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WO2022007752A1 - Nouvelle forme cristalline d'un composé benzamide et de son dichlorhydrate et procédé de préparation correspondant - Google Patents

Nouvelle forme cristalline d'un composé benzamide et de son dichlorhydrate et procédé de préparation correspondant 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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鲁霞
张晓宇
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Crystal Pharmatech Co Ltd
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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

La présente invention se rapporte au domaine des médicaments chimiques et concerne en particulier une nouvelle forme cristalline d'une base libre et de dichlorhydrate de composés benzamides et un procédé de préparation correspondant. La présente invention concerne un procédé de préparation d'une forme cristalline J de dichlorhydrate, forme cristalline M de dichlorhydrate, forme cristalline E de dichlorhydrate, forme cristalline F de dichlorhydrate, forme cristalline H de dichlorhydrate, forme cristalline N de dichlorhydrate, forme cristalline Q de dichlorhydrate, forme cristalline S de dichlorhydrate, forme cristalline T de dichlorhydrate, forme cristalline K de dichlorhydrate et forme cristalline A de base libre, forme cristalline B de base libre et forme cristalline C de base libre d'un composé de formule (I), ainsi qu'une utilisation associée. La présente invention concerne une forme cristalline J de dichlorhydrate, forme cristalline M de dichlorhydrate, forme cristalline E de dichlorhydrate, forme cristalline F de dichlorhydrate, forme cristalline H de dichlorhydrate, forme cristalline N de dichlorhydrate, forme cristalline Q de dichlorhydrate, forme cristalline S de dichlorhydrate, forme cristalline T de dichlorhydrate, forme cristalline K de dichlorhydrate et forme cristalline A de base libre, forme cristalline B de base libre et forme cristalline C de base libre du composé de formule (I). La présente invention a des avantages en termes d'au moins l'un des aspects suivants : solubilité, point de fusion, stabilité, vitesse de dissolution, hygroscopicité, adhérence, fluidité, biodisponibilité, performance de traitement, effet de purification, production de préparation, sécurité, etc, qui fournit un nouveau choix meilleur pour la préparation d'une préparation pharmaceutique contenant une base libre du composé de formule (I) et son dichlorhydrate, et présente une grande importance pour le développement de médicaments.
PCT/CN2021/104559 2020-07-06 2021-07-05 Nouvelle forme cristalline d'un composé benzamide et de son dichlorhydrate et procédé de préparation correspondant Ceased WO2022007752A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114853762A (zh) * 2021-02-03 2022-08-05 四川科伦药物研究院有限公司 一种咪唑并三嗪类化合物的固体形式及其制备方法和用途

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101641093A (zh) * 2006-11-22 2010-02-03 因塞特公司 作为激酶抑制剂的咪唑并三嗪和咪唑并嘧啶
CN102083814A (zh) * 2008-05-21 2011-06-01 因西特公司 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]苯甲酰胺的盐及与其相关的制备方法
CN104245701A (zh) * 2012-04-03 2014-12-24 诺华有限公司 有酪氨酸激酶抑制剂的组合产品和其应用
WO2016011658A1 (fr) * 2014-07-25 2016-01-28 Novartis Ag Polythérapie
US20160030559A1 (en) * 2014-07-30 2016-02-04 Samsung Electronics Co., Ltd. Biomarker hsp90 for predicting effect of a c-met inhibitor
CN106714784A (zh) * 2014-07-25 2017-05-24 诺华股份有限公司 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]苯甲酰胺的片剂制剂
CN108697794A (zh) * 2015-12-17 2018-10-23 诺华股份有限公司 C-met抑制剂和抗pd-1抗体分子的组合及其用途
CN110526916A (zh) * 2018-05-23 2019-12-03 成都海创药业有限公司 氘代Capmatinib化合物及其用途

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101641093A (zh) * 2006-11-22 2010-02-03 因塞特公司 作为激酶抑制剂的咪唑并三嗪和咪唑并嘧啶
CN102083814A (zh) * 2008-05-21 2011-06-01 因西特公司 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]苯甲酰胺的盐及与其相关的制备方法
CN104245701A (zh) * 2012-04-03 2014-12-24 诺华有限公司 有酪氨酸激酶抑制剂的组合产品和其应用
WO2016011658A1 (fr) * 2014-07-25 2016-01-28 Novartis Ag Polythérapie
CN106714784A (zh) * 2014-07-25 2017-05-24 诺华股份有限公司 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]苯甲酰胺的片剂制剂
CN106794180A (zh) * 2014-07-25 2017-05-31 诺华股份有限公司 联合疗法
US20160030559A1 (en) * 2014-07-30 2016-02-04 Samsung Electronics Co., Ltd. Biomarker hsp90 for predicting effect of a c-met inhibitor
CN108697794A (zh) * 2015-12-17 2018-10-23 诺华股份有限公司 C-met抑制剂和抗pd-1抗体分子的组合及其用途
CN110526916A (zh) * 2018-05-23 2019-12-03 成都海创药业有限公司 氘代Capmatinib化合物及其用途

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
X. LIU, Q. WANG, G. YANG, C. MARANDO, H. K. KOBLISH, L. M. HALL, J. S. FRIDMAN, E. BEHSHAD, R. WYNN, Y. LI, J. BOER, S. DIAMOND, C: "A Novel Kinase Inhibitor, INCB28060, Blocks c-MET-Dependent Signaling, Neoplastic Activities, and Cross-Talk with EGFR and HER-3", CLINICAL CANCER RESEARCH, ASSOCIATION FOR CANCER RESEARCH, vol. 17, no. 22, 15 November 2011 (2011-11-15), pages 7127 - 7138, XP055030185, ISSN: 10780432, DOI: 10.1158/1078-0432.CCR-11-1157 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114853762A (zh) * 2021-02-03 2022-08-05 四川科伦药物研究院有限公司 一种咪唑并三嗪类化合物的固体形式及其制备方法和用途

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