Polymorphs of a compound, processes for their preparation and uses thereof

Abstract

The application discloses a polymorph of a compound, a preparation method and application thereof. The crystal form III of compound A has characteristic peaks of X-ray powder diffraction expressed by 2θ angles at 12.15±0.20°, 15.98±0.20°, 16.62±0.20°, 17.14±0.20°, 24.32±0.20° and 26.08±0.20° using Cu-Kα radiation. The crystal form VII of compound A has characteristic peaks of X-ray powder diffraction expressed by 2θ angles at 12.94±0.20°, 14.41±0.20°, 15.64±0.20°, 17.25±0.20°, 21.75±0.20° and 24.23±0.20° using Cu-Kα radiation. The polymorph prepared by the application has good stability and can be stored stably under the condition of high temperature and low relative humidity.

Description

[0001] This application claims priority to an earlier application filed on March 19, 2021, with the China National Intellectual Property Administration, patent application number 202110297078.4, entitled "A Polymorph of a Compound and its Preparation Method and Application". The entire contents of the earlier application are incorporated herein by reference. Technical Field

[0002] This invention belongs to the field of pharmaceutical crystal forms, and relates to a polymorph of a compound, its preparation method and application, specifically to the polymorph of 2-((2-(trans-4-hydroxy-cis-4-methylcyclohexyl)-6-methoxy-2H-indazole-5-yl)carbamoyl)-6-methylpyridine 1-oxide, as well as the preparation method and application of the polymorph. Background Technology

[0003] Interleukin-1 receptor-associated kinases (IRAKs) are a family of serine / threonine protein kinases found within cells. Four members are IRAK1, IRAK2, IRAK-M, and IRAK4, all characterized by a typical N-terminal death domain. This domain mediates interactions between MyD88-family adaptors and the central kinase domain. IRAK1 and IRAK4 possess kinase activity. IRAK4 is a key downstream factor in the Toll-like receptor (TLR) / interleukin-1 receptor (IL-1R)-mediated inflammatory signaling pathway. The extracellular portion of the TLR recognizes pathogen-specific molecules (such as lipopolysaccharides, peptides, and viral DNA). After ligand binding, the intracellular portion recruits MyD88 and other molecules to form a complex, activating IRAK1 autophosphorylation. This, in turn, activates the downstream serine / threonine kinase TAK1, activating the NF-κB and MAPK signaling pathways. Subsequently, pro-inflammatory cytokines, chemokines, and destructive enzymes are produced, ultimately leading to an inflammatory response and mediating innate immunity. IL-1R is involved in host defense and hematopoiesis, and serves as a bridge between innate and adaptive immunity. (Flannery, et al. Biochem. Pharmacol., 2010, 80(12): 1981-1991).

[0004] Studies have shown that overactivation of the IRAK4-dependent TLR / IL-1R signaling pathway is closely related to the development of rheumatoid arthritis. In addition, many other studies have also confirmed that IRAK4 enzyme activation is closely related to the development of the following diseases, such as tumors, gout, systemic lupus erythematosus, multiple sclerosis, metabolic syndrome, atherosclerosis, myocardial infarction, sepsis, inflammatory bowel disease, asthma and allergies (Chaudhary D, et al., J. Med. Chem. 2015, 58(1): 96-110).

[0005] Currently, the applicant's patent application PCT / CN2020 / 117093 (priority CN201910906833.7) discloses a new compound that can be effectively used to prepare a drug for treating the aforementioned IRAK-mediated and / or interleukin-1 receptor-related diseases, especially for treating and / or preventing the aforementioned IRAK-mediated and / or interleukin-1 receptor-related diseases. How to develop drug crystal forms that are more suitable for drug preparation, especially crystal forms that improve stability, hygroscopicity, and / or efficacy, so as to achieve good results in the drug manufacturing and administration stages, has become an urgent technical problem to be solved. Summary of the Invention

[0006] To address the aforementioned problems in the prior art, the present invention provides a polymorph of 2-((2-(trans-4-hydroxy-cis-4-methylcyclohexyl)-6-methoxy-2H-indazol-5-yl)carbamoyl)-6-methylpyridine 1-oxide as shown in the following formula:

[0007]

[0008] The present invention provides crystal form I of compound A, wherein crystal form I has characteristic peaks in X-ray powder diffraction at 11.85±0.20°, 15.86±0.20°, 16.57±0.20°, 17.68±0.20°, 20.99±0.20°, and 23.99±0.20° when irradiated with Cu-Kα radiation and expressed in 2θ angles.

[0009] According to an embodiment of the present invention, crystal form I is an anhydrous form of compound A.

[0010] Preferably, the crystal form I is subjected to Cu-Kα radiation, and the X-ray powder diffraction, expressed in 2θ angles, has characteristic peaks at 6.02±0.20°, 11.85±0.20°, 15.86±0.20°, 16.26±0.20°, 16.57±0.20°, 17.68±0.20°, 20.99±0.20°, and 23.99±0.20°.

[0011] Preferably, the crystal form I, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at 6.02±0.20°, 11.85±0.20°, 15.86±0.20°, 16.26±0.20°, 16.57±0.20°, 17.40±0.20°, 17.68±0.20°, 18.33±0.20°, 20.99±0.20°, 23.99±0.20°, and 27.76±0.20°, as shown in Table 1, with an error range of ±0.20°.

[0012] Table 1. XRPD analysis data for crystal form I.

[0013]

[0014]

[0015] Preferably, the crystal form I has essentially the following characteristics: Figure 1 The powder X-ray diffraction pattern shown.

[0016] According to an embodiment of the present invention, differential scanning calorimetry (DSC) analysis of crystal form I shows that the first endothermic peak appears when heated to a peak temperature of 190.70°C.

[0017] According to an embodiment of the present invention, thermogravimetric analysis (TGA) of the crystal form I shows a weight loss of about 1.2% in the range of 140 to 200°C.

[0018] Preferably, the crystal form I has essentially the following characteristics: Figure 3 The DSC-TGA spectrum shown.

[0019] According to an embodiment of the present invention, crystal form I is an irregularly shaped crystal. Preferably, the grain size of crystal form I does not exceed 20 μm. Preferably, crystal form I has a substantially [structure described in the original text]. Figure 2 The PLM diagram shown.

[0020] According to an embodiment of the present invention, the purity of crystal form I is 95% or higher, preferably 99% or higher.

[0021] The present invention also provides a crystal form II of compound A, wherein the crystal form II exhibits characteristic peaks in X-ray powder diffraction at 13.49±0.20°, 17.51±0.20°, 17.72±0.20°, 20.97±0.20°, 23.67±0.20°, and 27.32±0.20° when irradiated by Cu-Kα radiation and expressed in 2θ angles.

[0022] According to an embodiment of the present invention, the crystal form II is a toluene solvate of compound A.

[0023] Preferably, the crystal form II is irradiated using Cu-Kα radiation, and the X-ray powder diffraction, expressed in 2θ angles, has characteristic peaks at 13.49±0.20°, 14.03±0.20°, 17.16±0.20°, 17.51±0.20°, 17.72±0.20°, 20.97±0.20°, 23.67±0.20°, and 27.32±0.20°.

[0024] Preferably, the crystal form II is subjected to Cu-Kα radiation, and the X-ray powder diffraction, expressed in 2θ angles, has characteristic peaks at 13.49±0.20°, 14.03±0.20°, 17.16±0.20°, 17.51±0.20°, 17.72±0.20°, 19.58±0.20°, 19.76±0.20°, 20.36±0.20°, 20.97±0.20°, 23.67±0.20°, and 27.32±0.20°.

[0025] Preferably, the crystal form II is subjected to Cu-Kα radiation, and the X-ray powder diffraction, expressed in 2θ angles, is shown in Table 2, with an error range of ±0.20°:

[0026] Table 2 XRPD analysis data for crystal form II

[0027]

[0028]

[0029] Preferably, the crystal form II has essentially the following characteristics: Figure 4 The powder X-ray diffraction pattern shown.

[0030] According to an embodiment of the present invention, differential scanning calorimetry (DSC) analysis of the crystal form II shows a first endothermic peak near the peak temperature of 136.92°C and a second endothermic peak near the peak temperature of 189.27°C.

[0031] According to an embodiment of the invention, thermogravimetric analysis (TGA) of the crystal form II shows a weight loss of about 9.6% between 100 and 160°C.

[0032] Preferably, the crystal form II has essentially the following characteristics: Figure 7 The DSC-TGA spectrum shown.

[0033] According to an embodiment of the present invention, crystal form II is an irregularly shaped crystal. Preferably, the grain size of crystal form II is less than 10 μm. Preferably, crystal form II has a substantially [structure described in the original text]. Figure 5 The PLM diagram shown.

[0034] According to an embodiment of the present invention, the purity of crystal form II is 95% or higher, preferably 99% or higher.

[0035] The present invention also provides a crystal form III of compound A, wherein the crystal form III exhibits characteristic peaks in X-ray powder diffraction at 12.15±0.20°, 15.98±0.20°, 16.62±0.20°, 17.14±0.20°, 24.32±0.20°, and 26.08±0.20° when irradiated with Cu-Kα radiation and expressed in 2θ angles.

[0036] According to an embodiment of the present invention, crystal form III is an anhydrous form of compound A.

[0037] Preferably, the crystal form III is irradiated using Cu-Kα radiation, and the X-ray powder diffraction, expressed in 2θ angles, has characteristic peaks at 12.15±0.20°, 15.04±0.20°, 15.98±0.20°, 16.62±0.20°, 17.14±0.20°, 21.09±0.20°, 24.32±0.20°, and 26.08±0.20°.

[0038] Preferably, the crystal form III is irradiated using Cu-Kα radiation, and the X-ray powder diffraction, expressed in 2θ angles, has characteristic peaks at 12.15±0.20°, 15.04±0.20°, 15.98±0.20°, 16.62±0.20°, 17.14±0.20°, 18.74±0.20°, 21.09±0.20°, 23.51±0.20°, 24.32±0.20°, and 26.08±0.20°.

[0039] Preferably, the crystal form III is obtained using Cu-Kα radiation, and the X-ray powder diffraction, expressed in 2θ angles, is shown in Table 3, with an error range of ±0.20°:

[0040] Table 3 XRPD analysis data for crystal form III

[0041]

[0042]

[0043] Preferably, the crystal form III has essentially the following characteristics: Figure 4 The powder X-ray diffraction pattern shown.

[0044] According to an embodiment of the present invention, differential scanning calorimetry (DSC) analysis of the crystal form III shows the appearance of the first endothermic peak near the peak temperature of 188.81°C after heating.

[0045] According to an embodiment of the invention, thermogravimetric analysis (TGA) of the crystal form III shows almost no weight loss before 180°C.

[0046] Preferably, the crystal form III has essentially the following characteristics: Figure 8 The DSC-TGA spectrum shown.

[0047] According to an embodiment of the present invention, crystal form III is an irregularly shaped crystal. Preferably, the grain size of crystal form III is less than 5 μm. Preferably, crystal form III has a substantially [structure described in the original text]. Figure 6 The PLM diagram shown.

[0048] According to an embodiment of the present invention, the purity of crystal form III is 95% or higher, preferably 99% or higher.

[0049] The present invention also provides crystal form IV of compound A, wherein crystal form IV exhibits characteristic peaks in X-ray powder diffraction at 5.38±0.20°, 6.68±0.20°, 9.76±0.20°, 19.69±0.20°, 27.48±0.20°, and 29.65±0.20° when irradiated with Cu-Kα radiation and expressed in 2θ angles.

[0050] According to an embodiment of the present invention, crystal form IV is a hydrate of compound A. Preferably, crystal form IV is a monohydrate of compound A. Preferably, the water content of crystal form IV is 4.2 wt%.

[0051] Preferably, the crystal form IV is irradiated using Cu-Kα radiation, and the X-ray powder diffraction, expressed in 2θ angles, has characteristic peaks at 5.38±0.20°, 6.68±0.20°, 9.76±0.20°, 19.69±0.20°, 20.13±0.20°, 25.53±0.20°, 27.48±0.20°, 27.81±0.20°, and 29.65±0.20°.

[0052] Preferably, the crystal form IV is obtained using Cu-Kα radiation, and the X-ray powder diffraction, expressed in 2θ angles, is shown in Table 4, with an error range of ±0.20°.

[0053] Table 4. XRPD analysis data for crystal form IV

[0054] 1 4.584 1.3 24 23.916 4.5 2 5.377 69.2 25 24.677 2.8 3 6.677 28.9 26 25.529 10.8 4 9.762 27.6 27 25.952 8.1 5 10.024 52 28 26.426 0.7 6 10.736 7.8 29 26.959 3 7 12.442 2.7 30 27.163 4.4 8 13.425 3.2 31 27.476 11.6 9 13.753 6.4 32 27.815 10.6 10 14.818 100 33 28.633 2 11 15.355 5.1 34 29.655 12.4 12 16.183 7.9 35 31.032 5.6 13 16.604 9.3 36 31.776 1.2 14 16.881 2.9 37 32.752 1.1 15 17.494 2.9 38 33.988 0.7 16 18.638 7.7 39 35.007 2.8 17 19.689 63.4 40 35.351 2 18 20.134 11 41 36.377 2.2 19 20.519 0.9 42 37.479 3 20 21.414 3 43 38.361 2.2 21 21.672 2.9 44 38.465 2.2 22 22.957 7.2 45 39.566 2.1 23 23.372 3.7

[0055] Preferably, the crystal form IV has essentially the following characteristics: Figure 11 The powder X-ray diffraction pattern shown.

[0056] According to an embodiment of the present invention, differential scanning calorimetry (DSC) analysis of crystal form IV shows a first endothermic peak near the peak temperature of 77.01°C, a second endothermic peak near the peak temperature of 190.76°C, a third endothermic peak near the peak temperature of 201.77°C, a fourth endothermic peak near the peak temperature of 215.93°C, and a fifth endothermic peak near the peak temperature of 218.05°C. Crystal form IV may undergo crystal transformation during the heating process.

[0057] According to an embodiment of the invention, thermogravimetric analysis (TGA) of the crystal form IV shows a weight loss of approximately 16.9% between room temperature and 150°C.

[0058] Preferably, the crystal form IV has essentially the following characteristics: Figure 13 The DSC-TGA spectrum shown.

[0059] According to an embodiment of the present invention, crystal form IV is an irregularly shaped crystal. Preferably, the grain size of crystal form IV is less than 10 μm. Preferably, crystal form IV has a substantially [structure described in the original text]. Figure 12 The PLM diagram shown.

[0060] According to an embodiment of the present invention, the purity of the crystal form IV is 95% or higher, preferably 99% or higher.

[0061] The present invention also provides a crystal form V of compound A, wherein the crystal form V exhibits characteristic peaks in X-ray powder diffraction at 7.11±0.20°, 9.62±0.20°, 14.07±0.20°, 19.23±0.20°, 21.59±0.20°, and 25.65±0.20° when irradiated with Cu-Kα radiation and expressed in 2θ angles.

[0062] According to an embodiment of the present invention, the crystal form V is an acetonitrile solvate of compound A.

[0063] Preferably, the crystal form V, when irradiated with Cu-Kα, exhibits characteristic peaks in X-ray powder diffraction at 7.11±0.20°, 9.62±0.20°, 11.23±0.20°, 14.07±0.20°, 19.23±0.20°, 21.59±0.20°, 22.98±0.20°, and 25.65±0.20° in 2θ angles.

[0064] Preferably, the crystal form V, when irradiated with Cu-Kα, exhibits characteristic peaks in X-ray powder diffraction at 7.11±0.20°, 9.62±0.20°, 11.23±0.20°, 14.07±0.20°, 19.23±0.20°, 21.59±0.20°, 22.05±0.20°, 22.98±0.20°, and 25.65±0.20°.

[0065] Preferably, the crystal form V is subjected to Cu-Kα radiation, and the X-ray powder diffraction, expressed in 2θ angles, is shown in Table 5, with an error range of ±0.20°.

[0066] Table 5. XRPD analysis data for crystal form V.

[0067] 1 5.547 0.6 15 25.649 18.5 2 7.11 98 16 26.371 1.5 3 8.514 4.2 17 27.582 1.6 4 9.617 26.1 18 28.447 2.3 5 11.234 16.2 19 29.246 1.5 6 12.556 0.3 20 30.219 2.6 7 14.069 43.3 21 32.477 4.1 8 16.038 100 22 33.462 0.9 9 17.587 1.1 23 34.307 0.6 10 19.229 16.9 24 36.429 3.7 11 21.592 26 25 37.624 1.2 12 22.051 5.8 26 38.187 0.5 13 22.985 8.1 27 39.331 3.7 14 23.602 2.1 28 39.632 3.4

[0068] Preferably, the crystal form V has essentially the following characteristics: Figure 14 The powder X-ray diffraction pattern shown.

[0069] According to an embodiment of the present invention, differential scanning calorimetry (DSC) analysis of crystal form V shows a first endothermic peak near the peak temperature of 135.05°C, a second endothermic peak near the peak temperature of 192.24°C, and a third endothermic peak near the peak temperature of 218.33°C. Crystal form V may undergo crystal transformation during the heating process.

[0070] According to an embodiment of the invention, thermogravimetric analysis (TGA) of the crystal form V shows a weight loss of about 6.4% between 70 and 150°C.

[0071] Preferably, the crystal form V has essentially the following characteristics: Figure 16 The DSC-TGA spectrum shown.

[0072] According to an embodiment of the present invention, crystal form V is an irregularly shaped crystal. Preferably, the grain size of crystal form V is less than 10 μm. Preferably, crystal form V has a substantially [structure described in the original text]. Figure 15 The PLM diagram shown.

[0073] According to an embodiment of the present invention, the purity of the crystal form V is 95% or higher, preferably 99% or higher.

[0074] The present invention also provides a crystal form IX of compound A, wherein the crystal form IX exhibits characteristic peaks in X-ray powder diffraction at 8.26±0.20°, 9.33±0.20°, 11.07±0.20°, 16.81±0.20°, 20.73±0.20°, and 21.01±0.20° when irradiated by Cu-Kα radiation and expressed in 2θ angles.

[0075] Preferably, the crystal form IX is subjected to Cu-Kα radiation, and the X-ray powder diffraction, expressed in 2θ angles, has characteristic peaks at 8.26±0.20°, 9.33±0.20°, 11.07±0.20°, 16.81±0.20°, 20.73±0.20°, 21.01±0.20°, 23.27±0.20°, and 26.87±0.20°.

[0076] Preferably, the crystal form IX is subjected to Cu-Kα radiation, and the X-ray powder diffraction, expressed in 2θ angles, has characteristic peaks at 8.26±0.20°, 9.33±0.20°, 11.07±0.20°, 16.81±0.20°, 20.73±0.20°, 21.01±0.20°, 23.27±0.20°, 24.76±0.20°, 25.09±0.20°, 26.87±0.20°, 29.17±0.20°, and 29.42±0.20°.

[0077] Preferably, the crystal form IX is subjected to Cu-Kα radiation, and the X-ray powder diffraction, expressed in 2θ angles, is shown in Table 6, with an error range of ±0.20°:

[0078] Table 6 XRPD analysis data for crystal form IX

[0079] 1 5.482 1 19 23.641 11.6 2 8.265 43.8 20 24.757 12.5 3 9.329 35.9 21 25.086 12.2 4 10.524 9.6 22 25.769 0.2 5 11.075 14.4 23 26.097 7.5 6 12.953 100 24 26.871 12.8 7 14.686 3.5 25 27.419 0.3 8 16.814 95.7 26 27.75 1 9 17.666 5.7 27 28.183 3.2 10 18.296 1 28 29.169 10.6 11 18.795 8.7 29 29.417 10.7 12 19.423 1.2 30 30.784 1.1 13 19.834 1 31 31.532 0.3 14 20.726 16.7 32 33.448 2.5 15 21.015 24.7 33 33.711 4.5 16 22.051 2 34 35.81 1.3 17 22.471 7.5 35 37.164 1 18 23.274 13.5 36 38.175 1.4

[0080] Preferably, the crystal form IX has a substantially similar shape to... Figure 17 The powder X-ray diffraction pattern shown.

[0081] According to an embodiment of the present invention, the crystal form IX is an anhydrous form of compound A.

[0082] According to an embodiment of the present invention, differential scanning calorimetry (DSC) analysis of crystal form IX shows a first endothermic peak near the peak temperature of 192.04°C, a second endothermic peak near the peak temperature of 201.20°C, and a third endothermic peak near the peak temperature of 217.55°C. Crystal form IX may undergo crystal transformation during the heating process.

[0083] According to an embodiment of the present invention, thermogravimetric analysis (TGA) of the crystal form IX shows almost no weight loss before 180°C.

[0084] Preferably, the crystal form IX has a substantially similar shape to... Figure 19 The DSC-TGA spectrum shown.

[0085] According to an embodiment of the present invention, crystal form IX is an irregularly shaped crystal. Preferably, the grain size of crystal form IX is less than 5 μm. Preferably, crystal form IX has a substantially [structure described in the original text]. Figure 18 The PLM diagram shown.

[0086] According to an embodiment of the present invention, the purity of the crystal form IX is 95% or higher, preferably 99% or higher.

[0087] The present invention also provides a crystal form VI of compound A, wherein crystal form VI exhibits characteristic peaks in X-ray powder diffraction at 5.23±0.20°, 5.63±0.20°, 6.90±0.20°, 13.77±0.20°, 18.14±0.20°, and 25.85±0.20° when irradiated with Cu-Kα, in terms of 2θ angles, at 5.23±0.20°, 5.63±0.20°, 6.90±0.20°, 13.77±0.20°, 16.26±0.20°, 18.14±0.20°, 18.37±0.20°, and 25.85±0.20°.

[0088] Preferably, the crystal form VI is subjected to Cu-Kα radiation, and the X-ray powder diffraction, expressed in 2θ angles, has characteristic peaks at 5.23±0.20°, 5.63±0.20°, 6.90±0.20°, 8.08±0.20°, 13.77±0.20°, 15.78±0.20°, 16.26±0.20°, 18.14±0.20°, 18.37±0.20°, 20.87±0.20°, 25.40±0.20°, and 25.85±0.20°.

[0089] Preferably, the crystal form VI is subjected to Cu-Kα radiation, and the X-ray powder diffraction, expressed in 2θ angles, is shown in Table 7, with an error range of ±0.20°:

[0090] Table 7 XRPD analysis data for crystal form VI

[0091] 1 3.475 0.9 20 18.375 20.1 2 4.537 3.4 21 18.785 0.8 3 5.232 39.2 22 19.493 0.7 4 5.627 31.6 23 20.247 0.5 5 6.898 44.5 24 20.871 14.2 6 8.081 12.9 25 21.406 0.8 7 9.013 7.1 26 22.186 1.5 8 10.354 100 27 22.458 2.4 9 11.325 2.2 28 22.913 1.3 10 12.43 2.2 29 23.233 2 11 13.164 4.3 30 23.826 0.6 12 13.767 20.6 31 24.546 1.3 13 14.926 0.8 32 25.401 10.1 14 15.775 12.5 33 25.848 20.9 15 16.262 19.2 34 26.306 9.3 16 16.906 0.3 35 28.947 1.1 17 17.273 3 36 29.64 1.2 18 17.746 2.2 37 31.611 1 19 18.139 20.9

[0092] Preferably, the crystal form VI has a substantially as follows Figure 20 The powder X-ray diffraction pattern shown.

[0093] According to an embodiment of the present invention, the crystal form VI is a methanol / hydrate of compound A.

[0094] According to an embodiment of the present invention, differential scanning calorimetry (DSC) analysis of the crystal form VI shows an endothermic peak appearing near the peak temperature of 201.31°C after heating.

[0095] According to an embodiment of the invention, thermogravimetric analysis (TGA) of the crystal form VI shows a weight loss of approximately 9.5% between room temperature and 130°C.

[0096] Preferably, the crystal form VI has a substantially as follows Figure 22 The DSC-TGA spectrum shown.

[0097] According to an embodiment of the present invention, crystal form VI is an irregularly shaped crystal. Preferably, the grain size of crystal form VI is less than 5 μm. Preferably, crystal form VI has a substantially [structure described in the original text]. Figure 21 The PLM diagram shown.

[0098] According to an embodiment of the present invention, the purity of the crystal form VI is 95% or higher, preferably 99% or higher.

[0099] The present invention also provides a crystal form VII of compound A, wherein the crystal form VII exhibits characteristic peaks in X-ray powder diffraction at 12.94±0.20°, 14.41±0.20°, 15.64±0.20°, 17.25±0.20°, 21.75±0.20°, and 24.23±0.20° when irradiated with Cu-Kα radiation and expressed in 2θ angles.

[0100] According to an embodiment of the present invention, the crystal form VII is an anhydrous form of compound A.

[0101] Preferably, the crystal form VII is irradiated with Cu-Kα radiation, and the X-ray powder diffraction, expressed in 2θ angles, has characteristic peaks at 12.94±0.20°, 13.18±0.20°, 14.41±0.20°, 15.64±0.20°, 17.25±0.20°, 21.75±0.20°, 22.54±0.20°, and 24.23±0.20°.

[0102] Preferably, the crystal form VII is irradiated using Cu-Kα radiation, and the X-ray powder diffraction, expressed in 2θ angles, has characteristic peaks at 12.94±0.20°, 13.18±0.20°, 14.41±0.20°, 15.64±0.20°, 17.25±0.20°, 21.11±0.20°, 21.75±0.20°, 22.54±0.20°, 24.23±0.20°, 26.62±0.20°, and 31.64±0.20°.

[0103] Preferably, the crystal form VII is obtained using Cu-Kα radiation, and the X-ray powder diffraction, expressed in 2θ angles, is shown in Table 8, with an error range of ±0.20°.

[0104] Table 8 XRPD analysis data for crystal form VII

[0105] 1 6.413 8 25 25.82 1.7 2 10.957 1.1 26 26.135 6.1 3 11.625 3.1 27 26.385 3 4 12.939 25.9 28 26.621 10.5 5 13.176 12.7 29 27.328 0.2 6 13.451 5.9 30 27.618 9.2 7 14.409 16.3 31 28.436 2 8 14.567 9.9 32 28.724 4.6 9 15.644 41.4 33 29.431 1.4 10 17.246 18.2 34 29.825 5.9 11 17.522 6.2 35 30.35 4.9 12 17.655 4.4 36 30.624 0.8 13 18.783 1.4 37 31.637 11.1 14 19.255 100 38 32.123 2.6 15 19.732 3.4 39 32.856 1.5 16 19.94 5.1 40 33.763 3.9 17 21.106 10.3 41 34.092 1.4 18 21.75 41 42 34.973 4.4 19 22.001 3.4 43 35.367 2.8 20 22.539 12.6 44 35.841 2.9 21 24.231 18 45 37.7 1.2 22 24.704 0.7 46 38.242 1.6 23 25.058 3.6 47 39.185 2.1 24 25.308 7 48 39.307 2.1

[0106] Preferably, the crystal form VII has essentially the following characteristics: Figure 23 The powder X-ray diffraction pattern shown.

[0107] According to an embodiment of the present invention, differential scanning calorimetry (DSC) analysis of the crystal form VII shows an endothermic peak appearing near the peak temperature of 201.07°C after heating.

[0108] According to an embodiment of the invention, thermogravimetric analysis (TGA) of the crystal form VII shows almost no weight loss before 200°C, for example, almost no weight loss before 180°C.

[0109] Preferably, the crystal form VII has essentially the following characteristics: Figure 25 The DSC-TGA spectrum shown.

[0110] According to an embodiment of the present invention, crystal form VII is an irregularly shaped crystal. Preferably, the grain size of crystal form VII is less than 5 μm. Preferably, crystal form VII has a substantially [structure described in the original text]. Figure 24 The PLM diagram shown.

[0111] According to an embodiment of the present invention, the purity of crystal form VII is 95% or higher, preferably 99% or higher.

[0112] The present invention also provides a method for preparing polymorphs of compound A.

[0113] According to an embodiment of the present invention, a method for preparing crystal form I includes the following steps:

[0114] Compound A was mixed with a first alcohol solvent and an ether solvent, heated and stirred until dissolved, cooled, filtered and dried to obtain the crystal form I.

[0115] According to an embodiment of the present invention, the first alcohol solvent may be selected from ethanol and / or isopropanol, preferably ethanol.

[0116] According to an embodiment of the present invention, the ether solvent may be selected from methyl tert-butyl ether and / or n-heptane, preferably methyl tert-butyl ether.

[0117] According to an embodiment of the present invention, the mass-volume ratio of compound A, the first alcohol solvent, and the ether solvent is 1g:(10-20)mL:(3-8)mL, preferably 1g:(12-18)mL:(4-6)mL, and exemplaryly 1g:15mL:5mL.

[0118] According to an embodiment of the present invention, the heating temperature is 50-70°C, preferably 55-65°C, and exemplarily 50°C.

[0119] According to an embodiment of the present invention, the heating and stirring time is 1-5 hours, preferably 2-4 hours, and exemplarily 3 hours.

[0120] According to an embodiment of the present invention, the material is filtered after being cooled to 0-10°C.

[0121] According to an exemplary embodiment of the present invention, the preparation method of the crystal form I includes the following steps: adding compound A to a mixed solvent of ethanol and methyl tert-butyl ether, heating and stirring, cooling and filtering, and vacuum drying to obtain the crystal form I;

[0122] The mass-to-volume ratio of compound A, ethanol, and methyl tert-butyl ether is 1 g:(10-20) mL:(3-8) mL.

[0123] The present invention also provides another method for preparing the crystal form I, comprising the following steps: heating the crystal form IV to obtain the crystal form I.

[0124] According to an embodiment of the present invention, the heating temperature is sufficient to completely remove the solvent from crystal form IV. Preferably, the solvent in crystal form IV is water. Preferably, the heating temperature is 100°C.

[0125] The present invention also provides a method for preparing the above-mentioned crystal form II, comprising the following steps:

[0126] Compound A was mixed with an aromatic solvent and stirred at room temperature until the solution was clear. The mixture was then filtered to obtain the crystal form II.

[0127] According to an embodiment of the present invention, the aromatic solvent is selected from toluene.

[0128] According to an embodiment of the present invention, the mass-to-volume ratio of compound A to aromatic solvent is 1g:(10-20)mL, preferably 1g:(12-18)mL, and exemplarily 1g:15mL.

[0129] According to an embodiment of the present invention, the ambient temperature refers to 15-30°C, preferably 20-25°C.

[0130] According to an embodiment of the present invention, the stirring time at room temperature is 1-5 hours, for example, 3 hours.

[0131] According to an exemplary embodiment of the present invention, the method for preparing crystal form II includes the following steps:

[0132] Compound A was mixed with toluene and stirred at room temperature until dissolved. The mixture was then filtered to obtain the crystal form II.

[0133] The mass-to-volume ratio of compound A to the aromatic solvent is 1 g:(10-20) mL.

[0134] The present invention also provides a method for preparing the above-mentioned crystal form III, comprising the following steps: heating the crystal form II to obtain the crystal form III.

[0135] According to an embodiment of the present invention, the heating temperature is such that the aromatic solvent in crystal form II is completely removed. For example, the heating temperature is 100-160°C.

[0136] This invention also provides a method for preparing the above-mentioned crystal form IV, comprising the following steps:

[0137] Compound A was mixed with a second alcohol solvent and water, stirred at room temperature until dissolved, filtered, and dried to obtain the crystal form IV.

[0138] According to an embodiment of the present invention, the second alcohol solvent is selected from isopropanol.

[0139] According to an embodiment of the present invention, the mass-volume ratio of compound A, the second alcohol solvent and water is 1g:(1-10)mL:(1-10)mL, preferably 1g:(3-8)mL:(3-8)mL, and exemplaryly 1g:5mL:5mL.

[0140] According to an embodiment of the present invention, the ambient temperature refers to 15-30°C, preferably 20-25°C.

[0141] According to an embodiment of the present invention, the stirring time at room temperature is 1-5 hours, for example 3 hours.

[0142] According to an exemplary embodiment of the present invention, the method for preparing crystal form IV includes the following steps:

[0143] Compound A was mixed with isopropanol and water, stirred at room temperature until dissolved, filtered, and dried under vacuum to obtain the crystal form IV.

[0144] The mass-to-volume ratio of compound A, isopropanol, and water is 1 g: 5 mL: 5 mL.

[0145] The present invention also provides a method for preparing the above-mentioned crystal form V, comprising the following steps:

[0146] Compound A was mixed with a nitrile solvent, stirred at room temperature until dissolved, filtered, and dried to obtain the crystal form V.

[0147] According to an embodiment of the present invention, the nitrile solvent is selected from acetonitrile.

[0148] According to an embodiment of the present invention, the mass-to-volume ratio of compound A to nitrile solvent is 1g:(5-15)mL, preferably 1g:(8-12)mL, and exemplarily 1g:10mL.

[0149] According to an embodiment of the present invention, the ambient temperature refers to 15-30°C, preferably 20-25°C.

[0150] According to an embodiment of the present invention, the stirring time at room temperature is 1-5 hours, for example 3 hours.

[0151] According to an embodiment of the present invention, the method for preparing crystal form V includes the following steps:

[0152] Compound A was mixed with acetonitrile at a mass-to-volume ratio of 1 g:(5-15) mL, stirred at room temperature until dissolved, filtered, and dried under vacuum to obtain the crystal form V.

[0153] The present invention also provides a method for preparing the above-mentioned crystal form VI, comprising the following steps:

[0154] Compound A was mixed with a third alcohol solvent, stirred at room temperature until dissolved, filtered, and dried to obtain the crystal form VI.

[0155] According to an embodiment of the present invention, the third alcohol solvent is selected from methanol.

[0156] According to an embodiment of the present invention, the mass-to-volume ratio of compound A to the third alcohol solvent is 1g:(5-15)mL, preferably 1g:(8-12)mL, and exemplarily 1g:10mL.

[0157] According to an embodiment of the present invention, the ambient temperature refers to 15-30°C, preferably 20-25°C.

[0158] According to an embodiment of the present invention, the stirring time at room temperature is 1-5 hours, for example 3 hours.

[0159] According to an embodiment of the present invention, the method for preparing the crystal form VI includes the following steps:

[0160] Compound A was mixed with methanol at a mass-to-volume ratio of 1 g:(5-15) mL, stirred at room temperature until dissolved, filtered, and dried under vacuum to obtain the crystal form VI.

[0161] This invention also provides a method for preparing the above-mentioned crystal form VII, comprising the following steps:

[0162] Compound A was mixed with a first organic solvent, stirred at room temperature until dissolved, filtered, and dried to obtain the crystal form VII.

[0163] According to an embodiment of the present invention, the first organic solvent may be selected from one, two or more of butanone, isopropyl acetate, ethanol and n-butanol, preferably butanone.

[0164] According to an embodiment of the present invention, the mass-to-volume ratio of compound A to the first organic solvent is 1g:(5-15)mL, preferably 1g:(8-12)mL, and exemplarily 1g:10mL.

[0165] According to an embodiment of the present invention, the ambient temperature refers to 15-30°C, preferably 20-25°C.

[0166] According to an embodiment of the present invention, the stirring time at room temperature is 1-5 hours, for example 3 hours.

[0167] According to an embodiment of the present invention, the method for preparing crystal form VII includes the following steps:

[0168] Compound A and butanone were mixed at a mass-to-volume ratio of 1 g:(5-15) mL, stirred at room temperature until dissolved, filtered, and dried under vacuum to obtain the crystal form VII.

[0169] The present invention also provides another method for preparing the above-mentioned crystal form VII, comprising the following steps: heating the crystal form VI to obtain the crystal form VII.

[0170] According to an embodiment of the invention, the heating temperature is sufficient to completely remove the solvent from crystal form VI. Preferably, the solvent comprises a third alcohol solvent and water. For example, the heating temperature is not lower than 130°C.

[0171] The present invention also provides another method for preparing the above-mentioned crystal form VII, comprising the following steps:

[0172] Compound A was mixed with a fourth alcohol solvent, heated and stirred until the system was clear, and then cooled. An organic acid ester was then added to the system, and the mixture was concentrated under vacuum until the volume ratio of the fourth alcohol solvent to the organic acid ester was less than 5%. Isopropyl acetate was then added to the system, and the mixture was cooled, stirred, filtered, and dried to obtain the crystal form VII.

[0173] According to an embodiment of the present invention, the fourth alcohol solvent may be selected from ethanol and / or n-butanol, preferably ethanol.

[0174] According to an embodiment of the present invention, the organic ester may be selected from isopropyl acetate and / or ethyl acetate, preferably isopropyl acetate.

[0175] According to an embodiment of the present invention, the mass-to-volume ratio of compound A to the fourth alcohol solvent is 1 g:(2-10) mL, preferably 1 g:(3-8) mL, and exemplarily 1 g:5 mL.

[0176] According to an embodiment of the present invention, the heating temperature is 65-80°C, preferably 70-75°C.

[0177] According to an embodiment of the present invention, the heating and stirring time is 0.5-3 hours, preferably 1 hour.

[0178] According to an embodiment of the present invention, the cooling temperature is 40-45°C.

[0179] According to an embodiment of the present invention, before vacuum concentration, the volume ratio of the organic acid ester added to the system to the mass of compound A is (5-15) mL:1 g, preferably (7-12) mL:1 g, and exemplaryly 10 mL:1 g. Preferably, the organic acid ester is added to the system in batches, for example, at least two batches. The fourth alcohol solvent is removed by dragging it out through multiple additions of the organic acid ester.

[0180] According to an embodiment of the present invention, the volume ratio of the added organic acid ester to the mass of compound A is (5-15) mL:1 g, preferably (7-12) mL:1 g, and exemplarily 8 mL:1 g.

[0181] According to an embodiment of the present invention, cooling continues to room temperature. Preferably, room temperature refers to 20-25°C.

[0182] According to an embodiment of the present invention, the stirring time after cooling is 1-5 hours, for example 3 hours.

[0183] According to an exemplary embodiment of the present invention, the method for preparing crystal form VII includes the following steps:

[0184] Compound A was mixed with ethanol, heated to 70-75°C, and stirred until the system was clear. The mixture was then cooled to 40-45°C. Isopropyl acetate was then added to the system in batches, and the mixture was concentrated under vacuum until the volume ratio of ethanol to isopropyl acetate in the system was less than 5%. Isopropyl acetate was then added to the system, and the mixture was further cooled to 20-25°C, stirred, filtered, and dried under vacuum to obtain the crystal form VII.

[0185] The mass-to-volume ratio of compound A to ethanol is 1 g:(2-10) mL; the volume ratio of the added isopropyl acetate to the mass of compound A is (5-15) mL:1 g.

[0186] The present invention also provides another method for preparing the above-mentioned crystal form VII, comprising the following steps: mixing a mixture of crystal form I, crystal form III, crystal form VII and crystal form IX with a second organic solvent to obtain the crystal form VII.

[0187] Preferably, the mass ratio of crystal form I, crystal form III, crystal form VII and crystal form IX is (0.9-1.1):(0.9-1.1):1:(0.9-1.1).

[0188] Preferably, the second organic solvent may be selected from one, two or more of butanone, ethyl acetate, isopropyl acetate, ethanol and n-butanol, and is preferably butanone or isopropyl acetate.

[0189] Preferably, the mass-to-volume ratio of the mixture to the second organic solvent is (15-30) mg:0.5 mL, for example, 20 mg:0.5 mL, 20 mg:0.4 mL, or 20 mg:1 mL.

[0190] Preferably, the pulping temperature is 15-60℃, for example 20-50℃.

[0191] The present invention also provides a method for preserving the crystal form III or crystal form VII, wherein the crystal form III or crystal form VII is placed under conditions of relative humidity less than 75% RH, for example, below 70% RH.

[0192] Preferably, according to the preservation method of crystal form III or crystal form VII, the storage temperature can be room temperature to 60°C, for example 40-60°C.

[0193] The present invention also provides a pharmaceutical composition comprising one, two or more of crystal forms I, II, III, IV, V, VI, VII and IX of compound A, and optionally a pharmaceutically acceptable pharmaceutical excipient.

[0194] The present invention also provides a formulation comprising one, two or more of crystal forms I, II, III, IV, V, VI, VII and IX of compound A, and optionally a pharmaceutically acceptable pharmaceutical excipient.

[0195] The present invention also provides the use of the crystal forms I, II, III, IV, V, VI, VII and / or IX of compound A as described above, or the use of the pharmaceutical composition thereof in the preparation of a medicament for the prevention and / or treatment of IRAK-mediated diseases or conditions.

[0196] According to an embodiment of the present invention, the IRAK-mediated diseases or conditions are selected from diseases such as tumors, gout, systemic lupus erythematosus, multiple sclerosis, metabolic syndrome, atherosclerosis, myocardial infarction, sepsis, inflammatory bowel disease, asthma, and allergies.

[0197] The present invention also provides the use of the crystal forms I, II, III, IV, V, VI, VII and / or IX of compound A as described above, or the use of the pharmaceutical composition thereof in the preparation of a medicament for the prevention and / or treatment of diseases or conditions related to interleukin-1 receptor-associated kinase.

[0198] The present invention also provides a method for the prevention and / or treatment of IRAK-mediated diseases or conditions, comprising administering to an individual in need a therapeutically effective amount of crystal form I, crystal form II, crystal form III, crystal form IV, crystal form V, crystal form VI, crystal form VII and / or crystal form IX of the compound A as described above, or the pharmaceutical composition, or the formulation thereof.

[0199] In some implementations, the IRAK is selected from IRAK4-associated kinases.

[0200] The present invention also provides a method for the prevention and / or treatment of diseases associated with interleukin-1 receptor, comprising administering to an individual in need a therapeutically effective amount of crystal form I, crystal form II, crystal form III, crystal form IV, crystal form V, crystal form VI, crystal form VII and / or crystal form IX of the compound A as described above, or the pharmaceutical composition, or the formulation thereof.

[0201] According to an embodiment of the present invention, the disease or condition associated with interleukin-1 receptor-related kinase is selected from diseases such as tumors, gout, systemic lupus erythematosus, multiple sclerosis, metabolic syndrome, atherosclerosis, myocardial infarction, sepsis, inflammatory bowel disease, asthma, rheumatoid arthritis, sepsis, autoimmune diseases, and allergies.

[0202] The method of the present invention may include administering one, two, or more crystal forms of compound A of the present invention alone, or combining one, two, or more crystal forms of compound A of the present invention with one, two, or more other chemotherapeutic agents. Administration of multiple drugs may be performed simultaneously or sequentially.

[0203] Beneficial effects of the present invention

[0204] 1) This invention provides a polymorph of compound A and a method for its preparation. The method for preparing the polymorph is simple, easy to implement, has mild reaction conditions, and yields a high product. Furthermore, it eliminates the need for multiple purification processes, is safe and environmentally friendly, and is beneficial for the industrial production of the polymorph.

[0205] 2) The polymorphs prepared by this invention have good stability and can be stored stably under high temperature and low relative humidity conditions. For example, crystal forms III and VII are physically and chemically stable after being placed at 60℃ (closed) for 7 days, and chemically stable after being placed at 40℃ / 75%RH (open) for 7 days; crystal forms III and VII are physically stable (purity, color, appearance, etc.) below 70%RH.

[0206] Furthermore, the crystal form described in this invention has good flowability, is easy to pulverize, and is readily used in the preparation of pharmaceutical compositions. Finally, the polymorph obtained by this invention has high purity and few impurities.

[0207] Terminology Definitions and Explanations

[0208] The various terms and phrases used in this invention have their general meanings known to those skilled in the art. Nevertheless, this invention still intends to provide a more detailed description and explanation of these terms and phrases. In the event of any inconsistency between the terms and phrases mentioned and their known meanings, the meanings expressed in this invention shall prevail.

[0209] The polymorphs of compound A of the present invention include the nonsolvent (anhydrous) form and the solvate form of compound A.

[0210] The polymorph of compound A of the present invention is represented by X-ray powder diffraction characteristic peaks at an angle of 2θ, wherein "±0.20°" is the allowable measurement error range.

[0211] The polymorph of compound A of the present invention can be used in combination with other active ingredients, as long as it does not produce other adverse effects, such as allergic reactions.

[0212] As used in this invention, the term "composition" means a product comprising specified amounts of each specified ingredient, and any product derived directly or indirectly from a combination of specified amounts of each specified ingredient.

[0213] Those skilled in the art can use known drug carriers to prepare suitable pharmaceutical compositions from the polymorph of compound A of the present invention. The pharmaceutical compositions can be specifically formulated for oral administration, parenteral injection, or rectal administration in solid or liquid form. The pharmaceutical compositions can be formulated into various dosage forms to facilitate administration, such as oral formulations (e.g., tablets, capsules, solutions, or suspensions), injectable formulations (e.g., injectable solutions or suspensions, or injectable dry powders that can be used immediately after addition of a drug solvent before injection).

[0214] As used in this invention, the term "therapeutic and / or preventive effective amount" is the amount of a drug or pharmaceutical preparation that elicits a biological or medical response in a tissue, system, animal, or human sought by a researcher, veterinarian, physician, or other person.

[0215] When used for the above-described therapeutic and / or preventative purposes, the total daily dosage of the polymorph of Compound A of the present invention and the pharmaceutical composition must be determined by the attending physician within the bounds of reliable medical judgment. For any given patient, the specific effective therapeutic dose level must be determined based on a number of factors, including the disorder being treated and its severity; the activity of the specific compound used; the specific composition used; the patient's age, weight, general health condition, sex, and diet; the timing, route of administration, and excretion rate of the specific compound used; the duration of treatment; drugs used in combination with or concurrently with the specific compound used; and similar factors known in the medical field. For example, it is practiced in the art to start the dosage of the compound below the level required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. Attached Figure Description

[0216] Figure 1 The image shows the XRPD pattern of crystal form I.

[0217] Figure 2 PLM spectrum of crystal form I (scale bar 20 μm).

[0218] Figure 3 The image shows the DSC-TGA spectrum of crystal form I.

[0219] Figure 4 XRPD spectra for crystal forms II and III.

[0220] Figure 5 PLM pattern of crystal form II (scale bar 10 μm).

[0221] Figure 6 PLM pattern of crystal form III (scale bar 2.5 μm).

[0222] Figure 7 This is the DSC-TGA spectrum of crystal form II.

[0223] Figure 8 This is the DSC-TGA spectrum of crystal form III.

[0224] Figure 9 This is the DVS pattern for crystal form III.

[0225] Figure 10 The XRPD comparison spectra before and after DVS testing for crystal form III are shown.

[0226] Figure 11 This is the XRPD pattern of crystal form IV.

[0227] Figure 12 PLM spectrum of crystal form IV (scale bar 10 μm).

[0228] Figure 13 This is the DSC-TGA spectrum of crystal form IV.

[0229] Figure 14 The image shows the XRPD pattern of crystal form V.

[0230] Figure 15 PLM spectrum of crystal form V (scale bar 10 μm).

[0231] Figure 16 This is the DSC-TGA spectrum of crystal form V.

[0232] Figure 17 This is the XRPD pattern of crystal form IX.

[0233] Figure 18 PLM spectrum of crystal form IX (scale bar 5 μm).

[0234] Figure 19 This is the DSC-TGA spectrum of crystal form IX.

[0235] Figure 20 This is the XRPD pattern of crystal form VI.

[0236] Figure 21 PLM pattern of crystal form VI (scale bar 2.5 μm).

[0237] Figure 22 The image shows the DSC-TGA spectrum of crystal form VI.

[0238] Figure 23 The XRPD pattern is for crystal form VII.

[0239] Figure 24 PLM spectrum of crystal form VII (scale bar 5 μm).

[0240] Figure 25 The image shows the DSC-TGA spectrum of crystal form VII.

[0241] Figure 26 This is the DVS pattern for crystal form VII.

[0242] Figure 27 The XRPD comparison spectra before and after DVS testing for crystal form VII are shown.

[0243] Figure 28 XRPD overlay pattern of stable sample.

[0244] Figure 29 XRPD overlay pattern of crystal form III sample for humidity effect test.

[0245] Figure 30 XRPD overlay pattern of crystal form VII sample for humidity effect test.

[0246] Figure 31 The dynamic curve of DVS for humidity effect test.

[0247] Figure 32 The image shows the XRPD overlay pattern of the dried crystal form III sample after humidity testing.

[0248] Figure 33 The XRPD overlay pattern of the VII crystal form sample after drying is shown in the humidity test.

[0249] Figure 34 This is the result of the solubility test.

[0250] Figure 35 This is an XRPD overlay pattern of the sample after solubility testing. Detailed Implementation

[0251] The technical solution of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of the present invention, and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0252] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0253] Synthesis of Compound A

[0254] Reaction formula:

[0255]

[0256] (1) Synthesis of compound 3

[0257] DMAP (42.5 g), compound 2 (63.4 g), and triethylamine (63.9 g) were added sequentially to a 500 mL solution of compound 1 (50 g) in dichloromethane at 15°C, and the mixture was stirred at 25°C for 18 hours. Dichloromethane (200 mL) was added to the reaction mixture, followed by washing with water (300 mL × 2), then with 1 M dilute hydrochloric acid (300 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 98 g of a yellow solid, yield: 99% (i.e., compound 3).

[0258] (2) Synthesis of compound 4

[0259] 1M dilute hydrochloric acid (300 mL) was added to a tetrahydrofuran solution (50 g) of compound 3 at 15°C, and the mixture was stirred at 25°C for 20 hours. The mixture was cooled to 0°C. The pH was adjusted to 9 with 1M sodium hydroxide solution. Extraction was performed with ethyl acetate (200 mL × 3). The extract was washed with saturated sodium chloride solution (300 mL). The solution was dried over anhydrous sodium sulfate. The mixture was filtered. The solution was concentrated under reduced pressure, and the residue was slurried with petroleum ether (150 mL) to give 39 g of a white solid, 91% yield (i.e., compound 4).

[0260] (3) Synthesis of compounds 5 & 6

[0261] At -40°C, a tetrahydrofuran solution (200 mL) of compound 4 (34.5 g) was added dropwise to a tetrahydrofuran solution (500 mL) of methyl magnesium bromide (85.8 mL). The mixture was stirred at -40°C for 4 hours. The reaction was quenched with a saturated ammonium chloride solution (100 mL). The mixture was extracted with ethyl acetate (500 mL × 3). The extract was washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give a colorless oily compound 5 (4.3 g, 10%), a colorless oily compound 6 (7.0 g, 17%), and a mixture of 12 g.

[0262] Compound 5

[0263] 1 H NMR (400MHz, CDCl3): δ7.79(d,J=8.0Hz,2H),7.32(d,J=8.4Hz,2H),4.52-4.41(m,1H ),2.44(s,3H),1.95-1.80(m,2H),1.77-1.61(m,4H),1.46-1.35(m,2H),1.19(s,3H).

[0264] Compound 6

[0265] 1 H NMR (400MHz, CDCl3): δ7.79(d,J=8.4Hz,2H),7.33(d,J=8.0Hz,2H),4.74-4.64(m,1H ),2.44(s,3H),1.92-1.79(m,2H),1.77-1.62(m,4H),1.49-1.38(m,2H),1.23(s,3H).

[0266] (4) Synthesis of compound 8

[0267] A mixture of concentrated sulfuric acid (1.6 mL, 98%) and nitric acid (1.6 mL, 70%) was added dropwise to a solution of compound 7 (2.0 g) in concentrated sulfuric acid (12 mL, 98%) at -15°C. After the addition was complete, the mixture was stirred at -15°C for 2 hours. The reaction solution was then slowly poured into ice water and stirred for 5 minutes. The mixture was filtered, washed with water, and the solid was collected and dried under reduced pressure to give 2.5 g of a yellow solid, yield: 97% (i.e., compound 8).

[0268] (5) Synthesis of compound 9

[0269] Hydrazine hydrate (2.4 mL, 98%) was added to a DMF (20 mL) solution of compound 8 (2.0 g) at room temperature. After the addition was complete, the mixture was heated to 120 °C and stirred for 16 hours. After cooling to room temperature, the mixture was slowly poured into ice water and stirred. The mixture was filtered, the solid was washed with water, and the solid was collected and concentrated under reduced pressure to obtain 1.3 g of yellow solid. Yield: 67% (i.e., compound 9).

[0270] (6) Synthesis of compound 10

[0271] Compound 9 (12.4 g) and palladium on carbon (7 g, 10%) were added sequentially to 400 mL of ethyl acetate at 15°C. After the addition was complete, the mixture was stirred for 18 hours under hydrogen protection at 15°C. The palladium on carbon was filtered off from the reaction solution, and the filtrate was concentrated and evaporated to dryness to obtain 10.4 g of white solid product, with a yield of 99% (i.e., compound 10).

[0272] (7) Synthesis of compound 12

[0273] EDCI·HCl (2.6 g) was added to a Py (15 mL) solution of compound 10 (1.5 g) and compound 11 (1.4 g) at 25°C. The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated and evaporated to dryness. The residue was slurried by passing MeOH / H2O (20 mL / 20 mL) to obtain 1.3 g of a yellow solid product, with a yield of 48% (i.e., compound 12).

[0274] (8) Synthesis of compound A

[0275]

[0276] Cesium carbonate (985 mg) was added to 5 mL of a DMF solution containing compound 12 (300 mg) and compound 5 (344 mg) at 25°C. The reaction mixture was stirred at 90°C for 16 hours. The reaction mixture was then added to 30 mL of water and extracted with ethyl acetate (10 mL × 3). The organic phase was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) using a column (CH3CN:H2O (0.1% NH4HCO3) = 15-45%, UV: 214 nm, Flowrate: 15 mL / min) to obtain 70 mg of a yellow solid, with a yield of 17% (i.e., compound A).

[0277] 1 H NMR (400MHz, DMSO-d6): δ14.16(s,1H),8.78(s,1H),8.34(s,1H),8.32-8.30(m,1H),7.77(d,J=7.6Hz,1H),7.58(t,J=8.0Hz,1H),7.13(s,1 H),4.45(s,1H),4.43-4.40(m,1H),3.95(s,3H),2.53(s,3H),2.09-2.00(m,4H),1.68-1.58(m,4H),1.22(s,3H).LCMS:Rt=3.646min,[M+H] + =411.1.

[0278] (9) Synthesis of compound 11

[0279] At 25°C, m-CPBA (25 g) was added to 200 mL of DCM solution containing 10 g of compound 13. The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was filtered, and the filtrate was quenched with a saturated solution of 15.6 g sodium sulfite. The mixture was stirred for 2 hours and extracted. The aqueous phase was adjusted to pH < 7 with dilute hydrochloric acid and extracted with DCM (50 mL × 3). The organic phases were combined and concentrated. The residue was slurried with 300 mL of EA to give 10.1 g of white solid, with a yield of 90% (i.e., compound 11).

[0280] In the following embodiments, the XRPD testing instrument is a PIXCEI. 1D Detector, test conditions: PANalyticalEMPYREAN;

[0281] The instrument used for DVS testing is a dynamic water vapor adsorption analyzer (Vsorp-Enhanced, proUmid). The test conditions are as follows: a sufficient amount of sample is added to the Vsorp-Enhanced instrument to simulate dynamic water vapor adsorption, and the weight change at different humidity equilibrations at 25°C is recorded. After DVS testing, the sample is subjected to XRPD testing.

[0282] Example 1

[0283] Preparation method of crystal form I:

[0284] Compound A (1g) was added to ethanol / methyl tert-butyl ether (15mL / 5mL), heated to 60℃ and stirred for 3 hours, cooled to 0-10℃ and filtered. The filter cake was dried under vacuum to obtain crystal form I (0.85g). The purity of crystal form I was above 99%.

[0285] Crystal form I was characterized by XRPD, PLM, DSC, and TGA. Crystal form I is an anhydrous product. The positions and intensities of the characteristic XRPD peaks are shown in Table 1, and the XRPD spectrum is shown in... Figure 1 The PLM image shows that the sample is an irregularly shaped crystal with a diameter of less than 20 μm. Figure 2 TGA testing showed that the sample experienced a 1.2% weight loss between 140 and 200°C. Figure 3 This corresponds to the NMR results showing 0.9% ethanol and 0.3% methyl tert-butyl ether residues in the sample. DSC analysis showed only one endothermic peak in the sample. Figure 3 The initial temperature was 191℃.

[0286] The XRPD pattern of crystal form I, expressed as an X-ray powder diffraction pattern with a 2θ angle, is shown in Table 1.

[0287] Table 1. XRPD characteristic peaks of crystal form I

[0288]

[0289]

[0290] Example 2

[0291] Preparation methods for crystal forms II and III:

[0292] Compound A (1g) was added to toluene (15mL), stirred at 20-25℃ for 3 hours, filtered, and the filter cake was crystal form II with a purity of over 99%.

[0293] The obtained crystal form II was dried in a vacuum at 50-60℃ to obtain crystal form III (0.90g), and the purity of crystal form III was over 99%.

[0294] Crystal form II was characterized by XRPD, PLM, DSC, and TGA. The positions and intensities of the characteristic XRPD peaks are shown in Table 2, and the XRPD spectra are shown below. Figure 4 PLM diagram ( Figure 5 The sample appears to be an irregularly shaped crystal with a grain size <10 μm and high crystallinity. TGA testing showed a 9.6% weight loss between 100 and 160 °C. Figure 7The presence of 9.5% toluene residue in the sample, as indicated by NMR spectroscopy, corresponds to this. Therefore, crystal form II is a toluene-solvent compound. DSC analysis shows that crystal form II exhibits its first endothermic peak near a peak temperature of 136.92℃ and a second endothermic peak near a peak temperature of 189.27℃. After solvent removal, crystal form II transforms into crystal form III.

[0295] Crystal form III was characterized by XRPD, PLM, DSC, TGA, and DVS. The positions and intensities of the characteristic XRPD peaks are shown in Table 3, and the XRPD spectrum is shown in... Figure 4 PLM diagram ( Figure 6 The sample appears to be an irregularly shaped crystal with a grain size <5 μm. It exhibits high crystallinity. TGA analysis shows that the sample shows almost no weight loss before 180℃. Figure 8 The DSC spectrum shows that the initial melting point of the sample is approximately 187℃. Figure 8 DVS results () Figure 9 The results showed that the sample had only 0.22% hygroscopicity within the 0-80% RH range, indicating slight hygroscopicity. However, after DVS testing, crystal form III transformed into a mixed crystal of crystal form III and crystal form IV. Figure 10 ).

[0296] The XRPD patterns of crystal forms II and III, expressed as 2θ angles in their X-ray powder diffraction patterns, are shown in Tables 2 and 3, respectively:

[0297] Table 2. XRPD characteristic peaks of crystal form II

[0298]

[0299]

[0300] Table 3. XRPD characteristic peaks of crystal form III

[0301]

[0302] Example 3

[0303] Method for preparing crystal form IV:

[0304] Compound A (1g) was added to isopropanol / water (5mL / 5mL), stirred at 20-25℃ for 3 hours, filtered, and the filter cake was dried under vacuum to obtain crystal form IV (0.90g). The purity of crystal form IV was above 99%.

[0305] After crystal form IV is heated to 100°C and completely dehydrated, crystal form IV transforms into crystal form I.

[0306] Crystal form IV was characterized by XRPD, PLM, DSC, and TGA. The positions and intensities of the characteristic peaks of XRPD are shown in Table 4, and the XRPD spectrum is shown in the figure. Figure 11 PLM diagram ( Figure 12 The sample appears to be an irregularly shaped crystal with a grain size <10 μm and high crystallinity. The DSC spectrum shows multiple endothermic peaks. Figure 13 This indicates that the sample may have undergone crystal transformation during heating. TGA showed that the sample experienced a 16.9% weight loss between room temperature and 150°C. Figure 13 The water content is 4.2 wt%, and crystal form IV is the monohydrate of compound A. After complete dehydration, crystal form IV transforms into crystal form I. Figure 11 ).

[0307] The XRPD pattern of crystal form IV, expressed as an X-ray powder diffraction pattern with a 2θ angle, is shown in Table 4.

[0308] Table 4. XRPD characteristic peaks of crystal form IV

[0309]

[0310] Example 4

[0311] Preparation methods of crystal forms V and IX:

[0312] Compound A (1g) was added to acetonitrile (10mL), stirred at 20-25℃ for 3 hours, filtered, and the filter cake was dried under vacuum to obtain crystal form V (0.90g). The purity of crystal form V was above 99%.

[0313] When crystal form IV is heated to 150°C, crystal form V transforms into crystal form IX, and the purity of crystal form IX is over 99%.

[0314] Crystal form V was characterized by XRPD, PLM, DSC, and TGA. The positions and intensities of the characteristic peaks of XRPD are shown in Table 5, and the XRPD spectrum is shown in the figure. Figure 14 PLM diagram ( Figure 15 The sample appears to be an irregularly shaped crystal with a grain size <10 μm. It exhibits high crystallinity. (DSC) Figure 16 The data shows that after the sample was desolventized (the first endothermic peak appeared near the peak temperature of 135.05℃), there were two more endothermic peaks (a second endothermic peak appeared near the peak temperature of 192.24℃, and a third endothermic peak appeared near the peak temperature of 218.33℃), possibly indicating crystal transformation during heating. TGA ( Figure 16 Tests showed that the sample experienced a 6.4% weight loss between 70 and 150°C, corresponding to the 5.1% acetonitrile residue observed in NMR spectroscopy. Therefore, crystal form V is an acetonitrile solvent compound. After solvent removal, crystal form V transforms into crystal form IX. Figure 14 and Figure 17 ).

[0315] The crystal form IX was characterized by XRPD, PLM, DSC, and TGA. The positions and intensities of the characteristic peaks of XRPD are shown in Table 6, and the XRPD spectrum is shown in the figure. Figure 17 PLM diagram ( Figure 18 The sample appears to be an irregularly shaped crystal with a grain size <5 μm. It exhibits high crystallinity. DSC analysis shows multiple endothermic peaks: the first peak appears near the peak temperature of 192.04℃, the second near 201.20℃, and the third near 217.55℃. The sample may have undergone crystal transformation during heating. Figure 19 This indicates that the sample may have undergone crystal transformation during heating. TGA showed that the sample experienced almost no weight loss before 180°C. Figure 19 ).

[0316] The XRPD patterns of crystal forms V and IX, expressed as 2θ angles in their X-ray powder diffraction patterns, are shown in Tables 5 and 6, respectively:

[0317] Table 5. XRPD characteristic peaks of crystal form V

[0318]

[0319] Table 6. XRPD characteristic peaks of crystal form IX

[0320]

[0321]

[0322] Example 5

[0323] Preparation method of crystal form VI:

[0324] Compound A (1g) was added to methanol (10mL) and stirred at 20-25℃ for 3 hours. After filtration, the filter cake was dried under vacuum to obtain crystal form VI (0.80g). The purity of crystal form VI was above 99%.

[0325] Crystal form VI was characterized by XRPD, PLM, DSC, and TGA. The positions and intensities of the characteristic peaks of XRPD are shown in Table 7, and the XRPD spectrum is shown in the figure. Figure 20 PLM diagram ( Figure 21 The sample appears to be an irregularly shaped crystal with a grain size <5 μm. It exhibits high crystallinity. (DSC) Figure 22 The data shows an endothermic peak after the sample has been desolventized, indicating sample melting. The initial temperature is 200℃, and the enthalpy is 30 J / g. (TGA) Figure 22 The data showed a 9.5% weight loss in the sample from room temperature to 130°C, corresponding to the broad endothermic peak in the DSC, indicating dehydration or desolventization of the sample. After complete desolventization and water removal at 40-50°C, crystal form VI transformed into crystal form VII. Figure 20 ).

[0326] The XRPD pattern of crystal form VI, expressed as an X-ray powder diffraction pattern with a 2θ angle, is shown in Table 7.

[0327] Table 7. XRPD characteristic peaks of crystal form VI

[0328]

[0329]

[0330] Example 6

[0331] Preparation method of crystal form VI:

[0332] Compound A (1g) was added to butanone (10mL), stirred at 20-25℃ for 3 hours, filtered, and the filter cake was dried under vacuum to obtain crystal form VI (0.85g). The purity of crystal form VI was above 99%.

[0333] XRPD pattern of crystal form VI as follows Figure 20 As shown.

[0334] Example 7

[0335] Preparation method of crystal form VII:

[0336] Compound A (1.5 kg) was added to ethanol (7.5 L) and stirred at 70-75 °C for 1 hour until the system became clear. The temperature was then lowered to 40-45 °C, and isopropyl acetate (15 L) was added in portions. The mixture was then concentrated under vacuum to remove the ethanol. Isopropyl acetate was added repeatedly to carry the mixture until the volume ratio of ethanol to isopropyl acetate in the system was less than 5%. Isopropyl acetate was added to maintain the total volume of the system at 12 L. The mixture was then cooled to 20-25 °C and stirred for 3 hours. After filtration, the filter cake was dried under vacuum to obtain crystal form VII (1.4 kg). The purity of crystal form VII was above 99%.

[0337] Crystal form VII was characterized by XRPD, PLM, DSC, TGA, and DVS. The positions and intensities of the characteristic peaks of XRPD are shown in Table 8, and the XRPD spectrum is shown in the figure. Figure 23 PLM diagram ( Figure 24 The sample appears to be an irregularly shaped crystal with a grain size <5 μm. It exhibits high crystallinity. (DSC) Figure 25 The display shows an endothermic peak, indicating sample melting, with an initial temperature of 200℃ and an enthalpy of 102 J / g. (TGA) Figure 25 The results showed that the sample experienced almost no weight loss before 200°C. (DVS) Figure 26 The results showed that it had only 0.29% hygroscopicity within the 0-80% RH range, indicating slight hygroscopicity, and the crystal form remained unchanged before and after the DVS test. Figure 27).

[0338] The XRPD pattern of crystal form VII, expressed as an X-ray powder diffraction pattern with a 2θ angle, is shown in Table 8.

[0339] Table 8. XRPD characteristic peaks of crystal form VII

[0340]

[0341]

[0342] Example 8

[0343] Competitive beating experiment

[0344] A certain amount of crystal forms I, III, VII and IX were taken and competitive pulping experiments were conducted in methyl ethyl ketone and isopropyl acetate. The results of the pulping experiments are shown in Table 9. The results show that crystal form VII can be obtained by various pulping methods.

[0345] Table 9 Results of competitive pulping experiments for multiple crystal forms

[0346]

[0347] Stability investigation of crystal forms III and VII

[0348] Solid-state and chemical stability experiments were conducted on crystal forms III and VII for 7 days at 60℃ (closed-loop) and 40℃ / 75%RH (open-loop) conditions. The results showed that crystal forms III and VII were physically and chemically stable after 7 days at 60℃ (closed-loop) and chemically stable after 7 days at 40℃ / 75%RH (open-loop). However, after 7 days at 40℃ / 75%RH (open-loop), a small amount of hydrated crystal form IV was formed in both forms. The amount of crystal form IV formed in crystal form III was slightly greater than that in crystal form VII. The experimental results are shown in Table 10. Figure 28 As shown.

[0349] Table 10 HPLC results of stable samples

[0350]

[0351] Test on the effect of humidity on crystal forms III and VII

[0352] According to the stability test results, both crystal forms III and VII, when placed under 40℃ / 75%RH (open) conditions for 7 days, produced a small amount of hydrated crystal form IV. Therefore, the effect of humidity was further studied at 40℃.

[0353] All experimental results are shown in Table 11 and Figures 29-33As shown. Crystal form III ( Figure 29 ) and crystal form VII ( Figure 30 The hydrate crystal form IV was physically stable after being placed at 70% RH for 23 hours. However, after being placed at 80% and 90% RH for 23 hours, a small amount of hydrate crystal form IV was formed. After being vacuum dried overnight at 40℃, hydrate crystal form IV transformed into hydrate crystal form XV. However, hydrate crystal form IV could be completely removed by vacuum drying at 80℃ for 3 days. Figure 32 , Figure 33 ).

[0354] According to humidity test results, crystal forms III and VII are physically stable below 70% RH, while a small amount of hydrate crystal form IV will be formed above 70% RH, and this hydrate can be removed by vacuum drying at 80℃.

[0355] Table 11 Test results of the effect of humidity on crystal form III and crystal form VII

[0356]

[0357] Solubility test

[0358] The solubility of both crystal forms III and VII increased as the pH of the biological medium decreased. Both crystal forms showed the highest solubility in SGF (0.323 mg / mL vs. 0.183 mg / mL @ 0.5 h) and the lowest solubility in FaSSIF (0.034 mg / mL vs. 0.025 mg / mL @ 0.5 h). In all three biological media, the solubility of crystal form III at 0.5 h was 1.5 times that of crystal form VII. Both crystal forms showed some degradation with increasing stirring time during the solubility test. All experimental results are shown in Table 12 and... Figures 34-35 As shown in Table 13, the crystal forms of crystal forms III and VII changed in all three biological media. In FaSSIF and SGF, crystal form III transformed into crystal form IV, and in FeSSIF, crystal form III transformed into a mixed crystal of crystal forms IV and XIII. In FaSSIF and FeSSIF, crystal form VII transformed into crystal form IV, and in SGF, crystal form VII transformed into a mixed crystal of crystal forms IV and XV. The HPLC purity of crystal forms III and VII decreased to some extent in all three biological media (based on HPLC purity of 100% before being placed in the biological media). Therefore, this compound is unstable in biological media.

[0359] Table 12 Solubility Test Results

[0360]

[0361] Table 13 HPLC Results of Solubility Test

[0362]

[0363] The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. Polymorphs of compound A: Compound A, The polymorph, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at 12.15±0.20°, 15.98±0.20°, 24.048±0.20°, and 24.32±0.20° in 2θ angles.

2. The polymorph according to claim 1, wherein, The polymorph, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at 12.15±0.20°, 15.98±0.20°, 16.62±0.20°, 17.14±0.20°, 24.048±0.20°, 24.32±0.20°, and 26.08±0.20° in 2θ angles.

3. The polymorph according to claim 1, wherein, The polymorph, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at 12.15±0.20°, 15.04±0.20°, 15.98±0.20°, 16.62±0.20°, 17.14±0.20°, 21.09±0.20°, 24.048±0.20°, 24.32±0.20°, and 26.08±0.20° in 2θ angles.

4. The polymorph according to claim 1, wherein, The polymorph, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at 12.15±0.20°, 15.04±0.20°, 15.98±0.20°, 16.62±0.20°, 17.14±0.20°, 18.74±0.20°, 21.09±0.20°, 23.51±0.20°, 24.048±0.20°, 24.32±0.20°, and 26.08±0.20° in 2θ angles.

5. The polymorph according to any one of claims 1-4, wherein: The polymorph is an anhydrous form of compound A; The polymorph has an X-ray powder diffraction pattern of crystal form III as shown in Figure 4. The polymorph showed its first endothermic peak at 188.8 °C in differential scanning calorimetry (DSC). The polymorph has a DSC-TGA pattern as shown in Figure 8; and / or The polymorph has a particle size of less than 5 μm.

6. The polymorph according to any one of claims 1-4, wherein the polymorph has a purity of 95% or higher.

7. Polymorphs of compound A: Compound A, The polymorph, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at 12.94±0.20°, 14.41±0.20°, and 21.75±0.20° when expressed in 2θ angles.

8. The polymorph according to claim 7, wherein, The polymorph, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at 12.94±0.20°, 14.41±0.20°, 15.64±0.20°, 17.25±0.20°, 21.75±0.20°, and 24.23±0.20° in 2θ angles.

9. The polymorph according to claim 7, wherein, The polymorph exhibits characteristic peaks in X-ray powder diffraction (expressed as 2θ angle) using Cu-Kα radiation at 12.94±0.20°, 13.18±0.20°, 14.41±0.20°, 15.64±0.20°, 17.25±0.20°, 21.75±0.20°, 22.54±0.20°, and 24.23±0.20°.

10. The polymorph according to claim 7, wherein, The polymorph exhibits characteristic peaks in X-ray powder diffraction (expressed as 2θ angle) using Cu-Kα radiation at 12.94±0.20°, 13.18±0.20°, 14.41±0.20°, 15.64±0.20°, 17.25±0.20°, 21.11±0.20°, 21.75±0.20°, 22.54±0.20°, 24.23±0.20°, 26.62±0.20°, and 31.64±0.20°.

11. The polymorph according to claim 7, wherein, The polymorph exhibits a characteristic peak at 19.255 ± 0.20° in X-ray powder diffraction using Cu-Kα radiation, expressed in 2θ angles.

12. The polymorph according to any one of claims 7-11, wherein: The polymorph is an anhydrous form of compound A; The polymorph has a basic X-ray powder diffraction pattern as shown in Figure 23; The polymorph exhibits an endothermic peak at 201 °C in the differential scanning calorimetry (DSC) spectrum. The polymorph has a DSC-TGA pattern as shown in Figure 25; and / or The polymorph has a particle size of less than 5 μm.

13. The polymorph according to any one of claims 7-11, wherein the polymorph has a purity of 95% or more.

14. A method for preparing the polymorph according to any one of claims 1-6, wherein, The method includes the following steps: heating crystal form II of compound A to a temperature of 100-160°C to obtain the polymorph, wherein: The crystal form II, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at 13.49±0.20°, 17.51±0.20°, 17.72±0.20°, 20.97±0.20°, 23.67±0.20°, and 27.32±0.20° when expressed in 2θ angles.

15. A method for preparing the polymorph according to any one of claims 7-13, wherein the method comprises the following steps: Compound A was mixed with a solvent and dissolved, then filtered and dried to obtain the polymorph. The solvent is selected from one, two or more of butanone, isopropyl acetate, ethanol and n-butanol.

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