Crystalline forms of pyrazolopyrimidine ester compounds and methods for preparing same

Abstract

Formula (I): [Formula 1] A crystalline form of a pyrazolopyrimidine ester compound (Form II crystal) is provided, having the structure shown in TIFF2025525738000008.tif55145. This crystalline form is characterized by powder X-ray diffraction, differential scanning calorimetry, and infrared spectroscopy. A method for preparing the crystalline form of a pyrazolopyrimidine ester compound (Form II crystal) is also provided. This crystalline form can be stored for long periods of time without special requirements regarding temperature, light, humidity, or oxygen level characteristics, and has significant advantages in terms of stability. Furthermore, this preparation method has simple steps, good reproducibility, and excellent purity, and is expected to be widely applied.

Description

[Technical Field]

[0001] The present invention relates to the field of chemical medicine, and in particular to crystalline forms of pyrazolopyrimidine ester compounds and methods for preparing same. [Background technology]

[0002] Bruton's tyrosine kinase (BTK) is a non-receptor cytoplasmic tyrosine protein kinase of the Tec family. BTK is involved in the transduction of TLR, BAFF-R, BCR, and CXCR4 / 5 signals, as well as the proliferation, differentiation, apoptosis, and migration of regulatory B cells. Because BTK plays an important role in the pathogenesis of malignant B-cell lymphoma, BTK inhibitors are used as important drugs for the treatment of B-cell lymphoma.

[0003] Chinese Patent Application Publication No. 202111131059.0 discloses a series of pyrazolopyrimidine ester compounds as BTK inhibitor prodrugs, which are rapidly absorbed into the blood upon oral administration and hydrolyzed to the active metabolite 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one, known as the 4-amino active metabolite (4-AAM), which is generally recognized as capable of exerting its intended therapeutic effects in current clinical practice. Among these compounds, the compound chemically designated 1-[(3R)-3-[4-(butoxycarbonyl)-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one and having the chemical structure represented by formula (I) has the most desirable properties as a prodrug, as it is most rapidly hydrolyzed in blood and has the highest 4-AAM AUC while exhibiting the lowest AUC itself.

[0004] [ka]

[0005] Chinese Patent Application Publication No. 202111131059.0 also provides a method for synthesizing this compound. The product obtained according to this method was found to be amorphous. The compound of formula (I) can be obtained by reacting commercially available 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidyl]-2-propen-1-one with butyl chloroformate. Studies have shown that this amorphous compound has poor stability and is susceptible to heat and humidity. Significant decomposition can be observed after storage at 40°C for 10 days, and almost complete decomposition can be observed after storage at 60°C and 75% RH for 10 days. As a result, undesirable substances can be generated under normal storage conditions, making the product difficult to store and process. In view of the potential clinical value of the compound of formula (I), it is particularly important to obtain a crystalline form thereof with desirable purity and stable properties. Summary of the Invention

[0006] A stable and reproducible crystalline form has been developed by the applicant and is designated Form II crystalline. A method for preparing Form II crystalline is also provided herein. The crystalline form, Form II crystalline, offers significant advantages in terms of stability by allowing long-term storage without special requirements regarding temperature, light, humidity, or oxygen levels.

[0007] The first object of the present invention is to provide a crystalline form of a pyrazolopyrimidine ester compound. To this end, the present invention provides the following technical solutions:

[0008] Form II crystalline, which is a crystalline form of the pyrazolopyrimidine ester compound of formula (I), has three or more (preferably four or more, five or more, six or more, seven or more, or eight) characteristic peaks, expressed in degrees 2θ, at 5.53°, 9.82°, 10.76°, 17.87°, 20.55°, 21.28°, 21.92°, and 25.15° in its powder X-ray diffraction (XRPD) pattern, with an error range of ±0.20° in degrees 2θ, wherein the XRPD pattern is obtained using Cu-Kα radiation.

[0009] [ka]

[0010] Additionally, the crystalline form Form II crystalline has characteristic peaks in its XRPD pattern at 5.53°, 9.82°, 10.76°, 14.25°, 14.81°, 16.72°, 17.87°, 18.33°, 19.06°, 19.67°, 20.55°, 20.78°, 21.28°, 21.92°, 22.93°, 23.38°, 23.85°, 25.15°, 26.09°, 26.51°, 26.97°, 27.52°, 27.90°, 28.37°, 29.00°, 29.70°, 31.57°, 32.57°, 33.94°, and 36.71° 2θ degrees, with an error range of ±0.20° 2θ degrees.

[0011] Additionally, the 2θ degrees and relative intensities I (expressed as a percentage relative to the most intense diffraction peak) of the crystalline form, Form II Crystal, in the XRPD pattern are listed in the table below.

[0012] [Table 1]

[0013] Additionally, the crystalline form, Form II Crystalline, is characterized by the XRPD pattern shown in FIG.

[0014] Additionally, the crystalline form, Form II crystals, is an irregularly shaped crystalline form.

[0015] Furthermore, the crystalline form, Form II Crystal, has an endothermic peak at 129.59°C in its differential scanning calorimetry (DSC) curve, with an error range of ±1.00°C for the endothermic peak temperature.

[0016] Furthermore, the crystalline form, Form II Crystal, is characterized by the DSC curve shown in FIG.

[0017] Furthermore, the crystalline form, Form II crystal, exhibits characteristic absorption bands at the wave numbers listed in the table below in its infrared (IR) spectrum, and the error range of the absorption band peaks is ±2 cm. -1 and the letter "w" (weak), "m" (medium), or "s" (strong) is added to indicate the intensity of the peak.

[0018] [Table 2]

[0019] Furthermore, the crystalline form, Form II crystal, has a peak at 423 cm in the IR spectrum. -1 , 449cm -1 , 485cm -1 , 517cm -1 , 564cm -1 , 584cm -1 , 616cm -1 , 652cm -1 , 679cm -1 , 693cm -1 , 708cm -1 , 739cm -1 , 754cm -1 , 787cm -1 , 827cm -1 , 849cm -1 , 862cm -1 , 896cm -1 , 941cm -1 , 959cm -1 , 971cm -1 , 996cm -1 , 1,011cm -1 , 1,030cm -1 , 1,078cm -1 , 1,095cm-1 , 1,138cm -1 , 1,159cm -1 , 1,197cm -1 , 1,233cm -1 , 1,277cm -1 , 1,303cm -1 , 1,345cm -1 , 1,376cm -1 , 1,416cm -1 , 1,445cm -1 , 1,455cm -1 , 1,488cm -1 , 1,504cm -1 , 1,524cm -1 , 1,556cm -1 , 1,588cm -1 , 1,606cm -1 , 1,642cm -1 , 1,711cm -1 , 1,750cm -1 , 1,901cm -1 , 2,865cm -1 , 2,897 cm -1 , 2,928cm -1 , 2,954cm -1 , 3,012 cm -1 , 3,027cm -1 , 3,044cm -1 , 3,076cm -1 , 3,166cm -1 and 3,195 cm -1 The error range of the absorption band peak is ±2cm. -1 is.

[0020] Additionally, the crystalline form, Form II Crystal, is characterized by the IR spectrum shown in FIG.

[0021] Additionally, the crystalline form, Form II crystalline, is nearly non-hygroscopic as determined by dynamic vapor sorption (DVS). The XRPD pattern of the crystalline form, Form II crystalline, remained the same before and after DVS determination.

[0022] Furthermore, in stability studies, the crystalline form, Form II, exhibited lower degradation than the amorphous form under several forced degradation conditions. In particular, samples of the crystalline form, Form II, were highly stable over 10 days of storage at room temperature and in light. The crystalline form, Form II, can be stored under normal conditions without special protection, as suggested by the studies, which is particularly important for pharmaceutical manufacturing.

[0023] A second object of the present invention is to provide a method for preparing Form II crystalline, which is a crystalline form of the pyrazolopyrimidine ester compound as described above, by crystallization of the compound of formula (I) in amorphous or crystalline (Form I crystalline) form.

[0024] To prepare crystalline Form II crystals by crystallization of an amorphous compound of Formula (I), the purity of the amorphous compound of Formula (I) must be as high as 98.5% or higher. Alternatively, to prepare crystalline Form II crystals by seeding crystalline Form II crystals and inducing the formation of crystalline Form II crystals, a high purity of the amorphous compound of Formula (I) is not required.

[0025] In preparing crystalline Form II crystals from crystalline Form I crystals of the compound of Formula (I), the crystalline Form I crystals are prepared by crystallizing an amorphous compound of Formula (I). The crystalline Form I crystals have three or more (preferably four or more, five or more, six or more, seven or more, or eight) characteristic peaks expressed in degrees 2θ at 11.26°, 14.03°, 14.80°, 17.07°, 19.78°, 21.21°, 22.39°, and 23.85° in their XRPD pattern, with an error range of ±0.20° in degrees 2θ, and the XRPD pattern is obtained using Cu-Kα radiation.

[0026] Additionally, the crystalline form, Form I Crystal, has characteristic peaks in its XRPD pattern at 6.99°, 8.62°, 10.72°, 11.05°, 11.26°, 11.86°, 12.07°, 13.08°, 14.03°, 14.80°, 16.28°, 17.07°, 19.33°, 19.78°, 20.19°, 20.69°, 21.21°, 22.39°, 22.86°, 23.08°, 23.85°, 24.40°, 24.73°, 25.95°, 26.23°, 26.95°, 29.21°, 30.17°, 32.71°, and 32.99° 2θ degrees, with an error range of ±0.20° 2θ degrees. Crystalline Form Form I crystals are characterized by the XRPD pattern shown in FIG.

[0027] Furthermore, the crystalline form, Form I, is an irregularly shaped crystalline form. The crystalline form, Form I, has an endothermic peak at 119.75°C in its DSC curve, with an error range of ±1.00°C for the endothermic peak temperature. In thermogravimetric analysis (TGA), the crystalline form, Form I, does not show significant weight loss before decomposition, indicating that the crystalline form, Form I, is an anhydrous crystalline form. The crystalline form, Form I, is characterized by the DSC and TGA curves shown in Figure 5.

[0028] Furthermore, the crystalline form, Form I crystal, has a peak at 493 cm in its IR spectrum. -1 , 519cm -1 , 587cm -1 , 609cm -1 , 676cm -1 , 692cm -1 , 759cm -1 , 774cm -1 , 794cm -1 , 808cm -1 , 869cm -1 , 895cm -1 , 934cm -1 , 963cm -1 , 1,000cm -1 , 1,027cm -1 , 1,073cm -1 , 1,102cm -1 , 1,134cm -1 , 1,158cm-1 , 1,229cm -1 , 1,342cm -1 , 1,382cm -1 , 1,448cm -1 , 1,490cm -1 , 1,523cm -1 , 1,559cm -1 , 1,589cm -1 , 1,645cm -1 , 1,681cm -1 , 1,753cm -1 , 2,870cm -1 , 2,954cm -1 , 3,067cm -1 , 3,149cm -1 and 3,406 cm -1 The error range of the absorption band peak is ±2cm. -1 The crystalline form, Form I Crystal, is characterized by the IR spectrum shown in FIG.

[0029] The crystalline form Form I, from which the crystalline form Form II can be prepared, can be prepared by crystallization according to a method comprising adding the amorphous compound of Formula (I) to a mixed solvent, stirring the resulting suspension, followed by filtering and drying at room temperature to obtain the crystalline form Form I of the pyrazolopyrimidine ester compound, wherein the mixed solvent is obtained by mixing a good solvent and a poor solvent, the good solvent being a solvent in which the compound of Formula (I) is soluble and selected from methanol, ethanol, isopropanol, acetonitrile, acetone, butanone, ethyl acetate, isopropyl acetate, and tetrahydrofuran, and the poor solvent being a solvent in which the compound of Formula (I) is insoluble, slightly soluble, or poorly soluble and selected from methyl tert-butyl ether, water, n-heptane, and cyclohexane. The mixed solvent is used in a volume to weight (v / w) ratio of 5 to 150 relative to the compound of formula (I), and the mixed solvent, poor solvent, and good solvent are used in a volume to volume (v / v) ratio of (1 to 14):1, where v is measured in milliliters (mL) and w is measured in grams (g).

[0030] Specifically, a method for preparing the crystalline Form II crystalline form from an amorphous or crystalline (Form I crystalline) compound of Formula (I) comprises dissolving the pyrazolopyrimidine ester compound of Formula (I) structure in a good solvent, then adding a poor solvent (antisolvent) to precipitate a solid, followed by stirring, followed by filtration and drying to obtain the crystalline Form II crystalline pyrazolopyrimidine ester compound, wherein the good solvent is a solvent in which the compound of Formula (I) is soluble, and the poor solvent is a solvent in which the compound of Formula (I) is insoluble, slightly soluble, or poorly soluble.

[0031] Furthermore, the poor solvent is slowly added in several portions, preferably in two portions.

[0032] Furthermore, the good solvent is selected from acetone, 2-methyltetrahydrofuran, methanol, acetonitrile, ethyl acetate and tetrahydrofuran, with acetone or 2-methyltetrahydrofuran being preferred, and the poor solvent is selected from n-heptane, methyl tert-butyl ether, water and cyclohexane, with n-heptane being preferred.

[0033] Further, in the method of preparing the crystalline form Form II crystal, a good solvent is used in a volume to weight (v / w) ratio of 5 to 10 relative to the compound of formula (I), and a poor solvent is used in a volume to weight (v / w) ratio of 10 to 150 relative to the compound of formula (I), where v is measured in milliliters (mL) and w is measured in grams (g).

[0034] Furthermore, in the method for preparing the crystalline form Form II crystal, the good solvent is used in a volume to weight (v / w) ratio of 5 to 7 relative to the compound of formula (I), and the poor solvent is used in a volume to weight (v / w) ratio of 14 to 21 relative to the compound of formula (I).

[0035] A third object of the present invention is to provide a use of Form II crystal, which is a crystalline form of the pyrazolopyrimidine ester compound described above, in the preparation of a medicament for treating blood disorders such as lymphoma and lymphocytic leukemia.

[0036] The present invention provides the following advantages:

[0037] The pyrazolopyrimidine ester compound of crystalline form II can be obtained according to the method described in the present invention.This crystalline form allows for long-term storage without special requirements regarding temperature, light, humidity or oxygen level, and is significantly superior to both amorphous and crystalline form I.In addition, this method has simple steps, good reproducibility and excellent purity.Therefore, this method has a promising prospect for widespread application. [Brief explanation of the drawings]

[0038] [Figure 1] FIG. 1 shows an X-ray powder diffraction (XRPD) spectrum of Form II crystal, which is a crystalline form of a pyrazolopyrimidine ester compound. [Figure 2] FIG. 1 shows a differential scanning calorimetry (DSC) curve of Form II crystal, which is a crystalline form of a pyrazolopyrimidine ester compound. [Figure 3] FIG. 1 shows an infrared (IR) spectrum of Form II crystal, which is a crystalline form of a pyrazolopyrimidine ester compound. [Figure 4] FIG. 1 shows an XRPD pattern of Form I crystal, which is a crystalline form of a pyrazolopyrimidine ester compound. [Figure 5] FIG. 1 shows DSC and thermogravimetric analysis (TGA) curves of Form I crystal, which is a crystalline form of a pyrazolopyrimidine ester compound. [Figure 6] FIG. 1 shows an IR spectrum of Form I crystal, which is a crystalline form of a pyrazolopyrimidine ester compound. DETAILED DESCRIPTION OF THE INVENTION

[0039] The present invention will be clearly and completely described below with reference to specific embodiments thereof. It should be understood that the embodiments described herein are only a portion of the possible embodiments of the present invention, and are not all of them. Any other embodiments that can be devised by those skilled in the art in light of the disclosed embodiments without resorting to inventive ideas are considered to fall within the scope of the present invention.

[0040] In the context of the present invention, room temperature is defined as a temperature in the range of 20°C to 30°C, preferably 25°C.

[0041] In the following examples, the ratios of good and poor solvents used relative to the compound of formula (I) are all enclosed in parentheses, for example, "(5V)" indicates that the solvent is used in a ratio of 5 (v / w) relative to the compound of formula (I), where v is measured in milliliters (mL) and w is measured in grams (g).

[0042] The amorphous compound of Formula (I) used in the following examples can be prepared according to the method disclosed in Chinese Patent Application Publication No. 202111131059.0. The reactants 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidyl]-2-propen-1-one, butyl chloroformate, and dichloromethane were added under nitrogen protection. The mixture was cooled to 10°C, pyridine was added dropwise, and the reaction mixture was stirred at this temperature for 3 to 4 hours. When TLC showed that almost no reactant remained, ice water was added to quench the reaction. The aqueous phase was separated and extracted with dichloromethane. The combined organic phase was washed with water. The organic phase was concentrated, and the residue was purified by column chromatography to obtain the compound of Formula (I).

[0043] The crystalline form of the compound of formula (I) in the following examples, Form I, can be prepared according to the above method. Specifically, this method can include the following steps: weighing a certain amount of amorphous compound of formula (I) and adding it to a mixed solvent (10V) (wherein the mixed solvent is obtained by mixing methyl tert-butyl ether as a poor solvent and ethanol as a good solvent in a volume to volume ratio of 9:1); stirring the resulting suspension at room temperature for 3 days, followed by filtering; drying the resulting solid to obtain Form I, which is a crystalline form of a pyrazolopyrimidine ester compound. [Example]

[0044] Example 1 200 g of amorphous compound of formula (I) with a purity of 98.5% was weighed and dissolved in 1000 mL (5 V) of acetone as a good solvent at room temperature (20-30 °C). Then, 600 mL (3 V) of n-heptane was added as a poor solvent to slowly precipitate the solid. After stirring at 5-15 °C for 2 hours, 2400 mL (12 V) of n-heptane was slowly added dropwise within 3 hours. After the addition was completed, stirring was continued at 0-10 °C for 2 hours and then filtered. The resulting solid was dried under vacuum at 50 °C for 4.5 hours to obtain a solid with a purified yield of 82.5%. The resulting solid was subjected to XRPD and DSC analysis, and the results indicated that the pyrazolopyrimidine ester compound was obtained as Form II crystals.

[0045] Example 2 200 g of amorphous compound of Formula (I) with a purity of 96% was weighed and dissolved in 1000 mL (5 V) of acetone as a good solvent at room temperature (20-30 °C). Then, 600 mL (3 V) of n-heptane as a poor solvent and 0.2 g of seed crystals of Form II crystals were added to slowly precipitate the solid. After stirring at 5-15 °C for 2 hours, 2400 mL (12 V) of n-heptane was slowly added dropwise within 3 hours. After the addition was completed, stirring was continued at 0-10 °C for 2 hours and then filtered. The resulting solid was dried under vacuum at 50 °C for 4.5 hours to obtain a solid with a purified yield of 80.5%. XRPD and DSC analyses of the resulting solid indicated that the pyrazolopyrimidine ester compound was obtained as Form II crystals.

[0046] Example 3 200 g of the compound of formula (I) in Form I crystals was weighed and dissolved in 1000 mL (5 V) of acetone as a good solvent at room temperature (20-30 °C). Then, 600 mL (3 V) of n-heptane was added as a poor solvent to slowly precipitate the solid. After stirring at 5-15 °C for 2 hours, 2400 mL (12 V) of n-heptane was slowly added dropwise within 3 hours. After the addition was completed, stirring was continued at 0-10 °C for 2 hours and then filtered. The resulting solid was dried under vacuum at 50 °C for 4.5 hours to obtain a solid with a purified yield of 81.1%. The resulting solid was subjected to XRPD and DSC analysis, and the results indicated that the pyrazolopyrimidine ester compound was obtained as Form II crystals.

[0047] Example 4 Thirty grams of amorphous compound of formula (I) with a purity of 98.5% was weighed and dissolved in 150 mL (5 V) of acetone as a good solvent at room temperature (20-30°C). Next, 90 mL (3 V) of n-heptane was added as a poor solvent to slowly precipitate the solid. After stirring at 5-15°C for 2 hours, 360 mL (12 V) of n-heptane was slowly added dropwise within 2.5 hours. After the addition was completed, stirring was continued at 0-10°C for 3 hours and then filtered. The resulting solid was dried under vacuum at 50°C for 4.5 hours to obtain a solid with a purified yield of 84.1%. XRPD and DSC analyses of the resulting solid indicated that the pyrazolopyrimidine ester compound was obtained as Form II crystals.

[0048] Example 5 Thirty grams of amorphous compound of formula (I) with a purity of 96% was weighed and dissolved in 150 mL (5 V) of acetone as a good solvent at room temperature (20-30°C). Next, 90 mL (3 V) of n-heptane as a poor solvent and 0.03 g of seed crystals of Form II crystals were added to slowly precipitate the solid. After stirring at 5-15°C for 2 hours, 360 mL (12 V) of n-heptane was slowly added dropwise within 2.5 hours. After the addition was completed, stirring was continued at 0-10°C for 3 hours and then filtered. The resulting solid was dried under vacuum at 50°C for 4.5 hours to obtain a solid with a purified yield of 81.0%. XRPD and DSC analyses of the resulting solid indicated that the pyrazolopyrimidine ester compound was obtained as Form II crystals.

[0049] Example 6 Thirty grams of the compound of formula (I) in Form I crystals was weighed and dissolved in 150 mL (5 V) of acetone as a good solvent at room temperature (20-30°C). Next, 90 mL (3 V) of n-heptane was added as a poor solvent to slowly precipitate the solid. After stirring at 5-15°C for 2 hours, 360 mL (12 V) of n-heptane was slowly added dropwise within 2.5 hours. After the addition was completed, stirring was continued at 0-10°C for 3 hours and then filtered. The resulting solid was dried under vacuum at 50°C for 4.5 hours to obtain a solid in 84.5% purified yield. XRPD and DSC analyses of the resulting solid indicated that the pyrazolopyrimidine ester compound was obtained as Form II crystals.

[0050] Example 7 Five grams of amorphous compound of formula (I) with a purity of 98.5% was weighed and dissolved in 35 mL (7 V) of acetone as a good solvent at 5°C to 15°C. Then, 25 mL (5 V) of n-heptane was added as a poor solvent to slowly precipitate the solid. After stirring at 5°C to 15°C for 1 hour, 45 mL (9 V) of n-heptane was slowly added dropwise within 30 minutes. After the addition was completed, stirring was continued at 0°C to 5°C for 1 hour and then filtered. The resulting solid was dried under vacuum at 50°C for 4.5 hours to obtain a solid with a purification yield of 41.0%. The resulting solid was subjected to XRPD and DSC analysis, and the results indicated that the pyrazolopyrimidine ester compound was obtained as Form II crystals.

[0051] Example 8 Five grams of amorphous compound of formula (I) with a purity of 96% was weighed and dissolved in 35 mL (7 V) of acetone as a good solvent at 5°C to 15°C. Then, 25 mL (5 V) of n-heptane as a poor solvent and 0.005 g of seed crystals of Form II crystals were added to slowly precipitate the solid. After stirring at 5°C to 15°C for 1 hour, 45 mL (9 V) of n-heptane was slowly added dropwise within 30 minutes. After the addition was completed, stirring was continued at 0°C to 5°C for 1 hour and then filtered. The resulting solid was dried under vacuum at 50°C for 4.5 hours to obtain a solid with a purified yield of 38.9%. XRPD and DSC analyses of the resulting solid indicated that the pyrazolopyrimidine ester compound was obtained as Form II crystals.

[0052] Example 9 Five grams of the compound of formula (I) in Form I crystals was weighed and dissolved in 35 mL (7 V) of acetone as a good solvent at 5°C to 15°C. Then, 25 mL (5 V) of n-heptane was added as a poor solvent to slowly precipitate the solid. After stirring at 5°C to 15°C for 1 hour, 45 mL (9 V) of n-heptane was slowly added dropwise within 30 minutes. After the addition was completed, stirring was continued at 0°C to 5°C for 1 hour and then filtered. The resulting solid was dried under vacuum at 50°C for 4.5 hours to obtain a solid with a purified yield of 42.7%. The resulting solid was subjected to XRPD and DSC analysis, and the results indicated that the pyrazolopyrimidine ester compound was obtained as Form II crystals.

[0053] Example 10 Five grams of amorphous compound of formula (I) with a purity of 98.5% was weighed and dissolved in 35 mL (7 V) of acetone as a good solvent at 5°C to 15°C. Then, 25 mL (5 V) of n-heptane was added as a poor solvent to slowly precipitate the solid. After stirring at 5°C to 15°C for 1 hour, 80 mL (16 V) of n-heptane was slowly added dropwise within 30 minutes. After the addition was completed, stirring was continued at 0°C to 5°C for 1 hour and then filtered. The resulting solid was dried under vacuum at 50°C for 4.5 hours to obtain a solid with a 48.0% purified yield. XRPD and DSC analyses of the resulting solid indicated that the pyrazolopyrimidine ester compound was obtained as Form II crystals.

[0054] Example 11 Five grams of amorphous compound of formula (I) with a purity of 96% was weighed and dissolved in 35 mL (7 V) of acetone as a good solvent at 5°C to 15°C. Then, 25 mL (5 V) of n-heptane as a poor solvent and 0.005 g of seed crystals of Form II crystals were added to slowly precipitate the solid. After stirring at 5°C to 15°C for 1 hour, 80 mL (16 V) of n-heptane was slowly added dropwise within 30 minutes. After the addition was completed, stirring was continued at 0°C to 5°C for 1 hour and then filtered. The resulting solid was dried under vacuum at 50°C for 4.5 hours to obtain a solid with a purification yield of 47.2%. XRPD and DSC analyses of the resulting solid indicated that the pyrazolopyrimidine ester compound was obtained as Form II crystals.

[0055] Example 12 Five grams of the compound of formula (I) in Form I crystals was weighed and dissolved in 35 mL (7 V) of acetone as a good solvent at 5°C to 15°C. Then, 25 mL (5 V) of n-heptane was added as a poor solvent to slowly precipitate the solid. After stirring at 5°C to 15°C for 1 hour, 80 mL (16 V) of n-heptane was slowly added dropwise within 30 minutes. After the addition was completed, stirring was continued at 0°C to 5°C for 1 hour and then filtered. The resulting solid was dried under vacuum at 50°C for 4.5 hours to obtain a solid with a 50.5% purified yield. XRPD and DSC analyses of the resulting solid indicated that the pyrazolopyrimidine ester compound was obtained as Form II crystals.

[0056] Example 13 Two grams of amorphous compound of formula (I) with a purity of 99% was weighed and dissolved in 10 mL (5V) of acetone as a good solvent at 0°C to 5°C. Then, 6 mL (3V) of n-heptane was added as a poor solvent to slowly precipitate the solid. After stirring at 0°C to 5°C for 1 hour, 24 mL (12V) of n-heptane was slowly added dropwise within 30 minutes. After the addition was completed, stirring was continued at 0°C to 5°C for 1 hour and then filtered. The resulting solid was dried under vacuum at 50°C for 4.5 hours to obtain a solid with a 90.0% purified yield. The resulting solid was subjected to XRPD and DSC analysis, and the results indicated that the pyrazolopyrimidine ester compound was obtained as Form II crystals.

[0057] Example 14 Two grams of amorphous compound of formula (I) with a purity of 97% was weighed and dissolved in 10 mL (5V) of acetone as a good solvent at 0°C to 5°C. Then, 6 mL (3V) of n-heptane as a poor solvent and 0.002 g of seed crystals of Form II crystals were added to slowly precipitate the solid. After stirring at 0°C to 5°C for 1 hour, 24 mL (12V) of n-heptane was slowly added dropwise within 30 minutes. After the addition was completed, stirring was continued at 0°C to 5°C for 1 hour and then filtered. The resulting solid was dried under vacuum at 50°C for 4.5 hours to obtain a solid with a purified yield of 89.3%. XRPD and DSC analyses of the resulting solid indicated that the pyrazolopyrimidine ester compound was obtained as Form II crystals.

[0058] Example 15 Two grams of Form I crystals of the compound of Formula (I) were weighed and dissolved in 10 mL (5 V) of acetone as a good solvent at 0-5°C. Then, 6 mL (3 V) of n-heptane was added as a poor solvent to slowly precipitate the solid. After stirring at 0-5°C for 1 hour, 24 mL (12 V) of n-heptane was slowly added dropwise within 30 minutes. After the addition was completed, stirring was continued at 0-5°C for 1 hour and then filtered. The resulting solid was dried under vacuum at 50°C for 4.5 hours to obtain a solid with a 92.2% purified yield. The resulting solid was subjected to XRPD and DSC analysis. The results indicated that the pyrazolopyrimidine ester compound was obtained as Form II crystals.

[0059] Example 16 Two grams of amorphous compound of formula (I) with a purity of 99% was weighed and dissolved in 10 mL (5V) of 2-methyltetrahydrofuran as a good solvent at 0°C to 5°C. Then, 10 mL (5V) of n-heptane was added as a poor solvent to slowly precipitate the solid. After stirring at 0°C to 5°C for 1 hour, 20 mL (10V) of n-heptane was slowly added dropwise within 30 minutes. After the addition was completed, stirring was continued at 0°C to 5°C for 1 hour and then filtered. The resulting solid was dried under vacuum at 50°C for 4.5 hours to obtain a solid with a 94.0% purified yield. The resulting solid was subjected to XRPD and DSC analysis, and the results indicated that the pyrazolopyrimidine ester compound was obtained as Form II crystals.

[0060] Example 17 Two grams of amorphous compound of formula (I) with a purity of 97% was weighed and dissolved in 10 mL (5V) of 2-methyltetrahydrofuran as a good solvent at 0°C to 5°C. Then, 10 mL (5V) of n-heptane as a poor solvent and 0.002 g of seed crystals of Form II crystals were added to slowly precipitate the solid. After stirring at 0°C to 5°C for 1 hour, 20 mL (10V) of n-heptane was slowly added dropwise within 30 minutes. After the addition was completed, stirring was continued at 0°C to 5°C for 1 hour and then filtered. The resulting solid was dried under vacuum at 50°C for 4.5 hours to obtain a solid with a purified yield of 93.4%. XRPD and DSC analyses of the resulting solid indicated that the pyrazolopyrimidine ester compound was obtained as Form II crystals.

[0061] Example 18 Two grams of Form I crystals of the compound of Formula (I) were weighed and dissolved in 10 mL (5V) of 2-methyltetrahydrofuran as a good solvent at 0-5°C. Then, 10 mL (5V) of n-heptane was added as a poor solvent to slowly precipitate the solid. After stirring at 0-5°C for 1 hour, 20 mL (10V) of n-heptane was slowly added dropwise within 30 minutes. After the addition was completed, stirring was continued at 0-5°C for 1 hour and then filtered. The resulting solid was dried under vacuum at 50°C for 4.5 hours to obtain a solid with a 94.8% purified yield. XRPD and DSC analyses of the resulting solid indicated that the pyrazolopyrimidine ester compound was obtained as Form II crystals.

[0062] Example 19: Stability studies Samples of amorphous and crystalline (Form I crystalline and Form II crystalline) compounds of formula (I) were stored under different conditions. They were then analyzed for changes in purity. The results are shown in the table below.

[0063] Storage conditions for the crystalline form, Form II crystals: 10 days at 60°C, 10 days at 60°C and 75% RH (relative humidity), 10 days in light, and 10 days at room temperature.

[0064] Storage conditions for amorphous and crystalline (Form I crystalline) forms: 10 days at 40°C, 10 days at 60°C and 75% RH, 10 days in light, and 10 days at room temperature.

[0065] Significant decomposition was observed for amorphous samples stored at 40°C for 10 days, and nearly complete decomposition was observed for amorphous samples stored at 60°C and 75% RH for 10 days. Form I crystalline samples exhibited a lower degree of decomposition than the amorphous compound and remained stable, especially when stored at room temperature and in light for 10 days. Form II crystalline samples were more stable, especially when stored at room temperature and in light, and were stable under decomposition conditions such as high temperature and humidity. The stability of Form II crystalline was significantly better than the amorphous form and even better than Form I crystalline.

[0066] The crystalline form, Form II Crystals, has proven its value in terms of stability, allowing for long-term storage without special requirements regarding temperature, light, humidity, or oxygen levels.

[0067] [Table 3]

Claims

1. Formula (I): 【Chemical 1】 1. A crystalline form II of a pyrazolopyrimidine ester compound having the structure:

2. In the XRPD pattern, the following angles are observed: 5.53°, 9.82°, 10.76°, 14.25°, 14.81°, 16.72°, 17.87°, 18.33°, 19.06°, 19.67°, 20.55°, 20.78°, 21.28°, 21.92°, 22.93°, 23.38°, 23.85°, 25.15°, 26.09°, 26.51°, 27.02°, 28.01°, 29.02°, 30.01°, 31.01°, 32.01°, 33.01°, 34.01°, 35.01°, 36.01°, 37.01°, 38.01°, 39.01°, 40.01°, 41.01°, 42.01°, 43.01°, 44.01°, 45.01°, 46.01°, 47.01°, 48.01°, 49.01°, 50.01°, 51.01°, 52.01°, 53.01°, 54.01°, 55.01°, 56.01°, 57.01°, 58.01°, 59.01°, 60.01°, 61.01°, 62.01°, 63.01°, 64.01°, 65.01°, 66.01°, 67.01°, 68.01°, 69.

2. The pyrazolopyrimidine ester compound of claim 1, wherein the crystalline form II crystal has characteristic peaks expressed in 2θ degree values at 26.97°, 27.52°, 27.90°, 28.37°, 29.00°, 29.70°, 31.57°, 32.57°, 33.94°, and 36.71°, with an error range of 2θ degrees of ±0.20°.

3. 3. Crystalline Form II, which is a crystalline form of the pyrazolopyrimidine ester compound of claim 2, wherein the XRPD pattern is as shown in FIG.

4. Form II crystal, which is a crystalline form of the pyrazolopyrimidine ester compound of claim 1, is an irregularly shaped crystalline form, has an endothermic peak at 129.59°C in its differential scanning calorimetry (DSC) curve, and the error range of the endothermic peak temperature is ±1.00°C.

5. 5. The crystalline form of the pyrazolopyrimidine ester compound of claim 4, wherein the DSC curve is that shown in FIG.

6. In the infrared (IR) spectrum, 1,030 cm －１ , 1,078 cm －１ , 1,138 cm －１ , 1,197 cm －１ , 1,233 cm －１ , 1,277 cm －１ , 1,376 cm －１ , 1,445 cm －１ , 1,455 cm －１ , 1,488 cm －１ , 1,504 cm －１ , 1,556 cm －１ , 1,588 cm －１ , 1,606 cm －１ , 1,642 cm －１ , 1,750 cm －１ , 2,865 cm －１ , 2,897 cm －１ , 2,928 cm －１ , 2,954 cm －１ , 3,012 cm －１ , 3,027 cm －１ , 3,044 cm －１ , 3,076 cm －１ , 3,166 cm －１ and 3,195 cm －１ The error range of the absorption band peak is ±2 cm －１ 2. The crystalline form II of the pyrazolopyrimidine ester compound of claim 1, wherein:

7. 7. The crystalline form of the pyrazolopyrimidine ester compound of claim 6, wherein the IR spectrum is as shown in FIG.

8. A method for preparing Form II crystal, which is a crystalline form of the pyrazolopyrimidine ester compound of any one of claims 1 to 7, comprising the steps of: The method comprises the steps of dissolving a pyrazolopyrimidine ester compound of the structure of formula (I) in a good solvent, then adding a poor solvent to precipitate a solid, stirring, followed by filtering and drying to obtain a crystalline form of the pyrazolopyrimidine ester compound of Form II, The pyrazolopyrimidine ester compound of formula (I) is amorphous or in a crystalline form, Form I Crystal, and the crystalline form, Form I Crystal, has characteristic peaks expressed in 2θ degrees at 11.26°, 14.03°, 14.80°, 17.07°, 19.78°, 21.21°, 22.39°, and 23.85° in its XRPD pattern; the good solvent is selected from acetone, 2-methyltetrahydrofuran, methanol, acetonitrile, ethyl acetate, and tetrahydrofuran, the poor solvent is selected from n-heptane, methyl tert-butyl ether, water, and cyclohexane, the good solvent is used in a volume to weight ratio of 5 to 10 relative to the compound of formula (I), and the poor solvent is used in a volume to weight ratio of 10 to 150 relative to the compound of formula (I).

9. 9. A method for preparing Form II crystal, which is a crystalline form of the pyrazolopyrimidine ester compound of claim 8, wherein the anti-solvent is added slowly in several portions.

10. Use of Form II Crystal, a crystalline form of the pyrazolopyrimidine ester compound of any one of claims 1 to 7, in the preparation of a medicament for treating lymphoma and lymphocytic leukemia.

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