A benzene sulfonate crystal and its preparation method

Abstract

The present invention relates to a crystal of a salt of a PI3Kδ / γ dual inhibitor compound (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one compound and a preparation method thereof. The crystal form of the present invention has more excellent properties in terms of physical properties and pharmacodynamic / pharmacokinetic properties.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceuticals, and particularly to a crystal of a salt of a PI3Kδ / γ dual inhibitor compound (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one compound and a preparation method thereof. Background Art

[0002] Phosphoinositide-3 kinase (PI3K) belongs to a class of intracellular lipid kinases that phosphorylate the 3-position hydroxyl group of the inositol ring of phosphoinositide lipids (PI), thereby generating lipid second messengers. It has been reported in the prior art that targeted inhibitors of the phosphoinositide-3-kinase (PI3K) pathway can act as immunomodulators.

[0003] A major problem 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 crystal polymorphs may change during manufacturing and / or storage, resulting in quality control problems and formulation irregularities. Such changes may affect the reproducibility of the manufacturing process, leading to the final formulation not meeting the high quality and strict requirements imposed on the formulation of pharmaceutical compositions. In this regard, it should be generally noted that any change in 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. In addition, it is crucial to develop a stable production method that always produces the active substance. The existence of multiple crystalline forms with similar solubilities poses a difficult challenge in the large-scale manufacture of pharmaceutical compounds.

[0004] 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 the polymorphs of a given substance have the same chemical composition, they can differ from each other in one or more physical properties such as solubility, dissociation degree, true density, dissolution, melting point, crystal shape, compaction behavior, flow properties, and / or solid-state stability.

[0005] Generally as described above, the polymorphic behavior of drugs can be very important in pharmacology. Differences in the physical properties exhibited by polymorphs affect practical parameters such as storage stability, compressibility, and density (important in formulation and product manufacturing), as well as dissolution rate (an important factor determining bioavailability). Changes in chemical reactivity (e.g., differential oxidation, causing discoloration to occur more rapidly when the dosage form is one polymorph than when it is another), mechanical changes (e.g., tablets crumbling after storage as the kinetically favored polymorph converts to the thermodynamically more stable polymorph), or both (e.g., tablets of one polymorph being more prone to decomposition at high humidity) can result in differences in stability. Additionally, the physical properties of crystals can be important in processing. For example, one polymorph may be more likely to form solvates, causing the solid form to agglomerate and increasing the difficulty of solid handling. Or, the particle shape and size distribution of one polymorph may differ from that of another, resulting in increased challenges in filtering the drug active substance to remove impurities.

[0006] Although drug formulations with improved chemical and physical properties are desired, there are no predictable means to prepare new drug forms (e.g., polymorphs and other new crystalline forms) of existing molecules for such formulations. These new forms would provide consistency in physical properties across a range of environments common in manufacturing and composition use.

[0007] The patent document WO2014195888A1 discloses the (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one compound, whose structural formula is Formula I, and shows dual PI3Kδ / γ inhibitory function as a free base.

[0008]

[0009] However, there is still an urgent desire to develop a PI3Kδ / γ dual inhibitor that has more excellent properties in terms of physical properties and pharmacodynamics / pharmacokinetics compared to (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one and has high suitability as a pharmaceutical. Summary of the Invention

[0010] The present invention provides a crystalline form of the benzenesulfonate of (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one compound, characterized in that the crystalline form shows peaks at diffraction angles 2θ of 13.28°, 20.72°, 21.70°, 18.80°, 18.14°, 17.26°, 23.81°, 23.02°, 11.12°, 14.00°, 23.44°, 22.14° (±0.2°) in the X-ray diffraction pattern.

[0011] Further, the benzenesulfonate crystalline form further includes peaks at diffraction angles 2θ of 27.25°, 28.31°, 22.43°, 26.47°, 34.51°, 28.84°, 20.32°, 16.52°, 27.97°, 27.251°, 26.91°, 33.14°, 31.07°, 24.96°, 8.94°, 29.31°, 29.65°, 32.60°, 31.32°, 38.81°, 33.51°, 37.77°, 37.09° (±0.2°).

[0012] Further, the benzenesulfonate crystalline form shows an X-ray diffraction pattern substantially as Figure 5 shown.

[0013] In addition, the present invention also provides a method for preparing a crystalline form of the benzenesulfonate of (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one compound, characterized by including the following steps:

[0014] Step (1): Weigh a certain mass of (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one free base compound, add it to a certain volume of isopropanol solvent and dissolve it in a water bath to obtain Solution 1;

[0015] Step (2): Weigh a certain mass of benzenesulfonic acid ligand, ultrasonically heat and dissolve it in a certain volume of isopropanol to obtain Solution 2;

[0016] Step (3): Dropwise add Solution 2 obtained in Step (2) to Solution 1 being stirred obtained in Step (1) to obtain Solution 3;

[0017] Step (4): Stir Solution 3 obtained in Step (3) until no solid is precipitated, add a certain volume of anti-solvent to the solution to precipitate a solid, and continue stirring to obtain a suspension;

[0018] Step (5): Filter the suspension obtained in step (4) under reduced pressure, rinse the surface of the filter cake with isopropanol, and vacuum dry the obtained solid at room temperature to obtain the crystalline form 1.

[0019] In a preferred technical solution of the present invention, the anti-solvent in step (4) is selected as n-heptane.

[0020] In a preferred technical solution of the present invention, the volume ratio of isopropanol in step (1) and step (2) to the volume of the anti-solvent in step (4) is 2:0.1 - 0.5:3.

[0021] In a preferred technical solution of the present invention, the molar ratio of the free base compound in step (1) to the benzenesulfonic acid ligand in step (2) is 1:1.5, preferably 1:1.1.

[0022] The crystal of the benzenesulfonate of the (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one compound of the present invention has good crystallinity, is slightly hygroscopic, the crystal form preparation is controllable, and exhibits excellent pharmacokinetics, and can be used as a PI3Kδ / γ inhibitor. Description of the Drawings

[0023] Attached Figure 1 XRPD diagram of the free base compound

[0024] Attached Figure 2 TGA diagram of the free base compound

[0025] Attached Figure 3 DSC diagram of the free base compound

[0026] Attached Figure 4 Of the free base compound 1 HNMR diagram

[0027] Attached Figure 5 XRPD diagram of the benzenesulfonate crystal form

[0028] Attached Figure 6 TGA diagram of the benzenesulfonate crystal form

[0029] Attached Figure 7 DSC diagram of the benzenesulfonate crystal form

[0030] Attached Figure 8 DVS diagram and isothermal adsorption curve of the benzenesulfonate crystal form

[0031] Attached Figure 9 PLM diagram of the benzenesulfonate crystal form

[0032] Attached Figure 10 Of the benzenesulfonate crystal form 1HNMR spectrum;

[0033] Attached Figure 11 XRPD pattern of amorphous citrate

[0034] Attached Figure 12 Amorphous citrate 1 HNMR spectrum

[0035] Attached Figure 13 XRPD pattern of amorphous L - malate

[0036] Attached Figure 14 Amorphous L - malate 1 HNMR spectrum

[0037] Attached Figure 15 XRPD pattern of amorphous sulfate

[0038] Attached Figure 16 XRPD pattern of amorphous L - tartrate

[0039] Attached Figure 17 Amorphous L - tartrate 1 HNMR spectrum

[0040] Attached Figure 18 XRPD pattern of amorphous p - toluenesulfonate

[0041] Attached Figure 19 Amorphous p - toluenesulfonate 1 HNMR spectrum

[0042] Attached Figure 20 XRPD pattern of amorphous hydrochloride

[0043] Attached Figure 21 XRPD pattern of amorphous maleate

[0044] Attached Figure 22 Amorphous maleate 1 HNMR spectrum

[0045] Attached Figure 23 XRPD pattern of amorphous mesylate

[0046] Attached Figure 24 Amorphous mesylate 1 HNMR spectrum Detailed implementation mode

[0047] I. Analysis method

[0048] 1.1 X - ray powder diffractometer (XRPD)

[0049] The crystal form of the sample was analyzed using an X-ray diffractometer. The 2θ scanning angle of the sample was from 3° to 40°, the scanning step was 0.02°, and the scanning time for each step was 0.2 s. The tube voltage and current were 40 kV and 40 mA respectively. When preparing the sample, an appropriate amount of the sample was placed on the sample carrier plate to ensure that the surface of the sample was smooth and flat.

[0050] 1.2 Differential Scanning Calorimetry (DSC)

[0051] The sample was analyzed using a TA instruments Q200 DSC. The weighed sample (0.5 mg - 5 mg) was placed in the sample carrier plate, and the sample was heated to the final temperature at a rate of 10 °C / min under the protection of nitrogen (50 mL / min).

[0052] 1.3 Thermogravimetric Analysis (TGA)

[0053] The sample was analyzed using a TA instruments Q500. The sample was placed in a platinum crucible with the tare weight removed, and the system automatically weighed it. Then, the sample was heated to the final temperature at a rate of 10 °C / min under the protection of nitrogen (40 mL / min).

[0054] 1.4 Polarizing Light Microscope (PLM)

[0055] The sample was analyzed using a polarizing light microscope, and the morphology and microstructure of the crystal were obtained by adjusting different magnifications.

[0056] 1.5 Dynamic Vapor Sorption (DVS)

[0057] Dynamic Vapor Sorption was performed using a TA Instruments Q5000 SA. Approximately 1 - 10 mg of the sample was placed on the sample plate and suspended in the sample chamber. The temperature in the chamber was maintained at a constant 25 ± 1 °C by a water bath. In the step mode, the sample was cycled and tested at a relative environmental humidity of 0% RH - 80% RH. The analysis was performed at 10% RH / step. The time for maintaining each humidity was set to 90 min to allow the sample to reach equilibrium with the indoor environment.

[0058] 1.6 Liquid Nuclear Magnetic Resonance Hydrogen Spectrum ( 1 1H NMR)

[0059] The sample was analyzed using a Bruker Ascend 500 MH, and the solvent was deuterated dimethyl sulfoxide.

[0060] II. Preparation Method

[0061] 2.1 Preparation Method of (S)-2-(1-(9H-Purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one Free Base Compound

[0062] Prepare the free base compound of (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one according to the method of the embodiment of patent document CN105358560A. Among them, the XRPD pattern of the free base compound is as shown in the appendix Figure 1 shown, and the TGA pattern is as shown in the appendix Figure 2 shown, and the DSC pattern is as shown in the appendix Figure 3 shown, 1 The HNMR pattern is as shown in the appendix Figure 4 shown.

[0063] 2.2 Preparation of the benzenesulfonate crystal form of (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one

[0064] Step (1): Add about 200 mg of the free base compound prepared in Example 2.1 to 2 mL of isopropanol and dissolve it in a water bath at 60 °C to obtain Solution 1;

[0065] Step (2): Ultrasonically heat and dissolve about 94 mg of benzenesulfonic acid in 0.4 mL of isopropanol to obtain Solution 2;

[0066] Step (3): Drop Solution 2 into Solution 1 under stirring to obtain Solution 3;

[0067] Step (4): Stir Solution 3 for about 1 day without precipitating solids, add 3 mL of n-heptane to precipitate solids, stir to form an oil, and continue stirring for about 2 days to obtain a suspension.

[0068] Step (5): Filter the suspension under reduced pressure, rinse the surface of the filter cake with isopropanol, and dry the obtained solid in vacuo at room temperature overnight to obtain benzenesulfonate Form 1 (about 200 mg).

[0069] Characterize the product, and its XRPD pattern is as shown in the appendix Figure 5 shown, and the TGA and DSC patterns are respectively as shown in the appendix Figure 6 and the appendix Figure 7 shown, the DVS and isothermal adsorption curves are as shown in the appendix Figure 8 shown, and the PLM is as shown in the appendix Figure 9 shown, 1 The HNMR is as shown in the appendix Figure 10 shown.

[0070] The crystal forms of the products obtained by selecting different solvents and experimental processes are shown in Table 1:

[0071] Table 1

[0072]

[0073] Among them, in the above table, API represents the free base compound prepared in Example 2.1, the base represents the free base compound, and the acid represents the p-toluenesulfonic acid counterion ligand.

[0074] 2.3 Preparation of amorphous (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one citrate

[0075] Step (1): Weigh about 200 mg of the free base compound prepared in Example 2.1, add 2 mL of isopropanol, and dissolve it in a water bath at 60 °C to obtain Solution 1.

[0076] Step (2): Dissolve about 103 mg of citric acid in 0.8 mL of isopropanol to obtain Solution 2.

[0077] Step (3): Slowly add Solution 2 dropwise to Solution 1 under stirring to obtain Solution 3.

[0078] Step (4): Stir Solution 3 overnight without precipitation of solids. Add 3 mL of n-heptane to Solution 3, and a solid precipitates and becomes an oil after stirring.

[0079] Step (5): Discard the supernatant. The obtained oil is dried under vacuum at room temperature overnight to obtain a solid. XRPD (attached Figure 11 ) detects that the citrate is amorphous, 1 HNMR is as attached Figure 12 shown.

[0080] 2.4 Preparation of amorphous (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one L-malate

[0081] Step (1): Weigh about 200 mg of the free base compound prepared in Example 2.1, add 2 mL of isopropanol, and dissolve it in a water bath at 60 °C to obtain Solution 1.

[0082] Step (2): Dissolve about 73 mg of L-malic acid in 0.8 mL of isopropanol to obtain Solution 2.

[0083] Step (3): Slowly add Solution 2 dropwise to Solution 1 under stirring to obtain Solution 3.

[0084] Step (4): Stir Solution 3 overnight without precipitation of solids. Add 3 mL of n-heptane to Solution 3, and stir for about 2 days to precipitate an oil.

[0085] Step (5): Discard the supernatant. The obtained oil is dried under vacuum at room temperature overnight to obtain a solid, obtaining amorphous L-malate. XRPD is as attached Figure 13 shown, 1HNMR is as attached Figure 14 as shown

[0086] Preparation of the amorphous form of 2.5(S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one sulfate

[0087] Step (1): Add about 200 mg of the free base compound prepared in Example 2.1 to 2 mL of isopropanol, dissolve it clearly in a water bath at 60 °C to obtain Solution 1;

[0088] Step (2): Dissolve about 55 mg of sulfuric acid in 0.4 mL of isopropanol to obtain Solution 2;

[0089] Step (3): Dropwise add Solution 2 to Solution 1 under stirring to obtain Solution 3;

[0090] Step (4): A solid immediately precipitates from Solution 3, stir for about 1 day until it becomes clear, add 4 mL of n-heptane, a solid precipitates, stir for about 2 days until it becomes an oil;

[0091] Step (5): Discard the supernatant, dry the obtained oil under vacuum at room temperature overnight to obtain a solid, and XRPD (attached Figure 15 ) detects that the sulfate is amorphous.

[0092] Preparation of the amorphous form of 2.6(S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one L-tartrate

[0093] Step (1): Add about 200 mg of the free base compound prepared in Example 2.1 to 2 mL of isopropanol, dissolve it clearly in a water bath at 60 °C to obtain Solution 1;

[0094] Step (2): Dissolve about 80 mg of L-tartaric acid in 0.8 mL of isopropanol to obtain Solution 2;

[0095] Step (3): Dropwise add Solution 2 to Solution 1 under stirring to obtain Solution 3;

[0096] Step (4): Solution 3 is slightly turbid, stir overnight and no large amount of solid precipitates, add 3 mL of n-heptane, a solid precipitates, stir for about 2 days until it becomes an oil;

[0097] Step (5): Discard the supernatant, dry the obtained oil under vacuum at room temperature overnight to obtain a solid, and XRPD (attached Figure 16 ) detects that the L-tartrate is amorphous, 1 HNMR is as attached Figure 17 as shown

[0098] Preparation of amorphous (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one p-toluenesulfonate

[0099] Step (1): Add about 200 mg of the free base compound prepared in Example 2.1 to 2 mL of isopropanol, and dissolve it in a water bath at 60 °C to obtain Solution 1;

[0100] Step (2): Dissolve about 93 mg of p-toluenesulfonic acid in 0.4 mL of isopropanol to obtain Solution 2;

[0101] Step (3): Dropwise add Solution 2 to Solution 1 under stirring to obtain Solution 3;

[0102] Step (4): Stir Solution 3 for about 1 day without precipitation of solid, add 3 mL of n-heptane, precipitate solid, and stir for about 2 days to form an oil;

[0103] Step (5): Discard the supernatant, and dry the obtained oil under vacuum at room temperature overnight to obtain the amorphous solid of p-toluenesulfonate. The XRPD is as shown in the appendix Figure 18 as follows, 1 HNMR is as shown in the appendix Figure 19 as follows.

[0104] Preparation of amorphous (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one hydrochloride

[0105] Step (1): Add about 200 mg of the free base compound prepared in Example 2.1 to 2 mL of isopropanol, and dissolve it in a water bath at 60 °C to obtain Solution 1;

[0106] Step (2): Dissolve about 44 μL of hydrochloric acid in 0.4 mL of isopropanol to obtain Solution 2;

[0107] Step (3): Dropwise add Solution 2 to Solution 1 under stirring to obtain Solution 3;

[0108] Step (4): Stir Solution 3 for about 1 day without precipitation of solid, add 3 mL of n-heptane to precipitate solid, and stir for about 2 days to form an oil;

[0109] Step (5): Discard the supernatant, and dry the obtained oil under vacuum at room temperature overnight to obtain the amorphous solid of hydrochloride. The XRPD is as shown in the appendix Figure 20 as follows.

[0110] Preparation of amorphous (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one maleate

[0111] Step (1): Add about 200 mg of the free base compound prepared in Example 2.1 to 2 mL of isopropanol, and dissolve it in a water bath at 60 °C to obtain Solution 1;

[0112] Step (2): Dissolve about 62 mg of maleic acid in 0.4 mL of isopropanol to obtain Solution 2;

[0113] Step (3): Dropwise add Solution 2 to Solution 1 under stirring to obtain Solution 3;

[0114] Step (4): Stir Solution 3 for about 1 day without precipitation of solid, add 3 mL of n-heptane, precipitate solid, and stir for about 2 days to form oil;

[0115] Step (5): Discard the supernatant, and vacuum dry the obtained oil overnight at room temperature to obtain the amorphous solid of maleate. The XRPD is as shown in the appendix Figure 21 as shown, 1 The 1H NMR is as shown in the appendix Figure 22 as shown.

[0116] Preparation of amorphous (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one mesylate

[0117] Step (1): Add about 200 mg of the free base compound prepared in Example 2.1 to 2 mL of isopropanol, and dissolve it in a water bath at 60 °C to obtain Solution 1;

[0118] Step (2): Dissolve about 53 mg of methanesulfonic acid in 0.4 mL of isopropanol to obtain Solution 2;

[0119] Step (3): Dropwise add Solution 2 to Solution 1 under stirring to obtain Solution 3;

[0120] Step (4): Stir Solution 3 for about 1 day without precipitation of solid, add 3 mL of n-heptane, precipitate solid, and stir for about 2 days to form oil;

[0121] Step (5): Discard the supernatant, and vacuum dry the obtained oil overnight at room temperature to obtain the amorphous solid of methanesulfonate. The XRPD is as shown in the appendix Figure 23 as shown, 1 The 1H NMR is as shown in the appendix Figure 24 as shown.

[0122] III. Comparison of physical properties of different counterion salts

[0123] The comparison of physical properties of different salt forms is shown in Table 2. From the results in Table 2, it can be seen that benzenesulfonate Form 1 is an anhydrate with relatively high crystallinity, controllable crystal form preparation, and relatively prominent property performance.

[0124] Table 2

[0125]

[0126] IV. Comparison of Pharmacokinetic Characteristics of Free Base and Benzenesulfonate Crystal Form

[0127] The present invention also studied the comparison of pharmacokinetic parameters of (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one free base and benzenesulfonate crystal form orally administered to Wistar rats. Each group of animals for oral administration of the free base consisted of 4 rats, and each group of animals for oral administration of the benzenesulfonate consisted of 3 rats, 6 - 8 weeks old, male. Oral administration was carried out with 10% Cremophor EL + 90% (10% HP-β-CD in 1% HPMC (pH 2.2) in water). The animals in the oral administration group were fasted overnight and resumed feeding 4 hours after administration. The blood sampling points for the animals in the oral administration group were before administration and at 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration. Blood was collected from the jugular vein, and the blood volume collected at each sampling point was approximately 150 μL, anticoagulated with EDTA-K2, centrifuged at 2000 g for 5 min at 4°C within 15 minutes after sampling, and analyzed by LCMSMS-28 (Triple Quad 6500+).

[0128] Results showed that: compared with the free base, the Tmax and T of the benzenesulfonate crystal form 1 / 2 were significantly prolonged, as shown in the following table:

[0129]

Claims

1. A crystalline form of the benzenesulfonate salt of an (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one compound, characterized in that, The described crystalline form shows peaks at diffraction angles 2θ of 13.28°, 20.72°, 21.70°, 18.80°, 18.14°, 17.26°, 23.81°, 23.02°, 11.12°, 14.00°, 23.44°, 22.14° (±0.2°) in the X-ray diffraction pattern.

2. The crystalline form of the benzenesulfonate according to claim 1, wherein, It also includes peaks at diffraction angles 2θ of 27.25°, 28.31°, 22.43°, 26.47°, 34.51°, 28.84°, 20.32°, 16.52°, 27.97°, 27.251°, 26.91°, 33.14°, 31.07°, 24.96°, 8.94°, 29.31°, 29.65°, 32.60°, 31.32°, 38.81°, 33.51°, 37.77°, 37.09° (±0.2°).

3. The crystalline form of the benzenesulfonate according to claim 1 or 2, wherein, The crystalline form of the benzenesulfonate shows an X-ray diffraction pattern substantially as shown in Figure 5.

4. The preparation method of the crystalline form of the benzenesulfonate according to any one of claims 1-3, characterized in that It includes the following steps: Step (1): Weigh a certain mass of the (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one free base compound, add it to a certain volume of isopropanol solvent and dissolve it clear in a water bath to obtain Solution 1. Step (2): Weigh a certain mass of the benzenesulfonic acid ligand, ultrasonically heat and dissolve it in a certain volume of isopropanol to obtain Solution 2. Step (3): Dropwise add Solution 2 obtained in Step (2) to Solution 1 being stirred obtained in Step (1) to obtain Solution 3. Step (4): Stir Solution 3 obtained in Step (3). Since no solid is precipitated, add a certain volume of anti-solvent to the solution to precipitate a solid, and continue stirring to obtain a suspension. Step (5): Filter the suspension obtained in Step (4) under reduced pressure, rinse the surface of the filter cake with isopropanol, and vacuum dry the obtained solid at room temperature to obtain the described crystalline form.

5. The method according to claim 4, wherein, The anti-solvent in Step (4) is selected as n-heptane.

6. The method according to claim 4, wherein, The volume ratio of isopropanol in Step (1), Step (2) to the anti-solvent in Step (4) is 2:0.1 - 0.5:

3.

7. The method according to claim 4, wherein The molar ratio of the free base compound in Step (1) to the benzenesulfonic acid ligand in Step (2) is 1:1.

5.

8. The method according to claim 4, wherein The molar ratio of the free base compound in Step (1) to the benzenesulfonic acid ligand in Step (2) is 1:1.1.

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