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WO2025218702A1 - Salt and crystal form of pharmaceutical intermediate, and preparation method therefor and use thereof - Google Patents

Salt and crystal form of pharmaceutical intermediate, and preparation method therefor and use thereof

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Publication number
WO2025218702A1
WO2025218702A1 PCT/CN2025/089305 CN2025089305W WO2025218702A1 WO 2025218702 A1 WO2025218702 A1 WO 2025218702A1 CN 2025089305 W CN2025089305 W CN 2025089305W WO 2025218702 A1 WO2025218702 A1 WO 2025218702A1
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WO
WIPO (PCT)
Prior art keywords
compound
formula
salt
crystalline form
ray powder
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2025/089305
Other languages
French (fr)
Chinese (zh)
Inventor
康惠燕
周巧云
马志强
周义鑫
李洪明
樊白白
胡娟
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Fujian Akeylink Biotechnology Co Ltd
Original Assignee
Fujian Akeylink Biotechnology Co Ltd
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Filing date
Publication date
Application filed by Fujian Akeylink Biotechnology Co Ltd filed Critical Fujian Akeylink Biotechnology Co Ltd
Publication of WO2025218702A1 publication Critical patent/WO2025218702A1/en
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Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/96—Spiro-condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D229/00—Heterocyclic compounds containing rings of less than five members having two nitrogen atoms as the only ring hetero atoms
    • C07D229/02—Heterocyclic compounds containing rings of less than five members having two nitrogen atoms as the only ring hetero atoms containing three-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic

Definitions

  • the present invention relates to a salt of a pharmaceutical intermediate, a crystal form thereof, a preparation method and an application thereof, and particularly to a salt of a compound of formula (II) and a preparation method thereof.
  • SARS-CoV-2 is a single-stranded, positive-strand RNA virus that shares a high degree of homology with SARS-CoV and MERS-CoV.
  • RNA Upon entry into host cells, the virus's genetic material, RNA, is first translated into two polyprotein precursors (pp1a and pp1ab) with the help of the host cell. These polyprotein precursors undergo intramolecular cleavage by the 3CL protease and PL protease to produce multiple nonstructural proteins. Because the 3CL protease is responsible for cleavage at at least 11 sites, it is also known as the main protease (Mpro).
  • Mpro main protease
  • the 3CL protease is a cysteine protease that is active as a homodimer.
  • the 3CL protease is highly conserved among coronaviruses, and substrates shared by different coronavirus 3CL proteases share common characteristics. Since no protease homologous to the 3CL protease exists in the human body, the 3CL protease is an ideal target for anti-coronavirus treatment.
  • Patent PCT/CN2022/087511 discovered a 3CL protease inhibitor with excellent anti-coronavirus activity.
  • the molecular structure of the 3CL protease inhibitor is as follows:
  • the present invention provides an intermediate compound of formula (II) or a pharmaceutically acceptable salt thereof, a crystalline form thereof, a preparation method thereof, and applications thereof.
  • the crystalline form of the intermediate compound of the present invention exhibits high crystallinity, good stability, resistance to high temperatures and high humidity, low hygroscopicity, and high product purity and yield.
  • the present invention solves the above technical problems through the following technical solutions.
  • the present invention provides a salt of a compound of formula (II), wherein the salt is a maleate, a methanesulfonate, a gentisate or a tartrate;
  • the molar ratio of maleic acid, methanesulfonic acid, gentisic acid or tartaric acid to the compound of formula (II) is 1.1:1 or 1.0:1, more preferably 1.0:1.
  • the present invention provides a crystalline form A of a maleate salt of a compound of formula (II), wherein an X-ray powder diffraction pattern expressed in 2 ⁇ using Cu-K ⁇ radiation has diffraction peaks at the following positions: 10.37° ⁇ 0.20°, 13.75° ⁇ 0.20°, 14.77° ⁇ 0.20°, 19.47° ⁇ 0.20°, 20.97° ⁇ 0.20°, and 21.67° ⁇ 0.20°;
  • the X-ray powder diffraction pattern of Form A of the maleate salt of the compound of formula (II) expressed in 2 ⁇ angles further has diffraction peaks at one or more of the following positions: 11.67° ⁇ 0.20°, 17.48° ⁇ 0.20°, 19.75° ⁇ 0.20°, 22.79° ⁇ 0.20°, 23.48° ⁇ 0.20°, 25.23° ⁇ 0.20°, 26.93° ⁇ 0.20°, 28.07° ⁇ 0.20°, 29.80° ⁇ 0.20°, 32.89° ⁇ 0.20°, 38.37° ⁇ 0.20°.
  • the crystalline form A of the maleate salt of the compound of formula (II) has an X-ray powder diffraction pattern expressed in 2 ⁇ with diffraction peaks at the following positions: 10.37° ⁇ 0.20°, 11.67° ⁇ 0.20°, 13.75° ⁇ 0.20°, 14.77° ⁇ 0.20°, 17.48° ⁇ 0.20°, 19.47° ⁇ 0.20°, 19.75 ° ⁇ 0.20°, 20.97° ⁇ 0.20°, 21.67° ⁇ 0.20°, 22.79° ⁇ 0.20°, 23.48° ⁇ 0.20°, 25.23° ⁇ 0.20°, 26.93° ⁇ 0.20°, 28.07° ⁇ 0.20°, 29.80° ⁇ 0.20°, 32.89° ⁇ 0.20°, 38.37° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the maleate salt of the compound of formula (II) in form A expressed in 2 ⁇ has the diffraction peaks shown in the following table:
  • the X-ray powder diffraction pattern of Form A of the maleate salt of the compound of formula (II) expressed in 2 ⁇ is shown in FIG1 .
  • the crystalline form A of the maleate salt of the compound of formula (II) is obtained by the following parameters:
  • the crystalline form A of the maleate salt of the compound of formula (II) has a differential scanning calorimetry (DSC) curve having an endothermic peak at 143.8 ⁇ 3.0°C (peak).
  • the crystalline form A of the maleate salt of the compound of formula (II) has a differential scanning calorimetry (DSC) curve with an endothermic peak at 135.6°C to 143.8°C and a heat of fusion of 89.25 J/g.
  • DSC differential scanning calorimetry
  • the differential scanning calorimetry curve of Form A of the maleate salt of the compound of formula (II) is shown in FIG2 .
  • the crystalline form A of the maleate salt of the compound of formula (II) has a thermogravimetric analysis (TGA) curve showing a weight loss of 0.68% at 130.0°C.
  • thermogravimetric analysis curve of Form A of the maleate salt of the compound of formula (II) is shown in FIG2 .
  • the crystalline form A of the maleate salt of the compound of formula (II) is obtained by the following parameters: TGA and/or DSC pattern of the crystalline form;
  • the crystalline form A of the maleate salt of the compound of formula (II) is an anhydrous crystalline form.
  • the molar ratio of the compound of formula (II) to the maleic acid is 1.0:1.
  • the present invention also provides a method for preparing the crystalline form A of the maleate salt of the compound of formula (II), which comprises the following steps:
  • the organic solvent is ethyl acetate
  • the molar ratio of maleic acid to the compound of formula (II) is 1.05:1;
  • the present invention provides a crystalline form A of a mesylate salt of a compound of formula (II), wherein an X-ray powder diffraction pattern expressed in 2 ⁇ using Cu-K ⁇ radiation has diffraction peaks at the following positions: 7.23° ⁇ 0.20°, 13.91° ⁇ 0.20°, 16.36° ⁇ 0.20°, 18.95° ⁇ 0.20°, 19.71° ⁇ 0.20°, 20.65° ⁇ 0.20°, and 21.94° ⁇ 0.20°;
  • the X-ray powder diffraction pattern of Form A of the methanesulfonate salt of the compound of formula (II) expressed in 2 ⁇ angles further has diffraction peaks at one or more of the following positions: 9.92° ⁇ 0.20°, 12.39° ⁇ 0.20°, 17.85° ⁇ 0.20°, 18.59° ⁇ 0.20°, 23.21° ⁇ 0.20°, 24.03° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystalline form A of the methanesulfonate salt of the compound of formula (II) expressed in 2 ⁇ has diffraction peaks at the following positions: 7.23° ⁇ 0.20°, 9.92° ⁇ 0.20°, 13.91° ⁇ 0.20°, 16.36° ⁇ 0.20°, 12.39° ⁇ 0.20°, 17.85° ⁇ 0.20°, 18.59° ⁇ 0.20°, 18.95° ⁇ 0.20°, 19.71° ⁇ 0.20°, 20.65° ⁇ 0.20°, 21.94° ⁇ 0.20°, 23.21° ⁇ 0.20°, and 24.03° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of Form A of the methanesulfonate salt of the compound of formula (II) expressed in 2 ⁇ further has diffraction peaks at one or more of the following positions: 10.35° ⁇ 0.20°, 11.83° ⁇ 0.20°, 14.66° ⁇ 0.20°, 21.36° ⁇ 0.20°, 22.87° ⁇ 0.20°, 24.92° ⁇ 0.20°, 25.27° ⁇ 0.20°, 26.60° ⁇ 0.20°, 27.30° ⁇ 0.20°, and 28.34° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystalline form A of the methanesulfonate salt of the compound of formula (II) expressed in 2 ⁇ has diffraction peaks at the following positions: 7.23° ⁇ 0.20°, 9.92° ⁇ 0.20°, 10.35° ⁇ 0.20°, 11.83° ⁇ 0.20°, 12.39° ⁇ 0.20°, 13.91° ⁇ 0.20°, 14.66° ⁇ 0.20°, 16.36° ⁇ 0.20°, 17.85° ⁇ 0.20°, 18.59° ⁇ 0.20°, 18.95° ⁇ 0.20°, 19.71° ⁇ 0.20°, 20.65° ⁇ 0.20°, 21.36° ⁇ 0.20°, 21.94° ⁇ 0.20°, 22.87° ⁇ 0.20°, 23.21° ⁇ 0.20°, 24.03° ⁇ 0.20°, 24.92° ⁇ 0.20°, 25.27° ⁇ 0.20°, 26.60° ⁇ 0.20°, 27.30° ⁇ 0.20°, 28.34° ⁇ 0.2
  • the X-ray powder diffraction pattern of the crystalline form A of the methanesulfonate salt of the compound of formula (II) expressed in 2 ⁇ further has diffraction peaks at one or more of the following positions: 8.23° ⁇ 0.20°, 15.20° ⁇ 0.20°, 22.57° ⁇ 0.20°, 24.43° ⁇ 0.20°, 26.32° ⁇ 0.20°, 29.00° ⁇ 0.20°, 29.40° ⁇ 0 .20°, 29.98° ⁇ 0.20°, 31.23° ⁇ 0.20°, 32.01° ⁇ 0.20°, 32.75° ⁇ 0.20°, 33.26° ⁇ 0.20°, 34.60° ⁇ 0.20°, 35.39° ⁇ 0.20°, 36.55° ⁇ 0.20°, 37.88° ⁇ 0.20°, 38.44° ⁇ 0.20°, 39.22° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystalline form A of the methanesulfonate salt of the compound of formula (II) expressed in 2 ⁇ has diffraction peaks at the following positions: 7.23° ⁇ 0.20°, 8.23° ⁇ 0.20°, 9.92° ⁇ 0.20°, 10.35° ⁇ 0.20°, 11.83° ⁇ 0.20°, 12.39° ⁇ 0.20°, 13.91° ⁇ 0.20°, 14.6 6° ⁇ 0.20°, 15.20° ⁇ 0.20°, 16.36° ⁇ 0.20°, 17.85° ⁇ 0.20°, 18.59° ⁇ 0.20°, 18.95° ⁇ 0.20°, 19.71° ⁇ 0.20°, 20.65° ⁇ 0.20°, 21.36° ⁇ 0.20°, 21.94° ⁇ 0.20°, 22.57° ⁇ 0.20°, 22.87° ⁇ 0.20°, 23.21° ⁇ 0.20°, 24.03° ⁇ 0.20°, 24.43° ⁇ 0.20°, 24.92° ⁇ 0.20°
  • the X-ray powder diffraction pattern of the crystalline form A of the methanesulfonate salt of the compound of formula (II) expressed in 2 ⁇ has the diffraction peaks shown in the following table:
  • the X-ray powder diffraction pattern of Form A of the methanesulfonate salt of the compound of formula (II) expressed in 2 ⁇ is shown in FIG4 .
  • the crystalline form A of the methanesulfonate salt of the compound of formula (II) is obtained by the following parameters:
  • the crystalline form A of the methanesulfonate salt of the compound of formula (II) has a differential scanning calorimetry (DSC) curve having an endothermic peak at 123.6 ⁇ 3.0°C (peak).
  • the crystalline form A of the methanesulfonate salt of the compound of formula (II) has a differential scanning calorimetry (DSC) curve with an endothermic peak at 119.6°C to 123.6°C and a heat of fusion of 81.65 J/g.
  • the differential scanning calorimetry curve of Form A of the methanesulfonate salt of the compound of formula (II) is shown in FIG5 .
  • the crystalline form A of the methanesulfonate salt of the compound of formula (II) has a thermogravimetric analysis (TGA) curve showing a weight loss of 0.41% at 160.0°C.
  • thermogravimetric analysis curve of Form A of the methanesulfonate salt of the compound of formula (II) is shown in FIG5 .
  • the crystalline form A of the methanesulfonate salt of the compound of formula (II) is obtained by the following parameters: TGA and/or DSC pattern of the crystalline form;
  • the mesylate salt crystalline form A of the compound of formula (II) is an anhydrous crystalline form.
  • the molar ratio of the compound of formula (II) to the methanesulfonic acid is 1.0:1.
  • the present invention also provides a method for preparing the crystalline form A of the methanesulfonate salt of the compound of formula (II), which comprises the following steps:
  • the organic solvent is butanone
  • the molar ratio of methanesulfonic acid to the compound of formula (II) is 1.05:1.
  • the present invention provides a crystalline form A of a gentisate salt of a compound of formula (II), wherein an X-ray powder diffraction pattern expressed in 2 ⁇ using Cu-K ⁇ radiation has diffraction peaks at the following positions: 8.54° ⁇ 0.20°, 8.89° ⁇ 0.20°, 12.70° ⁇ 0.20°, 17.42° ⁇ 0.20°, 18.04° ⁇ 0.20°, 19.45° ⁇ 0.20°, and 23.80° ⁇ 0.20°;
  • the X-ray powder diffraction pattern of the crystalline form A of the gentisate salt of the compound of formula (II) expressed in 2 ⁇ angles further has diffraction peaks at one or more of the following positions: 18.86° ⁇ 0.20°, 22.31° ⁇ 0.20°, 25.40° ⁇ 0.20°, 25.77° ⁇ 0.20°, 27.78° ⁇ 0.20°, 35.56° ⁇ 0.20°.
  • the crystalline form A of the gentisate salt of the compound of formula (II) has an X-ray powder diffraction pattern expressed as 2 ⁇ having diffraction peaks at the following positions: 8.54° ⁇ 0.20°, 8.89° ⁇ 0.20°, 12.70° ⁇ 0.20°, 17.42° ⁇ 0.20°, 18.04° ⁇ 0.20°, 18.86° ⁇ 0.20°, 19.45° ⁇ 0.20°, 22.31° ⁇ 0.20°, 23.80° ⁇ 0.20°, 25.40° ⁇ 0.20°, 25.77° ⁇ 0.20°, 27.78° ⁇ 0.20°, and 35.56° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystalline form A of the gentisate salt of the compound of formula (II) expressed in 2 ⁇ angles further has diffraction peaks at one or more of the following positions: 11.66° ⁇ 0.20°, 16.21° ⁇ 0.20°, 22.71° ⁇ 0.20°, 26.64° ⁇ 0.20°, 36.12° ⁇ 0.20°, 39.19° ⁇ 0.20°.
  • the crystalline form A of the gentisate salt of the compound of formula (II) has an X-ray powder diffraction pattern expressed in 2 ⁇ having diffraction peaks at the following positions: 8.54° ⁇ 0.20°, 8.89° ⁇ 0.20°, 11.66° ⁇ 0.20°, 12.70° ⁇ 0.20°, 16.21° ⁇ 0.20°, 17.42° ⁇ 0.20°, 18.04° ⁇ 0.20°, 18.86° ⁇ 0.20°, 19.45° ⁇ 0.20°, 22.31° ⁇ 0.20°, 22.71° ⁇ 0.20°, 23.80° ⁇ 0.20°, 25.40° ⁇ 0.20°, 25.77° ⁇ 0.20°, 26.64° ⁇ 0.20°, 27.78° ⁇ 0.20°, 35.56° ⁇ 0.20°, 36.12° ⁇ 0.20°, 39.19° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystalline form A of the gentisate salt of the compound of formula (II) expressed in 2 ⁇ has the diffraction peaks shown in the following table:
  • the X-ray powder diffraction pattern of Form A of the gentisate salt of the compound of formula (II) is shown in FIG7 .
  • the crystalline form A of the gentisate salt of the compound of formula (II) is obtained by the following parameters:
  • the crystalline form A of the gentisate salt of the compound of formula (II) has a differential scanning calorimetry (DSC) curve having an endothermic peak at 169.1 ⁇ 3.0°C (peak).
  • the crystalline form A of the gentisate salt of the compound of formula (II) has a differential scanning calorimetry (DSC) curve with an endothermic peak at 165.11°C to 169.12°C and a heat of fusion of 115.1 J/g.
  • the differential scanning calorimetry curve of the crystalline form A of the gentisate salt of the compound of formula (II) is shown in FIG8 .
  • the crystalline form A of the gentisate salt of the compound of formula (II) has a thermogravimetric analysis (TGA) curve showing a weight loss of 0.14% at 140.0°C.
  • thermogravimetric analysis curve of Form A of the gentisate salt of the compound of formula (II) is shown in FIG8 .
  • the crystal form A of the gentisate salt of the compound of formula (II) is obtained by the following parameters: TGA and/or DSC pattern of the crystal form;
  • the gentisate crystal form A of the compound of formula (II) is an anhydrous crystal form.
  • the molar ratio of the compound of formula (II) to the gentisic acid is 1.0:1.
  • the present invention also provides a method for preparing the crystalline form A of the gentisate salt of the compound of formula (II), which comprises the following steps:
  • the organic solvent is acetonitrile
  • the molar ratio of gentisic acid to the compound of formula (II) is 1.05.
  • the present invention provides a crystalline form A of a tartrate salt of a compound of formula (II), wherein an X-ray powder diffraction pattern expressed in 2 ⁇ using Cu-K ⁇ radiation has diffraction peaks at the following positions: 6.42° ⁇ 0.20°, 13.08° ⁇ 0.20°, 15.27° ⁇ 0.20°, 17.59° ⁇ 0.20°, 19.09° ⁇ 0.20°, and 20.05° ⁇ 0.20°;
  • the X-ray powder diffraction pattern of Form A of the tartrate salt of the compound of formula (II) expressed in 2 ⁇ angles further has diffraction peaks at one or more of the following positions: 16.30° ⁇ 0.20°, 19.74° ⁇ 0.20°, 26.47° ⁇ 0.20°.
  • the crystalline form A of the tartrate salt of the compound of formula (II) has an X-ray powder diffraction pattern expressed as 2 ⁇ having diffraction peaks at the following positions: 6.42° ⁇ 0.20°, 13.08° ⁇ 0.20°, 15.27° ⁇ 0.20°, 16.30° ⁇ 0.20°, 17.59° ⁇ 0.20°, 19.09° ⁇ 0.20°, 19.74° ⁇ 0.20°, 20.05° ⁇ 0.20°, and 26.47° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of Form A of the tartrate salt of the compound of formula (II) expressed in 2 ⁇ angles further has diffraction peaks at one or more of the following positions: 12.03° ⁇ 0.20°, 13.32° ⁇ 0.20°, 23.17° ⁇ 0.20°, 25.98° ⁇ 0.20°.
  • the crystalline form A of the tartrate salt of the compound of formula (II) has an X-ray powder diffraction pattern expressed as 2 ⁇ having diffraction peaks at the following positions: 6.42° ⁇ 0.20°, 12.03° ⁇ 0.20°, 13.08° ⁇ 0.20°, 13.32° ⁇ 0.20°, 15.27° ⁇ 0.20°, 16.30° ⁇ 0.20°, 17.59° ⁇ 0.20°, 19.09° ⁇ 0.20°, 19.74° ⁇ 0.20°, 20.05° ⁇ 0.20°, 23.17° ⁇ 0.20°, 25.98° ⁇ 0.20°, and 26.47° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of Form A of the tartrate salt of the compound of formula (II) expressed in 2 ⁇ angles further has diffraction peaks at one or more of the following positions: 16.59° ⁇ 0.20°, 21.02° ⁇ 0.20°, 22.93° ⁇ 0.20°, 28.47° ⁇ 0.20°, 31.32° ⁇ 0.20°, 32.13° ⁇ 0.20°, 35.34° ⁇ 0.20°.
  • the crystalline form A of the tartrate salt of the compound of formula (II) has an X-ray powder diffraction pattern expressed in 2 ⁇ having diffraction peaks at the following positions: 6.42° ⁇ 0.20°, 12.03° ⁇ 0.20°, 13.08° ⁇ 0.20°, 13.32° ⁇ 0.20°, 15.27° ⁇ 0.20°, 16.30° ⁇ 0.20°, 16.59° ⁇ 0.20°, 17.59° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of Form A of the tartrate salt of the compound of formula (II) expressed in 2 ⁇ angles further has diffraction peaks at one or more of the following positions: 21.70° ⁇ 0.20°, 27.04° ⁇ 0.20°, 30.82° ⁇ 0.20°, 35.78° ⁇ 0.20°.
  • the crystalline form A of the tartrate salt of the compound of formula (II) has an X-ray powder diffraction pattern expressed in 2 ⁇ having diffraction peaks at the following positions: 6.42° ⁇ 0.20°, 12.03° ⁇ 0.20°, 13.08° ⁇ 0.20°, 13.32° ⁇ 0.20°, 15.27° ⁇ 0.20°, 16.30° ⁇ 0.20°, 16.59° ⁇ 0.20°, 17.59° ⁇ 0.20°, 19.09° ⁇ 0.20°, 19.74° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystalline form A of the tartrate salt of the compound of formula (II) expressed in 2 ⁇ has the diffraction peaks shown in the following table:
  • the X-ray powder diffraction pattern of Form A of the tartrate salt of the compound of formula (II) is shown in FIG10 .
  • the crystalline form A of the tartrate salt of the compound of formula (II) is obtained by the following parameters:
  • the crystalline form A of the tartrate salt of the compound of formula (II) has a differential scanning calorimetry (DSC) curve having an endothermic peak at 132.7 ⁇ 3.0°C (peak).
  • the crystalline form A of the tartrate salt of the compound of formula (II) has a differential scanning calorimetry (DSC) curve with an endothermic peak at 126.9°C to 132.7°C and a heat of fusion of 89.60 J/g.
  • the differential scanning calorimetry curve of Form A of the tartrate salt of the compound of formula (II) is shown in FIG11 .
  • the crystalline form A of the tartrate salt of the compound of formula (II) has a thermogravimetric analysis (TGA) curve showing a weight loss of 0.34% at 130.0°C.
  • thermogravimetric analysis curve of Form A of the tartrate salt of the compound of formula (II) is shown in FIG11 .
  • the crystalline form A of the tartrate salt of the compound of formula (II) is obtained by the following parameters: TGA and/or DSC pattern of the crystalline form;
  • the tartrate crystal form A of the compound of formula (II) is an anhydrous crystal form.
  • the molar ratio of the compound of formula (II) to the tartaric acid is 1.1:1.
  • the present invention also provides a method for preparing the crystalline form A of the tartrate salt of the compound of formula (II) comprising the following steps:
  • the organic solvent is acetonitrile
  • the molar ratio of L-tartaric acid to the compound of formula (II) is 1.05.
  • the present invention also provides a use of a substance X in preparing a compound of formula (I), wherein the substance X is the compound of formula (II), a salt of the compound of formula (II), crystalline form A of the maleate salt, crystalline form A of the mesylate salt, crystalline form A of the gentisate salt, or crystalline form A of the tartrate salt;
  • the substance X is prepared into a compound of formula (I) by the following route:
  • the present invention provides a method for preparing a compound of formula (I), comprising the following steps:
  • the method for preparing the compound of formula (I) comprises the following steps:
  • the method for preparing the compound of formula (I) comprises the following steps:
  • the reagents and raw materials used in the present invention are commercially available.
  • the intermediate compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art.
  • Preferred embodiments include, but are not limited to, the examples of the present invention.
  • Those skilled in the art can refer to the contents of the present invention to appropriately change the raw materials, process conditions, and other aspects to achieve corresponding other purposes. Such related changes do not depart from the contents of the present invention. All similar substitutions and modifications are obvious to those skilled in the art and are considered to be included within the scope of the present invention.
  • Free state refers to the free base form of the compound represented by formula (II).
  • Crystal form or “crystalline form” refers to a solid with a highly regular chemical structure, including, but not limited to, single-component or multi-component crystals, and/or polymorphs, solvates, hydrates, inclusion compounds, co-crystals, salts, solvates of salts, and hydrates of salts. Crystalline forms of a substance can be obtained by a variety of methods known in the art.
  • melt crystallization melt cooling, solvent crystallization, crystallization in a confined space, such as in a nanopore or capillary, crystallization on a surface or template, such as on a polymer, crystallization in the presence of an additive such as a co-crystallizing countermolecule, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, antisolvent addition, milling, and solvent drop milling.
  • an additive such as a co-crystallizing countermolecule, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, antisolvent addition, milling, and solvent drop milling.
  • Solvent refers to a substance (typically a liquid) that can completely or partially dissolve another substance (typically a solid).
  • Solvents useful in the practice of the present invention include, but are not limited to, water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, tert-butanol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, butanone, 1-methyl-2-pyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, 2-acetone, pyridine, tetrahydrofuran, toluene, xylene, mixtures thereof
  • Anti-solvent refers to a fluid that promotes precipitation of a product (or product precursor) from a solvent.
  • the anti-solvent can include a cold gas, or a fluid that promotes precipitation by a chemical reaction, or a fluid that reduces the solubility of the product in the solvent; it can be the same liquid as the solvent but at a different temperature, or it can be a different liquid from the solvent.
  • Solidvate refers to a crystal having a solvent on the surface, in the crystal lattice, or both on the surface and in the crystal lattice, wherein the solvent may be water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, tert-butanol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, tricarboxylic acid, heptane, hexane, isopropanol, methanol, butanone, methylpyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, 2-propanone, pyridine, tetrahydrofuran, toluene, xylene, and mixtures thereof
  • a specific example of a solvate is a hydrate, in which the solvent on the surface, in the crystal lattice, or both on the surface and in the crystal lattice is water. Hydrates may or may not have other solvents besides water on the surface, in the crystal lattice, or both on the surface and in the crystal lattice.
  • the crystal form can be identified by a variety of technical means, such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point method, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetic resonance, Raman spectroscopy, X-ray single crystal diffraction, dissolution calorimetry, scanning electron microscopy (SEM), quantitative analysis, solubility and dissolution rate, etc.
  • XRPD X-ray powder diffraction
  • IR infrared absorption spectroscopy
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • Raman spectroscopy X-ray single crystal diffraction
  • dissolution calorimetry dissolution calorimetry
  • SEM scanning electron microscopy
  • X-ray powder diffraction can detect variations in form, crystallinity, and crystalline state, and is a common method for identifying crystalline forms.
  • the peak positions of an XRPD pattern are primarily determined by the structure of the crystalline form and are relatively insensitive to experimental details. However, their relative peak heights depend on many factors related to sample preparation and instrument geometry. Therefore, in some embodiments, the crystalline forms of the present invention are characterized by an XRPD pattern with certain peak positions, substantially as shown in the XRPD patterns provided in the accompanying drawings.
  • the measurement of 2 ⁇ in an XRPD pattern can be subject to experimental error, and the 2 ⁇ measurement of an XRPD pattern may vary slightly between different instruments and samples. Therefore, the 2 ⁇ values described cannot be considered absolute. Based on the instrumentation used in the present invention, the diffraction peaks have an error tolerance of ⁇ 0.20°.
  • Differential Scanning Calorimetry is a technique that measures the energy difference between a sample and an inert reference material (typically ⁇ -Al2O3) as a function of temperature by continuously heating or cooling the sample under program control.
  • the height of the melting peak in a DSC curve depends on many factors related to sample preparation and instrument geometry, while the peak position is relatively insensitive to experimental details. Therefore, in some embodiments, the crystalline form described herein is characterized by a DSC plot with characteristic peak positions, substantially as shown in the DSC plots provided in the accompanying drawings. DSC patterns are subject to experimental error; the peak positions and peak values may vary slightly between different instruments and samples. Therefore, the peak positions or peak values of the DSC endothermic peaks described herein should not be considered absolute. Based on the instrumentation used in the present invention, the melting peak has an error tolerance of ⁇ 3°C.
  • Thermogravimetric analysis is a technique that measures the mass change of a substance with temperature under program control. It is suitable for examining the loss of solvent from crystals or the sublimation or decomposition of a sample, and can infer the presence of water of crystallization or solvent in the crystals.
  • the mass change shown by the TGA curve depends on many factors, including sample preparation and instrumentation; the mass change detected by TGA varies slightly between different instruments and samples. Based on the instrumentation used in the present test, the mass change has an error tolerance of ⁇ 0.3%.
  • solvates specifically including stoichiometric solvates and non-stoichiometric solvates. All such solvates are encompassed within the scope of the present invention.
  • Boc represents tert-butyloxycarbonyl
  • MEK represents butanone
  • EtOAc and EA represent ethyl acetate
  • ACN represents acetonitrile
  • EtOH represents ethanol
  • n-Hep represents n-heptane
  • MTBE represents methyl tert-butyl ether
  • Toluene represents toluene.
  • the maleate salt form A, methanesulfonate salt form A, gentisate salt form A or tartrate salt form A of the compound of formula (II) provided by the present invention are all anhydrous crystals with high crystallinity, good stability, resistance to high temperature and high humidity, and low hygroscopicity.
  • the method for preparing maleate salt form A provided by the present invention has high product purity and yield, mild and easy-to-control conditions, and good reproducibility.
  • the method for preparing the compound of formula (I) of the present invention has the advantages of readily available commercial reagents, low material cost, high utilization rate, high process yield, greater safety, and suitability for industrial production.
  • FIG1 is a Cu-K ⁇ radiation XRPD spectrum of maleate salt form A of the compound of formula (II);
  • Figure 2 is a DSC/TGA spectrum of the maleate salt of the compound of formula (II) in Form A;
  • FIG3 is a 1 H NMR spectrum of the maleate salt of the compound of formula (II) in crystal form A;
  • FIG4 is a Cu-K ⁇ radiation XRPD spectrum of the mesylate salt form A of the compound of formula (II);
  • FIG5 is a DSC/TGA spectrum of the mesylate salt of the compound of formula (II) in Form A;
  • FIG6 is a 1 H NMR spectrum of the mesylate salt of the compound of formula (II) in Form A;
  • FIG7 is a Cu-K ⁇ radiation XRPD spectrum of the gentisate crystal form A of the compound of formula (II);
  • FIG8 is a DSC/TGA spectrum of the crystalline form A of the compound of formula (II);
  • FIG9 is a 1 H NMR spectrum of the crystalline form A of the compound of formula (II);
  • FIG10 is a Cu-K ⁇ radiation XRPD spectrum of the tartrate crystal form A of the compound of formula (II);
  • Figure 11 is a DSC/TGA spectrum of the tartrate crystal form A of the compound of formula (II);
  • FIG12 is a 1 H NMR spectrum of the tartrate salt form A of the compound of formula (II);
  • Figure 13 is a comparison of XRPD patterns of maleate salt A of compound of formula (II) after being stored under different conditions for 2 days;
  • FIG14 is a comparative XRPD diagram of gentisate A of the compound of formula (II) after being placed under different conditions for 2 days;
  • Figure 15 is a DVS spectrum of the maleate salt of the compound of formula (II) in Form A;
  • FIG16 is an XRPD spectrum of the maleate salt form A of the compound of formula (II) before and after DVS testing.
  • Methyltriphenylphosphonium bromide (103.47 g) was dissolved in toluene (650 mL), replaced with nitrogen three times, cooled to 0-5°C, added with potassium tert-butoxide (29.79 g), heated to 20-25°C, stirred and reacted for 1 hour, added with intermediate 1-B (65 g), stirred and reacted at 20-25°C for 16 hours.
  • water (1000 mL) was added, extracted and separated, methyl tert-butyl ether was added to the aqueous phase and extracted again, the organic phases were combined, washed with brine (1000 mL), and the organic phase was concentrated to dryness under reduced pressure.
  • the compound of formula II was synthesized by referring to the method of Example 1 above.
  • the compound of formula II (137 g) and (S)-N-Boc tert-leucine (192.32 g) were dissolved in a mixed solution of acetonitrile (1370 mL) and N,N-dimethylformamide (137 mL).
  • 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (159.41 g), N-methylmorpholine (152.93 g) and 1-hydroxybenzotriazole (102.14 g) were added at 25° C. and the reaction was continued for 16 hours.
  • the mixture was concentrated under reduced pressure to remove most of the acetonitrile, and ethyl acetate (1000 mL) and water (1000 mL) were added for extraction.
  • the organic phase was separated, and washed with 10% citric acid (500 mL*2), saturated sodium bicarbonate (500 mL), and saturated brine (500 mL), and concentrated to dryness under reduced pressure.
  • the concentrate was added with hydrochloric acid ethyl acetate solution (4 mol/L, 1.89 L) and methanol (200 mL) at 10-15°C. After the addition, the mixture was stirred at 20-25°C for 0.5 hour.
  • the organic phase was washed with 5% citric acid (1500 ml x 2), saturated sodium bicarbonate solution (1500 ml x 2), and saturated sodium chloride (2000 ml). The entire aqueous phase was extracted with EtOAc (1500 ml). The organic phase was washed with 5% citric acid (750 ml), saturated sodium bicarbonate solution (750 ml), and saturated sodium chloride solution (1000 ml). The combined organic phases were dried over anhydrous sodium sulfate, filtered under reduced pressure, and concentrated under reduced pressure at 50°C to obtain the crude product. The product was then beaten with MTBE (5 V) for 1 hr, filtered under reduced pressure, and the filter cake was dried under reduced pressure at 50°C to obtain intermediate 3 (312 g, 70.4% yield).
  • the aqueous phase was extracted with IPAc (1200 ml) and discarded.
  • the IPAc phase was washed with 5% citric acid (400 ml), saturated sodium bicarbonate solution (400 ml), and deionized water (400 ml x 3).
  • the above organic phases were combined, dried over anhydrous sodium sulfate, filtered under reduced pressure, and concentrated under reduced pressure at 50° C. to obtain about 350 g of the compound of formula (I).
  • the hygroscopicity of the maleate salt of the compound of formula (II) was evaluated using DVS at 25°C.
  • the specific method is as follows:
  • Relative humidity increase process 0% RH to 90% RH, the rate is 10% RH/stage; 90% RH to 95% RH, the rate is 5% RH/stage;
  • Relative humidity reduction process 95% RH to 90% RH, the rate is 5% RH/stage; 90% RH to 0% RH, the rate is 10% RH/stage;
  • DVS data showed that the maleate salt of compound (II) experienced a 0.1% weight gain during the first humidification cycle from 0% RH to 80% RH, indicating little or no hygroscopicity. Following the DVS test, samples were stored at 0% RH and then immediately removed to room temperature (16-20°C, 25-60% RH) for XRPD analysis. The crystal forms remained unchanged, demonstrating good crystal stability. DVS data are shown in Figures 15-16.

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Abstract

Disclosed in the present invention are a salt and a crystal form of a pharmaceutical intermediate, and a preparation method therefor and a use thereof. The present invention provides a salt of a compound as represented by formula (II), and a maleate crystal form A, a mesylate crystal form A, a gentisate crystal form A, and a tartrate crystal form A thereof. The crystal forms provided in the present invention are all anhydrous crystal forms, and has high crystallinity, good stability, resistance to high temperature and high humidity, and low hygroscopicity.

Description

一种药物中间体的盐、晶型及其制备方法和应用A salt, crystal form of a pharmaceutical intermediate, and preparation method and application thereof

本申请要求申请日为2024年4月17日的中国专利申请2024104641959的优先权。本申请引用上述中国专利申请的全文。This application claims the benefit of Chinese patent application No. 2024104641959, filed on April 17, 2024. This application incorporates the entirety of the aforementioned Chinese patent application.

技术领域Technical Field

本发明涉及一种药物中间体的盐、晶型及其制备方法和应用，具体涉及式(II)化合物的盐及其制备方法。The present invention relates to a salt of a pharmaceutical intermediate, a crystal form thereof, a preparation method and an application thereof, and particularly to a salt of a compound of formula (II) and a preparation method thereof.

背景技术Background Art

SARS-CoV-2属于单正链的RNA病毒，和SARS-CoV以及MERS-CoV具有较高的同源性。该病毒感染进入宿主细胞后，在宿主细胞的帮助下，其遗传物质RNA首先翻译表达出两条多聚蛋白前体(pp1a和pp1ab)，多聚蛋白前体在3CL蛋白酶和PL蛋白酶的作用下发生分子内的切割产生多个非结构蛋白，由于3CL蛋白酶至少负责11个位点的切割，故又称之为主蛋白酶(main protease，Mpro)。非结构蛋白参与了病毒亚基因RNA和四个结构蛋白(E蛋白、M蛋白、S蛋白和N蛋白)的产生，进而完成子代病毒的繁衍与释放；3CL蛋白酶属于半胱氨酸蛋白酶,活性形式为同源二聚体。3CL蛋白酶在冠状病毒中较为保守,并且不同冠状病毒3CL蛋白酶的底物之间具有共同特征；由于人体内不存在与3CL蛋白酶同源的蛋白酶，因此3CL蛋白酶成为理想的抗冠状病毒靶标之一。SARS-CoV-2 is a single-stranded, positive-strand RNA virus that shares a high degree of homology with SARS-CoV and MERS-CoV. Upon entry into host cells, the virus's genetic material, RNA, is first translated into two polyprotein precursors (pp1a and pp1ab) with the help of the host cell. These polyprotein precursors undergo intramolecular cleavage by the 3CL protease and PL protease to produce multiple nonstructural proteins. Because the 3CL protease is responsible for cleavage at at least 11 sites, it is also known as the main protease (Mpro). These nonstructural proteins participate in the production of the viral subgenomic RNA and four structural proteins (E, M, S, and N), thereby enabling the reproduction and release of progeny viruses. The 3CL protease is a cysteine protease that is active as a homodimer. The 3CL protease is highly conserved among coronaviruses, and substrates shared by different coronavirus 3CL proteases share common characteristics. Since no protease homologous to the 3CL protease exists in the human body, the 3CL protease is an ideal target for anti-coronavirus treatment.

开发能够有效抗冠状病毒的药物是目前临床用药所亟需的。专利PCT/CN2022/087511发现了一种具有良好的抗冠状病毒活性的3CL蛋白酶抑制剂。为了进一步提高药物的可及性和更有利于放大生产，有必要开发用于获得该3CL蛋白酶抑制剂的中间体的新方法，包括使用试剂和原料的可及性，加强成本控制，提高规模化生产放大程度，保证工艺生产安全性等。3CL蛋白酶抑制剂的分子结构如下：
The development of effective anti-coronavirus drugs is currently urgently needed for clinical use. Patent PCT/CN2022/087511 discovered a 3CL protease inhibitor with excellent anti-coronavirus activity. To further improve the accessibility of the drug and facilitate scale-up production, it is necessary to develop new methods for obtaining intermediates of the 3CL protease inhibitor, including using reagents and raw materials with accessibility, strengthening cost control, improving the scale-up of large-scale production, and ensuring process safety. The molecular structure of the 3CL protease inhibitor is as follows:

发明内容Summary of the Invention

针对现有技术中制备3CL蛋白酶抑制剂的相关问题，本发明提供一种式(II)化合物中间体或其药学可接受的盐、晶型及其制备方法及其应用。本发明中间体化合物的晶型结晶度高，具有良好的稳定性，能耐高温、高湿，且引湿性低，且产物纯度和收率高。To address the problems associated with the preparation of 3CL protease inhibitors in the prior art, the present invention provides an intermediate compound of formula (II) or a pharmaceutically acceptable salt thereof, a crystalline form thereof, a preparation method thereof, and applications thereof. The crystalline form of the intermediate compound of the present invention exhibits high crystallinity, good stability, resistance to high temperatures and high humidity, low hygroscopicity, and high product purity and yield.

本发明通过以下技术方案解决上述技术问题。The present invention solves the above technical problems through the following technical solutions.

本发明提供了一种式(II)化合物的盐，所述盐为马来酸盐、甲磺酸盐、龙胆酸盐或酒石酸盐；
The present invention provides a salt of a compound of formula (II), wherein the salt is a maleate, a methanesulfonate, a gentisate or a tartrate;

优选地，马来酸、甲磺酸、龙胆酸或酒石酸与式(II)化合物的摩尔比为1.1:1或1.0:1，更优选为1.0:1。Preferably, the molar ratio of maleic acid, methanesulfonic acid, gentisic acid or tartaric acid to the compound of formula (II) is 1.1:1 or 1.0:1, more preferably 1.0:1.

本发明提供了一种式(II)化合物马来酸盐的晶型A，使用Cu-Kα辐射，其以2θ表示的X射线粉末衍射图在下述位置具有衍射峰：10.37°±0.20°，13.75°±0.20°，14.77°±0.20°，19.47°±0.20°，20.97°±0.20°，21.67°±0.20°；
The present invention provides a crystalline form A of a maleate salt of a compound of formula (II), wherein an X-ray powder diffraction pattern expressed in 2θ using Cu-Kα radiation has diffraction peaks at the following positions: 10.37°±0.20°, 13.75°±0.20°, 14.77°±0.20°, 19.47°±0.20°, 20.97°±0.20°, and 21.67°±0.20°;

在本发明的一些方案中，所述式(II)化合物马来酸盐的晶型A以2θ角表示的X射线粉末衍射图还进一步在下述的一个或多个位置有衍射峰：11.67°±0.20°，17.48°±0.20°，19.75°±0.20°，22.79°±0.20°，23.48°±0.20°，25.23°±0.20°，26.93°±0.20°，28.07°±0.20°，29.80°±0.20°，32.89°±0.20°，38.37°±0.20°。In some embodiments of the present invention, the X-ray powder diffraction pattern of Form A of the maleate salt of the compound of formula (II) expressed in 2θ angles further has diffraction peaks at one or more of the following positions: 11.67°±0.20°, 17.48°±0.20°, 19.75°±0.20°, 22.79°±0.20°, 23.48°±0.20°, 25.23°±0.20°, 26.93°±0.20°, 28.07°±0.20°, 29.80°±0.20°, 32.89°±0.20°, 38.37°±0.20°.

在本发明的一些方案中，所述式(II)化合物马来酸盐的晶型A以2θ表示的X射线粉末衍射图在下述位置具有衍射峰：10.37°±0.20°，11.67°±0.20°，13.75°±0.20°，14.77°±0.20°，17.48°±0.20°，19.47°±0.20°，19.75°±0.20°，20.97°±0.20°，21.67°±0.20°，22.79°±0.20°，23.48°±0.20°，25.23°±0.20°，26.93°±0.20°，28.07°±0.20°，29.80°±0.20°，32.89°±0.20°，38.37°±0.20°。In some embodiments of the present invention, the crystalline form A of the maleate salt of the compound of formula (II) has an X-ray powder diffraction pattern expressed in 2θ with diffraction peaks at the following positions: 10.37°±0.20°, 11.67°±0.20°, 13.75°±0.20°, 14.77°±0.20°, 17.48°±0.20°, 19.47°±0.20°, 19.75 °±0.20°, 20.97°±0.20°, 21.67°±0.20°, 22.79°±0.20°, 23.48°±0.20°, 25.23°±0.20°, 26.93°±0.20°, 28.07°±0.20°, 29.80°±0.20°, 32.89°±0.20°, 38.37°±0.20°.

在本发明的一些方案中，所述式(II)化合物马来酸盐的晶型A以2θ表示的X射线粉末衍射图具有如下表所示的衍射峰：

In some embodiments of the present invention, the X-ray powder diffraction pattern of the maleate salt of the compound of formula (II) in form A expressed in 2θ has the diffraction peaks shown in the following table:

在本发明的一些方案中，所述式(II)化合物马来酸盐的晶型A以2θ表示的X射线粉末衍射图如图1所示。In some embodiments of the present invention, the X-ray powder diffraction pattern of Form A of the maleate salt of the compound of formula (II) expressed in 2θ is shown in FIG1 .

在本发明的一些方案中，所述式(II)化合物马来酸盐的晶型A通过以下参数获得X射线粉末衍射图；
In some embodiments of the present invention, the crystalline form A of the maleate salt of the compound of formula (II) is obtained by the following parameters:

在本发明的一些方案中，所述式(II)化合物马来酸盐的晶型A，其差示扫描量热曲线(DSC)在143.8±3.0℃(峰值)处具有一个吸热峰。In some embodiments of the present invention, the crystalline form A of the maleate salt of the compound of formula (II) has a differential scanning calorimetry (DSC) curve having an endothermic peak at 143.8±3.0°C (peak).

在本发明的一些方案中，所述式(II)化合物马来酸盐的晶型A，其差示扫描量热曲线(DSC)在135.6℃～143.8℃处吸热峰的熔化热为89.25J/g。In some embodiments of the present invention, the crystalline form A of the maleate salt of the compound of formula (II) has a differential scanning calorimetry (DSC) curve with an endothermic peak at 135.6°C to 143.8°C and a heat of fusion of 89.25 J/g.

在本发明的一些方案中，所述式(II)化合物马来酸盐的晶型A，其差示扫描量热曲线如图2所示。In some embodiments of the present invention, the differential scanning calorimetry curve of Form A of the maleate salt of the compound of formula (II) is shown in FIG2 .

在本发明的一些方案中，所述式(II)化合物马来酸盐的晶型A，其热重分析曲线(TGA)在130.0℃时失重0.68％。In some embodiments of the present invention, the crystalline form A of the maleate salt of the compound of formula (II) has a thermogravimetric analysis (TGA) curve showing a weight loss of 0.68% at 130.0°C.

在本发明的一些方案中，所述式(II)化合物马来酸盐的晶型A，其热重分析曲线如图2所示。In some embodiments of the present invention, the thermogravimetric analysis curve of Form A of the maleate salt of the compound of formula (II) is shown in FIG2 .

在本发明的一些方案中，所述式(II)化合物马来酸盐的晶型A通过以下参数获得晶体形式的TGA和/或DSC图案；

In some embodiments of the present invention, the crystalline form A of the maleate salt of the compound of formula (II) is obtained by the following parameters: TGA and/or DSC pattern of the crystalline form;

在本发明的一些方案中，所述式(II)化合物马来酸盐的晶型A为无水晶型。In some embodiments of the present invention, the crystalline form A of the maleate salt of the compound of formula (II) is an anhydrous crystalline form.

在本发明的一些方案中，所述式(II)化合物与所述马来酸的摩尔比为1.0:1。In some embodiments of the present invention, the molar ratio of the compound of formula (II) to the maleic acid is 1.0:1.

本发明还提供了上述式(II)化合物马来酸盐的晶型A的制备方法，其包括如下步骤：The present invention also provides a method for preparing the crystalline form A of the maleate salt of the compound of formula (II), which comprises the following steps:

在有机溶剂中，将式(II)化合物、马来酸混合，搅拌后分离即可；In an organic solvent, the compound of formula (II) and maleic acid are mixed, stirred and then separated;

优选地，所述有机溶剂为乙酸乙酯；Preferably, the organic solvent is ethyl acetate;

优选地，马来酸和式(II)化合物的摩尔比为1.05:1；Preferably, the molar ratio of maleic acid to the compound of formula (II) is 1.05:1;

本发明提供了一种式(II)化合物甲磺酸盐的晶型A，使用Cu-Kα辐射，以2θ表示的X射线粉末衍射图在下述位置具有衍射峰：7.23°±0.20°，13.91°±0.20°，16.36°±0.20°，18.95°±0.20°，19.71°±0.20°，20.65°±0.20°，21.94°±0.20°；
The present invention provides a crystalline form A of a mesylate salt of a compound of formula (II), wherein an X-ray powder diffraction pattern expressed in 2θ using Cu-Kα radiation has diffraction peaks at the following positions: 7.23°±0.20°, 13.91°±0.20°, 16.36°±0.20°, 18.95°±0.20°, 19.71°±0.20°, 20.65°±0.20°, and 21.94°±0.20°;

在本发明的一些方案中，所述式(II)化合物甲磺酸盐的晶型A以2θ角表示的X射线粉末衍射图还进一步在下述的一个或多个位置有衍射峰：9.92°±0.20°，12.39°±0.20°，17.85°±0.20°，18.59°±0.20°，23.21°±0.20°，24.03°±0.20°。In some embodiments of the present invention, the X-ray powder diffraction pattern of Form A of the methanesulfonate salt of the compound of formula (II) expressed in 2θ angles further has diffraction peaks at one or more of the following positions: 9.92°±0.20°, 12.39°±0.20°, 17.85°±0.20°, 18.59°±0.20°, 23.21°±0.20°, 24.03°±0.20°.

在本发明的一些方案中，所述式(II)化合物甲磺酸盐的晶型A以2θ表示的X射线粉末衍射图在下述位置具有衍射峰：7.23°±0.20°，9.92°±0.20°，13.91°±0.20°，16.36°±0.20°，12.39°±0.20°，17.85°±0.20°，18.59°±0.20°，18.95°±0.20°，19.71°±0.20°，20.65°±0.20°，21.94°±0.20°，23.21°±0.20°，24.03°±0.20°。In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form A of the methanesulfonate salt of the compound of formula (II) expressed in 2θ has diffraction peaks at the following positions: 7.23°±0.20°, 9.92°±0.20°, 13.91°±0.20°, 16.36°±0.20°, 12.39°±0.20°, 17.85°±0.20°, 18.59°±0.20°, 18.95°±0.20°, 19.71°±0.20°, 20.65°±0.20°, 21.94°±0.20°, 23.21°±0.20°, and 24.03°±0.20°.

在本发明的一些方案中，所述式(II)化合物甲磺酸盐的晶型A以2θ表示的X射线粉末衍射图还进一步在下述的一个或多个位置有衍射峰：10.35°±0.20°，11.83°±0.20°，14.66°±0.20°，21.36°±0.20°，22.87°±0.20°，24.92°±0.20°，25.27°±0.20°，26.60°±0.20°，27.30°±0.20°，28.34°±0.20°。In some embodiments of the present invention, the X-ray powder diffraction pattern of Form A of the methanesulfonate salt of the compound of formula (II) expressed in 2θ further has diffraction peaks at one or more of the following positions: 10.35°±0.20°, 11.83°±0.20°, 14.66°±0.20°, 21.36°±0.20°, 22.87°±0.20°, 24.92°±0.20°, 25.27°±0.20°, 26.60°±0.20°, 27.30°±0.20°, and 28.34°±0.20°.

在本发明的一些方案中，所述式(II)化合物甲磺酸盐的晶型A以2θ表示的X射线粉末衍射图在下述位置具有衍射峰：7.23°±0.20°，9.92°±0.20°，10.35°±0.20°，11.83°±0.20°，12.39°±0.20°，13.91°±0.20°，14.66°±0.20°，16.36°±0.20°，17.85°±0.20°，18.59°±0.20°，18.95°±0.20°，19.71°±0.20°，20.65°±0.20°，21.36°±0.20°，21.94°±0.20°，22.87°±0.20°，23.21°±0.20°，24.03°±0.20°，24.92°±0.20°，25.27°±0.20°，26.60°±0.20°，27.30°±0.20°，28.34°±0.20°。In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form A of the methanesulfonate salt of the compound of formula (II) expressed in 2θ has diffraction peaks at the following positions: 7.23°±0.20°, 9.92°±0.20°, 10.35°±0.20°, 11.83°±0.20°, 12.39°±0.20°, 13.91°±0.20°, 14.66°±0.20°, 16.36°±0.20°, 17.85°±0.20°, 18.59° ±0.20°, 18.95°±0.20°, 19.71°±0.20°, 20.65°±0.20°, 21.36°±0.20°, 21.94°±0.20°, 22.87°±0.20°, 23.21°±0.20°, 24.03°±0.20°, 24.92°±0.20°, 25.27°±0.20°, 26.60°±0.20°, 27.30°±0.20°, 28.34°±0.20°.

在本发明的一些方案中，所述式(II)化合物甲磺酸盐的晶型A以2θ表示的X射线粉末衍射图还进一步在下述的一个或多个位置有衍射峰：8.23°±0.20°，15.20°±0.20°，22.57°±0.20°，24.43°±0.20°，26.32°±0.20°，29.00°±0.20°，29.40°±0.20°，29.98°±0.20°，31.23°±0.20°，32.01°±0.20°，32.75°±0.20°，33.26°±0.20°，34.60°±0.20°，35.39°±0.20°，36.55°±0.20°，37.88°±0.20°，38.44°±0.20°，39.22°±0.20°。In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form A of the methanesulfonate salt of the compound of formula (II) expressed in 2θ further has diffraction peaks at one or more of the following positions: 8.23°±0.20°, 15.20°±0.20°, 22.57°±0.20°, 24.43°±0.20°, 26.32°±0.20°, 29.00°±0.20°, 29.40°±0 .20°, 29.98°±0.20°, 31.23°±0.20°, 32.01°±0.20°, 32.75°±0.20°, 33.26°±0.20°, 34.60°±0.20°, 35.39°±0.20°, 36.55°±0.20°, 37.88°±0.20°, 38.44°±0.20°, 39.22°±0.20°.

在本发明的一些方案中，所述式(II)化合物甲磺酸盐的晶型A以2θ表示的X射线粉末衍射图在下述位置具有衍射峰：7.23°±0.20°，8.23°±0.20°，9.92°±0.20°，10.35°±0.20°，11.83°±0.20°，12.39°±0.20°，13.91°±0.20°，14.66°±0.20°，15.20°±0.20°，16.36°±0.20°，17.85°±0.20°，18.59°±0.20°，18.95°±0.20°，19.71°±0.20°，20.65°±0.20°，21.36°±0.20°，21.94°±0.20°，22.57°±0.20°，22.87°±0.20°，23.21°±0.20°，24.03°±0.20°，24.43°±0.20°，24.92°±0.20°，25.27°±0.20°，26.32°±0.20°，26.60°±0.20°，27.30°±0.20°，28.34°±0.20°，29.00°±0.20°，29.40°±0.20°，29.98°±0.20°，31.23°±0.20°，32.01°±0.20°，32.75°±0.20°，33.26°±0.20°，34.60°±0.20°，35.39°±0.20°，36.55°±0.20°，37.88°±0.20°，38.44°±0.20°，39.22°±0.20°。In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form A of the methanesulfonate salt of the compound of formula (II) expressed in 2θ has diffraction peaks at the following positions: 7.23°±0.20°, 8.23°±0.20°, 9.92°±0.20°, 10.35°±0.20°, 11.83°±0.20°, 12.39°±0.20°, 13.91°±0.20°, 14.6 6°±0.20°, 15.20°±0.20°, 16.36°±0.20°, 17.85°±0.20°, 18.59°±0.20°, 18.95°±0.20°, 19.71°±0.20°, 20.65°±0.20°, 21.36°±0.20°, 21.94°±0.20°, 22.57°±0.20°, 22.87°± 0.20°, 23.21°±0.20°, 24.03°±0.20°, 24.43°±0.20°, 24.92°±0.20°, 25.27°±0.20°, 26.32°±0.20°, 26.60°±0.20°, 27.30°±0.20°, 28.34°±0.20°, 29.00°±0.20°, 29.40°±0.2 0°, 29.98°±0.20°, 31.23°±0.20°, 32.01°±0.20°, 32.75°±0.20°, 33.26°±0.20°, 34.60°±0.20°, 35.39°±0.20°, 36.55°±0.20°, 37.88°±0.20°, 38.44°±0.20°, 39.22°±0.20°.

在本发明的一些方案中，所述式(II)化合物甲磺酸盐的晶型A以2θ表示的X射线粉末衍射图具有如下表所示的衍射峰：

In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form A of the methanesulfonate salt of the compound of formula (II) expressed in 2θ has the diffraction peaks shown in the following table:

在本发明的一些方案中，所述式(II)化合物甲磺酸盐的晶型A以2θ表示的X射线粉末衍射图如图4所示。In some embodiments of the present invention, the X-ray powder diffraction pattern of Form A of the methanesulfonate salt of the compound of formula (II) expressed in 2θ is shown in FIG4 .

在本发明的一些方案中，所述式(II)化合物甲磺酸盐的晶型A通过以下参数获得X射线粉末衍射图；
In some embodiments of the present invention, the crystalline form A of the methanesulfonate salt of the compound of formula (II) is obtained by the following parameters:

在本发明的一些方案中，所述式(II)化合物甲磺酸盐的晶型A，其差示扫描量热曲线(DSC)在123.6±3.0℃(峰值)处具有一个吸热峰。In some embodiments of the present invention, the crystalline form A of the methanesulfonate salt of the compound of formula (II) has a differential scanning calorimetry (DSC) curve having an endothermic peak at 123.6±3.0°C (peak).

在本发明的一些方案中，所述式(II)化合物甲磺酸盐的晶型A，其差示扫描量热曲线(DSC)在119.6℃～123.6℃处吸热峰的熔化热为81.65J/g。In some embodiments of the present invention, the crystalline form A of the methanesulfonate salt of the compound of formula (II) has a differential scanning calorimetry (DSC) curve with an endothermic peak at 119.6°C to 123.6°C and a heat of fusion of 81.65 J/g.

在本发明的一些方案中，所述式(II)化合物甲磺酸盐的晶型A，其差示扫描量热曲线如图5所示。In some embodiments of the present invention, the differential scanning calorimetry curve of Form A of the methanesulfonate salt of the compound of formula (II) is shown in FIG5 .

在本发明的一些方案中，所述式(II)化合物甲磺酸盐的晶型A，其热重分析曲线(TGA)在160.0℃时失重0.41％。In some embodiments of the present invention, the crystalline form A of the methanesulfonate salt of the compound of formula (II) has a thermogravimetric analysis (TGA) curve showing a weight loss of 0.41% at 160.0°C.

在本发明的一些方案中，所述式(II)化合物甲磺酸盐的晶型A，其热重分析曲线如图5所示。In some embodiments of the present invention, the thermogravimetric analysis curve of Form A of the methanesulfonate salt of the compound of formula (II) is shown in FIG5 .

在本发明的一些方案中，所述式(II)化合物甲磺酸盐的晶型A通过以下参数获得晶体形式的TGA和/或DSC图案；

In some embodiments of the present invention, the crystalline form A of the methanesulfonate salt of the compound of formula (II) is obtained by the following parameters: TGA and/or DSC pattern of the crystalline form;

在本发明的一些方案中，所述式(II)化合物甲磺酸盐晶型A为无水晶型。In some embodiments of the present invention, the mesylate salt crystalline form A of the compound of formula (II) is an anhydrous crystalline form.

在本发明的一些方案中，所述式(II)化合物与所述甲磺酸的摩尔比为1.0:1。In some embodiments of the present invention, the molar ratio of the compound of formula (II) to the methanesulfonic acid is 1.0:1.

本发明还提供了上述式(II)化合物甲磺酸盐的晶型A的制备方法，其包括如下步骤：The present invention also provides a method for preparing the crystalline form A of the methanesulfonate salt of the compound of formula (II), which comprises the following steps:

在有机溶剂中，将式(II)化合物、甲磺酸混合，搅拌后分离即可；In an organic solvent, the compound of formula (II) and methanesulfonic acid are mixed, stirred and then separated;

优选地，所述有机溶剂为丁酮；Preferably, the organic solvent is butanone;

优选地，所述甲磺酸和式(II)化合物的摩尔比为1.05:1。Preferably, the molar ratio of methanesulfonic acid to the compound of formula (II) is 1.05:1.

本发明提供了一种式(II)化合物龙胆酸盐的晶型A，使用Cu-Kα辐射，以2θ表示的X射线粉末衍射图在下述位置具有衍射峰：8.54°±0.20°，8.89°±0.20°，12.70°±0.20°，17.42°±0.20°，18.04°±0.20°，19.45°±0.20°，23.80°±0.20°；
The present invention provides a crystalline form A of a gentisate salt of a compound of formula (II), wherein an X-ray powder diffraction pattern expressed in 2θ using Cu-Kα radiation has diffraction peaks at the following positions: 8.54°±0.20°, 8.89°±0.20°, 12.70°±0.20°, 17.42°±0.20°, 18.04°±0.20°, 19.45°±0.20°, and 23.80°±0.20°;

在本发明的一些方案中，所述式(II)化合物龙胆酸盐的晶型A以2θ角表示的X射线粉末衍射图还进一步在下述的一个或多个位置有衍射峰：18.86°±0.20°，22.31°±0.20°，25.40°±0.20°，25.77°±0.20°，27.78°±0.20°，35.56°±0.20°。In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form A of the gentisate salt of the compound of formula (II) expressed in 2θ angles further has diffraction peaks at one or more of the following positions: 18.86°±0.20°, 22.31°±0.20°, 25.40°±0.20°, 25.77°±0.20°, 27.78°±0.20°, 35.56°±0.20°.

在本发明的一些方案中，所述式(II)化合物龙胆酸盐的晶型A，以2θ表示的X射线粉末衍射图在下述位置具有衍射峰：8.54°±0.20°，8.89°±0.20°，12.70°±0.20°，17.42°±0.20°，18.04°±0.20°，18.86°±0.20°，19.45°±0.20°，22.31°±0.20°，23.80°±0.20°，25.40°±0.20°，25.77°±0.20°，27.78°±0.20°，35.56°±0.20°。In some embodiments of the present invention, the crystalline form A of the gentisate salt of the compound of formula (II) has an X-ray powder diffraction pattern expressed as 2θ having diffraction peaks at the following positions: 8.54°±0.20°, 8.89°±0.20°, 12.70°±0.20°, 17.42°±0.20°, 18.04°±0.20°, 18.86°±0.20°, 19.45°±0.20°, 22.31°±0.20°, 23.80°±0.20°, 25.40°±0.20°, 25.77°±0.20°, 27.78°±0.20°, and 35.56°±0.20°.

在本发明的一些方案中，所述式(II)化合物龙胆酸盐的晶型A以2θ角表示的X射线粉末衍射图还进一步在下述的一个或多个位置有衍射峰：11.66°±0.20°，16.21°±0.20°，22.71°±0.20°，26.64°±0.20°，36.12°±0.20°，39.19°±0.20°。In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form A of the gentisate salt of the compound of formula (II) expressed in 2θ angles further has diffraction peaks at one or more of the following positions: 11.66°±0.20°, 16.21°±0.20°, 22.71°±0.20°, 26.64°±0.20°, 36.12°±0.20°, 39.19°±0.20°.

在本发明的一些方案中，所述式(II)化合物龙胆酸盐的晶型A，以2θ表示的X射线粉末衍射图在下述位置具有衍射峰：8.54°±0.20°，8.89°±0.20°，11.66°±0.20°，12.70°±0.20°，16.21°±0.20°，17.42°±0.20°，18.04°±0.20°，18.86°±0.20°，19.45°±0.20°，22.31°±0.20°，22.71°±0.20°，23.80°±0.20°，25.40°±0.20°，25.77°±0.20°，26.64°±0.20°，27.78°±0.20°，35.56°±0.20°，36.12°±0.20°，39.19°±0.20°。In some embodiments of the present invention, the crystalline form A of the gentisate salt of the compound of formula (II) has an X-ray powder diffraction pattern expressed in 2θ having diffraction peaks at the following positions: 8.54°±0.20°, 8.89°±0.20°, 11.66°±0.20°, 12.70°±0.20°, 16.21°±0.20°, 17.42°±0.20°, 18.04°±0.20°, 18.86° ±0.20°, 19.45°±0.20°, 22.31°±0.20°, 22.71°±0.20°, 23.80°±0.20°, 25.40°±0.20°, 25.77°±0.20°, 26.64°±0.20°, 27.78°±0.20°, 35.56°±0.20°, 36.12°±0.20°, 39.19°±0.20°.

在本发明的一些方案中，所述式(II)化合物龙胆酸盐的晶型A以2θ表示的X射线粉末衍射图具有如下表所示的衍射峰：

In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form A of the gentisate salt of the compound of formula (II) expressed in 2θ has the diffraction peaks shown in the following table:

在本发明的一些方案中，所述式(II)化合物龙胆酸盐的晶型A，其X射线粉末衍射图谱如图7所示。In some embodiments of the present invention, the X-ray powder diffraction pattern of Form A of the gentisate salt of the compound of formula (II) is shown in FIG7 .

在本发明的一些方案中，所述式(II)化合物龙胆酸盐的晶型A通过以下参数获得X射线粉末衍射图；
In some embodiments of the present invention, the crystalline form A of the gentisate salt of the compound of formula (II) is obtained by the following parameters:

在本发明的一些方案中，所述式(II)化合物龙胆酸盐的晶型A，其差示扫描量热曲线(DSC)在169.1±3.0℃(峰值)处具有一个吸热峰。In some embodiments of the present invention, the crystalline form A of the gentisate salt of the compound of formula (II) has a differential scanning calorimetry (DSC) curve having an endothermic peak at 169.1±3.0°C (peak).

在本发明的一些方案中，所述式(II)化合物龙胆酸盐的晶型A，其差示扫描量热曲线(DSC)在165.11℃～169.12℃处吸热峰的熔化热为115.1J/g。In some embodiments of the present invention, the crystalline form A of the gentisate salt of the compound of formula (II) has a differential scanning calorimetry (DSC) curve with an endothermic peak at 165.11°C to 169.12°C and a heat of fusion of 115.1 J/g.

在本发明的一些方案中，所述式(II)化合物龙胆酸盐的晶型A，其差示扫描量热曲线如图8所示。In some embodiments of the present invention, the differential scanning calorimetry curve of the crystalline form A of the gentisate salt of the compound of formula (II) is shown in FIG8 .

在本发明的一些方案中，所述式(II)化合物龙胆酸盐的晶型A，其热重分析曲线(TGA)在140.0℃时失重0.14％。In some embodiments of the present invention, the crystalline form A of the gentisate salt of the compound of formula (II) has a thermogravimetric analysis (TGA) curve showing a weight loss of 0.14% at 140.0°C.

在本发明的一些方案中，所述式(II)化合物龙胆酸盐的晶型A，其热重分析曲线如图8所示。In some embodiments of the present invention, the thermogravimetric analysis curve of Form A of the gentisate salt of the compound of formula (II) is shown in FIG8 .

在本发明的一些方案中，所述式(II)化合物龙胆酸盐的晶型A通过以下参数获得晶体形式的TGA和/或DSC图案；
In some embodiments of the present invention, the crystal form A of the gentisate salt of the compound of formula (II) is obtained by the following parameters: TGA and/or DSC pattern of the crystal form;

在本发明的一些方案中，所述式(II)化合物龙胆酸盐晶型A为无水晶型。In some embodiments of the present invention, the gentisate crystal form A of the compound of formula (II) is an anhydrous crystal form.

在本发明的一些方案中，所述式(II)化合物与所述龙胆酸的摩尔比为1.0:1。In some embodiments of the present invention, the molar ratio of the compound of formula (II) to the gentisic acid is 1.0:1.

本发明还提供了上述式(II)化合物龙胆酸盐的晶型A的制备方法，其包括如下步骤：The present invention also provides a method for preparing the crystalline form A of the gentisate salt of the compound of formula (II), which comprises the following steps:

在有机溶剂中，将式(II)化合物、龙胆酸混合，搅拌后分离即可；In an organic solvent, the compound of formula (II) and gentisic acid are mixed, stirred and then separated;

优选地，所述有机溶剂为乙腈；Preferably, the organic solvent is acetonitrile;

优选地，所述龙胆酸和式(II)化合物的摩尔比为1.05。Preferably, the molar ratio of gentisic acid to the compound of formula (II) is 1.05.

本发明提供了一种式(II)化合物酒石酸盐的晶型A，使用Cu-Kα辐射，以2θ表示的X射线粉末衍射图在下述位置具有衍射峰：6.42°±0.20°，13.08°±0.20°，15.27°±0.20°，17.59°±0.20°，19.09°±0.20°，20.05°±0.20°；
The present invention provides a crystalline form A of a tartrate salt of a compound of formula (II), wherein an X-ray powder diffraction pattern expressed in 2θ using Cu-Kα radiation has diffraction peaks at the following positions: 6.42°±0.20°, 13.08°±0.20°, 15.27°±0.20°, 17.59°±0.20°, 19.09°±0.20°, and 20.05°±0.20°;

在本发明的一些方案中，所述式(II)化合物酒石酸盐的晶型A以2θ角表示的X射线粉末衍射图还进一步在下述的一个或多个位置有衍射峰：16.30°±0.20°，19.74°±0.20°，26.47°±0.20°。In some embodiments of the present invention, the X-ray powder diffraction pattern of Form A of the tartrate salt of the compound of formula (II) expressed in 2θ angles further has diffraction peaks at one or more of the following positions: 16.30°±0.20°, 19.74°±0.20°, 26.47°±0.20°.

在本发明的一些方案中，所述式(II)化合物酒石酸盐的晶型A，以2θ表示的X射线粉末衍射图在下述位置具有衍射峰：6.42°±0.20°，13.08°±0.20°，15.27°±0.20°，16.30°±0.20°，17.59°±0.20°，19.09°±0.20°，19.74°±0.20°，20.05°±0.20°，26.47°±0.20°。In some embodiments of the present invention, the crystalline form A of the tartrate salt of the compound of formula (II) has an X-ray powder diffraction pattern expressed as 2θ having diffraction peaks at the following positions: 6.42°±0.20°, 13.08°±0.20°, 15.27°±0.20°, 16.30°±0.20°, 17.59°±0.20°, 19.09°±0.20°, 19.74°±0.20°, 20.05°±0.20°, and 26.47°±0.20°.

在本发明的一些方案中，所述式(II)化合物酒石酸盐的晶型A以2θ角表示的X射线粉末衍射图还进一步在下述的一个或多个位置有衍射峰：12.03°±0.20°，13.32°±0.20°，23.17°±0.20°，25.98°±0.20°。In some embodiments of the present invention, the X-ray powder diffraction pattern of Form A of the tartrate salt of the compound of formula (II) expressed in 2θ angles further has diffraction peaks at one or more of the following positions: 12.03°±0.20°, 13.32°±0.20°, 23.17°±0.20°, 25.98°±0.20°.

在本发明的一些方案中，所述式(II)化合物酒石酸盐的晶型A，以2θ表示的X射线粉末衍射图在下述位置具有衍射峰：6.42°±0.20°，12.03°±0.20°，13.08°±0.20°，13.32°±0.20°，15.27°±0.20°，16.30°±0.20°，17.59°±0.20°，19.09°±0.20°，19.74°±0.20°，20.05°±0.20°，23.17°±0.20°，25.98°±0.20°，26.47°±0.20°。In some embodiments of the present invention, the crystalline form A of the tartrate salt of the compound of formula (II) has an X-ray powder diffraction pattern expressed as 2θ having diffraction peaks at the following positions: 6.42°±0.20°, 12.03°±0.20°, 13.08°±0.20°, 13.32°±0.20°, 15.27°±0.20°, 16.30°±0.20°, 17.59°±0.20°, 19.09°±0.20°, 19.74°±0.20°, 20.05°±0.20°, 23.17°±0.20°, 25.98°±0.20°, and 26.47°±0.20°.

在本发明的一些方案中，所述式(II)化合物酒石酸盐的晶型A以2θ角表示的X射线粉末衍射图还进一步在下述的一个或多个位置有衍射峰：16.59°±0.20°，21.02°±0.20°，22.93°±0.20°，28.47°±0.20°，31.32°±0.20°，32.13°±0.20°，35.34°±0.20°。In some embodiments of the present invention, the X-ray powder diffraction pattern of Form A of the tartrate salt of the compound of formula (II) expressed in 2θ angles further has diffraction peaks at one or more of the following positions: 16.59°±0.20°, 21.02°±0.20°, 22.93°±0.20°, 28.47°±0.20°, 31.32°±0.20°, 32.13°±0.20°, 35.34°±0.20°.

在本发明的一些方案中，所述式(II)化合物酒石酸盐的晶型A，以2θ表示的X射线粉末衍射图在下述位置具有衍射峰：6.42°±0.20°，12.03°±0.20°，13.08°±0.20°，13.32°±0.20°，15.27°±0.20°，16.30°±0.20°，16.59°±0.20°，17.59°±0.20°，19.09°±0.20°，19.74°±0.20°，20.05°±0.20°，21.02°±0.20°，22.93°±0.20°，23.17°±0.20°，25.98°±0.20°，26.47°±0.20°，28.47°±0.20°，31.32°±0.20°，32.13°±0.20°，35.34°±0.20°。In some embodiments of the present invention, the crystalline form A of the tartrate salt of the compound of formula (II) has an X-ray powder diffraction pattern expressed in 2θ having diffraction peaks at the following positions: 6.42°±0.20°, 12.03°±0.20°, 13.08°±0.20°, 13.32°±0.20°, 15.27°±0.20°, 16.30°±0.20°, 16.59°±0.20°, 17.59°±0.20°. , 19.09°±0.20°, 19.74°±0.20°, 20.05°±0.20°, 21.02°±0.20°, 22.93°±0.20°, 23.17°±0.20°, 25.98°±0.20°, 26.47°±0.20°, 28.47°±0.20°, 31.32°±0.20°, 32.13°±0.20°, 35.34°±0.20°.

在本发明的一些方案中，所述式(II)化合物酒石酸盐的晶型A以2θ角表示的X射线粉末衍射图还进一步在下述的一个或多个位置有衍射峰：21.70°±0.20°，27.04°±0.20°，30.82°±0.20°，35.78°±0.20°。In some embodiments of the present invention, the X-ray powder diffraction pattern of Form A of the tartrate salt of the compound of formula (II) expressed in 2θ angles further has diffraction peaks at one or more of the following positions: 21.70°±0.20°, 27.04°±0.20°, 30.82°±0.20°, 35.78°±0.20°.

在本发明的一些方案中，所述式(II)化合物酒石酸盐的晶型A，以2θ表示的X射线粉末衍射图在下述位置具有衍射峰：6.42°±0.20°，12.03°±0.20°，13.08°±0.20°，13.32°±0.20°，15.27°±0.20°，16.30°±0.20°，16.59°±0.20°，17.59°±0.20°，19.09°±0.20°，19.74°±0.20°，20.05°±0.20°，21.02°±0.20°，21.70°±0.20°，22.93°±0.20°，23.17°±0.20°，25.98°±0.20°，26.47°±0.20°，27.04°±0.20°，28.47°±0.20°，30.82°±0.20°，31.32°±0.20°，32.13°±0.20°，35.34°±0.20°，35.78°±0.20°。In some embodiments of the present invention, the crystalline form A of the tartrate salt of the compound of formula (II) has an X-ray powder diffraction pattern expressed in 2θ having diffraction peaks at the following positions: 6.42°±0.20°, 12.03°±0.20°, 13.08°±0.20°, 13.32°±0.20°, 15.27°±0.20°, 16.30°±0.20°, 16.59°±0.20°, 17.59°±0.20°, 19.09°±0.20°, 19.74°±0.20°. , 20.05°±0.20°, 21.02°±0.20°, 21.70°±0.20°, 22.93°±0.20°, 23.17°±0.20°, 25.98°±0.20°, 26.47°±0.20°, 27.04°±0.20°, 28.47°±0.20°, 30.82°±0.20°, 31.32°±0.20°, 32.13°±0.20°, 35.34°±0.20°, 35.78°±0.20°.

在本发明的一些方案中，所述式(II)化合物酒石酸盐的晶型A以2θ表示的X射线粉末衍射图具有如下表所示的衍射峰：

In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form A of the tartrate salt of the compound of formula (II) expressed in 2θ has the diffraction peaks shown in the following table:

在本发明的一些方案中，所述式(II)化合物酒石酸盐的晶型A，其X射线粉末衍射图谱如图10所示。In some embodiments of the present invention, the X-ray powder diffraction pattern of Form A of the tartrate salt of the compound of formula (II) is shown in FIG10 .

在本发明的一些方案中，所述式(II)化合物酒石酸盐的晶型A通过以下参数获得X射线粉末衍射图；
In some embodiments of the present invention, the crystalline form A of the tartrate salt of the compound of formula (II) is obtained by the following parameters:

在本发明的一些方案中，所述式(II)化合物酒石酸盐的晶型A，其差示扫描量热曲线(DSC)在132.7±3.0℃(峰值)处具有一个吸热峰。In some embodiments of the present invention, the crystalline form A of the tartrate salt of the compound of formula (II) has a differential scanning calorimetry (DSC) curve having an endothermic peak at 132.7±3.0°C (peak).

在本发明的一些方案中，所述式(II)化合物酒石酸盐的晶型A，其差示扫描量热曲线(DSC)在126.9℃～132.7℃处吸热峰的熔化热为89.60J/g。In some embodiments of the present invention, the crystalline form A of the tartrate salt of the compound of formula (II) has a differential scanning calorimetry (DSC) curve with an endothermic peak at 126.9°C to 132.7°C and a heat of fusion of 89.60 J/g.

在本发明的一些方案中，所述式(II)化合物酒石酸盐的晶型A，其差示扫描量热曲线如图11所示。In some embodiments of the present invention, the differential scanning calorimetry curve of Form A of the tartrate salt of the compound of formula (II) is shown in FIG11 .

在本发明的一些方案中，所述式(II)化合物酒石酸盐的晶型A，其热重分析曲线(TGA)在130.0℃时失重0.34％。In some embodiments of the present invention, the crystalline form A of the tartrate salt of the compound of formula (II) has a thermogravimetric analysis (TGA) curve showing a weight loss of 0.34% at 130.0°C.

在本发明的一些方案中，所述式(II)化合物酒石酸盐的晶型A，其热重分析曲线如图11所示。In some embodiments of the present invention, the thermogravimetric analysis curve of Form A of the tartrate salt of the compound of formula (II) is shown in FIG11 .

在本发明的一些方案中，所述式(II)化合物酒石酸盐的晶型A通过以下参数获得晶体形式的TGA和/或DSC图案；

In some embodiments of the present invention, the crystalline form A of the tartrate salt of the compound of formula (II) is obtained by the following parameters: TGA and/or DSC pattern of the crystalline form;

在本发明的一些方案中，所述式(II)化合物酒石酸盐晶型A为无水晶型。In some embodiments of the present invention, the tartrate crystal form A of the compound of formula (II) is an anhydrous crystal form.

在本发明的一些方案中，所述式(II)化合物与所述酒石酸的摩尔比为1.1:1。In some embodiments of the present invention, the molar ratio of the compound of formula (II) to the tartaric acid is 1.1:1.

本发明还提供了上述式(II)化合物酒石酸盐的晶型A的制备方法包括如下步骤：The present invention also provides a method for preparing the crystalline form A of the tartrate salt of the compound of formula (II) comprising the following steps:

在有机溶剂中，将式(II)化合物、L-酒石酸混合，搅拌后分离即可；In an organic solvent, the compound of formula (II) and L-tartaric acid are mixed, stirred and then separated;

优选地，所述有机溶剂为乙腈；Preferably, the organic solvent is acetonitrile;

优选地，所述L-酒石酸和式(II)化合物的摩尔比为1.05。Preferably, the molar ratio of L-tartaric acid to the compound of formula (II) is 1.05.

本发明还提供了一种物质X在制备式(I)化合物中的应用，所述的物质X为上述式(II)化合物、式(II)化合物的盐、马来酸盐的晶型A、甲磺酸盐的晶型A、龙胆酸盐的晶型A或酒石酸盐的晶型A；The present invention also provides a use of a substance X in preparing a compound of formula (I), wherein the substance X is the compound of formula (II), a salt of the compound of formula (II), crystalline form A of the maleate salt, crystalline form A of the mesylate salt, crystalline form A of the gentisate salt, or crystalline form A of the tartrate salt;

所述式(I)化合物为 The compound of formula (I) is

优选地，所述应用中，所述物质X通过以下路线制备式(I)化合物：
Preferably, in the application, the substance X is prepared into a compound of formula (I) by the following route:

本发明提供了一种式(I)化合物的制备方法，其包括如下步骤：
The present invention provides a method for preparing a compound of formula (I), comprising the following steps:

在本发明的一些方案中，所述式(I)化合物的制备方法，包括如下步骤：
In some embodiments of the present invention, the method for preparing the compound of formula (I) comprises the following steps:

在本发明的一些方案中，所述式(I)化合物的制备方法，包括如下步骤：
In some embodiments of the present invention, the method for preparing the compound of formula (I) comprises the following steps:

在符合本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。On the basis of conforming to the common sense in this field, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

本发明所用试剂和原料均市售可得。The reagents and raw materials used in the present invention are commercially available.

定义和说明：Definition and Explanation:

除非另有说明，本文所用的下列术语和短语旨在含有下列含义。一个特定的短语或术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文出现商品名时，旨在指代其对应的商品或其活性成分。Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular phrase or term should not be construed as ambiguous or unclear unless specifically defined, but rather should be understood in accordance with its ordinary meaning. When a trade name appears herein, it is intended to refer to the corresponding commercial product or its active ingredient.

本发明的中间体化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。本领域技术人员可以借鉴本发明的内容适当改变原料、工艺条件等环节来实现相应的其它目的，其相关改变都没有脱离本发明的内容，所有类似的替换和改动对于本领域技术人员来说是显而易见的，都被视为包括在本发明的范围之内。The intermediate compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present invention. Those skilled in the art can refer to the contents of the present invention to appropriately change the raw materials, process conditions, and other aspects to achieve corresponding other purposes. Such related changes do not depart from the contents of the present invention. All similar substitutions and modifications are obvious to those skilled in the art and are considered to be included within the scope of the present invention.

“游离态”是指式(II)所示化合物的游离碱形式。"Free state" refers to the free base form of the compound represented by formula (II).

“晶型”或“结晶形式”是指具有高度规则化学结构的固体,包括,但不限于,单组分或者多组分晶体,和/或化合物的多晶型物、溶剂化物、水合物、包合物、共晶、盐、盐的溶剂化物、盐的水合物。物质的结晶形式可通过本领域已知的许多方法得到。这种方法包括,但不限于,熔体结晶、熔体冷却、溶剂结晶、在限定的空间中结晶,例如,在纳米孔或者毛细管中,在表面或者模板上结晶,例如,在聚合物上,在添加剂如共结晶反分子的存在下结晶、去溶剂、脱水、快速蒸发、快速冷却、缓慢冷却、蒸气扩散、升华、反应结晶、反溶剂添加、研磨和溶剂滴研磨等。"Crystal form" or "crystalline form" refers to a solid with a highly regular chemical structure, including, but not limited to, single-component or multi-component crystals, and/or polymorphs, solvates, hydrates, inclusion compounds, co-crystals, salts, solvates of salts, and hydrates of salts. Crystalline forms of a substance can be obtained by a variety of methods known in the art. These methods include, but are not limited to, melt crystallization, melt cooling, solvent crystallization, crystallization in a confined space, such as in a nanopore or capillary, crystallization on a surface or template, such as on a polymer, crystallization in the presence of an additive such as a co-crystallizing countermolecule, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, antisolvent addition, milling, and solvent drop milling.

“溶剂”是指一种物质(典型地是一种液体),该物质能够完全地或部分地溶解另一种物质(典型地是一种固体)。用于本发明实施的溶剂包括但并不限于，水、乙酸、丙酮、乙腈、苯、氯仿、四氯化碳、二氯甲烷、二甲基亚砜、1,4-二氧六环、乙醇、乙酸乙酯、丁醇、叔丁醇、N,N-二甲基乙酰胺、N,N-二甲基甲酰胺、甲酰胺、蚁酸、庚烷、己烷、异丙醇、甲醇、丁酮、1-甲基-2-吡咯烷酮、均三甲苯、硝基甲烷、聚乙二醇、丙醇、2-丙酮、吡啶、四氢呋喃、甲苯、二甲苯、它们的混合物等等。"Solvent" refers to a substance (typically a liquid) that can completely or partially dissolve another substance (typically a solid). Solvents useful in the practice of the present invention include, but are not limited to, water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, tert-butanol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, butanone, 1-methyl-2-pyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, 2-acetone, pyridine, tetrahydrofuran, toluene, xylene, mixtures thereof, and the like.

“反溶剂”是指促进产物(或产物前体)从溶剂中沉淀的流体。反溶剂可以包括冷气体、或通过化学反应促进沉淀的流体、或降低产物在溶剂中的溶解度的流体；其可以是与溶剂相同的液体但是处于不同温度，或者它可以是与溶剂不同的液体。"Anti-solvent" refers to a fluid that promotes precipitation of a product (or product precursor) from a solvent. The anti-solvent can include a cold gas, or a fluid that promotes precipitation by a chemical reaction, or a fluid that reduces the solubility of the product in the solvent; it can be the same liquid as the solvent but at a different temperature, or it can be a different liquid from the solvent.

“溶剂化物”是指晶体在表面上、或在晶格中、或者在表面上和在晶格中具有溶剂,其中,所述溶剂可以是水、乙酸、丙酮、乙腈、苯、氯仿、四氯化碳、二氯甲烷、二甲基亚砜、1,4-二氧六环、乙醇、乙酸乙酯、丁醇、叔丁醇、N,N-二甲基乙酰胺、N,N-二甲基甲酰胺、甲酰胺、蚊酸、庚烷、己烷、异丙醇、甲醇、丁酮、甲基吡咯烷酮、均三甲苯、硝基甲烷、聚乙二醇、丙醇、2-丙酮、吡啶、四氢呋喃、甲苯、二甲苯以及它们的混合物等等。溶剂化物的一个具体例子是水合物，其中在表面上、或在晶格中、或者在表面上和在晶格中的溶剂是水。在物质的表面上、或在晶格中、或者在表面上和在晶格中,水合物可以具有或者不具有除了水以外的其它溶剂。"Solvate" refers to a crystal having a solvent on the surface, in the crystal lattice, or both on the surface and in the crystal lattice, wherein the solvent may be water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, tert-butanol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, tricarboxylic acid, heptane, hexane, isopropanol, methanol, butanone, methylpyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, 2-propanone, pyridine, tetrahydrofuran, toluene, xylene, and mixtures thereof. A specific example of a solvate is a hydrate, in which the solvent on the surface, in the crystal lattice, or both on the surface and in the crystal lattice is water. Hydrates may or may not have other solvents besides water on the surface, in the crystal lattice, or both on the surface and in the crystal lattice.

晶型可以通过多种技术手段进行鉴别，例如X射线粉末衍射(XRPD)、红外吸收光谱法(IR)、熔点法、差示扫描量热法(DSC)、热重分析法(TGA)、核磁共振法、拉曼光谱、X射线单晶衍射、溶解量热法、扫描电子显微镜(SEM)、定量分析、溶解度和溶解速度等等。The crystal form can be identified by a variety of technical means, such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point method, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetic resonance, Raman spectroscopy, X-ray single crystal diffraction, dissolution calorimetry, scanning electron microscopy (SEM), quantitative analysis, solubility and dissolution rate, etc.

X射线粉末衍射(XRPD)可检测品型的变化、结晶度、晶构状态等信息,是鉴别晶型的常用手段。XRPD图谱的峰位置主要取决于晶型的结构,对实验细节相对不敏感,而其相对峰高取决于与样品制备和仪器几何形状有关的许多因素。因此,在一些实施例中,本发明的晶型的特征在于具有某些峰位置的XRPD图,其基本上如本发明附图中提供的XRPD图所示。同时,XRPD图谱的2θ的量度可以有实验误差,不同仪器以及不同样品之间,XRPD图谱的2θ的量度可能会略有差别,因此所述2θ的数值不能视为绝对的。根据本发明试验所用仪器状况，衍射峰存在±0.20°的误差容限。X-ray powder diffraction (XRPD) can detect variations in form, crystallinity, and crystalline state, and is a common method for identifying crystalline forms. The peak positions of an XRPD pattern are primarily determined by the structure of the crystalline form and are relatively insensitive to experimental details. However, their relative peak heights depend on many factors related to sample preparation and instrument geometry. Therefore, in some embodiments, the crystalline forms of the present invention are characterized by an XRPD pattern with certain peak positions, substantially as shown in the XRPD patterns provided in the accompanying drawings. Furthermore, the measurement of 2θ in an XRPD pattern can be subject to experimental error, and the 2θ measurement of an XRPD pattern may vary slightly between different instruments and samples. Therefore, the 2θ values described cannot be considered absolute. Based on the instrumentation used in the present invention, the diffraction peaks have an error tolerance of ±0.20°.

差示扫描量热(DSC)是在程序控制下,通过不断加热或降温,测量样品与惰性参比物(常用α-Al2O3)之间的能量差随温度变化的一种技术。DSC曲线的熔化峰高取决于与样品制备和仪器几何形状有关的许多因素，而峰位置对实验细节相对不敏感。因此，在一些实施例中，本发明所述晶型的特征在于具有特征峰位置的DSC图，其基本上如本发明附图中提供的DSC图所示。同时，DSC图谱可以有实验误差,不同仪器以及不同样品之间,DSC图谱的峰位置和峰值可能会略有差别,因此所述DSC吸热峰的峰位置或峰值的数值不能视为绝对的。根据本发明试验所用仪器状况，熔化峰存在±3℃的误差容限。Differential Scanning Calorimetry (DSC) is a technique that measures the energy difference between a sample and an inert reference material (typically α-Al₂O₃) as a function of temperature by continuously heating or cooling the sample under program control. The height of the melting peak in a DSC curve depends on many factors related to sample preparation and instrument geometry, while the peak position is relatively insensitive to experimental details. Therefore, in some embodiments, the crystalline form described herein is characterized by a DSC plot with characteristic peak positions, substantially as shown in the DSC plots provided in the accompanying drawings. DSC patterns are subject to experimental error; the peak positions and peak values may vary slightly between different instruments and samples. Therefore, the peak positions or peak values of the DSC endothermic peaks described herein should not be considered absolute. Based on the instrumentation used in the present invention, the melting peak has an error tolerance of ±3°C.

热重分析(TGA)是在程序控制下,测定物质的质量随温度变化的一种技术,适用于检查晶体中溶剂的丧失或样品升华、分解的过程,可推测晶体中含结晶水或结晶溶剂的情况。TGA曲线显示的质量变化取决于样品制备和仪器等许多因素；不同仪器以及不同样品之间,TGA检测的质量变化略有差别。根据本发明试验所用的仪器状况,质量变化存在±0.3％的误差容限。Thermogravimetric analysis (TGA) is a technique that measures the mass change of a substance with temperature under program control. It is suitable for examining the loss of solvent from crystals or the sublimation or decomposition of a sample, and can infer the presence of water of crystallization or solvent in the crystals. The mass change shown by the TGA curve depends on many factors, including sample preparation and instrumentation; the mass change detected by TGA varies slightly between different instruments and samples. Based on the instrumentation used in the present test, the mass change has an error tolerance of ±0.3%.

在制备药物晶型时，药物分子与溶剂分子在接触的过程中，外部条件与内部因素造成溶剂分子与化合物分子形成共晶而残留在固体物质中的情况很难避免，从而形成溶剂合物，具体包括化学计量类溶剂合物和非化学计量类溶剂合物。所述的溶剂合物均包括在本发明的范围内。During the preparation of drug crystal forms, during the contact between drug molecules and solvent molecules, external conditions and internal factors can inevitably cause the solvent molecules to form a co-crystal with the compound molecules and remain in the solid material, thereby forming solvates, specifically including stoichiometric solvates and non-stoichiometric solvates. All such solvates are encompassed within the scope of the present invention.

本发明具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本发明的化学变化及其所需的试剂和物料。为了获得本发明的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。The chemical reactions of the present invention are carried out in suitable solvents that are compatible with the chemical transformations of the present invention and the reagents and materials required. To obtain the compounds of the present invention, it may sometimes be necessary for those skilled in the art to modify or select synthetic steps or reaction schemes based on existing embodiments.

本发明所使用的所有溶剂可经市售获得。All solvents used in the present invention are commercially available.

本发明采用下述缩略词：Boc代表叔丁氧羰基；MEK代表丁酮；EtOAc、EA代表乙酸乙酯；ACN代表乙氰；EtOH代表乙醇；n-Hep代表正庚烷；MTBE代表甲基叔丁基醚；Toluene代表甲苯。The present invention uses the following abbreviations: Boc represents tert-butyloxycarbonyl; MEK represents butanone; EtOAc and EA represent ethyl acetate; ACN represents acetonitrile; EtOH represents ethanol; n-Hep represents n-heptane; MTBE represents methyl tert-butyl ether; and Toluene represents toluene.

化合物经本领域常规命名方法，市售化合物采用供应商目录名称。The compounds were named according to conventional methods in the art, and commercially available compounds were named according to the supplier's catalogue names.

本发明的积极进步效果在于：The positive progress effect of the present invention is:

1)本发明提供的式(II)化合物马来酸盐晶型A、甲磺酸盐晶型A、龙胆酸盐晶型A或酒石酸盐晶型A均为无水晶型、结晶度高，具有良好的稳定性，能耐高温、高湿，且引湿性低。1) The maleate salt form A, methanesulfonate salt form A, gentisate salt form A or tartrate salt form A of the compound of formula (II) provided by the present invention are all anhydrous crystals with high crystallinity, good stability, resistance to high temperature and high humidity, and low hygroscopicity.

2)本发明提供的马来酸盐晶型A的制备方法获得的产物纯度和收率高，条件温和且容易控制，重现性好。2) The method for preparing maleate salt form A provided by the present invention has high product purity and yield, mild and easy-to-control conditions, and good reproducibility.

3)本发明式(I)化合物的制备方法具有试剂商业化易得，物料成本低、利用率高，工艺收率较高且更为安全，适宜工业化生产的优点。3) The method for preparing the compound of formula (I) of the present invention has the advantages of readily available commercial reagents, low material cost, high utilization rate, high process yield, greater safety, and suitability for industrial production.

附图说明BRIEF DESCRIPTION OF THE DRAWINGS

图1为式(II)化合物马来酸盐A晶型的Cu-Kα辐射XRPD谱图；FIG1 is a Cu-Kα radiation XRPD spectrum of maleate salt form A of the compound of formula (II);

图2为式(II)化合物马来酸盐A晶型的DSC/TGA谱图；Figure 2 is a DSC/TGA spectrum of the maleate salt of the compound of formula (II) in Form A;

图3为式(II)化合物马来酸盐A晶型的1H NMR谱图；FIG3 is a 1 H NMR spectrum of the maleate salt of the compound of formula (II) in crystal form A;

图4为式(II)化合物甲磺酸盐A晶型的Cu-Kα辐射XRPD谱图；FIG4 is a Cu-Kα radiation XRPD spectrum of the mesylate salt form A of the compound of formula (II);

图5为式(II)化合物甲磺酸盐A晶型的DSC/TGA谱图；FIG5 is a DSC/TGA spectrum of the mesylate salt of the compound of formula (II) in Form A;

图6为式(II)化合物甲磺酸盐A晶型的1H NMR谱图；FIG6 is a 1 H NMR spectrum of the mesylate salt of the compound of formula (II) in Form A;

图7为式(II)化合物龙胆酸盐A晶型的Cu-Kα辐射XRPD谱图；FIG7 is a Cu-Kα radiation XRPD spectrum of the gentisate crystal form A of the compound of formula (II);

图8为式(II)化合物龙胆酸盐A晶型的DSC/TGA谱图；FIG8 is a DSC/TGA spectrum of the crystalline form A of the compound of formula (II);

图9为式(II)化合物龙胆酸盐A晶型的1H NMR谱图；FIG9 is a 1 H NMR spectrum of the crystalline form A of the compound of formula (II);

图10为式(II)化合物酒石酸盐A晶型的Cu-Kα辐射XRPD谱图；FIG10 is a Cu-Kα radiation XRPD spectrum of the tartrate crystal form A of the compound of formula (II);

图11为式(II)化合物酒石酸盐A晶型的DSC/TGA谱图；Figure 11 is a DSC/TGA spectrum of the tartrate crystal form A of the compound of formula (II);

图12为式(II)化合物酒石酸盐A晶型的1H NMR谱图；FIG12 is a 1 H NMR spectrum of the tartrate salt form A of the compound of formula (II);

图13为式(II)化合物马来酸盐A不同条件下放置2天后的XRPD对比图；Figure 13 is a comparison of XRPD patterns of maleate salt A of compound of formula (II) after being stored under different conditions for 2 days;

图14为式(II)化合物龙胆酸盐A不同条件下放置2天后的XRPD对比图；FIG14 is a comparative XRPD diagram of gentisate A of the compound of formula (II) after being placed under different conditions for 2 days;

图15为式(II)化合物马来酸盐A晶型的DVS谱图；Figure 15 is a DVS spectrum of the maleate salt of the compound of formula (II) in Form A;

图16为式(II)化合物马来酸盐A晶型DVS测试前后的XRPD谱图。FIG16 is an XRPD spectrum of the maleate salt form A of the compound of formula (II) before and after DVS testing.

具体实施方式DETAILED DESCRIPTION

下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

仪器型号：
Instrument Model:

实施例1式(II)化合物的合成
Example 1 Synthesis of compound of formula (II)

合成路线：
Synthesis route:

步骤1：中间体1-B的合成Step 1: Synthesis of Intermediate 1-B

将中间体1-A(70g)和2,2,6,6-四甲基哌啶氮氧化物(0.2g)溶于二氯甲烷(700mL)中，降温至0-5℃，将碳酸氢钠(33.81g)、溴化钠(2.65g)溶于水(420mL)中，加入到反应液中，将次氯酸钠溶液(372.12g,8％含量)，水(200mL)，混合均匀，于0～10℃滴加到反应液中，搅拌反应1小时，反应结束后，将亚硫酸钠(100g)溶于水(1000mL)中，加入反应液中淬灭0.5小时，分液，有机相加入二氯甲烷(1L)再萃取一遍，合并有机相，加入食盐水(1L)洗涤一遍，浓缩得到中间体1-B(68g,收率：98％)。1H NMR(400MHz,CDCl3)δppm major[4.66(s,1H),4.00(s,1H),3.69(s,3H),2.94(s,1H),2.37–2.12(m,3H),1.80(s,1H),1.33(s,9H)].minor[4.53(s,1H),4.09(s,1H),3.69(s,3H),2.96(s,1H),2.37–2.12(m,3H),1.77(s,1H),1.41(s,9H)].MS m/z:168.0[M-Boc]+ Intermediate 1-A (70 g) and 2,2,6,6-tetramethylpiperidine nitrogen oxide (0.2 g) were dissolved in dichloromethane (700 mL), cooled to 0-5°C, sodium bicarbonate (33.81 g) and sodium bromide (2.65 g) were dissolved in water (420 mL) and added to the reaction solution, sodium hypochlorite solution (372.12 g, 8% content) and water (200 mL) were mixed evenly, and added dropwise to the reaction solution at 0-10°C. The reaction was stirred for 1 hour. After the reaction was completed, sodium sulfite (100 g) was dissolved in water (1000 mL) and added to the reaction solution for quenching for 0.5 hours. The liquids were separated, and the organic phase was extracted again with dichloromethane (1 L). The organic phases were combined, washed once with brine (1 L), and concentrated to obtain intermediate 1-B (68 g, yield: 98%). 1 H NMR (400MHz, CDCl 3 ) δppm major[4.66(s,1H),4.00(s,1H),3.69(s,3H),2.94(s,1H),2.37–2.12(m,3H),1.80(s,1H),1.33(s,9H)].m inor[4.53(s,1H),4.09(s,1H),3.69(s,3H),2.96(s,1H),2.37–2.12(m,3H),1.77(s,1H),1.41(s,9H)].MS m/z:168.0[M-Boc] +

步骤2：中间体1-C的合成Step 2: Synthesis of Intermediate 1-C

将甲基三苯基溴化膦(103.47g)溶于甲苯(650mL)中，氮气置换3次，降温至0-5℃，加入叔丁醇钾(29.79g)，升温至20-25℃，搅拌反应1小时，加入中间体1-B(65g)，20-25℃搅拌反应16小时，反应结束后，加入水(1000mL)，萃取分液，水相加入甲基叔丁基醚再萃取一遍，合并有机相，用食盐水(1000mL)洗涤，有机相减压浓缩至干，浓缩物用石油醚-乙酸乙酯进行柱层析纯化，得到中间体1-C(33g,收率：51％)。1H NMR(400MHz,CDCl3)δppm major[5.15(d,J＝6.0Hz,1H),4.85(d,J＝6.0Hz,1H),4.45(s,1H),3.87(s,1H),3.72(s,3H),3.09(s,1H),2.41–2.22(m,3H),1.84(s,1H),1.37(s,9H)].minor[5.15(d,J＝6.0Hz,1H),4.85(d,J＝6.0Hz,1H),4.31(s,1H),3.97(s,1H),3.72(s,3H),3.11(s,1H),2.37–2.12(m,3H),2.06(s,1H),1.40(s,9H)].MS m/z:166.0[M-Boc]+ Methyltriphenylphosphonium bromide (103.47 g) was dissolved in toluene (650 mL), replaced with nitrogen three times, cooled to 0-5°C, added with potassium tert-butoxide (29.79 g), heated to 20-25°C, stirred and reacted for 1 hour, added with intermediate 1-B (65 g), stirred and reacted at 20-25°C for 16 hours. After the reaction, water (1000 mL) was added, extracted and separated, methyl tert-butyl ether was added to the aqueous phase and extracted again, the organic phases were combined, washed with brine (1000 mL), and the organic phase was concentrated to dryness under reduced pressure. The concentrate was purified by column chromatography with petroleum ether-ethyl acetate to obtain intermediate 1-C (33 g, yield: 51%). 1 H NMR (400MHz, CDCl 3 ) δppm major[5.15(d,J＝6.0Hz,1H),4.85(d,J＝6.0Hz,1H),4.45(s,1H),3.87(s,1H ),3.72(s,3H),3.09(s,1H),2.41–2.22(m,3H),1.84(s,1H),1.37(s,9H)].m inor[5.15(d,J＝6.0Hz,1H),4.85(d,J＝6.0Hz,1H),4.31(s,1H),3.97(s,1H) ,3.72(s,3H),3.11(s,1H),2.37–2.12(m,3H),2.06(s,1H),1.40(s,9H)].MS m/z:166.0[M-Boc] +

步骤3：式(II)化合物的合成Step 3: Synthesis of compound of formula (II)

氯苯(250mL)中降温至-10-0℃，加入二乙基锌正己烷溶液(1mol/L,561mL)，滴加完毕后，再滴加三氟化硼乙醚(119.46g)，滴加完毕后继续搅拌0.5小时，降温至-10℃，滴加二碘甲烷(300.57g)，滴加完毕后继续搅拌0.5小时，将中间体1-C(50g)溶解于氯苯(50mL)中，滴加到反应液中，滴加完毕升温至35-40℃反应4小时，反应结束后，降温至-10～-5℃，滴加20％柠檬酸水溶液(1000mL)，滴加完毕后，加入乙酸乙酯(500mL)，继续搅拌10分钟，分液，有机相用20％柠檬酸水溶液(250mL)洗涤，合并水相，水相用乙酸乙酯(300mL*2)萃取，水相加入酒石酸钾钠水溶液[酒石酸钾钠(316g)+水(750mL)]，用氨水调节pH至9-10，加入二氯甲烷(500mL)，萃取分液，水相用二氯甲烷(300mL)再萃取一遍，合并有机相减压浓缩得到中间体1-D(24g,收率：70％)。1H NMR(400MHz,CDCl3)δppm3.71(s,3H),3.69(s,1H),3.64(d,J＝3.6Hz,1H),1.86(s,1H),1.72–1.67(m,2H),1.52–1.47(m,2H),0.70–0.59(m,3H),0.40–0.38(m,1H).MS m/z:182.1[M+H]+ Chlorobenzene (250 mL) was cooled to -10-0°C, and diethylzinc n-hexane solution (1mol/L, 561 mL) was added. After the addition was complete, boron trifluoride etherate (119.46 g) was added dropwise. After the addition was complete, stirring was continued for 0.5 hours. The temperature was lowered to -10°C, and diiodomethane (300.57 g) was added dropwise. After the addition was complete, stirring was continued for 0.5 hours. Intermediate 1-C (50 g) was dissolved in chlorobenzene (50 mL) and added dropwise to the reaction solution. After the addition was complete, the temperature was raised to 35-40°C and the reaction was carried out for 4 hours. After the reaction was completed, the temperature was lowered to -10 to -5°C, and 20% citric acid aqueous solution was added dropwise. (1000mL), after the dropwise addition is completed, ethyl acetate (500mL) is added, stirring is continued for 10 minutes, the liquid is separated, the organic phase is washed with 20% citric acid aqueous solution (250mL), the aqueous phases are combined, the aqueous phase is extracted with ethyl acetate (300mL*2), potassium sodium tartrate aqueous solution [potassium sodium tartrate (316g) + water (750mL)] is added to the aqueous phase, the pH is adjusted to 9-10 with aqueous ammonia, dichloromethane (500mL) is added, the liquid is separated, the aqueous phase is extracted again with dichloromethane (300mL), and the combined organic phases are concentrated under reduced pressure to obtain intermediate 1-D (24g, yield: 70%). 1H NMR (400MHz, CDCl 3 )δppm3.71(s,3H),3.69(s,1H),3.64(d,J＝3.6Hz,1H),1.86(s,1H),1.72 –1.67(m,2H),1.52–1.47(m,2H),0.70–0.59(m,3H),0.40–0.38(m,1H).MS m/z:182.1[M+H] +

实施例2中间体1-A的合成
Example 2 Synthesis of Intermediate 1-A

氮气保护下，将S1(39g，141.6mmol，1eq)投入1000mL圆底烧瓶中，加入甲醇160g，乙酸(10.2g，170mmol，1.2eq)搅拌溶解；加入10％钯碳4.0g，将氢气压力设定0.3～0.5MPa，温度10～20℃，保温搅拌8～10hr；中控TLC点板显示原料点消失；过滤；滤液转移至1000mL圆底烧瓶中，5～5℃滴加三乙胺，0～10℃滴加二碳酸二叔丁酯，滴毕升温至15～20℃，保温搅拌2～2.5hr，TLC中控至原料点消失；反应液减压浓缩，加入乙酸乙酯180g，饮用水100g萃洗分层；水相用乙酸乙酯复萃；合并有机相，依次用12％碳酸氢钠水溶液，和30％氯化钠水溶液洗涤；有机相用无水硫酸钠干燥2hr，过滤；减压浓缩干，浓缩结束加入正庚烷80.4g室温打浆2-3hr，过滤，收集滤饼40-45℃真空干燥，得到目标产物中间体1-A(33.0g，收率：85.9％)，1H NMR(400MHz,DMSO-d6,298K,δin ppm):5.03(m,1H,CH),3.94(m,1H,CH),3.71(s,9H,C(CH3)3),3.64(d,3H,CH3),3.60(d,1H,CH),3.34(m,2H,CH2),2.41(m,1H,OH),1.86(m,1H,CH),1.63(m,2H,CH2)。Under nitrogen protection, S1 (39 g, 141.6 mmol, 1 eq) was put into a 1000 mL round-bottom flask, and 160 g of methanol and acetic acid (10.2 g, 170 mmol, 1.2 eq) were added and stirred to dissolve; 4.0 g of 10% palladium carbon was added, the hydrogen pressure was set to 0.3-0.5 MPa, the temperature was 10-20 ° C, and the mixture was stirred for 8-10 hours; the TLC spot plate of the central control showed that the raw material point disappeared; filtered; the filtrate was transferred to a 1000 mL round-bottom flask, triethylamine was added dropwise at 5-5 ° C, di-tert-butyl dicarbonate was added dropwise at 0-10 ° C, and the temperature was raised to 15- 20 ℃, keep warm and stir for 2-2.5 hours, control by TLC until the raw material point disappears; the reaction solution is concentrated under reduced pressure, 180 g of ethyl acetate and 100 g of drinking water are added to wash the layers; the aqueous phase is re-extracted with ethyl acetate; the organic phases are combined and washed with 12% aqueous sodium bicarbonate solution and 30% aqueous sodium chloride solution in sequence; the organic phase is dried over anhydrous sodium sulfate for 2 hours and filtered; concentrated under reduced pressure to dryness, 80.4 g of n-heptane is added to the mixture after concentration, and the mixture is beaten at room temperature for 2-3 hours, filtered, and the filter cake is collected and dried in vacuo at 40-45 ℃ to obtain the target product intermediate 1-A (33.0 g, yield: 85.9%). 1 H NMR (400MHz, DMSO-d6, 298K, δin ppm): 5.03(m,1H,CH),3.94(m,1H,CH),3.71(s,9H,C(CH 3 ) 3 ),3.64(d,3H,CH 3 ),3.60(d,1H,CH),3.34(m,2H,CH 2 ), 2.41(m,1H,OH), 1.86(m,1H,CH), 1.63(m,2H,CH 2 ).

实施例3中间体1的合成
Example 3 Synthesis of Intermediate 1

参考上述实施例1的方法合成式II化合物。The compound of formula II was synthesized by referring to the method of Example 1 above.

步骤4：中间体1-E的合成Step 4: Synthesis of Intermediate 1-E

将式II化合物(137g)、(S)-N-Boc叔亮氨酸(192.32g)溶解于乙腈(1370mL)和N,N-二甲基甲酰胺(137mL)的混合溶液中，25℃条件下加入1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(159.41g)、N-甲基吗啉(152.93g)、1-羟基苯并三唑(102.14g)，继续反应16小时，反应完成后，减压浓缩除去大部分乙腈后，加入乙酸乙酯(1000mL)，水(1000mL)，萃取，分液，有机相用10％柠檬酸(500mL*2)洗涤，饱和碳酸氢钠(500mL)洗涤，饱和食盐水(500mL)洗涤，减压浓缩至干，浓缩物于10-15℃下加入盐酸乙酸乙酯溶液(4mol/L,1.89L)，甲醇(200mL)，加完后于20-25℃搅拌反应0.5小时，反应完成后，浓缩除1L溶剂，于25℃下搅拌0.5小时，过滤，滤饼加入乙酸乙酯(200mL)洗涤，滤饼除溶残后得到中间体1-E(212g,收率：85％)。1H NMR(400MHz,CDCl3)δppm 8.49(s,3H),4.51(s,1H),4.42(s,1H),4.03(d,J＝4.8Hz,1H),3.70(s,3H),2.26(d,J＝10.8Hz,1H),2.07(s,1H),1.97(s,1H),1.90(d,J＝10.0Hz,1H),1.90(d,J＝10.0Hz,1H),1.80(d,J＝12.4Hz,1H),1.23(s,9H),0.81–0.64(m,3H),0.48–0.46(m,1H).MS m/z:294.9[M+H]+ The compound of formula II (137 g) and (S)-N-Boc tert-leucine (192.32 g) were dissolved in a mixed solution of acetonitrile (1370 mL) and N,N-dimethylformamide (137 mL). 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (159.41 g), N-methylmorpholine (152.93 g) and 1-hydroxybenzotriazole (102.14 g) were added at 25° C. and the reaction was continued for 16 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to remove most of the acetonitrile, and ethyl acetate (1000 mL) and water (1000 mL) were added for extraction. The organic phase was separated, and washed with 10% citric acid (500 mL*2), saturated sodium bicarbonate (500 mL), and saturated brine (500 mL), and concentrated to dryness under reduced pressure. The concentrate was added with hydrochloric acid ethyl acetate solution (4 mol/L, 1.89 L) and methanol (200 mL) at 10-15°C. After the addition, the mixture was stirred at 20-25°C for 0.5 hour. After the reaction was completed, 1 L of solvent was concentrated and the mixture was stirred at 25°C for 0.5 hour. The mixture was filtered, and the filter cake was washed with ethyl acetate (200 mL). After removing the residual solvent from the filter cake, intermediate 1-E (212 g, yield: 85%) was obtained. 1 H NMR (400MHz, CDCl 3 ) δppm 8.49(s,3H),4.51(s,1H),4.42(s,1H),4.03(d,J＝4.8Hz,1H),3.70(s,3H),2.26(d,J＝10.8Hz,1H),2.07(s,1H),1.97(s,1H), 1.90(d,J＝10.0Hz,1H),1.90(d,J＝10.0Hz,1H),1.80(d,J＝12.4Hz,1H),1.23(s,9H),0.81–0.64(m,3H),0.48–0.46(m,1H).MS m/z:294.9[M+H] +

步骤5：中间体1的合成Step 5: Synthesis of Intermediate 1

将中间体1-E(211.59g)溶解于二氯甲烷(1300mL)中，于10-15℃下加入三氟乙酸酐(201.48g)，继续加入三乙胺(64.71g)，加完后于20-25℃继续反应1小时，反应结束后，将反应液降温至10-15℃，滴加水(500mL)，分液，有机相用10％柠檬酸水溶液(500mL)洗涤，饱和碳酸氢钠水溶液(500mL)洗涤，饱和食盐水(500mL)洗涤，浓缩至干得到中间体1的粗品，向粗品中加入醋酸异丙酯(50mL)、正庚烷(500mL)于50℃下打浆1-2小时，降温至10-20℃，过滤，得到中间体1(212g,收率：85％)。1HNMR(400MHz,CDCl3)δppm 8.49(d,J＝8.8Hz,1H),4.68(d,J＝9.6Hz,1H),4.59(s,1H),4.37(s,1H),3.72(s,3H),2.10(d,J＝10.0Hz,1H),1.99(s,1H),1.92–1.86(m,2H),1.59(dd,J＝12.4Hz,2.4Hz,1H),1.10(s,9H),0.75–0.63(m,3H),0.49–0.47(m,1H).MS m/z:391.1[M+H]+.Intermediate 1-E (211.59 g) was dissolved in dichloromethane (1300 mL), and trifluoroacetic anhydride (201.48 g) was added at 10-15°C, followed by triethylamine (64.71 g). After the addition was complete, the reaction was continued at 20-25°C for 1 hour. After the reaction was completed, the reaction solution was cooled to 10-15°C, water (500 mL) was added dropwise, and the liquid was separated. The organic phase was washed with 10% citric acid aqueous solution (500 mL), saturated sodium bicarbonate aqueous solution (500 mL), and saturated brine (500 mL), and concentrated to dryness to obtain the crude product of intermediate 1. Isopropyl acetate (50 mL) and n-heptane (500 mL) were added to the crude product, and the mixture was beaten at 50°C for 1-2 hours. The temperature was lowered to 10-20°C, and the mixture was filtered to obtain intermediate 1 (212 g, yield: 85%). 1 HNMR (400MHz, CDCl 3 ) δppm 8.49(d,J＝8.8Hz,1H),4.68(d,J＝9.6Hz,1H),4.59(s,1H),4.37(s,1H),3.72(s,3H),2.10(d,J＝10.0Hz,1H),1.99 (s,1H),1.92–1.86(m,2H),1.59(dd,J＝12.4Hz,2.4Hz,1H),1.10(s,9H),0.75–0.63(m,3H),0.49–0.47(m,1H).MS m/z:391.1[M+H] + .

实施例4式(I)化合物的合成
Example 4 Synthesis of Compound of Formula (I)

步骤6：中间体2的合成Step 6: Synthesis of Intermediate 2

将中间体1(640g)溶于MeOH(1280ml)，THF(3840ml)中，将LiOH.H2O水溶液(89.42gLiOH.H2O溶于1280ml H2O中)滴加进反应体系，反应温度控制在30℃以内，搅拌16hr。向反应液中加入MTBE(5000ml)、水(2500ml)，搅拌2分钟，分液，有机相再经水(2500ml)洗，合并水相，MTBE(5000ml)反萃水相，水相中加入1M HCl(3280ml)调节pH至～4，再加入EtOAc(5000ml×2)萃取水相，合并有机相，依次用1M HCl(2000ml)、饱和氯化钠溶液(2000ml)洗涤有机相，有机相经无水硫酸钠干燥后，减压抽滤，滤液50℃减压浓缩得到黄色固体粗产品。向粗产品中加入正庚烷(5V)(按照中间体1的质量计算)，搅拌10min，减压抽滤，滤饼在50℃下减压旋干。得到中间体2(505g，收率81.9％)。Intermediate 1 (640 g) was dissolved in MeOH (1280 ml) and THF (3840 ml). LiOH.H 2 O aqueous solution (89.42 g LiOH.H 2 O dissolved in 1280 ml H 2 O) was added dropwise into the reaction system. The reaction temperature was controlled below 30° C. and stirred for 16 hr. MTBE (5000 ml) and water (2500 ml) were added to the reaction solution, stirred for 2 minutes, and separated. The organic phase was washed with water (2500 ml) and the aqueous phases were combined. The aqueous phase was stripped with MTBE (5000 ml). 1M HCl (3280 ml) was added to the aqueous phase to adjust the pH to ~4. EtOAc (5000 ml x 2) was then added to extract the aqueous phase. The organic phases were combined and washed sequentially with 1M HCl (2000 ml) and saturated sodium chloride solution (2000 ml). The organic phases were dried over anhydrous sodium sulfate and filtered under reduced pressure. The filtrate was concentrated under reduced pressure at 50°C to obtain a crude yellow solid product. n-heptane (5 V) (calculated based on the mass of intermediate 1) was added to the crude product, stirred for 10 minutes, filtered under reduced pressure, and the filter cake was dried under reduced pressure at 50°C. Intermediate 2 (505 g, yield 81.9%) was obtained.

步骤7：中间体3的合成Step 7: Synthesis of Intermediate 3

将中间体2(315g)溶于2-butanone(3150ml)和DMF(315ml)中，加入HOBt(147.01g)，搅拌至澄清，加入BB-1(208.56g)，降温至0℃，缓慢加入DIPEA(324.50g)，体系升温至10℃左右，待温度降至0℃，加入EDCI(208.57g)，自然升温至25℃，搅拌16hr。向反应体系中加入水(1000ml)搅拌，加入EtOAc(3000ml)，分液，有机相用5％的柠檬酸(1500ml×2)洗涤，再用饱和碳酸氢钠溶液(1500ml×2)洗涤，饱和氯化钠(2000ml)洗涤，将所有水相用EtOAC(1500ml)萃取，有机相用5％的柠檬酸(750ml)洗涤，再用饱和碳酸氢钠溶液(750ml)洗涤，饱和氯化钠溶液(1000ml)洗涤，合并有机相用无水硫酸钠干燥，减压抽滤，50℃减压浓缩得粗产品。经MTBE(5V)打浆1hr，减压抽滤，滤饼50℃减压旋干得到中间体3(312g，收率70.4％)。Intermediate 2 (315 g) was dissolved in 2-butanone (3150 ml) and DMF (315 ml), HOBt (147.01 g) was added, and the mixture was stirred until clear. BB-1 (208.56 g) was added, and the temperature was lowered to 0°C. DIPEA (324.50 g) was slowly added, and the system was heated to about 10°C. When the temperature dropped to 0°C, EDCI (208.57 g) was added, and the temperature was naturally raised to 25°C and stirred for 16 hours. Water (1000 ml) was added to the reaction system and stirred. EtOAc (3000 ml) was added and the mixture was separated. The organic phase was washed with 5% citric acid (1500 ml x 2), saturated sodium bicarbonate solution (1500 ml x 2), and saturated sodium chloride (2000 ml). The entire aqueous phase was extracted with EtOAc (1500 ml). The organic phase was washed with 5% citric acid (750 ml), saturated sodium bicarbonate solution (750 ml), and saturated sodium chloride solution (1000 ml). The combined organic phases were dried over anhydrous sodium sulfate, filtered under reduced pressure, and concentrated under reduced pressure at 50°C to obtain the crude product. The product was then beaten with MTBE (5 V) for 1 hr, filtered under reduced pressure, and the filter cake was dried under reduced pressure at 50°C to obtain intermediate 3 (312 g, 70.4% yield).

步骤8：式(I)化合物的合成Step 8: Synthesis of compound of formula (I)

将中间体3(420g)溶于IPAc(4200ml)中，加入NMM(497g)，降低至0-5℃，缓慢滴加TFAA(516g)，缓慢升温至25℃，搅拌1hr。加入H2O(840ml)淬灭反应，20～25℃下搅拌16hr。反应液经半饱和氯化钠溶液(1400ml×2)洗涤，经5％柠檬酸溶液(1200ml×2)洗涤，饱和碳酸氢钠溶液(1200ml×2)洗涤，去离子水(600ml×3)洗涤。上述的水相经IPAc(1200ml)分别萃取后，丢弃，IPAc相分别经5％柠檬酸(400ml)洗，饱和碳酸氢钠溶液(400ml)洗，去离子水(400ml×3)洗。合并上述的有机相，无水硫酸钠干燥，减压抽滤，50℃减压浓缩，得到式(I)化合物约350g。Intermediate 3 (420 g) was dissolved in IPAc (4200 ml), and NMM (497 g) was added. The temperature was lowered to 0-5°C, and TFAA (516 g) was slowly added dropwise. The temperature was slowly raised to 25°C and stirred for 1 hour. H₂O (840 ml) was added to quench the reaction, and the mixture was stirred at 20-25°C for 16 hours. The reaction solution was washed with semi-saturated sodium chloride solution (1400 ml x 2), 5% citric acid solution (1200 ml x 2), saturated sodium bicarbonate solution (1200 ml x 2), and deionized water (600 ml x 3). The aqueous phase was extracted with IPAc (1200 ml) and discarded. The IPAc phase was washed with 5% citric acid (400 ml), saturated sodium bicarbonate solution (400 ml), and deionized water (400 ml x 3). The above organic phases were combined, dried over anhydrous sodium sulfate, filtered under reduced pressure, and concentrated under reduced pressure at 50° C. to obtain about 350 g of the compound of formula (I).

实施例5式(II)化合物优选盐型的制备Example 5 Preparation of the preferred salt form of the compound of formula (II)

1.马来酸盐晶型A1. Maleate salt form A

称量103.77mg实施例1制备得到的游离态式II化合物与67.62mg的马来酸(配体/游离态投料比为1.05)，在EtOAc体系室温下磁力搅拌过夜。样品离心分离后，置于30℃真空干燥3～4h，得到126.25mg固体，产率为78.1％。1H NMR(400MHz,DMSO-d6)δ9.01(s,2H),6.03(s,2H),4.18(d,J＝25.5Hz,2H),3.76(s,3H),2.20(d,J＝1.5Hz,1H),1.95(d,J＝11.2Hz,1H),1.82–1.71(m,2H),1.63(dq,J＝11.2,1.9Hz,1H),0.84(ddd,J＝9.9,5.8,4.0Hz,1H),0.73–0.54(m,2H),0.46(ddd,J＝9.6,6.1,4.0Hz,1H)(XRPD、DSC、TGA和1H NMR谱图分别见图1、图2和图3).Weigh 103.77 mg of the free form compound of Formula II prepared in Example 1 and 67.62 mg of maleic acid (ligand/free form ratio of 1.05) in EtOAc with magnetic stirring overnight at room temperature. The sample was centrifuged and dried under vacuum at 30°C for 3-4 hours to yield 126.25 mg of a solid, with a yield of 78.1%. 1H NMR (400 MHz, DMSO-d6) δ9.01 (s, 2H), 6.03 (s, 2H), 4.18 (d, J = 25.5 Hz, 2H), 3.76 (s, 3H), 2.20 (d, J = 1.5 Hz, 1H), 1.95 (d, J = 11.2 Hz, 1H), 1.82–1.71 (m, 2H), 1.63 (dq, J = 11.2, 1.9 Hz, 1H), 0.84 (ddd, J = 9.9, 5.8, 4.0 Hz, 1H), 0.73–0.54 (m, 2H), 0.46 (ddd, J = 9.6, 6.1, 4.0 Hz, 1H) (XRPD, DSC, TGA, and 1H NMR spectra are shown in Figures 1, 2, and 3, respectively).

2.甲磺酸盐晶型A2. Methanesulfonate Form A

称量100.15mg实施例1制备得到的游离态式II化合物与55.67mg的甲磺酸(配体/游离态投料比为1.05)，在MEK体系室温下磁力搅拌过夜。样品离心分离后，置于30℃真空干燥3～4h，得到70.37mg固体，产率为47.8％。1H NMR(400MHz,DMSO-d6)δ9.05(d,J＝306.0Hz,2H),4.19(d,J＝26.3Hz,2H),3.76(s,3H),2.31(s,3H),2.22–2.17(m,1H),1.99–1.91(m,1H),1.78(d,J＝2.7Hz,2H),1.63(dd,J＝11.3,2.0Hz,1H),0.84(ddd,J＝9.9,5.9,4.1Hz,1H),0.69–0.54(m,2H),0.46(ddd,J＝9.6,6.1,4.1Hz,1H)(XRPD、DSC、TGA和1H NMR谱图分别见图4、图5和图6).Weigh 100.15 mg of the free compound of Formula II prepared in Example 1 and 55.67 mg of methanesulfonic acid (ligand/free compound ratio of 1.05) in a MEK system with magnetic stirring overnight at room temperature. The sample was centrifuged and dried under vacuum at 30°C for 3-4 hours to yield 70.37 mg of a solid, with a yield of 47.8%. 1H NMR (400 MHz, DMSO-d6) δ9.05 (d, J = 306.0 Hz, 2H), 4.19 (d, J = 26.3 Hz, 2H), 3.76 (s, 3H), 2.31 (s, 3H), 2.22–2.17 (m, 1H), 1.99–1.91 (m, 1H), 1.78 (d, J = 2.7 Hz, 2H), 1.63 (dd, J = 11.3, 2.0 Hz, 1H), 0.84 (ddd, J = 9.9, 5.9, 4.1 Hz, 1H), 0.69–0.54 (m, 2H), 0.46 (ddd, J = 9.6, 6.1, 4.1 Hz, 1H) (XRPD, DSC, TGA, and 1H NMR spectra are shown in Figures 4, 5, and 6, respectively).

3.龙胆酸盐晶型A3. Gentisate Form A

称量100.07mg实施例1制备得到的游离态式II化合物与89.44mg的龙胆酸(配体/游离态投料比为1.05)，在ACN体系室温下磁力搅拌过夜。样品离心分离后，置于30℃真空干燥3～4h，得到129.66mg固体，产率为72.9％。1H NMR(400MHz,DMSO-d6)δ8.58(s,1H),7.12(d,J＝3.2Hz,1H),6.67(dd,J＝8.6,3.1Hz,1H),6.52(d,J＝8.7Hz,1H),4.16(s,1H),4.04(s,1H),3.72(d,J＝2.6Hz,3H),2.12(s,1H),1.88(d,J＝10.8Hz,1H),1.74(d,J＝2.2Hz,2H),1.61(d,J＝10.9Hz,1H),0.80(ddd,J＝9.8,5.8,3.9Hz,1H),0.68–0.49(m,2H),0.42(ddd,J＝9.6,6.0,3.9Hz,1H)(XRPD、DSC、TGA和1H NMR谱图分别见图7、图8和图9).100.07 mg of the free compound of formula II prepared in Example 1 and 89.44 mg of gentisic acid (ligand/free ratio of 1.05) were weighed and magnetically stirred overnight in an ACN system at room temperature. After centrifugation, the sample was placed at 30°C and vacuum dried for 3-4 hours to obtain 129.66 mg of solid with a yield of 72.9%. 1 H NMR (400 MHz, DMSO-d6) δ8.58 (s, 1H), 7.12 (d, J = 3.2 Hz, 1H), 6.67 (dd, J = 8.6, 3.1 Hz, 1H), 6.52 (d, J = 8.7 Hz, 1H), 4.16 (s, 1H), 4.04 (s, 1H), 3.72 (d, J = 2.6 Hz, 3H), 2.12 (s, 1H), 1 0.88 (d, J = 10.8 Hz, 1H), 1.74 (d, J = 2.2 Hz, 2H), 1.61 (d, J = 10.9 Hz, 1H), 0.80 (ddd, J = 9.8, 5.8, 3.9 Hz, 1H), 0.68–0.49 (m, 2H), 0.42 (ddd, J = 9.6, 6.0, 3.9 Hz, 1H) (XRPD, DSC, TGA, and 1 H NMR spectra are shown in Figures 7, 8, and 9, respectively).

4.L-酒石酸盐晶型A4. L-Tartrate Form A

称量102.03mg实施例1制备得到的游离态式II化合物与87.16mg的L-酒石酸(配体/游离态投料比为1.05)，在ACN体系室温下磁力搅拌过夜。样品离心分离后，置于30℃真空干燥3～4h，得到133.82mg固体，产率为74.7％。1H NMR(400MHz,DMSO-d6)δ4.05(d,J＝2.1Hz,2H),3.92(s,1H),3.83(d,J＝3.1Hz,1H),3.68(d,J＝2.1Hz,3H),2.00(s,1H),1.77(d,J＝10.3Hz,1H),1.72–1.57(m,2H),1.53(dq,J＝10.4,2.1Hz,1H),0.75(ddd,J＝9.7,5.9,3.9Hz,1H),0.62–0.48(m,2H),0.38(ddd,J＝9.5,6.1,3.9Hz,1H)(XRPD、DSC、TGA和1H NMR谱图分别见图10、图11和图12).Weigh 102.03 mg of the free compound of Formula II prepared in Example 1 and 87.16 mg of L-tartaric acid (ligand/free compound ratio of 1.05) and stir magnetically overnight in an ACN system at room temperature. After centrifugation, the sample was dried under vacuum at 30°C for 3-4 hours to yield 133.82 mg of a solid, with a yield of 74.7%. 1H NMR (400 MHz, DMSO-d6) δ 4.05 (d, J = 2.1 Hz, 2H), 3.92 (s, 1H), 3.83 (d, J = 3.1 Hz, 1H), 3.68 (d, J = 2.1 Hz, 3H), 2.00 (s, 1H), 1.77 (d, J = 10.3 Hz, 1H), 1.72–1.57 (m, 2H), 1.53 (dq, J = 10.4, 2.1 Hz, 1H), 0.75 (ddd, J = 9.7, 5.9, 3.9 Hz, 1H), 0.62–0.48 (m, 2H), 0.38 (ddd, J = 9.5, 6.1, 3.9 Hz, 1H) (XRPD, DSC, TGA, and 1H NMR spectra are shown in Figures 10, 11, and 12, respectively).

表1优选盐型制备及表征数据汇总

Table 1 Summary of the preparation and characterization data of preferred salt forms

实施例6式(II)化合物优选盐型稳定性研究Example 6 Stability Study of the Preferred Salt Form of the Compound of Formula (II)

为进一步考察优选盐型的固态性质，在25℃/60％RH和40℃/75％RH条件下，分别对马来酸盐晶型A、龙胆酸盐晶型A进行稳定性考察。具体为，称量～10mg样品，分别在25℃/60％RH和40℃/75％RH条件下，放置两天后，取样，进行XRPD和纯度检测。结果汇总如下表所示，在两个条件下放置两天后，马来酸盐晶型A和龙胆酸盐晶型晶型A未发生改变。XRPD结果见图13和图14。To further investigate the solid-state properties of the preferred salt forms, stability tests were conducted on the maleate salt Form A and the gentisate salt Form A at 25°C/60% RH and 40°C/75% RH, respectively. Specifically, ~10 mg of sample was weighed and stored at 25°C/60% RH and 40°C/75% RH for two days. Samples were then taken for XRPD and purity testing. The results are summarized in the table below. After two days of storage under both conditions, the maleate salt Form A and the gentisate salt Form A showed no changes. The XRPD results are shown in Figures 13 and 14.

表2优选盐型初步稳定性考察汇总(图13-14)
Table 2 Summary of preliminary stability studies of preferred salt forms (Figures 13-14)

实施例7式(II)化合物马来酸盐晶型A引湿性研究数据Example 7 Hygroscopicity Study Data of the Maleate Salt Form A of the Compound of Formula (II)

采用DVS在25℃下对式(II)化合物马来酸盐进行引湿性评估，具体方法：The hygroscopicity of the maleate salt of the compound of formula (II) was evaluated using DVS at 25°C. The specific method is as follows:

1)～30mg样品再0％RH湿度平衡后开始测试；1) After the ~30 mg sample has reached 0% RH, the test begins.

2)相对湿度增加过程：0％RH至90％RH，速率为10％RH/阶段；90％RH至95％RH，速率为5％RH/阶段；2) Relative humidity increase process: 0% RH to 90% RH, the rate is 10% RH/stage; 90% RH to 95% RH, the rate is 5% RH/stage;

3)相对湿度降低过程：95％RH至90％RH，速率为5％RH/阶段；90％RH至0％RH，速率为10％RH/阶段；3) Relative humidity reduction process: 95% RH to 90% RH, the rate is 5% RH/stage; 90% RH to 0% RH, the rate is 10% RH/stage;

4)DVS程序完成后，取样测试XRPD，测试前样品在0％RH下保存。4) After the DVS procedure was completed, samples were taken for XRPD testing. The samples were stored at 0% RH before testing.

DVS数据显示，第一轮增湿过程从0％RH至80％RH，式(II)化合物马来酸盐有0.1％的增重，表明无或几乎无引湿性；DVS测试结束样品保存在0％RH，取出到室温室湿(16～20℃，25～60％RH)立即测试XRPD，晶型均不变，表明均有较好的晶型稳定性。DVS数据见图15-16。DVS data showed that the maleate salt of compound (II) experienced a 0.1% weight gain during the first humidification cycle from 0% RH to 80% RH, indicating little or no hygroscopicity. Following the DVS test, samples were stored at 0% RH and then immediately removed to room temperature (16-20°C, 25-60% RH) for XRPD analysis. The crystal forms remained unchanged, demonstrating good crystal stability. DVS data are shown in Figures 15-16.

对比例1式(II)化合物盐型筛选Comparative Example 1 Screening of salt forms of compound of formula (II)

选用多种配体在4种溶剂体系中设置了52个盐型筛选实验。具体为：配制式(II)化合物起始游离碱的储备液(～20mg/实验)，称取等摩尔比的配体到HPLC小瓶中，加入0.2mL游离碱储备液，室温下磁力搅拌。室温磁力搅拌～1天后，1)对混悬样品，进行离心分离，测定样品XRPD；2)澄清或少量浑浊的样品，将转移至5℃降温结晶。若仍无明显固体析出，转移至-20℃静置。3)成胶样品，将转入50℃搅拌诱导转晶。将对所得固体进行离心分离，样品30℃真空干燥～3h用于表征。结果如表3所示：A variety of ligands were selected and 52 salt screening experiments were set up in 4 solvent systems. Specifically: prepare the stock solution of the starting free base of the compound of formula (II) (~20 mg/experiment), weigh the ligand in an equal molar ratio into an HPLC vial, add 0.2 mL of the free base stock solution, and stir magnetically at room temperature. After magnetic stirring at room temperature for ~1 day, 1) the suspended sample was centrifuged and the sample XRPD was measured; 2) the clear or slightly turbid sample was transferred to 5°C for cooling and crystallization. If there is still no obvious solid precipitation, transfer to -20°C and let it stand. 3) For the gelled sample, transfer to 50°C for stirring to induce crystallization. The obtained solid was centrifuged and the sample was vacuum dried at 30°C for ~3h for characterization. The results are shown in Table 3:

表3式(II)化合物盐型筛选结果
Table 3 Screening results of salt forms of compounds of formula (II)

对比例2式(II)化合物优选盐型溶剂筛选数据Comparative Example 2 Preferred Salt Solvent Screening Data for Compound of Formula (II)

对4种式(II)化合物盐型，选择6种溶剂体系进行打浆成盐筛选。具体实验过程为：称取等摩尔比的起始样品和酸配体到4mL小瓶中，加入对应溶剂，45℃下磁力搅拌6h后，降温至10℃继续搅拌6～7h。对固体较多的体系分离出固体，淋洗后测定样品纯度和XRPD。For four salt forms of the compound of Formula (II), six solvent systems were selected for slurry salt screening. The specific experimental procedure was as follows: equimolar ratios of the starting sample and acid ligand were weighed into a 4 mL vial, and the corresponding solvent was added. After magnetic stirring at 45°C for 6 hours, the temperature was lowered to 10°C and stirring was continued for 6-7 hours. For systems with a high concentration of solids, the solids were separated, washed, and the sample purity and XRPD analysis were performed.

表4 4种式(II)化合物盐的溶剂筛选数据

Table 4 Solvent screening data for four salts of compound of formula (II)

Claims (26)

一种式(II)化合物的盐，其特征在于，所述盐为马来酸盐、甲磺酸盐、龙胆酸盐或酒石酸盐；
A salt of a compound of formula (II), characterized in that the salt is a maleate, a methanesulfonate, a gentisate or a tartrate;
优选地，马来酸、甲磺酸、龙胆酸或酒石酸与式(II)化合物的摩尔比为1.1:1或1.0:1，更优选地，为1.0:1。Preferably, the molar ratio of maleic acid, methanesulfonic acid, gentisic acid or tartaric acid to the compound of formula (II) is 1.1:1 or 1.0:1, more preferably 1.0:1. 一种式(II)化合物马来酸盐的晶型A，其特征在于，其使用Cu-Kα辐射，其以2θ表示的X射线粉末衍射图在下述位置具有衍射峰：10.37°±0.20°，13.75°±0.20°，14.77°±0.20°，19.47°±0.20°，20.97°±0.20°，21.67°±0.20°；
A crystalline form A of a maleate salt of a compound of formula (II), characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern expressed in 2θ has diffraction peaks at the following positions: 10.37°±0.20°, 13.75°±0.20°, 14.77°±0.20°, 19.47°±0.20°, 20.97°±0.20°, 21.67°±0.20°;
如权利要求2所述的式(II)化合物马来酸盐的晶型A，其特征在于，其以2θ角表示的X射线粉末衍射图还进一步在下述的一个或多个位置有衍射峰：11.67°±0.20°，17.48°±0.20°，19.75°±0.20°，22.79°±0.20°，23.48°±0.20°，25.23°±0.20°，26.93°±0.20°，28.07°±0.20°，29.80°±0.20°，32.89°±0.20°，38.37°±0.20°。The crystalline form A of the maleate salt of the compound of formula (II) according to claim 2, characterized in that its X-ray powder diffraction pattern expressed in 2θ angles further has diffraction peaks at one or more of the following positions: 11.67°±0.20°, 17.48°±0.20°, 19.75°±0.20°, 22.79°±0.20°, 23.48°±0.20°, 25.23°±0.20°, 26.93°±0.20°, 28.07°±0.20°, 29.80°±0.20°, 32.89°±0.20°, 38.37°±0.20°. 如权利要求2所述的式(II)化合物马来酸盐的晶型A，其特征在于，其以2θ表示的X射线粉末衍射图在下述位置具有衍射峰：10.37°±0.20°，11.67°±0.20°，13.75°±0.20°，14.77°±0.20°，17.48°±0.20°，19.47°±0.20°，19.75°±0.20°，20.97°±0.20°，21.67°±0.20°，22.79°±0.20°，23.48°±0.20°，25.23°±0.20°，26.93°±0.20°，28.07°±0.20°，29.80°±0.20°，32.89°±0.20°，38.37°±0.20°；The crystalline form A of the maleate salt of the compound of formula (II) according to claim 2, characterized in that its X-ray powder diffraction pattern expressed in 2θ has diffraction peaks at the following positions: 10.37°±0.20°, 11.67°±0.20°, 13.75°±0.20°, 14.77°±0.20°, 17.48°±0.20°, 19.47°±0.20°, 19. 75°±0.20°, 20.97°±0.20°, 21.67°±0.20°, 22.79°±0.20°, 23.48°±0.20°, 25.23°±0.20°, 26.93°±0.20°, 28.07°±0.20°, 29.80°±0.20°, 32.89°±0.20°, 38.37°±0.20°; 优选地，所述式(II)化合物马来酸盐的晶型A以2θ表示的X射线粉末衍射图具有如下表所示的衍射峰：

Preferably, the X-ray powder diffraction pattern of the maleate salt of the compound of formula (II) in form A expressed in 2θ has the diffraction peaks shown in the following table:

更优选地，所述式(II)化合物马来酸盐的晶型A以2θ表示的X射线粉末衍射图如图1所示。More preferably, the X-ray powder diffraction pattern of Form A of the maleate salt of the compound of formula (II) expressed in 2θ is shown in FIG1 . 如权利要求2所述的式(II)化合物马来酸盐的晶型A，其特征在于，其满足以下条件的一个或多个：The crystalline form A of the maleate salt of the compound of formula (II) according to claim 2, characterized in that it satisfies one or more of the following conditions: (1)所述式(II)化合物马来酸盐的晶型A，其差示扫描量热曲线(DSC)在135.6℃～143.8℃处吸热峰的熔化热为89.25J/g；(1) Form A of the maleate salt of the compound of formula (II), wherein the heat of fusion of the endothermic peak at 135.6°C to 143.8°C in the differential scanning calorimetry (DSC) curve is 89.25 J/g; 优选地，所述式(II)化合物马来酸盐的晶型A，其差示扫描量热曲线如图2所示；Preferably, the differential scanning calorimetry curve of Form A of the maleate salt of the compound of formula (II) is shown in FIG2 ; (2)所述式(II)化合物马来酸盐的晶型A，其热重分析曲线(TGA)在130.0℃时失重0.68％；(2) Form A of the maleate salt of the compound of formula (II), whose thermogravimetric analysis (TGA) curve shows a weight loss of 0.68% at 130.0°C; 优选地，所述式(II)化合物马来酸盐的晶型A，其热重分析曲线如图2所示；Preferably, the thermogravimetric analysis curve of Form A of the maleate salt of the compound of formula (II) is shown in FIG2 ; (3)所述式(II)化合物马来酸盐的晶型A为无水晶型；(3) The crystalline form A of the maleate salt of the compound of formula (II) is an anhydrous crystalline form; (4)所述式(II)化合物与所述马来酸的摩尔比为1.0:1。(4) The molar ratio of the compound of formula (II) to the maleic acid is 1.0:1. 如权利要求5所述的式(II)化合物马来酸盐的晶型A，其特征在于，其满足以下条件的一个或多个：The crystalline form A of the maleate salt of the compound of formula (II) according to claim 5, characterized in that it satisfies one or more of the following conditions: (1)所述式(II)化合物马来酸盐的晶型A通过以下参数获得X射线粉末衍射图：
(1) The X-ray powder diffraction pattern of the maleate salt of the compound of formula (II) is obtained by the following parameters:
(2)所述式(II)化合物马来酸盐的晶型A通过以下参数获得晶体形式的TGA和/或DSC图案；

(2) Form A of the maleate salt of the compound of formula (II) is obtained by TGA and/or DSC patterns of the crystalline form using the following parameters;

一种如权利要求2所述的式(II)化合物马来酸盐的晶型A的制备方法，其特征在于，其包括如下步骤：A method for preparing the crystalline form A of the maleate salt of the compound of formula (II) as claimed in claim 2, characterized in that it comprises the following steps: 在有机溶剂中，将式(II)化合物、马来酸混合，搅拌后分离即可；In an organic solvent, the compound of formula (II) and maleic acid are mixed, stirred and then separated; 优选地，所述有机溶剂为乙酸乙酯；Preferably, the organic solvent is ethyl acetate; 优选地，马来酸和式(II)化合物的摩尔比为1.05:1。Preferably, the molar ratio of maleic acid to the compound of formula (II) is 1.05:1. 一种式(II)化合物甲磺酸盐的晶型A，其特征在于，其使用Cu-Kα辐射，以2θ表示的X射线粉末衍射图在下述位置具有衍射峰：7.23°±0.20°，13.91°±0.20°，16.36°±0.20°，18.95°±0.20°，19.71°±0.20°，20.65°±0.20°，21.94°±0.20°；
A crystalline form A of a mesylate salt of a compound of formula (II), characterized in that its X-ray powder diffraction pattern expressed in 2θ using Cu-Kα radiation has diffraction peaks at the following positions: 7.23°±0.20°, 13.91°±0.20°, 16.36°±0.20°, 18.95°±0.20°, 19.71°±0.20°, 20.65°±0.20°, 21.94°±0.20°;
如权利要求8所述的式(II)化合物甲磺酸盐的晶型A，其特征在于，其以2θ角表示的X射线粉末衍射图还进一步在下述的一个或多个位置有衍射峰：9.92°±0.20°，12.39°±0.20°，17.85°±0.20°，18.59°±0.20°，23.21°±0.20°，24.03°±0.20°；The crystalline form A of the mesylate of the compound of formula (II) according to claim 8, characterized in that its X-ray powder diffraction pattern expressed in 2θ angles further has diffraction peaks at one or more of the following positions: 9.92°±0.20°, 12.39°±0.20°, 17.85°±0.20°, 18.59°±0.20°, 23.21°±0.20°, 24.03°±0.20°; 优选地，所述式(II)化合物甲磺酸盐的晶型A以2θ表示的X射线粉末衍射图还进一步在下述的一个或多个位置有衍射峰：10.35°±0.20°，11.83°±0.20°，14.66°±0.20°，21.36°±0.20°，22.87°±0.20°，24.92°±0.20°，25.27°±0.20°，26.60°±0.20°，27.30°±0.20°，28.34°±0.20°；Preferably, the X-ray powder diffraction pattern of the crystalline form A of the methanesulfonate salt of the compound of formula (II) expressed in 2θ further has diffraction peaks at one or more of the following positions: 10.35°±0.20°, 11.83°±0.20°, 14.66°±0.20°, 21.36°±0.20°, 22.87°±0.20°, 24.92°±0.20°, 25.27°±0.20°, 26.60°±0.20°, 27.30°±0.20°, 28.34°±0.20°; 再优选地，所述式(II)化合物甲磺酸盐的晶型A以2θ表示的X射线粉末衍射图还进一步在下述的一个或多个位置有衍射峰：8.23°±0.20°，15.20°±0.20°，22.57°±0.20°，24.43°±0.20°，26.32°±0.20°，29.00°±0.20°，29.40°±0.20°，29.98°±0.20°，31.23°±0.20°，32.01°±0.20°，32.75°±0.20°，33.26°±0.20°，34.60°±0.20°，35.39°±0.20°，36.55°±0.20°，37.88°±0.20°，38.44°±0.20°，39.22°±0.20°。More preferably, the X-ray powder diffraction pattern of the crystalline form A of the methanesulfonate salt of the compound of formula (II) expressed in 2θ further has diffraction peaks at one or more of the following positions: 8.23°±0.20°, 15.20°±0.20°, 22.57°±0.20°, 24.43°±0.20°, 26.32°±0.20°, 29.00°±0.20°, 29.40°±0.20° °, 29.98°±0.20°, 31.23°±0.20°, 32.01°±0.20°, 32.75°±0.20°, 33.26°±0.20°, 34.60°±0.20°, 35.39°±0.20°, 36.55°±0.20°, 37.88°±0.20°, 38.44°±0.20°, 39.22°±0.20°. 如权利要求8所述的式(II)化合物甲磺酸盐的晶型A，其特征在于，其以2θ表示的X射线粉末衍射图在下述位置具有衍射峰：7.23°±0.20°，9.92°±0.20°，13.91°±0.20°，16.36°±0.20°，12.39°±0.20°，17.85°±0.20°，18.59°±0.20°，18.95°±0.20°，19.71°±0.20°，20.65°±0.20°，21.94°±0.20°，23.21°±0.20°，24.03°±0.20°；The crystalline form A of the mesylate of the compound of formula (II) according to claim 8, characterized in that its X-ray powder diffraction pattern expressed in 2θ has diffraction peaks at the following positions: 7.23°±0.20°, 9.92°±0.20°, 13.91°±0.20°, 16.36°±0.20°, 12.39°±0.20°, 17.85°±0.20°, 18.59°±0.20°, 18.95°±0.20°, 19.71°±0.20°, 20.65°±0.20°, 21.94°±0.20°, 23.21°±0.20°, 24.03°±0.20°; 优选地，所述式(II)化合物甲磺酸盐的晶型A以2θ表示的X射线粉末衍射图在下述位置具有衍射峰：7.23°±0.20°，9.92°±0.20°，10.35°±0.20°，11.83°±0.20°，12.39°±0.20°，13.91°±0.20°，14.66°±0.20°，16.36°±0.20°，17.85°±0.20°，18.59°±0.20°，18.95°±0.20°，19.71°±0.20°，20.65°±0.20°，21.36°±0.20°，21.94°±0.20°，22.87°±0.20°，23.21°±0.20°，24.03°±0.20°，24.92°±0.20°，25.27°±0.20°，26.60°±0.20°，27.30°±0.20°，28.34°±0.20°；Preferably, the X-ray powder diffraction pattern of the crystalline form A of the methanesulfonate salt of the compound of formula (II) expressed in 2θ has diffraction peaks at the following positions: 7.23°±0.20°, 9.92°±0.20°, 10.35°±0.20°, 11.83°±0.20°, 12.39°±0.20°, 13.91°±0.20°, 14.66°±0.20°, 16.36°±0.20°, 17.85°±0.20°, 18.59°±0.20° 0°, 18.95°±0.20°, 19.71°±0.20°, 20.65°±0.20°, 21.36°±0.20°, 21.94°±0.20°, 22.87°±0.20°, 23.21°±0.20°, 24.03°±0.20°, 24.92°±0.20°, 25.27°±0.20°, 26.60°±0.20°, 27.30°±0.20°, 28.34°±0.20°; 再优选地，所述式(II)化合物甲磺酸盐的晶型A以2θ表示的X射线粉末衍射图在下述位置具有衍射峰：7.23°±0.20°，8.23°±0.20°，9.92°±0.20°，10.35°±0.20°，11.83°±0.20°，12.39°±0.20°，13.91°±0.20°，14.66°±0.20°，15.20°±0.20°，16.36°±0.20°，17.85°±0.20°，18.59°±0.20°，18.95°±0.20°，19.71°±0.20°，20.65°±0.20°，21.36°±0.20°，21.94°±0.20°，22.57°±0.20°，22.87°±0.20°，23.21°±0.20°，24.03°±0.20°，24.43°±0.20°，24.92°±0.20°，25.27°±0.20°，26.32°±0.20°，26.60°±0.20°，27.30°±0.20°，28.34°±0.20°，29.00°±0.20°，29.40°±0.20°，29.98°±0.20°，31.23°±0.20°，32.01°±0.20°，32.75°±0.20°，33.26°±0.20°，34.60°±0.20°，35.39°±0.20°，36.55°±0.20°，37.88°±0.20°，38.44°±0.20°，39.22°±0.20°；More preferably, the X-ray powder diffraction pattern of the crystalline form A of the methanesulfonate salt of the compound of formula (II) expressed in 2θ has diffraction peaks at the following positions: 7.23°±0.20°, 8.23°±0.20°, 9.92°±0.20°, 10.35°±0.20°, 11.83°±0.20°, 12.39°±0.20°, 13.91°±0.20°, 14.66°±0 .20°, 15.20°±0.20°, 16.36°±0.20°, 17.85°±0.20°, 18.59°±0.20°, 18.95°±0.20°, 19.71°±0.20°, 20.65°±0.20°, 21.36°±0.20°, 21.94°±0.20°, 22.57°±0.20°, 22.87°±0.2 0°, 23.21°±0.20°, 24.03°±0.20°, 24.43°±0.20°, 24.92°±0.20°, 25.27°±0.20°, 26.32°±0.20°, 26.60°±0.20°, 27.30°±0.20°, 28.34°±0.20°, 29.00°±0.20°, 29.40°±0.20 °, 29.98°±0.20°, 31.23°±0.20°, 32.01°±0.20°, 32.75°±0.20°, 33.26°±0.20°, 34.60°±0.20°, 35.39°±0.20°, 36.55°±0.20°, 37.88°±0.20°, 38.44°±0.20°, 39.22°±0.20°; 更优选地，所述式(II)化合物甲磺酸盐的晶型A以2θ表示的X射线粉末衍射图具有如下表所示的衍射峰：

More preferably, the X-ray powder diffraction pattern of the crystalline form A of the methanesulfonate salt of the compound of formula (II) expressed in 2θ has the diffraction peaks shown in the following table:

最优选地，所述式(II)化合物甲磺酸盐的晶型A以2θ表示的X射线粉末衍射图如图4所示。Most preferably, the X-ray powder diffraction pattern of Form A of the methanesulfonate salt of the compound of formula (II) expressed in 2θ is shown in FIG4 . 如权利要求8所述的式(II)化合物甲磺酸盐的晶型A，其特征在于，其满足以下条件的一个或多个：The crystalline form A of the mesylate salt of the compound of formula (II) according to claim 8, characterized in that it satisfies one or more of the following conditions: (1)所述式(II)化合物甲磺酸盐的晶型A，其差示扫描量热曲线(DSC)在119.6℃～123.6℃处吸热峰的熔化热为81.65J/g；(1) Form A of the methanesulfonate salt of the compound of formula (II), wherein the heat of fusion of the endothermic peak at 119.6°C to 123.6°C as measured by differential scanning calorimetry (DSC) is 81.65 J/g; 优选地，所述式(II)化合物甲磺酸盐的晶型A，其差示扫描量热曲线如图5所示；Preferably, the differential scanning calorimetry curve of Form A of the methanesulfonate salt of the compound of formula (II) is shown in FIG5 ; (2)所述式(II)化合物甲磺酸盐的晶型A，其热重分析曲线(TGA)在160.0℃时失重0.41％；(2) Form A of the methanesulfonate salt of the compound of formula (II), whose thermogravimetric analysis (TGA) curve shows a weight loss of 0.41% at 160.0°C; 优选地，所述式(II)化合物甲磺酸盐的晶型A，其热重分析曲线如图5所示；Preferably, the thermogravimetric analysis curve of Form A of the methanesulfonate salt of the compound of formula (II) is shown in FIG5 ; (3)所述式(II)化合物甲磺酸盐晶型A为无水晶型；(3) The mesylate salt crystalline form A of the compound of formula (II) is an anhydrous crystalline form; (4)所述式(II)化合物与所述甲磺酸的摩尔比为1.0:1。(4) The molar ratio of the compound of formula (II) to the methanesulfonic acid is 1.0:1. 一种如权利要求8所述的式(II)化合物甲磺酸盐的晶型A的制备方法，其特征在于，其包括如下步骤：A method for preparing the crystalline form A of the mesylate salt of the compound of formula (II) as claimed in claim 8, characterized in that it comprises the following steps: 在有机溶剂中，将式(II)化合物、甲磺酸混合，搅拌后分离即可；In an organic solvent, the compound of formula (II) and methanesulfonic acid are mixed, stirred and then separated; 优选地，所述有机溶剂为丁酮；Preferably, the organic solvent is butanone; 优选地，所述甲磺酸和式(II)化合物的摩尔比为1.05:1。Preferably, the molar ratio of methanesulfonic acid to the compound of formula (II) is 1.05:1. 一种式(II)化合物龙胆酸盐的晶型A，其特征在于，其使用Cu-Kα辐射，以2θ表示的X射线粉末衍射图在下述位置具有衍射峰：8.54°±0.20°，8.89°±0.20°，12.70°±0.20°，17.42°±0.20°，18.04°±0.20°，19.45°±0.20°，23.80°±0.20°；
A crystalline form A of a gentisate salt of a compound of formula (II), characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern expressed in 2θ has diffraction peaks at the following positions: 8.54°±0.20°, 8.89°±0.20°, 12.70°±0.20°, 17.42°±0.20°, 18.04°±0.20°, 19.45°±0.20°, 23.80°±0.20°;
如权利要求13所述的式(II)化合物龙胆酸盐的晶型A，其特征在于，其以2θ角表示的X射线粉末衍射图还进一步在下述的一个或多个位置有衍射峰：18.86°±0.20°，22.31°±0.20°，25.40°±0.20°，25.77°±0.20°，27.78°±0.20°，35.56°±0.20°；The crystalline form A of the gentisate of the compound of formula (II) according to claim 13, characterized in that its X-ray powder diffraction pattern expressed in 2θ angles further has diffraction peaks at one or more of the following positions: 18.86°±0.20°, 22.31°±0.20°, 25.40°±0.20°, 25.77°±0.20°, 27.78°±0.20°, 35.56°±0.20°; 优选地，所述式(II)化合物龙胆酸盐的晶型A以2θ角表示的X射线粉末衍射图还进一步在下述的一个或多个位置有衍射峰：11.66°±0.20°，16.21°±0.20°，22.71°±0.20°，26.64°±0.20°，36.12°±0.20°，39.19°±0.20°。Preferably, the X-ray powder diffraction pattern of the crystalline form A of the gentisate salt of the compound of formula (II) expressed in 2θ angles further has diffraction peaks at one or more of the following positions: 11.66°±0.20°, 16.21°±0.20°, 22.71°±0.20°, 26.64°±0.20°, 36.12°±0.20°, 39.19°±0.20°. 如权利要求13所述的式(II)化合物龙胆酸盐的晶型A，其特征在于，其以2θ表示的X射线粉末衍射图在下述位置具有衍射峰：8.54°±0.20°，8.89°±0.20°，12.70°±0.20°，17.42°±0.20°，18.04°±0.20°，18.86°±0.20°，19.45°±0.20°，22.31°±0.20°，23.80°±0.20°，25.40°±0.20°，25.77°±0.20°，27.78°±0.20°，35.56°±0.20°；The crystalline form A of the gentisate of the compound of formula (II) according to claim 13, characterized in that its X-ray powder diffraction pattern expressed in 2θ has diffraction peaks at the following positions: 8.54°±0.20°, 8.89°±0.20°, 12.70°±0.20°, 17.42°±0.20°, 18.04°±0.20°, 18.86°±0.20°, 19.45°±0.20°, 22.31°±0.20°, 23.80°±0.20°, 25.40°±0.20°, 25.77°±0.20°, 27.78°±0.20°, 35.56°±0.20°; 优选地，所述式(II)化合物龙胆酸盐的晶型A以2θ表示的X射线粉末衍射图在下述位置具有衍射峰：8.54°±0.20°，8.89°±0.20°，11.66°±0.20°，12.70°±0.20°，16.21°±0.20°，17.42°±0.20°，18.04°±0.20°，18.86°±0.20°，19.45°±0.20°，22.31°±0.20°，22.71°±0.20°，23.80°±0.20°，25.40°±0.20°，25.77°±0.20°，26.64°±0.20°，27.78°±0.20°，35.56°±0.20°，36.12°±0.20°，39.19°±0.20°；Preferably, the X-ray powder diffraction pattern of the crystalline form A of the gentisate salt of the compound of formula (II) expressed in 2θ has diffraction peaks at the following positions: 8.54°±0.20°, 8.89°±0.20°, 11.66°±0.20°, 12.70°±0.20°, 16.21°±0.20°, 17.42°±0.20°, 18.04°±0.20°, 18.86°±0.2 0°, 19.45°±0.20°, 22.31°±0.20°, 22.71°±0.20°, 23.80°±0.20°, 25.40°±0.20°, 25.77°±0.20°, 26.64°±0.20°, 27.78°±0.20°, 35.56°±0.20°, 36.12°±0.20°, 39.19°±0.20°; 再优选地，所述式(II)化合物龙胆酸盐的晶型A以2θ表示的X射线粉末衍射图具有如下表所示的衍射峰：

More preferably, the X-ray powder diffraction pattern of the crystalline form A of the gentisate salt of the compound of formula (II) expressed in 2θ has the diffraction peaks shown in the following table:

更优选地，所述式(II)化合物龙胆酸盐的晶型A，其X射线粉末衍射图谱如图7所示。More preferably, the X-ray powder diffraction pattern of Form A of the gentisate salt of the compound of formula (II) is shown in FIG7 . 如权利要求13所述的式(II)化合物龙胆酸盐的晶型A，其特征在于，其满足以下条件的一个或多个：The crystalline form A of the gentisate of the compound of formula (II) according to claim 13, characterized in that it satisfies one or more of the following conditions: (1)所述式(II)化合物龙胆酸盐的晶型A，其差示扫描量热曲线(DSC)在165.11℃～169.12℃处吸热峰的熔化热为115.1J/g；(1) Form A of the gentisate salt of the compound of formula (II), wherein the heat of fusion of the endothermic peak at 165.11°C to 169.12°C in the differential scanning calorimetry (DSC) curve is 115.1 J/g; 优选地，所述式(II)化合物龙胆酸盐的晶型A，其差示扫描量热曲线如图8所示；Preferably, the differential scanning calorimetry curve of Form A of the gentisate salt of the compound of formula (II) is shown in FIG8 ; (2)所述式(II)化合物龙胆酸盐的晶型A，其热重分析曲线(TGA)在140.0℃时失重0.14％；(2) Form A of the gentisate salt of the compound of formula (II), whose thermogravimetric analysis (TGA) curve shows a weight loss of 0.14% at 140.0°C; 优选地，所述式(II)化合物龙胆酸盐的晶型A，其热重分析曲线如图8所示；Preferably, the thermogravimetric analysis curve of the crystalline form A of the gentisate salt of the compound of formula (II) is shown in FIG8 ; (3)所述式(II)化合物龙胆酸盐晶型A为无水晶型；(3) the gentisate crystal form A of the compound of formula (II) is an anhydrous crystal form; (4)所述式(II)化合物与所述龙胆酸的摩尔比为1.0:1。(4) The molar ratio of the compound of formula (II) to the gentisic acid is 1.0:1. 如权利要求16所述的式(II)化合物龙胆酸盐的晶型A，其特征在于，其满足以下条件的一个或多个：The crystalline form A of the gentisate of the compound of formula (II) according to claim 16, characterized in that it satisfies one or more of the following conditions: (1)所述式(II)化合物龙胆酸盐的晶型A通过以下参数获得X射线粉末衍射图；
(1) The X-ray powder diffraction pattern of Form A of the gentisate salt of the compound of formula (II) is obtained using the following parameters:
(2)所述式(II)化合物龙胆酸盐的晶型A通过以下参数获得晶体形式的TGA和/或DSC图案；
(2) Form A of the gentisate salt of the compound of formula (II) is obtained by TGA and/or DSC patterns of the crystalline form using the following parameters;
一种如权利要求13所述的式(II)化合物龙胆酸盐的晶型A的制备方法，其特征在于，其包括如下步骤：A method for preparing the crystalline form A of the gentisate salt of the compound of formula (II) as claimed in claim 13, characterized in that it comprises the following steps: 在有机溶剂中，将式(II)化合物、龙胆酸混合，搅拌后分离即可；In an organic solvent, the compound of formula (II) and gentisic acid are mixed, stirred and then separated; 优选地，所述有机溶剂为乙腈；Preferably, the organic solvent is acetonitrile; 优选地，所述龙胆酸盐和式(II)化合物的摩尔比为1.05。Preferably, the molar ratio of the gentisate to the compound of formula (II) is 1.05. 一种式(II)化合物酒石酸盐的晶型A，其特征在于，其使用Cu-Kα辐射，以2θ表示的X射线粉末衍射图在下述位置具有衍射峰：6.42°±0.20°，13.08°±0.20°，15.27°±0.20°，17.59°±0.20°，19.09°±0.20°，20.05°±0.20°；
A crystalline form A of a tartrate salt of a compound of formula (II), characterized in that its X-ray powder diffraction pattern expressed in 2θ using Cu-Kα radiation has diffraction peaks at the following positions: 6.42°±0.20°, 13.08°±0.20°, 15.27°±0.20°, 17.59°±0.20°, 19.09°±0.20°, 20.05°±0.20°;
如权利要求19所述的式(II)化合物酒石酸盐的晶型A，其特征在于，其以2θ角表示的X射线粉末衍射图还进一步在下述的一个或多个位置有衍射峰：16.30°±0.20°，19.74°±0.20°，26.47°±0.20°；The crystalline form A of the tartrate salt of the compound of formula (II) according to claim 19, characterized in that its X-ray powder diffraction pattern expressed in 2θ angles further has diffraction peaks at one or more of the following positions: 16.30°±0.20°, 19.74°±0.20°, 26.47°±0.20°; 优选地，所述式(II)化合物酒石酸盐的晶型A以2θ角表示的X射线粉末衍射图还进一步在下述的一个或多个位置有衍射峰：12.03°±0.20°，13.32°±0.20°，23.17°±0.20°，25.98°±0.20°；Preferably, the X-ray powder diffraction pattern of the crystalline form A of the tartrate salt of the compound of formula (II) expressed in 2θ angles further has diffraction peaks at one or more of the following positions: 12.03°±0.20°, 13.32°±0.20°, 23.17°±0.20°, 25.98°±0.20°; 再优选地，所述式(II)化合物酒石酸盐的晶型A以2θ角表示的X射线粉末衍射图还进一步在下述的一个或多个位置有衍射峰：16.59°±0.20°，21.02°±0.20°，22.93°±0.20°，28.47°±0.20°，31.32°±0.20°，32.13°±0.20°，35.34°±0.20°；More preferably, the X-ray powder diffraction pattern of the crystalline form A of the tartrate salt of the compound of formula (II) expressed in 2θ angles further has diffraction peaks at one or more of the following positions: 16.59°±0.20°, 21.02°±0.20°, 22.93°±0.20°, 28.47°±0.20°, 31.32°±0.20°, 32.13°±0.20°, 35.34°±0.20°; 更优选地，所述式(II)化合物酒石酸盐的晶型A以2θ角表示的X射线粉末衍射图还进一步在下述的一个或多个位置有衍射峰：21.70°±0.20°，27.04°±0.20°，30.82°±0.20°，35.78°±0.20°。More preferably, the X-ray powder diffraction pattern of form A of the tartrate salt of the compound of formula (II) expressed in 2θ angles further has diffraction peaks at one or more of the following positions: 21.70°±0.20°, 27.04°±0.20°, 30.82°±0.20°, 35.78°±0.20°. 如权利要求19所述的式(II)化合物酒石酸盐的晶型A，其特征在于，其以2θ表示的X射线粉末衍射图在下述位置具有衍射峰：6.42°±0.20°，13.08°±0.20°，15.27°±0.20°，16.30°±0.20°，17.59°±0.20°，19.09°±0.20°，19.74°±0.20°，20.05°±0.20°，26.47°±0.20°；The crystalline form A of the tartrate of the compound of formula (II) according to claim 19, characterized in that its X-ray powder diffraction pattern expressed in 2θ has diffraction peaks at the following positions: 6.42°±0.20°, 13.08°±0.20°, 15.27°±0.20°, 16.30°±0.20°, 17.59°±0.20°, 19.09°±0.20°, 19.74°±0.20°, 20.05°±0.20°, 26.47°±0.20°; 优选地，所述式(II)化合物酒石酸盐的晶型A，以2θ表示的X射线粉末衍射图在下述位置具有衍射峰：6.42°±0.20°，12.03°±0.20°，13.08°±0.20°，13.32°±0.20°，15.27°±0.20°，16.30°±0.20°，17.59°±0.20°，19.09°±0.20°，19.74°±0.20°，20.05°±0.20°，23.17°±0.20°，25.98°±0.20°，26.47°±0.20°；Preferably, the crystalline form A of the tartrate salt of the compound of formula (II) has an X-ray powder diffraction pattern expressed in 2θ having diffraction peaks at the following positions: 6.42°±0.20°, 12.03°±0.20°, 13.08°±0.20°, 13.32°±0.20°, 15.27°±0.20°, 16.30°±0.20°, 17.59°±0.20°, 19.09°±0.20°, 19.74°±0.20°, 20.05°±0.20°, 23.17°±0.20°, 25.98°±0.20°, 26.47°±0.20°; 再优选地，所述式(II)化合物酒石酸盐的晶型A，以2θ表示的X射线粉末衍射图在下述位置具有衍射峰：6.42°±0.20°，12.03°±0.20°，13.08°±0.20°，13.32°±0.20°，15.27°±0.20°，16.30°±0.20°，16.59°±0.20°，17.59°±0.20°，19.09°±0.20°，19.74°±0.20°，20.05°±0.20°，21.02°±0.20°，22.93°±0.20°，23.17°±0.20°，25.98°±0.20°，26.47°±0.20°，28.47°±0.20°，31.32°±0.20°，32.13°±0.20°，35.34°±0.20°；More preferably, the crystalline form A of the tartrate salt of the compound of formula (II) has an X-ray powder diffraction pattern expressed in 2θ having diffraction peaks at the following positions: 6.42°±0.20°, 12.03°±0.20°, 13.08°±0.20°, 13.32°±0.20°, 15.27°±0.20°, 16.30°±0.20°, 16.59°±0.20°, 17.59°±0.20°, 19 .09°±0.20°, 19.74°±0.20°, 20.05°±0.20°, 21.02°±0.20°, 22.93°±0.20°, 23.17°±0.20°, 25.98°±0.20°, 26.47°±0.20°, 28.47°±0.20°, 31.32°±0.20°, 32.13°±0.20°, 35.34°±0.20°; 更优选地，所述式(II)化合物酒石酸盐的晶型A，以2θ表示的X射线粉末衍射图在下述位置具有衍射峰：6.42°±0.20°，12.03°±0.20°，13.08°±0.20°，13.32°±0.20°，15.27°±0.20°，16.30°±0.20°，16.59°±0.20°，17.59°±0.20°，19.09°±0.20°，19.74°±0.20°，20.05°±0.20°，21.02°±0.20°，21.70°±0.20°，22.93°±0.20°，23.17°±0.20°，25.98°±0.20°，26.47°±0.20°，27.04°±0.20°，28.47°±0.20°，30.82°±0.20°，31.32°±0.20°，32.13°±0.20°，35.34°±0.20°，35.78°±0.20°；More preferably, the crystalline form A of the tartrate salt of the compound of formula (II) has an X-ray powder diffraction pattern expressed in 2θ having diffraction peaks at the following positions: 6.42°±0.20°, 12.03°±0.20°, 13.08°±0.20°, 13.32°±0.20°, 15.27°±0.20°, 16.30°±0.20°, 16.59°±0.20°, 17.59°±0.20°, 19.09°±0.20°, 19.74°±0.20°, 20 .05°±0.20°, 21.02°±0.20°, 21.70°±0.20°, 22.93°±0.20°, 23.17°±0.20°, 25.98°±0.20°, 26.47°±0.20°, 27.04°±0.20°, 28.47°±0.20°, 30.82°±0.20°, 31.32°±0.20°, 32.13°±0.20°, 35.34°±0.20°, 35.78°±0.20°; 更优选地，所述式(II)化合物酒石酸盐的晶型A以2θ表示的X射线粉末衍射图具有如下表所示的衍射峰：
More preferably, the X-ray powder diffraction pattern of the crystalline form A of the tartrate salt of the compound of formula (II) expressed in 2θ has the diffraction peaks shown in the following table:
最优选地，所述式(II)化合物酒石酸盐的晶型A，其X射线粉末衍射图谱如图10所示。Most preferably, the X-ray powder diffraction pattern of Form A of the tartrate salt of the compound of formula (II) is shown in FIG10 . 如权利要求19所述的式(II)化合物龙胆酸盐的晶型A，其特征在于，其满足以下条件的一个或多个：The crystalline form A of the gentisate of the compound of formula (II) as claimed in claim 19, characterized in that it satisfies one or more of the following conditions: (1)所述式(II)化合物酒石酸盐的晶型A，其差示扫描量热曲线在126.9℃～132.7℃处吸热峰的熔化热为89.60J/g；(1) Form A of the tartrate salt of the compound of formula (II), wherein the heat of fusion of the endothermic peak at 126.9°C to 132.7°C according to the differential scanning calorimetry curve is 89.60 J/g; 优选地，所述式(II)化合物酒石酸盐的晶型A，其差示扫描量热曲线如图11所示；Preferably, the differential scanning calorimetry curve of Form A of the tartrate salt of the compound of formula (II) is shown in FIG11 ; (2)所述式(II)化合物酒石酸盐的晶型A，其热重分析曲线(TGA)在130.0℃时失重0.34％；(2) Form A of the tartrate salt of the compound of formula (II), whose thermogravimetric analysis (TGA) curve shows a weight loss of 0.34% at 130.0°C; 优选地，所述式(II)化合物酒石酸盐的晶型A，其热重分析曲线如图11所示；Preferably, the thermogravimetric analysis curve of Form A of the tartrate salt of the compound of formula (II) is shown in FIG11 ; (3)所述式(II)化合物酒石酸盐晶型A为无水晶型；(3) The tartrate crystal form A of the compound of formula (II) is an anhydrous crystal form; (4)所述式(II)化合物与所述酒石酸的摩尔比为1.1:1。(4) The molar ratio of the compound of formula (II) to the tartaric acid is 1.1:1. 一种如权利要求19所述的式(II)化合物酒石酸盐的晶型A的制备方法，其特征在于，其包括如下步骤：A method for preparing the crystalline form A of the tartrate salt of the compound of formula (II) as claimed in claim 19, characterized in that it comprises the following steps: 在有机溶剂中，将式(II)化合物、L-酒石酸混合，搅拌后分离即可；In an organic solvent, the compound of formula (II) and L-tartaric acid are mixed, stirred and then separated; 优选地，所述有机溶剂为乙腈；Preferably, the organic solvent is acetonitrile; 优选地，所述L-酒石酸和式(II)化合物的摩尔比为1.05。Preferably, the molar ratio of L-tartaric acid to the compound of formula (II) is 1.05. 一种物质X在制备式(I)化合物中的应用，其特征在于，所述的物质X为权利要求1所述式(II)化合物、式(II)化合物的盐、权利要求2～6任一项所述马来酸盐的晶型A、权利要求8～11任一项所述甲磺酸盐的晶型A、权利要求13～17任一项所述龙胆酸盐的晶型A或权利要求19～22任一项所述酒石酸盐的晶型A；A use of a substance X in preparing a compound of formula (I), characterized in that the substance X is the compound of formula (II) according to claim 1, a salt of the compound of formula (II), the crystalline form A of the maleate according to any one of claims 2 to 6, the crystalline form A of the mesylate according to any one of claims 8 to 11, the crystalline form A of the gentisate according to any one of claims 13 to 17, or the crystalline form A of the tartrate according to any one of claims 19 to 22; 所述式(I)化合物为 The compound of formula (I) is 优选地，所述应用中，所述物质X通过以下路线制备式(I)化合物：
Preferably, in the application, the substance X is prepared into a compound of formula (I) by the following route:
一种式(I)化合物的制备方法，其特征在于，其包括如下步骤：
A method for preparing a compound of formula (I), characterized in that it comprises the following steps:
如权利要求25所述的制备方法，其特征在于，其包括如下步骤：
The preparation method according to claim 25, characterized in that it comprises the steps of:
PCT/CN2025/089305 2024-04-17 2025-04-16 Salt and crystal form of pharmaceutical intermediate, and preparation method therefor and use thereof Pending WO2025218702A1 (en)

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