Hydrate of quinazoline compound

Abstract

The invention provides a hydrate of a quinazoline compound and a preparation method thereof. The preparation method of the hydrate crystal form provided by the invention is simple and convenient to operate and suitable for industrial production. The hydrate crystal form provided by the invention has relatively good chemical stability and relatively good solubility.

Description

Technical Field

[0001] The invention relates to the field of pharmaceutical chemistry, and in particular to a hydrate of a quinazoline compound and a preparation method thereof. Background Art

[0002] The compound of formula (I) is a VEGFR inhibitor of quinazoline structure, its chemical name is 6-(6,7-dimethoxyquinazoline-4-oxo)-N,2-dimethylbenzofuran-3-carboxamide, and its chemical structure is as follows:

[0003]

[0004] Patent CN110981910B applied for by Hutchison Whampoa Pharmaceuticals discloses Form I, Form II, Form III, Form IV, Form VII and Form VIII of the compound of formula (I), wherein Form II, Form IV and Form VIII are all solvate forms, and Form I, Form III and Form VII are anhydrous crystals.

[0005] Compounds can exist in a variety of crystal forms. The crystal structure of compounds that are active ingredients often affects the chemical and physical stability of the drug. Different crystal forms, preparation methods, and storage conditions may lead to changes in the crystal structure of the compound, and sometimes other forms of crystals may be produced. The physical and chemical properties of different crystal forms are slightly different, which will also affect the efficacy and stability of the final drug. Therefore, it is necessary to improve the properties of the compound in all aspects, and in-depth research is needed to find new crystal forms with good physical and chemical stability. Summary of the invention

[0006] In one aspect, the present invention provides a trihydrate of a compound of formula (I),

[0007] The structure of the compound of formula (I) is:

[0008]

[0009] The X-ray powder diffraction pattern of the trihydrate crystalline form has characteristic diffraction peaks at the following 2θ angles:

[0010] 7.2±0.2°, 8.6±0.2°, 14.5±0.2° or 15.1±0.2°.

[0011] In some embodiments, the X-ray powder diffraction pattern of the trihydrate crystalline form has characteristic diffraction peaks at the following 2θ angles: 7.2±0.2°, 8.6±0.2°, 12.0±0.2°, 14.5±0.2°, 15.1±0.2°, 20.4±0.2°, or 22.4±0.2°.

[0012] In some embodiments, the X-ray powder diffraction pattern of the trihydrate crystalline form has a characteristic diffraction peak at the following 2θ angles: 7.2±0.2°, 8.6±0.2°, 12.0±0.2°, 14.5±0.2°, 15.1±0.2°, 20.4±0.2°, 22.4±0.2°, 26.1±0.2° or 29.2±0.2°.

[0013] In some embodiments, the X-ray powder diffraction pattern of the trihydrate crystalline form has characteristic diffraction peaks at the following 2θ angles: 4.8±0.2°, 7.2±0.2°, 8.6±0.2°, 12.0±0.2°, 14.5±0.2°, 15.1±0.2°, 20.4±0.2°, 22.4±0.2°, 26.1±0.2° or 29.2±0.2.

[0014] In some embodiments, the X-ray powder diffraction pattern of the trihydrate crystalline form is as follows: Figure 1 As shown, it has Figure 1 The features represented by the X-ray powder diffraction pattern shown. Despite the existence of experimental errors, instrument errors and orientation preferences, a person skilled in the art can still obtain sufficient information for identifying the hydrated crystalline form and other crystalline forms of the compound of formula (I) from the XRPD data provided in this patent.

[0015] In some embodiments, the DSC spectrum of the trihydrate crystalline form is as follows Figure 2 As shown, it has Figure 2 The DSC spectra shown represent the characteristics.

[0016] In some embodiments, the trihydrate crystalline form of the compound of formula (I) can be identified by thermogravimetric analysis (TGA). In some embodiments, the trihydrate crystalline form of the compound of formula (I) has the following characteristics: Figure 3 The TGA curve shown is Figure 3 The TGA spectra shown represent the features.

[0017] In some embodiments, the trihydrate crystalline form of the compound of formula (I) is substantially free of other crystalline forms described herein. For example, the weight content of the trihydrate crystalline form of the compound of formula (I) is at least 99%, at least 95%, at least 90%, or lower to 80%. Alternatively, the weight content of the trihydrate crystalline form of the compound of formula (I) is at least 70%, or at least 60%. Or further, the weight content of the trihydrate crystalline form of the compound of formula (I) is at least 50%.

[0018] In another aspect, the present invention also provides a method for preparing the trihydrate crystal form, comprising:

[0019] Solution 1: dissolving the compound of formula (I) in water or a mixed solvent of water and an organic solvent, heating to dissolve and filtering, cooling and filtering; or

[0020] Solution 2: Dissolve the compound of formula (I) in an organic solvent, filter with a membrane, add water to the filtrate, and stir and filter after precipitating a solid.

[0021] In some embodiments, in the method for preparing the trihydrate crystalline form, the organic solvent of Scheme 1 is selected from acetonitrile, acetone or tetrahydrofuran. In some typical embodiments, the organic solvent of Scheme 1 is selected from acetonitrile, acetone or tetrahydrofuran.

[0022] In some embodiments, in the preparation method of the above trihydrate crystal form, the mass volume ratio of the compound of formula (I) in Scheme 1 and water or a mixed solvent of water and an organic solvent is selected from 25 to 40 mg / mL; in some typical embodiments, the mass volume ratio of the compound of formula (I) in Scheme 1 and water or a mixed solvent of water and an organic solvent is selected from 25 to 38 mg / mL. In some more typical embodiments, the mass volume ratio of the compound of formula (I) in Scheme 1 and water or a mixed solvent of water and an organic solvent is selected from 25 mg / mL or 37.5 mg / mL.

[0023] In some embodiments, in the method for preparing the trihydrate crystalline form, the organic solvent of Scheme 2 is selected from methanol, ethanol, isopropanol, acetone, dichloromethane, chloroform, dimethyl sulfoxide and N,N-dimethylformamide. In some typical embodiments, the organic solvent of Scheme 2 is N,N-dimethylformamide.

[0024] In some embodiments, in the method for preparing the above-mentioned trihydrate crystal form, the mass volume ratio of the compound of formula (I) and the organic solvent in Scheme 2 is selected from 25 to 35 mg / mL; in some typical embodiments, the mass volume ratio of the compound of formula (I) and the organic solvent in Scheme 1 is 30 mg / mL.

[0025] In some embodiments, in the method for preparing the above-mentioned trihydrate crystal form, the volume ratio of the organic solvent to water in Scheme 2 is selected from 1:0.4 to 2.0.

[0026] In some embodiments, the method for preparing the above-mentioned trihydrate crystal form, in Scheme 2, is to slowly add water to the filtrate at room temperature.

[0027] On the other hand, the present application also provides a pharmaceutical composition, which is prepared by mixing the trihydrate crystal form of the compound represented by formula (I) described above with one or more pharmaceutically acceptable carriers, diluents or excipients.

[0028] In another aspect, the present invention provides use of a trihydrate crystalline form of the compound of formula (I) or a pharmaceutical composition thereof in the preparation of a medicament for treating a disease associated with abnormal angiogenesis.

[0029] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular phrase or term should not be considered ambiguous or unclear without special definition, but should be understood according to the ordinary meaning.

[0030] In the present invention, when referring to a spectrum and / or data in a graph, the term "diffraction peak" refers to a characteristic peak that a person skilled in the art would not attribute to background noise.

[0031] As used herein, "XRPD" means X-ray powder diffraction;

[0032] As used herein, "DSC" refers to differential scanning calorimetry;

[0033] As used herein, "TGA" refers to thermogravimetric analysis;

[0034] In the present invention, "h" means hour, "min" means minute, "ml" means milliliter, and "μl" means microliter;

[0035] In the present invention, "room temperature" refers to 25°C;

[0036] In the present invention, "suction filtration" means filtration under reduced pressure.

[0037] In the present invention, "dissolving solvent" refers to any appropriate organic solvent that can partially or completely dissolve the solute under appropriate conditions, such as appropriate amount, appropriate temperature, such as room temperature or elevated temperature.

[0038] In the present invention, "anti-solvent" refers to any appropriate organic solvent in which the solubility of a substance is lower than that of a substance in a solvent.

[0039] As described herein, the crystal forms of the present invention can be identified by one or more solid-state analysis methods. For example, the crystal forms of the present invention can be identified by one or more methods, such as powder X-ray diffraction, lattice parameters of single crystals, Fourier transform infrared spectroscopy, differential scanning calorimetry analysis data and / or thermogravimetric curves. And if the identification analysis results of one of the methods are consistent with the crystal forms of the present invention, it does not mean that the identification results of any other method are inconsistent with the crystal forms of the present invention.

[0040] In the present invention, the determination method of X-ray powder diffractometer (XRPD) is as follows:

[0041] Instrument model: D8 Advance

[0042] Test conditions:

[0043] X-ray generator: Cu, Kα,

[0044] Tube voltage: 40kV, tube current: 40mA.

[0045] Scattering slit: 0.6mm

[0046] Detector slit: 5mm

[0047] Anti-scattering slit: 0.6mm

[0048] Scanning range: 3-40°

[0049] Step size: 0.02°

[0050] Rate: 0.3S

[0051] It should be noted that in the X-ray powder diffraction pattern (XRPD), the diffraction pattern obtained by the crystalline compound is often characteristic for a specific crystal, wherein the relative intensity of the band (especially at low angles) may vary due to the difference in crystallization conditions, particle size and other measurement conditions resulting from the dominant orientation effect. Therefore, the relative intensity of the diffraction peak is not characteristic for the crystal targeted, and when judging whether it is the same as a known crystal, more attention should be paid to the relative position of the peak rather than their relative intensity. In addition, for any given crystal, the position of the peak may have a slight error, which is also well known in the field of crystallography. For example, due to changes in temperature, sample movement, or calibration of the instrument when analyzing the sample, the position of the peak may move, and the measurement error of the 2θ value is sometimes about ± 0.5°, preferably about ± 0.3°, and more preferably about ± 0.2°. Therefore, when determining each crystalline structure, this error should be taken into account, and the 2θ value within the error also belongs to the scope of the present invention. In XRPD spectra, the peak position is usually represented by the 2θ angle or the interplanar distance d, and there is a simple conversion relationship between the two: d = λ / 2sinθ, where d represents the interplanar distance (also known as "interplanar spacing"), λ represents the wavelength of the incident X-ray, and θ is the diffraction angle. For the same type of crystals of the same compound, the peak positions of their XRPD spectra are similar overall, and the relative intensity errors may be large. It should also be pointed out that in the identification of mixtures, some diffraction lines may be missing due to factors such as decreased content. At this time, there is no need to rely on all the bands observed in high-purity samples, and even one band may be characteristic for a given crystal.

[0052] The differential thermal analysis (also known as "differential scanning calorimetry", Differential Scanning Calorimeter, DSC) method of the present invention is as follows:

[0053] Test method: Take a sample (1-10 mg) and place it in a DSC aluminum pan for testing. The method is: starting temperature ~40°C, heating rate is 10°C / min.

[0054] DSC measures the transition temperature when a crystal absorbs or releases heat due to a change in its crystalline structure or melting of the crystal. For the same crystal of the same compound, the error of thermal transition temperature and melting point is typically within about 5°C, usually within about 3°C ​​in consecutive analyses. When we say that a compound has a given DSC peak or melting point, this refers to the DSC peak or melting point ±5°C. DSC provides an auxiliary method for distinguishing different crystals. Different crystalline forms can be identified by their different transition temperature characteristics. It should be pointed out that for mixtures, their DSC peaks or melting points may vary over a larger range. In addition, since decomposition is accompanied by the melting of the substance, the melting temperature is related to the heating rate.

[0055] Thermogravimetric analysis (TGA) method of the present invention

[0056] Instrument model: TGA550

[0057] Test conditions: Take a sample (1-10 mg) and place it in a TGA platinum pan for testing. The method is: starting temperature ~30°C, heating rate is 10°C / min.

[0058] In the present invention, when referring to, for example, an XRPD pattern, a DSC pattern or a TGA pattern, the term "as shown by..." includes patterns that are not necessarily the same as those depicted herein but fall within the limits of experimental error when considered by those skilled in the art.

[0059] The present invention provides a new hydrate crystal form of the compound of formula (I), which is different from the crystal forms disclosed in the existing literature. The preparation method of the hydrate crystal form disclosed in the present invention is simple to operate and suitable for industrial production. The hydrate crystal form provided by the present invention has good chemical stability and good solubility. BRIEF DESCRIPTION OF THE DRAWINGS

[0060] Figure 1 This is the X-ray powder diffraction pattern of the trihydrate crystalline form of the compound of formula (I) prepared in Scheme 1 of Example 1.

[0061] Figure 2 This is the DSC spectrum of the trihydrate crystalline form of the compound of formula (I) prepared in Scheme 1 of Example 1.

[0062] Figure 3 This is the TGA spectrum of the trihydrate crystalline form of the compound of formula (I) prepared in Scheme 1 of Example 1. DETAILED DESCRIPTION

[0063] The embodiments of the present invention disclose the crystalline form of the compound of formula (I), its preparation method and application. Those skilled in the art can refer to the contents of this article and appropriately improve the process parameters to achieve. It is particularly important to point out that all similar substitutions and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention. The method of the present invention has been described by preferred embodiments, and relevant personnel can obviously modify or appropriately change and combine the methods described herein without departing from the content, spirit and scope of the present invention to implement and apply the technology of the present invention.

[0064] The crystalline form I of the compound of formula (I) used in the examples of the present invention was purchased from Beijing Coupled Technology Co., Ltd., and can also be prepared by referring to the preparation method disclosed in patent CN110981910B.

[0065] Example 1 Preparation method of trihydrate crystal form

[0066] Scheme 1: 500 mg of Form I was added to a 100 mL glass bottle, and 20 mL of tetrahydrofuran / water (3:1, v:v) was added. The solid was dissolved when heated to 70°C, and the filtrate was filtered while hot, and the filtrate was slowly cooled; suction filtration was performed; the filter cake was naturally dried, and 350 mg of a sample of the hydrate crystal form of the compound of formula (I) was collected. The X-ray powder diffraction spectrum, DSC spectrum, and TGA spectrum of the crystal form are shown as follows: Figure 1 , Figure 2 and Figure 3 As shown, the TGA spectrum shows a weight loss of 11.035%, which can be confirmed to be a trihydrate through calculation.

[0067] Scheme 2: 30 mg of Form I and 0.8 mL of purified water or a mixed solvent of an organic solvent and water (the organic solvent is acetonitrile or acetone, and the volume ratio of the organic solvent to water is preferably 1:1) are added to an HPLC vial, and the resulting suspension is stirred (1000 rpm) at different temperatures (5 to 50° C.) for 1 to 3 days, centrifuged and the solid is collected. The X-ray powder diffraction pattern of the sample obtained by this method is consistent with the hydrate crystal sample of the compound of formula (I) obtained in Scheme 1 of Example 1.

[0068] Scheme 3: 30 mg of Form I was dissolved in 1.0 mL of N,N-dimethylacetamide and filtered through a 0.22 μm filter membrane; 0.4-2.0 mL of purified water was slowly added to the filtrate at room temperature to precipitate a large amount of white precipitate; stirred at room temperature for 0.5 hours; and filtered to obtain a solid. The X-ray powder diffraction pattern of the sample obtained by this method was consistent with the hydrated crystal sample of the compound of formula (I) obtained in Scheme 1 of Example 1.

[0069] Example 2: Water activity study

[0070] Weigh equal masses (about 10 mg) of the crystalline form I of the compound of formula (I) and the trihydrate crystalline form of the compound of formula (I) into HPLC vials, add 1.0 mL of the prepared tetrahydrofuran / water binary solvent, and place the resulting suspension under magnetic stirring (1000 rpm) at room temperature. Samples were taken at 1 hour and 1 day, respectively, and the solids were collected by centrifugation and subjected to X-ray powder diffraction test. The results are summarized in the table below. The results show that at room temperature, in the binary solvent system of tetrahydrofuran / water, when the water activity (a w ) is greater than or equal to 0.6, the crystalline form I of the compound of formula (I) has been completely transformed into a hydrate crystalline form within 1 hour; when the water activity (a w ) is equal to 0.4, within 1 hour, most of the crystalline form I of the compound of formula (I) is transformed into a hydrate crystalline form, and within 24 hours, all of it is transformed into a hydrate crystalline form. The results are shown in Table 1

[0071] Table 1. Results of investigation on key water activity for interconversion between Form I and hydrated forms

[0072]

[0073] Example 3: Stability under conditions of high temperature, high humidity, light, etc.

[0074] The trihydrate crystal sample was placed under high temperature 60°C, high humidity 92.5% RH, light, long-term (25°C / 60% RH) and accelerated (40°C / 75% RH) conditions, and the physical and chemical stability of the sample was investigated by XRD and HPLC. The results are shown in Table 2.

[0075] Table 2. Experimental results of factors affecting crystal form

[0076]

[0077] Example 4 Solubility Experiment

[0078] 10 mg of the trihydrate crystalline form of the compound of formula (I) was weighed into an HPLC vial, 1.0 mL of water was added, and the resulting suspension was oscillated (400 rpm) at room temperature for 24 hours, sampled and centrifuged (10000 rpm, 2 min), and the supernatant was filtered using a 0.22 μm PTFE filter membrane (the first two drops were discarded), and the HPLC concentration of the filtrate was determined. The remaining solid was confirmed by powder X-ray diffraction to confirm the crystalline form.

Claims

1. A trihydrate of a compound of formula (I), It is characterized in that The X-ray powder diffraction pattern of the trihydrate crystal form has characteristic diffraction peaks at the following 2θ angles: 7.2±0.2°, 8.6±0.2°, 14.5±0.2° or 15.1±0.2°, and the structure of the compound of formula (I) is: Preferably, the X-ray powder diffraction pattern of the trihydrate crystalline form has characteristic diffraction peaks at the following 2θ angles: 7.2±0.2°, 8.6±0.2°, 12.0±0.2°, 14.5±0.2°, 15.1±0.2°, 20.4±0.2° or 22.4±0.2°; Preferably, the X-ray powder diffraction pattern of the trihydrate crystalline form has characteristic diffraction peaks at the following 2θ angles: 7.2±0.2°, 8.6±0.2°, 12.0±0.2°, 14.5±0.2°, 15.1±0.2°, 20.4±0.2° or 22.4±0.2°. 0.2°, 22.4±0.2°, 26.1±0.2° or 29.2±0.2°; preferably, the X-ray powder diffraction pattern of the trihydrate crystalline form has characteristic diffraction peaks at the following 2θ angles: 4.8±0.2°, 7.2±0.2°, 8.6±0.2°, 12.0±0.2°, 14.5±0.2°, 15.1±0.2°, 20.4±0.2°, 22.4±0.2°, 26.1±0.2° or 29.2±0.2; preferably, the X-ray powder diffraction pattern of the trihydrate crystalline form is shown in Figure 1.

2. The trihydrate according to claim 1, It is characterized in that The trihydrate crystal form has a DSC spectrum as shown in FIG2 .

3. The trihydrate according to claim 1, It is characterized in that The trihydrate crystal form has a TGA spectrum as shown in FIG3 .

4. The trihydrate according to claim 1, It is characterized in that The trihydrate crystalline form of the compound of formula (I) substantially does not contain other crystalline forms.

5. A method for preparing the trihydrate according to any one of claims 1 to 4, include: Solution 1: dissolving the compound of formula (I) in water or a mixed solvent of water and an organic solvent, heating to dissolve and filtering, cooling and filtering; or Solution 2: Dissolve the compound of formula (I) in an organic solvent, filter with a membrane, add water to the filtrate, and stir and filter after precipitating a solid.

6. The preparation method according to claim 5, It is characterized in that The organic solvent of Scheme 1 is selected from acetonitrile, acetone or tetrahydrofuran; preferably, the organic solvent of Scheme 1 is selected from acetonitrile, acetone or tetrahydrofuran.

7. The preparation method according to claim 5, It is characterized in that The organic solvent of Scheme 2 is selected from methanol, ethanol, isopropanol, acetone, dichloromethane, chloroform, dimethyl sulfoxide and N,N-dimethylformamide; preferably, the organic solvent of Scheme 2 is N,N-dimethylformamide.

8. The preparation method according to claim 5, It is characterized in that The volume ratio of the organic solvent to water in Scheme 2 is selected from 1:0.4 to 2.

0.

9. A pharmaceutical composition, which is prepared by mixing the trihydrate crystal form of the compound represented by formula (I) with one or more pharmaceutically acceptable carriers, diluents or excipients.

10. Use of a trihydrate crystalline form of the compound of formula (I) or a pharmaceutical composition thereof in the preparation of a medicament for treating diseases associated with abnormal angiogenesis.

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