Crystal form of benzene sulfonate containing piperidine ring compound, and preparation method therefor and use thereof

Abstract

Disclosed in the present invention are a crystal form of a benzene sulfonate containing a piperidine ring compound, and a preparation method therefor and the use thereof. Provided in the present invention is a crystal form A1 of compound (2). In an X-ray powder diffraction pattern (Cu-Kα radiation) of the crystal form at diffraction angles as represented by the 2θ angle, diffraction peaks appear at 5.971°±0.200°, 7.088°±0.200°, 12.068°±0.200°, 15.881°±0.200°, 20.557°±0.200° and 21.599°±0.200°. The crystal form can exist stably, and the content of isomer impurities as represented by formula (1') can be obviously reduced by means of crystal form preparation steps.

Description

A crystalline form of a benzenesulfonate salt of a piperidine ring compound, its preparation method and application

[0001] This application claims priority to Chinese patent application CN2023115840114, filed on November 24, 2023. This application incorporates the entire text of the aforementioned Chinese patent application. Technical Field

[0002] The present invention relates to a crystal form of a benzenesulfonate salt of a piperidine ring-containing compound, a preparation method and application thereof. Background Art

[0003] Compound 1 is a compound with antiplatelet activity. The compound can generate active metabolites of clopidogrel through the action of hydrolases in the body, thereby further irreversibly inhibiting platelet coagulation activity.

[0004] The crude product of Compound 1 obtained by the prior art preparation process contains an isomeric impurity represented by Formula 1' (referred to as impurity 1'). Impurity 1' cannot be removed by conventional purification methods such as recrystallization and column chromatography. Compound 1 also cannot form a salt with a stable crystalline form with conventional acids or bases, such as hydrochloric acid, sulfuric acid, and sodium hydroxide.

[0005] Impurity 1' characterization data: LCMS: [M+H] + =472.1; 1 H NMR: (400MHz, DMSO-d6) δ = 12.52 (br s, 1H), 7.53-7.44 (m, 2H), 7.43-7.34 (m, 2H), 5.66 (s, 1H), 5.34 (br d, J=2.8Hz, 1H), 5.27 (d, J=12.1Hz, 1H), 5.10 (d, J=12.1Hz, 1H), 4.82-4.70 (m, 2H), 3.65 (s, 3H), 3.45 (d, J=12.1Hz, 1H), 3.10 (br d, J=12.5Hz, 1H), 2.75-2.57(m, 2H), 2.11-1.98(m, 1H), 1.82(br dd, J=1.8, 14.2Hz, 1H), 1.22 (dd, J=2.8, 6.2Hz, 6H). Summary of the Invention

[0006] The technical problem to be solved by the present invention is to overcome the drawback of the prior art that isomeric impurities such as those represented by Formula 1' are difficult to remove. In particular, the content of impurity 1' is reduced from approximately 2% to even lower, thereby providing a crystalline form of a benzenesulfonate salt of a piperidine ring-containing compound, a preparation method, and applications thereof. The present invention unexpectedly discovered that compound 1 can form a salt with benzenesulfonic acid, further yielding a stable crystalline form. By preparing this crystalline form, the aforementioned isomeric impurities can be removed. This step significantly reduces the content of the isomeric impurities represented by Formula 1'.

[0007] The present invention mainly solves the above technical problems through the following technical solutions.

[0008] The present invention provides a crystalline form A1 of compound 2, which has an X-ray powder diffraction pattern expressed in 2θ angles using Cu-Kα radiation, and has diffraction peaks at 5.971°±0.200°, 7.088°±0.200°, 12.068°±0.200°, 15.881°±0.200°, 20.557°±0.200° and 21.599°±0.200°;

[0009] In a preferred embodiment, the crystalline form A1 of the compound 2 has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, and further has characteristic peaks at one or more of 7.742°±0.200°, 17.257°±0.200°, 21.259°±0.200°, 23.137°±0.200° and 24.134°±0.200°; preferably, the crystalline form A1 of the compound 2 has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, and the diffraction peaks and relative intensities are:

[0010] For example, the crystalline form A1 of the compound 2 has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles as shown in FIG1 .

[0011] In a preferred embodiment, the thermogravimetric analysis (TGA) of the crystalline form A1 of the compound 2 shows a weight loss of 3.63% at 27-100° C., where “%” refers to mass percentage.

[0012] In a preferred embodiment, the TGA diagram of the crystalline form A1 of the compound 2 is substantially as shown in FIG3 .

[0013] The present invention provides a crystalline form F1 of compound 2, which has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, and has diffraction peaks at 17.006°±0.200°, 20.439°±0.200°, 22.149°±0.200° and 23.629°±0.200°;

[0014] In a preferred embodiment, the crystalline form F1 of the compound 2, which uses Cu-Kα radiation and an X-ray powder diffraction pattern expressed in 2θ angles, further has characteristic peaks at one or more of 17.891°±0.200°, 19.671°±0.200°, 27.740°±0.200° and 28.842°±0.200°; preferably, the crystalline form A1 of the compound 2, which uses Cu-Kα radiation and an X-ray powder diffraction pattern expressed in 2θ angles, has diffraction peaks and relative intensities as follows:

[0015] For example, the X-ray powder diffraction pattern of the crystalline form F1 of the compound 2 using Cu-Kα radiation and expressed in 2θ angles is substantially as shown in FIG4 .

[0016] In a preferred embodiment, the thermogravimetric analysis (TGA) of the crystalline form F1 of the compound 2 shows a weight loss of 0.5% at 32-130° C., where “%” refers to mass percentage.

[0017] In a preferred embodiment, the TGA diagram of the crystalline form F1 of the compound 2 is substantially as shown in FIG5 .

[0018] In a preferred embodiment, the differential scanning calorimetry (DSC) of the crystalline form F1 of compound 2 has an endothermic peak at 147.8°C.

[0019] In a preferred embodiment, the DSC graph of the crystalline form F1 of the compound 2 is substantially as shown in FIG6 .

[0020] The present invention also provides a method for preparing the crystalline form A1 of the compound 2, which comprises the following operations: crystallizing the compound 2 in a solvent, or mixing the compound 1 with benzenesulfonic acid in a solvent, wherein the solvent is a mixed solvent of an ether solvent and acetonitrile; further, the method comprises the following operations: mixing a solution 1 containing the compound 1 with a solution 2 containing the benzenesulfonic acid for reaction; wherein the solvent of the solution 1 is a mixed solvent of an ether solvent and acetonitrile; the solvent of the solution 2 is a mixed solvent of an ether solvent and / or acetonitrile; the ether solvent may be isopropyl ether;

[0021] In the preparation method of the crystalline form A1 of the compound 2, the purity of the compound 1 can be 90%-99.6%, for example, 92.6%, 94.3%, 95.8% or 99%.

[0022] In one embodiment, the compound 1 is a crude product of the compound 1, which is a mixture of the compound 1 and an isomeric impurity represented by formula 1'; the mass ratio of the compound 1 to the isomeric impurity may be (10-500):1, for example, 15.433:1, 23.575:1, 23.95:1 or 220:1;

[0023] In one embodiment, in the preparation method of the crystalline form A1 of the compound 2, when the solvent is an ether solvent and a nitrile solvent, the volume ratio of the ether solvent to the nitrile solvent can be (1-10):1, for example, 5:1 or 7:1.

[0024] In one embodiment, in the preparation method of the crystalline form A1 of the compound 2, the mass volume ratio of the compound 1 to the solvent of the solution 1 can be 1:(1-15) g / ml, or 1:(1-10) g / ml, for example, 1:6 g / ml and 1:10 g / ml.

[0025] In one embodiment, in the preparation method of the crystalline form A1 of the compound 2, the molar ratio of the benzenesulfonic acid to the compound 1 can be (0.9-1.2):1, for example, 1.1:1.

[0026] In one embodiment, in the preparation method of the crystalline form A1 of the compound 2, the mass volume ratio of the benzenesulfonic acid to the solvent of the solution 2 can be 1: (0.1-10) g / ml, for example, 1: 6 g / ml or 1: 10 g / ml.

[0027] In one embodiment, the preparation method of the crystalline form A1 of the compound 2 may further include the operation of mixing with the crystalline form A1 of the compound 2 as described above as a benzenesulfonate seed crystal; the mass ratio of the benzenesulfonate seed crystal to the compound 1 may be 1: (20-100), for example 1:50.

[0028] In one embodiment, in the preparation method of the crystalline form A1 of the compound 2, the mass volume ratio of the benzenesulfonate seed crystals to the solvent of the solution 3 can be 1: (6000-10000) g / ml, for example 1: 8000 g / ml.

[0029] In one embodiment, the method for preparing the crystalline form A1 of compound 2 can be performed by adding solution 2 containing benzenesulfonic acid to solution 1 containing compound 1, and the addition rate can be 0.1-1 V / h, for example, 1 V / h.

[0030] In one embodiment, the preparation method of the crystalline form A1 of the compound 2 may further include the operation of mixing with a solution 3 containing the crystalline form A1 of the compound 2 as described above as a benzenesulfonate seed crystal; the solvent of the solution 3 is an ether solvent and / or a mixed solvent of acetonitrile; the ether solvent may be isopropyl ether; further, the solution 1 containing the compound 1 and the solution 2 containing benzenesulfonic acid may be added to the solution 3 containing the benzenesulfonate seed crystal, and the addition rate may be 0.1-1V / h, for example, 0.4V / h or 0.8V / h.

[0031] In one embodiment, in the method for preparing the crystalline form A1 of compound 2, the mixing temperature can be a conventional temperature for this type of reaction in the art, such as 25°C.

[0032] In one embodiment, in the preparation method of the crystalline form A1 of compound 2, the mixing reaction time can be 0.1-100 hours, for example, 3 hours, 17 hours or 72 hours.

[0033] The present invention also provides a method for preparing the crystalline form F1 of the compound 2, comprising the following operations: crystallizing the compound 2 in a solvent, or mixing the compound 1 with benzenesulfonic acid in a solvent, wherein the solvent is an ester solvent; further comprising the following operations: mixing a solution 1 containing the compound 1 with a solution 2 containing benzenesulfonic acid; wherein the solvent of the solution 1 is an ester solvent or an ether solvent; the solvent of the solution 2 is an ester solvent; the ester solvent may be ethyl acetate and / or isopropyl acetate; the ether solvent may be tetrahydrofuran;

[0034] In the preparation method of the crystalline form F1 of the compound 2, the purity of the compound 1 can be 90%-99.6%, for example, 95.8%, 97.14% or 97.5%.

[0035] In one embodiment, the compound 1 is a crude product of the compound 1, which is a mixture of the compound 1 and an isomeric impurity represented by formula 1'; the mass ratio of the compound 1 to the isomeric impurity may be (10-500):1, for example, 23.95:1, 33.965:1 or 42.026:1;

[0036] In one embodiment, in the preparation method of the crystalline form F1 of the compound 2, the mass volume ratio of the compound 1 to the solvent of the solution 1 can be 1:(1-15) g / ml, or 1:(1-10) g / ml, for example, 1:2.3 g / ml, 1:4 g / ml or 1:6 g / ml.

[0037] In one embodiment, in the preparation method of the crystalline form F1 of the compound 2, the molar ratio of the benzenesulfonic acid to the compound 1 can be (0.9-1.2):1, for example, 0.98:1 or 1:1.

[0038] In one embodiment, in the preparation method of the crystalline form F1 of the compound 2, the mass volume ratio of the benzenesulfonic acid to the solvent of the solution 2 can be 1: (0.1-10) g / ml, for example, 1: 0.7 g / ml, 1: 1 g / ml or 1: 4 g / ml.

[0039] In one embodiment, the preparation method of the crystalline form F1 of the compound 2 may further include the operation of mixing with the crystalline form F1 of the compound 2 as described above as a benzenesulfonate seed crystal; the molar ratio of the compound 1 to the seed crystal is 1: (0.01%-1%), for example 1: 0.1%.

[0040] In one embodiment, the method for preparing Form F1 of Compound 2 may further include mixing with a solvent 3; the solvent 3 is an alkane solvent, which may be n-heptane. The mass-to-volume ratio of Compound 1 to Solvent 3 is 1:(3-45) g / ml, for example, 1:27 g / ml.

[0041] In one embodiment, the method for preparing the crystalline form F1 of compound 2 may further include adding solvent 3 to a mixed solution of solution 1 containing compound 1 and solution 2 containing benzenesulfonic acid, and the addition rate may be 0.1-3 V / h, for example, 1.5 V / h.

[0042] In one embodiment, the method for preparing Form F1 of Compound 2 may further include thermal cycling. The number of thermal cycles may be conventional for such reactions in the art, for example, 5 times. The temperature of the thermal cycle may be 25°C to -10°C.

[0043] The present invention also provides a use of the aforementioned crystalline form A1 or F1 of compound 2 in the preparation of compound 1;

[0044] The present invention also provides a method for purifying compound 1, which comprises the following steps:

[0045] Option 1:

[0046] S1: a method for preparing the crystalline form A1 of compound 2 as described in any of the previous schemes;

[0047] S2: The crystalline form A1 of the compound 2 is hydrolyzed to prepare compound 1;

[0048] Option 2:

[0049] S1: a method for preparing the crystalline form F1 of compound 2 as described in any of the previous schemes;

[0050] S2: Compound 1 is prepared by hydrolyzing the crystalline form F1 of compound 2.

[0051] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0052] The reagents and raw materials used in the present invention are commercially available.

[0053] The positive progress of the present invention is that: the present invention provides a crystalline form of a benzenesulfonate salt of a piperidine ring compound, a preparation method and application thereof, the crystalline form can exist stably, and the content of isomer impurities such as those shown in Formula 1' can be significantly reduced through the steps of preparing the crystalline form. BRIEF DESCRIPTION OF THE DRAWINGS

[0054] FIG1 is an XRPD pattern of Form A1 of Compound 2 in Example.

[0055] Figure 2 is a diagram of the crystalline form A1 of compound 2 in the example 1 H-NMR spectrum.

[0056] FIG3 is a TGA chart of Form A1 of Compound 2 in Example.

[0057] FIG4 is an XRPD pattern of Form F1 of Compound 2 in Example.

[0058] FIG5 is a TGA chart of Form F1 of Compound 2 in Example.

[0059] FIG6 is a DSC graph of Form F1 of Compound 2 in Example.

[0060] FIG7 is an XRPD pattern of Form A2 of Compound 2 in Example.

[0061] FIG8 is an XRPD pattern of Form A3 of Compound 2 in Example.

[0062] FIG9 is an XRPD pattern of Form A4 of Compound 2 in Example.

[0063] FIG10 is a TGA chart of Form A4 of Compound 2 in Example.

[0064] FIG11 is a DSC graph of Form A4 of Compound 2 in Example.

[0065] FIG12 is an XRPD pattern of Form A5 of Compound 2 in Example.

[0066] FIG13 is an XRPD pattern of Form B1 of Compound 2 in Example.

[0067] FIG14 is a TGA chart of Form B1 of Compound 2 in Example.

[0068] FIG15 is a DSC graph of Form B1 of Compound 2 in Example.

[0069] FIG16 is an XRPD pattern of Form B2 of Compound 2 in Example.

[0070] FIG17 is an XRPD pattern of Form B3 of Compound 2 in Example.

[0071] FIG18 is an XRPD pattern of Form C of Compound 2 in Example.

[0072] FIG19 is a TGA chart of Form C of Compound 2 in Example.

[0073] FIG20 is a DSC graph of Form C of Compound 2 in Example.

[0074] FIG21 is an XRPD pattern of Form D of Compound 2 in Example.

[0075] FIG22 is a TGA chart of Form D of Compound 2 in Example.

[0076] FIG23 is a DSC graph of Form D of Compound 2 in Example.

[0077] FIG24 is an XRPD pattern of Form E1 of Compound 2 in Example.

[0078] FIG25 is an XRPD pattern of Form E2 of Compound 2 in Example.

[0079] FIG26 is a TGA chart of Form E2 of Compound 2 in Example.

[0080] FIG27 is a DSC graph of Form E2 of Compound 2 in Example.

[0081] FIG28 is an XRPD pattern of Form F2 of Compound 2 in Example.

[0082] FIG29 is an XRPD pattern of Form G of Compound 2 in Example.

[0083] Figure 30 is a TGA chart of Form G of Compound 2 in Example.

[0084] FIG31 is a DSC graph of Form G of Compound 2 in Example.

[0085] FIG32 is an XRPD pattern of Form H of Compound 2 in Example.

[0086] FIG33 is an XRPD pattern of Form I of Compound 2 in Example.

[0087] Figure 34 is a diagram of the crystalline form F1 of compound 2 in the example 1 H-NMR spectrum. DETAILED DESCRIPTION

[0088] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0089] Abbreviation table:

[0090] The test methods involved in the following embodiments are as follows:

[0091] X-ray powder diffractometer (XRPD) method

[0092] Instrument model: PANalytical, Empyrean powder X-ray diffractometer

[0093] Test Method: Prepare samples on a zero-background silicon wafer by gently pressing on a flat surface. Approximately 10-20 mg of sample is used for XRPD analysis.

[0094] The detailed XRPD parameters are as follows:

[0095] Thermogravimetric analysis (TGA) method

[0096] Instrument model: TA Discovery TGA55 thermogravimetric analyzer

[0097] Test method: Place a sample (3-5 mg) in a pre-weighed aluminum pan, heat according to the parameters shown below, and analyze the data using TRIOS.

[0098] The detailed TGA parameters are as follows:

[0099] Differential Scanning Calorimeter (DSC) method

[0100] Instrument model: American TA differential scanning calorimeter Discovery DSC 250

[0101] Test method: Take a sample (2-3 mg) and place it in an aluminum pan with a pinhole and heat it according to the following parameters. Use TRIOS to analyze the data.

[0102] The detailed DSC parameters are as follows:

[0103] DVS:

[0104] Instrument model: SMS, DVS Intrinsic

[0105] Test method: Place 20-30 mg of sample into the oil-coated sample chamber and automatically weigh it. Analyze the sample according to the parameters set in Table 21.

[0106] The detailed DVS parameters are as follows:

[0107] 1 H-NMR method

[0108] Instrument model: Bruker 400MHz instrument

[0109] Test method: collected on a Bruker 400MHz instrument 1 H-NMR spectroscopy. Unless otherwise stated, samples were prepared in DMSO-d6 solvent and measured using the following parameters. Data were analyzed using MestReNova.

[0110] Detailed 1 H-NMR parameters are as follows:

[0111] High Performance Liquid Chromatography (HPLC)

[0112] The detailed parameters are as follows:

[0113] Example 1 Preparation of Compound 1

[0114] Compound 1 was prepared according to the protocol described in Example 1 of patent WO2022022559. The resulting compound 1 contained an impurity content of approximately 4%-6%. Purification of this compound by column chromatography (EA / PE = 1:10) reduced the impurity 1' content to 2.5%-3%, but this could not be further reduced.

[0115] Example 2 Preparation of Form A1

[0116] At 25°C, compound 1 (2 g, 95.8% purity, including 4% impurity 1') was dissolved in 6 V of IPE / ACN solution (5:1 by volume) to obtain mixture 1. Benzenesulfonic acid (684 mg) was added to the 6 V IPE / ACN solution (5:1 by volume) to obtain mixture 2. Mixtures 1 and 2 were mixed and stirred for 3 hours. The resulting mixture was filtered, and the filter cake was vacuum-dried at 30°C to obtain compound 1 benzenesulfonate salt Form A1. Form A1 had a purity of 98.54% and an impurity 1' content of 0.65%. Testing confirmed the crystalline form to be consistent with Example 3.

[0117] Example 3 Preparation of Form A1

[0118] Compound 1 (1 g, 99% purity, impurity 1' content 0.45%) was dissolved in a 10V IPE / ACN solution (7:1 by volume) at 25°C. A 10wt% solution of benzenesulfonic acid (335 mg) in IPE (3350 mL) was added to the solution at a rate of 1V / h, and the mixture was stirred for 3 days. The resulting mixture was filtered, and the filter cake was vacuum-dried at 30°C to obtain Compound 1 benzenesulfonate salt Form A1 with a purity of 99.5% and an impurity 1' content of less than 0.1%. The confirmation results of this form are shown in Figures 1-3.

[0119] Example 4 Preparation of Form A1

[0120] At 25°C, compound 1 (2 g, 94.3% purity, including 4% impurity 1') was dissolved in 6 V of IPE / ACN solution (5:1 by volume) to obtain mixture 1. Benzenesulfonic acid (684 mg) was added to the 6 V IPE / ACN solution (5:1 by volume) to obtain mixture 2. 40 mg of seed crystals (e.g., benzenesulfonate Form A1 prepared in Example 3) were added to 320 mL of IPE / ACN solution (5:1 by volume) to obtain mixture 3. Mixture 1 and mixture 2 were added to mixture 3 at a rate of 0.4 V / h, and the mixture was stirred for 3 hours. The resulting mixture was filtered, and the filter cake was vacuum-dried at 30°C to obtain compound 1 benzenesulfonate Form A1. Testing confirmed the crystalline form consistent with that of Example 3, with a purity of 99.04% and an impurity 1' content of 0.35%.

[0121] Example 5 Preparation of Form A1

[0122] At 25°C, compound 1 (5 g, 92.6% purity, including 6% impurity 1') was dissolved in 6 V of IPE / ACN solution (5:1 by volume) to obtain mixture 1. Benzenesulfonic acid (1.7 g) was added to 3000 mL of the 6 V IPE / ACN solution (5:1 by volume) to obtain mixture 2. 100 mg of seed crystals (e.g., benzenesulfonate Form A1 prepared in Example 3) were added to 800 mL of the 5:1 by volume IPE / ACN solution to obtain mixture 3. Mixture 1 and mixture 2 were added to mixture 3 at a rate of 0.8 V / h, and the mixture was stirred for 17 hours. The resulting mixture was filtered, and the filter cake was vacuum-dried at 30°C to obtain compound 1 benzenesulfonate Form A1 with a purity of 99.6% and an impurity 1' content of 0.21%.

[0123] Example 6 Preparation of Form F1

[0124] At 25°C, compound 1 (1 g, purity 95.8%, of which the impurity 1' content was 4%) was dissolved in THF (2.3 V), and benzenesulfonic acid (1 eq) was dissolved in THF (0.7 V). The two solutions were then mixed and stirred at 25°C for 2 hours. n-Heptane (27 V) was added to the mixed solution at a temperature of 25°C and a flow rate of 1.5 V / h. After the addition was completed, the mixture was kept warm for 3 hours. The mixture was filtered, and 50 mg of the filter cake was dried and dissolved in isopropanol (6 V) at 50°C. The resulting solution or thin suspension was filtered through a 0.45 μm syringe membrane filter, and the filtrate was then cooled to 5°C at a rate of 0.1°C / min. The sample without precipitate at 5°C was further cooled to -20°C. The mixture was filtered to obtain a filter cake, which was dried to obtain benzenesulfonate salt form F1.

[0125] Example 7 Preparation of Form F1

[0126] At 25°C, compound 1 (2 g, purity 97.14%, of which the impurity 1' content was 2.86%) was added to IPAc (4V), and then a solution of benzenesulfonic acid (0.98 eq) in IPAc (1V) was added thereto, stirred for 20 minutes, and Form F1 seed crystals (for example, the benzenesulfonate Form F1 prepared in Example 6) (0.1% eq) were added. After that, the mixture was subjected to 5 thermal cycles (temperature 25°C to -10°C), filtered and the filter cake was washed with IPAc (2V), and dried at 25°C with a nitrogen flow for 24 hours to obtain Compound 1 benzenesulfonate Form F1, whose characterization spectrum is shown in Figures 4-6 and 34, with a purity of 99.3%, and the content of impurity 1' is less than 0.1%.

[0127] Example 8 Preparation of Form F1

[0128] At 25°C, compound 1 (2 g, 97.5% purity, including 2.32% impurity 1') was added to ethyl acetate (6 V) to obtain mixture 1. Benzenesulfonic acid (0.98 eq) and ethyl acetate (4 V) were mixed to obtain mixture 2. A portion of mixture 2 was added to mixture 1, followed by the addition of Form F1 seed crystals (e.g., benzenesulfonate Form F1 prepared in Example 6) (0.1% eq), and then the remainder of mixture 2. After the addition was complete, the mixture was stirred for 19 hours, cooled to 0°C, and stirred for an additional 5.5 hours. The mixture was filtered, and the filter cake was washed with ethyl acetate (2 V) and dried at 25°C for 20 hours to obtain compound 1 benzenesulfonate Form F1 with a purity of 99.5% and an impurity 1' content of less than 0.1%.

[0129] Effect Example 1 Crystal Stability Study

[0130] Three portions of Compound 1 benzenesulfonate salt forms A1 and F1 were stored under different conditions for a certain period of time. The storage conditions and storage times are shown in the table below. Afterwards, the crystal state of each group was tested by XRPD, and the results are listed in the table below.

[0131] The results show that the crystal form has good stability at different temperatures and is not prone to crystal transformation.

[0132] Effect Example 2 Crystal Solubility Study

[0133] Prepare an aqueous solution of HCl at pH = 1. Then add 0.6 mL of the above solution to 8 mg of Form F1. After stirring and dissolving, adjust the solution to pH = 1 with 1N NaOH or 1N HCl. Start timing, and after T = 3 hours, check the pH. If the pH shift is large, adjust the pH to the target value again. At T = 4 hours, observe the dissolution state and select the dilution factor based on the dissolution situation. Use 50% ACN as the diluent and perform HPLC analysis. At T = 24 hours, observe the dissolution state and refer to the concentration data of 4 hours. Combined with the dissolution state of 24 hours, select the dilution factor and perform HPLC analysis. Calculate the solubility based on the above HPLC analysis results.

[0134] The pH=1 HCl aqueous solution in the above step was replaced with a 20 mM phosphate buffer solution with a pH of 7, and the above steps were repeated to calculate the solubility.

[0135] The dissolution conditions and solubility results are shown in the table below:

[0136] Comparative Example 1: Salt type screening

[0137] 25 mg of Compound 1 prepared in Example 1 was dissolved in 0.5 mL of each solvent. Acid or base (0.55-1.1 eq) was then added to the solution at room temperature to allow the reaction to proceed. Conventional crystallization methods (antisolvent, solvent evaporation, cooling crystallization, etc.) failed to induce solid precipitation. The salt formation and crystallization of the products, as well as the impurity removal effect, are listed in the table below:

[0138] The corresponding situations are as follows:

[0139] Note: “None” in the table means no impurity removal effect.

[0140] As can be seen from the above, compound 1 can form salts with some acids or bases, but the physical form of these salts is oily and cannot remove the isomer impurities shown in Formula 1'.

[0141] Comparative Example 2 Preparation of other crystal forms

[0142] 4 mL of ACN was added to 1 g of the benzenesulfonate salt of Compound 1. The mixture was then filtered through a 0.45 μm syringe filter. 32 mL of MTBE was slowly added to the filtrate. After stirring at 25°C for approximately 4 days, the solid was collected by filtration and characterized by XRPD to yield 530 mg of Compound 1 benzenesulfonate salt Form A4, as shown in Figures 9-11. However, Form A4 subsequently transformed into Form F1.

[0143] The present application also prepared other crystalline forms of Compound 2 by other conventional methods, and the characterizations are shown in Figures 7-8 and 12-33, but the stability of other crystalline forms is poor.

Claims

1. A crystalline form A1 of compound 2, characterized in that: Its X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles has diffraction peaks at 5.971°±0.200°, 7.088°±0.200°, 12.068°±0.200°, 15.881°±0.200°, 20.557°±0.200° and 21.599°±0.200°; 2. The crystalline form A1 of compound 2 according to claim 1, characterized in that: It meets one or both of the following conditions: (1) The crystalline form A1 of the compound 2, which uses Cu-Kα radiation and an X-ray powder diffraction pattern expressed in 2θ angles, also has characteristic peaks at one or more of 7.742°±0.200°, 17.257°±0.200°, 21.259°±0.200°, 23.137°±0.200° and 24.134°±0.200°; preferably, the crystalline form A1 of the compound 2, which uses Cu-Kα radiation and an X-ray powder diffraction pattern expressed in 2θ angles, has diffraction peaks and relative intensities as follows: Furthermore, the crystalline form A1 of the compound 2 has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles as shown in FIG1 ; (2) The thermogravimetric analysis (TGA) of the crystalline form A1 of the compound 2 shows a weight loss of 3.63% at 27-100°C, where "%" refers to mass percentage; further, the TGA graph of the crystalline form A1 of the compound 2 is substantially as shown in FIG3 .

3. A crystalline form F1 of compound 2, characterized in that: Its X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles has diffraction peaks at 17.006°±0.200°, 20.439°±0.200°, 22.149°±0.200° and 23.629°±0.200°; 4. The crystalline form F1 of compound 2 according to claim 3, characterized in that: It meets one or more of the following conditions: (1) The crystalline form F1 of the compound 2, whose X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles also has characteristic peaks at one or more of 17.891°±0.200°, 19.671°±0.200°, 27.740°±0.200° and 28.842°±0.200°; preferably, the crystalline form A1 of the compound 2, whose X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles has diffraction peaks and relative intensities as follows: Furthermore, the X-ray powder diffraction pattern of the crystalline form F1 of the compound 2 using Cu-Kα radiation and expressed in 2θ angles is substantially as shown in FIG4 ; (2) The thermogravimetric analysis (TGA) of the crystalline form F1 of the compound 2 shows a weight loss of 0.5% at 32-130° C., where “%” refers to mass percentage; further, the TGA graph of the crystalline form F1 of the compound 2 is substantially as shown in FIG5 ; and (3) The differential scanning calorimetry (DSC) diagram of the crystalline form F1 of the compound 2 has an endothermic peak at 147.8°C; further, the DSC diagram of the crystalline form F1 of the compound 2 is substantially as shown in FIG6 .

5. A method for preparing the crystalline form A1 of compound 2 according to any one of claims 1 to 2, characterized in that: The method comprises the following steps: compound 2 is crystallized in a solvent, or compound 1 is mixed with benzenesulfonic acid in a solvent, wherein the solvent is a mixed solvent of an ether solvent and acetonitrile; further, the method comprises the following steps: solution 1 containing compound 1 is mixed with solution 2 containing benzenesulfonic acid for reaction; wherein the solvent of solution 1 is a mixed solvent of an ether solvent and acetonitrile; the solvent of solution 2 is a mixed solvent of an ether solvent and / or acetonitrile; the ether solvent may be isopropyl ether; 6. The method for preparing the crystalline form A1 of compound 2 according to claim 5, characterized in that: It meets one or more of the following conditions: (1) The purity of compound 1 is 90%-99.6%, for example 92.6%, 94.3%, 95.8% or 99%; (2) The compound 1 is a crude product of the compound 1, which is a mixture of the compound 1 and an isomeric impurity as shown in Formula 1'; the mass ratio of the compound 1 to the isomeric impurity may be (10-500):1, for example, 15.433:1, 23.575:1, 23.95:1 or 220:1; (3) When the solvent is an ether solvent and a nitrile solvent, the volume ratio of the ether solvent to the nitrile solvent is (1-10):1, for example, 5:1 or 7:1; (4) The mass volume ratio of the compound 1 to the solvent of the solution 1 is 1:(1-15) g / ml, or 1:(1-10) g / ml, such as 1:6 g / ml and 1:10 g / ml; (5) The molar ratio of the benzenesulfonic acid to the compound 1 is (0.9-1.2):1, for example 1.1:1; (6) The mass volume ratio of the benzenesulfonic acid to the solvent of the solution 2 is 1:(0.1-10) g / ml, for example 1:6 g / ml or 1:10 g / ml; (7) The method for preparing the crystalline form A1 of the compound 2 further comprises the operation of mixing with the crystalline form A1 of the compound 2 as any one of claims 1-2 as benzenesulfonate seed crystals; the mass ratio of the benzenesulfonate seed crystals to the compound 1 can be 1:(20-100), for example 1:50; (8) The method for preparing the crystalline form A1 of compound 2 further comprises the operation of mixing with a solution 3 containing the crystalline form A1 of compound 2 as described in any one of claims 1-2 as a benzenesulfonate seed crystal; the solvent of the solution 3 is an ether solvent and / or a mixed solvent of acetonitrile; the ether solvent can be isopropyl ether; (9) The method for preparing the Form A1 of Compound 2 further comprises mixing the Form A1 of Compound 2 as described in any one of claims 1 to 2 with a solution 3 in which the Form A1 of Compound 2 is used as a benzenesulfonate seed crystal; the mass volume ratio of the benzenesulfonate seed crystal to the solvent of the solution 3 is 1: (6000-10000) g / ml, for example 1: 8000 g / ml; (10) The mixing temperature is 25°C; and (11) The mixing reaction time is 0.1-100 h, for example 3 h, 17 h or 72 h.

7. A method for preparing the crystalline form F1 of compound 2 according to any one of claims 3 to 4, characterized in that: The method comprises the following steps: compound 2 is crystallized in a solvent, or compound 1 is mixed with benzenesulfonic acid in a solvent, wherein the solvent is an ester solvent; further, the method comprises the following steps: solution 1 containing compound 1 is mixed with solution 2 containing benzenesulfonic acid; wherein the solvent of solution 1 is an ester solvent or an ether solvent; the solvent of solution 2 is an ester solvent; the ester solvent may be ethyl acetate and / or isopropyl acetate; the ether solvent may be tetrahydrofuran; 8. The method for preparing the crystalline form F1 of compound 2 according to claim 7, characterized in that: It meets one or more of the following conditions: (1) The purity of compound 1 is 90%-99.6%, for example 95.8%, 97.14% or 97.5%; (2) The compound 1 is a crude product of the compound 1, which is a mixture of the compound 1 and an isomeric impurity as shown in Formula 1'; the mass ratio of the compound 1 to the isomeric impurity may be (10-500):1, for example, 23.95:1, 33.965:1 or 42.026:1; (3) The mass volume ratio of the compound 1 to the solvent of the solution 1 is 1:(1-15) g / ml, or 1:(1-10) g / ml, such as 1:2.3 g / ml, 1:4 g / ml or 1:6 g / ml; (4) The molar ratio of the benzenesulfonic acid to the compound 1 is (0.9-1.2):1, for example 0.98:1 or 1:1; (5) The mass volume ratio of the benzenesulfonic acid to the solvent of the solution 2 is 1:(0.1-10) g / ml, for example, 1:0.7 g / ml, 1:1 g / ml or 1:4 g / ml; (6) The method for preparing the crystalline form F1 of the compound 2 further comprises the operation of mixing with a solvent 3; the solvent 3 is an alkane solvent, and the alkane solvent can be n-heptane; the mass volume ratio of the compound 1 to the solvent 3 is 1: (3-45) g / ml, for example 1: 27 g / ml; (7) The method for preparing the crystalline form F1 of the compound 2 further comprises thermal cycling; the number of thermal cycles may be 5 times; and (8) The method for preparing the crystalline form F1 of the compound 2 further comprises a thermal cycle; the temperature of the thermal cycle can be 25°C to -10°C.

9. Use of the crystalline form A1 of compound 2 according to any one of claims 1 to 2 or the crystalline form F1 of compound 2 according to any one of claims 3 to 4 in the preparation of compound 1; 10. A method for purifying compound 1, characterized in that: The purification method comprises the following steps: Solution 1: S1: A method for preparing the crystalline form A1 of compound 2 as claimed in claim 5 or 6; S2: The crystalline form A1 of the compound 2 is hydrolyzed to prepare compound 1; Option 2: S1: A method for preparing the crystalline form F1 of compound 2 according to any one of claims 7 or 8; S2: Compound 1 is prepared by hydrolyzing the crystalline form F1 of compound 2.

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