WO2023123742A1 - SEMI-FUMARATE CRYSTAL OF PI3Kδ/γ DUAL INHIBITOR COMPOUND, AND PREPARATION METHOD THEREFOR - Google Patents

Abstract

Provided are a semi-fumarate crystal of a PI3Kδ/γ dual inhibitor compound, i.e., (S)-2-(1-((9H-purin-6-yl)amino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one, and a preparation method for the crystal. The crystal has more excellent properties in terms of physical properties and pharmacodynamic/pharmacokinetics.

Description

Hemi-fumarate crystal of PI3Kδ/γ dual inhibitor compound and preparation method thereof

This application requires the Chinese patent application 202111679233.5 submitted to the State Intellectual Property Office of China on December 31, 2021 with the title of "PI3Kδ/γ dual inhibitor compound hemifumarate crystallization and its preparation method", and in 2022 The priority of the Chinese patent application 202210245006.X with the invention title "PI3Kδ/γ dual inhibitor compound hemifumarate crystallization and its preparation method" submitted to the State Intellectual Property Office of China on March 11, 202210245006.X, the content of the above application Both are incorporated herein by reference in their entirety.

technical field

The present invention relates to the field of medicine, in particular to a PI3Kδ/γ dual inhibitor compound (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl) - fumarate crystals of 4H-chromen-4-one compound and its preparation method.

Background technique

Phosphoinositide-3 kinases (PI3Ks) belong to a class of intracellular lipid kinases that phosphorylate the 3-hydroxyl of the inositol ring of phosphoinositide lipids (PI), thereby generating lipid second messengers. It has been reported in the art that targeted inhibitors of the phosphoinositide-3-kinase (PI3K) pathway can be used as immunomodulators.

A major issue in the large-scale production of pharmaceutical compounds is that the active substance should have stable crystalline polymorphs to ensure consistent processing parameters and drug quality. If an unstable crystalline form is used, the crystalline polymorph may change during manufacturing and/or storage, leading to quality control issues and formulation irregularities. Such variations may affect the reproducibility of the manufacturing process, resulting in a final formulation that does not meet the high quality and stringent requirements imposed on the formulation of pharmaceutical compositions. In this regard, it should generally be noted that any modification of the solid state of a pharmaceutical composition that improves its physical and chemical stability confers significant advantages over less stable forms of the same drug. Furthermore, it is crucial to develop stable production methods that consistently produce active substances. The existence of multiple crystalline forms with similar solubility poses a difficult challenge in the large-scale manufacture of pharmaceutical compounds.

When a compound crystallizes from a solution or slurry, it can crystallize in different spatial lattice arrangements, a property known as "polymorphism." Each crystal form is called a "polymorph". Although polymorphs of a given substance have the same chemical composition, they can differ in one or more physical properties such as solubility, degree of dissociation, true density, dissolution, melting point, crystal shape, compaction behavior, flow properties and and/or differ from each other in terms of solid-state stability.

As generally stated above, polymorphic behavior of drugs can be of great importance in pharmacology. Differences in physical properties exhibited by polymorphs affect practical parameters such as storage stability, compressibility and density (important in formulation and product manufacturing) and dissolution rate (an important factor in determining bioavailability). Changes in chemical reactivity (e.g., differential oxidation, causing color to change more quickly when the dosage form is one polymorph than when the dosage form is another polymorph), mechanical changes (e.g., tablet discoloration after storage) Kinetically favorable polymorphs convert to thermodynamically more stable polymorphs) or both (e.g. tablets of one polymorph disintegrate more easily at high humidity) may lead to loss of stability difference. Additionally, the physical properties of the crystals may be important in processing. For example, one polymorph may be more likely to form solvates, causing aggregation of the solid form and making solid handling more difficult. Alternatively, the particle shape and size distribution of one polymorph relative to another may differ, leading to increased challenges in filtering pharmaceutical actives to remove impurities.

While pharmaceutical formulations with improved chemical and physical properties are desirable, there is no predictable means to prepare new pharmaceutical forms (eg, polymorphs and other new crystalline forms) of existing molecules for such formulations. These new forms will provide consistency in physical properties across a range of environments common in fabrication and compositional use.

WO2014195888A1 patent document discloses (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromene-4-one compound, its structural formula It is formula I, and as a free base, it exhibits dual inhibitory functions of PI3Kδ/γ.

However, it is still urgently desired to develop a combination with (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one Compared with PI3Kδ/γ dual inhibitors that have superior properties in terms of physical properties and/or pharmacodynamics/pharmacokinetics, and have high applicability as pharmaceuticals.

Contents of the invention

The present invention provides a kind of (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one compound The crystalline form 1 of maleic acid salt is characterized in that the crystalline form shows 3.30°, 6.60°, 22.70°, 28.92°, 12.08°, 27.58°, 11.70°, 20.28°, 19.44° on the X-ray diffraction pattern , 23.54°, 29.454°, 24.22°, 16.10° (±0.2°) diffraction angles 2θ peaks.

Further, the crystalline form 1 also includes crystals at 15.66°, 14.54°, 12.98°, 24.92°, 25.28°, 13.32°, 9.82°, 18.96°, 23.54°, 29.45°, 10.80°, 17.18°, 35.85° , the peak at the diffraction angle 2θ of 21.43° (±0.2°).

Further, said crystalline form 1 exhibits an X-ray diffraction pattern substantially as shown in FIG. 5 .

In addition, the present invention also provides a preparation method of crystalline form 1, which is characterized by comprising the following steps:

Step (1): Weigh a certain mass of (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromene-4- A ketone free base compound is added to a certain volume of isopropanol solvent to obtain a suspension 1;

Step (2): Weighing a certain amount of fumaric acid ligand, ultrasonically heating and dissolving in a certain volume of mixed solution of isopropanol and water to obtain solution 1;

Step (3): adding the solution 1 obtained in step (2) dropwise to the stirring suspension 1 obtained in step (1) to obtain suspension 2;

Step (4): Dissolve the suspension 2 obtained in step (3) immediately after stirring, add a certain volume of antisolvent to the solution, stir overnight at low temperature to precipitate solids, and obtain suspension 3;

Step (5): The suspension 3 obtained in Step 4 was centrifuged, and the obtained solid was vacuum-dried at room temperature to obtain the crystalline Form 1.

In a preferred technical solution of the present invention, wherein, the molar ratio of the free base compound described in step (1) to the fumaric acid ligand described in step (2) is 1:1-1.5.

In the preferred technical solution of the present invention, wherein, the molar volume ratio of the free base compound to isopropanol in the step (1) is: 1mol:0.1-1L.

In the preferred technical solution of the present invention, wherein, the volume ratio of the step (2) isopropanol to water is 1:0.4-1.

In the preferred technical scheme of the present invention, wherein, the antisolvent in the described step (4) is selected from n-heptane.

In addition, the present invention also provides a (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromene- The crystalline form 1 of the hemifumarate of 4-ketone compound is characterized in that, described crystalline form shows 3.26 °, 9.64 °, 21.67 °, 22.46 °, 26.75 °, 16.00 ° (± 0.2°) peak at the diffraction angle 2θ.

Further, the hemifumarate salt crystalline form 1 also includes at 11.96°, 27.53°, 13.86°, 10.10°, 10.50°, 14.30°, 12.80°, 10.98°, 18.44°, 17.54°, 22.17°, Peaks at diffraction angles 2θ of 17.86°, 20.90°, 14.90°, 24.71° (±0.2°).

Further, the crystalline form 1 of the hemifumarate salt shows an X-ray diffraction pattern substantially as shown in FIG. 11 .

In addition, the present invention also provides a kind of (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromene - A process for the preparation of the crystalline form 1 of the hemifumarate salt of the 4-keto compound, characterized in that it comprises the following steps:

Step (1): Weigh a certain mass of (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromene-4- The ketone free base compound is added to a certain volume of acetonitrile and stirred to obtain a suspension 1;

Step (2): Weighing a certain mass of fumaric acid ligand and ultrasonically heating and dissolving it in a certain volume of acetonitrile and water mixed solution to obtain solution 1;

Step (3): adding the solution 1 obtained in step (2) dropwise to the suspension 1 obtained in step (1) under stirring to obtain suspension 2;

Step (4): After the suspension 2 was stirred, it was first dissolved, and then a solid was precipitated, and stirred at room temperature to obtain the suspension 3;

Step (5): Suspension 3 was subjected to solid-liquid separation and the resulting solid was vacuum-dried at room temperature to obtain the crystalline form 1 of hemifumarate.

In the preferred technical solution of the present invention, wherein, the molar ratio of the free base compound in step (1) to the fumaric acid ligand in step (2) is 1:1.5, preferably 1:1.1.

In the preferred technical solution of the present invention, wherein, the volume ratio of acetonitrile and water in step (2) is 2:1.

In the preferred technical solution of the present invention, wherein, the volume ratio of the acetonitrile in the step (1) to the acetonitrile in the step (2) is 5:1.

In addition, the present invention also provides a (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromene- The crystalline form 2 of the hemifumarate of the 4-keto compound is characterized in that the crystalline form shows 3.36°, 6.92°, 22.91°, 19.65°, 16.37°, 18.98°, 9.13 °, 27.52°, 6.37°, 26.32°, 25.18°, 11.64°, 9.84°, 10.92°, 15.80°, 20.26°, 24.13°, 20.98°, 27.77°, 12.12°(±0.2°) at the diffraction angle 2θ peak.

Further, the crystalline form 2 of hemifumarate also includes crystals at 22.532°, 12.67°, 24.45°, 22.03°, 17.75°, 17.52°, 23.61°, 29.08°, 13.12°, 13.74°, 17.18° The peak at the diffraction angle 2θ of (±0.2°).

Further, the crystalline form 2 of the hemifumarate salt shows an X-ray diffraction pattern substantially as shown in FIG. 17 .

In addition, the present invention also provides a (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromene- The preparation method of the crystalline form 2 of 4-ketone hemifumarate, is characterized in that, comprises the following steps:

Step (1): Weigh a certain mass of (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromene-4- A ketone free base compound, adding a certain volume of isopropanol to obtain a suspension 1;

Step (2): Weighing a certain mass of fumaric acid ligand and ultrasonically heating and dissolving it in a mixed solution of a certain volume of isopropanol and water to obtain solution 1;

Step (3): adding the solution 1 obtained in step (2) dropwise to the suspension 1 obtained in step (1) under stirring to obtain suspension 2;

Step (4): Dissolve the suspension 2 obtained in step (3) immediately after stirring. No solid precipitates after stirring at room temperature. Stir to precipitate a white solid, continue to stir to obtain a suspension 3;

Step (5): The suspension 3 was suction-filtered under reduced pressure, the surface of the filter cake was gently washed with water, and the obtained solid was vacuum-dried at room temperature to obtain the crystalline form 2 of hemifumarate.

In the preferred technical solution of the present invention, wherein the molar ratio of the free base compound in step (1) to the fumaric acid ligand in step (2) is 1:1-1.5, preferably 1:1.1.

In the above-mentioned preferred technical scheme of the present invention, wherein, the volume ratio of the Virahol and water in step (2) is 3:2.

In the above-mentioned preferred technical solution of the present invention, wherein, the volume ratio of the isopropanol in the step (1) to the isopropanol in the step (2) is 5:3.

In addition, the present invention also provides a pharmaceutical composition, which comprises any one of the above-mentioned fumarate crystalline form 1, hemifumarate crystalline form 1 or hemifumarate crystalline form 2 or a combination thereof, and a pharmaceutically acceptable carrier.

In addition, the present invention also provides a method for inhibiting phosphoinositide-3 kinase (PI3K), comprising making (S)-2-(1-(9H-purin-6-ylamino)propane of the present invention In crystalline form 1, hemifumarate crystalline form 1 or hemifumarate crystalline form 2 of the fumarate salt of the -3-(3-fluorophenyl)-4H-chromen-4-one compound Any one or combination thereof is exposed to phosphoinositide-3 kinase, preferably, the PI3K is selected from PI3Kδ/γ.

Fumarate of (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromene-4-one compound of the present invention The crystals have good crystallinity, slightly hygroscopicity, controllable crystal form preparation, and excellent pharmacokinetics, and can be used as PI3Kδ/γ inhibitors.

Description of drawings

The XRPD pattern of accompanying drawing 1 free base compound

The TGA collection of illustrative plates of accompanying drawing 2 free alkali compounds

The DSC collection of illustrative plates of accompanying drawing 3 free alkali compounds

The ¹ HNMR spectrum of accompanying drawing 4 free alkali compounds

XRPD pattern of accompanying drawing 5 fumarate Form 1

Accompanying drawing 6 TGA pattern of fumarate Form 1

Accompanying drawing 7 DSC pattern of Fumarate Form 1

Figure 8 DVS spectrum of fumarate Form 1

Figure 9 PLM spectrum of fumarate Form 1

Accompanying drawing 10 ¹ HNMR spectrum of hemifumarate Form 1

Accompanying drawing 11 XRPD patterns of hemifumarate Form 1

Accompanying drawing 12 TGA spectrum of hemifumarate Form 1

Figure 13 DSC spectrum of hemifumarate Form 1

Figure 14 DVS spectrum of hemifumarate Form 1

Figure 15 PLM spectrum of hemifumarate Form 1

Accompanying drawing 16 ¹ HNMR spectrum of hemifumarate Form 1

Accompanying drawing 17 XRPD pattern of hemifumarate Form 2

Accompanying drawing 18 TGA spectrum of hemifumarate Form 2

Accompanying drawing 19 DSC spectrum of hemifumarate Form 2

Figure 20 DVS spectrum of hemifumarate Form 2

Figure 21 PLM spectrum of hemifumarate Form 2

Accompanying drawing 22 ¹ HNMR spectrum of hemifumarate Form 2

Detailed ways:

1. Analysis method

1.1 X-ray powder diffractometer (XRPD)

The crystal form of the samples was analyzed by X-powder diffractometer. The 2θ scanning angle of the sample is from 3° to 40°, the scanning step is 0.02°, and the scanning time of each step is 0.2s. The light tube voltage and current were 40kV and 40mA, respectively. When preparing samples, place an appropriate amount of samples on the sample tray to ensure that the surface of the samples is smooth and flat.

1.2 Differential scanning calorimetry (DSC)

The samples were analyzed by TA instruments Q200DSC. Put the weighed sample (0.5mg-5mg) into the sample tray, and raise the sample to the final temperature at a rate of 10°C/min under the protection of nitrogen (50mL/min).

1.3 Thermogravimetric analysis (TGA)

The samples were analyzed by TA instruments Q500. The sample was put into a tared platinum crucible, the system automatically weighed, and then the sample was raised to the final temperature at a rate of 10°C/min under the protection of nitrogen (40mL/min).

1.4 Polarized Light Microscopy (PLM)

The samples were analyzed using a polarizing microscope, and the morphology and microstructure of the crystals were obtained by adjusting different magnifications.

1.5 Dynamic Moisture Sorption (DVS)

Dynamic moisture adsorption was carried out by TA Instruments Q5000SA. Approximately 1-10 mg of sample is placed in a sample pan and suspended from the sample chamber. The room temperature was maintained at a constant 25±1°C by a water bath. In the step mode, the sample is tested cyclically at the relative humidity of 0%RH-80%RH. Analysis was performed at 10% RH/step. Set the time to maintain each humidity to 90min, so that the sample and the indoor environment can reach equilibrium.

1.6 Liquid hydrogen nuclear magnetic spectrum ( ¹ H NMR)

The samples were analyzed using Bruker Ascend 500MH, and the solvent was deuterated dimethyl sulfoxide.

2. Preparation method

2.1 The preparation method of (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one free base compound

Prepare (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one with reference to the method of patent document CN105358560A embodiment free base compound.

2.2 Preparation method of (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one fumarate Form1

Step (1): Weigh about 200 mg of the free base compound prepared in Example 2.1 and add it to 1 mL of isopropanol to obtain a suspension 1;

Step (2): Weigh about 63 mg of fumaric acid, dissolve it in a mixed solution of 0.4 mL of isopropanol and 0.4 mL of water by ultrasonic heating, and obtain solution 1;

Step (3): adding the solution 1 obtained in step (2) dropwise to the stirring suspension 1 obtained in step (1) to obtain suspension 2;

Step (4): Dissolve the suspension 2 obtained in step (3) immediately after stirring, add 16 mL of n-heptane to the solution, stir overnight at 4°C to precipitate solids, and obtain suspension 3;

Step (5): The suspension 3 obtained in Step 4 was centrifuged, and the obtained solid was vacuum-dried at room temperature overnight to obtain about 198 mg of the product.

The product is characterized, and its XRPD spectrum is shown in accompanying drawing 5, and TGA and DSC collection of illustrative plates are shown in attached drawing respectively.

As shown in Fig. 6 and Fig. 7, DVS is shown in Fig. 8, PLM is shown in Fig. 9, and ¹ HNMR is shown in Fig.

Figure 10 shows.

2.3 (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one hemifumarate crystal form 1 preparation of

method one:

Step (1): Weigh about 200 mg of the free base compound prepared in Example 2.1, add 4 mL of acetonitrile and stir to obtain suspension 1;

Step (2): About 63 mg of fumaric acid was heated and dissolved in a mixed solution of 0.8 mL of acetonitrile and 0.4 mL of water to obtain solution 1;

Step (3): adding solution 1 dropwise to suspension 1 under stirring to obtain suspension 2;

Step (4): After the suspension 2 was stirred, it was first dissolved, and then a solid was precipitated, and stirred overnight at room temperature to obtain a suspension 3;

Step (5): The suspension 3 was centrifuged, and the obtained solid was vacuum-dried at room temperature overnight to obtain about 119 mg of hemifumarate Form 1;

Method Two:

Step (1): Weigh about 200 mg of the free base compound prepared in Example 2.1, add 2 mL of acetonitrile and stir to obtain suspension 1;

Step (2): About 64 mg of fumaric acid was heated and dissolved in a mixed solution of 0.8 mL of acetonitrile and 0.4 mL of water to obtain solution 1;

Step (3): adding solution 1 dropwise to suspension 1 under stirring to obtain suspension 2;

Step (4): After the suspension 2 was stirred, it was first dissolved, and then a solid was precipitated, and stirred at room temperature for 3 days to obtain a suspension 3;

Step (5): The suspension 3 was suction filtered under reduced pressure, the surface of the filter cake was washed with water, and the obtained solid was vacuum-dried overnight at room temperature to obtain about 210 mg of hemifumarate Form 1.

The product is characterized, the XRPD spectrum is shown in Figure 11, the TGA and DSC spectra are shown in Figure 12 and Figure 13 respectively, the DVS and isotherm adsorption curve is shown in Figure 14, and the PLM is shown in Figure 15 , ¹ HNMR is shown in Fig. 16 .

2.4 (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one hemifumarate crystal form 2 preparation of

method one:

Step (1): Weigh about 202 mg of the free base compound prepared in Example 2.1, add 1 mL of isopropanol to obtain a suspension 1;

Step (2): About 65 mg of fumaric acid was heated and dissolved in a mixed solution of 0.6 mL of isopropanol and 0.4 mL of water to obtain solution 1;

Step (3): adding solution 1 dropwise to suspension 1 under stirring to obtain suspension 2;

Step (4): Suspension 2 was dissolved immediately after stirring, and no solid precipitated after stirring at room temperature overnight. A small amount of transparent crystals precipitated on the bottle wall after volatilization through a small hole at room temperature for one day. Add a non-porous cap and stir at room temperature for 3 hours to precipitate a white solid. Stirring was continued for 1 day to obtain suspension 3;

Step (5): filter the suspension 3 under reduced pressure, gently rinse the surface of the filter cake with water, and dry the obtained solid under vacuum at room temperature overnight to obtain about 77 mg of hemifumarate Form 2;

Method Two:

Step (1): Weigh about 501 mg of the free base compound prepared in Example 2.1, and add 2.5 mL of isopropanol to obtain a suspension 1;

Step (2): About 156 mg of fumaric acid was heated and dissolved in a mixed solution of 1.5 mL of isopropanol and 1 mL of water to obtain solution 1;

Step (3): adding solution 1 dropwise to suspension 1 under stirring to obtain suspension 2;

Step (4): Suspension 2 dissolves immediately after stirring, continue to stir for 10 minutes, volatilize through small holes at room temperature for about 1 day, a white solid precipitates out at the bottle mouth, add a non-porous cap, stir at room temperature for 1 hour to precipitate a white solid, continue stirring 2 days, obtain suspension 3;

Step (5): The suspension 3 was suction filtered under reduced pressure, and the surface of the filter cake was gently washed with water, and the obtained solid was vacuum-dried at room temperature for about 5 days to obtain about 240 mg of hemifumarate Form 2.

To characterize the product, the XRPD spectrum is shown in Figure 17, the TGA and DSC spectra are shown in Figure 18 and Figure 19 respectively, the DVS and isotherm adsorption curve are shown in Figure 20, and the PLM is shown in Figure 21. ¹ HNMR is shown in Figure 22.

3. Comparison of the properties of free base and fumarate Form 1 (crystal form 1), hemifumarate Form 1 (crystal form 1), and hemifumarate Form 2 (crystal form 2)

From the observations in the table above, compared to fumarate Form 1, hemifumarate Form 1 salt form has good crystallinity; compared to hemifumarate Form2, hemifumarate Form1 has more Low hygroscopicity, which is more conducive to drug development.

4. Comparison of pharmacokinetic characteristics of free base and fumarate crystalline form 1, hemifumarate crystalline form 1, and hemifumarate crystalline form 2

The present invention also studies (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromene-4-one free base and rich Comparison of Kinetic Parameters of Oral Administration of Maleate Crystalline Form 1, Hemifumarate Salt Form 1, and Hemifumarate Salt Crystalline Form 2 in Wistar Rats, 4 Animals in Each Group of Oral Administration of Free Base , each group of animals administered orally with each salt type is 3, 6-8 weeks old, male. Oral administration of 10% Cremophor EL+90% (10% HP-β-CD in 1% HPMC (pH 2.2) in water, the animals in the oral administration group fasted overnight, and resumed eating after 4 hours of administration. Oral administration group Animal blood collection points are before and after administration and 0.25, 0.5, 1, 2, 4, 8 and 24 hours. Jugular vein blood collection, the blood collection volume of each blood collection point is about 150 μ L, EDTA-K2 anticoagulant, within 15 minutes after sampling 4 Centrifuge at 2000g for 5min, and analyze by LCMSMS-28 (Triple Quad 6500+).

It was found that the Tmax, AUC and F% of the hemifumarate crystalline form 1 were significantly higher than the other two crystalline forms; compared with the free base, the Tmax and T1 _/2 of the hemifumarate crystalline form 1 were significantly prolonged, F% improved significantly. See the table below for details:

Claims (21)

1. A fumarate salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one compound Crystalline form 1, characterized in that the crystalline form shows 3.30°, 6.60°, 22.70°, 28.92°, 12.08°, 27.58°, 11.70°, 20.28°, 19.44°, 23.54°, Peaks at diffraction angles 2θ of 29.45°, 24.22°, 16.10° (±0.2°).
2. The crystalline form 1 according to claim 1, wherein the crystalline form also includes 15.66°, 14.54°, 12.98°, 24.92°, 25.28°, 13.32°, 9.82°, 18.96°, 23.54°, Peaks at diffraction angles 2θ of 29.45°, 10.80°, 17.18°, 35.85°, 21.43° (±0.2°).
3. The crystalline form 1 of fumarate salt according to claim 1 or 2, characterized in that it exhibits an X-ray diffraction pattern substantially as shown in FIG. 5 .
4. The preparation method of fumarate salt crystal form 1 as described in any one of claims 1-3, is characterized in that comprising the following steps:

   Step (1): Weigh a certain mass of (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromene-4- A ketone free base compound is added to a certain volume of isopropanol solvent to obtain a suspension 1;

   Step (2): Weighing a certain amount of fumaric acid ligand, ultrasonically heating and dissolving in a certain volume of mixed solution of isopropanol and water to obtain solution 1;

   Step (3): adding the solution 1 obtained in step (2) dropwise to the stirring suspension 1 obtained in step (1) to obtain suspension 2;

   Step (4): Dissolve the suspension 2 obtained in step (3) immediately after stirring, add a certain volume of antisolvent to the solution, stir overnight at low temperature to precipitate solids, and obtain suspension 3;

   Step (5): The suspension 3 obtained in Step 4 was centrifuged, and the obtained solid was vacuum-dried at room temperature to obtain the crystalline Form 1.
5. The method according to claim 4, wherein the molar ratio of the free base compound described in the step (1) to the fumaric acid ligand described in the step (2) is 1:1-1.5.
6. The method according to claim 4, wherein, in the step (1), the molar volume ratio of the free base compound to isopropanol is: 1mol: 0.1-1L.
7. The method according to claim 4, wherein the volume ratio of the step (2) isopropanol to water is 1:0.4-1.
8. The method according to claim 4, wherein, the antisolvent in the described step (4) is selected from n-heptane.
9. A hemifumarate salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one compound The crystalline form 1 is characterized in that the crystalline form shows peaks at diffraction angles 2θ of 3.26°, 9.64°, 21.67°, 22.46°, 26.75°, 16.00° (±0.2°) on the X-ray diffraction pattern .
10. The hemifumarate crystalline form 1 as claimed in claim 9, wherein, also included in 11.96 °, 27.53 °, 13.86 °, 10.10 °, 10.50 °, 14.30 °, 12.80 °, 10.98 °, 18.44 °, 17.54 ° , 22.17°, 17.86°, 20.90°, 14.90°, 24.71° (±0.2°) diffraction angle 2θ peaks.
11. The crystalline form 1 of hemifumarate salt according to claim 9 or 10, wherein said crystalline form 1 of hemifumarate salt exhibits an X-ray diffraction pattern substantially as shown in FIG. 11 .
12. The preparation method of the crystalline form 1 of hemifumarate as claimed in any one of claims 9-11, is characterized in that comprising the following steps:

    Step (1): Weigh a certain mass of (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromene-4- The ketone free base compound is added to a certain volume of acetonitrile and stirred to obtain a suspension 1;

    Step (2): Weighing a certain mass of fumaric acid ligand and ultrasonically heating and dissolving it in a certain volume of acetonitrile and water mixed solution to obtain solution 1;

    Step (3): adding the solution 1 obtained in step (2) dropwise to the suspension 1 obtained in step (1) under stirring to obtain suspension 2;

    Step (4): After the suspension 2 was stirred, it was first dissolved, and then a solid was precipitated, and stirred at room temperature to obtain the suspension 3;

    Step (5): Suspension 3 was subjected to solid-liquid separation and the resulting solid was vacuum-dried at room temperature to obtain the crystalline form 1 of hemifumarate.
13. The method according to claim 12, wherein the molar ratio of the free base compound in step (1) and the fumaric acid ligand in step (2) is 1:1.5, preferably 1:1.1.
14. The method according to claim 12, wherein the volume ratio of acetonitrile and water in step (2) is 2:1.
15. The method according to claim 12, wherein the volume ratio of the acetonitrile in the step (1) to the acetonitrile in the step (2) is 5:1.
16. A hemifumarate salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one compound The crystalline form 2 is characterized in that the crystalline form shows 3.36°, 6.92°, 22.91°, 19.65°, 16.37°, 18.98°, 9.13°, 27.52°, 6.37°, 26.32° in the X-ray diffraction pattern , 25.18°, 11.64°, 9.84°, 10.92°, 15.80°, 20.26°, 24.13°, 20.98°, 27.77°, 12.12° (±0.2°) at the diffraction angle 2θ.
17. The crystalline form 2 of hemifumarate as claimed in claim 16, wherein it also includes the crystalline form 2 at 22.53°, 12.67°, 24.45°, 22.03°, 17.75°, 17.52°, 23.61°, 29.08°, 13.12°, 13.74 °, the peak at the diffraction angle 2θ of 17.18° (±0.2°).
18. The crystalline form 2 of hemifumarate salt according to claim 16 or 17, wherein said crystalline form 2 of hemifumarate salt exhibits an X-ray diffraction pattern substantially as shown in FIG. 17 .
19. The preparation method of the crystalline form 2 of hemifumarate as described in any one of claims 16-18, is characterized in that, comprises the following steps:

    Step (1): Weigh a certain mass of (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromene-4- A ketone free base compound, adding a certain volume of isopropanol to obtain a suspension 1;

    Step (2): Weighing a certain mass of fumaric acid ligand and ultrasonically heating and dissolving it in a mixed solution of a certain volume of isopropanol and water to obtain solution 1;

    Step (3): adding the solution 1 obtained in step (2) dropwise to the suspension 1 obtained in step (1) under stirring to obtain suspension 2;

    Step (4): Dissolve the suspension 2 obtained in step (3) immediately after stirring. No solid precipitates after stirring at room temperature. Stir to precipitate a white solid, continue to stir to obtain a suspension 3;

    Step (5): The suspension 3 was suction-filtered under reduced pressure, the surface of the filter cake was gently washed with water, and the obtained solid was vacuum-dried at room temperature to obtain the crystalline form 2 of hemifumarate.
20. The method according to claim 19, wherein the molar ratio of the free base compound in step (1) to the fumaric acid ligand in step (2) is 1:1-1.5, preferably 1:1.1.
21. The method according to claim 20, wherein the volume ratio of Virahol and water in step (2) is 3:2.

    The method according to claim 21, wherein the volume ratio of the isopropanol in step (1) to the isopropanol in step (2) is 5:3.

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