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US-12624009-B2 - Hydrate of VEGFR inhibitor, crystal form thereof and preparation method therefor

US12624009B2US 12624009 B2US12624009 B2US 12624009B2US-12624009-B2

Abstract

A hydrate of a VEGFR inhibitor, a crystal form thereof and a preparation method therefor are provided. The VEGFR inhibitor is 6-(6,7-dimethoxyquinazolin-4-yl-oxy)-N,2-dimethylbenzofuran-3-carboxamide, and the hydrate and the crystal form thereof have good physicochemical properties, and have good flowability, solubility, stability and bioavailability, and alleviated hygroscopicity. In addition, the preparation method is simple, has good repeatability, achieves high yield, and is easy to perform and environment-friendly, and the method requires only a small amount of solvents and facilitates recycling use, thus effectively reducing the cost on reagents, and enabling easy implementation of large-scale mass production.

Inventors

  • Leixin WANG
  • Huike GU
  • Xiaochao XIAN
  • Hong Chen
  • Ying Wang

Assignees

  • CHENGDU EASTON BIOPHARMACEUTICALS CO., LTD

Dates

Publication Date
20260512
Application Date
20250630
Priority Date
20230602

Claims (20)

  1. 1 . A fruquintinib hydrate of formula (II): wherein n is 3, and the fruquintinib hydrate has an X-ray powder diffraction pattern with 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°.
  2. 2 . The fruquintinib hydrate according to claim 1 , wherein the X-ray powder diffraction pattern of the fruquintinib hydrate 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°.
  3. 3 . The fruquintinib hydrate according to claim 1 , wherein the X-ray powder diffraction pattern of the fruquintinib hydrate has characteristic peaks at 2θ angles of 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°.
  4. 4 . The fruquintinib hydrate according to claim 1 , wherein a Differential Scanning calorimetry (DSC) profile of the fruquintinib hydrate has endothermic peaks at 95.23±5° C. and 245.71±5° C.
  5. 5 . The fruquintinib hydrate according to claim 1 , wherein the fruquintinib hydrate is in a crystalline form of a triclinic crystal system, with a space group of P-1 (No. 2); a molecular weight of 447.44 g·mol −1 ; Z′ of 1; the following unit cell parameters: a=4.880(5) Å, b=11.98(2) Å, c=17.916(17) Å, a=89.10(6)°, β=94.56(10)°, and γ=97.09(18)°; and a unit cell volume of V=1036(2) Å 3 .
  6. 6 . A crystal form α of fruquintinib, wherein an X-ray powder diffraction pattern 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°.
  7. 7 . The crystal form α of fruquintinib according to claim 6 , wherein a DSC profile of the crystal form α has endothermic peaks at 95.23±5° C. and 245.71±5° C.; and/or, the crystal form α has a water content of 11.00±2.0%.
  8. 8 . A preparation method for the fruquintinib hydrate according to claim 1 , comprising: mixing fruquintinib and an additive in a solvent A and crystallizing, wherein the additive is a polyol and the solvent A is an ether solvent; or comprising (1) mixing fruquintinib in a solvent B, and heating for dissolution; and (2) adding a crystal seed of the hydrate and crystallizing, wherein the solvent B is a mixture of water and an ether solvent.
  9. 9 . A preparation method for the crystal form α according to claim 6 , comprising: mixing fruquintinib and an additive in a solvent A and crystallizing, wherein the additive is a polyol and the solvent A is an ether solvent; or comprising: (1) mixing fruquintinib in a solvent B, and heating for dissolution; and (2) adding a crystal seed of the crystal form α and crystallizing, wherein the solvent B is a mixture of water and an ether solvent.
  10. 10 . The fruquintinib hydrate according to claim 1 , wherein the X-ray powder diffraction pattern of the fruquintinib hydrate 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°.
  11. 11 . The fruquintinib hydrate according to claim 1 , wherein the X-ray powder diffraction pattern of the fruquintinib hydrate 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°.
  12. 12 . The fruquintinib hydrate according to claim 1 , wherein the X-ray powder diffraction pattern of the fruquintinib hydrate is substantially as shown in FIG. 1 A , FIG. 1 B , or FIG. 1 C .
  13. 13 . The fruquintinib hydrate according to claim 1 , wherein, the DSC profile of the fruquintinib hydrate is substantially as shown in FIG. 2 A ; and/or, a Thermogravimetric Analysis (TGA) profile of the fruquintinib hydrate is substantially as shown in FIG. 3 ; and/or, the fruquintinib hydrate has a water content of 11.00±2.0%.
  14. 14 . The fruquintinib hydrate according to claim 6 , wherein the X-ray powder diffraction pattern of the fruquintinib 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°.
  15. 15 . The fruquintinib hydrate according to claim 6 , wherein the X-ray powder diffraction pattern of the fruquintinib hydrate crystal form α has characteristic peaks at 2θ angles of 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°.
  16. 16 . The fruquintinib hydrate according to claim 6 , wherein, the X-ray powder diffraction pattern of the crystal form α is substantially as shown in FIG. 1 A ; and/or the DSC profile of the crystal form α is substantially as shown in FIG. 2 A ; and/or a TGA profile of the crystal form α is substantially as shown in FIG. 3 .
  17. 17 . A preparation method for the hydrate according to claim 8 , comprising: mixing fruquintinib and an additive in a solvent A, ultrasonically dissolving the mixture, and allowing to stand for crystallization; the additive is selected from one or more of xylitol, mannitol, sorbitol, isomaltitol, and maltitol; the solvent A is selected from one or more of tetrahydrofuran, diethyl ether, propylene glycol methyl ether, methyl tert-butyl ether, isopropyl ether, and 1,4-dioxane; and/or, fruquintinib and the additive are in a mass ratio of (5-20):1; and/or, fruquintinib and the solvent A are in a mass-to-volume ratio of 1:(50-100); and/or, the ultrasonic dissolution is performed at a temperature of 10-25° C.; and/or, the ultrasonic dissolution is performed for an ultrasonic treatment period of 5-24 h; and/or, the standing for crystallization is performed at a crystallization temperature of 0-10° C.; and/or, the standing for crystallization is performed for a standing period of 1-10 days.
  18. 18 . A preparation method for the hydrate according to claim 8 , wherein, the ether solvent in the solvent B is one or more selected from tetrahydrofuran, diethyl ether, propylene glycol methyl ether, methyl tert-butyl ether, isopropyl ether, and 1,4-dioxane; and/or, in solvent B, water and the ether solvent are in a mass ratio of 1:(1-9); and/or, the crystal seed is used in an amount that is 1-20%, of a feeding amount of fruquintinib in step (1) by mass fraction; and/or, step (2) comprises: adding the crystal seed, cooling to 0-10° C., and stirring for suspension crystallization for 12-48 h.
  19. 19 . A preparation method for the hydrate according to claim 9 , comprising: mixing fruquintinib and an additive in a solvent A, ultrasonically dissolving the mixture, and allowing to stand for crystallization; the additive is one or more selected from xylitol, mannitol, sorbitol, isomaltitol, and maltitol; the solvent A is selected from one or more of tetrahydrofuran, diethyl ether, propylene glycol methyl ether, methyl tert-butyl ether, isopropyl ether, and 1,4-dioxane; and/or, fruquintinib and the additive are in a mass ratio of (5-20):1; and/or, fruquintinib and the solvent A are in a mass-to-volume ratio of 1:(50-100); and/or, the ultrasonic dissolution is performed at a temperature of 10-25° C.; and/or, the ultrasonic dissolution is performed for an ultrasonic treatment period of 5-24 h; and/or, the standing for crystallization is performed at a crystallization temperature of 0-10° C.; and/or, the standing for crystallization is performed for a standing period of 1-10 days.
  20. 20 . A preparation method for the hydrate according to claim 9 , wherein, 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; and/or, in solvent B, water and the ether solvent are in a mass ratio of 1:(1-9); and/or, the crystal seed is used in an amount that is 1-20%, of a feeding amount of fruquintinib in step (1) by mass fraction; and/or, step (2) comprises: adding the crystal seed, cooling to 0-10° C., and stirring for suspension crystallization for 12-48 h.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS The present application is a continuation of PCT International Application No. PCT/CN2024/096724, filed on May 31, 2024, which claims the priority to the prior application with the patent application No. 202310647472.5 filed with China National Intellectual Property Administration on Jun. 2, 2023, the prior application with the patent application No. 202311552719.1 filed with China National Intellectual Property Administration on Nov. 20, 2023, and the prior application with the patent application No. 202410117086.X filed with China National Intellectual Property Administration on Jan. 26, 2024, the content of each is incorporated herein by reference in its entirety. TECHNICAL FIELD The present application relates to the field of pharmaceutical crystal forms, in particular to a hydrate of a VEGFR inhibitor, a crystal form thereof, and a preparation method therefor. BACKGROUND Fruquintinib (trade name: Elunate) is a VEGFR inhibitor developed by Hutchison Whampoa Limited for the treatment of metastatic colorectal cancer, and its original formulation Elunate was approved for marketing in China on Sep. 4, 2018. Fruquintinib has a structure represented by formula (I) below: In the prior art, CN106604919B discloses six crystal forms of fruquintinib, i.e., crystal form I, crystal form II, crystal form III, crystal form VII, crystal form IV, and crystal form VIII. The crystal forms are all anhydrates or organic solvates. No fruquintinib hydrates and crystal forms thereof with good druggability have been developed in the prior art. Therefore, there is a need to further develop a hydrate form of fruquintinib and a crystal form thereof. SUMMARY In view of the problems described above in the prior art, the present application provides a hydrate of a VEGFR inhibitor, a crystal form thereof, and a preparation method therefor. The VEGFR inhibitor is fruquintinib, with the chemical name of 6-(6,7-dimethoxyquinazolin-4-yl-oxy)-N,2-dimethylbenzofuran-3-carboxamide. In a first aspect of the present application, provided is a fruquintinib hydrate. The hydrate has a structural formula shown in formula (II) below: wherein n is 0.5-3. In some embodiments of the present application, n is 0.5, 1, 2, or 3. In some embodiments of the present application, the hydrate is a fruquintinib trihydrate. In some embodiments of the present application, provided is a crystal form of the fruquintinib hydrate, and an X-ray powder diffraction pattern of the crystal form has characteristic peaks at 20 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°. 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 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°. 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°. 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°. 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°, 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°. 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°, 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°. 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°, 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°. 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°, 9.7064±0.2°,