6-((5,6-Diphenyl-1,2,4-triazin-3-yl)(isopropyl)amino)-N-(methylsulfonyl)hexanamide polymorph A, its uses and preparation method

Abstract

The present invention discloses a polymorph A of compound I (6-((5,6-diphenyl-1,2,4-triazin-3-yl)(isopropyl)amino)-N-(methylsulfonyl)hexanamide), its pharmaceutical composition, use and preparation method. The polymorph A of compound I in the present invention has diffraction peaks in its X-ray powder diffraction pattern at least at the following diffraction angles 2θ: 9.50±0.2°, 11.05±0.2°, 15.54±0.2°, 16.23±0.2°, 18.23±0.2° and 22.13±0.2°. The polymorph A of compound I of the present invention has the advantages of low hygroscopicity and good stability, and is of great significance for drug development.

Description

[0001] Cross-reference to Related Applications

[0002] This application claims the priority of Chinese Patent Application No. CN202410169645.1 with a filing date of February 6, 2024, and this application incorporates the entire text of the above-mentioned Chinese patent application by reference. Technical Field

[0003] The present invention belongs to the field of pharmacy, and particularly relates to the crystal forms of the compound 6-((5,6-diphenyl-1,2,4-triazin-3-yl)(isopropyl)amino)-N-(methylsulfonyl)hexanamide, its pharmaceutical compositions, uses, and preparation methods. Background Art

[0004] Pulmonary arterial hypertension (PAH) is a rare and incurable pulmonary vascular disorder that can gradually lead to right heart failure and ultimately death. PAH is characterized by pulmonary microvascular remodeling, resulting in a progressive increase in pulmonary vascular resistance (PVR), which leads to right heart failure, making it a progressive and fatal disease. 75% of PAH patients die within 5 years after diagnosis, and the average survival period after the onset of symptoms is 1.9 years. Therefore, it is also known as the "malignant tumor in the field of cardiopulmonary vessels".

[0005] Currently, global treatment methods for PAH include conventional treatment and targeted treatment. Conventional treatment often only improves symptoms and cannot effectively stop the progression of the disease. In terms of targeted treatment, there are three pathways for PAH targeted drugs, namely the nitric oxide pathway, the endothelin pathway, and the prostacyclin (PGI2) pathway. PGI2 is an important vasodilator of vascular endothelium, which causes relaxation of pulmonary vascular smooth muscle and inhibits the growth of smooth muscle by stimulating the generation of cyclic adenosine monophosphate (cAMP). Deficiency of PGI2 can cause pulmonary arterial hypertension. Therefore, PGI2 drugs are currently the most active method for treating PAH. PGI2 drugs include PGI2 analogs and PGI2 receptor agonists. PGI2 analogs have a natural PGI2 skeleton in their structure, have a fast metabolism rate in vivo, a very short biological half-life, and require high-frequency administration or intravenous infusion, resulting in poor patient compliance. In addition, their target selectivity is poor, and it is difficult to separate the therapeutic effect from other effects, making it easy to produce adverse reactions.

[0006] Compound I, with the chemical name of 6-((5,6-diphenyl-1,2,4-triazin-3-yl)(isopropyl)amino)-N-(methylsulfonyl)hexanamide, and the structural formula shown in Formula I, is a PGI2 receptor agonist with novel structure and good druggability. Compound I has strong target selectivity, and the agonist activity for the prostacyclin IP receptor is more than 1000 times that of the other 7 prostacyclin receptor targets. It mainly exerts its therapeutic effect on pulmonary arterial hypertension by activating the IP receptor, promoting the generation of cAMP in pulmonary artery smooth muscle cells, thereby inhibiting the abnormal contraction of the pulmonary artery, inhibiting the proliferation of pulmonary artery smooth muscle cells, and reducing pulmonary artery pressure. Compared with the marketed drugs of the same kind, it has higher efficacy and safety.

[0007]

[0008] Currently, the crystal forms of Compound I have not been publicly reported. This invention focuses on the crystal form research of Compound I during the drug development process, and provides a drug crystal form with good stability, as well as its pharmaceutical composition, uses, and preparation methods. Summary of the Invention

[0009] Through a large number of exploratory studies, it was found that Compound I exists in different crystalline forms. A large number of studies on the crystal forms of Compound I were conducted to determine and prepare the crystalline forms that meet the pharmaceutical requirements. Based on these studies, this invention provides Crystal Form A of Compound I, which has no hygroscopicity and good storage stability, and is suitable for formulation development. This invention also provides a pharmaceutical composition and uses of Crystal Form A of Compound I, and provides a preparation method for Crystal Form A of Compound I, with mild preparation process conditions and suitable for large-scale production.

[0010] To achieve the objectives of this invention, the following technical solutions are adopted:

[0011] One objective of this invention is to provide Crystal Form A of Compound I, whose X-ray powder diffraction pattern expressed in 2θ angles has diffraction peaks at 9.50±0.2°, 11.05±0.2°, 15.54±0.2°, 16.23±0.2°, 18.23±0.2°, and 22.13±0.2°.

[0012] In some embodiments, Crystal Form A of Compound I, whose X-ray powder diffraction pattern expressed in 2θ angles has characteristic peaks at 6.38±0.2°, 9.50±0.2°, 11.05±0.2°, 13.11±0.2°, 15.54±0.2°, 16.23±0.2°, 18.23±0.2°, 18.96±0.2°, 19.42±0.2°, 20.52±0.2°, 21.43±0.2°, 22.13±0.2°, 23.07±0.2°.

[0013] In some embodiments, Form A of Compound I has an X-ray powder diffraction pattern expressed in 2θ angles as Figure 1 shown.

[0014] In some embodiments, when Form A of Compound I is characterized by TGA / DSC, its TGA graph can determine that Form A does not contain crystal water or solvates.

[0015] In some embodiments, when Form A of Compound I is characterized by TGA / DSC, its DSC graph shows that the melting point of Form A is 130°C - 135°C.

[0016] In some embodiments, Form A of Compound I has a TGA / DSC graph as Figure 2 shown.

[0017] The second object of the present invention is to provide a first method for preparing Form A of Compound I, which comprises the following steps: heating and dissolving Compound I in a solvent, cooling to 25°C - 45°C, then slowly cooling for crystallization or holding at a constant temperature for crystallization, continuing to cool to 0°C - 10°C and holding at a constant temperature for crystallization, separating, and drying to obtain Form A.

[0018] In some embodiments, the solvent is one or a mixed solvent of alcohols, ethers, esters, alkanes, ketones, acetonitrile, and water.

[0019] In some embodiments, the solvent is one or a mixed solvent of methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran, methyl tert-butyl ether, ethyl acetate, dichloromethane, n-hexane, acetone, and water.

[0020] In certain preferred embodiments, the solvent is one or a mixed solvent of isopropanol, ethanol, or water.

[0021] In certain preferred embodiments, the solvent is isopropanol.

[0022] In some embodiments, the mass-volume ratio (g / mL) of Compound I to the solvent is 1:4 - 15.

[0023] In some embodiments, the heating and dissolving can be heating and dissolving in a single solvent or a mixed solvent, or heating and dissolving in one solvent first and then adding another one or two or more solvents.

[0024] In some embodiments, the heating condition is heating under reflux.

[0025] In some embodiments, for the cooling to 25°C - 45°C, the cooling method can be various conventional methods, such as cooling in a water bath or a cold water bath, or turning off the heating for cooling, or placing at room temperature for cooling, etc.

[0026] In some embodiments, the temperature is lowered to 25°C to 45°C, and the temperature-lowering time is 0 - 50 min.

[0027] In some embodiments, the temperature is lowered to 25°C to 45°C, and preferably the temperature-lowering temperature is 35 - 45°C.

[0028] In some embodiments, after the temperature is lowered to 25°C to 45°C, slow temperature-lowering crystallization or heat-preserving crystallization is carried out, which can be natural slow temperature-lowering crystallization at room temperature, or heat-preserving crystallization.

[0029] In some embodiments, for the slow temperature-lowering crystallization or heat-preserving crystallization, the crystallization method can be static crystallization or crystallization under stirring, such as paddle stirring, suspension stirring, etc.

[0030] In some embodiments, for the slow temperature-lowering crystallization or heat-preserving crystallization, the crystallization time is 1 - 24 h, preferably 1 - 3 h.

[0031] In some embodiments, the continued temperature-lowering is carried out in an ice bath or an ice-salt bath.

[0032] In some embodiments, during the continued temperature-lowering to 0°C to 10°C for heat-preserving crystallization, the crystallization method can be static crystallization or crystallization under stirring, such as paddle stirring, suspension stirring, etc.

[0033] In some embodiments, during the continued temperature-lowering to 0°C to 10°C for heat-preserving crystallization, the crystallization time is 1 - 24 h, preferably 1 - 2 h.

[0034] In some embodiments, the separation can be a conventional method, such as centrifugation or filtration, etc.

[0035] In some embodiments, the drying is a conventional drying method, such as vacuum drying.

[0036] In some embodiments, the drying needs to be dried to constant weight.

[0037] The third object of the present invention is to provide a second preparation method of crystal form A of compound I, which comprises the following steps: heating and dissolving compound I in a solvent, lowering the temperature to 0°C to 10°C, then carrying out heat-preserving crystallization, separation, and drying to obtain crystal form A.

[0038] In some embodiments, the solvent is one or a mixed solvent of alcohols, ethers, esters, alkanes, ketones, acetonitrile, and water.

[0039] In some embodiments, the solvent is one or a mixed solvent of methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran, methyl tert-butyl ether, ethyl acetate, dichloromethane, n-hexane, acetone, and water.

[0040] In some preferred embodiments, the solvent is one or a mixed solvent of isopropanol, ethanol or water.

[0041] In some preferred embodiments, the solvent is isopropanol.

[0042] In some embodiments, the mass-volume ratio (g / mL) of Compound I to the solvent is 1:3.5 to 15.

[0043] In some embodiments, the heating condition is heating under reflux.

[0044] In some embodiments, the heating and dissolving can be carried out by heating and dissolving in a single solvent or a mixed solvent, or by first heating and dissolving in one solvent and then adding another solvent or two or more solvents.

[0045] In some embodiments, the cooling to 0°C to 10°C is carried out in a cold water bath, an ice bath or an ice-salt bath.

[0046] In some embodiments, the cooling to 0°C to 10°C takes 5 - 15 minutes.

[0047] In some embodiments, in the heat-preserving crystallization, the crystallization method can be static crystallization or crystallization under stirring, such as paddle stirring, suspension stirring, etc.

[0048] In some embodiments, in the heat-preserving crystallization, the crystallization time is 2 - 24 hours, preferably 2 - 5 hours.

[0049] In some embodiments, the separation can be a conventional method, such as centrifugation or filtration.

[0050] In some embodiments, the drying is a conventional drying method, such as vacuum drying.

[0051] In some embodiments, the drying needs to be dried to a constant weight.

[0052] The fourth object of the present invention is to provide a third preparation method of crystalline form A of Compound I, which comprises the following steps: heating and dissolving Compound I in a solvent, cooling to 10°C to 25°C, then carrying out heat-preserving crystallization, continuing to cool to 0°C to 10°C, carrying out heat-preserving crystallization, separating, and drying to obtain crystalline form A.

[0053] In some embodiments, the solvent is one or a mixed solvent of alcohols, ethers, esters, alkanes, ketones, acetonitrile, and water.

[0054] In some embodiments, the solvent is one or a mixed solvent of methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran, methyl tert-butyl ether, ethyl acetate, dichloromethane, n-hexane, acetone, and water.

[0055] In some preferred embodiments, the solvent is one or a mixed solvent of isopropanol, ethanol or water.

[0056] In some preferred embodiments, the solvent is isopropanol.

[0057] In some embodiments, the mass-volume ratio (g / mL) of Compound I to the solvent is 1:4 to 15.

[0058] In some embodiments, the heating condition is heating under reflux.

[0059] In some embodiments, the heating and dissolving can be carried out by heating and dissolving in a single solvent or a mixed solvent, or by first heating and dissolving in one solvent and then adding another solvent or two or more solvents.

[0060] In some embodiments, the cooling to 10°C to 25°C is carried out in a cold water bath or a water bath.

[0061] In some embodiments, the cooling to 10°C to 25°C takes 10 to 40 minutes.

[0062] In some embodiments, after cooling to 10°C to 25°C and holding for crystallization, the crystallization method can be static crystallization or crystallization under stirring, such as paddle stirring, suspension stirring, etc.

[0063] In some embodiments, after cooling to 10°C to 25°C and holding for crystallization, the crystallization time is 0 to 24 hours, preferably 1 to 3 hours.

[0064] In some embodiments, the further cooling to 0°C to 10°C is carried out in an ice bath or an ice-salt bath.

[0065] In some embodiments, during the further cooling to 0°C to 10°C and holding for crystallization, the crystallization method can be static crystallization or crystallization under stirring, such as paddle stirring, suspension stirring, etc.

[0066] In some embodiments, during the further cooling to 0°C to 10°C and holding for crystallization, the crystallization time is 1 to 24 hours, preferably 1 to 2 hours.

[0067] In some embodiments, the separation can be a conventional method, such as centrifugation or filtration.

[0068] In some embodiments, the drying is a conventional drying method, such as vacuum drying.

[0069] In some embodiments, the drying needs to be dried to a constant weight.

[0070] The fifth object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective dose of polymorph A of compound I and a pharmaceutically acceptable excipient.

[0071] Furthermore, the pharmaceutical composition can be formulated into various dosage forms for easy administration. For example, oral preparations (such as tablets, capsules, granules, powders, solutions or suspensions, etc.); injectable preparations (such as injectable solutions or suspensions, or injectable dry powders that can be used immediately after adding a drug solvent before injection).

[0072] The sixth object of the present invention is to provide the use of a therapeutically effective dose of polymorph A of compound I or the pharmaceutical composition as described above in the preparation of a drug for preventing and / or treating a disease or disorder.

[0073] In certain preferred embodiments, the disease or disorder is related to PGI2 receptor agonism.

[0074] In certain preferred embodiments, the disease or disorder is selected from: pulmonary hypertension, cardiovascular and cerebrovascular diseases related to platelet aggregation, and diabetic nephropathy, etc.

[0075] The seventh object of the present invention is to provide the use of a therapeutically effective dose of polymorph A of compound I or the pharmaceutical composition as described above in the preparation of a PGI2 receptor agonist drug.

[0076] Term Definitions and Explanations

[0077] As used herein, the term "room temperature" or "RT" refers to an ambient temperature of 20 to 25 °C (68 - 77 °F).

[0078] Based on common general knowledge in the art, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred examples of the present invention.

[0079] The positive and progressive effects of the present invention are as follows: Polymorph A of compound I of the present invention has low hygroscopicity and good stability in accelerated and long-term stability studies, and is suitable for formulation development. And experiments show that the bioavailability of polymorph A is relatively high, indicating good drug absorption and more conducive to enhancing the drug effect. At the same time, its preparation process conditions are mild and suitable for large-scale production. Therefore, polymorph A has obvious advantages in terms of drug formation and industrial production, and is of great significance for drug development. Description of the Drawings

[0080] Figure 1 Represents the XRPD spectrum of polymorph A of compound I prepared in Example 1;

[0081] Figure 2 Represents the TGA / DSC spectrum of polymorph A of compound I prepared in Example 1;

[0082] Figure 3 Representing the 1 1H-NMR spectrum of crystalline form A of Compound I prepared in Example 1;

[0083] Figure 4 Representing the IR spectrum of crystalline form A of Compound I prepared in Example 1;

[0084] Figure 5 Representing the superimposed XRPD graphs of crystalline form A of Compound I prepared in Example 1 at the end of the 6th month of the accelerated test, the 6th month of the long-term test, and day 0;

[0085] Figure 6 Representing the average plasma concentration-time curve of Compound I in the first group of animals after intravenous administration in the bioavailability test of Experimental Example 7;

[0086] Figure 7 Representing the average plasma concentration-time curve of Compound I in the second group of animals after oral administration in the bioavailability test of Experimental Example 7. Detailed implementation mode

[0087] The present invention will be further described in detail below through specific implementation modes, but it is only used to help understand the present invention, enabling those skilled in the art to implement or use the present invention, and does not constitute any limitation to the present invention.

[0088] Example 1

[0089] 10 g of the API of Compound I was heated under reflux and dissolved in 150 mL of isopropanol, then placed in a water bath, rapidly cooled to 45 °C in 10 minutes, the water bath was removed, and it was slowly cooled naturally at room temperature with stirring for crystallization for 2 h. A large amount of solid precipitated during the slow cooling process. Subsequently, it was further cooled to 10 °C in an ice bath, kept warm and stirred for 1.5 h, filtered, and vacuum dried to constant weight to obtain a sample of crystalline form A of Compound I, with a yield of 91%.

[0090] Example 2

[0091] 10 g of the API of Compound I was heated under reflux and dissolved in 100 mL of absolute ethanol, then placed in a cold water bath, rapidly cooled to 35 °C in 5 minutes, the cold water bath was removed, and it was stirred at 35 °C for crystallization for 1.5 h. A large amount of solid precipitated. Subsequently, it was further cooled to 5 °C in an ice bath, kept warm and stirred for 2.0 h, filtered, and vacuum dried to constant weight to obtain a sample of crystalline form A of Compound I, with a yield of 82%. The X-ray powder diffraction pattern of the sample obtained by this method is consistent with that of the sample of crystalline form A of Compound I obtained in Example 1.

[0092] Example 3

[0093] 10 g of the raw material of Compound I was dissolved by heating under reflux in 80 mL of methanol. Heating was turned off, and the temperature was decreased to 40 °C over 35 minutes and then kept at 40 °C with stirring for crystallization for 1.0 h. A large amount of solid was precipitated. Subsequently, the temperature was further decreased to 0 °C in an ice-salt bath and kept with stirring for 2.0 h. It was filtered and dried under vacuum to constant weight to obtain a sample of polymorph A of Compound I with a yield of 68%. The X-ray powder diffraction pattern of the sample obtained by this method was consistent with that of the sample of polymorph A of Compound I obtained in Example 1.

[0094] Example 4

[0095] 10 g of the raw material of Compound I was dissolved by heating under reflux in 40 mL of acetonitrile. Heating was turned off, and the temperature was decreased to 45 °C over 25 minutes. Subsequently, it was placed at room temperature and slowly cooled naturally with stirring for crystallization for 1.0 h. A large amount of solid was precipitated during the slow cooling process. Subsequently, the temperature was further decreased to 0 °C in an ice-salt bath and kept with stirring for 10.0 h. It was filtered and dried under vacuum to constant weight to obtain a sample of polymorph A of Compound I with a yield of 61%. The X-ray powder diffraction pattern of the sample obtained by this method was consistent with that of the sample of polymorph A of Compound I obtained in Example 1.

[0096] Example 5

[0097] 10 g of the raw material of Compound I was dissolved by heating under reflux in 45 mL of ethyl acetate and then placed at room temperature. The temperature was decreased to 35 °C over 15 minutes and kept at 35 °C with stirring for crystallization for 1.5 h. A large amount of solid was precipitated. Subsequently, the temperature was further decreased to 5 °C in an ice bath and kept with stirring for 20.0 h. It was filtered and dried under vacuum to constant weight to obtain a sample of polymorph A of Compound I with a yield of 64%. The X-ray powder diffraction pattern of the sample obtained by this method was consistent with that of the sample of polymorph A of Compound I obtained in Example 1.

[0098] Example 6

[0099] 10 g of the raw material of Compound I was dissolved by heating under reflux in 40 mL of acetone and then placed at room temperature. The temperature was decreased to 26 °C over 25 minutes and kept at 26 °C for static crystallization for 20.0 h. A large amount of solid was precipitated. Subsequently, the temperature was further decreased to 10 °C in an ice bath and kept for static crystallization for 24.0 h. It was filtered and dried under vacuum to constant weight to obtain a sample of polymorph A of Compound I with a yield of 60%. The X-ray powder diffraction pattern of the sample obtained by this method was consistent with that of the sample of polymorph A of Compound I obtained in Example 1.

[0100] Example 7

[0101] Dissolve 10 g of the API of Compound I in 50 mL of tetrahydrofuran by heating under reflux. Add 100 mL of n-hexane, turn off the heating, cool down to 35 °C after 45 minutes, then naturally and slowly cool down at room temperature while stirring for crystallization for 3.0 h. A large amount of solid precipitates during the slow cooling process. Subsequently, continue to cool down to 8 °C in an ice bath, keep warm and stir for 12.0 h, filter, and vacuum dry to constant weight to obtain a sample of Compound I polymorph A with a yield of 78%. The X-ray powder diffraction pattern of the sample obtained by this method is consistent with that of the sample of Compound I polymorph A obtained in Example 1.

[0102] Example 8

[0103] Dissolve 10 g of the API of Compound I in 30 mL of dichloromethane by heating under reflux. Add 60 mL of methyl tert-butyl ether, naturally and slowly cool down at room temperature while stirring for crystallization for 3.0 h. A large amount of solid precipitates. Continue to cool down to 2 °C in an ice-salt bath, keep warm and stir for 5.0 h, filter, and vacuum dry to constant weight to obtain a sample of Compound I polymorph A with a yield of 73%. The X-ray powder diffraction pattern of the sample obtained by this method is consistent with that of the sample of Compound I polymorph A obtained in Example 1.

[0104] Example 9

[0105] Dissolve 10 g of the API of Compound I in a mixed solvent of 150 mL of isopropanol and ethanol (volume ratio 1:1) by heating under reflux. Turn off the heating, cool down to 35 °C after 50 minutes, and keep warm at 35 °C while stirring for crystallization for 2.0 h. A large amount of solid precipitates. Subsequently, continue to cool down to 6 °C in an ice bath, keep warm and stir for 2.0 h, filter, and vacuum dry to constant weight to obtain a sample of Compound I polymorph A with a yield of 87%. The X-ray powder diffraction pattern of the sample obtained by this method is consistent with that of the sample of Compound I polymorph A obtained in Example 1.

[0106] Example 10

[0107] Dissolve 10 g of the API of Compound I in 100 mL of 95% ethanol by heating under reflux, then place it in a water bath, quickly cool down to 35 °C after 15 minutes, remove the water bath, naturally and slowly cool down at room temperature while stirring for crystallization for 2.0 h. A large amount of solid precipitates during the slow cooling process. Subsequently, continue to cool down to 10 °C in an ice bath, keep warm and stir for 1.0 h, filter, and vacuum dry to constant weight to obtain a sample of Compound I polymorph A with a yield of 85%. The X-ray powder diffraction pattern of the sample obtained by this method is consistent with that of the sample of Compound I polymorph A obtained in Example 1.

[0108] Example 11

[0109] 10 g of the raw material drug of Compound I was dissolved by heating under reflux in a mixed solvent of 60 mL of acetone and water (volume ratio 5:3), then placed in a water bath, rapidly cooled to 28 °C in 15 minutes, the water bath was removed, and it was naturally and slowly cooled at room temperature with stirring for crystallization for 3.0 h. A large amount of solid precipitated during the slow cooling process. Subsequently, it was continuously cooled to 3 °C in an ice bath, kept warm and stirred for 1.6 h, filtered, and vacuum dried to constant weight to obtain a sample of Compound I polymorph A with a yield of 75%. The X-ray powder diffraction pattern of the sample obtained by this method was consistent with that of the sample of Compound I polymorph A obtained in Example 1.

[0110] Example 12

[0111] 10 g of the raw material drug of Compound I was dissolved by heating under reflux in 100 mL of isopropanol, then placed in an ice-salt bath, rapidly cooled to 0 °C in 15 minutes, kept warm and stirred for crystallization for 3.0 h, filtered, and vacuum dried to constant weight to obtain a sample of Compound I polymorph A with a yield of 94%. The X-ray powder diffraction pattern of the sample obtained by this method was consistent with that of the sample of Compound I polymorph A obtained in Example 1.

[0112] Example 13

[0113] 10 g of the raw material drug of Compound I was dissolved by heating under reflux in 90 mL of absolute ethanol, then placed in an ice bath, rapidly cooled to 5 °C in 15 minutes, kept warm and stirred for crystallization for 5.0 h, filtered, and vacuum dried to constant weight to obtain a sample of Compound I polymorph A with a yield of 84%. The X-ray powder diffraction pattern of the sample obtained by this method was consistent with that of the sample of Compound I polymorph A obtained in Example 1.

[0114] Example 14

[0115] 10 g of the raw material drug of Compound I was dissolved by heating under reflux in 50 mL of methanol, then placed in an ice bath, rapidly cooled to 10 °C in 5 minutes, kept warm and allowed to crystallize for 24.0 h, filtered, and vacuum dried to constant weight to obtain a sample of Compound I polymorph A with a yield of 75%. The X-ray powder diffraction pattern of the sample obtained by this method was consistent with that of the sample of Compound I polymorph A obtained in Example 1.

[0116] Example 15

[0117] 10 g of the raw material drug of Compound I was dissolved by heating under reflux in 35 mL of acetonitrile, then placed in an ice bath, rapidly cooled to 8 °C in 10 minutes, kept warm and stirred for crystallization for 10.0 h, filtered, and vacuum dried to constant weight to obtain a sample of Compound I polymorph A with a yield of 62%. The X-ray powder diffraction pattern of the sample obtained by this method was consistent with that of the sample of Compound I polymorph A obtained in Example 1.

[0118] Example 16

[0119] Dissolve 10 g of the raw material of Compound I by heating under reflux in 45 mL of ethyl acetate, then place it in an ice bath, rapidly cool it to 2 °C in 5 minutes, keep the temperature constant and stir for crystallization for 6.0 h, filter, and dry it under vacuum to constant weight to obtain a sample of Compound I polymorph A with a yield of 64%. The X-ray powder diffraction pattern of the sample obtained by this method is consistent with that of the sample of Compound I polymorph A obtained in Example 1.

[0120] Example 17

[0121] Dissolve 10 g of the raw material of Compound I by heating under reflux in 35 mL of acetone, then place it in an ice-salt bath, rapidly cool it to 0 °C in 10 minutes, keep the temperature constant and stir for crystallization for 5.0 h, filter, and dry it under vacuum to constant weight to obtain a sample of Compound I polymorph A with a yield of 63%. The X-ray powder diffraction pattern of the sample obtained by this method is consistent with that of the sample of Compound I polymorph A obtained in Example 1.

[0122] Example 18

[0123] Dissolve 10 g of the raw material of Compound I by refluxing in 50 mL of tetrahydrofuran, add 100 mL of n-hexane, then place it in an ice bath, rapidly cool it to 5 °C in 10 minutes, keep the temperature constant and stir for crystallization for 7.0 h, filter, and dry it under vacuum to constant weight to obtain a sample of Compound I polymorph A with a yield of 77%. The X-ray powder diffraction pattern of the sample obtained by this method is consistent with that of the sample of Compound I polymorph A obtained in Example 1.

[0124] Example 19

[0125] Dissolve 10 g of the raw material of Compound I by refluxing in 30 mL of dichloromethane, add 60 mL of methyl tert-butyl ether, then place it in an ice-salt bath, rapidly cool it to 0 °C in 8 minutes, keep the temperature constant and stir for crystallization for 2.0 h, filter, and dry it under vacuum to constant weight to obtain a sample of Compound I polymorph A with a yield of 74%. The X-ray powder diffraction pattern of the sample obtained by this method is consistent with that of the sample of Compound I polymorph A obtained in Example 1.

[0126] Example 20

[0127] Dissolve 10 g of the raw material of Compound I by heating under reflux in a mixed solvent of 100 mL of isopropanol and ethanol (volume ratio 1:1), then place it in an ice bath, rapidly cool it to 2 °C in 15 minutes, keep the temperature constant and let it stand for crystallization for 20.0 h, filter, and dry it under vacuum to constant weight to obtain a sample of Compound I polymorph A with a yield of 90%. The X-ray powder diffraction pattern of the sample obtained by this method is consistent with that of the sample of Compound I polymorph A obtained in Example 1.

[0128] Example 21

[0129] 10 g of the API of Compound I was dissolved by heating under reflux in 100 mL of 95% ethanol, and then placed in an ice-salt bath. After 10 minutes, the temperature was rapidly decreased to 0 °C, and crystallization was carried out with stirring for 3.0 h while maintaining the temperature. The mixture was filtered and dried under vacuum to constant weight to obtain a sample of crystalline form A of Compound I, with a yield of 86%. The X-ray powder diffraction pattern of the sample obtained by this method was identical to that of the sample of crystalline form A of Compound I obtained in Example 1.

[0130] Example 22

[0131] 10 g of the API of Compound I was dissolved by heating under reflux in a mixed solvent of 55 mL of acetone and water (volume ratio 5:3), and then placed in a cold water bath. After 15 minutes, the temperature was rapidly decreased to 10 °C, and crystallization was carried out with stirring for 15.0 h while maintaining the temperature. The mixture was filtered and dried under vacuum to constant weight to obtain a sample of crystalline form A of Compound I, with a yield of 76%. The X-ray powder diffraction pattern of the sample obtained by this method was identical to that of the sample of crystalline form A of Compound I obtained in Example 1.

[0132] Example 23

[0133] 10 g of the API of Compound I was dissolved by heating under reflux in 100 mL of isopropanol, and then placed in a cold water bath. After 40 minutes, the temperature was decreased to 20 °C, and crystallization was carried out with stirring for 1.0 h while maintaining the temperature. Subsequently, the temperature was further decreased to 10 °C in an ice bath, and crystallization was carried out with stirring for 2.0 h. The mixture was filtered and dried under vacuum to constant weight to obtain a sample of crystalline form A of Compound I, with a yield of 92%. The X-ray powder diffraction pattern of the sample obtained by this method was identical to that of the sample of crystalline form A of Compound I obtained in Example 1.

[0134] Example 24

[0135] 10 g of the API of Compound I was dissolved by heating under reflux in 100 mL of absolute ethanol, and then placed in a cold water bath. After 20 minutes, the temperature was decreased to 15 °C, and crystallization was carried out with stirring for 2.0 h while maintaining the temperature. Subsequently, the temperature was further decreased to 0 °C in an ice bath, and crystallization was carried out with stirring for 1.0 h. The mixture was filtered and dried under vacuum to constant weight to obtain a sample of crystalline form A of Compound I, with a yield of 84%. The X-ray powder diffraction pattern of the sample obtained by this method was identical to that of the sample of crystalline form A of Compound I obtained in Example 1.

[0136] Example 25

[0137] 10 g of the API of Compound I was dissolved by heating under reflux in 50 mL of methanol, and then placed in a water bath. After 15 minutes, the temperature was decreased to 25 °C, and crystallization was carried out with stirring for 3.0 h while maintaining the temperature. Subsequently, the temperature was further decreased to 5 °C in an ice bath, and crystallization was carried out with static standing for 24.0 h. The mixture was filtered and dried under vacuum to constant weight to obtain a sample of crystalline form A of Compound I, with a yield of 74%. The X-ray powder diffraction pattern of the sample obtained by this method was identical to that of the sample of crystalline form A of Compound I obtained in Example 1.

[0138] Example 26

[0139] 10 g of the raw material of Compound I was dissolved by heating under reflux in 40 mL of acetonitrile, then placed in a cold water bath. After 25 minutes, the temperature was lowered to 10 °C, and crystallization was carried out with stirring while maintaining the temperature for 8.0 h. Subsequently, the temperature was further lowered to 0 °C in an ice-salt bath, and crystallization was carried out with standing while maintaining the temperature for 20.0 h. Then, filtration was carried out, and vacuum drying was carried out until constant weight was achieved to obtain a sample of Compound I polymorph A, with a yield of 60%. The X-ray powder diffraction pattern of the sample obtained by this method was consistent with that of the sample of Compound I polymorph A obtained in Example 1.

[0140] Example 27

[0141] 10 g of the raw material of Compound I was dissolved by heating under reflux in 45 mL of ethyl acetate, then placed in a cold water bath. After 10 minutes, the temperature was lowered to 20 °C, and crystallization was carried out with standing while maintaining the temperature for 24.0 h. Subsequently, the temperature was further lowered to 2 °C in an ice bath, and crystallization was carried out with stirring while maintaining the temperature for 4.0 h. Then, filtration was carried out, and vacuum drying was carried out until constant weight was achieved to obtain a sample of Compound I polymorph A, with a yield of 65%. The X-ray powder diffraction pattern of the sample obtained by this method was consistent with that of the sample of Compound I polymorph A obtained in Example 1.

[0142] Example 28

[0143] 10 g of the raw material of Compound I was dissolved by heating under reflux in 40 mL of acetone, then placed in a cold water bath. After 10 minutes, the temperature was lowered to 10 °C, and crystallization was carried out with standing while maintaining the temperature for 15.0 h. Subsequently, the temperature was further lowered to 3 °C in an ice bath, and crystallization was carried out with stirring while maintaining the temperature for 8.0 h. Then, filtration was carried out, and vacuum drying was carried out until constant weight was achieved to obtain a sample of Compound I polymorph A, with a yield of 60%. The X-ray powder diffraction pattern of the sample obtained by this method was consistent with that of the sample of Compound I polymorph A obtained in Example 1.

[0144] Example 29

[0145] 10 g of the raw material of Compound I was dissolved by heating under reflux in 50 mL of tetrahydrofuran, 100 mL of n-hexane was added, and then placed in a water bath. After 20 minutes, the temperature was lowered to 25 °C. Without crystallization with maintaining the temperature, the temperature was directly further lowered to 5 °C in an ice bath, and crystallization was carried out with stirring while maintaining the temperature for 6.0 h. Then, filtration was carried out, and vacuum drying was carried out until constant weight was achieved to obtain a sample of Compound I polymorph A, with a yield of 76%. The X-ray powder diffraction pattern of the sample obtained by this method was consistent with that of the sample of Compound I polymorph A obtained in Example 1.

[0146] Example 30

[0147] 10 g of the API of Compound I was dissolved by heating under reflux in 30 mL of dichloromethane. 60 mL of methyl tert-butyl ether was added, and then the mixture was placed in a cold water bath. After 15 minutes, the temperature was lowered to 15 °C, and crystallization was carried out with stirring for 5.0 h while maintaining the temperature. Subsequently, the temperature was further lowered to 10 °C in an ice bath, and crystallization was carried out with stirring for 2.0 h while maintaining the temperature. The mixture was filtered and dried under vacuum to constant weight to obtain a sample of polymorph A of Compound I, with a yield of 72%. The X-ray powder diffraction pattern of the sample obtained by this method was identical to that of the sample of polymorph A of Compound I obtained in Example 1.

[0148] Example 31

[0149] 10 g of the API of Compound I was dissolved by heating under reflux in a mixed solvent of 100 mL of isopropanol and ethanol (volume ratio 1:1). Then the mixture was placed in a cold water bath. After 20 minutes, the temperature was lowered to 20 °C, and crystallization was carried out with stirring for 1.0 h while maintaining the temperature. Subsequently, the temperature was further lowered to 0 °C in an ice-salt bath, and crystallization was carried out with stirring for 1.0 h while maintaining the temperature. The mixture was filtered and dried under vacuum to constant weight to obtain a sample of polymorph A of Compound I, with a yield of 88%. The X-ray powder diffraction pattern of the sample obtained by this method was identical to that of the sample of polymorph A of Compound I obtained in Example 1.

[0150] Example 32

[0151] 10 g of the API of Compound I was dissolved by heating under reflux in 100 mL of 95% ethanol. Then the mixture was placed in a water bath. After 25 minutes, the temperature was lowered to 25 °C, and crystallization was carried out with stirring for 10.0 h while maintaining the temperature. Subsequently, the temperature was further lowered to 1 °C in an ice-salt bath, and crystallization was carried out with stirring for 3.0 h while maintaining the temperature. The mixture was filtered and dried under vacuum to constant weight to obtain a sample of polymorph A of Compound I, with a yield of 87%. The X-ray powder diffraction pattern of the sample obtained by this method was identical to that of the sample of polymorph A of Compound I obtained in Example 1.

[0152] Example 33

[0153] 10 g of the API of Compound I was dissolved by heating under reflux in a mixed solvent of 55 mL of acetone and water (volume ratio 5:1). Then the mixture was placed in a cold water bath. After 20 minutes, the temperature was lowered to 10 °C, and crystallization was carried out with stirring for 3.0 h while maintaining the temperature. Subsequently, the temperature was further lowered to 5 °C in an ice bath, and crystallization was carried out with stirring for 2.0 h while maintaining the temperature. The mixture was filtered and dried under vacuum to constant weight to obtain a sample of polymorph A of Compound I, with a yield of 77%. The X-ray powder diffraction pattern of the sample obtained by this method was identical to that of the sample of polymorph A of Compound I obtained in Example 1.

[0154] Experimental Example 1: Determination of the diffraction angle (2θ) of the X-ray powder diffraction peaks

[0155] Regarding the sample of polymorph A of Compound I prepared in Example 1, its X-ray powder diffraction (XRPD) spectrum is shown in Figure 1, the values of the diffraction angles (2θ) of its X-ray powder diffraction peaks are shown in Table 1.

[0156] It should be noted that the physical property data of each crystal in Experimental Example 1 were measured under the following conditions.

[0157] Detection instrument: Rigaku SmartLab SE fully automatic multi-functional X-ray diffractometer in Japan.

[0158] Operating conditions: X-ray tube anode: copper target; tube voltage: 40 kV; tube current: 30 mA; scanning mode: one-dimensional scanning; scanning rate: 10° / min; scanning axis: θ / 2θ; scanning range: 3 - 35°; step interval: 0.01°.

[0159] Detection result: For crystal form A, characteristic peaks occur at diffraction angles 2θ of 6.38 ± 0.2°, 9.50 ± 0.2°, 11.05 ± 0.2°, 13.11 ± 0.2°, 15.54 ± 0.2°, 16.23 ± 0.2°, 18.23 ± 0.2°, 18.96 ± 0.2°, 19.42 ± 0.2°, 20.52 ± 0.2°, 21.43 ± 0.2°, 22.13 ± 0.2°, 23.07 ± 0.2° by X-ray powder diffraction.

[0160] Table 1 Values of the diffraction angles (2θ) of the X-ray powder diffraction peaks of the crystal form A sample of Compound I prepared in Example 1

[0161]

[0162] Experimental Example 2: Thermogravimetric-differential scanning calorimetry

[0163] Regarding the crystal form A sample of Compound I prepared in Example 1, its thermogravimetric-differential scanning calorimetry (TGA / DSC) spectrum is shown in Figure 2 .

[0164] Model of detection instrument: Simultaneous thermal analyzer STA449F3

[0165] Test conditions: Temperature: 25°C, Humidity: 35% RH

[0166] Crucible: DSC / TG pan Al2O3

[0167] Atmosphere: AIR(80 / 20)-- / NITROGEN / 50 / NITROGEN / 20

[0168] Detection result: The TGA graph can determine that crystal form A does not contain crystal water or solvates; the DSC graph can confirm that the melting point (extrapolated onset temperature) of crystal form A is 132.6 ± 2°C.

[0169] Experimental Example 3: Nuclear Magnetic Resonance Spectrum( 1 H-NMR)

[0170] Regarding the sample of Compound I Crystal Form A prepared in Example 1, its nuclear magnetic resonance( 1 H-NMR) spectrum is shown in Figure 3 .

[0171] Measurement conditions: Collected on a Bruker 500 MHz nuclear magnetic resonance spectrometer, with CDCl3 as the solvent.

[0172] Test results: 1 H-NMR: δ: 10.144 (br, 1H), 7.480 - 7.497 (m, 2H), 7.447 - 7.466 (m, 2H), 7.379 - 7.414 (m, 1H), 7.293 - 7.328 (m, 5H), 5.075 (m, 1H), 3.622 (m, 2H), 3.236 (s, 3H), 2.370 - 2.399 (t, 2H), 1.854 - 1.746 (m, 4H), 1.460 - 1.487 (m, 2H), 1.292 - 1.306 (m, 6H), ppm.

[0173] Experimental Example 4: Infrared Spectrum (IR)

[0174] Regarding the sample of Compound I Crystal Form A prepared in Example 1, its infrared (IR) spectrum is shown in Figure 4 .

[0175] Instrument model: Nicolet.

[0176] Detection method: Take an appropriate amount of this product (about 1 - 2 mg), take an appropriate amount of dried potassium bromide after grinding, place it in an agate mortar, mix and grind, take an appropriate amount, press into a tablet, and measure the infrared spectrum.

[0177] Test results: The infrared spectrum of the sample has characteristic peaks at 3243 ± 5 cm -1 、2931 ± 5 cm -1 、1706 ± 5 cm -1 、1530 ± 5 cm -1 、1488 ± 5 cm -1 、1446 ± 5 cm -1 、1430 ± 5 cm -1 、1226 ± 5 cm -1 、1125 ± 5 cm -1 、1110 ± 5 cm -1 、706 ± 5 cm -1 、692 ± 5 cm -1 .

[0178] Experimental Example 5: Hygroscopicity

[0179] Regarding the sample of polymorph A of Compound I prepared in Example 1, its hygroscopicity was determined with reference to General Rule 9103 in Part IV of the Chinese Pharmacopoeia (2020 Edition).

[0180] Test result: The weight gain due to hygroscopicity was less than 0.2%, indicating that the obtained polymorph A of the present invention has no hygroscopicity.

[0181] Experimental Example 6: Stability Test

[0182] For the sample of polymorph A of Compound I prepared in Example 1, a stability study was carried out. The sample was placed under the conditions of 40°C ± 2°C / 75% RH ± 5% RH for 6 months for the accelerated stability test, and under the conditions of 30°C ± 2°C / 65% RH ± 5% RH for 6 months for the long-term stability test. The XRPD spectra of the sample were measured at the 0th day, 1st month, 2nd month, 3rd month, and 6th month ends respectively to determine the polymorph changes. At the same time, high performance liquid chromatography was used to measure its purity to investigate the changes in related substances.

[0183] The stability test results of the polymorph A sample for 6 months of acceleration and 6 months of long term are shown in Table 2 and Table 3. The superimposed XRPD diagrams at the 6th month end in the accelerated test and at the 6th month end in the long-term test compared with the 0th day are shown in Figure 5 .

[0184] The results showed that during the 6-month accelerated stability test (40°C ± 2°C / 75% RH ± 5%) and 6-month long-term stability test (30°C ± 2°C / 65% RH ± 5%) of polymorph A, compared with the 0th day, the polymorph remained unchanged, and there were no significant changes in related substances. After being placed for 6 months, the purity was above 99.9%, with high purity and stability. The stability study results indicated that this polymorph is suitable for formulation development.

[0185] Table 2 Stability test results of polymorph A sample for 6 months of acceleration

[0186]

[0187] Table 3 Stability test results of polymorph A sample for 6 months of long term

[0188]

[0189] Experimental Example 7: Bioavailability Test

[0190] For the sample of polymorph A of Compound I prepared in Example 1, a bioavailability test was carried out. First, the sample of polymorph A of Compound I was prepared into an injection and a suspension by conventional methods respectively.

[0191] In this study, 12 Beagle dogs (6 males and 6 females) were randomly divided into 2 groups, with 3 male and 3 female animals in each group. The animals in Group 1 were not fasted and were given a single intravenous injection of 0.5 mg / kg of Compound I (injection solution). Blood samples were collected up to 24 h after dosing. The specific sampling time points were before dosing, 0.083, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 h after dosing. The animals in Group 2 were fasted and given a single oral gavage of 0.5 mg / kg of Compound I (suspension). Blood samples were collected up to 24 h after dosing. The specific sampling time points were before dosing, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 h after dosing. The validated HPLC-UV analytical method was used for the uniformity and concentration analysis of the administered preparations. The validated liquid chromatography-tandem mass spectrometry (LC-MS / MS) analytical method was used to detect the concentration of Compound I in plasma samples. Based on the blood concentration data, Phoenix 7.0 software was used to calculate its bioavailability using a non-compartmental model.

[0192] The mean plasma concentration-time curves of Compound I in Group 1 animals after intravenous administration and in Group 2 animals after oral administration in the bioavailability study are shown in Figure 6 and Figure 7 .

[0193] The results showed that the bioavailability of Polymorph A was 95.81%, indicating a relatively high bioavailability, suggesting good drug absorption and being more conducive to enhancing the drug efficacy.

[0194] The Polymorph A samples of Compound I prepared in Examples 2 to 33 have comparable properties to the Polymorph A sample of Compound I prepared in Example 1, including hygroscopicity, stability, and bioavailability, etc.

[0195] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present invention shall be included within the protection scope of the present invention.

Claims

1. Polymorph A of a compound of formula I, characterized in that, The free base crystalline form A of the compound of formula I has X-ray powder diffraction peaks at 9.50±0.2°, 11.05±0.2°, 15.54±0.2°, 16.23±0.2°, 18.23±0.2° and 22.13±0.2° in terms of 2θ angle. 。 2. The crystalline form A of the compound of formula I as claimed in claim 1, characterized in that, The free base crystalline form A of the compound of formula I has X-ray powder diffraction peaks at 6.38±0.2°, 9.50±0.2°, 11.05±0.2°, 13.11±0.2°, 15.54±0.2°, 16.23±0.2°, 18.23±0.2°, 18.96±0.2°, 19.42±0.2°, 20.52±0.2°, 21.43±0.2°, 22.13±0.2° and 23.07±0.2° in terms of 2θ angle.

3. The crystalline form A of the compound of formula I as claimed in claim 2, characterized in that, The free base crystalline form A of the compound of formula I has the X-ray powder diffraction pattern shown in Figure 1 in terms of 2θ angle.

4. The crystalline form A of the compound of formula I as claimed in claim 1, characterized in that, The free base crystalline form A of the compound of formula I has a melting point of 130°C - 135°C as determined by differential scanning calorimetry.

5. The crystalline form A of the compound of formula I as claimed in claim 1, characterized in that, The free base crystalline form A of the compound of formula I has the thermogravimetry-differential scanning calorimetry spectrum shown in Figure 2.

6. The preparation method of polymorph A according to any one of claims 1-5, characterized in that, Comprising: Heating and dissolving the compound of formula I in a solvent, cooling to 25°C - 45°C, then slowly cooling for crystallization or holding at a constant temperature for crystallization, continuing to cool to 0°C - 10°C and holding at a constant temperature for crystallization, separating, and drying to obtain crystalline form A; the solvent is one or more of methanol, ethanol, isopropanol, acetonitrile, ethyl acetate, acetone, or a mixed solvent of tetrahydrofuran and n-hexane, or a mixed solvent of dichloromethane and methyl tert-butyl ether, or a mixed solvent of methanol, ethanol, isopropanol, acetonitrile, acetone and water.

7. The preparation method of polymorph A according to any one of claims 1-5, characterized in that, Comprising: Heating and dissolving compound I in a solvent, cooling to 0°C - 10°C, then holding at a constant temperature for crystallization, separating, and drying to obtain crystalline form A; the solvent is one or more of methanol, ethanol, isopropanol, acetonitrile, ethyl acetate, acetone, or a mixed solvent of tetrahydrofuran and n-hexane, or a mixed solvent of dichloromethane and methyl tert-butyl ether, or a mixed solvent of methanol, ethanol, isopropanol, acetonitrile, acetone and water.

8. The preparation method of crystalline form A according to any one of claims 1-5, characterized in that, Comprising: Heating and dissolving compound I in a solvent, cooling to 10°C - 25°C, then holding at a constant temperature for crystallization, continuing to cool to 0°C - 10°C and holding at a constant temperature for crystallization, separating, and drying to obtain crystalline form A; the solvent is one or more of methanol, ethanol, isopropanol, acetonitrile, ethyl acetate, acetone, or a mixed solvent of tetrahydrofuran and n-hexane, or a mixed solvent of dichloromethane and methyl tert-butyl ether, or a mixed solvent of methanol, ethanol, isopropanol, acetonitrile, acetone and water.

9. The preparation method of polymorph A according to any one of claims 6-8, characterized in that, The solvent is isopropanol or ethanol, or any mixed solvent of isopropanol, ethanol and water.

10. The preparation method of crystalline form A according to claim 9, wherein The solvent is isopropanol.

11. The preparation method of polymorph A according to any one of claims 6-8, characterized in that, The mass-volume ratio of the compound of formula I to the solvent is 1 g : 3.5 mL - 15 mL.

12. The preparation method of polymorph A according to any one of claims 6-8, characterized in that, The heating and dissolution is as follows: heating and dissolving in a single solvent or a mixed solvent, or first heating and dissolving in one solvent and then adding one or more other solvents.

13. The preparation method of crystalline form A according to claim 6, characterized in that, After cooling to 25°C to 45°C, the steps of slow cooling crystallization or heat preservation crystallization are as follows: after cooling to 25°C to 45°C, naturally slow cooling crystallization at room temperature for 1 to 24 hours or heat preservation crystallization for 1 to 24 hours after cooling to 25°C to 45°C; the step of continuing to cool to 0°C to 10°C and heat preservation crystallization is: continuing to cool to 0°C to 10°C and heat preservation crystallization for 1 to 24 hours.

14. The preparation method of polymorph A according to claim 7, characterized in that, After cooling to 0°C to 10°C, heat preservation crystallization is carried out for 2 to 24 hours.

15. The preparation method of polymorph A according to claim 8, characterized in that, During the heat preservation crystallization process after cooling to 10°C to 25°C, the crystallization time is 0 to 24 hours; during the heat preservation crystallization process of continuing to cool to 0°C to 10°C, the crystallization time is 1 to 24 hours.

16. A pharmaceutical composition, characterized in that, Containing a pharmaceutically acceptable excipient and a therapeutically effective dose of the crystalline form A of the compound of formula I according to any one of claims 1-5.

17. Use of a therapeutically effective dose of the crystalline form A of the compound of formula I according to any one of claims 1-5 or the pharmaceutical composition according to claim 16 in the preparation of a drug for preventing and / or treating pulmonary hypertension, cardiovascular and cerebrovascular diseases related to platelet aggregation or diabetic nephropathy.

18. Use of a therapeutically effective dose of the crystalline form A of the compound of formula I according to any one of claims 1-5 or the pharmaceutical composition according to claim 16 in the preparation of a PGI2 receptor agonist drug.

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