Imidazole derivative crystal form as well as preparation method and application thereof

Abstract

The invention provides an imidazole derivative crystal form as well as a preparation method and application thereof. The chemical structural formula of the crystal form is as shown in formula (I): # imgabs0 #, the imidazole derivative crystal form A is radiated by Cu-K alpha, and an X-ray powder diffraction pattern expressed by a 2 theta angle has diffraction peaks at 8.60 degrees + / -0.2, 11.36 degrees + / -0.2, 14.41 degrees + / -0.2 and 18.17 degrees + / -0.2; the imidazole derivative crystal form B is radiated by Cu-K alpha, and an X-ray powder diffraction pattern expressed by a 2 theta angle has diffraction peaks at the positions of 8.33 degrees + / -0.2, 11.17 degrees + / -0.2, 12.34 degrees + / -0.2 and 19.87 degrees + / -0.2; the imidazole derivative crystal form E is radiated by Cu-K alpha, and an X-ray powder diffraction pattern expressed by a 2 theta angle has diffraction peaks at the positions of 8.33 degrees + / -0.2, 10.73 degrees + / -0.2, 12.30 degrees + / -0.2 and 14.16 degrees + / -0.2. The imidazole derivative crystal form, especially the crystal form A, provided by the invention has good stability under the conditions of high temperature, high humidity, illumination and the like, and the product is not easy to degrade and can meet the pharmaceutical requirements of production, transportation and storage.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry, and particularly relates to imidazole derivative crystal forms, their preparation methods and uses. Background Art

[0002] The emergence of anesthetic drugs is of great significance to modern medicine. Anesthesia can relieve the pain and other discomfort symptoms of patients during surgery. Once discovered, anesthetic drugs have been widely used clinically. Anesthetic drugs are mainly divided into intravenous anesthetics (imidazole derivatives (such as etomidate), propofol), inhaled anesthetics (isoflurane, sevoflurane) and local anesthetics (procaine, tetracaine), etc.

[0003] Imidazole derivatives are widely used in clinical anesthesia and ICU sedation. When used for general anesthesia, it has the characteristics of rapid onset and short duration. It has a high metabolic rate in the body and no obvious accumulation. Imidazole derivatives have no obvious inhibitory effect on respiration, have a slight impact on cardiovascular function, and have stable hemodynamics. However, imidazole derivatives also have certain side effects. For example, by inhibiting the related activity of 11-β hydroxylase, and then inhibiting the synthesis of adrenal cortical hormones, it causes symptoms such as general discomfort, fatigue, loss of appetite, nausea, dizziness and hypotension in patients. Continuous application will lead to inhibition of adrenal cortical function and even increase the mortality rate of critically ill patients. At the same time, as the dosage of imidazole derivatives increases, its recovery time is prolonged, which limits its application in continuous infusion. Therefore, it is necessary to optimize and transform imidazole derivatives to make them metabolize rapidly, so as to achieve the effect of reducing the inhibition of corticosteroids.

[0004] Based on the mechanism of action of anesthetic drugs and combined with the characteristics of current anesthetic drugs, the inventors of the present invention have developed a new imidazole derivative compound (Formula (1), abbreviated as ETG-9) that meets clinical applications. As a target compound of a new anesthetic drug with development value, the study of its crystal form is beneficial to improving the drug-likeness. Summary of the Invention

[0005] The object of the present invention is to provide imidazole derivative crystal forms, their preparation methods and uses. The inventors of the present invention have investigated the crystallization products obtained by imidazole derivatives under different crystallization conditions, and carried out X-ray diffraction, DSC analysis, thermogravimetric analysis and Raman analysis on the obtained crystallization products, and found that under certain specific crystallization conditions, three imidazole derivative crystal forms with good stability can be obtained.

[0006] Crystal Form A

[0007] In the first aspect, the present invention provides an imidazole derivative crystal form (A), whose chemical structural formula is shown as Formula (I):

[0008]

[0009] Among them, the X-ray powder diffraction pattern of the imidazole derivative crystal form, expressed in 2θ angle using Cu-Kα radiation, has diffraction peaks at 8.60° ± 0.2, 11.36° ± 0.2, 14.41° ± 0.2, and 18.17° ± 0.2.

[0010] Preferably, the X-ray powder diffraction pattern of the imidazole derivative crystal form, expressed in 2θ angle using Cu-Kα radiation, has diffraction peaks at 8.60° ± 0.2, 11.36° ± 0.2, 12.56° ± 0.2, 14.41° ± 0.2, 18.17° ± 0.2, 20.31° ± 0.2, and 22.57° ± 0.2.

[0011] More preferably, the X-ray powder diffraction pattern of the imidazole derivative crystal form, expressed in 2θ angle using Cu-Kα radiation, has diffraction peaks at 8.60° ± 0.2, 11.36° ± 0.2, 12.56° ± 0.2, 14.41° ± 0.2, 16.92° ± 0.2, 18.17° ± 0.2, 20.31° ± 0.2, 22.57° ± 0.2, 24.36° ± 0.2, and 26.72° ± 0.2.

[0012] Even more preferably, the X-ray powder diffraction pattern of the imidazole derivative crystal form, expressed in 2θ angle using Cu-Kα radiation, has diffraction peaks at 8.60° ± 0.2, 11.36° ± 0.2, 12.56° ± 0.2, 14.41° ± 0.2, 16.92° ± 0.2, 18.17° ± 0.2, 20.31° ± 0.2, 22.57° ± 0.2, 24.36° ± 0.2, 26.72° ± 0.2, 28.15° ± 0.2, and 30.28° ± 0.2.

[0013] More preferably, the X-ray powder diffraction pattern of the imidazole derivative crystal form, expressed in 2θ angle using Cu-Kα radiation, is as Figure 1 shown.

[0014] Preferably, the differential scanning calorimetry curve of the imidazole derivative crystal form has an endothermic peak at 72.5 ± 8 °C.

[0015] Preferably, the imidazole derivative crystal form is an anhydrate.

[0016] Preferably, the Raman spectrum of the imidazole derivative crystal form is at 170.90 ± 5 cm -1 、205.19 ± 5 cm -1 、835.82 ± 5 cm -1 、1007.27 ± 5 cm -1 、1375.36 ± 5 cm-1 and at 1709.17 ± 5 cm -1 there is a characteristic absorption peak.

[0017] Further preferably, the Raman spectrum of the imidazole derivative crystal form is at 170.90 ± 5 cm -1 , 205.19 ± 5 cm -1 , 278.06 ± 5 cm -1 , 835.82 ± 5 cm -1 , 1007.27 ± 5 cm -1 , 1037.28 ± 5 cm -1 , 1375.36 ± 5 cm -1 , 1478.24 ± 5 cm -1 and at 1709.17 ± 5 cm -1 there is a characteristic absorption peak.

[0018] Further preferably, the Raman spectrum of the imidazole derivative crystal form is at 170.90 ± 5 cm -1 , 205.19 ± 5 cm -1 , 278.06 ± 5 cm -1 , 317.17 ± 5 cm -1 , 835.82 ± 5 cm -1 , 1007.27 ± 5 cm -1 , 1037.28 ± 5 cm -1 , 1187.84 ± 5 cm -1 , 1375.36 ± 5 cm -1 , 1407.51 ± 5 cm -1 , 1478.24 ± 5 cm -1 and at 1709.17 ± 5 cm -1 there is a characteristic absorption peak.

[0019] More preferably, the Raman spectrum of the imidazole derivative crystal form is at 170.90 ± 5 cm -1 , 205.19 ± 5 cm -1 , 278.06 ± 5 cm -1 , 317.17 ± 5 cm -1 , 349.32 ± 5 cm -1 , 449.51 ± 5 cm -1 , 835.82 ± 5 cm -1 , 911.36 ± 5 cm -1 , 1007.27 ± 5 cm -1 , 1037.28 ± 5 cm -1 , 1187.84 ± 5 cm -1 , 1375.36 ± 5 cm-1 、1407.51 ± 5 cm -1 、1478.24 ± 5 cm -1 and 1709.17 ± 5 cm -1 have characteristic absorption peaks at these positions.

[0020] In a second aspect, the present invention provides a method for preparing the imidazole derivative crystal form (A) according to the first aspect of the present invention, which includes:

[0021] Method 1

[0022] Dissolve the imidazole derivative in a first solvent or in a mixed solvent of a second solvent and a third solvent, and allow it to crystallize by standing;

[0023] Wherein, the first solvent is selected from one of methyl isobutyl ketone, C2-C5 alcohols, and an aqueous ethanol solution of 90-99% by volume; the second solvent is selected from one of dihalohydrocarbons, 1,4-dioxane, C5-C8 ethers, acetonitrile, N,N-dimethylformamide, C2-C6 ketones, C2-C5 alcohols, and an aqueous ethanol solution of 90-99% by volume; the third solvent is selected from one of C5-C8 ethers, water, acetonitrile, tetrahydrofuran, C2-C5 alcohols, C5-C 10 hydrocarbons, and C2-C6 ketones; the second solvent and the third solvent are different, and the volume ratio of the second solvent to the third solvent is 1:(0.1-2.5), preferably 1:(0.5-1.5).

[0024] Preferably, in Method 1, the dihalohydrocarbon is dichloromethane.

[0025] Preferably, in Method 1, the C5-C 10 hydrocarbons are selected from one of petroleum ether, n-hexane, n-heptane, and cyclohexane.

[0026] Preferably, in Method 1, the C5-C8 ether is isopropyl ether or methyl tert-butyl ether.

[0027] Preferably, in Method 1, the C2-C5 alcohols are selected from one of ethanol, tert-butanol, n-propanol, n-butanol, and isopropyl alcohol.

[0028] Preferably, in Method 1, the C2-C6 ketones are selected from one of methyl isobutyl ketone, acetone, and N-methylpyrrolidone.

[0029] Preferably, in Method 1, the aqueous ethanol solution of 90-99% by volume is an aqueous ethanol solution of 95% by volume.

[0030] Preferably, in Method 1, the ratio of the weight of the imidazole derivative to the volume of the first solvent or the volume ratio of the mixed solvent of the second solvent and the third solvent is 1 g: 10 - 100 mL, preferably 1 g: 20 - 80 mL, more preferably 1 g: 20 - 50 mL.

[0031] Preferably, in Method 1, the dissolution is carried out at a temperature of 50 - 70 °C, preferably 55 - 65 °C.

[0032] Preferably, in Method 1, the static crystallization is carried out at a temperature of 5 - 30 °C, preferably 10 - 30 °C.

[0033] Preferably, in Method 1, the static crystallization is carried out under sealed conditions.

[0034] Preferably, in Method 1, the method further includes the steps of filtering and drying the crystals after static crystallization.

[0035] Or Method 2

[0036] Add the imidazole derivative to the mixed solvent of the fourth solvent and the fifth solvent, dissolve it under reflux conditions and continue stirring for a period of time, then stop heating and carry out static crystallization;

[0037] Among them, the fourth solvent is selected from one of C2 - C5 alcohols and 90 - 99 vol% aqueous ethanol solution; the fifth solvent is selected from one of acetonitrile, acetone, ethyl acetate, n - hexane and cyclohexane; the fourth solvent and the fifth solvent are different, and the volume ratio of the fourth solvent to the fifth solvent is 1: (0.1 - 2), preferably 1: (0.5 - 1.5).

[0038] Preferably, in Method 2, the C2 - C5 alcohol is selected from one of ethanol, n - propanol, isopropanol and n - butanol.

[0039] Preferably, in Method 2, the 90 - 99 vol% aqueous ethanol solution is 95 vol% aqueous ethanol solution.

[0040] Preferably, in Method 2, the ratio of the weight of the imidazole derivative to the volume of the mixed solvent of the fourth solvent and the fifth solvent is 1 g: 5 - 50 mL, preferably 1 g: 10 - 30 mL.

[0041] Preferably, in Method 2, after dissolution under reflux conditions, continue stirring for 10 min - 120 min, preferably 20 min - 40 min.

[0042] Preferably, in Method 2, the static crystallization is carried out at a temperature of 5 - 30 °C, preferably 10 - 30 °C.

[0043] Preferably, in Method 2, the static crystallization is carried out under sealed conditions.

[0044] Preferably, in Method 2, the method further includes the steps of filtering and drying the crystals after static crystallization.

[0045] Crystal Form B

[0046] In a third aspect, the present invention provides an imidazole derivative crystal form (B) whose chemical structural formula is shown in Formula (I):

[0047]

[0048] Among them, the X-ray powder diffraction pattern of the imidazole derivative crystal form expressed in 2θ angle using Cu-Kα radiation has diffraction peaks at 8.33° ± 0.2, 11.17° ± 0.2, 12.34° ± 0.2, and 19.87° ± 0.2.

[0049] Preferably, the X-ray powder diffraction pattern of the imidazole derivative crystal form expressed in 2θ angle using Cu-Kα radiation has diffraction peaks at 8.33° ± 0.2, 11.17° ± 0.2, 12.34° ± 0.2, 16.65° ± 0.2, 19.87° ± 0.2, 22.13° ± 0.2, and 24.13° ± 0.2.

[0050] More preferably, the X-ray powder diffraction pattern of the imidazole derivative crystal form expressed in 2θ angle using Cu-Kα radiation has diffraction peaks at 8.33° ± 0.2, 11.17° ± 0.2, 12.34° ± 0.2, 16.65° ± 0.2, 17.95° ± 0.2, 19.87° ± 0.2, 22.13° ± 0.2, 24.13° ± 0.2, and 26.49° ± 0.2.

[0051] More preferably, the X-ray powder diffraction pattern of the imidazole derivative crystal form expressed in 2θ angle using Cu-Kα radiation is as Figure 5 shown.

[0052] Preferably, the differential scanning calorimetry curve of the imidazole derivative crystal form has an endothermic peak at 74.2 ± 8 °C.

[0053] Preferably, the imidazole derivative crystal form is an anhydrous substance.

[0054] Preferably, the Raman spectrum of the imidazole derivative crystal form has characteristic absorption peaks at 173.04 ± 5 cm -1 , 210.01 ± 5 cm -1 , 317.17 ± 5 cm -1 and 1009.42 ± 5 cm -1 .

[0055] Further preferably, the Raman spectrum of the imidazole derivative crystal form has characteristic absorption peaks at 173.04 ± 5 cm -1 , 210.01 ± 5 cm -1 , 317.17 ± 5 cm -1 , 840.64 ± 5 cm -1 , 1009.42 ± 5 cm -1 , 1375.36 ± 5 cm -1 and 1709.17 ± 5 cm -1 .

[0056] Further preferably, the Raman spectrum of the imidazole derivative crystal form has characteristic absorption peaks at 173.04 ± 5 cm -1 , 210.01 ± 5 cm -1 , 282.88 ± 5 cm -1 , 317.17 ± 5 cm -1 , 840.64 ± 5 cm -1 , 915.65 ± 5 cm -1 , 1009.42 ± 5 cm -1 , 1032.46 ± 5 cm -1 , 1375.36 ± 5 cm -1 and 1709.17 ± 5 cm -1 .

[0057] More preferably, the Raman spectrum of the imidazole derivative crystal form has characteristic absorption peaks at 173.04 ± 5 cm -1 , 210.01 ± 5 cm -1 , 282.88 ± 5 cm -1 , 317.17 ± 5 cm -1 , 840.64 ± 5 cm -1 , 915.65 ± 5 cm -1 , 1009.42 ± 5 cm -1 , 1032.46 ± 5 cm -1 , 1299.82 ± 5 cm -1 , 1375.36 ± 5 cm -1 , 1455.20 ± 5 cm -1 and 1709.17 ± 5 cm -1 .

[0058] Fourthly, the present invention provides a preparation method of the imidazole derivative crystal form (B) according to the third aspect of the present invention, which includes: dissolving the imidazole derivative in acetone and allowing it to crystallize by standing.

[0059] Preferably, the weight ratio of the imidazole derivative to the volume of acetone is 1 g∶10 - 100 mL, preferably 1 g∶10 - 50 mL.

[0060] Preferably, the dissolution is carried out at a temperature of 50 - 70 °C, preferably 55 - 65 °C.

[0061] Preferably, the static crystallization is carried out at a temperature of 5 - 30 °C, preferably 10 - 30 °C.

[0062] Preferably, the static crystallization is carried out under sealed conditions.

[0063] Preferably, the method further includes the steps of filtering and drying the crystals after static crystallization.

[0064] Crystal form E

[0065] In a fifth aspect, the present invention provides a crystal form (E) of an imidazole derivative, whose chemical structural formula is shown in formula (I):

[0066]

[0067] Among them, the X-ray powder diffraction pattern of the crystal form of the imidazole derivative represented by 2θ angle using Cu-Kα radiation has diffraction peaks at 8.33°±0.2, 10.73°±0.2, 12.30°±0.2 and 14.16°±0.2.

[0068] Preferably, the X-ray powder diffraction pattern of the crystal form of the imidazole derivative represented by 2θ angle using Cu-Kα radiation has diffraction peaks at 8.33°±0.2, 10.73°±0.2, 12.30°±0.2, 14.16°±0.2, 16.48°±0.2, 17.98°±0.2 and 19.90°±0.2.

[0069] More preferably, the X-ray powder diffraction pattern of the crystal form of the imidazole derivative represented by 2θ angle using Cu-Kα radiation has diffraction peaks at 8.33°±0.2, 10.73°±0.2, 12.30°±0.2, 14.16°±0.2, 16.48°±0.2, 17.98°±0.2, 19.90°±0.2, 24.13°±0.2 and 34.02°±0.2.

[0070] Further preferably, the X-ray powder diffraction pattern of the imidazole derivative crystal form, using Cu-Kα radiation and expressed in 2θ angle, has diffraction peaks at 8.33° ± 0.2, 10.73° ± 0.2, 12.30° ± 0.2, 14.16° ± 0.2, 16.48° ± 0.2, 17.98° ± 0.2, 19.90° ± 0.2, 20.61° ± 0.2, 21.50° ± 0.2, 22.30° ± 0.2, 24.13° ± 0.2 and 34.02° ± 0.2.

[0071] Further preferably, the X-ray powder diffraction pattern of the imidazole derivative crystal form, using Cu-Kα radiation and expressed in 2θ angle, has diffraction peaks at 8.33° ± 0.2, 10.73° ± 0.2, 12.30° ± 0.2, 14.16° ± 0.2, 16.48° ± 0.2, 17.98° ± 0.2, 19.90° ± 0.2, 20.61° ± 0.2, 21.50° ± 0.2, 22.30° ± 0.2, 24.13° ± 0.2, 26.62° ± 0.2, 28.23° ± 0.2 and 34.02° ± 0.2.

[0072] More preferably, the X-ray powder diffraction pattern of the imidazole derivative crystal form, using Cu-Kα radiation and expressed in 2θ angle, is as Figure 9 shown.

[0073] Preferably, the differential scanning calorimetry curve of the imidazole derivative crystal form has endothermic peaks at 57.7 ± 6 °C and 72.0 ± 8 °C.

[0074] Preferably, the imidazole derivative crystal form is an anhydrate.

[0075] Preferably, the Raman spectrum of the imidazole derivative crystal form is at 173.04 ± 5 cm -1 、203.04 ± 5 cm -1 、1005.13 ± 5 cm -1 、1377.51 ± 5 cm -1 and 1706.48 ± 5 cm -1 has characteristic absorption peaks.

[0076] Further preferably, the Raman spectrum of the imidazole derivative crystal form is at 173.04 ± 5 cm -1 、203.04 ± 5 cm -1 、616.68 ± 5 cm -1 、837.96 ± 5 cm -1 、1005.13 ± 5 cm -1 、1185.70 ± 5 cm -1 、1377.51 ± 5 cm-1 and at 1706.48 ± 5 cm -1 there are characteristic absorption peaks.

[0077] More preferably, the Raman spectrum of the imidazole derivative crystal form has characteristic absorption peaks at 173.04 ± 5 cm -1 , 203.04 ± 5 cm -1 , 616.68 ± 5 cm -1 , 837.96 ± 5 cm -1 , 1005.13 ± 5 cm -1 , 1032.46 ± 5 cm -1 , 1185.70 ± 5 cm -1 , 1377.51 ± 5 cm -1 , 1478.23 ± 5 cm -1 , 1610.60 ± 5 cm -1 and at 1706.48 ± 5 cm -1 there are characteristic absorption peaks.

[0078] In a sixth aspect, the present invention provides a method for preparing the imidazole derivative crystal form (E) according to the fifth aspect of the present invention, which includes: adding the imidazole derivative to ethanol, dissolving it under reflux conditions and then continuing to stir for a period of time, and then stopping heating and allowing it to crystallize by standing.

[0079] Preferably, the weight ratio of the imidazole derivative to the volume of ethanol is 1 g∶10 - 100 mL, preferably 1 g∶20 - 75 mL.

[0080] Preferably, after dissolving under reflux conditions, continue to stir for 10 min - 120 min, preferably 20 min - 40 min.

[0081] Preferably, the crystallization by standing is carried out at a temperature of 5 - 30 °C, preferably 10 - 30 °C.

[0082] Preferably, the crystallization by standing is carried out under sealed conditions.

[0083] Preferably, the method further includes the steps of filtering and drying the crystals after crystallization by standing.

[0084] In a seventh aspect, the present invention provides a raw material drug for sedative - hypnotic and / or anesthetic effects, which contains the imidazole derivative crystal form according to the first aspect, the third aspect or the fifth aspect of the present invention or the imidazole derivative crystal form prepared by the preparation method according to the second aspect, the fourth aspect or the sixth aspect of the present invention.

[0085] Preferably, the weight percentage of the imidazole derivative crystal form in the raw material drug is 95 - 99.99%, preferably 99 - 99.99%.

[0086] In the eighth aspect, the present invention provides a pharmaceutical composition for sedative-hypnotic and / or anesthetic effects, wherein the pharmaceutical composition comprises an imidazole derivative crystal form according to the first, third or fifth aspect of the present invention or an imidazole derivative crystal form prepared by the preparation method according to the second, fourth or sixth aspect of the present invention, and one or more pharmaceutically acceptable carriers.

[0087] In the ninth aspect, the present invention provides the use of an imidazole derivative crystal form according to the first, third or fifth aspect of the present invention or an imidazole derivative crystal form prepared by the preparation method according to the second, fourth or sixth aspect of the present invention in the preparation of a central inhibitory drug for sedative-hypnotic and / or anesthetic effects.

[0088] In the tenth aspect, the present invention provides a method for single crystal diffraction of an imidazole derivative crystal form according to the first, third or fifth aspect of the present invention or an imidazole derivative crystal form prepared by the preparation method according to the second, fourth or sixth aspect of the present invention to confirm the absolute configuration of the imidazole derivative single crystal.

[0089] The present invention has at least the following beneficial effects:

[0090] 1. The imidazole derivative crystal form A provided by the present invention has good stability under conditions such as high temperature, high humidity, and light, and the product is not easily degraded, which can meet the pharmaceutical requirements of production, transportation, and storage.

[0091] 2. The imidazole derivative crystal forms B and E provided by the present invention can be converted into crystal form A under certain conditions, realizing the controllable transformation between crystal forms, which is beneficial to meeting the pharmaceutical needs.

[0092] 3. The imidazole derivative crystal forms A, B, and E provided by the present invention, especially crystal form A, can be dissolved in a variety of solvents, and are advantageous crystal forms suitable for medicinal use.

[0093] 4. The preparation method of the present invention can obtain imidazole derivative crystal forms A, B, and E with high purity and high yield.

[0094] 5. The preparation methods of the imidazole derivative crystal forms A, B, and E provided by the present invention are simple, controllable, and repeatable, and can meet the needs of industrial production. Description of the Drawings

[0095] The specific implementation manners of the present invention are described in conjunction with the following drawings, wherein:

[0096] Figure 1 is the X-ray powder diffraction pattern of the imidazole derivative crystal form A prepared in Example 1 of the present invention.

[0097] Figure 2It is the DSC spectrum of imidazole derivative crystal form A prepared in Example 1 of the present invention.

[0098] Figure 3 It is the TG spectrum of imidazole derivative crystal form A prepared in Example 1 of the present invention.

[0099] Figure 4 It is the Raman spectrum of imidazole derivative crystal form A prepared in Example 1 of the present invention.

[0100] Figure 5 It is the X-ray powder diffraction pattern of imidazole derivative crystal form B prepared in Example 1 of the present invention.

[0101] Figure 6 It is the DSC spectrum of imidazole derivative crystal form B prepared in Example 1 of the present invention.

[0102] Figure 7 It is the TG spectrum of imidazole derivative crystal form B prepared in Example 1 of the present invention.

[0103] Figure 8 It is the Raman spectrum of imidazole derivative crystal form B prepared in Example 1 of the present invention.

[0104] Figure 9 It is the X-ray powder diffraction pattern of imidazole derivative crystal form E prepared in Example 2 of the present invention.

[0105] Figure 10 It is the DSC spectrum of imidazole derivative crystal form E prepared in Example 2 of the present invention.

[0106] Figure 11 It is the TG spectrum of imidazole derivative crystal form E prepared in Example 2 of the present invention.

[0107] Figure 12 It is the Raman spectrum of imidazole derivative crystal form E prepared in Example 2 of the present invention.

[0108] Figure 13 It is the comparative X-ray powder diffraction pattern of imidazole derivative crystal form A prepared in Example 1 of the present invention after 30 days under the conditions of high temperature of 60 °C, relative humidity of 92.5%, and light intensity of 4500 lx. Detailed Description of the Invention

[0109] The present invention will be further described in detail below in conjunction with the detailed description of the invention. The examples given are only for clarifying the present invention and not for limiting the scope of the present invention.

[0110] The experimental methods used in the following examples are all conventional methods unless otherwise specified. The reagents used in the following examples are all commercially available products unless otherwise specified.

[0111] Among them, the sources of some reagents and experimental methods are described as follows:

[0112] 1. Preparation of human-simulated pH buffer solution:

[0113] (1) pH = 2.0: Weigh 0.292 g of sodium chloride and dissolve it in 50 mL of pure water. While stirring, slowly add concentrated hydrochloric acid solution and adjust the pH to 2.0 to obtain it.

[0114] (2) pH = 4.5: Weigh 0.410 g of sodium acetate into a beaker, add 50 mL of pure water, and after complete dissolution, while stirring, slowly add acetic acid solution and adjust the pH to 4.5 to obtain it.

[0115] (3) pH = 6.8: Weigh 0.688 g of potassium dihydrogen phosphate and dissolve it in 80 mL of pure water. After complete dissolution, add water to about 100 mL. While stirring, slowly add 1 M sodium hydroxide solution and adjust the pH to 6.8 to obtain it.

[0116] (4) 5% glucose: sourced from Sinopharm Group.

[0117] (5) 0.9% sodium chloride injection, sourced from Sinopharm Group.

[0118] (6) Purified water, sourced from Wahaha Group Co., Ltd.

[0119] 2. Instruments and parameters

[0120] (1) PXRD instrument and parameters

[0121] Model: D8 FOCUS; Brand: Bruker, Germany; Equipment number: JSZX-FXS-065; Voltage: 40 V; Current: 40 mA; Measurement range: 3 - 60°; Step size: 0.02°; Number of steps: 0.5 s / step; Slit: 0.6 mm (vs), 3 mm (ss); Radiation source: copper target.

[0122] (2) DSC instrument and parameters

[0123] Model: DSC 3500 Sirius; Brand: Netzsch, Germany; Equipment number: JSZX-FXS-053; Measurement range: 30 - 360 °C; Heating rate: 10 K / min; Protection gas: N2 (60 mL / min); Purge gas: N2 (40 mL / min).

[0124] (3) TG instrument and parameters

[0125] Model: TG209 F3 Thermogravimetric Analyzer; Manufacturer: NETZSCH Germany; Equipment Number: JSZX-FXS-068; Protection Gas: N2 (20 mL / min); Purge Gas: N2 (40 mL / min); Temperature Program: 40 - 360 °C; Heating Rate: 10 K / min.

[0126] (4) HPLC Instrument and Experimental Parameters for Purity and Concentration Determination Methods

[0127] Model: Agilent 1260 Binary Pump Liquid Chromatograph;

[0128] Instrument Number: TSZX-FXS-096;

[0129] Chromatographic Column: Agilent Poroshell 120 EC-C18 (4.6 * 100 mm, 4 μm);

[0130] Mobile Phase: Methanol - Water (75:25);

[0131] Flow Rate: 1.0 mL / min;

[0132] Column Temperature: 40 °C;

[0133] Wavelength: 241 nm;

[0134] Injection Volume: 20 μL.

[0135] 3. Preparation of Amorphous Imidazole Derivatives

[0136] The specific preparation method is as follows:

[0137] The structure of the amorphous imidazole derivative is determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). NMR shifts (δ) are given in ppm units. The NMR measurement is performed using a Bruker AVANCE III HD 500 nuclear magnetic resonance spectrometer, with deuterated chloroform (CDCl3) as the solvent and tetramethylsilane (TMS) as the internal standard.

[0138] The MS measurement is carried out using an Agilent 1260 - 6120 Quadrupole (Manufacturer: Agilent, MS Model: 6120 Quadrupole).

[0139] Unless otherwise specified in the following preparation methods, the reaction temperature is room temperature, which is 10 - 30 °C.

[0140] In the following preparation methods, the reaction progress was monitored by thin-layer chromatography (TLC). The eluent system for column chromatography used to purify the compounds and the developing agent system for thin-layer chromatography in the reaction included: B: petroleum ether / ethyl acetate system, and the volume ratio of the solvents was adjusted according to the polarity of the compounds.

[0141] (1) Synthesis of ethyl 1-(1-phenylethyl-2,2,2-d3)-1H-imidazole-5-carboxylate

[0142]

[0143] 2,2,2-d3-1-Phenylethanol (10 g, 80.5 mmol) was added to DMF (50 mL). Triphenylphosphine (25.35 g, 96.6 mmol) was added with stirring. 1,2-Diiodoethane (27.24 g, 96.6 mmol) was slowly added under an ice-water bath. After reacting for 0.5 h, ethyl imidazole-4-carboxylate (13.54 g, 96.6 mmol) was added, and the reaction ended after 24 h. Post-treatment: 250 mL of water and 100 mL of DCM were added to the reaction solution. After stirring and standing for separation, the organic layer was washed once with sodium bisulfite and once with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a pale yellow oily substance, which was eluted with the eluent B system to obtain 12.3 g of ethyl 1-(1-phenylethyl-2,2,2-d3)-1H-imidazole-5-carboxylate. 1H NMR (500 MHz, CDCl3) δ 7.79 (d, J = 16.4 Hz, 2H), 7.39 - 7.30 (m, 3H), 7.21 (d, J = 7.2 Hz, 2H), 6.28 (s, 1H), 4.36 - 4.22 (m, 2H), 1.35 - 1.32 (t, J = 7.1 Hz, 3H). (+)-ESI-MS [M+H]+ m / z 248.1.

[0144] (2) Synthesis of 1-(1-phenylethyl-2,2,2-d3)-1H-imidazole-5-carboxylic acid

[0145] Ethyl 1-(1-phenylethyl-2,2,2-d3)-1H-imidazole-5-carboxylate (25 g, 101.2 mmol) prepared in step (1) was added to 158 mL of ethanol. While stirring, 50 g of 40% (w / w) sodium hydroxide was added. The reaction was stirred at room temperature for 1 h, and a sample was taken for TLC to determine the end of the reaction. Under an ice-water bath, concentrated hydrochloric acid was added dropwise to the reaction solution to adjust the pH to 2 - 3. Ethanol and water were evaporated to dryness. 100 mL of ethanol and 25 g of anhydrous sodium sulfate were added, and the mixture was stirred and dried for 0.5 h. It was filtered, and the filter cake was washed with ethanol to remove inorganic salts. The solvent in the filtrate was evaporated to dryness, 100 mL of dichloromethane was added for crystallization for 2 h, and the white solid obtained by filtration was dried at 50 °C to obtain 18.6 g of 1-(1-phenethyl-2,2,2-d3)-1H-imidazole-5-carboxylic acid.

[0146] (3) Synthesis of isopropyl 1-(1-phenethyl-2,2,2-d3)-1H-imidazole-5-carboxylate (ETG-9)

[0147] 1-(1-Phenethyl-2,2,2-d3)-1H-imidazole-5-carboxylic acid (1.0 g, 5.23 mmol) prepared in step (2) was added to 15 mL of DCM. While stirring, DMAP (0.1 g, 0.819 mmol) and isopropanol (0.35 g, 5.75 mmol) were added. At room temperature, EDCI (1.0 g, 6.44 mmol) was added, and the reaction was carried out at room temperature for 2 h. After the reaction was completed, 30 mL of water was added for washing, the aqueous layer was washed once with 15 mL of DCM, the combined organic layers were washed once with dilute hydrochloric acid and once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain an oily substance, and eluted with eluent B system by column chromatography to obtain 1.05 g of amorphous ETG-9. 1H NMR (500 MHz, CDCl3) δ 7.73 (d, J = 18.7 Hz, 2H), 7.29 (dt, J = 28.6, 7.3 Hz, 3H), 7.17 (d, J = 7.5 Hz, 2H), 6.34 (d, J = 6.0 Hz, 1H), 5.11 (dd, J = 12.5, 6.2 Hz, 1H), 1.31 - 1.22 (m, 6H). (+)-ESI-MS [M + H]+ m / z 262.2.

[0148] Example 1 Static recrystallization

[0149] The amorphous imidazole derivative was weighed and placed in a container, dissolved in a solvent under a water bath condition of 50 - 70 °C, sealed, and allowed to crystallize by standing at 10 - 30 °C. The precipitated solid was collected, dried, and subjected to crystal form detection. The specific experimental scheme and experimental results are shown in Table 1.

[0150] The experimental results in Table 1 show that the solvent type has a great influence on the crystal form of the imidazole derivatives. Under the conditions in Table 1, when the solvent is acetone, the crystal form B is obtained; and when the solvent is other single-phase or two-phase systems shown in Table 1, the crystal form A is obtained.

[0151] Figure 1 It is the X-ray powder diffraction (PXRD) pattern of Form A, which has diffraction peaks at 8.60°±0.2, 11.36°±0.2, 12.56°±0.2, 14.41°±0.2, 16.92°±0.2, 18.17°±0.2, 20.31°±0.2, 22.57°±0.2, 24.36°±0.2, 26.72°±0.2, 28.15°±0.2 and 30.28°±0.2. Figure 2 It is the DSC spectrum of Form A, which has an endothermic peak at 72.5±8°C, with a peak value of 72.5°C. Figure 3 This is the TG spectrum of crystal form A. It can be seen that the imidazole derivative crystal form is anhydrous. Figure 4 This is the Raman spectrum of Form A, which is at 170.90±5cm -1 、205.19±5cm -1 、278.06±5cm -1 、317.17±5cm -1 、349.32±5cm -1 、449.51±5cm -1 、835.82±5cm -1 、911.36±5cm -1 、1007.27±5cm -1 、1037.28±5cm -1 、1187.84±5cm -1 、1375.36±5cm -1 、1407.51±5cm -1 、1478.24±5cm -1 and 1709.17±5cm -1 It has a characteristic absorption peak.

[0152] Figure 5 is the X-ray powder diffraction pattern of Form B, which has diffraction peaks at 8.33°±0.2, 11.17°±0.2, 12.34°±0.2, 13.85°±0.2, 16.65°±0.2, 17.95°±0.2, 19.87°±0.2, 22.13°±0.2, 24.13°±0.2, 25.96°±0.2, 26.49°±0.2 and 27.70°±0.2. Figure 6It is the DSC spectrum of crystal form B, which has an endothermic peak at 68.1 - 77.7 °C, and the peak value is 74.2 °C. Figure 7 It is the TG spectrum of crystal form B. It can be seen that the crystal form of this imidazole derivative is anhydrous. Figure 8 It is the Raman spectrum of crystal form B, which has characteristic absorption peaks at 173.04 ± 5 cm -1 , 210.01 ± 5 cm -1 , 282.88 ± 5 cm -1 , 317.17 ± 5 cm -1 , 840.64 ± 5 cm -1 , 915.65 ± 5 cm -1 , 1009.42 ± 5 cm -1 , 1032.46 ± 5 cm -1 , 1299.82 ± 5 cm -1 , 1375.36 ± 5 cm -1 , 1455.20 ± 5 cm -1 and 1709.17 ± 5 cm -1 .

[0153] Table 1. Experimental Scheme and Results of Static Recrystallization of Imidazole Derivative

[0154]

[0155]

[0156]

[0157] Example 2 Reflux Recrystallization

[0158] Weigh the amorphous imidazole derivative and place it in a flask. Add a solvent to dissolve it under reflux conditions, then continue stirring for 10 - 120 min, stop heating, and let it stand at 10 - 30 °C to slowly crystallize. Collect the precipitated solid, dry it, and conduct crystal form detection. The specific experimental scheme and results are shown in Table 2.

[0159] The experimental results in Table 2 show that the type of solvent has a great influence on the crystal form of the imidazole derivative. Under the conditions in Table 2, when the solvent is ethanol, the obtained crystal form is E, while when the solvent is other single-phase or two-phase systems shown in Table 2, the obtained crystal form is A.

[0160] Figure 9It is the X-ray powder diffraction pattern of crystal form E, which has diffraction peaks at 8.33°±0.2, 10.73°±0.2, 12.30°±0.2, 14.16°±0.2, 16.48°±0.2, 17.98°±0.2, 19.90°±0.2, 20.61°±0.2, 21.50°±0.2, 22.30°±0.2, 24.13°±0.2, 26.62°±0.2, 28.23°±0.2 and 34.02°±0.2. Figure 10 It is the DSC pattern of crystal form E, which has endothermic peaks at 54.5 - 61.8 °C and 66.9 - 75.2 °C, and the peak values are 57.7 °C and 72.0 °C respectively. Figure 11 It is the TG pattern of crystal form E. It can be seen that it is an anhydrous substance. Figure 12 It is the Raman spectrum of crystal form E, which has characteristic absorption peaks at 173.04±5 cm -1 、203.04±5 cm -1 、616.68±5 cm -1 、837.96±5 cm -1 、1005.13±5 cm -1 、1032.46±5 cm -1 、1185.70±5 cm -1 、1377.51±5 cm -1 、1478.23±5 cm -1 、1610.60±5 cm -1 and 1706.48±5 cm -1 respectively.

[0161] Table 2. Experimental Scheme and Results of Reflux Recrystallization of Imidazole Derivatives

[0162]

[0163]

[0164] Example 3 Experiment on the Stability and Influencing Factors of Imidazole Derivative Crystal Form A

[0165] (1) High-temperature experiment

[0166] Place the imidazole derivative crystal form A prepared under the test conditions of No. 2 in Example 1 in a clean petri dish, place it at 60 °C for 30 days, and take samples on the 0th day, 5th day, 10th day, and 30th day. Conduct PXRD and purity analysis.

[0167] (2) High-humidity experiment

[0168] The imidazole derivative crystal form A prepared under the test conditions of No. 2 in Example 1 was placed in a clean watch glass, and placed for 30 days under the conditions of a relative humidity of 92.5% and a temperature of 25 °C, and samples were taken on the 0th day, 5th day, 10th day, and 30th day. PXRD and purity analysis were carried out.

[0169] (3) Light irradiation experiment

[0170] The imidazole derivative crystal form A prepared under the test conditions of No. 2 in Example 1 was placed in a clean watch glass, laid flat and placed in a light box (illuminance of 4500 lx ± 500 lx) for 30 days, and samples were taken on the 0th day, 5th day, 10th day, and 30th day. PXRD and purity analysis were carried out.

[0171] Experimental results: The imidazole derivative crystal form A remained stable under the conditions of a high temperature of 60 °C, a relative humidity of 92.5%, and light irradiation of 4500 lx. The specific experimental results are shown in the following table. The X-ray powder diffraction pattern measured by sampling on the 30th day is as Figure 13 shown.

[0172] Table 3. Experimental results of the high-temperature stability of the imidazole derivative crystal form A

[0173]

[0174] Table 4. Experimental results of the high-humidity stability of the imidazole derivative crystal form A

[0175]

[0176] Table 5. Experimental results of the light irradiation stability of the imidazole derivative crystal form A

[0177]

[0178] Example 4 Stability and influencing factor experiment of the imidazole derivative crystal form B

[0179] Using the imidazole derivative crystal form B prepared under the test conditions of No. 1 in Example 1 as the test sample, high-temperature, high-humidity and light irradiation experiments were carried out respectively, and the experimental conditions were the same as those in Example 3.

[0180] Experimental results: Under the conditions of a high temperature of 60 °C, a relative humidity of 92.5%, and light irradiation of 4500 lx ± 500 lx, the ETG-9 crystal form B was partially transformed into the crystal form A, indicating that the crystal form B is a metastable crystal form of the crystal form A. The specific experimental results are shown in the following table.

[0181] Table 6. Experimental results of the high-temperature stability of the imidazole derivative crystal form B

[0182]

[0183] Table 7. Experimental results of high humidity stability of imidazole derivative crystal form B

[0184]

[0185] Table 8. Experimental results of light stability of imidazole derivative crystal form B

[0186]

[0187]

[0188] Example 5. Experiments on the stability and influencing factors of imidazole derivative crystal form E

[0189] Using the imidazole derivative crystal form E prepared under the test conditions of No. 1 in Example 2 as the test sample, high temperature, high humidity and light experiments were carried out respectively, and the experimental conditions were the same as those in Example 3.

[0190] Experimental results: Under the conditions of high temperature of 60 °C and light of 4500 lx ± 500 lx, part of the ETG-9 crystal form E was transformed into crystal form A; under the condition of relative humidity of 92.5%, the crystal form was relatively stable, indicating that crystal form E is a metastable crystal form of crystal form A and is relatively stable under high humidity conditions. The specific experimental results are shown in the following table.

[0191] Table 9. Experimental results of high temperature stability of imidazole derivative crystal form E

[0192]

[0193] Table 10. Experimental results of high humidity stability of imidazole derivative crystal form E

[0194]

[0195] Table 11. Experimental results of light stability of imidazole derivative crystal form E

[0196]

[0197] Example 6. Solubility experiments of imidazole derivative crystal form A in different solutions

[0198] Excess crystal form A was dissolved in 1 mL of different solutions, and after standing at room temperature for 24 hours, the concentration was measured by HPLC method. The types of solutions were: pure water, 0.9% sodium chloride solution, 5% glucose solution, pH = 2.0, 4.5, 6.8 buffer solutions, and the experimental results are shown in Table 12 below. (Note: The average peak area is the result of parallel injection three times.) The experimental results show that crystal form A has good solubility in the solvents shown in Table 12.

[0199] Table 12 Solubility experiments of crystal form A in different solutions

[0200]

[0201] Example 7 Solubility Experiment of Imidazole Derivative Crystal Form B in Different Solutions

[0202] Using imidazole derivative crystal form B as the test sample, a solubility experiment was carried out under the same experimental conditions as in Example 6. The experimental results show that crystal form B has good solubility in the solvents shown in Table 13.

[0203] Table 13. Solubility Experiment of Imidazole Derivative Crystal Form B in Different Solutions

[0204]

[0205] Example 8 Solubility Experiment of Imidazole Derivative Crystal Form E in Different Solutions

[0206] Using imidazole derivative crystal form E as the test sample, a solubility experiment was carried out under the same experimental conditions as in Example 6. The experimental results show that crystal form E has good solubility in the solvents shown in Table 14.

[0207] Table 14. Solubility Experiment of Imidazole Derivative Crystal Form E in Different Solutions

[0208]

[0209] Comparative Example 1 Stability and Influencing Factor Experiment of Imidazole Derivative Amorphous Solid

[0210] Using the imidazole derivative amorphous solid as the test sample, stability experiments were carried out under high temperature, high humidity and light respectively, and the experimental conditions were the same as in Example 3.

[0211] Experimental Results: When the imidazole derivative amorphous solid was under the conditions of high temperature of 60 °C, relative humidity of 92.5%, and light of 45001x ± 5001x, the purity decreased significantly, indicating that the stability of the imidazole derivative in the form of amorphous solid is poor. The specific experimental results are shown in the following table.

[0212] Table 15. Experimental Results of High Temperature Stability of Imidazole Derivative Amorphous Solid

[0213]

[0214] Table 16. Experimental Results of High Humidity Stability of Imidazole Derivative Amorphous Solid

[0215]

[0216]

[0217] Table 17. Experimental Results of Light Stability of Imidazole Derivative Amorphous Solid

[0218]

[0219] The above are only several exemplary embodiments of the present invention and do not impose any form of limitation on the present invention. Although the present invention is disclosed as above with preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art, without departing from the scope of the technical solution of the present invention, makes some changes or modifications using the technical content disclosed above to obtain equivalent or equivalent embodiments, which all fall within the scope of the present invention.

Claims

1. A crystalline form of an imidazole derivative, whose chemical structural formula is shown in Formula (I): Among them, The X-ray powder diffraction pattern of the crystalline form of the imidazole derivative, expressed in 2θ angle using Cu-Kα radiation, has diffraction peaks at 8.60° ± 0.2, 11.36° ± 0.2, 14.41° ± 0.2 and 18.17° ± 0.2; Preferably, the X-ray powder diffraction pattern of the crystalline form of the imidazole derivative, expressed in 2θ angle using Cu-Kα radiation, has diffraction peaks at 8.60° ± 0.2, 11.36° ± 0.2, 12.56° ± 0.2, 14.41° ± 0.2, 18.17° ± 0.2, 20.31° ± 0.2 and 22.57° ± 0.2; More preferably, the X-ray powder diffraction pattern of the crystalline form of the imidazole derivative, expressed in 2θ angle using Cu-Kα radiation, has diffraction peaks at 8.60° ± 0.2, 11.36° ± 0.2, 12.56° ± 0.2, 14.41° ± 0.2, 16.92° ± 0.2, 18.17° ± 0.2, 20.31° ± 0.2, 22.57° ± 0.2, 24.36° ± 0.2 and 26.72° ± 0.2; More preferably, the X-ray powder diffraction pattern of the crystalline form of the imidazole derivative, expressed in 2θ angle using Cu-Kα radiation, has diffraction peaks at 8.60° ± 0.2, 11.36° ± 0.2, 12.56° ± 0.2, 14.41° ± 0.2, 16.92° ± 0.2, 18.17° ± 0.2, 20.31° ± 0.2, 22.57° ± 0.2, 24.36° ± 0.2, 26.72° ± 0.2, 28.15° ± 0.2 and 30.28° ± 0.2; More preferably, the X-ray powder diffraction pattern of the crystalline form of the imidazole derivative, expressed in 2θ angle using Cu-Kα radiation, is shown in Figure 1; 2. The imidazole derivative crystal form according to claim 1, wherein The differential scanning calorimetry curve of the crystalline form of the imidazole derivative has an endothermic peak at 72.5 ± 8 °C; Preferably, the crystalline form of the imidazole derivative is an anhydrate; Preferably, the Raman spectrum of the imidazole derivative crystal form has characteristic absorption peaks at 170.90±5 cm -1 , 205.19±5 cm -1 , 835.82±5 cm -1 , 1007.27±5 cm -1 , 1375.36±5 cm -1 and 1709.17±5 cm -1 ; More preferably, the Raman spectrum of the imidazole derivative crystal form has characteristic absorption peaks at 170.90±5 cm -1 , 205.19±5 cm -1 , 278.06±5 cm -1 , 835.82±5 cm -1 , 1007.27±5 cm -1 , 1037.28±5 cm -1 , 1375.36±5 cm -1 , 1478.24±5 cm -1 and 1709.17±5 cm -1 ; More preferably, the Raman spectrum of the imidazole derivative crystal form has characteristic absorption peaks at 170.90±5 cm -1 , 205.19±5 cm -1 , 278.06±5 cm -1 , 317.17±5 cm -1 , 835.82±5 cm -1 , 1007.27±5 cm -1 , 1037.28±5 cm -1 , 1187.84±5 cm -1 , 1375.36±5 cm -1 , 1407.51±5 cm -1 , 1478.24±5 cm -1 and 1709.17±5 cm -1 ; More preferably, the Raman spectrum of the imidazole derivative crystal form has characteristic absorption peaks at 170.90 ± 5 cm -1 , 205.19 ± 5 cm -1 , 278.06 ± 5 cm -1 , 317.17 ± 5 cm -1 , 349.32 ± 5 cm -1 , 449.51 ± 5 cm -1 , 835.82 ± 5 cm -1 , 911.36 ± 5 cm -1 , 1007.27 ± 5 cm -1 , 1037.28 ± 5 cm -1 , 1187.84 ± 5 cm -1 , 1375.36 ± 5 cm -1 , 1407.51 ± 5 cm -1 , 1478.24 ± 5 cm -1 and 1709.17 ± 5 cm -1 .

3. The preparation method of the imidazole derivative crystal form according to claim 1 or 2, wherein, The method includes: Method 1 Dissolving the imidazole derivative in a first solvent or in a mixed solvent of a second solvent and a third solvent, and standing for crystallization; Among them, the first solvent is selected from one of methyl isobutyl ketone, C2-C5 alcohols, and an ethanol aqueous solution of 90-99% by volume; the second solvent is selected from one of dihalohydrocarbons, 1,4-dioxane, C5-C8 ethers, acetonitrile, N,N-dimethylformamide, C2-C6 ketones, C2-C5 alcohols, and an ethanol aqueous solution of 90-99% by volume; the third solvent is selected from one of C5-C8 ethers, water, acetonitrile, tetrahydrofuran, C2-C5 alcohols, C5-C 10 hydrocarbons, and C2-C6 ketones; the second solvent and the third solvent are different, and the volume ratio of the second solvent to the third solvent is 1:(0.1-2.5), preferably 1:(0.5-1.5); Preferably, in Method 1, the dihalohydrocarbon is dichloromethane; Preferably, in Method 1, the C5-C 10 hydrocarbon is selected from one of petroleum ether, n-hexane, n-heptane, and cyclohexane; Preferably, in Method 1, the C5-C8 ether is isopropyl ether or methyl tert-butyl ether; Preferably, in Method 1, the C2-C5 alcohol is selected from one of ethanol, tert-butanol, n-propanol, n-butanol and isopropanol; Preferably, in Method 1, the C2-C6 ketone is selected from one of methyl isobutyl ketone, acetone and N-methylpyrrolidone; Preferably, in Method 1, the 90-99 vol% aqueous ethanol solution is a 95 vol% aqueous ethanol solution; Preferably, in Method 1, the ratio of the weight of the imidazole derivative to the volume of the first solvent or to the volume of the mixed solvent of the second solvent and the third solvent is 1 g: 10-100 mL, preferably 1 g: 20-80 mL, more preferably 1 g: 20-50 mL; Preferably, in Method 1, the dissolution is carried out at a temperature of 50 - 70°C, preferably 55 - 65°C; Preferably, in Method 1, the static crystallization is carried out at a temperature of 5 - 30°C, preferably 10 - 30°C; Preferably, in Method 1, the static crystallization is carried out under sealed conditions; Preferably, in Method 1, the method further includes the steps of filtering and drying the crystals after static crystallization; Or Method 2 The imidazole derivative is added to a mixed solvent of a fourth solvent and a fifth solvent, dissolved under reflux conditions and then stirred for a period of time, and then the heating is stopped and static crystallization is carried out; Wherein, the fourth solvent is selected from one of C2 - C5 alcohols and an aqueous ethanol solution of 90 - 99% by volume; the fifth solvent is selected from one of acetonitrile, acetone, ethyl acetate, n - hexane and cyclohexane; the fourth solvent and the fifth solvent are different, and the volume ratio of the fourth solvent to the fifth solvent is 1:(0.1 - 2), preferably 1:(0.5 - 1.5); Preferably, in Method 2, the C2 - C5 alcohol is selected from one of ethanol, n - propanol, isopropanol and n - butanol; Preferably, in Method 2, the aqueous ethanol solution of 90 - 99% by volume is an aqueous ethanol solution of 95% by volume; Preferably, in Method 2, the weight ratio of the imidazole derivative to the volume of the mixed solvent of the fourth solvent and the fifth solvent is 1 g:5 - 50 mL, preferably 1 g:10 - 30 mL; Preferably, in Method 2, after dissolution under reflux conditions, stirring is continued for 10 min - 120 min, preferably 20 min - 40 min; Preferably, in Method 2, the static crystallization is carried out at a temperature of 5 - 30°C, preferably 10 - 30°C; Preferably, in Method 2, the static crystallization is carried out under sealed conditions; Preferably, in Method 2, the method further includes the steps of filtering and drying the crystals after static crystallization.

4. An imidazole derivative crystal form, the chemical structural formula of which is shown in Formula (I): Among them, The X - ray powder diffraction pattern of the imidazole derivative crystal form represented by 2θ angle using Cu - Kα radiation has diffraction peaks at 8.33°±0.2, 11.17°±0.2, 12.34°±0.2 and 19.87°±0.2; Preferably, the X - ray powder diffraction pattern of the imidazole derivative crystal form represented by 2θ angle using Cu - Kα radiation has diffraction peaks at 8.33°±0.2, 11.17°±0.2, 12.34°±0.2, 16.65°±0.2, 19.87°±0.2, 22.13°±0.2 and 24.13°±0.2; More preferably, the X - ray powder diffraction pattern of the imidazole derivative crystal form represented by 2θ angle using Cu - Kα radiation has diffraction peaks at 8.33°±0.2, 11.17°±0.2, 12.34°±0.2, 16.65°±0.2, 17.95°±0.2, 19.87°±0.2, 22.13°±0.2, 24.13°±0.2 and 26.49°±0.2; More preferably, the X-ray powder diffraction pattern of the imidazole derivative crystal form, represented by 2θ angle using Cu-Kα radiation, is as shown in Figure 5.

5. The imidazole derivative crystal form according to claim 4, wherein, The differential scanning calorimetry curve of the imidazole derivative crystal form has an endothermic peak at 74.2 ± 8 °C; Preferably, the imidazole derivative crystal form is an anhydrate; Preferably, the Raman spectrum of the imidazole derivative crystal form has characteristic absorption peaks at 173.04 ± 5 cm -1 , 210.01 ± 5 cm -1 , 317.17 ± 5 cm -1 and 1009.42 ± 5 cm -1 ; More preferably, the Raman spectrum of the imidazole derivative crystal form has characteristic absorption peaks at 173.04 ± 5 cm -1 , 210.01 ± 5 cm -1 , 317.17 ± 5 cm -1 , 840.64 ± 5 cm -1 , 1009.42 ± 5 cm -1 , 1375.36 ± 5 cm -1 and 1709.17 ± 5 cm -1 ; More preferably, the Raman spectrum of the imidazole derivative crystal form has characteristic absorption peaks at 173.04 ± 5 cm -1 , 210.01 ± 5 cm -1 , 282.88 ± 5 cm -1 , 317.17 ± 5 cm -1 , 840.64 ± 5 cm -1 , 915.65 ± 5 cm -1 , 1009.42 ± 5 cm -1 , 1032.46 ± 5 cm -1 , 1375.36 ± 5 cm -1 and 1709.17 ± 5 cm -1 ; More preferably, the Raman spectrum of the imidazole derivative crystal form has characteristic absorption peaks at 173.04 ± 5 cm -1 , 210.01 ± 5 cm -1 , 282.88 ± 5 cm -1 , 317.17 ± 5 cm -1 , 840.64 ± 5 cm -1 , 915.65 ± 5 cm -1 , 1009.42 ± 5 cm -1 , 1032.46 ± 5 cm -1 , 1299.82 ± 5 cm -1 , 1375.36 ± 5 cm -1 , 1455.20 ± 5 cm -1 and 1709.17 ± 5 cm -1 .

6. The preparation method of the imidazole derivative crystal form according to claim 4 or 5, wherein The method includes: dissolving the imidazole derivative in acetone and allowing it to crystallize by standing; Preferably, the weight ratio of the imidazole derivative to the volume of acetone is 1 g: 10 - 100 mL, preferably 1 g: 10 - 50 mL; Preferably, the dissolution is carried out at a temperature of 50 - 70 °C, preferably 55 - 65 °C; Preferably, the crystallization by standing is carried out at a temperature of 5 - 30 °C, preferably 10 - 30 °C; Preferably, the crystallization by standing is carried out under sealed conditions; Preferably, the method further includes the steps of filtering and drying the crystals after crystallization by standing.

7. An imidazole derivative crystal form, the chemical structural formula of which is as shown in formula (I): Among them, The X-ray powder diffraction pattern of the imidazole derivative crystal form, represented by 2θ angle using Cu-Kα radiation, has diffraction peaks at 8.33° ± 0.2, 10.73° ± 0.2, 12.30° ± 0.2, and 14.16° ± 0.2; Preferably, the X-ray powder diffraction pattern of the imidazole derivative crystal form, represented by 2θ angle using Cu-Kα radiation, has diffraction peaks at 8.33° ± 0.2, 10.73° ± 0.2, 12.30° ± 0.2, 14.16° ± 0.2, 16.48° ± 0.2, 17.98° ± 0.2, and 19.90° ± 0.2; More preferably, the X-ray powder diffraction pattern of the imidazole derivative crystal form, represented by 2θ angle using Cu-Kα radiation, has diffraction peaks at 8.33° ± 0.2, 10.73° ± 0.2, 12.30° ± 0.2, 14.16° ± 0.2, 16.48° ± 0.2, 17.98° ± 0.2, 19.90° ± 0.2, 24.13° ± 0.2, and 34.02° ± 0.2; More preferably, the X-ray powder diffraction pattern of the imidazole derivative crystal form, represented by 2θ angle using Cu-Kα radiation, has diffraction peaks at 8.33° ± 0.2, 10.73° ± 0.2, 12.30° ± 0.2, 14.16° ± 0.2, 16.48° ± 0.2, 17.98° ± 0.2, 19.90° ± 0.2, 20.61° ± 0.2, 21.50° ± 0.2, 22.30° ± 0.2, 24.13° ± 0.2, and 34.02° ± 0.2; More preferably, the X-ray powder diffraction pattern of the imidazole derivative crystal form, represented by 2θ angle using Cu-Kα radiation, has diffraction peaks at 8.33°±0.2, 10.73°±0.2, 12.30°±0.2, 14 - 16°±0.2, 16.48°±0.2, 17.98°±0.2, 19.90°±0.2, 20.61°±0.2, 21.50°±0.2, 22.30°±0.2, 24.13°±0.2, 26.62°±0.2, 28.23°±0.2 and 34.02°±0.2; More preferably, the X-ray powder diffraction pattern of the imidazole derivative crystal form, represented by 2θ angle using Cu-Kα radiation, is shown in Figure 9.

8. The imidazole derivative crystal form according to claim 7, wherein, The differential scanning calorimetry curve of the imidazole derivative crystal form has endothermic peaks at 57.7±6 °C and 72.0±8 °C; Preferably, the imidazole derivative crystal form is an anhydrate; Preferably, the Raman spectrum of the imidazole derivative crystal form has characteristic absorption peaks at 173.04±5 cm -1 , 203.04±5 cm -1 , 1005.13±5 cm -1 , 1377.51±5 cm -1 and 1706.48±5 cm -1 ; More preferably, the Raman spectrum of the imidazole derivative crystal form has characteristic absorption peaks at 173.04±5 cm -1 , 203.04±5 cm -1 , 616.68±5 cm -1 , 837.96±5 cm -1 , 1005.13±5 cm -1 , 1185.70±5 cm -1 , 1377.51±5 cm -1 and 1706.48±5 cm -1 ; More preferably, the Raman spectrum of the imidazole derivative crystal form has characteristic absorption peaks at 173.04 ± 5 cm -1 , 203.04 ± 5 cm -1 , 616.68 ± 5 cm -1 , 837.96 ± 5 cm -1 , 1005.13 ± 5 cm -1 , 1032.46 ± 5 cm -1 , 1185.70 ± 5 cm -1 , 1377.51 ± 5 cm -1 , 1478.23 ± 5 cm -1 , 1610.60 ± 5 cm -1 and 1706.48 ± 5 cm -1 .

9. The method for preparing the crystalline form of the imidazole derivative according to claim 7 or 8, wherein, The method includes: adding the imidazole derivative to ethanol, dissolving it under reflux conditions and then continuing to stir for a period of time, then stopping heating and allowing crystallization to occur by standing; Preferably, the weight ratio of the imidazole derivative to the volume of ethanol is 1 g: 10 - 100 mL, preferably 1 g: 20 - 75 mL; Preferably, after dissolution under reflux conditions, stirring is continued for 10 min - 120 min, preferably 20 min - 40 min; Preferably, the crystallization by standing is carried out at a temperature of 5 - 30 °C, preferably 10 - 30 °C; Preferably, the crystallization by standing is carried out under sealed conditions; Preferably, the method further includes the steps of filtering and drying the crystals after crystallization by standing.

10. A pharmaceutical raw material for sedative-hypnotic and / or anesthetic effects, which comprises the imidazole derivative crystal form according to claim 1, 2, 4, 5, 7 or 8 or the imidazole derivative crystal form prepared by the preparation method according to claim 3, 6 or 9; Preferably, the weight percentage of the imidazole derivative crystal form in the pharmaceutical raw material is 95 - 99.99%, preferably 99 - 99.99%.

11. A pharmaceutical composition for sedative-hypnotic and / or anesthetic effects, wherein, The pharmaceutical composition comprises the imidazole derivative crystal form according to claim 1, 2, 4, 5, 7 or 8 or the imidazole derivative crystal form prepared by the preparation method according to claim 3, 6 or 9, and one or more pharmaceutically acceptable carriers.

12. Use of the imidazole derivative crystal form according to claim 1, 2, 4, 5, 7 or 8 or the imidazole derivative crystal form prepared by the preparation method according to claim 3, 6 or 9 in the preparation of a central inhibitory drug for sedative-hypnotic and / or anesthetic effects.

13. A method for single crystal diffraction of the imidazole derivative crystal form according to claim 1, 2, 4, 5, 7 or 8 or the imidazole derivative crystal form prepared by the preparation method according to claim 3, 6 or 9 to confirm the absolute configuration of the imidazole derivative single crystal.

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