Addition salt of S1P1 receptor agonist and crystal form thereof, and pharmaceutical composition

Abstract

Disclosed in the present application are a salt form and a crystal form of an S1P1 receptor mediated disease or symptom drug 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazole-3-yl]benzyl}-3-azetidinecarboxylic acid (formula A). Also disclosed in the present invention are a preparation method for the salt form or the crystal form, a pharmaceutical composition of the salt form or the crystal form, and use of the salt form or the crystal form in the preparation of a drug for treating and/or preventing an S1P1 receptor mediated disease or symptom. ##STR00001##

Claims

1. A maleate of the compound 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazole-3-yl]benzyl}-3-azetidinecarboxylic acid, having a structure represented by the following formula: ##STR00006##

2. The maleate according to claim 1, wherein the maleate is substantially a crystal form, wherein with Cu-Kα radiation, the crystal form has an X-ray powder diffraction pattern characterized by angle 2θ having characteristic peaks at the following positions: 10.6±0.2°, 16.3±0.2°, 19.5±0.2°, 21.5±0.2°, and 26.9±0.2°.

3. The maleate according to claim 2, wherein the crystal form has an X-ray powder diffraction pattern characterized by angle 2θ having characteristic peaks at the following positions: 7.0±0.2°, 10.6±0.2°, 13.6±0.2°, 16.3±0.2°, 19.5±0.2°, 20.1±0.2°, 21.5±0.2°, 24.5±0.2°, and 26.9±0.2°.

4. The maleate according to claim 2, wherein the crystal form has a Fourier transform infrared spectrum having characteristic peaks at wavenumbers 1734 cm.sup.−1, 1574 cm.sup.−1, 1485 cm.sup.−1, 1439 cm.sup.−1, 1364 cm.sup.−1, 1346 cm.sup.−1, 1080 cm.sup.−1, 1003 cm.sup.−1, 893 cm.sup.−1, 871 cm.sup.−1, 757 cm.sup.−1, and 729 cm.sup.−1.

5. A method for preparing the maleate according to claim 1, comprising the following steps: forming a suspension or solution of the compound 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazole-3-yl]benzyl}-3-azetidinecarboxylic acid in a solvent selected from the group consisting of a C.sub.1-C.sub.4 alcohol, a C.sub.3-C.sub.4 ketone, C.sub.4-C.sub.6 ether, a C.sub.2-C.sub.5 ester, and water, and mixtures thereof and a suspension or solution of maleic acid in a solvent selected from the group consisting of a C.sub.1-C.sub.4 alcohol, a C.sub.3-C.sub.4 ketone, C.sub.4-C.sub.6 ether, a C.sub.2-C.sub.5 ester, and water, and mixtures thereof; mixing the suspension or solution of the compound 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazole-3-yl]benzyl}-3-azetidinecarboxylic acid and the suspension or solution of maleic acid in a molar ratio of 1:1 to 1:5 of the compound 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazole-3-yl]benzyl}-3-azetidinecarboxylic acid to maleic acid for reaction; removing the solvent after the reaction is complete; and performing drying.

6. The maleate according to claim 2, wherein the crystal form has an X-ray powder diffraction pattern characterized by angle 2θ having characteristic peaks at the following positions with relative intensities as follows: TABLE-US-00012 2θ Relative intensity %  5.3 ± 0.2° 3.4  7.0 ± 0.2° 5.8 10.6 ± 0.2° 100 13.6 ± 0.2° 6.6 14.5 ± 0.2° 3.2 16.3 ± 0.2° 12.2 19.5 ± 0.2° 37.7 20.1 ± 0.2° 8.6 20.7 ± 0.2° 2.8 21.5 ± 0.2° 18.3 24.5 ± 0.2° 11.4 24.7 ± 0.2° 9.6 25.3 ± 0.2° 1.8 26.1 ± 0.2° 1.9 26.9 ± 0.2° 34.5 28.7 ± 0.2° 2.2.

7. The maleate according to claim 2, wherein the crystal form has an X-ray powder diffraction pattern substantially as illustrated in FIG. 10.

8. The maleate according to claim 1, wherein the maleate is an anhydrate, a hydrate, or a non-solvate.

9. The method according to claim 5, wherein the solvent is selected from the group consisting of ethanol, acetone, ether, water, ethyl acetate, and 1,4-dioxane, and mixtures thereof.

10. The method according to claim 5, wherein the molar ratio of the compound 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazole-3-yl]benzyl}-3-azetidinecarboxylic acid to maleic acid is 1:1.0 to 1:2.6.

11. The method according to claim 5, wherein the reaction is performed at 10° C. to 60° C.

12. The method according to claim 5, wherein the reaction is performed under stirring.

13. The method according to claim 5, wherein the drying is performed at a temperature of 10° C. to 60° C.

14. The method according to claim 5, wherein the ratio of mass of the compound 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazole-3-yl]benzyl}-3-azetidinecarboxylic acid to volume of the solvent in the method is 1 mg:1 mL to 50 mg:1 mL.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 is an IR pattern of the sodium salt of the compound represented by formula A according to Example 3 of the present application.

(2) FIG. 2 is an XRPD pattern of the sodium salt of the compound represented by formula A according to Example 3 of the present application.

(3) FIG. 3 is a TGA pattern of the sodium salt of the compound represented by formula A according to Example 3 of the present application.

(4) FIG. 4 is a DSC pattern of the sodium salt of the compound represented by formula A according to Example 3 of the present application.

(5) FIG. 5 is an IR pattern of the sulfate of the compound represented by formula A according to Example 13 of the present application.

(6) FIG. 6 is an XRPD pattern of the sulfate of the compound represented by formula A according to Example 13 of the present application.

(7) FIG. 7 is a TGA pattern of the sulfate of the compound represented by formula A according to Example 13 of the present application.

(8) FIG. 8 is a DSC pattern of the sulfate of the compound represented by formula A according to Example 13 of the present application.

(9) FIG. 9 is an IR pattern of the maleate of the compound represented by formula A according to Example 21 of the present application.

(10) FIG. 10 is an XRPD pattern of the maleate of the compound represented by formula A according to Example 21 of the present application.

(11) FIG. 11 is a TGA pattern of the maleate of the compound represented by formula A according to Example 21 of the present application.

(12) FIG. 12 is a DSC pattern of the maleate of the compound represented by formula A according to Example 21 of the present application.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

(13) The following Examples will facilitate a further understanding of the present application, and are not used to limit the present application.

(14) Detection instruments and methods:

(15) X-Ray Powder Diffraction (XPRD): the instrument was Bruker D8 Advance diffractometer. Samples were tested at room temperature. Detection conditions were as follows: angle range: 3-40° 2θ; step size: 0.02°2θ; speed: 0.2 second/step.

(16) Differential Scanning Calorimetry (DSC) data were collected with TA Instruments Q200 MDSC. The detection method used was as follows: 1-10 mg of a sample was placed in an airtight small-hole aluminum crucible, and the temperature of the sample was increased from room temperature to 250° C. at a heating rate of 10° C./min under the protection of 40 mL/min dry N.sub.2.

(17) Thermogravimetric Analysis (TGA) data were collected with TA Instruments Q500 TGA. The detection method used was as follows: 5-15 mg of a samples was placed in a platinum crucible, and a segmented high-resolution detection method was adopted in which the temperature of the sample was increased from room temperature to 300° C. at a heating rate of 10° C./min under the protection of 40 mL/min dry N.sub.2.

(18) 1H Nuclear Magnetic Resonance (.sup.1HNMR) data were obtained with Bruker Avance II DMX 400 MHZ nuclear magnetic resonance spectrometer. 1-5 mg of a sample was weighed and dissolved in about 0.5 mL of deuterated reagent in a sample tube for nuclear magnetic resonance, and was detected.

(19) Infrared Spectroscopy (IR) data were collected with Bruker Tensor 27. Both instrument control software and data analysis software were OPUS. Infrared absorption spectrum in a range of 600-4000 cm.sup.−1 was collected with ATR equipment generally.

(20) Dynamic Vapor Sorption (DVS) data and isothermal sorption analysis data were collected with TA Instruments Q5000 TGA. The detection method used was as follows: 1-10 mg of a sample was placed in a platinum crucible, and weight change with the change of relative humidity from 20% to 80% was detected.

(21) HPLC solubility data were collected with Agilent 1260 high performance liquid chromatograph. The chromatographic column used was Poroshell 120 EC-C18 (2.7*50 mm, 4.6 μm), the detection wavelength was 254 nm, column temperature for detection was 40° C., flow rate was 1.5 mL/min, and the sample volume was 5 μL. A sample was dissolved in mobile phase B to prepare a sample solution of a concentration about 0.45 mg/mL, and HPLC detection was performed according to the following gradient elution mode to obtain concentration in the sample.

(22) TABLE-US-00004 Time (min) % mobile phase A % mobile phase B Gradient 0 95 5 0.2 95 5 3.7 5 95 6 5 95 6.01 95 5 9.0 95 5 Mobile phase A Water:trifluoroacetic acid = 1000:0.5 Mobile phase B Acetonitrile:trifluoroacetic acid = 1000:0.5

(23) Ion Chromatography (IC) data were collected with Dionex ICS-900. Both workstation and analysis software were Chromeleon Console. Ion content detection was performed by using External Standard Method.

(24) Ultrasonication operations described in the Examples can facilitate the dissolution of the samples. The equipment was an ultrasonic cleaner, and the ultrasonication was performed for 15 min at power of 40 kHz.

Preparation Example 1: Preparation of the Compound Represented by Formula A

(25) The compound represented by formula A can be prepared according to the preparation method described in Example 2 of patent document CN103450171A.

(26) Specifically, at room temperature, a solution of 2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazole-3-yl]-benzaldehyde (9.0 g, 27.8 mmol), azetidine-3-carboxylic acid (2.8 g, 27.8 mmol) and acetic acid (10 mL) in methanol-tetrahydrofuran (200 mL/200 mL) was stirred for 2 h. Then a solution (600 mL) of sodium cyanoborohydrate (10.3 g, 163.5 mmol) in methanol (600 mL) was added to the reaction mixture and then resulting mixture was stirred for additional 16 h at room temperature. Filtration was performed to obtain a filter cake, and the filter cake was washed with methanol (100 mL), and dried to obtain 2.0 g of white solid product.

(27) .sup.1H-NMR (400 MHz, CD3OD) δ: 8.13 (d, J=8.4 Hz, 2H), 8.05 (m, 1H), 7.97 (m, 1H), 7.68 (t, J=8.0 Hz, 7.6 Hz, 1H), 7.42 (d, J=8.4 Hz, 2H), 4.40 (s, 2H), 4.15 (m, 4H), 3.41 (m, 1H), 2.61 (d, J=7.2 Hz, 2H), 1.95 (m, 1H), 0.94 (d, J=7.2 Hz, 6H) indicated the product was the compound represented by formula A, i.e., 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazole-3-yl]benzyl}-3-azetidinecarboxylic acid.

Preparation Example 2: Screening and Preparation of Salt Forms of the Compound Represented by Formula A

(28) 2.1 Salt Screening

(29) According to the structure of the compound represented by formula A, 12 type I acids and 3 type I alkalis were selected for a salt screening experiment. Experiment setup and results were shown in Table 1.

(30) TABLE-US-00005 TABLE 1 Salt screening experiment setup and results Solvent/molar ratio of reactants (free state of the compound IC represented by character- Counter formula A: Post- ization ion counter ion) Temperature treatment Result of salt Citric Ethanol/1:2.4, Room Nitrogen Salt could be 1:1 acid isopropanol/1:2.2, temperature blowing or formed in water/1:2.5, filtration acetone, and no acetone/1:1.3, or salt was formed aeetonitrile/1:1.3 in other solvents or salt could not be obtained repeatedly. Phosphoric Ethanol/1:4.0 or Room Nitrogen Salt could be 1:1 acid 1:1.3, acetone/1:4.3 temperature or blowing or formed in or 1:1.3, 40° C. filtration acetone or acetonitrile/1:1.2, ethanol, and no water/1:8.5, diethyl salt was formed ether: in other solvents ethanol = 5:1/1:3.0, or salt could not tetrahydrofuran/1:6.4, be obtained isopropanol/1:1.0 repeatedly. Sulfuric Methanol/1:4.1, Room Nitrogen Salt could be 2:1 acid ethanol/1:3.0, temperature or blowing or formed in all n-propanol/1:7.9, 40° C. filtration solvents. water/1:3.2 or 1:3.0, acetone: water = 5:1/1:3.3, tetrahydrofuran: water = 5:1/1:3.1, acetonitrile:water = 4:1/1:3.2 Hydrochloric Methanol/1:10.0, Room Nitrogen Salt could be 1:1 acid methanol/1:9.8, temperature blowing or formed in isopropanol/1:5.9, filtration methanol, water/1:5.7 or 1:3.9, isopropanol, acetone/1:4.8 or acetone or 1:3.2, diethyl ethanol, and no ether/1:4.5, ethyl salt was formed acetate/1:5.9, in other solvents acetonitrile/1:3.2 or salt could not be obtained repeatedly. Maleic Acetone/1:1.2, Room Nitrogen Salt could be 1:1 acid ethanol/1:1.3, temperature blowing or formed in all water/1:2.1, diethyl filtration solvents. ether/1:1.2, ethyl acetate/1:2.0, 1,4-dioxane/1:2.6 Sodium Methanol/1:1.3 or Room Nitrogen Salt could be 1:1 1:1.0, water/1:1.3, temperature blowing or formed in all acetone: filtration or solvents except water = 4:1/1:1.2, subjecting ethyl acetate: diethyl ether: filtrate ethanol. ethanol = 4:1/1:1.3, obtained ethyl acetate: after ethanol = 4:1/1:3.2, filtration to acetonitrile: nitrogen water = 4:1/1:1.4 blowing Potassium Methanol/1:1.0, Room Nitrogen Salt could be 1:1 water/1:1.4, acetone: temperature blowing or formed in all water = 4:1/1:1.4, filtration or solvents. isopropyl acetate: subjecting ethanol = 4:1/1:1.0, filtrate 1,4-dioxane: obtained water = 4:1/1:1.2, after acetonitrile: filtration to water = 4:1/1:1.3 nitrogen blowing Calcium Methanol/1:0.6 or Room Nitrogen Salt could be 2:1 1:1.6, water/1:1.2 or temperature blowing or formed in 1:2.8 or 1:1.4 or filtration methanol, water 1:1.3, ethanol/1:1.7 and ethanol. or 1:1.3, isopropanol/1:1.5 D-gluconic Methanol/1:1.2, Room Nitrogen No salt was acid ethanol: temperature or blowing formed. water = 1:1/1:2.8, 40° C. water/1:2.2, acetone: water = 5:1/1:1.1, tetrahydrofuran: water = 5:1/1:2.3, acetonitrile: water = 4:1/1:2.0 L-malic Ethanol/1:2.5, Room Nitrogen No salt was acid acetone/1:1.2, temperature or blowing formed. diethyl ether/1:1.2, 40° C. 1,4-dioxane/1:3.0, acetonitrile/1:2.1 Succinic Methanol/1:1.3, Room Nitrogen No salt was acid water/1:2.7, temperature or blowing or formed. acetone/1:1.3, 40° C. filtration diethyl ether/1:2.0, tetrahydrofuran/1:3.1, tetrahydrofuran/1:1.5 L-tartaric Ethanol/1:1.3, Room Nitrogen No salt was acid water/1:1.2, temperature or blowing or formed. acetone/1:1.5, 40° C. filtration diethyl ether/1:2.5, tetrahydrofuran/1:1.5, acetonitrile/1:2.1 Glacial Ethanol/1:2.7, Room Nitrogen No salt was acetic water/1:8.1, temperature or blowing formed. acid acetone/1:7.3, 40° C. diethyl ether/1:9.6, tetrahydrofuran/1:7.5, tetrahydrofuran/1:6.0 Fumaric Ethanol/1:2.8, Room Nitrogen No salt was acid water/1:1.4, temperature or blowing formed. acetone/1:2.5, 40° C. diethyl ether/1:1.2, ethyl acetate/1:2.0 Hippuric Isopropanol/1:1.2, Room Nitrogen No salt was acid water/1:2.1, temperature or blowing formed. acetone/1:2.1, 40° C. diethyl ether/1:2.1, tetrahydrofuran/1:2.2, acetonitrile/1:2.0

(31) 2.2 Preparation of Some Salts

(32) Acetone and water were selected as reaction solvents, free state of the compound represented by formula A and counter ions in a molar ratio of 1:1.2 were used for salt formation, and the ratio in the salt formed was detected by using IC. A citrate of the compound represented by formula A, a phosphate of the compound represented by formula A, a hydrochloride of the compound represented by formula A, a potassium salt of the compound represented by formula A and a calcium salt of the compound represented by formula A were prepared.

Example 1: Preparation of Sodium Salt of the Compound Represented by Formula A

(33) 14.50 mg of the compound represented by formula A prepared in Preparation Example 1 were weighed and added into 0.5 mL of methanol, and the obtained mixture was stirred to form a suspension. A sodium hydroxide solution (1.75 mg of sodium hydroxide was added into 0.45 mL of methanol) was dropped into the suspension of the compound represented by formula A in methanol, and the obtained mixture was stirred for about 10 min at room temperature to form a clear solution, which was stirred for additional 3 h. Then the solvent was removed from the solution by nitrogen blowing at room temperature, to obtain 0.2 mL of a colorless transparent clear solution, which was cooled to 5° C. to obtain a suspension. Centrifugation was performed, and the obtained solid was dried for 16 h at room temperature under vacuum to obtain a sodium salt of the compound represented by formula A according to the present application.

(34) IC characterization showed that the sodium salt of the compound represented by formula A was formed through the reaction of the compound represented by formula A and sodium ion in a molar ratio of 1:1.

Example 2: Preparation of Sodium Salt of the Compound Represented by Formula A

(35) 40.71 mg of the compound represented by formula A prepared in Preparation Example 1 were weighed and added into 0.4 mL of methanol, and the obtained mixture was stirred to form a suspension. A sodium hydroxide solution (4.0 mg of sodium hydroxide was added into 2.8 mL of methanol) was dropped into the suspension of the compound represented by formula A in methanol, and the obtained mixture was stirred for about 1 h at room temperature to form a clear solution. The solution was stirred for additional 2 h, then filtration was performed, and the solvent was removed from the filtrate through volatilization at room temperature to obtain 0.2 mL of a suspension. Centrifugation was performed, and the obtained solid was dried for 24 h at room temperature under vacuum to obtain a sodium salt of the compound represented by formula A according to the present application.

(36) IC characterization showed that the sodium salt of the compound represented by formula A was formed through the reaction of the compound represented by formula A and sodium ion in a molar ratio of 1.1.

Example 3: Preparation of Sodium Salt of the Compound Represented by Formula A

(37) 4.9 mg of sodium hydroxide was weighed and added into 1.0 mL of water, and ultrasonication was performed to obtain a clear solution. The clear solution was dropped into 40.7 mg of the compound represented by formula A prepared in Preparation Example 1, and the obtained mixture was stirred for 24 h at room temperature. Filtration was performed, and the solvent was removed from the filtrate by nitrogen blowing at 60° C. to obtain 0.2 mL of a light yellow transparent clear solution. The solution was cooled to room temperature to precipitate a solid, then centrifugation was performed, and the solid obtained was dried for 1 h at 40° C. under vacuum to obtain a sodium salt of the compound represented by formula A according to the present application.

(38) IC characterization showed that the sodium salt of the compound represented by formula A was formed through the reaction of the compound represented by formula A and sodium ion in a molar ratio of 1:1.

(39) An IR pattern of the sodium salt was as illustrated in FIG. 1.

(40) An XRD pattern of the sodium salt was as illustrated in FIG. 2.

(41) A TGA pattern of the sodium salt was as illustrated in FIG. 3.

(42) A DSC pattern of the sodium salt was as illustrated in FIG. 4.

Example 4: Preparation of Sodium Salt of the Compound Represented by Formula A

(43) 3.5 mg of sodium hydroxide was weighed and added into 1.0 mL of acetone, water (4:1), and ultrasonication was performed to obtain a clear solution. The clear solution was dropped into 29.2 mg of the compound represented by formula A prepared in Preparation Example 1, and the obtained mixture was stirred for 16 h at room temperature. Filtration was performed, and the filter cake obtained was dried for 1 h at 40° C. under vacuum to obtain a sodium salt of the compound represented by formula A according to the present application.

(44) IC characterization showed that the sodium salt of the compound represented by formula A was formed through the reaction of the compound represented by formula A and sodium ion in a molar ratio of 1:1.

Example 5: Preparation of Sodium Salt of the Compound Represented by Formula A

(45) 5.05 mg of the compound represented by formula A prepared in Preparation Example 1 were weighed and added into 0.2 mL of diethyl ether:ethanol (4:1), and the obtained mixture was stirred to form a suspension. A sodium hydroxide solution (0.65 mg of sodium hydroxide was added into 0.3 mL of diethyl ether:ethanol (4:1 by volume)) was dropped into the suspension of the compound represented by formula A in diethyl ether:ethanol, and the obtained mixture was stirred for 24 h at room temperature. Filtration was performed, and the solvents were removed from the filtrate through volatilization at 60° C. The solid obtained was slurried with 0.2 mL of diethyl ether for 1 h, then centrifugation was performed, and the solid obtained after centrifugation was dried for 19 h at room temperature under vacuum to obtain a sodium salt of the compound represented by formula A according to the present application.

(46) IC characterization showed that the sodium salt of the compound represented by formula A was formed through the reaction of the compound represented by formula A and sodium ion in a molar ratio of 1:1.

Example 6: Preparation of Sodium Salt of the Compound Represented by Formula A

(47) 8.02 mg of the compound represented by formula A prepared in Preparation Example 1 were weighed. 8.0 mL of n-butanol:methyl tert-butyl ether (1:1) and 2.5 mg of sodium hydroxide were added into the compound, and the obtained mixture was stirred for 1 h at 60° C. Filtration was performed, and the solvents were removed from the filtrate through rotary evaporation at 60° C. The solid obtained was slurried with 0.2 mL of n-butanol:methyl tert-butyl ether (1:1) for 1 h, then centrifugation was performed, and the solid obtained after centrifugation was dried for 48 h at 40° C. under vacuum to obtain a sodium salt of the compound represented by formula A according to the present application.

(48) IC characterization showed that the sodium salt of the compound represented by formula A was formed through the reaction of the compound represented by formula A and sodium ion in a molar ratio of 1:1.

Example 7: Preparation of Sodium Salt of the Compound Represented by Formula A

(49) 45.01 mg of the compound represented by formula A prepared in Preparation Example 1 were weighed. 0.9 mL of butanone:n-propanol (2:1) and 19.5 mg of sodium hydroxide were added into the compound, and the obtained mixture was stirred for 48 h at 60° C. Filtration was performed, and the solvents were removed from the filtrate through rotary evaporation at room temperature. The solid obtained was slurried with 0.2 mL of butanone:n-propanol (2:1) for 1 h, then centrifugation was performed, and the solid obtained after centrifugation was dried for 40 h at 60° C. under vacuum to obtain a sodium salt of the compound represented by formula A according to the present application.

(50) IC characterization showed that the sodium salt of the compound represented by formula A was formed through the reaction of the compound represented by formula A and sodium ion in a molar ratio of 1:1.

Example 8: Preparation of Sodium Salt of the Compound Represented by Formula A

(51) 4.69 mg of sodium hydroxide was weighed and added into 1.0 mL of water, and ultrasonication was performed to obtain a clear solution. The clear solution was dropped into 38.77 mg of the compound represented by formula A prepared in Preparation Example 1, then 14.0 mL of water were added, and the obtained mixture was stirred for 16 h at room temperature. Filtration was performed, and the solvent was removed from the filtrate by nitrogen blowing at 50° C. to obtain 0.2 mL of a light yellow transparent clear solution. The solution is cooled to 5° C. to precipitate a solid, then centrifugation was performed, and the solid obtained was dried for 24 h at 40° C. under vacuum to obtain a sodium salt of the compound represented by formula A according to the present application.

(52) IC characterization showed that the sodium salt of the compound represented by formula A was formed through the reaction of the compound represented by formula A and sodium ion in a molar ratio of 1:1.

Example 9: Preparation of Sodium Salt of the Compound Represented by Formula A

(53) 6.15 mg of the compound represented by formula A prepared in Preparation Example 1 were weighed. 3.0 mL of methanol:isopropyl ether (1:1) and 1.3 mg of sodium hydroxide solid were added into the compound, and the obtained mixture was stirred for 1 h at 40° C. Filtration was performed, and the solvents were removed from the filtrate through rotary evaporation at 50° C. The solid obtained was slurried with 0.1 mL of methanol:isopropyl ether (1:1) for 1 h, then centrifugation was performed, and the solid obtained after centrifugation was dried for 24 h at 25° C. under vacuum to obtain a sodium salt of the compound represented by formula A according to the present application.

(54) IC characterization showed that the sodium salt of the compound represented by formula A was formed through the reaction of the compound represented by formula A and sodium ion in a molar ratio of 1:1.

Example 10: Preparation of Sodium Salt of the Compound Represented by Formula A

(55) 35.62 mg of the compound represented by formula A prepared in Preparation Example 1 were weighed. 1.2 mL of acetonitrile and 8.7 mg of sodium hydroxide solid were added into the compound, and the obtained mixture was stirred for 3 h at 35° C. Filtration was performed, and the solvent was removed from the filtrate through rotary evaporation at room temperature to obtain 0.2 mL of a colorless transparent clear solution. The solution was cooled to 5° C. to precipitate a solid, then centrifugation was performed, and the solid obtained was dried for 30 h at 40° C. under vacuum to obtain a sodium salt of the compound represented by formula A according to the present application.

(56) IC characterization showed that the sodium salt of the compound represented by formula A was formed through the reaction of the compound represented by formula A and sodium ion in a molar ratio of 1:1.

Example 11: Preparation of Sulfate of the Compound Represented by Formula A

(57) 76.02 mg of the compound represented by formula A prepared in Preparation Example 1 was weighed and added into 5.2 mL of methanol, and the obtained mixture was stirred to form a suspension. A sulfuric acid solution (7.3 mg of 98% sulfuric acid was added into 7.6 mL of methanol) was dropped into the suspension of the compound represented by formula A in methanol, and the obtained mixture was stirred for 5 h at room temperature to obtain a suspension. The suspension was stirred for additional 1 h after addition of 5.0 mL of methanol, then filtration was performed, and the solvent was removed from the filtrate by nitrogen blowing at room temperature to obtain 1.0 mL of a suspension. Filtration was performed, and the solid obtained was dried for 20 h at room temperature under vacuum to obtain a sulfate of the compound represented by formula A according to the present application.

(58) IC characterization showed that the sulfate of the compound represented by formula A was formed through the reaction of the compound represented by formula A and sulfuric acid in a molar ratio of 2:1.

Example 12: Preparation of Sulfate of the Compound Represented by Formula A

(59) 34.41 mg of the compound represented by formula A prepared in Preparation Example 1 were weighed and added into 1.0 mL of ethanol, and the obtained mixture was stirred to form a suspension. 24.82 mg of 98% sulfuric acid was added into the suspension of the compound represented by formula A in ethanol, and the obtained mixture was stirred for 24 h at room temperature. Filtration was performed, and the filter cake obtained was dried for 10 h at 40° C. under vacuum to obtain a sulfate of the compound represented by formula A according to the present application.

(60) IC characterization showed that the sulfate of the compound represented by formula A was formed through the reaction of the compound represented by formula A and sulfuric acid in a molar ratio of 2:1.

Example 13: Preparation of Sulfate of the Compound Represented by Formula A

(61) 4.63 mg of the compound represented by formula A prepared in Preparation Example 1 were weighed and added into 0.2 mL of n-propanol, and the obtained mixture was stirred to form a suspension. A sulfuric acid solution (8.79 mg of 98% sulfuric acid was added into 0.3 mL of n-propanol) was dropped into the suspension of the compound represented by formula A in n-propanol, and the obtained mixture was stirred for 16 h at room temperature. Filtration was performed, and the solvent was removed from the filtrate by nitrogen blowing at room temperature to obtain an oily substance. Water was added into the oily substance, and ultrasonication was performed to form a suspension. Centrifugation was performed, and the obtained solid was dried for 24 h at room temperature under vacuum to obtain a sulfate of the compound represented by formula A according to the present application.

(62) IC characterization showed that the sulfate of the compound represented by formula A was formed through the reaction of the compound represented by formula A and sulfuric acid in a molar ratio of 2:1.

(63) An IR pattern of the sulfate was as illustrated in FIG. 5.

(64) An XRD pattern of the sulfate was as illustrated in FIG. 6.

(65) A TGA pattern of the sulfate was as illustrated in FIG. 7.

(66) A DSC pattern of the sulfate was as illustrated in FIG. 8.

Example 14: Preparation of Sulfate of the Compound Represented by Formula A

(67) 10.02 mg of the compound represented by formula A prepared in Preparation Example 1 were weighed and added into 1.0 mL of water, and the obtained mixture was stirred to form a suspension. 7.88 mg of 98% sulfuric acid was added into the suspension of the compound represented by formula A in water, and the obtained mixture was stirred for 24 h at 40° C. Filtration was performed, and the filter cake obtained was dried for 1 h at 60° C. under vacuum to obtain a sulfate of the compound represented by formula A according to the present application.

(68) IC characterization showed that the sulfate of the compound represented by formula A was formed through the reaction of the compound represented by formula A and sulfuric acid in a molar ratio of 2:1.

Example 15: Preparation of Sulfate of the Compound Represented by Formula A

(69) 34.4 mg of the compound represented by formula A prepared in Preparation Example 1 were weighed and added into 1.0 mL of water, and the obtained mixture was stirred to form a suspension. A sulfuric acid solution (25.0 mg of 98% sulfuric acid was added into 0.5 mL of water) was dropped into the suspension of the compound represented by formula A in water, and the obtained mixture was stirred for 24 h at room temperature. Filtration was performed, and the filter cake obtained was dried for 1 h at 40° C. under vacuum to obtain a sulfate of the compound represented by formula A according to the present application.

(70) IC characterization showed that the sulfate of the compound represented by formula A was formed through the reaction of the compound represented by formula A and sulfuric acid in a molar ratio of 2:1.

Example 16: Preparation of Sulfate of the Compound Represented by Formula A

(71) 10.25 mg of the compound represented by formula A prepared in Preparation Example 1 were weighed and added into 0.2 mL of water, and the obtained mixture was stirred to form a suspension. 8.25 mg of 98% sulfuric acid and 1.0 mL of acetone were sequentially added into the suspension of the compound represented by formula A in water, and the obtained mixture was stirred for 1 h at room temperature to obtain a clear solution. Filtration was performed, then the solvents were removed from the filtrate by nitrogen blowing at room temperature, and the solid obtained was dried for 24 h at room temperature under vacuum to obtain a sulfate of the compound represented by formula A according to the present application.

(72) IC characterization showed that the sulfate of the compound represented by formula A was formed through the reaction of the compound represented by formula A and sulfuric acid in a molar ratio of 2:1.

Example 17: Preparation of Sulfate of the Compound Represented by Formula A

(73) 10.40 mg of the compound represented by formula A prepared in Preparation Example 1 were weighed. 0.2 mL of water, 7.92 mg of 98% sulfuric acid and 1.0 mL of tetrahydrofuran were sequentially added into the compound represented by formula A, and the obtained mixture was stirred for 3 h at room temperature to obtain a clear solution. Filtration was performed, and the solvents were removed from the filtrate by nitrogen blowing at 60° C. to obtain 0.3 mL of a suspension. Centrifugation was performed, and the solid obtained was dried for 20 h at 40° C. under vacuum to obtain a sulfate of the compound represented by formula A according to the present application.

(74) IC characterization showed that the sulfate of the compound represented by formula A was formed through the reaction of the compound represented by formula A and sulfuric acid in a molar ratio of 2:1.

Example 18: Preparation of Sulfate of the Compound Represented by Formula A

(75) 4.15 mg of the compound represented by formula A prepared in Preparation Example 1 were weighed and added into 0.2 mL of water:acetonitrile (1:4), and the obtained mixture was stirred to form a suspension. A sulfuric acid solution (3.2 mg of 98% sulfuric acid was added into 0.3 mL of water:acetonitrile (1:4)) was dropped into the suspension of the compound represented by formula A in water:acetonitrile (1:4), and the obtained mixture was stirred for 24 h at room temperature. Filtration was performed, and the solvents were removed from the filtrate by nitrogen blowing at room temperature to obtain 0.1 mL of a suspension. Centrifugation was performed, and the solid obtained was dried for 1 h at 50° C. under vacuum to obtain a sulfate of the compound represented by formula A according to the present application.

(76) IC characterization showed that the sulfate of the compound represented by formula A was formed through the reaction of the compound represented by formula A and sulfuric acid in a molar ratio of 2:1.

Example 19: Preparation of Sulfate of the Compound Represented by Formula A

(77) 5.0 mg of the compound represented by formula A prepared in Preparation Example 1 were weighed. 5.0 mL of s-butanol:butanone (1:4) and 10.3 mg of 98% sulfuric acid were added into the compound, and the obtained mixture was stirred for 30 h at −10° C. Filtration was performed, and the solvents were removed from the filtrate by nitrogen blowing at 40° C. to obtain 0.1 mL of a suspension. Centrifugation was performed, and the solid obtained was dried for 10 h at 60° C. under vacuum to obtain a sulfate of the compound represented by formula A according to the present application.

(78) IC characterization showed that the sulfate of the compound represented by formula A was formed through the reaction of the compound represented by formula A and sulfuric acid in a molar ratio of 2:1.

Example 20: Preparation of Sulfate of the Compound Represented by Formula A

(79) 40.0 mg of the compound represented by formula A prepared in Preparation Example 1 were weighed and added into 0.4 mL of 1,4-dioxane:water (1:1), and the obtained mixture was stirred to form a suspension. A sulfuric acid solution (96.7 mg of 98% sulfuric acid was added into 0.4 mL of 1,4-dioxane:water (1:1)) was dropped into the suspension of the compound represented by formula A in 1,4-dioxane:water (1:1), and the obtained mixture was stirred for 72 h at 60° C. Filtration was performed, and the solvents were removed from the filtrate by nitrogen blowing at 60° C. The solid obtained was slurried with 0.2 mL of 1,4-dioxane:water (1:1) for 1 h, then centrifugation was performed, and the solid obtained after centrifugation was dried for 48 h at 40° C. under vacuum to obtain a sulfate of the compound represented by formula A according to the present application.

(80) IC characterization showed that the sulfate of the compound represented by formula A was formed through the reaction of the compound represented by formula A and sulfuric acid in a molar ratio of 2:1.

Example 21: Preparation of Maleate of the Compound Represented by Formula A

(81) 51.7 mg of the compound represented by formula A prepared in Preparation Example 1 were weighed and added into 1.0 mL of acetone. A maleic acid solution (17.7 mg of maleic acid was added into 1.0 mL of acetone) was dropped into the system of the compound represented by formula A in acetone under stirring, and the obtained mixture was stirred for 24 h at room temperature. Filtration was performed, and drying was performed for 16 h at 40° C. under vacuum to obtain a maleate of the compound represented by formula A according to the present application.

(82) IC characterization showed that the maleate of the compound represented by formula A was formed through the reaction of the compound represented by formula A and maleic acid in a molar ratio of 1:1.

(83) An IR pattern of the maleate was as illustrated in FIG. 9.

(84) An XRD pattern of the maleate was as illustrated in FIG. 10.

(85) A TGA pattern of the maleate was as illustrated in FIG. 11.

(86) A DSC pattern of the maleate was as illustrated in FIG. 12.

Example 22: Preparation of Maleate of the Compound Represented by Formula A

(87) 10.37 mg of the compound represented by formula A prepared in Preparation Example 1 were weighed. A maleic acid solution (3.91 mg of maleic acid was added into 1.0 mL of ethanol) was dropped into the compound, and the obtained mixture was stirred for 10 h at room temperature. Filtration was performed, and the filter cake obtained was dried for 20 h at 25° C. under vacuum to obtain a maleate of the compound represented by formula A according to the present application.

(88) IC characterization showed that the maleate of the compound represented by formula A was formed through the reaction of the compound represented by formula A and maleic acid in a molar ratio of 1:1.

Example 23: Preparation of Maleate of the Compound Represented by Formula A

(89) 7.63 mg of the compound represented by formula A prepared in Preparation Example 1 were weighed. A maleic acid solution (4.47 mg of maleic acid was added into 1.0 mL of water) was dropped into the compound, and the obtained mixture was stirred for 24 h at 40° C. Filtration was performed, and the filter cake obtained was dried for 1 h at 40° C. under vacuum to obtain a maleate of the compound represented by formula A according to the present application.

(90) IC characterization showed that the maleate of the compound represented by formula A was formed through the reaction of the compound represented by formula A and maleic acid in a molar ratio of 1:1.

Example 24: Preparation of Maleate of the Compound Represented by Formula A

(91) 10.70 mg of the compound represented by formula A prepared in Preparation Example 1 were weighed. 3.52 mg of maleic acid and 1.0 mL of diethyl ether were added into the compound, and the obtained mixture was stirred for 24 h at room temperature. Filtration was performed, and the filter cake obtained was dried for 24 h at 10° C. under vacuum to obtain a maleate of the compound represented by formula A according to the present application.

(92) IC characterization showed that the maleate of the compound represented by formula A was formed through the reaction of the compound represented by formula A and maleic acid in a molar ratio of 1:1.

Example 25: Preparation of Maleate of the Compound Represented by Formula A

(93) 13.33 mg of the compound represented by formula A prepared in Preparation Example 1 were weighed and added into 1.5 mL of ethyl acetate. A maleic acid solution (5.14 mg of maleic acid was added into 1.0 mL of ethyl acetate) was dropped into the system of the compound represented by formula A in ethyl acetate under stirring, and the obtained mixture was stirred for 18 h at room temperature. Filtration was performed, and the filter cake obtained was dried for 1 h at 40° C. under vacuum to obtain a maleate of the compound represented by formula A according to the present application.

(94) IC characterization showed that the maleate of the compound represented by formula A was formed through the reaction of the compound represented by formula A and maleic acid in a molar ratio of 1:1.

Example 26: Preparation of Maleate of the Compound Represented by Formula A

(95) 6.04 mg of the compound represented by formula A prepared in Preparation Example 1 were weighed and added into 1.0 mL of 1,4-dioxane. A maleic acid solution (4.4 mg of maleic acid was added into 0.4 mL of 1,4-dioxane) was dropped into the system of the compound represented by formula A in 1,4-dioxane under stirring, and the obtained mixture was stirred for 20 h at room temperature. Filtration was performed, and the filter cake obtained was dried for 24 h at 50° C. under vacuum to obtain 34.3 mg of a maleate of the compound represented by formula A according to the present application.

(96) IC characterization showed that the maleate of the compound represented by formula A was formed through the reaction of the compound represented by formula A and maleic acid in a molar ratio of 1:1.

Example 27: Preparation of Maleate of the Compound Represented by Formula A

(97) 5.0 mg of the compound represented by formula A prepared in Preparation Example 1 were weighed. 4.7 mg of maleic acid and 5.0 mL of butanone:methyl formate (2:1) were added into the compound, and the obtained mixture was stirred for 30 h at 60° C. Filtration was performed, and drying was performed for 37 h at 56° C. under vacuum to obtain a maleate of the compound represented by formula A according to the present application.

(98) IC characterization showed that the maleate of the compound represented by formula A was formed through the reaction of the compound represented by formula A and maleic acid in a molar ratio of 1:1.

Example 28: Preparation of Maleate of the Compound Represented by Formula A

(99) 40.5 mg of the compound represented by formula A prepared in Preparation Example 1 were weighed and added into 0.6 mL of methanol:methyl tert-butyl ether (1:1). A maleic acid solution (11.5 mg of maleic acid was added into 0.4 mL of methanol:methyl tert-butyl ether (1:1)) was dropped into the system of the compound represented by formula A in methanol:methyl tert-butyl ether (1:1) under stirring, and the obtained mixture was stirred for 48 h at 45° C. Filtration was performed, and drying was performed for 48 h at 40° C. under vacuum to obtain a maleate of the compound represented by formula A according to the present application.

(100) IC characterization showed that the maleate of the compound represented by formula A was formed through the reaction of the compound represented by formula A and maleic acid in a molar ratio of 1:1.

Example 29: Preparation of Maleate of the Compound Represented by Formula A

(101) 50.0 mg of the compound represented by formula A prepared in Preparation Example 1 were weighed and added into 0.5 mL of n-butanol:isopropyl acetate (3:1). A maleic acid solution (70.9 mg of maleic acid was added into 0.5 mL of n-butanol:isopropyl acetate (3:1)) was dropped into the system of the compound represented by formula A in n-butanol:isopropyl acetate (3:1) under stirring, and the obtained mixture was stirred for 72 h at −10° C. Filtration was performed, and drying was performed for 30 h at 60° C. under vacuum to obtain a maleate of the compound represented by formula A according to the present application.

(102) IC characterization showed that the maleate of the compound represented by formula A was formed through the reaction of the compound represented by formula A and maleic acid in a molar ratio of 1:1.

Comparative Example 1: Solubility of Sodium Salt of the Compound Represented by Formula A

(103) The sodium salt of the compound represented by formula A according to the present application was taken to perform a solubility experiment in water. Specific operation was as follows: 5 mg of the sodium salt of the compound represented by formula A according to the present application was taken and put into a 20 ml glass bottle, and deionized water was gradually added at 25° C. into the bottle, and ultrasonication was performed to obtain a clear solution. The solubility of the sample in water was calculated.

(104) TABLE-US-00006 TABLE 2 Solubility of sodium salt of the compound represented by formula A according to the present application in water Sample name Solubility (mg/mL) Sodium salt of the compound 10 represented by formula A

(105) It can be seen from Table 2 that the sodium salt of the compound represented by formula A according to the present application has a high solubility, so it has a better bioavailability.

Comparative Example 2: Comparison of Thermal Stability of Salt Forms of the Compound Represented by Formula A

(106) The sodium salt of the compound represented by formula A according to the present application and conventional salts (citrate of the compound represented by formula A, phosphate of the compound represented by formula A and hydrochloride of the compound represented by formula A) were taken to perform DSC and TGA assays, and melting point and decomposition temperature data of each salt form were obtained.

(107) TABLE-US-00007 TABLE 3 Melting point data of sodium salt and other conventional salts of the compound represented by formula A according to the present application Melting Decomposition Salt form point (° C.) temperature (° C.) Sodium salt of the compound represented 234 275 by formula A Citrate of the compound represented by 152 154 formula A Phosphate of the compound represented 160 190 by formula A Hydrochloride of the compound 163 145 represented by formula A

(108) It can be seen from Table 3 that, compared with the conventional salts (citrate of the compound represented by formula A, phosphate of the compound represented by formula A and hydrochloride of the compound represented by formula A), the sodium salt of the compound represented by formula A according to the present application has very high melting point and decomposition temperature, so it has a better thermal stability.

Comparative Example 3: Comparison of Solubility of Salt Forms of the Compound Represented by Formula A

(109) The known free state of the compound represented by formula A, conventional salts (calcium salt of the compound represented by formula A, citrate of the compound represented by formula A, phosphate of the compound represented by formula A, and hydrochloride of the compound represented by formula A), and the sulfate of the compound represented by formula A and the maleate of the compound represented by formula A according to the present application were taken to perform a solubility experiment in water. Specific operation was as follows: 5 mg of the known free state of the compound represented by formula A, conventional salts (calcium salt of the compound represented by formula A, citrate of the compound represented by formula A, phosphate of the compound represented by formula A, and hydrochloride of the compound represented by formula A), and the sulfate of the compound represented by formula A and the maleate of the compound represented by formula A according to the present application prepared were taken and put into 20 ml glass bottles respectively, and 15 ml of deionized water was added into each of the bottles and stirred for 2 h at 25° C. Then samples were taken and filtered, and the concentrations were detected by HPLC. The solubility of the active ingredient in each of the samples in water was calculated.

(110) TABLE-US-00008 TABLE 4 Solubility of free state and salt forms of the compound represented by formula A in water Solubility Sample name (μg/mL) Free state of the compound represented by formula A 1.1 Sulfate of the compound represented by formula A 19.2 Maleate of the compound represented by formula A 16.1 Calcium salt of the compound represented by formula A 2.5 Citrate of the compound represented by formula A 5.3 Phosphate of the compound represented by formula A 6.7 Hydrochloride of the compound represented by formula A 3.8

(111) It can be seen from Table 4 that, the solubility of the sulfate of the compound represented by formula A and the maleate of the compound represented by formula A according to the present application in water at 25° C. is about 10-20 times higher than that of the known free state of the compound represented by formula A; and is about 3-8 times higher than those of other conventional salts (calcium salt of the compound represented by formula A, citrate salt of the compound represented by formula A, phosphate of the compound represented by formula A, and hydrochloride of the compound represented by formula A), so the sulfate and the maleate have a better solubility, and a better bioavailability.

Comparative Example 4: Comparison of Hygroscopicity of Salt Forms of the Compound Represented by Formula A

(112) The sulfate of the compound represented by formula A and the maleate of the compound represented by formula A according to the present application, and conventional salts (potassium salt of the compound represented by formula A, calcium salt of the compound represented by formula A, citrate of the compound represented by formula A, phosphate of the compound represented by formula A, and hydrochloride of the compound represented by formula A) were taken to perform DVS assay, and hygroscopicity data of each salt form were obtained.

(113) TABLE-US-00009 TABLE 5 Hygroscopicity data of sulfate of the compound represented by formula A and maleate of the compound represented by formula A according to the present application, and other conventional salts Salt form Moisture uptake (%) Appearance Sulfate of the compound 0.7 Powder represented by formula A Maleate of the compound 0.4 Powder represented by formula A Potassium salt of the compound 17.5 Deliquesced represented by formula A into a solution Calcium salt of the compound 1.2 Powder represented by formula A Citrate of the compound 0.7 Powder represented by formula A Phosphate of the compound 1.2 Powder represented by formula A Hydrochloride of the compound 1.2 Powder represented by formula A

(114) It can be seen from Table 5 that, compared with conventional salts (potassium salt of the compound represented by formula A, calcium salt of the compound represented by formula A, citrate of the compound represented by formula A, phosphate of the compound represented by formula A, and hydrochloride of the compound represented by formula A), the sulfate of the compound represented by formula A and the maleate of the compound represented by formula A according to the present application have a lower hygroscopic weight gain, thus have better storage stability, and can be better at avoiding quality, safety and stability problems during drug manufacture and/or storage, etc.

Comparative Example 5: Comparison of Stability of Crystal Forms of Salts of the Compound Represented by Formula A

(115) The crystal form of the sulfate of the compound represented by formula A and the crystal form of the maleate of the compound represented by formula A according to the present application were taken to perform a stability experiment. Specific operation was as follows: 60 mg of the samples of the crystal form of the sulfate of the compound represented by formula A and the crystal form of the maleate of the compound represented by formula A according to the present application were taken and placed for 30 days respectively under conventional condition (sealed and placed in a dark place at 25° C.), high-temperature condition (sealed and placed in a dark place at 60° C.) and accelerated condition (opened and placed in a dark place at 40° C.-75% relative humidity) to study crystal form stability.

(116) TABLE-US-00010 TABLE 6 Results of stability test of crystal form of sulfate of the compound represented by formula A and crystal form of maleate of the compound represented by formula A according to the present application Sulfate of the Maleate of the compound represented compound represented Stability by formula A by formula A condition Crystal form Melting point Crystal form Melting point Conventional No obvious No obvious No obvious No obvious change change change change High- No obvious No obvious No obvious No obvious temperature change change change change Accelerated No obvious No obvious No obvious No obvious change change change change

(117) It can be seen from Table 6 that, the crystal form of the sulfate of the compound represented by formula A and the crystal form of the maleate of the compound represented by formula A according to the present application have good stability, which is beneficial to adapt to various environmental conditions during manufacture, storage and transportation.

Comparative Example 6: Comparison of Stability of Crystal Forms of Salts of the Compound Represented by Formula A

(118) The crystal form of the sodium salt of the compound represented by formula A, the crystal form of the sulfate of the compound represented by formula A and the crystal form of the maleate of the compound represented by formula A were respectively taken to form suspensions in solvents as shown in Table 7, and the suspensions were stirred for 3 days at room temperature. Crystal form stability was studied, and results obtained were compared with the results in Comparative Example 1 in patent document CN105315266A.

(119) TABLE-US-00011 TABLE 7 Results of crystal form stability test of salt forms of the compound represented by formula A according to the present application and free state of the compound represented by formula A in solvents Free state of the compound represented by formula A Crystal form I, crystal form IV, crystal form XII, crystal form II crystal form III, crystal form V , crystal form VI, crystal form VII, Crystal Crystal Crystal crystal form form of form of form of VIII, crystal sodium salt sulfate of maleate of form IX, crystal Crystal Crystal of the the the form X, crystal form form XII compound compound compound form XI and XII and and represented represented represented amorphous crystal crystal by by by Solvent form form IV form I formula A formula A formula A Isopropanol Crystal form IV — — No change No change No change Water Crystal form I Crystal — No change No change No change form XII Water:ethanol = Crystal form I — — No change No change No change 1:1 Water:ethanol = Crystal form I — — No change No change No change 1:5 Water:ethanol = Crystal form I — — No change No change No change 1:10 Water:ethanol = Crystal form I — — No change No change No change 1:100 Ethanol Crystal form IV — Crystal No change No change No change form IV Water:acetone = Crystal form I — — No change No change No change 1:1 Water:acetone = Crystal form I — — No change No change No change 1:5 Water:acetone = Crystal form I — — No change No change No change 1:10 Water:acetone = Crystal form I — — No change No change No change 1:100 Acetone Crystal form IV Crystal — No change No change No change form IV

(120) It can be seen from Table 7 that, the free state of the compound represented by formula A is present in various final crystal forms in different solvents, which indicates that the free state of the compound represented by formula A is prone to problems that mixed crystals are formed and crystal form is difficult to control during drug preparation. In contrast, the crystal form of each salt form of the compound represented by formula A according to the present application is relatively single, the selection of solvents to be used in production is more flexible, and the crystal form is more stable.

(121) All patent documents and non-patent publications cited in the description are incorporated herein by reference in their entireties.

(122) What are described above are only particular embodiments of the present application, and the scope of protection of the present application is not limited thereto. Any change or replacement that can be conceived by those skilled in the art within the technical scope disclosed by the present application without any inventive labor shall be covered within the scope of protection of the present application.