VEGFR inhibitor hydrate, and crystal form and preparation method thereof

Abstract

Relates to a VEGFR inhibitor hydrate, and a crystal form and a preparation method thereof. The VEGFR inhibitor is 6-(6, 7-dimethoxyquinazoline-4-oxygen)-N, 2-dimethylbenzofuran-3-formamide, the hydrate and the crystal form thereof have good physical and chemical properties, also have good fluidity, solubility, stability and bioavailability, can improve hygroscopicity, and the preparation method is simple, good in repeatability, high in yield, easy to operate and suitable for industrial production. The method is green and environment-friendly, the required solvent amount is small, recycling is facilitated, the reagent cost can be effectively reduced, and large-scale production is easy to realize.

Description

A hydrate of a VEGFR inhibitor, its crystal form and its preparation method

[0001] This application claims priority to three prior applications: Patent Application No. 202310647472.5 filed with the State Intellectual Property Office of China on June 2, 2023; Patent Application No. 202311552719.1 filed with the State Intellectual Property Office of China on November 20, 2023; and Patent Application No. 202410117086.X filed with the State Intellectual Property Office of China on January 26, 2024. The entire contents of the three prior applications are incorporated herein by reference. Technical Field

[0002] The present application relates to the field of drug crystal forms, and specifically to a hydrate of a VEGFR inhibitor, its crystal form and a preparation method thereof. Background Art

[0003] Fruquintinib (trade name Elunate) is a VEGFR inhibitor developed by Hutchison Whampoa for the treatment of metastatic colorectal cancer. Its original formulation, Elunate, was approved for marketing in China on September 4, 2018. The structure of fruquintinib is shown in Formula (I):

[0004] Prior art CN106604919B discloses six crystalline forms of fruquintinib: Form I, Form II, Form III, Form VII, Form IV, and Form VIII. These crystalline forms are all anhydrates or organic solvates. The prior art has not yet developed a hydrate of fruquintinib or its crystalline forms with good drugability. Therefore, further research is needed to develop hydrate forms of fruquintinib and its crystalline forms.

[0005] Summary of the Invention

[0006] In response to the above-mentioned problems existing in the prior art, the present application provides a hydrate of a VEGFR inhibitor, a crystal form thereof, and a preparation method thereof. The VEGFR inhibitor is fruquintinib, whose chemical name is: 6-(6,7-dimethoxyquinazoline-4-oxy)-N,2-dimethylbenzofuran-3-carboxamide.

[0007] In a first aspect, the present application provides a fruquintinib hydrate.

[0008] The hydrate structural formula is shown in the following formula (II):

[0009] Among them, n is 0.5~3.

[0010] In some embodiments of the present application, n is 0.5, 1, 2, or 3.

[0011] In some embodiments of the present application, the hydrate is fruquintinib trihydrate.

[0012] In some embodiments of the present application, a crystalline form of the furiquintinib hydrate is provided, and its X-ray powder diffraction pattern has characteristic peaks 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°.

[0013] In some embodiments of the present application, the X-ray powder diffraction pattern of the hydrate crystalline form 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°.

[0014] In some embodiments of the present application, the X-ray powder 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°.

[0015] In some embodiments of the present application, the X-ray powder diffraction pattern of the hydrate crystal form has characteristic peaks at 2θ angles of 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°.

[0016] In some embodiments of the present application, the X-ray powder diffraction pattern of the hydrate crystalline 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°, 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 X-ray powder diffraction pattern of the hydrate crystal form at 2θ angle is 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°, There are characteristic peaks at 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 embodiments of the present application, the X-ray powder diffraction pattern of the hydrate crystalline form 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°.

[0019] In some embodiments of the present application, the X-ray powder diffraction pattern of the hydrate crystal form at 2θ angle is 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°, 20.4 There are characteristic peaks at 23±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°.

[0020] In some specific embodiments of the present application, the X-ray powder diffraction pattern of the hydrate crystal form is substantially as shown in FIG1 .

[0021] In some embodiments of the present application, the X-ray powder diffraction pattern of the hydrate crystal form at 2θ angles 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°, 2 There are characteristic peaks at 0.4±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°.

[0022] In some specific embodiments of the present application, the X-ray powder diffraction pattern of the hydrate crystal form is shown in Figures 1-2.

[0023] In some specific embodiments of the present application, the X-ray powder diffraction patterns of the hydrate crystal form are shown in Figures 1-3.

[0024] In some embodiments of the present application, the DSC spectrum of the hydrate crystal form has endothermic peaks at 95.23±5°C and 245.71±5°C.

[0025] In some specific embodiments of the present application, the DSC spectrum of the hydrate crystal form is basically as shown in Figure 2.

[0026] In some specific embodiments of the present application, the TGA spectrum of the hydrate crystal form is basically as shown in Figure 3.

[0027] In some specific embodiments of the present application, the moisture content of the hydrated crystal form is 11.00±2.0%. For example, the moisture content of the hydrated 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%, or 12.50%.

[0028] In some specific embodiments of the present application, the water content of the hydrate crystal form is 11.90±0.20%.

[0029] In some specific embodiments of the present application, the water content of the hydrate crystal form is 11.90%.

[0030] In some specific embodiments of the present application, the hydrate crystal form is triclinic, the space group is P-1 (No. 2), and the molecular weight is 447.44 g·mol -1 , Z' is 1, and the unit cell parameters are α=89.10(6)°,β=94.56(10)°,γ=97.09(18)°,unit cell volume

[0031] In a second aspect of the present application, a crystalline form α of furiquintinib is provided, whose X-ray powder diffraction pattern has characteristic peaks 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°.

[0032] In some embodiments of the present application, the X-ray powder 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°.

[0033] In some embodiments of the present application, the X-ray powder 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°, 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°.

[0034] In some embodiments of the present application, the X-ray powder diffraction pattern of the crystalline form α has characteristic peaks at 2θ angles of 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°.

[0035] In some embodiments of the present application, the X-ray powder 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°.

[0036] In some embodiments of the present application, the X-ray powder diffraction pattern of the crystalline form α at 2θ angle is 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°, There are characteristic peaks at 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 embodiments of the present application, the X-ray powder 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°.

[0038] In some embodiments of the present application, the X-ray powder diffraction pattern of the crystalline form α at 2θ angle is 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°, 20.4 There are characteristic peaks at 23±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°.

[0039] In some specific embodiments of the present application, the X-ray powder diffraction pattern of the crystalline form α is substantially as shown in FIG1 .

[0040] In some embodiments of the present application, the DSC spectrum of the crystalline form α has endothermic peaks at 95.23±5°C and 245.71±5°C.

[0041] In some specific embodiments of the present application, the DSC spectrum of the crystalline form α is substantially as shown in FIG2 .

[0042] In some specific embodiments of the present application, the TGA spectrum of the crystalline form α is substantially as shown in FIG3 .

[0043] In some specific embodiments of the present application, the moisture content of the crystalline form α is 11.00±2.0%. For example, the moisture content of the hydrated crystalline form is 11.50%, 11.60%, 11.70%, 11.80%, 11.90%, 12.00%, 12.10%, 12.20%, 12.30%, 12.40%, or 12.50%.

[0044] In some specific embodiments of the present application, the moisture content of the crystalline form α is 11.90±0.20%.

[0045] In some specific embodiments of the present application, the moisture content of the crystalline form α is 11.90%.

[0046] In some specific embodiments of the present application, the crystal form α is a triclinic system with a space group of P-1 (No. 2) and a molecular weight of 447.44 g·mol -1 , Z' is 1, and the unit cell parameters are α=89.10(6)°,β=94.56(10)°,γ=97.09(18)°,unit cell volume

[0047] In some specific embodiments of the present application, the crystalline form α is a hydrate, and the structural formula is shown in the following formula (II):

[0048] Among them, n is 0.5~3.

[0049] In some embodiments of the present application, n is 0.5, 1, 2, or 3.

[0050] In some embodiments of the present application, the hydrate crystal form is fruquintinib trihydrate.

[0051] The third aspect of the present application provides a method for preparing the hydrate and its crystal form described in the first aspect, and the furquintinib crystal form α described in the second aspect, which comprises: mixing furquintinib and additives in solvent A and crystallizing.

[0052] In some embodiments of the present application, the preparation method specifically comprises: mixing furiquintinib and additives in solvent A, dissolving by ultrasonication, and standing for crystallization.

[0053] In some embodiments of the present application, the ultrasonic dissolution process is performed at a temperature of 10 to 25°C;

[0054] In some embodiments of the present application, the ultrasonic dissolution process has an ultrasonic treatment time of 5 to 24 hours, preferably 12 hours;

[0055] In some embodiments of the present application, the crystallization temperature during the static crystallization process is 0 to 10° C., preferably 5° C.;

[0056] In some embodiments of the present application, the standing crystallization process has a standing time of 1 to 10 days, preferably 5 days.

[0057] In some embodiments of the present application, the additive is a polyol;

[0058] Preferably, the polyol is a sugar alcohol;

[0059] More preferably, the polyol is selected from one or more of xylitol, mannitol, sorbitol, isomalt and maltitol;

[0060] Most preferably, the polyol is xylitol.

[0061] In some embodiments of the present application, the solvent A is an ether solvent;

[0062] Preferably, the ether solvent is selected from one or more of tetrahydrofuran, diethyl ether, propylene glycol methyl ether, methyl tert-butyl ether, isopropyl ether and 1,4-dioxane;

[0063] More preferably, the ether solvent is tetrahydrofuran.

[0064] In some embodiments of the present application, the mass ratio of the furquintinib to the additive is 5 to 20:1, preferably 10:1.

[0065] In some embodiments of the present application, the mass-to-volume ratio of furquintinib to solvent A is 1:50-100, preferably 1:62.

[0066] In some specific embodiments of the present application, after the standing crystallization, the obtained solid is collected and stored under the protection of an inert gas.

[0067] In some specific embodiments of the present application, the storage temperature is 5 to 10°C;

[0068] In some specific embodiments of the present application, the inert gas is nitrogen, argon or helium, preferably nitrogen.

[0069] The fourth aspect of the present application provides a method for preparing the hydrate and its crystal form described in the first aspect, and the furquintinib crystal form α described in the second aspect, comprising:

[0070] (1) Fruquintinib is mixed with solvent B and heated to dissolve;

[0071] (2) adding seed crystals of the hydrate or its crystal form or the crystal form α to perform crystallization.

[0072] In some embodiments of the present application, the heating to dissolve is heating to reflux temperature to dissolve.

[0073] In some embodiments of the present application, in the step (1), the mass ratio of the furquintinib to the solvent B is 1:3 to 40; for example: 1:40, 1:36.7, 27.36, 1:10, 1:4.1, 1:3.

[0074] In some embodiments of the present application, in step (1), the mass ratio of furquintinib to solvent B is 1:3 to 10; preferably 1:4.1.

[0075] In some embodiments of the present application, the solvent B is a mixed solvent of water and an ether solvent; the mass ratio of water to ether solvent is preferably 1:1 to 9, more preferably 1:3.1;

[0076] Preferably, the ether solvent in the solvent B is selected from one or more of tetrahydrofuran, diethyl ether, propylene glycol methyl ether, methyl tert-butyl ether, isopropyl ether and 1,4-dioxane;

[0077] More preferably, the ether solvent in the solvent B is tetrahydrofuran.

[0078] In some embodiments of the present application, the amount of the seed crystals used is 1 to 20% of the mass fraction of the amount of furquintinib fed in step (1); preferably 5%.

[0079] In some embodiments of the present application, the step (2) specifically includes: adding the seed crystals, cooling, stirring and suspending to crystallize;

[0080] Preferably, the step (2) specifically comprises: adding the seed crystals, cooling to 0-10°C, stirring and suspending for crystallization for 12-48 hours;

[0081] More preferably, the step (2) specifically comprises: adding the seed crystals, cooling by 5° C., stirring and suspending the crystals for 24 hours.

[0082] In some embodiments of the present application, the preparation method further includes a step of preparing the seed crystal, which includes: mixing fruquintinib and additives in solvent B and crystallizing.

[0083] In some embodiments of the present application, the preparation method of the hydrate or its crystal form, or crystal form α includes:

[0084] (a) Preparing seed crystals of the crystalline form α: mixing fruquintinib and additives in solvent A and crystallizing;

[0085] (b) mixing fruquintinib with solvent B, and heating the mixture to reflux to obtain a solution;

[0086] (c) adding seed crystals of the crystalline form α and performing crystallization.

[0087] The additives, solvent A, and solvent B are as defined above.

[0088] The hydrate or its crystal form or crystal form α prepared by the preparation method of the third aspect of the present application can be used as the seed crystal in step (2) of the preparation method of the fourth aspect.

[0089] The hydrate or its crystal form or crystal form α prepared in the fourth aspect of the present application can also be used as the seed crystal in step (2) described in the fourth aspect.

[0090] The fruquintinib crystalline form α of the second aspect of the present application is prepared by the preparation method of the third aspect or the fourth aspect.

[0091] The fruquintinib hydrate and its crystal form in the first aspect of the present application are prepared by the preparation method in the third aspect or the fourth aspect.

[0092] Compared with the prior art, the present invention has the following beneficial effects:

[0093] (1) The inventors discovered that the prior art CN106604919B discloses that Form II is a hemiethanolate, Form IV is an acetic acidate, and Form VIII is a dioxane. Forms I, III, and VII are all anhydrous forms. Among them, the solvate forms all contain organic solvents and are not suitable for drug development. The anhydrous form is unstable, for example, there is a risk of converting to a hydrate when exposed to moisture, or it is easily converted to the corresponding hydrate during processing and storage. At the same time, the inventors discovered that Form C disclosed in CN105777722A is also an anhydrous form.

[0094] (2) The present invention obtains for the first time a hydrate of furiquintinib and its hydrate crystal form α, which has good physical and chemical properties, as well as good fluidity, solubility, stability, and bioavailability. It can improve hygroscopicity, especially good stability in water, and can be used in a wider range of pharmaceutical preparation processes, such as wet granulation, which helps to improve the controllability and safety of drug quality.

[0095] (3) The furiquintinib hydrate and hydrate form α involved in the present invention have a simple preparation process, good reproducibility, high yield, easy operation, green and environmentally friendly, require a small amount of solvent and are conducive to recycling, can effectively reduce reagent costs, and easily achieve large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0096] Figure 1 is an XRD pattern of Fruquintinib Form α;

[0097] Figure 1-2 is the XRD pattern of Fruquintinib Form α after grinding;

[0098] Figure 1-3 is a simulated XRD pattern of a single crystal of Fruquintinib Form α;

[0099] FIG2 is a DSC graph of Fruquintinib Form α;

[0100] Figure 2-2 is a DSC diagram of Fruquintinib Form C;

[0101] FIG3 is a TGA diagram of Fruquintinib Form α;

[0102] Figure 4 is a comparison diagram of the crystal forms of Fruquintinib Form α after 2-month stability test;

[0103] Figure 5 is a comparison diagram of the crystal forms of Fruquintinib Form α after 6-month stability test;

[0104] Figure 5-2 is a comparison of the crystal forms of Fruquintinib Form α after grinding and storage for 6 months;

[0105] Figure 6 is a diagram of the asymmetric unit in the unit cell of the α form of fruquintinib. DETAILED DESCRIPTION

[0106] In order to make the present application easier to understand, the present application will be described in detail below with reference to embodiments. These embodiments are merely illustrative and do not limit the scope of application of the present application.

[0107] The terms used in this application are explained as follows:

[0108] XRD: X-ray powder diffraction

[0109] The X-ray powder diffraction (XRD) measurements described in this application were performed using a Malvern Panalytical Empyrean X-ray powder diffractometer. Specific parameters are as follows:

[0110] Table 1

[0111] Herein, “the X-ray powder diffraction pattern is substantially as shown in FIG1 ” means that the X-ray powder diffraction pattern is substantially the same as FIG1 , and the term “substantially the same” for the X-ray powder diffraction pattern means that changes in representative peak positions and intensities are taken into account.

[0112] DSC: Differential Scanning Calorimetry

[0113] The differential scanning calorimetry (DSC) measurements described herein were performed using a METTLER TOLEDO model DSC-1 with a heating rate of 10°C / min over a temperature range of 25-250°C. The nitrogen purge rate during the test was 60 mL / min.

[0114] Herein, “the DSC spectrum is substantially as shown in FIG2 ” means that the DSC spectrum is substantially the same as FIG2 , and the term “substantially the same” of the DSC spectrum means that the representative characteristic peak positions are taken into consideration.

[0115] TGA: Thermogravimetric analysis

[0116] The thermogravimetric analysis (TGA) measurements described herein were performed using a METTLER TOLEDO model TGA-2 with a heating rate of 10°C / min over a temperature range of 30-300°C. The nitrogen purge rate during the test was 20 mL / min.

[0117] The error of TGA can be within about ±0.5 mass %. Herein, "TGA spectrum is substantially as shown in FIG3 " means that the TGA spectrum is substantially the same as FIG3 , and the term "substantially the same" of the TGA spectrum means that such error variation is taken into account.

[0118] The "room temperature" mentioned in this application refers to a temperature of 10 to 25°C.

[0119] Herein, percentages are by weight unless otherwise indicated.

[0120] Micro ED: Microcrystal Electron Diffraction

[0121] The crystal structure of the Form α described in this application was determined using microcrystal electron diffraction (Micro ED) technology, and the specific parameters are as follows:

[0122] Table 2

[0123] Herein, Form I, Form II, Form III, Form IV, Form VII, and Form VIII are Form I, Form II, Form III, Form IV, Form VII, and Form VIII prepared according to the method disclosed in CN106604919B.

[0124] Herein, Form C is the Form C prepared according to the method disclosed in CN105777722A.

[0125] The DSC spectrum of the crystalline form C has an endothermic peak at approximately 245.65° C. The DSC spectrum of the crystalline form C is substantially as shown in FIG2-2 .

[0126] In this article, furquintinib, whose chemical name is 6-(6,7-dimethoxyquinazoline-4-oxy)-N,2-dimethylbenzofuran-3-carboxamide, is a compound represented by formula (I):

[0127] Example 1: Preparation of Fruquintinib Form α

[0128] Weigh 50 mg of furiquintinib and 5 mg of xylitol, dissolve them in 3.1 g of tetrahydrofuran at 50°C, ultrasonicate the solution at room temperature (10-25°C) for 12 hours, and let it stand at 5°C for 5 days to obtain furiquintinib Form α. Collect the resulting solid (furiquintinib Form α) and store it at low temperature (5-10°C) under nitrogen protection.

[0129] The obtained fruquintinib crystalline form α was subjected to XRD analysis, DSC analysis and TGA analysis. The XRD spectrum of the fruquintinib crystalline form α is shown in Figure 1, the specific values ​​of the characteristic peaks are shown in Table 3, the DSC spectrum is shown in Figure 2, and the TGA spectrum is shown in Figure 3.

[0130] Table 3 Characteristic peak data of XRD pattern of Fruquintinib Form α

[0131] Example 2: Preparation of Fruquintinib Form α

[0132] 50 mg of furiquintinib and 2.5 mg of xylitol were weighed and dissolved in 2.5 g of tetrahydrofuran at 50°C. The solution was ultrasonicated at room temperature (10-25°C) for 5 hours and allowed to stand at 0°C for 1 day. The resulting solid was collected and stored at low temperature (5-10°C) under nitrogen protection to obtain furiquintinib Form α. The XRD pattern was basically consistent with Figure 1.

[0133] Example 3: Preparation of Fruquintinib Form α

[0134] 50 mg of furiquintinib and 10 mg of xylitol were weighed and dissolved in 5.0 g of tetrahydrofuran at 50°C. The solution was ultrasonicated at room temperature (10-25°C) for 24 hours and allowed to stand at 10°C for 10 days. The resulting solid was collected and stored at low temperature (5-10°C) under nitrogen protection to obtain furiquintinib Form α. The XRD pattern was basically consistent with Figure 1.

[0135] Example 4: Preparation of Fruquintinib Form α

[0136] 5.0 g of furiquintinib was weighed, added to tetrahydrofuran (15.5 g) and water (5.0 g), and heated to reflux temperature for dissolution. 0.25 g of furiquintinib form α prepared in Example 1 was added as a seed crystal, and the mixture was slowly cooled to 5°C, stirred, suspended and crystallized for 24 hours. The resulting solid was collected to obtain 4.55 g of furiquintinib form α. The Karl Fischer test results showed that the moisture content was 11.90%, the yield was 86.67%, and the XRD pattern was basically consistent with Figure 1.

[0137] Grinding step: Weigh 0.5 g of the fruquintinib crystalline form α prepared in Example 4 of the present application, place it in a planetary ball mill and grind it at 60 Hz for about 30 seconds.

[0138] The XRD pattern after grinding is basically consistent with Figure 1-2.

[0139] Table 3-2 Characteristic peak data of XRD pattern of Fruquintinib crystalline form α after grinding

[0140] Example 5: Preparation of Fruquintinib Form α

[0141] 5.0 g of fruquintinib was weighed and added to tetrahydrofuran (7.5 g) and water (7.5 g). The mixture was heated to reflux temperature for dissolution. 0.05 g of fruquintinib Form α prepared in Example 4 was added as a seed crystal and then slowly cooled to 0°C and stirred for suspension for crystallization for 12 h. The resulting solid was collected to obtain 4.05 g of fruquintinib Form α with a yield of 80.20%. The XRD pattern was basically consistent with Figure 1.

[0142] Example 6: Preparation of Fruquintinib Form α

[0143] 5.0 g of fruquintinib was weighed, added to tetrahydrofuran (45.0 g) and water (5.0 g), and heated to reflux temperature for dissolution. 1.0 g of fruquintinib form α prepared in Example 4 was added as a seed crystal, and the temperature was slowly lowered to 10° C., stirred, suspended, and crystallized for 48 hours. The resulting solid was collected to obtain 4.86 g of fruquintinib form α with a yield of 81.0%. The XRD pattern was basically consistent with Figure 1.

[0144] Example 7: Preparation of Fruquintinib Form α

[0145] 1.0 g of fruquintinib was weighed and added to tetrahydrofuran (26.7 g) and water (10.0 g). The mixture was heated to reflux temperature for dissolution. 0.05 g of fruquintinib Form α prepared in Example 1 was added as a seed crystal and then slowly cooled to 5°C and stirred for suspension for crystallization for 24 hours. The resulting solid was collected to obtain 0.85 g of fruquintinib Form α with a yield of 85.00%. The XRD pattern was basically consistent with Figure 1.

[0146] The resulting fruquintinib Form α was analyzed using MicroED technology for crystal structure analysis. The asymmetric unit diagram within the unit cell of this fruquintinib Form α is shown in Figure 6 . Z' is 1, and the asymmetric unit consists of one API molecule and three H2O molecules. This fruquintinib Form α is a trihydrate. Detailed crystal structure data are shown in Table 4.

[0147] Table 4 Specific data of the crystal structure of Fruquintinib Form α

[0148] Figure 1-3 shows a simulated XRD pattern of a single crystal of Fruquintinib Form α. Comparing Figures 1-2 and 1-3, it can be seen that Fruquintinib Form α did not undergo crystallization after grinding.

[0149] Example 8: Preparation of Fruquintinib Form α

[0150] 190.0 g of fruquintinib was weighed, added to tetrahydrofuran (4058.4 g) and water (1140 g), and heated to reflux temperature for dissolution. 1.0 g of fruquintinib Form α prepared in Example 4 was added as a seed crystal, and the mixture was slowly cooled to 5°C and stirred for suspension and crystallization for 48 hours. The resulting solid was collected to obtain 185.5 g of fruquintinib Form α with a yield of 97.63%. The XRD pattern was basically consistent with Figure 1.

[0151] Test Example 1: Fruquintinib crystal stability test

[0152] In order to investigate the storage stability of the fruquintinib crystalline form α, fruquintinib crystalline form α (after grinding) prepared in Example 4 of the present application, the crystalline form I and crystalline form III disclosed in CN106604919B, and the crystalline form C disclosed in CN105777722A, the samples were placed under stability conditions of 25°C / RH60% and 40°C / RH75% for 2 months and 6 months to investigate their crystalline stability. The results are shown in Table 5 below:

[0153] Table 5 Stability test of Fruquintinib Form α, Form C and Form III

[0154] Stability test results:

[0155] As shown in Figure 4 (after 2 months) and Figure 5 (after 6 months), Fruquintinib Form α has good crystal stability under the conditions investigated;

[0156] As shown in Figure 5-2 (after 6 months), the fruquintinib crystal form α has good crystal stability under the conditions studied after grinding.

[0157] Test Example 2: Stability test of Fruquintinib crystal form α and the crystal form disclosed in CN106604919B in water

[0158] The fruquintinib crystalline form α prepared in Example 4 of the present application, the crystalline forms I, II, III, VII, IV and VIII disclosed in CN106604919B, and the crystalline form C disclosed in CN105777722A were suspended in water and stirred at different temperatures for 5 h and 24 h, and the solids were filtered for XRD characterization. The results are shown in Table 6 below:

[0159] Table 6 Stability test of Fruquintinib Form α, each crystal form in CN106604919B and Form C in water

[0160] The experimental results show that in water, the crystal form α of furiquintinib has better crystal stability than the crystal form I, crystal form II, crystal form III, crystal form VII, crystal form IV, crystal form VIII and crystal form C.

[0161] Fruquintinib hydrate and its crystalline form α have good stability in water, providing new options for the preparation of pharmaceuticals. They can be used in a wider range of pharmaceutical preparation processes, such as wet granulation, helping to improve the controllability and safety of drug quality.

[0162] Unless otherwise defined, each technical and scientific term used herein has the same meaning as that generally understood by those of ordinary skill in the art to which the present disclosure belongs. For the purpose of description and disclosure, all patents, patent applications and other publications are expressly incorporated herein by reference. These publications are provided only because they are disclosed earlier than the filing date of the present application. All statements about the dates of these documents or the statements about the contents of these documents are based on information available to the applicant and do not constitute any recognition of the correctness of the dates of these documents or the contents of these documents. Moreover, any reference to these publications in this document does not constitute an acknowledgment that the publication has become a part of the common general knowledge in this area in any country.

[0163] Those skilled in the art will recognize that the scope of the present application is not limited to the various specific implementation modes and examples described above, but that various modifications, replacements, or recombinations can be made without departing from the spirit of the present application, which all fall within the scope of protection of the present application.

Claims

1. A furiquintinib hydrate, characterized in that: The hydrate structural formula is shown in the following formula (II): Wherein, n is 0.5 to 3; Preferably, n is 0.5, 1, 2, 3; Preferably, the hydrate is furiquintinib trihydrate.

2. The furiquintinib hydrate according to claim 1, characterized in that The hydrate is a crystalline form, and its X-ray powder diffraction pattern has characteristic peaks 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°; Preferably, the X-ray powder diffraction pattern of the hydrate crystalline form 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°; Preferably, the X-ray powder diffraction pattern of the hydrate crystalline 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°; Preferably, the X-ray powder diffraction pattern of the hydrate crystalline form has characteristic peaks at 2θ angles of 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 X-ray powder diffraction pattern of the hydrate crystalline 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°, 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, the X-ray powder diffraction pattern of the hydrate crystal form at 2θ angle is 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°, 22 There are characteristic peaks at .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 X-ray powder diffraction pattern of the hydrate crystalline form 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°; Preferably, the X-ray powder diffraction pattern of the hydrate crystal form at 2θ angle is 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°, 20.423±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°; Preferably, the X-ray powder diffraction pattern of the hydrate crystal form is substantially as shown in FIG1 .

3. The furiquintinib hydrate according to claim 1, characterized in that The hydrate is a crystalline form, and its X-ray powder diffraction pattern at 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. There are characteristic peaks at 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°; Preferably, the X-ray powder diffraction pattern of the hydrate crystal form is shown in Figure 1-2; Preferably, the X-ray powder diffraction pattern of the hydrate crystal form is shown in Figures 1-3.

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

5. The furiquintinib hydrate according to any one of claims 1 to 3, characterized in that The hydrate is a crystalline form, the crystalline form is a triclinic system, the space group is P-1 (No. 2), and the molecular weight is 447.44 g·mol -1 , Z' is 1, and the unit cell parameters are α=89.10(6)°,β=94.56(10)°,γ=97.09(18)°,unit cell volume 6. A crystalline form α of furiquintinib, characterized in that: The X-ray powder diffraction spectrum of the crystal form has characteristic peaks 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°; Preferably, the X-ray powder 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°; Preferably, the X-ray powder 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°, 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 X-ray powder diffraction pattern of the crystalline form α has characteristic peaks at 2θ angles of 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 X-ray powder 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°; Preferably, the X-ray powder diffraction pattern of the crystalline form α at 2θ angle is 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°, 22. There are characteristic peaks at 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 X-ray powder 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°; Preferably, the X-ray powder diffraction pattern of the crystalline form α at 2θ angle is 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°, 20.423±0.2°, There are characteristic peaks at 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 X-ray powder diffraction pattern of the crystalline form α is substantially as shown in FIG1 .

7. A crystalline form α of furiquintinib according to claim 6, characterized in that: The DSC spectrum of the crystalline form α has endothermic peaks at 95.23±5°C and 245.71±5°C; Preferably, the DSC spectrum of the crystalline form α is substantially as shown in FIG2 ; Preferably, the TGA spectrum of the crystalline form α is substantially as shown in FIG3 ; 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%.

8. A crystalline form α of fruquintinib according to claim 6 or 7, characterized in that: The crystalline form α is furiquintinib trihydrate.

9. A method for preparing the hydrate according to any one of claims 1 to 5 or the crystal form α according to any one of claims 5 to 8, comprising: Fruquintinib and additives are mixed in solvent A and crystallized; The preferred method comprises: mixing furiquintinib and additives in solvent A, dissolving by ultrasonication, and standing for crystallization; Preferably, the temperature of the ultrasonic dissolution process is 10-25°C; Preferably, in the ultrasonic dissolution process, the ultrasonic treatment time is 5 to 24 hours, preferably 12 hours; Preferably, during the static crystallization process, the crystallization temperature is 0 to 10° C., preferably 5° C.; Preferably, the standing crystallization process has a standing time of 1 to 10 days, preferably 5 days; Preferably, the additive is a polyol; Preferably, the polyol is a sugar alcohol; Preferably, the polyol is selected from one or more of xylitol, mannitol, sorbitol, isomalt and maltitol; Preferably, the polyol is xylitol; Preferably, the solvent A is an ether solvent; Preferably, the ether solvent is selected from one or more of tetrahydrofuran, diethyl ether, propylene glycol methyl ether, methyl tert-butyl ether, isopropyl ether and 1,4-dioxane; Preferably, the ether solvent is tetrahydrofuran; Preferably, the mass ratio of the furquintinib to the additive is 5 to 20:1, preferably 10:1; Preferably, the mass volume ratio of furiquintinib to solvent A is 1:50-100, preferably 1:62; Preferably, after standing and crystallizing, the obtained solid is collected and stored under the protection of an inert gas; Preferably, the storage temperature is 5 to 10°C; Preferably, the inert gas is nitrogen, argon or helium; preferably nitrogen.

10. A method for preparing the hydrate according to any one of claims 1 to 5 or the crystal form α according to any one of claims 5 to 8, comprising: (1) mixing furiquintinib in solvent B and heating to dissolve; (2) adding seed crystals of the hydrate or its crystal form or the crystal form α to perform crystallization; Preferably, the heating to dissolve is heating to reflux temperature to dissolve; Preferably, in the step (1), the mass ratio of the furiquintinib to the solvent B is 1:3-40; Preferably, in the step (1), the mass ratio of the furquintinib to the solvent B is 1:3-10; preferably 1:4.1; Preferably, the solvent B is a mixed solvent of water and an ether solvent; the mass ratio of water to the ether solvent is preferably 1:1-9, more preferably 1:3.1; Preferably, the ether solvent in the solvent B is selected from one or more of tetrahydrofuran, diethyl ether, propylene glycol methyl ether, methyl tert-butyl ether, isopropyl ether and 1,4-dioxane; Preferably, the ether solvent in the solvent B is tetrahydrofuran; Preferably, the amount of the seed crystals is 1 to 20% of the mass fraction of the amount of furiquintinib fed in step (1); preferably 5%; Preferably, the step (2) specifically comprises: adding the seed crystals, cooling, stirring and suspending for crystallization; Preferably, the step (2) specifically comprises: adding the seed crystals, cooling to 0-10° C., stirring and suspending for crystallization for 12-48 hours; Preferably, the step (2) specifically comprises: adding the seed crystals, cooling by 5°C, stirring and suspending for crystallization for 24 hours.

Images