A tyrosine kinase inhibitor compound and a preparation method thereof

Abstract

The present application relates to the field of drug crystal forms, in particular to a new crystal form of a compound of formula 1 and a preparation method thereof. The new crystal form of the compound of formula 1 of the present application has excellent physical stability and chemical stability, high solubility and bioavailability, good flowability and low hygroscopicity. In addition, the new crystal form of the compound of formula 1 of the present application has mild preparation conditions, simple operation, good process reproducibility, high purity and is suitable for industrial production.

Description

Technical Field

[0001] This application belongs to the field of drug crystal forms, specifically relating to a new crystal form of compound of formula 1 and its preparation method. Background Technology

[0002] Compound Formula 1 is a Class 1.1 anti-tumor new drug independently developed by Chia Tai Tianqing Pharmaceutical Group. It was approved for marketing in May 2018 for the treatment of patients with advanced non-small cell lung cancer. Subsequently, the drug was approved for the treatment of patients with soft tissue sarcoma, small cell lung cancer, and medullary thyroid carcinoma. The chemical structure of compound Formula 1 is shown below:

[0003]

[0004] Patent CN102344438A discloses three crystalline forms of the compound of formula 1: anhydrous crystalline form A, anhydrous crystalline form B, and dihydrate crystalline form C. According to this patent, the impurity content of all three crystalline forms increases significantly after being exposed to light for 10 days, indicating that the compound of formula 1 has poor photostability. Furthermore, the preparation conditions for crystalline forms A and B are quite demanding, both requiring vacuum drying at 80-85℃. The high drying temperature may further lead to the generation of degradation impurities, increasing the difficulty of process control.

[0005] It is well known that different crystal forms of the same drug can vary significantly in appearance, solubility, melting point, and dissolution rate, thus affecting the drug's stability, bioavailability, and efficacy. Generally, stable crystal forms have higher melting points, lower solubility, and slower dissolution rates; unstable crystal forms, on the other hand, are prone to transforming into other crystal forms. Selecting the most thermodynamically stable crystal form can ensure that crystal transformation does not occur during the production and storage of the active pharmaceutical ingredient. However, stable crystal forms often have poor bioavailability due to their lower solubility. Therefore, it is necessary to develop pharmaceutical crystal forms that can simultaneously balance stability and solubility / bioavailability. Thus, it is necessary to study the crystal forms of compounds of Formula 1 and develop one or more crystal forms that are simple to prepare, chemically stable, have good solubility, high purity, are not hygroscopic, and are suitable for industrial production. Summary of the Invention

[0006] In view of the shortcomings of existing technologies, such as poor photostability and harsh preparation conditions of Formula I compounds, this application provides one or more pharmaceutically usable crystal forms with advantages in terms of stability, hygroscopicity, solubility, bioavailability, etc., as well as a method for preparing Formula I compound crystal forms that is simple, low-cost, and conducive to industrial production.

[0007] This application provides a crystal form I of the compound of formula 1, whose X-ray powder diffraction pattern has characteristic peaks at 2θ angles of 6.3±0.2°, 8.5±0.2°, 10.1±0.2°, 12.4±0.2°, 16.0±0.2°, 17.0±0.2°, 24.5±0.2° and 28.3±0.2°.

[0008] Furthermore, the X-ray powder diffraction pattern of crystal form I has characteristic peaks at 2θ angles of 6.3±0.2°, 7.8±0.2°, 8.5±0.2°, 9.4±0.2°, 10.1±0.2°, 12.4±0.2°, 15.7±0.2°, 16.0±0.2°, 17.0±0.2°, 19.5±0.2°, 24.5±0.2°, 28.3±0.2°, and 29.4±0.2°.

[0009] Furthermore, the X-ray powder diffraction pattern of crystal form I is basically as follows: Figure 1 As shown.

[0010] This application also relates to a method for preparing crystal form I of compound 1, specifically: adding compound 1 to pure water or a mixed solvent of organic solvent and water to dissolve it, and then slowly evaporating it, the resulting solid being crystal form I of compound 1.

[0011] Furthermore, the organic solvent is selected from isopropanol, ethyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, methyl isobutyl ketone, diethyl ether, methyl tert-butyl ether, petroleum ether, dichloromethane, or toluene.

[0012] Furthermore, the evaporation temperature is 5–50°C.

[0013] Furthermore, the method for preparing crystal form I of compound 1 specifically involves dissolving the compound 1 in a mixed solvent of organic solvent and water (with a water volume fraction of 5%), allowing the solution to slowly evaporate at 5–50°C, and obtaining the solid as crystal form I of compound 1.

[0014] Furthermore, another method for preparing crystal form I of compound 1 is as follows: dissolve compound 1 in pure water, and slowly evaporate the solution at 5-50°C. The resulting solid is crystal form I of compound 1.

[0015] This application provides a crystal form II of the compound of Formula 1, whose X-ray powder diffraction pattern has characteristic peaks at 2θ angles of 8.6±0.2°, 10.1±0.2°, 14.5±0.2°, 17.3±0.2°, 18.0±0.2°, 22.5±0.2°, 25.9±0.2° and 28.4±0.2°.

[0016] Furthermore, the X-ray powder diffraction pattern of crystal form II has characteristic peaks at 2θ angles of 8.6±0.2°, 10.1±0.2°, 14.5±0.2°, 17.3±0.2°, 18.0±0.2°, 22.2±0.2°, 22.5±0.2°, 22.7±0.2°, 25.9±0.2°, 27.8±0.2°, and 28.4±0.2°.

[0017] Furthermore, the X-ray powder diffraction pattern of crystal form II has characteristic peaks at 2θ angles of 8.6±0.2°, 10.1±0.2°, 13.7±0.2°, 14.5±0.2°, 15.3±0.2°, 15.7±0.2°, 17.3±0.2°, 18.0±0.2°, 22.2±0.2°, 22.5±0.2°, 22.7±0.2°, 25.9±0.2°, 27.8±0.2°, and 28.4±0.2°.

[0018] Furthermore, the X-ray powder diffraction pattern of crystal form II is basically as follows: Figure 2 As shown.

[0019] This application also relates to a method for preparing crystal form II, specifically: adding the compound of formula 1 to pure water to dissolve, then adding acetonitrile and stirring to precipitate crystals, filtering, and drying to obtain crystal form II of the compound of formula 1.

[0020] Furthermore, the volume ratio of the pure water to acetonitrile is 1:10 to 1:60.

[0021] Furthermore, the preparation method specifically involves dissolving the compound of Formula 1 in pure water, adding acetonitrile at 0–40°C, stirring at 0–40°C to crystallize, filtering, and drying in a forced-air or vacuum environment at 30–60°C for 6–48 hours to obtain crystal form II of the compound of Formula 1.

[0022] This application provides a crystal form III of the compound of formula 1, whose X-ray powder diffraction pattern has characteristic peaks at 2θ angles of 5.9±0.2°, 8.8±0.2°, 13.8±0.2°, 15.9±0.2°, 18.1±0.2°, 21.4±0.2° and 22.1±0.2°.

[0023] Furthermore, the X-ray powder diffraction pattern of crystal form III has characteristic peaks at 2θ angles of 5.9±0.2°, 8.8±0.2°, 13.8±0.2°, 15.9±0.2°, 18.1±0.2°, 20.5±0.2°, 20.8±0.2°, 21.4±0.2°, 22.1±0.2°, 22.5±0.2°, 23.5±0.2°, 24.4±0.2°, and 26.6±0.2°.

[0024] Furthermore, the X-ray powder diffraction pattern of the crystal form III of compound 1 has characteristic peaks at 2θ angles of 5.9±0.2°, 7.9±0.2°, 8.8±0.2°, 13.8±0.2°, 14.8±0.2°, 15.9±0.2°, 18.1±0.2°, 20.5±0.2°, 20.8±0.2°, 21.4±0.2°, 22.1±0.2°, 22.5±0.2°, 23.5±0.2°, 24.4±0.2°, and 26.6±0.2°.

[0025] Furthermore, the X-ray powder diffraction pattern of crystal form III of compound 1 is basically as follows: Figure 3 As shown.

[0026] This application also relates to a method for preparing crystal form III of compound 1, specifically: adding compound 1 to dimethyl sulfoxide to obtain a clear solution, then adding N,N-dimethylacetamide and stirring to crystallize, filtering, and drying to obtain crystal form III of compound 1.

[0027] Furthermore, the preparation method specifically involves: adding the compound of Formula 1 to dimethyl sulfoxide to obtain a clear solution, adding N,N-dimethylacetamide and stirring to induce crystallization, filtering, and drying at 30–60°C for 6–24 h to obtain crystal form III of the compound of Formula 1.

[0028] This application provides a compound of formula 1 with crystal form IV, whose X-ray powder diffraction pattern has characteristic peaks at 2θ angles of 5.0±0.2°, 7.4±0.2°, 8.4±0.2°, 9.9±0.2°, 14.2±0.2° and 19.8±0.2°.

[0029] Furthermore, the X-ray powder diffraction pattern of crystal form IV has characteristic peaks at 2θ angles of 5.0±0.2°, 7.4±0.2°, 8.4±0.2°, 9.9±0.2°, 14.2±0.2°, 14.9±0.2°, 19.8±0.2°, 22.0±0.2°, 24.2±0.2° and 25.3±0.2°.

[0030] Furthermore, the X-ray powder diffraction pattern of crystal form IV has characteristic peaks at 2θ angles of 5.0±0.2°, 7.4±0.2°, 8.4±0.2°, 8.7±0.2°, 9.9±0.2°, 13.3±0.2°, 14.2±0.2°, 14.9±0.2°, 18.3±0.2°, 19.8±0.2°, 22.0±0.2°, 24.2±0.2°, and 25.3±0.2°.

[0031] Furthermore, the X-ray powder diffraction pattern of crystal form IV is basically as follows: Figure 4 As shown.

[0032] This application also relates to a method for preparing crystal form IV, specifically: adding the compound of formula 1 into tetrahydrofuran, suspending at high temperature, filtering, and drying to obtain crystal form IV of the compound of formula 1.

[0033] Furthermore, the high temperature is 50–60°C.

[0034] Furthermore, the preparation method specifically involves adding the compound of Formula 1 into tetrahydrofuran, suspending it at 50–60°C for 12–24 h, filtering, and drying it at 30–60°C for 6–24 h to obtain crystal form IV of the compound of Formula 1.

[0035] This application provides a compound of formula 1, crystal form V, whose X-ray powder diffraction pattern has characteristic peaks at 2θ angles of 5.9±0.2°, 9.7±0.2°, 11.8±0.2°, 15.5±0.2°, 17.8±0.2°, 20.5±0.2° and 25.9±0.2°.

[0036] Furthermore, the X-ray powder diffraction pattern of type V has characteristic peaks at 2θ angles of 5.9±0.2°, 9.7±0.2°, 11.8±0.2°, 15.5±0.2°, 17.8±0.2°, 20.5±0.2°, 23.4±0.2°, 23.9±0.2° and 25.9±0.2°.

[0037] Furthermore, the X-ray powder diffraction pattern of crystal form V is basically as follows: Figure 5 As shown.

[0038] This application also relates to a method for preparing crystal form V, specifically: adding the compound of formula 1 into hexafluoroisopropanol, suspending at high temperature, filtering, and drying to obtain crystal form V of the compound of formula 1.

[0039] Furthermore, the high temperature is 50–60°C.

[0040] Furthermore, the preparation method specifically involves adding the compound of formula 1 into hexafluoroisopropanol, suspending it at 50–60°C for 12–24 h, filtering, and drying at 30–60°C for 6–24 h to obtain crystal form V of the compound of formula 1.

[0041] This application provides a crystal form VI of compound of formula 1, whose X-ray powder diffraction pattern has characteristic peaks at 2θ angles of 6.8±0.2°, 10.5±0.2°, 14.9±0.2°, 19.3±0.2°, 22.0±0.2° and 25.6±0.2°.

[0042] Furthermore, the X-ray powder diffraction pattern of the crystal form VI has characteristic peaks at 2θ angles of 6.8±0.2°, 10.5±0.2°, 14.9±0.2°, 17.1±0.2°, 19.3±0.2°, 22.0±0.2°, 25.6±0.2°, 27.1±0.2° and 28.3±0.2°.

[0043] Furthermore, the X-ray powder diffraction pattern of the crystal form VI has characteristic peaks at 2θ angles of 6.8±0.2°, 9.3±0.2°, 10.5±0.2°, 14.9±0.2°, 15.9±0.2°, 17.1±0.2°, 19.3±0.2°, 22.0±0.2°, 25.6±0.2°, 27.1±0.2°, and 28.3±0.2°.

[0044] Furthermore, the X-ray powder diffraction pattern of crystal form VI is essentially as follows: Figure 6 As shown.

[0045] This application also relates to a method for preparing crystal form VI, specifically: adding the compound of formula 1 to a mixed solvent of trifluoroethanol / water, stirring to dissolve, and slowly evaporating to obtain crystal form VI of the compound of formula 1.

[0046] Furthermore, the preparation method specifically involves adding the compound of Formula 1 to a mixed solvent of trifluoroethanol / water, stirring to dissolve, and slowly evaporating at 5–35°C to obtain crystal form VI of the compound of Formula 1.

[0047] This application provides a compound of Formula 1 with crystal form VII, whose X-ray powder diffraction pattern has characteristic peaks at 2θ angles of 4.4±0.2°, 8.4±0.2°, 15.2±0.2°, 19.9±0.2°, 23.5±0.2° and 26.2±0.2°.

[0048] Furthermore, the X-ray powder diffraction pattern of the crystal form VII has characteristic peaks at 2θ angles of 4.4±0.2°, 8.4±0.2°, 15.2±0.2°, 19.9±0.2°, 22.3±0.2°, 23.5±0.2°, 26.2±0.2°, 26.9±0.2°, 28.5±0.2°, and 31.7±0.2°.

[0049] Furthermore, the X-ray powder diffraction pattern of crystal form VII has characteristic peaks at 2θ angles of 4.4±0.2°, 7.5±0.2°, 8.4±0.2°, 13.0±0.2°, 15.2±0.2°, 19.9±0.2°, 22.3±0.2°, 23.5±0.2°, 26.2±0.2°, 26.9±0.2°, 28.5±0.2°, and 31.7±0.2°.

[0050] Furthermore, the X-ray powder diffraction pattern of crystal form VII is basically as follows: Figure 7 As shown.

[0051] This application also relates to a method for preparing crystal form VII, specifically: drying crystal form I of compound 1 at high temperature to obtain crystal form VII of compound 1.

[0052] Furthermore, the high temperature is 40–60°C.

[0053] Furthermore, the preparation method specifically involves drying the crystal form I of compound 1 at 40–60°C under forced air or vacuum for 6–48 hours to obtain the crystal form VII of compound 1.

[0054] The beneficial effects of this application are:

[0055] 1. The compound of formula 1, crystal form II prepared in this application has higher crystallinity, better physical stability and chemical stability, which is beneficial to the production and storage of active pharmaceutical ingredients and formulations.

[0056] 2. The crystal form II of the compound of formula 1 prepared in this application has improved photostability, which is beneficial to reducing the content of photochemical degradation products generated during the storage of the active pharmaceutical ingredient and the formulation, and also beneficial to reducing the possibility of photosensitivity reaction caused by exposure to sunlight in patients receiving the corresponding drug.

[0057] 3. The crystal form II of compound of formula 1 prepared in this application has high solubility and bioavailability.

[0058] 4. The crystal form II of compound of formula 1 prepared in this application has lower hygroscopicity while maintaining high solubility, overcoming the defect of existing crystal forms that are prone to crystal transformation due to high hygroscopicity.

[0059] 5. The crystal form II of compound of formula 1 prepared in this application has good dispersibility and flowability, and is not prone to adhesion and agglomeration when filling capsules, and the filled capsules have good content uniformity.

[0060] 6. The compound of Formula 1 obtained in this application has crystal form II with low solubility and high purity. Moreover, the preparation conditions are mild, the operation is simple, and the process has good reproducibility, which makes the conditions for industrial production controllable and conducive to large-scale industrialization. Attached Figure Description

[0061] Figure 1 The image shows the XRD pattern of crystal form I of compound 1.

[0062] Figure 2 The image shows the XRD pattern of crystal form II of compound 1.

[0063] Figure 3 The image shows the XRD pattern of crystal form III of compound 1.

[0064] Figure 4 The image shows the XRD pattern of crystal form IV of compound 1.

[0065] Figure 5 The image shows the XRD pattern of crystal form V of compound 1.

[0066] Figure 6 The image shows the XRD pattern of crystal form VI of compound 1.

[0067] Figure 7 The image shows the XRD pattern of crystal form VII of compound 1.

[0068] Figure 8 The image shows the XRD pattern of crystal form A of compound of formula 1.

[0069] Figure 9 The image shows the XRD pattern of crystal form C of compound 1.

[0070] Figure 10 The XRD patterns of compound II of Formula 1 before and after the application of influencing factors are shown.

[0071] Figure 11 The XRD patterns of compound A of Formula 1 before and after the influencing factors are compared.

[0072] Figure 12 The XRD patterns of compound C of Formula 1 before and after the influencing factors are compared.

[0073] Figure 13 DVS curve of crystal form II of compound of formula 1

[0074] Figure 14 DVS curve of crystal form A of compound of formula 1

[0075] Figure 15 DVS curve of crystal form C of compound of formula 1 Detailed Implementation

[0076] The following detailed description of the present application is provided in conjunction with embodiments, but is not intended to limit the present application. Any equivalent substitutions made in the art based on the disclosure of the present application shall fall within the protection scope of the present application.

[0077] The abbreviations used in this application are explained as follows:

[0078] XRD: X-ray powder diffraction

[0079] The X-ray powder diffraction (XRD) tests described in this application were performed using a Malvern-Panaco Empyrea powder diffractometer, and the specific parameters are shown in the table below:

[0080]

[0081] In the X-ray powder diffraction pattern of this application, the error of the 2θ diffraction angle is ±0.20°.

[0082] The compound of Formula 1 used in this application was purchased from Shanghai Yuanhua Pharmaceutical Technology Co., Ltd.

[0083] Example 1: Preparation of Crystal Form I of Compound Formula 1

[0084] At 25°C, 300 mg of compound 1 was added to 31.5 mL of a mixed solvent of ethyl acetate and water (water volume fraction 5%). After stirring, a clear solution was obtained. This solution was slowly evaporated at 50°C for 48 h, and the resulting solid was the crystal form I of compound 1. X-ray powder diffraction of the obtained sample was performed using Cu-Ka rays. The resulting spectra showed the diffraction angles, interplanar spacings, and relative intensities as shown in Table 1. The X-ray powder diffraction patterns were basically as follows: Figure 1 As shown.

[0085] Table 1 shows the diffraction angles, interplanar spacings, and relative intensities of crystal form I of compound formula 1.

[0086]

[0087] Example 2: Preparation of Crystal Form I of Compound Formula 1

[0088] At 25°C, 20 mg of compound 1 was added to a mixed solvent of 2 mL methyl isobutyl ketone and 0.1 mL water to obtain a clear solution. This solution was slowly evaporated at 5°C for 48 h, and the resulting solid was the crystal form I of compound 1. The obtained sample was subjected to Cu-Ka X-ray powder diffraction, and its X-ray powder diffraction pattern was basically consistent with that of Example 1.

[0089] Example 3: Preparation of Crystal Form II of Compound of Formula 1

[0090] At 20℃, 1.0 g of compound 1 was dissolved in 0.67 mL of pure water, followed by the addition of 20.1 mL of acetonitrile. The mixture was stirred for 30 min, then placed in a 0℃ cryogenic bath for crystallization. After filtration, the solution was dried in a vacuum drying oven at 30℃ for 48 h to obtain crystal form II of compound 1, with a purity of 99.26% and acetonitrile residue of 0.006%. X-ray powder diffraction of the obtained sample was performed using Cu-Ka rays. The resulting spectra showed the diffraction angles, interplanar spacings, and relative intensities as shown in Table 2. The X-ray powder diffraction patterns were basically as follows: Figure 2 As shown.

[0091] Table 2 shows the diffraction angles, interplanar spacings, and relative intensities of crystal form II of compound formula 1.

[0092]

[0093]

[0094] Example 4: Preparation of Crystal Form II of Compound Formula 1

[0095] At 20°C, 1.0 g of compound 1 was dissolved in 0.67 mL of pure water, followed by the addition of 40.2 mL of acetonitrile. The mixture was stirred for 30 min, then placed in a 15°C low-temperature bath for crystallization. After filtration, the solution was dried in a vacuum drying oven at 60°C for 6 h to obtain crystal form II of compound 1, with a purity of 99.18% and a acetonitrile residue of 0.005%. The obtained sample was subjected to Cu-Ka X-ray powder diffraction, and its X-ray powder diffraction pattern was basically consistent with that of Example 3.

[0096] Example 5: Preparation of Crystal Form II of Compound of Formula 1

[0097] At 40°C, 1.0 g of compound 1 was dissolved in 0.67 mL of pure water, followed by the addition of 26.8 mL of acetonitrile. The mixture was stirred at this temperature for 36 h, filtered, and dried in a forced-air drying oven at 60°C for 36 h to obtain crystal form II of compound 1 with a purity of 99.11% and acetonitrile residue of 0%. X-ray powder diffraction of the obtained sample was performed using Cu-Ka rays, and the X-ray powder diffraction pattern was essentially consistent with that of Example 3.

[0098] Example 6: Preparation of Crystal Form II of Compound Formula 1

[0099] At 25°C, 60 mg of compound 1 was dissolved in 0.08 mL of pure water, followed by the addition of 1.0 mL of acetonitrile. The mixture was stirred for 30 min, then placed in a 5°C low-temperature bath for crystallization. After filtration, the solution was dried in a 40°C forced-air drying oven for 24 h to obtain crystal form II of compound 1, with a purity of 99.41% and acetonitrile residue of 0.009%. X-ray powder diffraction of the obtained sample using Cu-Ka radiation was performed, and the X-ray powder diffraction pattern was essentially consistent with that of Example 3.

[0100] Example 7: Preparation of Crystal Form III of Compound Formula 1

[0101] At 25°C, 20 mg of compound 1 was added to 0.12 mL of dimethyl sulfoxide solvent to obtain a clear solution. 0.5 mL of N,N-dimethylacetamide was added and stirred to induce crystallization. The solution was filtered and dried in a vacuum drying oven at 60°C for 6 h to obtain crystal form III of compound 1. X-ray powder diffraction of the obtained sample was performed using Cu-Ka rays. The resulting spectra showed the diffraction angles, interplanar spacings, and relative intensities as shown in Table 3. The X-ray powder diffraction patterns were basically as follows: Figure 3 As shown.

[0102] Table 3 shows the diffraction angles, interplanar spacings, and relative intensities of crystal form III of compound formula 1.

[0103]

[0104]

[0105] Example 8: Preparation of Crystal Form III of Compound Formula 1

[0106] At 25°C, 20 mg of compound 1 was added to 0.12 mL of dimethyl sulfoxide solvent to obtain a clear solution. 1.2 mL of N,N-dimethylacetamide was added and stirred to induce crystallization. The solution was filtered and dried in a vacuum drying oven at 30°C for 24 h to obtain crystal form III of compound 1. X-ray powder diffraction of the obtained sample was performed using Cu-Ka rays, and the X-ray powder diffraction pattern was essentially consistent with that of Example 7.

[0107] Example 9: Preparation of Crystal Form IV of Compound Formula 1

[0108] At 60℃, 20 mg of compound 1 was added to 2 mL of tetrahydrofuran, suspended for 24 h, filtered, and dried in a vacuum drying oven at 60℃ for 6 h to obtain crystal form IV of compound 1. X-ray powder diffraction of the obtained sample was performed using Cu-Ka rays. The resulting spectra showed the diffraction angles, interplanar spacings, and relative intensities as shown in Table 4. The X-ray powder diffraction patterns were basically as follows: Figure 4 As shown.

[0109] Table 4 shows the diffraction angles, interplanar spacings, and relative intensities of crystal form IV of compound formula 1.

[0110]

[0111]

[0112] Example 10: Preparation of Crystal Form IV of Compound Formula 1

[0113] At 50°C, 20 mg of compound 1 was added to 2 mL of 2-methyltetrahydrofuran, suspended for 12 h, filtered, and dried in a vacuum drying oven at 30°C for 24 h to obtain crystal form IV of compound 1. X-ray powder diffraction of the obtained sample was performed using Cu-Ka rays, and its X-ray powder diffraction pattern was essentially consistent with that of Example 9.

[0114] Example 11: Preparation of crystal form V of compound of formula 1

[0115] At 50℃, 20 mg of compound 1 was added to 2 mL of hexafluoroisopropanol, suspended for 24 h, filtered, and dried in a vacuum drying oven at 60℃ for 6 h to obtain crystal form V of compound 1. X-ray powder diffraction of the obtained sample was performed using Cu-Ka rays. The resulting spectra showed the diffraction angles, interplanar spacings, and relative intensities as shown in Table 5. The X-ray powder diffraction patterns were basically as follows: Figure 5 As shown.

[0116] Table 5 shows the diffraction angles, interplanar spacings, and relative intensities of crystal form V of compound formula 1.

[0117]

[0118]

[0119] Example 12: Preparation of crystal form V of compound of formula 1

[0120] At 60°C, 20 mg of compound 1 was added to 2 mL of hexafluoroisopropanol, suspended for 12 h, filtered, and dried in a vacuum drying oven at 30°C for 24 h to obtain crystal form V of compound 1. X-ray powder diffraction of the obtained sample was performed using Cu-Ka rays, and the X-ray powder diffraction pattern was essentially consistent with that of Example 11.

[0121] Example 13: Preparation of Crystal Form VI of Compound Formula 1

[0122] At 25°C, 20 mg of compound 1 was added to a mixed solvent of 1 mL trifluoroethanol and 0.1 mL water to obtain a clear solution. The solution was then slowly evaporated at 5°C for 72 h to obtain crystal form VI of compound 1. X-ray powder diffraction of the obtained sample was performed using Cu-Ka rays. The resulting spectra showed the diffraction angles, interplanar spacings, and relative intensities as shown in Table 6. The X-ray powder diffraction patterns were basically as follows: Figure 6 As shown.

[0123] Table 6 shows the diffraction angles, interplanar spacings, and relative intensities of crystal form VI of compound formula 1.

[0124]

[0125] Example 14: Preparation of Crystal Form VI of Compound Formula 1

[0126] At 25°C, 20 mg of compound 1 was added to a mixed solvent of 1 mL trifluoroethanol and 0.1 mL water to obtain a clear solution. The solution was then slowly evaporated at 35°C for 48 h to obtain crystal form VI of compound 1. X-ray powder diffraction of the obtained sample was performed using Cu-Ka rays, and the X-ray powder diffraction pattern was essentially consistent with that of Example 13.

[0127] Example 15: Preparation of Crystal Form VII of Compound 1

[0128] Crystal form I of compound 1 was dried in a vacuum oven at 40°C for 48 hours to obtain crystal form VII of compound 1. X-ray powder diffraction of the obtained sample was performed using Cu-Ka rays. The resulting spectra showed the diffraction angles, interplanar spacings, and relative intensities as shown in Table 7. The X-ray powder diffraction patterns were basically as follows: Figure 7 As shown.

[0129] Table 7 shows the diffraction angles, interplanar spacings, and relative intensities of crystal form VII of compound formula 1.

[0130]

[0131] Example 16: Preparation of Crystal Form VII of Compound 1

[0132] The crystal form I of compound 1 was dried in a vacuum oven at 60°C for 6 hours to obtain crystal form VII of compound 1. The obtained sample was subjected to X-ray powder diffraction using Cu-Ka rays, and its X-ray powder diffraction pattern was basically consistent with that of Example 15.

[0133] Comparative Example 1: Preparation of Crystal Form A of Compound 1

[0134] At room temperature, 20 mg of compound 1 was added to 2 mL of ethyl acetate, suspended at 25 °C for 24 h, filtered, and dried to obtain crystal form A of compound 1. The obtained sample was subjected to Cu-Ka X-ray powder diffraction, and its powder diffraction pattern is shown below. Figure 8 As shown.

[0135] Comparative Example 2: Preparation of Crystal Form C of Compound 1

[0136] At room temperature, 20 mg of the amorphous compound of formula 1 was added to 2 mL of 1,4-dioxane, suspended at 25 °C for 24 h, filtered, and dried to obtain crystalline form C of compound 1. The obtained sample was subjected to Cu-Ka X-ray powder diffraction, and its powder diffraction pattern is shown below. Figure 9 As shown.

[0137] Experimental Example 1: Stability Study of Influencing Factors

[0138] To investigate the stability of the novel crystal form of the compound of formula 1 prepared in this application, crystal form II prepared in Example 3, crystal form A prepared in Comparative Example 1, and crystal form C prepared in Comparative Example 2 were placed under high temperature (60°C), high humidity (92.5% RH), and strong light irradiation (4500 lx ± 500 lx) for 30 days. Samples were taken for XRD and HPLC testing, and the results were compared with those of day 0. Specific data are shown in Tables 8-10 below. Figure 10-12 As shown:

[0139] Table 8. Factors affecting the stability of crystal form A of compound of formula 1 in this invention.

[0140]

[0141]

[0142] Table 9. Factors affecting the stability of crystal form C of compound of formula 1 in this invention.

[0143]

[0144] Table 10. Factors affecting the stability of crystal form II of compound of formula 1 in this invention.

[0145]

[0146] From Table 8-10 and Figure 10-12 It can be seen that after 30 days under the influencing factors, crystal form II did not undergo crystal transformation, and its purity did not decrease under high temperature and high humidity conditions, although it decreased slightly after 30 days under light conditions. Crystal forms A and C, however, not only under high humidity conditions, under high temperature and light conditions, showed a greater decrease in purity than crystal form II. In summary, the compound of formula 1, crystal form II, prepared in this application, exhibits superior crystal form stability and chemical stability under the influencing factors.

[0147] Experimental Example 2: Accelerated and Long-Term Stability Study

[0148] To investigate the stability of the novel crystal form of the compound of formula 1 prepared in this application, crystal form II prepared in Example 3 and crystal form A prepared in Comparative Example 1 were placed under accelerated (25°C, 60% RH) and long-term (40°C, 75% RH) conditions for 1, 2, 3, and 6 months, respectively. Samples were taken for XRD and HPLC testing, and the results were compared with those of day 0. The specific data are shown in Table 11 below:

[0149] Table 11 Comparison of long-term / accelerated stability of crystal form A and crystal form II of compound of formula 1 of this invention

[0150]

[0151] As shown in Table 11, neither crystal form II nor crystal form A underwent crystal transformation after 6 months of storage under both accelerated and long-term conditions. However, the purity of crystal form A decreased significantly after 6 months of storage under both accelerated and long-term conditions. In summary, the crystal form II of the compound of formula 1 prepared in this application exhibits superior crystal form stability and chemical stability under both accelerated and long-term conditions.

[0152] Experimental Example 3: Solubility Investigation

[0153] To investigate the solubility of crystal forms II, A, and C of compound 1, the solubility of crystal form II of compound 1 prepared in Example 3, crystal form A prepared in Comparative Example 1, and crystal form C prepared in Comparative Example 2 at room temperature were tested in pure water. The results are shown in Table 12.

[0154] Table 12 shows the solubility of compound form II, A, and C in pure water.

[0155] Sample types Crystal form II Crystal form A Crystal form C solubility >200mg / mL >200mg / mL >200mg / mL

[0156] As can be seen from Table 12, the solubility of compound II of Formula 1 in pure water is greater than 200 mg / mL.

[0157] Experimental Example 4: Hygroscopicity Investigation

[0158] To investigate the hygroscopicity of crystal form II of compound 1 prepared in this application, crystal form II of compound 1 prepared in Example 3, crystal form A prepared in Comparative Example 1, and crystal form C prepared in Comparative Example 2 were placed in a dynamic moisture adsorption apparatus, and the weight change of the samples was investigated within the humidity range of 0-98%-0. The hygroscopicity results of crystal form II, crystal form A, and crystal form C of compound 1 are shown in Table 13 and... Figure 13-15 As shown:

[0159] Table 13 Hygroscopicity of Compound 1, Crystal Forms II, A, and C, in 80% RH to 98% RH

[0160]

[0161] From Table 13 and Figure 13-15 It can be seen that, compared with crystal forms A and C, compound II of Formula 1 has lower hygroscopicity, resulting in better quality control during the storage of active pharmaceutical ingredients and formulations. Combined with the results of Experiments 1 and 4, it can be concluded that compound II of Formula 1 maintains high solubility while exhibiting lower hygroscopicity, overcoming the defect of existing crystal forms that are prone to crystal transformation due to high hygroscopicity.

[0162] Experimental Example 5: Pharmacokinetic Study in Beagle Dogs

[0163] (1) Experimental Objective

[0164] The study investigated the plasma concentration levels and pharmacokinetic characteristics of compound form II and form A in beagle dogs after a single oral administration of the same dosage.

[0165] (2) Materials and Methods

[0166] ① Test drug

[0167] Crystal form II of compound of formula 1 prepared in Example 3;

[0168] Crystal form A of compound of formula 1 prepared in Comparative Example 1;

[0169] ②Experimental animals

[0170] There are 12 beagles, 6 females and 6 males.

[0171] ③ Test methods

[0172] Different crystal forms of compound 1 were orally administered to beagle dogs. 0.2 mL of blood was collected from the jugular vein before administration and at 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 24 h, 48 h, and 72 h after administration. The blood samples were placed in EDTA-K2 anticoagulant tubes, centrifuged at 4500 r / min for 10 min, and 50 μL of the supernatant was separated and stored in a centrifuge tube at -80 °C.

[0173] ④LC / MS / MS analysis of biological samples:

[0174] Take 50 μL of plasma and mix it with 5 mL of working solution or blank diluent. Add 150 μL of acetonitrile precipitant containing internal standard, vortex for 2 min, centrifuge at 12000 r / min for 10 min, take 20 μL of supernatant and mix it with 200 μL of acetonitrile aqueous solution (acetonitrile:water = 1:1). Inject the mixture into 5 μL for analysis.

[0175] ⑤ Experimental Results:

[0176] Table 14 shows the main pharmacokinetic parameters in plasma of beagle dogs after a single oral administration of different crystalline forms:

[0177] Table 14. Major pharmacokinetic parameters in plasma of beagle dogs after a single oral administration of different crystalline forms.

[0178]

[0179] As can be seen from Table 14, the maximum blood concentration of the self-developed crystal form II in female / male beagle dogs was significantly higher than that of the original crystal form A; the crystal form II of Formula 1 compound had good bioavailability in beagle dogs.

[0180] In summary, the compound of Formula 1, crystal form II prepared in this application exhibits improved crystal form stability, chemical stability, and bioavailability. The improved photostability of the compound of Formula 1 not only helps reduce the content of photochemical degradation products generated during the storage of the active pharmaceutical ingredient and formulation, but also helps reduce the likelihood of photosensitivity reactions in patients receiving the corresponding drug due to exposure to sunlight. Furthermore, crystal form II maintains high solubility while exhibiting lower hygroscopicity, overcoming the defect of existing crystal forms that are prone to crystal transformation due to high hygroscopicity.

[0181] Meanwhile, the preparation conditions for crystal form II in this application are mild, the operation is simple, and the process has good reproducibility, making industrial production conditions controllable and conducive to large-scale industrialization. It is worth noting that although acetonitrile, a type II solvent, is used in the preparation process of crystal form II in this application, the residual acetonitrile in the obtained crystal form II sample is extremely low, ensuring the quality control of the active pharmaceutical ingredient.

[0182] It will be apparent to those skilled in the art that various modifications and variations can be made to the compounds and their preparation methods without departing from the spirit or scope of this application. Therefore, the scope of protection of this application covers various modifications and variations made to this application, as long as the modifications or variations are within the scope covered by the claims and their equivalent embodiments.

Claims

1. A crystal form II of a compound of formula 1, characterized in that, The X-ray powder diffraction pattern of crystal form II shows characteristic peaks at 2θ angles of 8.6±0.2°, 10.1±0.2°, 14.5±0.2°, 17.3±0.2°, 18.0±0.2°, 22.5±0.2°, 25.9±0.2°, and 28.4±0.2°. Formula 1.

2. The crystal form II as described in claim 1, characterized in that, The X-ray powder diffraction pattern of crystal form II has characteristic peaks at 2θ angles of 8.6±0.2°, 10.1±0.2°, 14.5±0.2°, 17.3±0.2°, 18.0±0.2°, 22.2±0.2°, 22.5±0.2°, 22.7±0.2°, 25.9±0.2°, 27.8±0.2°, and 28.4±0.2°.

3. The crystal form II as described in claim 2, characterized in that, The X-ray powder diffraction pattern of crystal form II has characteristic peaks at 2θ angles of 8.6±0.2°, 10.1±0.2°, 13.7±0.2°, 14.5±0.2°, 15.3±0.2°, 15.7±0.2°, 17.3±0.2°, 18.0±0.2°, 22.2±0.2°, 22.5±0.2°, 22.7±0.2°, 25.9±0.2°, 27.8±0.2°, and 28.4±0.2°.

4. The crystal form II as described in claim 3, characterized in that, The X-ray powder diffraction pattern of crystal form II is basically shown in Figure 2.

5. A method for preparing crystal form II according to any one of claims 1 to 4, characterized in that, The preparation method is as follows: the compound of formula 1 is dissolved in pure water, then acetonitrile is added and stirred to precipitate crystals, filtered, and dried to obtain crystal form II.

6. The method for preparing crystal form II as described in claim 5, characterized in that, The volume ratio of pure water to acetonitrile is 1:10 to 1:

60.

7. The method for preparing crystal form II as described in claim 5, characterized in that, The crystallization temperature is 0~40℃.

8. The method for preparing crystal form II as described in claim 5, characterized in that, The drying method is either blower drying or vacuum drying.

9. The method for preparing crystal form II as described in claim 5, characterized in that, The drying temperature is 30~60℃.

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