WO2019154273A1 - 喹啉衍生物的结晶 - Google Patents

喹啉衍生物的结晶 Download PDF

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WO2019154273A1
WO2019154273A1 PCT/CN2019/074183 CN2019074183W WO2019154273A1 WO 2019154273 A1 WO2019154273 A1 WO 2019154273A1 CN 2019074183 W CN2019074183 W CN 2019074183W WO 2019154273 A1 WO2019154273 A1 WO 2019154273A1
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crystal
compound
formula
cancer
crystals
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English (en)
French (fr)
Inventor
赵锐
李新路
刘飞
张喜全
杨铁
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Chia Tai Tianqing Pharmaceutical Group Co Ltd
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Chia Tai Tianqing Pharmaceutical Group Co Ltd
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Priority to CN202210428672.7A priority Critical patent/CN114716410A/zh
Priority to CN201980011060.4A priority patent/CN111630045A/zh
Publication of WO2019154273A1 publication Critical patent/WO2019154273A1/zh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present application relates to the field of medical technology, and relates to crystallization of a quinoline derivative, in particular to a crystal and an amorphous form of a quinoline derivative hydrate, a methanolate, a tetrahydrofuran, and a method for preparing the crystal, comprising the crystal.
  • Tyrosine kinases are a group of enzymes that catalyze the phosphorylation of protein tyrosine residues and play an important role in signal transduction in cells. They are involved in the regulation, signaling and development of normal cells, as well as in tumor cells. Proliferation, differentiation, migration and apoptosis are closely related. Many receptor tyrosine kinases are involved in tumor formation and can be divided into epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), and vascular endothelial growth factor receptor depending on their extracellular domain structure. Body (VEGFR), fibroblast growth factor receptor (FGFR), and the like.
  • EGFR epidermal growth factor receptor
  • PDGFR platelet-derived growth factor receptor
  • FGFR fibroblast growth factor receptor
  • WO2008112407 discloses in Example 24 the compound 1-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy) )methyl)cyclopropylamine and its preparation method, its structural formula is as shown in formula I:
  • VEGFR1 vascular endothelial growth factor receptor
  • VEGFR2 vascular endothelial growth factor receptor
  • VEGFR3 stem cell factor receptor
  • platelet-derived growth factor receptor vascular endothelial growth factor receptor
  • Solid drugs generally have a variety of crystal forms, such as polymorphs, solvates (hydrates), salts, and eutectic.
  • the crystal form change of the same drug usually leads to different melting points, solubility, stability, biological activity, etc., which are important factors affecting the preparation of the drug, storage stability, formulation difficulty and bioavailability.
  • a compound has multiple crystal forms, since the specific crystalline drug has specific thermodynamic properties and stability, it is important to understand the crystal form of the compound applied in each dosage form during the preparation process to ensure the production process. Apply the same form of the drug. Therefore, it is necessary to ensure that the compound is a single crystal form or a known mixture of some crystal forms.
  • Form 1 of the free base anhydrate of the compound of formula I and a process for its preparation are disclosed in WO2016179123.
  • the crystallization of an anhydrate and a dihydrate of a quinoline derivative dihydrochloride and a process for the preparation thereof are disclosed in CN201010245688.1.
  • the application provides 1-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy) A Form A crystal of cyclopropylamine (compound of formula I).
  • the present application provides 1-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy) Crystallization of methyl)cyclopropylamine (compound of formula I) methanolate.
  • the present application provides 1-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy) Crystallization of methyl)cyclopropylamine (compound of formula I) tetrahydrofuran.
  • the present application provides 1-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy) Methyl)cyclopropylamine (compound of formula I) is amorphous.
  • the application provides 1-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)
  • a Crystallization of cyclopropylamine (compound of formula I) (hereinafter referred to as type A crystal) in which Cu-K ⁇ radiation is used, and type A crystal is in the X-ray powder diffraction (XRD) pattern at the following 2 ⁇ degrees of about 9.03, 9.20 There are diffraction peaks at 11.02, 13.26, 17.08, 17.77, 18.43, 20.81, and 22.47.
  • the Form A crystal has diffraction peaks at the following 2 ⁇ degrees of about 9.03, 9.20, 11.02, 13.26, 14.96, 17.08, 17.77, 18.43, 18.64, 19.20, 19.87, 20.13, 20.81, 22.47, 24.37, 25.11. .
  • the Type A crystal is at the following 2 ⁇ degrees of about 9.03, 9.20, 11.02, 13.26, 14.96, 15.50, 15.83, 17.08, 17.77, 18.43, 18.64, 19.20, 19.87, 20.13, 20.81, 21.33, 22.47, There are diffraction peaks at 22.81, 24.37, 25.11, 26.05, 26.73, 27.80, 28.35, 29.45, and 30.58.
  • the water content is from 2.0 to 8.1%, and in some embodiments, the water content is from 4.0 to 7.2%, and in some specific embodiments, the water content is from 4.2 to 4.4%.
  • the present application provides Form A crystals of a compound of Formula I containing 1 mole of water. In some specific embodiments, Form A crystals of the compound I monohydrate of Formula I are provided.
  • thermogravimetric-micro-commercial thermogravimetric analysis (TG-DTG) pattern of Form A crystals is shown in Figure 4 with a weight loss of 4.00% and about 1 mole of water.
  • the present application provides 1-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy) Methyl)cyclopropylamine (compound of formula I) methanolate (hereinafter referred to as type B crystal) in which Cu-K ⁇ radiation is used, and type B crystal is in X-ray powder diffraction (XRD) pattern, and the following 2 ⁇ degrees are approximately There are diffraction peaks at 9.36, 10.17, 10.70, 12.47, 14.22, 16.76, 17.42, 23.34, and 23.95.
  • XRD X-ray powder diffraction
  • Form B crystal has diffraction peaks at the following 2 ⁇ degrees of about 8.69, 9.36, 10.17, 10.70, 12.47, 14.22, 16.76, 17.42, 18.15, 19.02, 20.46, 21.21, 23.34, 23.95.
  • Type B crystals are at the following 2 ⁇ degrees of about 8.69, 9.36, 10.17, 10.70, 12.47, 14.22, 15.65, 15.89, 16.76, 17.42, 18.15, 19.02, 20.46, 21.21, 21.81, 22.64, 23.34, There are diffraction peaks at 23.95, 25.11, 25.37, 26.28, 26.88, 31.03, 31.61, and 32.17.
  • the methanol content is from 3.0 to 14.0%, and in some embodiments, the methanol content is from 7.0 to 10.0%, and in some specific embodiments, the methanol content is from 7.2 to 7.4%.
  • the present application provides Form B crystals of a methanolic compound of formula I containing 1 mole of methanol.
  • Form B crystals of a compound of formula I, a methanolate are provided.
  • the present application provides 1-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy) Methyl)cyclopropylamine (compound of formula I) tetrahydrofuran (hereinafter referred to as C-form crystal) in which Cu-K ⁇ radiation is used, and C-type crystal is in the X-ray powder diffraction (XRD) pattern, and the following 2 ⁇ degrees are approximately There are diffraction peaks at 7.42, 9.79, 15.45, 18.23, and 22.48.
  • XRD X-ray powder diffraction
  • the C-type crystal has diffraction peaks at the following 2 ⁇ angles of about 7.42, 9.79, 14.90, 15.45, 18.23, 19.67, 22.48, 24.44.
  • the C-type crystals have an angle of about 7.42, 8.84, 9.79, 10.13, 10.53, 12.95, 14.90, 15.45, 16.45, 16.88, 17.79, 18.23, 19.10, 19.67, 20.34, 20.73, 21.28 at the following 2 ⁇ angles. There are diffraction peaks at 21.84, 22.48, and 24.44.
  • the tetrahydrofuran content is from 8.0 to 26.0%, and in some embodiments, the tetrahydrofuran content is from 14.8 to 20.0%, and in some specific embodiments, the tetrahydrofuran content is from 14.9 to 15.2%.
  • the present application provides a Form C crystal of a tetrahydrofuran compound of formula I containing 1 mole of tetrahydrofuran.
  • a Form C crystal of a compound of formula I, tetrahydrofuran is provided.
  • the present application provides 1-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy) Methyl)cyclopropylamine (compound of formula I) is amorphous, using Cu-K ⁇ radiation, and its typical XRD pattern is shown in FIG.
  • the present application provides a method of preparing the above-described Form A crystal, Form B crystal, Form C crystal, and amorphous form of the compound of Formula I.
  • a process for the preparation of a Form A crystal of a compound of Formula I comprising mixing a compound of Formula I with a solvent, optionally adding activated carbon, filtering, crystallization of the resulting solution, and separation of the crystals.
  • the solvent described therein is a mixture of an organic solvent and water, including but not limited to ethanol/water, ethyl acetate/water, N,N-dimethylformamide/water. It will be understood by those skilled in the art that commonly available organic solvents, unless otherwise subjected to additional water removal treatments, typically contain a certain amount of moisture, in this case also understood to be a mixture of an organic solvent and water.
  • the mass to volume ratio (m/v/v) of the compound of Formula I, organic solvent to water is from 1:7 to 15:1 to 5, preferably from 1:8 to 10:2 to 4.
  • the crystal When the crystal is separated, it may be further washed with an organic solvent such as petroleum ether, diisopropyl ether, methyl tert-butyl ether, n-heptane or n-hexane.
  • an organic solvent such as petroleum ether, diisopropyl ether, methyl tert-butyl ether, n-heptane or n-hexane.
  • the solution is cooled to a temperature of from -10 ° C to 10 ° C, preferably from -5 ° C to 0 ° C. In a particular embodiment, the temperature is 0 °C.
  • a method of preparing Form B crystals comprising mixing a compound of Formula I with a solvent, adding activated carbon as needed, filtering, and crystallization of the resulting solution to separate crystals.
  • the solvent described therein is methanol or a mixture of methanol and other organic solvents including, but not limited to, methanol, ethanol/methanol, ethyl acetate/methanol, N,N-dimethylformamide/methanol.
  • the mass to volume ratio (m/v) of the compound of the formula I to methanol is from 1:7 to 15, preferably 1:8.
  • precipitation of crystals can be promoted by a conventional method such as stirring, seeding, or standing crystallization.
  • the crystal When the crystal is separated, it may be further washed with an organic solvent such as petroleum ether, diisopropyl ether, methyl tert-butyl ether, n-heptane or n-hexane.
  • the solution is cooled to a temperature of from -10 ° C to 10 ° C, preferably from -5 ° C to 0 ° C. In a particular embodiment, the temperature is 0 °C.
  • a method of preparing a Form C crystal comprising mixing a compound of Formula I with a solvent, optionally adding activated carbon, filtering, and crystallization of the resulting solution, provides crystals.
  • the solvent described therein is tetrahydrofuran or a mixture of tetrahydrofuran and other organic solvents including, but not limited to, tetrahydrofuran, ethanol/tetrahydrofuran, ethyl acetate/tetrahydrofuran, N,N-dimethylformamide/tetrahydrofuran.
  • the mass to volume ratio (m/v) of the compound of the formula I to tetrahydrofuran is from 1:7 to 20, preferably from 1:12 to 15.
  • precipitation of crystals can be promoted by a conventional method such as stirring, seeding, or standing crystallization.
  • the crystal When the crystal is separated, it may be further washed with an organic solvent such as petroleum ether, diisopropyl ether, methyl tert-butyl ether, n-heptane or n-hexane.
  • an organic solvent such as petroleum ether, diisopropyl ether, methyl tert-butyl ether, n-heptane or n-hexane.
  • the solution is cooled to a temperature of from -10 ° C to 10 ° C, preferably from -5 ° C to 0 ° C. In a particular embodiment, the temperature is 0 °C.
  • the present application provides a crystalline composition of the above-described A-type crystal, B-type crystal, or C-type crystal.
  • the crystal composition of the type A crystal means that the type A crystal in the composition accounts for 50% or more, preferably 70% or more, more preferably 90% or more, and most preferably 95% or more, of the composition.
  • Other crystals or amorphous forms which may contain minor amounts of the compound of formula I.
  • the crystal composition of the B-form crystal means that the B-form crystal in the composition accounts for 50% or more, preferably 70% or more, more preferably 90% or more, and most preferably 95% or more, of the composition.
  • the crystal composition of the C-form crystal means that the C-form crystal in the composition accounts for 50% or more by weight of the composition, preferably 70% or more, more preferably 90% or more, and most preferably 95% or more.
  • the active substance of the present application can be administered by any route suitable for the disease to be treated, including by oral, topical (e.g., buccal, sublingual, etc.), parenteral (e.g., subcutaneous, intramuscular, intravenous, spinal, intradermal, intrathecal, etc.) ), rectal, vaginal and other routes of administration.
  • topical e.g., buccal, sublingual, etc.
  • parenteral e.g., subcutaneous, intramuscular, intravenous, spinal, intradermal, intrathecal, etc.
  • rectal e.g., vaginal and other routes of administration.
  • vaginal e.g., vaginal and other routes of administration.
  • a preferred mode of administration is oral administration.
  • the active substance of the present application can be administered in the form of a pure substance, it is usually administered in the form of a pharmaceutical composition.
  • the pharmaceutical composition of the active substance of the present application further comprises one or more pharmaceutically acceptable excipients, and may further comprise other therapeutically active ingredients, if desired. It can also be administered in combination with chemotherapy, radiation therapy, and surgery.
  • compositions suitable for oral administration include tablets, capsules, powders, granules, pills, pastes, powders, elixirs, and the like, preferably tablets and capsules.
  • the tablet may be a common tablet, a dispersible tablet, an effervescent tablet, a sustained release tablet, a controlled release tablet or an enteric coated tablet
  • the capsule may be a general capsule, a sustained release capsule, a controlled release capsule or an enteric coated capsule.
  • compositions of the present application can be prepared by conventional methods using conventional pharmaceutical excipients well known in the art.
  • Conventional pharmaceutical excipients include fillers, absorbents, wetting agents, binders, disintegrants, lubricants, and the like.
  • Fillers include starch, lactose, mannitol, microcrystalline cellulose, etc.; absorbents include calcium sulfate, calcium hydrogen phosphate, calcium carbonate, magnesium oxide, etc.; wetting agents include water, ethanol, etc.; binders include hypromellose fibers , povidone, microcrystalline cellulose, etc.; disintegrants include croscarmellose sodium, crospovidone, surfactant, low-substituted hydroxypropyl cellulose, etc.; lubricants include stearic acid Magnesium, talc, polyethylene glycol, magnesium lauryl sulfate, micronized silica gel, talc, etc.
  • Pharmaceutical excipients also include coloring agents,
  • the amount of the active substance to be used in the unit preparation for tablets and capsules for oral administration must be varied depending on the condition of the patient and the particular route of administration.
  • the unit preparation for oral administration may conveniently contain, for example, 1 mg to 100 mg of the active substance, preferably 3 mg to 30 mg of the active substance.
  • the active substance of the present application and the pharmaceutical composition thereof have the activity of inhibiting receptor tyrosine kinase and can be used for treating tumors such as liver cancer, kidney cancer, colon cancer, gastrointestinal stromal tumor, soft tissue sarcoma, gastric cancer, medullary thyroid carcinoma , esophageal squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, endometrial cancer, ovarian cancer, cervical cancer, fallopian tube cancer.
  • tumors such as liver cancer, kidney cancer, colon cancer, gastrointestinal stromal tumor, soft tissue sarcoma, gastric cancer, medullary thyroid carcinoma , esophageal squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, endometrial cancer, ovarian cancer, cervical cancer, fallopian tube cancer.
  • the diffraction spectrum obtained from the crystalline compound is often characteristic for a particular crystal, wherein the relative intensity of the band may be due to crystallization conditions, particle size, and others.
  • the advantage orientation effect produced by the difference in the measurement conditions changes. Therefore, the relative intensity of the diffraction peaks is not characteristic for the crystal to be targeted.
  • the position of the peak can be shifted due to changes in temperature during sample analysis, sample movement, or calibration of the instrument, and the measurement error of the 2 ⁇ value is usually ⁇ 0.2°. Therefore, this error should be taken into account when determining each crystal structure.
  • DSC Differential Scanning Calorimetry
  • the thermal transition temperature and melting point error is typically within about 5 ° C, usually within about 3 ° C, when we say a compound has a given DSC At the peak or melting point, this means the DSC peak or melting point ⁇ 5 °C.
  • DSC provides an auxiliary method for identifying different crystal forms. Different crystalline forms can be identified based on their different transition temperature characteristics. It should be noted that for the mixture, the DSC peak or melting point may vary over a larger range. In addition, the melting temperature is closely related to the rate of temperature increase due to decomposition during the melting of the substance.
  • the crystal prepared by the preparation has the advantages of high purity, high crystallinity, good stability, small moisture absorption, good fluidity, and easier preparation of the preparation; the present application also provides a preparation method thereof, the yield is high, and the crystallization condition is mild. Suitable for industrial production, it can better meet the needs of the pharmaceutical industry.
  • Figure 13 is a single crystal molecular structure diagram of the compound I monohydrate of the formula I
  • the X-ray powder diffraction (XRD) pattern was measured under the following conditions, instrument and model: D/Max-RA Japan Rigaku X MiniFlex II X-ray powder diffractometer; ray: monochromatic Cu-Ka ray Scanning mode: ⁇ /2 ⁇ , scanning range: 0 to 40°, voltage: 30Kv, current 15mA; detection environmental conditions: temperature: 23.9 ° C, humidity: 38.6%.
  • XRD X-ray powder diffraction
  • DSC Differential scanning calorimetry
  • Thermogravimetric analysis was carried out under the following conditions, instrument and its model: TG 209 F3 thermogravimetric analyzer; scanning rate: l0 ° C / min; scanning range: 30 ° C ⁇ 300 ° C; protective gas: nitrogen.
  • thermogravimetric (DTG) curve is a differential curve of the TG curve versus temperature. The relationship between the rate of change in weight loss of the sample and the temperature was measured under constant temperature rising conditions.
  • the moisture measurement method is Karl Fischer moisture measurement method.
  • the dynamic vapor sorption test was measured under the following conditions, instrument and model: DVS Intrinsic Dynamic Water Vapor Adsorber; temperature was 25 ° C, relative humidity range was 0-90%, and the step size was 10%.
  • the single crystal-X-ray diffraction method was measured under the following conditions, apparatus and its model: single crystal X-ray diffractometer (SC-XRD) (D8VENTURE); temperature: 173 (2) K, wavelength: 1.54178 A.
  • SC-XRD single crystal X-ray diffractometer
  • the compound of the formula I (prepared according to the method of Example 1) was 3.0 g, 24 mL of ethanol and 12 mL of purified water were added, and the mixture was heated to reflux for 30 min, then dehydrated to room temperature for 2 h, and filtered to obtain Form A crystal.
  • XRD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • TG- The DTG spectrum is shown in Figure 4 with a weight loss of 4.00% and about 1 mole of water. The moisture content was measured to be 4.35%.
  • a well-formed single crystal of the compound of formula I monohydrate can be obtained by slowly volatilizing a solution of the compound of formula I in methanol at ambient temperature.
  • the single crystal molecular structure of the A-type crystal was measured by single crystal X-ray diffraction method as shown in Fig. 13.
  • the XRD pattern obtained by fitting the single crystal data is basically the same as that of FIG. 2.
  • the compound of the formula I (prepared according to the method of Example 1) was 3.0 g, and 36 mL of tetrahydrofuran was added thereto, and the mixture was heated to reflux with stirring, filtered, and then crystallized at room temperature, and filtered to obtain crystals of type C.
  • the compound of the formula I (prepared according to the method of Example 1) was 3.0 g, 30 mL of ethanol was added, and the mixture was heated to reflux for 30 min, and then filtered, and the filtrate was crystallized to room temperature for 2 h, and filtered to obtain crystal form 1 of the compound of formula I.
  • the X-ray powder diffraction (XRD) pattern was obtained using Cu-K ⁇ radiation as shown in Fig. 1.
  • Example 3.1 The Form A crystal obtained in Example 3.1 was dried by blasting at a temperature of 120 ° C to obtain Form 1 of the compound of Formula I.
  • Example 3.1 The Form A crystal obtained in Example 3.1 was dried by blasting at a temperature of 100 ° C to obtain Form 1 of the compound of Formula I.
  • Example 3.1 and 3.2 were subjected to high performance liquid chromatography (HPLC) before and after purification, and the purity of the main component and the content of each impurity were measured by the peak area normalization method.
  • HPLC high performance liquid chromatography
  • the test results are shown in Table 1.
  • the content of the main component of the compound I was about 99.5% after the purification of the mixed solution of ethanol and water, and the content of each impurity component was significantly reduced.
  • the impurity 1 was identified by structure, and its chemical name was 4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxy-7-hydroxyquinoline.
  • Example 3.1 An appropriate amount of the compound of the formula I in Example 3.1 was placed in two vials, respectively, and added with 3 mL of water and ethanol, dissolved and supersaturated, and suspended at room temperature at 20 ° C for 12 hours and 24 hours, respectively. An appropriate amount of 1.5 ml of the suspension was taken in an hour, the suspension was centrifuged, the supernatant was discarded, and the centrifuged solid was dried at 45 ° C for 2 hours to test XRD. The results showed that the crystal form remained unchanged and was still type A crystal.
  • Example 3.1 Approximately 45 mg of the sample of Example 3.1 was weighed and added to a sample pan of a dynamic moisture adsorber (model DVS Intrinsic). Set the initial humidity of the sample chamber to 0%, dry the sample under high-purity compressed air to lose weight less than 0.002% in 1min, and then increase the relative humidity absorption to 10, 20, 30, 40, 50, 60, 70 in each step. , 80 and 90%, the equilibrium is defined as the weight change is less than 0.002% in 1min, and then under the same equilibrium conditions, the relative humidity is reduced to (desorbed) 90, 80, 70, 60, 50, 40, 30, 20, 10,0%.
  • the DVS curve (y-axis: weight-% change versus x-axis: %RH) is described in Figure 12.
  • High temperature test The temperature was 60 ° C for 10 days, and the sample was taken on the 10th day;
  • High-humidity test the temperature was 25 ° C, the relative humidity was 90 ⁇ 5% for 10 days, and the sample was taken on the 10th day;
  • Accelerated test The temperature was 40 ° C, and the relative humidity was 70 ⁇ 5% for 10 days, and the sample was taken on the 10th day.

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Abstract

本申请涉及医药领域，涉及喹啉衍生物的结晶，具体涉及喹啉衍生物水合物、甲醇化物、四氢呋喃化物的结晶和无定型物，以及所述结晶的制备方法、含所述结晶的药物组合物和在医药领域的用途。本申请还提供其制备方法，收率高，结晶条件温和，适合工业化生产，能够更好地满足制药业需求。

Description

喹啉衍生物的结晶 技术领域
本申请属于医药技术领域，涉及喹啉衍生物的结晶，具体涉及喹啉衍生物水合物、甲醇合物、四氢呋喃合物的结晶和无定型物，以及所述结晶的制备方法、含所述结晶的药物组合物和在医药领域的用途。
背景技术
酪氨酸激酶是一组催化蛋白质酪氨酸残基磷酸化的酶，在细胞内的信号转导中起着重要的作用，它参与正常细胞的调节、信号传递和发育，也与肿瘤细胞的增殖、分化、迁移和凋亡密切相关。许多受体酪氨酸激酶都与肿瘤的形成相关，根据其细胞外区域结构的不同可分为表皮生长因子受体(EGFR)、血小板衍化生长因子受体(PDGFR)、血管内皮细胞生长因子受体(VEGFR)、成纤维细胞生长因子受体(FGFR)等等。
WO2008112407在实施例24中公开了化合物1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)环丙胺及其制备方法，它的结构式如式I所示：
Figure PCTCN2019074183-appb-000001
它是一个多靶点的受体酪氨酸激酶抑制剂，能抑制血管内皮细胞生长因子受体(VEGFR1、VEGFR2/KDR和VEGFR3)、干细胞因子受体、血小板源生长因子受体等激酶活性，抑制VEGFR2介导的下游信号转导，从而抑制肿瘤新生血管生成。
固体药物一般都存在多种晶体形态，比如多晶型、溶剂合物(水合物)、盐和共晶等。而同一种药物的晶型变化通常导致化合物具有不同的熔点、溶解度、稳定性、生物活性等，这些均是影响药物制备的难易、储存稳定性、制剂难易和生物利用度等的重要因素。当化合物存在多种晶体形态时，由于特定晶型药物具有特异性的热力学性质和稳定性，因此在制备的过程中，了解在各个剂型中应用的化合物的晶型是重要的，以保证生产过程应用相同形态的药物。因此，保证化合物是单一的晶型或是一些晶型的已知混和物是必要的。
WO2016179123中公开了式I化合物游离碱无水物的晶型1及其制备方法。CN201010245688.1中公开了喹啉衍生物二盐酸盐的无水物和二水物的结晶及其制备方法。
药用化合物的新的多种晶体形态的发现提供了改善药物物理特性的机会，即扩展了物质的全部性质，从而可以更好地指导化合物及其制剂的研究，因此本申请提供的喹啉衍生物结晶及含所述结晶的药物组合物在药物的制造及其它应用中有商业价值。
发明概述
一方面，本申请提供了1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)环丙胺(式I化合物)的A型结晶。
第二方面，本申请提供了1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)环丙胺(式I化合物)甲醇合物的结晶。
第三方面，本申请提供了1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)环丙胺(式I化合物)四氢呋喃合物的结晶。
第四方面，本申请提供了1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)环丙胺(式I化合物)无定型物。
发明内容
一方面，本申请提供了1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)环丙胺(式I化合物)的结晶(以下称为A型结晶)，其中使用Cu-Kα辐射，A型结晶在X-射线粉末衍射(XRD)图谱中，在以下2θ度数约9.03,9.20,11.02,13.26,17.08,17.77,18.43,20.81,22.47处有衍射峰。
进一步典型地，所述A型结晶在以下2θ度数约为9.03,9.20,11.02,13.26,14.96,17.08,17.77,18.43,18.64,19.20,19.87,20.13,20.81,22.47,24.37,25.11处有衍射峰。
再进一步典型地，所述A型结晶在以下2θ度数约为9.03,9.20,11.02,13.26,14.96,15.50,15.83,17.08,17.77,18.43,18.64,19.20,19.87,20.13,20.81,21.33,22.47,22.81,24.37,25.11,26.05,26.73,27.80,28.35,29.45,30.58处有衍射峰。
在一些实施方案中，其水含量为2.0～8.1％，在一些实施方案中，其水含量为4.0～7.2％，在一些具体的实施方案中，其水含量为4.2～4.4％。
在一个具体的实施方案中，本申请提供了含1摩尔水的式I化合物的A型结晶。在一些具体的实施方案中，提供了式I化合物一水合物的A型结晶。
在一个具体的实施方案中，使用Cu-Kα辐射，A型结晶的典型的XRD的图谱如附图2 所示，其具有如下特征：
Figure PCTCN2019074183-appb-000002
在一个特定的实施方案中，A型结晶的热重-微商热重分析(TG-DTG)图谱如附图4所示，重量损失为4.00％，约为1摩尔的水。
第二方面，本申请提供了1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)环丙胺(式I化合物)甲醇合物(以下称为B型结晶)，其中使用Cu-Kα辐射，B型结晶在X-射线粉末衍射(XRD)图谱中，在以下2θ度数约为9.36,10.17,10.70,12.47,14.22,16.76,17.42,23.34,23.95处有衍射峰。
进一步典型地，所述B型结晶在以下2θ度数约为8.69,9.36,10.17,10.70,12.47,14.22,16.76,17.42,18.15,19.02,20.46,21.21,23.34,23.95处有衍射峰。
再进一步典型地，所述B型结晶在以下2θ度数约为8.69,9.36,10.17,10.70,12.47,14.22,15.65,15.89,16.76,17.42,18.15,19.02,20.46,21.21,21.81,22.64,23.34,23.95,25.11,25.37,26.28,26.88,31.03,31.61,32.17处有衍射峰。
在一些实施方案中，其甲醇含量为3.0～14.0％，在一些实施方案中，其甲醇含量为7.0～10.0％，在一些具体的实施方案中，其甲醇含量为7.2～7.4％。
在一个具体的实施方案中，本申请提供了含1摩尔甲醇的式I化合物甲醇合物的B型结晶。在一些具体的实施方案中，提供了式I化合物一甲醇合物的B型结晶。
在一个具体的实施方案中，使用Cu-Kα辐射，B型结晶的典型的XRD的图谱如附图5所示，其具有如下特征：
Figure PCTCN2019074183-appb-000003
第三方面，本申请提供了1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)环丙胺(式I化合物)四氢呋喃合物(以下称为C型结晶)，其中使用Cu-Kα辐射，C型结晶在X-射线粉末衍射(XRD)图谱中，在以下2θ度数约为7.42,9.79,15.45,18.23,22.48处有衍射峰。
进一步典型地，所述C型结晶在以下2θ角度数约为7.42,9.79,14.90,15.45,18.23,19.67,22.48,24.44处有衍射峰。
再进一步典型地，所述C型结晶在以下2θ角度数约为7.42,8.84,9.79,10.13,10.53,12.95,14.90,15.45,16.45,16.88,17.79,18.23,19.10,19.67,20.34,20.73,21.28,21.84,22.48,24.44处有衍射峰。
在一些实施方案中，其四氢呋喃含量为8.0～26.0％，在一些实施方案中，其四氢呋喃含量为14.8～20.0％，在一些具体的实施方案中，其四氢呋喃含量为14.9～15.2％。
在一个具体的实施方案中，本申请提供了含1摩尔四氢呋喃的式I化合物四氢呋喃合物的C型结晶。在一些具体的实施方案中，提供了式I化合物一四氢呋喃合物的C型结晶。
在一个具体的实施方案中，使用Cu-Kα辐射，C型结晶的典型的XRD的图谱如附图8所示，其具有如下特征：
Figure PCTCN2019074183-appb-000004
Figure PCTCN2019074183-appb-000005
第四方面，本申请提供了1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)环丙胺(式I化合物)无定型物，使用Cu-Kα辐射，其典型的XRD的图谱如附图11所示。
另一方面，本申请提供了上述A型结晶、B型结晶、C型结晶、式I化合物无定形物的制备方法。
在一些实施方案中，提供了一种式I化合物A型结晶的制备方法，包括将式I化合物与溶剂混合，视需要可加入活性炭，过滤，所得溶液析晶，分离得到晶体。
其中所述的溶剂为有机溶剂与水的混合物，包括但不限于乙醇/水、乙酸乙酯/水、N,N二甲基甲酰胺/水。本领域技术人员可以理解的是，通常市售的有机溶剂除非进行额外的除水处理，通常是含有一定的水分，此时也可理解为有机溶剂和水的混合物。在一些实施方案中，式I化合物、有机溶剂与水的质量体积比(m/v/v)为1:7～15:1～5，优选1:8～10:2～4。析晶时，可通过搅拌、加入晶种或者静置析晶等常规的方法促进晶体的析出。在分离晶体时可进一步用有机溶剂(例如石油醚、异丙醚、甲基叔丁基醚、正庚烷或正己烷)洗涤。在优选的实施方案中，溶液降低温度至-10℃～10℃析晶，优选为-5℃～0℃。在一个特定的实施方案中，所述的温度为0℃。
在一些实施方案中，提供了一种B型结晶的制备方法，包括将式I化合物与溶剂混合，视需要可加入活性炭，过滤，所得溶液析晶，分离得到晶体。
其中所述的溶剂为甲醇或者甲醇与其它有机溶剂的混合物，包括但不限于甲醇、乙醇/甲醇、乙酸乙酯/甲醇、N,N二甲基甲酰胺/甲醇。式I化合物与甲醇的质量体积比(m/v)为1:7～15，优选1:8。析晶时，可通过搅拌、加入晶种或者静置析晶等常规的方法促进晶体的析出。在分离晶体时可进一步用有机溶剂(例如石油醚、异丙醚、甲基叔丁基醚、正庚烷或正己烷)洗涤。在优选的实施方案中，溶液降低温度至-10℃～10℃析晶，优选为-5℃～0℃。在一个特定的实施方案中，所述的温度为0℃。
在一些实施方案中，提供了一种C型结晶的制备方法，包括将式I化合物与溶剂混合，视需要可加入活性炭，过滤，所得溶液析晶，分离得到晶体。
其中所述的溶剂为四氢呋喃或者四氢呋喃与其它有机溶剂的混合物，包括但不限于四氢呋喃、乙醇/四氢呋喃、乙酸乙酯/四氢呋喃、N,N二甲基甲酰胺/四氢呋喃。式I化合物与四氢 呋喃的质量体积比(m/v)为1:7～20，优选1:12～15。析晶时，可通过搅拌、加入晶种或者静置析晶等常规的方法促进晶体的析出。在分离晶体时可进一步用有机溶剂(例如石油醚、异丙醚、甲基叔丁基醚、正庚烷或正己烷)洗涤。在优选的实施方案中，溶液降低温度至-10℃～10℃析晶，优选为-5℃～0℃。在一个特定的实施方案中，所述的温度为0℃。
再一方面，本申请提供了上述A型结晶、B型结晶、C型结晶的结晶组合物。其中A型结晶的结晶组合物是指，组合物中A型结晶占组合物重量的50％以上，优选在70％以上，更优选在90％以上，最优选在95％以上，该组合物中可含有少量式I化合物的其它结晶或无定型物。
B型结晶的结晶组合物是指，组合物中B型结晶占组合物重量的50％以上，优选在70％以上，更优选在90％以上，最优选在95％以上，该组合物中可含有少量式I化合物的其它结晶或无定型物。
C型结晶的结晶组合物是指，组合物中C型结晶占组合物重量的50％以上，优选在70％以上，更优选在90％以上，最优选在95％以上，该组合物中可含有少量式I化合物的其它结晶或无定型物。
本申请所述的A型结晶或A型结晶的结晶组合物、B型结晶或B型结晶的结晶组合物、C型结晶或C型结晶的结晶组合物，以及式I化合物无定形物，在下文中总称为“本申请活性物质”。
本申请活性物质可以通过任何适合所治疗疾病的途径给药，包括通过口服、局部(如口腔、舌下等)、非胃肠(如皮下、肌肉、静脉内、脊髓、皮内、鞘内等)、直肠、阴道等途径给药。优选的给药方式是口服给药。
虽然本申请活性物质能够以纯物质的形式给药，但通常以药物组合物的形式给药。本申请活性物质的药物组合物还包含一种或多种药用辅料，视需要，还可包含其它治疗活性成分。也可以与化学治疗、放射治疗、外科手术这些疗法联合给药。
适合口服的药物组合物包括片剂、胶囊剂、粉剂、颗粒剂、滴丸、糊剂、散剂、酊剂等，优选片剂和胶囊剂。其中片剂可以是普通片剂、分散片、泡腾片、缓释片、控释片或肠溶片，胶囊剂可以是普通胶囊、缓释胶囊、控释胶囊或肠溶胶囊。
本申请药物组合物可使用本领域公知的常规药用辅料通过常规方法制得。常规的药用辅料包括填充剂、吸收剂、润湿剂、粘合剂、崩解剂、润滑剂等。填充剂包括淀粉、乳糖、甘露醇、微晶纤维素等；吸收剂包括硫酸钙、磷酸氢钙、碳酸钙、氧化镁等；润湿剂包括水、乙醇等；粘合剂包括羟丙甲纤维素、聚维酮、微晶纤维素等；崩解剂包括交联羧甲基纤维素 钠、交联聚维酮、表面活性剂、低取代羟丙基纤维素等；润滑剂包括硬脂酸镁、滑石粉、聚乙二醇、十二烷基硫酸镁、微粉硅胶、滑石粉等。药用辅料还包括着色剂、甜味剂等。
用于口服的片剂和胶囊剂的单位制剂中本申请活性物质的用量必需根据患者的治疗情况和具体给药途径改变。例如，供口服给药的单位制剂可方便的含有例如1mg～100mg的活性物质，优选包含3mg～30mg的活性物质。
本申请活性物质及其药物组合物具有抑制受体酪氨酸激酶的活性，可用于治疗肿瘤，如肝癌、肾癌、结肠癌、胃肠道间质瘤、软组织肉瘤、胃癌、甲状腺髓样癌、食管鳞状细胞癌、小细胞肺癌、非小细胞肺癌、子宫内膜癌、卵巢癌、宫颈癌、输卵管癌等。
需要说明的是，在X-射线衍射光谱(XRD)中，由结晶化合物得到的衍射谱图对于特定的晶体往往是特征性的，其中谱带的相对强度可能会因为结晶条件、粒径和其它测定条件的差异而产生的优势取向效果而变化。因此，衍射峰的相对强度对所针对的晶体并非是特征性的，判断是否与已知的晶体相同时，更应该注意的是峰的相对位置而不是它们的相对强度。此外，对任何给定的晶体而言，峰的位置可能存在轻微误差，这在结晶学领域中也是公知的。例如，由于分析样品时温度的变化、样品移动或仪器的标定等，峰的位置可以移动，2θ值的测定误差通常为±0.2°。因此，在确定每种晶体结构时，应该将此误差考虑在内。在XRD图谱中通常用2θ角或晶面距d表示峰位置，两者之间具有简单的换算关系：d＝λ/2sinθ，其中d代表晶面距，λ代表入射X射线的波长，θ为衍射角。
示差扫描量热法(DSC)测定当结晶由于其晶体结构发生变化或晶体熔融而吸收或释放热时的转变温度。对于同种化合物的同种晶型，在连续的分析中，热转变温度和熔点误差典型的在约5℃之内，通常在约3℃之内，当我们说一个化合物具有一给定的DSC峰或熔点时，这是指该DSC峰或熔点±5℃。DSC提供了一种辨别不同晶型的辅助方法。不同的结晶形态可根据其不同的转变温度特征而加以识别。需要指出的是对于混合物而言，其DSC峰或熔点可能会在更大的范围内变动。此外，由于在物质熔化的过程中伴有分解，因此熔化温度与升温速率密切相关。
本申请制备得到的结晶，具有纯度高、结晶度高、稳定性好、吸湿度小、流动性好、更易于制备制剂等优点；本申请还提供其制备方法，收率高，结晶条件温和，适合工业化生产，能够更好地满足制药业需求。
附图说明
图1 式I化合物晶型1的XRD图谱
图2 A型结晶的XRD图谱
图3 A型结晶的DSC图谱
图4 A型结晶的TG-DTG图谱
图5 B型结晶的XRD图谱
图6 B型结晶的DSC图谱
图7 B型结晶的TG-DTG图谱
图8 C型结晶的XRD图谱
图9 C型结晶的DSC图谱
图10 C型结晶的TG-DTG图谱
图11 式I化合物无定型物的XRD图谱
图12 A型结晶的DVS曲线
图13 式I化合物一水合物的单晶分子结构图
具体实施方式
以具体的实施例说明本申请的技术方案，但本申请的保护范围不限于下述的实施例范围。所采用的试剂均为市售产品。
采集数据所用的仪器及方法：
X-射线粉末衍射(XRD)图谱在下述条件下测定，仪器及其型号：D/Max-RA日本RigakuXMiniFlex Ⅱ X-射线粉末衍射仪；射线：单色Cu-Ka射线
Figure PCTCN2019074183-appb-000006
扫描方式：θ/2θ，扫描范围：0～40°，电压：30Kv，电流15mA；检测环境条件：温度：23.9℃，湿度：38.6％。
示差扫描量热法(DSC)在下述条件下测定，扫描速率：l0℃/min；扫描范围：30℃～300℃
热重分析(TGA)在下述条件下测定，仪器及其型号：TG 209 F3热重分析仪；扫描速率：l0℃/min；扫描范围：30℃～300℃；保护气体：氮气。
微商热重(DTG)曲线是TG曲线对温度的一次微分曲线。在等速升温条件下，测定试样失重变化率与温度的关系。水分测定方法为卡尔费休水分测定法。
动态蒸汽吸附试验(DVS)在下述条件下测定，仪器及其型号：DVS Intrinsic动态水蒸汽吸附仪；温度为25℃，相对湿度范围是0-90％，步长为10％。
单晶-X射线衍射法在下述条件下测定，仪器及其型号：单晶X射线衍射仪(SC-XRD)(D8VENTURE)；温度：173(2)K，波长：1.54178A。
实施例1 1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)环丙胺(式I化合物)的制备
Figure PCTCN2019074183-appb-000007
于2L玻璃反应瓶中依次投入中间体1(其化学名称为(1-(((4-(4-氟-2-甲基-1H-吲哚-5-基)氧基-6-甲氧基喹啉-7-基)氧基)甲基)环丙基)氨基甲酸苄酯)100g，10％钯碳30g，甲酸铵50g及甲醇800ml。于45-55℃保温反应，TLC跟踪显示反应完全，过滤，滤饼用少量甲醇洗涤，滤液减压浓缩至干，加入乙酸乙酯及2mol/L的盐酸，搅拌10min后，静置10min后，分出水相，水相用4N氢氧化钠调PH＝12以上，有大量固体析出，甩滤，水洗至中性后，甩滤，得到标题所述化合物粗品。
实施例2式I化合物无定型物的制备
按照WO2008112407实施例24中公开的制备方法，1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)环丙胺由(1-(((4-(4-氟-2-甲基-1H-吲哚-5-基)氧基-6-甲氧基喹啉-7-基)氧基)甲基)环丙基)氨基甲酸苄酯(中间体1)按照如下2.1和2.2的方法制备得到。
2.1取100mg中间体1和Pd/C(10％，40mg)加入乙醇(20ml)中，并且在50psi下加氢12小时。将反应液以硅藻土过滤，蒸发得到式I化合物无定型物，得到其X射线粉末衍射(XRD)图谱如附图11所示。
2.2取100mg中间体1、乙酸(1ml)和33％氢溴酸/乙酸(1ml)混合。在室温下将搅拌反应1小时，用乙酸乙酯/水稀释，然后用碳酸钠碱化。干燥有机层、浓缩，硅胶柱纯化，得到式I化合物无定型物。
实施例3式I化合物的A型结晶的制备
3.1取式I化合物(按照实施例1方法制备得到)3.0g，加入乙醇24mL、纯化水12mL，搅拌升温至回流30min，之后降至室温析晶2h，过滤，得到A型结晶。使用Cu-Kα辐射，得到其X射线粉末衍射(XRD)图谱如附图2所示，示差扫描量热法(DSC)图谱如附图3所示，热重-微商热重分析(TG-DTG)图谱如附图4所示，重量损失为4.00％，约为1摩尔的 水。测得其水分含量为4.35％。
3.2取式I化合物(按照实施例1方法制备得到)3.0g，加入乙醇24mL，加热至回流，加入纯化水12mL(先澄清后析出)，回流30min，降温搅拌析晶，即得A型结晶，测得其水分含量为4.31％。
3.3取式I化合物(按照实施例1方法制备得到)3.0g，加入乙醇30mL，加热至回流溶清，之后加入纯化水6mL(先澄清后析出)，过滤，静置析晶，即得A型结晶，测得其水分含量为4.34％。
3.4取式I化合物(按照实施例1方法制备得到)3.0g，加入乙酸乙酯45mL，加热至回流，加入纯化水3mL，有部分固体溶解，过滤，滤液搅拌析晶，即得A型结晶，测得其水分含量为4.42％。
3.5取式I化合物(按照实施例1方法制备得到)5.0g，加入DMF15mL，溶清后加入纯化水30mL，析出白色固体，即得标题所述结晶，测得其水分含量为7.16％。
3.6取3.5制备得到的结晶3.0g，加入二氯甲烷和甲醇的混合溶液33mL(体积比v/v为10:1)，溶清后滴加石油醚，过滤，滤液搅拌析晶，即得A型结晶，测得其水分含量为4.28％。
3.7外形良好的式I化合物一水合物的单晶可通过在环境温度下缓慢挥发式I化合物的甲醇溶液而获得。采用单晶X-射线衍射法，测得A型结晶的单晶分子结构如附图13所示，该单晶晶体学数据如下：晶系Monoclinic，空间群Cc；晶胞参数为
Figure PCTCN2019074183-appb-000008
Figure PCTCN2019074183-appb-000009
α＝γ＝90°，β＝109.68°，体积
Figure PCTCN2019074183-appb-000010
依据所述单晶数据拟合得到的XRD图与附图2基本一致。
实施例4式I化合物甲醇合物的B型结晶的制备
4.1取式I化合物(按照实施例1方法制备得到)5.0g，加入50mL甲醇，搅拌加热至回流，澄清后过滤，滤液室温析晶，即得标题所述结晶。使用Cu-Kα辐射，得到其X射线粉末衍射(XRD)图谱如附图5所示，示差扫描量热法(DSC)图谱如附图6所示，热重-微商热重分析(TG-DTG)图谱如附图7所示。
4.2取4.1制备得到的结晶3.0g，加入二氯甲烷和甲醇的混合溶液33mL(体积比v/v为10:1)，溶清后滴加石油醚，过滤，滤液搅拌析晶，即得B型结晶。
实施例5式I化合物四氢呋喃合物的C型结晶的制备
5.1取式I化合物(按照实施例1方法制备得到)3.0g，加入四氢呋喃45mL，搅拌加热至回流，澄清后过滤，室温析晶，过滤，即得标题所述晶体。使用Cu-Kα辐射，得到其X射 线粉末衍射(XRD)图谱如附如图8所示，示差扫描量热法(DSC)图谱如附图9所示，热重-微商热重分析(TG-DTG)图谱如附图10所示。
5.2取式I化合物(按照实施例1方法制备得到)3.0g，加入四氢呋喃36mL，搅拌加热至回流，澄清后过滤，室温析晶，过滤，即得C型结晶。
实施例6式I化合物晶型1的制备
6.1取式I化合物(按照实施例1方法制备得到)3.0g，加入乙醇30mL，搅拌升温至回流30min，之后过滤，滤液降至室温析晶2h，过滤，即得式I化合物晶型1。使用Cu-Kα辐射，得到其X射线粉末衍射(XRD)图谱如附图1所示。
6.2取实施例3.1得到的A型结晶，在温度为120℃的条件下，鼓风烘干，即得到式I化合物晶型1。
6.3取实施例3.1得到的A型结晶，在温度为100℃的条件下，鼓风烘干，即得到式I化合物晶型1。
6.4取实施例2.1得到的式I化合物无定型物3.0g，加入二氯甲烷30mL和甲醇3mL，滴加石油醚30mL，即得到式I化合物晶型1。
实施例7式I化合物A型结晶的纯度分析
将实施例3.1、3.2的样品在精制前后，分别采用高效液相色谱法(HPLC)测定其主成分的纯度以及各个杂质的含量，按照峰面积归一法，检测结果如表1所示。结果发现，经过乙醇、水混合溶液的精制，主成分式I化合物的含量均达到约99.5％，各杂质成分含量均明显降低。其中，杂质1经结构鉴定，其化学名称为4-((4-氟-2-甲基-1H-吲哚-5-基)氧基)-6-甲氧基-7-羟基喹啉。
表1式I化合物A型结晶的纯度分析
Figure PCTCN2019074183-appb-000011
实施例8溶剂中的稳定性
将适量实施例3.1的式I化合物A型结晶置于两个样品瓶中，分别加入3mL水、乙醇， 使其溶解并呈过饱和态，于室温20℃下混悬，分别于12小时和24小时取1.5ml适量悬浮液，将悬浮液离心，弃去上清液，将离心后的固体于45℃条件下干燥2小时，测试XRD。结果显示晶型保持不变，仍为A型结晶。
实施例9吸湿性
称取大约45mg的实施例3.1的样品，加至动态水分吸附仪(型号DVS Intrinsic)的样品盘中。设定样品室初始湿度为0％，将样品在高纯度压缩空气下干燥至在1min内失重小于0.002％，然后再每一步增加相对湿度吸收至10，20，30，40，50，60，70，80及90％，平衡定义为重量变化在1min内小于0.002％，然后在相同的平衡条件下，相对湿度减至(解吸附)90，80，70，60，50，40，30，20，10，0％。DVS曲线(y-轴：重量-％变化对x-轴：％RH)见附图12的描述。
结果显示，在所考察的相对湿度范围内，其水含量的质量百分比无明显增加，不吸湿，数据如表2所示，且其XRD保持不变，仍为A型结晶。
表2动态水分吸附数据
Figure PCTCN2019074183-appb-000012
实施例10
取实施例3.1的式I化合物A型结晶，参照原料药物与制剂稳定性试验指导原则(中国药典2015年版四部通则9001)的方法，进行了如下的高温、高湿、光照和加速试验：
高温试验：温度为60℃下放置10天，于第10天取样；
高湿试验：温度为25℃，相对湿度90±5％下放置10天，于第10天取样；
光照试验：照度为4500lx±500lx的条件下放置10天，于第10天取样；
加速试验：温度40℃，相对湿度70±5％条件下放置10天，于第10天取样。
结果显示，式I化合物A型结晶的粉末XRD相对于各试验前均保持一致，没有发生晶 型变化。在高湿试验条件下，10天后重量变化仅为0.17％，不易吸湿。

Claims (9)

  1. 式I化合物的结晶，
    Figure PCTCN2019074183-appb-100001
    其特征在于，使用Cu-Kα辐射，所述结晶的X-射线粉末衍射在以下2θ度数约9.03、9.20、11.02、13.26、17.08、17.77、18.43、20.81、22.47处有衍射峰。
  2. 根据权利要求1所述的结晶，在以下2θ度数约为9.03、9.20、11.02、13.26、14.96、17.08、17.77、18.43、18.64、19.20、19.87、20.13、20.81、22.47、24.37、25.11处有衍射峰。
  3. 根据权利要求1所述的结晶，在以下2θ度数约为9.03,9.20,11.02,13.26,14.96,15.50,15.83,17.08,17.77,18.43,18.64,19.20,19.87,20.13,20.81,21.33,22.47,22.81,24.37,25.11,26.05,26.73,27.80,28.35,29.45,30.58处有衍射峰。
  4. 根据权利要求1-3中任一项所述的结晶，所述结晶为一水合物。
  5. 式I化合物的甲醇合物的结晶，其特征在于，使用Cu-Kα辐射，所述结晶的X-射线粉末衍射在以下2θ度数约为9.36、10.17、10.70、12.47、14.22、16.76、17.42、23.34、23.95处有衍射峰。
  6. 式I化合物的四氢呋喃合物的结晶，其特征在于，使用Cu-Kα辐射，所述结晶的X-射线粉末衍射在以下2θ度数约为7.42、9.79、15.45、18.23、22.48处有衍射峰。
  7. 一种结晶组合物，其中根据权利要求1-6中任一项所述的结晶占组合物重量的50％以上，优选在70％以上，更优选在90％以上，最优选在95％以上。
  8. 一种药物组合物，其含有根据权利要求1-6任一项所述的结晶或权利要求7所述的结晶组合物以及一种或多种药学上可接受的载体。
  9. 根据权利要求1-6任一项所述的结晶，在制备治疗肿瘤的药物中的应用，优选的肿瘤包括肝癌、肾癌、结肠癌、胃肠道间质瘤、软组织肉瘤、胃癌、甲状腺髓样癌、食管鳞状细胞癌、小细胞肺癌、非小细胞肺癌、子宫内膜癌、卵巢癌、宫颈癌、输卵管癌。
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