Crystal form of pyrazolopyrimidine ester compound and preparation method therefor

Abstract

Provided is a crystal form (Form II) of a pyrazolopyrimidine ester compound having a structure as shown in formula (I). The crystal form is characterized by a powder X-ray diffraction pattern, differential scanning calorimetry and infrared. Further provided is a method for preparing the crystal form (Form II) of the pyrazolopyrimidine ester compound. The present crystal form allows storage thereof for a long period of time without special requirements regarding the characteristics of temperature, light, humidity or oxygen level, and has very significant advantages in terms of stability. Moreover, the preparation method has simple steps, good reproducibility and excellent purity, and has broad application prospects.

Description

A pyrazolopyrimidine ester compound crystal form and preparation method thereof Technical Field

[0001] The present invention belongs to the field of chemical medicines, and in particular relates to a pyrazolopyrimidine ester compound crystal form and a preparation method thereof. Background Art

[0002] BTK (Bruton's tyrosine kinase) is a non-receptor, cytoplasmic tyrosine protein kinase in the Tec family. It participates in TLR, BAFF-R, BCR, and CXCR4 / 5 signal transduction, regulating B cell proliferation, differentiation, apoptosis, and migration. BTK plays a key role in the pathogenesis of malignant B-cell lymphoma, and BTK inhibitors are important drugs for the treatment of B-cell lymphoma.

[0003] CN 202111131059.0 discloses a series of pyrazolopyrimidine ester BTK inhibitor prodrug compounds, which rapidly enter the plasma after oral absorption and are hydrolyzed into the active metabolite 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-D]pyrimidin-1-yl]-1-piperidinyl]-2-propene-1-one, that is, hydrolyzed into 4-amino active metabolite (4-AAM) to exert its pharmacological effect. The 4-amino active metabolite is an active substance currently widely recognized in clinical practice. Among the above series of compounds, the chemical name is 1-[(3R)-3-[4-(butoxycarbonyl)-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-D]pyrimidin-1-yl]-1-piperidinyl]-2-propene-1-one, which has a chemical structure as shown in formula (I). It has the highest hydrolysis rate in plasma, the 4-amino active metabolite has the highest AUC, and the AUC of the prodrug itself is relatively the lowest, which is most consistent with the characteristics of a prodrug.

[0004] CN 202111131059.0 also provides a method for synthesizing the compound, and the obtained product is detected to be amorphous. The compound shown in formula (Ⅰ) is obtained by reacting commercially available 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-D]pyrimidin-1-yl]-1-piperidinyl]-2-propene-1-one with butyl chloroformate. Studies have shown that the stability of the amorphous compound is poor and it is sensitive to both temperature and humidity. It will undergo significant degradation after being placed at 40°C for 10 days and will almost completely decompose after being placed at 60°C / 75%RH for 10 days. Under conventional storage conditions, problems such as the increase of related substances are prone to occur, which brings great difficulties to the storage and processing of the product. In view of the potential clinical value of the compound shown in formula (I), it is particularly important to obtain a crystalline form with excellent purity and stable properties.

[0005] Summary of the Invention

[0006] The applicant has now developed a stable and reproducible crystalline form, named Form II, and also provided a method for preparing Form II. Form II shows significant advantages in stability, allowing it to be stored for long periods of time without any special requirements for 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 achieve the above object, the present invention adopts the following technical solution:

[0008] A crystalline form II of a pyrazolopyrimidine ester compound having a structure as shown in formula (I) has an X-ray powder diffraction (XRPD) pattern, wherein the X-ray powder diffraction (XRPD) pattern has characteristic peaks at three or more diffraction angles (preferably four or more, five or more, six or more, seven or more, or eight characteristic peaks) among 2θ values ​​of 5.53°, 9.82°, 10.76°, 17.87°, 20.55°, 21.28°, 21.92°, and 25.15°, wherein the 2θ value error range is ±0.20°, and the XRPD uses Cu-Kα radiation.

[0009] Furthermore, the crystal form Form II has characteristic peaks at diffraction angles of 2θ values ​​of 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° in the XRPD pattern, and the error range of the 2θ value is ±0.20°.

[0010] Furthermore, the 2θ values ​​and relative intensities I (expressed as a percentage relative to the strongest diffraction peak) of the characteristic peaks of the crystalline form Form II in the XRPD spectrum are as follows:

[0011] Furthermore, the crystalline form Form II has an XRPD pattern as shown in FIG1 .

[0012] Furthermore, the crystal form Form II is an irregularly shaped crystal.

[0013] Furthermore, the differential scanning calorimetry (DSC) curve of the crystalline form Form II has an endothermic peak at 129.59° C., and the temperature has an error margin of ±1.00° C.

[0014] Furthermore, the crystal form Form II has a DSC curve as shown in FIG2 .

[0015] Furthermore, the infrared (IR) spectrum of the crystal form Form II shows characteristic absorption bands at the wave numbers described in the table below, wherein each peak has a ±2 cm -1 The error margin is for the intensity of each peak, w = weak, m = medium, s = strong.

[0016] Furthermore, in the infrared (IR) spectrum of the crystalline form Form II, at wave numbers of 423, 449, 485, 517, 564, 584, 616, 652, 679, 693, 708, 739, 754, 787, 827, 849, 862, 896, 941, 959, 971, 996, 1011, 1030, 1078, 1095, 1138, 1159, 1197, 233, 1277, 1303, 1345, 1376, 1416, 1445, 1455, 1488, 1504, 1524, 1556, 1588, 1606, 1642, 1711, 1750, 1901, 2865, 2897, 2928, 2954, 3012, 3027, 3044, 3076, 3166, and 3195 cm - 1 The characteristic absorption bands are shown at , where each peak has ± 2 cm -1 margin of error.

[0017] Furthermore, the crystal form Form II has an IR spectrum as shown in FIG3 .

[0018] Furthermore, the dynamic vapor sorption (DVS) results of the crystalline form Form II showed that Form II had almost no hygroscopicity; the XRPD pattern of the crystalline form Form II remained unchanged before and after the DVS test.

[0019] Further stability studies revealed that Form II degraded less than the amorphous form under multiple forced degradation conditions, particularly after 10 days at room temperature and under light exposure, remaining very stable. This study suggests that Form II can be stored under standard conditions without requiring special protective measures, which is particularly important during drug production.

[0020] A second object of the present invention is to provide a method for preparing the crystalline form Form II of the pyrazolopyrimidine ester compound, wherein the crystalline form Form II is obtained by crystallization of the amorphous compound represented by formula (I) or the crystalline form Form I represented by formula (I), wherein:

[0021] When preparing Form II by crystallizing the amorphous compound represented by Formula (I), the purity of the amorphous compound represented by Formula (I) is required to be higher, and its purity is required to be not less than 98.5%; or in the preparation method, by adding seed crystals of Form II to induce the formation of Form II, when seed crystals of Form II are added, there is no special requirement for the purity of the amorphous compound represented by Formula (I).

[0022] When preparing crystalline Form II from the compound represented by Formula (I) in crystalline Form I, the crystalline Form I is prepared by crystallizing the amorphous compound represented by Formula (I). The crystalline Form I is a crystalline form having characteristic peaks at three or more (preferably four or more, five or more, six or more, seven or more, or eight characteristic peaks) at diffraction angles of 2θ values ​​of 11.26°, 14.03°, 14.80°, 17.07°, 19.78°, 21.21°, 22.39°, and 23.85° in an X-ray powder diffraction (XRPD) pattern, wherein the 2θ value error range is ±0.20°, and XRPD uses Cu-Kα radiation.

[0023] Furthermore, the crystal form Form I includes characteristic peaks at diffraction angles of 2θ values ​​of 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° in the XRPD pattern, wherein the error range of the 2θ value is ±0.20°; the crystal form Form I has an XRPD pattern as shown in FIG4 .

[0024] Furthermore, the crystalline Form I is an irregularly shaped crystal; the differential scanning calorimetry (DSC) curve of the crystalline Form I has an endothermic peak at 119.75°C, and the temperature has an error margin of ±1.00°C; the thermogravimetric analysis (TGA) of the crystalline Form I shows no obvious weight loss before decomposition, and the crystalline Form I is an anhydrous crystalline form; the crystalline Form I has a DSC curve and a TGA curve as shown in Figure 5.

[0025] Furthermore, the infrared (IR) spectrum of the crystalline form Form I has wavelengths of 493, 519, 587, 609, 676, 692, 759, 774, 794, 808, 869, 895, 934, 963, 1000, 1027, 1073, 1102, 1134, 1158, 1229, 1342, 1382, 1448, 1490, 1523, 1559, 1589, 1645, 1681, 1753, 2870, 2954, 3067, 3149 and 3406 cm -1 The characteristic absorption bands are shown at , where each peak has ± 2 cm -1 The error margin is ; the crystalline Form I has an IR spectrum as shown in FIG6 .

[0026] The crystalline form Form I used to prepare the crystalline form Form II can be crystallized by the following preparation method, which specifically comprises the following steps: adding the amorphous compound represented by formula (I) to a mixed solvent, stirring the resulting suspension at room temperature, filtering, and drying to obtain the crystalline form Form II. I pyrazolopyrimidine ester compound; the mixed solvent is a mixture of a good solvent and a poor solvent; wherein the good solvent is a solvent capable of dissolving the compound represented by formula (I), and is selected from one of methanol, ethanol, isopropanol, acetonitrile, acetone, butanone, ethyl acetate, isopropyl acetate, and tetrahydrofuran; the poor solvent is a solvent incapable of dissolving, poorly soluble, or slightly soluble in the compound represented by formula (I), and is selected from one of methyl tert-butyl ether, water, n-heptane, and cyclohexane; the amount ratio of the mixed solvent to the compound represented by formula (I) is a volume-to-mass ratio of 5 to 150 (v / w), and the amount ratio of the poor solvent to the good solvent in the mixed solvent is a volume ratio of (1 to 14):1 (v / v), wherein the unit of v is milliliter (mL) and the unit of w is gram (g).

[0027] Specifically, the method for preparing the crystalline form Form II from the amorphous or crystalline form of the compound represented by formula (I) comprises the following steps:

[0028] A pyrazolopyrimidine ester compound having a structure as shown in formula (I) is dissolved in a good solvent, and then a poor solvent (anti-solvent) is added until a solid precipitates, and the mixture is stirred, filtered, and dried to obtain a pyrazolopyrimidine ester compound having the crystal form Form II; wherein the good solvent is a solvent that can dissolve the compound represented by formula (I), and the poor solvent is a solvent that cannot dissolve, poorly dissolves, or slightly dissolves the compound represented by formula (I).

[0029] Furthermore, the poor solvent is added slowly in batches, preferably in two batches.

[0030] Furthermore, the good solvent is selected from one of acetone, 2-methyltetrahydrofuran, methanol, acetonitrile, ethyl acetate, and tetrahydrofuran, preferably acetone or 2-methyltetrahydrofuran; the poor solvent is selected from one of n-heptane, methyl tert-butyl ether, water, and cyclohexane, preferably n-heptane.

[0031] Furthermore, in the method for preparing the crystalline form Form II, the amount ratio of the good solvent to the compound represented by formula (I) is a volume mass ratio of 5 to 10 (v / w), and the amount ratio of the poor solvent to the compound represented by formula (I) is a volume mass ratio of 10 to 150 (v / w), where v is in milliliters (mL) and w is in grams (g).

[0032] Furthermore, in the method for preparing the crystalline form Form II, the amount ratio of the good solvent to the compound represented by formula (I) is a volume mass ratio of 5 to 7 (v / w), and the amount ratio of the poor solvent to the compound represented by formula (I) is a volume mass ratio of 14 to 21 (v / w).

[0033] The third object of the present invention is to provide the use of the above-mentioned pyrazolopyrimidine ester compound crystal form II for preparing drugs for treating blood diseases such as lymphoma and lymphocytic leukemia.

[0034] The present invention has the following beneficial effects:

[0035] The preparation method of the present invention can obtain a pyrazolopyrimidine ester compound having the crystalline form Form II. This crystalline form allows for long-term storage without particular requirements for temperature, light, humidity, or oxygen levels, and has significant advantages in stability over amorphous and crystalline Form I pyrazolopyrimidine ester compounds. Furthermore, the preparation method has simple steps, good reproducibility, and excellent purity, and has broad application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] FIG1 is an X-ray powder diffraction (XRPD) pattern of the crystalline form II of the pyrazolopyrimidine ester compound;

[0037] FIG2 is a differential scanning calorimetry (DSC) diagram of the crystalline form II of the pyrazolopyrimidine ester compound;

[0038] FIG3 is an infrared (IR) spectrum of the crystalline form II of the pyrazolopyrimidine ester compound;

[0039] FIG4 is an X-ray powder diffraction (XRPD) pattern of the crystalline form I of the pyrazolopyrimidine ester compound;

[0040] FIG5 is a differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) diagram of the crystalline form I of the pyrazolopyrimidine ester compound;

[0041] FIG6 is an infrared (IR) spectrum of the crystalline form Form I of the pyrazolopyrimidine ester compound. DETAILED DESCRIPTION

[0042] The technical solutions of the present invention are described clearly and completely below with reference to specific embodiments. It should be understood that the described embodiments are only a portion of the embodiments of the present invention, rather than all of the embodiments. All other embodiments derived by persons of ordinary skill in the art based on the embodiments of the present invention without creative effort are considered to fall within the scope of the present invention.

[0043] In the context of the present invention, room temperature refers to 20-30°C, preferably 25°C.

[0044] In the following examples, the dosage ratios of the good solvent and the poor solvent to the compound represented by formula (I) are indicated in brackets. Taking 5V as an example, it means that the dosage ratio of the solvent to the compound represented by formula (I) is 5 (v / w), where v is in milliliters (mL) and w is in grams (g).

[0045] The amorphous compound of formula (I) used in the following examples can be prepared according to the method described in CN 202111131059.0: under nitrogen protection, raw materials 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-D]pyrimidin-1-yl]-1-piperidinyl]-2-propene-1-one, butyl chloroformate and dichloromethane are added, the temperature is lowered to 10°C, pyridine is added dropwise, and the reaction is kept warm for 3-4 hours. The reaction is stopped when TLC monitoring shows that there is almost no raw material; ice water is added, the liquids are separated, the aqueous phase is extracted with dichloromethane, the separated liquids and the extracted organic phase are combined, washed with water, concentrated and column-filtered to obtain the compound of formula (I).

[0046] The compound of formula (I) in crystalline form Form I used in the following examples can be prepared according to the aforementioned preparation method. Specifically, the following steps can be adopted: weighing the amorphous compound of formula (I) and adding it to a mixed solvent (10V), wherein the mixed solvent is a poor solvent methyl tert-butyl ether and a good solvent ethanol mixed in a volume ratio of 9:1, stirring the resulting suspension at room temperature for 3 days and then filtering, and drying the resulting solid to obtain the pyrazolopyrimidine ester compound having the crystalline form Form I.

[0047] Example 1

[0048] 200 g of amorphous compound (I) with a purity of 98.5% was weighed and dissolved in 1000 mL (5V) of acetone, a good solvent, at room temperature (20-30°C). 600 mL (3V) of n-heptane, a poor solvent, was then added to slowly precipitate a solid. The mixture was stirred at 5-15°C for 2 hours. 2400 mL (12V) of n-heptane was then slowly added dropwise over 3 hours. Stirring was continued at 0-10°C for 2 hours after the addition was complete. The mixture was filtered and dried under vacuum at 50°C for 4.5 hours to obtain a solid with a purification yield of 82.5%. XRPD and DSC analysis of the resulting solid revealed Form II of the pyrazolopyrimidine ester compound.

[0049] Example 2

[0050] 200 g of amorphous compound of formula (I) with a purity of 96% was weighed and dissolved in 1000 mL (5V) of acetone, a good solvent, at room temperature (20-30°C). 600 mL (3V) of n-heptane, a poor solvent, and 0.2 g of seed crystals of Form II were then added. A solid slowly precipitated, and the mixture was stirred at 5-15°C for 2 hours. 2400 mL (12V) of n-heptane was then slowly added dropwise over 3 hours. After complete addition, stirring was continued at 0-10°C for 2 hours, followed by filtration. The resulting solid was dried under vacuum at 50°C for 4.5 hours to obtain a solid with a purification yield of 80.5%. XRPD and DSC analysis of the resulting solid revealed Form II of the pyrazolopyrimidine ester compound.

[0051] Example 3

[0052] 200 g of the compound of formula (I) in crystalline Form I was weighed and dissolved in 1000 mL (5V) of acetone, a good solvent, at room temperature (20-30°C). 600 mL (3V) of n-heptane, a poor solvent, was then added to slowly precipitate a solid. The mixture was stirred at 5-15°C for 2 hours. 2400 mL (12V) of n-heptane was then slowly added dropwise over 3 hours. After complete addition, stirring was continued at 0-10°C for 2 hours. The mixture was filtered and dried under vacuum at 50°C for 4.5 hours to obtain a solid with a purification yield of 81.1%. XRPD and DSC analysis of the resulting solid revealed Form II of the pyrazolopyrimidine ester compound.

[0053] Example 4

[0054] 30 g of the amorphous compound of formula (I) with a purity of 98.5% was weighed and dissolved in 150 mL (5V) of acetone, a good solvent, at room temperature (20-30°C). 90 mL (3V) of n-heptane, a poor solvent, was then added to slowly precipitate a solid. The mixture was stirred at 5-15°C for 2 hours. 360 mL (12V) of n-heptane was then slowly added dropwise over 2.5 hours. Stirring was continued at 0-10°C for 3 hours after the addition was complete. The mixture was filtered and dried under vacuum at 50°C for 4.5 hours to obtain a solid with a purification yield of 84.1%. XRPD and DSC analysis of the resulting solid revealed Form II of the pyrazolopyrimidine ester compound.

[0055] Example 5

[0056] 30 g of the 96% pure amorphous compound of formula (I) was weighed and dissolved in 150 mL (5V) of acetone, a good solvent, at room temperature (20-30°C). Then, 0.03 g of n-heptane, a poor solvent (90 mL (3V)), and seed crystals of Form II were added. A solid slowly precipitated, and the mixture was stirred at 5-15°C for 2 hours. Then, 360 mL (12V) of n-heptane was slowly added dropwise over 2.5 hours. After complete addition, stirring was continued at 0-10°C for 3 hours, followed by filtration. The resulting solid was dried under vacuum at 50°C for 4.5 hours to obtain a solid with a purification yield of 81.0%. XRPD and DSC analysis of the resulting solid revealed Form II of the pyrazolopyrimidine ester compound.

[0057] Example 6

[0058] 30 g of the compound of formula (I) in Form I was weighed and dissolved in 150 mL (5V) of acetone, a good solvent, at room temperature (20-30°C). 90 mL (3V) of n-heptane, a poor solvent, was then added to slowly precipitate a solid. The mixture was stirred at 5-15°C for 2 hours. 360 mL (12V) of n-heptane was then slowly added dropwise over 2.5 hours. Stirring was continued at 0-10°C for 3 hours after the addition was complete. The mixture was filtered and dried under vacuum at 50°C for 4.5 hours to obtain a solid with a purification yield of 84.5%. XRPD and DSC analysis of the resulting solid revealed Form II of the pyrazolopyrimidine ester compound.

[0059] Example 7

[0060] 5 g of amorphous compound (I) with a purity of 98.5% was weighed and dissolved in 35 mL (7V) of acetone, a good solvent, at 5-15°C. 25 mL (5V) of n-heptane, a poor solvent, was then added to slowly precipitate a solid. The mixture was stirred at 5-15°C for 1 hour. Then, 45 mL (9V) of n-heptane was slowly added dropwise over 30 minutes. Stirring was continued at 0-5°C for 1 hour after the addition. The mixture was filtered and dried under vacuum at 50°C for 4.5 hours to obtain a solid with a purification yield of 41.0%. XRPD and DSC analysis of the resulting solid revealed Form II of the pyrazolopyrimidine ester compound.

[0061] Example 8

[0062] 5 g of amorphous compound of formula (I) with a purity of 96% was weighed and dissolved in 35 mL (7V) of acetone, a good solvent, at 5-15°C. 25 mL (5V) of n-heptane, a poor solvent, and 0.005 g of seed crystals of Form II were then added, allowing a solid to slowly precipitate. The mixture was stirred at 5-15°C for 1 hour, and then 45 mL (9V) of n-heptane was slowly added dropwise over 30 minutes. After complete addition, stirring was continued at 0-5°C for 1 hour. The mixture was filtered, and the resulting solid was dried under vacuum at 50°C for 4.5 hours to obtain a solid with a purification yield of 38.9%. XRPD and DSC analysis of the resulting solid revealed Form II of the pyrazolopyrimidine ester compound.

[0063] Example 9

[0064] 5 g of the compound of formula (I) in crystalline Form I was weighed and dissolved in 35 mL (7V) of acetone, a good solvent, at 5-15°C. 25 mL (5V) of n-heptane, a poor solvent, was then added to slowly precipitate a solid. The mixture was stirred at 5-15°C for 1 hour. Then, 45 mL (9V) of n-heptane was slowly added dropwise over 30 minutes. After complete addition, stirring was continued at 0-5°C for 1 hour. The mixture was filtered and dried under vacuum at 50°C for 4.5 hours to obtain a solid with a purification yield of 42.7%. XRPD and DSC analysis of the resulting solid revealed Form II of the pyrazolopyrimidine ester compound.

[0065] Example 10

[0066] 5 g of amorphous compound (I) with a purity of 98.5% was weighed and dissolved in 35 mL (7V) of acetone, a good solvent, at 5-15°C. 25 mL (5V) of n-heptane, a poor solvent, was then added to slowly precipitate a solid. The mixture was stirred at 5-15°C for 1 hour. 80 mL (16V) of n-heptane was then slowly added dropwise over 30 minutes. Stirring was continued at 0-5°C for 1 hour after the addition. The mixture was filtered and dried under vacuum at 50°C for 4.5 hours to obtain a solid with a purification yield of 48.0%. XRPD and DSC analysis of the resulting solid revealed Form II of the pyrazolopyrimidine ester compound.

[0067] Example 11

[0068] 5 g of amorphous compound of formula (I) with a purity of 96% was weighed and dissolved in 35 mL (7V) of acetone, a good solvent, at 5-15°C. 25 mL (5V) of n-heptane, a poor solvent, and 0.005 g of seed crystals of Form II were then added. A solid slowly precipitated and stirred at 5-15°C for 1 hour. 80 mL (16V) of n-heptane was then slowly added dropwise over 30 minutes. After complete addition, stirring was continued at 0-5°C for 1 hour. The mixture was filtered and dried under vacuum at 50°C for 4.5 hours to obtain a solid with a purification yield of 47.2%. XRPD and DSC analysis of the resulting solid revealed Form II of the pyrazolopyrimidine ester compound.

[0069] Example 12

[0070] 5 g of the compound of formula (I) in crystalline Form I was weighed and dissolved in 35 mL (7V) of acetone, a good solvent, at 5-15°C. 25 mL (5V) of n-heptane, a poor solvent, was then added to slowly precipitate a solid. The mixture was stirred at 5-15°C for 1 hour. 80 mL (16V) of n-heptane was then slowly added dropwise over 30 minutes. Stirring was continued at 0-5°C for 1 hour after the addition. The mixture was filtered and dried under vacuum at 50°C for 4.5 hours to obtain a solid with a purification yield of 50.5%. XRPD and DSC analysis of the resulting solid revealed Form II of the pyrazolopyrimidine ester compound.

[0071] Example 13

[0072] 2 g of amorphous compound (I) with a purity of 99% was weighed and dissolved in 10 mL (5V) of acetone, a good solvent, at 0-5°C. 6 mL (3V) of n-heptane, a poor solvent, was then added to slowly precipitate a solid. The mixture was stirred at 0-5°C for 1 hour. 24 mL (12V) of n-heptane was then slowly added dropwise over 30 minutes. Stirring was continued at 0-5°C for 1 hour after the addition. The mixture was filtered and dried under vacuum at 50°C for 4.5 hours to obtain a solid with a purification yield of 90.0%. XRPD and DSC analysis of the resulting solid revealed Form II of the pyrazolopyrimidine ester compound.

[0073] Example 14

[0074] 2 g of amorphous compound of formula (I) with a purity of 97% was weighed and dissolved in 10 mL (5V) of acetone, a good solvent, at 0-5°C. 6 mL (3V) of n-heptane, a poor solvent, and 0.002 g of seed crystals of Form II were then added. A solid slowly precipitated and stirred at 0-5°C for 1 hour. 24 mL (12V) of n-heptane was then slowly added dropwise over 30 minutes. Stirring was continued at 0-5°C for 1 hour after the addition was complete. The mixture was filtered and dried under vacuum at 50°C for 4.5 hours to obtain a solid with a purification yield of 89.3%. XRPD and DSC analysis of the resulting solid revealed Form II of the pyrazolopyrimidine ester compound.

[0075] Example 15

[0076] 2 g of the compound of formula (I) in crystalline Form I was weighed and dissolved in 10 mL (5V) of acetone, a good solvent, at 0-5°C. 6 mL (3V) of n-heptane, a poor solvent, was then added to slowly precipitate a solid. The mixture was stirred at 0-5°C for 1 hour. 24 mL (12V) of n-heptane was then slowly added dropwise over 30 minutes. Stirring was continued at 0-5°C for 1 hour after the addition. The mixture was filtered and dried under vacuum at 50°C for 4.5 hours to obtain a solid with a purification yield of 92.2%. XRPD and DSC analysis of the resulting solid revealed Form II of the pyrazolopyrimidine ester compound.

[0077] Example 16

[0078] 2 g of amorphous compound (I) with a purity of 99% was weighed and dissolved in 10 mL (5V) of 2-methyltetrahydrofuran (a good solvent) at 0-5°C. 10 mL (5V) of n-heptane (a poor solvent) was then added to allow a solid to slowly precipitate. The mixture was stirred at 0-5°C for 1 hour. 20 mL (10V) of n-heptane was then slowly added dropwise over 30 minutes. Stirring was continued at 0-5°C for 1 hour after the addition, and the mixture was filtered. The resulting solid was dried under vacuum at 50°C for 4.5 hours to obtain a solid with a purification yield of 94.0%. XRPD and DSC analysis of the resulting solid revealed Form II of the pyrazolopyrimidine ester compound.

[0079] Example 17

[0080] 2 g of amorphous compound of formula (I) with a purity of 97% was weighed and dissolved in 10 mL (5V) of 2-methyltetrahydrofuran (a good solvent) at 0-5°C. Then, 10 mL (5V) of n-heptane (a poor solvent) and 0.002 g of seed crystals of Form II were added, allowing a solid to slowly precipitate. The mixture was stirred at 0-5°C for 1 hour, and then 20 mL (10V) of n-heptane was slowly added dropwise over 30 minutes. After complete addition, stirring was continued at 0-5°C for 1 hour. The mixture was filtered, and the resulting solid was dried under vacuum at 50°C for 4.5 hours to obtain a solid with a purification yield of 93.4%. XRPD and DSC analysis of the resulting solid revealed Form II of the pyrazolopyrimidine ester compound.

[0081] Example 18

[0082] 2 g of the compound of formula (I) in crystalline Form I was weighed and dissolved in 10 mL (5V) of 2-methyltetrahydrofuran (a good solvent) at 0-5°C. Then, 10 mL (5V) of n-heptane (a poor solvent) was added to slowly precipitate a solid. The mixture was stirred at 0-5°C for 1 hour. Then, 20 mL (10V) of n-heptane was slowly added dropwise over 30 minutes. After complete addition, stirring was continued at 0-5°C for 1 hour. The mixture was filtered and dried under vacuum at 50°C for 4.5 hours to obtain a solid with a purification yield of 94.8%. XRPD and DSC analysis of the resulting solid revealed that Form II of the pyrazolopyrimidine ester compound was obtained.

[0083] Example 19 Stability Study

[0084] The purity changes of the amorphous compound of formula (I), the compound of formula (I) having crystalline form Form I and the compound of formula (I) having crystalline form Form II were analyzed under different sampling conditions, as shown in the following table.

[0085] Form II deposition conditions: 60°C for 10 days, 60°C / 75% RH (relative humidity) for 10 days, light exposure for 10 days, and room temperature for 10 days.

[0086] The amorphous and crystalline Form I deposition conditions were: 40°C for 10 days, 60°C / 75% RH (relative humidity) for 10 days, light exposure for 10 days, and room temperature for 10 days.

[0087] The amorphous sample will undergo significant degradation after 10 days at 40°C and will almost completely decompose after 10 days at 60°C / 75% RH. The degradation degree of Form I is less than that of the amorphous sample, especially after 10 days at room temperature and light exposure, where the sample is stable. The Form II sample is even more stable, especially at room temperature and light conditions, and is relatively stable under degradation conditions such as high temperature and high humidity. Its stability is significantly better than that of the amorphous sample and is superior to that of Form I.

[0088] Form II exhibits valuable properties in terms of stability, allowing for long-term storage without particular requirements regarding temperature, light, humidity or oxygen levels.

Claims

1. A crystalline form II of a pyrazolopyrimidine ester compound having a structure as shown in formula (I), characterized in that: The X-ray powder diffraction (XRPD) pattern has characteristic peaks at diffraction angles of 2θ values ​​of 5.53°, 9.82°, 10.76°, 17.87°, 20.55°, 21.28°, 21.92°, and 25.15°, where the error range of the 2θ value is ±0.20°, and XRPD uses Cu-Kα radiation.

2. The crystalline form II of the pyrazolopyrimidine ester compound according to claim 1, characterized in that: The crystalline form Form II includes characteristic peaks at diffraction angles of 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° in the XRPD spectrum, wherein the error range of the 2θ value is ±0.20°.

3. The crystalline form II of the pyrazolopyrimidine ester compound according to claim 2, characterized in that: The crystalline form Form II has an XRPD pattern as shown in FIG1 .

4. The crystalline form II of the pyrazolopyrimidine ester compound according to claim 1, characterized in that: The crystal form Form II is an irregularly shaped crystal; the differential scanning calorimetry (DSC) curve of the crystal form Form II has an endothermic peak at 129.59° C., and the temperature has an error margin of ±1.00° C.

5. The crystalline form II of the pyrazolopyrimidine ester compound according to claim 4, characterized in that: The crystal form Form II has a DSC curve as shown in FIG2 .

6. The crystalline form II of the pyrazolopyrimidine ester compound according to claim 1, characterized in that: The infrared (IR) spectrum of the crystalline form II has the following wavelengths: 1030, 1078, 1138, 1197, 1233, 1277, 1376, 1445, 1455, 1488, 1504, 1556, 1588, 1606, 1642, 1750, 2865, 2897, 2928, 2954, 3012, 3027, 3044, 3076, 3166 and 3195 cm -1 The characteristic absorption bands are shown at , where each peak has ± 2 cm -1 margin of error.

7. The crystalline form II of the pyrazolopyrimidine ester compound according to claim 6, characterized in that: The crystal form Form II has an IR spectrum as shown in FIG3 .

8. A method for preparing the crystalline form II of the pyrazolopyrimidine ester compound according to any one of claims 1 to 7, characterized in that: The steps include: The pyrazolopyrimidine ester compound having the structure of formula (I) is dissolved in a good solvent, and then a poor solvent is added until a solid is precipitated, and the mixture is stirred, filtered, and dried to obtain the pyrazolopyrimidine ester compound having the crystal form Form II; The pyrazolopyrimidine ester compound represented by formula (I) is an amorphous compound represented by formula (I), or a crystalline form of the compound represented by formula (I) in Form I; the crystalline form I is a crystalline form of the compound represented by formula (I) having characteristic peaks at diffraction angles of 2θ values ​​of 11.26°, 14.03°, 14.80°, 17.07°, 19.78°, 21.21°, 22.39°, and 23.85° in an X-ray powder diffraction (XRPD) pattern; The good solvent is selected from one of acetone, 2-methyltetrahydrofuran, methanol, acetonitrile, ethyl acetate, and tetrahydrofuran, and the poor solvent is selected from one of n-heptane, methyl tert-butyl ether, water, and cyclohexane; the amount ratio of the good solvent to the compound represented by formula (I) is a volume mass ratio = 5 to 10, and the amount ratio of the poor solvent to the compound represented by formula (I) is a volume mass ratio = 10 to 150.

9. The method for preparing the crystal form II of the pyrazolopyrimidine ester compound according to claim 8, characterized in that: The poor solvent is added in batches and slowly.

10. Use of the crystalline form II of the pyrazolopyrimidine ester compound according to any one of claims 1 to 7, characterized in that: Used for preparing medicines for treating lymphoma and lymphocytic leukemia.