Crystalline forms of GLP-1 receptor agonists and methods for preparing same

Abstract

A crystalline form of a GLP-1 receptor agonist and a method for its preparation, wherein the agonist is the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

Description

[Technical field]

[0001] This application claims priority to Chinese patent application No. 2021115865413, filed on December 23, 2021. This application cites the above Chinese patent application in full.

[0002] (Technical field) The present disclosure is in the medical field and relates to pharma- ceutically acceptable salts, crystalline forms of GLP-1 receptor agonists and methods for their preparation. [Background technology]

[0003] Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted by L cells in the lower gastrointestinal tract. GLP-1 plays a corresponding role by binding to its ubiquitous specific receptor, and currently, the organs in which GLP-1 receptors are obviously present include pancreatic islet cells, gastrointestinal tract, lungs, brain, kidneys, hypothalamus and cardiovascular system, and GLP-1 receptors may also be present in the liver, adipose tissue and skeletal muscle. GLP-1 not only acts on β cells to promote insulin secretion, but also on α cells to inhibit glucagon secretion. In general, there is no significant difference in serum GLP-1 levels in patients with normal glucose tolerance, impaired glucose tolerance and type II diabetes. However, there is a defect in the response of β cells to GLP-1 after a meal, and under certain conditions, this response reaction is significantly enhanced after continuous infusion of GLP-1. Because the duration of action of the human body's own GLP-1 is very short (t1 / 2 of intravenous injection < 1.5 minutes), the human body's own GLP-1 is not suitable for clinical treatment of diabetes.

[0004] Peptide-type GLP-1 receptor agonists (liraglutide, exenatide, etc.) have the effect of lowering fasting and postprandial glucose levels and improving blood glucose in type II diabetes patients. However, because peptide-type GLP-1 has poor oral bioavailability and is inconvenient to take, there is a strong demand for small molecule GLP-1 receptor agonists with good oral bioavailability.

[0005] 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid is a novel compound with GLP-1 receptor agonist activity (structural formula is as follows, PCT / CN2021 / 115915). [ka] [Prior art documents] [Patent documents]

[0006] [Patent Document 1] PCT / CN2021 / 115915 Summary of the Invention [Problem to be solved by the invention]

[0007] Crystals of pharmaceutical active ingredients often affect the chemical stability of medicines, and differences in crystallization and storage conditions can cause the crystal structure of the compound to change, and in some cases may be accompanied by the formation of other forms of crystals. In general, amorphous drugs do not have a regular crystal structure and often suffer from defects such as poor product stability, fine crystals, difficulty in filtration, prone to aggregation, and poor flowability. Pharmaceutical polymorphism has various requirements for product storage, production, and scale-up. Therefore, it is necessary to deeply study the crystals of the above compounds and improve the various properties of the above compounds. [Means for solving the problem]

[0008] (Summary of the invention) The present disclosure provides an amorphous compound of 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, in which the powder X-ray diffraction pattern expressed by the diffraction angle 2θ has no significant characteristic peak. In some embodiments, the powder X-ray diffraction pattern of the amorphous compound expressed by the diffraction angle 2θ has no obvious characteristic peak in the range of 0 to 40°. The powder X-ray diffraction pattern is as shown in FIG. 1.

[0009] The present disclosure further provides a method for preparing an amorphous form of the above compound, comprising the steps of mixing and stirring the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid with water.

[0010] In certain embodiments, the working volume (μL) of solvent 1 described in the present disclosure may be 1 to 200 times the mass (mg) of the compound, and in non-limiting embodiments, is 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200, or a value between any two of the numbers.

[0011] In another aspect, the disclosure further provides Form A crystals of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

[0012] In some embodiments, the A-type crystal of the compound has a powder X-ray diffraction pattern represented by diffraction angles 2θ, which has characteristic peaks at 9.587, 10.216, 11.812, 18.204, and 23.404.

[0013] In some embodiments, crystalline Form A of the compound has characteristic peaks at 9.587, 10.216, 11.812, 12.645, 13.956, 15.488, 17.541, 18.204, 19.462, 23.404.

[0014] In some embodiments, crystalline Form A of the compound has characteristic peaks at 7.654, 9.587, 10.216, 11.812, 12.645, 13.956, 15.488, 16.503, 17.541, 18.204, 19.462, 20.041, 20.697, 21.477, 21.812, 22.615, 23.404, 24.533, 26.618, 28.168, 29.406, 31.044.

[0015] In some embodiments, the powder X-ray diffraction pattern, expressed as a diffraction angle 2θ, of the A-type crystal of the compound is as shown in FIG.

[0016] The present disclosure relates to (a) mixing the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid with a solvent (1) and dissolving it by stirring or heating; and (b) crystallizing, wherein the solvent (1) is selected from one or more of n-propanol, nitromethane, tetrahydrofuran, isopropanol, isopropyl acetate, methyl tert-butyl ether, acetonitrile, ethyl acetate, and n-hexane.

[0017] In some embodiments, the crystallization method for the Form A crystals of the compound is stirred crystallization, static crystallization, cooling crystallization, cooling stirred crystallization, or evaporative crystallization.

[0018] In some embodiments, the method for preparing the above-mentioned compound A-type crystals includes mixing the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid with tetrahydrofuran, stirring or heating to dissolve, and evaporating and crystallizing.

[0019] In certain embodiments, the volume (μL) of the solvent (1) used according to the present disclosure may be 1 to 200 times the mass (mg) of the compound, and in non-limiting embodiments, is 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200, or a value between any two of the above values.

[0020] In certain embodiments, the preparation methods described herein further comprise a filtering, washing, or drying step.

[0021] The present disclosure further provides Form B1 crystals of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

[0022] In some embodiments, the B1 form of the compound has a powder X-ray diffraction pattern represented by diffraction angles 2θ, which has characteristic peaks at 8.135, 8.915, 11.259, 11.508, 19.024, and 25.271.

[0023] In some embodiments, crystalline Form B1 of the compound has characteristic peaks at 8.135, 8.915, 10.507, 11.259, 11.508, 12.223, 16.751, 19.024, 22.736, 25.271.

[0024] In some embodiments, Form B1 crystals of the compound have characteristic peaks at 8.135, 8.915, 10.507, 11.259, 11.508, 12.223, 13.632, 15.055, 16.751, 17.836, 19.024, 20.541, 22.205, 22.736, 25.271, 26.849.

[0025] In some embodiments, the powder X-ray diffraction pattern, expressed as diffraction angles 2θ, of the B1 crystal form of the compound is as shown in FIG.

[0026] The present disclosure further provides a method for preparing crystalline Form B1 of the above compound, selected from any one of the following methods:

[0027] Method 1: (a) mixing the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid with a solvent (2) and dissolving it by stirring or heating, the solvent being selected from one or more of isopropanol, isoamyl alcohol, 1,2-dichloroethane, acetone, isopropyl acetate, propylene glycol methyl ether, and p-xylene; (b) crystallizing; Or, Method 2: (a) the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid is mixed with a solvent (3) and dissolved by stirring or heating, the solvent (3) being tetrahydrofuran; (b) adding a solvent (4) to cause crystallization, the solvent (4) being water; Or, Method 3: (a) mixing the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid with a solvent (5), said solution (5) being selected from dioxane; (b) Stir to form a slurry.

[0028] In some embodiments, the method of crystallization of Form B1 crystals of the compound is stirred crystallization, static crystallization, cooling crystallization, cooling stirred crystallization, or evaporative crystallization.

[0029] In some embodiments, the method for preparing the B1 type crystal of the above compound includes mixing the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid with acetone, stirring or heating to dissolve, and evaporating and crystallizing.

[0030] In certain embodiments, the volume (μL) of the solvents (2), (3), (4), and (5) used in the present disclosure may be 1 to 200 times the mass (mg) of the compound, and in non-limiting embodiments, is 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200, or a value between any two of the above values.

[0031] The present disclosure further provides crystalline Form B2 of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

[0032] In some embodiments, the B2 type crystal of the compound has a powder X-ray diffraction pattern represented by diffraction angles 2θ, which has characteristic peaks at 8.182, 8.839, 10.401, 11.168, and 18.906.

[0033] In some embodiments, crystalline Form B2 of the compound has characteristic peaks at 8.182, 8.839, 10.401, 11.168, 11.679, 13.714, 18.906, 20.245, 21.895, 25.134.

[0034] In some embodiments, crystalline Form B2 of the compound has characteristic peaks at 8.182, 8.839, 10.401, 11.168, 11.679, 13.714, 14.880, 16.592, 17.660, 18.906, 20.245, 21.895, 22.600, and 25.134.

[0035] In some embodiments, the powder X-ray diffraction pattern, expressed as a diffraction angle 2θ, of the B2 crystal form of the compound is as shown in FIG.

[0036] The present disclosure relates to (a) the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid is mixed with a solvent (6) and dissolved by stirring or heating, the solvent (6) being selected from methyl isobutyl ketone; The present invention further provides a method for preparing crystalline Form B2 of the above compound, comprising: (b) crystallizing the compound.

[0037] In some embodiments, the method of crystallization of the Form B2 crystals of the compound is stirred crystallization, static crystallization, cooling crystallization, cooling stirred crystallization, or evaporative crystallization.

[0038] In certain embodiments, the volume (μL) of the solvent (6) used according to the present disclosure may be 1 to 200 times the mass (mg) of the compound, and in non-limiting embodiments, is 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200, or a value between any two of the above values.

[0039] The present disclosure further provides crystalline Form B3 of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

[0040] In some embodiments, the B3 type crystal of the compound has a powder X-ray diffraction pattern represented by diffraction angles 2θ, which has characteristic peaks at 10.548, 11.496, 17.557, 19.135, 19.751, and 25.360.

[0041] In some embodiments, crystalline Form B3 of the compound has characteristic peaks at 10.548, 11.269, 11.496, 17.557, 18.103, 19.135, 19.751, 20.605, 22.767, 25.360.

[0042] In some embodiments, crystalline Form B3 of the compound has characteristic peaks at 8.224, 8.976, 10.548, 11.269, 11.496, 12.264, 13.730, 14.829, 17.557, 18.103, 19.135, 19.751, 20.605, 22.767, 23.522, 24.738, 25.360, 26.556, 26.893.

[0043] In some embodiments, the powder X-ray diffraction pattern, expressed as a diffraction angle 2θ, of the B3 crystal form of the compound is as shown in FIG.

[0044] The present disclosure relates to (a) mixing the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid with a solvent (7) and dissolving by stirring or heating, the solvent (7) being selected from one or more of ethyl acetate, dichloromethane, and 10% water / acetone; The present invention further provides a method for preparing crystalline Form B3 of the above compound, comprising: (b) crystallizing the compound.

[0045] In some embodiments, the method of crystallization of the Form B3 crystals of the compound is stirred crystallization, static crystallization, cooling crystallization, cooling stirred crystallization, or volatile crystallization.

[0046] In certain embodiments, the volume (μL) of the solvent (7) used according to the present disclosure may be 1 to 200 times the mass (mg) of the compound, and in non-limiting embodiments, is 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200, or a value between any two of the above values.

[0047] The present disclosure further provides Form C crystals of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

[0048] In some embodiments, the C-type crystal of the compound has a powder X-ray diffraction pattern represented by diffraction angles 2θ having characteristic peaks at 10.094, 11.511, 17.378, and 20.113.

[0049] In some embodiments, crystalline Form C of the compound has characteristic peaks at 10.094, 11.511, 15.875, 17.378, 17.763, 18.573, 20.113, 22.925.

[0050] In some embodiments, Form C crystals of the compound have characteristic peaks at 5.470, 10.094, 11.511, 12.138, 14.975, 15.875, 17.378, 17.763, 18.573, 19.413, 20.113, 22.925, 23.881, 26.177, 28.163.

[0051] In some embodiments, the powder X-ray diffraction pattern, expressed as a diffraction angle 2θ, of the C-type crystal of the compound is as shown in FIG.

[0052] The present disclosure further provides a method for preparing crystalline Form C of the above compound, selected from any one of the following methods:

[0053] Method (1): (a) the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid is mixed with a solvent (8) and dissolved by stirring or heating, the solvent (8) being selected from toluene; (b) crystallizing; Or, Method (2): (a) mixing the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid with a solvent (9), said solvent (9) being selected from isopropyl acetate; (b) Stir to form a slurry.

[0054] In some embodiments, the crystallization method for the Form C crystals of the compound is stirred crystallization, static crystallization, cooling crystallization, cooling stirred crystallization, or evaporative crystallization.

[0055] In certain embodiments, the volume (μL) of the solvents (8) and (9) used according to the present disclosure may be 1 to 200 times the mass (mg) of the compound, and in non-limiting embodiments, is 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200, or a value between any two of the above values.

[0056] The present disclosure further provides a crystalline form D of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

[0057] In some embodiments, the D-form crystal of the compound has a powder X-ray diffraction pattern having characteristic peaks at 10.940, 12.216, 18.344, 19.931, and 22.979, expressed as diffraction angles 2θ.

[0058] In some embodiments, crystalline Form D of the compound has characteristic peaks at 6.343, 10.940, 12.216, 17.695, 18.344, 18.973, 19.472, 19.931, 21.753, 22.979, 24.685.

[0059] In some embodiments, crystalline Form D of the compound has characteristic peaks at 6.343, 10.940, 12.216, 12.762, 14.684, 16.167, 16.510, 17.695, 18.344, 18.973, 19.472, 19.931, 21.753, 22.979, 24.306, 24.685, 25.898.

[0060] In some embodiments, the powder X-ray diffraction pattern, expressed as a diffraction angle 2θ, of the D-form crystal of the compound is as shown in FIG.

[0061] The present disclosure further provides a method for preparing crystalline Form D of the above compound, selected from any one of the following methods:

[0062] Method 1: (a) mixing the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid with a solvent (10) and dissolving it by stirring or heating, the solvent (10) being selected from 50% methanol / water and 50% acetonitrile / methanol; (b) crystallizing; Or, Method 2: (a) the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid is mixed with a solvent (11) and dissolved by stirring or heating, the solvent (11) being selected from tetrahydrofuran or chloroform; (b) adding a solvent (12) to cause crystallization, the solvent (12) being selected from methanol; Or, Method 3: (a) mixing the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid with a solvent (13), said solvent (13) being selected from methanol; (b) Stir to form a slurry.

[0063] In some embodiments, the crystallization method for the crystalline Form D of the compound is stirred crystallization, static crystallization, cooling crystallization, cooling stirred crystallization, or evaporative crystallization.

[0064] In certain embodiments, the volume (μL) of the solvents (11), (12), and (13) used in the present disclosure may be 1 to 200 times the mass (mg) of the above compounds, and in non-limiting embodiments, is 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200, or any value between two such values.

[0065] The present disclosure further provides Form E crystals of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

[0066] In some embodiments, the E-form crystal of the compound has a powder X-ray diffraction pattern represented by diffraction angles 2θ, which has characteristic peaks at 11.591, 17.645, 19.060, 20.066, 20.667, and 26.987.

[0067] In some embodiments, crystalline Form E of the compound has characteristic peaks at 9.261, 10.735, 11.591, 13.946, 17.645, 18.291, 19.060, 20.066, 20.667, 26.987.

[0068] In some embodiments, Form E crystals of the compound have characteristic peaks at 8.245, 8.738, 9.261, 10.735, 11.591, 12.056, 13.946, 14.925, 16.922, 17.645, 18.291, 19.060, 20.066, 20.667, 22.474, 24.608, 26.987.

[0069] In some embodiments, the powder X-ray diffraction pattern, expressed as a diffraction angle 2θ, of the E-form crystal of the compound is as shown in FIG.

[0070] The present disclosure further provides a method for preparing crystalline Form E of the above compound, selected from any one of the following methods:

[0071] Method 1: (a) the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid is mixed with a solvent (14) and dissolved by stirring or heating, the solvent (14) being selected from acetonitrile; (b) crystallizing; Or, Method 2: (a) the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid is mixed with a solvent (15) and dissolved by stirring or heating, the solvent (15) being selected from tetrahydrofuran; (b) adding a solvent (16) to cause crystallization, said solvent (16) being selected from acetonitrile;

[0072] In some embodiments, the crystallization method for Form E crystals of the compound is stirred crystallization, static crystallization, cooling crystallization, cooling stirred crystallization, or evaporative crystallization.

[0073] In certain embodiments, the volume (μL) of the solvents (14), (15), and (16) used in the present disclosure may be 1 to 200 times the mass (mg) of the compound, and in non-limiting embodiments, is 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200, or any value between two such values.

[0074] The present disclosure further provides Form F crystals of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

[0075] In some embodiments, the F-type crystal of the compound has a powder X-ray diffraction pattern represented by a diffraction angle 2θ having characteristic peaks at 9.543, 19.405, and 22.153.

[0076] In some embodiments, crystalline Form F of the compound has characteristic peaks at 9.543, 11.421, 14.557, 16.175, 17.886, 19.405, 22.153, 25.821.

[0077] In some embodiments, the powder X-ray diffraction pattern, represented by the diffraction angle 2θ, of the F-type crystal of the compound is as shown in FIG.

[0078] The present disclosure further provides a method for preparing crystalline Form F of the above compound, selected from any one of the following methods:

[0079] Method 1: (a) the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid is mixed with a solvent (17) and dissolved by stirring or heating, the solvent (17) being selected from dimethyl sulfoxide; (b) crystallizing; Or, Method 2: (a) the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid is mixed with a solvent (18) and dissolved by stirring or heating, the solvent (18) being selected from dimethyl sulfoxide; (b) adding a solvent (19) to cause crystallization, said solvent (19) being selected from water;

[0080] In some embodiments, the crystallization method for Form F crystals of the compound is stirred crystallization, static crystallization, cooling crystallization, cooling stirred crystallization, or evaporative crystallization.

[0081] In certain embodiments, the volume (μL) of the solvents (17), (18), and (19) used in the present disclosure may be 1 to 200 times the mass (mg) of the compound, and in non-limiting embodiments, is 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200, or any value between two such values.

[0082] The present disclosure further provides Form G crystals of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

[0083] In some embodiments, the G-type crystal of the compound has a powder X-ray diffraction pattern represented by diffraction angles 2θ having characteristic peaks at 9.096, 11.107, 17.239, and 17.744.

[0084] In some embodiments, Form G crystals of the compound have characteristic peaks at 6.120, 9.096, 11.107, 12.302, 13.387, 17.239, 17.744, 22.984, 23.981, 25.879.

[0085] In some embodiments, Form G crystals of the compound have characteristic peaks at 6.120, 9.096, 9.519, 11.107, 12.302, 13.387, 14.833, 17.239, 17.744, 20.302, 20.905, 22.416, 22.984, 23.342, 23.981, 25.879, 28.791.

[0086] In some embodiments, the powder X-ray diffraction pattern, represented by the diffraction angle 2θ, of the G-type crystal of the compound is as shown in FIG.

[0087] The present disclosure relates to (a) the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid is mixed with a solvent (20) and dissolved by stirring or heating, the solvent (20) being selected from n-propanol; The present invention further provides a method for preparing a crystalline form G of the above compound, comprising: (b) crystallizing the compound.

[0088] In some embodiments, the crystallization method for the Form G crystals of the compound is stirred crystallization, static crystallization, cooling crystallization, cooling stirred crystallization, or evaporative crystallization.

[0089] In certain embodiments, the working volume (μL) of the solvent (20) described herein may be 1-200 times the mass (mg) of the compound, and in non-limiting embodiments, is 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200, or any value between two such values.

[0090] In addition, the method of preparing the above crystals of the present disclosure further comprises one or more steps of filtering, washing, or drying.

[0091] The present disclosure further provides a pharmaceutical composition comprising the above-mentioned A, B1, B2, B3, C, D, E, F or G type crystals, or the A, B1, B2, B3, C, D, E, F and G type crystals prepared by the above-mentioned method, and a pharmaceutical auxiliary agent optionally selected from pharma- ceutically acceptable excipients.

[0092] The present disclosure further provides a method for preparing a pharmaceutical composition, comprising mixing the above-mentioned A, B1, B2, B3, C, D, E, F or G type crystals, or the A, B1, B2, B3, C, D, E, F and G type crystals prepared by the above-mentioned method, with a pharma- ceutically acceptable excipient.

[0093] The present disclosure further provides use of the above-mentioned A, B1, B2, B3, C, D, E, F or G type crystals, or A, B1, B2, B3, C, D, E, F or G type crystals prepared by the above-mentioned method, or said composition, in the preparation of a medicament for treating or preventing a disease associated with the GLP-1 receptor.

[0094] The present disclosure further provides use of the above-mentioned A, B1, B2, B3, C, D, E, F or G type crystals, or A, B1, B2, B3, C, D, E, F or G type crystals prepared by the above-mentioned method, or said composition, in the preparation of a medicament for treating or preventing diabetes.

[0095] "2θ or 2θ angle" as used in this disclosure refers to the diffraction angle, where θ is the Bragg angle, and is expressed in ° or degrees, and the error range for each characteristic peak 2θ is ±0.2 (including numbers beyond one decimal place after rounding), and includes the following: -0.20, -0.19, -0.18, -0.17, -0.16, -0.15, -0.14, -0.13, -0.12, -0.11, -0.10, -0. 0.09, -0.08, -0.07, -0.06, -0.05, -0.04, -0.03, -0.02, -0.01, 0.00, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20.

[0096] According to the description of hygroscopic properties and the definition of hygroscopic weight increase in the 2015 edition of the Chinese Pharmacopoeia, Part 4, "9103 Guidelines on Hygroscopicity of Pharmaceuticals," Deliquescence: Absorption of enough water to form a liquid Extremely hygroscopic: Hygroscopic weight increase is 15% or more; Hygroscopic: Hygroscopic weight increase is less than 15% and is 2% or more; Slightly hygroscopic: Hygroscopic weight increase is less than 2% and more than 0.2%; No or little hygroscopicity: Hygroscopic weight increase is less than 0.2%.

[0097] "Differential scanning calorimetry or DSC" as used herein refers to the measurement of temperature and heat flow differences between a sample and a reference material during the heating or isothermal process of the sample in order to characterize all physical and chemical changes associated with thermal effects and obtain phase change information of the sample.

[0098] The drying temperature described in the present disclosure is generally 25° C. to 100° C., preferably 40° C. to 70° C., and may be dried at normal pressure or reduced pressure, with the pressure being <−0.08 MPa.

[0099] An "excipient" as referred to in this disclosure includes, but is not limited to, any adjuvant, carrier, glidant, sweetener, diluent, preservative, dye / colorant, flavoring, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, or emulsifying agent approved by the U.S. Food and Drug Administration as acceptable for human or veterinary use.

[0100] The term "slurrying" in this disclosure refers to a purification method that utilizes the poor solubility of a substance in a solvent and the good solubility of impurities in a solvent, and slurry purification can remove color, change crystals, and remove small amounts of impurities.

[0101] The starting materials used in the method for preparing crystals of the present disclosure may be compounds in any form, and specific forms include, but are not limited to, amorphous, any crystal, hydrate, solvate, etc.

[0102] The numerical values ​​such as the content of the substance in this disclosure are measured and calculated data, and some error is unavoidable. Generally, ±10% is within a reasonable error range. There will be some error variation depending on the context of use, and this error variation will not exceed ±10%, and may be ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2% or ±1%, and is preferably ±5%.

[0103] The compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (hereinafter referred to as compound A) in the present disclosure is prepared by referring to the method in PCT / CN2021 / 115915, the relevant contents of which are hereby incorporated by reference. [Brief description of the drawings]

[0104] [Figure 1] 1 is an XRPD pattern of the amorphous compound A prepared in Example 1. [Diagram 2] 1 is an XRPD pattern of the A-type crystals of Compound A prepared in Example 3. [Diagram 3] 1 is an XRPD pattern of the B1 type crystal of Compound A prepared in Example 10. [Figure 4] 1 is an XRPD pattern of the B2 type crystal of Compound A prepared in Example 15. [Diagram 5] 1 is an XRPD pattern of the B3 type crystal of compound A prepared in Example 16. [Figure 6] 2 is an XRPD pattern of the C-type crystals of Compound A prepared in Example 22. [Figure 7] 1 is an XRPD pattern of the D-type crystals of Compound A prepared in Example 23. [Figure 8] 1 is an XRPD pattern of E-type crystals of Compound A prepared in Example 28. [Figure 9] 1 is an XRPD pattern of F-type crystals of Compound A prepared in Example 29. [Figure 10] 1 is an XRPD pattern of the G-type crystals of Compound A prepared in Example 32. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0105] Hereinafter, the contents of the present disclosure will be described in more detail through examples or experimental examples. However, the examples or experimental examples of the present disclosure are only used to explain the technical solutions of the present disclosure, and do not limit the essence and scope of the present disclosure.

[0106] Test conditions for the equipment used in the experiments of this disclosure:

[0107] 1. Differential Scanning Calorimeter (DSC) Equipment Model: Mettler Toledo DSC 3+STARe System Purge gas: Nitrogen gas, Nitrogen gas purge rate: 50mL / min Heating rate: 10.0℃ / min Temperature range: 25~350℃ or 25~300℃

[0108] 2. X-ray Powder Diffraction (XRPD) Instrument model: BRUKER D8 Discover powder X-ray diffractometer Light: Monochromatic Cu-Kα radiation (λ=1.5406) Scan mode: θ / 2θ, Scan range (2θ range): 3~50° Voltage: 40kV, Current: 40mA

[0109] 3. Thermogravimetric Analysis (TGA) Equipment Model: Mettler Toledo TGA2 Purge gas: Nitrogen gas, Nitrogen gas purge rate: 50mL / min Heating rate: 10.0℃ / min Temperature range: 30~350℃

[0110] 4. DVS: Dynamic Vapor Sorption Detection was performed using Surface Measurement Systems advantage 2 at 25°C, with humidity of 50%-95%-0%-95%-50% RH, with a step size of 10%, and the criteria was that the mass change dM / dT for each gradient was less than 0.002%, with a TMAX of 360 min for two cycles.

[0111] 5. The reaction process monitoring in the examples is carried out by thin layer chromatography (TLC), and the developer used in the reaction, the column chromatography eluent system used for the purification of the compound and the thin layer chromatography developer system include A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system. The thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm-0.2mm, and the specification used in thin layer chromatography separation and purification of the product is 0.4mm-0.5mm. Silica gel column chromatography generally uses Yantai Yellow Sea silica gel 200-300 mesh silica gel as the carrier.

[0112] 6. The structure of the compound is determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR shift (δ) is 10 -6 It is expressed in units of (ppm).

[0113] NMR measurements were performed using a Bruker AVANCE NEO 500M, with the measurement solvents being deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), and the internal standard was tetramethylsilane (TMS).

[0114] The MS measurements were performed using an Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid mass spectrometer (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS), waters ACQuity UPLC-QD / SQD (manufacturer: waters, MS model: waters ACQuity Qda Detector / waters SQ Detector), and THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0115] 7. Known starting materials in the present disclosure can be synthesized by methods known in the art or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Shanghai Darui Fine Chemicals Co., Ltd.

[0116] 8. HPLC measurements were performed using an Agilent 1260DAD high-performance liquid chromatograph (ACE Excel C18 150 x 4.6 mm column) and a Thermo Dionex Ultimate 3000 high-pressure liquid chromatograph (Waters Xbridge C18 150 x 4.6 mm column). EXAMPLES

[0117] Example 1 [ka] [ka]

[0118] Step 1 2-(4-Chloro-2-fluorophenyl)oxirane 2b Potassium tert-butoxide (1.70g, 15.14mmol, Accela Chembio Co., Ltd.) was added to tetrahydrofuran (30mL), trimethylsulfonium iodide (3.09g, 15.14mmol, Adamas Reagent Co., Ltd.) was added under ice bath and stirred for 5 minutes. 4-Chloro-2-fluorobenzaldehyde 2a (2.0g, 12.61mmol, Accela Chembio Co., Ltd.) was added, filtered, diluted with ethyl acetate (80mL), washed with saturated ammonium chloride aqueous solution (30mL x 2), washed with saturated saline (30mL x 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the obtained residue was purified by silica gel column chromatography using elution system B to obtain the title compound 2b (650mg, yield: 29.9%).

[0119] 1 H NMR (500 MHz, CDCl3) δ 7.05-7.13 (m, 3H), 4.01-4.15 (m, 1H), 3.17(dd, 1H), 3.75(dd, 1H).

[0120] Step 2 2-(4-chloro-2-fluorophenyl)-2-(2,6-dibromophenoxy)ethanol 2d 1-(4-chloro-2-fluorophenyl)-2-(2,6-dibromophenoxy)ethanol 2e Compound 2b (520 mg, 3.01 mmol) and 2,6-dibromophenol 2c (759 mg, 3.01 mmol, TCI (SHANGHAI) Development Co., Ltd.) were mixed, and sodium methoxide (16 mg, 0.30 mmol, Adamas Reagent Co., Ltd.) was added and stirred at 130° C. for 2 hours. After cooling, the resulting residue was purified by silica gel column chromatography using elution system B to obtain the title compound 2d (210 mg, yield: 16.4%) and compound 2e (140 mg, yield: 10.9%).

[0121] 2d MS m / z (ESI):422.9 [M-1]. 2d 1 H NMR (500 MHz, DMSO-d6) δ 7.69 (t, 1H), 7.63(d, 2H), 7.40 (dd, 1H), 7.35 (dd, 1H), 7.00 (t, 1H), 5.59 (t, 1H), 5.02 (t, 1H), 3.98-4.03 (m, 1H), 3.81-3.90 (m, 1H).

[0122] 2e 1 H NMR (500 MHz, DMSO-d6) δ 7.64(d, 2H), 7.62 (t, 1H), 7.39 (dd, 1H), 7.32 (dd, 1H), 7.02 (t, 1H), 5.82-6.01 (m, 1H), 5.28 (t, 1H), 4.07-4.12 (m, 1H), 3.95-4.00 (m, 1H).

[0123] Step 3 8-Bromo-2-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxane 2f Compound 2d (595 mg, 1.40 mmol) was dissolved in anhydrous toluene (8 mL), and S-1,1'-bi-2-naphthol (159 mg, 0.55 mmol, Accela Chembio Co., Ltd.), cuprous iodide (52 mg, 0.27 mmol, Sinopharm Chemical Reagent Co., Ltd.), and cesium carbonate (912 mg, 2.80 mmol, Accela Chembio Co., Ltd.) were added in sequence, heated to reflux, and stirred for 18 hours. The mixture was cooled and concentrated under reduced pressure to remove the solvent, and the resulting residue was purified by silica gel column chromatography using elution system B to give the title compound 2f (380 mg, yield: 78.9%).

[0124] MS m / z (ESI): 343.1 [M-1]. 1H NMR (500 MHz, DMSO-d6) δ 7.57 (dd, 1H), 7.54(t, 1H), 7.43 (dd, 1H), 7.19 (dd, 1H), 6.98 (dd, 1H), 6.85 (t, 1H), 5.58 (dd, 1H), 4.51 (dd, 1H), 4.20 (dd, 1H).

[0125] Step 4 tert-Butyl 4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate 2g Compound 2f (354 mg, 1.03 mmol) and compound 1d (350 mg, 1.13 mmol, Accela Chembio Co., Ltd.) were dissolved in a mixed solution of 24 mL of 1,4-dioxane and water (V / V=5:1), sodium carbonate (218 mg, 2.06 mmol), and tetrakis(triphenylphosphine)palladium(0) (119 mg, 1.03 mmol) were added, and the mixture was stirred at 90° C. for 4 hours under nitrogen gas protection. The mixture was cooled to room temperature, filtered, and concentrated under reduced pressure to remove the solvent. The resulting residue was purified by silica gel column chromatography using elution system B to obtain the title compound 2g (410 mg, yield: 89.2%).

[0126] MS m / z (ESI): 390.1 [M-55]. 1 H NMR (500 MHz, CDCl3) δ 7.39 (t, 1H), 7.19-7.23 (m, 1H), 7.15 (dd, 1H), 6.83-6.89 (m, 2H), 6.77-6.81 (m, 1H), 5.76-5.91 (m, 1H), 5.32-5.46 (m, 1H), 5.41 (dd, 1H), 3.99-4.08 (m, 2H),3.97 (dd, 1H),3.43-3.69 (m, 2H),2.40-2.63 (m, 2H), 1.47 (s, 9H).

[0127] Step 5 tert-Butyl 4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine-1-carboxylate 2h Compound 2g (220 mg, 0.49 mmol) was dissolved in ethyl acetate (10 mL) and 1,2-dichlorobenzene (0.5 mL, TCI (SHANGHAI) Development Co., Ltd.), 10% palladium carbon (50 mg, 0.47 mmol) was added, and the mixture was hydrogenated at room temperature under 1 atm of hydrogen gas for 1 hour, filtered, and concentrated under reduced pressure to remove the solvent. The resulting residue was purified by silica gel column chromatography using elution system B to obtain the title compound 2h (178 mg, yield: 80.5%).

[0128] MS m / z (ESI): 392.1 [M-55]. 1 H NMR (500 MHz, CDCl3) δ 7.40 (t, 1H), 7.21-7.24 (m, 1H), 7.16 (dd, 1H), 6.82-6.88(m, 1H), 6.76-6.81(m, 2H), 5.35-5.45(m, 1H), 4.40(dd, 1H), 4.09-4.33 (m, 2H), 3.96 (dd, 1H), 2.99-3.11 (m, 1H),2.67-2.90 (m, 2H), 1.72-1.91 (m, 2H), 1.58-1.69 (m, 2H), 1.46 (s, 9H).

[0129] Step 6 4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine p-toluenesulfonate 2i Compound 2h (178 mg, 0.40 mmol) was dissolved in ethyl acetate (5 mL), p-toluenesulfonic acid monohydrate (189 mg, 0.99 mmol) was added, and the mixture was stirred at 60° C. for 2 h. The mixture was cooled to room temperature and concentrated under reduced pressure to give the crude title product 2i (206 mg), which was used directly in the next step reaction without purification.

[0130] MS m / z (ESI): 348.1 [M+1].

[0131] Step 7 Methyl 2-((4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-((S)-oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate 2j Compound 1g (175 mg, 0.59 mmol) and 2i (206 mg, 0.59 mmol) were dissolved in acetonitrile (10 mL), potassium carbonate (410 mg, 2.97 mmol) was added, and the mixture was stirred at 60° C. for 3 hours. The mixture was filtered and concentrated under reduced pressure to remove the solvent, and the resulting residue was purified by silica gel column chromatography using elution system B to obtain the title compound 2j (207 mg, yield: 57.7%).

[0132] MS m / z (ESI): 606.2 [M+1].

[0133] Step 8 Methyl 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate Ia Methyl 2-((4-((R)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate Ib Compound 2j (830 mg, 1.37 mmol) was subjected to chiral preparation (separation conditions: CHIRALPAK IG 250 × 20 mm, 5 μm (with guard column); mobile phase: hexane / EtOH (0.1% DEA) = 70 / 30 (V / V), flow rate: 20 mL / min), and the corresponding components were collected and concentrated under reduced pressure to give the title product (415 mg, 340 mg).

[0134] Single configuration compound (shorter retention time Ia): MS m / z (ESI): 606.0 [M+1]; Chiral HPLC analysis: retention time 13.653 min. Single configuration compound (longer retention time Ib): MS m / z (ESI): 606.0 [M+1]; Chiral HPLC analysis: retention time 16.422 min.

[0135] Step 9 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound A) Ia (415 mg, 0.68 mmol) was dissolved in 36 mL of a mixed solvent of acetonitrile and water (V:V=6:1), lithium hydroxide monohydrate (145 mg, 3.46 mmol) was added, and the mixture was stirred at 40 ° C for 18 hours. The reaction solution was cooled to room temperature, the pH was adjusted to 5-6 with aqueous citric acid (1 M), extracted with ethyl acetate (30 mL × 3), and the organic phase was concentrated under reduced pressure, and then purified by high performance liquid chromatography (Gilson 281, chromatography column: Boston Phlex C18 150 × 30 mm, 5 μm; mobile phase 1: water (containing 10 mmol / L ammonium bicarbonate); mobile phase 2: acetonitrile; 15 min gradient: 30% to 50%, flow rate: 30 mL / min) to obtain the title product Compound A (310 mg, yield: 76.46%).

[0136] MS m / z (ESI): 592.2 [M+1]. 1H NMR (500 MHz, DMSO-d6) δ 12.42-12.97 (brs, 1H), 8.20-8.28(m, 1H), 7.74-7.83 (m, 1H), 7.61 (d, 1H), 7.55-7.58 (m, 1H), 7.48-7.54 (m, 1H), 7.38-7.44 (m, 1H), 6.70-6.90 (m, 3H), 5.40-7.49 (m, 1H), 5.01-5.13 (m, 1H), 4.72-4.84 (m, 1H), 4.59-4.67 (m, 1H), 4.39-4.51 (m, 2H), 4.31-4.38 (m, 1H), 4.04-4.13 (m, 1H), 3.86-3.95 (m, 1H), 3.71-3.79 (m, 1H), 2.91-3.01 (m, 1H), 2.77-2.88 (m, 2H), 2.61-2.72 (m, 1H), 2.33-2.44 (m, 1H), 2.07-2.25 (m, 2H), 1.73-1.81 (m, 1H), 1.63-1.73 (m, 2H), 1.54-1.63 (m, 1H).

[0137] Test Example 1: Evaluation of GLP-1 receptor agonist activity

[0138] 1. Purpose of the test The purpose of this study is to test the agonistic activity of compound molecules on the GLP-1 receptor and to evaluate the EC 50 The aim of this study is to evaluate the in vitro activity of molecules based on their size. TM Luciferase Assay System (ONE-Glo TM Using the ONE-Glo Luciferase Assay System (Promega, E6110), the compound molecules activated the GLP-1R downstream signaling pathway, causing an increase in cAMP levels. The binding of cAMP to CRE initiated transcriptional expression of the luciferase gene downstream of CRE. Luciferase emitted fluorescence when it reacted with its substrate, and the results were analyzed using the ONE-Glo Luciferase Assay System (Promega, E6110). TM The fluorescent signal can be measured via the reagent to reflect the agonistic activity of the compound on the GLP-1 receptor.

[0139] II. Experimental Method Construct a cell line stably transfected with CHO-K1 / CRE-luc / GLP-1 receptor (GLP-1 receptor plasmid self-construct, CRE-luc plasmid Promega E8471). Digest, centrifuge and resuspend CHO-K1 / CRE-luc / GLP-1 receptor cells, mix homogenously to a single cell suspension, and culture in cell culture medium (DME / F-12 + 10% FBS) to a density of 2.5 × 10 live cells. 5 Adjust the volume to cells / mL and add 90 μl / well to a 96-well cell culture plate (Corning, #3903). Culture the plate in an incubator (37° C., 5% CO2) for 16 hours.

[0140] Dissolve the compounds in DMSO to prepare a stock solution with an initial concentration of 20 mM. The starting concentration of the small molecule compounds is 0.2 mM, diluted 3 times, diluted 10 points, the 11th point is DMSO. Take another 96-well plate, add 95 μl of cell culture medium (DME / F-12+10%FBS) to each well, then add 5 μl of different concentrations of test samples to each well, mix evenly, then add 10 μl / well of different concentrations of test samples to the cell culture plate, set up two duplicate wells for each sample. Incubate the culture plate in an incubator for 6 hours (37℃, 5% CO2). Take out the 96-well cell culture plate, add 100 μl of ONE-Glo to each well, and set up two duplicate wells for each sample. TM Add reagent and incubate for 10 minutes at room temperature. Measure chemiluminescence using a microplate reader (EnVision 2105, PE).

[0141] Data analysis Data were processed and analyzed using Microsoft Excel and Graphpad Prism 5. EC 50 Got the value.

[0142] [Table 1]

[0143] Example 2: Preparation of amorphous Compound A 10 mg of compound A was weighed, 500 μL of water was added, and the mixture was slurried at room temperature, centrifuged, and dried to obtain a solid. Powder X-ray diffraction detection showed that the powder X-ray diffraction pattern represented by the diffraction angle 2θ had no obvious characteristic peaks, and the XRPD pattern was shown in Figure 1, indicating that the product was amorphous.

[0144] Example 3: Preparation of A-type crystals of Compound A 10 mg of compound A was weighed, 500 μL of n-propanol was added, and the sample was dissolved at 60 ° C until it became transparent, and precipitated after cooling, centrifuged, and dried to obtain a solid. By powder X-ray diffraction detection, the XRPD pattern is shown in Figure 2, and its characteristic peak positions are shown in Table 2, which was defined as A-type crystal. The DSC pattern showed that the endothermic peak was at 197.60 ° C. The TGA pattern showed that the weight loss was 0.35% from 30 to 150 ° C.

[0145] [Table 2]

[0146] Example 4: Preparation of A-type crystals of Compound A 10 mg of compound A was weighed out, 100 μL of THF was added, and the mixture was heated and cooled at 50° C. to 5° C. without any precipitation. The sample was evaporated at room temperature to obtain a solid. The product was found to be type A crystal by powder X-ray diffraction detection.

[0147] Example 5: Preparation of A-type crystals of Compound A 10 mg of compound A was weighed out, 500 μL of nitromethane was added, and the mixture was heated and cooled at 50° C. to 5° C. to precipitate a solid, which was then centrifuged and dried to obtain a solid. The product was found to be type A crystal by powder X-ray diffraction detection.

[0148] Example 6: Preparation of A-type crystals of Compound A Weigh out 2g of compound A, add 50mL of n-propanol, and dissolve at 65℃ with stirring until transparent. After stopping heating, slowly cool to 35℃, add 5mg of seed crystals and stir. After stirring, solids are precipitated. After stirring, the mixture is transferred to 2-8℃ and stirred overnight. Centrifugation and drying give a solid. Powder X-ray diffraction detection revealed that the product was type A crystal.

[0149] Example 7: Preparation of A-type crystals of Compound A 30 mg of compound A was weighed and dispersed in 0.3 mL of isopropanol. The solution became cloudy, and the mixture was slurried at room temperature for 3 days, filtered, and the cake was collected and dried in vacuum. The product was type A crystal.

[0150] Example 8: Preparation of A-type crystals of Compound A Weigh out 17g of crude compound A, add it to 180mL of ethyl acetate, heat it to 80℃, stir, solid gradually precipitate during the stirring process, slowly add 90mL of n-hexane dropwise, after the dropwise addition is completed, stir at 80℃ for 30 minutes, naturally cool to room temperature, further stir in ice bath for 30 minutes, filter, collect the cake and vacuum dry, the product is A-type crystal.

[0151] Example 9: Preparation of A-type crystals of Compound A 30 mg of compound A was weighed and dispersed in 0.3 mL of isopropyl acetate. The solution became cloudy and was slurried at room temperature for 3 days, filtered, the cake was collected and dried in vacuum, and the product was type A crystal.

[0152] Example 10: Preparation of B1 type crystals of Compound A 10 mg of compound A was weighed, 500 μL of acetone was added, and the sample was dissolved at 50 ° C until it became transparent, and then heated and cooled from 50 ° C to 5 ° C to cause volatilization and crystallization. By powder X-ray diffraction detection, the XRPD pattern is shown in Figure 3, and its characteristic peak positions are shown in Table 3, which was defined as B1 type crystal. The DSC pattern showed endothermic peaks at 129.48 ° C and 140.82 ° C. The TGA pattern showed that the weight loss was 4.62% at 30 to 160 ° C.

[0153] [Table 3]

[0154] Example 11: Preparation of B1 type crystals of Compound A 10 mg of compound A was weighed out, 500 μL of isopropanol was added, and after cooling, a solid was precipitated, centrifuged, and dried to obtain a solid. The product was found to be B1 type crystals by powder X-ray diffraction detection.

[0155] Example 12: Preparation of B1 type crystals of Compound A 10 mg of compound A was weighed, 500 μL of isoamyl alcohol was added, and the mixture was cooled to precipitate a solid, which was then centrifuged and dried to obtain a solid. The product was found to be B1 type crystals by powder X-ray diffraction detection.

[0156] Example 13: Preparation of B1 type crystals of Compound A 10 mg of compound A was weighed, 150 μL of THF was added, and the solution was dissolved until transparent, and water was added to precipitate a solid until the total amount became 600 μL, and the solid was centrifuged and dried to obtain a solid. The product was found to be B1 type crystals by powder X-ray diffraction detection.

[0157] Example 14: Preparation of B1 type crystals of Compound A 10 mg of compound A was weighed out, 100 μL of 1,2-dichloroethane was added, and the mixture was cooled to precipitate a solid, which was then centrifuged and dried to obtain a solid. The product was found to be B1 type crystals by powder X-ray diffraction detection.

[0158] Example 15: Preparation of B2 type crystals of Compound A 10 mg of compound A was weighed, 100 μL of methyl isobutyl ketone was added, and the solid was precipitated after cooling, centrifuged, and dried to obtain a solid. By powder X-ray diffraction detection, the XRPD pattern is shown in FIG. 4, and its characteristic peak positions are shown in Table 4, which was defined as B2 type crystal. The DSC pattern showed that the endothermic peak was at 137.59 ° C. The TGA pattern showed that the weight loss was 9.27% ​​at 30 to 160 ° C.

[0159] [Table 4]

[0160] Example 16: Preparation of B3 type crystals of Compound A 10 mg of compound A was weighed, 500 μL of ethyl acetate was added, and the mixture was dissolved until transparent, stirred, precipitated, centrifuged, and dried to obtain a solid. Powder X-ray diffraction detection revealed that the XRPD pattern was shown in FIG. 5 and its characteristic peak positions were shown in Table 5, which was defined as B3 type crystal. The DSC pattern showed endothermic peaks at 114.84 ° C and 146.66 ° C. The TGA pattern showed that the weight loss was 2.08% at 30 to 160 ° C.

[0161] [Table 5]

[0162] Example 17: Preparation of B3 type crystals of Compound A Weigh out 10 mg of compound A, add 100 μL of dichloromethane, dissolve until transparent, cool, precipitate solid, centrifuge, and dry to obtain solid. Powder X-ray diffraction detection showed that the product was B3 type crystal.

[0163] Example 18: Preparation of B3 type crystals of Compound A Weigh out 10 mg of compound A, add 100 μL of 10% water / acetone solution, dissolve until transparent, cool, precipitate solid, centrifuge, and dry to obtain solid. Powder X-ray diffraction detection showed that the product was B3 type crystal.

[0164] Example 19: Preparation of B1 type crystals of Compound A Weigh out 10 mg of compound A, add 500 μL of isopropyl acetate, dissolve until transparent, stir, precipitate, centrifuge, and dry to obtain a solid. Powder X-ray diffraction detection showed that the product was B1 type crystal.

[0165] Example 20: Preparation of B1 type crystals of Compound A 10 mg of compound A was weighed, 100 μL of propylene glycol methyl ether was added, and the mixture was heated and cooled at 50° C. to 5° C. to precipitate a solid, which was then centrifuged and dried to obtain a solid. The product was found to be B1 type crystals by powder X-ray diffraction detection.

[0166] Example 21: Preparation of B1 type crystals of Compound A 10 mg of compound A was weighed out, 100 μL of p-xylene was added, and the mixture was heated and cooled at 50° C. to 5° C. to precipitate a solid, which was then centrifuged and dried to obtain a solid. The product was found to be B1 type crystals by powder X-ray diffraction detection.

[0167] Example 22: Preparation of C-type crystals of Compound A Weigh out 10mg of compound A, add 500μL of toluene, slurried at room temperature, centrifuged and dried to obtain a solid. Powder X-ray diffraction detection showed that the product was C-type crystal, and the XRPD pattern is shown in Figure 6, and its characteristic peak positions are shown in Table 6.

[0168] [Table 6]

[0169] Example 23: Preparation of D-type crystals of Compound A 10 mg of compound A was weighed, 500 μL of methanol was added, and the mixture was slurried at room temperature, centrifuged, and dried to obtain a solid. Powder X-ray diffraction detection revealed that the XRPD pattern was shown in FIG. 7 and its characteristic peak positions were shown in Table 7, which was defined as D-type crystal. The DSC pattern showed that the endothermic peak was at 190.72 °C. The TGA pattern showed that the weight loss was 1.88% from 30 to 220 °C.

[0170] [Table 7]

[0171] Example 24: Preparation of D-type crystals of Compound A 10 mg of compound A was weighed out, and 500 μL of a mixed solution of methanol:water=1:1 was added, and the mixture was heated and cooled at 50° C. to 5° C. to precipitate a solid, which was then centrifuged and dried to obtain a solid. The product was found to be a D-type crystal by powder X-ray diffraction detection.

[0172] Example 25: Preparation of D-type crystals of Compound A 10 mg of compound A was weighed out, dissolved in 150 μL of THF, and then methanol was added to precipitate a solid until the total volume reached 800 μL. The solid was centrifuged and dried to obtain a solid. The product was found to be a D-type crystal by powder X-ray diffraction detection.

[0173] Example 26: Preparation of D-type crystals of Compound A 10 mg of compound A was weighed out, and 500 μL of a mixed solution of acetonitrile:methanol=1:1 was added, and the mixture was heated and cooled at 50° C. to 5° C. to precipitate a solid, which was then centrifuged and dried to obtain a solid. The product was found to be a D-type crystal by powder X-ray diffraction detection.

[0174] Example 27: Preparation of D-type crystals of Compound A 10 mg of compound A was weighed out, dissolved in 50 μL of chloroform, and then added with methanol to precipitate a solid until the total volume reached 800 μL. The solid was centrifuged and dried to obtain a solid. The product was found to be a D-type crystal by powder X-ray diffraction detection.

[0175] Example 28: Preparation of E-type crystals of Compound A 10 mg of compound A was weighed, 500 μL of acetonitrile mixed solution was added, and the mixture was heated and cooled at 50 ° C to 5 ° C., after which the solid was precipitated, centrifuged, and dried to obtain a solid. Powder X-ray diffraction detection was performed, and the XRPD pattern is shown in FIG. 8, and its characteristic peak positions are shown in Table 8. The DSC pattern showed endothermic peaks at 118.74 ° C and 125.07 ° C, which was defined as E-type crystals. The TGA pattern showed a weight loss of 3.50% at 30 to 170 ° C.

[0176] [Table 8]

[0177] Example 29: Preparation of E-type crystals of Compound A 10 mg of compound A was weighed out, dissolved in 150 μL of THF, and precipitated with acetonitrile until the total volume reached 800 μL. The precipitate was centrifuged and dried to obtain a solid. The product was found to be E-type crystals by powder X-ray diffraction detection.

[0178] Example 30: Preparation of F-type crystals of Compound A 10 mg of compound A was weighed, dissolved in 50 μL of DMSO, and then added with water to precipitate a solid until the volume was 800 μL. The solid was centrifuged and dried to obtain a solid. Powder X-ray diffraction detection showed that the product was F-type crystals, and the XRPD pattern is shown in FIG. 9, and its characteristic peak positions are shown in Table 9. The DSC pattern showed that the endothermic peak was at 111.89 ° C. The TGA pattern showed that the weight loss was 3.16% at 30 to 150 ° C.

[0179] [Table 9]

[0180] Example 31: Preparation of F-type crystals of Compound A 10 mg of compound A was weighed out, 50 μL of DMSO was added, and the mixture was heated and cooled at 50° C. to 5° C. without precipitation. The sample was evaporated at room temperature to obtain a solid. Powder X-ray diffraction detection revealed that the product was F-type crystals.

[0181] Example 32: Preparation of G-type crystals of Compound A Weigh out 2g of compound A, add 50ml of n-propanol, stir and dissolve at 65℃ until transparent, slowly cool to 5℃, stir overnight, centrifuge, and vacuum dry the solid at 60℃ for 1 hour. Powder X-ray diffraction detection showed that the XRPD pattern is shown in Figure 10 and its characteristic peak positions are shown in Table 10, which was defined as G-type crystal. DSC pattern showed endothermic peaks at 115.06℃ and 200.24℃. TGA pattern showed that the weight loss was 7.35% from 30 to 150℃.

[0182] [Table 10]

[0183] Test Example 2: Hygroscopicity study of crystals of Compound A The Surface Measurement Systems intrinsic DVS was used, and the temperature was 25°C. The humidity range was 0% to 95%, the step size was 10%, and the criterion was that the mass change dM / dT for each gradient was less than 0.002%, with two cycles performed at TMAX 360 min.

[0184] [Table 11]

[0185] Test Example 3: Stability study of crystals of Compound A The crystal samples of compound A were placed open and the stability of the samples was examined under the conditions of light (4500 Lux), high temperature (40°C, 60°C), and high humidity (RH75%, RH92.5%). The sampling period was 30 days.

[0186] [Table 12]

[0187] [Table 13]

[0188] The experimental results showed that the A-type and D-type crystals of Compound A had good physical and chemical stability.

[0189] Test Example 4: Long-term / accelerated stability The crystal samples of Compound A were sealed in aluminum foil bags and placed under conditions of 25°C / 60% RH and 40°C / 75% RH, respectively, and the stability was examined. The results are shown below.

[0190] [Table 14]

[0191] The experimental results showed that the A-type crystals of Compound A had good physical and chemical stability when placed under long-term accelerated conditions for 6 months, and the D-type crystals had good physical and chemical stability when placed under long-term accelerated conditions for 3 months.

Claims

1. The compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid is a crystal, Here, (1) The powder X-ray diffraction pattern of the crystal, represented by the diffraction angle 2θ, has characteristic peaks at 9.587, 10.216, 11.812, 18.204, and 23.404, or (2) The powder X-ray diffraction pattern of the crystal, represented by the diffraction angle 2θ, has characteristic peaks at 9.096, 11.107, 17.239, and 17.

744. The error range of the aforementioned 2θ value is ±0.

2. Crystals of compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

2. The powder X-ray diffraction pattern of the crystal, represented by a diffraction angle of 2θ, has characteristic peaks at 9.587, 10.216, 11.812, 18.204, and 23.

404. The crystal according to claim 1, wherein the error range of the 2θ value is ±0.

2.

3. The powder X-ray diffraction pattern of the crystal, represented by a diffraction angle of 2θ, has characteristic peaks at 9.587, 10.216, 11.812, 12.645, 13.956, 15.488, 17.541, 18.204, 19.462, and 23.

404. The crystal according to claim 1, wherein the error range of the 2θ value is ±0.

2.

4. The powder X-ray diffraction pattern of the crystal, represented by a diffraction angle of 2θ, has characteristic peaks at 7.654, 9.587, 10.216, 11.812, 12.645, 13.956, 15.488, 16.503, 17.541, 18.204, 19.462, 20.041, 20.697, 21.477, 21.812, 22.615, 23.404, 24.533, 26.618, 28.168, 29.406, and 31.

044. The crystal according to claim 1, wherein the error range of the 2θ value is ±0.

2.

5. The crystal according to claim 1, wherein the crystal is a type A crystal.

6. The powder X-ray diffraction pattern of the crystal, represented by a diffraction angle of 2θ, has characteristic peaks at 9.096, 11.107, 17.239, and 17.

744. The crystal according to claim 1, wherein the error range of the 2θ value is ±0.

2.

7. The powder X-ray diffraction pattern of the crystal, represented by a diffraction angle of 2θ, has characteristic peaks at 6.120, 9.096, 11.107, 12.302, 13.387, 17.239, 17.744, 22.984, 23.981, and 25.

879. The crystal according to claim 1, wherein the error range of the 2θ value is ±0.

2.

8. The powder X-ray diffraction pattern of the crystal, represented by a diffraction angle of 2θ, has characteristic peaks at 6.120, 9.096, 9.519, 11.107, 12.302, 13.387, 14.833, 17.239, 17.744, 20.302, 20.905, 22.416, 22.984, 23.342, 23.981, 25.879, and 28.

791. The crystal according to claim 1, wherein the error range of the 2θ value is ±0.

2.

9. The crystal according to claim 1, wherein the crystal is a G-type crystal.

10. (a) Mix compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid with a solvent, stir or heat to dissolve, and (b) Crystallize, A method for preparing crystals according to any one of claims 2 to 5, wherein the solvent is selected from one or more of n-propanol, nitromethane, tetrahydrofuran, isopropanol, isopropyl acetate, methyl tert-butyl ether, acetonitrile, ethyl acetate, and n-hexane.

11. (a) Mix compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid with a solvent and dissolve by stirring or heating, (b) Crystallize, A method for preparing crystals according to any one of claims 6 to 9, wherein the solvent is n-propanol.

12. The method according to claim 10, further comprising one or more steps of filtering, washing, or drying.

13. The method according to claim 11, further comprising one or more steps of filtering, washing, or drying.

14. A pharmaceutical composition comprising a crystal according to any one of claims 1 to 9 and an optionally selected pharmaceutically acceptable excipient.

15. A method for preparing a pharmaceutical composition, comprising the step of mixing the crystals described in any one of claims 1 to 9 with a pharmaceutically acceptable excipient.

16. The pharmaceutical composition according to claim 14 for treating or preventing a disease related to the GLP-1 receptor.

17. A pharmaceutical composition according to claim 14 for treating or preventing diabetes.

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