula I to tetrahydrofuran is preferably 5 mg / 2 to 4 mL, for example, 5 mg / 3 mL.

[0097] In the production method 3 for the crystalline form 3, the mass / volume ratio of the compound of formula I to tetrahydrofuran is preferably 10 mg / 1.0-1.4 mL, for example, 10 mg / 1.2 mL. In the aqueous ethanol solution, the volume ratio of ethanol to water is preferably 5:0.5-1.5, for example, 5:1.

[0098] In the method 4 for preparing crystalline form 3, the crystalline form of the compound of formula I is preferably crystalline form 1. The stirring temperature is preferably 4 to 30°C. The stirring time is preferably 20 hours to 6 days. The mass / volume ratio of the compound of formula I to the solvent is preferably 10 mg / (0.4 to 0.8 mL), for example, 10 mg / 0.5 mL, 10 mg / 0.8 mL, 200 mg / 8 mL, 200 mg / 10 mL, or 201 mg / 15 mL. When the solvent is an aqueous tetrahydrofuran solution, the volume ratio of tetrahydrofuran to water is preferably 1:0.5 to 1.5, for example, 1:1. The solid-liquid separation may be carried out by a method and conditions conventional in the art, but is generally carried out by filtration or centrifugation followed by filtration. When solid-liquid separation is carried out by filtration alone, the filtration is generally suction filtration. The drying method and conditions may be those commonly used in the art, but vacuum drying is preferred, and vacuum drying at room temperature for 10 to 16 hours is more preferred.

[0099] In one specific example of the method for preparing Form 3, 201.0 mg of the compound of Formula I is mixed with 15 mL of ethanol to form a suspension, which is then stirred at room temperature at 800 rpm for 20 hours. The resulting slurry is filtered under suction, and the solid is separated and dried at 60°C for 1 hour.

[0100] In Method 5 for Preparing Crystalline Form 3, the mixing may be performed under heated conditions to dissolve the compound of Formula I, but typically, a water bath heating method is employed; the mixing temperature is preferably 45-55°C, for example, 50°C. Based on common knowledge in the art, hot filtration may be performed after the compound of Formula I is fully dissolved to ensure a transparent solution. The target temperature for the cooling is preferably 4-20°C. The mass / volume ratio of the compound of Formula I to acetone is preferably 20 mg / (0.4-5 mL). When the solvent is a mixture of methanol and tetrahydrofuran, the volume ratio of methanol to tetrahydrofuran is preferably 1:0.8-1.2, for example, 1:1.

[0101] (4) Method 1 for preparing the above crystalline form 5, which includes the following steps: mixing the compound of formula I with acetone to obtain a clear solution, which can be prepared by cooling and stirring to crystallize; Method 2 for preparing Crystalline Form 5 includes the following steps: Crystalline Form 5 can be prepared by mixing the compound of Formula I with a solvent, stirring the mixture, and then subjecting the resulting crystal slurry to solid-liquid separation and drying; or Crystalline Form 5 can be prepared by mixing the compound of Formula I with a solvent, adding seed crystals of Crystalline Form 5, stirring the mixture, and then subjecting the resulting crystal slurry to solid-liquid separation and drying; the solvent is methyl tert-butyl ether or acetone.

[0102] In the method 1 for preparing Crystalline Form 5, the mixing may be performed under heating conditions to dissolve the compound of Formula I, and typically, a water bath heating method is employed; the mixing temperature is preferably 45-55°C, for example, 50°C. Based on common knowledge in the art, hot filtration may be performed after the compound of Formula I is fully dissolved to ensure a transparent solution. The target temperature for the cooling is preferably 4-20°C. The mass / volume ratio of the compound of Formula I to acetone is preferably 20 mg / 4-6 mL, for example, 20 mg / 5 mL.

[0103] In the method for producing crystalline form 5 (Production Method 2), the crystalline form of the compound of formula I is preferably crystalline form 1. Seed crystals of crystalline form 5 may be added selectively, but they can be produced by any method for producing crystalline form 5; the amount of seed crystals of crystalline form 5 added is preferably 2% or less of the total mass of the crystal slurry. The stirring temperature is preferably room temperature, and the stirring time is preferably 1 to 6 days. The mass-volume ratio of the compound of formula I to the solvent is preferably (18 to 22 mg) / mL, for example (19.9 to 20 mg) / mL. The solid-liquid separation may be carried out by a method and conditions conventional in the art, and is generally carried out by filtration or centrifugation followed by filtration. When solid-liquid separation is carried out by filtration alone, the filtration is generally suction filtration. The drying method and conditions may be carried out by a method and conditions conventional in the art, but is preferably vacuum drying, more preferably vacuum drying at room temperature for 10 to 16 hours. (5) Method 1 for preparing the above crystalline form 6, which includes the following steps: the compound of formula I can be prepared by mixing the compound of formula I with a mixture of toluene and methanol to obtain a clear solution, and then evaporating the solvent at room temperature; Method 2 for preparing the crystalline form 6 includes the following steps: the compound of formula I is mixed with methanol to obtain a clear solution, and the clear solution is mixed with toluene under stirring to precipitate a solid; Method 3 for preparing crystalline form 6 includes the following steps: the compound of formula I is mixed with toluene and stirred for 16 hours or more, and the resulting crystal slurry is dried; or the compound of formula I is mixed with toluene, and then seed crystals of crystalline form 6 are added and stirred, and the resulting crystal slurry is dried.

[0104] In the method 1 for producing Crystalline Form 6, the mass / volume ratio of the compound of Formula I to the mixture of toluene and methanol is preferably 10 mg / 0.3-0.5 mL, for example, 10 mg / 0.4 mL. In the mixture of toluene and methanol, the volume ratio of toluene to methanol is preferably 1:0.7-1.3, for example, 1:1. Based on common knowledge in the art, a transparent solution can be obtained by using ultrasonic dispersion as an auxiliary means in the mixing step. After ultrasonic dispersion, a purified and transparent solution can be obtained by filtration.

[0105] In the method 2 for producing Crystalline Form 6, the mixing may be performed under heating conditions to dissolve the compound of Formula I, and the mixing temperature is preferably 45 to 55°C. Based on common knowledge in the art, to ensure a transparent solution, hot filtration may be performed after the compound of Formula I is fully dissolved. The mass / volume ratio of the compound of Formula I to methanol is preferably 20 mg / 1.2 to 1.6 mL, for example, 20 mg / 1.4 mL. The mass / volume ratio of the compound of Formula I to toluene is preferably 20 mg / 2.5 to 12.0 mL, for example, 20 mg / 3.0 to 11.2 mL.

[0106] In the method 3 for preparing crystalline form 6, the crystalline form of the compound of formula I is preferably crystalline form 1. Seed crystals of crystalline form 6 are selectively added. The seed crystals of crystalline form 6 can be prepared by any one of the methods for preparing crystalline form 6; the amount of seed crystals of crystalline form 6 added is preferably 2% or less of the total mass of the crystal slurry. The stirring temperature is preferably room temperature, and the stirring time is preferably 16 to 24 hours. The mass-volume ratio of the compound of formula I to the solvent is preferably 5 to 15 mg / mL, e.g., 10 mg / mL. The drying method and conditions may be those commonly used in the art, but are preferably vacuum drying, more preferably vacuum drying at 50 to 60°C for about 1 hour. (6) Method 1 for preparing the above crystalline form 7, which includes the following steps: mixing the compound of formula I with ethyl acetate, stirring at 45-55°C, for example 50°C, for about 30 minutes, and then drying the resulting crystalline slurry after solid-liquid separation; Method 2 for preparing the crystalline form 7 includes the following steps: the compound of formula I is mixed and stirred with a mixture of N,N-dimethylacetamide and toluene, and then dried after solid-liquid separation; Method 3 for producing the above Crystalline Form 7, which includes the following steps: Crystalline Form 1 and / or Crystalline Form 5 can be produced by mixing and stirring with water, separating the crystal slurry into a solid solution, and then drying.

[0107] In the method 1 for producing crystalline form 7, the crystalline form of the compound of formula I is preferably crystalline form 1. The mass / volume ratio of the compound of formula I to the solvent is preferably (18 to 22 mg) / mL, for example (19.9 to 20 mg) / mL. The solid-liquid separation may be carried out by a method and conditions conventional in the art, but is generally carried out by filtration or centrifugation followed by filtration. When solid-liquid separation is carried out by filtration alone, the filtration is usually suction filtration. The drying may be carried out by a method and conditions conventional in the art, but is preferably carried out by vacuum drying, more preferably at 60°C for about 1 hour.

[0108] In Production Method 2 for Crystalline Form 7, the stirring time is preferably about 1 hour. In the mixture of N,N-dimethylacetamide and toluene, the volume ratio of N,N-dimethylacetamide to toluene is preferably 1:8-10, e.g., 1:9. The solid-liquid separation method and conditions may be those conventional in the art, but generally, filtration or centrifugation followed by filtration is employed; when solid-liquid separation is performed by filtration alone, the filtration is usually suction filtration. The drying method and conditions are those conventional in the art.

[0109] In the method 3 for producing the crystalline form 7, the stirring temperature is preferably room temperature, and the stirring time is preferably about 24 hours.

[0110] In the present invention, the method and conditions for volatilizing the solvent may be those commonly used in the art, and generally, the solvent is evaporated naturally in an open container until it becomes dry.

[0111] Unless otherwise specified, the method for producing each of the above crystalline forms may further include a step of drying the obtained crystalline form. The drying may be performed under atmospheric pressure or in a vacuum. The temperature for the vacuum drying is about 35°C or higher, for example, about 40°C or higher, about 45°C or higher, or about 50°C or higher, for example, about 40 to 60°C. The vacuum degree for the vacuum drying may be, for example, 200 to 1500 Pa, for example, 500 to 1000 Pa.

[0112] According to the method for preparing each crystalline form of the present invention, the compound of formula I as the raw material can be pure or a crude product prepared by known methods or the method of the present invention. When the crude product is selected as the raw material, the purity of the product can be improved by adding an appropriate amount of activated carbon when mixing the raw material with a solvent.

[0113] The present invention further provides a pharmaceutical composition comprising an effective amount of a crystalline form according to the present invention or a crystalline form produced by the production method of the present invention required for treatment and / or prevention, and at least one pharmaceutically acceptable adjuvant.

[0114] The crystalline form is one or more selected from the crystalline form 1, crystalline form 2, crystalline form 3, crystalline form 5, crystalline form 6 and crystalline form 7.

[0115] Pharmaceutically acceptable auxiliaries (e.g., carriers, excipients, etc.) used in the pharmaceutical compositions of the present invention include, but are not limited to, ion exchange agents, aluminum, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) (e.g., d-α-tocopherol polyethylene glycol 1000 succinate), surfactants used in pharmaceutical formulations (e.g., Tween or other similar polymeric delivery matrices), serum proteins (e.g., human serum proteins), buffer substances (e.g., phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated fatty acids, water, salts or electrolytes (e.g., protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene - Polyoxypropylene block polymers, polyethylene glycol and lanolin, cyclodextrins (e.g., α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin) or chemically modified derivatives (e.g., hydroxyalkyl cyclodextrins, including 2-hydroxypropyl-β-cyclodextrin and 3-hydroxypropyl-β-cyclodextrin), or other soluble derivatives may also be used to enhance delivery of compounds of the formulas described in the present invention.

[0116] And, the pharmaceutical compositions may contain or be essentially free of other forms of the compound of formula I, such as other crystalline and / or amorphous forms.

[0117] According to a preferred embodiment of the pharmaceutical composition of the present invention, the ratio of the total molar amount of Crystalline Form 1, Crystalline Form 2, Crystalline Form 3, Crystalline Form 5, Crystalline Form 6, and Crystalline Form 7 to the total molar amount of other forms of the compound of Formula I may be greater than 50:50, for example, 60:40 or more, 70:30 or more, 80:20 or more, 90:10 or more, 95:5 or more, 99:1 or more, or 100:0. As an exemplary embodiment, in the pharmaceutical composition of the present invention, the ratio of the molar amount of Crystalline Form 1 to the total molar amount of Crystalline Form 2, Crystalline Form 3, Crystalline Form 5, Crystalline Form 6, and Crystalline Form 7 and other forms of the compound of Formula 1 may be greater than 50:50, for example, 60:40 or more, 70:30 or more, 80:20 or more, 90:10 or more, 95:5 or more, 99:1 or more, or 100:0. Alternatively, the ratio of the molar amount of Form 2 to the total molar amount of Form 1, Form 3, Form 5, Form 6, Form 7 and other forms of the compound of Formula 1 may be greater than 50:50, such as 80:20 or more, 90:10 or more, 95:5 or more, 99:1 or more, or 100:0.

[0118] The pharmaceutical compositions of the present invention may be solid or liquid, such as solid oral dosage forms including tablets, granules, powders, pills, and capsules; liquid oral dosage forms including liquids, syrups, suspensions, dispersions, and emulsions; and injectable forms including liquids, dispersions, and lyophilized formulations. The formulations are suitable for rapid release, delayed release, or controlled release of the active ingredient. They may be conventional, dispersible, chewable, orally dissolvable, or rapidly dissolving formulations. Routes of administration include oral, intravenous subcutaneous injection, tissue injection, transdermal, rectal, and intranasal administration.

[0119] For example, the pharmaceutical composition is a capsule, which contains an effective amount of the crystalline form of the present invention, Pearlitol 200 SD, sodium bicarbonate, sodium lauryl sulfate, and cross-linked carmellose sodium required for treatment and / or prevention.

[0120] For example, the pharmaceutical composition is a tablet, the tablet core of which comprises an effective amount of the crystalline form according to the present invention required for treatment and / or prevention, mannitol, microcrystalline cellulose, sodium bicarbonate powder, anhydrous citric acid, cross-linked carmellose sodium, sodium lauryl sulfate, crospovidone, fumed silica, sodium stearyl fumarate, and optionally the presence or absence of water; Preferably, one or more of the ingredients in the pharmaceutical composition are milled and / or sieved.

[0121] According to the present invention, the pharmaceutical composition may further comprise one or more therapeutic or prophylactic active ingredients other than the various forms of the compound of Formula I. When the composition of the present invention comprises such active ingredients, the various forms of the compound of Formula I and the other active ingredient are typically provided in a dosage of about 1% to 100%, more preferably about 5% to 95%, of the dosage administered in a single treatment regimen. The other active ingredient may be administered separately from the various forms of the compound of Formula I of the present invention as part of a multiple-dose administration regimen. Alternatively, the other active ingredient may be part of a single dosage form, mixed together with the various forms of the compound of Formula I of the present invention in a single composition.

[0122] The pharmaceutical compositions can be prepared by methods known to those skilled in the art. For example, one or more of the crystalline forms of the present invention can be mixed with one or more pharmaceutically acceptable adjuvants and optionally other ingredients. For example, solid formulations can be prepared by direct mixing, granulation, etc. The present invention also provides a method for treating or preventing a disease or condition, comprising administering to a subject an effective amount of a crystalline form or pharmaceutical composition according to the present invention.

[0123] The invention also provides a method of modulating (e.g., inhibiting, antagonizing, activating) kinase activity, said method comprising contacting the kinase with a crystalline form or pharmaceutical composition described in the invention.

[0124] The present invention also provides pharmaceutical applications of the crystalline forms or pharmaceutical compositions, such as medicaments for modulating kinase activity in subjects in need thereof, or for treating or preventing a disease or condition.

[0125] Preferably, the disease or condition is any one of diseases or conditions mediated by kinases (e.g., one or more of VEGFR, PDGFR, Flt-3, KIT, RET, or CSF1R). The disease or condition may be cancer, including, for example, renal cell carcinoma and gastrointestinal stromal tumor, tumor, or proliferative disorder.

[0126] The present invention also provides a method for improving the therapeutic effect or reducing the side effects (e.g., neutropenia and / or fatigue toxicity) of sunitinib or a derivative thereof, which comprises administering to the subject an effective amount of one of the crystalline forms or pharmaceutical compositions described in the present invention as an alternative to sunitinib or a derivative thereof.

[0127] The present invention also provides a method for preparing a compound of formula I. The method comprises carrying out the following reaction:

[0128] [ka]

[0129] Among them, HOBt represents hydroxybenzotriazole, EDCI represents 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, Et3N represents triethylamine, and DMF represents N,N-dimethylformamide.

[0130] The molar ratio of compounds A and B may be 1:1 to 1:3, for example, 1:1 to 1:1.5, for example, 1:1.2; The molar ratio of compound A to triethylamine may be 1:1 to 1:10, for example, 1:5; The molar ratio of compound A to EDCI may be 1:1 to 1:3, for example, 1:1.2 to 1:1.8, for example, 1:1.5; Preferably, the reaction is carried out in an inert atmosphere (e.g., a nitrogen gas atmosphere); Preferably, the reaction temperature may be 5-45°C, for example 20-30°C; Preferably, after the reaction is completed, an ether solvent, such as methyl tert-butyl ether, is added to the reaction mixture, stirred, filtered, and the filter cake is washed with methyl tert-butyl ether; Preferably, the product from the methyl tert-butyl ether wash is mixed with methanol or an aqueous solution thereof, such as anhydrous methanol, and heated to reflux.

[0131] The reflux time is preferably not more than 2 hours, for example, 0.5 to 1 hour; Preferably, after refluxing, the reaction mixture is cooled to 10-20°C, stirred for 1-3 hours, and then filtered; Preferably, the filter cake is washed with methanol, e.g., chilled methanol, and dried to obtain the initial product of the compound of Formula I. The drying includes drying at atmospheric pressure or vacuum drying. The temperature for vacuum drying may be about 35°C or higher, for example, about 40°C or higher, about 45°C or higher, or about 50°C or higher, for example, about 40 to 60°C. The vacuum degree for vacuum drying may be, for example, 200 to 1500 Pa, for example, 500 to 1000 Pa. [Terminology & Definitions] The term "subject" refers to an animal, e.g., a mammal, including, but not limited to, primates, e.g., humans, cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc. In the present invention, the "subject" refers to a human.

[0132] The term "about" means that, in accordance with the present invention, a stated numerical value may include a range of ±20%, for example, ±10%, ±5%, ±1%, ±0.5%, or ±0.1% of the specific numerical value, so as to implement the technical solution of the present invention.

[0133] In the present invention, the term "crystalline form" is not merely understood as "a type of crystal" or "a crystal structure", but "crystalline form" in the technical solution is understood as "a substance having a specific crystalline structure" or "a crystal of a specific crystalline type".

[0134] In the present invention, the above-mentioned "crystalline forms" are all characterized by X-ray diffraction patterns. Those skilled in the art will understand that experimental error is determined by instrument conditions, sample preparation, and sample purity. As those skilled in the art will appreciate, X-ray diffraction patterns typically vary slightly depending on instrument conditions. Furthermore, experimental error in peak angles is typically 5% or less, and these angle errors should also be taken into consideration, with an error of ±0.2° typically being tolerated. Furthermore, experimental factors such as sample height can lead to overall shifts in peak angles, and a certain degree of deviation is typically tolerated. Therefore, those skilled in the art will understand that any crystalline form having the same or similar pattern as the characteristic peaks in the diagrams of the present invention is within the scope of the present invention.

[0135] The term "anhydrous" means that the product contains not more than 3.0% water by weight, such as not more than 1.5%, such as not more than 1%, as determined by thermogravimetric analysis (TGA).

[0136] In the present invention, "room temperature" refers to room temperature in the usual sense in the art, which is generally 10 to 30°C.

[0137] In the present invention, the term "crystal slurry" refers to a "supersaturated solution containing the compound of formula I above" (ie, there are undissolved solids in the solution).

[0138] "Pharmaceutically acceptable" refers to a drug present in a form or amount that does not have an adverse effect on the subject to which it is administered.

[0139] In the present invention, unless otherwise specified, the information of each measuring instrument and the parameters of the measuring method are as follows:

[0140] (1) Powder X-ray diffractometer (XRD) & hot stage XRD, Bruker D8 Advance diffractometer; technical indicators: copper target, Kα radiation with a wavelength of 1.54 Å (40 Kv, 40 mA), θ-2θ angle measuring instrument, Mo monochromator, Lynxeye detector; standard material: Al2O3; collection software: Diffrac Plus XRD Commander; analysis software: MDI Jade 6; Method settings: Measurement angle: 3-40° 2θ / 3-30° 2θ (hot stage XRD); Step length: 0.02° 2θ; Speed: 0.15 s.step -1 ;Measurement sample amount > 2mg.

[0141] (2) Differential scanning calorimetry (DSC), TA Instruments Q200 DSC; control software: Thermal Advantage; analysis software: Universal Analysis; sample plate: aluminum crucible; measurement sample size: 0.5-5 mg; protective gas: nitrogen gas; gas flow rate: 40 mL / min; measurement method: heating rate 10°C / min, equilibrated at 20°C, then heated to 300°C.

[0142] (3) Thermogravimetric analyzer (TGA), TA Instruments Q500 TGA; control software: Thermal Advantage; analysis software: Universal Analysis; sample plate: platinum crucible; measurement sample amount: 1-10 mg; protective gas: nitrogen gas; gas flow rate: 40 mL / min; measurement method: high resolution 3.0 (Hi-Res sensitivity 3.0), heating rate 10°C / min, heating up to 350°C.

[0143] (4) Dynamic moisture sorption spectrometer (DVS), TA Instruments Q5000 TGA; control software: Thermal Advantage; analysis software: Universal Analysis; sample plate: platinum crucible; measurement sample size: 1-10 mg; protective gas: nitrogen gas; gas flow rate: 10 mL / min; measurement method: equilibrate at 25°C, humidity: 0%, isothermal: 90 minutes, and measure the weight change within the range of 0%RH to 80%RH; Criteria: non-hygroscopic is not more than 0.2%; slightly hygroscopic is more than 0.2% but not more than 2.0%; hygroscopic is more than 2% but not more than 15%; very hygroscopic is more than 15%.

[0144] (5) Hot-stage polarizing microscope (PLM), XP-500E; Shanghai Changfang Optical Instrument Co., Ltd.

[0145] (6) Solubility measurement, visual method: At 25°C, weigh a known amount of sample, add solvent to the sample in several portions, and stir or sonicate to promote dissolution until the sample becomes transparent to the naked eye. Record the amount of solvent consumed. If the sample has not yet dissolved and become transparent at a specific concentration, the solubility is marked as "< specific concentration."

[0146] Criteria for judgment: very soluble is greater than 1 g / mL; freely soluble is greater than 100 mg / mL but less than or equal to 1 g / mL; soluble is greater than 33.3 mg / mL but less than or equal to 100 mg / mL; slightly soluble is greater than 10 mg / mL but less than or equal to 33.3 mg / mL; slightly soluble is greater than 1 mg / mL but less than or equal to 10 mg / mL; very slightly soluble is greater than 0.1 mg / mL but less than or equal to 1 mg / mL; almost insoluble or insoluble is less than 0.1 mg / mL.

[0147] Each preferred embodiment of the present invention can be obtained by arbitrarily combining the above preferred conditions, provided that it is consistent with common knowledge in the art.

[0148] All reagents and raw materials used in the present invention are commercially available.

[0149] The beneficial effects of the present invention are: The crystalline forms of the present invention have good stability and chemical stability, resulting in a reduction in the purity of the main component of less than 2% under stability test conditions. Furthermore, the crystalline forms of the present invention have improved pharmaceutical properties, pharmacokinetic properties, tissue accumulation, and stability (e.g., polishing stability), making them suitable for pharmaceutical use. The inventors further discovered that crystalline form 2 has good stability and hygroscopicity, while crystalline form 1, while possessing sufficient stability and improved hygroscopicity, also possesses excellent overall performance in other aspects, resulting in excellent druggability. Crystalline forms 1 and 2 have the highest solubility in methanol. Furthermore, the preparation method of the crystalline forms described in the present invention, for example, obtaining crystalline form 1 from methanol, can produce the crystalline form of the compound of Formula I in good yield and with high purity. Furthermore, the preparation method of the present invention is suitable for large-scale production.

[0150] [Attached Drawings] FIG. 1 is the powder X-ray diffraction pattern of crystalline form 1.

[0151] FIG. 2 is a polarizing microscope photograph of crystalline form 1.

[0152] FIG. 3 is a thermogravimetric analysis diagram of crystalline form 1.

[0153] FIG. 4 is a differential scanning calorimetry diagram of crystalline form 1.

[0154] FIG. 5 shows the dynamic moisture sorption diagram of crystalline form 1.

[0155] FIG. 6 shows the structure of a compound of formula I of the present invention. 1 H-NMR spectra of crystalline forms 1, 2, 3, 5, 6 and 7 samples. 1 All H-NMR spectra are consistent with Figure 6.

[0156] FIG. 7 is the powder X-ray diffraction pattern of crystalline form 2.

[0157] FIG. 8 is a polarized light microscope photograph of crystalline form 2.

[0158] FIG. 9 is a thermogravimetric analysis diagram of crystalline form 2.

[0159] FIG. 10 is a differential scanning calorimetry diagram of crystalline form 2.

[0160] FIG. 11 shows the dynamic moisture sorption diagram of crystalline form 2.

[0161] FIG. 12 is the powder X-ray diffraction pattern of crystalline form 3.

[0162] FIG. 13 is a polarized light microscope photograph of crystalline form 3.

[0163] FIG. 14 is a thermogravimetric analysis diagram of crystalline form 3.

[0164] FIG. 15 is a differential scanning calorimetry diagram of crystalline form 3.

[0165] FIG. 16 shows the dynamic moisture sorption diagram of crystalline form 3.

[0166] FIG. 17 is the powder X-ray diffraction pattern of crystalline form 5.

[0167] FIG. 18 is a polarized light microscope photograph of crystalline form 5.

[0168] FIG. 19 is a thermogravimetric analysis diagram of crystalline form 5.

[0169] FIG. 20 is a differential scanning calorimetry diagram of crystalline form 5.

[0170] FIG. 21 is a dynamic moisture sorption diagram for crystalline form 5.

[0171] FIG. 22 is the powder X-ray diffraction pattern of crystalline form 6.

[0172] FIG. 23 is a polarized light microscope photograph of crystalline form 6.

[0173] FIG. 24 is a thermogravimetric analysis diagram of crystalline form 6.

[0174] FIG. 25 is a differential scanning calorimetry diagram of crystalline form 6.

[0175] FIG. 26 is a dynamic moisture sorption diagram for crystalline form 6.

[0176] FIG. 27 is the powder X-ray diffraction pattern of crystalline form 7.

[0177] FIG. 28 is a polarized light micrograph of crystalline form 7.

[0178] FIG. 29 is a thermogravimetric analysis diagram of crystalline form 7.

[0179] FIG. 30 is a differential scanning calorimetry diagram of crystalline form 7.

[0180] FIG. 31 shows the dynamic moisture sorption diagram for crystalline form 7.

[0181] FIG. 32 is the adsorption isotherm of crystalline form 1.

[0182] FIG. 33 is the adsorption isotherm of crystalline form 2.

[0183] FIG. 34 is the adsorption isotherm of crystalline form 3.

[0184] FIG. 35 is the adsorption isotherm of crystalline form 5.

[0185] FIG. 36 is the adsorption isotherm of crystalline form 6.

[0186] FIG. 37 is the adsorption isotherm of crystalline form 7.

[0187] FIG. 38 is a stability XRD pattern of Form 1.

[0188] FIG. 39 is a stability DSC pattern of Form 1.

[0189] FIG. 40 is the stability XRD pattern of Form 2.

[0190] FIG. 41 is a stability DSC pattern of Form 2.

[0191] FIG. 42 is the stability XRD pattern of Form 3.

[0192] FIG. 43 is a stability DSC pattern of Form 3.

[0193] FIG. 44 is the stability XRD pattern of Form 5.

[0194] FIG. 45 is a stability DSC pattern of Form 5.

[0195] FIG. 46 is the stability XRD pattern of Form 6.

[0196] FIG. 47 is a stability DSC pattern of Form 6.

[0197] FIG. 48 is the stability XRD pattern of Form 7.

[0198] FIG. 49 shows that Form 1, Form 2, Form 3 and Form 7 are transformed into Form 2 in acetone, ethyl acetate, methanol or water.

[0199] FIG. 50 shows the transformation of Form 1, Form 2, Form 3 and Form 7 into Form 3 in tetrahydrofuran (THF).

[0200] FIG. 51 shows a comparison of the XRD patterns of crystalline form 1 and crystalline form 2, where the upper pattern is crystalline form 1 and the lower pattern is crystalline form 2.

[0201] FIG. 52 shows the relationship between the peak area at 10.1° 2θ and the weight percentage content of Form 2 in Form 1.

[0202] Figure 53 shows a comparison of the XRD patterns of crystalline form 1 before and after polishing, where the upper pattern is the XRD pattern before polishing and the lower pattern is the XRD pattern after polishing.

[0203] Specific implementation methods The present invention will be further described by the following examples, but is not intended to be limited to the scope of the examples. In the following examples, experimental methods for which no specific conditions are specified are carried out according to conventional methods and conditions or in accordance with the product instructions.

[0204] Unless otherwise specified, the measurement equipment information and measurement method settings used in the following examples and effect examples are as follows: (1) Powder X-ray diffractometer (XRD) & hot stage XRD, Bruker D8 Advance diffractometer; Technical parameters: copper target, Kα radiation (40 Kv, 40 mA) with a wavelength of 1.54 Å, θ-2θ angle measuring instrument, Mo monochromator, Lynxeye detector; Standard material: Al2O3; Collection software: Diffrac Plus XRD Commander; Analysis software: MDI Jade 6 Method settings: Measurement angle 3-40° 2θ / 3-30° 2θ (hot stage XRD); Step length 0.02° 2θ; Speed ​​0.15 s.step -1 ;Measurement sample amount >2 mg.

[0205] (2) Differential scanning calorimetry (DSC), TA Instruments Q200 DSC; control software: Thermal Advantage; analysis software: Universal Analysis; sample plate: aluminum crucible; measurement sample amount: 0.5-5 mg; protective gas: nitrogen gas; gas flow rate: 40 mL / min; measurement method: heating rate 10°C / min, equilibrated at 20°C, then heated to 300°C.

[0206] (3) Thermogravimetric analyzer (TGA), TA Instruments Q500 TGA; control software: Thermal Advantage; analysis software: Universal Analysis; sample plate: platinum crucible; measurement sample amount: 1-10 mg; protective gas: nitrogen gas; gas flow rate: 40 mL / min; measurement method: high resolution 3.0 (Hi-Res sensitivity 3.0), heating rate 10°C / min, heating up to 350°C.

[0207] (4) Dynamic moisture sorption spectrometer (DVS), TA Instruments Q5000 TGA; control software: Thermal Advantage; analysis software: Universal Analysis; sample plate: platinum crucible; measurement sample size: 1-10 mg; protective gas: nitrogen gas; gas flow rate: 10 mL / min; measurement method: equilibrate at 25°C, maintain at 0% humidity for 90 minutes, and measure the weight change within the range of 0%RH to 80%RH; Criteria: non-hygroscopic is not more than 0.2%; slightly hygroscopic is more than 0.2% but not more than 2.0%; hygroscopic is more than 2% but not more than 15%; very hygroscopic is more than 15%.

[0208] (5) Hot-stage polarizing microscope (PLM), XP-500E; Shanghai Changfang Optical Instrument Co., Ltd.

[0209] (6) Solubility is measured visually; specific method: weigh a known amount of sample at 25°C, add solvent to the sample in several portions, and use stirring or ultrasonic waves to promote dissolution until the sample becomes transparent to the naked eye, and record the amount of solvent consumed. If the sample has not yet dissolved and become transparent at a specific concentration, its solubility is marked as "< specific concentration."

[0210] Criteria for judgment: very soluble is greater than 1 g / mL; freely soluble is greater than 100 mg / mL but less than or equal to 1 g / mL; soluble is greater than 33.3 mg / mL but less than or equal to 100 mg / mL; slightly soluble is greater than 10 mg / mL but less than or equal to 33.3 mg / mL; slightly soluble is greater than 1 mg / mL but less than or equal to 10 mg / mL; very slightly soluble is greater than 0.1 mg / mL but less than or equal to 1 mg / mL; almost insoluble or insoluble is less than 0.1 mg / mL.

[0211] (7) Nuclear magnetic resonance (NMR) was performed on a Bruker Ascend 500; measurement type: nuclear magnetic proton spectrum; full frequency excitation, 30 ppm spectral width single pulse, 16 scans at 30° angular excitation, digital quadrature detection, and temperature control at 298 K.

[0212] (8) High-performance liquid chromatography (HPLC), Ultimate 3000; measurement purpose: solubility measurement (area method), related substances (area normalization method).

[0213] Measurement method parameters: Column: Shimadzu shim-pack VP-ODS (150L*4.6), Waters symmetry C18 (3.9*150mm 5m); Column temperature: 25℃; Flow rate: 1.0mL / min; Measurement wavelength: 214nm; Sample feed volume: 10μL; Run time: 20min; Sample solvent: ACN; Sample feed concentration: 0.2mg / mL; Mobile phase: Mobile phase A: H2O:CAN:H3PO4 = 90:10:0.1, Mobile phase B: H2O:CAN:H3PO4 = 10:90:0.1; Gradient elution as shown in Table 7 below:

[0214] [Table 7]

[0215] In the following examples, "solvent evaporation" refers to natural evaporation of the solvent in an open wide-mouth container until the solvent dries; "room temperature" refers to 10 to 30°C (30 to 70% RH); "crystal slurry" refers to a supersaturated solution containing the compound of formula I; and "overnight" refers to overnight, typically 10 to 16 hours.

[0216] In the tables of examples below, "NA" stands for "not applicable" or "not used."

[0217] [Manufacturing Example]

[0218] [ka]

[0219] Compound A (13.00 kg, 1 eq.) was added to DMF (97.8 kg) in a reactor at 20-30°C under a nitrogen atmosphere. Then, triethylamine (TEA, 21.88 kg, 5 eq.), hydroxybenzotriazole (HOBt, 8.78 kg, 1.5 eq.), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI, 12.42 kg, 1.5 eq.), and compound B (10.1 kg, 1.2 eq.) were added to the reactor at 20-30°C under a nitrogen atmosphere. The mixture was stirred for 22 hours at 20-30°C under a nitrogen atmosphere. After completion of the reaction, the reaction mixture was transferred to a clean container and weighed (163.8 kg).

[0220] Approximately 1 / 4 (40.90 kg) of the reaction mixture was added to the reactor, and then methyl tert-butyl ether ("MTBE", 62.8 kg) was added to the reaction mixture at 10-20°C. The resulting suspension was stirred at 10-20°C for 2 hours and then filtered. The remaining 3 / 4 of the reaction mixture was treated in the same manner. The combined filter cake was washed with MTBE (46.2 kg).

[0221] A portion of the combined solid (20.0 kg) was added to anhydrous methanol (74.2 kg), and the resulting mixture was heated to reflux for 45 minutes. The reaction mixture was then cooled to 10-20°C within 1-2 hours and then stirred at 10-20°C for 1.5 hours. The resulting suspension was filtered. The other MTBE-washed material was treated in the same manner. The filter cakes were combined, cooled, and washed with methanol (44.2 kg). The wet crude product was dried under reduced pressure (500-1000 Pa) at 50°C for 13 hours, and then at 76°C for 23 hours, yielding approximately 12 kg of the initial product of the compound of Formula I.

[0222] [Example 1] Method 1 for preparing crystalline form 1 of the compound of formula I: The compound of formula I can be prepared by mixing 5 mg of the compound of formula I with a single solvent, or by mixing 10 mg of the compound of formula I with solvent 1 and solvent 2, and then allowing the resulting transparent liquid to evaporate at the corresponding temperature until dry. See Table 8 for specific preparation parameters.

[0223] [Table 8]

[0224] As a result, all products produced by the above manufacturing method were crystalline form 1. The powder X-ray diffraction pattern of crystalline form 1 is shown in Figure 1, and detailed data of the powder X-ray diffraction pattern are shown in Table 1. A polarizing microscope photograph of crystalline form 1 is shown in Figure 2, which shows that they are elongated rod-like crystals. Crystal form 1 has a thermogravimetric analysis diagram as shown in Figure 3, which shows that crystalline form 1 lost 2.6% weight before 170°C. It is an anhydrous form with a decomposition temperature of 320°C. Crystal form 1 has a differential scanning calorimetry diagram as shown in Figure 4, which shows an exothermic peak between 150 and 170°C. XRD analysis confirmed this to be an exothermic crystal transformation peak. The crystalline form after transformation is crystalline form 3, and the melting point of crystalline form 1 is 260°C. Crystal form 1 has a dynamic moisture sorption diagram as shown in Figure 5, which shows a weight change of 2.8% within the range of 0%RH to 80%RH.

[0225] The compound of formula I and the crystalline form 1 1 The H-NMR spectra are all shown in Figure 6, and indicate that the chemical structure is as shown in Formula I:

[0226] [ka]

[0227] Solubility measurements of Form 1 in common solvents at 25°C are as follows: in methanol, 5-12.5 mg / mL; in ethanol, 1-2.5 mg / mL; in water, <1 mg / mL; in acetone, 1-2.5 mg / mL; in ethyl acetate, <1 mg / mL; in methyl tert-butyl ether, <1 mg / mL; in tetrahydrofuran, 1-2.5 mg / mL; in acetonitrile, <1 mg / mL; in toluene, <1 mg / mL; and in n-heptane, <1 mg / mL.

[0228] [Example 2] Preparation Methods 2 and 3 of Crystalline Form 1 of the Compound of Formula I: 20 mg of the compound of Formula I is weighed out and mixed with 1.4 mL of methanol. Heat to 50°C to obtain a clear solution, then hot filter to obtain a clear solution. Add solvent 2 to the clear solution with stirring (forward addition, corresponding to Preparation Method 2). Add the clear solution to solvent 2 with stirring (reverse addition, corresponding to Preparation Method 3). When solids begin to precipitate, continue stirring until the solids are completely precipitated. The specific preparation parameters are as shown in Table 9.

[0229] [Table 9]

[0230] As a result of the measurements, all of the products obtained by the above manufacturing method are crystalline form 1. Their XRD, PLM, TGA, DSC, DVS, 1 The results of measurements such as H-NMR and solubility were all the same as in Example 1.

[0231] [Example 3] Method 4 for preparing crystalline form 1 of the compound of formula I: The compound of formula I (20 mg) is dissolved in a suitable solvent in a 50°C water bath, filtered to obtain a clear solution, and then cooled to 4°C. The solution is stirred and crystallized to precipitate a solid. The specific preparation parameters are shown in Table 10.

[0232] [Table 10]

[0233] As a result of the measurements, all the products produced by the above manufacturing method are crystalline form 1. Their XRD, PLM, TGA, DSC, DVS, 1 The results of measurements such as H-NMR and solubility were all the same as in Example 1.

[0234] [Example 4] Method 4 for preparing crystalline form 1 of the compound of formula I: The initial product of the compound of Formula I (2.0 kg), anhydrous methanol (72.0 kg), and activated carbon (0.20 kg) were added to a reactor and heated to reflux for 1.5 hours. The reaction mixture was filtered, and the filtrate was heated to reflux for 40 minutes. The resulting solution was filtered hot into a reactor and concentrated under reduced pressure (500-1000 Pa) for approximately 4 hours to remove approximately 85 L of methanol. The resulting suspension was cooled to 10-20°C and then stirred at 10-20°C for approximately 45 minutes before filtering. The filter cake was washed with methanol and had a purity of 99.9% as determined by HPLC. The resulting solid was dried at 40-60°C under reduced pressure (500-1000 Pa). The resulting product was determined to be crystalline form 1 by XRD, with a yield of over 80%.

[0235] [Example 5] This is a method for preparing crystalline form 2 of the compound of formula I. The crystalline form of the compound of formula I used is crystalline form 1.

[0236] Preparation of samples Nos. 1 to 9: 10 mg of the compound of formula I is mixed with a suitable solvent to obtain a suspension, stirred at a suitable temperature for 5 to 6 days, centrifuged the crystalline slurry, and dried the solid.

[0237] Preparation of sample No. 10: 199 mg of the compound of formula I was mixed with a suitable solvent to obtain a suspension, which was then stirred at 50°C for 2 hours and then at room temperature for another 2 days. The crystalline slurry was filtered, and the solid was dried under vacuum at room temperature overnight.

[0238] Preparation of sample No. 11: 200 mg of the compound of formula I is mixed with a suitable solvent to obtain a suspension, stirred at 4°C for 5 days, filtered the crystalline slurry, and then vacuum dried the solid at room temperature overnight.

[0239] Preparation of sample No. 12: 200 mg of the compound of formula I is mixed with a suitable solvent to obtain a suspension, stirred at room temperature for 3 days, filtered the crystalline slurry, and then vacuum dried the solid at room temperature overnight.

[0240] The specific manufacturing parameters are as shown in Table 11 below.

[0241] [Table 11]

[0242] As a result, all the products produced by the above manufacturing method were crystalline form 2. The powder X-ray diffraction pattern of crystalline form 2 is shown in Figure 7, and detailed data of the powder X-ray diffraction pattern is shown in Table 2. The polarizing microscope photograph of crystalline form 2 is shown in Figure 8, which shows that they are fine needle-like crystals. The thermogravimetric analysis diagram of crystalline form 2 is shown in Figure 9, which shows that crystalline form 2 lost 0.3% weight before 200°C. It is an anhydrous form with a decomposition temperature of 320°C. The differential scanning calorimetry diagram of crystalline form 2 is shown in Figure 10, which shows that the melting point of crystalline form 2 is 258°C. The dynamic moisture sorption diagram of crystalline form 2 is shown in Figure 11, which shows that the weight change within the range of 0%RH to 80%RH is 0.05%. The 1 The H-NMR spectrum is consistent with Figure 6.

[0243] [Example 6] Methods 1, 2 and 3 for preparing crystalline form 3 of the compound of formula I: The compound of formula I can be prepared by mixing 5 mg of the compound with a single solvent, or by mixing 10 mg of the compound of formula I with solvent 1 and solvent 2 to obtain a transparent liquid, which is then left to evaporate at a suitable temperature until dry. The specific preparation parameters are shown in Table 12 below.

[0244] [Table 12]

[0245] As a result, all the products produced by the above manufacturing method were crystalline form 3. The powder X-ray diffraction pattern of crystalline form 3 is shown in Figure 12, and the detailed data of the powder X-ray diffraction pattern is shown in Table 3 above. The polarizing microscope photograph of crystalline form 3 is shown in Figure 13, which shows that the particles are small and there are partial aggregates. The thermogravimetric analysis diagram of crystalline form 3 is shown in Figure 14, which shows that crystalline form 3 lost 0.2% weight before 200°C. It is an anhydrous form with a decomposition temperature of 320°C. The differential scanning calorimetry diagram of crystalline form 3 is shown in Figure 15, which shows that the melting point of crystalline form 3 is 261°C. The dynamic moisture sorption diagram of crystalline form 3 is shown in Figure 16, which shows that the weight change within the range of 0%RH to 80%RH is 0.08%. The crystalline form 3 1 The H-NMR spectrum is consistent with Figure 6.

[0246] [Example 7] This is Method 4 for preparing Crystalline Form 3 of the compound of Formula I. The crystalline form of the compound of Formula I used is Crystalline Form 1.

[0247] Preparation of samples Nos. 1-3: 10 mg of the compound of formula I is mixed with a suitable solvent to obtain a suspension, stirred at a suitable temperature for 5-6 days, centrifuged the crystalline slurry, and dried the solid.

[0248] Preparation of samples 4 to 6: 200 mg of the compound of formula I is mixed with a suitable solvent to obtain a suspension, stirred at a suitable temperature for 5 days, filtered, and the solid is vacuum dried at room temperature overnight.

[0249] Preparation of sample No. 7: 201.0 mg of the compound of formula I is mixed with a suitable solvent to obtain a suspension, which is stirred at a suitable temperature at 800 rpm for 20 hours, and the crystal slurry is filtered under suction to separate the solid, which is then dried at 60°C for 1 hour.

[0250] The specific manufacturing parameters are as shown in Table 13 below.

[0251] [Table 13]

[0252] As a result of the measurements, all the products produced by the above manufacturing method are crystalline form 3. Their XRD, PLM, TGA, DSC, DVS, 1 The results of measurements such as H-NMR are all the same as in Example 4.

[0253] [Example 8] Method 5 for preparing crystalline form 3 of the compound of formula I: The compound of formula I (20 mg) can be prepared by mixing it with a suitable solvent in a water bath at 50°C to form a clear solution, filtering the solution while hot, allowing it to cool to 4°C, and then stirring to crystallize the solid.

[0254] The specific manufacturing parameters are as shown in Table 14 below.

[0255] [Table 14]

[0256] As a result of the measurements, all the products produced by the above manufacturing method are crystalline form 3. Their XRD, PLM, TGA, DSC, DVS, 1 The results of measurements such as H-NMR are all the same as in Example 4.

[0257] [Example 9] Method 6 for preparing crystalline form 3 of the compound of formula I: Crystalline Form 1 can be prepared by heating it to 180° C. and cooling it to room temperature.

[0258] As a result of the measurements, all the products produced by the above manufacturing method are crystalline form 3. Their XRD, PLM, TGA, DSC, DVS, 1 The results of measurements such as H-NMR are all the same as in Example 4.

[0259] [Example 10] Method 1 for preparing crystalline form 5 of the compound of formula I: 20 mg of the compound of formula I is mixed with 5 mL of acetone in a water bath at 50° C. to form a clear solution, which is then filtered while hot and allowed to cool to 4° C. A solid is precipitated by stirring and crystallization, and the solid is centrifuged and vacuum dried at room temperature to produce the product.

[0260] As a result, the product produced by the above manufacturing method is crystalline form 5. The powder X-ray diffraction pattern of crystalline form 5 is shown in Figure 17, and the detailed data of the powder X-ray diffraction pattern are shown in Table 4 above. The polarizing microscope photograph of crystalline form 5 is shown in Figure 18, which shows that it is made of small particles and there is partial aggregation. The thermogravimetric analysis diagram of crystalline form 5 is shown in Figure 19, which shows that crystalline form 5 lost 1.2% weight before 200°C. It is an anhydrous form and its decomposition temperature is 319°C. The differential scanning calorimetry diagram of crystalline form 5 is shown in Figure 20, which shows that the melting point of crystalline form 5 is 258°C, and the broad endothermic peak before 100°C is due to the removal of surface solvent. The dynamic moisture sorption diagram of crystalline form 5 is shown in Figure 21, which shows that its weight change within the range of 0%RH to 80%RH is 2.5%. The 1 The H-NMR spectrum is consistent with Figure 6.

[0261] [Example 11] This is Method 2 for preparing Crystalline Form 5 of the compound of Formula I, in which the crystalline form of the compound of Formula I used is Crystalline Form 1.

[0262] Preparation of sample No. 1: 199 mg of the compound of formula I can be prepared by mixing with 10 mL of methyl tert-butyl ether to obtain a suspension, stirring at room temperature for 2 days, filtering the crystalline slurry, and drying the solid under vacuum at room temperature overnight.

[0263] Preparation of sample No. 2: 600 mg of the compound of formula I can be prepared by mixing with 30 mL of methyl tert-butyl ether, adding 2% by mass of crystalline form 5 as seed crystals to the crystal slurry, stirring at room temperature for 1 day, filtering the crystal slurry, and vacuum drying the solid at room temperature overnight.

[0264] Preparation of sample No. 3: The preparation method is the same as that of sample No. 1, except that acetone is substituted for methyl tert-butyl ether.

[0265] As a result of the measurement, all the products produced by the above manufacturing method are crystalline form 5. The XRD, PLM, TGA, DSC, DVS, 1 The results of measurements such as H-NMR are all the same as in Example 9.

[0266] [Example 12] Method 1 for preparing crystalline form 6 of the compound of formula I: The compound of formula I (10 mg) can be mixed with 0.4 mL of a mixture of toluene and methanol (the volume ratio of toluene to methanol is 1:1), sonicated, and filtered to obtain a clear solution, which can be evaporated to dryness at room temperature.

[0267] As a result, the product produced by the above manufacturing method is crystalline form 6. The powder X-ray diffraction pattern of crystalline form 6 is shown in Figure 22, and the detailed data of the powder X-ray diffraction pattern are shown in Table 5 above. The polarizing microscope photograph of crystalline form 6 is shown in Figure 23, which shows that the particles are small and there are partial aggregates. The thermogravimetric analysis diagram of crystalline form 6 is shown in Figure 24, which shows that crystalline form 6 lost 0.7% weight before 200°C, and it is anhydrous and has a decomposition temperature of 320°C; the differential scanning calorimetry diagram of crystalline form 6 is shown in Figure 25, which shows that the melting point of crystalline form 6 is 259°C; and the dynamic moisture sorption diagram of crystalline form 6 is shown in Figure 26, which shows that the weight change within the range of 0%RH to 80%RH is 0.26%. The crystalline form 6 1 The H-NMR spectrum is consistent with Figure 6.

[0268] [Example 13] 2 is a method for preparing crystalline form 6 of the compound of formula I.

[0269] Preparation of sample No. 1: 20 mg of the compound of formula I is mixed with 1.4 mL of methanol, heated to 50°C, and dissolved. Then, hot filtration is performed to form a clear solution. 3.0 mL of toluene is added to the clear solution while stirring. When a solid begins to precipitate, stirring is continued until the solid is completely precipitated.

[0270] Preparation of sample No. 2: 20 mg of the compound of formula I is mixed with 1.4 mL of methanol, heated to 50°C, and dissolved. Then, hot filtration is performed to obtain a clear solution. The clear solution is added to 11.2 mL of toluene while stirring. When a solid begins to precipitate, stirring is continued until the solid is completely precipitated.

[0271] As a result of the measurement, all the products produced by the above manufacturing method are crystalline form 6. The XRD, PLM, TGA, DSC, DVS, 1 The results of measurements such as H-NMR are all the same as in Example 12.

[0272] [Example 14] This is Method 3 for preparing Crystalline Form 6 of the compound of Formula I. The crystalline form of the compound of Formula I used is Crystalline Form 1.

[0273] Preparation of sample No. 1: 200 mg of the compound of formula I can be prepared by mixing with 20 mL of toluene, stirring at room temperature for 16-22 hours, and then vacuum drying the crystalline slurry at 60° C. for 1 hour.

[0274] Preparation of sample No. 2: 600 mg of the compound of formula I was mixed with 60 mL of toluene, and then 2% of the crystalline slurry was seeded with crystalline form 6. The mixture was stirred at room temperature for 1 day, and the resulting crystalline slurry was then dried at 50°C for 1 hour.

[0275] As a result of the measurement, all the products produced by the above manufacturing method are crystalline form 6. The XRD, PLM, TGA, DSC, DVS, 1 The results of measurements such as H-NMR are all the same as in Example 11.

[0276] During the production of sample No. 1, the mixture was stirred at room temperature for 6 hours, after which a sample was taken and filtered under suction. A lump was found, and it was detected that the wet product contained crystalline form 1.

[0277] [Example 15] 1 is a method for preparing crystalline form 7 of the compound of formula I.

[0278] Preparation of sample No. 1: 199 mg of the compound of formula I can be prepared by mixing with 10 mL of ethyl acetate, stirring at 50°C for 30 minutes, filtering, and then vacuum drying the filter cake at 60°C for 1 hour.

[0279] Preparation of sample No. 2: 600 mg of the compound of formula I can be prepared by mixing with 30 mL of ethyl acetate, stirring at 50°C for 30 minutes, filtering, and then vacuum drying the filter cake at 60°C for 1 hour.

[0280] As a result, all the products produced by the above manufacturing method were crystalline form 7. The powder X-ray diffraction pattern of crystalline form 7 is shown in Figure 27, and the detailed data of the powder X-ray diffraction pattern are shown in Table 7 above. The polarizing microscope photograph of crystalline form 7 is shown in Figure 28, which shows that it is made of small particles and has partial aggregation. The thermogravimetric analysis diagram of crystalline form 7 is shown in Figure 29, which shows that crystalline form 7 lost 0.5% weight before 200°C, but it is anhydrous and has a decomposition temperature of 320°C. The differential scanning calorimetry diagram of crystalline form 7 is shown in Figure 30, which shows that the melting point of crystalline form 7 is 259°C. The dynamic moisture sorption diagram of crystalline form 7 is shown in Figure 31, which shows that its weight change within the range of 0%RH to 80%RH is 0.27%. The 1 The H-NMR spectrum is consistent with Figure 6.

[0281] [Example 16] Preparation Method 2 of Crystalline Form 7 of the compound of Formula I (wherein the crystalline form of the compound of Formula I used is Crystalline Form 1): The compound of formula I can be prepared by mixing and stirring with a mixture of N,N-dimethylacetamide and toluene (volume ratio of N,N-dimethylacetamide to toluene is 1:9), filtering the resulting crystalline slurry, and then drying it.

[0282] As a result of the measurements, all the products produced by the above manufacturing method are in crystalline form 7. Their XRD, PLM, TGA, DSC, DVS, 1 All the measurement results such as H-NMR were the same as in Example 14.

[0283] [Effective Example 1] The isothermal adsorption curves of samples of crystalline forms 1, 2, 3, 5, 6 and 7 are shown in Figures 32-37.

[0284] [Effective Example 2] Crystal form stability studies are conducted on crystalline forms 1, 2, 3, 5, 6 and 7.

[0285] Experimental conditions: The container was left sealed at 80°C for 24 hours, and then left open at 25°C / 60%RH (relative humidity) and 40°C / 75%RH for 7 days.

[0286] Measurement methods: HPLC (only starting sample and sample left at 80°C for 24 hours), XRD, DSC.

[0287] Survey results: 1) XRD and DSC measurements show that the crystal forms and melting points of samples of crystalline forms 1, 2, 3, 5, 6, and 7 are essentially unchanged and relatively stable. Specific measurement results are shown in Figures 38-48, and the crystal form stability DSC spectrum of crystalline form 7 is shown in Figure 30.

[0288] 2) HPLC analysis showed that the purity of the major component of all crystalline samples stored at 80°C for 24 hours was lower than that of the starting sample, but was still less than 2%; specific data are shown in Table 15. Note: The impurity at a retention time of 4.73 minutes is the trans isomer of the compound, and the results are related to the degree of shading during measurement.

[0289] [Table 15]

[0290] The long-term stability of Form 1 was then investigated at 25°C / 60%RH for 12 months, 24 months, 36 months, and 48 months, and the results showed that Form 1 remained essentially unchanged.

[0291] [Effective Example 3] Thermodynamic Stability Experiments: The thermodynamic stability of Forms 1, 2, 3, and 7 of the compound of Formula I was investigated by mixing each with acetone, ethyl acetate, methanol, water, and tetrahydrofuran, respectively, and then incubating at 60°C for 1 day. The insoluble solids were collected by filtration and analyzed by XRD. Analysis conditions: Shimadzu XRD-6000, CuK source (1.54056 Å), 40 kV, 30 mA; scanning angle: 5-50°, scanning rate: 5° / min.

[0292] The results show that Form 1, Form 2, Form 3, and Form 7 can all be converted to Form 2 by treating them with acetone, ethyl acetate, methanol, and water. However, as can be seen from the peak at about 13° 2θ in Figure 49, the use of methanol did not result in complete conversion to Form 2. Figure 50 shows that the use of THF can provide Form 3.

[0293] [Effective Example 4] Stability of crystalline form 1 in methanol The stability results of Form 1 in aqueous methanol at various temperatures and times are as follows: The results show that high temperature and moisture promote the conversion of Form 1 to Form 2.

[0294] [Table 16]

[0295] [Effective Example 5] Quantitative detection of Form 2 in Form 1 The XRD spectrum was measured using a Shimadzu XRD-6000 with a CuK source (1.54056 Å, 40 kV, 30 mA) to analyze the content of crystalline form 2 in crystalline form 1 of the compound of formula I. Measurement angle: 9.6-10.4° 2θ; step width: 0.02° 2θ; counting time: 10 s.

[0296] The XRD spectra of Form 1 and Form 2 are compared in Figure 51. The peak at 10.1° 2θ for Form 1 is very weak, while Form 2 has a strong characteristic peak. Therefore, the peak area of ​​this peak can be used to determine the amount of Form 2 in Form 1. Form 1 and Form 2 are sieved (100 mesh) to ensure that the samples have similar particle sizes. The samples were prepared by mixing appropriate amounts (by weight) of Form 1 and Form 2, as shown in Table 17. Three parallel measurements were performed, and the average value was used as the peak intensity at 10.1° 2θ.

[0297] [Table 17]

[0298] As shown in Figure 52, there is a linear relationship between the peak area at 10.1° 2θ and the weight percentage of crystalline form 2 in crystalline form 1. This indicates that the content of crystalline form 2 in crystalline form 1 can be accurately measured by this method when the content is 0.96% to 15.55%.

[0299] Samples containing 4.75 wt% and 6.36 wt% of crystalline form 2 were prepared, and the peak areas at 10.1° 2θ were measured. The peak areas were calculated from the linear relationship shown in Figure 52. As shown below, the deviations of the calculated values ​​are within 10% of the measured values.

[0300] [Table 18]

[0301] [Effective Example 6] Solubility measurement Solubility measurement method: A suitable amount of sample was taken, suspended in water, and stirred in a water bath at 25°C. The solution was subjected to HPLC concentration measurement at 0.5 hours and 4 hours, respectively.

[0302] Crystalline form 1 was used as the standard, and the concentration of the solution was 204.2 μg*mL -1 The content was set to 100% and HPLC measurement was performed seven times. The average peak area was 159.691 mAU*min (retention time 7.4 min).

[0303] Analysis results: The solubility measurement results of the crystalline forms are shown in Table 19. The results show that the solubility of crystalline form 1 is much higher than that of the most stable crystalline form 2.

[0304] [Table 19]

[0305] [Effective Example 7] Moisture-sensitive crystallization experiments of crystalline form 1 Approximately 10 mg of crystalline form 1 was left in a suitable environment and the solid was subjected to XRD characterization at different times. The characterization results showed that only the known crystalline form 1 appeared in this experiment. The specific experiments and results are shown in Table 20 below. The results show that crystalline form 1 is stable under these conditions.

[0306] [Table 20]

[0307] [Effective Example 8] Pharmaceutical properties experiments of crystalline form 1 and crystalline form 2 The water content, solubility, and dissolution rate of crystalline forms 1 and 2 were measured using the above methods. The results are shown in Table 21. The results showed that the solubility, dissolution rate, and water content (overall pharmaceutical properties) of crystalline form 1 were higher than those of crystalline form 2. Forms 1 and 2 had the highest solubility in methanol.

[0308] [Table 21]

[0309] [Effective Example 9] Pharmacokinetic experiments Twelve Sprague-Dawley rats weighing 230-250 g were randomly divided into two groups, each consisting of three males and three females. Crystalline Forms 1 and 2 were each prepared as suspensions in 0.5% carboxymethylcellulose (CMC). The rats were allowed free access to water and fasted for 12 hours before oral administration at a dose of 10 mg / kg. Blood samples (0.2-0.3 ml) were collected in heparin-anticoagulated tubes at pre-dose and 15, 30, 60, 120, 240, 360, 480, 720, and 1440 minutes after oral administration. The plasma obtained by centrifugation was stored at -20°C and then analyzed using an API4000 MS-HPLC unit. The pharmacokinetic parameters Cmax and AUC were calculated based on the measured plasma concentrations and are summarized in Table 22. As a result, Form 1 has a Cmax that is about 4 times higher than Form 2 and an exposure (AUC) that is about 3 times higher than Form 2.

[0310] [Table 22]

[0311] [Effective Example 10] Tissue accumulation experiment of crystalline form 1 Human colon carcinoma H-29 cells were implanted into the armpits of BALB / cA nude mice. Seven days after implantation of the H-29 cells, eight female mice were treated with either 40 mg / kg of crystalline form 1 (twice daily) or 40 mg / kg of sunitinib (once daily). Treatment was continued for 21 consecutive days. Plasma, tissue, and tumor samples were collected and analyzed 4 hours after treatment on the morning of day 22. The results are summarized in Table 23. As can be seen from the data, tissue accumulation of crystalline form 1 was significantly lower than that of sunitinib in all test tissues, but its plasma content was comparable.

[0312] [Table 23]

[0313] [Effective Example 11] Polishing stability experiment of crystalline form 1 Crystalline Form 1 was polished and sieved, and a sample was collected through a 200-300 mesh US standard sieve for XRD analysis. Analysis conditions: Shimadzu XRD-6000, CuK source (1.54056 Å), 40 kV, 30 mA; detection angle: 5-50°, speed: 5° / min.

[0314] As shown in Figure 53, the XRD spectra are essentially unchanged before and after polishing, indicating that Form 1 is stable during polishing.

[0315] [Effective Example 12] Capsule manufacturing 1) Weighing, polishing and sieving Approximately 1 / 4 of the volume of crystalline form 1 was added to a mortar. The crystalline form 1 was ground with a pestle to reduce the particle size. It was then sieved through a 250 μm (#60) mesh sieve and collected on a collection plate. The ground and sieved crystalline form 1 was transferred into a container. The above procedure was repeated until all crystalline form 1 had been ground and sieved. The total amount of crystalline form 1 to be used in the production of capsules was calculated.

[0316] Sieve the Pearlitol 200 SD through a 500 μm (#35) sieve and collect in a suitable container.

[0317] 2) Mixing The contents of sieved Pearlitol container #1 (830.3 ± 0.1 g), sodium bicarbonate powder (1,417.5 ± 0.1 g), sodium lauryl sulfate (405.0 ± 0.1 g), and cross-linked carmellose sodium (405.0 ± 0.1 g) were transferred into the formulation container containing crystalline Form 1 (162.0 ± 0.1 g). The container containing the ground and sieved Form 1 was dry washed three times with the sieved Pearlitol in container #2 (830.3 ± 0.1 g), and the material obtained by the dry washing was transferred into the formulation container of crystalline Form 1. The remaining sieved Pearlitol was then transferred into the formulation container of crystalline Form 1.

[0318] 3) Blend A Turbula Type T10B Shaker Mixer was set up according to the manufacturer's instructions, and the Form 1 formulation container was placed in it. The Turbula Type T10B Shaker Mixer was run and blended for 10 minutes. The Form 1 formulation was sieved through a 500 μm mesh sieve, and the sieved material was blended for 2 minutes. Three samples (900-2000 mg each) were taken from the top, middle, and bottom of the Form 1 formulation container to determine the content uniformity during production.

[0319] 4) Capsules Determine the average viscous weight of No. 0 Swedish Orange Opaque Coni-Snap Capsule capsules. Calculate the acceptable encapsulation weight limit. Prepare two Profill manual encapsulators for encapsulation. The dosage of formulation sample required for 100 capsules per plate is 51.0 g (add a 2% overage per plate). Weigh out the amount of formulation required to fill one plate of capsules (51.0 ± 0.1 g). Pack the formulation evenly into the capsules. Tap the Profill gently to completely and evenly pack all the formulation into the capsules. Seal the capsules using the Profill manual encapsulator. Replace the capsule caps on the filled capsule bodies and press down to ensure a secure seal. If necessary, repeat this process to ensure all capsule caps are securely fitted to the capsule bodies. Visually inspect the capsules and remove any with physical defects (i.e., broken capsule caps). Perform a weight check on each plate. Repeat the above process until all usable formulation has been encapsulated. All usable capsules are de-dusted.

[0320] [Effective Example 13] tablet manufacturing 1) The formulation is as shown in the table below:

[0321] [Table 24]

[0322] The manufacturing procedure for the above tablets is as follows: 1)API polishing / sieving Crystalline Form 1 is polished and sieved twice through a Comil sieve with 459 μm mesh.

[0323] 2) Excipient polishing / sieving All excipients were mixed in a V-blender for 5 minutes and sieved through a Comil mesh and once through a 1 mm mesh to remove any lumps.

[0324] 3) Blend The ground and sieved material is transferred to a V-blender and dry blended for 45 minutes.

[0325] 4) Tablet compression The final blended product is pressed into oval (100 mg) or round (50 mg) tablet cores in a high-speed rotary tablet press. During compression, tablets are inspected for weight, thickness, and hardness, followed by metallurgical measurements along with dedusting and finishing.

[0326] 5) Coating The tablet cores are dried together with the coating in a rotary coater. Tablets that do not meet requirements are sorted and rejected. Tablets that meet requirements are visually inspected for defects and relevant quality measurements are performed.

[0327] The tablets are stored in a double-layered polyethylene bag and a container with a desiccant until the packaging process.

[0328] 6) Final packaging The tablets were packaged in high density polyethylene (HDPE) bottles, which were sealed with seal-sensing polypropylene lids.

[0329] The product is stored at controlled room temperature until labeling.

[0330] 7) At the labeling and distribution center, the products are labeled.

[0331] Although the above describes exemplary embodiments of the present invention, the technical solutions of the present invention are not limited thereto. Those skilled in the art should understand that any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention are all within the scope of protection of the present invention. [Brief explanation of the drawings]

[0332] [Figure 1] FIG. 1 is the powder X-ray diffraction pattern of crystalline form 1. [Figure 2] FIG. 2 is a polarizing microscope photograph of crystalline form 1. [Figure 3]FIG. 3 is a thermogravimetric analysis diagram of crystalline form 1. [Figure 4] FIG. 4 is a differential scanning calorimetry diagram of crystalline form 1. [Figure 5] FIG. 5 shows the dynamic moisture sorption diagram of crystalline form 1. [Figure 6] FIG. 6 shows the 1H-NMR spectrum of the compound of formula I of the present invention, and the 1H-NMR spectra of the samples of crystalline forms 1, 2, 3, 5, 6 and 7 all coincide with FIG. 6. [Figure 7] FIG. 7 is the powder X-ray diffraction pattern of crystalline form 2. [Figure 8] FIG. 8 is a polarized light microscope photograph of crystalline form 2. [Figure 9] FIG. 9 is a thermogravimetric analysis diagram of crystalline form 2. [Figure 10] FIG. 10 is a differential scanning calorimetry diagram of crystalline form 2. [Figure 11] FIG. 11 shows the dynamic moisture sorption diagram of crystalline form 2. [Figure 12] FIG. 12 is the powder X-ray diffraction pattern of crystalline form 3. [Figure 13] FIG. 13 is a polarized light microscope photograph of crystalline form 3. [Figure 14] FIG. 14 is a thermogravimetric analysis diagram of crystalline form 3. [Figure 15] FIG. 15 is a differential scanning calorimetry diagram of crystalline form 3. [Figure 16] FIG. 16 shows the dynamic moisture sorption diagram of crystalline form 3. [Figure 17] FIG. 17 is the powder X-ray diffraction pattern of crystalline form 5. [Figure 18] FIG. 18 is a polarized light microscope photograph of crystalline form 5. [Figure 19] FIG. 19 is a thermogravimetric analysis diagram of crystalline form 5. [Figure 20] FIG. 20 is a differential scanning calorimetry diagram of crystalline form 5. [Figure 21] FIG. 21 is a dynamic moisture sorption diagram for crystalline form 5. [Figure 22] FIG. 22 is the powder X-ray diffraction pattern of crystalline form 6. [Figure 23] FIG. 23 is a polarized light microscope photograph of crystalline form 6. [Figure 24] FIG. 24 is a thermogravimetric analysis diagram of crystalline form 6. [Figure 25] FIG. 25 is a differential scanning calorimetry diagram of crystalline form 6. [Figure 26] FIG. 26 is a dynamic moisture sorption diagram for crystalline form 6. [Figure 27] FIG. 27 is the powder X-ray diffraction pattern of crystalline form 7. [Figure 28] FIG. 28 is a polarized light micrograph of crystalline form 7. [Figure 29] FIG. 29 is a thermogravimetric analysis diagram of crystalline form 7. [Figure 30] FIG. 30 is a differential scanning calorimetry diagram of crystalline form 7. [Figure 31] FIG. 31 shows the dynamic moisture sorption diagram for crystalline form 7. [Figure 32] FIG. 32 is the adsorption isotherm of crystalline form 1. [Figure 33] FIG. 33 is the adsorption isotherm of crystalline form 2. [Figure 34] FIG. 34 is the adsorption isotherm of crystalline form 3. [Figure 35] FIG. 35 is the adsorption isotherm of crystalline form 5. [Figure 36] FIG. 36 is the adsorption isotherm of crystalline form 6. [Figure 37] FIG. 37 is the adsorption isotherm of crystalline form 7. [Figure 38] FIG. 38 is a stability XRD pattern of Form 1. [Figure 39] FIG. 39 is a stability DSC pattern of Form 1. [Figure 40] FIG. 40 is the stability XRD pattern of Form 2. [Figure 41] FIG. 41 is a stability DSC pattern of Form 2. [Figure 42] FIG. 42 is the stability XRD pattern of Form 3. [Figure 43] FIG. 43 is a stability DSC pattern of Form 3. [Figure 44]FIG. 44 is the stability XRD pattern of Form 5. [Figure 45] FIG. 45 is a stability DSC pattern of Form 5. [Figure 46] FIG. 46 is the stability XRD pattern of Form 6. [Figure 47] FIG. 47 is a stability DSC pattern of Form 6. [Figure 48] FIG. 48 is the stability XRD pattern of Form 7. [Figure 49] FIG. 49 shows that Form 1, Form 2, Form 3 and Form 7 are transformed into Form 2 in acetone, ethyl acetate, methanol or water. [Figure 50] FIG. 50 shows the transformation of Form 1, Form 2, Form 3 and Form 7 into Form 3 in tetrahydrofuran (THF). [Figure 51] FIG. 51 shows a comparison of the XRD patterns of crystalline form 1 and crystalline form 2, where the upper pattern is crystalline form 1 and the lower pattern is crystalline form 2. [Figure 52] FIG. 52 shows the relationship between the peak area at 10.1° 2θ and the weight percentage content of Form 2 in Form 1. [Figure 53] Figure 53 shows a comparison of the XRD patterns of crystalline form 1 before and after polishing, where the upper pattern is the XRD pattern before polishing and the lower pattern is the XRD pattern after polishing.

Claims

1. A crystal of the compound of formula I having crystalline form 3: 【Chemistry 1】 Crystals having characteristic peaks at diffraction angles 2θ of 7.8±0.2°, 9.3±0.2°, and 13.7±0.2° in the powder X-ray diffraction pattern.

2. 2. The crystal of claim 1, wherein the powder X-ray diffraction pattern of crystalline form 3 has characteristic peaks at diffraction angles 2θ of 3.9±0.2°, 7.8±0.2°, 9.3±0.2°, 13.7±0.2°, and 16.0±0.2°.

3. 2. The crystal of claim 1, wherein the powder X-ray diffraction pattern of crystalline form 3 has characteristic peaks at diffraction angles 2θ of 3.9±0.2°, 7.8±0.2°, 9.3±0.2°, 13.7±0.2°, and 18.2±0.2°.

4. having a differential scanning calorimetry (DSC) diagram as shown in Figure 15 below, The melting point is about 261°C, and The crystal of claim 1, which exhibits a weight loss of about 0.2% before 200°C in a thermogravimetric analysis (TGA) diagram. [Figure 15]

5. A composition comprising a compound of formula I, 【Chemistry 2】 Crystals of the compound of formula I having crystalline form 3, and at least one crystalline form selected from crystalline form 2, crystalline form 5, crystalline form 6 and crystalline form 7, The crystalline form 2 has characteristic peaks at diffraction angles 2θ of 8.8±0.2°, 10.1±0.2°, 23.8±0.2°, and 26.7±0.2° in a powder X-ray diffraction pattern; The crystalline form 3 has characteristic peaks at diffraction angles 2θ of 3.9±0.2°, 7.8±0.2°, and 13.7±0.2° in a powder X-ray diffraction pattern; The crystalline form 5 has characteristic peaks at diffraction angles 2θ of 8.7±0.2°, 9.4±0.2°, 10.5±0.2°, and 18.1±0.2° in a powder X-ray diffraction pattern; The crystalline form 6 has characteristic peaks at diffraction angles 2θ of 3.9±0.2°, 7.9±0.2°, 9.1±0.2°, 9.6±0.2°, 13.2±0.2°, and 17.7±0.2° in a powder X-ray diffraction pattern; The crystalline form 7 has characteristic peaks at diffraction angles 2θ of 9.5±0.2°, 10.6±0.2°, and 16.0±0.2° in a powder X-ray diffraction pattern; The above powder X-ray diffraction patterns are all measured using Kα radiation from a Cu target.

6. 6. A composition comprising a mixture of crystalline form 3 and crystalline form 7 according to claim 5, wherein the composition has characteristic peaks at diffraction angles 2θ of 3.9±0.2°, 7.8±0.2°, 9.5±0.2°, 10.6±0.2°, and 16.0±0.2° in a powder X-ray diffraction pattern.

7. A pharmaceutical composition comprising an effective amount of the crystal of claim 1 required for treatment and / or prevention, and at least one pharmaceutically acceptable adjuvant.

8. A pharmaceutical composition comprising an effective amount of the composition of claim 5 required for treatment and / or prevention, and at least one pharmaceutically acceptable adjuvant.

9. A pharmaceutical composition comprising an effective amount of the composition of claim 6 required for treatment and / or prevention, and at least one pharmaceutically acceptable adjuvant.

10. 1. A pharmaceutical composition comprising an effective amount of a compound of formula I: 【Transformation 3】 The composition comprises the crystal of claim 1 .

11. 1. A pharmaceutical composition comprising an effective amount of a compound of formula I: 【Chemistry 4】 The composition comprises the crystal of claim 2.

12. A crystal of the compound of formula I having crystalline form 5: 【Transformation 5】 The powder X-ray diffraction pattern of the crystalline form 5 has characteristic peaks at diffraction angles 2θ of 4.1±0.2°, 8.7±0.2°, 9.4±0.2°, 10.5±0.2°, and 18.1±0.2°; The above powder X-ray diffraction patterns are all measured using Kα radiation from a Cu target.

13. A composition comprising a compound of formula I, 【Transformation 6】 Crystals of the compound of formula I having crystalline form 5, and at least one crystalline form selected from crystalline form 2, crystalline form 6, and crystalline form 7, The crystalline form 2 has characteristic peaks at diffraction angles 2θ of 10.1±0.2°, 23.8±0.2°, and 26.7±0.2° in a powder X-ray diffraction pattern; The crystalline form 5 has characteristic peaks at diffraction angles 2θ of 4.1±0.2°, 8.7±0.2°, 10.5±0.2°, and 18.1±0.2° in a powder X-ray diffraction pattern; The crystalline form 6 has characteristic peaks at diffraction angles 2θ of 7.9±0.2°, 9.1±0.2°, and 17.7±0.2° in a powder X-ray diffraction pattern; The crystalline form 7 has characteristic peaks at diffraction angles 2θ of 9.5±0.2°, 10.6±0.2°, and 16.0±0.2° in a powder X-ray diffraction pattern; The above powder X-ray diffraction patterns are all measured using Kα radiation from a Cu target.

14. A pharmaceutical composition comprising an effective amount of the crystal of claim 12 required for treatment and / or prevention, and at least one pharmaceutically acceptable adjuvant.

15. A pharmaceutical composition comprising an effective amount of the composition of claim 13 required for treatment and / or prevention, and at least one pharmaceutically acceptable adjuvant.

16. 1. A pharmaceutical composition comprising an effective amount of a compound of formula I: 【Transformation 7】 The composition comprises the crystal of claim 12.

17. A crystal of the compound of formula I having crystalline form 6: 【Transformation 8】 Crystals having characteristic peaks at diffraction angles 2θ of 3.9±0.2°, 7.9±0.2°, 9.1±0.2°, 9.6±0.2°, 13.2±0.2°, and 17.7±0.2° in a powder X-ray diffraction pattern.

18. having a differential scanning calorimetry (DSC) pattern as shown in Figure 25 below; and 18. The crystal of claim 17, which exhibits a weight loss of about 0.7% before 200°C in a thermogravimetric analysis (TGA) diagram. [Figure 25]

19. A pharmaceutical composition comprising an effective amount of the crystal of claim 17 required for treatment and / or prevention, and at least one pharmaceutically acceptable adjuvant.

20. 1. A pharmaceutical composition comprising an effective amount of a compound of formula I: 【Chemistry 9】 The composition comprises the crystal of claim 17.

21. A crystalline form of the compound of formula I having crystalline form 7: 【Chemistry 10】 Crystals having characteristic peaks at diffraction angles 2θ of 4.8±0.2°, 9.5±0.2°, 10.6±0.2°, and 16.0±0.2° in a powder X-ray diffraction pattern.

22. 22. The crystal of claim 21, wherein the powder X-ray diffraction pattern of crystalline form 7 has characteristic peaks at diffraction angles 2θ of 4.8±0.2°, 9.5±0.2°, 10.6±0.2°, 16.0±0.2°, and 25.1±0.2°.

23. 22. The crystal of claim 21, wherein the powder X-ray diffraction pattern of crystalline form 7 has characteristic peaks at diffraction angles 2θ of 9.5±0.2°, 10.6±0.2°, 13.8±0.2°, 14.3±0.2°, 16.0±0.2°, and 18.2±0.2°.

24. having a differential scanning calorimetry (DSC) diagram as shown in Figure 30 below, 22. The crystal of claim 21, which exhibits a weight loss of about 0.5% before 200°C in a thermogravimetric analysis (TGA) diagram. [Figure 30]

25. A composition comprising a compound of formula I, 【Chemistry 11】 Crystals of the compound of formula I having at least one crystalline form selected from crystalline form 7, crystalline form 2, and crystalline form 6, The crystalline form 2 has characteristic peaks at diffraction angles 2θ of 8.8±0.2°, 10.1±0.2°, 23.8±0.2°, and 26.7±0.2° in a powder X-ray diffraction pattern; The crystalline form 6 has characteristic peaks at diffraction angles 2θ of 3.9±0.2°, 7.9±0.2°, 9.1±0.2°, 9.6±0.2°, 13.2±0.2°, and 17.7±0.2° in a powder X-ray diffraction pattern; The crystalline form 7 has characteristic peaks at diffraction angles 2θ of 9.5±0.2°, 10.6±0.2°, and 16.0±0.2° in a powder X-ray diffraction pattern; The above powder X-ray diffraction patterns are all measured using Kα radiation from a Cu target.

26. A pharmaceutical composition comprising an effective amount of the crystal of claim 21 required for treatment and / or prevention, and at least one pharmaceutically acceptable adjuvant.

27. A pharmaceutical composition comprising an effective amount of the composition of claim 25 required for treatment and / or prevention, and at least one pharmaceutically acceptable adjuvant.

28. 1. A pharmaceutical composition comprising an effective amount of a compound of formula I: 【Chemistry 12】 The composition comprises the crystal of claim 21 .

29. A crystalline compound of formula I: 【Chemistry 13】 A crystal having a crystalline form having the powder X-ray diffraction pattern shown in Figure 1, Figure 12, Figure 17, Figure 22, or Figure 27 below. [Figure 1] 【change】 [Figure 12] 【change】 [Figure 17] 【change】 [Figure 22] 【change】 [Figure 27] 【change】

30. 1. A pharmaceutical composition comprising an effective amount of a compound of formula I: 【Chemistry 14】 30. A pharmaceutical composition comprising the crystal of claim 29.

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