Polymorphic forms of compound and preparation method therefor and application thereof

Abstract

To develop pharmaceutical crystals suitable for formulation of a compound.SOLUTION: Polymorphic forms of a compound and a preparation method therefor and an application thereof are disclosed. A crystal form III of a compound A uses Cu-Kα radiation, and X-ray powder diffraction expressed at 2θ angles has characteristic peaks 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°. A crystal form VII of the compound A uses Cu-Kα radiation, and X-ray powder diffraction expressed at 2θ angles has characteristic peaks 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°. The polymorphic forms prepared by the present invention are good in stability, and can be stably stored under the conditions of high temperature and low relative humidity.SELECTED DRAWING: Figure 28

Description

[Technical Field]

[0001] This application claims priority from a prior application bearing patent application number 202110297078.4 and entitled "Polymorphs of Compounds and Their Preparation and Use," filed with the State Intellectual Property Administration of China on March 19, 2021, the entire text of which is incorporated herein by reference.

[0002] (Technical field) The present invention relates to the field of pharmaceutical crystals and to polymorphs of compounds and their preparation and use, particularly to polymorphs of 2-((2-(trans-4-hydroxy-cis-4-methylcyclohexyl)-6-methoxy-2H-indazol-5-yl)carbamoyl)-6-methylpyridine 1-oxide, and the preparation and use of the polymorphs. [Background technology]

[0003] Interleukin-1 receptor-associated kinases (IRAKs) are a family of intracellular serine / threonine protein kinases. There are four members: IRAK1, IRAK2, IRAK-M, and IRAK4. A common feature is that they contain a typical N-terminal apoptotic domain that mediates the interaction between MyD88 family adaptor proteins and a centrally located kinase domain. Among these, 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. After binding of pathogen-specific molecules (e.g., lipopolysaccharide, polypeptides, viral DNA, etc.) recognized by the extracellular portion of TLRs, the intracellular portion recruits MyD88 and other receptors to form a complex, activating IRAK1 autophosphorylation, which further activates the downstream serine / threonine kinase TAK1, which activates the NF-κB and MAPK signaling pathways, resulting in the production of proinflammatory cytokines, chemokines, and destructive enzymes, ultimately triggering an inflammatory response that mediates 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 excessive activation of the IRAK4-dependent TLR / IL-1R signaling pathway is closely related to the onset and progression of rheumatoid arthritis, and many other studies have also demonstrated that activation of the IRAK4 enzyme is closely related to the onset and progression of 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). [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Flannery, et. al. Biochem. Pharmacol., 2010, 80 (12): 1981-1991 [Non-patent document 2] Chaudhary D, et. al., J. Med. Chem. 2015, 58 (1): 96-110 Summary of the Invention [Problem to be solved by the invention]

[0006] Currently, patent application PCT / CN2020 / 117093 (priority: CN201910906833.7) filed by the applicant describes new compounds that can be effectively used as therapeutic agents for the above-mentioned IRAK-mediated and / or interleukin-1 receptor-related diseases, in particular drugs for treating and / or preventing the above-mentioned IRAK-mediated diseases and / or interleukin-1 receptor-related diseases, and it has become an urgent technical problem to develop pharmaceutical crystals that are more suitable for formulating these compounds, in particular crystals with improved stability, hygroscopicity and / or efficacy, so as to achieve good effects in the production and use of medicines. [Means for solving the problem]

[0007] (Summary of the Invention) In order to improve the above-mentioned problems existing in the prior art, the present invention provides a polymorph of Compound A, 2-((2-(trans-4-hydroxy-cis-4-methylcyclohexyl)-6-methoxy-2H-indazol-5-yl)carbamoyl)-6-methylpyridine 1-oxide, represented by the following formula:

[0008] [ka] Compound A

[0009] The present invention provides a type I crystal of Compound A, which has characteristic diffraction peaks 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° in its powder X-ray diffraction spectrum expressed as 2θ angles using Cu-Kα radiation.

[0010] According to one embodiment of the present invention, the Form I crystal is an anhydrous form of Compound A.

[0011] Preferably, the powder X-ray diffraction spectrum of the Type I crystal expressed as 2θ angles using Cu-Kα radiation has characteristic diffraction 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°.

[0012] Preferably, the powder X-ray diffraction spectrum of the type I crystal, expressed as 2θ angles using Cu-Kα radiation, has characteristic diffraction peaks 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°. Preferably, the powder X-ray diffraction spectrum of the type I crystal, expressed as 2θ angles using Cu-Kα radiation, is as shown in Table 1, with an error range of ±0.20°.

[0013] [Table 1]

[0014] Preferably, the Form I crystal has a powder X-ray diffraction spectrum essentially as shown in FIG.

[0015] According to one embodiment of the present invention, differential scanning calorimetry (DSC) analysis of the Form I crystals shows that the first endothermic peak appears when heated to a peak temperature of around 190.70°C.

[0016] According to one embodiment of the present invention, thermogravimetric analysis (TGA) of the Form I crystal shows that the weight decreases by about 1.2% in the range of 140 to 200°C.

[0017] Preferably, the Form I crystal has a DSC-TGA spectrum essentially as shown in FIG.

[0018] According to one embodiment of the present invention, the type I crystal is an irregularly shaped crystal. Preferably, the type I crystal has a particle size of 20 μm or less. Preferably, the type I crystal has a PLM spectrum essentially as shown in FIG.

[0019] According to one embodiment of the present invention, the purity of the type I crystal is 95% or more, preferably 99% or more.

[0020] The present invention further provides a Form II crystal of Compound A, wherein the Form II crystal has characteristic diffraction peaks 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° in a powder X-ray diffraction spectrum expressed as 2θ angles using Cu-Kα radiation.

[0021] According to one embodiment of the present invention, the Form II crystal is a toluene solvate of Compound A.

[0022] Preferably, the powder X-ray diffraction spectrum of the Type II crystal expressed in 2θ angles using Cu-Kα radiation has characteristic diffraction 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°.

[0023] Preferably, the powder X-ray diffraction spectrum of the Type II crystal expressed in 2θ angles using Cu-Kα radiation has characteristic diffraction 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°.

[0024] Preferably, the type II crystal uses Cu-Kα radiation, and the powder X-ray diffraction spectrum expressed in 2θ angles is as shown in Table 2, with an error range of ±0.20°.

[0025] [Table 2]

[0026] Preferably, the Form II crystal has a powder X-ray diffraction spectrum essentially as shown in FIG.

[0027] According to one embodiment of the present invention, differential scanning calorimetry (DSC) analysis of the Form II crystals shows that a first endothermic peak appears when heated to a peak temperature of approximately 136.92°C, and a second endothermic peak appears when heated to a peak temperature of approximately 189.27°C.

[0028] According to one embodiment of the present invention, thermogravimetric analysis (TGA) of the Type II crystal shows that the weight decreases by about 9.6% in the range of 100 to 160°C.

[0029] Preferably, the Form II crystal has a DSC-TGA spectrum essentially as shown in FIG.

[0030] According to one embodiment of the present invention, the type II crystals are irregularly shaped crystals. Preferably, the type II crystals have a particle size of less than 10 μm. Preferably, the type II crystals have a PLM spectrum essentially as shown in FIG.

[0031] According to one embodiment of the present invention, the purity of the type II crystal is 95% or more, preferably 99% or more.

[0032] The present invention further provides a type III crystal of Compound A, wherein the type III crystal has characteristic diffraction peaks 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° in a powder X-ray diffraction spectrum expressed as 2θ angles using Cu-Kα radiation.

[0033] According to one embodiment of the present invention, the Form III crystal is an anhydrous form of Compound A.

[0034] Preferably, the type III crystal has characteristic diffraction 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° in a powder X-ray diffraction spectrum expressed as 2θ angles using Cu-Kα radiation.

[0035] Preferably, the type III crystal has characteristic diffraction 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° in its powder X-ray diffraction spectrum expressed as 2θ angles using Cu-Kα radiation. Preferably, the type III crystal uses Cu-Kα radiation, and the powder X-ray diffraction spectrum expressed in 2θ angles is as shown in Table 3, with an error range of ±0.20°.

[0036] [Table 3]

[0037] Preferably, the Form III crystal has a powder X-ray diffraction spectrum essentially as shown in FIG.

[0038] According to one embodiment of the present invention, differential scanning calorimetry (DSC) analysis of the Form III crystals shows that a first endothermic peak appears upon heating to a peak temperature of approximately 188.81°C.

[0039] According to one embodiment of the present invention, thermogravimetric analysis (TGA) of the type III crystal shows almost no weight loss before 180°C.

[0040] Preferably, the type III crystal has a DSC-TGA spectrum essentially as shown in FIG.

[0041] According to one embodiment of the present invention, the type III crystal is an irregularly shaped crystal. Preferably, the particle size of the type III crystal is less than 5 μm. Preferably, the type III crystal has a PLM spectrum essentially as shown in FIG.

[0042] According to one embodiment of the present invention, the purity of the type III crystal is 95% or more, preferably 99% or more.

[0043] The present invention further provides a type IV crystal of Compound A, wherein the type IV crystal has characteristic diffraction peaks 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° in a powder X-ray diffraction spectrum expressed as 2θ angles using Cu-Kα radiation.

[0044] According to one embodiment of the present invention, the Form IV crystal is a hydrate of Compound A. Preferably, the Form IV crystal is a monohydrate of Compound A. Preferably, the water content of the Form IV crystal is 4.2 wt%.

[0045] Preferably, the type IV crystal has characteristic diffraction 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° in a powder X-ray diffraction spectrum expressed as 2θ angles using Cu-Kα radiation.

[0046] Preferably, the IV-type crystal uses Cu-Kα radiation, and the powder X-ray diffraction spectrum expressed in 2θ angles is as shown in Table 4, with an error range of ±0.20°.

[0047] [Table 4]

[0048] Preferably, the Type IV crystal has a powder X-ray diffraction spectrum essentially as shown in FIG.

[0049] According to one embodiment of the present invention, differential scanning calorimetry (DSC) analysis of the Form IV crystals shows that a first endothermic peak appears when heated to a peak temperature of about 77.01°C, a second endothermic peak appears when heated to a peak temperature of about 190.76°C, a third endothermic peak appears when heated to a peak temperature of about 201.77°C, a fourth endothermic peak appears when heated to a peak temperature of about 215.93°C, and a fifth endothermic peak appears when heated to a peak temperature of about 218.05°C. The crystalline Form IV may undergo a crystal transition during heating.

[0050] According to one embodiment of the present invention, thermogravimetric analysis (TGA) of the Type IV crystal shows that the weight decreases by about 16.9% in the range of room temperature to 150°C.

[0051] Preferably, the Type IV crystal has a DSC-TGA spectrum essentially as shown in FIG.

[0052] According to one embodiment of the present invention, the type IV crystal is an irregularly shaped crystal. Preferably, the type IV crystal has a particle size of less than 10 μm. Preferably, the type IV crystal has a PLM spectrum essentially as shown in FIG.

[0053] According to one embodiment of the present invention, the purity of the type IV crystal is 95% or more, preferably 99% or more.

[0054] The present invention further provides a type V crystal of Compound A, wherein the type V crystal has characteristic diffraction peaks 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° in a powder X-ray diffraction spectrum expressed as 2θ angles using Cu-Kα radiation.

[0055] According to one embodiment of the present invention, the Type V crystal is an acetonitrile solvate of Compound A.

[0056] Preferably, the powder X-ray diffraction spectrum of the V-type crystal expressed in 2θ angles using Cu-Kα radiation has characteristic diffraction peaks 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°.

[0057] Preferably, the powder X-ray diffraction spectrum of the V-type crystal expressed in 2θ angles using Cu-Kα radiation has characteristic diffraction peaks 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°.

[0058] Preferably, the V-type crystal uses Cu-Kα radiation, and the powder X-ray diffraction spectrum expressed in 2θ angles is as shown in Table 5, with an error range of ±0.20°.

[0059] [Table 5]

[0060] Preferably, the Form V crystal has a powder X-ray diffraction spectrum essentially as shown in FIG.

[0061] According to one embodiment of the present invention, differential scanning calorimetry (DSC) analysis of the V-type crystals shows that a first endothermic peak appears when heated to a peak temperature of approximately 135.05° C., a second endothermic peak appears when heated to a peak temperature of approximately 192.24° C., and a third endothermic peak appears when heated to a peak temperature of approximately 218.33° C. The V-type crystals may undergo a crystal transition during heating.

[0062] According to one embodiment of the present invention, thermogravimetric analysis (TGA) of the V-type crystals shows that the weight decreases by about 6.4% in the range of 70 to 150°C.

[0063] Preferably, the Type V crystal has a DSC-TGA spectrum essentially as shown in FIG.

[0064] According to one embodiment of the present invention, the V-type crystals are irregularly shaped crystals. Preferably, the V-type crystals have a particle size of less than 10 μm. Preferably, the V-type crystals have a PLM spectrum essentially as shown in FIG.

[0065] According to one embodiment of the present invention, the purity of the V-type crystals is 95% or more, preferably 99% or more.

[0066] The present invention further provides a type IX crystal of Compound A, wherein the type IX crystal has characteristic diffraction peaks 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° in a powder X-ray diffraction spectrum expressed as 2θ angles using Cu-Kα radiation.

[0067] Preferably, the powder X-ray diffraction spectrum of the Type IX crystal expressed in terms of 2θ angles using Cu-Kα radiation has characteristic diffraction 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°.

[0068] Preferably, the powder X-ray diffraction spectrum of the Type IX crystal expressed in 2θ angles using Cu-Kα radiation has characteristic diffraction 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°.

[0069] Preferably, the IX-type crystal uses Cu-Kα radiation, and the powder X-ray diffraction spectrum expressed in 2θ angles is as shown in Table 6, with an error range of ±0.20°.

[0070] [Table 6]

[0071] Preferably, the Form IX crystal has a powder X-ray diffraction spectrum essentially as shown in FIG.

[0072] According to one embodiment of the present invention, the Form IX crystal is an anhydrous form of Compound A.

[0073] According to one embodiment of the present invention, differential scanning calorimetry (DSC) analysis of the Form IX crystal shows that the first endothermic peak appears when heated to a peak temperature of approximately 192.04° C., the second endothermic peak appears when heated to a peak temperature of approximately 201.20° C., and the third endothermic peak appears when heated to a peak temperature of approximately 217.55° C. The Form IX may undergo a crystal transition during heating.

[0074] According to one embodiment of the present invention, thermogravimetric analysis (TGA) of the IX-type crystal shows almost no weight loss before 180°C.

[0075] Preferably, the Form IX crystal has a DSC-TGA spectrum essentially as shown in FIG.

[0076] According to one embodiment of the present invention, the type IX crystal is an irregularly shaped crystal. Preferably, the particle size of the type IX crystal is less than 5 μm. Preferably, the type IX crystal has a PLM spectrum essentially as shown in FIG.

[0077] According to one embodiment of the present invention, the purity of the Type IX crystal is 95% or more, preferably 99% or more.

[0078] The present invention further provides a type VI crystal of Compound A, wherein the type VI crystal has characteristic diffraction peaks 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° in a powder X-ray diffraction spectrum expressed as 2θ angles using Cu-Kα radiation. Preferably, the type VI crystal has characteristic diffraction peaks 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° in a powder X-ray diffraction spectrum expressed as 2θ angles using Cu-Kα radiation.

[0079] Preferably, the powder X-ray diffraction spectrum of the Type VI crystal expressed in 2θ angles using Cu-Kα radiation has characteristic diffraction 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°.

[0080] Preferably, the VI-type crystal uses Cu-Kα radiation, and the powder X-ray diffraction spectrum expressed in 2θ angles is as shown in Table 7, with an error range of ±0.20°.

[0081] [Table 7]

[0082] Preferably, the Form VI crystal has a powder X-ray diffraction spectrum essentially as shown in FIG.

[0083] According to one embodiment of the present invention, the Form VI crystal is a methanol / hydrate of Compound A.

[0084] According to one embodiment of the present invention, differential scanning calorimetry (DSC) analysis of the Form VI crystal shows that it exhibits one endothermic peak upon heating to a peak temperature of approximately 201.31°C.

[0085] According to one embodiment of the present invention, thermogravimetric analysis (TGA) of the VI crystal shows that the weight decreases by about 9.5% in the range of room temperature to 130°C.

[0086] Preferably, the Form VI crystal has a DSC-TGA spectrum essentially as shown in FIG.

[0087] According to one embodiment of the present invention, the VI type crystal is an irregularly shaped crystal. Preferably, the particle size of the VI type crystal is less than 5 μm. Preferably, the VI type crystal has a PLM spectrum essentially as shown in FIG.

[0088] According to one embodiment of the present invention, the purity of the VI type crystal is 95% or more, preferably 99% or more.

[0089] The present invention further provides a Type VII crystal of Compound A, wherein the Type VII crystal has characteristic diffraction peaks 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 a powder X-ray diffraction spectrum expressed as 2θ angles using Cu-Kα radiation.

[0090] According to one embodiment of the present invention, the Form VII crystal is an anhydrous form of Compound A.

[0091] Preferably, the powder X-ray diffraction spectrum of the Type VII crystal expressed in 2θ angles using Cu-Kα radiation has characteristic diffraction 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°.

[0092] Preferably, the powder X-ray diffraction spectrum of the Type VII crystal expressed in 2θ angles using Cu-Kα radiation has characteristic diffraction 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°.

[0093] Preferably, the powder X-ray diffraction spectrum of the Type VII crystal is obtained using Cu-Kα radiation and expressed as 2θ angles as shown in Table 8, with an error range of ±0.20°.

[0094] [Table 8]

[0095] Preferably, the Form VII crystal has a powder X-ray diffraction spectrum essentially as shown in FIG.

[0096] According to one embodiment of the present invention, differential scanning calorimetry (DSC) analysis of the Form VII crystal shows that one endothermic peak appears upon heating to a peak temperature of around 201.07°C.

[0097] According to one embodiment of the present invention, thermogravimetric analysis (TGA) of the Form VII crystal shows little weight loss before 200°C, for example, little weight loss before 180°C.

[0098] Preferably, the Form VII crystal has a DSC-TGA spectrum essentially as shown in FIG.

[0099] According to one embodiment of the present invention, the Type VII crystal is an irregularly shaped crystal. Preferably, the particle size of the Type VII crystal is less than 5 μm. Preferably, the Type VII crystal has a PLM spectrum essentially as shown in FIG.

[0100] According to one embodiment of the present invention, the purity of the Type VII crystal is 95% or more, preferably 99% or more.

[0101] The present invention further provides a method for preparing polymorphs of Compound A.

[0102] According to one embodiment of the present invention, the method for producing the I-type crystal includes the steps of:

[0103] The method includes the steps of mixing compound A with a primary alcohol solvent and an ether solvent, heating and stirring until completely dissolved, cooling, filtering, and drying to obtain the Form I crystals.

[0104] According to one embodiment of the present invention, the first alcoholic solvent may be selected from ethanol and / or isopropanol, preferably ethanol.

[0105] According to one 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.

[0106] According to one embodiment of the present invention, the mass / volume ratio of the compound A, the primary alcohol solvent, and the ether solvent is 1 g:(10-20) mL:(3-8) mL, preferably 1 g:(12-18) mL:(4-6) mL, and exemplarily 1 g:15 mL:5 mL.

[0107] According to one embodiment of the present invention, the heating temperature is 50 to 70°C, preferably 55 to 65°C, and illustratively 50°C.

[0108] According to one embodiment of the present invention, the heating and stirring time is 1 to 5 hours, preferably 2 to 4 hours, and illustratively 3 hours.

[0109] According to one embodiment of the present invention, the mixture is cooled to 0 to 10°C and then filtered.

[0110] According to one embodiment of the present invention, the method for preparing the type I crystals includes the steps of adding compound A to a mixed solvent of ethanol and methyl tert-butyl ether, heating and stirring, cooling, filtering, and vacuum drying to obtain type I crystals.

[0111] The mass / volume ratio of the compound A, ethanol, and methyl tert-butyl ether is 1 g:(10 to 20) mL:(3 to 8) mL.

[0112] The present invention further provides another method for producing the type I crystal, which method comprises the step of heating the type IV crystal to obtain the type I crystal.

[0113] According to one embodiment of the present invention, the IV-type crystal is heated to a temperature at which the solvent can be completely removed. Preferably, the solvent for the IV-type crystal is water. Preferably, the IV-type crystal is heated to 100°C.

[0114] The present invention further provides a method for producing the type II crystal,

[0115] The method includes the steps of mixing Compound A with an arene-based solvent, stirring at room temperature until dissolved, and filtering to obtain the Form II crystals.

[0116] According to one embodiment of the present invention, the arene-based solvent is selected from toluene.

[0117] According to one embodiment of the present invention, the mass / volume ratio of the compound A to the arene solvent is 1 g:(10 to 20) mL, preferably 1 g:(12 to 18) mL, and illustratively 1 g:15 mL.

[0118] According to one embodiment of the present invention, the room temperature is 15 to 30°C, preferably 20 to 25°C.

[0119] According to one embodiment of the present invention, the time for stirring at room temperature is 1 to 5 hours, for example, 3 hours.

[0120] According to an exemplary embodiment of the present invention, the method for producing the type II crystal includes the steps of:

[0121] The method includes the steps of mixing Compound A with toluene, stirring at room temperature until completely dissolved, and filtering to obtain the Form II crystals.

[0122] The mass / volume ratio of the compound A to the arene solvent is 1 g:(10 to 20) mL.

[0123] The present invention further provides a method for producing the III-type crystal, which comprises the step of heating the II-type crystal to obtain the III-type crystal.

[0124] According to one embodiment of the present invention, the type II crystal is heated to a temperature at which the arene solvent can be completely removed, for example, at a heating temperature of 100 to 160°C.

[0125] The present invention further provides a method for producing the type IV crystal, The method includes the steps of mixing Compound A and a secondary alcohol solvent with water, stirring at room temperature until completely dissolved, filtering, and drying to obtain the Form IV crystals.

[0126] According to one embodiment of the present invention, the second alcoholic solvent is selected from isopropanol.

[0127] According to one embodiment of the present invention, the mass / volume ratio of the compound A, the secondary alcohol solvent, and water is 1 g:(1-10) mL:(1-10) mL, preferably 1 g:(3-8) mL:(3-8) mL, and exemplarily 1 g:5 mL:5 mL.

[0128] According to one embodiment of the present invention, the room temperature is 15 to 30°C, preferably 20 to 25°C.

[0129] According to one embodiment of the present invention, the time for stirring at room temperature is 1 to 5 hours, for example, 3 hours.

[0130] According to an exemplary embodiment of the present invention, the method for producing the Type IV crystal includes the steps of: The method includes the steps of mixing Compound A and isopropanol with water, stirring at room temperature until completely dissolved, filtering, and drying under vacuum to obtain the Form IV crystals.

[0131] The mass / volume ratio of the compound A, isopropanol, and water was 1 g:5 mL:5 mL.

[0132] The present invention further provides a method for producing the V-type crystal, The method includes the steps of mixing compound A with a nitrile solvent, stirring at room temperature until completely dissolved, filtering, and drying to obtain the type V crystals.

[0133] According to one embodiment of the present invention, the nitrile solvent is selected from acetonitrile.

[0134] According to one embodiment of the present invention, the mass / volume ratio of the compound A to the nitrile-based solvent is 1 g:(5 to 15) mL, preferably 1 g:(8 to 12) mL, and illustratively 1 g:10 mL.

[0135] According to one embodiment of the present invention, the room temperature is 15 to 30°C, preferably 20 to 25°C.

[0136] According to one embodiment of the present invention, the time for stirring at room temperature is 1 to 5 hours, for example, 3 hours.

[0137] According to one embodiment of the present invention, the method for producing the V-type crystal includes the steps of: The method includes the steps of mixing compound A and acetonitrile in a mass / volume ratio of 1 g:(5-15) mL, stirring at room temperature until completely dissolved, filtering, and drying under vacuum to obtain the type V crystals.

[0138] The present invention further provides a method for producing the VI type crystal, The method includes the steps of mixing compound A with a tertiary alcohol solvent, stirring at room temperature until completely dissolved, filtering, and drying to obtain the Type VI crystals.

[0139] According to one embodiment of the present invention, the tertiary alcohol solvent is selected from methanol.

[0140] According to one embodiment of the present invention, the mass / volume ratio of the compound A to the tertiary alcohol solvent is 1 g:(5-15) mL, preferably 1 g:(8-12) mL, and illustratively 1 g:10 mL.

[0141] According to one embodiment of the present invention, the room temperature is 15 to 30°C, preferably 20 to 25°C.

[0142] According to one embodiment of the present invention, the time for stirring at room temperature is 1 to 5 hours, for example, 3 hours.

[0143] According to one embodiment of the present invention, the method for producing the VI type crystal includes the steps of: The method includes the steps of mixing compound A and methanol in a mass / volume ratio of 1 g:(5-15) mL, stirring at room temperature until completely dissolved, filtering, and vacuum drying to obtain the type VI crystal.

[0144] The present invention further provides a method for producing the VII type crystal, The method includes the steps of mixing Compound A with a first organic solvent, stirring at room temperature until completely dissolved, filtering, and drying to obtain the Type VII crystals.

[0145] According to one 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.

[0146] According to one embodiment of the present invention, the mass / volume ratio of the compound A to the first organic solvent is 1 g:(5 to 15) mL, preferably 1 g:(8 to 12) mL, and illustratively 1 g:10 mL.

[0147] According to one embodiment of the present invention, the room temperature is 15 to 30°C, preferably 20 to 25°C.

[0148] According to one embodiment of the present invention, the time for stirring at room temperature is 1 to 5 hours, for example, 3 hours.

[0149] According to one embodiment of the present invention, the method for producing the VII type crystal includes the steps of: The method includes a step of stirring Compound A and butanone at a mass / volume ratio of 1 g:(5-15) mL at room temperature until completely dissolved, filtering, and vacuum drying to obtain the Type VII crystal.

[0150] The present invention further provides another method for producing the VII-type crystal, which comprises the step of heating the VI-type crystal to obtain the VII-type crystal.

[0151] According to one embodiment of the present invention, the VI crystal is heated to a temperature at which the solvent can be completely removed, preferably a tertiary alcohol solvent and water, for example, 130°C or higher.

[0152] The present invention further provides another method for producing the VII type crystal, The method includes the steps of mixing compound A with a quaternary alcohol solvent, heating and stirring the reaction system until the reaction system is completely dissolved, cooling, adding an organic acid ester to the reaction system, concentrating the reaction system under vacuum until the volume ratio of the quaternary alcohol solvent to the organic acid ester in the reaction system is less than 5%, further adding isopropyl acetate to the reaction system, continuing to cool, stirring, filtering, and drying to obtain the Type VII crystals.

[0153] According to one embodiment of the present invention, the fourth alcohol solvent may be selected from ethanol and / or n-butanol, preferably ethanol.

[0154] According to one embodiment of the present invention, the organic acid ester may be selected from isopropyl acetate and / or ethyl acetate, preferably isopropyl acetate.

[0155] According to one embodiment of the present invention, the mass / volume ratio of the compound A to the quaternary alcohol solvent is 1 g:(2-10) mL, preferably 1 g:(3-8) mL, and illustratively 1 g:5 mL.

[0156] According to one embodiment of the present invention, the heating temperature is 65 to 80°C, and preferably 70 to 75°C.

[0157] According to one embodiment of the present invention, the heating and stirring time is 0.5 to 3 hours, preferably 1 hour.

[0158] According to one embodiment of the present invention, the cooling temperature is 40 to 45°C.

[0159] According to one embodiment of the present invention, before vacuum concentration, an organic acid ester is added to the reaction system so that the mass ratio of the organic acid ester to compound A is (5-15) mL:1 g, preferably (7-12) mL:1 g, and typically 10 mL:1 g. Preferably, the organic acid ester is added to the reaction system in batches, for example, in at least two batches. The organic acid ester is added multiple times to remove the quaternary alcohol solvent.

[0160] According to one embodiment of the present invention, the mass ratio of the organic acid ester to be replenished to compound A is (5-15) mL:1 g, preferably (7-12) mL:1 g, and illustratively 8 mL:1 g.

[0161] According to one embodiment of the present invention, the mixture is cooled to room temperature, preferably 20°C to 25°C.

[0162] According to one embodiment of the present invention, the stirring time after cooling is 1 to 5 hours, for example, 3 hours.

[0163] According to an exemplary embodiment of the present invention, the method for producing the VII type crystal includes the steps of: The method includes the steps of mixing compound A and ethanol, heating to 70-75°C, stirring until the reaction system is completely dissolved, cooling to 40-45°C, adding isopropyl acetate to the reaction system in batches, concentrating under vacuum until the volume ratio of ethanol to isopropyl acetate in the reaction system is less than 5%, further adding isopropyl acetate to the reaction system, continuing to cool to 20-25°C, stirring, filtering, and drying under vacuum to obtain the Type VII crystals.

[0164] Here, the mass / volume ratio of compound A to ethanol is 1 g:(2-10) mL, and the mass ratio of the volume of isopropyl acetate to be replenished to compound A is (5-15) mL:1 g.

[0165] The present invention further provides another method for producing the VII-type crystal, which comprises mixing a mixture of the I-type crystal, the III-type crystal, the VII-type crystal and the IX-type crystal with a second organic solvent to form a slurry, thereby obtaining the VII-type crystal.

[0166] Preferably, the mass ratio of the I-type crystal, III-type crystal, VII-type crystal to the IX-type crystal is (0.9 to 1.1):(0.9 to 1.1):1:(0.9 to 1.1).

[0167] Preferably, the second organic solvent may be selected from one, two or more of butanone, ethyl acetate, isopropyl acetate, ethanol and n-butanol, preferably butanone or isopropyl acetate.

[0168] Preferably, the mass / volume ratio of the mixture to the second organic solvent is (15 to 30) mg:0.5 mL, for example, 20 mg:0.5 mL, 20 mg:0.4 mL, or 20 mg:1 mL.

[0169] Preferably, the temperature for forming the slurry is 15 to 60°C, for example, 20 to 50°C.

[0170] The present invention also provides a method for storing the type III crystal or type VII crystal, wherein the type III crystal or type VII crystal is left under conditions of relative humidity of less than 75% RH, for example, less than 70% RH.

[0171] Preferably, according to the method for storing the Type III crystal or Type VII crystal, the storage temperature may be room temperature to 60°C, for example, 40 to 60°C.

[0172] The present invention further provides pharmaceutical compositions comprising one, two or more of Form I crystals, Form II crystals, Form III crystals, Form IV crystals, Form V crystals, Form VI crystals, Form VII crystals and Form IX crystals of Compound A, and any pharmaceutically acceptable pharmaceutical excipients.

[0173] The present invention further provides a formulation comprising one, two or more of Form I crystals, Form II crystals, Form III crystals, Form IV crystals, Form V crystals, Form VI crystals, Form VII crystals and Form IX crystals of Compound A, and any pharmaceutically acceptable pharmaceutical excipient.

[0174] The present invention further provides use of the above-mentioned Form I crystals, Form II crystals, Form III crystals, Form IV crystals, Form V crystals, Form VI crystals, Form VII crystals and Form IX crystals of Compound A, or said pharmaceutical composition, in the manufacture of a medicament for preventing and / or treating a disease or condition mediated by IRAK.

[0175] According to one embodiment of the present invention, the IRAK-mediated disease or condition is selected from the group consisting of tumors, gout, systemic lupus erythematosus, multiple sclerosis, metabolic syndrome, atherosclerosis, myocardial infarction, sepsis, inflammatory bowel disease, asthma, and allergies.

[0176] The present invention further provides use of the above-mentioned Form I crystals, Form II crystals, Form III crystals, Form IV crystals, Form V crystals, Form VI crystals, Form VII crystals and Form IX crystals of Compound A, or said pharmaceutical composition, in the manufacture of a medicament for preventing and / or treating a disease or condition of interleukin-1 receptor-associated kinase.

[0177] The present invention further provides a method for preventing and / or treating a disease or condition mediated by IRAK, comprising administering to an individual in need thereof a therapeutically effective amount of the above-mentioned Form I crystals, Form II crystals, Form III crystals, Form IV crystals, Form V crystals, Form VI crystals, Form VII crystals and / or Form IX crystals of Compound A, or said pharmaceutical composition, or said formulation.

[0178] In some embodiments, the IRAK is selected from IRAK4-related kinases.

[0179] The present invention further provides a method for preventing and / or treating an interleukin-1 receptor-associated disease, which comprises administering to an individual in need thereof a therapeutically effective amount of the above-mentioned Form I crystals, Form II crystals, Form III crystals, Form IV crystals, Form V crystals, Form VI crystals, Form VII crystals, and Form IX crystals of Compound A, or said pharmaceutical composition, or said formulation.

[0180] According to one embodiment of the present invention, the interleukin-1 receptor-associated kinase disease or condition is selected from the group consisting of tumor, gout, systemic lupus erythematosus, multiple sclerosis, metabolic syndrome, atherosclerosis, myocardial infarction, sepsis, inflammatory bowel disease, asthma, rheumatoid arthritis, sepsis, autoimmune diseases, and allergies.

[0181] The method of the present invention can include administering one, two or more crystals of Compound A of the present invention alone, and administering one, two or more crystals of Compound A of the present invention in combination with one, two or more other chemotherapeutic agents. The administration of multiple drugs can be carried out simultaneously or sequentially.

[0182] (Beneficial Effects of the Present Invention)

[0183] 1) The present invention provides a polymorph of compound A and a method for preparing the same, which involves simple steps, is easy to carry out, has mild reaction conditions, and produces a high product yield. Furthermore, the process does not require multiple purification steps, and the operation is safe and environmentally friendly, which is beneficial for the industrial production of polymorphs.

[0184] 2) The polymorphs obtained by the present invention are stable and can be stably stored under high temperature and low relative humidity conditions. For example, the physical and chemical properties of the III and VII crystals are stable when stored at 60°C (closed) for 7 days, and the chemical properties are stable when stored at 40°C / 75%RH (open) for 7 days. The III and VII crystals also maintain stable physical properties (purity, color, appearance, etc.) at 70%RH or less.

[0185] Furthermore, the crystals of the present invention have good flowability and are easily pulverized, making them suitable for preparation into pharmaceutical compositions.Finally, the polymorphs prepared by the present invention have high purity and few impurities.

[0186] (Definitions and Explanations)

[0187] Various terms and phrases used in the present invention have common meanings known to those skilled in the art, but are still explained and interpreted in detail in the present invention, and if the meaning of the mentioned terms and phrases contradicts the known meaning, the meaning described in the present invention shall prevail.

[0188] Polymorphs of Compound A of the present invention include unsolvated (anhydrate) and solvated crystalline forms of Compound A.

[0189] The characteristic diffraction peaks in the powder X-ray diffraction spectrum of the polymorph of Compound A of the present invention are expressed as 2θ angles, and the allowable range of measurement error is "±0.20°".

[0190] The polymorphs of Compound A of the present invention can be used in combination with other active ingredients, provided that they do not cause other side effects, such as allergic reactions.

[0191] As used herein, the term "composition" is intended to include a product containing each of the specified ingredients in the specified amounts, and any product resulting directly or indirectly from combining the specified amounts of each of the specified ingredients.

[0192] Those skilled in the art can prepare the polymorph of Compound A of the present invention into a suitable pharmaceutical composition using known pharmaceutical carriers. The pharmaceutical composition can be prepared in solid or liquid form, particularly for oral administration, parenteral injection, or rectal administration. The pharmaceutical composition can be prepared in various dosage forms to facilitate administration, such as oral preparations (tablets, capsules, solutions or suspensions, etc.), injectable preparations (injectable solutions or suspensions, or injectable dry powders, etc., which can be used immediately by adding a drug solvent before injection).

[0193] As used herein, the term "therapeutically and / or prophylactically effective amount" is an amount of a drug or pharmaceutical preparation that elicits the biological or medical response of a tissue, system, animal or human that is desired by a researcher, veterinarian, physician or other person.

[0194] When used for the above-mentioned therapeutic and / or prophylactic purposes, the total daily dosage of the polymorphs and pharmaceutical compositions of Compound A of the present invention should be determined by the attending physician within the scope of sound medical judgment. For any particular patient, the specific therapeutically effective dose level will be determined by a variety of factors, including the disease and severity of the disease being treated, the activity of the specific compound used, the specific composition used, the patient's age, weight, general health, sex, and diet, the administration time, route of administration and excretion rate of the specific compound used, the duration of treatment, drugs used in combination with or concomitantly with the specific compound used, and similar factors known in the medical arts. For example, it is common practice in the art to start with a dose of the compound at a level below that required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. [Brief explanation of the drawings]

[0195] [Figure 1] 1 is an XRPD spectrum of type I crystal. [Figure 2] This is a PLM spectrum of type I crystal (scale bar: 20 μm). [Figure 3] This is a DSC-TGA spectrum of type I crystal. [Figure 4] 1 shows XRPD spectra of type II crystals and type III crystals. [Figure 5] This is a PLM spectrum of type II crystal (scale bar: 10 μm). [Figure 6] This is a PLM spectrum of type III crystal (scale bar: 2.5 μm). [Figure 7] This is a DSC-TGA spectrum of type II crystals. [Figure 8] This is a DSC-TGA spectrum of type III crystals. [Figure 9]This is a DVS spectrum of type III crystal. [Figure 10] 1 is a comparative XRPD spectrum of type III crystal before and after DVS test. [Figure 11] 1 is an XRPD spectrum of type IV crystal. [Figure 12] This is a PLM spectrum of type IV crystal (scale bar: 10 μm). [Figure 13] 1 is a DSC-TGA spectrum of type IV crystals. [Figure 14] 1 is an XRPD spectrum of type V crystals. [Figure 15] This is a PLM spectrum of type V crystal (scale bar: 10 μm). [Figure 16] 1 is a DSC-TGA spectrum of type V crystals. [Figure 17] 9 is an XRPD spectrum of type IX crystal. [Figure 18] This is a PLM spectrum of type IX crystal (scale bar: 5 μm). [Figure 19] 9 is a DSC-TGA spectrum of type IX crystal. [Figure 20] 1 is an XRPD spectrum of VI type crystal. [Figure 21] This is a PLM spectrum of the VI crystal (scale bar: 2.5 μm). [Figure 22] 1 is a DSC-TGA spectrum of the VI type crystal. [Figure 23] 1 is an XRPD spectrum of the VII crystal. [Figure 24] This is a PLM spectrum of type VII crystal (scale bar: 5 μm). [Figure 25] 1 is a DSC-TGA spectrum of the VII-type crystal. [Figure 26] This is a DVS spectrum of type VII crystal. [Figure 27] 1 shows comparative XRPD spectra of type VII crystal before and after DVS test. [Figure 28] 1 is an XRPD overlay spectrum of a stability sample. [Figure 29]1 is an XRPD overlay spectrum of a type III crystal sample in a humidity influence test. [Figure 30] 1 is an XRPD overlay spectrum of a Type VII crystal sample in a humidity influence test. [Figure 31] FIG. 1 is a DVS dynamic curve diagram in a humidity influence test. [Figure 32] 1 is an XRPD overlay spectrum of a type III crystal sample after drying in a humidity test. [Figure 33] 1 is an XRPD overlay spectrum of a Type VII crystal sample after drying in a humidity test. [Figure 34] The solubility test results are shown below. [Figure 35] 1 is an XRPD overlay spectrum of a sample after solubility testing. DETAILED DESCRIPTION OF THE INVENTION

[0196] The technical solutions of the present invention will be described in more detail below in combination with specific embodiments. It should be understood that the following examples are intended to illustrate the present invention by way of example and should not be construed as limiting the scope of protection of the present invention. All technologies realized based on the above content of the present invention belong to the scope of the present invention.

[0197] Unless otherwise specified, all raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0198] Synthesis of Compound A

[0199] Reaction scheme: [ka]

[0200] (1) Synthesis of Compound 3 DMAP (42.5 g), compound 2 (63.4 g), and triethylamine (63.9 g) were added to a dichloromethane solution (500 mL) of compound 1 (50 g) at 15° C., and the mixture was stirred at 25° C. for 18 hours. Dichloromethane (200 mL) was added to the reaction solution, which was then washed with water (300 mL × 2) and 1 M diluted hydrochloric acid (300 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 98 g of a yellow solid, a yield of 99% (i.e., compound 3).

[0201] (2) Synthesis of Compound 4 1M dilute hydrochloric acid (300mL) was added to a solution of compound 3 (50g) in tetrahydrofuran (300mL) at 15°C, and the reaction was stirred at 25°C for 20 hours. The mixture was cooled to 0°C. The pH was adjusted to 9 with 1M aqueous sodium hydroxide solution. Extraction was performed with ethyl acetate (200mL x 3). The extract was washed with saturated sodium chloride solution (300mL). The mixture was dried over anhydrous sodium sulfate and filtered. After concentration under reduced pressure, the residue was slurried with petroleum ether (150mL) to give 39g of a white solid, with a yield of 91% (Compound 4).

[0202] (3) Synthesis of Compounds 5 & 6 A solution of compound 4 (34.5 g) in tetrahydrofuran (200 mL) was added dropwise to a solution of methylmagnesium bromide (85.8 mL) in tetrahydrofuran (500 mL) at −40° C., and the mixture was stirred at −40° C. for 4 hours. The reaction was quenched with saturated ammonium chloride solution (100 mL), extracted with ethyl acetate (500 mL × 3), the extract was washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give 12 g of a mixture of colorless oily compound 5 (4.3 g, 10%) and colorless oily compound 6 (7.0 g, 17%).

[0203] compound 5 1 H NMR (400 MHz, CDCl3): δ 7.79 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 8.4 Hz, 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).

[0204] compound 6 1 H NMR (400 MHz, CDCl3): δ 7.79 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.0 Hz, 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).

[0205] (4) Synthesis of Compound 8 A mixed solution of nitric acid (1.6 mL, 70%) and concentrated sulfuric acid (1.6 mL, 98%) 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 reaction mixture was mixed and stirred at -15°C for 2 hours. The reaction solution was then slowly poured into ice water and stirred for 5 minutes, filtered with suction, washed with water, and the solid was collected and dried under reduced pressure to give 2.5 g of a yellow solid, with a yield of 97% (i.e., compound 8).

[0206] (5) Synthesis of Compound 9 Hydrazine hydrate (2.4 mL, 98%) was added to a solution of compound 8 (2.0 g) in DMF (20 mL) at room temperature. After the addition was complete, the reaction mixture was mixed, heated to 120°C, and stirred for 16 hours. The mixture was then cooled to room temperature, mixed, and slowly poured into ice water with stirring. The mixture was filtered with suction, and the solid was washed with water. The solid was collected and concentrated under reduced pressure to give 1.3 g of a yellow solid, with a yield of 67% (i.e., compound 9).

[0207] (6) Synthesis of Compound 10 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 completed, the reaction mixture was mixed and stirred at 15° C. under hydrogen gas protection for 18 hours. The palladium on carbon was removed from the reaction solution by filtration, and the filtrate was concentrated and dried to give 10.4 g of a white solid product, with a yield of 99% (i.e., compound 10).

[0208] (7) Synthesis of Compound 12 EDCI.HCl (2.6 g) was added to a solution of compound 10 (1.5 g) and compound 11 (1.4 g) in Py (15 mL) at 25° C., and the reaction solution was stirred for 16 hours at 25° C. The reaction solution was concentrated to dryness, and the residue was slurried with MeOH / HO (20 mL / 20 mL) to give 1.3 g of a yellow solid product, a yield of 48% (i.e., compound 12).

[0209] (8) Synthesis of Compound A [ka]

[0210] Cesium carbonate (985 mg) was added to a 5 mL DMF solution of compound 12 (300 mg) and compound 5 (344 mg) at 25 °C, and the reaction solution was stirred at 90 °C for 16 hours. The reaction solution was 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 high-performance liquid chromatography (CHCN:H2O (0.1% NH4HCO3) = 15-45%, UV: 214 nm, flow rate: 15 mL / min) to give 70 mg of a yellow solid, a yield of 17% (i.e., compound A).

[0211] 1H NMR (400 MHz, DMSO-d6): δ 14.16 (s, 1H), 8.78 (s, 1H), 8.34 (s, 1H), 8.32-8.30 (m, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.58 (t, J = 8.0 Hz, 1H), 7.13 (s, 1H), 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 = 3.646 min, [M+H] + = 411.1.

[0212] (9) Synthesis of Compound 11 At 25° C., m-CPBA (25 g) was added to a solution of compound 13 (10 g) in 200 mL of DCM, and the reaction solution was stirred for 16 hours at 25° C. The reaction solution was filtered, and the filtrate was quenched with a saturated solution of 15.6 g of sodium sulfite. The mixture was stirred for 2 hours, extracted, and the aqueous phase was adjusted to pH < 7 with dilute hydrochloric acid and extracted with DCM (50 mL × 3). The combined organic phase was concentrated, and the residue was slurried in 300 mL of EA to give 10.1 g of a white solid, a 90% yield (i.e., compound 11).

[0213] In the following examples, the XRPD test instrument was PIXcel. 1D The detector is a Nalytic EMPYREAN, and the test conditions are

[0214] The DVS test equipment was a dynamic water vapor sorption apparatus (Vsorp-Enhanced, proUmid). The test conditions were as follows: a sufficient amount of sample was added to the Vsorp-Enhanced instrument to simulate dynamic water vapor sorption; the weight change at different humidity equilibrations at 25°C was recorded; and XRPD tests were performed on the DVS-tested samples.

[0215] Example 1

[0216] Form I crystal manufacturing method: Compound A (1 g) was added to ethanol / methyl tert-butyl ether (15 mL / 5 mL), heated to 60°C, stirred for 3 hours, cooled to 0-10°C, filtered, and the cake was vacuum-dried to obtain type I crystals (0.85 g). The purity of the type I crystals was 99% or more.

[0217] Form I crystals were characterized by XRPD, PLM, DSC, and TGA. Form I crystals were anhydrous. 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 diagram indicates that the sample is composed of irregular crystals of less than 20 μm in size (Figure 2). TGA analysis showed that the sample lost 1.2% weight between 140 and 200 °C (Figure 3), which corresponds to the NMR analysis that the sample contained 0.9% ethanol and 0.3% methyl tert-butyl ether. DSC analysis indicated that the sample had only one endothermic peak (Figure 3), with an initial temperature of 191 °C.

[0218] The XRPD spectrum of the I-type crystal is a powder X-ray diffraction spectrum expressed in 2θ angles, and the 2θ values ​​are as shown in Table 1 below.

[0219] [Table 1] Example 2

[0220] Manufacturing method of type II crystals and type III crystals: Compound A (1 g) was added to toluene (15 mL), and the mixture was stirred at 20 to 25°C for 3 hours and filtered. The cake was Type II crystals, and the purity of the Type II crystals was 99% or more.

[0221] The obtained type II crystals were dried in vacuum at 50 to 60°C, and after drying, type III crystals (0.90 g) were obtained, and the purity of the type III crystals was 99% or more.

[0222] The Form II crystals were characterized by XRPD, PLM, DSC, and TGA. The positions and intensities of the characteristic XRPD peaks are shown in Table 2, and the XRPD spectrum is shown in Figure 4. The PLM diagram (Figure 5) indicated that the sample was irregularly crystalline, with a particle size of <10 μm and a relatively high degree of crystallinity. The TGA test showed that the sample lost 9.6% weight between 100 and 160 °C (Figure 7), corresponding to the 9.5% toluene remaining in the sample indicated by the NMR test. Therefore, the Form II crystals were a toluene solvate. DSC showed that the first endothermic peak appeared when the Form II crystals were heated to a peak temperature of 136.92 °C, and a second endothermic peak appeared when heated to a peak temperature of 136.92 °C. After desolvation, the Form II crystals transformed into the Form III crystals.

[0223] The type III crystals were 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. The PLM diagram (Figure 6) indicates that the sample is irregularly crystalline, with a particle size of <5 μm. The crystallinity is relatively high. TGA indicates that the sample shows little weight loss before 180°C (Figure 8). The DSC spectrum indicates that the sample has an initial melting point of approximately 187°C (Figure 8). The DVS results (Figure 9) indicate that the sample is slightly hygroscopic, with a hygroscopicity of only 0.22% within the 0-80% RH range. However, after the DVS test, the type III crystals transformed into a mixed crystal of type III and type IV crystals (Figure 10).

[0224] The XRPD spectra of the II-type crystals and the III-type crystals have 2θ values ​​in the powder X-ray diffraction spectra expressed as 2θ as shown in Tables 2 and 3, respectively.

[0225] [Table 2]

[0226] [Table 3]

[0227] Example 3

[0228] Method for producing type IV crystals: Compound A (1 g) was added to isopropanol / water (5 mL / 5 mL), stirred at 20-25°C for 3 hours, filtered, and the cake was dried in vacuo to obtain type IV crystals (0.90 g). The purity of the type IV crystals was 99% or more.

[0229] After the type IV crystals were heated to 100°C to completely dehydrate them, the type IV crystals transformed into type I crystals.

[0230] The Form IV crystals were characterized by XRPD, PLM, DSC, and TGA. The positions and intensities of the characteristic XRPD peaks are shown in Table 4, and the XRPD spectrum is shown in Figure 11. The PLM diagram (Figure 12) showed that the sample was irregularly crystalline, with a particle size of <10 μm and a relatively high degree of crystallinity. The DSC spectrum showed multiple endothermic peaks (Figure 13), indicating that the sample may undergo a crystalline transformation during heating. TGA showed that the sample lost 16.9% weight between room temperature and 150°C (Figure 13), and the water content was 4.2 wt%, indicating that the Form IV crystals were a monohydrate of Compound A. After complete dehydration, the Form IV crystals transformed into Form I crystals (Figure 11).

[0231] The XRPD spectrum of the IV type crystal is a powder X-ray diffraction spectrum expressed in terms of 2θ angles, and the 2θ values ​​are as shown in Table 4 below.

[0232] [Table 4]

[0233] Example 4

[0234] Manufacturing method of type V crystals and type IX crystals: Compound A (1 g) was added to acetonitrile (10 mL), stirred at 20-25°C for 3 hours, filtered, and the cake was dried in vacuo to obtain type V crystals (0.90 g). The purity of the type V crystals was 99% or more.

[0235] After heating the IV type crystals to 150°C, the V type crystals changed to IX type crystals, and the purity of the IX type crystals was 99% or more.

[0236] The V-type crystals were characterized by XRPD, PLM, DSC, and TGA. The positions and intensities of the characteristic XRPD peaks are listed in Table 5, and the XRPD spectrum is shown in Figure 14. The PLM diagram (Figure 15) showed that the sample was irregularly crystalline, with a particle size of <10 μm and a relatively high degree of crystallinity. DSC (Figure 16) showed that the sample, after complete desolvation (the first endothermic peak appears at a peak temperature of approximately 135.05 °C), exhibited two endothermic peaks (the second endothermic peak appears upon heating to a peak temperature of approximately 192.24 °C, and the third endothermic peak appears upon heating to a peak temperature of approximately 218.33 °C), suggesting that a crystalline transition may occur during heating. TGA (Figure 16) showed that the sample lost 6.4% weight between 70 and 150 °C, corresponding to the 5.1% acetonitrile remaining in the sample as indicated by the NMR analysis. Therefore, the V-type crystal was an acetonitrile solvate. After complete desolvation, the V-type crystal transformed into the IX-type crystal (Figures 14 and 17).

[0237] Form IX crystals were characterized by XRPD, PLM, DSC, and TGA. The positions and intensities of the characteristic XRPD peaks are listed in Table 6, and the XRPD spectrum is shown in Figure 17. The PLM diagram (Figure 18) indicated that the sample was irregularly crystalline with a particle size of <5 μm. The crystallinity was relatively high. DSC showed multiple endothermic peaks, with the first appearing when heated to a peak temperature of approximately 192.04°C, the second appearing when heated to a peak temperature of approximately 201.20°C, and the third appearing when heated to a peak temperature of approximately 217.55°C (Figure 19), indicating that the sample may undergo a crystalline transition during heating. TGA showed that the sample showed little weight loss before 180°C (Figure 19).

[0238] The XRPD spectra of the V-type crystals and the IX-type crystals are powder X-ray diffraction spectra represented by 2θ, and the 2θ values ​​are as shown in Tables 5 and 6 below.

[0239] [Table 5]

[0240] [Table 6]

[0241] Example 5

[0242] Method for producing type VI crystals: Compound A (1 g) was added to methanol (10 mL), stirred at 20-25°C for 3 hours, filtered, and the cake was dried in vacuo to obtain type VI crystals (0.80 g). The purity of the type VI crystals was 99% or more.

[0243] Crystalline Form VI was characterized by XRPD, PLM, DSC, and TGA. The positions and intensities of the characteristic XRPD peaks are shown in Table 7, and the XRPD spectrum is shown in Figure 20. The PLM diagram (Figure 21) shows that the sample is irregularly crystalline with a particle size of <5 μm. The crystallinity is relatively high. DSC (Figure 22) shows that after the sample is completely desolvated, there is one endothermic peak, indicating the sample is melting. The onset temperature is 200°C and the enthalpy value is 30 J / g. TGA (Figure 22) shows that the sample loses 9.5% weight between room temperature and 130°C, which corresponds to the broad endothermic peak in DSC. After the sample is dehydrated or desolvated and the solvent and water are removed at 40-50°C, the crystalline Form VI transforms into crystalline Form VII (Figure 20).

[0244] The XRPD spectrum of the VI-type crystal is a powder X-ray diffraction spectrum expressed in terms of 2θ angles, and the 2θ values ​​are as shown in Table 7 below.

[0245] [Table 7]

[0246] Example 6

[0247] Method for producing type VI crystals: Compound A (1 g) was added to butanone (10 mL), stirred at 20 to 25°C for 3 hours, filtered, and the cake was dried in vacuo to obtain type VI crystals (0.85 g). The purity of the type VI crystals was 99% or more.

[0248] The XRPD spectrum of the VI crystal is shown in FIG.

[0249] Example 7

[0250] Manufacturing method of type VII crystal: Compound A (1.5 kg) was added to ethanol (7.5 L) and stirred at 70-75°C for 1 hour. The reaction mixture was clear and cooled to 40-45°C. Isopropyl acetate (15 L) was added in batches. The mixture was then concentrated under vacuum to remove ethanol. Isopropyl acetate was added several times to maintain the volume of the reaction mixture at 12 L. The mixture was cooled to 20-25°C, stirred for 3 hours, filtered, and the cake was dried under vacuum to obtain Type VII crystals (1.4 kg). The purity of Type VII crystals was greater than 99%.

[0251] Crystalline Form VII was characterized by XRPD, PLM, DSC, TGA, and DVS. The positions and intensities of the characteristic XRPD peaks are shown in Table 8, and the XRPD spectrum is shown in Figure 23. PLM (Figure 24) showed that the sample was irregularly crystalline with a particle size of <5 μm. The crystallinity was relatively high. DSC (Figure 25) showed that the sample had one endothermic peak, melting at an onset temperature of 200°C with an enthalpy value of 102 J / g. TGA (Figure 25) showed that the sample showed almost no weight loss before 200°C. DVS (Figure 26) showed only 0.29% moisture absorption in the 0-80% RH range, indicating slight hygroscopicity, and the crystal structure remained unchanged before and after the DVS test (Figure 27).

[0252] The XRPD spectrum of the VII-form crystal is a powder X-ray diffraction spectrum expressed as 2θ angles, and the 2θ values ​​are as shown in Table 8 below.

[0253] [Table 8]

[0254] Example 8

[0255] Competitive slurry experiment A predetermined amount of crystals I, III, VII and IX were used to carry out competitive slurry experiments with butanone and isopropyl acetate, respectively. The results of the slurry experiments are shown in Table 9. The results show that crystals VII can be obtained from all of the multiple slurry experiments.

[0256] [Table 9]

[0257] Stability studies of Form III and Form VII crystals Solid-state stability and chemical stability experiments were performed on Form III crystals and Form VII crystals at 60°C (closed) and 40°C / 75% RH (open) for 7 days, respectively. The results showed that Form III crystals and Form VII crystals were stable in terms of physical and chemical properties when stored at 60°C (closed) for 7 days, and stable in terms of chemical properties when stored at 40°C / 75% RH (open) for 7 days. However, when stored at 40°C / 75% RH (open) for 7 days, both crystals produced a small amount of hydrate Form IV crystals. The amount of Form IV crystals produced in Form III crystals was greater than that of Form VII crystals. The experimental results are shown in Table 10 and Figure 28.

[0258] [Table 10]

[0259] Humidity effect test for type III crystals and type VII crystals The results of the stability experiment showed that both the III and VII crystals produced a small amount of hydrate IV crystals when left at 40°C / 75%RH (open air) for 7 days. Therefore, further humidity effects were investigated at 40°C.

[0260] All experimental results are shown in Table 11 and Figures 29 to 33. When Type III crystals (Figure 29) and Type VII crystals (Figure 30) were left at 70% RH for 23 hours, their physical properties were stable. When left at 80% and 90% RH for 23 hours, a small amount of Compound IV crystals was produced. After drying overnight in a vacuum at 40°C, the Compound IV crystals changed to Compound XV crystals. However, the Compound IV crystals could be completely removed by drying in a vacuum at 80°C for 3 days (Figures 32 and 33).

[0261] The humidity test results show that the physical properties of the Type III crystals and Type VII crystals are stable at 70% RH or less, but a small amount of hydrate Type IV crystals is formed at 70% RH or more, and the hydrate can be removed by vacuum drying at 80°C.

[0262] [Table 11]

[0263] Solubility Test The solubilities of both Form III and Form VII crystals increased with decreasing pH in the biological media. Both crystals were most soluble in SGF (0.323 mg / mL vs. 0.183 mg / mL at 0.5 h) and least soluble in FaSSIF (0.034 mg / mL vs. 0.025 mg / mL at 0.5 h). In the three biological media, the solubility of Form III crystals at 0.5 h was 1.5 times that of Form VII crystals. During the solubility test, the two crystals showed significant decomposition with increasing stirring time. All experimental results are shown in Table 12 and Figures 34-35. Form III and Form VII crystals underwent crystalline transformation in all three biological media. In FaSSIF and SGF, both Form III crystals transformed into Form IV crystals. In FeSSIF, Form III crystals transformed into a mixture of Form IV and Form XIII crystals. In FaSSIF and FeSSIF, all of the Form VII crystals transformed into Form IV crystals, while in SGF, Form VII crystals transformed into a mixture of Form IV and Form XV crystals. The HPLC purity of Form III and Form VII crystals decreased significantly in the three biological media (the HPLC purity before addition to the biological media was assumed to be 100%). Therefore, the compound is unstable in biological media (Table 13).

[0264] [Table 12]

[0265] [Table 13]

[0266] The above describes the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A polymorph of 2-((2-(trans-4-hydroxy-cis-4-methylcyclohexyl)-6-methoxy-2H-indazol-5-yl)carbamoyl)-6-methylpyridine 1-oxide represented by Compound A of the following formula: 【Chemistry 1】 Compound A

2. The polymorph is a Form III crystal, and the Form III crystal has characteristic diffraction peaks 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° in a powder X-ray diffraction spectrum expressed as 2θ angles using Cu-Kα radiation; Preferably, the Form III crystal is an anhydrous form of Compound A; Preferably, the Form III crystal has a powder X-ray diffraction spectrum essentially as shown in FIG. Preferably, differential scanning calorimetry (DSC) analysis of the Form III crystal shows that a first endothermic peak appears when heated to a peak temperature of approximately 188.81°C; Preferably, thermogravimetric analysis (TGA) of the Form III crystal shows little weight loss before 180°C; Preferably, the Form III crystal has a DSC-TGA spectrum essentially as shown in FIG. Preferably, the type III crystal is an irregular crystal, preferably the particle size of the type III crystal is less than 5 μm, preferably the type III crystal has a PLM spectrum essentially as shown in FIG. 6; 2. The polymorph of claim 1, wherein the purity of the Form III crystal is 95% or greater.

3. The polymorph is a Type VII crystal, and the Type VII crystal has characteristic diffraction peaks 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 a powder X-ray diffraction spectrum expressed as 2θ angles using Cu-Kα radiation; Preferably, the Type VII crystal is an anhydrous form of Compound A; Preferably, the Type VII crystal has a powder X-ray diffraction spectrum essentially as shown in Figure 23, Preferably, differential scanning calorimetry (DSC) analysis of the Form VII crystal shows that one endothermic peak appears when heated to a peak temperature of around 201.07°C; Preferably, thermogravimetric analysis (TGA) of said Form VII crystal shows little weight loss before 200°C, preferably little weight loss before 180°C; Preferably, the Type VII crystal has a DSC-TGA spectrum essentially as shown in FIG. 25, Preferably, the Type VII crystal is an irregular crystal, preferably the particle size of the Type VII crystal is less than 5 μm, and preferably the Type VII crystal has a PLM spectrum essentially as shown in FIG. 24; 2. The polymorph of claim 1, wherein the purity of Form VII is preferably 95% or greater.

4. The polymorph is a type I crystal, and the type I crystal has characteristic diffraction peaks 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° in a powder X-ray diffraction spectrum expressed as 2θ angles using Cu-Kα radiation; 2. The polymorph of claim 1, wherein the Form I crystal preferably has an X-ray powder diffraction spectrum essentially as shown in FIG.

5. The polymorph is a type II crystal, and the type II crystal has characteristic diffraction peaks 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° in a powder X-ray diffraction spectrum expressed as 2θ angles using Cu-Kα radiation; 2. The polymorph of claim 1, wherein the Form II crystalline form has an X-ray powder diffraction spectrum essentially as shown in FIG.

6. The polymorph is a Type IV crystal, and the Type IV crystal has characteristic diffraction peaks 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° in a powder X-ray diffraction spectrum expressed as 2θ angles using Cu-Kα radiation; 10. The polymorph of claim 1, wherein the Form IV crystal preferably has an X-ray powder diffraction spectrum essentially as shown in Figure 11.

7. The polymorph is a V-type crystal, and the V-type crystal has characteristic diffraction peaks 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° in a powder X-ray diffraction spectrum expressed as 2θ angles using Cu-Kα radiation; 10. The polymorph of claim 1, wherein the Form V crystals have an X-ray powder diffraction spectrum essentially as shown in FIG.

8. The polymorph is a Type IX crystal, and the Type IX crystal has characteristic diffraction peaks 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° in a powder X-ray diffraction spectrum expressed as 2θ angles using Cu-Kα radiation; 10. The polymorph of claim 1, wherein the Form IX crystal preferably has an X-ray powder diffraction spectrum essentially as shown in Figure 17.

9. The polymorph is a VI type crystal, and the VI type crystal has characteristic diffraction peaks 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° in a powder X-ray diffraction spectrum expressed as 2θ angles using Cu-Kα radiation; 2. The polymorph of claim 1, wherein the Form VI crystal preferably has an X-ray powder diffraction spectrum essentially as shown in Figure 20.

10. 3. The method for producing a type III crystal according to claim 2, comprising the step of heating a type II crystal to obtain the type III crystal, The type II crystal has characteristic diffraction peaks 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° in a powder X-ray diffraction spectrum expressed as 2θ angles using Cu-Kα radiation, Preferably, the Form II crystal is a toluene solvate of Compound A.

11. A method for producing the VII-type crystal according to claim 3, selected from any one of the methods described below. (Method 1 is mixing compound A with a first organic solvent, stirring at room temperature until completely dissolved, filtering, and drying to obtain the Type VII crystals; the first organic solvent may be selected from one, two or more of butanone, isopropyl acetate, ethanol and n-butanol; Method 2 comprises heating the Type VI crystal to obtain the Type VII crystal, The VI type crystal has characteristic diffraction peaks 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° in a powder X-ray diffraction spectrum expressed as 2θ angles using Cu-Kα radiation, Preferably, the Type VI crystal is a methanol / hydrate of Compound A; Method three is the method comprises the steps of mixing compound A with an alcoholic solvent, heating and stirring the reaction system until the entire reaction system is dissolved, cooling the reaction system, adding an organic acid ester to the reaction system, concentrating the reaction system under vacuum until the volume ratio of the alcoholic solvent to the organic acid ester in the reaction system is less than 5%, further adding the organic acid ester to the reaction system, cooling the reaction system, continuing to stir, filtering, and drying to obtain type VII crystals; Preferably, the alcoholic solvent is selected from ethanol and / or n-butanol; Preferably, the organic acid ester is selected from isopropyl acetate and / or ethyl acetate; Preferably, the heating temperature is 65 to 80°C. Method 4 includes mixing a mixture of the Type I crystal, the Type III crystal, the Type VII crystal, and the Type IX crystal with a second organic solvent to form a slurry, thereby obtaining the Type VII crystal; The type I crystal has characteristic diffraction peaks 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° in a powder X-ray diffraction spectrum expressed as 2θ angles using Cu-Kα radiation, The type IX crystal has characteristic diffraction peaks 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° in a powder X-ray diffraction spectrum expressed as 2θ angles using Cu-Kα radiation, Preferably, the mass ratio of the I-type crystal, the III-type crystal, the VII-type crystal to the IX-type crystal is (0.9 to 1.1):(0.9 to 1.1):1:(0.9 to 1.1), Preferably, the second organic solvent is selected from one, two or more of butanone, ethyl acetate, isopropyl acetate, ethanol and n-butanol; Preferably, the slurrying temperature is 15 to 60°C.

12. leaving the type III crystal or type VII crystal under conditions of a relative humidity of less than 75% RH; Preferably, the method for storing the type III crystal according to claim 2 or the type VII crystal according to claim 3, wherein the temperature for leaving the crystal is from room temperature to 60°C.

13. A pharmaceutical composition comprising the polymorph of any one of claims 1 to 9.

14. A formulation comprising the polymorph of any one of claims 1 to 9, and optionally a pharmaceutically acceptable pharmaceutical excipient.

15. 10. Use of a polymorph according to any one of claims 1 to 9 or a pharmaceutical composition according to claim 7 in the manufacture of a medicament for the prevention and / or treatment of a disease or condition mediated by IRAK, comprising: Preferably, the disease or condition mediated by IRAK is selected from diseases such as tumors, gout, systemic lupus erythematosus, multiple sclerosis, metabolic syndrome, atherosclerosis, myocardial infarction, sepsis, inflammatory bowel disease, asthma, or allergies.

16. Use of the polymorph of any one of claims 1 to 9 or the pharmaceutical composition of claim 13 in the manufacture of a medicament for the prevention and / or treatment of a disease or condition of interleukin-1 receptor associated kinase.

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