Salts of GLP-1R receptor agonist compounds and their crystalline forms, methods for their preparation, and use

Abstract

This invention discloses salts of GLP-1R receptor agonist compounds, their crystalline forms, methods for their preparation, and their uses. Specifically, 2-amino-2-(hydroxymethyl)-1,3-propanediol salts or solvates thereof of the compound of formula I are disclosed. The 2-amino-2-(hydroxymethyl)-1,3-propanediol salts or solvates thereof of the compound of formula I provided by this invention have good crystalline morphological stability and good medical prospects. [Formula 1] JPEG2026519940000052.jpg45103

Description

[Technical Field]

[0001] This application claims priority to Chinese Patent Application No. 2023104355011, filed on 21 April 2023. The contents of the aforementioned Chinese Patent Application are incorporated herein by reference in their entirety.

[0002] This disclosure relates to salts of GLP-1R receptor agonist compounds, their crystalline forms, methods for preparing them, and their use, and more specifically to the 2-amino-2-(hydroxymethyl)-1,3-propanediol salt of (S)-2-((4-(2-((4-chloro-2-fluorobenzyl)oxy)phenyl)piperidine-1-yl)methyl)-1-(oxetane-2-aminomethyl)-1H-benzo[d]imidazole-6-carboxylate, methods for preparing it, and its use. [Background technology]

[0003] (S)-2-((4-(2-((4-chloro-2-fluorobenzyl)oxy)phenyl)piperidine-1-yl)methyl)-1-(oxetane-2-aminomethyl)-1H-benzo[d]imidazole-6-carboxylic acid is a GLP-1R receptor agonist used to treat metabolic disorders such as diabetes, obesity, non-alcoholic fatty liver disease, and hypertension.

[0004] Glucagon-like peptide-1 (GLP-1) is an endogenous incretin that can stimulate insulin release. It binds to and activates the GLP-1 receptor (GLP-1R) of the BG protein-coupled receptor (GPCR) family, thereby exerting its regulatory function. GLP-1 receptor agonists (GLP-1RAs) are synthetic drugs used to mimic the physiological function of GLP-1. After binding to GLP-1R in pancreatic cells, GLP-1RAs can stimulate insulin synthesis and secretion in a glucose-dependent manner, reduce glucagon release, act on GLP-1Rs in the central nervous system to reduce food intake, increase energy expenditure by promoting thermogenesis in brown adipose tissue and lipolysis in white adipose tissue, and delay gastric emptying. GLP-1RAs are clinically suitable for adult patients with T2DM, exhibiting a significant glucose-lowering effect while reducing body weight and systolic blood pressure and improving dyslipidemia. GLP-1RAs can be used alone or in combination with other glucose-lowering drugs. Results from multiple clinical trials have shown that adding a GLP-1 receptor agonist (GLP-1RA) to a patient who has not responded to monotherapy with oral hypoglycemic agents (metformin, sulfonylurea) is effective.

[0005] The preparation of the compound of formula I is described in Example 3 of Chinese Patent CN202110334388, filed on March 29, 2021. The structure of the compound of formula I is as follows: [ka] Compound of formula I

[0006] In formula I, the compound of formula I is (S)-2-((4-(2-((4-chloro-2-fluorobenzyl)oxy)phenyl)piperidine-1-yl)methyl)-1-(oxetane-2-aminomethyl)-1H-benzo[d]imidazole-6-carboxylic acid, and the compound of formula I is prepared according to Example 3 of CN202110334388.

[0007] Compounds of formula I are used to treat metabolic disorders. Metabolic disorders are selected from one or more of the following: impaired glucose tolerance, hyperglycemia, dyslipidemia, type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM), hypertriglyceridemia, insulin resistance, impaired glucose tolerance (IGT), diabetic dyslipidemia, hyperlipidemia, arteriosclerosis, atherosclerosis, hypertension, obesity, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, hepatic fibrosis, cirrhosis, and lethargy. However, compounds of formula I have poor stability at room temperature and high-temperature conditions, and their solid properties are insufficient. Under conditions such as grinding, compression, and mixing, the stability and crystalline morphology of the compounds are easily altered. Therefore, there is an urgent need to improve the properties, stability, and pharmaceutical processability of the compounds through novel approaches, and to provide a solid foundation for subsequent applications of the compounds. [Overview of the project]

[0008] The technical problem that this disclosure aims to solve is that existing GLP-1R receptor agonist compounds are inferior in solid form and have low stability. To this end, this disclosure provides salts of GLP-1R receptor agonist compounds, their crystalline forms, methods for preparing them, and their uses. The crystalline forms of the salts provided by this disclosure exhibit good stability and have promising pharmaceutically acceptable prospects.

[0009] This disclosure provides a 2-amino-2-(hydroxymethyl)-1,3-propanediol salt of a compound of formula I or a solvate thereof (a solvate of a 2-amino-2-(hydroxymethyl)-1,3-propanediol salt of a compound of formula I). [ka]

[0010] In some embodiments, the 2-amino-2-(hydroxymethyl)-1,3-propanediol salt of the compound of formula I is the compound of formula II. [ka]

[0011] In some embodiments, the solvate of the 2-amino-2-(hydroxymethyl)-1,3-propanediol salt of the compound of formula I is water or 1,4-dioxane, and the molar ratio of the 2-amino-2-(hydroxymethyl)-1,3-propanediol salt of the compound of formula I to the solvent is preferably 1:(1~0.5). For example, the molar ratio of the 2-amino-2-(hydroxymethyl)-1,3-propanediol salt of the compound of formula I to water is 1:1. In another example, the molar ratio of the 2-amino-2-(hydroxymethyl)-1,3-propanediol salt of the compound of formula I to 1,4-dioxane is 1:0.5.

[0012] This disclosure provides a crystalline form A of the monohydrate of the compound of formula II, obtained using Cu-Kα radiation, having an X-ray powder diffraction pattern expressed with respect to a 2θ angle, and including diffraction peaks at 4.1±0.2°, 8.2±0.2°, 10.7±0.2°, 12.3±0.2°, and 20.7±0.2°.

[0013] The structure of the monohydrate of the compound of formula II is as follows: [ka]

[0014] Preferably, the single crystal of the monohydrate of the compound of formula II is orthorhombic.

[0015] In some embodiments, the X-ray powder diffraction pattern of crystalline form A of the monohydrate of compound II, obtained using Cu-Kα radiation and expressed with respect to the 2θ angle, further includes diffraction peaks at one or more of the following positions: 14.1±0.2°, 14.9±0.2°, 20.5±0.2°, and 21.8±0.2°.

[0016] In some embodiments, the X-ray powder diffraction pattern of crystalline Form A of the monohydrate of the compound of Formula II, obtained using Cu-Kα radiation and expressed in terms of 2θ angle, includes diffraction peaks at 4.1 ± 0.2°, 8.2 ± 0.2°, 10.7 ± 0.2°, 12.3 ± 0.2°, 14.1 ± 0.2°, 14.9 ± 0.2°, 20.5 ± 0.2° and 21.8 ± 0.2°.

[0017] In some embodiments, the X-ray powder diffraction pattern of crystalline Form A of the monohydrate of the compound of Formula II, obtained using Cu-Kα radiation and expressed in terms of 2θ angle, includes the diffraction peaks shown in Table 1.

[0018] [Table 1-1] [Table 1-2]

[0019] In some embodiments, the X-ray powder diffraction (XRPD) pattern of crystalline Form A of the monohydrate of the compound of Formula II obtained using Cu-Kα radiation is substantially as shown in Figure 1.

[0020] In some embodiments, crystalline Form A of the monohydrate of the compound of Formula II has a differential scanning calorimetry (DSC) curve showing endothermic peaks at 129.98 ± 3 °C and 196.25 ± 3 °C.

[0021] In some embodiments, the differential scanning calorimetry curve of crystalline Form A of the monohydrate of the compound of Formula II is as shown in Figure 2.

[0022] In some embodiments, crystalline Form A of the monohydrate of the compound of Formula II has a thermogravimetric analysis (TGA) curve showing a weight loss of 2.468% within the temperature range of 30 °C ± 3 to 135 ± 3 °C.

[0023] In some embodiments, the thermogravimetric analysis curve of crystalline Form A of the monohydrate of the compound of Formula II is as shown in Figure 3.

[0024] In some embodiments, the present disclosure provides single crystals of monohydrates of compounds of formula II having the following unit cell parameters. ·Space group P212121 a = 6.13580 (4) Å, α = 90° b = 12.99957 (8) Å, β = 90° · c = 42.4637 (3) Å, γ = 90° Unit cell volume = 3387.02 (4) Å 3 • Number of asymmetric units in the unit cell Z = 4 ·Crystal density 1.379mg / m 3

[0025] Here, the structure of the monohydrate of the compound of formula II is as follows: [ka]

[0026] Preferably, the single crystal of the monohydrate of the compound of formula II is orthorhombic.

[0027] This disclosure provides crystalline form B of the 1,4-dioxane solvate of the compound of formula II, which is obtained using Cu-Kα radiation and has an X-ray powder diffraction pattern expressed with respect to a 2θ angle including diffraction peaks at 3.4±0.2°, 7.4±0.2°, 11.2±0.2°, and 14.6±0.2°.

[0028] The structure of the 1,4-dioxane solvate of the compound of formula II is as follows: [ka]

[0029] In some embodiments, the X-ray powder diffraction pattern of crystalline form B of the 1,4-dioxane solvate of the compound of formula II, obtained using Cu-Kα radiation and expressed with respect to the 2θ angle, further includes one or more diffraction peaks at the following positions: 8.2±0.2°, 12.3±0.2°, 13.7±0.2°, 16.1±0.2°, 20.0±0.2°, 22.0±0.2°, 22.5±0.2°, and 29.3±0.2°.

[0030] In some embodiments, the X-ray powder diffraction pattern of crystalline form B of the 1,4-dioxane solvate of the compound of formula II, obtained using Cu-Kα radiation and expressed with respect to the 2θ angle, includes diffraction peaks at 3.4±0.2°, 7.4±0.2°, 8.2±0.2°, 11.2±0.2°, 12.3±0.2°, 13.7±0.2°, 14.6±0.2°, 16.1±0.2°, 20.0±0.2°, 22.0±0.2°, 22.5±0.2°, and 29.3±0.2°.

[0031] In some embodiments, the X-ray powder diffraction pattern of crystalline form B of the 1,4-dioxane solvate of compound II, obtained using Cu-Kα radiation and expressed with respect to the 2θ angle, includes the diffraction peaks shown in Table 2.

[0032] [Table 2]

[0033] In some embodiments, the X-ray powder diffraction (XRPD) patterns of crystalline form B of the 1,4-dioxane solvate of the compound of formula II obtained using Cu-Kα radiation are substantially as shown in Figure 6.

[0034] In some embodiments, the crystalline form B of the 1,4-dioxane solvate of the compound of formula II has a differential scanning calorimetry (DSC) curve showing endothermic peaks at 107.2±3°C and 186.6±3°C.

[0035] In some embodiments, the differential scanning calorimetry curve of crystalline form B of the 1,4-dioxane solvate of the compound of formula II is as shown in Figure 7.

[0036] In some embodiments, the crystalline form B of the 1,4-dioxane solvate of the compound of formula II has a thermogravimetric analysis (TGA) curve showing a weight loss of 2.029% in the temperature range of 33±3°C to 150±3°C.

[0037] In some embodiments, the thermogravimetric analysis curve of crystalline form B of the 1,4-dioxane solvate of the compound of formula II is as shown in Figure 8.

[0038] This disclosure provides a crystalline form C of a compound of formula II having an X-ray powder diffraction pattern obtained using Cu-Kα radiation, with diffraction peaks at 3.7±0.2°, 7.5±0.2°, 9.7±0.2°, and 15.5±0.2°, expressed with respect to the 2θ angle. [ka]

[0039] In some embodiments, the X-ray powder diffraction pattern of the crystalline form C of the compound of formula II, expressed with respect to the 2θ angle and obtained using Cu-Kα radiation, further includes one or more diffraction peaks at the following positions: 11.3±0.2°, 12.3±0.2°, 14.4±0.2°, 14.7±0.2°, 17.2±0.2°, 20.5±0.2°, 21.8±0.2°, and 29.5±0.2°.

[0040] In some embodiments, the X-ray powder diffraction pattern of the crystalline form C of the compound of formula II, expressed with respect to the 2θ angle and obtained using Cu-Kα radiation, includes diffraction peaks at 3.7±0.2°, 7.5±0.2°, 9.7±0.2°, 11.3±0.2°, 12.3±0.2°, 14.4±0.2°, 14.7±0.2°, 15.5±0.2°, 17.2±0.2°, 20.5±0.2°, 21.8±0.2°, and 29.5±0.2°.

[0041] In some embodiments, the X-ray powder diffraction pattern of the crystalline form C of the compound of formula II, obtained using Cu-Kα radiation and expressed with respect to the 2θ angle, includes the diffraction peaks shown in Table 3.

[0042] [Table 3]

[0043] In some embodiments, the X-ray powder diffraction (XRPD) patterns of crystalline form C of the compound of formula II obtained using Cu-Kα radiation are substantially as shown in Figure 9.

[0044] In some embodiments, the crystalline form C of the compound of formula II has a differential scanning calorimetry (DSC) curve showing an endothermic peak at 196.9 ± 3°C.

[0045] In some embodiments, the differential scanning calorimetry curve of the crystalline form C of the compound of formula II is as shown in Figure 10.

[0046] In some embodiments, the crystalline form C of the compound of formula II has a thermogravimetric analysis (TGA) curve that does not show weight loss within the temperature range of 30±3℃ to 180±3℃.

[0047] In some embodiments, the thermogravimetric analysis curve of the crystalline form C of the compound of formula II is as shown in Figure 11.

[0048] In some embodiments, the crystalline form C of the compound of formula II is a non-solvated crystalline form.

[0049] In some embodiments, the crystalline form C of the compound of formula II is solvent-free.

[0050] This disclosure provides a crystalline form D of a compound of formula II having an X-ray powder diffraction pattern obtained using Cu-Kα radiation, with diffraction peaks at 3.9±0.2°, 8.1±0.2°, 10.6±0.2°, and 14.9±0.2°, expressed with respect to the 2θ angle. [ka]

[0051] In some embodiments, the X-ray powder diffraction pattern of the crystalline form D of the compound of formula II, expressed with respect to the 2θ angle and obtained using Cu-Kα radiation, further includes one or more diffraction peaks at the following positions: 10.2±0.2°, 10.6±0.2°, 14.3±0.2°, 17.8±0.2°, 20.0±0.2°, and 20.2±0.2°.

[0052] In some embodiments, the X-ray powder diffraction pattern of the crystalline form D of the compound of formula II, expressed with respect to the 2θ angle and obtained using Cu-Kα radiation, includes diffraction peaks at 3.9±0.2°, 8.1±0.2°, 10.2±0.2°, 10.6±0.2°, 14.3±0.2°, 14.9±0.2°, 17.8±0.2°, 20.0±0.2°, and 20.2±0.2°.

[0053] In some embodiments, the X-ray powder diffraction pattern of the crystalline form D of the compound of formula II, obtained using Cu-Kα radiation and expressed with respect to the 2θ angle, includes the diffraction peaks shown in Table 4.

[0054] [Table 4]

[0055] In some embodiments, the X-ray powder diffraction (XRPD) patterns of crystalline morphology D of the compound of formula II obtained using Cu-Kα radiation are substantially as shown in Figure 12.

[0056] In some embodiments, the crystalline form D of the compound of formula II has a differential scanning calorimetry (DSC) curve showing endothermic peaks at 178.3±3°C and 194.0±3°C.

[0057] In some embodiments, the differential scanning calorimetry curve of crystalline form D of the compound of formula II is as shown in Figure 13.

[0058] In some embodiments, the crystalline form D of the compound of formula II has a thermogravimetric analysis (TGA) curve showing a weight loss of 0.59% in the temperature range of 30±3°C to 101±3°C and a weight loss of 0.81% in the temperature range of 140±3°C to 180±3°C.

[0059] In some embodiments, the thermogravimetric analysis curve of the crystalline form D of the compound of formula II is as shown in Figure 14.

[0060] In some embodiments, the crystalline form D of the compound of formula II is a non-solvated crystalline form.

[0061] In some embodiments, the crystalline form D of the compound of formula II is solvent-free.

[0062] This disclosure provides a crystalline form E of a compound of formula II having an X-ray powder diffraction pattern obtained using Cu-Kα radiation and expressed with respect to the 2θ angle, with diffraction peaks at 3.7±0.2°, 7.6±0.2°, 9.8±0.2°, and 14.7±0.2°. [ka]

[0063] In some embodiments, the X-ray powder diffraction pattern of the crystalline form E of the compound of formula II, expressed with respect to the 2θ angle and obtained using Cu-Kα radiation, further includes one or more diffraction peaks at the following positions: 11.2±0.2°, 15.6±0.2°, 17.4±0.2°, 19.8±0.2°, 20.3±0.2°, 21.9±0.2°, 29.5±0.2°, and 19.0±0.2°.

[0064] In some embodiments, the X-ray powder diffraction pattern of the crystalline form E of the compound of formula II, expressed with respect to the 2θ angle and obtained using Cu-Kα radiation, includes diffraction peaks at 3.7±0.2°, 7.6±0.2°, 9.8±0.2°, 11.2±0.2°, 14.7±0.2°, 15.6±0.2°, 17.4±0.2°, 19.8±0.2°, 20.3±0.2°, 21.9±0.2°, and 29.5±0.2°.

[0065] In some embodiments, the X-ray powder diffraction pattern of the crystalline form E of the compound of formula II, obtained using Cu-Kα radiation and expressed with respect to the 2θ angle, includes the diffraction peaks shown in Table 5.

[0066] [Table 5]

[0067] In some embodiments, the X-ray powder diffraction (XRPD) patterns of crystalline form E of the compound of formula II obtained using Cu-Kα radiation are substantially as shown in Figure 15.

[0068] In some embodiments, the crystalline form E of the compound of formula II has a differential scanning calorimetry (DSC) curve showing an endothermic peak at 192.0 ± 3°C.

[0069] In some embodiments, the differential scanning calorimetry curve of the crystalline form E of the compound of formula II is as shown in Figure 16.

[0070] In some embodiments, the crystalline form E of the compound of formula II has a thermogravimetric analysis (TGA) curve that does not show weight loss in the range of 30±3℃ to 160±3℃.

[0071] In some embodiments, the thermogravimetric analysis curve of the crystalline form E of the compound of formula II is as shown in Figure 17.

[0072] In some embodiments, the crystalline form E of the compound of formula II is a non-solvated crystalline form.

[0073] In some embodiments, the crystalline form E of the compound of formula II is solvent-free.

[0074] This disclosure relates to a method for preparing the crystalline form of a compound of formula II,

[0075] (1) A step of mixing the above 2-amino-2-(hydroxymethyl)-1,3-propanediol salt of the compound of formula I with a solvent to obtain a mixed solution.

[0076] (2) A step of filtering the mixture and drying it to obtain the crystalline form of the 2-amino-2-(hydroxymethyl)-1,3-propanediol salt of the compound of formula I, Includes,

[0077] When the solvent is an alcohol solvent (e.g., methanol), the crystalline form A of the monohydrate of the compound of formula II is obtained.

[0078] When the solvent is 1,4-dioxane, the crystalline form B of the 1,4-dioxane solvate of the compound of formula II is obtained.

[0079] When the solvent is tetrahydrofuran, crystalline form C of the compound of formula II is obtained.

[0080] In the preparation method, the mixture may be mixed while stirring to form a suspension.

[0081] In the above preparation method, the mixture obtained in (1) may be a suspension.

[0082] In the preparation method, drying is carried out by conventional methods in the art, such as drying under reduced pressure or drying under normal pressure.

[0083] In the preparation method, when obtaining crystalline form A of the monohydrate of the compound of formula II, the mass-to-volume ratio of the compound of formula II to the solvent may be 1:(1~100)g / mL, for example, 1:30g / mL.

[0084] In the preparation method, when obtaining crystalline form A of the monohydrate of the compound of formula II, the mixing temperature may be 0 to 150°C, for example, 20 to 80°C, and is preferably heated under reflux.

[0085] In the preparation method, when obtaining crystalline form A of the monohydrate of the compound of formula II, the mixing time is conventional in the art and is, for example, 2 hours.

[0086] In the preparation method, when obtaining crystalline form A of the monohydrate of the compound of formula II, filtration may be performed at room temperature, or for example, the mixture may be cooled to room temperature and then filtered.

[0087] In the preparation method, if crystalline form B of the 1,4-dioxane solvate of the compound of formula II is obtained, the mass-to-volume ratio of the compound of formula II to the solvent may be 1:(10~50)g / mL, for example, 1:20g / mL.

[0088] In the preparation method, if crystalline form B of the 1,4-dioxane solvate of the compound of formula II is obtained, the mixing temperature may be room temperature, where room temperature is 20-30°C, for example, 25°C.

[0089] In the preparation method, if crystalline form B of the 1,4-dioxane solvate of the compound of formula II is obtained, the mixing time is conventional in the art, for example, 24 hours.

[0090] In the preparation method, if crystalline form B of the 1,4-dioxane solvate of the compound of formula II is obtained, the mixing is carried out by conventional methods in the art, such as mixing with stirring.

[0091] In the preparation method, if crystalline form B of the 1,4-dioxane solvate of the compound of formula II is obtained, filtration may be performed at room temperature.

[0092] In the preparation method, if crystalline form C of the compound of formula II is obtained, the mass-to-volume ratio of the compound of formula II to the solvent may be 1:(5~20)g / mL, for example, 1:10g / mL.

[0093] In the preparation method, if crystalline form C of the compound of formula II is obtained, the mixing temperature may be 45 to 55°C, for example, 25 to 50°C, preferably 50°C.

[0094] In the preparation method, if crystalline form C of the compound of formula II is obtained, the mixing time is conventional in the art, for example, 48 hours.

[0095] In the preparation method, if crystalline form C of the compound of formula II is obtained, the mixing is carried out by conventional methods in the art, such as mixing while stirring.

[0096] This disclosure provides a method for preparing crystalline form D of a compound of formula II, comprising the step of heating crystalline form C of the compound of formula II or crystalline form B of the 1,4-dioxane solvate of the compound of formula II at 160°C for 5 to 10 minutes (for example, after cooling) to obtain crystalline form D of the compound of formula II.

[0097] This disclosure provides a method for preparing crystalline form E of a compound of formula II, comprising the step of heating crystalline form B of the 1,4-dioxane solvate of the compound of formula II or crystalline form C of the compound of formula II to 80 to 100°C for 24 to 96 hours (for example, 48 hours) to obtain crystalline form E of the compound of formula II.

[0098] The method for preparing the crystalline form of the compound of formula II further includes the following steps:

[0099] (1a) A step in which the compound of formula I is mixed with solvent A to obtain a mixed solution A,

[0100] (1b) A step in which 2-amino-2-(hydroxymethyl)-1,3-propanediol is mixed with solvent B to obtain a mixture B,

[0101] Here, the order of process (1a) and process (1b) does not matter.

[0102] (2) A step in which mixed solution A and mixed solution B are mixed, crystallized, filtered, and dried to obtain the compound of formula II.

[0103] In step (1a), solvent A is a conventional solvent in the art, preferably one or more of the following: alcohol solvents, ester solvents, ether solvents, ketone solvents, chlorinated hydrocarbon solvents, aromatic hydrocarbon solvents, nitrile solvents, alkane solvents, and nitrogen-containing compound solvents. Examples of alcohol solvents include methanol, ethanol, or isopropanol; examples of ether solvents include methyl tert-butyl ether, isopropyl ether, tetrahydrofuran, or 2-methyltetrahydrofuran; examples of nitrogen-containing compound solvents include N-methylpyrrolidone; and examples of ester solvents include methyl formate, ethyl formate, ethyl acetate, or isopropyl acetate. More preferably, solvent A is methanol, ethanol, acetone, ethyl acetate, a mixed solution of N-heptane and ethyl acetate, a mixed solution of N-heptane and tetrahydrofuran, a mixed solution of methanol and water, a mixed solution of acetone and water, a mixed solution of ethanol and water, a mixed solution of tetrahydrofuran and water, a mixed solution of methanol, water and dimethyl sulfoxide, a mixed solution of 2-methyltetrahydrofuran, ethyl acetate and methanol, a mixed solution of ethyl acetate, tetrahydrofuran and water, or a mixed solution of ethyl acetate, 2-methyltetrahydrofuran and water.

[0104] Preferably, in step (1a), solvent A is an alcohol solvent, such as methanol.

[0105] In step (1a), if solvent A is a mixed solution of 2-methyltetrahydrofuran, ethyl acetate, and methanol, the volume ratio of 2-methyltetrahydrofuran, ethyl acetate, and methanol may be 5:5:2.

[0106] In step (1a), the mass-to-volume ratio of the compound of formula I to solution A is conventional in the art and preferably 10:(10~500) g / mL, for example 10:200 g / mL.

[0107] In step (1a), the temperature for mixing is conventional in the art, for example, 10 to 160°C, preferably 20 to 30°C.

[0108] In step (1a), the mixture A may be filtered further after mixing.

[0109] In step (1b), solvent B is one or more of the conventional solvents in the art, preferably water, an alcohol solvent, and a sulfur-containing compound solvent, wherein the alcohol solvent may be ethanol or methanol, and the sulfur-containing compound solvent may be dimethyl sulfoxide.

[0110] Preferably, in step (1b), solvent B is water.

[0111] In step (1b), the mass ratio of 2-amino-2-(hydroxymethyl)-1,3-propanediol to solvent B is conventional in the art, for example, 1:(1~260), preferably 3.2:800.

[0112] In step (2), mixing is carried out by conventional methods in the art, for example, by dropping mixture B into mixture A.

[0113] In step (2), the temperature for crystallization is conventional in the art, for example, 20-30°C.

[0114] In step (2), the time for crystallization is under conventional conditions in the art, and is generally carried out until no more of the compound of formula II precipitates. The mixing time is, for example, 1 to 24 hours, preferably 12 to 24 hours.

[0115] In step (2), filtration may include steps of filtration, washing (e.g., washing with solution A and / or solution B) and pH adjustment (e.g., washing with water to pH = 7 to 8).

[0116] In step (2), drying is carried out by conventional methods in the art, such as drying under vacuum at 45°C.

[0117] This disclosure provides a pharmaceutical composition comprising the above 2-amino-2-(hydroxymethyl)-1,3-propanediol salt of the compound of formula I or its solvate (solvate of the 2-amino-2-(hydroxymethyl)-1,3-propanediol salt of the compound of formula I) and a pharmaceutically acceptable carrier. Preferably, the 2-amino-2-(hydroxymethyl)-1,3-propanediol salt or solvate of the compound of formula I is the single crystal of the monohydrate of the compound of formula II, crystalline form A of the monohydrate of the compound of formula II, crystalline form B of the 1,4-dioxane solvate of the compound of formula II, crystalline form C of the compound of formula II, crystalline form D of the compound of formula II, or crystalline form E of the compound of formula II.

[0118] This disclosure provides the use of the compound of formula I or its solvate in the manufacture of pharmaceuticals for the prevention and / or treatment of metabolic diseases, the above pharmaceutical composition or the above 2-amino-2-(hydroxymethyl)-1,3-propanediol salt (solvate of the 2-amino-2-(hydroxymethyl)-1,3-propanediol salt of the compound of formula I), preferably the 2-amino-2-(hydroxymethyl)-1,3-propanediol salt of the compound of formula I or its solvate is the above single crystal of the monohydrate of the compound of formula II, crystalline form A of the monohydrate of the compound of formula II, crystalline form B of the 1,4-dioxane solvate of the compound of formula II, crystalline form C of the compound of formula II, crystalline form D of the compound of formula II, or crystalline form E of the compound of formula II.

[0119] For use, metabolic disorders may be selected from any one of the following: impaired glucose tolerance, hyperglycemia, dyslipidemia, type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM), hypertriglyceridemia, insulin resistance, impaired glucose tolerance (IGT), diabetic dyslipidemia, hyperlipidemia, arteriosclerosis, atherosclerosis, hypertension, obesity, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, hepatic fibrosis, cirrhosis, or lethargy.

[0120] The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present disclosure without violating common sense in the art.

[0121] All reagents and starting materials used in this disclosure are commercially available.

[0122] A positive and progressive effect of this disclosure is that the salts of the GLP-1R receptor agonist compounds provided herein have good stability and excellent solid properties. They are stable under compression, grinding, and high humidity conditions. Therefore, they have good pharmaceutically prospects. [Brief explanation of the drawing]

[0123] [Figure 1] Figure 1 shows the X-ray powder diffraction pattern of crystalline form A of the monohydrate of the compound of formula II. [Figure 2] Figure 2 shows the differential scanning calorimetry curve of crystalline form A of the monohydrate of the compound of formula II. [Figure 3] Figure 3 shows the thermogravimetric analysis curve of crystalline form A of the monohydrate of the compound of formula II. [Figure 4] Figure 4 shows the single-crystal simulated X-ray powder diffraction pattern of the monohydrate of the compound of formula II. [Figure 5] Figure 5 shows the single crystal structure of the monohydrate of the compound of formula II. [Figure 6] Figure 6 shows the X-ray powder diffraction pattern of crystalline form B of the 1,4-dioxane solvate of the compound of formula II. [Figure 7] Figure 7 shows the differential scanning calorimetry curve of crystalline form B of the 1,4-dioxane solvate of compound II. [Figure 8] Figure 8 shows the thermogravimetric analysis curve of crystalline form B of the 1,4-dioxane solvate of the compound of formula II. [Figure 9] Figure 9 shows the X-ray powder diffraction pattern of crystalline form C of the compound of formula II. [Figure 10] Figure 10 shows the differential scanning calorimetry curve for crystalline form C of the compound of formula II. [Figure 11] Figure 11 shows the thermogravimetric analysis curve of crystalline form C of the compound of formula II. [Figure 12] Figure 12 shows the X-ray powder diffraction pattern of crystalline form D of the compound of formula II. [Figure 13] Figure 13 shows the differential scanning calorimetry curve for crystalline form D of the compound of formula II. [Figure 14] Figure 14 shows the thermogravimetric analysis curve of crystalline form D of the compound of formula II. [Figure 15] Figure 15 shows the X-ray powder diffraction pattern of crystalline form E of the compound of formula II. [Figure 16] Figure 16 shows the differential scanning calorimetry curve of crystalline form E of the compound of formula II. [Figure 17] Figure 17 shows the thermogravimetric analysis curve of crystalline form E of the compound of formula II. [Figure 18] Figure 18 shows the X-ray powder diffraction pattern of crystalline form I of the compound of formula I. [Figure 19] Figure 19 shows the X-ray powder diffraction pattern of crystalline form II of the compound of formula I. [Figure 20] Figure 20 shows the X-ray powder diffraction pattern of crystalline form III of the compound of formula I. [Figure 21] Figure 21 shows the X-ray powder diffraction patterns of crystalline form I of the compound of formula I from tableting and grinding tests. [Figure 22] Figure 22 shows the X-ray powder diffraction patterns of the crystalline form II of the compound of formula I from tableting and grinding tests. [Figure 23]Figure 23 shows the X-ray powder diffraction patterns of the crystalline form III of the compound of formula I from tableting and grinding tests. [Figure 24] Figure 24 shows the X-ray powder diffraction pattern of a tablet test of crystalline form A of the monohydrate of the compound of formula II. [Figure 25] Figure 25 shows the X-ray powder diffraction patterns of the monohydrate of compound II in crystalline form A from tablet compression and grinding tests. [Modes for carrying out the invention]

[0124] The present disclosure will be described in detail below with reference to examples, but the scope of the disclosure is not limited thereto. Experimental methods that do not specify particular conditions in the following examples should be selected according to conventional methods and conditions or according to product specifications.

[0125] All actual methods and techniques used in the examples of this disclosure are conventional reagents and methods in the art. Unless otherwise specified, temperatures are expressed in degrees Celsius (°C), as will be apparent to those skilled in the art. The operating temperature is room temperature, which is in the range of 10 to 30°C.

[0126] Equipment and methods

[0127] The obtained reaction samples were analyzed using various detection and analytical methods.

[0128] (1) X-ray diffraction patterns were collected using a Bruker D2 PhAser instrument with the following instrument parameters. [Table 6]

[0129] (2) DSC DSC curves were acquired using a TA INSTRUMENTS-WATERS LLC DSC250. Samples were weighed into a sample pan, accurately measured, and recorded. The samples were then punctured into an aluminum crucible and tested. The temperature was increased from 25°C to a final temperature of 300°C at a heating rate of 10°C / min.

[0130] (3) TGA TGA curves were obtained using a TGA 550 from TA INSTRUMENTS-WATERS LLC. Samples were weighed into sample pans and subjected to ambient air testing at a heating rate of 10°C / min from 40°C to 300°C.

[0131] (4) HPLC, the measurement parameters are shown in the table below. [Table 7]

[0132] Detection method:

[0133] Purity test: The sample to be tested was dissolved in methanol solution, and the sample purity was measured by HPLC.

[0134] Hygroscopicity Test Method (DVS): The hygroscopicity of the sample was measured using SMS Intrinsic Plus. The sample was weighed into a sample pan, equilibrated at 25°C until dm / dt was less than 0.002%, and then measured in time mode. Humidity was adjusted from 60%-90%-0%-90%-0%RH in increments of 10%RH per step, and each humidity level was maintained for 1 hour.

[0135] Grinding test: An appropriate amount of the crystalline compound to be tested was placed in a mortar and ground for 2 minutes and 5 minutes, followed by XRPD detection.

[0136] Compressibility test: The crystalline compound to be tested was compressed into a tablet under a pressure of 20 mPa, and the XRPD results were subsequently detected.

[0137] Solubility test:

[0138] Approximately 10 mg of the crystalline compound was weighed, added to 3 mL of water, shaken, and maintained at 37°C. After 24 hours, a sample was taken and its solubility was measured by HPLC.

[0139] Example 1: (S)-2-((4-(2-((4-chloro-2-fluorobenzyl)oxy)phenyl)piperidine-1-yl)methyl)-1-(oxetane-2-aminomethyl)-1H-benzo[d]imidazole-6-carboxylate hydrochloride

[0140] Methanol (20 mL) was added to the flask, and then acetyl chloride (1.53 g) was added dropwise. After the addition was complete, the mixture was stirred for 1 hour and then left to stand.

[0141] (S)-2-((4-(2-((4-chloro-2-fluorobenzyl)oxy)phenyl)piperidine-1-yl)methyl)-1-(oxetane-2-aminomethyl)-1H-benzo[d]imidazole-6-carboxylic acid (10 g) (i.e., the compound of formula I prepared according to the method described in Example 3 of patent CN202110334388) was added to methanol (200 mL) and stirred at 20-30°C. The methanol solution of acetyl chloride described above was slowly added dropwise to the methanol solution of the compound of formula I. After the addition was complete, the mixture was stirred for 1 hour, followed by the dropwise addition of water (100 mL). After stirring for 3 hours, the mixture was filtered, and the filtered cake was washed twice with methanol / water (50 mL x 2, 2:1). The filtered cake was dried under vacuum at 45°C until it reached a constant weight to obtain 9.1 g of product. 1H NMR(400MHz CD3OD)9.62-9.72(1H,m),8.12(1H,d),7.99-8.01(1H,dd),7.72-7.73(1H,d),7.4 5-7.48(1H,m),7.32-7.34(1H,dd),7.22-7.26(3H,m),7.09-7.12(1H,td),6.85-6. 86(1H,dd),5.19-5.20(2H,d),4.55-4.60(1H,q),4.09-4.22(2H,ABq),3.94-3.96( 1H,d),3.77-3.89(2H,m),3.06-3.20(4H,m),2.31-2.48(5H,m),2.22-2.29(1H,m).

[0142] HPLC purity: 94.74%

[0143] Example 2: Sodium salt of (S)-2-((4-(2-((4-chloro-2-fluorobenzyl)oxy)phenyl)piperidine-1-yl)methyl)-1-(oxetane-2-aminomethyl)-1H-benzo[d]imidazole-6-carboxylate

[0144] (S)-2-((4-(2-((4-chloro-2-fluorobenzyl)oxy)phenyl)piperidine-1-yl)methyl)-1-(oxetane-2-aminomethyl)-1H-benzo[d]imidazole-6-carboxylic acid (2 g) (prepared according to the method described in Example 3 of Specification No. CN202110334388) was added to dimethyl sulfoxide (1 mL) and stirred at 20-30°C. Sodium hydroxide solution (3.75 mL, 1 mol / L) was added dropwise, and acetone (20 mL) was added dropwise while stirring. After stirring for 5 hours, the mixture was filtered by suction. The filtration cake was quickly washed twice with acetone and then transferred to a flask to dry under reduced pressure to obtain an off-white solid (1.5 g). 1H NMR(400MHz CD3OD)8.13(1H,m),8.09-8.10(1H,dd),7.74-7.76(1H,d),7.41-7.44(1H, ddt),7.31-7.32(1H,dd),7.23-7.26(3H,m),7.15-7.11(1H,m),6.85-6.87( 1H,m),5.19-5.20(2H,d),4.55-4.60(1H,m),4.04-4.21(2H,ABq),3.77-3.8 8(2H,m),3.63(2H,s),2.85-2.95(3H,m),2.72-2.78(2H,m).HPLC purity: 99.90%

[0145] Example 3: 2-amino-2-(hydroxymethyl)-1,3-propanediol salt of (S)-2-((4-(2-((4-chloro-2-fluorobenzyl)oxy)phenyl)piperidine-1-yl)methyl)-1-(oxetane-2-aminomethyl)-1H-benzo[d]imidazole-6-carboxylate

[0146] (S)-2-((4-(2-((4-chloro-2-fluorobenzyl)oxy)phenyl)piperidine-1-yl)methyl)-1-(oxetane-2-aminomethyl)-1H-benzo[d]imidazole-6-carboxylic acid (10 g prepared according to the method described in Example 3 of Patent CN202110334388) was added to methanol (200 mL), stirred at 20-30°C until clear, and then filtered. Tris(hydroxymethyl)aminomethane (3.2 g) was dissolved in water (800 g) and slowly added dropwise to the above reaction mixture while stirring at 20-30°C, and a solid precipitated. The above mixture was stirred for 12-24 hours. After filtration, the filter cake was washed twice with methanol / water (500 mL x 2, 2:1), and then washed with water until the pH was 7-8. The filtered cake was dried under vacuum at 45°C to a constant weight, yielding 11.0 g of the product, i.e., the compound of formula II. 1H NMR(400MHz CD3OD)8.21(1H,d),7.96-7.97(1H,dd),7.94-7.95(1H,d),7.50-7.61(1H,td),7.25-7.29(2H,m),7 .20-7.22(2H,m),6.96-7.02(1H,dd),6.94-6.96(1H,t),5.12(1H,m),4.95(2H,s),4.85-4.89(2H,m) ,4.73-4.74(1H,m),4.63-4.70(1H,m),4.47-4.48(1H,m),3.67-4.46(2H,ABq),3.67(6H,s),2.96-3 .02(3H,m),2.78-2.88(1H,m),2.48-2.58(1H,m)2.20-2.28(2H,m)1.75-1.80(4H,m).HPLC purity: 99.95%

[0147] Example 3-1: 2-amino-2-(hydroxymethyl)-1,3-propanediol salt of (S)-2-((4-(2-((4-chloro-2-fluorobenzyl)oxy)phenyl)piperidine-1-yl)methyl)-1-(oxetane-2-aminomethyl)-1H-benzo[d]imidazole-6-carboxylate

[0148] (S)-2-((4-(2-((4-chloro-2-fluorobenzyl)oxy)phenyl)piperidine-1-yl)methyl)-1-(oxetane-2-aminomethyl)-1H-benzo[d]imidazole-6-carboxylic acid (10 g prepared according to the method described in Example 3 of Patent CN202110334388) was added to tetrahydrofuran (400 mL), stirred at 20-30°C until clear, and then filtered. Tris(hydroxymethyl)aminomethane (2.1 g) was dissolved in water (150 g) and slowly added dropwise to the above reaction mixture while stirring at 20-30°C, causing a solid to precipitate. The above mixture was stirred for 10-16 hours. After filtration, the filter cake was washed twice with tetrahydrofuran / water (80 mL x 2, 3:1), and then washed with water until the pH was 7-8. The filtered cake was dried under vacuum at 45°C to a constant weight, yielding 11.4 g of the product, i.e., the compound of formula II.

[0149] Example 3-2: 2-amino-2-(hydroxymethyl)-1,3-propanediol salt of (S)-2-((4-(2-((4-chloro-2-fluorobenzyl)oxy)phenyl)piperidine-1-yl)methyl)-1-(oxetane-2-aminomethyl)-1H-benzo[d]imidazole-6-carboxylate

[0150] (S)-2-((4-(2-((4-chloro-2-fluorobenzyl)oxy)phenyl)piperidine-1-yl)methyl)-1-(oxetane-2-aminomethyl)-1H-benzo[d]imidazole-6-carboxylic acid (10 g prepared according to the method described in Example 3 of Patent CN202110334388) was added to N-methylpyrrolidone (20 mL), stirred at 120-150°C until clear, and then filtered. Tris(hydroxymethyl)aminomethane (4.2 g) was dissolved in water (50 g) and slowly added dropwise to the above reaction mixture while stirring at 20-30°C, causing a solid to precipitate. The above mixture was stirred for 10-16 hours. After filtration, the filter cake was washed twice with ethyl acetate (30 mL x 2), and then washed with water until the pH was 7-8. The filtered cake was dried under vacuum at 45°C to a constant weight, yielding 9.1 g of the product, i.e., the compound of formula II.

[0151] Example 3-3: 2-amino-2-(hydroxymethyl)-1,3-propanediol salt of (S)-2-((4-(2-((4-chloro-2-fluorobenzyl)oxy)phenyl)piperidine-1-yl)methyl)-1-(oxetane-2-aminomethyl)-1H-benzo[d]imidazole-6-carboxylate

[0152] (S)-2-((4-(2-((4-chloro-2-fluorobenzyl)oxy)phenyl)piperidine-1-yl)methyl)-1-(oxetane-2-aminomethyl)-1H-benzo[d]imidazole-6-carboxylic acid (10 g prepared according to the method described in Example 3 of Patent CN202110334388) was added to 2-methyltetrahydrofuran (50 mL), ethyl acetate (50 mL), and methanol (20 mL), and the mixture was stirred at 20-30°C until clear, and then filtered. Tris(hydroxymethyl)aminomethane (2.1 g) was dissolved in water (30 g) and slowly added dropwise to the above reaction mixture while stirring at 20-30°C, and a solid precipitated. The above mixture was stirred for 2-3 hours. After filtration, the filter cake was washed twice with ethyl acetate (10 mL x 2), and then washed with water until the pH was 7-8. The filtered cake was dried under vacuum at 45°C to a constant weight, yielding 11.9 g of the product, i.e., the compound of formula II.

[0153] Examples 3-4: 2-amino-2-(hydroxymethyl)-1,3-propanediol salt of (S)-2-((4-(2-((4-chloro-2-fluorobenzyl)oxy)phenyl)piperidine-1-yl)methyl)-1-(oxetane-2-aminomethyl)-1H-benzo[d]imidazole-6-carboxylate

[0154] (S)-2-((4-(2-((4-chloro-2-fluorobenzyl)oxy)phenyl)piperidine-1-yl)methyl)-1-(oxetane-2-aminomethyl)-1H-benzo[d]imidazole-6-carboxylic acid (10 g prepared according to the method described in Example 3 of Patent CN202110334388) was added to ethanol (300 mL), stirred at 78°C until clear, and then filtered. Tris(hydroxymethyl)aminomethane (3.2 g) was dissolved in ethanol (100 mL) and slowly added dropwise to the above reaction mixture while stirring at 20-30°C, and a solid precipitated. The above mixture was stirred for about 8 hours. After filtration, the filtration cake was washed twice with ethanol (50 mL x 2). The filtration cake was dried to a constant weight under vacuum at 45°C to obtain 12.0 g of the product, i.e., the compound of formula II.

[0155] Crystal transformation process

[0156] Example 4: Crystalline form A (compound of formula II) of monohydrate of 2-amino-2-(hydroxymethyl)-1,3-propanediol salt of (S)-2-((4-(2-((4-chloro-2-fluorobenzyl)oxy)phenyl)piperidine-1-yl)methyl)-1-(oxetane-2-aminomethyl)-1H-benzo[d]imidazole-6-carboxylate

[0157] Add 1 g of the 2-amino-2-(hydroxymethyl)-1,3-propanediol salt of (S)-2-((4-(2-((4-chloro-2-fluorobenzyl)oxy)phenyl)piperidine-1-yl)methyl)-1-(oxetane-2-aminomethyl)-1H-benzo[d]imidazole-6-carboxylate prepared in Example 3 to 30 mL of methanol, stir, heat under reflux for 2 hours, allow to cool naturally to room temperature, and stir for another 2 hours. The mixture was mixed and filtered to obtain a solid, which was then dried to a constant weight under reduced pressure to obtain 0.80 g of product A, which is the crystalline form of monohydrate of the 2-amino-2-(hydroxymethyl)-1,3-propanediol salt of (S)-2-((4-(2-((4-chloro-2-fluorobenzyl)oxy)phenyl)piperidine-1-yl)methyl)-1-(oxetane-2-aminomethyl)-1H-benzo[d]imidazole-6-carboxylate (compound of formula II).

[0158] Table 1 shows the XRPD pattern analysis data for crystalline form A of the monohydrate of the compound of formula II.

[0159] [Table 8-1] [Table 8-2]

[0160] The following is the characterization data for crystalline form A of the monohydrate of the compound of formula II. [Table 9]

[0161] The obtained crystalline form A of the monohydrate of compound II is a single crystal of the monohydrate of compound II, its simulated XRPD pattern is shown in Figure 4, its single crystal structure is shown in Figure 5, and its main crystallographic parameters are as follows. [Table 10]

[0162] Example 5: Crystalline form B of the 1,4-dioxane solvate of the 2-amino-2-(hydroxymethyl)-1,3-propanediol salt of (S)-2-((4-(2-((4-chloro-2-fluorobenzyl)oxy)phenyl)piperidine-1-yl)methyl)-1-(oxetane-2-aminomethyl)-1H-benzo[d]imidazole-6-carboxylate (compound of formula II)

[0163] 2g of the 2-amino-2-(hydroxymethyl)-1,3-propanediol salt of (S)-2-((4-(2-((4-chloro-2-fluorobenzyl)oxy)phenyl)piperidine-1-yl)methyl)-1-(oxetane-2-aminomethyl)-1H-benzo[d]imidazole-6-carboxylate prepared in Example 3 was added to 40mL of 1,4-dioxane, stirred at room temperature for 24 hours, filtered to obtain a solid, dried under reduced pressure to a constant weight to obtain 1.90g of the product (i.e., crystalline form B of the 1,4-dioxane solvate of the compound of formula II (the molar ratio of the compound of formula II to 1,4-dioxane is 1:0.5)). 1H NMR(400MHz CD3OD)8.22(1H,s),7.95-7.97(1H,dd),7.60-7.62(1H,d),7.51-7.53(1H,t),7.27-2.29(2H,m ),7.15-7.21(1H,m),7.01-7.05(1H,d),6.93-6.97(1H,t),5.27-5.30(1H,m),4.63-4.75(2H,m) ,4.47-4.49(1H,m),3.85-4.03(2H,ABq),3.67-3.68(10H,m),3.32-3.34(4H,m),2.94-3.06(3H ,m),2.79-2.83(1H,m),2.52-2.57(1H,m),2.22-2.34(1H,m),1.73-1.82(4H,m).HPLC purity: 99.99%

[0164] Table 2 shows the XRPD pattern analysis data for crystalline form B of the 1,4-dioxane solvate of compound II.

[0165] [Table 11]

[0166] The following table shows the characterization data for crystalline form B of the 1,4-dioxane solvate of compound II. [Table 12]

[0167] Example 6: Crystalline form C of the 2-amino-2-(hydroxymethyl)-1,3-propanediol salt of (S)-2-((4-(2-((4-chloro-2-fluorobenzyl)oxy)phenyl)piperidine-1-yl)methyl)-1-(oxetane-2-aminomethyl)-1H-benzo[d]imidazole-6-carboxylate (compound of formula II)

[0168] 2g of the 2-amino-2-(hydroxymethyl)-1,3-propanediol salt of (S)-2-((4-(2-((4-chloro-2-fluorobenzyl)oxy)phenyl)piperidine-1-yl)methyl)-1-(oxetane-2-aminomethyl)-1H-benzo[d]imidazole-6-carboxylate prepared in Example 3 was added to tetrahydrofuran (20mL), stirred at 25-50°C for 48 hours, filtered to obtain a solid, dried under reduced pressure until constant weight was obtained, yielding 2.10g of the product (crystalline form C of compound II). 1 H NMR(400MHz DMSO-d6)8.19(1H,d),7.79-7.81(1H,dd),7.51-7.60(2H,m),7.36-7.39(1H,dd),7.16-7.21(2H,m),7.07-7.09(1 H,dd),6.92-6.96(1H,td),5.15(2H,s),5.06-5.15(1H,m),4.73-4.79(2H,dd),4.60-4.65(1H,dd),4.47-4.52(1H Table 3 shows the XRPD pattern analysis data for the crystalline morphology C of the compound of formula II.

[0169] [Table 13]

[0170] The characterization data for crystalline form C of the compound of formula II is as follows: [Table 14]

[0171] Example 7: Crystalline form D of the 2-amino-2-(hydroxymethyl)-1,3-propanediol salt of (S)-2-((4-(2-((4-chloro-2-fluorobenzyl)oxy)phenyl)piperidine-1-yl)methyl)-1-(oxetane-2-aminomethyl)-1H-benzo[d]imidazole-6-carboxylate (compound of formula II).

[0172] The 2-amino-2-(hydroxymethyl)-1,3-propanediol salt (0.50 g, crystalline form B of the 1,4-dioxane solvate of the compound of formula II or crystalline form C of the compound of formula II) of (S)-2-((4-(2-((4-chloro-2-fluorobenzyl)oxy)phenyl)piperidine-1-yl)methyl)-1-(oxetane-2-aminomethyl)-1H-benzo[d]imidazole-6-carboxylate prepared in Example 5 or 6 was heated to 160°C, maintained for 5-10 minutes, and cooled to obtain 0.46 g of solid (i.e., crystalline form D of the compound of formula II). 1 H NMR(400 MHz,CD3OD)δ 8.22(1H,s),7.95-7.97(1H,dd),7.60-7.62(1H,d),7.52-7.56(1H,t),7.27-7.30(2H,m),7.21-7.24 (1H,dd),7.15-7.20(1H,td),7.02-7.04(1H,dd),6.93-6.97(1H,td),5.25-5.32(1H,qd),5.14(1H,s) ,4.71-4.75(1H,dd),4.62-4.67(1H,m),4.45-4.50(1H,m),3.90-4.03(2H,ABq),3.66(6H,s),2.95-3 .06(4H,m),2.77-2.85(1H,m),2.50-2.59(1H,m),2.22-2.34(1H,m),1.71-1.81(4H,m).HPLC purity: 99.9%

[0173] Table 4 shows the XRPD pattern analysis data for the crystalline form D of compound II.

[0174] [Table 15]

[0175] The characteristic evaluation data of crystalline form D of the compound of formula II are as follows.

Table 16

[0176] Example 8: Crystalline form E of the 2-amino-2-(hydroxymethyl)-1,3-propanediol salt of (S)-2-((4-(2-((4-chloro-2-fluorobenzyl)oxy)phenyl)piperidin-1-yl)methyl)-1-(oxetan-2-aminomethyl)-1H-benzo[d]imidazole-6-carboxylate (compound of formula II)

[0177] The 2-amino-2-(hydroxymethyl)-1,3-propanediol salt of (S)-2-((4-(2-((4-chloro-2-fluorobenzyl)oxy)phenyl)piperidin-1-yl)methyl)-1-(oxetan-2-aminomethyl)-1H-benzo[d]imidazole-6-carboxylate (0.20 g, crystalline form B of the 1,4-dioxane solvate of the compound of formula II or crystalline form C of the compound of formula II) prepared in Example 5 or 6 was heated to 80 - 100 °C and dried for 48 hours to obtain 0.18 g of a solid (i.e., crystalline form E of the compound of formula II). 1H NMR(400 MHz,CD3OD)δ 8.22(1H,s),7.95-7.97(1H,dd),7.60-7.62(1H,d),7.51-7.55(1H,t),7.27-7.30(2H,m),7.21-7.23 (1H,m),7.15-7.20(1H,td),7.01-7.04(1H,dd),6.93-6.97(1H,td),5.25-5.32(1H,qd),5.14(1H,s) ,4.71-4.75(1H,dd),4.62-4.67(1H,m),4.45-4.50(1H,m),3.90-4.03(2H,ABq),3.64(6H,s),2.94-3 .06(4H,m),2.77-2.85(1H,m),2.50-2.59(1H,m),2.22-2.34(1H,m),1.75-1.81(4H,m).HPLC purity: 99.9%

[0178] Table 5 shows the XRPD pattern analysis data for the crystalline form E of the compound of formula II.

[0179] [Table 17]

[0180] The characterization data for crystalline form E of the compound of formula II is as follows: [Table 18]

[0181] Example 9: Crystalline form A (compound of formula II) of monohydrate of 2-amino-2-(hydroxymethyl)-1,3-propanediol salt of (S)-2-((4-(2-((4-chloro-2-fluorobenzyl)oxy)phenyl)piperidine-1-yl)methyl)-1-(oxetane-2-aminomethyl)-1H-benzo[d]imidazole-6-carboxylate

[0182] 0.20 g of the 2-amino-2-(hydroxymethyl)-1,3-propanediol salt of (S)-2-((4-(2-((4-chloro-2-fluorobenzyl)oxy)phenyl)piperidine-1-yl)methyl)-1-(oxetane-2-aminomethyl)-1H-benzo[d]imidazole-6-carboxylate prepared in Example 5 or 6 was added to 50 mL of N-heptane, stirred, heated to 50°C, and refluxed for 96 hours with stirring. The mixture was allowed to cool naturally to room temperature, stirred for a further 2 hours, and filtered to obtain a solid. The solid was dried under reduced pressure to a constant weight to obtain 0.18 g of the product, which was confirmed to be crystalline form A of the monohydrate of the compound of formula II, and the HPLC purity was 99.8%.

[0183] Example 10: (S)-2-((4-(2-((4-chloro-2-fluorobenzyl)oxy)phenyl)piperidine-1-yl)methyl)-1-(oxetane-2-aminomethyl)-1H-benzo[d]imidazole-6-carboxylate 2-amino-2-(hydroxymethyl)-1,3-propanediol salt (crystal form A of the monohydrate of the compound of formula II)

[0184] 0.20 g of the 2-amino-2-(hydroxymethyl)-1,3-propanediol salt (S)-2-((4-(2-((4-chloro-2-fluorobenzyl)oxy)phenyl)piperidine-1-yl)methyl)-1-(oxetane-2-aminomethyl)-1H-benzo[d]imidazole-6-carboxylate prepared in Example 8 was left at 25°C / 90%RH for 4-5 days to obtain 0.21 g of product, which was confirmed to be crystalline form A of the monohydrate of the compound of formula II, and the HPLC purity was 99.9%.

[0185] Example 11: (S)-2-((4-(2-((4-chloro-2-fluorobenzyl)oxy)phenyl)piperidine-1-yl)methyl)-1-(oxetane-2-aminomethyl)-1H-benzo[d]imidazole-6-carboxylic acid (crystal form I of compound of formula I)

[0186] 200 mg of the 2-amino-2-(hydroxymethyl)-1,3-propanediol salt (S)-2-((4-(2-((4-chloro-2-fluorobenzyl)oxy)phenyl)piperidine-1-yl)methyl)-1-(oxetane-2-aminomethyl)-1H-benzo[d]imidazole-6-carboxylate prepared in Example 3 was added to acetone (1.2 mL), heated to 50 °C to dissolve, cooled to approximately 25 °C, water (0.5 mL) was slowly added dropwise, stirred at room temperature for 24 hours, filtered to obtain a solid, and dried to a constant weight under reduced pressure to obtain 150 mg of the compound of formula I in crystalline form I (see Figure 18 for XRPD). DSC: 144.32~154.74 °C, endothermic.

[0187] Table 6 shows the XRPD diffraction pattern analysis data for crystalline form I of the compound of formula I.

[0188] [Table 19]

[0189] Example 12: (S)-2-((4-(2-((4-chloro-2-fluorobenzyl)oxy)phenyl)piperidine-1-yl)methyl)-1-(oxetane-2-aminomethyl)-1H-benzo[d]imidazole-6-carboxylic acid (crystal form II of compound of formula I)

[0190] 200 mg of the 2-amino-2-(hydroxymethyl)-1,3-propanediol salt (S)-2-((4-(2-((4-chloro-2-fluorobenzyl)oxy)phenyl)piperidine-1-yl)methyl)-1-(oxetane-2-aminomethyl)-1H-benzo[d]imidazole-6-carboxylate prepared in Example 3 was added to tetrahydrofuran (1 mL) and N-heptane (2 mL), heated to 50°C, stirred for 24 hours, cooled to room temperature, filtered to obtain a solid, and dried under reduced pressure to a constant weight to obtain 180 mg of the compound of formula I in crystalline form II (see Figure 19 for XRPD). DSC: 111.96~129.32°C, endothermic.

[0191] Table 7 shows the XRPD diffraction pattern analysis data for the crystalline form II of the compound of formula I.

[0192] [Table 20]

[0193] Example 13: (S)-2-((4-(2-((4-chloro-2-fluorobenzyl)oxy)phenyl)piperidine-1-yl)methyl)-1-(oxetane-2-aminomethyl)-1H-benzo[d]imidazole-6-carboxylic acid (crystal form III of the compound of formula I)

[0194] 200 mg of the 2-amino-2-(hydroxymethyl)-1,3-propanediol salt (S)-2-((4-(2-((4-chloro-2-fluorobenzyl)oxy)phenyl)piperidine-1-yl)methyl)-1-(oxetane-2-aminomethyl)-1H-benzo[d]imidazole-6-carboxylate prepared in Example 3 was added to methanol (1 mL) and water (1 mL), stirred at 25°C for 24 hours, cooled to room temperature, filtered to obtain a solid, and dried under reduced pressure to a constant weight to obtain 163 mg of the compound of formula I in crystalline form III (see Figure 20 for XRPD). DSC: 101.13~121.83°C, endothermic and 136.87~147.61°C, endothermic.

[0195] The resulting crystalline form III of the compound of formula I was the anhydrous crystalline form of the compound of formula I.

[0196] Table 8 shows the XRPD diffraction pattern analysis data for crystalline form III of the compound of formula I.

[0197] [Table 21]

[0198] Efficacy Test 1

[0199] The purity and hygroscopicity of the crystalline form A of the monohydrate of the compound of formula I obtained in Example 1 (S)-2-((4-(2-((4-chloro-2-fluorobenzyl)oxy)phenyl)piperidine-1-yl)methyl)-1-(oxetane-2-aminomethyl)-1H-benzo[d]imidazole-6-carboxylate (hydrochloride salt of the compound of formula I) obtained in Example 2 (sodium salt of the compound of formula I) and the compound of formula II obtained in Example 4 were tested.

[0200] Table 9 shows a comparison of the properties of the three different salts.

[0201] [Table 22]

[0202] Efficacy Test 2: Comparison of the crystalline form of the 2-amino-2-(hydroxymethyl)-1,3-propanediol salt of compound I.

[0203] The crystalline forms A of the monohydrate of the compound of formula II obtained in Examples 4 to 8, the crystalline forms B of the 1,4-dioxane solvate of the compound of formula II, the crystalline forms C of the compound of formula II, the crystalline forms D of the compound of formula II, and the crystalline forms E of the compound of formula II were compared.

[0204] X-ray powder diffraction patterns of each crystal form revealed that crystal form A of the monohydrate of compound II had a higher degree of crystallinity. Furthermore, crystal forms B of the 1,4-dioxane solvate of compound II and crystal form C of compound II were unstable during the preparation process, prone to crystal form transformation during preparation, and had low reproducibility. The preparation process for crystal forms D and E of compound II involved heating under high-temperature conditions to obtain the corresponding crystal forms, making it unsuitable for scale-up production (see Table 10).

[0205]

Table 23

[0206] Effect Test 3

[0207] The grindability, compressibility, hygroscopicity, and solubility of crystalline form I, crystalline form II, and crystalline form III of the compound of formula I obtained in Examples 11 to 13, and crystalline form A of the monohydrate of the compound of formula II obtained in Example 4 were tested.

[0208] The DVS test data of crystalline form I of the compound of formula I obtained in Example 11 are shown in Table 11.

[0209]

Table 24

[0210] The DVS test data of crystalline form A of the monohydrate of the compound of formula II obtained in Example 4 are as shown in Table 12.

[0211]

Table 25

[0212] Comparative data regarding the compound stability are shown in Table 13.

[0213]

Table 26

[0214] Note:

[0215] a The preparation method is the same as the preparation method described in Example 3 of Patent CN202110334388.

[0216] b In the purity test, the sample was placed in an oven at the temperature set in the table, and its purity was tested after the specified time.

[0217] c Results after leaving it at 80°C for 30 days.

[0218] From the table above, it can be seen that the compound of formula I has poor thermal stability, decomposes when heated or at room temperature, has poor processability, and clearly decomposes after grinding and tableting.

[0219] Of these, crystalline forms I, II, and III of the compound of formula I exhibit poor processability, as shown in Figures 21, 22, and 23. Compared to crystalline forms I, II, and III of the compound of formula I, the degree of decrease in crystallinity differs for crystalline forms I, II, and III after tableting, crystalline forms I, II, and III after grinding for 5 minutes, and crystalline forms I, II, and III after grinding for 2 minutes. In contrast, as shown in Figures 24 and 25, the crystallinity of crystalline form A of the monohydrate of the compound of formula II remains basically stable after the first tableting at 20 MPa, the second tableting at 20 MPa, tableting at 40 MPa, and grinding for 1 minute, 3 minutes, and 5 minutes. This indicates that crystalline form A of the monohydrate of the compound of formula II has good processability. Furthermore, crystalline form A of the monohydrate of compound II is stable, exhibits good experimental reproducibility, has good hygroscopicity and solubility, and has broad medical prospects.

[0220] Efficacy study 4: Pharmacokinetic evaluation in rats

[0221] Rats were used as test animals, and plasma drug concentrations were measured at different time points after forced oral administration of the test sample. The pharmacokinetic behavior of the compounds disclosed herein in rats was studied to evaluate their metabolic characteristics. Three rats of similar body weight were selected for each experimental group and administered a single dose of 10 mg / kg orally. Blood samples were collected 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours after animal administration. The compound content in plasma was determined by LC-MS / MS analysis, with a limit of quantification of 20 ng / mL. Pharmacokinetic parameters were calculated using non-compartmental analysis (NCA) based on plasma concentration data with the metabolic kinetics data analysis software WinNonlin 7.0.

[0222] Experimental drugs: Crystalline form A of the monohydrate of the compound of formula II obtained in Example 4, and the compound of formula I (free acid).

[0223] Drug preparation

[0224] A 0.5% CMC NA aqueous solution was used as the preparation solvent, and a test sample was prepared for oral administration to a final concentration (based on the content of the compound in formula I) of 1.0 mg / mL. After preparation, a milky white, homogeneous suspension was obtained.

[0225] Administration: After a 12-hour fast, rats were administered 10 mg / kg via gastric tube.

[0226] Procedure: Rats were force-fed the drug via a gastric tube, and blood samples were collected from the tail vein before administration and at 15, 30, 1, 2, 4, 6, 8, 12, and 24 minutes after administration. The blood samples were placed in heparinized sample tubes, centrifuged at 4°C and 3500 rpm for 10 minutes to separate the plasma, and then stored at -20°C. The rats were fed 2 hours after administration.

[0227] Determination of the content of the target compound in rat plasma after forced oral administration: After thawing the plasma samples at room temperature, 300 μL of internal standard (terfenadine 200 ng / mL, acetonitrile) was added to each sample. The mixture was vortexed for 1 minute and then centrifuged at 4°C and 15400 rpm for 10 minutes. The supernatant was diluted 20-fold with 80% acetonitrile-water and then injected for LC / MS / MS analysis. [Table 27]

[0228] As shown in the table above, crystalline form A of the monohydrate of the compound of formula II in this disclosure has significantly better oral absorption than the compound of formula I (free acid).

Claims

1. The 2-amino-2-(hydroxymethyl)-1,3-propanediol salt or solvate thereof of the compound of formula I. 【Chemistry 1】

2. A 2-amino-2-(hydroxymethyl)-1,3-propanediol salt or solvate thereof of the compound of formula I described in claim 1, which satisfies one or more of the following conditions: (1) The 2-amino-2-(hydroxymethyl)-1,3-propanediol salt of the compound of formula I is the compound of formula II, and 【Chemistry 2】 (2) In the solvate of the 2-amino-2-(hydroxymethyl)-1,3-propanediol salt of the compound of formula I, the solvent is water or 1,4-dioxane, and in the solvate of the 2-amino-2-(hydroxymethyl)-1,3-propanediol salt of the compound of formula I, the molar ratio of the 2-amino-2-(hydroxymethyl)-1,3-propanediol salt of the compound of formula I to the solvent is preferably 1:(1 to 0.5), for example, the molar ratio of the 2-amino-2-(hydroxymethyl)-1,3-propanediol salt of the compound of formula I to water is 1:1, and in another example, the molar ratio of the 2-amino-2-(hydroxymethyl)-1,3-propanediol salt of the compound of formula I to 1,4-dioxane is 1:0.

5.

3. A crystalline form of the compound of formula II or its solvate, wherein the crystalline form of the compound of formula II or its solvate is crystalline form A of the monohydrate of the compound of formula II, crystalline form B of the 1,4-dioxane solvate of the compound of formula II, crystalline form C of the compound of formula II, crystalline form D of the compound of formula II, or crystalline form E of the compound of formula II. The monohydrate of the compound of formula II has the following structure: 【Transformation 3】 The 1,4-dioxane solvate of the compound of formula II has the following structure: 【Chemistry 4】 The compound of formula II has the following structure: 【Transformation 5】 The crystalline form A of the monohydrate of the compound of formula II is obtained using Cu-Kα radiation and has an X-ray powder diffraction pattern expressed with respect to the 2θ angle, with diffraction peaks at 4.1±0.2°, 8.2±0.2°, 10.7±0.2°, 12.3±0.2° and 20.7±0.2°. The crystalline form B of the 1,4-dioxane solvate of the compound of formula II is obtained using Cu-Kα radiation and has an X-ray powder diffraction pattern with diffraction peaks at 3.4±0.2°, 7.4±0.2°, 11.2±0.2° and 14.6±0.2°, expressed with respect to the 2θ angle. The crystalline form C of the compound of formula II is obtained using Cu-Kα radiation and has an X-ray powder diffraction pattern that includes diffraction peaks at 3.7±0.2°, 7.5±0.2°, 9.7±0.2°, and 15.5±0.2°, expressed as a 2θ angle. The crystalline form D of the compound of formula II is obtained using Cu-Kα radiation and has an X-ray powder diffraction pattern with diffraction peaks at 3.9±0.2°, 8.1±0.2°, 10.6±0.2°, and 14.9±0.2°, expressed as a 2θ angle. The crystalline form E of the compound of formula II is obtained using Cu-Kα radiation and has an X-ray powder diffraction pattern with diffraction peaks at 3.7±0.2°, 7.6±0.2°, 9.8±0.2°, and 14.7±0.2°, expressed as a 2θ angle. The crystalline form of the compound of formula II or its solvate.

4. The crystalline form of the compound of formula II or its solvate according to claim 3, wherein the crystalline form of the compound of formula II satisfies one or more of the following conditions. (1) The X-ray powder diffraction pattern of crystalline form A of the monohydrate of the compound of formula II, obtained using Cu-Kα radiation and expressed with respect to the 2θ angle, further includes diffraction peaks at one or more of the following positions: 14.1±0.2°, 14.9±0.2°, 20.5±0.2°, and 21.8±0.2°. Preferably, the X-ray powder diffraction pattern of crystalline form A of the monohydrate of the compound of formula II, obtained using Cu-Kα radiation and expressed with respect to the 2θ angle, contains diffraction peaks at 4.1±0.2°, 8.2±0.2°, 10.7±0.2°, 12.3±0.2°, 14.1±0.2°, 14.9±0.2°, 20.5±0.2°, and 21.8±0.2°. (2) The X-ray powder diffraction pattern of crystalline form B of the 1,4-dioxane solvate of the compound of formula II, obtained using Cu-Kα radiation and expressed with respect to the 2θ angle, further includes diffraction peaks at one or more of the following positions: 8.2±0.2°, 12.3±0.2°, 13.7±0.2°, 16.1±0.2°, 20.0±0.2°, 22.0±0.2°, 22.5±0.2° and 29.3±0.2°, Preferably, the X-ray powder diffraction pattern of crystalline form B of the 1,4-dioxane solvate of the compound of formula II, obtained using Cu-Kα radiation and expressed with respect to the 2θ angle, contains diffraction peaks at 3.4±0.2°, 7.4±0.2°, 8.2±0.2°, 11.2±0.2°, 12.3±0.2°, 13.7±0.2°, 14.6±0.2°, 16.1±0.2°, 20.0±0.2°, 22.0±0.2°, 22.5±0.2°, and 29.3±0.2°. (3) The X-ray powder diffraction pattern of the crystalline form C of the compound of formula II, obtained using Cu-Kα radiation and expressed with respect to the 2θ angle, further includes diffraction peaks at one or more of the following positions: 11.3±0.2°, 12.3±0.2°, 14.4±0.2°, 14.7±0.2°, 17.2±0.2°, 20.5±0.2°, 21.8±0.2°, and 29.5±0.2°. Preferably, the X-ray powder diffraction pattern of the crystalline form C of the compound of formula II, obtained using Cu-Kα radiation and expressed with respect to the 2θ angle, includes diffraction peaks at 3.7±0.2°, 7.5±0.2°, 9.7±0.2°, 11.3±0.2°, 12.3±0.2°, 14.4±0.2°, 14.7±0.2°, 15.5±0.2°, 17.2±0.2°, 20.5±0.2°, 21.8±0.2°, and 29.5±0.2°. (4) The X-ray powder diffraction pattern of the crystalline form D of the compound of formula II, obtained using Cu-Kα radiation and expressed with respect to the 2θ angle, further includes diffraction peaks at one or more of the following positions: 10.2±0.2°, 10.6±0.2°, 14.3±0.2°, 17.8±0.2°, 20.0±0.2° and 20.2±0.2°. Preferably, the X-ray powder diffraction pattern of the crystalline form D of the compound of formula II, obtained using Cu-Kα radiation and expressed with respect to the 2θ angle, includes diffraction peaks at 3.9±0.2°, 8.1±0.2°, 10.2±0.2°, 10.6±0.2°, 14.3±0.2°, 14.9±0.2°, 17.8±0.2°, 20.0±0.2° and 20.2±0.2°, and (5) The X-ray powder diffraction pattern of the crystalline form E of the compound of formula II, obtained using Cu-Kα radiation and expressed with respect to the 2θ angle, further includes diffraction peaks at one or more of the following positions: 11.2±0.2°, 15.6±0.2°, 17.4±0.2°, 19.8±0.2°, 20.3±0.2°, 21.9±0.2°, 29.5±0.2° and 19.0±0.2°, Preferably, the X-ray powder diffraction pattern of the crystalline form E of the compound of formula II, obtained using Cu-Kα radiation and expressed with respect to the 2θ angle, includes diffraction peaks at 3.7±0.2°, 7.6±0.2°, 9.8±0.2°, 11.2±0.2°, 14.7±0.2°, 15.6±0.2°, 17.4±0.2°, 19.8±0.2°, 20.3±0.2°, 21.9±0.2°, and 29.5±0.2°.

5. The crystalline form of the compound of formula II or its solvate according to claim 4, wherein the crystalline form of the compound of formula II satisfies one or more of the following conditions. (1) The X-ray powder diffraction pattern of crystalline form A of the monohydrate of the compound of formula II, obtained using Cu-Kα radiation and expressed with respect to the 2θ angle, includes the diffraction peaks shown in Table 1. Table 1-1 Table 1-2 Preferably, the X-ray powder diffraction pattern of crystalline form A of the monohydrate of the compound of formula II obtained using Cu-Kα radiation is substantially as shown in Figure 1. (2) The crystalline form A of the monohydrate of the compound of formula II has a differential scanning calorimetry curve showing endothermic peaks at 129.98 ± 3°C and 196.25 ± 3°C. Preferably, the differential scanning calorimetry curve of the crystalline form A of the monohydrate of the compound of formula II is as shown in Figure 2. (3) The crystalline form A of the monohydrate of the compound of formula II has a thermogravimetric analysis curve showing a weight loss of 2.468% within a temperature range of 30±3°C to 135±3°C. Preferably, the thermogravimetric analysis curve of the crystalline form A of the monohydrate of the compound of formula II is as shown in Figure 3. (4) The X-ray powder diffraction pattern of crystalline form B of the 1,4-dioxane solvate of the compound of formula II, obtained using Cu-Kα radiation and expressed with respect to the 2θ angle, shall include the diffraction peaks shown in Table 2. Table 2 Preferably, the X-ray powder diffraction pattern of crystalline form B of the 1,4-dioxane solvate of the compound of formula II obtained using Cu-Kα radiation is substantially as shown in Figure 6. (5) The crystalline form B of the 1,4-dioxane solvate of the compound of formula II has a differential scanning calorimetry curve showing endothermic peaks at 107.2 ± 3°C and 186.6 ± 3°C. Preferably, the differential scanning calorimetry curve of crystalline form B of the 1,4-dioxane solvate of the compound of formula II is as shown in Figure 7. (6) The crystalline form B of the 1,4-dioxane solvate of the compound of formula II has a thermogravimetric analysis curve showing a weight loss of 2.029% in the temperature range of 33±3°C to 150±3°C. Preferably, the thermogravimetric analysis curve of the crystalline form B of the 1,4-dioxane solvate of the compound of formula II is as shown in Figure 8. (7) The X-ray powder diffraction pattern of the crystalline form C of the compound of formula II, obtained using Cu-Kα radiation and expressed with respect to the 2θ angle, shall include the diffraction peaks shown in Table 3. Table 3 Preferably, the X-ray powder diffraction pattern of crystalline form C of the compound of formula II obtained using Cu-Kα radiation is substantially as shown in Figure 9. (8) The crystalline form C of the compound of formula II has a differential scanning calorimetry curve that shows an endothermic peak at 196.9 ± 3°C. Preferably, the differential scanning calorimetry curve of the crystalline form C of the compound of formula II is as shown in Figure 10. (9) The crystalline form C of the compound of formula II has a thermogravimetric analysis curve that does not show weight loss within a temperature range of 30±3°C to 180±3°C. Preferably, the thermogravimetric analysis curve of the crystalline form C of the compound of formula II is as shown in Figure 11. (10) The crystalline form C of the compound of formula II is a non-solvated crystalline form. (11) The X-ray powder diffraction pattern of the crystalline form D of the compound of formula II, obtained using Cu-Kα radiation and expressed with respect to the 2θ angle, includes the diffraction peaks shown in Table 4. Table 4 Preferably, the X-ray powder diffraction pattern of crystalline form D of the compound of formula II obtained using Cu-Kα radiation is substantially as shown in Figure 12. (12) The crystalline form D of the compound of formula II has a differential scanning calorimetry curve showing endothermic peaks at 178.3 ± 3°C and 194.0 ± 3°C. Preferably, the differential scanning calorimetry curve of the crystalline form D of the compound of formula II is as shown in Figure 13. (13) The crystalline form D of the compound of formula II has a thermogravimetric analysis curve showing a weight loss of 0.59% in the temperature range of 30±3°C to 101±3°C and a weight loss of 0.81% in the temperature range of 140±3°C to 180±3°C. Preferably, the thermogravimetric analysis curve of the crystalline form D of the compound of formula II is as shown in Figure 14. (14) The crystalline form D of the compound of formula II is a non-solvated crystalline form. (15) The X-ray powder diffraction pattern of the crystalline form E of the compound of formula II, obtained using Cu-Kα radiation and expressed with respect to the 2θ angle, shall include the diffraction peaks shown in Table 5. Table 5 Preferably, the X-ray powder diffraction pattern of the crystalline form E of the compound of formula II obtained using Cu-Kα radiation is substantially as shown in Figure 15. (16) The crystalline form E of the compound of formula II has a differential scanning calorimetry curve that shows an endothermic peak at 192.0 ± 3°C. Preferably, the differential scanning calorimetry curve of the crystalline form E of the compound of formula II is as shown in Figure 16. (17) The crystalline form E of the compound of formula II has a thermogravimetric analysis curve that does not show weight loss in the range of 30±3°C to 160±3°C. Preferably, the thermogravimetric analysis curve of the crystalline form E of the compound of formula II is as shown in Figure 17, and (18) The crystalline form E of the compound of formula II is a non-solvated crystalline form.

6. A single crystal of the monohydrate of the compound of formula II, wherein the single crystal has the following unit cell parameters: Space group P2 １ 2 １ 2 １ , a=6.13580(4)Å, α＝９０°、 b=12.99957(8)Å, β＝９０°、 c=42.4637(3)Å, γ = 90°, Unit cell volume = 3387.02 (4) Å ３ , The number of asymmetric units within a unit cell Z = 4, and Crystallization density = 1.379 mg / m³ ３ , The monohydrate of the compound of formula II has the following structure: 【Transformation 6】 Preferably, the single crystal of the monohydrate of the compound of formula II is orthorhombic. A single crystal of the monohydrate of the compound of formula II.

7. A method for preparing a crystalline form of a compound of formula II or a solvate thereof as described in any one of claims 3 to 5, wherein the preparation method comprises the following steps: (1) A step of mixing the 2-amino-2-(hydroxymethyl)-1,3-propanediol salt of the compound of formula I described in claim 1 or claim 2 with a solvent to obtain a mixed solution. (2) A step of filtering the mixture and drying it to obtain the crystalline form of the compound of formula II or its solvate. Here, when the solvent is an alcohol solvent, crystalline form A of the monohydrate of the compound of formula II is obtained. When the solvent is 1,4-dioxane, crystalline form B of the 1,4-dioxane solvate of the compound of formula II is obtained. When the solvent is tetrahydrofuran, the crystalline form C of the compound of formula II is obtained in the following step: Preferably, a method for preparing the crystalline form of the compound of formula II or its solvate, satisfying one or more of the following conditions: (1) In the preparation method described above, the alcohol solvent is methanol. (2) In the preparation method, the mixing is carried out while stirring to form a suspension. (3) In the preparation method described above, the mixture obtained in step (1) is a suspension. (4) In the preparation method, the drying is carried out under reduced pressure or normal pressure. (5) In the preparation method described above, if crystalline form A of the monohydrate of the compound of formula II is obtained, the mass-to-volume ratio of the compound of formula II to the solvent is 1:(1-100) g / mL, for example, 1:30 g / mL. (6) In the preparation method, if crystalline form A of the monohydrate of the compound of formula II is obtained, the mixing temperature is 0 to 150°C, for example, 20 to 80°C, and preferably, heating under reflux is performed. (7) In the preparation method, if crystalline form A of the monohydrate of the compound of formula II is obtained, filtration is performed at room temperature, for example, after the mixture is cooled to room temperature, filtration is performed. (8) In the preparation method described above, if crystalline form B of the 1,4-dioxane solvate of the compound of formula II is obtained, the mass-to-volume ratio of the compound of formula II to the solvent is 1:(10-50) g / mL, for example, 1:20 g / mL. (9) In the preparation method described above, if crystalline form B of the 1,4-dioxane solvate of the compound of formula II is obtained, the mixing temperature is room temperature, which is 20 to 30°C, for example, 25°C. (10) In the preparation method described above, if crystalline form B of the 1,4-dioxane solvate of the compound of formula II is obtained, the mixture is mixed while stirring. (11) In the preparation method described above, if crystalline form B of the 1,4-dioxane solvate of the compound of formula II is obtained, filtration shall be performed at room temperature. (12) In the preparation method described above, if crystalline form C of the compound of formula II is obtained, the mass-to-volume ratio of the compound of formula II to the solvent is 1:(5-20) g / mL, for example, 1:10 g / mL. (13) In the preparation method described above, if crystalline form C of the compound of formula II is obtained, the mixing temperature is 45 to 55°C, for example 25 to 50°C, preferably 50°C, and (14) In the preparation method described above, if crystalline form C of the compound of formula II is obtained, the mixture is stirred.

8. A preparation method according to claim 7, further comprising the following steps: Step (1a): A step of mixing the compound of formula I with solvent A to obtain a mixed solution A. Step (1b): A step to obtain mixture B by mixing 2-amino-2-(hydroxymethyl)-1,3-propanediol with solvent B. Here, the order of process (1a) and process (1b) does not matter. Step (2): A step of mixing the mixture A and the mixture B, crystallizing, filtering, and drying to obtain the compound of formula II. Preferably, the preparation method satisfies one or more of the following conditions: (1) In step (1a), the solvent A is one or more of the following: alcohol solvent, ester solvent, ether solvent, ketone solvent, chlorinated hydrocarbon solvent, aromatic hydrocarbon solvent, nitrile solvent, alkane solvent and nitrogen-containing compound solvent, the alcohol solvent is, for example, methanol, ethanol or isopropanol, the ether solvent is, for example, methyl tert-butyl ether, isopropyl ether, tetrahydrofuran or 2-methyltetrahydrofuran, the nitrogen-containing compound solvent is, for example, N-methylpyrrolidone, and the ester solvent is, for example, methyl formate, ethyl formate, ethyl acetate Solvent A is methanol, ethanol, acetone, ethyl acetate, a mixed solution of n-heptane and ethyl acetate, a mixed solution of n-heptane and tetrahydrofuran, a mixed solution of methanol and water, a mixed solution of acetone and water, a mixed solution of ethanol and water, a mixed solution of tetrahydrofuran and water, a mixed solution of methanol, water and dimethyl sulfoxide, a mixed solution of 2-methyltetrahydrofuran, ethyl acetate and methanol, a mixed solution of ethyl acetate, tetrahydrofuran and water, or a mixed solution of ethyl acetate, 2-methyltetrahydrofuran and water. Furthermore, in step (1a), the solvent A is an alcohol solvent, for example, the solvent A is methanol. (2) In step (1a), the mass-to-volume ratio of the compound of formula I to solution A is 10:(10-500) g / mL, for example 10:200 g / mL. (3) In step (1a), the mixing temperature is 10 to 160°C, preferably 20 to 30°C. (4) In step (1a), the mixed liquid A is filtered after the mixing. (5) In step (1b), the solvent B is one or more of water, an alcohol solvent, and a sulfur-containing compound solvent, the alcohol solvent is, for example, ethanol or methanol, and the sulfur-containing compound solvent may be dimethyl sulfoxide. Preferably, in step (1b), the solvent B is water. (6) In step (1b), the mass ratio of 2-amino-2-(hydroxymethyl)-1,3-propanediol to solvent B is 1:(1 to 260), preferably 3.2:

800. (7) In step (2), add the mixed liquid B to the mixed liquid A dropwise and mix. (8) In step (2), the crystallization temperature is 20 to 30°C. (9) In step (2), the filtration includes a filtration step, a washing step and a pH adjustment step. (10) In step (2), drying is performed under vacuum at 45°C, and (11) In step (1a), if solvent A is a mixed solution of 2-methyltetrahydrofuran, ethyl acetate, and methanol, the volume ratio of 2-methyltetrahydrofuran, ethyl acetate, and methanol is 5:5:

2.

9. A method for preparing the crystalline form D of a compound of formula II according to any one of claims 3 to 5, comprising the following steps: A step of heating the crystalline form C of the compound of formula II described in any one of claims 3 to 5, or the crystalline form B of the 1,4-dioxane solvate of the compound of formula II described in any one of claims 3 to 5, at 160°C for 5 to 10 minutes to obtain the crystalline form D of the compound of formula II.

10. A method for preparing the crystalline form E of a compound of formula II according to any one of claims 3 to 5, comprising the following steps: A step of heating the crystalline form B of the 1,4-dioxane solvate of the compound of formula II described in any one of claims 3 to 5, or the crystalline form C of the compound of formula II described in any one of claims 3 to 5, at 80 to 100°C for 24 to 96 hours to obtain the crystalline form E of the compound of formula II.

11. A pharmaceutical composition comprising a 2-amino-2-(hydroxymethyl)-1,3-propanediol salt or solvate thereof of a compound of formula I according to any one of claims 1 to 2, and a pharmaceutically acceptable carrier, Preferably, the 2-amino-2-(hydroxymethyl)-1,3-propanediol salt or solvate of the compound of formula I is a single crystal of the monohydrate of the compound of formula II described in claim 6, or a crystalline form of the compound of formula II described in any one of claims 3 to 5, in a pharmaceutical composition.

12. In the manufacture of a pharmaceutical for the prevention and / or treatment of metabolic diseases, use of the pharmaceutical composition according to claim 11 or the 2-amino-2-(hydroxymethyl)-1,3-propanediol salt or solvate thereof of the compound of formula I according to any one of claims 1 to 2, Preferably, the 2-amino-2-(hydroxymethyl)-1,3-propanediol salt or solvate of the compound of formula I is a single crystal of the monohydrate of the compound of formula II described in claim 6, or a crystalline form of the compound of formula II described in any one of claims 3 to 5, In the use described above, the metabolic-related disease may be selected from any one of the following: impaired glucose tolerance, hyperglycemia, dyslipidemia, type 1 diabetes, type 2 diabetes, hypertriglyceridemia, insulin resistance, impaired glucose tolerance, diabetic dyslipidemia, hyperlipidemia, arteriosclerosis, atherosclerosis, hypertension, obesity, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, hepatic fibrosis, cirrhosis, and lethargy. Use of the 2-amino-2-(hydroxymethyl)-1,3-propanediol salt or solvate thereof of the compound of formula I.

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