Crystalline forms of pyrazolopyrimidine ester compounds and methods for preparing same

Abstract

Formula (I): [Formula 1] Form I crystals are provided, which are crystalline forms of pyrazolopyrimidine ester compounds having the structure shown in TIFF2025525737000007.tif59168. These crystalline forms are characterized by powder X-ray diffraction patterns, differential scanning calorimetry, thermogravimetric analysis, and the like. A method for preparing Form I crystals, which are crystalline forms of pyrazolopyrimidine ester compounds, is also provided. These crystalline forms can be stored for long periods without special requirements for temperature, light, humidity, or oxygen level, and have significant advantages in terms of stability. Furthermore, this preparation method has simple steps, good reproducibility, and excellent purity, making it suitable for a wide range of applications.

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】 China Patent Application Publication No. 202111131059.0 discloses a series of pyrazolopyrimidine ester compounds as BTK inhibitor prodrugs, which, upon oral administration, are rapidly absorbed into the blood 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, i.e., the 4-amino active metabolite (4-AAM), which is the active metabolite commonly recognized in current clinical practice, and can exert its intended therapeutic effect. 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 because it is hydrolyzed most rapidly 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 I crystals. Methods for preparing Form I crystals are also provided herein. Crystalline Form Form I crystals offer significant advantages in terms of stability by allowing for 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】 The crystalline form of the pyrazolopyrimidine ester compound of formula (I), Form 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 11.26°, 14.03°, 14.80°, 17.07°, 19.78°, 21.21°, 22.39°, and 23.85° 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 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. 【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 I Crystal, in the XRPD pattern are listed in the table below. 【0012】 [Table 1] 【0013】 Additionally, the crystalline form, Form I Crystalline, is characterized by the XRPD pattern shown in FIG. 【0014】 Furthermore, the crystalline form, Form I crystals, is an irregularly shaped crystalline form. 【0015】 Furthermore, the crystalline form, Form I crystals, has an endothermic peak at 119.75°C in its differential scanning calorimetry (DSC) curve, with an error range of ±1.00°C for the endothermic peak temperature. In thermogravimetric analysis (TGA), the crystalline form, Form I crystals, does not show significant weight loss before decomposition, indicating that Form I crystals is an anhydrous crystalline form. 【0016】 Additionally, the crystalline form, Form I Crystal, is characterized by the DSC and TGA curves shown in FIG. 【0017】 Furthermore, the crystalline form, Form I crystal, has a peak at 493 cm in its infrared (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 is. 【0018】 Additionally, the crystalline form, Form I Crystal, is characterized by the IR spectrum shown in FIG. 【0019】 Additionally, the crystalline form, Form I, is nearly non-hygroscopic as determined by dynamic vapor sorption (DVS). The XRPD pattern of the crystalline form, Form I, remained the same before and after DVS determination. 【0020】 Furthermore, in stability studies, the crystalline form, Form I, exhibited lower degradation than the amorphous form under several forced degradation conditions. In particular, samples of the crystalline form, Form I, were highly stable over 10 days of storage at room temperature and in light. As suggested by the studies, the crystalline form, Form I, can be stored under normal conditions without special protection, which is particularly important for pharmaceutical manufacturing. 【0021】 A second object of the present invention is to provide two methods for preparing Form I crystals, which are crystalline forms of the pyrazolopyrimidine ester compound described above. Method I comprises the steps of adding the pyrazolopyrimidine ester compound of formula (I) in an amorphous form to a mixed solvent, stirring the resulting suspension at room temperature, followed by filtration and drying to obtain Form I crystals of the pyrazolopyrimidine ester compound, which is a crystalline form, wherein the mixed solvent is a solvent 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 the poor solvent being a solvent in which the compound of formula (I) is insoluble, slightly soluble, or poorly soluble. 【0022】 Furthermore, the good solvent in the mixed solvent is selected from methanol, ethanol, isopropanol, acetonitrile, acetone, butanone, ethyl acetate, isopropyl acetate, and tetrahydrofuran, and the poor solvent is selected from methyl tert-butyl ether, water, n-heptane, and cyclohexane. 【0023】 Further, 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 in the mixed solvent, the poor solvent and the 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). 【0024】 Method II comprises adding a pyrazolopyrimidine ester compound of the structure of Formula (I) in amorphous form to a pure solvent, stirring the resulting suspension at room temperature, followed by filtering and drying to obtain a crystalline form of the pyrazolopyrimidine ester compound, Form I, wherein the pure solvent is selected from methanol, ethanol, isopropanol, isopropyl acetate, acetonitrile, methyl tert-butyl ether, n-heptane, isopropyl ether, and cyclohexane. 【0025】 Additionally, the pure solvent is used in a volume to weight (v / w) ratio relative to the compound of formula (I) of not more than 10, preferably 10, where v is measured in milliliters (mL) and w is measured in grams (g). 【0026】 A third object of the present invention is to provide a use of Form I crystalline, 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. 【0027】 The present invention provides the following advantages: 【0028】 Form I crystals, which are the crystalline form of pyrazolopyrimidine ester compounds, 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 in stability to amorphous pyrazolopyrimidine ester compounds.In addition, this method has simple steps, good reproducibility and excellent purity.Therefore, it has a promising prospect for widespread application. [Brief explanation of the drawings] 【0029】 [Figure 1] FIG. 1 shows an X-ray powder diffraction (XRPD) spectrum of Form I crystal, a crystalline form of a pyrazolopyrimidine ester compound, according to the present invention. [Figure 2] FIG. 1 shows differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) curves of Form I crystal, which is a crystalline form of a pyrazolopyrimidine ester compound according to the present invention. [Figure 3] FIG. 1 shows an infrared (IR) spectrum of Form I crystal, a crystalline form of a pyrazolopyrimidine ester compound according to the present invention. DETAILED DESCRIPTION OF THE INVENTION 【0030】 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. 【0031】 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). 【0032】 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. [Example] 【0033】 Example 1: Preparation of crystalline form Form I crystals by Method I 50 mg of the amorphous compound of formula (I) was weighed and added to 0.5 mL of a mixed solvent. The mixed solvent was used in a ratio (v / w) of 10 to the compound of formula (I). The mixed solvent was obtained by mixing methyl tert-butyl ether (MTBE) as a poor solvent and ethanol as a good solvent in a volume-to-volume ratio of 9:1. The resulting suspension was stirred at room temperature for 3 days and then filtered to obtain a solid, which was then dried and subjected to XRPD, TGA, and DSC analyses. The results showed that the pyrazolopyrimidine ester compound was obtained as Form I crystals, which is a crystalline form. 【0034】 Example 2: Preparation of crystalline form Form I crystals by Method I 50 mg of the amorphous compound of formula (I) was weighed and added to 0.5 mL of a mixed solvent. The mixed solvent was used in a ratio (v / w) of 10 to the compound of formula (I). The mixed solvent was obtained by mixing MTBE as a poor solvent and tetrahydrofuran (THF) as a good solvent in a volume-to-volume ratio of 9:1. The resulting suspension was stirred at room temperature for 3 days and then filtered to obtain a solid, which was then dried and subjected to XRPD analysis. The results showed that the pyrazolopyrimidine ester compound was obtained as Form I crystals. 【0035】 Example 3: Preparation of crystalline form Form I crystals by Method I 50 mg of the amorphous compound of formula (I) was weighed and added to 0.5 mL of a mixed solvent. The mixed solvent was used in a ratio (v / w) of 10 to the compound of formula (I). The mixed solvent was obtained by mixing MTBE as a poor solvent and isopropyl acetate as a good solvent in a volume-to-volume ratio of 9:1. The resulting suspension was stirred at room temperature for 3 days and then filtered to obtain a solid, which was then dried and subjected to XRPD analysis. The results showed that the pyrazolopyrimidine ester compound was obtained as Form I crystals, which is a crystalline form. 【0036】 Example 4: Preparation of crystalline form Form I crystals by Method I 50 mg of the amorphous compound of formula (I) was weighed and added to 0.5 mL of a mixed solvent. The mixed solvent was used in a ratio (v / w) of 10 to the compound of formula (I). The mixed solvent was obtained by mixing MTBE as a poor solvent and ethyl acetate as a good solvent in a volume-to-volume ratio of 9:1. The resulting suspension was stirred at room temperature for 3 days and then filtered to obtain a solid, which was then dried and subjected to XRPD analysis. The results showed that the pyrazolopyrimidine ester compound was obtained as Form I crystals. 【0037】 Example 5: Preparation of crystalline form Form I crystals by Method I 50 mg of the amorphous compound of formula (I) was weighed and added to 0.5 mL of a mixed solvent. The mixed solvent was used in a ratio (v / w) of 10 to the compound of formula (I). The mixed solvent was obtained by mixing MTBE as a poor solvent and acetonitrile as a good solvent in a volume-to-volume ratio of 9:1. The resulting suspension was stirred at room temperature for 3 days and then filtered to obtain a solid, which was then dried and subjected to XRPD analysis. The results showed that the pyrazolopyrimidine ester compound was obtained as Form I crystals, which is a crystalline form. 【0038】 Example 6: Preparation of crystalline form Form I crystals by Method I 50 mg of the amorphous compound of formula (I) was weighed and added to 0.5 mL of a mixed solvent. The mixed solvent was used in a ratio (v / w) of 10 to the compound of formula (I). The mixed solvent was obtained by mixing MTBE as a poor solvent and ethanol as a good solvent in a volume-to-volume ratio of 7:1. The resulting suspension was stirred at room temperature for 3 days and then filtered to obtain a solid, which was then dried and subjected to XRPD analysis. The results showed that the pyrazolopyrimidine ester compound was obtained as Form I crystals. 【0039】 Example 7: Preparation of crystalline form Form I crystals by Method I 50 mg of the amorphous compound of formula (I) was weighed and added to 0.5 mL of a mixed solvent. The mixed solvent was used in a ratio (v / w) of 10 to the compound of formula (I). The mixed solvent was obtained by mixing n-heptane as a poor solvent and THF as a good solvent in a volume-to-volume ratio of 2:1. The resulting suspension was stirred at room temperature for 3 days and then filtered to obtain a solid, which was then dried and subjected to XRPD analysis. The results showed that the pyrazolopyrimidine ester compound was obtained as Form I crystals. 【0040】 Example 8: Preparation of crystalline form Form I crystals by Method I 50 mg of the amorphous compound of formula (I) was weighed and added to 0.5 mL of a mixed solvent. The mixed solvent was used in a ratio (v / w) of 10 to the compound of formula (I). The mixed solvent was obtained by mixing n-heptane as a poor solvent and isopropyl acetate as a good solvent in a volume-to-volume ratio of 2:1. The resulting suspension was stirred at room temperature for 3 days and then filtered to obtain a solid, which was then dried and subjected to XRPD analysis. The results showed that the pyrazolopyrimidine ester compound was obtained as Form I crystals, which is a crystalline form. 【0041】 Example 9: Preparation of crystalline form Form I crystals by Method I 50 mg of the amorphous compound of formula (I) was weighed and added to 0.5 mL of a mixed solvent. The mixed solvent was used in a ratio (v / w) of 10 to the compound of formula (I). The mixed solvent was obtained by mixing n-heptane as a poor solvent and ethyl acetate as a good solvent in a volume-to-volume ratio of 2:1. The resulting suspension was stirred at room temperature for 3 days and then filtered to obtain a solid, which was then dried and subjected to XRPD analysis. The results showed that the pyrazolopyrimidine ester compound was obtained as Form I crystals, which is a crystalline form. 【0042】 Example 10: Preparation of crystalline form Form I crystals by Method I 50 mg of the amorphous compound of formula (I) was weighed and added to 0.5 mL of a mixed solvent. The mixed solvent was used in a ratio (v / w) of 10 to the compound of formula (I). The mixed solvent was obtained by mixing n-heptane as a poor solvent and acetone as a good solvent in a volume-to-volume ratio of 2:1. The resulting suspension was stirred at room temperature for 3 days and then filtered to obtain a solid, which was then dried and subjected to XRPD analysis. The results showed that the pyrazolopyrimidine ester compound was obtained as Form I crystals, which is a crystalline form. 【0043】 Example 11: Preparation of crystalline form Form I crystals by Method I 50 mg of the amorphous compound of formula (I) was weighed and added to 0.5 mL of a mixed solvent. The mixed solvent was used in a ratio (v / w) of 10 to the compound of formula (I). The mixed solvent was obtained by mixing water as a poor solvent and methanol as a good solvent in a volume-to-volume ratio of 2:1. The resulting suspension was stirred at room temperature for 3 days and then filtered to obtain a solid, which was then dried and subjected to XRPD analysis. The results showed that the pyrazolopyrimidine ester compound was obtained as Form I crystals, which is a crystalline form. 【0044】 Example 12: Preparation of crystalline form Form I crystals by Method I 50 mg of the amorphous compound of formula (I) was weighed and added to 0.5 mL of a mixed solvent. The mixed solvent was used in a ratio (v / w) of 10 to the compound of formula (I). The mixed solvent was obtained by mixing water as a poor solvent and butanone as a good solvent in a volume-to-volume ratio of 2:1. The resulting suspension was stirred at room temperature for 3 days and then filtered to obtain a solid, which was then dried and subjected to XRPD analysis. The results showed that the pyrazolopyrimidine ester compound was obtained as Form I crystals, which is a crystalline form. 【0045】 Example 13: Preparation of crystalline form Form I crystals by Method I 50 mg of the amorphous compound of formula (I) was weighed and added to 0.5 mL of a mixed solvent. The mixed solvent was used in a ratio (v / w) of 10 to the compound of formula (I). The mixed solvent was obtained by mixing water as a poor solvent and acetonitrile as a good solvent in a volume-to-volume ratio of 2:1. The resulting suspension was stirred at room temperature for 3 days and then filtered to obtain a solid, which was then dried and subjected to XRPD analysis. The results showed that the pyrazolopyrimidine ester compound was obtained as Form I crystals, which is a crystalline form. 【0046】 Example 14: Preparation of crystalline form Form I crystals by Method I 50 mg of the amorphous compound of formula (I) was weighed and added to 0.5 mL of a mixed solvent. The mixed solvent was used in a ratio (v / w) of 10 to the compound of formula (I). The mixed solvent was obtained by mixing water as a poor solvent and isopropanol as a good solvent in a volume-to-volume ratio of 2:1. The resulting suspension was stirred at room temperature for 3 days and then filtered to obtain a solid, which was then dried and subjected to XRPD analysis. The results showed that the pyrazolopyrimidine ester compound was obtained as Form I crystals, which is a crystalline form. 【0047】 Example 15: Preparation of crystalline form Form I crystals by Method I 50 mg of the amorphous compound of formula (I) was weighed and added to 0.75 mL of a mixed solvent. The mixed solvent was used in a ratio (v / w) of 15 to the compound of formula (I). The mixed solvent was obtained by mixing cyclohexane as a poor solvent and acetone as a good solvent in a volume-to-volume ratio of 9:1. The resulting suspension was stirred at room temperature for 3 days and then filtered to obtain a solid, which was then dried and subjected to XRPD analysis. The results showed that the pyrazolopyrimidine ester compound was obtained as Form I crystals. 【0048】 Example 16: Preparation of crystalline form Form I crystals by Method I 50 mg of the amorphous compound of formula (I) was weighed and added to 0.75 mL of a mixed solvent. The mixed solvent was used in a ratio (v / w) of 15 to the compound of formula (I). The mixed solvent was obtained by mixing cyclohexane as a poor solvent and butanone as a good solvent in a volume-to-volume ratio of 9:1. The resulting suspension was stirred at room temperature for 3 days and then filtered to obtain a solid, which was then dried and subjected to XRPD analysis. The results showed that the pyrazolopyrimidine ester compound was obtained as Form I crystals. 【0049】 Example 17: Preparation of crystalline form Form I crystals by Method I 50 mg of the amorphous compound of formula (I) was weighed and added to 0.25 mL of a mixed solvent. The mixed solvent was used in a ratio (v / w) of 5 to the compound of formula (I). The mixed solvent was obtained by mixing cyclohexane as a poor solvent and isopropanol as a good solvent in a volume-to-volume ratio of 9:1. The resulting suspension was stirred at room temperature for 3 days and then filtered to obtain a solid, which was then dried and subjected to XRPD analysis. The results showed that the pyrazolopyrimidine ester compound was obtained as Form I crystals. 【0050】 Example 18: Preparation of crystalline form Form I crystals by Method I 50 mg of the amorphous compound of formula (I) was weighed and added to 3.5 mL of a mixed solvent. The mixed solvent was used in a ratio (v / w) of 70 to the compound of formula (I). The mixed solvent was obtained by mixing n-heptane as a poor solvent and acetone as a good solvent in a volume-to-volume ratio of 6:1. The resulting suspension was stirred at room temperature for 3 days and then filtered to obtain a solid, which was then dried and subjected to XRPD analysis. The results showed that the pyrazolopyrimidine ester compound was obtained as Form I crystals, which is a crystalline form. 【0051】 Example 19: Preparation of crystalline form Form I crystals by Method I 50 mg of the amorphous compound of formula (I) was weighed and added to 7.5 mL of a mixed solvent. The mixed solvent was used in a ratio (v / w) of 150 to the compound of formula (I). The mixed solvent was obtained by mixing cyclohexane as a poor solvent and acetone as a good solvent in a volume-to-volume ratio of 14:1. The resulting suspension was stirred at room temperature for 3 days and then filtered to obtain a solid, which was then dried and subjected to XRPD analysis. The results showed that the pyrazolopyrimidine ester compound was obtained as Form I crystals. 【0052】 Example 20: Preparation of crystalline form Form I crystals by Method I 50 mg of the amorphous compound of formula (I) was weighed and added to 2.0 mL of a mixed solvent. The mixed solvent was used in a ratio (v / w) of 40 to the compound of formula (I). The mixed solvent was obtained by mixing water as a poor solvent and acetonitrile as a good solvent in a volume-to-volume ratio of 1:1. The resulting suspension was stirred at room temperature for 3 days and then filtered to obtain a solid, which was then dried and subjected to XRPD analysis. The results showed that the pyrazolopyrimidine ester compound was obtained as Form I crystals, which is a crystalline form. 【0053】 Example 21: Preparation of crystalline form Form I crystals by Method I 50 mg of the amorphous compound of formula (I) was weighed and added to 4.0 mL of a mixed solvent. The mixed solvent was used in a ratio (v / w) of 80 to the compound of formula (I). The mixed solvent was obtained by mixing n-heptane as a poor solvent and ethyl acetate as a good solvent in a volume-to-volume ratio of 7:1. The resulting suspension was stirred at room temperature for 3 days and then filtered to obtain a solid, which was then dried and subjected to XRPD analysis. The results showed that the pyrazolopyrimidine ester compound was obtained as Form I crystals, which is a crystalline form. 【0054】 Example 22: Preparation of crystalline form Form I crystals by Method I 50 mg of the amorphous compound of formula (I) was weighed and added to 7.5 mL of a mixed solvent. The mixed solvent was used in a ratio (v / w) of 150 to the compound of formula (I). The mixed solvent was obtained by mixing cyclohexane as a poor solvent and ethyl acetate as a good solvent in a volume-to-volume ratio of 14:1. The resulting suspension was stirred at room temperature for 3 days and then filtered to obtain a solid, which was then dried and subjected to XRPD analysis. The results showed that the pyrazolopyrimidine ester compound was obtained as Form I crystals. 【0055】 Example 23: Preparation of crystalline form Form I crystals by Method I 50 mg of the amorphous compound of formula (I) was weighed and added to 3.5 mL of a mixed solvent. The mixed solvent was used in a ratio (v / w) of 70 to the compound of formula (I). The mixed solvent was obtained by mixing n-heptane as a poor solvent and THF as a good solvent in a volume-to-volume ratio of 6:1. The resulting suspension was stirred at room temperature for 3 days and then filtered to obtain a solid, which was then dried and subjected to XRPD analysis. The results showed that the pyrazolopyrimidine ester compound was obtained as Form I crystals, which is a crystalline form. 【0056】 Example 24: Preparation of crystalline form Form I crystals by Method I 50 mg of the amorphous compound of formula (I) was weighed and added to 7.5 mL of a mixed solvent. The mixed solvent was used in a ratio (v / w) of 150 to the compound of formula (I). The mixed solvent was obtained by mixing cyclohexane as a poor solvent and THF as a good solvent in a volume-to-volume ratio of 14:1. The resulting suspension was stirred at room temperature for 3 days and then filtered to obtain a solid, which was then dried and subjected to XRPD analysis. The results showed that the pyrazolopyrimidine ester compound was obtained as Form I crystals. 【0057】 Example 25: Preparation of crystalline form Form I crystals by Method II 50 mg of the amorphous compound of formula (I) was weighed and added to 0.5 mL of pure solvent. The pure solvent was methanol, used in a ratio (v / w) of 10 to the compound of formula (I). The resulting suspension was stirred at room temperature for 3 days, then filtered to obtain a solid, which was then dried and subjected to XRPD analysis. The results showed that the pyrazolopyrimidine ester compound was obtained as Form I crystals, which is a crystalline form. 【0058】 Example 26: Preparation of crystalline form Form I crystals by Method II 50 mg of the amorphous compound of formula (I) was weighed and added to 0.5 mL of pure solvent. The pure solvent was ethanol, used in a ratio (v / w) of 10 to the compound of formula (I). The resulting suspension was stirred at room temperature for 3 days, then filtered to obtain a solid, which was then dried and subjected to XRPD analysis. The results showed that the pyrazolopyrimidine ester compound was obtained as Form I crystals, which is a crystalline form. 【0059】 Example 27: Preparation of crystalline form Form I crystals by Method II 50 mg of the amorphous compound of formula (I) was weighed and added to 0.5 mL of pure solvent. The pure solvent was isopropanol, used in a ratio (v / w) of 10 to the compound of formula (I). The resulting suspension was stirred at room temperature for 3 days and then filtered to obtain a solid, which was then dried and subjected to XRPD analysis. The results showed that the pyrazolopyrimidine ester compound was obtained as Form I crystals, which is a crystalline form. 【0060】 Example 28: Preparation of crystalline form Form I crystals by Method II 50 mg of the amorphous compound of formula (I) was weighed and added to 0.5 mL of pure solvent. The pure solvent was isopropyl acetate, used in a ratio (v / w) of 10 to the compound of formula (I). The resulting suspension was stirred at room temperature for 3 days and then filtered to obtain a solid, which was then dried and subjected to XRPD analysis. The results showed that the pyrazolopyrimidine ester compound was obtained as Form I crystals, which is a crystalline form. 【0061】 Example 29: Preparation of crystalline form Form I crystals by Method II 50 mg of the amorphous compound of formula (I) was weighed and added to 0.5 mL of pure solvent. The pure solvent was acetonitrile, used in a ratio (v / w) of 10 to the compound of formula (I). The resulting suspension was stirred at room temperature for 3 days and then filtered to obtain a solid, which was then dried and subjected to XRPD analysis. The results showed that the pyrazolopyrimidine ester compound was obtained as Form I crystals, which is a crystalline form. 【0062】 Example 30: Preparation of crystalline form Form I crystals by Method II 50 mg of the amorphous compound of formula (I) was weighed and added to 0.5 mL of pure solvent. The pure solvent was MTBE, used in a ratio (v / w) of 10 to the compound of formula (I). The resulting suspension was stirred at room temperature for 3 days and then filtered to obtain a solid, which was then dried and subjected to XRPD analysis. The results showed that the pyrazolopyrimidine ester compound was obtained as Form I crystals, which is a crystalline form. 【0063】 Example 31: Preparation of crystalline form Form I crystals by Method II 50 mg of the amorphous compound of formula (I) was weighed and added to 0.5 mL of pure solvent. The pure solvent was n-heptane, used in a ratio (v / w) of 10 to the compound of formula (I). The resulting suspension was stirred at room temperature for 3 days and then filtered to obtain a solid, which was then dried and subjected to XRPD analysis. The results showed that the pyrazolopyrimidine ester compound was obtained as Form I crystals, which is a crystalline form. 【0064】 Example 32: Preparation of crystalline form Form I crystals by Method II 50 mg of the amorphous compound of formula (I) was weighed and added to 0.5 mL of pure solvent. The pure solvent was isopropyl ether, used in a ratio (v / w) of 10 to the compound of formula (I). The resulting suspension was stirred at room temperature for 3 days and then filtered to obtain a solid, which was then dried and subjected to XRPD analysis. The results showed that the pyrazolopyrimidine ester compound was obtained as Form I crystals, which is a crystalline form. 【0065】 Example 33: Preparation of crystalline form Form I crystals by Method II 50 mg of the amorphous compound of formula (I) was weighed and added to 0.5 mL of pure solvent. The pure solvent was cyclohexane, used in a ratio (v / w) of 10 to the compound of formula (I). The resulting suspension was stirred at room temperature for 3 days and then filtered to obtain a solid, which was then dried and subjected to XRPD analysis. The results showed that the pyrazolopyrimidine ester compound was obtained as Form I crystals, which is a crystalline form. 【0066】 Comparative Example 1 50 mg of the amorphous compound of formula (I) was weighed and added to 0.5 mL of pure solvent. The pure solvent was water. The resulting suspension was stirred at room temperature for 3 days, then filtered to obtain a solid, which was then dried and subjected to XRPD analysis. The results showed that the resulting solid was amorphous. 【0067】 Comparative Example 2 50 mg of amorphous compound of formula (I) was weighed and added to 0.5 mL of pure solvent, which was ethyl acetate. The resulting suspension appeared as a clear solution with no solid precipitate present after stirring at room temperature for 3 days. 【0068】 Comparative Example 3 50 mg of amorphous compound of formula (I) was weighed and added to 0.5 mL of pure solvent. The pure solvent was acetone. The resulting suspension appeared as a clear solution with no solid precipitate after stirring at room temperature for 3 days. 【0069】 Example 34: Stability studies Samples of the amorphous compound of formula (I) and the crystalline compound (Form I crystal) were stored under different conditions: 40°C for 10 days, 150°C for 10 days, 25°C and 92.5%RH (relative humidity) for 10 days, 60°C and 75%RH for 10 days, in the light for 10 days, and at room temperature for 10 days. They were then analyzed for changes in purity. The results are shown in the table below. 【0070】 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 highly stable, especially when stored at room temperature and in light for 10 days. Form I crystalline, a crystalline form, demonstrated its value in terms of stability, allowing for long-term storage without special requirements regarding temperature, light, humidity, or oxygen levels. 【0071】 [Table 2]

Claims

[Claim 1] Equation (I): 【Chemistry 1】 A crystal of a pyrazolopyrimidine ester compound having the structure represented by and having morphology I, wherein the powder X-ray diffraction (XRPD) pattern has characteristic peaks represented by 2θ degrees at 11.26°, 14.03°, 14.80°, 17.07°, 19.78°, 21.21°, 22.39°, and 23.85°, with an error range of ±0.20° for 2θ degrees, and the XRPD pattern is obtained using Cu-Kα emission, and the crystal of the pyrazolopyrimidine ester compound having morphology I. [Claim 2] In the aforementioned XRPD pattern, the angles were 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°, and 23.08°. A crystal of a pyrazolopyrimidine ester compound having characteristic peaks represented by 2θ-degree values ​​at 23.85°, 24.40°, 24.73°, 25.95°, 26.23°, 26.95°, 29.21°, 30.17°, 32.71°, and 32.99°, wherein the crystalline form according to claim 1 is form I, and the crystal has characteristic peaks represented by 2θ-degree values ​​at 2θ-degree values ​​of ±0.20°. [Claim 3] The aforementioned XRPD pattern is shown in the figure below: Table 1 A crystal of a pyrazolopyrimidine ester compound, wherein the crystalline form described in claim 2 is form I. [Claim 4] A crystal of a pyrazolopyrimidine ester compound, having an irregular anhydrous crystalline form, exhibiting an endothermic peak at 119.75°C in its differential scanning calorimetry (DSC) curve, with an error range of ±1.00°C for the endothermic peak temperature, wherein the crystalline form according to claim 1 is form I. [Claim 5] The DSC curve and thermogravimetric analysis (TGA) curve are shown in the figure below: Table 2 A crystal of a pyrazolopyrimidine ester compound, wherein the crystalline form described in claim 4 is form I. [Claim 6] In the infrared (IR) spectrum, 493 cm －１ , 519 cm －１ , 587 cm －１ , 609 cm －１ , 676 cm －１ , 692 cm －１ , 759 cm －１ , 774 cm －１ , 794 cm －１ , 808 cm －１ , 869 cm －１ , 895 cm －１ , 934 cm －１ , 963 cm －１ , 1,000 cm －１ , 1,027 cm －１ , 1,073 cm －１ , 1,102 cm －１ , 1,134 cm －１ , 1,158 cm －１ , 1,229 cm －１ , 1,342 cm －１ , 1,382 cm －１ , 1,448 cm －１ , 1,490 cm －１ , 1,523 cm －１ , 1,559 cm －１ , 1,589 cm －１ , 1,645 cm －１ , 1,681 cm －１ , 1,753 cm －１ , 2,870 cm －１ , 2,954 cm －１ , 3,067 cm －１ , 3,149 cm －１ and absorption bands characteristic of wave numbers of 3,406 cm －１ , and the error range of the absorption band peak is ±2 cm －１ , a crystal of a pyrazolopyrimidine ester compound having a crystal form of Form I according to claim 1. [Claim 7] The aforementioned IR spectrum is shown in the figure below: Table 3 A crystal of a pyrazolopyrimidine ester compound, wherein the crystalline form described in claim 6 is form I. [Claim 8] A method for preparing crystals of a pyrazolopyrimidine ester compound having the crystalline form described in any one of claims 1 to 7 as form I, The process includes the steps of adding a pyrazolopyrimidine ester compound having the structure of formula (I) in an amorphous form to a mixed solvent, and stirring the resulting suspension, followed by filtration and drying to obtain crystals of the pyrazolopyrimidine ester compound having the crystalline form of form I, wherein the mixed solvent is a solvent obtained by mixing a good solvent and a poor solvent. A method wherein the good solvent in the mixed solvent is selected from methanol, ethanol, isopropanol, acetonitrile, acetone, butanone, ethyl acetate, isopropyl acetate, and tetrahydrofuran, the poor solvent is selected from methyl tert-butyl ether, water, n-heptane, and cyclohexane, the mixed solvent is used in a volume-to-weight ratio of 5 to 150 with respect to the compound of formula (I), and the poor solvent and the good solvent are used in a volume-to-volume ratio of (1 to 14):1 in the mixed solvent. [Claim 9] A method for preparing crystals of a pyrazolopyrimidine ester compound having the crystalline form described in any one of claims 1 to 7 as form I, The process comprises the steps of adding a pyrazolopyrimidine ester compound having the structure of formula (I) in an amorphous form to a pure solvent, stirring the resulting suspension, followed by filtration and drying to obtain crystals of the pyrazolopyrimidine ester compound having form I, wherein the pure solvent is selected from methanol, ethanol, isopropanol, isopropyl acetate, acetonitrile, methyl tert-butyl ether, n-heptane, isopropyl ether, and cyclohexane. A method comprising using the pure solvent in a volume-to-weight ratio not exceeding 10 relative to the compound of formula (I). [Claim 10] Use of crystals of a pyrazolopyrimidine ester compound having the crystalline form described in any one of claims 1 to 7 as form I, in the preparation of a drug for treating lymphoma and lymphocytic leukemia.

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