Fnerenone single crystal as well as preparation method and application thereof

Abstract

The invention relates to the technical field of fenerenone medicines, and particularly discloses a fenerenone single crystal as well as a preparation method and application thereof. The crystal of the fenerenone single crystal belongs to an orthorhombic crystal system, the space group is P212121, the unit cell volume is 1927.44 (5) 3, the number of molecules in the unit cell is 4, and the unit cell parameters are as follows: a is equal to 7.932 (1), b is equal to 11.982 (1), and c is equal to 20.281 (1). According to the fenerenone single crystal, the steric configuration of a fenerenone sample can be determined by adopting single crystal X-ray diffraction analysis, and whether the absolute configuration of the fenerenone sample is S configuration or R configuration is detected, so that the medicinal requirements of the fenerenone are met; therefore, the defect that the space structure cannot be determined by detection means such as nuclear magnetic resonance, mass spectrum, infrared, ultraviolet, elemental analysis, thermogravimetric analysis and X-ray powder diffraction at present is overcome, and the method has high market application value.

Description

Technical Field

[0001] The present invention relates to the technical field of finerenone medicines, and in particular to a finerenone single crystal and a preparation method and application thereof. Background Art

[0002] Finerenone (BAY 94-8862) is a non-steroidal selective mineralocorticoid receptor antagonist that has been shown in preclinical studies to block the harmful effects caused by excessive activation of the mineralocorticoid receptor. Finerenone contains a chiral center in its structure, and its absolute configuration cannot be determined by existing nuclear magnetic resonance, mass spectrometry, infrared and other detection methods. However, the S configuration has medicinal value, and the synthetic finerenone API needs to be tested for its absolute configuration, whether it is S or R, to meet medicinal requirements.

[0003] Therefore, there is an urgent need to develop a single crystal of finerenone to determine the spatial configuration of the finerenone sample through single crystal X-ray diffraction analysis, thereby making up for the deficiency that the current detection methods such as nuclear magnetic resonance, mass spectrometry, infrared, ultraviolet, elemental analysis, thermogravimetric analysis, and X-ray powder diffraction cannot determine the spatial structure. Summary of the invention

[0004] In view of the above problems, the present invention provides a finerenone single crystal and a preparation method and application thereof.

[0005] In order to solve the above technical problems, the present invention adopts the following technical solutions: In the first aspect, the present invention provides a single crystal of finerenone, wherein the crystal belongs to the orthorhombic system and the space group is P 212121, unit cell volume is 1927.44(5)Å 3 , the number of molecules in the unit cell is 4, and the unit cell parameters are: a =7.932(1)Å, b =11.982(1)Å, c =20.281(1)Å.

[0006] Compared with the prior art, the finerenone single crystal provided by the present invention is in a colorless and transparent block. The finerenone single crystal can be used to determine the spatial configuration of the finerenone sample by single crystal X-ray diffraction analysis, and detect whether the absolute configuration of the finerenone sample is S configuration or R configuration, so as to meet the medicinal requirements of finerenone, thereby making up for the deficiency that the current detection means such as nuclear magnetic resonance, mass spectrometry, infrared, ultraviolet, elemental analysis, thermogravimetric analysis, X-ray powder diffraction, etc. cannot determine the spatial structure, and has a high market application value.

[0007] Preferably, the size of the finerenone single crystal is (0.08-0.12) mm×(0.20-0.25) mm×(0.28-0.33) mm.

[0008] In a second aspect, the present invention provides a method for preparing the finerenone single crystal, comprising the following steps: The finerenone sample and acetonitrile are mixed and crystallized at 5°C to 35°C to obtain a finerenone single crystal.

[0009] The method for preparing a single crystal of finerenone provided by the present invention uses acetonitrile as a solvent and can obtain a single crystal of finerenone by growing the crystal at room temperature (5°C to 35°C). The operation method is simple and easy and the conditions are mild. The inventor has found through a large number of experiments that only when acetonitrile is used as a solvent can a transparent block single crystal be obtained by growing the crystal, while other single agents or mixed agents can only precipitate fine crystals that cannot be enlarged or even cannot precipitate solids.

[0010] It should be noted that the present invention does not require the preparation of finerenone samples, and the finerenone sample can be prepared by conventional preparation methods in the art.

[0011] Preferably, the method for preparing the finerenone single crystal comprises the following steps: The finerenone sample and acetonitrile are mixed, filtered, and the filtrate is placed open at 10°C to 30°C for crystal growth to obtain finerenone single crystals.

[0012] Preferably, the mass volume ratio of the finerenone sample to the acetonitrile is (5-50) mg:1 mL, and more preferably (10-40) mg:1 mL.

[0013] Preferably, the mixing temperature is 20°C to 40°C.

[0014] Further preferably, the filtration is microporous membrane filtration, and the pore size of the microporous membrane is 0.22 μm~0.45 μm.

[0015] Preferably, the crystal growing time is 5 to 10 days.

[0016] In a third aspect, the present invention provides a use of the finerenone single crystal in determining the spatial configuration of a finerenone sample. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 is the absolute configuration diagram of the molecule of the single crystal of finerenone in Example 1 of the present invention; Figure 2 is a molecular ellipsoid diagram of a single crystal of finerenone in Example 1 of the present invention; Figure 3 This is a molecular unit cell stacking diagram of the single crystal of finerenone in Example 1 of the present invention. DETAILED DESCRIPTION

[0018] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0019] The method for preparing the finerenone sample in the embodiment of the present invention (refer to patent CN 106795155 A, 2015) comprises the following steps: S1, add 3.537m / m isopropanol to the reaction vessel, start stirring, add 1.0m / m 4-cyano-2-methoxybenzaldehyde, 0.0745m / m glacial acetic acid and 0.0528m / m piperidine in sequence, control the temperature at 27℃~33℃, slowly drop 1.078m / m ethyl 2-cyanoacetoacetate into the system, the dropping time is 2h~3h; after the reaction is completed, cool to 0℃~5℃ for 1.5h~2.5h, keep warm and stir for 1h~2h, centrifuge, rinse the filter cake with isopropanol, collect the filter cake, and obtain the wet product of intermediate 1.

[0020] S2, add 7.274m / m isopropanol and 0.874m / m N,N-dimethylformamide into the reaction vessel, start stirring, add the wet product of intermediate 1 and 0.693m / m 4-amino-5-methyl-2-hydroxypyridine, replace with nitrogen three times, and keep the temperature under reflux for 22h~24h; after the reaction, control the temperature to slowly decrease to 0℃~5℃ over 4h~5h, keep the temperature under stirring for 3h~4h, centrifuge, rinse the filter cake with isopropanol, collect the filter cake, dry the filter cake at 75℃~85℃ and vacuum degree ≤-0.09MPa for 8h~10h, and discharge to obtain intermediate 2.

[0021] S3, add 5.622m / m N,N-dimethylacetamide to the reaction vessel, start stirring, add intermediate 2, heat the system to 100℃~120℃, and after it is completely dissolved, distill under reduced pressure at a vacuum degree of ≤-0.07MPa to remove (2.343±0.469)m / m N,N-dimethylacetamide; after distillation, quickly cool to 25℃~35℃, and remove 0.061m / m 98% sulfuric acid was added dropwise to the reaction system. After 20 min~30 min of dropping, 1.003 m / m triethyl orthoacetate was added to the reaction system. The temperature was raised to 105°C~115°C and the reaction was kept warm for 1.5 h. After the reaction was completed, the temperature was lowered to 50°C~55°C, and purified water was slowly added dropwise to the system, and the temperature was controlled at 45°C~55°C. After the dropping was completed, the system was kept warm and stirred for 0.5 h~1 h, and a large amount of solid precipitated. The temperature was controlled at 45°C~55°C, and purified water was continued to be added dropwise. After the dropping was completed, the temperature was controlled to lower to 0°C~5°C for 3 h~4 h, and the system was kept warm and stirred for 1~1.5 h. Centrifugation was performed, and the filter cake was rinsed with purified water and then with methyl tert-butyl ether. The filter cake was collected to obtain intermediate 3 (wet product).

[0022] S4, add 3.556 m / m tetrahydrofuran and 3.0 m / m purified water to the reaction vessel, start stirring, add intermediate 3, cool the system to 0°C~5°C, and add 33.3% aqueous sodium hydroxide solution dropwise under temperature control (add 0.278 m / m purified water, start stirring, add 0.139 m / m sodium hydroxide in batches, stir to dissolve, and prepare 33.3% aqueous sodium hydroxide solution), after adding, keep warm and stir for 2 h, until the raw material point of intermediate 3 disappears, and stop the reaction.

[0023] Add methyl tert-butyl ether to the reaction system, stir for 10min~20min, stand for phase separation, and place the aqueous phase in another pre-cooled 3000L glass-lined reaction tank, and store it at 0℃~5℃ temporarily. Add purified water to the methyl tert-butyl ether phase, stir for 10min~20min, stand for phase separation, retain the aqueous phase, discard the organic phase, and combine the two aqueous phases. Keep the internal temperature at 0℃~5℃, add methyl tert-butyl ether to the aqueous phase, stir for 10min~20min, stand for phase separation, discard the organic phase, and retain the aqueous phase. Keep the internal temperature at 0℃~5℃, add ethyl acetate to the aqueous phase again, stir for 10min~20min, stand for phase separation, discard the organic phase, and retain the aqueous phase.

[0024] The temperature was controlled at 0℃~5℃, 2N hydrochloric acid was added dropwise to the aqueous phase to adjust the pH to 6~7, and the mixture was stirred for 30min~1h at this temperature, and then centrifuged. The filter cake was rinsed with purified water, and then with methyl tert-butyl ether and acetonitrile in sequence; the filter cake was then placed in a double cone dryer and vacuum dried at 35℃~45℃ and a vacuum degree of ≤-0.09MPa for 8h~10h to obtain intermediate 4.

[0025] S5, add 7.112m / m tetrahydrofuran (anhydrous grade) to the reaction container, start stirring, add intermediate 4, 0.556m / m N,N-carbonyldiimidazole and 0.032m / m 4-dimethylaminopyridine in sequence, stir at 20℃~30℃ for 1h~2h, heat to 50℃~55℃ for reaction for 2h~3h, until the raw material point of intermediate 4 disappears, and obtain an activated intermediate state; add 1.702m / m hexamethyldisilazane to the reaction solution, heat to reflux, reflux reaction for 14h~16h, until the activated intermediate state disappears, stop the reaction. Cool the reaction system to 0℃~5℃, keep warm and slowly add purified water to the reaction solution to quench, after the dripping is completed, heat to 20℃~30℃ and stir for 1h~1.5h, then heat to reflux and stir for 1h~1.5h. The reaction system was cooled to 0℃~5℃, stirred for 2~3h; centrifuged, and the filter cake was rinsed with tetrahydrofuran and purified water in turn; the filter cake was transferred to a reaction vessel, purified water was added, stirred at room temperature for 20min~30min, centrifuged, and the filter cake was rinsed with purified water. The filter cake was then placed in a double cone dryer, vacuum dried at 65℃~75℃ and vacuum degree ≤-0.09MPa for 8h~9h, and the intermediate 5 was obtained.

[0026] S6, add 8.995m / m anhydrous ethanol and 3.8m / m purified water to the reaction vessel, start stirring, add intermediate 5 and 0.510m / m D-DTTA, heat the system to 70℃~80℃, keep warm and stir for 3h~3.5h; then control the temperature to slowly cool to 50℃~55℃ for 3h~4h, and then control the temperature to slowly cool to 28℃~32℃ for 3h~4h, keep warm and stir for 1h~2h. Centrifuge, and rinse the filter cake with a mixed solution of anhydrous ethanol and purified water. Then put the filter cake into a double cone dryer, vacuum dry it at 45℃~55℃ and vacuum degree ≤-0.09MPa for 6h~8h, and discharge it to obtain intermediate 6.

[0027] S7, add 0.527 m / m potassium phosphate, 0.316 m / m anhydrous ethanol and 1.6 m / m purified water into the reaction container, start stirring, and prepare a potassium phosphate solution for later use.

[0028] Add 0.789m / m anhydrous ethanol and 4.0m / m purified water to another reaction container, start stirring, add intermediate 6, drop the prepared potassium phosphate solution, adjust the pH to 7.5~8, heat the system to 45℃~55℃, and keep stirring for 3h~4h (retest the pH after 0.5~1h and still keep 7.5~8). Then control the temperature to 28℃~32℃ for 1.5h~2.5h, keep stirring for 12h~16h; centrifuge, and rinse the filter cake with a mixed solution of anhydrous ethanol and purified water; then put the filter cake into a double cone dryer, dry it at 50℃~60℃ and vacuum degree ≤-0.09MPa for 6h~8h, and discharge the material to obtain a crude product.

[0029] S8, add 8.100m / m 95% ethanol and crude product to the reaction vessel in sequence, N2 protection, stir and heat to reflux, add 0.030m / m activated carbon after the system is clarified, and reflux for 20min~40min. The reaction solution is filtered while hot into another reaction vessel, slowly cooled to 45℃~55℃, and stirred for crystallization for 1.5h~2.5h. The reaction solution is concentrated under reduced pressure at a jacket temperature of 55℃~60℃ and a vacuum degree of ≤-0.07MPa to a remaining 3±0.5 (v / m) system. After concentration, control the temperature to -5℃~5℃ for 2h~3h, and stir and crystallize for 6h~8h. Centrifuge, rinse the filter cake with anhydrous ethanol, discharge, and dry the wet material at 80℃~90℃ and a vacuum degree of ≤-0.09MPa for 6h~16h, and discharge to obtain fenareline.

[0030] In order to better illustrate the present invention, further examples are given below.

[0031] Example 1 This embodiment provides a method for preparing a single crystal of finerenone, comprising the following steps: 1000 mg of phenerenone sample and 50 mL of acetonitrile were added to the reaction bottle respectively, and ultrasonically vibrated for 10 min at room temperature, filtered through a microporous filter membrane with a pore size of 0.22 μm, and the filtrate was left open at room temperature and allowed to stand for 6 days to grow crystals; the supernatant was poured out, the crystals were rinsed with acetonitrile, and the acetonitrile remaining on the crystals was blown dry with nitrogen to obtain colorless, transparent, blocky single crystals of phenerenone.

[0032] Example 2 This embodiment provides a method for preparing a single crystal of finerenone, comprising the following steps: Add 1000 mg of phenerenone sample and 35 mL of acetonitrile to the reaction bottle respectively, shake it ultrasonically at 30°C for 10 min, filter it with a microporous filter membrane with a pore size of 0.35 μm, take the filtrate and place it at room temperature, and let it stand for 7 days to grow crystals; pour out the supernatant, rinse the crystals with acetonitrile, and use nitrogen to blow dry the acetonitrile remaining on the crystals to obtain colorless and transparent block-like single crystals of phenerenone.

[0033] Example 3 This embodiment provides a method for preparing a single crystal of finerenone, comprising the following steps: Add 1000 mg of phenerenone sample and 20 mL of acetonitrile to the reaction bottle respectively, shake it ultrasonically at 40°C for 10 min, filter it with a microporous filter membrane with a pore size of 0.40 μm, take the filtrate and place it at room temperature, and let it stand for 5 days to grow crystals; pour out the supernatant, rinse the crystals with acetonitrile, and use nitrogen to blow dry the acetonitrile remaining on the crystals to obtain colorless and transparent block-like single crystals of phenerenone.

[0034] Example 4 This embodiment provides a method for preparing a single crystal of finerenone, comprising the following steps: 1000 mg of phenerenone sample and 200 mL of acetonitrile were added to the reaction bottle respectively, and ultrasonically vibrated for 10 min at room temperature, filtered through a microporous filter membrane with a pore size of 0.45 μm, and the filtrate was left open at room temperature for 10 days to grow crystals; the supernatant was poured out, the crystals were rinsed with acetonitrile, and the acetonitrile remaining on the crystals was blown dry with nitrogen to obtain colorless and transparent block-like single crystals of phenerenone.

[0035] Comparative Example 1 This comparative example provides a method for preparing a single crystal of phenerenol, comprising the following steps: 100 mg of phenerenone sample and 10 mL of methanol were added to the reaction bottle respectively, and ultrasonically vibrated for 10 min at room temperature. The solution was filtered through a microporous filter membrane with a pore size of 0.22 μm. The filtrate was left open at room temperature. After standing for 6 days to grow crystals, no solid was precipitated.

[0036] Comparative Example 2 This comparative example provides a method for preparing a single crystal of phenerenol, comprising the following steps: 100 mg of phenerenone sample and 10 mL of ethanol were added to the reaction bottle, respectively. The mixture was ultrasonically shaken at room temperature for 10 min, filtered using a microporous filter membrane with a pore size of 0.22 μm, and the filtrate was left open at room temperature. After standing for 6 days to grow crystals, no solid was precipitated.

[0037] Comparative Example 3 This comparative example provides a method for preparing a single crystal of phenerenol, comprising the following steps: 100 mg of phenerenone sample and 10 mL of isopropanol were added to the reaction bottle respectively, and ultrasonically vibrated for 10 min at room temperature. The solution was filtered through a microporous filter membrane with a pore size of 0.22 μm. The filtrate was left open at room temperature and allowed to stand for 5 days to grow crystals. A powder solid was precipitated and did not increase in size after 10 days.

[0038] Comparative Example 4 This comparative example provides a method for preparing a single crystal of phenerenol, comprising the following steps: 100 mg of phenerenone sample and 10 mL of dichloroethane were added to the reaction bottle respectively, and ultrasonically shaken at room temperature for 10 min. The solution was filtered through a microporous filter membrane with a pore size of 0.22 μm. The filtrate was left open at room temperature and allowed to stand for 6 days to grow crystals without precipitation of solids.

[0039] Comparative Example 5 This comparative example provides a method for preparing a single crystal of phenerenol, comprising the following steps: 100 mg of phenerenone sample and 10 mL of propanol were added to the reaction bottle respectively, and ultrasonically vibrated for 10 min at room temperature. The solution was filtered through a microporous filter membrane with a pore size of 0.22 μm. The filtrate was left open at room temperature and allowed to stand for 5 days to grow crystals. A powder solid was precipitated and did not increase in size after 10 days.

[0040] Comparative Example 6 This comparative example provides a method for preparing a single crystal of phenerenol, comprising the following steps: 100 mg of phenerenone sample and 10 mL of tetrahydrofuran were added to the reaction bottle respectively, and ultrasonically vibrated for 10 min at room temperature. The solution was filtered through a microporous filter membrane with a pore size of 0.22 μm. The filtrate was left open at room temperature and allowed to stand for 5 days to grow fine crystals, which precipitated and did not increase in size after 10 days.

[0041] Comparative Example 7 This comparative example provides a method for preparing a single crystal of phenerenol, comprising the following steps: 100 mg of phenerenone sample and 10 mL of methyl tert-butyl ether were added to the reaction bottle respectively, and ultrasonically shaken at room temperature for 10 min. The solution was filtered through a microporous filter membrane with a pore size of 0.22 μm. The filtrate was left open at room temperature and allowed to stand for 5 days to grow crystals. A powder solid was precipitated and did not increase in size after 10 days.

[0042] Comparative Example 8 This comparative example provides a method for preparing a single crystal of phenerenol, comprising the following steps: 100 mg of phenerenone sample and 10 mL of ethyl acetate were added to the reaction bottle respectively, and ultrasonically shaken at room temperature for 10 min. The solution was filtered through a microporous filter membrane with a pore size of 0.22 μm. The filtrate was left open at room temperature. After standing for 6 days to grow crystals, no solid was precipitated.

[0043] Comparative Example 9 This comparative example provides a method for preparing a single crystal of phenerenol, comprising the following steps: 100 mg of phenerenone sample and 10 mL of n-hexane were added to the reaction bottle respectively, and ultrasonically shaken at room temperature for 10 min. The solution was filtered through a microporous filter membrane with a pore size of 0.22 μm. The filtrate was left open at room temperature and allowed to stand for 5 days to grow fine crystals, which precipitated and did not increase in size after 10 days.

[0044] Comparative Example 10 This comparative example provides a method for preparing a single crystal of phenerenol, comprising the following steps: 100 mg of phenerenone sample, 5 mL of acetone and 5 mL of dichloromethane were added to the reaction bottle respectively, and ultrasonic vibration was performed at room temperature for 10 min. The solution was filtered through a microporous filter membrane with a pore size of 0.22 μm. The filtrate was left open at room temperature. After standing for 6 days to grow crystals, no solid was precipitated.

[0045] Comparative Example 11 This comparative example provides a method for preparing a single crystal of phenerenol, comprising the following steps: Add 100 mg of phenerenone sample, 10 mL of dichloromethane and 1 mL of n-hexane to the reaction bottle respectively, ultrasonically shake at room temperature for 10 min, filter with a microporous filter membrane with a pore size of 0.22 μm, take the filtrate and leave it open at room temperature. After standing for 4 days to grow crystals, a powder solid precipitated and did not increase in size after 10 days.

[0046] Comparative Example 12 This comparative example provides a method for preparing a single crystal of phenerenol, comprising the following steps: 100 mg of phenerenone sample, 5 mL of ethyl acetate and 5 mL of acetone were added to the reaction bottle respectively, and ultrasonic vibration was performed at room temperature for 10 min. The solution was filtered through a microporous filter membrane with a pore size of 0.22 μm. The filtrate was left open at room temperature and allowed to stand for 3 days to grow fine crystals, which precipitated and did not increase in size after 10 days.

[0047] Comparative Example 13 This comparative example provides a method for preparing a single crystal of phenerenol, comprising the following steps: Add 100 mg of phenerenone sample, 5 mL of ethyl acetate and 5 mL of acetonitrile to the reaction bottle respectively, shake it ultrasonically at room temperature for 10 min, filter it with a microporous filter membrane with a pore size of 0.22 μm, take the filtrate and place it at room temperature in an open state. After standing for 3 days to grow crystals, fine crystals precipitated and did not increase in size after 10 days.

[0048] Application Examples According to the first method of X-ray diffraction in General Chapter 0451 of Part IV of the Pharmacopoeia (2020 Edition), the single crystal of phenareline from Example 1 was subjected to single crystal X-ray diffraction analysis (22°C, RH=30%). The single crystal of phenareline is colorless and transparent, with a size of 0.10 mm×0.23 mm×0.31 mm. The crystal belongs to the orthorhombic system, and the space group is P 212121, unit cell volume V =1927.44(5)Å 3 , the number of molecules in the unit cell Z =4, the unit cell parameters are: a =7.932(1)Å, b =11.982(1)Å, c =20.281(1)Å.

[0049] Diffraction intensity data were collected using a Rigaku XtaLAB Synergy-DW single-product diffractometer, CuKa radiation, a multilayer film lens as a monochromator, a tube voltage of 40 kV, a tube current of 30 mA, a HlyPix 6000HE detector, and a crystal-detector distance of 1.3 Å. d =43mm, test temperature 295K, ω and φ scanning mode, maximum 2θ angle is 152.56°, independent diffraction points are 3562, observable points (|F| 2 ≥2σ|F| 2 ) is 3342, and the data completeness is 100.0%.

[0050] The crystal structure was analyzed by the direct method (SHELXL 2019 / 3) on a microcomputer. The positions of all 28 non-hydrogen atoms were directly obtained from the E map. The least squares method was used to correct the structural parameters and identify the atomic types. The geometric calculation method and the difference Fourier method were used to obtain the positions of all hydrogen atoms. The final reliability factors R1=0.035 and wR2=0.100 (w=1 / σ|F| 2 ), S = 1.052. The final chemical formula of the asymmetric unit was determined to be C 21 H 22 N4O3, calculated molecular weight is 378.2, calculated crystal density is 1.304 g / cm 3 The molecular arrangement in the crystalline state belongs to the first space group, and the sample should be optically active. The Flack coefficient of the crystal structure was calculated to be -0.01 (11), and the absolute configuration of the molecule was obtained (see Figures 1 to 3 and Tables 1~2).

[0051] The results show that the molecular skeleton of the compound is composed of a six-membered ring A (near planar form), a pyridine ring B (planar form) and a benzene ring C (planar form). The calculated molecular dihedral angles are: A / B: 3.4°, A / C: 84.9°, B / C: 81.6°. There is no hydrogen bond connection within the molecule in the crystalline state; the hydrogen bond between molecules is: N2...O1(x-1 / 2,-y+3 / 2,-z+1): 3.043Å. In the crystalline state, the molecules are maintained in a stable arrangement in space by hydrogen bonds and van der Waals forces.

[0052] Table 1 Atomic coordinate parameters Equivalent temperature factor values

[0053]

[0054] Table 2 Bond lengths and bond angles of bonding atoms

[0055]

[0056]

[0057] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modification, equivalent substitution or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A single crystal of finerenone, characterized in that: Its crystal belongs to the orthorhombic system, and its space group is P 212121, unit cell volume is 1927.44(5)Å 3 , the number of molecules in the unit cell is 4, and the unit cell parameters are: a =7.932(1)Å, b =11.982(1)Å, c =20.281(1)Å.

2. The phenerenone single crystal according to claim 1, characterized in that: The size of the phenerenone single crystal is (0.08-0.12) mm×(0.20-0.25) mm×(0.28-0.33) mm.

3. The method for preparing a single crystal of finerenone according to claim 1 or 2, characterized in that: The following steps are involved: The finerenone sample and acetonitrile are mixed and crystallized at 5°C to 35°C to obtain a finerenone single crystal.

4. The method for preparing a single crystal of phenerenone according to claim 3, characterized in that: The method for preparing the finerenone single crystal comprises the following steps: The finerenone sample and acetonitrile are mixed, filtered, and the filtrate is placed open at 10°C to 30°C for crystal growth to obtain finerenone single crystals.

5. The method for preparing a single crystal of finerenone according to claim 3 or 4, characterized in that: The mass volume ratio of the finerenone sample to the acetonitrile is (5-50) mg:1 mL.

6. The method for preparing a single crystal of finerenone according to claim 5, characterized in that: The mass volume ratio of the finerenone sample to the acetonitrile is (10-40) mg:1 mL.

7. The method for preparing a single crystal of finerenone according to claim 3 or 4, characterized in that: The mixing temperature is 20°C to 40°C.

8. The method for preparing a single crystal of finerenone according to claim 4, characterized in that: The filtration is performed by microporous membrane filtration, and the pore size of the microporous membrane is 0.22 μm to 0.45 μm.

9. The method for preparing a single crystal of finerenone according to claim 3 or 4, characterized in that: The crystal growing time is 5 to 10 days.

10. Use of the finerenone single crystal according to claim 1 or 2 or the finerenone single crystal prepared by the method for preparing a finerenone single crystal according to any one of claims 3 to 9 in determining the spatial configuration of a finerenone sample.

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