A crystalline form of a pyrazolo[3,4-c]pyridine compound and its preparation method and use

Abstract

The present invention provides a crystalline form A of a compound (I), a preparation method and use thereof. The obtained crystalline form A has the characteristics of high purity, no organic solvent residue, good stability during mechanical processing, heating and influencing factor experiments, and the preparation process is simple to operate and is suitable for industrial use.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry, and specifically relates to a crystal form of a pyrazolo[3,4-c]pyridine compound, a preparation method and use thereof. Background Art

[0002] Thrombosis is caused by thrombosis and embolism. Under certain pathological conditions, blood components form thrombi in blood vessels. Thrombi fall off from the site of formation and partially or completely block veins or blood supply arteries during blood flow, causing a series of pathological processes such as vascular or systemic ischemia, hypoxia and necrosis. Common thrombotic diseases include myocardial infarction, cerebral thrombosis, deep vein thrombosis, pulmonary embolism and peripheral arterial thromboembolism, which seriously endanger people's lives and quality of life. Coronary heart disease is an important type of thrombotic disease, including myocardial infarction and angina pectoris.

[0003] Coagulation factor X is a relatively good target for antithrombotic therapy, among which factor Xa is the most important drug target in the coagulation cascade. Factor Xa inhibitors can bind tightly to the active site of factor Xa, resulting in the inactivation of free and fibrin-bound factor Xa, thus playing an anticoagulant role. Compared with low molecular weight heparin, factor Xa inhibitors can significantly reduce the occurrence of venous thrombosis without increasing the incidence of bleeding. Compared with warfarin, this type of drug not only has the convenience of not requiring dosage adjustment and routine monitoring, but also has almost no interaction with food and drugs, and can be taken at the same time.

[0004] Although the bleeding tendency of factor Xa inhibitors is lower than that of traditional anticoagulants, bleeding is still the main adverse reaction in clinical practice. Therefore, reducing the risk of bleeding and improving the therapeutic window are research hotspots in this field.

[0005] Compound I is a factor Xa inhibitor with the chemical name 1-(4-ethoxyphenyl)-7-oxo-6-[3-methyl-4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide, which has good antithrombotic effect and lower bleeding risk.

[0006]

[0007] Chinese patent CN105384739A discloses compounds of formula I and their analogs, preparation methods and uses. Since the drug crystal form is directly related to the quality and efficacy of the drug, different crystal forms will affect the drug stability, bioavailability and safety during production, processing and storage to varying degrees. Therefore, discovering a crystal form with excellent properties is critical to subsequent drug research and development. Summary of the invention

[0008] After research, it was found that the purity of the compound I sample prepared by the method in Chinese patent CN105384739A could not meet the pharmaceutical standard, the residual organic solvent exceeded the limit requirement and could not be removed by washing and drying, and the sample crystal form changed during the grinding process. In addition, under high temperature and light conditions, the total impurity content increased. Therefore, it could not meet the processing and safety requirements of pharmaceutical preparations.

[0009] In order to solve these problems in the prior art, the inventors conducted a large number of experimental studies on the crystal form of Compound I, and finally obtained a crystal form A of Compound I with high purity, no organic solvent residue and good stability, which is suitable for storage and use as a raw material medicine, overcoming the defects of the prior art.

[0010] The present invention provides a crystalline form A of compound I, characterized in that, using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angles (°) has characteristic diffraction peaks at the following positions: 5.0±0.2°, 7.4±0.2°, 8.7±0.2°, 10.3±0.2°, and 17.5±0.2°.

[0011] In some embodiments of the present invention, the relative intensity of the above characteristic peak (±0.2°) is:

[0012] .

[0013] Note: Relative intensity is calculated based on peak area, the same below.

[0014] Preferably, the relative intensity of the above characteristic peak (±0.2°) is:

[0015] .

[0016] In some embodiments of the present invention, the crystalline form A is characterized in that, using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angles (°) has characteristic diffraction peaks at the following positions: 5.0±0.2°, 7.4±0.2°, 8.7±0.2°, 10.3±0.2°, 11.3±0.2°, 12.8±0.2°, and 17.5±0.2°.

[0017] Preferably, the relative intensity of the above characteristic peak (±0.2°) is:

[0018] .

[0019] Preferably, the relative intensity of the above characteristic peak (±0.2°) is:

[0020] .

[0021] In some embodiments of the present invention, the crystalline form A is characterized in that, using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angles (°) has characteristic diffraction peaks at the following positions: 5.0±0.2°, 7.4±0.2°, 8.7±0.2°, 10.3±0.2°, 11.3±0.2°, 12.8±0.2°, 17.5±0.2°, and 22.3±0.2°.

[0022] Preferably, the relative intensity of the above characteristic peak (±0.2°) is:

[0023] .

[0024] Preferably, the relative intensity of the above characteristic peak (±0.2°) is:

[0025] .

[0026] In some embodiments of the present invention, the crystalline form A is characterized in that, using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angles (°) has characteristic diffraction peaks at the following positions: 5.0±0.2°, 7.4±0.2°, 8.7±0.2°, 10.3±0.2°, 11.3±0.2°, 12.8±0.2°, 15.7±0.2°, 17.5±0.2°, and 22.3±0.2°.

[0027] Preferably, the relative intensity of the above characteristic peak (±0.2°) is:

[0028] .

[0029] Preferably, the relative intensity of the above characteristic peak (±0.2°) is:

[0030] .

[0031] In some embodiments of the present invention, the crystalline form A is characterized in that, using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angles (°) has characteristic diffraction peaks at the following positions: 5.0±0.2°, 7.4±0.2°, 8.7±0.2°, 10.3±0.2°, 11.3±0.2°, 12.8±0.2°, 15.7±0.2°, 17.5±0.2°, 20.6±0.2°, and 22.3±0.2°.

[0032] Preferably, the relative intensity of the above characteristic peak (±0.2°) is:

[0033] .

[0034] Preferably, the relative intensity of the above characteristic peak (±0.2°) is:

[0035] .

[0036] In some embodiments of the present invention, the crystalline form A is characterized in that, using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angles (°) has characteristic diffraction peaks at the following positions: 5.0±0.2°, 7.4±0.2°, 8.7±0.2°, 10.3±0.2°, 11.3±0.2°, 12.8±0.2°, 14.7±0.2°, 15.7±0.2°, 17.5±0.2°, and 22.3±0.2°.

[0037] Preferably, the relative intensity of the above characteristic peak (±0.2°) is:

[0038] .

[0039] Preferably, the relative intensity of the above characteristic peak (±0.2°) is:

[0040] .

[0041] In some embodiments of the present invention, the crystalline form A is characterized in that, using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angles (°) has characteristic diffraction peaks at the following positions: 5.0±0.2°, 7.4±0.2°, 8.7±0.2°, 10.3±0.2°, 11.3±0.2°, 12.8±0.2°, 14.7±0.2°, 15.7±0.2°, 17.5±0.2°, 20.6±0.2°, 22.3±0.2°, and 25.3±0.2°.

[0042] Preferably, the relative intensity of the above characteristic peak (±0.2°) is:

[0043] .

[0044] Preferably, the relative intensity of the above characteristic peak (±0.2°) is:

[0045] .

[0046] In some embodiments of the present invention, the crystalline form A is characterized in that, using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angles (°) has characteristic diffraction peaks at the following positions: 5.0±0.2°, 7.4±0.2°, 8.7±0.2°, 10.3±0.2°, 11.3±0.2°, 12.8±0.2°, 14.1±0.2°, 14.7±0.2°, 15.7±0.2°, 17.5±0.2°, 20.6±0.2°, 22.3±0.2°, 25.3±0.2°, and 28.4±0.2°.

[0047] Preferably, the relative intensity of the above characteristic peak (±0.2°) is:

[0048] .

[0049] Preferably, the relative intensity of the above characteristic peak (±0.2°) is:

[0050] .

[0051] In some embodiments of the present invention, the crystal form A, using Cu-Kα radiation, has a powder X-ray diffraction pattern substantially as follows: Figure 2 or Figure 8 shown.

[0052] In some embodiments of the present invention, the XRPD spectrum analysis data of the crystal form A is shown in the following table:

[0053] .

[0054] In some embodiments of the present invention, the differential scanning calorimetry curve of the crystalline form A has an endothermic peak starting point at 242.10±3°C.

[0055] In some embodiments of the present invention, the differential scanning calorimetry curve of the crystalline form A has an endothermic peak at 244.28±5°C.

[0056] In some embodiments of the present invention, the crystalline form A has substantially Figure 3 DSC graph shown.

[0057] On the other hand, the present invention also provides a method for preparing the above-mentioned crystal form A, which comprises: adding the crude product of compound I to solvent 1, heating until it is completely dissolved, cooling to the target temperature, adding solvent 2, continuing crystallization, and separating to obtain crystal form A.

[0058] In some embodiments of the present invention, the method comprises: adding compound I to solvent 1, heating until completely dissolved, cooling to the target temperature, continuing crystallization, and separating to obtain form A.

[0059] In some embodiments of the present invention, the above-mentioned preparation method, wherein the solvent 1 is selected from ROH, RCN, RCOR1, RCOOR1, DMSO, DMF, dichloromethane or a heterocyclic organic solvent (for example, furan, tetrahydrofuran, pyridine, 1,4-dioxane, etc.), and the solvent 2 is selected from water, n-hexane, n-heptane, petroleum ether, cyclohexane or methyl tert-butyl ether, wherein R and R1 are selected from C1-C4 straight chain or branched alkyl; preferably, solvent 1 is ROH, solvent 2 is water, wherein R is selected from C1-C4 straight chain or branched alkyl; further preferably, solvent 1 is methanol.

[0060] Preferably, in the above preparation method, the solvent 1 is ROH or DMF, and the solvent 2 is selected from water; further preferably, the solvent 1 is methanol, ethanol or DMF; further preferably, the solvent 1 is methanol.

[0061] In some embodiments of the present invention, in the above-mentioned preparation method, the volume ratio of the solvent 1 to the solvent 2 is 1~10:1~100, preferably 1~10:1~50, further preferably 1~10:1~20, further preferably 1~5:1~10, further preferably 1~5:1~5.

[0062] In some embodiments of the present invention, in the above-mentioned preparation method, the mass volume ratio of the crude compound I to the solvent 1 is 1g:10~50mL; preferably 1g:10~30mL; further preferably 1g:15~25mL.

[0063] In some embodiments of the present invention, the above-mentioned preparation method, wherein the mass volume ratio of the compound I to the solvent 1 is 1g:1~50mL; preferably 1g:2~30mL; more preferably 1g:3~25mL; more preferably 1g:3~20mL.

[0064] In some embodiments of the present invention, in the above-mentioned preparation method, the heating temperature is 30°C to reflux temperature; or, the heating temperature is 30 to 120°C; or, the heating temperature is 30 to 100°C.

[0065] In some embodiments of the present invention, in the above-mentioned preparation method, the continued crystallization time is 0.5h~5h; preferably 1h~3h; more preferably 1h~2h.

[0066] In some embodiments of the present invention, the above-mentioned preparation method, wherein the cooling target temperature is -30°C~30°C; preferably, the target temperature is 0°C~25°C; further preferably, the target temperature is 0°C~15°C; further preferably, the target temperature is 5°C~15°C.

[0067] In some embodiments of the present invention, in the above-mentioned preparation method, the separation step includes separating the obtained crystal form A from the crystallization solution by using a suitable method such as filtration and centrifugation.

[0068] In some embodiments of the present invention, the above preparation method, in consideration of removing the free solvent in the product, further comprises a drying step after the separation step. The drying method may be any suitable known method, preferably reduced pressure (vacuum) drying. Specific drying conditions are, for example, preferably a temperature of 30 to 70°C, more preferably 40 to 65°C, more preferably 55 to 65°C; preferably a drying time of 4 to 20 hours, more preferably 8 to 16 hours. Regardless of the drying method used, it is preferred that the residual solvent content in the obtained product meets the quality standards.

[0069] The crude compound I or compound I described in the present invention is prepared by the known method disclosed in CN105384739A, and can also be prepared by any known method disclosed in other prior arts.

[0070] Another aspect of the present invention provides a pharmaceutical composition comprising the above-mentioned Form A or the Form A prepared by the above-mentioned preparation method, and optionally, the pharmaceutical composition further comprises other therapeutic components. The other therapeutic components refer to other active ingredients or drugs for preventing and / or treating diseases that inhibit the positive effects of Factor Xa. Preferably, the other therapeutic components can produce a synergistic effect with Compound I.

[0071] Another aspect of the present invention provides a pharmaceutical composition comprising the above-mentioned Form A or the Form A prepared by the above-mentioned preparation method and a pharmaceutically acceptable carrier, and optionally, the pharmaceutical composition further comprises other therapeutic components. The other therapeutic components refer to other active ingredients or drugs for preventing and / or treating diseases that inhibit the positive effects of Factor Xa. Preferably, the other therapeutic components can produce a synergistic effect with Compound I.

[0072] The above-mentioned pharmaceutical composition is prepared into clinically accepted preparations, such as oral preparations, injection preparations, local administration preparations, external preparations, etc., preferably oral preparations. The oral preparations are preferably solid preparations, such as tablets, capsules, granules, etc. These preparations can be prepared using corresponding excipients known to those skilled in the art and using corresponding known pharmaceutical preparation preparation techniques.

[0073] On the other hand, the present invention provides use of the above-mentioned crystal form A, or the crystal form A prepared by the above-mentioned preparation method, or a pharmaceutical composition comprising the crystal form A in the preparation of a factor Xa inhibitor drug.

[0074] On the other hand, the present invention provides the use of the above-mentioned crystal form A, or the crystal form A prepared according to the above-mentioned preparation method, or a pharmaceutical composition containing the crystal form A in the preparation of anticoagulant, preventive or therapeutic thrombosis or embolism drugs.

[0075] On the other hand, the present invention provides use of the above-mentioned crystalline form A, or crystalline form A prepared according to the above-mentioned preparation method, or a pharmaceutical composition containing crystalline form A in the preparation of a drug for treating thromboembolism or disseminated intravascular coagulation.

[0076] On the other hand, the present invention provides the use of the above-mentioned crystal form A, or the crystal form A prepared according to the above-mentioned preparation method, or a pharmaceutical composition containing the crystal form A in the preparation of a drug for treating myocardial infarction, angina pectoris, re-blockage and restenosis after angioplasty or aortocoronary bypass surgery, stroke, transient local attack, peripheral arterial occlusive disease, pulmonary embolism, deep vein thrombosis, and venous thromboembolism in adult patients undergoing elective hip or knee replacement.

[0077] On the other hand, the present invention also provides the use of the above-mentioned crystal form A, or the crystal form A prepared according to the above-mentioned preparation method, or a pharmaceutical composition containing crystal form A in the preparation of related drugs for preventing and / or treating diseases that inhibit the positive effects of factor Xa.

[0078] On the other hand, the present invention also relates to the above-mentioned crystal form A, or the crystal form A prepared by the above-mentioned preparation method, or a pharmaceutical composition comprising the crystal form A, which is used for preventing and / or treating diseases that inhibit the positive effects of factor Xa.

[0079] On the other hand, the present invention also relates to a method for treating a patient, wherein the patient's disease is a disease positively affected by inhibition of factor Xa, by administering the above-mentioned crystalline form A, or the crystalline form A prepared according to the above-mentioned preparation method, or a pharmaceutical composition comprising crystalline form A to the patient.

[0080] In some embodiments of the present invention, the diseases described in the above aspects are selected from thromboembolism or disseminated intravascular coagulation.

[0081] In some embodiments of the present invention, the diseases described in the above aspects are selected from myocardial infarction, angina pectoris, re-occlusion and restenosis after angioplasty or aortocoronary bypass surgery, stroke, transient local attack, peripheral arterial occlusive disease, pulmonary embolism, deep vein thrombosis, and venous thromboembolism in adult patients undergoing elective hip or knee replacement.

[0082] The above-mentioned "patient" includes all members of the animal kingdom, including, but not limited to, mammals (eg, mice, rats, cats, monkeys, dogs, etc.) and humans.

[0083] Definition and Description

[0084] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular phrase or term should not be considered to be uncertain or unclear in the absence of a special definition, but should be understood according to its ordinary meaning. When a trade name appears in this article, it is intended to refer to its corresponding trade name and its active ingredient.

[0085] Unless otherwise specified, the "2θ, 2θ angle or 2θ angle" mentioned in the present invention refers to the diffraction angle, with the unit of ° or degree, and the error range of 2θ can be ±0.5, ±0.4, ±0.3, ±0.2 or ±0.1°.

[0086] Unless otherwise specified, the "heating temperature, cooling temperature or crystallization temperature" mentioned in the present invention is in degrees Celsius, and the error range may be ±10, ±5, ±4, ±3, ±2 or ±1°C.

[0087] The term "substantially as shown in the accompanying drawings" means that at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99% of the peaks in the powder X-ray diffraction pattern or DSC pattern or crystal shape diagram of a substantially pure crystalline form appear in the given pattern. Further, when the content of a crystalline form in the product gradually decreases, some diffraction peaks attributable to the crystalline form in its powder X-ray diffraction pattern may become less due to the detection sensitivity of the instrument.

[0088] The intermediate compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the embodiments of the present invention.

[0089] The chemical reactions of the specific embodiments of the present invention are carried out in a suitable solvent, which must be suitable for the chemical changes of the present invention and the reagents and materials required. In order to obtain the compounds of the present invention, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction processes based on the existing embodiments.

[0090] The present invention will be specifically described below by way of examples, which can be used without further purification.

[0091] The solvent used in the present invention is commercially available.

[0092] Technical Effects

[0093] The beneficial effects of the crystal form A of the present invention are:

[0094] (1) The crystal form A of the present invention has high purity and no organic solvent residue.

[0095] (2) The crystal form A of the present invention has excellent stability. On the one hand, the crystal form A has good physical stability, especially thermal stability. For example, the crystal form A has a high melting point and does not undergo crystal form transformation after grinding and pulverization, which has better stability in subsequent transportation or formulation processing operations. On the other hand, the crystal form A has good chemical stability. When the crystal form A obtained by the present invention is placed under high temperature, high humidity and strong light conditions, the maximum single impurity, total impurity and content of the sample under investigation do not change significantly, and the crystal form does not change, which is more suitable for storage and use as a raw material drug. BRIEF DESCRIPTION OF THE DRAWINGS

[0096] Figure 1 : Powder X-ray diffraction pattern of Form B obtained in Preparation Example 1.

[0097] Figure 2 : Powder X-ray diffraction pattern of Form A obtained in Example 1.

[0098] Figure 3 : Differential scanning calorimetry curve of Form A obtained in Example 1.

[0099] Figure 4 : Powder X-ray diffraction pattern of Form C obtained in Example 2.

[0100] Figure 5 : Differential scanning calorimetry curve of Form C obtained in Example 2.

[0101] Figure 6 : Powder X-ray diffraction pattern of Form B obtained in Preparation Example 1 after grinding.

[0102] Figure 7 : Powder X-ray diffraction pattern of the grinding crystal form A obtained in Example 1.

[0103] Figure 8 : Powder X-ray diffraction pattern of Form A obtained in Example 3. DETAILED DESCRIPTION

[0104] 、X-ray powder diffractometer (XRPD)

[0105] Instrument model: Bruker D8 Advance X-ray diffractometer

[0106] Sample dosage: 100 mg

[0107] Target: Cu (40KV, 150mA)

[0108] Step angle: 0.02°

[0109] Scanning range: 0.0~40.0°

[0110] Scanning speed: 0.02° / 0.30s.

[0111] , Differential Scanning Calorimeter (DSC)

[0112] Instrument model: PerkinElmer Diamond Differential Scanning Calorimeter

[0113] Test method: Take a sample (about 2 mg) and place it in a DSC aluminum pan for testing. Under 20mL / min N2 conditions, heat the sample from 50℃ to 300℃ at a heating rate of 20℃ / min.

[0114] , Infrared Spectroscopy (IR)

[0115] Detection instrument: Perkin Elmer infrared spectrometer

[0116] Test method: Take a sample (about 1 mg), dilute it with KBr and press it into a tablet. Monitor it at room temperature. The specific parameters are: Detection range: 4000-400 cm -1 Wave number, resolution: 4 cm -1 .

[0117] , hygroscopicity

[0118] The method in the Chinese Pharmacopoeia was used for determination. The specific test method is as follows:

[0119] 1) Take a dry stoppered glass weighing bottle (outer diameter 50mm, height 15mm), place it in a suitable 25℃±1℃ constant temperature drying oven (with ammonium chloride or ammonium sulfate saturated solution placed at the bottom) or artificial climate box (set temperature 25℃±1℃, relative humidity 80%±2%) one day before the test, and accurately weigh the weight (m1);

[0120] 2) Take an appropriate amount of the test sample and spread it flat in the above-mentioned weighing bottle. The thickness of the test sample is generally about 1mm. Accurately weigh the weight (m2);

[0121] 3) Open the weighing bottle and place it under the above constant temperature and humidity conditions with the bottle cap on for 24 hours;

[0122] 4) Cover the weighing bottle and accurately weigh the weight (m3);

[0123] Weight gain percentage = (m3-m2) / (m2-m1) × 100%;

[0124] 5) Description of hygroscopic characteristics and definition of hygroscopic weight gain:

[0125]

[0126] The preferred embodiments of the present invention will be described in detail below with reference to the accompanying drawings. The examples are provided to better illustrate the contents of the present invention, but the contents of the present invention are not limited to the examples. Those skilled in the art may make non-essential improvements and adjustments to the implementation scheme based on the above-mentioned invention contents, which still fall within the protection scope of the present invention.

[0127] Preparation Example 1 Preparation of Compound I

[0128] Compound I was prepared by referring to the method disclosed in CN105384739A, and dried in a vacuum oven at 45°C for 12 h to obtain an off-white solid. A sample was taken for powder X-ray diffraction, which showed Form B. The results are shown in Table 1, and the spectrum is shown in the attached Figure 1 .

[0129] Table 1 Powder-X-ray diffraction peak data of Form B obtained in Preparation Example 1

[0130]

[0131] Example 1 Preparation of Form A of Compound I

[0132] Add 5.6 g of the sample of Preparation Example 1 to the reaction bottle, add methanol (about 100 mL), stir and heat under reflux until the solution is clear, cool to 5°C ± 5°C, add purified water (about 80 mL) after a lot of solid precipitates, continue stirring for 2 hours after addition, filter, wash the filter cake with purified water (about 10 mL) and methanol (about 6 mL), dry it in a vacuum drying oven at 55-65°C for 11 hours, and obtain 4.38 g of off-white solid, with a yield of 87.19% and a HPLC purity of 99.43%. IR (KBr, cm -1 ): 3081.8, 3060.1, 3026.3, 3002.4, 2923.6, 2850.1, 1678.55, 1505.09, 1330.28, 1300.05, 1247.59. The sample was taken for powder X-ray diffraction, showing that it was form A. The results are shown in Table 1 and the spectrum is attached. Figure 2 The sample was taken for TGA test, which showed that it was anhydrous crystalline.

[0133] Table 2 Powder-X-ray diffraction peak data of Form A obtained in Example 1

[0134]

[0135] Example 2 Preparation of Form C of Compound I

[0136] 5.6 g of the sample of Preparation Example 1 was added to the reaction bottle, and N-methylpyrrolidone (about 45 mL) was added. The mixture was stirred until dissolved. Purified water (about 50 mL) was slowly added dropwise. After a stable solid was precipitated, the addition of purified water was stopped. After 0.5 to 1 h, purified water (about 140 mL) was slowly added. The mixture was stirred for crystallization for 2 h, filtered, and the filter cake was washed with purified water (about 50 mL). The mixture was dried in a vacuum drying oven at 45 ° C for 12 h to obtain 5.03 g of off-white solid with a yield of 95.4% and a HPLC purity of 99.26%. The sample was taken for powder X-ray diffraction, which showed Form C. The results are shown in Table 3 and the spectrum is shown in the attached figure. Figure 4 .

[0137] Table 3 Powder-X-ray characteristic peak data of Form C obtained in Example 2

[0138]

[0139] Example 3 Preparation of Form A of Compound I

[0140] The sample of Preparation Example 1 (0.5 g) was added to the reaction bottle, and ethanol (about 12 mL) was added. The mixture was stirred and heated under reflux until the solution was clear. The temperature was lowered to 5-15°C. After a large amount of solid precipitated, purified water (10 mL) was slowly added. After the addition, the mixture was stirred for 2 h. The mixture was filtered and the filter cake was washed with purified water (about 3 mL) and ethanol (about 3 mL) successively. The mixture was dried in a vacuum drying oven at 50-65°C to obtain a white solid (0.43 g) with a yield of 86%. The sample was subjected to powder X-ray diffraction, which showed that it was Form A. The results are shown in Table 4 and the spectrum is shown in the attached figure. Figure 8 .

[0141] Table 4 Powder-X-ray diffraction peak data of Form A obtained in Example 3

[0142]

[0143] Note: The table only lists the diffraction peaks with relative peak intensity > 4%.

[0144] Example 4 Preparation of Form A of Compound I

[0145] The sample of Preparation Example 1 (0.5 g) was added to a reaction flask, and methanol (about 9 mL) was added. The mixture was stirred and heated under reflux until the solution became clear. The temperature was maintained and stirred for 30 min, then the temperature was slowly lowered to 0-15°C, and stirring was continued for 2 h. The mixture was filtered, and the filter cake was washed with methanol (about 3 mL). The mixture was dried in a vacuum drying oven at 50-65°C to obtain a white solid (0.38 g) with a yield of 76%. The sample was taken for powder X-ray diffraction, which showed Form A.

[0146] Example 5 Preparation of Form A of Compound I

[0147] The sample of Preparation Example 1 (1 g) was added to a reaction bottle, and N,N-dimethylformamide (DMF) (about 4 mL) was added. The mixture was heated to 60-80°C with stirring, and purified water (about 16 mL in total for about 2 h in total) was slowly added dropwise to the solution while maintaining the temperature. The mixture was stirred for 1 h while maintaining the temperature. The mixture was cooled to 5-15°C and stirred for 1 h. The mixture was filtered and the filter cake was washed with purified water (about 3 mL). The mixture was dried in a vacuum drying oven at 50-65°C to obtain a white solid (0.67 g) with a yield of 67%. The sample was subjected to powder X-ray diffraction, which showed that the solid was Form A.

[0148] Experimental Example 1 DSC Test

[0149] The crystal samples obtained in Example 1 and Example 2 were subjected to DSC test, and the test results are shown in the following table:

[0150] Table 5 DSC results of different samples

[0151]

[0152] Conclusion: During the DSC test of Form C obtained in Example 2, Form C melted first, and then a crystal transformation occurred after complete melting, that is, it transformed into Form A, and then showed the melting point of Form A. No endothermic peak was found when heating was continued, indicating that Form A can remain stable when heated and is more suitable for storage and use as a raw material.

[0153] Experimental Example 2 Grinding Experiment

[0154] An appropriate amount (about 300 mg) of the samples obtained in Preparation Example 1 and Example 1 were placed in a mortar and ground for about 20-30 minutes, and the samples were collected for XRPD detection. The test results are shown in the following table:

[0155] Table 6 Grinding test results of different samples

[0156]

[0157] Table 7 Powder-X-ray diffraction peak data of the sample after grinding in Preparation Example 1

[0158]

[0159] Table 8 Powder-X-ray diffraction peak data of the sample after grinding in Example 1

[0160]

[0161] Experimental Example 3 Detection of residual amount of organic solvent

[0162] Since the preparation of the samples obtained in Preparation Example 1 and Examples 1 to 5 all involve organic solvents, in order to ensure the safety of medication, the residual amount of organic solvents was tested on five samples, and the test results are shown in the following table:

[0163] Table 9 Detection results of residual organic solvents in different samples

[0164]

[0165] Note: ① Ethylene glycol, methanol, N-methylpyrrolidone and DMF are all Class II solvents (use should be restricted), and their limits should not exceed 0.062%, 0.300%, 0.053% and 0.088% respectively; ethanol belongs to Class III solvents, and its limit should not exceed 0.5% (refer to the Technical Guidelines for the Study of Residual Solvents in Chemical Drugs, 2005 edition); ② The sample in Preparation Example 1 was tested using nuclear magnetic resonance hydrogen spectrum, and an obvious ethylene glycol solvent peak was found, with a content of about 0.695%.

[0166] Conclusion: According to the above results, the residual solvent content of the crystal form B and crystal form C samples obtained in Preparation Example 1 and Example 2 exceeded the prescribed limit and did not meet the drug quality requirements, and the residual solvent was still not completely removed after washing with an organic solvent in the crystal form C sample of Example 2. Among them, the crystal form A samples obtained in Example 1 and Examples 3-5 did not contain organic solvents and were suitable for use and development as APIs.

[0167] Experimental Example 4 Influencing Factors Test

[0168] Take appropriate amounts of the Form B sample of Preparation Example 1 and the Form A sample of Example 1, respectively place them in medicinal low-density polyethylene bags, and place them under high temperature (60°C ± 2°C), high humidity (92.5%RH), and strong light (4500Lx) conditions for 10 days, and compare them with the 0-day data. The experimental results are shown in Table 10.

[0169] Table 10 Experimental results of influencing factors of samples obtained in Example 1 and Preparation Example 1

[0170]

[0171] Conclusion: The crystal form A of Example 1 is relatively stable under high temperature, high humidity and strong light, and the content has not changed significantly. The maximum single impurity and total impurities have no obvious change trend. After testing, the crystal form has not changed, that is, the quality of crystal form A is stable and it is suitable for storage as a raw material drug. Although the crystal form B of the preparation example did not undergo crystal form transformation in the influencing factor experiment, the contents of the maximum single impurity and total impurities exceeded the general standards, and after being placed under high temperature and light conditions for 5 days, the total impurity content increased, which did not meet the requirements of the raw material drug.

[0172] Experimental Example 5: Moisture absorption test

[0173] An appropriate amount of the sample of Form A of Example 1 was taken to conduct a hygroscopicity test. The results are shown in Table 11.

[0174] Table 11 Hygroscopicity results of Form A samples of Example 1

[0175]

[0176] Conclusion: The crystal form A of Example 1 is slightly hygroscopic, which meets the requirements of the raw material drug, and no crystal form transformation occurs after the test. It can be seen that the crystal form A is stable in a humid environment.

Claims

1. Form A of Compound I, ， It is characterized in that Using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angle (°) has characteristic peaks at the following positions: 5.0±0.2°, 7.4±0.2°, 8.7±0.2°, 10.3±0.2°, and 17.5±0.2°.

2. The crystalline form A according to claim 1, characterized in that Using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angle (°) has characteristic peaks at the following positions: 5.0±0.2°, 7.4±0.2°, 8.7±0.2°, 10.3±0.2°, 11.3±0.2°, 12.8±0.2°, and 17.5±0.2°.

3. The crystalline form A according to claim 1, characterized in that Using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angle (°) has characteristic peaks at the following positions: 5.0±0.2°, 7.4±0.2°, 8.7±0.2°, 10.3±0.2°, 11.3±0.2°, 12.8±0.2°, 17.5±0.2°, and 22.3±0.2°.

4. The crystalline form A according to claim 1, characterized in that Using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angle (°) has characteristic peaks at the following positions: 5.0±0.2°, 7.4±0.2°, 8.7±0.2°, 10.3±0.2°, 11.3±0.2°, 12.8±0.2°, 15.7±0.2°, 17.5±0.2°, and 22.3±0.2°.

5. The crystalline form A according to claim 1, characterized in that Using Cu—Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angle (°) is substantially as shown in FIG. 2 or FIG. 8 .

6. The crystalline form A according to any one of claims 1 to 5, characterized in that Its differential scanning calorimetry curve has an endothermic peak at 244.28±5℃.

7. The crystalline form A according to any one of claims 1 to 5, characterized in that It has a DSC graph substantially as shown in FIG3 .

8. The method for preparing the crystalline form A according to any one of claims 1 to 7, comprising: The crude product of Compound I is added to Solvent 1, heated until completely dissolved, cooled to the target temperature, Solvent 2 is added, and crystallization is continued to separate to obtain Form A; Alternatively, the method comprises: adding compound I to solvent 1, heating until completely dissolved, cooling to a target temperature, continuing crystallization, and separating to obtain crystal form A; Wherein, the solvent 1 is selected from methanol, ethanol and N,N-dimethylformamide, and the solvent 2 is selected from water.

9. The method for preparing Form A according to claim 8, wherein the heating temperature is 30-120°C.

10. The method for preparing Form A according to claim 8, wherein the heating temperature is 30-100°C.

11. The method for preparing Form A according to claim 8, wherein the cooling target temperature is -30°C to 30°C.

12. The method for preparing Form A according to claim 8, wherein the cooling target temperature is 0°C to 25°C.

13. The method for preparing Form A according to claim 8, wherein the cooling target temperature is 0°C to 15°C.

14. A pharmaceutical composition comprising the crystalline form A as described in any one of claims 1 to 7, or the crystalline form A prepared by the preparation method as described in any one of claims 8 to 13; optionally, the pharmaceutical composition further contains other therapeutic components.

15. The pharmaceutical composition according to claim 14, characterized in that The pharmaceutical composition is prepared into clinically accepted preparations, including oral preparations, injection preparations, and external preparations.

16. The pharmaceutical composition according to claim 14, characterized in that The pharmaceutical composition is prepared into a clinically acceptable preparation, which is a preparation for local administration.

17. The pharmaceutical composition according to claim 15, characterized in that The preparation is an oral preparation.

18. The pharmaceutical composition according to claim 17, characterized in that The preparation is a tablet or a capsule.

19. The pharmaceutical composition according to claim 14, characterized in that The other therapeutic components refer to other active ingredients or drugs for preventing and / or treating diseases that inhibit the positive effects of Factor Xa.

20. The pharmaceutical composition according to claim 14 or 19, characterized in that The other therapeutic ingredients can produce a synergistic effect with Compound I.

21. Use of the crystalline form A according to any one of claims 1 to 7, or the crystalline form A prepared by the preparation method according to any one of claims 8 to 13, or the pharmaceutical composition according to any one of claims 14 to 20 in the preparation of related drugs for preventing and / or treating thrombotic diseases.

22. The use according to claim 21, characterized in that The thrombotic disease is selected from cerebral thrombosis, deep vein thrombosis, pulmonary embolism, peripheral arterial thromboembolism and coronary heart disease.

23. The use according to claim 22, characterized in that The coronary heart disease is selected from myocardial infarction and angina pectoris.

24. Use of the crystalline form A according to any one of claims 1 to 7, or the crystalline form A prepared by the preparation method according to any one of claims 8 to 13, or the pharmaceutical composition according to any one of claims 14 to 20 in the preparation of anticoagulant drugs.

25. Use of the crystalline form A according to any one of claims 1 to 7, or the crystalline form A prepared by the preparation method according to any one of claims 8 to 13, or the pharmaceutical composition according to any one of claims 14 to 20 in the preparation of a drug for preventing or treating thrombosis.

26. Use of the crystalline form A according to any one of claims 1 to 7, or the crystalline form A prepared by the preparation method according to any one of claims 8 to 13, or the pharmaceutical composition according to any one of claims 14 to 20 in preparing a drug for preventing or treating embolism.

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