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 shown as a formula (I): # imgabs0 #, the imidazole derivative crystal form is radiated by Cu-K alpha, and an X-ray powder diffraction pattern expressed by a 2 theta angle has diffraction peaks at 8.51 degrees + / -0.2, 12.47 degrees + / -0.2, 16.65 degrees + / -0.2 and 18.04 degrees + / -0.2. The imidazole derivative crystal form provided by the invention has good stability under the conditions of high temperature, high humidity, illumination and the like, is not easy to degrade, can meet the pharmaceutical requirements of production, transportation and storage, and is an advantageous crystal form suitable for medicine. The preparation method of the imidazole derivative crystal form provided by the invention is simple, controllable and repeatable, and can meet the requirements of industrial production.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry, and particularly relates to an imidazole derivative crystal form, a preparation method thereof, and uses thereof. 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 the operation. 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 the inhibition of adrenal cortical function and even increase the mortality 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 enable them to be metabolized rapidly, so as to achieve the effect of reducing the inhibition of corticosteroids. Summary of the Invention

[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 novel imidazole derivative compound (Formula (1), abbreviated as ETG-9) that meets clinical applications. As a target compound for a novel anesthetic drug with development value, the study of its crystal form is more conducive to improving its drugability.

[0005] The object of the present invention is to provide an imidazole derivative crystal form (denoted as crystal form D), a preparation method thereof, and uses thereof. The inventors of the present invention have investigated the crystallization products obtained by imidazole derivatives under different crystallization conditions, and have 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, a stable imidazole derivative crystal form can be obtained.

[0006] In the first aspect, the present invention provides an imidazole derivative crystal form, the chemical structural formula of which is shown in Formula (I):

[0007]

[0008] 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 8.51° ± 0.2, 12.47° ± 0.2, 16.65° ± 0.2, and 18.04° ± 0.2.

[0009] 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 8.51° ± 0.2, 11.36° ± 0.2, 12.47° ± 0.2, 16.65° ± 0.2, 18.04° ± 0.2, 20.04° ± 0.2, and 20.53° ± 0.2.

[0010] 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 8.51° ± 0.2, 11.36° ± 0.2, 12.47° ± 0.2, 16.65° ± 0.2, 18.04° ± 0.2, 20.04° ± 0.2, 20.53° ± 0.2, 22.57° ± 0.2, 24.09° ± 0.2, and 26.62° ± 0.2.

[0011] Even 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.

[0012] Preferably, the differential scanning calorimetry curve of the imidazole derivative crystal form has an endothermic peak at 74.4 ± 8 °C; more preferably, the differential scanning calorimetry curve of the imidazole derivative crystal form is as Figure 2 shown.

[0013] Preferably, the imidazole derivative crystal form is a non-hydrated crystal form.

[0014] Preferably, the Raman spectrum of the imidazole derivative crystal form has characteristic absorption peaks at 1005 ± 5 cm -1 , 1189 ± 5 cm -1 , 1603 ± 5 cm -1 , and 1713 ± 5 cm -1 .

[0015] More preferably, the Raman spectrum of the imidazole derivative crystal form has characteristic absorption peaks at 785 ± 5 cm -1 , 1005 ± 5 cm -1 , 1037 ± 5 cm -1 , 1189 ± 5 cm -1 , 1407 ± 5 cm -1 , 1603 ± 5 cm -1 , and 1713 ± 5 cm-1 has a characteristic absorption peak at

[0016] Further preferably, the Raman spectrum of the crystalline form of the imidazole derivative has characteristic absorption peaks at 616±5 cm -1 、785±5 cm -1 、835±5 cm -1 、1005±5 cm -1 、1037±5 cm -1 、1189±5 cm -1 、1375±5 cm -1 、1407±5 cm -1 、1603±5 cm -1 and 1713±5 cm -1 has a characteristic absorption peak at

[0017] Further preferably, the Raman spectrum of the crystalline form of the imidazole derivative has characteristic absorption peaks at 616±5 cm -1 、785±5 cm -1 、835±5 cm -1 、1005±5 cm -1 、1037±5 cm -1 、1130±5 cm -1 、1189±5 cm -1 、1375±5 cm -1 、1407±5 cm -1 、1480±5 cm -1 、1603±5 cm -1 and 1713±5 cm -1 has a characteristic absorption peak at

[0018] More preferably, the Raman spectrum of the crystalline form of the imidazole derivative is as Figure 4 shown.

[0019] In a second aspect, the present invention provides a method for preparing the crystalline form of the imidazole derivative according to the first aspect of the present invention, which includes: dissolving the imidazole derivative in a mixed solvent of chloroform and petroleum ether, and allowing it to crystallize by standing.

[0020] Preferably, the volume ratio of chloroform to petroleum ether is 1∶0.5 to 2, preferably 1∶0.8 to 1.2.

[0021] Preferably, the weight ratio of the imidazole derivative to the volume of the mixed solvent is 1 g∶10 to 100 mL, preferably 1 g∶10 to 50 mL.

[0022] Preferably, the dissolution is carried out at a temperature of 40 to 70 °C, preferably 45 to 65 °C.

[0023] Preferably, the static crystallization is carried out at a temperature of 10-30 °C, preferably 15-25 °C.

[0024] Preferably, the static crystallization is carried out under sealed conditions.

[0025] Preferably, the method further includes the steps of filtering and drying the crystals after static crystallization.

[0026] According to a specific embodiment of the present invention, the method includes the following steps:

[0027] Weigh about 19-21 g of the imidazole derivative sample into a test tube, add a mixed solvent of 200 mL of chloroform and 200 mL of petroleum ether under a water bath condition at 60 °C, seal it, carry out static crystallization at 10-30 °C, filter and collect the precipitated solid, and dry it.

[0028] In a third aspect, the present invention provides a raw material drug for sedative-hypnotic and / or anesthetic effects, which comprises the imidazole derivative crystal form according to the first aspect of the present invention or the imidazole derivative crystal form prepared by the preparation method according to the second aspect of the present invention.

[0029] Preferably, the weight percentage of the imidazole derivative crystal form in the raw material drug is 95-99.99%, preferably 99-99.99%.

[0030] In a fourth aspect, the present invention provides a pharmaceutical composition for sedative-hypnotic and / or anesthetic effects, wherein the pharmaceutical composition comprises the imidazole derivative crystal form according to the first aspect of the present invention or the imidazole derivative crystal form prepared by the preparation method according to the second aspect of the present invention, and one or more pharmaceutically acceptable carriers.

[0031] In a fifth aspect, the present invention provides the use of the imidazole derivative crystal form according to the first aspect of the present invention or the imidazole derivative crystal form prepared by the preparation method according to the second aspect of the present invention in the preparation of a central inhibitory drug for sedative-hypnotic and / or anesthetic effects.

[0032] In a sixth aspect, the present invention provides a method for performing single crystal diffraction on the imidazole derivative crystal form according to the first aspect of the present invention or the imidazole derivative crystal form prepared by the preparation method according to the second aspect of the present invention to confirm the absolute configuration of the imidazole derivative single crystal.

[0033] The present invention has at least the following beneficial effects:

[0034] 1. The imidazole derivative crystal form 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 for production, transportation, and storage.

[0035] 2. The imidazole derivative crystal form provided by the present invention can be dissolved in a variety of solvents and is an advantageous crystal form suitable for pharmaceutical use.

[0036] 3. The preparation method of the present invention can obtain the imidazole derivative crystal form with high purity and high yield.

[0037] 4. The preparation method of the imidazole derivative crystal form provided by the present invention is simple, controllable, and repeatable, and can meet the needs of industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] The specific embodiments of the present invention will be described below in conjunction with the following drawings, where:

[0039] Figure 1 is the X-ray powder diffraction pattern of the imidazole derivative crystal form prepared in Example 1 of the present invention.

[0040] Figure 2 is the DSC spectrum of the imidazole derivative crystal form prepared in Example 1 of the present invention.

[0041] Figure 3 is the TG spectrum of the imidazole derivative crystal form prepared in Example 1 of the present invention.

[0042] Figure 4 is the Raman spectrum of the imidazole derivative crystal form prepared in Example 1 of the present invention.

[0043] Figure 5 is the X-ray powder diffraction comparison diagram of the stability test of the imidazole derivative crystal form prepared in Example 1 of the present invention. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0044] The present invention will be further described in detail below in conjunction with the specific embodiments. The examples given are only for clarifying the present invention and not for limiting the scope of the present invention.

[0045] 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.

[0046] Among them, the sources of some reagents and experimental methods are described as follows:

[0047] 1. Preparation of human-simulated pH buffer solution:

[0048] (1) pH = 2.0: Weigh 0.292 g of sodium chloride and dissolve it in 50 mL of pure water. Slowly add concentrated hydrochloric acid solution dropwise with stirring and adjust the pH to 2.0 to obtain.

[0049] (2) pH = 4.5: Weigh 0.410 g of sodium acetate in a beaker, add 50 mL of pure water, dissolve all of it, and slowly add acetic acid solution dropwise with stirring and adjust the pH to 4.5 to obtain.

[0050] (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 approximately 100 mL, and slowly add 1 M sodium hydroxide solution dropwise with stirring to adjust the pH to 6.8.

[0051] (4) 5% Glucose: sourced from Sinopharm Group.

[0052] (5) 0.9% Sodium chloride injection, sourced from Sinopharm Group.

[0053] (6) Purified water, sourced from Wahaha Group Co., Ltd.

[0054] 2. Instruments and parameters

[0055] (1) PXRD instrument and parameters

[0056] 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.

[0057] (2) DSC instrument and parameters

[0058] Model: DSC 3500 Sirius; Brand: Netzsch, Germany; Equipment number: JSZX - FXS - 053; Measurement range: 30 - 360 °C; Heating rate: 10 K / min; Protective gas: N2 (60 mL / min); Purge gas: N2 (40 mL / min).

[0059] (3) TG instrument and parameters

[0060] Model: TG209 F3 thermogravimetric analyzer; Manufacturer: Netzsch, Germany; Equipment number: JSZX - FXS - 068; Protective gas: N2 (20 mL / min); Purge gas: N2 (40 mL / min); Heating program: 40 - 360 °C; Heating rate: 10 K / min.

[0061] (4) Experimental parameters for sample purity determination

[0062] HPLC model: Agilent 1260 binary pump liquid chromatograph;

[0063] Instrument number: TSZX - FXS - 096;

[0064] Chromatographic column: Agilent Poroshell 120 EC - C18 (4.6 * 100 mm, 4 μm);

[0065] Mobile phase: methanol - water (75∶25);

[0066] Flow rate: 1.0 mL / min;

[0067] Column temperature: 40 °C;

[0068] Wavelength: 241 nm;

[0069] Injection volume: 20 μL.

[0070] 3. Preparation of amorphous imidazole derivatives

[0071] The specific preparation method is as follows:

[0072] The structure of the amorphous imidazole derivative is determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). The NMR shift (δ) is given in ppm units. The NMR measurement is carried out using a Bruker AVANCE III HD 500 nuclear magnetic resonance instrument, with deuterated chloroform (CDCl3) as the solvent and tetramethylsilane (TMS) as the internal standard.

[0073] The MS measurement is performed using an Agilent 1260 - 6120 Quadrupole (manufacturer: Agilent, MS model: 6120 Quadrupole).

[0074] Unless otherwise specified in the following preparation methods, the reaction temperature is room temperature, which is 20 - 30 °C.

[0075] In the following preparation methods, the reaction progress is monitored by thin - layer chromatography (TLC), and the eluent B system is a petroleum ether / ethyl acetate system. The volume ratio of the solvents is adjusted according to the polarity of the compound.

[0076] (1) Synthesis of ethyl 1 - (1 - phenylethyl - 2,2,2 - d3)-1H - imidazole - 5 - carboxylate

[0077]

[0078] 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 phase 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 oil, which was eluted with 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.

[0079] (2) Synthesis of 1-(1-phenylethyl-2,2,2-d3)-1H-imidazole-5-carboxylic acid

[0080] 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. 50 g of 40% (w / w) sodium hydroxide was added with stirring. 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, 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 was obtained by filtration and dried at 50 °C to obtain 18.6 g of 1-(1-phenylethyl-2,2,2-d3)-1H-imidazole-5-carboxylic acid.

[0081] (3) Synthesis of isopropyl 1-(1-phenylethyl-2,2,2-d3)-1H-imidazole-5-carboxylate (ETG-9)

[0082] 1-(1-Phenylethyl-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. DMAP (0.1 g, 0.819 mmol) and isopropanol (0.35 g, 5.75 mmol) were added under stirring, and EDCI (1.0 g, 6.44 mmol) was added at room temperature. 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 organic layers were combined, washed once with dilute hydrochloric acid, washed 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. 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.

[0083] Example 1 Preparation of Crystal Form D of Imidazole Derivative

[0084] 20.81 g of amorphous imidazole derivative was weighed into a test tube and dissolved in a mixed solvent of 200 mL of chloroform and 200 mL of petroleum ether under a water bath condition at 60 °C. It was sealed and allowed to crystallize by standing at 20 °C. The precipitated solid was collected by filtration and dried to obtain 18.5 g of long strip crystals with a purity of 99.6%, and then crystal form detection was carried out. Figure 1 is the X-ray powder diffraction (PXRD) pattern of this crystal form, which has diffraction peaks at 8.51° ± 0.2, 11.36° ± 0.2, 12.47° ± 0.2, 16.65° ± 0.2, 18.04° ± 0.2, 20.04° ± 0.2, 20.53° ± 0.2, 22.57° ± 0.2, 23.29° ± 0.2, 24.09° ± 0.2, 24.93° ± 0.2, 26.62° ± 0.2 and 27.52° ± 0.2; Figure 2 is the DSC pattern of this crystal form, which has an endothermic peak at 68.6 - 77.4 °C, and the peak value is 74.4 °C; Figure 3 is the TG pattern of this crystal form. It can be seen that this crystal form of imidazole derivative is a non-hydrous crystal form; Figure 4 is the Raman spectrum of this crystal form, which is at 616 ± 5 cm -1 、785 ± 5 cm -1 、835 ± 5 cm -1 、1005 ± 5 cm -1 、1037 ± 5 cm -1, 1130 ± 5 cm -1 , 1189 ± 5 cm -1 , 1375 ± 5 cm -1 , 1407 ± 5 cm -1 , 1480 ± 5 cm -1 , 1603 ± 5 cm -1 and 1713 ± 5 cm -1 There are characteristic absorption peaks at these positions.

[0085] Investigation on the preparation conditions of imidazole derivative crystal form D in Example 2

[0086] According to the method of Example 1, prepare imidazole derivative crystal form D under the conditions shown in the following table. Compare the X-ray diffraction pattern of the obtained crystal sample with Figure 1 the research comparison, and it is determined to be consistent with the crystal form obtained in Example 1.

[0087] Table 1 Investigation on the preparation conditions of crystal form D

[0088]

[0089] Example 3 Stability experiment of imidazole derivative crystal form D

[0090] (1) High-temperature experiment

[0091] Place the imidazole derivative crystal form D prepared in Example 1 in a clean petri dish, place it at 60 °C for 30 days, and take samples for detection on the 0th day, 5th day, 10th day, and 30th day. The results are shown in Table 2.

[0092] (2) High-humidity experiment

[0093] Place the imidazole derivative crystal form D prepared in Example 1 in a clean petri dish, place it at a relative humidity of 92.5% and a temperature of 25 °C for 30 days, and take samples for detection on the 0th day, 5th day, 10th day, and 30th day. The results are shown in Table 3.

[0094] (3) Light irradiation experiment

[0095] Place the imidazole derivative crystal form D prepared in Example 1 in a clean petri dish, lay it flat and place it in a light box (illuminance is 4500 lx ± 500 lx) for 30 days, and take samples for detection on the 0th day, 5th day, 10th day, and 30th day. The results are shown in Table 4.

[0096] Experimental results: Imidazole derivative crystal form D remains stable under the conditions of high temperature of 60 °C, relative humidity of 92.5%, and light irradiation of 4500 lx. Among them, the X-ray powder diffraction patterns of imidazole derivative crystal form D placed at 60 °C, relative humidity of 92.5%, and light irradiation of 4500 lx for 30 days are asFigure 5 As shown, the above X-ray diffraction pattern is compared with Figure 1 the research comparison, and it is determined to be consistent with the crystal form obtained in Example 1.

[0097] Table 2. Experimental results of high-temperature stability of imidazole derivative crystal form D

[0098]

[0099] Table 3. Experimental results of high-humidity stability of imidazole derivative crystal form D

[0100]

[0101] Table 4. Experimental results of light stability of imidazole derivative crystal form D

[0102]

[0103]

[0104] Example 4 Solubility experiment of imidazole derivative crystal form D in different solutions

[0105] Excess imidazole derivative crystal form D was dissolved in 1 mL of different solutions. After standing at room temperature for 24 hours, the concentration was measured by HPLC method. The solutions were: pure water, 0.9% sodium chloride solution, 5% glucose solution, pH = 2.0, 4.5, 6.8 buffer solutions. The experimental results are shown in the following table (note: the average peak area is the result of three parallel repeated injections). The experimental results show that crystal form D has good solubility in the solvents shown in the following table.

[0106] Table 5. Solubility experiment of imidazole derivative crystal form D in different solutions

[0107]

[0108] Comparative Example 1 Stability and influencing factor experiment of imidazole derivative amorphous solid

[0109] Using imidazole derivative amorphous solid as the test sample, stability experiments were carried out under high temperature, high humidity and light respectively. The experimental conditions were the same as those in Example 3.

[0110] Experimental results: When imidazole derivative amorphous solid was at 60 °C, relative humidity of 92.5% and light of 45001x ± 5001x, the purity decreased significantly, indicating that its stability was poor when in the form of imidazole derivative amorphous solid. The specific experimental results are shown in Tables 6 - 8 below.

[0111] Table 6. Experimental results of high-temperature stability of imidazole derivative amorphous solid

[0112]

[0113] Table 7. Experimental results of the high humidity stability of imidazole derivatives amorphous solids

[0114]

[0115] Table 8. Experimental results of the light stability of imidazole derivatives amorphous solids

[0116]

[0117] 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 equivalent or equivalent embodiments obtained by making some changes or modifications using the disclosed technical content by those skilled in the art within the scope of the technical solution of the present invention belong to the scope of the present invention.

Claims

1. An imidazole derivative crystal form, whose chemical structural formula is shown in formula (I): 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 8.51° ± 0.2, 12.47° ± 0.2, 16.65° ± 0.2 and 18.04° ± 0.

2.

2. The imidazole derivative crystal form according to claim 1, wherein The X-ray powder diffraction pattern of the imidazole derivative crystal form expressed in 2θ angle using Cu-Kα radiation has diffraction peaks at 8.51° ± 0.2, 11.36° ± 0.2, 12.47° ± 0.2, 16.65° ± 0.2, 18.04° ± 0.2, 20.04° ± 0.2 and 20.53° ± 0.2; 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 8.51° ± 0.2, 11.36° ± 0.2, 12.47° ± 0.2, 16.65° ± 0.2, 18.04° ± 0.2, 20.04° ± 0.2, 20.53° ± 0.2, 22.57° ± 0.2, 24.09° ± 0.2 and 26.62° ± 0.2; 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 8.51° ± 0.2, 11.36° ± 0.2, 12.47° ± 0.2, 16.65° ± 0.2, 18.04° ± 0.2, 20.04° ± 0.2, 20.53° ± 0.2, 22.57° ± 0.2, 23.29° ± 0.2, 24.09° ± 0.2, 24.93° ± 0.2, 26.62° ± 0.2 and 27.52° ± 0.2; More preferably, the X-ray powder diffraction pattern of the imidazole derivative crystal form expressed in 2θ angle using Cu-Kα radiation is shown in Figure 1.

3. The imidazole derivative crystal form according to claim 1 or 2, wherein, The differential scanning calorimetry curve of the imidazole derivative crystal form has an endothermic peak at 74.4 ± 8 °C; Preferably, the imidazole derivative crystal form is a crystal form without water.

4. The imidazole derivative crystal form according to any one of claims 1 to 3, wherein The Raman spectrum of the imidazole derivative crystal form has characteristic absorption peaks at 1005±5 cm -1 , 1189±5 cm -1 , 1603±5 cm -1 and 1713±5 cm -1 ; Preferably, the Raman spectrum of the imidazole derivative crystal form has characteristic absorption peaks at 785±5 cm -1 , 1005±5 cm -1 , 1037±5 cm -1 , 1189±5 cm -1 , 1407±5 cm -1 , 1603±5 cm -1 and 1713±5 cm -1 ; More preferably, the Raman spectrum of the imidazole derivative crystal form has characteristic absorption peaks at 616±5 cm -1 , 785±5 cm -1 , 835±5 cm -1 , 1005±5 cm -1 , 1037±5 cm -1 , 1189±5 cm -1 , 1375±5 cm -1 , 1407±5 cm -1 , 1603±5 cm -1 and 1713±5 cm -1 ; More preferably, the Raman spectrum of the imidazole derivative crystal form has characteristic absorption peaks at 616 ± 5 cm -1 , 785 ± 5 cm -1 , 835 ± 5 cm -1 , 1005 ± 5 cm -1 , 1037 ± 5 cm -1 , 1130 ± 5 cm -1 , 1189 ± 5 cm -1 , 1375 ± 5 cm -1 , 1407 ± 5 cm -1 , 1480 ± 5 cm -1 , 1603 ± 5 cm -1 and 1713 ± 5 cm -1 .

5. The preparation method of the imidazole derivative crystal form according to any one of claims 1 to 4, which comprises: Dissolve the imidazole derivative in a mixed solvent of chloroform and petroleum ether, and let it stand for crystallization.

6. The preparation method according to claim 5, wherein The volume ratio of the chloroform to the petroleum ether is 1:0.5 - 2, preferably 1:0.8 - 1.2; Preferably, the weight ratio of the imidazole derivative to the volume of the mixed solvent is 1 g:10 - 100 mL, preferably 1 g:10 - 50 mL; Preferably, the dissolution is carried out at a temperature of 40 - 70 °C, preferably 45 - 65 °C; Preferably, the standing crystallization is carried out at a temperature of 10 - 30 °C, preferably 15 - 25 °C; Preferably, the standing crystallization is carried out under sealed conditions; Preferably, the method further includes the steps of filtering and drying the crystals after standing crystallization.

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

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

9. Use of the imidazole derivative crystal form according to any one of claims 1 to 4 or the imidazole derivative crystal form prepared by the preparation method according to claim 5 or 6 in the preparation of a central inhibitory drug for sedative-hypnotic and / or anesthetic effects.

10. A method for performing single crystal diffraction on the imidazole derivative crystal form according to any one of claims 1 to 4 or the imidazole derivative crystal form prepared by the preparation method according to claim 5 or 6 to confirm the absolute configuration of the imidazole derivative single crystal.

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