Hydrate of a VEGFR inhibitor, its crystalline form, and method for preparing it.

Abstract

This invention relates to a hydrate of a VEGFR inhibitor, its crystalline form, and a method for preparing it. The VEGFR inhibitor is 6-(6,7-dimethoxyquinazoline-4-oxy)-N,2-dimethylbenzofuran-3-carboxamide. The hydrate and its crystalline form have relatively good physical and chemical properties, as well as relatively good fluidity, solubility, stability, and bioavailability, and their hygroscopicity can be improved. The preparation method is simple, highly reproducible, yields high yields, is easy to operate, environmentally friendly, requires little solvent, and is easily recyclable, thus effectively reducing reagent costs and facilitating production scale-up.

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the priority of three prior applications, namely, Patent Application No. 202310647472.5 filed with the China National Intellectual Property Administration on June 2, 2023, Patent Application No. 202311552719.1 filed with the China National Intellectual Property Administration on November 20, 2023, and Patent Application No. 202410117086.X filed with the China National Intellectual Property Administration on January 26, 2024. The full texts of the three prior applications are incorporated into the present invention by reference.

[0002] Technical Field This application relates to the field of drug crystal forms, specifically to hydrates of VEGFR inhibitors, their crystal forms, and methods for their preparation.

Background Art

[0003] Fruquintinib (trade name: Elunate) is a VEGFR inhibitor developed by Hutchison Whampoa as a therapeutic drug for metastatic colorectal cancer. Its original drug, Elunate, obtained sales approval in China on September 4, 2018. The structure of fruquintinib is shown by formula (I).

Chemical Formula

[0004] Prior art CN106604919B discloses six crystal forms of fruquintinib, namely Crystal Form I, Crystal Form II, Crystal Form III, Crystal Form VII, Crystal Form IV, and Crystal Form VIII. All of the above crystal forms are anhydrates or organic solvates. In the prior art, hydrates of fruquintinib having good drugability or their crystal forms have not yet been developed. Therefore, further research is needed for the development of hydrates of fruquintinib and their crystal forms.

Summary of the Invention

Problems to be Solved by the Invention

[0005] In response to the problems described above in the prior art, this application provides a hydrate of a VEGFR inhibitor, its crystalline form, and a method for preparing the same. The VEGFR inhibitor is fluquintinib, whose chemical name is 6-(6,7-dimethoxyquinazoline-4-oxy)-N,2-dimethylbenzofuran-3-carboxamide. [Means for solving the problem]

[0006] A first aspect of the present application provides fluquintinib hydrate.

[0007] The structural formula of the hydrate is shown by the following formula (II). [ka] Here, n is between 0.5 and 3.

[0008] In some embodiments of the present application, n is 0.5, 1, 2, or 3.

[0009] In some embodiments of the present application, the hydrate is fluquintinib trihydrate.

[0010] In some embodiments of the present application, the fluquintinib hydrate crystal form is provided, having characteristic peaks in its powder X-ray diffraction pattern at 2θ angles of 7.2±0.2°, 8.6±0.2°, 14.4±0.2°, 15.2±0.2°, 20.4±0.2°, 22.3±0.2°, 24.0±0.2°, 26.1±0.2°, 26.4±0.2°, and 29.1±0.2°.

[0011] In some embodiments of the present application, the powder X-ray diffraction pattern of the hydrate crystal form has characteristic peaks at the following 2θ angles: 7.212±0.2°, 8.643±0.2°, 14.445±0.2°, 15.182±0.2°, 20.423±0.2°, 22.348±0.2°, 23.960±0.2°, 26.100±0.2°, 26.446±0.2°, and 29.119±0.2°.

[0012] In some embodiments of the present application, the powder X-ray diffraction pattern of the hydrate crystal form has characteristic peaks at 2θ angles of 4.9±0.2°, 7.2±0.2°, 8.6±0.2°, 12.0±0.2°, 14.4±0.2°, 15.2±0.2°, 16.2±0.2°, 20.4±0.2°, 22.3±0.2°, 24.0±0.2°, 25.4±0.2°, 26.1±0.2°, 26.4±0.2°, 28.3±0.2°, and 29.1±0.2°.

[0013] In some embodiments of the present application, the powder X-ray diffraction pattern of the hydrate crystal form has characteristic peaks at the following 2θ angles: 4.861±0.2°, 7.212±0.2°, 8.643±0.2°, 12.018±0.2°, 14.445±0.2°, 15.182±0.2°, 16.171±0.2°, 20.423±0.2°, 22.348±0.2°, 23.960±0.2°, 25.370±0.2°, 26.100±0.2°, 26.446±0.2°, 28.326±0.2°, and 29.119±0.2°.

[0014] In some embodiments of the present application, the powder X-ray diffraction pattern of the hydrate crystal form has characteristic peaks at the following 2θ angles: 4.9±0.2°, 7.2±0.2°, 8.6±0.2°, 12.0±0.2°, 14.4±0.2°, 15.2±0.2°, 16.2±0.2°, 17.3±0.2°, 20.4±0.2°, 22.3±0.2°, 24.0±0.2°, 24.4±0.2°, 25.4±0.2°, 26.1±0.2°, 26.4±0.2°, 28.3±0.2°, 28.6±0.2°, 29.1±0.2°, 29.6±0.2°, and 32.7±0.2°.

[0015] In some embodiments of the present application, the 2θ angles in the powder X-ray diffraction patterns of the hydrate crystal form are 4.861±0.2°, 7.212±0.2°, 8.643±0.2°, 12.018±0.2°, 14.445±0.2°, 15.182±0.2°, 16.171±0.2°, 17.316±0.2°, 20.423±0.2°, Characteristic peaks are found at the following positions: 22.348±0.2°, 23.960±0.2°, 24.428±0.2°, 25.370±0.2°, 26.100±0.2°, 26.446±0.2°, 28.326±0.2°, 28.610±0.2°, 29.119±0.2°, 29.598±0.2°, and 32.656±0.2°.

[0016] In some embodiments of the present application, the powder X-ray diffraction pattern of the hydrate crystal form has characteristic peaks at the following 2θ angles: 4.9±0.2°, 7.2±0.2°, 8.6±0.2°, 9.7±0.2°, 12.0±0.2°, 14.4±0.2°, 15.2±0.2°, 16.2±0.2°, 17.3±0.2°, 20.4±0.2°, 22.3±0.2°, 24.0±0.2°, 24.4±0.2°, 25.4±0.2°, 26.1±0.2°, 26.4±0.2°, 28.3±0.2°, 28.6±0.2°, 29.1±0.2°, 29.6±0.2°, and 32.7±0.2°.

[0017] In some embodiments of the present application, the 2θ angles in the powder X-ray diffraction patterns of the hydrate crystal form are 4.861±0.2°, 7.212±0.2°, 8.643±0.2°, 9.7064±0.2°, 12.018±0.2°, 14.445±0.2°, 15.182±0.2°, 16.171±0.2°, 17.316±0.2°, and 20.423. Characteristic peaks are found at the following positions: ±0.2°, 22.348±0.2°, 23.960±0.2°, 24.428±0.2°, 25.370±0.2°, 26.100±0.2°, 26.446±0.2°, 28.326±0.2°, 28.610±0.2°, 29.119±0.2°, 29.598±0.2°, and 32.656±0.2°.

[0018] In some specific embodiments of the present application, the powder X-ray diffraction pattern of the hydrate crystal form is substantially as shown in FIG. 1.

[0019] In some embodiments of the present application, in the powder X-ray diffraction pattern of the hydrate crystal form, characteristic peaks are present at positions where the 2θ angle is 4.8 ± 0.2°, 7.2 ± 0.2°, 8.6 ± 0.2°, 9.7 ± 0.2°, 12.0 ± 0.2°, 14.4 ± 0.2°, 15.2 ± 0.2°, 16.2 ± 0.2°, 17.3 ± 0.2°, 19.9 ± 0.2°, 20.4 ± 0.2°, 21.8 ± 0.2°, 22.3 ± 0.2°, 24.0 ± 0.2°, 24.3 ± 0.2°, 25.4 ± 0.2°, 26.0 ± 0.2°, 26.4 ± 0.2°, 28.2 ± 0.2°, 28.6 ± 0.2°, 29.1 ± 0.2°, 29.6 ± 0.2°, and 32.7 ± 0.2°.

[0020] In some specific embodiments of the present application, the powder X-ray diffraction pattern of the hydrate crystal form is shown in FIGS. 1 to 2.

[0021] In some specific embodiments of the present application, the powder X-ray diffraction pattern of the hydrate crystal form is shown in FIGS. 1 to 3.

[0022] In some embodiments of the present application, in the DSC pattern of the hydrate crystal form, endothermic peaks are present at positions of 95.23 ± 5°C and 245.71 ± 5°C.

[0023] In some specific embodiments of the present application, the DSC pattern of the hydrate crystal form is substantially as shown in FIG. 2.

[0024] In some specific embodiments of the present application, the TGA pattern of the hydrate crystal form is substantially as shown in FIG. 3.

[0025] In some specific embodiments of the present application, the water content of the hydrate crystal form is 11.00 ± 2.0%. For example, the water content of the hydrate crystal form is 11.50%, 11.60%, 11.70%, 11.80%, 11.90%, 12.00%, 12.05%, 12.07%, 12.10%, 12.20%, 12.30%, 12.40%, and 12.50%.

[0026] In some specific embodiments of the present application, the water content of the hydrate crystal form is 11.90 ± 0.20%.

[0027] In some specific embodiments of the present application, the water content of the hydrate crystal form is 11.90%.

[0028] In some specific embodiments of the present application, the hydrate crystal form is triclinic, with a space group of P-1 (No. 2) and a molecular weight of 447.44 g·mol. -1 Z' is 1, unit cell parameters are a=4.880(5)Å, b=11.98(2)Å, c=17.916(17)Å, α=89.10(6)°, β=94.56(10)°, γ=97.09(18)°, and unit cell volume is V=1036(2)Å 3 That is the case.

[0029] A second aspect of the present application provides a crystalline form α of fluquintinib having characteristic peaks in its powder X-ray diffraction pattern at 2θ angles of 7.2±0.2°, 8.6±0.2°, 14.4±0.2°, 15.2±0.2°, 20.4±0.2°, 22.3±0.2°, 24.0±0.2°, 26.1±0.2°, 26.4±0.2°, and 29.1±0.2°.

[0030] In some embodiments of the present application, the powder X-ray diffraction pattern of the crystalline form α has characteristic peaks at 2θ angles of 7.212±0.2°, 8.643±0.2°, 14.445±0.2°, 15.182±0.2°, 20.423±0.2°, 22.348±0.2°, 23.960±0.2°, 26.100±0.2°, 26.446±0.2°, and 29.119±0.2°.

[0031] In some embodiments of the present application, the powder X-ray diffraction pattern of the crystal form α has characteristic peaks at 2θ angles of 4.9±0.2°, 7.2±0.2°, 8.6±0.2°, 12.0±0.2°, 14.4±0.2°, 15.2±0.2°, 16.2±0.2°, 20.4±0.2°, 22.3±0.2°, 24.0±0.2°, 25.4±0.2°, 26.1±0.2°, 26.4±0.2°, 28.3±0.2°, and 29.1±0.2°.

[0032] In some embodiments of the present application, the powder X-ray diffraction pattern of the crystal form α has characteristic peaks at the following 2θ angles: 4.861±0.2°, 7.212±0.2°, 8.643±0.2°, 12.018±0.2°, 14.445±0.2°, 15.182±0.2°, 16.171±0.2°, 20.423±0.2°, 22.348±0.2°, 23.960±0.2°, 25.370±0.2°, 26.100±0.2°, 26.446±0.2°, 28.326±0.2°, and 29.119±0.2°.

[0033] In some embodiments of the present application, the powder X-ray diffraction pattern of the crystalline form α has characteristic peaks at 2θ angles of 4.9±0.2°, 7.2±0.2°, 8.6±0.2°, 12.0±0.2°, 14.4±0.2°, 15.2±0.2°, 16.2±0.2°, 17.3±0.2°, 20.4±0.2°, 22.3±0.2°, 24.0±0.2°, 24.4±0.2°, 25.4±0.2°, 26.1±0.2°, 26.4±0.2°, 28.3±0.2°, 28.6±0.2°, 29.1±0.2°, 29.6±0.2°, and 32.7±0.2°.

[0034] In some embodiments of the present application, the 2θ angles in the powder X-ray diffraction pattern of the crystal form α are 4.861±0.2°, 7.212±0.2°, 8.643±0.2°, 12.018±0.2°, 14.445±0.2°, 15.182±0.2°, 16.171±0.2°, 17.316±0.2°, 20.423±0.2°, 2 Characteristic peaks are found at the following positions: 2.348±0.2°, 23.960±0.2°, 24.428±0.2°, 25.370±0.2°, 26.100±0.2°, 26.446±0.2°, 28.326±0.2°, 28.610±0.2°, 29.119±0.2°, 29.598±0.2°, and 32.656±0.2°.

[0035] In some embodiments of the present application, the powder X-ray diffraction pattern of the crystalline form α has characteristic peaks at 2θ angles of 4.9±0.2°, 7.2±0.2°, 8.6±0.2°, 9.7±0.2°, 12.0±0.2°, 14.4±0.2°, 15.2±0.2°, 16.2±0.2°, 17.3±0.2°, 20.4±0.2°, 22.3±0.2°, 24.0±0.2°, 24.4±0.2°, 25.4±0.2°, 26.1±0.2°, 26.4±0.2°, 28.3±0.2°, 28.6±0.2°, 29.1±0.2°, 29.6±0.2°, and 32.7±0.2°.

[0036] In some embodiments of the present application, the 2θ angles in the powder X-ray diffraction pattern of the crystal form α are 4.861±0.2°, 7.212±0.2°, 8.643±0.2°, 9.7064±0.2°, 12.018±0.2°, 14.445±0.2°, 15.182±0.2°, 16.171±0.2°, 17.316±0.2°, and 20.423± Characteristic peaks are found at the following positions: 0.2°, 22.348±0.2°, 23.960±0.2°, 24.428±0.2°, 25.370±0.2°, 26.100±0.2°, 26.446±0.2°, 28.326±0.2°, 28.610±0.2°, 29.119±0.2°, 29.598±0.2°, and 32.656±0.2°.

[0037] In some specific embodiments of the present application, the powder X-ray diffraction pattern of crystal form α is substantially as shown in Figure 1.

[0038] In some embodiments of the present application, the DSC pattern of the crystal form α has endothermic peaks at 95.23±5°C and 245.71±5°C.

[0039] In some specific embodiments of the present application, the DSC pattern of the crystal form α is substantially as shown in Figure 2.

[0040] In some specific embodiments of the present application, the TGA pattern of the crystal form α is substantially as shown in Figure 3.

[0041] In some specific embodiments of the present application, the water content of the crystalline form α is 11.00 ± 2.0%. For example, the water content of the hydrate crystalline forms is 11.50%, 11.60%, 11.70%, 11.80%, 11.90%, 12.00%, 12.10%, 12.20%, 12.30%, 12.40%, and 12.50%.

[0042] In some specific embodiments of the present application, the water content of the crystalline form α is 11.90 ± 0.20%.

[0043] In some specific embodiments of the present application, the water content of the crystalline form α is 11.90%.

[0044] In some specific embodiments of the present application, the crystal form α is triclinic, has a space group of P-1 (No.2), and a molecular weight of 447.44 g·mol. -1 Z' is 1, unit cell parameters are a=4.880(5)Å, b=11.98(2)Å, c=17.916(17)Å, α=89.10(6)°, β=94.56(10)°, γ=97.09(18)°, and unit cell volume is V=1036(2)Å 3 That is the case.

[0045] In some specific embodiments of the present application, the crystalline form α is a hydrate whose structural formula is represented by the following formula (II). [ka] Here, n is between 0.5 and 3.

[0046] In some embodiments of the present application, n is 0.5, 1, 2, or 3.

[0047] In some embodiments of the present application, the hydrate crystal form is fluquintinib trihydrate.

[0048] A third aspect of the present application provides a method for preparing the hydrate and its crystalline form described in the first aspect, and the fluquintinib crystalline form α described in the second aspect, the method comprising the step of mixing fluquintinib and an additive in solvent A and performing crystallization.

[0049] In some embodiments of the present application, the preparation method specifically includes the steps of mixing fluquintinib and an additive in solvent A, dissolving them with ultrasound, and allowing them to stand to crystallize.

[0050] In some embodiments of the present application, the temperature conditions in the ultrasonic dissolution process are 10 to 25°C. In some embodiments of the present application, the ultrasonic treatment time in the ultrasonic dissolution process is 5 to 24 hours, preferably 12 hours. In some embodiments of the present application, the crystallization temperature in the static crystallization process is 0 to 10°C, preferably 5°C. In some embodiments of the present application, the standing time in the static crystallization process is 1 to 10 days, preferably 5 days.

[0051] In some embodiments of the present application, the additive is a polyol, Preferably, the polyol is a sugar alcohol. More preferably, the polyol is one or more selected from xylitol, mannitol, sorbitol, isomaltitol, and maltitol. Most preferably, the polyol is xylitol.

[0052] In some embodiments of the present application, the solvent A is an ethere-based solvent, Preferably, the ether-based solvent is one or more selected from tetrahydrofuran, ethyl ether, propylene glycol methyl ether, methyl tert-butyl ether, isopropyl ether, and 1,4-dioxane. More preferably, the ethere-based solvent is tetrahydrofuran.

[0053] In some embodiments of the present application, the mass ratio of fluquintinib to the additive is 5 to 20:1, preferably 10:1.

[0054] In some embodiments of the present application, the mass-volume ratio of fluquintinib to solvent A is 1:50 to 100, preferably 1:62.

[0055] In some specific embodiments of this application, after the static crystallization, the obtained solid is collected and stored under protection of an inert gas.

[0056] In some specific embodiments of the present application, the storage temperature is 5 to 10°C. In some specific embodiments of the present application, the inert gas is nitrogen gas, argon gas, or helium gas, preferably nitrogen gas.

[0057] A fourth aspect of this application is a method for preparing the hydrate and its crystalline form as described in the first aspect, and the fluquintinib crystalline form α as described in the second aspect, Step (1) involves mixing fluquintinib with solvent B and heating to dissolve it, The present invention provides a preparation method comprising the step (2) of adding the hydrate, or its crystalline form, or a seed crystal of the crystalline form α, and performing crystallization.

[0058] In some embodiments of this application, the heating and dissolution refers to dissolving by heating to the reflux temperature.

[0059] In some embodiments of the present application, in step (1), the mass ratio of fluquintinib to solvent B is 1:3 to 40, for example, 1:40, 1:36.7, 27.36, 1:10, 1:4.1, or 1:3.

[0060] In some embodiments of the present application, in step (1), the mass ratio of fluquintinib to solvent B is 1:3 to 10, preferably 1:4.1.

[0061] In some embodiments of the present application, solvent B is a mixed solvent of water and an ether-based solvent, and the mass ratio of water to the ether-based solvent is preferably 1:1 to 9, more preferably 1:3.1. Preferably, the ether-based solvent of solvent B is one or more selected from tetrahydrofuran, ethyl ether, propylene glycol methyl ether, methyl tert-butyl ether, isopropyl ether, and 1,4-dioxane. More preferably, the ethere solvent of solvent B is tetrahydrofuran.

[0062] In some embodiments of the present application, the amount of seed crystal used is 1 to 20%, preferably 5%, of the mass fraction of the amount of fluquintinib added in step (1).

[0063] In some embodiments of the present application, step (2) specifically includes adding the seed crystal, lowering the temperature, stirring to suspend, and crystalline precipitation. Preferably, step (2) specifically includes adding the seed crystal, lowering the temperature to 0-10°C, stirring to suspend, and allowing crystallization to occur for 12-48 hours. More preferably, step (2) specifically includes adding the seed crystal, lowering the temperature to 5°C, stirring to suspend, and crystallizing for 24 hours.

[0064] In some embodiments of the present application, the preparation method further includes the step of preparing the seed crystal, which includes mixing fluquintinib and an additive in solvent B and precipitation.

[0065] In some embodiments of the present application, the method for preparing the hydrate or its crystalline form, or crystalline form α, is as follows: Preparation of seed crystals of the aforementioned crystal form α: step (a) mix fluquintinib and additives in solvent A and perform crystallization, (b) A step in which fluquintinib is mixed with solvent B, and the mixture is heated under reflux to obtain a solution, The process includes (c) adding a seed crystal of the aforementioned crystal form α and performing crystallization.

[0066] The aforementioned additives, solvent A, and solvent B are as defined above.

[0067] The hydrate, or its crystalline form, or crystalline form α, prepared by the preparation method of the third aspect of this application can be used as a seed crystal in step (2) of the preparation method of the fourth aspect.

[0068] The hydrate, or its crystalline form, or crystalline form α, prepared according to the fourth aspect of this application may be used as a seed crystal in step (2) of the fourth aspect.

[0069] The fluquintinib crystal form α of the second aspect of this application is prepared by the preparation method of the third or fourth aspect.

[0070] The fluquintinib hydrate and its crystalline form according to the first aspect of this application are prepared by the preparation method of the third or fourth aspect. [Effects of the Invention]

[0071] This invention offers the following beneficial effects compared to the prior art.

[0072] (1) The present inventors have discovered that in the prior art document CN106604919B, crystalline form II is hemiethanol solvate, crystalline form IV is monoacetic acid solvate, and crystalline form VIII is monodioxane solvate, while crystalline forms I, III, and VII are all anhydrous crystalline forms. Of these, the solvates contain organic solvents and are therefore unsuitable for drug development. Furthermore, the anhydrous crystalline forms are unstable and, for example, there is a risk of them changing into hydrates when exposed to water, and they are also easily converted to the corresponding hydrates during processing and storage. The present inventors have also discovered that crystalline form C disclosed in CN105777722A is also an anhydrous form.

[0073] (2) The present invention provides for the first time fluquintinib hydrate and its hydrate crystal form α, which have good physical and chemical properties, as well as good fluidity, solubility, stability, and bioavailability, can improve hygroscopicity, have particularly excellent stability in water, can be used in a wider range of drug preparation processes such as wet granulation, and contribute to improving the controllability and safety of drug quality.

[0074] (3) The fluquintinib hydrate and hydrate crystal form α according to the present invention have a simple preparation process, good reproducibility, high yield, ease of operation, are environmentally friendly, require less solvent, and are favorable for recycling, thus effectively reducing reagent costs and enabling easy scale-up of production. [Brief explanation of the drawing]

[0075] [Figure 1] This is the XRD pattern of fluquintinib crystal form α. [Figure 1-2] This is the XRD pattern of fluquintinib crystal form α after grinding. [Figure 1-3] This is a simulated XRD pattern of a single crystal of fluquintinib crystal form α. [Figure 2] This is the DSC pattern of fluquintinib crystal form α. [Figure 2-2] This is the DSC pattern of fluquintinib crystal form C. [Figure 3] This is the TGA pattern of fluquintinib crystal form α. [Figure 4] This is a comparative diagram of crystal forms in which stability of fluquintinib crystal form α is observed after being left undisturbed for two months. [Figure 5] This is a comparative diagram of crystal forms in which the stability of fluquintinib crystal form α is observed after being left undisturbed for 6 months. [Figure 5-2] This is a comparative diagram of crystal forms in which stability was observed after pulverizing fluquintinib crystal form α and leaving it for 6 months. [Figure 6] This is a diagram of the asymmetric unit in the unit cell of fluquintinib crystal form α. [Modes for carrying out the invention]

[0076] The present application will be described in detail below with reference to examples to make it easier to understand. These examples are for illustrative purposes only and do not limit the scope of application of the present application.

[0077] The terms used in this application are as follows: XRD: Powder X-ray diffraction The powder X-ray diffraction (XRD) measurements described in this application are collected using an Empyrean powder X-ray diffractometer from Malvern Panalytical. The specific parameters are shown in the table below.

[0078] [Table 1]

[0079] In this specification, “the powder X-ray diffraction pattern is substantially as shown in Figure 1” means that the powder X-ray diffraction pattern is substantially the same as that in Figure 1, and the term “substantially the same” with respect to the powder X-ray diffraction pattern means that variations in the position and intensity of representative peaks are taken into consideration. DSC: Differential Scanning Calorimetry

[0080] The differential scanning calorimetry (DSC) measurements described in this application were performed using a Mettler-Toledo DSC-1 system, with data collected at a heating rate of 10°C / min in a temperature range of 25 to 250°C. During the test, the nitrogen purge rate was set to 60 mL / min.

[0081] In this specification, "the DSC pattern is substantially as shown in Figure 2" means that the DSC pattern is substantially identical to that in Figure 2. The term "substantially identical" with respect to the DSC pattern means that the positions of representative feature peaks are taken into consideration. TGA: Thermogravimetric analysis

[0082] The thermogravimetric analysis (TGA) measurements described in this application were performed using a Mettler-Toledo TGA-2 system, with data collected at a heating rate of 10°C / min within a temperature range of 30 to 300°C. During the test, the nitrogen purge rate was set to 20 mL / min.

[0083] The error in TGA may be within approximately ±0.5 mass%. In this specification, "the TGA pattern is substantially as shown in Figure 3" means that the TGA pattern is substantially the same as that in Figure 3. The term "substantially the same" with respect to the TGA pattern means that this error variation is taken into account.

[0084] As used herein, "room temperature" refers to a temperature between 10°C and 25°C.

[0085] In this specification, unless otherwise specified, percentages are expressed as weight fractions. Micro ED: Microcrystalline electron diffraction

[0086] The crystal structure of crystal form α described in this application is collected using microcrystalline electron diffraction (micro-ED) technique. The specific parameters are shown in the table below.

[0087] [Table 2]

[0088] In this specification, crystal forms I, II, III, IV, VII, and VIII are crystal forms I, II, III, IV, VII, and VIII prepared by the method disclosed in CN106604919B.

[0089] In this specification, crystalline form C is crystalline form C prepared according to the method disclosed in CN105777722 A.

[0090] The DSC pattern of the aforementioned crystal form C has an endothermic peak at approximately 245.65°C. The DSC pattern of the aforementioned crystal form C is substantially as shown in Figure 2-2.

[0091] In this specification, fluquintinib is a compound with the chemical name 6-(6,7-dimethoxyquinazoline-4-oxy)-N,2-dimethylbenzofuran-3-carboxamide, represented by formula (I). [ka] Example 1: Preparation of fluquintinib crystal form α

[0092] 50 mg of fluquintinib and 5 mg of xylitol were weighed and dissolved in 3.1 g of tetrahydrofuran at 50°C. This solution was sonicated at room temperature (10-25°C) for 12 hours, and then allowed to stand at 5°C for 5 days to obtain fluquintinib crystalline form α. The obtained solid (fluquintinib crystalline form α) was collected, protected with nitrogen gas, and stored at a low temperature (5-10°C). XRD analysis, DSC analysis, and TGA analysis were performed on the obtained fluquintinib crystal form α. The XRD pattern of the fluquintinib crystal form α is shown in Figure 1, the specific values ​​of the characteristic peaks are shown in Table 3, the DSC pattern is shown in Figure 2, and the TGA pattern is shown in Figure 3.

[0093] [Table 3] Example 2: Preparation of fluquintinib crystalline form α

[0094] 50 mg of fluquintinib and 2.5 mg of xylitol were weighed and dissolved in 2.5 g of tetrahydrofuran at 50°C. This solution was sonicated at room temperature (10-25°C) for 5 hours, allowed to stand for 1 day in a 0°C environment, and the resulting solid was collected, protected with nitrogen gas, and stored at a low temperature (5-10°C) to obtain fluquintinib crystalline form α. Its XRD pattern substantially matches that of Figure 1. Example 3: Preparation of fluquintinib crystal form α

[0095] 50 mg of fluquintinib and 10 mg of xylitol were weighed and dissolved in 5.0 g of tetrahydrofuran at 50°C. This solution was sonicated at room temperature (10-25°C) for 24 hours, allowed to stand for 10 days at 10°C, and the resulting solid was collected, protected with nitrogen gas, and stored at a low temperature (5-10°C) to obtain fluquintinib crystalline form α. Its XRD pattern substantially matches that of Figure 1. Example 4: Preparation of fluquintinib crystal form α

[0096] 5.0 g of fluquintinib was weighed and added to tetrahydrofuran (15.5 g) and water (5.0 g). The mixture was heated to reflux temperature and dissolved. 0.25 g of fluquintinib crystalline form α prepared in Example 1 was added as a seed crystal. The mixture was then cooled to 5°C, stirred, and suspended. Crystallization was performed for 24 hours, and the resulting solid was collected to obtain 4.55 g of fluquintinib crystalline form α. Karl Fischer testing showed a water content of 11.90% and a yield of 86.67%. The XRD pattern was substantially in agreement with that shown in Figure 1. Grinding step: 0.5 g of fluquintinib crystalline form α prepared in Example 4 of this application was weighed and placed in a planetary ball mill and ground for approximately 30 seconds under conditions of 60 Hz. The XRD pattern after grinding is substantially consistent with that shown in Figure 1-2.

[0097] [Table 3-2] Example 5: Preparation of fluquintinib crystal form α

[0098] 5.0 g of fluquintinib was weighed and added to tetrahydrofuran (7.5 g) and water (7.5 g). The mixture was heated to reflux temperature and dissolved. 0.05 g of fluquintinib crystalline form α prepared in Example 4 was added as a seed crystal. The mixture was then slowly cooled to 0°C, stirred to suspend, and allowed to crystallize for 12 hours. The resulting solid was collected to obtain 4.05 g of fluquintinib crystalline form α in 80.20% yield. Its XRD pattern substantially matches that of Figure 1. Example 6: Preparation of fluquintinib crystal form α

[0099] 5.0 g of fluquintinib was weighed and added to tetrahydrofuran (45.0 g) and water (5.0 g). The mixture was heated to reflux temperature and dissolved. 1.0 g of fluquintinib crystalline form α prepared in Example 4 was added as a seed crystal. The mixture was then slowly cooled to 10°C, stirred, and suspended. Crystallization was performed for 48 hours, and the resulting solid was collected to obtain 4.86 g of fluquintinib crystalline form α in 81.0% yield. Its XRD pattern substantially matches that of Figure 1. Example 7: Preparation of fluquintinib crystal form α

[0100] 1.0 g of fluquintinib was weighed and added to tetrahydrofuran (26.7 g) and water (10.0 g). The mixture was heated to reflux temperature and dissolved. 0.05 g of fluquintinib crystalline form α prepared in Example 1 was added as a seed crystal. The mixture was then slowly cooled to 5°C, stirred to suspend, and allowed to crystallize for 24 hours. The resulting solid was collected to obtain 0.85 g of fluquintinib crystalline form α in 85.00% yield. Its XRD pattern substantially matches that of Figure 1. The obtained fluquintinib crystal form α was analyzed for its crystal structure using micro-ED technology. The diagram of the asymmetric unit in the unit cell of fluquintinib crystal form α is shown in Figure 6, where Z' is 1, and the asymmetric unit consists of one API molecule and three H2O molecules. Thus, fluquintinib crystal form α is a trihydrate crystal form. Specific data on the crystal structure are shown in Table 4.

[0101] [Table 4] Figure 1-3 shows the single-crystal simulated XRD pattern of the fluquintinib crystal form α. A comparison of Figure 1-2 and Figure 1-3 revealed that fluquintinib crystal form α did not undergo crystallization even after grinding. Example 8: Preparation of fluquintinib crystal form α

[0102] 190.0 g of fluquintinib was weighed and added to tetrahydrofuran (4058.4 g) and water (1140 g). The mixture was heated to reflux temperature and dissolved. 1.0 g of fluquintinib crystalline form α prepared in Example 4 was added as a seed crystal. The mixture was then slowly cooled to 5°C, stirred, and suspended. Crystallization was performed for 48 hours, and the resulting solid was collected to obtain 185.5 g of fluquintinib crystalline form α in a yield of 97.63%. Its XRD pattern substantially matches that of Figure 1. Experiment Example 1: Experiment to observe the stability of the fluquintinib crystal form

[0103] To observe the storage stability of fluquintinib crystal form α, fluquintinib crystal form α (after grinding), crystal forms I and III disclosed in CN106604919B, and crystal form C disclosed in CN105777722A, the samples were left to stand for 2 months and 6 months under stable conditions of 25°C / RH60% and 40°C / RH75%, respectively, and the stability of their crystal forms was observed. The results are shown in Table 5 below.

[0104] [Table 5] Stability test results:

[0105] Figures 4 (after 2 months of storage) and 5 (after 6 months of storage) show that fluquintinib crystal form α exhibits good crystal stability under all observed conditions. Figure 5-2 (after 6 months of storage) shows that under all observed conditions, fluquintinib crystal form α exhibits good crystal stability after grinding. Experiment Example 2: Experiment to observe the water stability of fluquintinib crystal form α and the crystal forms disclosed in CN106604919B.

[0106] Fluquintinib crystal form α prepared in Example 4 of this application, crystal forms I, II, III, VII, IV, and VIII disclosed in CN106604919B, and crystal form C disclosed in CN105777722A were suspended in water at different temperatures, stirred for 5 and 24 hours, and then the solids were filtered off and characterized by XRD. The results are shown in Table 6 below.

[0107] [Table 6]

[0108] Experimental results show that in water, fluquintinib crystal form α exhibits superior crystal stability compared to crystal forms I, II, III, VII, IV, VIII, and C.

[0109] Fluquintinib hydrate and its crystalline form α exhibit excellent stability in water, offering a new option in drug preparation and enabling its use in a wider range of drug preparation processes, such as wet granulation, thereby contributing to improved drug quality control and safety.

[0110] Each technical and scientific term used herein has the same meaning as that generally understood by those skilled in the art, unless otherwise defined. All patents, patent applications, and other publications are incorporated herein by express reference for descriptive and disclosure purposes. These publications are provided solely because their publication predates the filing date of this application. All statements regarding the dates of these documents or descriptions of their contents are based on information available to the applicant and do not constitute any recognition of the dates of these documents or the accuracy of their contents. Furthermore, no reference herein to any such publication in any country constitutes an acknowledgment that such publication is part of common knowledge in the art.

[0111] Those skilled in the art should recognize that the scope of this application is not limited to the various specific embodiments and examples described above, and that various modifications, substitutions, or rearrangements are possible without departing from the spirit of this application, all of which fall within the scope of protection.

Claims

1. Fluquintinib hydrate, wherein the structural formula of the hydrate is represented by the following formula (II), 【Chemistry 1】 Here, n is between 0.5 and 3. Preferably, n is 0.5, 1, 2, or 3. Preferably, the hydrate is fluquintinib trihydrate, characterized in that the hydrate is fluquintinib trihydrate.

2. The hydrate is a crystalline form having characteristic peaks at the following 2θ angles in the powder X-ray diffraction pattern: 7.2±0.2°, 8.6±0.2°, 14.4±0.2°, 15.2±0.2°, 20.4±0.2°, 22.3±0.2°, 24.0±0.2°, 26.1±0.2°, 26.4±0.2°, and 29.1±0.2°. Preferably, the powder X-ray diffraction pattern of the hydrate crystal form has characteristic peaks at the following 2θ angles: 7.212±0.2°, 8.643±0.2°, 14.445±0.2°, 15.182±0.2°, 20.423±0.2°, 22.348±0.2°, 23.960±0.2°, 26.100±0.2°, 26.446±0.2°, and 29.119±0.2°. Preferably, the powder X-ray diffraction pattern of the hydrate crystal form has characteristic peaks at the following 2θ angles: 4.9±0.2°, 7.2±0.2°, 8.6±0.2°, 12.0±0.2°, 14.4±0.2°, 15.2±0.2°, 16.2±0.2°, 20.4±0.2°, 22.3±0.2°, 24.0±0.2°, 25.4±0.2°, 26.1±0.2°, 26.4±0.2°, 28.3±0.2°, and 29.1±0.2°. Preferably, the powder X-ray diffraction pattern of the hydrate crystal form has characteristic peaks at the following 2θ angles: 4.861±0.2°, 7.212±0.2°, 8.643±0.2°, 12.018±0.2°, 14.445±0.2°, 15.182±0.2°, 16.171±0.2°, 20.423±0.2°, 22.348±0.2°, 23.960±0.2°, 25.370±0.2°, 26.100±0.2°, 26.446±0.2°, 28.326±0.2°, and 29.119±0.2°. Preferably, the powder X-ray diffraction pattern of the hydrate crystal form has characteristic peaks at the following 2θ angles: 4.9±0.2°, 7.2±0.2°, 8.6±0.2°, 12.0±0.2°, 14.4±0.2°, 15.2±0.2°, 16.2±0.2°, 17.3±0.2°, 20.4±0.2°, 22.3±0.2°, 24.0±0.2°, 24.4±0.2°, 25.4±0.2°, 26.1±0.2°, 26.4±0.2°, 28.3±0.2°, 28.6±0.2°, 29.1±0.2°, 29.6±0.2°, and 32.7±0.2°. Preferably, in the powder X-ray diffraction pattern of the hydrate crystal form, the 2θ angles are 4.861±0.2°, 7.212±0.2°, 8.643±0.2°, 12.018±0.2°, 14.445±0.2°, 15.182±0.2°, 16.171±0.2°, 17.316±0.2°, 20.423±0.2°, and 22.3 It has characteristic peaks at the following positions: 48±0.2°, 23.960±0.2°, 24.428±0.2°, 25.370±0.2°, 26.100±0.2°, 26.446±0.2°, 28.326±0.2°, 28.610±0.2°, 29.119±0.2°, 29.598±0.2°, and 32.656±0.2°. Preferably, the powder X-ray diffraction pattern of the hydrate crystal form has characteristic peaks at the following 2θ angles: 4.9±0.2°, 7.2±0.2°, 8.6±0.2°, 9.7±0.2°, 12.0±0.2°, 14.4±0.2°, 15.2±0.2°, 16.2±0.2°, 17.3±0.2°, 20.4±0.2°, 22.3±0.2°, 24.0±0.2°, 24.4±0.2°, 25.4±0.2°, 26.1±0.2°, 26.4±0.2°, 28.3±0.2°, 28.6±0.2°, 29.1±0.2°, 29.6±0.2°, and 32.7±0.2°. Preferably, in the powder X-ray diffraction pattern of the hydrate crystal form, the 2θ angles are 4.861±0.2°, 7.212±0.2°, 8.643±0.2°, 9.7064±0.2°, 12.018±0.2°, 14.445±0.2°, 15.182±0.2°, 16.171±0.2°, 17.316±0.2°, and 20.423±0.2°. It has characteristic peaks at the following positions: °, 22.348±0.2°, 23.960±0.2°, 24.428±0.2°, 25.370±0.2°, 26.100±0.2°, 26.446±0.2°, 28.326±0.2°, 28.610±0.2°, 29.119±0.2°, 29.598±0.2°, and 32.656±0.2°. Preferably, the fluquintinib hydrate according to claim 1 is characterized in that the powder X-ray diffraction pattern of the hydrate crystal form is substantially as shown in Figure 1.

3. The hydrate exhibits the following 2θ angles in the powder X-ray diffraction pattern: 4.8±0.2°, 7.2±0.2°, 8.6±0.2°, 9.7±0.2°, 12.0±0.2°, 14.4±0.2°, 15.2±0.2°, 16.2±0.2°, 17.3±0.2°, 19.9±0.2°, 20.4±0.2°, and 21.8± The crystal form has characteristic peaks at the following positions: 0.2°, 22.3±0.2°, 24.0±0.2°, 24.3±0.2°, 25.4±0.2°, 26.0±0.2°, 26.4±0.2°, 28.2±0.2°, 28.6±0.2°, 29.1±0.2°, 29.6±0.2°, and 32.7±0.2°. Preferably, the powder X-ray diffraction pattern of the hydrate crystal form is as shown in Figure 1-2. Preferably, the powder X-ray diffraction pattern of the hydrate crystal form is as shown in Figure 1-3, characterized in that the fluquintinib hydrate according to claim 1.

4. The hydrate is in crystalline form, and in the DSC pattern of the hydrate crystal form, it has endothermic peaks at 95.23±5°C and 245.71±5°C. Preferably, the DSC pattern of the hydrate crystal form is substantially as shown in Figure 2. Preferably, the TGA pattern of the hydrate crystal form is substantially as shown in Figure 3. Preferably, the water content of the hydrate crystal form is 11.00 ± 2.0%. Preferably, the fluquintinib hydrate according to any one of claims 1 to 3 is characterized in that the water content of the hydrate crystal form is 11.90 ± 0.20%.

5. The hydrate is in crystalline form, and its crystalline form is triclinic, with a space group of P-1 (No. 2) and a molecular weight of 447.44 g / mol. －１ Z' is 1, unit cell parameters are a = 4.880 (5) Å, b = 11.98 (2) Å, c = 17.916 (17) Å, α = 89.10 (6)°, β = 94.56 (10)°, γ = 97.09 (18)°, and unit cell volume is V = 1036 (2) Å ３ A fluquintinib hydrate according to any one of claims 1 to 3, characterized in that it is the same as described above.

6. The crystalline form α of fluquintinib has characteristic peaks at the following positions in the powder X-ray diffraction pattern of the crystalline form: 7.2±0.2°, 8.6±0.2°, 14.4±0.2°, 15.2±0.2°, 20.4±0.2°, 22.3±0.2°, 24.0±0.2°, 26.1±0.2°, 26.4±0.2°, and 29.1±0.2°. Preferably, the powder X-ray diffraction pattern of the crystalline form α has characteristic peaks at the following 2θ angles: 7.212±0.2°, 8.643±0.2°, 14.445±0.2°, 15.182±0.2°, 20.423±0.2°, 22.348±0.2°, 23.960±0.2°, 26.100±0.2°, 26.446±0.2°, and 29.119±0.2°. Preferably, the powder X-ray diffraction pattern of the crystal form α has characteristic peaks at the following 2θ angles: 4.9±0.2°, 7.2±0.2°, 8.6±0.2°, 12.0±0.2°, 14.4±0.2°, 15.2±0.2°, 16.2±0.2°, 20.4±0.2°, 22.3±0.2°, 24.0±0.2°, 25.4±0.2°, 26.1±0.2°, 26.4±0.2°, 28.3±0.2°, and 29.1±0.2°. Preferably, the powder X-ray diffraction pattern of the crystalline form α has characteristic peaks at the following 2θ angles: 4.861±0.2°, 7.212±0.2°, 8.643±0.2°, 12.018±0.2°, 14.445±0.2°, 15.182±0.2°, 16.171±0.2°, 20.423±0.2°, 22.348±0.2°, 23.960±0.2°, 25.370±0.2°, 26.100±0.2°, 26.446±0.2°, 28.326±0.2°, and 29.119±0.2°. Preferably, the powder X-ray diffraction pattern of the crystal form α has characteristic peaks at the following 2θ angles: 4.9±0.2°, 7.2±0.2°, 8.6±0.2°, 12.0±0.2°, 14.4±0.2°, 15.2±0.2°, 16.2±0.2°, 17.3±0.2°, 20.4±0.2°, 22.3±0.2°, 24.0±0.2°, 24.4±0.2°, 25.4±0.2°, 26.1±0.2°, 26.4±0.2°, 28.3±0.2°, 28.6±0.2°, 29.1±0.2°, 29.6±0.2°, and 32.7±0.2°. Preferably, in the powder X-ray diffraction pattern of the crystal form α, the 2θ angles are 4.861±0.2°, 7.212±0.2°, 8.643±0.2°, 12.018±0.2°, 14.445±0.2°, 15.182±0.2°, 16.171±0.2°, 17.316±0.2°, 20.423±0.2°, and 22.

34. It has characteristic peaks at the following positions: 8±0.2°, 23.960±0.2°, 24.428±0.2°, 25.370±0.2°, 26.100±0.2°, 26.446±0.2°, 28.326±0.2°, 28.610±0.2°, 29.119±0.2°, 29.598±0.2°, and 32.656±0.2°. Preferably, the powder X-ray diffraction pattern of the crystal form α has characteristic peaks at the following 2θ angles: 4.9±0.2°, 7.2±0.2°, 8.6±0.2°, 9.7±0.2°, 12.0±0.2°, 14.4±0.2°, 15.2±0.2°, 16.2±0.2°, 17.3±0.2°, 20.4±0.2°, 22.3±0.2°, 24.0±0.2°, 24.4±0.2°, 25.4±0.2°, 26.1±0.2°, 26.4±0.2°, 28.3±0.2°, 28.6±0.2°, 29.1±0.2°, 29.6±0.2°, and 32.7±0.2°. Preferably, in the powder X-ray diffraction pattern of the crystalline form α, the 2θ angles are 4.861±0.2°, 7.212±0.2°, 8.643±0.2°, 9.7064±0.2°, 12.018±0.2°, 14.445±0.2°, 15.182±0.2°, 16.171±0.2°, 17.316±0.2°, and 20.423±0.2°. It has characteristic peaks at the following positions: 22.348±0.2°, 23.960±0.2°, 24.428±0.2°, 25.370±0.2°, 26.100±0.2°, 26.446±0.2°, 28.326±0.2°, 28.610±0.2°, 29.119±0.2°, 29.598±0.2°, and 32.656±0.2°. Preferably, the crystalline form α of fluquintinib is characterized in that the powder X-ray diffraction pattern of the crystalline form α is substantially as shown in Figure 1.

7. In the DSC pattern of the aforementioned crystal form α, there are endothermic peaks at the positions of 95.23±5°C and 245.71±5°C. Preferably, the DSC pattern of the crystal form α is substantially as shown in Figure 2. Preferably, the TGA pattern of the crystal form α is substantially as shown in Figure 3. Preferably, the water content of the hydrate crystal form is 11.00 ± 2.0%. Preferably, the water content of the hydrate crystal form is 11.90 ± 0.20%, characterized in that the crystalline form α of fluquintinib according to claim 6.

8. The crystalline form α of fluquintinib according to claim 6 or 7, characterized in that the crystalline form α is fluquintinib trihydrate.

9. A method for preparing the hydrate according to any one of claims 1 to 5 or the crystalline form α according to any one of claims 5 to 8, comprising the step of mixing fluquintinib and an additive in solvent A and performing crystallization, Preferably, the process includes the steps of mixing fluquintinib and additives in solvent A, dissolving them with ultrasound, and allowing them to stand to crystallize. Preferably, in the ultrasonic dissolution process, the temperature conditions are 10 to 25°C. Preferably, in the ultrasonic dissolution process, the ultrasonic treatment time is 5 to 24 hours, preferably 12 hours. Preferably, in the static crystallization process, the crystallization temperature is 0 to 10°C, preferably 5°C. Preferably, in the static crystallization process, the standing time is 1 to 10 days, preferably 5 days. Preferably, the additive is a polyol. Preferably, the polyol is a sugar alcohol. Preferably, the polyol is one or more selected from xylitol, mannitol, sorbitol, isomaltitol, and maltitol. Preferably, the polyol is xylitol. Preferably, the solvent A is an ethere-based solvent. Preferably, the ether-based solvent is one or more selected from tetrahydrofuran, ethyl ether, propylene glycol methyl ether, methyl tert-butyl ether, isopropyl ether, and 1,4-dioxane. Preferably, the ethere solvent is tetrahydrofuran. Preferably, the mass ratio of fluquintinib to the additive is 5 to 20:1, preferably 10:

1. Preferably, the mass-volume ratio of fluquintinib to solvent A is 1:50 to 100, preferably 1:

62. Preferably, after the static crystallization, the obtained solid is collected and stored under protection of an inert gas. Preferably, the storage temperature is 5 to 10°C. Preferably, the inert gas is nitrogen gas, argon gas, or helium gas, preferably nitrogen gas, in the preparation method.

10. A method for preparing the hydrate according to any one of claims 1 to 5 or the crystalline form α according to any one of claims 5 to 8, Step (1) involves mixing fluquintinib with solvent B and heating to dissolve it, The process includes (2) adding the hydrate, or its crystalline form, or a seed crystal of the crystalline form α, and performing crystallization. Preferably, the heating and dissolution involves heating to the reflux temperature to dissolve the substance. Preferably, in step (1), the mass ratio of fluquintinib to solvent B is 1:3 to 40. Preferably, in step (1), the mass ratio of fluquintinib to solvent B is 1:3 to 10, preferably 1:4.

1. Preferably, solvent B is a mixed solvent of water and an ether-based solvent, and the mass ratio of water to the ether-based solvent is preferably 1:1 to 9, more preferably 1:3.

1. Preferably, the ether-based solvent of solvent B is one or more selected from tetrahydrofuran, ethyl ether, propylene glycol methyl ether, methyl tert-butyl ether, isopropyl ether, and 1,4-dioxane. Preferably, the ethere solvent of solvent B is tetrahydrofuran. Preferably, the amount of seed crystal used is 1 to 20%, preferably 5%, of the mass fraction of the amount of fluquintinib added in step (1). Preferably, step (2) specifically includes adding the seed crystal, lowering the temperature, stirring to suspend, and precipitation. Preferably, step (2) includes adding the seed crystal, lowering the temperature to 0 to 10°C, stirring to suspend, and precipitation for 12 to 48 hours. Preferably, step (2) is a preparation method that specifically includes adding the seed crystal, lowering the temperature to 5°C, stirring to suspend, and crystallizing for 24 hours.

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