POLYMORPHIC FORMS OF KINASE INHIBITOR COMPOUND, PHARMACEUTICAL COMPOSITION CONTAINING SAME, PREPARATION METHOD THEREFOR AND USE THEREOF

Abstract

The invention discloses polymorphic forms of a compound of formula I, pharmaceutical compositions containing same, preparation method therefor and use thereof. The compound of formula I of 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 purity of their main ingredient less than 2%. The preparation method of the present invention may be used to produce the various crystalline forms of the compound of formula I with high purity, and suitable for large scale production.

##STR00001##

Claims

1. Crystalline form 1 of the compound of formula I: ##STR00007## having an X-ray powder diffraction pattern with characteristic peaks at the diffraction angle 2θ of 4.3±0.2°, 8.6±0.2°, and 12.9±0.2°.

2. A composition of the compound of formula I: ##STR00008## comprises the crystalline form 1 of the compound of formula I according to claim 1 and at least one crystalline form of compound of formula I selected from crystalline form 2, crystalline form 3, crystalline form 5, crystalline form 6, and crystalline form 7, wherein, the crystalline form 2 has an X-ray powder diffraction pattern with characteristic peaks at the diffraction angle 2θ of 8.8±0.2°, 10.1±0.2°, 23.8±0.2°, and 26.7±0.2°, the crystalline form 3 has an X-ray powder diffraction pattern with a characteristic peak at the diffraction angle 2θ of 7.8±0.2°, the crystalline form 5 has an X-ray powder diffraction pattern with characteristic peaks at the diffraction angle 2θ of 8.7±0.2°, 17.0±0.2°, and 17.4±0.2°, the crystalline form 6 has an X-ray powder diffraction pattern with characteristic peaks at the diffraction angle 2θ of 7.9±0.2°, 9.0±0.2°, and 17.7±0.2°, the crystalline form 7 has an X-ray powder diffraction pattern with characteristic peaks at the diffraction angle 2θ of 9.5±0.2°, 10.6±0.2°, and 16.0±0.2°, and wherein the X-ray powder diffraction patterns were all measured using Kα spectrum of the Cu target.

3. The composition according to claim 2, wherein, the X-ray powder diffraction pattern of the crystalline form 1 has characteristic peaks at the diffraction angle 2θ of 4.3±0.2°, 7.6±0.2°, 8.6±0.2°, 12.9±0.2°, and 18.3±0.2°, the X-ray powder diffraction pattern of the crystalline form 2 has characteristic peaks at the diffraction angle 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°, the X-ray powder diffraction pattern of the crystalline form 3 has characteristic peaks at diffraction angle 2θ of 7.8±0.2°, 9.3±0.2°, 13.7±0.2°, and 16.0±0.2°, the X-ray powder diffraction pattern of the crystalline form 5 has characteristic peaks at diffraction angle 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°, the X-ray powder diffraction pattern of the crystalline form 6 has characteristic peaks at diffraction angle 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°, and the X-ray powder diffraction pattern of crystalline form 7 has characteristic peaks at diffraction angle 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°.

4. The composition according to claim 2, wherein, the X-ray powder diffraction pattern of the crystalline form 1 has characteristic peaks at the diffraction angle 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°, the X-ray powder diffraction pattern of the crystalline form 2 has characteristic peaks at the diffraction angle 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°, the X-ray powder diffraction pattern of the crystalline form 3 has characteristic peaks at diffraction angle 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°, the X-ray powder diffraction pattern of the crystalline form 5 has characteristic peaks at diffraction angle 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°, the X-ray powder diffraction pattern of the crystalline form 6 has characteristic peaks at diffraction angle 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°, and the X-ray powder diffraction pattern of the crystalline form 7 has characteristic peaks at diffraction angle 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°.

5. The composition according to claim 2, wherein, the X-ray powder diffraction pattern of the crystalline form 1 has characteristic peaks at the diffraction angle 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°, 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°, 32.9±0.2°, 33.4±0.2°, 35.0±0.2°, 37.5±0.2°, and 39.2±0.2°, the X-ray powder diffraction pattern of the crystalline form 2 has characteristic peaks at the diffraction angle 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°, 19.9±0.2°, 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°, the X-ray powder diffraction pattern of the crystalline form 3 has characteristic peaks at diffraction angle 2θ of 3.9±0.2°, 7.8±0.2°, 9.3±0.2°, 10.5±0.2°, 11.0±0.2°, 11.7±0.2°, 12.9±0.2°, 13.7±0.2°, 16.0±0.2°, 16.8±0.2°, 17.7±0.2°, 18.2±0.2°, 19.3±0.2°, 20.2±0.2°, 20.8±0.2°, 22.1±0.2°, 22.9±0.2°, 23.2±0.2°, 23.9±0.2°, 24.7±0.2°, 25.3±0.2°, 26.3±0.2°, 27.2±0.2°, 27.5±0.2°, 28.7±0.2°, 30.1±0.2°, 31.3±0.2°, 32.2±0.2°, 32.6±0.2°, 33.4±0.2°, 33.9±0.2°, 35.3±0.2°, 38.6±0.2° and 39.2±0.2°, the X-ray powder diffraction pattern of the crystalline form 5 has characteristic peaks at diffraction angle 2θ of 3.3±0.2°, 4.1±0.2°, 8.3±0.2°, 8.7±0.2°, 9.4±0.2°, 10.5±0.2°, 13.4±0.2°, 15.0±0.2°, 17.0±0.2°, 17.4±0.2°, 18.1±0.2°, 19.9±0.2°, 20.5±0.2°, 21.0±0.2°, 22.4±0.2°, 23.8±0.2°, 26.8±0.2°, 27.2±0.2° and 33.0±0.2°, the X-ray powder diffraction pattern of the crystalline form 6 has characteristic peaks at diffraction angle 2θ of 3.9±0.2°, 7.9±0.2°, 9.1±0.2°, 9.6±0.2°, 10.6±0.2°, 11.8±0.2°, 13.2±0.2°, 14.8±0.2°, 16.4±0.2°, 17.7±0.2°, 18.0±0.2°, 19.8±0.2°, 20.2±0.2°, 21.6±0.2°, 22.4±0.2°, 23.8±0.2°, 26.2±0.2°, 26.8±0.2°, 27.7±0.2°, 30.8±0.2°, 35.0±0.2° and 35.9±0.2°, and the X-ray powder diffraction pattern of the crystalline form 7 has characteristic peaks at diffraction angle 2θ of 4.8±0.2°, 7.8±0.2°, 8.8±0.2°, 9.5±0.2°, 10.1±0.2°, 10.6±0.2°, 13.8±0.2°, 14.3±0.2°, 16.0±0.2°, 17.5±0.2°, 18.2±0.2°, 18.6±0.2°, 19.1±0.2°, 19.9±0.2°, 21.5±0.2°, 21.8±0.2°, 22.5±0.2°, 23.0±0.2°, 23.9±0.2°, 24.5±0.2°, 25.1±0.2°, 26.8±0.2°, 27.1±0.2°, 27.8±0.2°, 28.9±0.2°, 30.5±0.2°, 31.2±0.2°, 32.1±0.2°, 32.4±0.2°, 33.1±0.2°, 33.6±0.2°, 38.2±0.2°, 38.8±0.2°.

6. Crystalline form 5 of the compound of formula I: ##STR00009## having an X-ray powder diffraction pattern with characteristic peaks at the diffraction angle 2θ of 8.7±0.2°, 17.0±0.2°, and 17.4±0.2°.

7. A composition of the compound of formula I: ##STR00010## comprises the crystalline form 5 of the compound of formula I according to claim 6 and at least one crystalline form of compound of formula I selected from crystalline form 1, crystalline form 2, crystalline form 3, crystalline form 6, and crystalline form 7, wherein, the crystalline form 1 has an X-ray powder diffraction pattern with characteristic peaks at the diffraction angle 2θ of 4.3±0.2°, 8.6±0.2°, and 12.9±0.2°, the crystalline form 2 has an X-ray powder diffraction pattern with characteristic peaks at the diffraction angle 2θ of 8.8±0.2°, 10.1±0.2°, 23.8±0.2°, and 26.7±0.2°, the crystalline form 3 has an X-ray powder diffraction pattern with a characteristic peak at the diffraction angle 2θ of 7.8±0.2°, the crystalline form 6 has an X-ray powder diffraction pattern with characteristic peaks at the diffraction angle 2θ of 7.9±0.2°, 9.0±0.2°, and 17.7±0.2°, the crystalline form 7 has an X-ray powder diffraction pattern with characteristic peaks at the diffraction angle 2θ of 9.5±0.2°, 10.6±0.2°, and 16.0±0.2°, and wherein the X-ray powder diffraction patterns were all measured using Kα spectrum of the Cu target.

8. The composition of claim 7, comprising the crystalline form 5 and the crystalline form 1.

9. A pharmaceutical composition, comprising a therapeutically and/or prophylactically effective amount of the crystalline form 1 according to claim 1, and at least one pharmaceutically acceptable adjuvant.

10. A pharmaceutical composition, comprising a therapeutically and/or prophylactically effective amount of the composition according to claim 2, and at least one pharmaceutically acceptable adjuvant.

11. A pharmaceutical composition, comprising a therapeutically and/or prophylactically effective amount of the crystalline form 5 according to claim 6, and at least one pharmaceutically acceptable adjuvant.

12. A pharmaceutical composition, comprising a therapeutically and/or prophylactically effective amount of the composition according to claim 7, and at least one pharmaceutically acceptable adjuvant.

13. A method of treating a disease or condition, comprising administering to a subject an effective amount of the crystalline form 1 according to claim 1, wherein the disease or condition is mediated by VEGFR, PDGFR, Flt-3, KIT, RET, or CSF1R.

14. A method of treating a disease or condition, comprising administering to a subject an effective amount of the crystalline form 1 according to claim 1, wherein the disease or condition is selected from renal cell carcinoma, gastrointestinal stromal tumor, tumor, and proliferative disorder.

15. A method of treating a disease or condition, comprising administering to a subject an effective amount of the composition according to claim 2, wherein the disease or condition is mediated by VEGFR, PDGFR, Flt-3, KIT, RET, or CSF1R.

16. A method of treating a disease or condition, comprising administering to a subject an effective amount of the composition according to claim 2, wherein the disease or condition is selected from renal cell carcinoma, gastrointestinal stromal tumor, tumor, and proliferative disorder.

17. A method of treating a disease or condition, comprising administering to a subject an effective amount of the crystalline form 5 according to claim 6, wherein the disease or condition is mediated by VEGFR, PDGFR, Flt-3, KIT, RET, or CSF1R.

18. A method of treating a disease or condition, comprising administering to a subject an effective amount of the crystalline form 5 according to claim 6, wherein the disease or condition is selected from renal cell carcinoma, gastrointestinal stromal tumor, tumor, and proliferative disorder.

19. A method of treating a disease or condition, comprising administering to a subject an effective amount of the composition according to claim 7, wherein the disease or condition is mediated by VEGFR, PDGFR, Flt-3, KIT, RET, or CSF1R.

20. A method of treating a disease or condition, comprising administering to a subject an effective amount of the composition according to claim 7, wherein the disease or condition is selected from renal cell carcinoma, gastrointestinal stromal tumor, tumor, and proliferative disorder.

21. Crystalline form 2 of the compound of formula I: ##STR00011## having an X-ray powder diffraction pattern with characteristic peaks at the diffraction angle 2θ of 8.8±0.2°, 10.1±0.2°, 23.8±0.2° and 26.7±0.2°.

22. Crystalline form 3 of the compound of formula I: ##STR00012## having an X-ray powder diffraction pattern of the crystalline form 3 with a characteristic peak at the diffraction angle 2θ of 7.8±0.2°.

23. Crystalline form 6 of the compound of formula I: ##STR00013## having an X-ray powder diffraction pattern with characteristic peaks at the diffraction angle 2θ of 7.9±0.2°, 9.1±0.2°, and 17.7±0.2°.

Description

ADVANTAGEOUS EFFECTS

[0174] The crystalline forms according to the present invention have good stability and chemical stability. The reduction in the purity of the main ingredient under the stability experimental condition is less than 2%. In addition, the crystalline forms of the present invention have improved pharmaceutical properties, pharmacokinetic properties, tissue accumulation and stability (such as milling stability), thereby possessing good prospect of pharmaceutical applications. Surprisingly, the inventors have also found that the crystalline form 2 has good stability and hygroscopicity. Furthermore, in addition to its excellent stability and improved hygroscopicity, the crystalline form 1 can further achieve good overall performance in other aspects, thus having excellent drug-forming properties. Also, the crystalline form 1 and form 2 have the highest solubility in methanol. Additionally, the method for preparing the crystalline forms described in the present invention, such as the method for obtaining the crystalline form 1 from methanol, can produce the crystalline forms of the compound of formula I in good yield and high purity. Also, the preparation methods according to the invention are suitable for large-scale production.

DESCRIPTION OF THE DRAWINGS

[0175] FIG. 1 shows the X-ray powder diffraction pattern of the crystalline form 1.

[0176] FIG. 2 shows the polarizing microscope photograph of the crystalline form 1.

[0177] FIG. 3 shows the thermogravimetric analysis pattern of the crystalline form 1.

[0178] FIG. 4 shows the differential scanning calorimetry pattern of the crystalline form 1.

[0179] FIG. 5 shows the dynamic vapor sorption pattern of the crystalline form 1.

[0180] FIG. 6 shows the .sup.1H-NMR spectrum of the compound of formula I of the present invention. Furthermore, all the .sup.1H-NMR spectrum of the samples of crystalline forms 1, 2, 3, 5, 6 and 7 are consistent with FIG. 6.

[0181] FIG. 7 shows the X-ray powder diffraction pattern of the crystalline form 2.

[0182] FIG. 8 shows the polarizing microscope photograph of the crystalline form 2.

[0183] FIG. 9 shows the thermogravimetric analysis pattern of the crystalline form 2.

[0184] FIG. 10 shows the differential scanning calorimetry pattern of the crystalline form 2.

[0185] FIG. 11 shows the dynamic vapor sorption pattern of the crystalline form 2.

[0186] FIG. 12 shows the X-ray powder diffraction pattern of the crystalline form 3.

[0187] FIG. 13 shows the polarizing microscope photograph of the crystalline form 3.

[0188] FIG. 14 shows the thermogravimetric analysis pattern of the crystalline form 3.

[0189] FIG. 15 shows the differential scanning calorimetry pattern of the crystalline form 3.

[0190] FIG. 16 shows the dynamic vapor sorption pattern of the crystalline form 3.

[0191] FIG. 17 shows the X-ray powder diffraction pattern of the crystalline form 5.

[0192] FIG. 18 shows the polarizing microscope photograph of the crystalline form 5.

[0193] FIG. 19 shows the thermogravimetric analysis pattern of the crystalline form 5.

[0194] FIG. 20 shows the differential scanning calorimetry pattern of the crystalline form 5.

[0195] FIG. 21 shows the dynamic vapor sorption pattern of the crystalline form 5.

[0196] FIG. 22 shows the X-ray powder diffraction pattern of the crystalline form 6.

[0197] FIG. 23 shows the polarizing microscope photograph of the crystalline form 6.

[0198] FIG. 24 shows the thermogravimetric analysis pattern of the crystalline form 6.

[0199] FIG. 25 shows the differential scanning calorimetry pattern of the crystalline form 6.

[0200] FIG. 26 shows the dynamic vapor sorption pattern of the crystalline form 6.

[0201] FIG. 27 shows the X-ray powder diffraction pattern of the crystalline form 7.

[0202] FIG. 28 shows the polarizing microscope photograph of the crystalline form 7.

[0203] FIG. 29 shows the thermogravimetric analysis pattern of the crystalline form 7.

[0204] FIG. 30 shows the differential scanning calorimetry pattern of the crystalline form 7.

[0205] FIG. 31 shows the dynamic vapor sorption pattern of the crystalline form 7.

[0206] FIG. 32 shows the isothermal adsorption curve of the crystalline form 1.

[0207] FIG. 33 shows the isothermal adsorption curve of the crystalline form 2.

[0208] FIG. 34 shows the isothermal adsorption curve of the crystalline form 3.

[0209] FIG. 35 shows the isothermal adsorption curve of the crystalline form 5.

[0210] FIG. 36 shows the isothermal adsorption curve of the crystalline form 6.

[0211] FIG. 37 shows the isothermal adsorption curve of the crystalline form 7.

[0212] FIG. 38 shows the XRD pattern of crystalline stability of the crystalline form 1.

[0213] FIG. 39 shows the DSC pattern of crystalline stability of the crystalline form 1.

[0214] FIG. 40 shows the XRD pattern of crystalline stability of the crystalline form 2.

[0215] FIG. 41 shows the DSC pattern of crystalline stability of the crystalline form 2.

[0216] FIG. 42 shows the XRD pattern of crystalline stability of crystalline form 3.

[0217] FIG. 43 shows the DSC pattern of crystalline stability of the crystalline form 3.

[0218] FIG. 44 shows the XRD pattern of crystalline stability of the crystalline form 5.

[0219] FIG. 45 shows the DSC pattern of crystalline stability of the crystalline form 5.

[0220] FIG. 46 shows the XRD pattern of crystalline stability of the crystalline form 6.

[0221] FIG. 47 shows the DSC pattern of crystalline stability of the crystalline form 6.

[0222] FIG. 48 shows the XRD pattern of crystalline stability of the crystalline form 7.

[0223] FIG. 49 shows the transformation of the crystalline form 1, crystalline form 2, crystalline form 3 and crystalline form 7 to crystalline form 2 in acetone, ethyl acetate, methanol or water.

[0224] FIG. 50 shows the transformation of the crystalline form 1, crystalline form 2, crystalline form 3 and crystalline form 7 to crystalline form 3 in tetrahydrofuran (THF).

[0225] FIG. 51 shows the XRD pattern comparison between the crystalline form 1 and crystalline form 2, wherein the upper spectrum line represents the crystalline form 1 and the lower spectrum line represents the crystalline form 2.

[0226] FIG. 52 shows the relationship between the peak area at 20 of 10.1° and the weight percentage of the crystalline form 2 in the crystalline form 1.

[0227] FIG. 53 shows the XRD pattern comparison of crystalline form 1 before and after grinding, wherein the upper spectrum line is the XRD pattern before grinding, and the lower spectrum line is the XRD pattern after grinding.

EXAMPLES

[0228] The present invention will be further illustrated by the following examples, but it should not be construed that the present invention is confined to the scope of the examples. In the experimental methods of the following examples, where the specific conditions were not specifically described, they could be selected from conventional methods and conditions, or those recited in commercially available instructions.

[0229] Unless otherwise specified, the information and parameters of the detection instruments and methods used in the following examples and effect examples are as follows:

[0230] (1) X-ray powder diffractometer (XRD) & hot stage XRD, Bruker D8 Advance diffractometer; technical specifications: Kα irradiation (40 Kv, 40 mA) with a copper target wavelength of 1.54 Å, θ-2θ goniometer, Mo monochromator, Lynxeye detector; standard material: Al.sub.2O.sub.3; acquisition software: Diffrac Plus XRD Commander; analysis software: MDI Jade 6;

[0231] Method parameters: detection angle, 3-40° 2θ/3-30° 20 (hot stage XRD); step length, 0.02° 2θ; velocity, 0.15 s/step; weight of the sample to be detected >2 mg.

[0232] (2) Differential Thermal Scanner (DSC), TA Instruments Q200 DSC; controlling software: Thermal Advantage; analytical software: Universal Analysis; sample plate: aluminium crucible; amount of the sample to be detected: 0.5-5 mg; protective gas: nitrogen; gas flow rate: 40 mL/min; detection method: the temperature is raised at a rate of 10° C./min, and then raised to 300° C. after equilibration at 20° C.

[0233] (3) Thermogravimetric Analyzer (TGA), TA Instruments Q500 TGA; controlling software: Thermal Advantage; analysis software: Universal Analysis; sample plate: platinum crucible; amount of the sample to be detected: 1-10 mg; protective gas: nitrogen; gas flow fate: 40 mL/min; detection method: high resolution 3.0 (Hi-Res sensitivity 3.0), the temperature is raised at a rate of 10° C./min to 350° C.;

[0234] (4) Dynamic Water Adsorption (DVS), TA Instruments Q5000 TGA; controlling software: Thermal Advantage; analysis software: Universal Analysis; sample plate: platinum crucible; amount of the sample to be detected: 1-10 mg; protective gas: nitrogen; gas flow fate: 10 mL/min; detection method: equilibration at 25° C., humidity: 0%, isothermal treatment: 90 min, weight change to be detected: from 0% RH to 80% RH;

[0235] Criterion: non-hygroscopic: no more than 0.2%; slightly hygroscopic: more than 0.2%, but no more than 2.0%; easily hygroscopic: higher than 2%, but no higher than 15%; extremely easily hygroscopic: higher than 15%.

[0236] (5) Hot Stage Polarized Light Microscope (PLM), XP-500E; Shanghai Changfang Optical Instrument Co., Ltd.

[0237] (6) Determination of solubility: visual inspection method, comprising the following specific process: the known amount of sample is weighed at 25° C., added with a solvent gradually, stirred or supplemented with ultrasound until the sample is dissolved to clear visually; the amount of the consumed solvent is recorded. If the sample is still not dissolved at a specific concentration, its solubility is expressed as “<specific concentration”;

[0238] Criterion: extremely easily soluble: greater than 1 g/mL; easily soluble: greater than 100 mg/mL but less than or equal to 1 g/mL; soluble: greater than 33.3 mg/mL but less than or equal to 100 mg/mL; more slightly soluble: greater than 10 mg/mL but less than or equal to 33.3 mg/mL; slightly soluble: greater than 1 mg/mL but less than or equal to 10 mg/mL; extremely slightly dissolved: greater than 0.1 mg/mL, but less than or equal to 1 mg/mL; practically insoluble or insoluble: less than 0.1 mg/mL.

[0239] (7) Nuclear magnetic apparatus (NMR), Bruker Ascend 500; detection type: nuclear magnetic proton spectrum; full frequency excitation, spectral width: 30 ppm single pulse, 30° angle excitation scanning for 16 times, digital orthogonal detection, temperature control: 298K.

[0240] (8) High Performance Liquid Chromatography (HPLC), Ultimate 3000; test purpose: solubility test (area method), related substances (area normalization method).

[0241] The method parameters are as follows:

[0242] Chromatographic column: Shimadzu shim-pack VP-ODS (150 L*4.6), Waters symmetry C18 (3.9*150 mm 5 μm); column temperature: 25° C.; flow rate: 1.0 mL/min; detection wavelength: 214 nm; injection volume: 10 μL; running time: 20 min; Sample solvent: ACN; injection concentration: 0.2 mg/mL;

[0243] Mobile phase: Mobile phase A, H.sub.2O:CAN:H.sub.3PO.sub.4=90:10:0.1, Mobile phase B: H.sub.2O:CAN: H.sub.3PO.sub.4=10:90:0.1; the elution gradient is shown in Table 7 below:

TABLE-US-00007 TABLE 7 Time (min) A (%) B (%) 0 90 10 10 0 100 15 0 100 15.1 90 10 20 Stop

[0244] In the following examples, “volatilizing the solvent” refers to natural volatilization of a solvent to dryness in an open vessel; “room temperature” means the temperature of 10 to 30° C. (30 to 70% RH); “crystal slurry” refers to a supersaturated solution of the compound of formula I described herein; “overnight” refers to the time spanning the evening, usually 10 to 16 hours.

[0245] In the following example tables, “NA” means “not applicable” or “not used.”

Preparation Example

[0246] ##STR00005##

[0247] Compound A (13.00 kg, 1 eq.) was added to DMF (97.8 kg) in a reactor under nitrogen atmosphere at 20-30° C. Subsequently, 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 under nitrogen atmosphere at 20-30° C. The mixture was stirred for 22 hours under nitrogen atmosphere at 20-30° C. After the reaction was completed, the reaction mixture was transferred to a clean container and weighed (163.8 kg).

[0248] About ¼ of the reaction mixture (40.90 kg) was added to a 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 filtered. The remaining ¾ reaction solution was treated similarly. The filter cakes were combined and washed with MTBE (46.2 kg).

[0249] A portion of the combined solids (20.0 kg) was added to anhydrous methanol (74.2 kg) and the resulting mixture was heated to reflux for 45 minutes. Subsequently, the reaction mixture was cooled to 10-20° C. within 1-2 hours, and then continuously stirred at 10-20° C. for 1.5 hours. The resulting suspension was filtered. The other MTBE-washed materials were treated similarly. The filter cakes were combined and washed with cold methanol (44.2 kg). The wet crude product was dried under reduced pressure (500-1000 Pa) at 50° C. for 13 hours, and then dried at 76° C. for 23 hours to obtain about 12 kg of the initial product of the compound of formula I.

Example 1

[0250] Preparation Method 1 of the Crystalline Form 1 of the Compound of Formula I:

[0251] 5 mg of the compound of formula I was mixed with a single solvent, or 10 mg of the compound of formula I was mixed with solvent 1 and solvent 2 to obtain a clear solution, which was naturally volatilized to dryness at the corresponding temperature to obtain crystalline form 1. The specific preparation parameters are shown in Table 8 below.

TABLE-US-00008 TABLE 8 Solvent 1/ Solvent 2 Result Temperature Solvent 1 Solvent 2 (mL) analysis room methanol NA 1.0 crystalline temperature form 1 40° C. methanol NA 1.0 crystalline form 1 room methanol acetone 0.2/0.4 crystalline temperature form 1 40° C. methanol water 1.2/0.2 crystalline form 1

[0252] The products obtained by the above preparation methods are all found to be the crystalline form 1 by detection. The X-ray powder diffraction pattern of the crystalline form 1 is shown in FIG. 1 and the detailed data of the X-ray powder diffraction pattern thereof is shown in Table 1 above. The polarized light micrograph of crystalline form 1 is shown in FIG. 2, which shows that crystalline form 1 is a slender rod-like crystal. Crystalline form 1 has a thermogravimetric analysis pattern as shown in FIG. 3, which shows that crystalline form 1 has a weight loss of 2.6% before 170° C., which is an anhydrous substance with a decomposition temperature of about 320° C.; crystalline form 1 has the differential scanning calorimetry pattern shown in FIG. 4, which shows an exothermic peak at 150-170° C., confirmed by XRD as an exothermic peak of crystal transformation. Crystalline form 1 was transformed to crystalline form 3 and the melting point of crystalline form 1 is 260° C. Crystalline form 1 has a dynamic moisture adsorption pattern as shown in FIG. 5, showing a weight change of 2.8% in the range of 0% RH to 80% RH.

[0253] The .sup.1H-NMR spectrum of the compound of formula I and the crystalline form 1 is shown in FIG. 6, indicating that the chemical structure is shown in formula I:

##STR00006##

[0254] The results of solubility test showed that the solubility of the crystalline form 1 in conventional solvents at 25° C. is as follows: the solubility in methanol was 5 to 12.5 mg/mL; the solubility in ethanol was 1 to 2.5 mg/mL; the solubility in water was <1 mg/mL; the solubility in acetone was 1 to 2.5 mg/mL; the solubility in ethyl acetate was <1 mg/mL; the solubility in methyl tert-butyl ether was <1 mg/mL; the solubility in tetrahydrofuran was 1 to 2.5 mg/mL; the solubility in acetonitrile was <1 mg/mL; the solubility in toluene was <1 mg/mL; the solubility in n-heptane was <1 mg/mL.

Example 2

[0255] Preparation method 2 and preparation method 3 of crystalline form 1 of the compound of formula I:

[0256] 20 mg of the compound of the formula I was mixed with 1.4 mL of methanol, heated to 50° C. to dissolve, and then hot filtered to obtain a clear solution. The operation of adding the solvent 2 to the dissolved solution under stirring was recorded as a positive addition (corresponding to the preparation method 2) and the operation of adding the clear solution to the solvent 2 under stirring was recorded as a reverse addition (corresponding to the preparation method 3). Stirring was continued once the solid was precipitated until the solid was completely precipitated to obtain the crystalline form 1. The specific preparation parameters are shown in Table 9 below.

TABLE-US-00009 TABLE 9 Solvent 1/ Solvent 2 Result Addition method Solvent 1 Solvent 2 (mL) analysis positive addition methanol acetone 1.4/3.0 crystalline form 1 positive addition methanol ethyl acetate 1.4/3.0 crystalline form 1 positive addition methanol methyl tert- 1.4/3.0 crystalline butyl ether form 1 positive addition methanol acetonitrile 1.4/3.0 crystalline form 1 reverse addition methanol water 1.4/5.2 crystalline form 1 reverse addition methanol methyl tert-  1.4/11.2 crystalline butyl ether form 1

[0257] The products obtained by the above preparation methods were all found to be crystalline form 1 by detection, and the detection results of XRD, PLM, TGA, DSC, DVS, .sup.1H-NMR and solubility were the same as in Example 1.

Example 3

[0258] Preparation Method 4 of Crystalline Form 1 of the Compound of Formula I:

[0259] 20 mg of the compound of formula I was mixed with the corresponding solvent in a water bath at 50° C., and then filtered while hot to obtain a clear solution, which is naturally cooled to 4° C., stirred and crystallized to precipitate a solid product, so as to obtain the crystalline form 1. The specific preparation parameters are shown in table 10 below.

TABLE-US-00010 TABLE 10 Crystallization Solvent 1/ Result temperature Solvent 1 Solvent 2 Solvent 2(mL) analysis 4° C. methanol NA 1.4 crystalline form 1 4° C. methanol water 1.4/0.4 crystalline form 1 4° C. methanol ethyl acetate 0.4/0.8 crystalline form 1 4° C. methanol methyl tert- 0.8/1.4 crystalline butyl ether form 1 4° C. methanol acetonitrile 0.4/0.4 crystalline form 1

[0260] The products obtained by the above preparation methods were all found to be crystalline form 1 by detection, and the detection results of XRD, PLM, TGA, DSC, DVS, .sup.1H-NMR and solubility were the same as in Example 1.

Example 4

[0261] Preparation Method 4 of Crystalline Form 1 of the Compound of Formula I:

[0262] The initial product of the compound of formula I (2.0 kg), anhydrous methanol (72.0 kg) and activated charcoal (0.20 kg) were added to a reactor and heated to reflux for 1.5 hours. The reaction solution was filtered and the filtrate was heated to reflux for 40 minutes. The resulting solution was hot filtered into a reactor and then concentrated under reduced pressure (500-1000 Pa) for about 4 hours to remove about 85 L of methanol. The resulting suspension was cooled to 10-20° C., stirred at 10-20° C. for about 45 minutes and then filtered. After the filter cake was washed with methanol, the purity was 99.9% detected by HPLC. The obtained solid was dried under reduced pressure (500-1000 Pa) at 40-60° C. The obtained product was detected as crystalline form 1 by XRD, with a yield over 80%.

Example 5

[0263] The preparation method of crystalline form 2 of the compound of formula I was as follows, wherein the crystalline form of the compound of formula I used below was crystalline form 1.

[0264] The preparation of No. 1 to 9 samples: 10 mg of the compound of formula I was mixed with the corresponding solvent to obtain a suspension, which was stirred at the corresponding temperature for 5 to 6 days. The crystal slurry was centrifuged and the solid was dried to obtain the samples.

[0265] The preparation of No. 10 sample: 199 mg of the compound of formula I was mixed with the corresponding solvent to obtain a suspension, which was stirred at 50° C. for 2 hours and then stirred at room temperature for 2 days. After the crystal slurry was filtered, the solid was dried under vacuum at room temperature overnight to obtain the sample.

[0266] The preparation of No. 11 sample: 200 mg of the compound of formula I was mixed with the corresponding solvent to obtain a suspension, which was stirred at 4° C. for 5 days. The crystal slurry was filtered and the solid was dried at room temperature under vacuum overnight to obtain the sample.

[0267] The preparation of No. 12 sample: 200 mg of the compound of formula I was mixed with the corresponding solvent to obtain a suspension, which was stirred at room temperature for 3 days. The crystal slurry was filtered and the solid was dried at room temperature under vacuum overnight to obtain the sample.

[0268] The specific preparation parameters are shown in table 11 below.

TABLE-US-00011 TABLE 11 Solvent 1/ Solvent 2 Result No. Temperature Solvent 1 Solvent 2 (mL) analysis 1 room water NA 0.5 crystalline temperature form 2 2 50° C. ethyl acetate NA 0.5 crystalline form 2 3 50° C. toluene NA 0.5 crystalline form 2 4 room water acetone 0.2/0.4 crystalline temperature form 2 5 room water acetonitrile 0.1/0.5 crystalline temperature form 2 6 50° C. ethanol toluene 0.4/0.4 crystalline form 2 7 50° C. water acetonitrile 0.2/0.4 crystalline form 2 8 4° C. water methanol 0.4/0.4 crystalline form 2 9 — ethyl acetate NA 5   crystalline form 2 10 4° C. water methanol 8/8 crystalline form 2 11 room water acetonitrile  2/10 crystalline temperature form 2

[0269] The products obtained by the above preparation methods were all found to be the crystalline form 2 by detection. The X-ray powder diffraction pattern of the crystalline form 2 is shown in FIG. 7 and the detailed data of the X-ray powder diffraction pattern thereof is shown in Table 2 above. The polarized light micrograph of crystalline form 2 is shown in FIG. 8, which shows that crystalline form 2 is a fine needle crystal. Crystalline form 2 has a thermogravimetric analysis pattern as shown in FIG. 9, which shows that crystalline form 1 has a weight loss of 0.3% before 200° C., which is an anhydrous substance with a decomposition temperature of 320° C. Further, the crystalline form 2 has a differential scanning calorimetry (DSC) pattern substantially as shown in FIG. 10, showing a melting point of the crystalline form 2 of 258° C. The crystalline form 2 has a dynamic moisture adsorption pattern as shown in FIG. 11, showing a weight change of 0.05% in the range of 0% RH to 80% RH. The .sup.1H-NMR spectrum of the crystal form 2 is consistent with FIG. 6.

Example 6

[0270] Preparation Methods 1, 2 and 3 of the Crystalline Form 3 of the Compound of Formula I:

[0271] 5 mg of the compound of formula I was mixed with a single solvent, or 10 mg of the compound of formula I was mixed with solvent 1 and solvent 2 to obtain a clear solution, which was naturally volatilized to dryness at the corresponding temperature, so as to obtain the crystalline form 3. The specific preparation parameters are shown in Table 12 below.

TABLE-US-00012 TABLE 12 Solvent 1/ Preparation Solvent Solvent Solvent 2 Result method Temperature 1 2 (mL) analysis preparation room ethanol NA 3.0 crystalline method 2 temperature form 3 preparation room tetrahy- NA 5.0 crystalline method 1 temperature drofuran form 3 preparation 40° C. tetrahy- NA 5.0 crystalline method 1 drofuran form 3 preparation 60° C. ethanol water 1.0/0.2 crystalline method 3 form 3

[0272] The products obtained by the above preparation methods were all found to be crystalline form 3 by detection. The X-ray powder diffraction pattern of crystalline form 3 is shown in FIG. 12 and the detailed data of the X-ray powder diffraction pattern thereof is shown in Table 3 above. The polarized light micrograph of crystalline form 3 is shown in FIG. 13, which shows that crystalline form 3 is fine particles. Crystalline form 3 has a thermogravimetric analysis pattern as shown in FIG. 14, which shows that crystalline form 3 has a weight loss of 0.2% before 200° C., which is an anhydrous substance with a decomposition temperature of 320° C. Moreover, the crystalline form 3 has a differential scanning calorimetry (DSC) pattern substantially as shown in FIG. 15, showing that the melting point of crystalline form 3 is 261° C. The crystalline form 3 has a dynamic moisture adsorption pattern as shown in FIG. 16, showing a weight change of 0.08% in the range of 0% RH to 80% RH. The .sup.1H-NMR spectrum of crystalline form 3 is consistent with FIG. 6.

Example 7

[0273] The preparation method 4 of crystalline form 3 of the compound of formula I was as follows, wherein the crystalline form of the compound of formula I used below was the crystalline form 1.

[0274] The preparation of No. 1 to 3 samples: 10 mg of the compound of formula I was mixed with the corresponding solvent to obtain a suspension, which was stirred at the corresponding temperature for 5 to 6 days. The crystal slurry was centrifuged and the solid was dried to obtain the samples.

[0275] The preparation of No. 4 to 6 samples: 200 mg of the compound of formula I was mixed with the corresponding solvent to obtain a suspension, which was stirred at the corresponding temperature for 5 days. The crystal slurry was filtered and the solid was dried at room temperature under vacuum overnight to obtain the samples.

[0276] The preparation of No. 7 sample: 201.0 mg of the compound of formula I was mixed with the corresponding solvent to obtain a suspension, which was stirred at 800 rpm for 20 hours at the corresponding temperature. The crystal slurry was filtered and the solid was separated and dried at 60° C. for 1 hour to obtain the sample.

[0277] The specific preparation parameters are shown in Table 13 below.

TABLE-US-00013 TABLE 13 Solvent 1/ Solvent 2 Result No. Temperature Solvent 1 Solvent 2 (mL) analysis 1 room ethanol NA 0.5 crystalline temperature form 3 2 4° C. acetone NA 0.5 crystalline form 3 3 room water tetrahy- 0.4/0.4 crystalline temperature drofuran form 3 4 room ethanol NA 8 crystalline temperature form 3 5 4° C. acetone NA 8 crystalline form 3 6 room water tetrahy- 5/5 crystalline temperature drofuran form 3 7 room ethanol NA 15 crystalline temperature form 3

[0278] The products obtained by the above preparation methods were all found to be crystalline form 3 by detection, wherein the detection results of XRD, PLM, TGA, DSC, DVS, 1H-NMR and solubility were the same as in Example 4.

Example 8

[0279] Preparation Method 5 for Crystalline Form 3 of the Compound of Formula I:

[0280] 20 mg of the compound of formula I was mixed with the corresponding solvent and dissolved in a water bath at 50° C., and then hot filtered to obtain a clear solution, which was naturally cooled to 4° C., stirred and crystallized to precipitate a solid. The specific preparation parameters are shown in Table 14 below.

TABLE-US-00014 TABLE 14 Crystallization Solvent 1/ Result temperature Solvent 1 Solvent 2 Solvent 2(mL) analysis 4° C. tetrahy- NA 5 crystalline drofuran form 3 4° C. methanol tetrahy- 0.2/0.2 crystalline drofuran form 3

[0281] The products obtained by the above preparation methods were all found to be crystalline form 3 by detection, wherein the detection results of XRD, PLM, TGA, DSC, DVS, 1H-NMR and solubility were the same as in Example 4.

Example 9

[0282] Preparation Method 6 for Crystalline Form 3 of the Compound of Formula I:

[0283] The crystalline form 1 was heated to 180° C. and cooled to room temperature to obtain the crystalline form 3.

[0284] The product obtained by the above preparation method was found to be the crystalline form 3 by detection, and the detection results of XRD, PLM, TGA, DSC, DVS, 1H-NMR and solubility was the same as in Example 4.

Example 10

[0285] Preparation Method 1 for Crystalline Form 5 of the Compound of Formula I:

[0286] 20 mg of the compound of formula I was dissolved with 5 mL of acetone in a water bath at 50° C., then hot filtered to obtain a clear solution, which was naturally cooled to 4° C., stirred and crystallized to precipitated a solid. The mixture was centrifuged and dried at room temperature in vacuum to obtain the crystalline form 5.

[0287] The product obtained by the above preparation method was found to be the crystalline form 5 by detection. The X-ray powder diffraction pattern of crystalline form 5 is shown in FIG. 17 and the detailed data of the X-ray powder diffraction pattern thereof is shown in Table 4 above. The polarized light micrograph of crystalline form 5 is shown in FIG. 18, which shows that crystalline form 5 is fine particles. Crystalline form 5 has a thermogravimetric analysis pattern as shown in FIG. 19, which shows that crystalline form 5 has a weight loss of 1.2% before 200° C., which is an anhydrous substance with a decomposition temperature of 319° C.; crystalline form 5 has a differential scanning calorimetry diagram as shown in FIG. 20, which shows that the melting point of crystalline form 5 is 258° C., and the broad endothermic peak before 100° C. is caused by the removal of the surface solvent. Moreover, the crystalline form 5 has a dynamic moisture adsorption diagram as shown in FIG. 21, showing a weight change of 2.5% in the range of 0% RH to 80% RH. The .sup.1H-NMR spectrum of crystalline form 5 is consistent with FIG. 6.

Example 11

[0288] Preparation method 2 of crystalline form 5 of the compound of formula I was as follows. wherein the crystalline form of the compound of formula I used below was crystalline form 1.

[0289] Preparation of No. 1 sample: 199 mg of the compound of formula I was mixed with 10 ml of methyl t-butyl ether to obtain a suspension, which was stirred at room temperature for 2 days, and the crystal slurry was filtered, and the solid was dried under vacuum at room temperature overnight to obtain the sample.

[0290] Preparation of No. 2 sample: 600 mg of the compound of formula I was mixed with 30 ml of methyl t-butyl ether, added with the seed of crystalline form 5 of 2% of the crystal slurry mass, and stirred at room temperature for 1 day, and the crystal slurry was filtered. The solid was dried under vacuum at room temperature overnight to obtain the sample.

[0291] Preparation of No. 3 sample: The sample was prepared in the same manner as the preparation method of the No. 1 sample, only except that acetone was used instead of methyl tert-butyl ether.

[0292] The products obtained by the above preparation methods were all found to be crystalline form 5 by detection, wherein the detection results of XRD, PLM, TGA, DSC, DVS, .sup.1H-NMR and solubility were the same as in Example 9.

Example 12

[0293] Preparation Method 1 of Crystalline Form 6 of the Compound of Formula I:

[0294] 10 mg of the compound of the formula I and 0.4 mL was mixed with a mixture of toluene and methanol (volume ratio of toluene to methanol was 1:1), sonicated for dissolution and filtered to obtain a clear solution, which was naturally volatilized to dryness at room temperature to obtain the crystal.

[0295] The product obtained by the above preparation method was found to be the crystalline form 6 by detection. The X-ray powder diffraction pattern of crystalline form 6 is shown in FIG. 22 and the detailed data of the X-ray powder diffraction pattern thereof is shown in Table 5 above. The polarized light micrograph of crystalline form 6 is shown in FIG. 23, which shows that crystalline form 6 is fine particles and partially agglomerated. Crystalline form 6 has a thermogravimetric analysis pattern as shown in FIG. 24, which shows that the crystalline form 6 has a weight loss of 0.7% before 200° C., which is an anhydrous substance with a decomposition temperature of 320° C.; crystalline form 6 has a differential scanning calorimetry diagram as shown in FIG. 25, which shows that the melting point of crystalline form 6 is 259° C. Moreover, the crystalline form 6 has a dynamic moisture adsorption diagram as shown in FIG. 26, showing a weight change of 0.26% in the range of 0% RH to 80% RH.

[0296] The .sup.1H-NMR spectrum of crystalline form 6 is consistent to that of FIG. 6.

Example 13

[0297] Preparation Method 2 of Crystalline Form 6 of the Compound of Formula I:

[0298] Preparation of No. 1 sample: 20 mg of the compound of formula I was mixed with 1.4 mL of methanol, heated to 50° C. to dissolve, and then hot filtered to obtain a clear solution, and 3.0 mL of toluene was added to the solution under stirring. When the solid was precipitated, stirring was continued until the solid was completely precipitated to obtain the crystalline form 6.

[0299] Preparation of No. 2 sample: 20 mg of the compound of formula I was mixed with 1.4 mL of methanol, heated to 50° C. to dissolve, and then hot filtered to obtain a clear solution, and the clear solution was added to 11.2 ml of toluene under stirring. When the solid was precipitated, stirring was continued until the solid was completely precipitated.

[0300] The product obtained by the above preparation methods was all found to be crystalline form 6 by detection, wherein the detection results of XRD, PLM, TGA, DSC, DVS, 1H-NMR and solubility were the same as in Example 12.

Example 14

[0301] Preparation method 3 of crystalline form 6 of the compound of formula I, wherein the crystalline form of the compound of formula I used therein is the crystalline form 1.

[0302] Preparation of No. 1 sample: 200 mg of the compound of formula I was mixed with 20 mL of toluene, stirred at room temperature for 16-22 hours, and then the crystal slurry was dried under vacuum at 60° C. for 1 hour to obtain the sample.

[0303] Preparation of No. 2 sample: 600 mg of the compound of formula I was mixed with 60 mL of toluene, added with the seed of crystalline form 6 of 2% of the crystal slurry mass, and stirred at room temperature for 1 day, and then the crystal slurry was dried under vacuum at 50° C. for 1 hour to obtain the sample.

[0304] The products obtained by the above preparation methods were all found to be crystalline form 6 by detection, wherein the detection results of XRD, PLM, TGA, DSC, DVS, 1H-NMR and solubility were the same as in Example 11.

[0305] Further, in the preparation process of the No. 1 sample, a sample taken after the mixture was stirring at room temperature for 6 hours was found containing an agglomerate product after suction filtration. Additionally, the wet product was found comprising crystalline form 1 by detection.

Example 15

[0306] Preparation Method 1 of Crystalline Form 7 of the Compound of Formula I:

[0307] Preparation of No. 1 sample: 199 mg of the compound of formula I was mixed with 10 mL of ethyl acetate and stirred at 50° C. for 30 minutes. After filtration, the filter cake was dried under vacuum at 60° C. for 1 hour to obtain the sample.

[0308] Preparation of No. 2 sample: 600 mg of the compound of formula I was mixed with 30 mL of ethyl acetate and stirred at 50° C. for 30 minutes. After filtration, the filter cake was dried under vacuum at 60° C. for 1 hour.

[0309] The products obtained by the above preparation methods were all found to be crystalline form 7 by detection. The X-ray powder diffraction pattern of crystalline form 7 is shown in FIG. 27 and the detailed data of the X-ray powder diffraction pattern thereof is shown in Table 7 above. The polarized light micrograph of crystalline form 7 is shown in FIG. 28, which shows that crystalline form 7 is fine particles and partially agglomerated. Crystalline form 7 has a thermogravimetric analysis pattern as shown in FIG. 29, which shows that crystalline form 6 has a weight loss of 0.5% before 200° C., which is an anhydrous substance with a decomposition temperature of 320° C.; crystalline form 7 has a differential scanning calorimetry diagram as shown in FIG. 30, which shows that the melting point of crystalline form 7 is 259° C., and the crystalline form 7 has a dynamic moisture adsorption diagram as shown in FIG. 31, showing a weight change of 0.27% in the range of 0% RH to 80% RH. The .sup.1H-NMR spectrum of crystalline form 7 is consistent to that of FIG. 6.

Example 16

[0310] Preparation method 2 of crystalline form 7 of the compound of formula I (wherein the crystalline form of the compound of formula I used below is the crystalline form 1):

[0311] The compound of formula I was mixed with a mixture of N,N-dimethylacetamide and toluene (the volume ratio of N,N-dimethylacetamide to toluene was 1:9), and after stirring, the crystal slurry was filtered and dried to obtain the crystalline form 7.

[0312] The products obtained by the above preparation methods were all found to be the crystalline form 7 by detection, wherein the detection results of XRD, PLM, TGA, DSC, DVS, 1H-NMR and solubility were the same as in Example 14.

Effect Example 1

[0313] The isothermal adsorption curves of the samples of crystalline forms 1, 2, 3, 5, 6 and 7 were shown in FIGS. 32 to 37.

Effect Example 2

[0314] The stability of the crystalline forms 1, 2, 3, 5, 6, and 7 was investigated.

[0315] Experimental conditions: the samples were sealed and placed at 80° C. for 24 hours, and then placed in an open dish at 25° C./60% RH (relative humidity) and 40° C./75% RH for 7 days. Detection method: HPLC (only for the starting samples and samples placed at 80° C. for 24 hours), XRD, DSC.

[0316] Investigation Results:

[0317] 1) The XRD and DSC tests showed that the crystalline forms and melting points of crystalline forms 1, 2, 3, 5, 6 and 7 are substantially unchanged and relatively stable. The specific test results are shown in FIGS. 38-48, and the DSC spectrum of the crystalline form 7 to show its crystal stability is shown in FIG. 30;

[0318] 2) HPLC analysis showed that as compared with the initial samples, although decreases in the purity of the main ingredient were found in all the crystalline forms at 80° C. for 24 hours, but they were all kept lower than 2%, as can be seen from the specific data shown in Table 15. Note: the impurity with a retention time of 4.73 min was the trans-form of the compound, of which the content was related to the degree of protection from light while detection.

TABLE-US-00015 TABLE 15 HPLC Maximum single impurity % Samples Purity % (retention time, min) crystalline form 1 (0 day) 99.67 0.22 (4.73) crystalline form 2 (0 day) 97.76 2.15 (4.73) crystalline form 5 (0 day) 99.86 0.05 (8.82) crystalline form 6 (0 day) 99.09 0.80 (4.73) crystalline form 7 (0 day) 99.28 0.58 (4.73) crystalline form 3 (0 day) 99.14 0.76 (4.73) crystalline form 1 (80° C./24 h) 98.87 1.03 (4.73) crystalline form 2 (80° C./24 h) 98.95 0.96 (4.73) crystalline form 5 (80° C./24 h) 98.80 1.10 (4.73) crystalline form 6 (80° C./24 h) 99.12 0.78 (4.73) crystalline form 7 (80° C./24 h) 98.70 1.19 (4.73) crystalline form 3 (80° C./24 h) 98.32 1.58 (4.73)

[0319] In addition, the long-term stabilities of the crystalline form 1 for 12 months, 24 months, 36 months, and 48 months at 25° C./60% RH were also investigated. The results showed that the crystalline forms are substantially unchanged.

Effect Example 3: Thermodynamic Stability Experiment

[0320] The crystalline form 1, crystalline form 2, crystalline form 3 and crystalline form 7 of the compound of formula I were mixed with acetone, ethyl acetate, methanol, water and tetrahydrofuran respectively, and then kept at 60° C. for one day for the investigation of the thermodynamic stability of each crystalline form. Insoluble solid was recovered by filtration and analyzed by XRD. Analysis conditions: Shimadzu XRD-6000, CuK source (1.54056 A) 40 kV, 30 mA; detection angle: 5-50°, speed: 5°/min.

[0321] The results showed that the crystalline form 1, crystalline form 2, crystalline form 3 and crystalline form 7 could be converted to crystalline form 2 while being treated with acetone, ethyl acetate, methanol or water. However, according to the peak having a 20 angle of 13° in FIG. 49, it was found that the conversion to the crystalline form 2 was not completely achieved when methanol was used. FIG. 50 showed that the crystalline form 3 could be provided using THF.

Effect Example 4: Stability of Crystalline Form 1 in Methanol

[0322] The stability of the crystalline form 1 in aqueous methanol solution at different temperature and for different time is as follows. The results showed that high temperature and moisture can accelerate the conversion of the crystalline form 1 to the crystalline form 2.

TABLE-US-00016 TABLE 16 condition form 1 Moisture XRPD detection Experiment batch No. (g) methanol (KF) temperature 2 hrs 4 hrs 8 hrs 21 hrs 1 0556-023-A 5.0 50 mL 0.1% reflux form 1 form 1 form 2 form 2 2 0556-023-B 5.0 50 mL 5.2% reflux form 1 form 1 + form 2 form 2 form 2 3 0556-023-C 5.0 50 mL  10% reflux form 1 form 2 form 2 form 2 4 0556-023-D 2.0 50 mL 0.1% 20-30° C. form 1 form 1 form 1 form 1 5 0556-023-E 2.0 50 mL 5.2% 20-30° C. form 1 form 1 form 1 form 1 6 0556-023-F 2.0 50 mL  10% 20-30° C. form 1 form 1 form 1 form 1

Effect Example 5: Quantitative Detection of Crystalline Form 2 in the Crystalline Form 1

[0323] The content of crystalline form 2 in the crystalline form 1 of the compound of formula I was analyzed by XRD pattern obtained from Shimadzu XRD-6000, CuK source (1.54056 Å, 40 kV, 30 mA). Detection angle: 9.6-10.4° 2θ; step size: 0.02° 2θ; counting time: 10 s.

[0324] The XRD patterns of the crystalline form 1 and crystalline form 2 are compared in FIG. 51, wherein the peak of the crystalline form 1 at 2θ of 10.1° is very weak, while the crystalline form 2 has a strong characteristic peak. Therefore, the area of the peak may be used to determine the content of crystalline form 2 in crystalline form 1. Crystalline forms 1 and 2 were passed through a 100 mesh screen to ensure that the samples had similar particle sizes. The samples were prepared by mixing an appropriate amount (weight percent) of the crystalline forms 1 and 2 as shown in Table 17. The detection was performed three times in parallel, and the average was taken as the peak intensity at 2θ of 10.1°.

TABLE-US-00017 TABLE 17 Peak area of the samples with different content (weight percent) of the crystalline form 2 in the crystalline form 1 at 2θ of 10.1° crystalline form 2% 0.96% 2.01% 3.89% 5.10% 10.41% 15.55% Area 3528 6648 16148 18025 35106 57326 3454 6517 15875 18135 35510 56696 3263 6794 16145 18333 35587 57621 Average area 3415 6653 16056 18164.3 35401 57214.3 Relative 3.27 1.7 0.8 0.7 0.6 0.67 standard deviation (%)

[0325] As shown in FIG. 52, the peak area at 2θ of 10.1° is linear with the weight percentage of the crystalline form 2 in the crystalline form 1, which indicates that when the content of the crystalline form 2 in the crystalline form 1 is from 0.96% to 15.55%, the content may be accurately determined by this method.

[0326] Samples containing 4.75 wt % and 6.36 wt % crystalline form 2 were prepared separately, and the peak area at 2θ of 10.1° thereof was determined. Also, the peak area was calculated by the linear relationship shown in FIG. 52. As shown below, the calculated value deviation is within 10% of the measured value.

TABLE-US-00018 TABLE 18 Crystalline form 2% 4.75% 6.36% Measured 15976 21546 15520 21238 15707 22177 Average area 15734.3 21653.7 Relative standard deviation (%) 1.19 1.8 Calculated value 17156 22961 Calculated value/measured value % 109.0 106.0

Effect Example 6: Solubility Determination

[0327] The solubility detection method was as follows: an appropriate amount of the sample was added into water to form a suspension, stirred at 25° C. in a water bath, and the solution was taken after 0.5 hour and 4 hours respectively for HPLC concentration detection.

[0328] HPLC detection was performed using the crystalline form 1 as a standard, with its concentration of 204.2 μg*mL.sup.−1 and its content set as 100%, and the detection was performed 7 times. The average peak area was 159.691 mAU*min (retention time was 7.4 min).

[0329] Analysis of results: The results of solubility detection of the crystalline forms were shown in Table 19 below. The results show that the solubility of crystalline form 1 is much higher than that of the most stable crystalline form 2.

TABLE-US-00019 TABLE 19 0.5 hours 4 hours concen- concen- peak area tration peak area tration crystalline form mAU*min ug*mL.sup.−1 mAU*min ug*mL.sup.−1 crystalline form 1 0.829 1.12 0.984 1.32 crystalline form 2 0.143 0.19 0.191 0.26 crystalline form 5 1.232 1.66 0.313 0.42 crystalline form 6 0.217 0.29 0.275 0.37 crystalline form 7 0.389 0.52 0.450 0.61 crystalline form 3 0.432 0.58 0.574 0.77

Effect Example 7: Moisture-Induced Crystallization Experiment of the Crystalline Form 1

[0330] About 10 mg of the crystalline form 1 was taken and placed in the corresponding environment, and the solid was detection by XRD at different time. The characterization results showed that only the known crystalline form 1 was detected in this experiment. The specific experiment details and results are shown in Table 20 below, which shows that the crystalline form 1 is stable under these conditions.

TABLE-US-00020 TABLE 20 Temperature- Result analysis relative humidity 1 day 5 days 10 days Room temperature- crystalline crystalline crystalline 58% RH form 1 form 1 form 1 Room temperature - crystalline crystalline crystalline 75% RH form 1 form 1 form 1 Room temperature - crystalline crystalline crystalline 97% RH form 1 form 1 form 1

Effect Example 8: Pharmacological Properties of the Crystalline Forms 1 and 2

[0331] The moisture content, solubility and dissolution rate of the crystalline forms 1 and 2 were detected using the methods described above. The results are shown in Table 21, which indicate that the solubility, dissolution, and moisture content (total pharmaceutical properties) of the crystalline form 1 are higher than that of the crystalline form 2. Moreover, the crystalline forms 1 and 2 have the highest solubility in methanol.

TABLE-US-00021 TABLE 21 Crystalline Crystalline Parameters form 2 form 1 Moisture RH 50% 0.064 2.015 absorption RH 80% 0.112 2.578 (%) Solubility aqueous solution with 0.0048-0.04 0.12-0.53 (μg/ml) pH of 1.0-7.5 acetonitrile 270 680 methanol 3500 8170 ethanol 1940 2460 PEG 400 2670 3660 glycerin 120 570 1% sodium lauryl sulfate 580 3480 2% sodium lauryl sulfate 950 3790 1% Tween 80 20 60 Internal dissolution rate mg/(min .Math. cm.sup.2) 0.0062 0.022 Solubility of artificial gastric juice 2.25 10.15 (4 hours) Solubility of artificial gastric juice 0.00 0.43 (4 hours)

Effect Example 9: Pharmacokinetic Experiment

[0332] Twelve Sprague Dawley rats with weight of 230-250 g were randomly divided into 2 groups, wherein each group consisted of 3 males and 3 females. Crystalline forms 1 and 2 were separately prepared as suspensions in 0.5% carboxymethylcellulose (CMC). The rats were fasted for 12 hours with free access to water and then orally administered at a dose of 10 mg/kg. Blood samples (0.2-0.3 ml) before and after 15, 30, 60, 120, 240, 360, 480, 720, 1440 minutes of the oral administration were collected in heparin anticoagulation tubes, which were then centrifuged to obtain plasma. The plasma was stored at −20° C., followed by analysis using API 4000 MS in conjunction with a HPLC unit. The pharmacokinetic parameters Cmax and AUC were calculated according to the determined plasma concentrations and summarized in Table 22. The results show that the crystalline form 1 has a Cmax of about 4 times higher than the crystalline form 2, and about 3 times more exposure (AUC) than the crystalline form 2.

TABLE-US-00022 TABLE 22 female 1 female 2 female 3 male 1 male 2 male 3 average value crystalline form 1 Cmax 593.9 2649.0 2033.3 716.6 1071.3 977.7 1340.3 (ng/ml) AUC(0-t) 3536.6 28571.4 16634.2 3180.0 6766.0 4241.5 10488.3 (ng .Math. hr/ml) crystalline form 2 Cmax 317.0 451.4 614.6 204.4 114.7 180.4 313.8 (ng/ml) AUC(0-t) 4344.4 3899.2 7850.6 1557.1 925.0 1349.3 3320.9 (ng .Math. hr/ml)

Effect Example 10: Tissue Accumulation Experiment of the Crystalline Form 1

[0333] Human colon cancer H-29 cells were implanted into the armpits of BALB/cA nude mice. Seven days after the implantation of H-29 cells, 8 female mice were administered with the crystalline form 1 (twice a day) at 40 mg/kg or sunitinib at 40 mg/kg (once a day). The drug administration was continuous for 21 days. Plasma, tissue and tumor samples were collected for analysis 4 hours after the administration on the 22nd day morning. The results were summarized in Table 23. The data shows that the tissue accumulation of crystalline form 1 in all tested tissues is significantly lower than that of sunitinib, while the content of crystalline form 1 in plasma was comparable to that of sunitinib.

TABLE-US-00023 TABLE 23 Samples Plasma Tumor Liver Kidney Heart Lung Muscle Brain crystalline form 1 191.6 153.4 1,715.3 418.3 124.8 144.9 77.6 9.3 Sunitinib 261.3 27,137.2 14,816.6 14,852.0 3,881.2 15,713.5 1,483.2 333.9

Effect Example 11: Grinding Stability Experiment of the Crystalline Form 1

[0334] Crystalline form 1 was ground and sieved. The US standard 200-300 mesh sieved samples were collected and XRD analyzed. Analysis conditions: Shimadzu XRD-6000, CuK source (1.54056 Å) 40 kV, 30 mA; detection angle: 5-50°, speed: 5°/min.

[0335] FIG. 53 shows that the XRD pattern substantially did not change before and after grinding, indicating that the crystalline form 1 remained stable during the grinding process.

Effect Example 12: Preparation of Capsules

[0336] 1) Weighing, Grinding and Sieving

[0337] About ¼ volume of crystalline form 1 was added to the mortar. The crystalline form 1 was ground with a muller to reduce the particle size, and sieved through 250 μm (#60) to the sieve collection tray. The ground and sieved crystalline form 1 was transferred into a container. The above steps were repeated until all the crystalline form 1 was ground and sieved. The total amount of crystalline form 1 that may be used to prepare the capsule was calculated.

[0338] The Pearlitol 200 SD was sieved through a 500 μm (#35) sieve and collected into a suitable container.

[0339] 2) Mixing

[0340] 830.3±0.1 g of the sieved Pearlitol in Container #1, 1417.5±0.1 g of sodium bicarbonate powder, 405.0±0.1 g of sodium lauryl sulfate and 405.0±0.1 g of croscarmellose sodium were transferred to a preparation container containing the crystalline form 1 (162.0±0.1 g). The container of the crystalline form 1 which was ground and sieved was dry-cleaned three times by the sieved Pearlitol (830.3±0.1 g) in Container #2, and the dry-cleaned product was transferred to the preparation container of the crystalline form 1. Subsequently, the remaining sieved Pearlitol was transferred to the preparation container of crystalline form 1.

[0341] 3) Blending

[0342] Turbula Type T10B Shaker Mixer and the preparation container of crystalline form 1 were installed according to the manufacturer's instructions. After blending in Turbula Type T10B Shaker Mixer for 10 minutes, the preparation of crystalline form 1 was sieved using a 500 μm sieve and the sieved materials were blended for 2 minutes. Three samples (900-2000 mg each) were taken from the top, middle and bottom of the crystalline form 1 preparation container to carry out the content uniformity test during the preparation.

[0343] 4) Capsule Filling

[0344] The average weight of the No. 0 Swedish Orange Opaque Coni-Snap Capsule was determined. Weight limits of acceptable capsule fill were calculated. Two Profill manual capsule fillers were prepared for filling. The amount of preparation required for 100 capsules per plate was 51.0 g (2% excess per plate). The preparation required for each filling tray (51.0±0.1 g) was weighed and filled into the capsule evenly. The Profill was tapped to fill all of the preparations into the capsules completely and evenly, and then adjusted to seal the capsules. The capsule cap was placed back over the capsule body filled with the preparation and pressed to secure the closure. The step can be repeated, if necessary, to ensure that all capsule caps are placed over the capsule body. The capsules were visually inspected and all capsules with physical defects (i.e., the capsule cap was broken) were removed. A weight check was performed on each capsule. The above steps were repeated until all available preparations were filled into the capsule. All acceptable capsules were dusted.

Effect Example 13: Preparation of Tablets

[0345] 1) The formulation is shown in the following table:

TABLE-US-00024 TABLE 24 100 mg 50 mg Intensity tablet Intensity tablet Component (kg/batch) (kg/batch) Batch (number of tablets) 65,000 pills 40,000 pills Crystalline form 1 6.5754.sup.1 2.0232.sup.1 Mannitol, USP 13.0000 9.0112 Microcrystalline cellulose 13.0000 9.0112 Sodium bicarbonate powder, USP 11.7000 7.2000 Anhydrous citric, BP, Ph Eur, USP 4.4590 2.7440 Croscarmellose Sodium, NF 4.7450 2.9200 Sodium lauryl sulfate, NF 3.2500 2.0000 Crospovidone, USP 2.8600 1.7600 Fumed silica 1.8525 1.1400 Sodium stearyl fumarate, NF 0.3088 0.1900 Purified water .sup.2 QS (sufficient QS quantity) Total amount (core) 61.7507 37.9996 Opadry II Orange 1.8525 1.1400 Total amount (coated tablets) 63.6032 39.1396 .sup.1The unit content of the active pharmaceutical ingredient (API) crystalline form 1 has been adjusted for impurities and moisture content. .sup.2 Removed during processing

[0346] The manufacturing process of the tablet is as follows:

[0347] 1) API Grinding/Sieving

[0348] Crystalline form 1 was ground and sieved twice using a Comil sieve equipped with a 459 μm screen.

[0349] 2) Excipient Grinding/Sieving

[0350] All excipients were mixed in a V-type blender for 5 minutes, sieved through a Comil screen, and removed agglomeration once through a 1 mm screen.

[0351] 3) Blending

[0352] The ground and sieved material was transferred to a V-type blender and blended under dry conditions for 45 minutes.

[0353] 4) Tableting

[0354] The blended final product was pressed into an oval (100 mg) or round (50 mg) core on a high-speed rotary tablet press. The weight, thickness and hardness of the tablet during the process were detected, followed by dusting, polishing and metal detection.

[0355] 5) Coating

[0356] The core was coated with a film in a rotary disc coater and dried. Unqualified tablets were separated and removed. The tablets that meet the requirements were visually inspected for defects and could be tested for quality.

[0357] The loose pieces were placed in a container lined with a double polyethylene bag and a desiccant and stored until the packaging process.

[0358] 6) Final Packaging

[0359] The tablets were packaged in high density polyethylene (HDPE) bottles that were sealed using an inductively sealed polypropylene lid.

[0360] The product is stored at a controlled room temperature until the labeling process.

[0361] 7) The products were labelled in the labeling and logistics center.

[0362] The exemplary embodiments of the present invention have been described above. However, the technical solution of the present invention is not limited thereto. Those skilled in the art will appreciate that any modifications, equivalent substitutions, improvements, etc., which are within the spirit and scope of the invention, are intended to be included within the scope of the invention.