Crystalline forms of compounds and methods for their preparation

Abstract

The present invention relates to a compound of formula (I) (2 2 R,2 4 S,5S)-2 4 ,3 5 The present invention relates to a crystalline form of 5-difluoro-5-methyl-4-oxa-7,9-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidine-3(3,2)-pyridine-2(1,2)-pyrrolidinecyclononan-8-one and its preparation method. The crystalline form provided by the present invention has advantageous properties in terms of stability and hygroscopicity, and is suitable for pharmaceutical research and industrial production, which is valuable for the future optimization and development of the drug.

Description

[Technical field]

[0001] The present invention relates to a crystalline form of a TRK inhibitor (2 2 R,2 4 S,5S)-2 4 ,3 5 The present invention relates to -difluoro-5-methyl-4-oxa-7,9-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidine-3(3,2)-pyridine-2(1,2)-pyrrolidinecyclononan-8-one and a process for its preparation. [Background technology]

[0002] Heterocyclic compounds used as TRK inhibitors (2 2 R,2 4 S,5S)-2 4 ,3 5 -difluoro-5-methyl-4-oxa-7,9-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidine-3(3,2)-pyridine-2(1,2)-pyrrolidinecyclononan-8-one (hereinafter referred to as the compound of formula (I)) has the structure shown in the following formula (I): Preparation of the compound of formula (I) and the use of this compound for treating or preventing TRK-mediated related diseases (e.g., tumors) are disclosed in Chinese patent application CN110627812. Summary of the Invention

[0003] The Applicant has made a continuous effort to find a form which is not particularly sensitive to the test, storage and use conditions and is therefore more suitable for use in the formulation of pharmaceutical preparations and has now found a crystalline form of the compound of formula (I) which has excellent properties with regard to stability, in particular thermal stability and / or hygroscopicity.

[0004] Specifically, the present invention relates to a compound of formula (I) (2 2 R,2 4 S,5S)-2 4 ,3 5The present invention provides crystalline form A of -difluoro-5-methyl-4-oxa-7,9-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidine-3(3,2)-pyridine-2(1,2)-pyrrolidinecyclononan-8-one, and a process for its preparation.

[0005] [ka]

[0006] The present invention provides a novel crystalline form A of compound of formula (I) which has at least one advantageous property in terms of stability and hygroscopicity and is therefore suitable for pharmaceutical research and industrial production.

[0007] On the other hand, the present invention is characterized in that the powder X-ray diffraction pattern obtained from a CuKα radiation source has characteristic peaks at 2θ values ​​of 22.2°±0.2°, 19.9°±0.2°, and 20.9°±0.2°. 2 R,2 4 S,5S)-2 4 ,3 5 The present invention provides crystalline form A of -difluoro-5-methyl-4-oxa-7,9-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidine-3(3,2)-pyridine-2(1,2)-pyrrolidinylcyclononan-8-one (compound of formula (I)).

[0008] Meanwhile, the present invention provides crystalline form A of the compound of formula (I), characterized in that it further has characteristic peaks at one or more 2θ values ​​of 21.4°±0.2°, 9.8°±0.2°, and 12.1°±0.2° in a powder X-ray diffraction pattern.

[0009] Meanwhile, the present invention provides crystalline form A of the compound of formula (I), characterized in that it further has characteristic peaks at one or more 2θ values ​​of 18.0°±0.2°, 24.6°±0.2°, and 11.2°±0.2° in a powder X-ray diffraction pattern.

[0010] Meanwhile, the present invention provides crystalline form A of the compound of formula (I) described above, characterized in that the powder X-ray diffraction pattern is substantially as shown in FIG.

[0011] On the other hand, the present invention relates to a method for preparing crystalline form A of compound of formula (I), comprising the steps of: In free base form (2 2 R,2 4 S,5S)-2 4 ,3 5 The method includes the steps of dissolving -difluoro-5-methyl-4-oxa-7,9-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidine-3(3,2)-pyridine-2(1,2)-pyrrolidinecyclononan-8-one in a solvent having a solubility of more than 2 mg / mL at a temperature ranging from room temperature to 50° C. to obtain a clear solution, and cooling and allowing to stand or allowing to precipitate crystals by evaporation to obtain crystalline form A. Here, the solvent is selected from methanol, acetone, dichloromethane, dimethylsulfoxide, etc., or any mixture thereof.

[0012] On the other hand, the present invention relates to a method for preparing crystalline form A of compound of formula (I), comprising the steps of: In free base form (2 2 R,2 4 S,5S)-2 4 ,3 5 The method includes dissolving 1-difluoro-5-methyl-4-oxa-7,9-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidine-3(3,2)-pyridine-2(1,2)-pyrrolidinecyclononan-8-one in a solvent to obtain a clear solution, and then adding an antisolvent to precipitate crystals. 2 R,2 4 S,5S)-2 4 ,3 5 The poor solvent is a solvent in which the solubility of -difluoro-5-methyl-4-oxa-7,9-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidine-3(3,2)-pyridine-2(1,2)-pyrrolidinecyclononan-8-one is more than 2 mg / mL. 2 R,2 4 S,5S)-24 ,3 5 a solvent in which the solubility of -difluoro-5-methyl-4-oxa-7,9-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidine-3(3,2)-pyridine-2(1,2)-pyrrolidinecyclononan-8-one is less than 2 mg / mL, said solvent being selected from methanol, acetone, dichloromethane, dimethylsulfoxide, etc., or any mixture thereof, and said anti-solvent being selected from isopropanol, n-heptane, water, or any mixture thereof.

[0013] In the method for preparing the crystalline form A of the compound of formula (I) according to the present invention, 2 R,2 4 S,5S)-2 4 ,3 5 -difluoro-5-methyl-4-oxa-7,9-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidine-3(3,2)-pyridine-2(1,2)-pyrrolidinecyclononan-8-one is 0.2-10 ml:25 mg, preferably 0.8 ml:25 mg.

[0014] On the other hand, the crystalline form A of the compound of formula (I) provided by the present invention is anhydrous.

[0015] On the other hand, the crystalline form A of the compound of formula (I) provided by the present invention is characterized in that, when a differential scanning calorimetry (DSC) is performed, a heat absorption peak occurs when the compound is heated to 304°C (initiation temperature), and the DSC diagram is essentially as shown in Figure 2.

[0016] On the other hand, the crystalline form A of the compound of formula (I) provided by the present invention is characterized in that, when thermogravimetric analysis is performed, it has a weight loss gradient of about 0.69% when heated to 200°C, and its thermogravimetric analysis diagram is essentially as shown in Figure 3.

[0017] In addition, the free base form (2 2 R,2 4 S,5S)-2 4 ,3 5-difluoro-5-methyl-4-oxa-7,9-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidine-3(3,2)-pyridine-2(1,2)-pyrrolidinecyclononan-8-one is suspended in a solvent and stirred to obtain the TRK inhibitor (2 2 R,2 4 S,5S)-2 4 ,3 5 A crystalline form of -difluoro-5-methyl-4-oxa-7,9-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidine-3(3,2)-pyridine-2(1,2)-pyrrolidinecyclononan-8-one was obtained.

[0018] Further, the solvent is a solvent or mixed solvent with a solubility of 20 mg / mL>S>0.1 mg / mL.

[0019] Furthermore, in the above preparation method, the solvent and the TRK inhibitor (2 2 R,2 4 S,5S)-2 4 ,3 5 -difluoro-5-methyl-4-oxa-7,9-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidine-3(3,2)-pyridine-2(1,2)-pyrrolidinecyclononan-8-one is 0.2 to 10 mL:25 mg, preferably 0.8 mL:25 mg.

[0020] Furthermore, the temperature at which the method is carried out is from -20 to 100°C.

[0021] The crystalline form A of the compound of formula (I) of the present invention was stable when placed under high temperature 60°C (1 month), high humidity 25°C / 90%±5%RH (1 month) and light (13 days), and was also stable when placed under 30°C / 65%RH for 12 months. The crystalline form A of the compound of formula (I) of the present invention had a weight increase of 0.46% after equilibration at 80%RH, indicating that it was slightly hygroscopic, and the crystalline form A maintained its crystalline form under different humidity conditions. Furthermore, experimental studies of suspension competition in solution showed that the crystalline form B of the compound of formula (I) of the present invention could be converted to crystalline form A at room temperature, and the crystalline form A of the compound of formula (I) had better thermodynamic stability. [Brief description of the drawings]

[0022] [Figure 1] FIG. 2 is an XRPD diagram of crystalline form A. [Diagram 2] FIG. 2 is a DSC diagram of crystalline form A. [Diagram 3] FIG. 2 is a TGA diagram of crystalline form A. [Figure 4] FIG. 2 is an XRPD diagram of crystalline form B. [Diagram 5] FIG. 2 is a DVS diagram of crystalline form A. [Figure 6] FIG. 1 is a comparison of XRPD of crystalline form A before and after DVS test. [Figure 7] XRPD spectrum of the suspension competition of crystal forms. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] The present invention will be described in more detail below with specific examples, which do not limit the scope of protection of the present invention. Those skilled in the art may make improvements to the preparation methods and devices used within the scope of the claims, and these improvements shall also be considered as the scope of protection of the present invention. Therefore, the scope of protection of the patent of the present invention shall be subject to the scope of the attached claims.

[0024] The compound of formula (I) of the present invention (2 2 R,2 4S,5S)-2 4 ,3 5 -Difluoro-5-methyl-4-oxa-7,9-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidine-3(3,2)-pyridine-2(1,2)-pyrrolidinecyclononan-8-one can be prepared by methods known in the art, and the solvents and reagents used to carry out the crystallization can be obtained by conventional means, such as from commercial sources.

[0025] Unless otherwise specified, all terms referred to herein have their art-recognized meaning or commonly used meaning in the art.

[0026] The term "stability" as used herein means that, as a result of measuring the crystal form by an analytical means such as liquid phase or XRPD, decomposition of the crystal form or conversion to another crystal form is not detected.

[0027] The term "hygroscopicity" as used herein refers to the ability of a substance to absorb moisture under certain temperature and humidity conditions or the degree of the property. Regarding the description of the characteristics of hygroscopicity and the regulation of weight gain due to hygroscopicity (experiment according to the Chinese Pharmacopoeia 2015 Edition, Part 4 Guideline 9103 method, experimental conditions: 25°C±1°C, relative humidity 80%±2%): Deliquescence: Absorbs enough water to form a liquid. Very hygroscopic: Weight increase due to moisture absorption is 15% or more. Hygroscopic: Weight increase due to moisture absorption is less than 15% and more than 2%. Slightly hygroscopic: Weight increase due to moisture absorption is less than 2% and more than 0.2%. No or little moisture absorption: Weight increase due to moisture absorption is less than 0.2%.

[0028] The abbreviations used in the present invention are explained below. XRPD: X-ray powder diffraction DSC: Differential scanning calorimetry TGA: Thermogravimetric analysis DVS: Dynamic moisture sorption

[0029] The powder X-ray diffraction patterns described in this invention were obtained on a Bruker D8 ADVANCE X-ray powder diffractometer. The parameters of the powder X-ray diffraction method described in this invention are as follows: X-ray reflectivity parameters: Cu, Kα Kα1(Å):1.540598;Kα2(Å):1.544426 Kα2 / Kα1 intensity ratio: 0.50 Voltage: 40 kilovolts (kV) Current: 40 milliamps (mA) Scanning range: 3.0~40.0 degrees

[0030] The Differential Scanning Calorimetry (DSC) diagrams described in this invention were obtained on a TA DSC250. The parameters of the Differential Scanning Calorimetry (DSC) method described in this invention are as follows: Scanning speed: 10℃ / min Protective gas: Nitrogen

[0031] The thermogravimetric analysis (TGA) diagrams described in this invention were obtained on a TA TGA 550. The parameters of the thermogravimetric analysis (TGA) method described in this invention are as follows: Scanning speed: 10℃ / min Protective gas: Nitrogen

[0032] The dynamic moisture sorption (DVS) diagrams described in this invention were obtained with an Intrinsic dynamic moisture sorption instrument manufactured by SMS (Surface Measurement Systems Ltd.) The method parameters of said dynamic moisture sorption instrument are as follows: Temperature: 25°C Carrier gas, flow rate: N2, 200 milliliters / min. Mass change per unit time: 0.002% / min Relative humidity range: 0%RH~95%RH

[0033] The compound of formula (I) (2 2 R,2 4 S,5S)-2 4 ,3 5-Difluoro-5-methyl-4-oxa-7,9-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidine-3(3,2)-pyridine-2(1,2)-pyrrolidinecyclononan-8-one was prepared according to the preparation method described in patent application WO2020 / 001415.

[0034] Example 1 (2 2 R,2 4 S,5S)-2 4 ,3 5 Preparation of crystalline form A of -difluoro-5-methyl-4-oxa-7,9-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidin-3(3,2)-pyridine-2(1,2)-pyrrolidinecyclononan-8-one (compound of formula (I))

[0035] 25.1 mg of the compound of formula (I) in free base form was weighed out and stirred in 0.8 mL of methanol at 50° C. for 2 hours, filtered to obtain a saturated solution, and cooled to 5° C. at 0.1° C. / min to precipitate a solid, which was designated as crystalline form A of the compound of formula (I).

[0036] The powder X-ray diffraction data of the thus obtained crystalline form A is shown in Table 1, the XRPD pattern in FIG. 1, the DSC pattern in FIG. 2, and the TGA pattern in FIG.

[0037] [Table 1]

[0038] Example 2 Preparation of crystalline form B of compound of formula (I)

[0039] 24.9 mg of the compound of formula (I) in free base form was weighed out and stirred in 0.8 mL of 1,4-dioxane / acetone (1:1) at 50° C. for 2 hours, filtered to obtain a saturated solution, cooled to 5° C. at a rate of 0.1° C. / min, transferred to room temperature, and allowed to evaporate in the open air to obtain a solid, designated as crystalline form B of compound of formula (I).

[0040] The powder X-ray diffraction data of the obtained crystalline form B is shown in Table 2, and the XRPD diagram is shown in FIG.

[0041] [Table 2]

[0042] Example 3 Stability evaluation of crystalline form A

[0043] The crystalline form A solid was subjected to an accelerated stability test under high temperature, high humidity and light conditions (open) for one month to observe the purity of the sample and the stability of the crystalline form.

[0044] A stability test was carried out on a solid sample of crystalline form A for 12 months under 30°C / 65% RH conditions (airtight), and the purity of the sample and the stability of the crystalline form were observed (XRPD diagram).

[0045] The results are shown in Table 3.

[0046] [Table 3]

[0047] From the test results in Table 3, it can be seen that under the accelerated and 12-month conditions, the crystal morphology of the sample did not change, and the purity did not change significantly. It can be seen that crystalline form A can be stably maintained under the above conditions, and has good stability.

[0048] Example 4 Hygroscopicity evaluation of crystalline form A

[0049] About 30 mg of the crystalline form A of the present invention was taken and subjected to a dynamic moisture sorption test using a dynamic moisture sorption (DVS) apparatus. Specifically, the dynamic moisture sorption (DVS) diagram was obtained using an Intrinsic dynamic moisture sorption apparatus manufactured by SMS (Surface Measurement Systems Ltd.). The method parameters of the dynamic moisture sorption apparatus are as follows: temperature: 25°C, carrier gas and flow rate: N2, 200 mL / min, mass change per unit time: 0.002% / min, relative humidity range: 0%RH to 95%RH. XRPD was measured before and after the test, and as a result, the crystalline form A of the present invention showed a weight increase of 0.46% at 80% relative humidity and was slightly hygroscopic, and its DVS diagram is shown in FIG. 5. There was no change in the crystalline form before and after the dynamic moisture sorption test, and its XRPD comparison diagram is shown in FIG. 6.

[0050] Example 5 Study on the relationship between crystal form stability and transformation

[0051] The relationship between the conversion of crystal forms was investigated by a suspension competition experiment in solution. A suspension competition experiment was carried out between crystal forms A and B at room temperature, and crystal form A was obtained by adding equal amounts of crystal forms A and B to a saturated solution of isopropanol and water, suspending and stirring for two days. This shows that crystal form A has higher thermodynamic stability at room temperature. The XRPD spectrum of the suspension competition experiment between the crystal forms is shown in Figure 7.

[0052] From the results of the above hygroscopicity and stability studies, it is believed that the compound of formula (I) of the present invention (2 2 R,2 4 S,5S)-2 4 ,3 5 The crystalline form A of -difluoro-5-methyl-4-oxa-7,9-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidine-3(3,2)-pyridine-2(1,2)-pyrrolidinecyclononan-8-one has excellent stability and hygroscopicity, and is more druggable.

[0053] The above examples are only intended to explain the technical concepts and features of the present invention, so as to enable those skilled in the art to understand and appropriately implement the contents of the present invention, and are not intended to limit the protection scope of the present invention. Any equivalent changes or modifications made according to the spirit of the present invention shall be included in the protection scope of the present invention.

Claims

1. The compound of formula (I) in crystalline form (2 ２ R, 2 ４ S,5S)-2 ４ , 3 ５ crystalline form A of -difluoro-5-methyl-4-oxa-7,9-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidin-3(3,2)-pyridin-2(1,2)-pyrrolidinecyclononan-8-one, 【Chemistry 1】 A compound characterized in that in a powder X-ray diffraction pattern obtained from a CuKα radiation source, it has characteristic peaks at 2θ values ​​of 19.9°±0.2°, 20.9°±0.2°, and 22.2°±0.2°.

2. The crystalline form A according to claim 1, further comprising characteristic peaks at one or more of the following 2θ values ​​in the powder X-ray diffraction pattern: 21.4°±0.2°, 9.8°±0.2°, and 12.1°±0.2°.

3. The crystalline form A according to claim 2, further comprising characteristic peaks at one or more of the following 2θ values ​​in the powder X-ray diffraction pattern: 18.0°±0.2°, 24.6°±0.2°, and 11.2°±0.2°.

4. The crystalline form A according to any one of claims 1 to 3, characterized in that the powder X-ray diffraction pattern is substantially as shown in Figure 1.

5. The free base form (2 ２ R, 2 ４ S,5S)-2 ４ , 3 ５ 5. A method for preparing crystalline form A according to any one of claims 1 to 4, comprising the steps of dissolving -difluoro-5-methyl-4-oxa-7,9-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidine-3(3,2)-pyridine-2(1,2)-pyrrolidinecyclononan-8-one in a solvent having a solubility of more than 2 mg / mL at a temperature ranging from room temperature to 50°C to obtain a clear solution, and cooling and allowing to stand or allowing to precipitate crystals by evaporation to obtain crystalline form A.

6. 6. The method of claim 5, wherein the solvent and mixture of solvents is selected from methanol, acetone, dichloromethane, dimethylsulfoxide or any mixture thereof.

7. The free base form (2 ２ R, 2 ４ S,5S)-2 ４ , 3 ５ -difluoro-5-methyl-4-oxa-7,9-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidine-3(3,2)-pyridine-2(1,2)-pyrrolidinecyclononan-8-one is dissolved in a solvent to obtain a clear solution, and then a poor solvent is added to precipitate crystals; The solvent is (2 ２ R, 2 ４ S,5S)-2 ４ , 3 ５ The poor solvent is a solvent in which the solubility of -difluoro-5-methyl-4-oxa-7,9-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidine-3(3,2)-pyridine-2(1,2)-pyrrolidinecyclononan-8-one exceeds 2 mg / mL. ２ R, 2 ４ S,5S)-2 ４ , 3 ５ 5. A method for preparing crystalline form A according to any one of claims 1 to 4, wherein the solvent is one in which the solubility of -difluoro-5-methyl-4-oxa-7,9-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidine-3(3,2)-pyridin-2(1,2)-pyrrolidinecyclononan-8-one is less than 2 mg / mL.

8. 8. The method of claim 7, wherein the solvent is selected from methanol, acetone, dichloromethane, dimethylsulfoxide, or any mixture thereof, and the anti-solvent is selected from isopropanol, n-heptane, water, or any mixture thereof.

9. The solvent and (2 ２ R, 2 ４ S,5S)-2 ４ , 3 ５ 8. The method according to claim 5 or 7, wherein the dosage ratio of -difluoro-5-methyl-4-oxa-7,9-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidine-3(3,2)-pyridin-2(1,2)-pyrrolidinecyclononan-8-one is 0.2-10 mL:25 mg, preferably 0.8 mL:25 mg.

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