WO2023125418A1 - Benzenesulfonic acid salt crystals and preparation method therefor - Google Patents

Abstract

The present invention relates to crystals of a benzenesulfonic acid salt of a PI3Kδ/γ dual inhibitor compound (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromene-one compound, and a preparation method therefor. A crystalline form of the present invention has excellent properties in terms of physical properties and pharmacodynamics/pharmacokinetics.

Description

A kind of benzene sulfonate crystal and preparation method thereof

This application claims the priority of the following Chinese patent applications: 1) Submitted to the State Intellectual Property Office of China on December 31, 2021, the application number is 202111679211.9, and the title of the invention is "a benzenesulfonate crystal and its preparation method" Chinese patent application; 2) A Chinese patent application submitted to the State Intellectual Property Office of China on March 11, 2022 with the application number 202210245007.4 and the title of the invention "a benzenesulfonate crystal and its preparation method". The entire contents of the above-mentioned Chinese patent applications are incorporated in this application by reference.

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) Crystallization of besylate salt of 4H-chromen-4-one compound and process for its preparation.

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 for 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 a significant advantage in stability relative to 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 are expected to have improved chemical and physical properties, 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, which have superior properties in terms of physical properties and pharmacodynamics/pharmacokinetics, and have higher applicability as pharmaceuticals.

Contents of the invention

The invention provides a benzene compound of (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromene-4-one compound A crystalline form of sulfonate, characterized in that the crystalline form shows 13.28°, 20.72°, 21.70°, 18.80°, 18.14°, 17.26°, 23.81°, 23.02°, 11.12°, Peaks at diffraction angles 2θ of 14.00°, 23.44°, 22.14° (±0.2°).

Further, the benzenesulfonate crystalline form also includes crystals at 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°) at the diffraction angle 2θ.

Further, the crystalline form of besylate salt shows an X-ray diffraction pattern substantially as shown in FIG. 5 .

In addition, the present invention also provides a (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromene- Process for the preparation of crystalline forms of besylate salts of 4-keto compounds, 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 isopropanol solvent and dissolved in a water bath to obtain solution 1;

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

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

Step (4): Stir the solution 3 obtained in step (3), and no solid is precipitated, and a certain volume of anti-solvent is added to the solution to precipitate a solid, and the stirring is continued 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 crystalline form.

In the preferred technical solution of the present invention, wherein, the anti-solvent in step (4) is selected from n-heptane.

In the preferred technical solution of the present invention, wherein, the volume ratio of the volume of isopropanol in step (1), step (2) to the antisolvent in step (4) is 2:0.1-0.5:3.

In the preferred technical solution of the present invention, wherein, 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.

Benzenesulfonate 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 exhibit excellent pharmacokinetics, and can be used as PI3K δ/γ inhibitors.

Description of drawings

The XRPD figure of accompanying drawing 1 free base compound

The TGA figure of accompanying drawing 2 free alkali compounds

The DSC figure of accompanying drawing 3 free alkali compounds

The ¹ HNMR figure of accompanying drawing 4 free base compound

The XRPD figure of accompanying drawing 5 besylate crystal form

The TGA figure of accompanying drawing 6 besylate crystal form

The DSC figure of accompanying drawing 7 besylate crystal form

DVS figure and isotherm adsorption curve of accompanying drawing 8 besylate crystalline forms

The PLM figure of accompanying drawing 9 besylate crystal form

The ¹ HNMR figure of accompanying drawing 10 besylate crystal form;

Accompanying drawing 11 XRPD pattern of citrate amorphous

Accompanying drawing 12 The ¹ HNMR figure of amorphous citrate

Accompanying drawing 13L-malate amorphous XRPD pattern

Accompanying drawing 14 L-malate amorphous ¹ HNMR figure

Accompanying drawing 15 XRPD pattern of amorphous sulfate

Accompanying drawing 16L-tartrate amorphous XRPD pattern

Accompanying drawing 17L-tartrate amorphous ¹ HNMR figure

Accompanying drawing 18 is the XRPD pattern of p-toluenesulfonic acid amorphous

Accompanying drawing 19 p-toluenesulfonic acid amorphous ¹ HNMR figure

Accompanying drawing 20 hydrochloride amorphous XRPD pattern

Accompanying drawing 21 XRPD pattern of maleate salt amorphous

Accompanying drawing 22 maleate salt amorphous ¹ HNMR figure

Accompanying drawing 23 XRPD pattern of the amorphous form of mesylate

Accompanying drawing 24 mesylate amorphous ¹ HNMR figure

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 Q200 DSC. 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 adsorption (DVS)

Dynamic moisture adsorption was performed using TA Instruments Q5000 SA. 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 subjected to a cycle test in 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-chromene-4-one free base compound

(S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromene-4-one is prepared by referring to the method of patent document CN105358560A embodiment Free base compound, wherein, the XRPD spectrum of the free base compound is shown in Figure 1, the TGA spectrum is shown in Figure 2, the DSC spectrum is shown in Figure 3, and ^{the 1} HNMR spectrum is shown in Figure 4.

2.2 Preparation of (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromene-4-one benzenesulfonate crystal form

Step (1): About 200 mg of the free base compound prepared in Example 2.1 was added to 2 mL of isopropanol, and dissolved in a water bath at 60 ° C to obtain solution 1;

Step (2): about 94 mg of benzenesulfonic acid was dissolved in 0.4 mL of isopropanol by ultrasonic heating to obtain solution 2;

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

Step (4): The solution 3 was stirred for about 1 day without solid precipitation, and 3 mL of n-heptane was added to precipitate a solid, which turned into oil after stirring, and continued stirring for about 2 days to obtain a suspension.

Step (5): The suspension was suction-filtered under reduced pressure, the surface of the filter cake was washed with isopropanol, and the obtained solid was vacuum-dried overnight at room temperature to obtain crystalline form 1 of besylate salt (about 200 mg).

The product is characterized, its XRPD spectrum is shown in accompanying drawing 5, TGA and DSC collection of illustrative plates are shown in accompanying drawing 6 and accompanying drawing 7 respectively, DVS and isothermal adsorption curve are as shown in accompanying drawing 8, and PLM is as shown in accompanying drawing 9 ¹ HNMR is shown in Figure 10.

The crystalline form of the product obtained by selecting different solvents and the test process is shown in Table 1:

Table 1. Crystalline morphology of products obtained in different solvents and test procedures

Wherein, in the above table, API represents the free base compound prepared in Example 2.1, base represents the free base compound, and acid represents the benzenesulfonic acid pair ion ligand.

2.3 Preparation of (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one citric acid amorphous salt

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

Step (2): about 103 mg of citric acid was dissolved in 0.8 mL of isopropanol to obtain solution 2;

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

Step (4): Solution 3 was stirred overnight without solid precipitation, and 3 mL of n-heptane was added to solution 3 to precipitate solid, which turned into oil after stirring;

Step (5): The supernatant was discarded, and the obtained oil was vacuum-dried at room temperature overnight to obtain an amorphous solid of citrate, whose XRPD is shown in Figure 11 and ¹ HNMR is shown in Figure 12 .

2.4 (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one L-malic acid amorphous salt preparation

Step (1): about 200mg of the free base compound prepared in Example 2.1, add 2mL of isopropanol, dissolve in a water bath at 60°C, solution 1;

Step (2): about 73mg L-malic acid was dissolved in 0.8mL isopropanol to obtain solution 2;

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

Step (4): Solution 3 was stirred overnight without solid precipitation, and 3 mL of n-heptane was added to Solution 3, and oil was precipitated after stirring for about 2 days;

Step (5): The supernatant was discarded, and the obtained oil was vacuum-dried overnight at room temperature to obtain an amorphous solid of L-malate, whose XRPD is shown in Figure 13 and ¹ HNMR is shown in Figure 14 .

2.5 Preparation of (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromene-4-one sulfate

Step (1): About 200 mg of the free base compound prepared in Example 2.1 was added to 2 mL of isopropanol, and dissolved in a water bath at 60°C to obtain solution 1;

Step (2): About 55 mg of sulfuric acid was dissolved in 0.4 mL of isopropanol to obtain solution 2;

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

Step (4): Solids were precipitated from solution 3 immediately, dissolved after stirring for about 1 day, and 4 mL of n-heptane was added, solids were precipitated, and oil was formed after stirring for about 2 days;

Step (5): The supernatant was discarded, and the obtained oil was vacuum-dried overnight at room temperature to obtain an amorphous sulfate sulfate solid, whose XRPD is shown in Figure 15 .

2.6 Preparation of amorphous form of (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromene-4-one L-tartrate

Step (1): about 200mg of the free base compound prepared in Example 2.1, add 2mL of isopropanol, dissolve in a water bath at 60°C, solution 1;

Step (2): about 80mg L-tartaric acid was dissolved in 0.8mL isopropanol to obtain solution 2;

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

Step (4): The solution 3 was slightly turbid, and a large amount of solids did not precipitate out after stirring overnight. Add 3mL of n-heptane, the solids precipitated, and stirred for about 2 days to form an oil;

Step (5): The supernatant was discarded, and the obtained oil was vacuum-dried at room temperature overnight to obtain an amorphous solid of L-tartrate salt, whose XRPD is shown in Figure 16 and ¹ HNMR is shown in Figure 17 .

2.7 (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one p-toluenesulfonate amorphous preparation

Step (1): About 200 mg of the free base compound prepared in Example 2.1 was added to 2 mL of isopropanol, and dissolved in a water bath at 60 ° C to obtain solution 1;

Step (2): about 93 mg of p-toluenesulfonic acid was dissolved in 0.4 mL of isopropanol to obtain solution 2;

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

Step (4): Solution 3 was stirred for about 1 day without solid precipitation, added 3 mL of n-heptane, solid was precipitated, and stirred for about 2 days to form an oil;

Step (5): The supernatant was discarded, and the obtained oil was vacuum-dried overnight at room temperature to obtain an amorphous solid of p-toluenesulfonate, whose XRPD is shown in Figure 18 and ¹ HNMR is shown in Figure 19 .

2.8 Preparation of amorphous form of (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromene-4-one hydrochloride

Step (1): About 200 mg of the free base compound prepared in Example 2.1 was added to 2 mL of isopropanol, and dissolved in a water bath at 60 ° C to obtain solution 1;

Step (2): about 44 μL of hydrochloric acid was dissolved in 0.4 mL of isopropanol to obtain solution 2;

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

Step (4): Solution 3 was stirred for about 1 day without precipitation of solids, and 3 mL of n-heptane was added to precipitate solids, and stirred for about 2 days to form an oil;

Step (5): The supernatant was discarded, and the obtained oil was vacuum-dried at room temperature overnight to obtain an amorphous hydrochloride solid, and its XRPD is shown in Figure 20.

2.9 Preparation of amorphous form of (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromene-4-one maleate

Step (1): About 200 mg of the free base compound prepared in Example 2.1 was added to 2 mL of isopropanol, and dissolved in a water bath at 60 ° C to obtain solution 1;

Step (2): About 62 mg of maleic acid was dissolved in 0.4 mL of isopropanol to obtain solution 2;

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

Step (4): Solution 3 was stirred for about 1 day without solid precipitation, added 3 mL of n-heptane, solid was precipitated, and stirred for about 2 days to form an oil;

Step (5): The supernatant was discarded, and the obtained oil was vacuum-dried overnight at room temperature to obtain an amorphous maleate salt, whose XRPD is shown in Figure 21 and ¹ HNMR is shown in Figure 22 .

3.0 Preparation of amorphous form of (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromene-4-one methanesulfonate

Step (1): About 200 mg of the free base compound prepared in Example 2.1 was added to 2 mL of isopropanol, and dissolved in a water bath at 60 ° C to obtain solution 1;

Step (2): about 53 mg of methanesulfonic acid was dissolved in 0.4 mL of isopropanol to obtain solution 2;

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

Step (4): Solution 3 was stirred for about 1 day without solid precipitation, added 3 mL of n-heptane, solid was precipitated, and stirred for about 2 days to form an oil;

Step (5): The supernatant was discarded, and the obtained oil was vacuum-dried overnight at room temperature to obtain an amorphous solid of mesylate salt, whose XRPD is shown in Figure 23 and ¹ HNMR is shown in Figure 24 .

3. Comparison of physical properties of different counterion salt types

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 the crystalline form 1 of besylate salt is an anhydrous substance with high crystallinity, controllable crystal form preparation, and relatively outstanding properties.

Table 2. Comparison of physical properties of different salt types

4. Comparison of pharmacokinetic characteristics of free base and crystalline form of besylate

The present invention also studies (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one free base and benzene The comparison of the pharmacokinetic parameters of the oral administration of the sulfonate crystalline form to Wistar rats, the oral administration of the free base is 4 animals, and the oral administration of the besylate salt is 3 animals, 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 compared with the free base, the Tmax and T1 _/2 of the crystalline form of besylate are significantly prolonged, as shown in the table below:

Table 3. Comparison of Pharmacokinetic Profiles of Free Base and Besylate Salt Crystalline Forms

Claims (7)

1. A kind of benzenesulfonate of (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one compound A crystalline form, characterized in that the crystalline form shows 13.28°, 20.72°, 21.70°, 18.80°, 18.14°, 17.26°, 23.81°, 23.02°, 11.12°, 14.00°, 23.44° on the X-ray diffraction pattern °, the peak at the diffraction angle 2θ of 22.14° (±0.2°).
2. The crystalline form of besylate salt as claimed in claim 1, wherein, also included at 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°) diffraction angle 2θ peaks .
3. The crystalline form of besylate salt according to claim 1 or 2, wherein said crystalline form of besylate salt exhibits an X-ray diffraction pattern substantially as shown in FIG. 5 .
4. The preparation method of the crystalline form of besylate as claimed 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- The ketone free base compound is added to a certain volume of isopropanol solvent and dissolved in a water bath to obtain solution 1;

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

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

   Step (4): Stir the solution 3 obtained in step (3), and no solid is precipitated, and a certain volume of anti-solvent is added to the solution to precipitate a solid, and the stirring is continued 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 crystalline form.
5. The method according to claim 4, wherein the antisolvent in step (4) is selected n-heptane.
6. The method according to claim 4, wherein the volume ratio of the volume of isopropanol in step (1), step (2) to the antisolvent 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, preferably 1:1.1.

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