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WO2022007752A1 - 苯甲酰胺类化合物及其二盐酸盐的新晶型及其制备方法 - Google Patents

苯甲酰胺类化合物及其二盐酸盐的新晶型及其制备方法 Download PDF

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WO2022007752A1
WO2022007752A1 PCT/CN2021/104559 CN2021104559W WO2022007752A1 WO 2022007752 A1 WO2022007752 A1 WO 2022007752A1 CN 2021104559 W CN2021104559 W CN 2021104559W WO 2022007752 A1 WO2022007752 A1 WO 2022007752A1
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dihydrochloride
crystal form
formula
ray powder
dihydrochloride salt
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PCT/CN2021/104559
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English (en)
French (fr)
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鲁霞
张晓宇
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苏州晶云药物科技股份有限公司
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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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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
    • C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
    • C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
    • C07D253/06—1,2,4-Triazines
    • C07D253/065—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members
    • C07D253/07—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members with hetero atoms, or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • 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
    • C07D401/10—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 carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the invention relates to the field of chemical medicine, in particular to a new crystal form of a free base of a benzamide compound and a dihydrochloride salt and a preparation method thereof.
  • c-Met is a tyrosine kinase receptor overexpressed or mutated in a variety of tumor cells and plays an important role in tumor cell proliferation, survival, invasion, metastasis and tumor angiogenesis.
  • Formula (I) can selectively bind to c-Met, thereby inhibiting c-Met phosphorylation and blocking the c-Met signal transduction pathway. This may lead to cell death in tumor cells overexpressing c-Met protein or expressing constitutively activated c-Met protein, with potential antitumor activity.
  • formula (I) has been shown in clinical trials to have certain therapeutic potential in melanoma, gliosarcoma, solid tumors, colorectal cancer and liver injury. Has been granted Breakthrough by the U.S.
  • FDA Food and Drug Administration
  • Patent WO2008064157A1 discloses the preparation method of free base of formula (I) and its hydrochloride for the first time
  • patent US8420645B2 discloses a dihydrochloride crystal form of formula (I) (hereinafter referred to as crystal form A, its X X-ray powder diffraction has characteristic peaks at 26.0°, 24.7°, 18.2°, 29.3° and 7.8°), and the solubility of dihydrochloride crystal form A in different pH media is studied.
  • Polymorphic forms of the same drug may change its physicochemical properties, such as solubility, dissolution rate, melting point and stability, which in turn may affect the effect of the drug in the human body. Therefore, it is necessary to conduct a comprehensive and systematic crystal form screening of the free form of formula (I) and the dihydrochloride salt to develop crystal forms with good solubility and high stability, which provide more and better choices for the subsequent development of drugs.
  • the present invention provides formula (I) dihydrochloride salt crystal form J, dihydrochloride salt crystal form M, dihydrochloride salt crystal form E, dihydrochloride salt crystal form F, dihydrochloride salt crystal form H, disalt Acid salt crystal form N, dihydrochloride salt crystal form Q, dihydrochloride salt crystal form S, dihydrochloride salt crystal form T, dihydrochloride salt crystal form K and free base crystal form A, free base crystal form B, Preparation method and use of free base crystal form C.
  • the dihydrochloride salt J crystal of oxazin-2-yl]benzamide, namely the dihydrochloride salt form J, is characterized in that, using Cu-K ⁇ radiation, the X-ray powder of the dihydrochloride salt form J Diffraction has characteristic peaks at 2 ⁇ values of 6.3° ⁇ 0.2°, 15.0° ⁇ 0.2°, 26.8° ⁇ 0.2°,
  • the dihydrochloride salt of the compound of formula (I) is dissolved in a positive solvent, and an antisolvent is added dropwise to it after filtration to obtain the crystal form J of the dihydrochloride salt.
  • the dihydrochloride salt of the compound of formula (I) is dissolved in a positive solvent, and an antisolvent is added dropwise to it after filtration to obtain the crystal form M of the dihydrochloride salt.
  • the dihydrochloride salt type E crystal of oxazin-2-yl]benzamide namely the dihydrochloride salt form E, is characterized in that, using Cu-K ⁇ radiation, the X-ray powder of the dihydrochloride salt form E Diffraction has characteristic peaks at 2 ⁇ values of 5.6° ⁇ 0.2°, 16.8° ⁇ 0.2°, 11.2° ⁇ 0.2°,
  • the dihydrochloride salt of the compound of formula (I) is dissolved in a positive solvent, and an antisolvent is added dropwise thereto after filtration to obtain the dihydrochloride salt crystal form E.
  • the dihydrochloride salt F-type crystal of oxazin-2-yl]benzamide that is, the dihydrochloride salt form F, characterized in that, using Cu-K ⁇ radiation, the X-ray powder of the dihydrochloride salt form F Diffraction has characteristic peaks at 2 ⁇ values of 6.2° ⁇ 0.2°, 13.0° ⁇ 0.2°, 14.6° ⁇ 0.2°,
  • the dihydrochloride salt of the compound of formula (I) is dissolved in a positive solvent, and an antisolvent is added dropwise to it after filtration to obtain the dihydrochloride salt crystal form F.
  • the dihydrochloride H-type crystal of oxazin-2-yl]benzamide namely the dihydrochloride crystalline form H
  • the dihydrochloride H-type crystal of oxazin-2-yl]benzamide is characterized in that, using Cu-K ⁇ radiation, the X-ray powder of the dihydrochloride crystalline form H Diffraction has characteristic peaks at 2 ⁇ values of 9.7° ⁇ 0.2°, 6.5° ⁇ 0.2°, 13.0° ⁇ 0.2°,
  • the dihydrochloride salt of the compound of formula (I) is dissolved in a positive solvent, and the temperature is lowered after filtration to obtain the dihydrochloride salt crystal form H.
  • the dihydrochloride N-type crystal of oxazin-2-yl]benzamide that is, the dihydrochloride crystalline form N, characterized in that, using Cu-K ⁇ radiation, the X-ray powder of the dihydrochloride crystalline form N Diffraction has characteristic peaks at 2 ⁇ values of 15.1° ⁇ 0.2°, 16.2° ⁇ 0.2°, 8.8° ⁇ 0.2°,
  • the compound of formula (I) is dissolved in a positive solvent, then placed in a sealed environment containing an anti-solvent of hydrochloric acid, and osmotically crystallized to obtain a dihydrochloride salt crystal form N.
  • the dihydrochloride salt Q-type crystal of oxazin-2-yl]benzamide namely the dihydrochloride salt form Q
  • the dihydrochloride salt Q Diffraction has characteristic peaks at 2 ⁇ values of 9.2° ⁇ 0.2°, 5.8° ⁇ 0.2°, 10.4° ⁇ 0.2°,
  • the dihydrochloride salt of the compound of formula (I) is dissolved in a positive solvent, and the temperature is cooled after filtration, and no solid is precipitated, and it is transferred to room temperature for volatilization to obtain the dihydrochloride salt crystal form Q.
  • the dihydrochloride S-type crystal of oxazin-2-yl]benzamide that is, the dihydrochloride crystalline form S, characterized in that, using Cu-K ⁇ radiation, the X-ray powder of the dihydrochloride crystalline form S Diffraction has characteristic peaks at 2 ⁇ values of 26.7° ⁇ 0.2°, 13.2° ⁇ 0.2°, 10.5° ⁇ 0.2°,
  • the dihydrochloride of the compound of formula (I) is dissolved in a positive solvent, then placed in a sealed environment containing an anti-solvent of hydrochloric acid, infiltrated, without solid precipitation, transferred to room temperature and volatilized to obtain dihydrochloride crystal form S .
  • the dihydrochloride T-type crystal of oxazin-2-yl]benzamide that is, the dihydrochloride crystalline form T, is characterized in that, using Cu-K ⁇ radiation, the X-ray powder of the dihydrochloride crystalline form T Diffraction has characteristic peaks at 2 ⁇ values of 6.5° ⁇ 0.2°, 4.4° ⁇ 0.2°, 10.9° ⁇ 0.2°,
  • the dihydrochloride compound of formula (I) is dissolved in a positive solvent, then placed in a sealed environment of an anti-solvent, and osmotically crystallized to obtain the dihydrochloride crystal form T.
  • the K-type crystal of dihydrochloride salt of oxazin-2-yl]benzamide that is, the crystal form K of the dihydrochloride salt, characterized in that, using Cu-K ⁇ radiation, the X-ray powder of the crystal form K of the dihydrochloride salt Diffraction has characteristic peaks at 2 ⁇ values of 6.8° ⁇ 0.2°, 20.4° ⁇ 0.2°, 15.8° ⁇ 0.2°,
  • the dihydrochloride salt of the compound of formula (I) is dissolved in a positive solvent, and an antisolvent is added dropwise thereto after filtration to obtain the dihydrochloride salt crystal form K.
  • the compound represented by formula (I) 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]tri
  • the A-type crystal of oxazin-2-yl]benzamide, namely the free base crystal form A is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction of the free base crystal form A has a 2 ⁇ value of 5.7° ⁇ There are characteristic peaks at 0.2°, 13.6° ⁇ 0.2°, and 12.7° ⁇ 0.2°,
  • the dihydrochloride compound of formula (I) is dissociated in an alkaline aqueous solution, and the free base crystal form A is obtained after the solid is separated and dried.
  • the compound represented by formula (I) 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]tri
  • the B-type crystal of oxazin-2-yl]benzamide namely the free base crystal form B, is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction of the free base crystal form B has a 2 ⁇ value of 15.7° ⁇ There are characteristic peaks at 0.2°, 6.3° ⁇ 0.2°, and 12.8° ⁇ 0.2°,
  • the free base crystal form A described in the above 21 was suspended and stirred in ethyl acetate at room temperature overnight, and the free base crystal form B was obtained after the solid was separated and dried.
  • the free base crystal form A described in the above 21 is heated to a certain temperature and then cooled to room temperature to obtain the free base crystal form C.
  • a pharmaceutical composition comprising the crystal of any one of the above 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23 and 25 and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition with c-Met inhibitory activity comprising the crystal described in any one of the above 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23 and 25 as Active ingredients.
  • the crystal form J, crystal form M, crystal form E, crystal form F and crystal form H of the compound of formula (I) provided by the invention are in solubility, melting point, stability, dissolution, hygroscopicity,
  • adhesion, fluidity, bioavailability, processing performance, purification effect, preparation production, safety, etc. which provide a new method for the preparation of pharmaceutical preparations of this novel c-Met inhibitor. It is of great significance for drug development.
  • the dihydrochloride salt J crystal of 2-yl]benzamide, that is, the dihydrochloride salt form J is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction of the dihydrochloride salt form J is in the The 2 ⁇ value is 6.3° ⁇ 0.2°, 15.0° ⁇ 0.2°, and there are characteristic peaks at 26.8° ⁇ 0.2°,
  • the X-ray powder diffraction of the dihydrochloride salt form J has one or both of the 2 ⁇ values of 13.2° ⁇ 0.2°, 17.5° ⁇ 0.2°, 25.4° ⁇ 0.2° There are characteristic peaks at or three places.
  • the X-ray powder diffraction of the dihydrochloride salt crystal form J has characteristic peaks at 2 ⁇ values of 13.2° ⁇ 0.2°, 17.5° ⁇ 0.2°, and 25.4° ⁇ 0.2°.
  • the X-ray powder diffraction of the dihydrochloride salt form J has one or both of the 2 ⁇ values of 16.8° ⁇ 0.2°, 24.1° ⁇ 0.2°, 10.3° ⁇ 0.2° There are characteristic peaks at or three places.
  • the X-ray powder diffraction of the dihydrochloride salt crystal form J has characteristic peaks at 2 ⁇ values of 16.8° ⁇ 0.2°, 24.1° ⁇ 0.2°, and 10.3° ⁇ 0.2°.
  • the X-ray powder diffraction of the dihydrochloride salt form J has 2 ⁇ values of 6.3° ⁇ 0.2°, 15.0° ⁇ 0.2°, 26.8° ⁇ 0.2°, 13.2° ⁇ 0.2° , 17.5° ⁇ 0.2°, 25.4° ⁇ 0.2°, 16.8° ⁇ 0.2°, 24.1° ⁇ 0.2°, 10.3° ⁇ 0.2° any 4, or 5, or 6, or 7, or 8 There are characteristic peaks at or at 9.
  • the X-ray powder diffraction of the dihydrochloride salt form J has 2 ⁇ values of 6.3° ⁇ 0.2°, 15.0° ⁇ 0.2°, 26.8° ⁇ 0.2°, 13.2° ⁇ 0.2° , 17.5° ⁇ 0.2°, 25.4° ⁇ 0.2°, 16.8° ⁇ 0.2°, 24.1° ⁇ 0.2°, 10.3° ⁇ 0.2° have characteristic peaks.
  • the X-ray powder diffraction pattern of the dihydrochloride salt form J is shown in FIG. 1 .
  • the preparation method of the dihydrochloride crystal form J is characterized in that,
  • the dihydrochloride compound of formula (I) is dissolved in methanol, added dropwise to cyclopentyl methyl ether after filtration to carry out reverse anti-solvent addition, the sample is dissolved and clear, transferred to a low temperature and left to stand, and the solid is precipitated overnight to obtain two.
  • Form J hydrochloride is dissolved in methanol, added dropwise to cyclopentyl methyl ether after filtration to carry out reverse anti-solvent addition, the sample is dissolved and clear, transferred to a low temperature and left to stand, and the solid is precipitated overnight to obtain two.
  • Form J hydrochloride Form J hydrochloride.
  • the dissolution temperature is 20°C to 30°C.
  • the precipitation temperature is -20°C to 5°C.
  • the X-ray powder diffraction of the dihydrochloride salt crystal form M is at one or both of the 2 ⁇ values of 24.7° ⁇ 0.2°, 8.2° ⁇ 0.2°, 7.6° ⁇ 0.2° There are characteristic peaks at or three places.
  • the X-ray powder diffraction of the dihydrochloride salt crystal form M has characteristic peaks at 2 ⁇ values of 24.7° ⁇ 0.2°, 8.2° ⁇ 0.2°, and 7.6° ⁇ 0.2°.
  • the X-ray powder diffraction of the dihydrochloride salt crystal form M is at one or both of the 2 ⁇ values of 15.3° ⁇ 0.2°, 28.3° ⁇ 0.2°, 23.1° ⁇ 0.2° There are characteristic peaks at or three places.
  • the X-ray powder diffraction of the dihydrochloride salt crystal form M has characteristic peaks at 2 ⁇ values of 15.3° ⁇ 0.2°, 28.3° ⁇ 0.2°, and 23.1° ⁇ 0.2°.
  • the X-ray powder diffraction of the dihydrochloride salt form M has 2 ⁇ values of 6.4° ⁇ 0.2°, 10.4° ⁇ 0.2°, 14.0° ⁇ 0.2°, 24.7° ⁇ 0.2° , 8.2° ⁇ 0.2°, 7.6° ⁇ 0.2°, 15.3° ⁇ 0.2°, 28.3° ⁇ 0.2°, 23.1° ⁇ 0.2° any 4, or 5, or 6, or 7, or 8 There are characteristic peaks at or at 9.
  • the X-ray powder diffraction of the dihydrochloride salt form M has 2 ⁇ values of 6.4° ⁇ 0.2°, 10.4° ⁇ 0.2°, 14.0° ⁇ 0.2°, 24.7° ⁇ 0.2° , 8.2° ⁇ 0.2°, 7.6° ⁇ 0.2°, 15.3° ⁇ 0.2°, 28.3° ⁇ 0.2°, 23.1° ⁇ 0.2° have characteristic peaks.
  • the X-ray powder diffraction pattern of the dihydrochloride salt form M is shown in FIG. 2 .
  • the dihydrochloride compound of formula (I) is dissolved in methanol at high temperature, and after filtration, pre-cooled methyl tert-butyl ether is added dropwise to carry out anti-solvent addition, and the solid is precipitated to obtain the dihydrochloride crystal form M sample.
  • the high temperature is 40°C to 60°C.
  • the pre-cooling temperature is -20°C to 0°C.
  • the X-ray powder diffraction of the dihydrochloride salt form E has one or both of the 2 ⁇ values of 22.5° ⁇ 0.2°, 14.6° ⁇ 0.2°, 15.3° ⁇ 0.2° There are characteristic peaks at or three places.
  • the X-ray powder diffraction of the dihydrochloride crystal form E has characteristic peaks at 2 ⁇ values of 22.5° ⁇ 0.2°, 14.6° ⁇ 0.2°, and 15.3° ⁇ 0.2°.
  • the X-ray powder diffraction of the dihydrochloride salt form E has a 2 ⁇ value of 24.0° ⁇ 0.2°, 12.0° ⁇ 0.2°, 17.4° ⁇ 0.2° at one or both of There are characteristic peaks at or three places.
  • the X-ray powder diffraction of the dihydrochloride salt form E has characteristic peaks at 2 ⁇ values of 24.0° ⁇ 0.2°, 12.0° ⁇ 0.2°, and 17.4° ⁇ 0.2°.
  • the X-ray powder diffraction of the dihydrochloride salt form E has 2 ⁇ values of 5.6° ⁇ 0.2°, 16.8° ⁇ 0.2°, 11.2° ⁇ 0.2°, 22.5° ⁇ 0.2° , 14.6° ⁇ 0.2°, 15.3° ⁇ 0.2°, 24.0° ⁇ 0.2°, 12.0° ⁇ 0.2°, 17.4° ⁇ 0.2° any 4, or 5, or 6, or 7, or 8 There are characteristic peaks at or at 9.
  • the X-ray powder diffraction of the dihydrochloride salt form E has 2 ⁇ values of 5.6° ⁇ 0.2°, 16.8° ⁇ 0.2°, 11.2° ⁇ 0.2°, 22.5° ⁇ 0.2° , 14.6° ⁇ 0.2°, 15.3° ⁇ 0.2°, 24.0° ⁇ 0.2°, 12.0° ⁇ 0.2°, 17.4° ⁇ 0.2° have characteristic peaks.
  • the X-ray powder diffraction pattern of the dihydrochloride salt form E is shown in FIG. 3 .
  • the preparation method of the dihydrochloride crystal form E is characterized in that,
  • the dihydrochloride compound of formula (I) is dissolved in methanol, and after filtration, acetonitrile is added dropwise to the filtrate, stirred to obtain a suspension, and then the solid is separated to obtain the dihydrochloride crystal form E.
  • the dissolution temperature is 20°C to 55°C, preferably 20°C to 30°C.
  • the anti-solvent addition temperature is 20°C to 30°C.
  • the stirring temperature is -25°C to 30°C.
  • the anti-solvent is slowly added dropwise to the filtrate after filtration.
  • the X-ray powder diffraction of the dihydrochloride salt form F is at one or both of the 2 ⁇ values of 18.4° ⁇ 0.2°, 9.9° ⁇ 0.2°, 23.9° ⁇ 0.2° There are characteristic peaks at or three places.
  • the X-ray powder diffraction of the dihydrochloride salt crystal form F has characteristic peaks at 2 ⁇ values of 18.4° ⁇ 0.2°, 9.9° ⁇ 0.2°, and 23.9° ⁇ 0.2°.
  • the X-ray powder diffraction of the dihydrochloride salt crystal form F has characteristic peaks at one or two places in the 2 ⁇ value of 7.7° ⁇ 0.2° and 15.6° ⁇ 0.2°.
  • the X-ray powder diffraction of the dihydrochloride salt form F has characteristic peaks at 2 ⁇ values of 7.7° ⁇ 0.2° and 15.6° ⁇ 0.2°.
  • the X-ray powder diffraction of the dihydrochloride salt form F has 2 ⁇ values of 6.2° ⁇ 0.2°, 13.0° ⁇ 0.2°, 14.6° ⁇ 0.2°, 18.4° ⁇ 0.2° , 9.9° ⁇ 0.2°, 23.9° ⁇ 0.2°, 7.7° ⁇ 0.2°, 15.6° ⁇ 0.2° any 4, or 5, or 6, or 7, or 8 characteristic peaks.
  • the X-ray powder diffraction of the dihydrochloride salt form F has 2 ⁇ values of 6.2° ⁇ 0.2°, 13.0° ⁇ 0.2°, 14.6° ⁇ 0.2°, 18.4° ⁇ 0.2° , 9.9° ⁇ 0.2°, 23.9° ⁇ 0.2°, 7.7° ⁇ 0.2°, and 15.6° ⁇ 0.2° have characteristic peaks.
  • the X-ray powder diffraction pattern of the dihydrochloride salt form F is shown in FIG. 4 .
  • the dihydrochloride compound of formula (I) was dissolved in methanol, and after filtration, methyl tert-butyl ether, ethyl acetate or cyclopentyl methyl ether was added dropwise to the filtrate to obtain a suspension, which was heated at a certain temperature. After suspending and stirring, the solid was separated to obtain dihydrochloride crystal form F.
  • the dissolution temperature is 20°C to 55°C, preferably 20°C to 30°C.
  • the anti-solvent addition temperature is 20°C to 30°C.
  • the stirring temperature is -25°C to 30°C.
  • the anti-solvent is slowly added dropwise to the filtrate after filtration.
  • stirring is performed for 0.5 hours to 1 day until solids are precipitated, for example, stirring for 0.5 hours.
  • the dihydrochloride H-type crystal of 2-yl]benzamide that is, the dihydrochloride crystalline form H, is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction of the dihydrochloride crystalline form H is in the The 2 ⁇ value is 9.7° ⁇ 0.2°, 6.5° ⁇ 0.2°, and there are characteristic peaks at 13.0° ⁇ 0.2°,
  • the X-ray powder diffraction of the dihydrochloride salt crystal form H has characteristic peaks at one or two places in the 2 ⁇ value of 26.7° ⁇ 0.2° and 14.2° ⁇ 0.2°.
  • the X-ray powder diffraction of the dihydrochloride salt crystal form H has characteristic peaks at 26.7° ⁇ 0.2° and 14.2° ⁇ 0.2° in 2 ⁇ value.
  • the X-ray powder diffraction of the dihydrochloride salt crystal form H has characteristic peaks at one or both of the 2 ⁇ values of 14.7° ⁇ 0.2° and 12.7° ⁇ 0.2°.
  • the X-ray powder diffraction of the dihydrochloride salt crystal form H has characteristic peaks at 2 ⁇ values of 14.7° ⁇ 0.2° and 12.7° ⁇ 0.2°.
  • the X-ray powder diffraction of the dihydrochloride salt form H has 2 ⁇ values of 9.7° ⁇ 0.2°, 6.5° ⁇ 0.2°, 13.0° ⁇ 0.2°, 26.7° ⁇ 0.2° , 14.2° ⁇ 0.2°, 14.7° ⁇ 0.2°, 12.7° ⁇ 0.2° in any 4 places, or 5 places, or 6 places, or 7 places with characteristic peaks.
  • the X-ray powder diffraction of the dihydrochloride salt form H has 2 ⁇ values of 9.7° ⁇ 0.2°, 6.5° ⁇ 0.2°, 13.0° ⁇ 0.2°, 26.7° ⁇ 0.2° , 14.2° ⁇ 0.2°, 14.7° ⁇ 0.2°, 12.7° ⁇ 0.2° have characteristic peaks.
  • the X-ray powder diffraction pattern of the dihydrochloride salt form H is shown in FIG. 5 .
  • the dihydrochloride compound of formula (I) is dissolved in a positive solvent at a high temperature, and the temperature is cooled after filtration to obtain a dihydrochloride crystal form H by precipitating a solid.
  • the positive solvent is selected from methanol, methanol/dichloromethane (volume ratio 4:1), and ethanol.
  • the dissolution conditions are 40°C to 60°C, for example 50°C.
  • the crystallization temperature is -20°C to 5°C, eg -20°C.
  • the cooling is rapid cooling.
  • the cooling is a cooling rate of 0.05°C/min to 0.5°C/min.
  • the dihydrochloride N-type crystal of 2-yl]benzamide that is, the dihydrochloride crystalline form N, is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction of the dihydrochloride crystalline form N is in the The 2 ⁇ value is 15.1° ⁇ 0.2°, 16.2° ⁇ 0.2°, and there are characteristic peaks at 8.8° ⁇ 0.2°,
  • the X-ray powder diffraction of the dihydrochloride salt form N has one or both of the 2 ⁇ values of 7.6° ⁇ 0.2°, 14.2° ⁇ 0.2°, 27.6° ⁇ 0.2° There are characteristic peaks at or three places.
  • the X-ray powder diffraction of the dihydrochloride salt crystal form N has characteristic peaks at 2 ⁇ values of 7.6° ⁇ 0.2°, 14.2° ⁇ 0.2°, and 27.6° ⁇ 0.2°.
  • the X-ray powder diffraction of the dihydrochloride salt form N has one or both of the 2 ⁇ values of 12.7° ⁇ 0.2°, 19.8° ⁇ 0.2°, 23.3° ⁇ 0.2° There are characteristic peaks at or three places.
  • the X-ray powder diffraction of the dihydrochloride salt crystal form N has characteristic peaks at 2 ⁇ values of 12.7° ⁇ 0.2°, 19.8° ⁇ 0.2°, and 23.3° ⁇ 0.2°.
  • the X-ray powder diffraction of the dihydrochloride salt form N has 2 ⁇ values of 15.1° ⁇ 0.2°, 16.2° ⁇ 0.2°, 8.8° ⁇ 0.2°, 7.6° ⁇ 0.2° , 14.2° ⁇ 0.2°, 27.6° ⁇ 0.2°, 12.7° ⁇ 0.2°, 19.8° ⁇ 0.2°, 23.3° ⁇ 0.2° any 4, or 5, or 6, or 7, or 8 There are characteristic peaks at or at 9.
  • the X-ray powder diffraction of the dihydrochloride salt form N has 2 ⁇ values of 15.1° ⁇ 0.2°, 16.2° ⁇ 0.2°, 8.8° ⁇ 0.2°, 7.6° ⁇ 0.2° , 14.2° ⁇ 0.2°, 27.6° ⁇ 0.2°, 12.7° ⁇ 0.2°, 19.8° ⁇ 0.2°, 23.3° ⁇ 0.2° have characteristic peaks.
  • the X-ray powder diffraction pattern of the dihydrochloride salt form N is shown in FIG. 6 .
  • the preparation method of the dihydrochloride crystal form N is characterized in that,
  • the compound of formula (I) is dissolved in methanol, and then gas-liquid infiltration is carried out for a period of time in an anti-solvent atmosphere containing hydrochloric acid to obtain the dihydrochloride salt crystal form N.
  • the anti-solvent is selected from a mixed solvent of ethyl acetate saturated hydrochloride solution and ethyl acetate hydrochloride saturated solution/methyl tert-butyl ether (volume ratio 1:1).
  • the dissolution and penetration temperature is 20°C to 30°C.
  • the penetration time is 1 to 4 weeks, eg 2 weeks.
  • the X-ray powder diffraction of the dihydrochloride salt form Q has one or both of the 2 ⁇ values of 18.5° ⁇ 0.2°, 14.7° ⁇ 0.2°, 16.2° ⁇ 0.2° There are characteristic peaks at or three places.
  • the X-ray powder diffraction of the dihydrochloride salt crystal form Q has characteristic peaks at 2 ⁇ values of 18.5° ⁇ 0.2°, 14.7° ⁇ 0.2°, and 16.2° ⁇ 0.2°.
  • the X-ray powder diffraction of the dihydrochloride salt crystal form Q is characterized at one or two or three places in the 2 ⁇ value of 11.8° ⁇ 0.2° and 20.5° ⁇ 0.2° peak.
  • the X-ray powder diffraction of the dihydrochloride salt crystal form Q has characteristic peaks at 2 ⁇ values of 11.8° ⁇ 0.2° and 20.5° ⁇ 0.2°.
  • the X-ray powder diffraction of the dihydrochloride salt form Q has 2 ⁇ values of 9.2° ⁇ 0.2°, 5.8° ⁇ 0.2°, 10.4° ⁇ 0.2°, 18.5° ⁇ 0.2° , 14.7° ⁇ 0.2°, 16.2° ⁇ 0.2°, 11.8° ⁇ 0.2°, 20.5° ⁇ 0.2° in any 4, or 5, or 6, or 7, or 8 characteristic peaks.
  • the X-ray powder diffraction of the dihydrochloride salt form Q has 2 ⁇ values of 9.2° ⁇ 0.2°, 5.8° ⁇ 0.2°, 10.4° ⁇ 0.2°, 18.5° ⁇ 0.2° , 14.7° ⁇ 0.2°, 16.2° ⁇ 0.2°, 11.8° ⁇ 0.2°, and 20.5° ⁇ 0.2° have characteristic peaks.
  • the X-ray powder diffraction pattern of the dihydrochloride salt form Q is shown in FIG. 7 .
  • the dihydrochloride compound of formula (I) is dissolved in pure water, then rapidly cooled, no solid is precipitated, and transferred to room temperature for volatilization for a period of time to obtain the dihydrochloride crystal form Q.
  • the dihydrochloride S-type crystal of 2-yl]benzamide that is, the dihydrochloride crystalline form S, is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction of the dihydrochloride crystalline form S is in the The 2 ⁇ value is 26.7° ⁇ 0.2°, 13.2° ⁇ 0.2°, and there are characteristic peaks at 10.5° ⁇ 0.2°,
  • the X-ray powder diffraction of the dihydrochloride salt form S has one or both of the 2 ⁇ values of 6.7° ⁇ 0.2°, 12.7° ⁇ 0.2°, 19.2° ⁇ 0.2° There are characteristic peaks.
  • the X-ray powder diffraction of the dihydrochloride salt crystal form S has characteristic peaks at 2 ⁇ values of 6.7° ⁇ 0.2°, 12.7° ⁇ 0.2°, and 19.2° ⁇ 0.2°.
  • the X-ray powder diffraction of the dihydrochloride salt form S is at one or both of the 2 ⁇ values of 18.5° ⁇ 0.2°, 8.1° ⁇ 0.2°, 29.6 ⁇ 0.2° or three characteristic peaks.
  • the X-ray powder diffraction of the dihydrochloride salt crystal form S has characteristic peaks at 2 ⁇ values of 18.5° ⁇ 0.2°, 8.1° ⁇ 0.2°, and 29.6 ⁇ 0.2°.
  • the X-ray powder diffraction of the dihydrochloride salt form S has 2 ⁇ values of 26.7° ⁇ 0.2°, 13.2° ⁇ 0.2°, 10.5° ⁇ 0.2°, 6.7° ⁇ 0.2° , 12.7° ⁇ 0.2°, 19.2° ⁇ 0.2°, 18.5° ⁇ 0.2°, 8.1° ⁇ 0.2°, 29.6 ⁇ 0.2° any 4, or 5, or 6, or 7, or 8 , or 9 with characteristic peaks.
  • the X-ray powder diffraction of the dihydrochloride salt form S has 2 ⁇ values of 26.7° ⁇ 0.2°, 13.2° ⁇ 0.2°, 10.5° ⁇ 0.2°, 6.7° ⁇ 0.2° , 12.7° ⁇ 0.2°, 19.2° ⁇ 0.2°, 18.5° ⁇ 0.2°, 8.1° ⁇ 0.2°, and 29.6 ⁇ 0.2° have characteristic peaks.
  • the X-ray powder diffraction pattern of the dihydrochloride salt form S is shown in FIG. 8 .
  • the preparation method of the dihydrochloride crystal form S is characterized in that,
  • the compound of formula (I) was dissolved in methanol, placed in the atmosphere of ethyl acetate saturated solution of hydrochloric acid/methyl ethyl ketone (volume ratio 1:1) mixed solution to carry out gas-liquid infiltration, no solid was precipitated, and transferred to room temperature Under volatilization, the dihydrochloride salt form S is obtained.
  • the dihydrochloride T-type crystal of 2-yl]benzamide that is, the dihydrochloride crystalline form T, is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction of the dihydrochloride crystalline form T is in the The 2 ⁇ value is 6.5° ⁇ 0.2°, 4.4° ⁇ 0.2°, and there are characteristic peaks at 10.9° ⁇ 0.2°,
  • the X-ray powder diffraction of the dihydrochloride salt crystal form T is at one or both of the 2 ⁇ values of 15.2° ⁇ 0.2°, 17.0° ⁇ 0.2°, 24.0° ⁇ 0.2° There are characteristic peaks at or three places.
  • the X-ray powder diffraction of the dihydrochloride salt crystal form T has characteristic peaks at 2 ⁇ values of 15.2° ⁇ 0.2°, 17.0° ⁇ 0.2°, and 24.0° ⁇ 0.2°.
  • the X-ray powder diffraction of the dihydrochloride salt form T is at one or both of the 2 ⁇ values of 12.4° ⁇ 0.2°, 22.4° ⁇ 0.2°, 27.6 ⁇ 0.2° or three characteristic peaks.
  • the X-ray powder diffraction of the dihydrochloride salt crystal form T has characteristic peaks at 2 ⁇ values of 12.4° ⁇ 0.2°, 22.4° ⁇ 0.2°, and 27.6 ⁇ 0.2°.
  • the X-ray powder diffraction of the dihydrochloride salt crystal form T has 2 ⁇ values of 6.5° ⁇ 0.2°, 4.4° ⁇ 0.2°, 10.9° ⁇ 0.2°, 15.2° ⁇ 0.2° , 17.0° ⁇ 0.2°, 24.0° ⁇ 0.2°, 12.4° ⁇ 0.2°, 22.4° ⁇ 0.2°, 27.6 ⁇ 0.2° any 4 places, or 5 places, or 6 places, or 7 places, or 8 places , or 9 with characteristic peaks.
  • the X-ray powder diffraction of the dihydrochloride salt crystal form T has 2 ⁇ values of 6.5° ⁇ 0.2°, 4.4° ⁇ 0.2°, 10.9° ⁇ 0.2°, 15.2° ⁇ 0.2° , 17.0° ⁇ 0.2°, 24.0° ⁇ 0.2°, 12.4° ⁇ 0.2°, 22.4° ⁇ 0.2°, 27.6 ⁇ 0.2° have characteristic peaks.
  • the X-ray powder diffraction pattern of the dihydrochloride salt form T is shown in FIG. 9 .
  • the compound of formula (I) is dissolved in methanol, and then gas-liquid permeation is carried out for a period of time under the atmosphere of isopropanol to obtain the crystal form T of the dihydrochloride.
  • the dissolution and penetration temperature is 20°C to 30°C.
  • the period of time is 1 to 4 weeks, eg 2 weeks.
  • the dihydrochloride K-type crystal of 2-yl]benzamide that is, the dihydrochloride crystalline form K, is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction of the dihydrochloride crystalline form K is in the The 2 ⁇ value is 6.8° ⁇ 0.2°, 20.4° ⁇ 0.2°, and there are characteristic peaks at 15.8° ⁇ 0.2°,
  • the X-ray powder diffraction of the dihydrochloride salt form K has one or both of the 2 ⁇ values of 14.5° ⁇ 0.2°, 22.0° ⁇ 0.2°, 27.8° ⁇ 0.2° There are characteristic peaks at or three places.
  • the X-ray powder diffraction of the dihydrochloride crystal form K has characteristic peaks at 2 ⁇ values of 14.5° ⁇ 0.2°, 22.0° ⁇ 0.2°, and 27.8° ⁇ 0.2°.
  • the X-ray powder diffraction of the dihydrochloride salt form K has one or both of the 2 ⁇ values of 27.1° ⁇ 0.2°, 21.3° ⁇ 0.2°, 30.8° ⁇ 0.2° There are characteristic peaks at or three places.
  • the X-ray powder diffraction of the dihydrochloride crystal form K has characteristic peaks at 2 ⁇ values of 27.1° ⁇ 0.2°, 21.3° ⁇ 0.2°, and 30.8° ⁇ 0.2°.
  • the X-ray powder diffraction of the dihydrochloride salt form K has 2 ⁇ values of 6.8° ⁇ 0.2°, 20.4° ⁇ 0.2°, 15.8° ⁇ 0.2°, 14.5° ⁇ 0.2° , 22.0° ⁇ 0.2°, 27.8° ⁇ 0.2°, 27.1° ⁇ 0.2°, 21.3° ⁇ 0.2°, 30.8° ⁇ 0.2° any 4, or 5, or 6, or 7, or 8 There are characteristic peaks at or at 9.
  • the X-ray powder diffraction of the dihydrochloride salt form K has 2 ⁇ values of 6.8° ⁇ 0.2°, 20.4° ⁇ 0.2°, 15.8° ⁇ 0.2°, 14.5° ⁇ 0.2° , 22.0° ⁇ 0.2°, 27.8° ⁇ 0.2°, 27.1° ⁇ 0.2°, 21.3° ⁇ 0.2°, 30.8° ⁇ 0.2° have characteristic peaks.
  • the X-ray powder diffraction pattern of the dihydrochloride salt form K is shown in FIG. 10 .
  • the dihydrochloride compound of formula (I) is dissolved in methanol at high temperature, and after filtration, pre-cooled acetonitrile is added dropwise to carry out anti-solvent addition, and the solid is precipitated to obtain the dihydrochloride crystal form K sample.
  • the dissolution temperature is 40°C to 60°C.
  • the pre-cooling temperature is -20°C to 0°C.
  • the A-type crystal of 2-yl]benzamide that is, the free base crystal form A, characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction of the free base crystal form A has a 2 ⁇ value of 5.7° ⁇ 0.2° , 13.6° ⁇ 0.2°, there are characteristic peaks at 12.7° ⁇ 0.2°,
  • the X-ray powder diffraction of the free base crystal form A is at one or both of the 2 ⁇ values of 17.5° ⁇ 0.2°, 16.6° ⁇ 0.2°, 24.9° ⁇ 0.2°, or There are three characteristic peaks.
  • the X-ray powder diffraction of the free base crystal form A has characteristic peaks at 2 ⁇ values of 17.5° ⁇ 0.2°, 16.6° ⁇ 0.2°, and 24.9° ⁇ 0.2°.
  • the X-ray powder diffraction of the free base crystal form A is at one or both of the 2 ⁇ values of 14.1° ⁇ 0.2°, 23.8° ⁇ 0.2°, 19.1° ⁇ 0.2°, or There are three characteristic peaks.
  • the X-ray powder diffraction of the free base crystal form A has characteristic peaks at 2 ⁇ values of 14.1° ⁇ 0.2°, 23.8° ⁇ 0.2°, and 19.1° ⁇ 0.2°.
  • the X-ray powder diffraction of the free base crystal form A has 2 ⁇ values of 5.7° ⁇ 0.2°, 13.6° ⁇ 0.2°, 12.7° ⁇ 0.2°, 17.5° ⁇ 0.2°, 16.6 ° ⁇ 0.2°, 24.9° ⁇ 0.2°, 14.1° ⁇ 0.2°, 23.8° ⁇ 0.2°, 19.1° ⁇ 0.2° any 4, or 5, or 6, or 7, or 8, or 9 with characteristic peaks.
  • the X-ray powder diffraction of the free base crystal form A has 2 ⁇ values of 5.7° ⁇ 0.2°, 13.6° ⁇ 0.2°, 12.7° ⁇ 0.2°, 17.5° ⁇ 0.2°, 16.6 There are characteristic peaks at ° ⁇ 0.2°, 24.9° ⁇ 0.2°, 14.1° ⁇ 0.2°, 23.8° ⁇ 0.2°, and 19.1° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the free base Form A is shown in FIG. 11 .
  • the preparation method of the free base crystal form A is characterized in that,
  • the dihydrochloride compound of formula (I) is stirred overnight at room temperature with sodium bicarbonate solution, and the free base crystal form A is obtained after the solid is separated and dried.
  • the B-type crystal of 2-yl]benzamide namely the free base crystal form B, is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction of the free base crystal form B has a 2 ⁇ value of 15.7° ⁇ 0.2° , 6.3° ⁇ 0.2°, there are characteristic peaks at 12.8° ⁇ 0.2°,
  • the X-ray powder diffraction of the free base crystal form B is at one or both of the 2 ⁇ values of 16.7° ⁇ 0.2°, 17.9° ⁇ 0.2°, 19.2° ⁇ 0.2°, or There are three characteristic peaks.
  • the X-ray powder diffraction of the free base crystal form B has characteristic peaks at 2 ⁇ values of 16.7° ⁇ 0.2°, 17.9° ⁇ 0.2°, and 19.2° ⁇ 0.2°.
  • the X-ray powder diffraction of the free base crystal form B is at one or both of the 2 ⁇ values of 25.1° ⁇ 0.2°, 10.8° ⁇ 0.2°, 14.0° ⁇ 0.2°, or There are three characteristic peaks.
  • the X-ray powder diffraction of the free base crystal form B has characteristic peaks at 2 ⁇ values of 25.1° ⁇ 0.2°, 10.8° ⁇ 0.2°, and 14.0° ⁇ 0.2°.
  • the X-ray powder diffraction of the free base crystal form B has 2 ⁇ values of 15.7° ⁇ 0.2°, 6.3° ⁇ 0.2°, 12.8° ⁇ 0.2°, 16.7° ⁇ 0.2°, 17.9 ° ⁇ 0.2°, 19.2° ⁇ 0.2°, 25.1° ⁇ 0.2°, 10.8° ⁇ 0.2°, 14.0° ⁇ 0.2° any 4, or 5, or 6, or 7, or 8, or 9 with characteristic peaks.
  • the X-ray powder diffraction of the free base crystal form B has 2 ⁇ values of 15.7° ⁇ 0.2°, 6.3° ⁇ 0.2°, 12.8° ⁇ 0.2°, 16.7° ⁇ 0.2°, 17.9 There are characteristic peaks at ° ⁇ 0.2°, 19.2° ⁇ 0.2°, 25.1° ⁇ 0.2°, 10.8° ⁇ 0.2°, 14.0° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the free base Form B is shown in FIG. 12 .
  • the preparation method of the free base crystal form B is characterized in that,
  • the crystal form sample described in claim 21 was stirred overnight in ethyl acetate at room temperature, and the free base crystal form B was obtained after the solid was separated and dried.
  • the C-type crystal of 2-yl]benzamide namely the free base crystal form C, is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction of the free base crystal form C has a 2 ⁇ value of 6.6° ⁇ 0.2° , 16.7° ⁇ 0.2°, there are characteristic peaks at 15.4° ⁇ 0.2°,
  • the X-ray powder diffraction of the free base crystal form C has a 2 ⁇ value of 12.8° ⁇ 0.2°, 10.7° ⁇ 0.2°, 21.1° ⁇ 0.2° at one or both or There are three characteristic peaks.
  • the X-ray powder diffraction of the free base crystal form C has characteristic peaks at 2 ⁇ values of 12.8° ⁇ 0.2°, 10.7° ⁇ 0.2°, and 21.1° ⁇ 0.2°.
  • the X-ray powder diffraction of the free base crystal form C has a 2 ⁇ value of 26.7° ⁇ 0.2°, 24.9° ⁇ 0.2°, 23.1° ⁇ 0.2° at one or both or There are three characteristic peaks.
  • the X-ray powder diffraction of the free base crystal form C has characteristic peaks at 2 ⁇ values of 26.7° ⁇ 0.2°, 24.9° ⁇ 0.2°, and 23.1° ⁇ 0.2°.
  • the X-ray powder diffraction of the free base crystal form C has 2 ⁇ values of 6.6° ⁇ 0.2°, 16.7° ⁇ 0.2°, 15.4° ⁇ 0.2°, 12.8° ⁇ 0.2°, 10.7 ° ⁇ 0.2°, 21.1° ⁇ 0.2°, 26.7° ⁇ 0.2°, 24.9° ⁇ 0.2°, 23.1° ⁇ 0.2° any 4, or 5, or 6, or 7, or 8, or 9 with characteristic peaks.
  • the X-ray powder diffraction of the free base crystal form C has 2 ⁇ values of 6.6° ⁇ 0.2°, 16.7° ⁇ 0.2°, 15.4° ⁇ 0.2°, 12.8° ⁇ 0.2°, 10.7 There are characteristic peaks at ° ⁇ 0.2°, 21.1° ⁇ 0.2°, 26.7° ⁇ 0.2°, 24.9° ⁇ 0.2°, 23.1° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the free base Form C is shown in FIG. 13 .
  • the preparation method of the free base crystal form C is characterized in that,
  • the crystal form sample of claim 21 is heated to a certain temperature and cooled to obtain the free base crystal form C.
  • the heating temperature ranges from 105°C to 250°C.
  • the temperature after cooling is 0°C to 30°C.
  • said formula (I) and/or its salts as raw materials refer to its solid (crystalline or amorphous), semi-solid, wax or oil form.
  • the compounds and/or their salts as raw materials are in the form of solid powders.
  • the "stirring" is accomplished by conventional methods in the art, such as magnetic stirring or mechanical stirring, and the stirring speed is 50-1800 rev/min, wherein the magnetic stirring is preferably 300-900 rev/min, and the mechanical stirring is preferably 100-1800 rev/min. 300 rpm.
  • crystalline or “polymorphic form” means as evidenced by the characterization of the X-ray diffraction pattern shown.
  • X-ray diffraction patterns generally vary with the conditions of the instrument.
  • the relative intensities of X-ray diffraction patterns may also vary with experimental conditions, so the order of peak intensities cannot be used as the sole or decisive factor.
  • the relative intensities of diffraction peaks in XRPD patterns are related to the preferred orientation of the crystals, and the peak intensities shown here are illustrative and not for absolute comparison.
  • the experimental error of the peak angle is usually 5% or less, the error of these angles should also be taken into account, usually an error of ⁇ 0.2° is allowed.
  • the overall shift of the peak angle will be caused, and a certain shift is usually allowed.
  • the X-ray diffraction pattern of a crystal form in the present invention does not necessarily have to be exactly the same as the X-ray diffraction pattern in the examples mentioned here, and the "same XRPD pattern" mentioned herein does not mean absolutely the same , the same peak position can differ by ⁇ 0.2° and the peak intensity allows some variability. Any crystalline form having the same or similar pattern as the characteristic peaks in these patterns is within the scope of the present invention. Those skilled in the art can compare the patterns listed in the present invention with a pattern of an unknown crystal form to confirm whether the two sets of patterns reflect the same or different crystal forms.
  • the dihydrochloride salts of the present invention are Form J, Form M, Form E, Form F, Form H, Form N, Form Q, Form S, Form T and free
  • the alkali crystal form A, crystal form B, and crystal form C are pure, single, and substantially not mixed with any other crystal forms.
  • substantially free when used to refer to a new crystal form means that the crystal form contains less than 20% by weight of other crystal forms, especially less than 10% by weight of other crystal forms, and even less More than 5% (weight) of other crystal forms, more than 1% (weight) of other crystal forms.
  • the present invention provides dihydrochloride salt crystal form J, crystal form M, crystal form E, crystal form F, crystal form H, crystal form N, crystal form Q, crystal form S, crystal form T and free base Form A, Form B, Form C, in terms of solubility, melting point, stability, dissolution, hygroscopicity, adhesion, fluidity, bioavailability, processing performance, purification, preparation production, safety, etc.
  • formula (I) which provides a new and better choice for the preparation of the pharmaceutical preparation containing the compound of formula (I), which is of great significance for drug development.
  • the new crystal form of the dihydrochloride salt of formula (I) and free base provided by the invention has the advantages of solubility, melting point, stability, dissolution, hygroscopicity, adhesion, fluidity, bioavailability and There are advantages in at least one aspect of processability, purification, preparation production, safety, etc., which provide new and better options for the preparation of pharmaceutical preparations of MET inhibitors, and are of great significance for drug development.
  • room temperature generally refers to 22°C to 28°C unless otherwise specified.
  • the X-ray powder diffraction patterns of the present invention were collected on Empyrean and X'Pert3 ray powder diffractometers of PANalytacal.
  • the method parameters of X-ray powder diffraction of the present invention are as follows:
  • the differential scanning calorimetry analysis curve of the present invention is collected on the Q2000 type and Discovery DSC 2500 type differential scanning calorimeter of TA company.
  • the method parameters of the differential scanning calorimetry analysis of the present invention are as follows:
  • thermogravimetric analysis curve of the present invention is collected on the Discovery TGA 5500 type and Q5000 type thermogravimetric analyzer of TA company.
  • the method parameters of the thermogravimetric analysis of the present invention are as follows:
  • UPLC high performance liquid chromatography
  • PDA diode array detector
  • Chromatographic column Waters Xbridge C18, 150 ⁇ 4.6mm, 5 ⁇ m
  • the elution gradient is as follows:
  • ion chromatography (IC) data is collected from ThermoFisher ICS-1100, and the IC method parameters of the test chloride ion content of the present invention are as follows:
  • Chromatographic column IonPac AS18 Analytical Column (4 ⁇ 250mm)
  • the dynamic moisture adsorption diagram of the present invention is collected on the Intrinsic type and Intrinsic Plus type dynamic moisture adsorption instrument of SMS company.
  • the method parameters of the dynamic moisture adsorption test of the present invention are as follows:
  • Relative humidity gradient 10% (0%RH-90%RH-0%RH), 5% (90%RH-95%RH and 95%RH-90%RH)
  • Microtrac S3500 is equipped with SDC (Sample Delivery Controller) sampling system. This test adopts the wet method, and the test dispersion medium is Isopar G (containing 0.2% lecithin).
  • the method parameters of the described laser particle size analyzer are as follows:
  • Particle shape irregular filter: enabled Ultrasonic power: 30 watts Ultrasound time: Ultrasound for 30 seconds
  • the intrinsic dissolution rate data described in the present invention were collected on the Agilent 708DS type dissolution apparatus of Agilent. Described inherent dissolution test conditions are as follows:
  • the polarized light microscope photos described in the present invention were collected at room temperature by a Zeiss microscope Axio Scope.A1 equipped with an Axiocam 305 color camera and 5 ⁇ , 10 ⁇ , 20 ⁇ and 50 ⁇ objective lenses.
  • the starting material of compound (I) dihydrochloride salt used in the following examples can be prepared according to the prior art, for example, according to the method described in US8420645, but the starting crystal form is not for preparing the crystal form of the present invention Qualifications.
  • dihydrochloride of formula (I) was dissolved in 1.0 ml of methanol/dichloromethane (volume ratio 4:1) at 50°C to make it clear, using 0.45 micron pore size polytetrafluoroethylene
  • the sample solution was filtered by a filter membrane, and then quickly placed at -20° C. to stand, and the crystal form H of the dihydrochloride compound of formula (I) was obtained by solid-liquid separation.
  • Example 9 At room temperature, 15.0 mg of the compound of formula (I) dihydrochloride was placed in a 3 mL glass vial, and 1.0 mL of ethanol was added to obtain a suspension. After the suspension was magnetically stirred at 50°C (about 1000 rpm) for about two hours, the sample solution was filtered while hot using a 0.45-micron pore size polytetrafluoroethylene filter into a new 3-mL glass vial. After sealing the clarified filtrate, the temperature was lowered from 50°C to 5°C at a rate of 0.1°C per minute, and then kept at a constant temperature of 5°C for about two days without solid precipitation. When the sample was transferred, the sample was transferred to -20°. It was left to stand at low temperature, and no solid was precipitated, and it was transferred to room temperature and volatilized until solid precipitation to obtain the dihydrochloride compound of formula (I) in crystal form H.
  • Example 10 At room temperature, 14.6 mg of the compound of formula (I) dihydrochloride was placed in a 3 ml glass vial, and 1.0 ml of methanol was added to obtain a suspension. After the suspension was magnetically stirred at 50°C (about 1000 rpm) for about two hours, the sample solution was filtered while hot using a 0.45-micron pore size polytetrafluoroethylene filter into a new 3-mL glass vial. After sealing the clarified filtrate, the temperature was lowered from 50°C to 5°C at a rate of 0.1°C per minute, and then kept at a constant temperature of 5°C for about two days without solid precipitation. When the sample was transferred, the sample was transferred to -20°. It was allowed to stand at low temperature, and a solid was precipitated to obtain the crystal form H of the dihydrochloride compound of formula (I).
  • the DSC data is shown in FIG. 29
  • the 1 H NMR data is shown in FIG. 30
  • the molar ratio of compound (I) and acetonitrile is 1:0.7.
  • the molar ratio of formula (I) and chloride ion in the dihydrochloride salt form K is 1:2.
  • Example 17 At room temperature, 9.9 mg of the free base crystal form A sample described in Example 17 was placed in 0.5 ml of ethyl acetate solution and stirred overnight at room temperature to obtain a suspension, centrifuged, and air-dried to obtain a crystal of the compound of formula (I).
  • Type B The X-ray powder diffraction data of the sample is shown in Table 16, and its diffraction pattern is shown in Figure 12.
  • the TGA data is shown in FIG. 34
  • the DSC data is shown in FIG. 35
  • the 1 H NMR data is shown in FIG. 36 .
  • Example 17 At room temperature, 0.9 mg of the free base crystalline form A described in Example 17 was heated to 230° C. to obtain the crystalline form C of the compound of formula (I).
  • the X-ray powder diffraction data of the sample is shown in Table 17, and its diffraction pattern is shown in Figure 13.
  • the TGA data is shown in Figure 37, and the DSC data is shown in Figure 38.
  • the crystal form J prepared by the method of Example 1 of the present invention, the crystal form M prepared by the method of Example 2 and the crystal form A in US8420645B2 were prepared with FaSSIF (artificial intestinal fluid in fasting state) and FeSSIF (artificial intestinal fluid in satiety state) respectively.
  • a suspension was obtained, which was equilibrated at 37°C for 24 hours and filtered to obtain a saturated solution.
  • the content of the sample in the saturated solution was determined by high performance liquid chromatography (HPLC).
  • the solubility of crystal forms J and M of the present invention in FaSSIF are respectively 207.7 ⁇ g/ml and 263.0 ⁇ g/ml, which are higher than the solubility 145.5 ⁇ g/ml of crystal form A disclosed in the prior art; the present invention
  • the solubility of crystal forms J and M in FeSSIF are 31.7 ⁇ g/ml and 26.5 ⁇ g/ml, respectively, which are higher than the solubility of crystal form A disclosed in the prior art, which is 14.4 ⁇ g/ml.
  • crystal form J prepared by the method of Example 1 of the present invention
  • crystal form M prepared by the method of Example 2
  • crystal form A in US8420645B2
  • Isopar G containing 0.2% lecithin
  • the sample to be tested is fully mixed and then added to the SDC sampling system, so that the shading degree reaches an appropriate range, the experiment is started, and the particle size distribution test is carried out after sonicating for 30 seconds.
  • the crystal form of the present invention has a more uniform particle size distribution.

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Abstract

本发明涉及化学医药领域，特别是涉及一种苯甲酰胺类化合物的游离碱及二盐酸盐的新晶型及其制备方法。本发明提供了式(I)二盐酸盐晶型J，二盐酸盐晶型M，二盐酸盐晶型E，二盐酸盐晶型F，二盐酸盐晶型H，二盐酸盐晶型N，二盐酸盐晶型Q，二盐酸盐晶型S，二盐酸盐晶型T，二盐酸盐晶型K及游离碱晶型A，游离碱晶型B，游离碱晶型C制备方法和用途。本发明提供的式(I)化合物的二盐酸盐晶型J，二盐酸盐晶型M，二盐酸盐晶型E，二盐酸盐晶型F，二盐酸盐晶型H，二盐酸盐晶型N，二盐酸盐晶型Q，二盐酸盐晶型S，二盐酸盐晶型T，二盐酸盐晶型K及游离碱晶型A，游离碱晶型B，游离碱晶型C在溶解度、熔点、稳定性、溶出度、引湿性、黏附性、流动性、生物有效性以及加工性能、提纯作用、制剂生产、安全性等方面中的至少一方面上存在优势，为含式(I)化合物的游离碱及其二盐酸盐的药物制剂的制备提供了新的更好的选择，对于药物开发具有非常重要的意义。

Description

苯甲酰胺类化合物及其二盐酸盐的新晶型及其制备方法 技术领域
本发明涉及化学医药领域，特别是涉及一种苯甲酰胺类化合物的游离碱及二盐酸盐的新晶型及其制备方法。
背景技术
c-Met是一种在多种肿瘤细胞中过表达或突变的酪氨酸激酶受体，在肿瘤细胞增殖、存活、侵袭、转移和肿瘤血管生成等过程中起重要作用。2-氟-N-甲基-4-[7-(喹啉-6-基甲基)咪唑并[1,2-b][1,2,4]三嗪-2-基]苯甲酰胺是一种口服活性、强效、选择性的c-Met抑制剂，其结构式如下所示：
Figure PCTCN2021104559-appb-000001
式(I)可选择性地与c-Met结合，从而抑制了c-Met磷酸化，阻断了c-Met信号转导途径。这可能导致肿瘤细胞中过表达c-Met蛋白或表达组成性激活的c-Met蛋白的细胞死亡，具有潜在的抗肿瘤活性。式(I)除用于治疗非小细胞肺癌外，临床试验表明在黑素瘤、胶质肉瘤、实体肿瘤、结直肠癌和肝损伤等方面也有一定的治疗潜力。已被美国食品和药物管理局(FDA)授予治疗接受含铂化疗期间或之后疾病进展、携带MET外显子14跳跃突变(MET exon14 skipping)的转移性非小细胞肺癌(NSCLC)患者的突破性药物资格(BTD)，以及一线治疗携带MET外显子14跳跃突变(MET exon14 skipping)的转移性非小细胞肺癌(NSCLC)患者的BTD。
专利WO2008064157A1中首次公开了式(I)的游离碱及其盐酸盐的制备方法，在专利US8420645B2公开了一种式(I)的二盐酸盐晶体形式(以下称为晶型A，其X射线粉末衍射在2θ值为26.0°、24.7°、18.2°、29.3°和7.8°处有特征峰)，并研究了二盐酸盐晶型A在不同pH介质中溶解度，研究结果表明，式(I)的二盐酸盐晶型A在pH为7.4或8的缓冲溶液中的溶解度为0.002mg/mL，较难满足药物在生物体吸收利用的溶解需求，影响药物的生物利用度。
同一药物的多晶型可能会改变其物理化学性质，如溶解度、溶解速率、熔点和稳定性，进而可能会影响药物在人体内的作用效果。因此，有必要对式(I)的游离形式以及二盐酸盐进行全面系统的晶型筛选，开发出溶解度好、稳定性高的晶型，为药物的后续开发提供更多更好的选择。
发明内容
本发明提供了式(I)二盐酸盐晶型J，二盐酸盐晶型M，二盐酸盐晶型E，二盐酸盐晶型F，二盐酸盐晶型H，二盐酸盐晶型N，二盐酸盐晶型Q，二盐酸盐晶型S，二盐酸盐晶型T，二盐酸盐晶型K及游离碱晶型A，游离碱晶型B，游离碱晶型C制备方法和用途。
1.式(I)所示化合物2-氟-N-甲基-4-[7-(喹啉-6-基甲基)咪唑并[1,2-b][1,2,4]三嗪-2- 基]苯甲酰胺的二盐酸盐J型晶体、即二盐酸盐晶型J，其特征在于，使用Cu-Kα辐射，所述二盐酸盐晶型J的X射线粉末衍射在2θ值为6.3°±0.2°,15.0°±0.2°,26.8°±0.2°处有特征峰，
Figure PCTCN2021104559-appb-000002
2.上述1中所述的二盐酸盐晶型J的制备方法，其特征在于，
将式(I)化合物的二盐酸盐溶解于正溶剂中，过滤后向其中逐滴加入反溶剂，得到二盐酸盐晶型J。
3.式(I)所示化合物2-氟-N-甲基-4-[7-(喹啉-6-基甲基)咪唑并[1,2-b][1,2,4]三嗪-2-基]苯甲酰胺的二盐酸盐M型晶体、即二盐酸盐晶型M，其特征在于，使用Cu-Kα辐射，所述二盐酸盐晶型M的X射线粉末衍射在2θ值为6.4°±0.2°,10.4°±0.2°,14.0°±0.2°处有特征峰，
Figure PCTCN2021104559-appb-000003
4.上述3中所述的二盐酸盐晶型M的制备方法，其特征在于，
将式(I)化合物的二盐酸盐溶解于正溶剂中，过滤后向其中逐滴加入反溶剂，得到二盐酸盐晶型M。
5.式(I)所示化合物2-氟-N-甲基-4-[7-(喹啉-6-基甲基)咪唑并[1,2-b][1,2,4]三嗪-2-基]苯甲酰胺的二盐酸盐E型晶体、即二盐酸盐晶型E，其特征在于，使用Cu-Kα辐射，所述二盐酸盐晶型E的X射线粉末衍射在2θ值为5.6°±0.2°,16.8°±0.2°,11.2°±0.2°处有特征峰，
Figure PCTCN2021104559-appb-000004
6.上述5中所述的二盐酸盐晶型E的制备方法，其特征在于，
将式(I)化合物的二盐酸盐溶解于正溶剂中，过滤后向其中逐滴加入反溶剂，得到二盐酸盐晶型E。
7.式(I)所示化合物2-氟-N-甲基-4-[7-(喹啉-6-基甲基)咪唑并[1,2-b][1,2,4]三嗪-2-基]苯甲酰胺的二盐酸盐F型晶体、即二盐酸盐晶型F，其特征在于，使用Cu-Kα辐射，所述二盐酸盐晶型F的X射线粉末衍射在2θ值为6.2°±0.2°,13.0°±0.2°,14.6°±0.2°处有特征峰，
Figure PCTCN2021104559-appb-000005
8.上述7中所述的二盐酸盐晶型F的制备方法，其特征在于，
将式(I)化合物的二盐酸盐溶解于正溶剂中，过滤后向其中逐滴加入反溶剂，得到二盐酸盐晶型F。
9.式(I)所示化合物2-氟-N-甲基-4-[7-(喹啉-6-基甲基)咪唑并[1,2-b][1,2,4]三嗪-2-基]苯甲酰胺的二盐酸盐H型晶体、即二盐酸盐晶型H，其特征在于，使用Cu-Kα辐射，所述二盐酸盐晶型H的X射线粉末衍射在2θ值为9.7°±0.2°,6.5°±0.2°,13.0°±0.2°处有特征峰，
Figure PCTCN2021104559-appb-000006
10.上述9中所述的二盐酸盐晶型H的制备方法，其特征在于，
将式(I)化合物的二盐酸盐溶解于正溶剂中，过滤后将其降温，得到二盐酸盐晶型H。
11.式(I)所示化合物2-氟-N-甲基-4-[7-(喹啉-6-基甲基)咪唑并[1,2-b][1,2,4]三嗪-2-基]苯甲酰胺的二盐酸盐N型晶体、即二盐酸盐晶型N，其特征在于，使用Cu-Kα辐射，所述二盐酸盐晶型N的X射线粉末衍射在2θ值为15.1°±0.2°,16.2°±0.2°,8.8°±0.2°处有特征峰，
Figure PCTCN2021104559-appb-000007
12.上述11中所述的二盐酸盐晶型N的制备方法，其特征在于，
将式(I)化合物的溶于正溶剂中，然后置于含有盐酸的反溶剂的密封环境中，渗透析晶，得到二盐酸盐晶型N。
13.式(I)所示化合物2-氟-N-甲基-4-[7-(喹啉-6-基甲基)咪唑并[1,2-b][1,2,4]三嗪-2-基]苯甲酰胺的二盐酸盐Q型晶体、即二盐酸盐晶型Q，其特征在于，使用Cu-Kα辐射，所述二盐酸盐晶型Q的X射线粉末衍射在2θ值为9.2°±0.2°,5.8°±0.2°,10.4°±0.2°处有特征峰，
Figure PCTCN2021104559-appb-000008
14.上述13中所述的二盐酸盐晶型Q的制备方法，其特征在于，
将式(I)化合物的二盐酸盐溶解于正溶剂中，过滤后将其降温，无固体析出，转移至室温下挥发，得到二盐酸盐晶型Q。
15.式(I)所示化合物2-氟-N-甲基-4-[7-(喹啉-6-基甲基)咪唑并[1,2-b][1,2,4]三嗪-2-基]苯甲酰胺的二盐酸盐S型晶体、即二盐酸盐晶型S，其特征在于，使用Cu-Kα辐射，所述二盐酸盐晶型S的X射线粉末衍射在2θ值为26.7°±0.2°,13.2°±0.2°,10.5°±0.2°处有特征峰，
Figure PCTCN2021104559-appb-000009
16.上述15中所述的二盐酸盐晶型S的制备方法，其特征在于，
将式(I)化合物的二盐酸盐溶于正溶剂中，然后置于含有盐酸的反溶剂的密封环境中，渗透，无固体析出，转移至室温下挥发，得到二盐酸盐晶型S。
17.式(I)所示化合物2-氟-N-甲基-4-[7-(喹啉-6-基甲基)咪唑并[1,2-b][1,2,4]三嗪-2-基]苯甲酰胺的二盐酸盐T型晶体、即二盐酸盐晶型T，其特征在于，使用Cu-Kα辐射，所述二盐酸盐晶型T的X射线粉末衍射在2θ值为6.5°±0.2°,4.4°±0.2°,10.9°±0.2°处有特征峰，
Figure PCTCN2021104559-appb-000010
18.上述17中所述的二盐酸盐晶型T的制备方法，其特征在于，
将式(I)二盐酸盐化合物溶于正溶剂中，然后置于反溶剂的密封环境中，渗透析晶，得到二盐酸盐晶型T。
19.式(I)所示化合物2-氟-N-甲基-4-[7-(喹啉-6-基甲基)咪唑并[1,2-b][1,2,4]三嗪-2-基]苯甲酰胺的二盐酸盐K型晶体、即二盐酸盐晶型K，其特征在于，使用Cu-Kα辐射，所述二盐酸盐晶型K的X射线粉末衍射在2θ值为6.8°±0.2°,20.4°±0.2°,15.8°±0.2°处有特征峰，
Figure PCTCN2021104559-appb-000011
20.上述19中所述的二盐酸盐晶型K的制备方法，其特征在于，
将式(I)化合物的二盐酸盐溶解于正溶剂中，过滤后向其中逐滴加入反溶剂，得到二盐酸盐晶型K。
21.式(I)所示化合物2-氟-N-甲基-4-[7-(喹啉-6-基甲基)咪唑并[1,2-b][1,2,4]三嗪-2- 基]苯甲酰胺的A型晶体、即游离碱晶型A，其特征在于，使用Cu-Kα辐射，所述游离碱晶型A的X射线粉末衍射在2θ值为5.7°±0.2°,13.6°±0.2°,12.7°±0.2°处有特征峰，
Figure PCTCN2021104559-appb-000012
22.上述21中所述的游离碱晶型A的制备方法，其特征在于，
将式(I)二盐酸盐化合物在碱性水溶液中解离，分离固体干燥后即得游离碱晶型A。
23.式(I)所示化合物2-氟-N-甲基-4-[7-(喹啉-6-基甲基)咪唑并[1,2-b][1,2,4]三嗪-2-基]苯甲酰胺的B型晶体、即游离碱晶型B，其特征在于，使用Cu-Kα辐射，所述游离碱晶型B的X射线粉末衍射在2θ值为15.7°±0.2°,6.3°±0.2°,12.8°±0.2°处有特征峰，
Figure PCTCN2021104559-appb-000013
24.上述23中所述的游离碱晶型B的制备方法，其特征在于，
将上述21中所述游离碱晶型A在乙酸乙酯中室温悬浮搅拌过夜，分离固体干燥后即得游离碱晶型B。
25.式(I)所示化合物2-氟-N-甲基-4-[7-(喹啉-6-基甲基)咪唑并[1,2-b][1,2,4]三嗪-2-基]苯甲酰胺的C型晶体、即游离碱晶型C，其特征在于，使用Cu-Kα辐射，所述游离碱晶型C的X射线粉末衍射在2θ值为6.6°±0.2°,16.7°±0.2°,15.4°±0.2°处有特征峰，
Figure PCTCN2021104559-appb-000014
26.上述25中所述的游离碱晶型C的制备方法，其特征在于，
将上述21中所述游离碱晶型A加热到一定温度后冷却至室温，即得游离碱晶型C。
27.药物组合物，其包含上述1、3、5、7、9、11、13、15、17、19、21、23和25中任一项所述的晶体和制药学可接受的载体。
28.具有c-Met抑制活性的药物组合物，其含有上述1、3、5、7、9、11、13、15、17、19、21、23和25中任一项所述的晶体作为有效成分。
29.非小细胞肺癌及黑素瘤、胶质肉瘤、实体肿瘤、结直肠癌和肝损伤等方面的预防药或治疗药，其含有上述1、3、5、7、9、11、13、15、17、19、21、23和25中任一项所述的晶体作为有效成分。
与现有技术相比，发明提供的式(I)化合物的晶型J、晶型M、晶型E、晶型F和晶型H，在溶解度、熔点、稳定性、溶出度、引湿性、黏附性、流动性、生物有效性以及加工性能、提纯作用、制剂生产、安全性等方面中的至少一方面上存在优势，为这种新型的c-Met抑制剂的药物制剂的制备提供了新的更好的选择，对于药物开发具有非常重要的意义。
附图说明
图1二盐酸盐晶型J的XRPD图
图2二盐酸盐晶型M的XRPD图
图3二盐酸盐晶型E的XRPD图
图4二盐酸盐晶型F的XRPD图
图5二盐酸盐晶型H的XRPD图
图6二盐酸盐晶型N的XRPD图
图7二盐酸盐晶型Q的XRPD图
图8二盐酸盐晶型S的XRPD图
图9二盐酸盐晶型T的XRPD图
图10二盐酸盐晶型K的XRPD图
图11游离碱晶型A的XRPD图
图12游离碱晶型B的XRPD图
图13游离碱晶型C的XRPD图
图14二盐酸盐晶型M的TGA曲线
图15二盐酸盐晶型M的DSC曲线
图16二盐酸盐晶型M的 1H NMR图
图17二盐酸盐晶型E的TGA曲线
图18二盐酸盐晶型E的DSC曲线
图19二盐酸盐晶型E的 1H NMR图
图20二盐酸盐晶型F的TGA曲线
图21二盐酸盐晶型F的DSC曲线
图22二盐酸盐晶型F的 1H NMR图
图23二盐酸盐晶型H的TGA曲线
图24二盐酸盐晶型H的DSC曲线
图25二盐酸盐晶型H的 1H NMR图
图26二盐酸盐晶型N的TGA曲线
图27二盐酸盐晶型N的DSC曲线
图28二盐酸盐晶型K的TGA曲线
图29二盐酸盐晶型K的DSC曲线
图30二盐酸盐晶型K的 1H NMR图
图31游离碱晶型A的TGA曲线
图32游离碱晶型A的DSC曲线
图33游离碱晶型A的 1H NMR图
图34游离碱晶型B的TGA曲线
图35游离碱晶型B的DSC曲线
图36游离碱晶型B的 1H NMR图谱
图37游离碱晶型C的TGA曲线
图38游离碱晶型C的DSC曲线
具体实施方式
式(I)所示化合物2-氟-N-甲基-4-[7-(喹啉-6-基甲基)咪唑并[1,2-b][1,2,4]三嗪-2-基]苯甲酰胺的二盐酸盐J型晶体、即二盐酸盐晶型J，其特征在于，使用Cu-Kα辐射，所述二盐酸盐晶型J的X射线粉末衍射在2θ值为6.3°±0.2°,15.0°±0.2°,26.8°±0.2°处有特征峰，
Figure PCTCN2021104559-appb-000015
在本发明的一个实施方式中，所述二盐酸盐晶型J的X射线粉末衍射在2θ值为13.2°±0.2°,17.5°±0.2°,25.4°±0.2°中的一处或两处或三处有特征峰。
在本发明的一个实施方式中，所述二盐酸盐晶型J的X射线粉末衍射在2θ值为13.2°±0.2°,17.5°±0.2°,25.4°±0.2°处有特征峰。
在本发明的一个实施方式中，所述二盐酸盐晶型J的X射线粉末衍射在2θ值为16.8°±0.2°,24.1°±0.2°,10.3°±0.2°中的一处或两处或三处有特征峰。
在本发明的一个实施方式中，所述二盐酸盐晶型J的X射线粉末衍射在2θ值为16.8°±0.2°,24.1°±0.2°,10.3°±0.2°处有特征峰。
在本发明的一个实施方式中，所述二盐酸盐晶型J的X射线粉末衍射在2θ值为6.3°±0.2°,15.0°±0.2°,26.8°±0.2°,13.2°±0.2°,17.5°±0.2°,25.4°±0.2°,16.8°±0.2°,24.1°±0.2°,10.3°±0.2°中的任意4处、或5处、或6处、或7处、或8处、或9处有特征峰。
在本发明的一个实施方式中，所述二盐酸盐晶型J的X射线粉末衍射在2θ值为6.3°±0.2°,15.0°±0.2°,26.8°±0.2°,13.2°±0.2°,17.5°±0.2°,25.4°±0.2°,16.8°±0.2°,24.1°±0.2°,10.3°±0.2°处有特征峰。
在本发明的一个实施方式中，二盐酸盐晶型J的X射线粉末衍射图如图1所示。
所述二盐酸盐晶型J的制备方法，其特征为，
将式(I)二盐酸盐化合物溶解于甲醇，过滤后滴加到环戊基甲醚进行反向反溶剂添加，样品溶清，转移至低温下静置，过夜后固体析出，即得二盐酸盐晶型J。
在本发明的一个实施方式中，所述溶解温度为20℃至30℃。
在本发明的一个实施方式中，所述析出温度为-20℃至5℃。
式(I)所示化合物2-氟-N-甲基-4-[7-(喹啉-6-基甲基)咪唑并[1,2-b][1,2,4]三嗪-2-基]苯甲酰胺的二盐酸盐M型晶体、即二盐酸盐晶型M，其特征在于，使用Cu-Kα辐射，所述二盐酸盐晶型M的X射线粉末衍射在2θ值为6.4°±0.2°,10.4°±0.2°,14.0°±0.2°处有特征峰，
Figure PCTCN2021104559-appb-000016
在本发明的一个实施方式中，所述二盐酸盐晶型M的X射线粉末衍射在2θ值为24.7°±0.2°,8.2°±0.2°,7.6°±0.2°中的一处或两处或三处有特征峰。
在本发明的一个实施方式中，所述二盐酸盐晶型M的X射线粉末衍射在2θ值为24.7°±0.2°,8.2°±0.2°,7.6°±0.2°处有特征峰。
在本发明的一个实施方式中，所述二盐酸盐晶型M的X射线粉末衍射在2θ值为15.3°±0.2°,28.3°±0.2°,23.1°±0.2°中的一处或两处或三处有特征峰。
在本发明的一个实施方式中，所述二盐酸盐晶型M的X射线粉末衍射在2θ值为15.3°±0.2°,28.3°±0.2°,23.1°±0.2°处有特征峰。
在本发明的一个实施方式中，所述二盐酸盐晶型M的X射线粉末衍射在2θ值为6.4°±0.2°,10.4°±0.2°,14.0°±0.2°,24.7°±0.2°,8.2°±0.2°,7.6°±0.2°,15.3°±0.2°,28.3°±0.2°,23.1°±0.2°中的任意4处、或5处、或6处、或7处、或8处、或9处有特征峰。
在本发明的一个实施方式中，所述二盐酸盐晶型M的X射线粉末衍射在2θ值为6.4°±0.2°,10.4°±0.2°,14.0°±0.2°,24.7°±0.2°,8.2°±0.2°,7.6°±0.2°,15.3°±0.2°,28.3°±0.2°,23.1°±0.2°处有特征峰。
在本发明的一个实施方式中，二盐酸盐晶型M的X射线粉末衍射图如图2所示。
所述二盐酸盐晶型M的制备方法，其特征为，
将式(I)二盐酸盐化合物高温溶解于甲醇中，过滤后滴加预冷的甲基叔丁基醚进行反溶剂添加，固体析出，即得二盐酸盐晶型M样品。
在本发明的一个实施方式中，所述高温为40℃至60℃。
在本发明的一个实施方式中，所述预冷温度为-20℃至0℃。
式(I)所示化合物2-氟-N-甲基-4-[7-(喹啉-6-基甲基)咪唑并[1,2-b][1,2,4]三嗪-2-基]苯甲酰胺的二盐酸盐E型晶体、即二盐酸盐晶型E，其特征在于，使用Cu-Kα辐射，所述二盐酸盐晶型E的X射线粉末衍射在2θ值为5.6°±0.2°,16.8°±0.2°,11.2°±0.2°处有特征峰，
Figure PCTCN2021104559-appb-000017
在本发明的一个实施方式中，所述二盐酸盐晶型E的X射线粉末衍射在2θ值为22.5°±0.2°, 14.6°±0.2°,15.3°±0.2°中的一处或两处或三处有特征峰。
在本发明的一个实施方式中，所述二盐酸盐晶型E的X射线粉末衍射在2θ值为22.5°±0.2°,14.6°±0.2°,15.3°±0.2°处有特征峰。
在本发明的一个实施方式中，所述二盐酸盐晶型E的X射线粉末衍射在2θ值为24.0°±0.2°,12.0°±0.2°,17.4°±0.2°中的一处或两处或三处有特征峰。
在本发明的一个实施方式中，所述二盐酸盐晶型E的X射线粉末衍射在2θ值为24.0°±0.2°,12.0°±0.2°,17.4°±0.2°处有特征峰。
在本发明的一个实施方式中，所述二盐酸盐晶型E的X射线粉末衍射在2θ值为5.6°±0.2°,16.8°±0.2°,11.2°±0.2°,22.5°±0.2°,14.6°±0.2°,15.3°±0.2°,24.0°±0.2°,12.0°±0.2°,17.4°±0.2°中的任意4处、或5处、或6处、或7处、或8处、或9处有特征峰。
在本发明的一个实施方式中，所述二盐酸盐晶型E的X射线粉末衍射在2θ值为5.6°±0.2°,16.8°±0.2°,11.2°±0.2°,22.5°±0.2°,14.6°±0.2°,15.3°±0.2°,24.0°±0.2°,12.0°±0.2°,17.4°±0.2°处有特征峰。
在本发明的一个实施方式中，所述二盐酸盐晶型E的X射线粉末衍射图如图3所示。
所述二盐酸盐晶型E的制备方法，其特征在于，
将式(I)二盐酸盐化合物溶解于甲醇中，过滤之后，向滤液中滴加乙腈，搅拌得到悬浊液，之后将固体分离即得二盐酸盐晶型E。
在本发明的一个实施方式中，所述溶解温度为20℃到55℃，优选20℃到30℃。
在本发明的一个实施方式中，所述反溶剂添加温度为20℃到30℃。
在本发明的一个实施方式中，所述搅拌温度为-25℃到30℃。
在本发明的一个实施方式中，过滤后向滤液中缓慢滴加反溶剂。
式(I)所示化合物2-氟-N-甲基-4-[7-(喹啉-6-基甲基)咪唑并[1,2-b][1,2,4]三嗪-2-基]苯甲酰胺的二盐酸盐F型晶体、即二盐酸盐晶型F，其特征在于，使用Cu-Kα辐射，所述二盐酸盐晶型F的X射线粉末衍射在2θ值为6.2°±0.2°,13.0°±0.2°,14.6°±0.2°处有特征峰，
Figure PCTCN2021104559-appb-000018
在本发明的一个实施方式中，所述二盐酸盐晶型F的X射线粉末衍射在2θ值为18.4°±0.2°,9.9°±0.2°,23.9°±0.2°中的一处或两处或三处有特征峰。
在本发明的一个实施方式中，所述二盐酸盐晶型F的X射线粉末衍射在2θ值为18.4°±0.2°,9.9°±0.2°,23.9°±0.2°处有特征峰。
在本发明的一个实施方式中，所述二盐酸盐晶型F的X射线粉末衍射在2θ值为7.7°±0.2°,15.6°±0.2°中的一处或两处有特征峰。
在本发明的一个实施方式中，所述二盐酸盐晶型F的X射线粉末衍射在2θ值为7.7°±0.2°,15.6°±0.2°处有特征峰。
在本发明的一个实施方式中，所述二盐酸盐晶型F的X射线粉末衍射在2θ值为6.2°±0.2°,13.0°±0.2°,14.6°±0.2°,18.4°±0.2°,9.9°±0.2°,23.9°±0.2°,7.7°±0.2°,15.6°±0.2°中的任意4处、或5处、或6处、或7处、或8处有特征峰。
在本发明的一个实施方式中，所述二盐酸盐晶型F的X射线粉末衍射在2θ值为6.2°±0.2°,13.0°±0.2°,14.6°±0.2°,18.4°±0.2°,9.9°±0.2°,23.9°±0.2°,7.7°±0.2°,15.6°±0.2°处有特征峰。
在本发明的一个实施方式中，二盐酸盐晶型F的X射线粉末衍射图如图4所示。
所述二盐酸盐晶型F的制备方法，其特征在于，
将式(I)二盐酸盐化合物溶解于甲醇中，过滤之后，向滤液中滴加甲基叔丁基醚、乙酸乙酯或环戊基甲醚，得到悬浊液，在一定温度下之悬浮搅拌后，分离固体即得二盐酸盐晶型F。
在本发明的一个实施方式中，所述溶解温度为20℃到55℃，优选20℃到30℃。
在本发明的一个实施方式中，所述反溶剂添加温度为20℃到30℃。
在本发明的一个实施方式中，所述搅拌温度为-25℃到30℃。
在本发明的一个实施方式中，过滤后向滤液中缓慢滴加反溶剂。
在本发明的一个实施方式中，搅拌0.5小时到1天至有固体析出，例如搅拌0.5小时。
式(I)所示化合物2-氟-N-甲基-4-[7-(喹啉-6-基甲基)咪唑并[1,2-b][1,2,4]三嗪-2-基]苯甲酰胺的二盐酸盐H型晶体、即二盐酸盐晶型H，其特征在于，使用Cu-Kα辐射，所述二盐酸盐晶型H的X射线粉末衍射在2θ值为9.7°±0.2°,6.5°±0.2°,13.0°±0.2°处有特征峰，
Figure PCTCN2021104559-appb-000019
在本发明的一个实施方式中，所述二盐酸盐晶型H的X射线粉末衍射在2θ值为26.7°±0.2°,14.2°±0.2°中的一处或两处有特征峰。
在本发明的一个实施方式中，所述二盐酸盐晶型H的X射线粉末衍射在2θ值为26.7°±0.2°,14.2°±0.2°处有特征峰。
在本发明的一个实施方式中，所述二盐酸盐晶型H的X射线粉末衍射在2θ值为14.7°±0.2°,12.7°±0.2°中的一处或两处有特征峰。
在本发明的一个实施方式中，所述二盐酸盐晶型H的X射线粉末衍射在2θ值为14.7°±0.2°,12.7°±0.2°处有特征峰。
在本发明的一个实施方式中，所述二盐酸盐晶型H的X射线粉末衍射在2θ值为9.7°±0.2°,6.5°±0.2°,13.0°±0.2°,26.7°±0.2°,14.2°±0.2°,14.7°±0.2°,12.7°±0.2°中的任意4处、或5处、或6处、或7处有特征峰。
在本发明的一个实施方式中，所述二盐酸盐晶型H的X射线粉末衍射在2θ值为9.7°±0.2°,6.5°±0.2°,13.0°±0.2°,26.7°±0.2°,14.2°±0.2°,14.7°±0.2°,12.7°±0.2°处有特征峰。
在本发明的一个实施方式中，二盐酸盐晶型H的X射线粉末衍射图如图5所示。
所述二盐酸盐晶型H的制备方法，其特征包括，
将式(I)二盐酸盐化合物在高温下溶于正溶剂中，过滤后将其降温，析出固体即得二盐酸盐晶型H。其中，所述正溶剂选自甲醇、甲醇/二氯甲烷(体积比4:1)、乙醇。
在本发明的一个实施方式中，所述溶解条件为40℃至60℃，例如50℃。
在本发明的一个实施方式中，所述析晶温度为-20℃至5℃，例如-20℃。
在本发明的一个实施方式中，所述降温为快速降温。
在本发明的一个实施方式中，所述降温为降温速率为0.05℃/分钟至0.5℃/分钟。
式(I)所示化合物2-氟-N-甲基-4-[7-(喹啉-6-基甲基)咪唑并[1,2-b][1,2,4]三嗪-2-基]苯甲酰胺的二盐酸盐N型晶体、即二盐酸盐晶型N，其特征在于，使用Cu-Kα辐射，所述二盐酸盐晶型N的X射线粉末衍射在2θ值为15.1°±0.2°,16.2°±0.2°,8.8°±0.2°处有特征峰，
Figure PCTCN2021104559-appb-000020
在本发明的一个实施方式中，所述二盐酸盐晶型N的X射线粉末衍射在2θ值为7.6°±0.2°,14.2°±0.2°,27.6°±0.2°中的一处或两处或三处有特征峰。
在本发明的一个实施方式中，所述二盐酸盐晶型N的X射线粉末衍射在2θ值为7.6°±0.2°,14.2°±0.2°,27.6°±0.2°处有特征峰。
在本发明的一个实施方式中，所述二盐酸盐晶型N的X射线粉末衍射在2θ值为12.7°±0.2°,19.8°±0.2°,23.3°±0.2°中的一处或两处或三处有特征峰。
在本发明的一个实施方式中，所述二盐酸盐晶型N的X射线粉末衍射在2θ值为12.7°±0.2°,19.8°±0.2°,23.3°±0.2°处有特征峰。
在本发明的一个实施方式中，所述二盐酸盐晶型N的X射线粉末衍射在2θ值为15.1°±0.2°,16.2°±0.2°,8.8°±0.2°,7.6°±0.2°,14.2°±0.2°,27.6°±0.2°,12.7°±0.2°,19.8°±0.2°,23.3°±0.2°中的任意4处、或5处、或6处、或7处、或8处、或9处有特征峰。
在本发明的一个实施方式中，所述二盐酸盐晶型N的X射线粉末衍射在2θ值为15.1°±0.2°,16.2°±0.2°,8.8°±0.2°,7.6°±0.2°,14.2°±0.2°,27.6°±0.2°,12.7°±0.2°,19.8°±0.2°,23.3°±0.2°处有特征峰。
在本发明的一个实施方式中，二盐酸盐晶型N的X射线粉末衍射图如图6所示。
所述二盐酸盐晶型N的制备方法，其特征为，
将式(I)化合物溶解于甲醇中，然后在含有盐酸的反溶剂氛围下进行气液渗透一段时间，得到二盐酸盐晶型N。其中，所述反溶剂选自盐酸乙酸乙酯饱和溶液、盐酸乙酸乙酯饱和溶液/甲基叔丁基醚(体积比1:1)混合溶剂。
在本发明的一个实施方式中，所述溶解与渗透温度为20℃至30℃。
在本发明的一个实施方式中，所述渗透时间为1至4周，例如2周。
式(I)所示化合物2-氟-N-甲基-4-[7-(喹啉-6-基甲基)咪唑并[1,2-b][1,2,4]三嗪-2-基]苯 甲酰胺的二盐酸盐Q型晶体、即二盐酸盐晶型Q，其特征在于，使用Cu-Kα辐射，所述二盐酸盐晶型Q的X射线粉末衍射在2θ值为9.2°±0.2°,5.8°±0.2°,10.4°±0.2°处有特征峰，
Figure PCTCN2021104559-appb-000021
在本发明的一个实施方式中，所述二盐酸盐晶型Q的X射线粉末衍射在2θ值为18.5°±0.2°,14.7°±0.2°,16.2°±0.2°中的一处或两处或三处有特征峰。
在本发明的一个实施方式中，所述二盐酸盐晶型Q的X射线粉末衍射在2θ值为18.5°±0.2°,14.7°±0.2°,16.2°±0.2°处有特征峰。
在本发明的一个实施方式中，所述二盐酸盐晶型Q的X射线粉末衍射在2θ值为11.8°±0.2°,20.5°±0.2°中的一处或两处或三处有特征峰。
在本发明的一个实施方式中，所述二盐酸盐晶型Q的X射线粉末衍射在2θ值为11.8°±0.2°,20.5°±0.2°处有特征峰。
在本发明的一个实施方式中，所述二盐酸盐晶型Q的X射线粉末衍射在2θ值为9.2°±0.2°,5.8°±0.2°,10.4°±0.2°,18.5°±0.2°,14.7°±0.2°,16.2°±0.2°,11.8°±0.2°,20.5°±0.2°中的任意4处、或5处、或6处、或7处、或8处有特征峰。
在本发明的一个实施方式中，所述二盐酸盐晶型Q的X射线粉末衍射在2θ值为9.2°±0.2°,5.8°±0.2°,10.4°±0.2°,18.5°±0.2°,14.7°±0.2°,16.2°±0.2°,11.8°±0.2°,20.5°±0.2°处有特征峰。
在本发明的一个实施方式中，二盐酸盐晶型Q的X射线粉末衍射图如图7所示。
所述二盐酸盐晶型Q的制备方法，其特征为，
将式(I)二盐酸盐化合物溶解于纯水中，之后快速降温，无固体析出，转移至室温下挥发一段时间，即得二盐酸盐晶型Q。
式(I)所示化合物2-氟-N-甲基-4-[7-(喹啉-6-基甲基)咪唑并[1,2-b][1,2,4]三嗪-2-基]苯甲酰胺的二盐酸盐S型晶体、即二盐酸盐晶型S，其特征在于，使用Cu-Kα辐射，所述二盐酸盐晶型S的X射线粉末衍射在2θ值为26.7°±0.2°,13.2°±0.2°,10.5°±0.2°处有特征峰，
Figure PCTCN2021104559-appb-000022
在本发明的一个实施方式中，所述二盐酸盐晶型S的X射线粉末衍射在2θ值为6.7°±0.2°,12.7°±0.2°,19.2°±0.2°中的一处或两处有特征峰。
在本发明的一个实施方式中，所述二盐酸盐晶型S的X射线粉末衍射在2θ值为6.7°±0.2°,12.7°±0.2°,19.2°±0.2°处有特征峰。
在本发明的一个实施方式中，所述二盐酸盐晶型S的X射线粉末衍射在2θ值为18.5°±0.2°, 8.1°±0.2°,29.6±0.2°中的一处或两处或三处有特征峰。
在本发明的一个实施方式中，所述二盐酸盐晶型S的X射线粉末衍射在2θ值为18.5°±0.2°,8.1°±0.2°,29.6±0.2°处有特征峰。
在本发明的一个实施方式中，所述二盐酸盐晶型S的X射线粉末衍射在2θ值为26.7°±0.2°,13.2°±0.2°,10.5°±0.2°,6.7°±0.2°,12.7°±0.2°,19.2°±0.2°,18.5°±0.2°,8.1°±0.2°,29.6±0.2°中的任意4处、或5处、或6处、或7处、或8处、或9处有特征峰。
在本发明的一个实施方式中，所述二盐酸盐晶型S的X射线粉末衍射在2θ值为26.7°±0.2°,13.2°±0.2°,10.5°±0.2°,6.7°±0.2°,12.7°±0.2°,19.2°±0.2°,18.5°±0.2°,8.1°±0.2°,29.6±0.2°处有特征峰。
在本发明的一个实施方式中，二盐酸盐晶型S的X射线粉末衍射图如图8所示。
所述二盐酸盐晶型S的制备方法，其特征为，
将式(I)化合物溶解于甲醇中，置于盐酸乙酸乙酯饱和溶液/甲基乙基酮(体积比1:1)混合溶液的氛围下进行气液渗透，未有固体析出，转移至室温下挥发，得到二盐酸盐晶型S。
式(I)所示化合物2-氟-N-甲基-4-[7-(喹啉-6-基甲基)咪唑并[1,2-b][1,2,4]三嗪-2-基]苯甲酰胺的二盐酸盐T型晶体、即二盐酸盐晶型T，其特征在于，使用Cu-Kα辐射，所述二盐酸盐晶型T的X射线粉末衍射在2θ值为6.5°±0.2°,4.4°±0.2°,10.9°±0.2°处有特征峰，
Figure PCTCN2021104559-appb-000023
在本发明的一个实施方式中，所述二盐酸盐晶型T的X射线粉末衍射在2θ值为15.2°±0.2°,17.0°±0.2°,24.0°±0.2°中的一处或两处或三处有特征峰。
在本发明的一个实施方式中，所述二盐酸盐晶型T的X射线粉末衍射在2θ值为15.2°±0.2°,17.0°±0.2°,24.0°±0.2°处有特征峰。
在本发明的一个实施方式中，所述二盐酸盐晶型T的X射线粉末衍射在2θ值为12.4°±0.2°,22.4°±0.2°,27.6±0.2°中的一处或两处或三处有特征峰。
在本发明的一个实施方式中，所述二盐酸盐晶型T的X射线粉末衍射在2θ值为12.4°±0.2°,22.4°±0.2°,27.6±0.2°处有特征峰。
在本发明的一个实施方式中，所述二盐酸盐晶型T的X射线粉末衍射在2θ值为6.5°±0.2°,4.4°±0.2°,10.9°±0.2°,15.2°±0.2°,17.0°±0.2°,24.0°±0.2°,12.4°±0.2°,22.4°±0.2°,27.6±0.2°中的任意4处、或5处、或6处、或7处、或8处、或9处有特征峰。
在本发明的一个实施方式中，所述二盐酸盐晶型T的X射线粉末衍射在2θ值为6.5°±0.2°,4.4°±0.2°,10.9°±0.2°,15.2°±0.2°,17.0°±0.2°,24.0°±0.2°,12.4°±0.2°,22.4°±0.2°,27.6±0.2°处有特征峰。
在本发明的一个实施方式中，二盐酸盐晶型T的X射线粉末衍射图如图9所示。
所述二盐酸盐晶型T的制备方法，其特征为，
将式(I)化合物溶解于甲醇中，然后在异丙醇氛围下进行气液渗透一段时间，得到二盐酸盐晶型T。
在本发明的一个实施方式中，所述溶解与渗透温度为20℃至30℃。
在本发明的一个实施方式中，所述一段时间为1至4周，例如2周。
式(I)所示化合物2-氟-N-甲基-4-[7-(喹啉-6-基甲基)咪唑并[1,2-b][1,2,4]三嗪-2-基]苯甲酰胺的二盐酸盐K型晶体、即二盐酸盐晶型K，其特征在于，使用Cu-Kα辐射，所述二盐酸盐晶型K的X射线粉末衍射在2θ值为6.8°±0.2°,20.4°±0.2°,15.8°±0.2°处有特征峰，
Figure PCTCN2021104559-appb-000024
在本发明的一个实施方式中，所述二盐酸盐晶型K的X射线粉末衍射在2θ值为14.5°±0.2°,22.0°±0.2°,27.8°±0.2°中的一处或两处或三处有特征峰。
在本发明的一个实施方式中，所述二盐酸盐晶型K的X射线粉末衍射在2θ值为14.5°±0.2°,22.0°±0.2°,27.8°±0.2°处有特征峰。
在本发明的一个实施方式中，所述二盐酸盐晶型K的X射线粉末衍射在2θ值为27.1°±0.2°,21.3°±0.2°,30.8°±0.2°中的一处或两处或三处有特征峰。
在本发明的一个实施方式中，所述二盐酸盐晶型K的X射线粉末衍射在2θ值为27.1°±0.2°,21.3°±0.2°,30.8°±0.2°处有特征峰。
在本发明的一个实施方式中，所述二盐酸盐晶型K的X射线粉末衍射在2θ值为6.8°±0.2°,20.4°±0.2°,15.8°±0.2°,14.5°±0.2°,22.0°±0.2°,27.8°±0.2°,27.1°±0.2°,21.3°±0.2°,30.8°±0.2°中的任意4处、或5处、或6处、或7处、或8处、或9处有特征峰。
在本发明的一个实施方式中，所述二盐酸盐晶型K的X射线粉末衍射在2θ值为6.8°±0.2°,20.4°±0.2°,15.8°±0.2°,14.5°±0.2°,22.0°±0.2°,27.8°±0.2°,27.1°±0.2°,21.3°±0.2°,30.8°±0.2°处有特征峰。
在本发明的一个实施方式中，二盐酸盐晶型K的X射线粉末衍射图如图10所示。
所述二盐酸盐晶型K的制备方法，其特征为，
将式(I)二盐酸盐化合物高温溶解于甲醇中，过滤后滴加预冷的乙腈进行反溶剂添加，固体析出，即得二盐酸盐晶型K样品。
在本发明的一个实施方式中，所述溶解温度为40℃至60℃。
在本发明的一个实施方式中，所述预冷温度为-20℃至0℃。
式(I)所示化合物2-氟-N-甲基-4-[7-(喹啉-6-基甲基)咪唑并[1,2-b][1,2,4]三嗪-2-基]苯甲酰胺的A型晶体、即游离碱晶型A，其特征在于，使用Cu-Kα辐射，所述游离碱晶型A的X射线粉末衍射在2θ值为5.7°±0.2°,13.6°±0.2°,12.7°±0.2°处有特征峰，
Figure PCTCN2021104559-appb-000025
在本发明的一个实施方式中，所述游离碱晶型A的X射线粉末衍射在2θ值为17.5°±0.2°,16.6°±0.2°,24.9°±0.2°中的一处或两处或三处有特征峰。
在本发明的一个实施方式中，所述游离碱晶型A的X射线粉末衍射在2θ值为17.5°±0.2°,16.6°±0.2°,24.9°±0.2°处有特征峰。
在本发明的一个实施方式中，所述游离碱晶型A的X射线粉末衍射在2θ值为14.1°±0.2°,23.8°±0.2°,19.1°±0.2°中的一处或两处或三处有特征峰。
在本发明的一个实施方式中，所述游离碱晶型A的X射线粉末衍射在2θ值为14.1°±0.2°,23.8°±0.2°,19.1°±0.2°处有特征峰。
在本发明的一个实施方式中，所述游离碱晶型A的X射线粉末衍射在2θ值为5.7°±0.2°,13.6°±0.2°,12.7°±0.2°,17.5°±0.2°,16.6°±0.2°,24.9°±0.2°,14.1°±0.2°,23.8°±0.2°,19.1°±0.2°中的任意4处、或5处、或6处、或7处、或8处、或9处有特征峰。
在本发明的一个实施方式中，所述游离碱晶型A的X射线粉末衍射在2θ值为5.7°±0.2°,13.6°±0.2°,12.7°±0.2°,17.5°±0.2°,16.6°±0.2°,24.9°±0.2°,14.1°±0.2°,23.8°±0.2°,19.1°±0.2°处有特征峰。
在本发明的一个实施方式中，游离碱晶型A的X射线粉末衍射图如图11所示。
所述游离碱晶型A的制备方法，其特征为，
将式(I)二盐酸盐化合物使用碳酸氢钠溶液室温搅拌过夜，分离固体干燥后即得游离碱晶型A。
式(I)所示化合物2-氟-N-甲基-4-[7-(喹啉-6-基甲基)咪唑并[1,2-b][1,2,4]三嗪-2-基]苯甲酰胺的B型晶体、即游离碱晶型B，其特征在于，使用Cu-Kα辐射，所述游离碱晶型B的X射线粉末衍射在2θ值为15.7°±0.2°,6.3°±0.2°,12.8°±0.2°处有特征峰，
Figure PCTCN2021104559-appb-000026
在本发明的一个实施方式中，所述游离碱晶型B的X射线粉末衍射在2θ值为16.7°±0.2°,17.9°±0.2°,19.2°±0.2°中的一处或两处或三处有特征峰。
在本发明的一个实施方式中，所述游离碱晶型B的X射线粉末衍射在2θ值为16.7°±0.2°,17.9°±0.2°,19.2°±0.2°处有特征峰。
在本发明的一个实施方式中，所述游离碱晶型B的X射线粉末衍射在2θ值为25.1°±0.2°,10.8°±0.2°,14.0°±0.2°中的一处或两处或三处有特征峰。
在本发明的一个实施方式中，所述游离碱晶型B的X射线粉末衍射在2θ值为25.1°±0.2°,10.8°±0.2°,14.0°±0.2°处有特征峰。
在本发明的一个实施方式中，所述游离碱晶型B的X射线粉末衍射在2θ值为15.7°±0.2°,6.3°±0.2°,12.8°±0.2°,16.7°±0.2°,17.9°±0.2°,19.2°±0.2°,25.1°±0.2°,10.8°±0.2°,14.0°±0.2°中的任意4处、或5处、或6处、或7处、或8处、或9处有特征峰。
在本发明的一个实施方式中，所述游离碱晶型B的X射线粉末衍射在2θ值为15.7°±0.2°,6.3°±0.2°,12.8°±0.2°,16.7°±0.2°,17.9°±0.2°,19.2°±0.2°,25.1°±0.2°,10.8°±0.2°,14.0°±0.2°处有特征峰。
在本发明的一个实施方式中，游离碱晶型B的X射线粉末衍射图如图12所示。
所述游离碱晶型B的制备方法，其特征为，
将权利要求21中所述晶型样品在乙酸乙酯中室温搅拌过夜，分离固体干燥后即得游离碱晶型B。
式(I)所示化合物2-氟-N-甲基-4-[7-(喹啉-6-基甲基)咪唑并[1,2-b][1,2,4]三嗪-2-基]苯甲酰胺的C型晶体、即游离碱晶型C，其特征在于，使用Cu-Kα辐射，所述游离碱晶型C的X射线粉末衍射在2θ值为6.6°±0.2°,16.7°±0.2°,15.4°±0.2°处有特征峰，
Figure PCTCN2021104559-appb-000027
在本发明的一个实施方式中，所述游离碱晶型C的X射线粉末衍射在2θ值为12.8°±0.2°,10.7°±0.2°,21.1°±0.2°中的一处或两处或三处有特征峰。
在本发明的一个实施方式中，所述游离碱晶型C的X射线粉末衍射在2θ值为12.8°±0.2°,10.7°±0.2°,21.1°±0.2°处有特征峰。
在本发明的一个实施方式中，所述游离碱晶型C的X射线粉末衍射在2θ值为26.7°±0.2°,24.9°±0.2°,23.1°±0.2°中的一处或两处或三处有特征峰。
在本发明的一个实施方式中，所述游离碱晶型C的X射线粉末衍射在2θ值为26.7°±0.2°,24.9°±0.2°,23.1°±0.2°处有特征峰。
在本发明的一个实施方式中，所述游离碱晶型C的X射线粉末衍射在2θ值为6.6°±0.2°,16.7°±0.2°,15.4°±0.2°,12.8°±0.2°,10.7°±0.2°,21.1°±0.2°,26.7°±0.2°,24.9°±0.2°,23.1°±0.2°中的任意4处、或5处、或6处、或7处、或8处、或9处有特征峰。
在本发明的一个实施方式中，所述游离碱晶型C的X射线粉末衍射在2θ值为6.6°±0.2°,16.7°±0.2°,15.4°±0.2°,12.8°±0.2°,10.7°±0.2°,21.1°±0.2°,26.7°±0.2°,24.9°±0.2°,23.1°±0.2°处有特征峰。
在本发明的一个实施方式中，游离碱晶型C的X射线粉末衍射图如图13所示。
所述游离碱晶型C的制备方法，其特征为，
将权利要求21中所述晶型样品加热到一定温度冷却后得到游离碱晶型C。
在本发明的一个实施方式中，所述的加热温度范围为105℃至250℃。
在本发明的一个实施方式中，所述的冷却后的温度为0℃至30℃。
根据本发明，作为原料的所述式(I)和/或其盐指其固体(晶体或无定形)、半固体、蜡或油形式。优选地，作为原料的化合物和/或其盐为固体粉末形式。所述“搅拌”，采用本领域的常规方法完成，例如磁力搅拌或机械搅拌，搅拌速度为50-1800转/分钟，其中，磁力搅拌优选为300-900转/分钟，机械搅拌优选为100-300转/分钟。
本发明中，“晶体”或“多晶型”指的是被所示的X射线衍射图表征所证实的。本领域技术人员能够理解，这里所讨论的理化性质可以被表征，其中的实验误差取决于仪器的条件、样品的准备和样品的纯度。特别是，本领域技术人员公知，X射线衍射图通常会随着仪器的条件而有所改变。特别需要指出的是，X射线衍射图的相对强度也可能随着实验条件的变化而变化，所以峰强度的顺序不能作为唯一或决定性因素。事实上，XRPD图谱中衍射峰的相对强度与晶体的择优取向有关，本文所示的峰强度为说明性而非用于绝对比较。另外，峰角度的实验误差通常在5％或更少，这些角度的误差也应该被考虑进去，通常允许有±0.2°的误差。另外，由于样品厚度等实验因素的影响，会造成峰角度的整体偏移，通常允许一定的偏移。因而，本领域技术人员可以理解的是，本发明中一个晶型的X射线衍射图不必和这里所指的例子中的X射线衍射图完全一致，本文所述“XRPD图相同”并非指绝对相同，相同峰位置可相差±0.2°且峰强度允许一定可变性。任何具有和这些图谱中的特征峰相同或相似的图的晶型均属于本发明的范畴之内。本领域技术人员能够将本发明所列的图谱和一个未知晶型的图谱相比较，以证实这两组图谱反映的是相同还是不同的晶型。
在一些实施方案中，本发明的二盐酸盐晶型J，晶型M，晶型E，晶型F，晶型H，晶型N，晶型Q，晶型S，晶型T和游离碱晶型A，晶型B，晶型C是纯的、单一的，基本没有混合任何其他晶型。本发明中，“基本没有”当用来指新晶型时指这个晶型含有少于20％(重量)的其他晶型，尤其指少于10％(重量)的其他晶型，更指少于5％(重量)的其他晶型，更指少于1％(重量)的其他晶型。
需要说明的是，本发明中提及的数值及数值范围不应被狭隘地理解为数值或数值范围本身，本领域技术人员应当理解其可以根据具体技术环境的不同，在不背离本发明精神和原则的基础上围绕具体数值有所浮动，本发明中，这种本领域技术人员可预见的浮动范围多以术语“约”来表示。
本发明提供的式(I)二盐酸盐晶型J，晶型M，晶型E，晶型F，晶型H，晶型N，晶型Q，晶型S，晶型T和游离碱晶型A，晶型B，晶型C，在溶解度、熔点、稳定性、溶出度、引湿性、黏附性、流动性、生物有效性以及加工性能、提纯作用、制剂生产、安全性等方面中的至少一方面上存在优势，为含式(I)化合物的药物制剂的制备提供了新的更好的选择，对于药物开发具有非常重要的意义。
与现有技术相比，发明提供的式(I)二盐酸盐及游离碱的新晶型，在溶解度、熔点、稳定性、溶出度、引湿性、黏附性、流动性、生物有效性以及加工性能、提纯作用、制剂生产、安全性等方面中的至少一方面上存在优势，为MET抑制剂的药物制剂的制备提供了新的更好的选择，对于药物开发具有非常重要的意义。
实施例
以下将通过具体实施例进一步阐述本发明，但并不用于限制本发明的保护范围。本领域技术人员可在权利要求范围内对制备方法和使用仪器作出改进，这些改进也应视为本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。
本发明中“室温”如果没有特别说明，通常是指22℃至28℃。
本发明中所用到的缩写的解释如下：
XRPD：X射线粉末衍射
DSC：差示扫描量热分析
TGA：热重分析
UPLC：超高效液相色谱
1H NMR：液态氢谱核磁
本发明所述的X射线粉末衍射图在PANalytacal(帕纳科)公司的Empyrean型及X’Pert3型射线粉末衍射仪上采集。本发明所述的X射线粉末衍射的方法参数如下：
X射线光源：Cu,Kα
Figure PCTCN2021104559-appb-000028
1.540598；
Figure PCTCN2021104559-appb-000029
1.544426
Kα2/Kα1强度比例：0.50
电压：45仟伏特(kV)
电流：40毫安培(mA)
扫描范围：自3.0至40.0度
本发明所述的差示扫描量热分析曲线在TA公司的Q2000型及Discovery DSC 2500型差式扫描量热仪上采集。本发明所述的差示扫描量热分析的方法参数如下：
扫描速率：10℃/min
保护气体：氮气
本发明所述的热重分析曲线在TA公司的Discovery TGA 5500型及Q5000型热重分析仪上采集。本发明所述的热重分析的方法参数如下：
扫描速率：10℃/min
保护气体：氮气
本发明中高效液相色谱(UPLC)数据采自于Waters H Class，所用检测器为二极管阵列检测器(PDA)。本发明所述的测试纯度和溶解度的UPLC方法参数如下：
1、色谱柱：Waters Xbridge C18,150×4.6mm,5μm
2、流动相：A：0.05％TFA水溶液
B：0.05％TFA乙腈溶液
洗脱梯度如下：
Time(min) ％B
0.0 5.0
3.0 40.0
3.5 90.0
3.8 90.0
3.9 5.0
5.0 5.0
3、流速：0.5mL/min
4、进样量：1μl
5、检测波长：254nm
6、柱温：30℃
7、稀释剂：Acetonitrile/H 2O 1:1
本发明中离子色谱(IC)数据采自于ThermoFisher ICS-1100，本发明所述的测试氯离子含量的IC方法参数如下：
1、色谱柱：IonPac AS18 Analytical Column(4×250mm)
2、流动相：25mM氢氧化钠水溶液
3、流速：1.0mL/min
4、进样量：25μl
6、柱温：35℃
7、样品室温度：35℃
8、电流：80mA
7、运行时间：7min
本发明所述的动态水分吸附图在SMS公司的Intrinsic型及Intrinsic Plus型动态水分吸附仪上采集。本发明所述的动态水分吸附测试的方法参数如下：
温度：25℃
保护气体及流量：N 2，200毫升/分钟
dm/dt：0.002％/分钟
最小dm/dt平衡时间：10分钟
最大平衡时间：180分钟
相对湿度范围：0％RH-95％RH-0％RH
相对湿度梯度：10％(0％RH-90％RH-0％RH)、5％(90％RH-95％RH和95％RH-90％RH)
本发明中所述的粒径分布结果是在Microtrac公司的S3500型激光粒度分析仪上采集。
Microtrac S3500配备SDC(Sample Delivery Controller)进样系统。本测试采用湿法，测试分散介质为Isopar G(含0.2％卵磷脂)。所述的激光粒度分析仪的方法参数如下：
粒度分布：体积分布 采集时间：10秒
分散介质：Isopar G 粒度坐标：标准
采集次数：3次 分散介质折射率：1.42
透明度：透明 残差：启用
颗粒折射率：1.59 流速：60％*
颗粒形状：不规则 过滤：启用
超声功率：30瓦 超声时间：超声30秒
*：流速60％为65毫升/s的60％
本发明中所述的固有溶出速率数据是在Agilent公司的Agilent 708DS型溶出仪上采集。所述的固有溶出测试条件如下：
溶出仪 Agilent 708DS
方法 浆法
介质 pH 6.8磷酸盐缓冲液
介质体积 900毫升
转速 100转/分
介质温度 37℃
取样点 1,2,3,4,5,10,15,20,25,30分钟
补充介质 No
本发明中所述的偏光显微镜照片是通过蔡司显微镜Axio Scope.A1在室温条件下采集，显微镜配备Axiocam 305彩色相机以及5×、10×、20×和50×物镜。
下述实施例中所使用的化合物(I)二盐酸盐起始物可根据现有技术制备得到，例如根据US8420645中所记载的方法制备获得，但起始晶型并非制备本发明晶型的限定条件。
实施例1：二盐酸盐晶型J的制备
室温条件下，将14.9毫克式(I)二盐酸盐化合物溶解于0.5毫升甲醇中使其溶清，之后缓慢滴加到环戊基甲醚中，得到澄清溶液，之后将该样品放入-20℃下快速降温，得到悬浊液后离心分离，晾干后得到式(I)二盐酸盐晶型J。其X射线粉末衍射数据如表1所示，衍射图如图1所示。
表1
衍射角2θ d值 强度％
6.29 14.04 56.85
7.46 11.85 11.22
7.81 11.30 15.00
8.08 10.95 19.98
10.26 8.62 19.29
12.12 7.31 11.36
12.67 6.99 12.86
13.22 6.70 23.16
13.72 6.46 30.82
14.33 6.18 9.63
14.95 5.93 39.06
15.84 5.59 12.69
16.20 5.47 12.38
16.76 5.29 41.17
17.55 5.05 21.69
18.21 4.87 24.84
20.62 4.31 19.59
22.39 3.97 12.29
22.88 3.89 15.54
23.23 3.83 22.89
24.06 3.70 65.45
24.73 3.60 36.45
25.38 3.51 43.68
26.06 3.42 32.58
26.83 3.32 100.00
27.39 3.25 22.48
28.21 3.16 26.90
28.91 3.09 17.81
29.29 3.05 24.31
29.59 3.02 23.97
31.12 2.87 28.43
实施例2：二盐酸盐晶型M的制备
室温条件下，将50.4毫克式(I)二盐酸盐化合物溶解于1.0毫升甲醇中50℃条件下使其溶清，使用0.45微米孔径的聚四氟乙烯滤膜将其过滤，之后缓慢加入-20℃预冷的甲基叔丁基醚4毫升，得到悬浊液，置-20℃下过夜，之后离心分离，-20℃晾干后得到式(I)二盐酸盐化合物晶型M。其样品X射线粉末衍射数据如表2所示，衍射图如图2所示。TGA数据如图14所示，DSC数据如图15所示， 1H NMR数据如图16所示，基本无溶剂残留。根据UPLC和IC的结果计算，二盐酸盐晶型M中式(I)和氯离子的摩尔比为1:2。
表2
衍射角2θ d值 强度％
6.40 13.80 100.00
7.62 11.60 22.45
8.21 10.77 54.36
10.45 8.47 93.38
11.82 7.48 4.43
12.87 6.88 7.65
13.83 6.40 82.35
13.97 6.34 73.65
14.82 5.98 8.45
15.33 5.78 23.79
16.55 5.36 30.19
16.70 5.31 32.13
17.34 5.11 5.42
17.99 4.93 27.48
18.32 4.84 30.26
19.75 4.50 17.90
20.58 4.32 8.28
21.09 4.21 11.86
21.78 4.08 17.88
23.05 3.86 35.04
24.27 3.67 39.77
24.72 3.60 67.17
25.80 3.45 10.62
27.04 3.30 30.65
27.60 3.23 14.44
28.28 3.16 52.75
实施例3：二盐酸盐晶型E的制备
室温条件下，将约14.6毫克式(I)二盐酸盐化合物溶解在0.5毫升甲醇中，采用0.45微米聚四氟乙烯膜过滤得到澄清溶液，向滤液中缓慢滴加乙腈进行反溶剂添加，得到悬浊液，离心分离，得到式(I)二盐酸盐化合物晶型E。其X射线粉末衍射数据如表3所示，衍射图如图3所示。TGA数据如图17所示，DSC数据如图18所示， 1H NMR数据如图19所示，无溶剂残留。根据UPLC和IC的结果计算，二盐酸盐晶型E中式(I)和氯离子的摩尔比为1:2。
表3
衍射角2θ d值 强度％
5.56 15.89 100.00
7.68 11.51 2.12
11.16 7.93 10.61
11.96 7.40 3.77
12.66 6.99 0.83
14.63 6.06 7.18
15.30 5.79 5.85
15.86 5.59 1.83
16.80 5.28 36.56
17.43 5.09 3.75
18.00 4.93 1.15
18.82 4.72 1.23
21.23 4.19 2.77
21.77 4.08 0.97
22.48 3.96 9.64
22.77 3.91 4.37
24.04 3.70 3.31
25.47 3.50 1.77
26.45 3.37 2.04
26.70 3.34 1.51
27.13 3.29 4.03
27.60 3.23 2.31
28.23 3.16 1.60
29.37 3.04 3.85
30.29 2.95 2.17
31.56 2.83 0.79
32.28 2.77 1.29
34.02 2.64 2.28
实施例4：二盐酸盐晶型F的制备
室温条件下，将约50.6毫克式(I)二盐酸盐化合物，在50℃下溶于1.0毫升甲醇中，采用0.45微米聚四氟乙烯膜过滤得到澄清溶液，向澄清滤液中缓慢滴加4毫升环戊基甲醚(-20℃预冷)，得到悬浊液，之后转入-20℃下搅拌过夜，离心分离，晾干后得到式(I)二盐酸盐化合物晶型F。其X射线粉末衍射数据如表4所示，衍射图如图4所示。TGA数据如图 20所示，DSC数据如图21所示， 1H NMR数据如图22所示，无溶剂残留。根据UPLC和IC的结果计算，二盐酸盐晶型F中式(I)和氯离子的摩尔比为1:2。
表4
衍射角2θ d值 强度％
6.16 14.34 100.00
7.66 11.54 34.99
9.85 8.98 36.11
10.05 8.81 22.23
10.44 8.47 16.50
12.45 7.11 14.75
12.99 6.82 35.63
13.12 6.75 34.46
13.53 6.55 20.52
14.61 6.07 39.02
14.80 5.99 33.12
15.44 5.74 23.27
15.61 5.68 30.77
16.75 5.29 19.74
17.02 5.21 18.41
17.89 4.96 11.69
18.37 4.83 38.04
19.57 4.54 10.51
20.25 4.38 13.23
20.61 4.31 9.74
21.52 4.13 7.26
22.77 3.90 12.66
23.94 3.72 69.50
24.57 3.62 17.53
25.46 3.50 13.90
26.50 3.36 30.83
27.67 3.22 20.85
27.99 3.19 15.37
实施例5～6：二盐酸盐晶型F的制备(反溶剂添加法)
室温条件下，将适量式(I)二盐酸盐化合物固体置于5毫升的玻璃小瓶中，加入相应体 积的甲醇，采用0.45微米聚四氟乙烯膜过滤得到澄清溶液。随后磁力搅拌(转速约为1000转/分钟)澄清溶液，并向其中逐滴加入相应的反溶剂，固体析出，即得二盐酸盐晶型F。
本实施例中所涉及的详细试验条件如表5所示，实施例6样品的X射线粉末衍射数据如表6所示。
表5
Figure PCTCN2021104559-appb-000030
表6
衍射角2θ d值 强度％
6.17 14.31 100.00
7.72 11.46 8.12
8.17 10.82 0.39
9.88 8.95 8.16
12.03 7.36 2.75
12.44 7.12 5.16
12.99 6.81 20.85
14.14 6.26 2.64
14.61 6.06 10.37
15.68 5.65 5.84
16.30 5.44 1.72
16.61 5.34 2.18
17.02 5.21 1.81
18.14 4.89 3.87
18.41 4.82 9.69
18.64 4.76 3.36
20.24 4.39 3.36
22.69 3.92 1.61
23.95 3.72 14.04
24.58 3.62 3.66
25.01 3.56 5.03
26.05 3.42 1.89
26.97 3.31 2.81
27.60 3.23 3.59
实施例7：二盐酸盐晶型H的制备
室温条件下，将14.8毫克式(I)二盐酸盐化合物溶解于1.0毫升甲醇中50℃条件下搅拌使其溶清，使用0.45微米孔径的聚四氟乙烯滤膜将样品溶液过滤，之后将滤液置于-20℃条件下快速降温，得到悬浮液，离心分离，得到式(I)二盐酸盐化合物晶型H。其样品X射线粉末衍射数据如表7所示，衍射图如图5所示，TGA数据如图23所示，DSC数据如图24所示， 1H NMR数据如图25所示，无溶剂残留。根据UPLC和IC的结果计算，二盐酸盐晶型H中式(I)和氯离子的摩尔比为1:2。
表7
衍射角2θ d值 强度％
6.49 13.62 44.78
9.73 9.09 52.28
11.48 7.70 14.97
11.84 7.47 15.52
12.69 6.97 17.60
12.98 6.82 42.17
14.20 6.24 32.17
14.69 6.03 20.54
18.62 4.76 9.30
26.69 3.34 100.00
28.23 3.16 3.67
实施例8：二盐酸盐晶型H的制备(快速降温法)
室温条件下，将15.1毫克式(I)二盐酸盐溶解于1.0毫升甲醇/二氯甲烷(体积比4:1)中50℃条件下使其溶清，使用0.45微米孔径的聚四氟乙烯滤膜将样品溶液过滤，之后迅速置于-20℃静置，固液分离得到式(I)二盐酸盐化合物晶型H。
实施例9～10：二盐酸盐晶型H的制备(缓慢降温法)
实施例9：室温条件下，将15.0毫克式(I)化合物二盐酸盐化合物置于3毫升的玻璃小瓶中，加入1.0毫升乙醇得到悬浊液。将该悬浊液在50℃条件下磁力搅拌(转速约为1000转 /分钟)约两小时后，使用0.45微米孔径的聚四氟乙烯滤膜将样品溶液趁热过滤至新的3毫升玻璃小瓶中，将澄清滤液封口后以0.1℃每分钟的速率从50℃降温至5℃，而后于5℃恒温静置约两天时间，无固体析出，将样品转移则将样品转移至-20°条件下静置，依旧无固体析出，将其转移至室温下挥发至固体析出，得到式(I)二盐酸盐化合物晶型H。
实施例10：室温条件下，将14.6毫克式(I)化合物二盐酸盐化合物置于3毫升的玻璃小瓶中，加入1.0毫升甲醇得到悬浊液。将该悬浊液在50℃条件下磁力搅拌(转速约为1000转/分钟)约两小时后，使用0.45微米孔径的聚四氟乙烯滤膜将样品溶液趁热过滤至新的3毫升玻璃小瓶中，将澄清滤液封口后以0.1℃每分钟的速率从50℃降温至5℃，而后于5℃恒温静置约两天时间，无固体析出，将样品转移则将样品转移至-20°条件下静置，析出固体，得到式(I)二盐酸盐化合物晶型H，其X射线粉末衍射数据如表8所示。
表8
衍射角2θ d值 强度％
6.51 13.57 87.43
9.75 9.07 100.00
11.42 7.75 22.96
11.90 7.44 21.20
12.73 6.95 7.60
13.00 6.81 76.04
14.18 6.24 49.02
14.70 6.03 32.25
19.49 4.56 7.11
23.26 3.82 6.85
26.69 3.34 36.61
29.40 3.04 8.31
实施例11：二盐酸盐晶型N的制备
室温条件下，将14.6毫克式(I)溶于2毫升甲醇，之后将该溶液置于盛有4毫升盐酸-乙酸乙酯的氛围中，进行气液渗透实验，约3周后固体析出，得到式(I)二盐酸盐化合物晶型N。其样品X射线粉末衍射数据如表9所示，衍射图如图6所示。TGA数据如图26所示，DSC数据如图27所示。
表9
衍射角2θ d值 强度％
5.29 16.71 7.64
7.55 11.70 31.56
8.83 10.02 8.47
12.72 6.96 3.02
14.16 6.26 7.44
15.11 5.86 100.00
15.88 5.58 4.06
16.23 5.46 60.25
16.58 5.35 2.98
17.91 4.95 1.59
18.05 4.91 2.28
19.41 4.57 4.99
19.76 4.49 5.97
21.07 4.22 2.68
21.63 4.11 4.07
22.44 3.96 9.95
22.80 3.90 7.56
23.31 3.82 5.37
25.27 3.52 2.80
26.91 3.31 12.86
27.57 3.24 18.83
28.29 3.15 8.34
28.65 3.12 8.39
29.23 3.06 4.60
30.46 2.93 3.75
30.99 2.89 1.52
实施例12：二盐酸盐晶型N的制备(气液渗透法)
室温条件下，将15.2毫克式(I)室温下溶于2mL甲醇，之后将该溶液置于盛有4毫升盐酸-乙酸乙酯/甲基叔丁基醚(体积比1:1)气氛中，进行气液渗透实验，约3周后固体析出，得到式(I)二盐酸盐化合物晶型N。其X射线粉末衍射数据如表10所示。
表10
衍射角2θ d值 强度％
4.84 18.27 6.12
5.29 16.70 23.69
7.50 11.79 19.88
8.78 10.07 14.17
12.67 6.99 13.76
14.09 6.29 8.40
15.04 5.89 100.00
15.82 5.60 38.31
16.16 5.49 59.38
16.67 5.32 6.01
17.32 5.12 3.04
17.90 4.96 5.74
18.43 4.81 2.88
18.76 4.73 3.71
19.33 4.59 15.50
19.76 4.49 17.95
21.05 4.22 9.69
21.64 4.11 8.94
22.43 3.96 23.45
22.52 3.95 30.33
22.84 3.89 13.52
23.26 3.82 13.23
24.34 3.66 3.53
24.83 3.59 6.47
25.18 3.54 11.48
26.48 3.37 4.84
26.90 3.31 28.92
27.51 3.24 45.56
28.22 3.16 24.17
28.51 3.13 20.47
29.17 3.06 10.17
30.10 2.97 5.77
30.36 2.94 8.02
31.03 2.88 8.10
31.64 2.83 1.77
32.72 2.74 4.13
33.01 2.71 4.94
33.69 2.66 2.58
34.41 2.61 3.06
34.87 2.57 2.84
35.38 2.54 0.52
实施例13：二盐酸盐晶型Q的制备
50℃条件下，将14.6毫克式(I)二盐酸盐化合物溶解于1.0毫升纯水中使其溶清，之后将其放置于5℃条件下，无固体析出。之后将其转移至室温下挥发，固体析出，得到式(I)二盐酸盐化合物晶型Q。其X射线粉末衍射数据如表11所示，其衍射图如图7所示。
表11
衍射角2θ d值 强度％
4.77 18.51 28.83
5.83 15.16 89.18
9.17 9.65 100.00
9.49 9.31 26.50
10.36 8.54 73.84
11.75 7.53 20.09
14.68 6.03 50.80
16.24 5.46 31.15
16.86 5.25 16.02
17.08 5.19 14.68
18.50 4.80 53.63
19.03 4.66 10.07
19.88 4.46 9.85
20.52 4.33 15.93
26.41 3.37 4.78
实施例14：二盐酸盐晶型S的制备
室温条件下，将14.6毫克式(I)室温下溶于2mL甲醇，之后将该溶液置于盛有4毫升盐酸-乙酸乙酯/甲基乙基酮(体积比1:1)的氛围中，进行气液渗透实验，约3周后未有固体析出，转移至室温下挥发，得到式(I)二盐酸盐化合物晶型S。其样品X射线粉末衍射数据如表12所示，其衍射图如图8所示。
表12
衍射角2θ d值 强度％
6.66 13.27 38.77
8.09 10.93 12.98
9.97 8.86 18.51
10.52 8.41 37.73
12.71 6.96 31.68
13.25 6.68 98.62
18.46 4.80 15.69
19.17 4.63 29.98
19.76 4.49 10.84
23.38 3.80 8.46
26.68 3.34 100.00
28.66 3.11 10.17
29.63 3.01 12.23
实施例15：二盐酸盐晶型T的制备
室温条件下，将14.8毫克的式(I)二盐酸盐化合物固体置于3毫升的玻璃小瓶中，加入适0.5毫升甲醇以溶解固体，使用0.45微米孔径的聚四氟乙烯滤膜将样品溶液过滤至新的3毫升玻璃小瓶中，之后将该溶液置于盛有4毫升异丙醇的封闭环境中静置。约两周后有固体析出，得到式(I)二盐酸盐化合物晶型T。其样品X射线粉末衍射数据如表13所示，其衍射图如图9所示。
表13
衍射角2θ d值 强度％
4.40 20.10 45.55
6.55 13.51 100.00
8.73 10.13 13.44
9.01 9.81 8.96
10.89 8.13 39.66
12.37 7.15 12.24
12.95 6.84 4.91
15.18 5.84 37.91
16.11 5.50 7.52
16.47 5.38 5.54
16.98 5.22 19.97
17.47 5.08 3.75
18.03 4.92 12.83
18.51 4.79 6.56
20.73 4.28 4.83
21.09 4.21 13.43
21.82 4.07 12.23
22.38 3.97 15.35
23.72 3.75 6.06
24.02 3.70 22.49
24.31 3.66 8.18
25.38 3.51 7.31
25.74 3.46 9.28
26.14 3.41 15.25
27.57 3.24 24.36
28.44 3.14 5.66
29.37 3.04 3.19
30.39 2.94 6.20
32.52 2.75 2.58
36.73 2.45 1.88
37.44 2.40 5.14
实施例16：二盐酸盐晶型K的制备
室温条件下，将50.0毫克式(I)二盐酸盐化合物溶解于1.0毫升甲醇中50℃条件下使其溶清，使用0.45微米孔径的聚四氟乙烯滤膜将其过滤，之后向滤液中缓慢加入8毫升-20℃预冷的乙腈中，得到悬浊液，置-20℃下搅拌两小时后静置过夜，之后离心分离，-20℃晾干后得到式(I)二盐酸盐化合物晶型K。其样品X射线粉末衍射数据如表14所示，衍射图如图10所示。TGA数据如图28所示，DSC数据如图29所示， 1H NMR数据如图30所示，化合物(I)和乙腈的摩尔比为1:0.7。根据UPLC和IC的结果计算，二盐酸盐晶型K中式(I)和氯离子的摩尔比为1:2。
表14
衍射角2θ d值 强度％
6.78 13.03 100.00
13.56 6.53 12.02
14.48 6.12 29.30
15.04 5.89 21.24
15.79 5.61 62.81
20.40 4.35 68.46
21.29 4.17 15.98
22.03 4.04 36.02
23.33 3.81 16.97
24.35 3.66 6.92
25.31 3.52 34.56
25.71 3.46 22.97
27.12 3.29 27.69
27.85 3.20 32.72
29.24 3.05 21.08
30.34 2.95 5.90
30.83 2.90 7.77
32.85 2.73 22.07
33.34 2.69 7.80
34.22 2.62 6.95
35.39 2.54 13.57
36.68 2.45 6.04
实施例17：游离碱晶型A的制备
室温条件下，将1508.1毫克式(I)二盐酸盐化合物固体置于约90毫升20毫克/毫升的碳酸氢钠溶液中，室温搅拌过夜后得到悬浊液，离心分离，晾干后得到式(I)化合物晶型A。其样品X射线粉末衍射数据如表15所示，其衍射图如图11所示。TGA数据如图31所示，DSC数据如图32所示， 1H NMR数据如图33所示，无溶剂残留。IC未检出氯离子。
表15
衍射角2θ d值 强度％
5.65 15.64 100.00
12.69 6.98 20.59
13.65 6.49 29.27
14.14 6.26 12.11
15.79 5.61 3.60
16.65 5.33 15.16
17.48 5.07 20.41
19.13 4.64 9.30
23.81 3.74 5.10
24.85 3.58 14.77
实施例18：游离碱晶型B的制备
室温条件下，将9.9毫克实施例17中所述游离碱晶型A样品置于0.5毫升乙酸乙酯溶液中室温搅拌过夜后得到悬浊液，离心分离，晾干后得到式(I)化合物晶型B。其样品X射线粉末衍射数据如表16所示，其衍射图如图12所示。TGA数据如图34所示，DSC数据如图35所示， 1H NMR数据如图36所示。
表16
衍射角2θ d值 强度％
6.35 13.92 66.51
6.64 13.32 22.63
10.77 8.22 7.54
12.43 7.12 16.01
12.83 6.90 33.01
13.97 6.34 6.97
15.71 5.64 100.00
16.68 5.31 30.13
17.85 4.97 15.37
19.19 4.62 10.96
22.32 3.98 3.41
23.17 3.84 4.10
24.17 3.68 6.39
25.14 3.54 11.34
25.67 3.47 9.00
26.61 3.35 14.01
27.35 3.26 17.84
28.20 3.16 3.12
30.90 2.89 1.94
31.72 2.82 4.49
32.32 2.77 4.08
实施例19：游离碱晶型C的制备
室温条件下，将0.9毫克实施例17中所述游离碱晶型A加热至230℃即得到式(I)化合物晶型C。其样品X射线粉末衍射数据如表17所示，其衍射图如图13所示。TGA数据如图37所示，DSC数据如图38所示。
表17
衍射角2θ d值 强度％
6.62 13.36 100.00
10.74 8.24 23.83
12.82 6.91 33.51
13.25 6.68 17.67
15.38 5.76 9.22
16.67 5.32 79.22
20.54 4.32 8.41
21.07 4.22 14.37
22.07 4.03 4.91
23.11 3.85 7.67
24.85 3.58 11.46
25.56 3.48 14.00
26.71 3.34 66.53
26.95 3.31 37.02
实施例20：二盐酸盐晶型M/J的稳定性考察
称取采用本发明实施例1方法制备的晶型J与实施例2方法制备的晶型M各约15毫克，密闭放置于-20℃/5℃/室温下储存，在7天、14天和28天后取样测XRPD。由结果可知，在-20℃/5℃/室温下密闭储存25天，二盐酸盐晶型M的晶型未发生变化，其X射线粉末衍射对比图如图39所示。在室温/40％RH条件下储存10天，二盐酸盐晶型J的晶型未发生变化，其X射线粉末衍射对比图如图40所示。
实施例21：晶型的溶解度
将采用本发明实施例1方法制备的晶型J、实施例2方法制备的晶型M和US8420645B2中晶型A用FaSSIF(空腹状态下人工肠液)与FeSSIF(饱食状态下人工肠液)分别配制成悬浊液，在37℃下平衡24小时后过滤，得到饱和溶液。通过高效液相色谱法(HPLC)测定饱和溶液中样品的含量。由结果可知(表18)，本发明晶型J、M在FaSSIF中的溶解度分别为207.7 微克/毫升与263.0微克/毫升，高于现有技术中披露晶型A溶解度145.5微克/毫升；本发明晶型J、M在FeSSIF中的溶解度分别为31.7微克/毫升与26.5微克/毫升，均高于现有技术中披露晶型A溶解度14.4微克/毫升。
表18
Figure PCTCN2021104559-appb-000031
实施例22：晶型的固有溶出速率
称取采用本发明实施例1方法制备的晶型J、实施例2方法制备的晶型M和US8420645B2中晶型A各约100毫克，倒入固有溶出模具，在5kN压力下持续1分钟，制成表面积0.5cm 2的薄片，取完整压片转移至溶出仪测试固有溶出速率，溶出条件如表18所示，根据10～30分钟之间的测定点计算斜率，以毫克/毫升表示，根据斜率进一步计算固有溶出速率(Intrinsic dissolution rate,IDR)，以毫克/分钟/cm 2表示。结果表明，本发明晶型的溶出速率较US8420645B2中晶型A更快。
表18
溶出仪 CSE-051 Agilent 708DS
方法 浆法
介质 pH 6.8磷酸盐缓冲液
介质体积 900毫升
转速 100转/分
介质温度 37℃
取样点 1,2,3,4,5,10,15,20,25,30min
补充介质 No
实施例23：晶习对比研究
称取采用本发明实施例1方法制备的晶型J、实施例2方法制备的晶型M和US8420645B2中晶型A各约10毫克，分别置于载玻片上，滴加少许真空硅油分散样品，然后盖上盖玻片，置于偏光显微镜下观察。本发明晶型与现有技术晶型相比具有更优的晶习。
实施例24：粒径分布对比研究
称取采用本发明实施例1方法制备的晶型J、实施例2方法制备的晶型M和US8420645B2中晶型A约10-30毫克，然后加入约5毫升Isopar G(含有0.2％卵磷脂)，将待测样品充分混合均匀后加入SDC进样系统中，使遮光度达到合适范围，开始实验，超声30秒后进行粒径分布的测试。本发明晶型与US8420645B2中晶型A相比具有更加均匀的粒径分布。
实施例25：黏附性对比研究
称取采用本发明实施例1方法制备的晶型J、实施例2方法制备的晶型M和US8420645B2中晶型A各约30毫克，然后加入到6毫米圆形平冲中，采用10kN的压力进行压片处理，压片后停留约半分钟，称量冲头吸附的粉末量。结果如表19所示，本发明晶型J与晶型M的黏附百分比分别为3.7％与5.3％，均低于晶型A的黏附百分比6.4％，说明本发明晶型J、M的黏附性优于US8420645B2中晶型A。
表19
晶型 样品量(毫克) 黏附量(毫克) 黏附百分比％
US8420645B2晶型A 34.3 2.2 6.4
本发明晶型J 40.3 1.5 3.7
本发明晶型M 33.9 1.8 5.3
上述实施例只为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。

Claims (29)

  1. 式(I)所示化合物2-氟-N-甲基-4-[7-(喹啉-6-基甲基)咪唑并[1,2-b][1,2,4]三嗪-2-基]苯甲酰胺的二盐酸盐J型晶体、即二盐酸盐晶型J，其特征在于，使用Cu-Kα辐射，所述二盐酸盐晶型J的X射线粉末衍射在2θ值为6.3°±0.2°,15.0°±0.2°,26.8°±0.2°处有特征峰，
    Figure PCTCN2021104559-appb-100001
  2. 权利要求1中所述的二盐酸盐晶型J的制备方法，其特征在于，
    将式(I)化合物的二盐酸盐溶解于正溶剂中，过滤后向其中逐滴加入反溶剂，得到二盐酸盐晶型J。
  3. 式(I)所示化合物2-氟-N-甲基-4-[7-(喹啉-6-基甲基)咪唑并[1,2-b][1,2,4]三嗪-2-基]苯甲酰胺的二盐酸盐M型晶体、即二盐酸盐晶型M，其特征在于，使用Cu-Kα辐射，所述二盐酸盐晶型M的X射线粉末衍射在2θ值为6.4°±0.2°,10.4°±0.2°,14.0°±0.2°处有特征峰，
    Figure PCTCN2021104559-appb-100002
  4. 权利要求3中所述的二盐酸盐晶型M的制备方法，其特征在于，
    将式(I)化合物的二盐酸盐溶解于正溶剂中，过滤后向其中逐滴加入反溶剂，得到二盐酸盐晶型M。
  5. 式(I)所示化合物2-氟-N-甲基-4-[7-(喹啉-6-基甲基)咪唑并[1,2-b][1,2,4]三嗪-2-基]苯甲酰胺的二盐酸盐E型晶体、即二盐酸盐晶型E，其特征在于，使用Cu-Kα辐射，所述二盐酸盐晶型E的X射线粉末衍射在2θ值为5.6°±0.2°,16.8°±0.2°,11.2°±0.2°处有特征峰，
    Figure PCTCN2021104559-appb-100003
  6. 权利要求5中所述的二盐酸盐晶型E的制备方法，其特征在于，
    将式(I)化合物的二盐酸盐溶解于正溶剂中，过滤后向其中逐滴加入反溶剂，得到二盐酸盐晶型E。
  7. 式(I)所示化合物2-氟-N-甲基-4-[7-(喹啉-6-基甲基)咪唑并[1,2-b][1,2,4]三嗪-2-基]苯甲酰胺的二盐酸盐F型晶体、即二盐酸盐晶型F，其特征在于，使用Cu-Kα辐射，所述二盐酸盐晶型F的X射线粉末衍射在2θ值为6.2°±0.2°,13.0°±0.2°,14.6°±0.2°处有特征峰，
    Figure PCTCN2021104559-appb-100004
  8. 权利要求7中所述的二盐酸盐晶型F的制备方法，其特征在于，
    将式(I)化合物的二盐酸盐溶解于正溶剂中，过滤后向其中逐滴加入反溶剂，得到二盐酸盐晶型F。
  9. 式(I)所示化合物2-氟-N-甲基-4-[7-(喹啉-6-基甲基)咪唑并[1,2-b][1,2,4]三嗪-2-基]苯甲酰胺的二盐酸盐H型晶体、即二盐酸盐晶型H，其特征在于，使用Cu-Kα辐射，所述二盐酸盐晶型H的X射线粉末衍射在2θ值为9.7°±0.2°,6.5°±0.2°,13.0°±0.2°处有特征峰，
    Figure PCTCN2021104559-appb-100005
  10. 权利要求9中所述的二盐酸盐晶型H的制备方法，其特征在于，
    将式(I)化合物的二盐酸盐溶解于正溶剂中，过滤后将其降温，得到二盐酸盐晶型H。
  11. 式(I)所示化合物2-氟-N-甲基-4-[7-(喹啉-6-基甲基)咪唑并[1,2-b][1,2,4]三嗪-2-基]苯甲酰胺的二盐酸盐N型晶体、即二盐酸盐晶型N，其特征在于，使用Cu-Kα辐射，所述二盐酸盐晶型N的X射线粉末衍射在2θ值为15.1°±0.2°,16.2°±0.2°,8.8°±0.2°处有特征峰，
    Figure PCTCN2021104559-appb-100006
  12. 权利要求11中所述的二盐酸盐晶型N的制备方法，其特征在于，
    将式(I)化合物的溶于正溶剂中，然后置于含有盐酸的反溶剂的密封环境中，渗透析晶，得到二盐酸盐晶型N。
  13. 式(I)所示化合物2-氟-N-甲基-4-[7-(喹啉-6-基甲基)咪唑并[1,2-b][1,2,4]三嗪-2-基]苯甲酰胺的二盐酸盐Q型晶体、即二盐酸盐晶型Q，其特征在于，使用Cu-Kα辐射，所述二盐酸盐晶型Q的X射线粉末衍射在2θ值为9.2°±0.2°,5.8°±0.2°,10.4°±0.2°处有特征峰，
    Figure PCTCN2021104559-appb-100007
  14. 权利要求13中所述的二盐酸盐晶型Q的制备方法，其特征在于，
    将式(I)化合物的二盐酸盐溶解于正溶剂中，过滤后将其降温，无固体析出，转移至室温下挥发，得到二盐酸盐晶型Q。
  15. 式(I)所示化合物2-氟-N-甲基-4-[7-(喹啉-6-基甲基)咪唑并[1,2-b][1,2,4]三嗪-2-基]苯甲酰胺的二盐酸盐S型晶体、即二盐酸盐晶型S，其特征在于，使用Cu-Kα辐射，所述二盐酸盐晶型S的X射线粉末衍射在2θ值为26.7°±0.2°,13.2°±0.2°,10.5°±0.2°处有特征峰，
    Figure PCTCN2021104559-appb-100008
  16. 权利要求15中所述的二盐酸盐晶型S的制备方法，其特征在于，
    将式(I)化合物的二盐酸盐溶于正溶剂中，然后置于含有盐酸的反溶剂的密封环境中，渗透，无固体析出，转移至室温下挥发，得到二盐酸盐晶型S。
  17. 式(I)所示化合物2-氟-N-甲基-4-[7-(喹啉-6-基甲基)咪唑并[1,2-b][1,2,4]三嗪-2-基]苯甲酰胺的二盐酸盐T型晶体、即二盐酸盐晶型T，其特征在于，使用Cu-Kα辐射，所述二盐酸盐晶型T的X射线粉末衍射在2θ值为6.5°±0.2°,4.4°±0.2°,10.9°±0.2°处有特征峰，
    Figure PCTCN2021104559-appb-100009
  18. 权利要求17中所述的二盐酸盐晶型T的制备方法，其特征在于，
    将式(I)二盐酸盐化合物溶于正溶剂中，然后置于反溶剂的密封环境中，渗透析晶，得到二盐酸盐晶型T。
  19. 式(I)所示化合物2-氟-N-甲基-4-[7-(喹啉-6-基甲基)咪唑并[1,2-b][1,2,4]三嗪-2-基]苯甲酰胺的二盐酸盐K型晶体、即二盐酸盐晶型K，其特征在于，使用Cu-Kα辐射，所述二盐酸盐晶型K的X射线粉末衍射在2θ值为6.8°±0.2°,20.4°±0.2°,15.8°±0.2°处有特征峰，
    Figure PCTCN2021104559-appb-100010
  20. 权利要求19中所述的二盐酸盐晶型K的制备方法，其特征在于，
    将式(I)化合物的二盐酸盐溶解于正溶剂中，过滤后向其中逐滴加入反溶剂，得到二盐酸盐晶型K。
  21. 式(I)所示化合物2-氟-N-甲基-4-[7-(喹啉-6-基甲基)咪唑并[1,2-b][1,2,4]三嗪-2-基]苯甲酰胺的A型晶体、即游离碱晶型A，其特征在于，使用Cu-Kα辐射，所述游离碱晶型A的X射线粉末衍射在2θ值为5.7°±0.2°,13.6°±0.2°,12.7°±0.2°处有特征峰，
    Figure PCTCN2021104559-appb-100011
  22. 权利要求21中所述的游离碱晶型A的制备方法，其特征在于，
    将式(I)二盐酸盐化合物在碱性水溶液中解离，分离固体干燥后即得游离碱晶型A。
  23. 式(I)所示化合物2-氟-N-甲基-4-[7-(喹啉-6-基甲基)咪唑并[1,2-b][1,2,4]三嗪-2-基]苯甲酰胺的B型晶体、即游离碱晶型B，其特征在于，使用Cu-Kα辐射，所述游离碱晶型B的X射线粉末衍射在2θ值为15.7°±0.2°,6.3°±0.2°,12.8°±0.2°处有特征峰，
    Figure PCTCN2021104559-appb-100012
  24. 权利要求23中所述的游离碱晶型B的制备方法，其特征在于，
    将权利要求21中所述游离碱晶型A在乙酸乙酯中室温悬浮搅拌过夜，分离固体干燥后即得游离碱晶型B。
  25. 式(I)所示化合物2-氟-N-甲基-4-[7-(喹啉-6-基甲基)咪唑并[1,2-b][1,2,4]三嗪-2-基]苯甲酰胺的C型晶体、即游离碱晶型C，其特征在于，使用Cu-Kα辐射，所述游离碱晶型C的X射线粉末衍射在2θ值为6.6°±0.2°,16.7°±0.2°,15.4°±0.2°处有特征峰，
    Figure PCTCN2021104559-appb-100013
  26. 权利要求25中所述的游离碱晶型C的制备方法，其特征在于，
    将权利要求21中所述游离碱晶型A加热到一定温度后冷却至室温，即得游离碱晶型C。
  27. 药物组合物，其包含权利要求1、3、5、7、9、11、13、15、17、19、21、23和25中任一项所述的晶体和制药学可接受的载体。
  28. 具有c-Met抑制活性的药物组合物，其含有权利要求1、3、5、7、9、11、13、15、17、19、21、23和25中任一项所述的晶体作为有效成分。
  29. 非小细胞肺癌及黑素瘤、胶质肉瘤、实体肿瘤、结直肠癌和肝损伤等方面的预防药或治疗药，其含有权利要求1、3、5、7、9、11、13、15、17、19、21、23和25中任一项所述的晶体作为有效成分。
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