Solid form of quinazoline derivative and preparation method thereof

Abstract

The invention discloses a solid form of a quinazoline derivative and a preparation method thereof. The invention provides a crystal form of a compound as shown in a formula II, in which X is an organic solvent, water or a combination thereof, and n is all numerical values between 0 and 1; the organic solvent is selected from trifluoroethanol, an ether solvent and a combination thereof; wherein the ether solvent is selected from methyl tert-butyl ether, ethylene glycol dimethyl ether and tetrahydrofuran; the crystal form is a crystal form XT-1-I, a crystal form XT-1-II, a crystal form XT-1-III or a crystal form XT-1-IV. The crystal form XT-1-I provided by the invention has good mechanical stability and physical and chemical stability, and has better solubility and purification effect.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical chemistry, and particularly relates to a solid form of a quinazoline derivative and a preparation method thereof. BACKGROUND

[0002] Fruquintinib is a small molecule quinazoline vascular inhibitor developed by Hengrui Medicine (Shanghai) Co., Ltd., and its main target is VEGFR kinase family (VEGFR1, 2 and 3). It is suitable for patients with metastatic colorectal cancer who have previously received fluorouracil, oxaliplatin and irinotecan-based chemotherapy, and have previously received or are not suitable for receiving anti-vascular endothelial growth factor (VEGF) therapy and anti-epidermal growth factor receptor (EGFR) therapy (RAS wild type). Its chemical name is: 6-((6,7-dimethoxyquinazoline-4-yl)oxy)-N,2-dimethylbenzofuran-3-formamide, and the molecular structure formula is shown as formula (I):

[0003]

[0004] At present, only patent WO2016037550A1 discloses the free form crystal form I, crystal form II, crystal form III, crystal form IV, crystal form VII and crystal form VIII of Fruquintinib. It is disclosed in the patent text that crystal form II is a semi-ethanol compound, crystal form IV is an acetic acid compound, and crystal form VIII is a dioxane compound, and the above crystal forms are not suitable for medicinal use. The present inventors repeated the preparation method of example 34 in patent WO2016037550A1, successfully obtained crystal form III and characterized its properties, and the results showed that the solubility of formula I compound in tetrahydrofuran / water system was very poor, and the solvent volume multiple reached more than 90 times. With the expansion of production scale, the industrialization cost is greatly increased. The grinding stability of crystal form III is poor, and under the condition of ethanol wet grinding, it is converted into crystal form I mixed crystal. Most importantly, crystal form III has poor crystal stability at high temperature, and is converted into crystal form I mixed crystal, so crystal form III does not have medicinal prospects. In addition, the present inventors repeatedly prepared the preparation method of example 42 in patent WO2016037550A1, only obtained crystal form I or crystal form III, and failed to successfully prepare crystal form VII, and the results showed that crystal form VII does not have reproducibility.

[0005] Patent WO2016037550A1 protects the pharmaceutical crystal form I, and the patent text discloses that the crystal form I maintains the physical and chemical stability under high temperature, high humidity and light conditions, but the solubility of the crystal form I is poor, and the particle size greatly affects the dissolution rate of the preparation product in the preparation patent WO2020098795A1. It is well known that the polymorphism of drugs is an important factor affecting the safety and effectiveness of drugs, and different crystal forms of the same drug may have significant differences in appearance, solubility, melting point, dissolution rate, biological effectiveness, etc., thereby affecting the stability, bioavailability and efficacy of the drug. This phenomenon is particularly evident in poorly soluble solid preparations and non-true solution preparations (such as tablets, capsules, oral suspensions, etc.). Therefore, it is imperative to develop a crystalline form of the compound of formula I with high solubility and good physical and chemical stability. SUMMARY

[0006] In view of the defects of the existing fuqi qini crystal form, the present application provides a fuqi qini crystal form and a preparation method thereof. The crystal form XT-1-I has good mechanical stability and physical and chemical stability, and has better solubility and purification effect.

[0007] The present application solves the above technical problems through the following technical solutions.

[0008] The present application provides a crystal form of a compound as shown in formula II,

[0009]

[0010] wherein X is an organic solvent, water or a combination thereof, and n is all numbers between 0 and 1;

[0011] The organic solvent is selected from trifluoroethanol, ether solvent and a combination thereof; wherein the ether solvent is selected from methyl tert-butyl ether, ethylene glycol dimethyl ether and tetrahydrofuran; and the crystal form is selected from the group consisting of crystal form XT-1-I, crystal form XT-1-II, crystal form XT-1-III and crystal form XT-1-IV;

[0012] The crystal form XT-1-I uses Cu-Kα radiation, and the X-ray powder diffraction pattern expressed in 2θ has diffraction peaks at the following positions: 9.9±0.2°, 10.7±0.2°, 11.8±0.2°, 13.1±0.2° and 14.5±0.2°;

[0013] The crystal form XT-1-II uses Cu-Kα radiation, and the X-ray powder diffraction pattern expressed in 2θ has diffraction peaks at the following positions: 9.8±0.2°, 10.7±0.2°, 11.8±0.2°, 13.0±0.2°, 14.4±0.2°, 19.1±0.2°, 22.5±0.2° and 23.7±0.2°;

[0014] The crystalline Form XT-1-III has an X-ray powder diffraction pattern, expressed in terms of 2-theta using Cu-Kalpharadiation, having diffraction peaks at 9.8±0.2°, 10.7±0.2°, 11.7±0.2°, 13.0±0.2°, 14.4±0.2°, 14.9±0.2°, 22.5±0.2°, 23.7±0.2°, 25.4±0.2° and 26.5±0.2°;

[0015] The crystalline Form XT-1-IV has an X-ray powder diffraction pattern, expressed in terms of 2-theta using Cu-Kalpharadiation, having diffraction peaks at 9.8±0.2°, 10.7±0.2°, 11.8±0.2°, 13.1±0.2°, 14.4±0.2°, 14.9±0.2°, 18.7±0.2°, 19.2±0.2° and 22.5±0.2°.

[0016] In a certain embodiment, the crystalline Form XT-1-I has an X-ray powder diffraction pattern, expressed in terms of 2-theta using Cu-Kalpharadiation, further having one or more of the following additional diffraction peaks: 9.3±0.2°, 15.0±0.2°, 18.5±0.2°, 18.8±0.2°, 19.2±0.2°, 21.6±0.2°, 22.6±0.2°, 23.8±0.2° and 26.2±0.2°.

[0017] In a certain embodiment, the crystalline Form XT-1-I has an X-ray powder diffraction pattern, expressed in terms of 2-theta using Cu-Kalpharadiation, having diffraction peaks at 9.3±0.2°, 9.9±0.2°, 10.7±0.2°, 11.8±0.2°, 13.1±0.2°, 14.5±0.2°, 15.0±0.2°, 18.5±0.2°, 18.8±0.2°, 19.2±0.2°, 21.6±0.2°, 22.6±0.2°, 23.8±0.2° and 26.2±0.2°.

[0018] In a certain embodiment, the crystalline Form XT-1-I has an X-ray powder diffraction pattern, expressed in terms of 2-theta using Cu-Kalpharadiation, further having one or more of the following additional diffraction peaks: 3.7±0.2°, 11.2±0.2°, 17.6±0.2°, 24.6±0.2°, 25.5±0.2°, 27.0±0.2°, 27.5±0.2°, 28.3±0.2°, 28.7±0.2°, 29.3±0.2°, 30.7±0.2°, 31.6±0.2° and 32.6±0.2°.

[0019] In an embodiment, the crystalline Form XT-1-I has an X-ray powder diffraction pattern, using Cu-Ka radiation, as shown in the following table:

[0020] Diffractogram in X-ray powder Relative intensity [%] Diffractogram in X-ray powder Relative intensity [%] 3.7 6.1 22.6 15.0 9.3 9.3 23.8 8.8 9.9 23.9 24.6 4.1 10.7 26.3 25.5 6.1 11.2 7.1 26.2 8.6 11.8 76.5 27.0 3.6 13.1 100.0 27.5 3.1 14.5 42.7 28.3 4.0 15.0 16.5 28.7 3.1 17.6 5.8 29.3 2.8 18.5 15.5 30.7 2.3 18.8 14.2 31.6 3.3 19.2 16.3 32.6 2.1 21.6 9.0 - - .

[0021] In an embodiment, the crystalline Form XT-1-I has an X-ray powder diffraction pattern, using Cu-Ka radiation, as shown in the following table: Figure 1

[0022] In an embodiment, the crystalline Form XT-1-I has a differential scanning calorimetry curve (DSC) with an endothermic peak at 207.0 °C ± 3 °C, which is a dehydration peak.

[0023] In an embodiment, the crystalline Form XT-1-I has a differential scanning calorimetry curve (DSC) with an endothermic peak at 246.9 °C ± 3 °C peak; for example, a heat of fusion of 144.32 J / g.

[0024] In an embodiment, the crystalline Form XT-1-I has a differential scanning calorimetry curve (DSC) with an endothermic peak at 246.9 °C ± 3 °C peak; for example, a heat of fusion of 144.32 J / g. Figure 2

[0025] In an embodiment, the crystalline Form XT-1-I has a thermogravimetric analysis curve (TGA) with a weight loss of 0.15% ± 0.01% from 195 °C ± 3 °C to 245 °C ± 1 °C.

[0026] In an embodiment, the crystalline Form XT-1-I has a thermogravimetric analysis curve (TGA) with a weight loss of 0.15% ± 0.01% from 195 °C ± 3 °C to 245 °C ± 1 °C. Figure 3

[0027] In an embodiment, the crystalline Form XT-1-I has a nuclear magnetic resonance detection result showing no solvent residue.

[0028] In an embodiment, the crystalline Form XT-1-I has a nuclear magnetic resonance hydrogen spectrum as shown in the following table: Figure 4

[0029] In an embodiment, the crystalline Form XT-1-I has a nuclear magnetic resonance hydrogen spectrum as shown in the following table:

[0030] In an embodiment, the crystalline Form XT-1-I has a nuclear magnetic resonance hydrogen spectrum as shown in the following table:

[0031] In an embodiment, the crystalline Form XT-1-I has a nuclear magnetic resonance hydrogen spectrum as shown in the following table:

[0032] ​​​​The present application also provides a preparation method of the crystalline form XT-1-I, which comprises the following steps: mixing fuqiqini with trifluoroethanol, adding into a solvent, filtering, and drying to obtain the crystalline form XT-1-I; the solvent is water or a mixed solvent of an alcohol solvent and water.

[0033] Preferably, the alcohol solvent is one or a combination of methanol and isopropanol.

[0034] More preferably, the volume ratio of the trifluoroethanol and the solvent is 1:5-1:20, for example, 1:5-1:10.

[0035] In a certain scheme, the preparation method comprises the following steps: mixing fuqiqini with trifluoroethanol, dissolving at 60-70°C, filtering, adding dropwise into a mixed solvent of methanol and water at 0-5°C, stirring, filtering, and drying at 50-60°C to obtain the crystalline form XT-1-I.

[0036] In a certain scheme, the crystalline form XT-1-II has an X-ray powder diffraction pattern further comprising one or more peaks at 2-theta expressed in degrees at 9.3±0.2°, 14.9±0.2°, 18.4±0.2°, 18.7±0.2°, 21.5±0.2°, 22.8±0.2°, 23.9±0.2°, 25.4±0.2°, 26.1±0.2° and 26.5±0.2° using Cu-Kα radiation.

[0037] In a certain scheme, the crystalline form XT-1-II has an X-ray powder diffraction pattern further comprising one or more peaks at 2-theta expressed in degrees at 9.3±0.2°, 14.9±0.2°, 18.4±0.2°, 18.7±0.2°, 21.5±0.2°, 22.8±0.2°, 23.9±0.2°, 25.4±0.2°, 26.1±0.2° and 26.5±0.2° using Cu-Kα radiation.

[0038] In a certain scheme, the crystalline form XT-1-II has an X-ray powder diffraction pattern further comprising one or more peaks at 2-theta expressed in degrees at 9.3±0.2°, 14.9±0.2°, 18.4±0.2°, 18.7±0.2°, 21.5±0.2°, 22.8±0.2°, 23.9±0.2°, 25.4±0.2°, 26.1±0.2° and 26.5±0.2° using Cu-Kα radiation.

[0039] In one embodiment, the crystal form XT-1-II, using Cu-Kα radiation, exhibits the diffraction peaks shown in the table below in its X-ray powder diffraction pattern expressed in 2θ:

[0040] Diffractogram in X-ray powder Relative intensity [%] Diffractogram in X-ray powder Relative intensity [%] 3.7 15.6 22.5 18.5 9.3 12.0 22.8 14.5 9.8 26.6 23.7 18.8 10.7 28.1 23.9 11.3 11.1 8.5 24.6 10.0 11.8 77.4 25.4 15.9 13.0 100.0 26.1 14.1 14.4 44.9 26.5 15.5 14.9 16.7 27.0 8.8 17.5 8.7 27.6 7.2 18.4 17.2 28.2 7.9 18.7 16.6 28.8 6.3 19.1 19.7 31.5 5.8 21.5 11.8 33.6 3.9 .

[0041] In one embodiment, the crystal form XT-1-II is subjected to Cu-Kα radiation, and the X-ray powder diffraction pattern, expressed in 2θ, is essentially as follows: Figure 5 As shown.

[0042] In one embodiment, the differential scanning calorimetry (DSC) curve of the crystal form XT-1-II has an endothermic peak at 201.8℃±3℃, which is a desolvation peak.

[0043] In one embodiment, the differential scanning calorimetry (DSC) curve of the crystal form XT-1-II has an endothermic peak at a peak of 244.8℃±3℃; for example, the heat of fusion is 149.98J / g.

[0044] In one embodiment, the differential scanning calorimetry curve of the crystal form XT-1-II is essentially as follows: Figure 6 As shown.

[0045] In one embodiment, the thermogravimetric analysis (TGA) curve of the crystal form XT-1-II showed a weight loss of 2.6% ± 0.1% when heated from 180℃ ± 3℃ to 240℃ ± 1℃.

[0046] In one particular scheme, the thermogravimetric analysis curve of the crystal form XT-1-II is basically as follows: Figure 7 As shown.

[0047] In one embodiment, the NMR results of the crystal form XT-1-II showed that it contained 0.05 equivalents of methyl tert-butyl ether and 0.05 equivalents of trifluoroethanol.

[0048] In one embodiment, the 1H NMR spectrum of the crystalline form XT-1-II is essentially as follows: Figure 8 As shown.

[0049] In one embodiment, in the crystal form XT-1-II, X is trifluoroethanol-methyl tert-butyl ether; preferably, the content ratio of trifluoroethanol to methyl tert-butyl ether is 1:1.

[0050] In one embodiment, in the crystal form XT-1-II, n is 0.05.

[0051] In one embodiment, in the crystal form XT-1-II, X is trifluoroethanol-methyl tert-butyl ether, and n is 0.05.

[0052] The present application also provides a preparation method of the crystal form XT-1-II, which comprises the following steps: mixing fuqiqini with a mixed solvent of trifluoroethanol and water, adding into an ether solvent, filtering, drying to obtain the crystal form XT-1-II; adding the crystal form XT-1-I into the ether solvent;

[0053] Preferably, the ether solvent is methyl tert-butyl ether;

[0054] More preferably, the volume ratio of the mixed solvent to the ether solvent is 1:4-1:10, for example, 1:4-1:7;

[0055] More preferably, the volume ratio of the trifluoroethanol to the water is 10:1.

[0056] In a certain scheme, the preparation method comprises the following steps: mixing fuqiqini with a mixed solvent (10 / 1, V / V) of trifluoroethanol and water, filtering, adding the crystal form XT-1-I into a methyl tert-butyl ether solution at 0-5 ℃, adding dropwise the mixed solvent after dissolving fuqiqini, stirring, filtering, and drying at 40-50 ℃ to obtain the crystal form XT-1-II.

[0057] In a certain scheme, the X-ray powder diffraction pattern of the crystal form XT-1-III using Cu-Kα radiation, expressed by 2θ angle, further has diffraction peaks at one or more of the following positions: 18.4±0.2°, 18.7±0.2°, 19.1±0.2°, 21.5±0.2°, 22.8±0.2°, 23.9±0.2°, 24.6±0.2°, 26.1±0.2°, 26.9±0.2°, 27.5±0.2° and 28.2±0.2°.

[0058] In a certain scheme, the X-ray powder diffraction pattern of the crystal form XT-1-III using Cu-Kα radiation, expressed by 2θ angle, further has diffraction peaks at one or more of the following positions: 18.4±0.2°, 18.7±0.2°, 19.1±0.2°, 21.5±0.2°, 22.8±0.2°, 23.9±0.2°, 24.6±0.2°, 26.1±0.2°, 26.9±0.2°, 27.5±0.2° and 28.2±0.2°.

[0059] In one aspect, the crystalline Form XT-1-III has an X-ray powder diffraction pattern, using Cu-Ka radiation, further comprising one or more of the following peaks, in terms of 2 theta (°) values: 3.7±0.2°, 9.3±0.2°, 11.1±0.2°, 17.5±0.2°, 28.7±0.2°, 29.5±0.2°, 31.5±0.2°, 32.0±0.2°, 32.5±0.2°, 33.4±0.2°, 33.7±0.2°, 37.9±0.2°, and 38.9±0.2°.

[0060] In one version, the crystalline form XT-1-III has an X-ray powder diffractogram in 2 theta using Cu-Ka radiation with the following table the indicated diffraction peaks:

[0061] Diffractogram in X-ray powder Relative intensity [%] Diffractogram in X-ray powder Relative intensity [%] 3.7 6.3 23.9 11.1 9.3 7.3 24.6 11.0 9.8 19.5 25.4 20.5 10.7 22.0 26.1 18.1 11.1 7.3 26.5 20.4 11.7 69.9 26.9 9.7 13.0 100.0 27.5 8.6 14.4 45.7 28.2 8.2 14.9 21.1 28.7 6.0 17.5 7.4 29.5 4.0 18.4 14.1 31.5 7.3 18.7 15.6 32.0 4.0 19.1 17.2 32.5 4.5 21.5 11.9 33.4 3.6 22.5 25.4 33.7 4.4 22.8 15.4 37.9 3.6 23.7 22.6 38.9 3.5 .

[0062] In one aspect, the crystalline Form XT-1-III has an X-ray powder diffraction pattern, using Cu-Ka radiation, substantially as shown in Figure 9 .

[0063] In one aspect, the crystalline Form XT-1-III has a differential scanning calorimetry curve (DSC) with an endothermic peak at 196.1 °C ± 3 °C peak value, which is a desolvation peak.

[0064] In one aspect, the crystalline Form XT-1-III has a differential scanning calorimetry curve (DSC) with an endothermic peak at 244.8 °C ± 3 °C peak value; for example, a heat of fusion of 135.42 J / g.

[0065] In one aspect, the crystalline Form XT-1-III has a differential scanning calorimetry curve substantially as shown in Figure 10 .

[0066] In one aspect, the crystalline Form XT-1-III has a thermogravimetric analysis curve (TGA) with a weight loss of 1.7% ± 0.1% from 190 °C ± 3 °C to 245 °C ± 1 °C.

[0067] In one aspect, the crystalline Form XT-1-III has a thermogravimetric analysis curve substantially as shown in Figure 11 .

[0068] In one aspect, the crystalline Form XT-1-III has a nuclear magnetic resonance detection showing 0.1 equivalent of tetrahydrofuran.

[0069] In one aspect, the crystalline Form XT-1-III has a nuclear magnetic resonance hydrogen spectrum substantially as shown in Figure 12 .

[0070] In one aspect, the crystalline Form XT-1-III, the X is tetrahydrofuran.

[0071] In a certain embodiment, in the crystalline form XT-1-III, the n is 0.1.

[0072] In a certain embodiment, in the crystalline form XT-1-III, the X is tetrahydrofuran, and the n is 0.1.

[0073] The present application also provides a preparation method of the crystalline form XT-1-III as described above, which comprises the following steps: mixing fuqiqini with a mixed solvent of tetrahydrofuran and water, filtering, adding the crystalline form XT-1-I as described above, and concentrating to obtain the crystalline form XT-1-III.

[0074] Preferably, the volume ratio of tetrahydrofuran to water is 50:1.

[0075] More preferably, the concentration is under reduced pressure at 30-50°C.

[0076] In a certain embodiment, the crystalline form XT-1-IV has an X-ray powder diffraction pattern further comprising one or more peaks at 11.2±0.2°, 17.5±0.2°, 18.4±0.2°, 21.5±0.2°, 22.8±0.2°, 23.7±0.2°, 25.4±0.2°, 26.1±0.2°, 26.3±0.2° and 26.5±0.2°, when measured using Cu-Kα radiation at an angle 2θ.

[0077] In a certain embodiment, the crystalline form XT-1-IV has an X-ray powder diffraction pattern further comprising one or more peaks at 11.2±0.2°, 17.5±0.2°, 18.4±0.2°, 21.5±0.2°, 22.8±0.2°, 23.7±0.2°, 25.4±0.2°, 26.1±0.2°, 26.3±0.2° and 26.5±0.2°, when measured using Cu-Kα radiation at an angle 2θ.

[0078] In a certain embodiment, the X-ray powder diffraction pattern of the crystalline form XT-1-IV, using Cu-Ka radiation, expressed in degrees 2-theta further comprises one or more peaks at 3.7 ± 0.2°, 9.3 ± 0.2°, 24.0 ± 0.2°, 24.6 ± 0.2°, 27.0 ± 0.2°, 27.6 ± 0.2°, 27.9 ± 0.2°, 28.2 ± 0.2°, 28.8 ± 0.2°, 31.5 ± 0.2°, 32.5 ± 0.2°, 33.7 ± 0.2°, 37.9 ± 0.2°, and 38.9 ± 0.2°.

[0079] In a certain embodiment, the X-ray powder diffraction pattern of the crystalline form XT-1-IV, using Cu-Ka radiation, expressed in degrees 2-theta further comprises one or more peaks at 3.7 ± 0.2°, 9.3 ± 0.2°, 24.0 ± 0.2°, 24.6 ± 0.2°, 27.0 ± 0.2°, 27.6 ± 0.2°, 27.9 ± 0.2°, 28.2 ± 0.2°, 28.8 ± 0.2°, 31.5 ± 0.2°, 32.5 ± 0.2°, 33.7 ± 0.2°, 37.9 ± 0.2°, and 38.9 ± 0.2°.

[0080]

[0081] .

[0082] In a certain embodiment, the X-ray powder diffraction pattern of the crystalline form XT-1-IV, using Cu-Ka radiation, expressed in degrees 2-theta further comprises one or more peaks at 3.7 ± 0.2°, 9.3 ± 0.2°, 24.0 ± 0.2°, 24.6 ± 0.2°, 27.0 ± 0.2°, 27.6 ± 0.2°, 27.9 ± 0.2°, 28.2 ± 0.2°, 28.8 ± 0.2°, 31.5 ± 0.2°, 32.5 ± 0.2°, 33.7 ± 0.2°, 37.9 ± 0.2°, and 38.9 ± 0.2°. Figure 13

[0083] In a certain embodiment, the nuclear magnetic detection of the crystalline form XT-1-IV shows that it contains 0.05 equivalent of ethylene glycol dimethyl ether.

[0084] In a certain embodiment, the nuclear magnetic hydrogen spectrum of the crystalline form XT-1-IV is substantially as shown in Figure 6. Figure 14

[0085] In a certain embodiment, the X of the crystalline form XT-1-IV is ethylene glycol dimethyl ether.

[0086] In a certain embodiment, the n of the crystalline form XT-1-IV is 0.05.

[0087] In a certain embodiment, the X of the crystalline form XT-1-IV is ethylene glycol dimethyl ether, and the n is 0.05.

[0088] The present application also provides a preparation method of the crystalline form XT-1-IV as described above, which comprises the following steps: mixing fuqiqini with a mixed solvent of ethylene glycol dimethyl ether and water, filtering, adding the crystalline form XT-1-I as described above, and concentrating to obtain the crystalline form XT-1-IV.

[0089] Preferably, the volume ratio of the ethylene glycol dimethyl ether to water is 10:1.

[0090] More preferably, the concentration is a concentration under reduced pressure at 30-50°C.

[0091] ​​In one embodiment, n is all values between 0 and 1, but n is not 0.

[0092] The fuqiutini in the preparation method is selected from any solid form other than the crystal form of the present application, including but not limited to one or a combination of two or more of free form crystal form I, free form crystal form III, free form other crystal form described in the prior art, or a solvent complex of fuqiutini.

[0093] On the basis of not violating the common sense of the art, the above-mentioned preferred conditions can be combined arbitrarily, i.e. to obtain each preferred example of the present application.

[0094] The reagents and raw materials used in the present application are commercially available.

[0095] The positive progress effect of the present application is that:

[0096] 1) The crystal form XT-1-I of the present application has good mechanical stability. The crystal form does not change after dry grinding and wet grinding with ethanol of the raw material drug of the crystal form XT-1-I. During the preparation process, the raw material often needs to be ground and crushed or granulated by dry method or wet method, and good physical stability can reduce the risk of decrease in crystallinity and crystal transformation of the raw material drug during the process.

[0097] 2) The crystal form XT-1-I of the present application has good physicochemical stability. The crystal form does not change when the raw material drug of the crystal form XT-1-I is placed at 40℃ / 75%RH under open and closed conditions for at least 1 month, and the purity remains basically unchanged during storage. It is shown that the crystal form XT-1-I has good stability under accelerated conditions, which is conducive to avoiding the changes in drug dissolution rate, bioavailability and toxicity caused by changes in crystal form or impurities, and has great practical significance for ensuring the efficacy and safety of the drug.

[0098] 3) Compared with the prior art, the crystal form XT-1-I of the present application has more optimal solubility, especially under the condition of pH 1.0, the solubility is more than 1.5 times of the prior art. Fuqiutini is a poorly water-soluble drug, belonging to BCS IV, i.e. a drug with low solubility and low permeability. Such drugs are not easy to release and absorb in the human body. The crystal form XT-1-I provided by the present application has higher solubility, which is conducive to improving the absorption of the drug in the human body.

[0099] 4) Compared with the prior art, the crystal form XT-1-I of the present application has more optimal purification effect. BRIEF DESCRIPTION OF DRAWINGS

[0100] Figure 1 The XRPD pattern of the crystal form XT-1-I obtained in Example 1 is shown in Figure 1.

[0101] Figure 2 The DSC pattern of the crystal form XT-1-I obtained in Example 1 is shown in Figure 2.

[0102] Figure 3 TGA pattern of crystalline form XT-1-I obtained in Example 1;

[0103] Figure 4 TGA pattern of crystalline form XT-1-I obtained in Example 1; 1 H NMR pattern;

[0104] Figure 5 XRPD pattern of crystalline form XT-1-II obtained in Example 3;

[0105] Figure 6 DSC pattern of crystalline form XT-1-II obtained in Example 3;

[0106] Figure 7 TGA pattern of crystalline form XT-1-II obtained in Example 3;

[0107] Figure 8 TGA pattern of crystalline form XT-1-II obtained in Example 3; 1 H NMR pattern;

[0108] Figure 9 XRPD pattern of crystalline form XT-1-III obtained in Example 4;

[0109] Figure 10 DSC pattern of crystalline form XT-1-III obtained in Example 4;

[0110] Figure 11 TGA pattern of crystalline form XT-1-III obtained in Example 4;

[0111] Figure 12 TGA pattern of crystalline form XT-1-III obtained in Example 4; 1 H NMR pattern;

[0112] Figure 13 XRPD pattern of crystalline form XT-1-IV obtained in Example 5;

[0113] Figure 14 TGA pattern of crystalline form XT-1-IV obtained in Example 5; 1 H NMR pattern;

[0114] Figure 15 XRPD pattern of patent crystalline form I obtained in Preparation 1. DETAILED DESCRIPTION

[0115] The application will be further described in the following by way of examples, but the application is not intended to be limited to the examples described. The experimental methods in the following examples, for which no specific conditions are indicated, are carried out according to conventional methods and conditions, or according to the instructions of the commercial suppliers.

[0116] The drying mentioned in the present application can adopt vacuum drying, air blowing drying, normal pressure drying, hygroscopic drying and the like, and the drying temperature is sufficient to remove the low-boiling-point substances such as solvents and water adsorbed by the solid without causing changes in the structure and physical and chemical properties of the dried material.

[0117] The method for separating the solid from the liquid mentioned in the present application includes but is not limited to centrifugation, normal pressure filtration, reduced pressure filtration, hot filtration and the like, and a person skilled in the art can adopt a conventional solid-liquid separation method according to specific needs.

[0118] The powder X-ray diffraction pattern of the present application is collected on a Bruker D8 advance powder X-ray diffractometer, and the specific method parameters are as follows:

[0119] X-ray reflection parameters: Cu, Kα

[0120] Voltage: 40 kV

[0121] Current: 40 mA

[0122] Scan range: from 3.0 to 40.0 degrees

[0123] Step size: 0.02 degrees

[0124] Scan rate: 0.2 seconds per step

[0125] Soller slit: 2.5 degrees

[0126] Emission slit: 0.6 mm

[0127] The differential scanning calorimetry (DSC) pattern mentioned in the present application is collected on a TA DSC 25 in the United States, and the method parameters of the differential scanning calorimetry (DSC) mentioned in the present application are as follows:

[0128] Measurement temperature range: 30-300℃

[0129] Temperature rise rate: 10℃ / min

[0130] Nitrogen flow rate: 50 mL / min

[0131] Protective atmosphere: 100-200 mL / min

[0132] The thermogravimetric analysis (TGA) pattern mentioned in the present application is collected on a platinum gold TGA 8000, and the method parameters of the thermogravimetric analysis (TGA) mentioned in the present application are as follows:

[0133] Measurement temperature range: room temperature-350℃

[0134] Temperature rise rate: 10℃ / min

[0135] Nitrogen flow rate: 50 mL / min

[0136] Protective atmosphere: 100-200 mL / min

[0137] The specific parameters of the chemical purity determination method (HPLC) described in this invention are shown in Table 1:

[0138] Table 1

[0139]

[0140] 1H NMR (1H NMR) spectrum 1 H NMR was collected from a Bruker Avance II 400MHz instrument. 5–10 mg of sample was weighed and dissolved in about 0.5 mL of deuterated reagent in the NMR sample tube for detection.

[0141] The KF measurement results were obtained from a Mettler Toledo Karl Fischer moisture analyzer C30S, and the specific method is as follows:

[0142] Titration mode: Cubic furnace coulometric method

[0143] Furnace temperature: 220℃

[0144] Speed: 45%

[0145] Mixing time: 60s

[0146] The solvent residue determination results are from an Agilent 7890B, and the specific method is as follows:

[0147] Chromatographic column: DB-624, 30m, 0.53mm, 3μm

[0148] Inlet temperature: 200℃

[0149] Detector temperature: 250℃

[0150] Flow rate: 2 mL / min

[0151] Hydrogen flow rate: 30 mL / min

[0152] Airflow rate: 300 mL / min

[0153] Temperature program: Initially set at 45℃, hold for 5 minutes, then increase to 240℃ at a rate of 10℃ / min, hold for 3 minutes.

[0154] Headspace parameters: headspace temperature 110℃; equilibration time 20 min; injection time 0.5 min.

[0155] Example 1: Preparation method of crystal form XT-1-I

[0156] Weigh 30 mg of fruquintinib solid into 0.3 mL of trifluoroethanol, heat to approximately 70 °C to dissolve completely, and filter. Pre-cool 3 mL of methanol / water (1 / 1, V / V) to approximately 0 °C, add dropwise to the dissolved fruquintinib trifluoroethanol solution, incubate in an ice-water bath with stirring for 1 hour, and then filter. Dry the wet product under vacuum at 60 °C for approximately 16 hours to obtain crystal form XT-1-I.

[0157] Its X-ray powder diffraction pattern is basically as follows Figure 1 As shown;

[0158] Its DSC spectrum is as follows Figure 2 As shown: An endothermic peak appears near 207.0℃, which is a dehydration peak; an endothermic peak appears near 245.9℃, which is a melting endothermic peak.

[0159] Its TGA spectrum is as follows Figure 3 As shown, heating from 195℃ to 245℃ results in a weight loss of approximately 0.15%, which is basically consistent with the KF test results.

[0160] That 1 H NMR spectrum as follows Figure 4 As shown: There is no obvious solvent residue on the spectrum.

[0161] The Karl Fischer moisture analyzer showed that it contained approximately 0.14% water, or 0.03 equivalents, which is basically consistent with the TGA results.

[0162] Example 2: Preparation method of crystal form XT-1-I

[0163] Weigh 1.3 g of fruquintinib solid into 13 mL of trifluoroethanol, heat to approximately 70 °C to dissolve completely, and filter. Pre-cool 130 mL of methanol / water (1 / 1, V / V) to approximately 0 °C, then add an appropriate amount of the XT-1-I crystal seed prepared in Example 1, stir to disperse, and then dropwise add the dissolved fruquintinib trifluoroethanol solution. Maintain the mixture in an ice-water bath with stirring for 1 hour, then filter. Dry the wet product under vacuum at 60 °C for approximately 3 days to obtain the XT-1-I solid. Characterization results were consistent with those of Example 1.

[0164] Example 3: Preparation method of crystal form XT-1-II

[0165] Weigh 2g of fruquintinib solid into 30mL of trifluoroethanol / purified water (10 / 1, V / V), dissolve, and filter. Pre-cool 120mL of methyl tert-butyl ether to approximately 0°C, then add an appropriate amount of the XT-1-I crystal seed prepared in Example 1. After stirring and dispersing, dropwise add the dissolved trifluoroethanol / water solution of fruquintinib. Stir in an ice-water bath for approximately 0.5 hours, then filter. Dry the wet product under vacuum at 50°C for approximately 17 hours to obtain the XT-1-II solid, which is a trifluoroethanol-methyl tert-butyl ether compound.

[0166] its X-ray powder diffraction pattern is substantially as shown in Figure 5 ;

[0167] its DSC pattern is shown in Figure 6 : an endothermic peak appears at about 201.8°C, which is a desolvation peak, and an endothermic peak appears at about 244.8°C, which is a melting endothermic peak;

[0168] its TGA pattern is shown in Figure 7 : from 180°C to 240°C, it has a weight loss of about 2.6%, which is basically consistent with the GC test result;

[0169] its 1 its H NMR spectrum is shown in Figure 8 : containing 0.05 equivalent of methyl tert-butyl ether and 0.05 equivalent of trifluoroethanol;

[0170] its gas chromatography test result confirms that it contains about 1.2%, 0.05 equivalent of methyl tert-butyl ether and 1.3%, 0.05 equivalent of trifluoroethanol, which is basically consistent with the TGA test result.

[0171] Example 4: Preparation method of crystal form XT-1-III

[0172] 0.5 g of fuqi qini solid was weighed in 100 mL of tetrahydrofuran / purified water (50 / 1, V / V), filtered after dissolving, and then a proper amount of crystal seed of crystal form XT-1-I prepared in Example 1 was added. After concentration under reduced pressure in a water bath at about 40°C, the crystal form XT-1-III solid, which is a tetrahydrofuran complex, was obtained after drying.

[0173] its X-ray powder diffraction pattern is substantially as shown in Figure 9 ;

[0174] its DSC pattern is shown in Figure 10 : an endothermic peak appears at about 196.1°C, which is a desolvation peak, and an endothermic peak appears at about 244.8°C, which is a melting endothermic peak;

[0175] its TGA pattern is shown in Figure 11 : from 190°C to 245°C, it has a weight loss of about 1.7%, which is consistent with the NMR calculation result;

[0176] its 1 its H NMR spectrum is shown in Figure 12 : containing 0.1 equivalent of tetrahydrofuran.

[0177] Example 5: Preparation method of crystal form XT-1-IV

[0178] Weigh 0.03 g of solid form of Fruquidini into 10 mL of ethylene glycol dimethyl ether / purified water (10 / 1, V / V), filter after dissolving, then add a proper amount of crystal seed of crystal form XT-1-I prepared in Example 1, concentrate under reduced pressure in a water bath at about 40℃, and dry to obtain the solid form of crystal form XT-1-IV, which is an ethylene glycol dimethyl ether compound.

[0179] The X-ray powder diffraction pattern thereof is substantially as shown in Figure 13

[0180] The X-ray powder diffraction pattern thereof is substantially as shown in 1 The H NMR spectrum is as shown in Figure 14

[0181] Preparation Example 1: Preparation of Fruquidini crystal form I

[0182] The solid form of Fruquidini is prepared according to the method described in Example 18 of patent document WO2016037550A1.

[0183] The X-ray powder diffraction pattern thereof is substantially as shown in Figure 15 The solid form of Fruquidini prepared according to the method described in Example of patent document WO2016037550A1 is crystal form I.

[0184] Test Example 1: Mechanical stability test

[0185] The crystal form XT-1-I prepared in Example 1, the crystal form XT-1-II prepared in Example 3, and the sample of prior art crystal form I are manually ground or 1-2 drops of solvent are added dropwise, and after being sufficiently wetted, they are manually ground for 5 min to simulate the stability of the crystal form in the dry granulation and wet granulation processes. The test results are shown in Table 2.

[0186] Table 2: Grinding stability data

[0187]

[0188]

[0189] Experimental results: Crystal form I has a large static electricity under dry grinding conditions, which is not conducive to sample collection, while the crystallinity of crystal form XT-1-I and crystal form XT-1-II does not change significantly after grinding, indicating that crystal form XT-1-I and crystal form XT-1-II have good mechanical stability.

[0190] Test Example 2: Solid-state stability

[0191] ​​About 30-40 mg of the crystal form XT-1-I prepared in Example 1, the crystal form XT-1-II prepared in Example 3 and the sample of the prior art crystal form I were weighed respectively and spread in glass bottles, which were open or closed, and placed at 60°C, 25°C / 92.5% RH, 30°C / 65% RH and 40°C / 75% RH respectively to investigate the physical and chemical stability at different time points, and the results are shown in Table 3.

[0192] Table 3 Stability data

[0193]

[0194] The experimental results show that the crystal form and purity of the crystal form XT-1-I do not change obviously under the conditions of high temperature, high humidity, 30°C / 65% RH and 40°C / 75% RH, the purity of the crystal form XT-1-II decreases slightly under the condition of 40°C / 75% RH and open, but the crystal form remains stable under each condition. The crystal form I remains stable under each condition, but the purity decreases slightly under the condition of high temperature. Therefore, compared with the prior art, the crystal form XT-1-I has better stability under severe conditions and can also maintain good stability under long-term and accelerated conditions.

[0195] Test Example 3: Solubility test

[0196] About 10 mg of the crystal form XT-1-I prepared in Example 1, the crystal form XT-1-II prepared in Example 3 and the prior art crystal form I were weighed and placed in 5 mL of pH 1.0 or pH 2.0 hydrochloric acid solution to prepare a suspension with an initial concentration of 2 mg / mL, and three replicates were prepared for each medium at each sampling time point. The samples were continuously shaken at 37°C, sampled after 2 hours, and the content in the saturated solution was determined by high performance liquid chromatography (HPLC), and the results are shown in Table 4.

[0197] Table 4 Solubility data

[0198]

[0199] The experimental results show that the solubility of the crystal form XT-1-I and the crystal form XT-1-II is similar to that of the prior art crystal form I under the condition of pH 2.0, but under the condition of pH 1.0, the solubility of the crystal form XT-1-II is slightly larger than that of the prior art crystal form I, about 1.2 times that of the prior art crystal form I. The crystal form XT-1-I has higher solubility than the crystal form XT-1-II, about 1.5 times that of the prior art crystal form I.

[0200] Test Example 4: Purification effect of the crystal form XT-1-I

[0201] The crystal form XT-1-I of the present application and the prior art crystal form I were prepared by using the same starting material of Example 1. The chemical purity of the starting material, the crystal form XT-1-I of the present application and the prior art crystal form I were determined by HPLC, and the test results are shown in Table 5.

[0202] Table 5 Purity test data

[0203] Crystalline form Chemical purity Purity improvement Starting material 97.43％ - Crystalline form XT-1-I 99.86％ 2.43％ Crystalline form XT-1-II 99.15％ 1.72％ Crystalline form I 98.79％ 1.36％

[0204] The experimental results show that the purity of the crystal form XT-1-I and XT-1-II is higher than that of the prior art crystal form I, and the purification effect of the crystal form XT-1-I and XT-1-II is better, especially the crystal form XT-1-I, the purity is increased by 2.43%.

[0205] The above shows and describes the basic principles and main features of the present application and the advantages of the present application. Those skilled in the art should understand that the present application is not limited to the above examples, and the above examples and descriptions in the specification are only to illustrate the principles of the present application. Without departing from the spirit and scope of the present application, various changes and improvements can be made to the present application, and these changes and improvements all fall within the scope of the present application.

Claims

1. A crystal form of a compound as shown in Formula II, characterized in that, Where X is an organic solvent, water, or a combination thereof, and n is any value between 0 and 1; The organic solvent is selected from trifluoroethanol, ether solvents, and combinations thereof; wherein the ether solvent is selected from methyl tert-butyl ether, ethylene glycol dimethyl ether, and tetrahydrofuran; the crystal form is crystal form XT-1-I, crystal form XT-1-II, crystal form XT-1-III, or crystal form XT-1-IV. The crystal form XT-1-I, when subjected to Cu-Kα radiation, exhibits X-ray powder diffraction patterns at the following positions, represented by 2θ: 9.9±0.2°, 10.7±0.2°, 11.8±0.2°, 13.1±0.2°, and 14.5±0.2°. The crystal form XT-1-II, when subjected to Cu-Kα radiation, exhibits X-ray powder diffraction peaks at the following positions in its 2θ X-ray powder diffraction pattern: 9.8±0.2°, 10.7±0.2°, 11.8±0.2°, 13.0±0.2°, 14.4±0.2°, 19.1±0.2°, 22.5±0.2°, and 23.7±0.2°. The XT-1-III crystal form, when subjected to Cu-Kα radiation, exhibits diffraction peaks at the following positions in its 2θ X-ray powder diffraction pattern: 9.8±0.2°, 10.7±0.2°, 11.7±0.2°, 13.0±0.2°, 14.4±0.2°, 14.9±0.2°, 22.5±0.2°, 23.7±0.2°, 25.4±0.2°, and 26.5±0.2°. The crystal form XT-1-IV, when subjected to Cu-Kα radiation, exhibits X-ray powder diffraction patterns (denoted as 2θ) with diffraction peaks at the following positions: 9.8±0.2°, 10.7±0.2°, 11.8±0.2°, 13.1±0.2°, 14.4±0.2°, 14.9±0.2°, 18.7±0.2°, 19.2±0.2°, and 22.5±0.2°.

2. The crystal form as described in claim 1, characterized in that, The crystal form XT-1-I satisfies one or more of the following conditions: (1) The crystal form XT-1-I, when subjected to Cu-Kα radiation, has an X-ray powder diffraction pattern expressed in 2θ angles, which further shows diffraction peaks at one or more of the following positions: 9.3±0.2°, 15.0±0.2°, 18.5±0.2°, 18.8±0.2°, 19.2±0.2°, 21.6±0.2°, 22.6±0.2°, 23.8±0.2° and 26.2±0.2°; (2) The differential scanning calorimetry curve of the crystal form XT-1-I has an endothermic peak at 207.0℃±3℃, which is a dehydration peak; (3) The differential scanning calorimetry curve of the crystal form XT-1-I has an endothermic peak at the peak value of 246.9℃±3℃; (4) The thermogravimetric analysis curve of the crystal form XT-1-I shows a weight loss of 0.15% ± 0.01% when heated from 195℃ ± 3℃ to 245℃ ± 1℃; (5) The NMR results of the crystal form XT-1-I showed no solvent residue; (6) In the crystal form XT-1-I, X is water; (7) In the crystal form XT-1-I, n is 0.

03.

3. The crystal form as described in claim 1, characterized in that, The crystal form XT-1-I satisfies one or more of the following conditions: (1) The crystal form XT-1-I, when subjected to Cu-Kα radiation, exhibits X-ray powder diffraction patterns (denoted as 2θ) with diffraction peaks at the following positions: 9.3±0.2°, 9.9±0.2°, 10.7±0.2°, 11.8±0.2°, 13.1±0.2°, 14.5±0.2°, 15.0±0.2°, 18.5±0.2°, 18.8±0.2°, 19.2±0.2°, 21.6±0.2°, 22.6±0.2°, 23.8±0.2°, and 26.2±0.2°. (2) The differential scanning calorimetry curve of the crystal form XT-1-I is basically shown in Figure 2; (3) The thermogravimetric analysis curve of the crystal form XT-1-I is basically shown in Figure 3; (4) The basic 1H NMR spectrum of the crystal form XT-1-I is shown in Figure 4; (5) X is water and n is 0.

03.

4. The crystal form as described in claim 1, characterized in that, The XT-1-I crystal form, when subjected to Cu-Kα radiation, exhibits an X-ray powder diffraction pattern (denoted as 2θ) with diffraction peaks at one or more of the following locations: 3.7±0.2°, 11.2±0.2°, 17.6±0.2°, 24.6±0.2°, 25.5±0.2°, 27.0±0.2°, 27.5±0.2°, 28.3±0.2°, 28.7±0.2°, 29.3±0.2°, 30.7±0.2°, 31.6±0.2°, and 32.6±0.2°. Preferably, the crystal form XT-1-I, when subjected to Cu-Kα radiation, exhibits the following diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ, as shown in the table below: ； More preferably, the crystal form XT-1-I is subjected to Cu-Kα radiation, and the X-ray powder diffraction pattern represented by 2θ is basically as shown in Figure 1.

5. A method for preparing the crystal form XT-1-I as described in any one of claims 1 to 4, characterized in that, The process includes the following steps: mixing fruquintinib with trifluoroethanol, adding the mixture to a solvent, filtering, and drying to obtain the crystal form XT-1-I; the solvent is water or a mixture of an alcohol solvent and water; Preferably, the alcohol solvent is one or a combination of methanol, isopropanol; More preferably, the volume ratio of the trifluoroethanol to the solvent is 1:5 to 1:20, for example, 1:5 to 1:10; More preferably, the preparation method includes the following steps: fruquintinib is mixed with trifluoroethanol, dissolved at 60-70°C, filtered, added dropwise to a mixed solvent of methanol and water at 0-5°C, stirred, filtered, and dried at 50-60°C to obtain crystal form XT-1-I.

6. The crystal form as described in claim 1, characterized in that, The crystal form XT-1-II satisfies one or more of the following conditions: (1) The crystal form XT-1-II, when subjected to Cu-Kα radiation, has an X-ray powder diffraction pattern expressed in 2θ angles, which further shows diffraction peaks at one or more of the following positions: 9.3±0.2°, 14.9±0.2°, 18.4±0.2°, 18.7±0.2°, 21.5±0.2°, 22.8±0.2°, 23.9±0.2°, 25.4±0.2°, 26.1±0.2° and 26.5±0.2°; (2) The differential scanning calorimetry curve of the crystal form XT-1-II has an endothermic peak at 201.8℃±3℃, which is a desolvation peak; (3) The differential scanning calorimetry curve of the crystal form XT-1-II has an endothermic peak at the peak value of 244.8℃±3℃; (4) The thermogravimetric analysis curve of the crystal form XT-1-II shows a weight loss of 2.6% ± 0.1% when heated from 180℃ ± 3℃ to 240℃ ± 1℃; (5) In the crystal form XT-1-II, X is trifluoroethanol-methyl tert-butyl ether; (6) In the crystal form XT-1-II, n is 0.

05.

7. The crystal form as described in claim 1, characterized in that, The crystal form XT-1-II satisfies one or more of the following conditions: (1) The crystal form XT-1-II, when subjected to Cu-Kα radiation, exhibits diffraction peaks at the following positions in its X-ray powder diffraction pattern, expressed as 2θ: 9.3±0.2°, 9.8±0.2°, 10.7±0.2°, 11.8±0.2°, 13.0±0.2°, 14.4±0.2°, 14.9±0.2°, 18.4±0.2°, 18.7±0.2°, 19.1±0.2°, 21.5±0.2°, 22.5±0.2°, 22.8±0.2°, 23.7±0.2°, 23.9±0.2°, 25.4±0.2°, 26.1±0.2°, and 26.5±0.2°. (2) The differential scanning calorimetry curve of the crystal form XT-1-II is basically shown in Figure 6; (3) The thermogravimetric analysis curve of the crystal form XT-1-II is basically shown in Figure 7; (4) The basic 1H NMR spectrum of the crystal form XT-1-II is shown in Figure 8; (5) The content ratio of the trifluoroethanol to the methyl tert-butyl ether is 1:1; (6) X is trifluoroethanol-methyl tert-butyl ether, and n is 0.

05.

8. The crystal form as described in claim 1, characterized in that, The XT-1-II crystal form, when subjected to Cu-Kα radiation, exhibits an X-ray powder diffraction pattern at an angle of 2θ, further showing diffraction peaks at one or more of the following locations: 3.7±0.2°, 11.1±0.2°, 17.5±0.2°, 24.6±0.2°, 27.0±0.2°, 27.6±0.2°, 28.2±0.2°, 28.8±0.2°, 31.5±0.2°, and 33.6±0.2°. Preferably, the crystal form XT-1-II, when subjected to Cu-Kα radiation, exhibits the following diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ, as shown in the table below: More preferably, the crystal form XT-1-II is subjected to Cu-Kα radiation, and the X-ray powder diffraction pattern represented by 2θ is basically as shown in Figure 5.

9. A method for preparing the crystal form XT-1-II as described in claim 1 or any one of claims 6 to 8, characterized in that, The process includes the following steps: mixing fruquintinib with a mixed solvent of trifluoroethanol and water, adding the mixture to an ether solvent, filtering, and drying to obtain the crystal form XT-1-II; adding the crystal form XT-1-I as described in any one of claims 1-4 or the crystal form XT-1-I prepared by the preparation method described in claim 5 to the ether solvent; Preferably, the ether solvent is methyl tert-butyl ether; More preferably, the volume ratio of the mixed solvent to the ether solvent is 1:4 to 1:10, for example, 1:4 to 1:7; More preferably, the volume ratio of the trifluoroethanol to the water is 10:1; Most preferably, the preparation method includes the following steps: fruquintinib is dissolved in a mixed solvent of trifluoroethanol and water (10 / 1, V / V), filtered, and crystal form XT-1-I is added to a methyl tert-butyl ether solution at 0-5°C. Then, the mixed solvent after fruquintinib dissolution is added dropwise, stirred, filtered, and dried at 40-50°C to obtain crystal form XT-1-II.

10. The crystal form as described in claim 1, characterized in that, The crystal form XT-1-III satisfies one or more of the following conditions: (1) The crystal form XT-1-III, when subjected to Cu-Kα radiation, has an X-ray powder diffraction pattern expressed in 2θ angles, which further shows diffraction peaks at one or more of the following positions: 18.4±0.2°, 18.7±0.2°, 19.1±0.2°, 21.5±0.2°, 22.8±0.2°, 23.9±0.2°, 24.6±0.2°, 26.1±0.2°, 26.9±0.2°, 27.5±0.2°, and 28.2±0.2°; (2) The differential scanning calorimetry curve of the crystal form XT-1-III has an endothermic peak at the peak of 196.1℃±3℃, which is a desolvation peak; (3) The differential scanning calorimetry curve of the crystal form XT-1-III has an endothermic peak at the peak value of 244.8℃±3℃; (4) The thermogravimetric analysis curve of the crystal form XT-1-III shows a weight loss of 1.7% ± 0.1% when heated from 190℃ ± 3℃ to 245℃ ± 1℃; (5) In the crystal form XT-1-III, X is tetrahydrofuran; (6) In the crystal form XT-1-III, n is 0.

1.

11. The crystal form as described in claim 1, characterized in that, The crystal form XT-1-III satisfies one or more of the following conditions: (1) The crystal form XT-1-III, when subjected to Cu-Kα radiation, exhibits diffraction peaks at the following positions in its X-ray powder diffraction pattern, expressed as 2θ: 9.8±0.2°, 10.7±0.2°, 11.7±0.2°, 13.0±0.2°, 14.4±0.2°, 14.9±0.2°, 18.4±0.2°, 18.7±0.2°, 19.1±0.2°, 21.5±0.2°, 22.5±0.2°, 22.8±0.2°, 23.7±0.2°, 23.9±0.2°, 24.6±0.2°, 25.4±0.2°, 26.1±0.2°, 26.5±0.2°, 26.9±0.2°, 27.5±0.2°, and 28.2±0.2°. (2) The differential scanning calorimetry curve of the crystal form XT-1-III is basically shown in Figure 10; (3) The thermogravimetric analysis curve of the crystal form XT-1-III is basically shown in Figure 11; (4) The basic 1H NMR spectrum of the crystal form XT-1-III is shown in Figure 12; (5) X is tetrahydrofuran and n is 0.

1.

12. The crystal form as described in claim 1, characterized in that, The XT-1-III crystal form, when subjected to Cu-Kα radiation, exhibits an X-ray powder diffraction pattern at an angle of 2θ, further showing diffraction peaks at one or more of the following locations: 3.7±0.2°, 9.3±0.2°, 11.1±0.2°, 17.5±0.2°, 28.7±0.2°, 29.5±0.2°, 31.5±0.2°, 32.0±0.2°, 32.5±0.2°, 33.4±0.2°, 33.7±0.2°, 37.9±0.2°, and 38.9±0.2°. Preferably, the crystal form XT-1-III, when subjected to Cu-Kα radiation, exhibits the following diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ, as shown in the table below: ； More preferably, the crystal form XT-1-III is subjected to Cu-Kα radiation, and the X-ray powder diffraction pattern represented by 2θ is basically as shown in Figure 9.

13. A method for preparing crystal form XT-1-III as described in claim 1 or any one of claims 10-12, characterized in that, It includes the following steps: mixing fruquintinib with a mixed solvent of tetrahydrofuran and water, filtering, adding crystal form XT-1-I as described in any one of claims 1-4 or crystal form XT-1-I prepared by the preparation method as described in claim 5, and concentrating to obtain crystal form XT-1-III; Preferably, the volume ratio of the tetrahydrofuran to the water is 50:1; More preferably, the concentration is a vacuum concentration at 30–50°C.

14. The crystal form as described in claim 1, characterized in that, The crystal form XT-1-IV satisfies one or more of the following conditions: (1) The crystal form XT-1-IV, when subjected to Cu-Kα radiation, has an X-ray powder diffraction pattern expressed in 2θ angles, which further shows diffraction peaks at one or more of the following positions: 11.2±0.2°, 17.5±0.2°, 18.4±0.2°, 21.5±0.2°, 22.8±0.2°, 23.7±0.2°, 25.4±0.2°, 26.1±0.2°, 26.3±0.2° and 26.5±0.2°; (2) In the crystal form XT-1-IV, X is ethylene glycol dimethyl ether; (3) In the crystal form XT-1-IV, n is 0.

05.

15. The crystal form as described in claim 1, characterized in that, The crystal form XT-1-IV satisfies one or more of the following conditions: (1) The crystal form XT-1-IV, when subjected to Cu-Kα radiation, exhibits X-ray powder diffraction peaks at the following positions in 2θ: 9.8±0.2°, 10.7±0.2°, 11.2±0.2°, 11.8±0.2°, 13.1±0.2°, 14.4±0.2°, 14.9±0.2°, 17.5±0.2°, 18.4±0.2°, 18.7±0.2°, 19.2±0.2°, 21.5±0.2°, 22.5±0.2°, 22.8±0.2°, 23.7±0.2°, 25.4±0.2°, 26.1±0.2°, 26.3±0.2°, and 26.5±0.2°. (2) The basic 1H NMR spectrum of the crystal form XT-1-IV is shown in Figure 14; (3) X is ethylene glycol dimethyl ether, and n is 0.

05.

16. The crystal form as described in claim 1, characterized in that, The XT-1-IV crystal form, when subjected to Cu-Kα radiation, exhibits an X-ray powder diffraction pattern at an angle of 2θ, further showing diffraction peaks at one or more of the following locations: 3.7±0.2°, 9.3±0.2°, 24.0±0.2°, 24.6±0.2°, 27.0±0.2°, 27.6±0.2°, 27.9±0.2°, 28.2±0.2°, 28.8±0.2°, 31.5±0.2°, 32.5±0.2°, 33.7±0.2°, 37.9±0.2°, and 38.9±0.2°. Preferably, the crystal form XT-1-IV, when subjected to Cu-Kα radiation, exhibits diffraction peaks at the following positions in its X-ray powder diffraction pattern expressed as 2θ: More preferably, the crystal form XT-1-IV is subjected to Cu-Kα radiation, and the X-ray powder diffraction pattern represented by 2θ is basically as shown in Figure 13.

17. A method for preparing the crystal form XT-1-IV as described in claim 1 or any one of claims 14 to 16, characterized in that, It includes the following steps: mixing fruquintinib with a mixed solvent of ethylene glycol dimethyl ether and water, filtering, adding crystal form XT-1-I as described in any one of claims 1-4 or crystal form XT-1-I prepared by the preparation method as described in claim 5, and concentrating to obtain crystal form XT-1-IV; Preferably, the volume ratio of the ethylene glycol dimethyl ether to the water is 10:1; More preferably, the concentration is carried out under reduced pressure at 30–50°C.

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