WO2024017299A1 - Crystal of bridged heterocycle substituted benzoic acid derivative or salt thereof, and preparation method therefor - Google Patents

Crystal of bridged heterocycle substituted benzoic acid derivative or salt thereof, and preparation method therefor Download PDF

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WO2024017299A1
WO2024017299A1 PCT/CN2023/108171 CN2023108171W WO2024017299A1 WO 2024017299 A1 WO2024017299 A1 WO 2024017299A1 CN 2023108171 W CN2023108171 W CN 2023108171W WO 2024017299 A1 WO2024017299 A1 WO 2024017299A1
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compound
formula
crystal form
crystal
radiation
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PCT/CN2023/108171
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French (fr)
Chinese (zh)
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丁照中
颜小兵
孙翔
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正大天晴药业集团股份有限公司
南京明德新药研发有限公司
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Publication of WO2024017299A1 publication Critical patent/WO2024017299A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the invention belongs to the field of medical technology and relates to the crystallization of a bridged heterocyclic substituted benzoic acid derivative or its salt and its preparation method, specifically to the crystallization of the compound of formula (II), the hydrochloride of the compound of formula (II) and its crystallization , and preparation method thereof.
  • the complement system is an important component of the body's innate immunity against infections such as foreign pathogens, bacteria, and parasites.
  • the complement system is also an important component of the connection between innate immunity and adaptive immunity.
  • Complement consists of plasma proteins, including soluble proteins, membrane-bound proteins and complement receptors. It is mainly produced by membrane proteins expressed in the liver or cell surface and plays a role in plasma, tissues or cells.
  • the complement system is mainly activated through three pathways: the classical pathway (CP), the lectin pathway (LP), and the alternative pathway (AP).
  • the AP pathway always maintains a low-level activation state to monitor the invasion status of foreign pathogens at any time.
  • Complement proteins are distributed on the surface of apoptotic cells, and complement activation is strictly regulated and is only used to clear apoptotic cells without further activating other innate or adaptive immune responses.
  • the complement system In the case of infection by foreign pathogens, the complement system is fully activated, producing inflammatory responses, opsonization or phagocytosis, etc., destroying the pathogens and ultimately activating the adaptive immune response.
  • Both complement inefficiency and overstimulation can be harmful and are associated with increased susceptibility to infections or non-communicable diseases, such as autoimmune diseases, chronic inflammation, thrombotic microangiopathies, transplant rejection and tumors.
  • Complement factor B acts on the AP pathway. Inhibiting Factor B activity can prevent the activation of the API pathway without interfering with the CP and LP pathways, and can avoid increasing the risk of infection due to complement system inhibition.
  • Factor B inhibitors There are currently no small molecule Factor B inhibitors on the market.
  • Novartis' factor B inhibitor LNP023 is in the clinical phase III research stage and is used for the treatment of PNH, IgAN, C3G and other diseases. Therefore, it is necessary to develop new small molecule inhibitors of the complement system Factor B, increase clinical research and verification, and use them in the treatment of various diseases caused by complement abnormalities to provide new treatment methods for unmet clinical needs.
  • the invention provides crystallization of a compound of formula (II),
  • the crystallization of the compound of formula (II) according to the present invention may be in the form of a non-solvate or a solvate, such as a hydrate.
  • the crystal of the compound of formula (II) is crystal form A
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the crystal form A has a characteristic diffraction peak at the following 2 ⁇ angle: 7.15 ⁇ 0.20°, 9.28 ⁇ 0.20° and 14.31 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned A crystal form has at least 3 or 4 characteristic diffraction peaks at the following 2 ⁇ angles: 7.15 ⁇ 0.20°, 9.28 ⁇ 0.20°, 14.31 ⁇ 0.20°, 19.52 ⁇ 0.20° and 21.77 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 7.15 ⁇ 0.20°, 9.28 ⁇ 0.20°, 14.31 ⁇ 0.20°, 19.52 ⁇ 0.20 ° and 21.77 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 7.15°, 9.28°, 14.31°, 19.52° and 21.77°.
  • the XRPD pattern of Cu K ⁇ radiation of the above-mentioned crystal form A is shown in Figure 1.
  • the peak position and relative intensity of the diffraction peak are as shown in Table 1-1:
  • the peak position and relative intensity of the diffraction peak are as shown in Table 1:
  • the present invention also provides the hydrochloride salt of the compound of formula (II),
  • the invention provides crystallization of the hydrochloride salt of the compound of formula (II).
  • the crystallization of the hydrochloride of the compound of formula (II) according to the present invention may be in the form of a non-solvate or in the form of a solvate, such as a hydrate.
  • the invention provides compounds of formula (II-1),
  • n is selected from 0 to 2.5;
  • n is selected from 0 to 2.5.
  • the above m is selected from 0, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3 or 2.0.
  • the above m is selected from 1.0 or 2.0.
  • the above m is selected from 1.0.
  • n is selected from 0, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4 or 2.5.
  • n is selected from 0, 1.0 or 2.0.
  • n is selected from 0.
  • the above-mentioned compound of formula (II-1) is selected from the group consisting of compounds of formula (I),
  • the present invention also provides crystallization of the compound of formula (I),
  • the crystallization of the compound of formula (I) according to the present invention may be in the form of a non-solvate or a solvate, such as a hydrate.
  • the crystal of the compound of formula (I) is crystal form B, and the X-ray powder diffraction pattern of Cu K ⁇ radiation of the crystal form B has a characteristic diffraction peak at the following 2 ⁇ angle: 6.16 ⁇ 0.20°, 8.96 ⁇ 0.20° and 10.53 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 6.16 ⁇ 0.20°, 8.96 ⁇ 0.20°, 10.53 ⁇ 0.20°, 18.55 ⁇ 0.20 ° and 24.62 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned B crystal form has at least 6 or 7 characteristic diffraction peaks at the following 2 ⁇ angles: 6.16 ⁇ 0.20°, 8.96 ⁇ 0.20°, 10.53 ⁇ 0.20°, 12.30 ⁇ 0.20°, 16.74 ⁇ 0.20°, 18.55 ⁇ 0.20°, 19.95 ⁇ 0.20° and 24.62 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 6.16 ⁇ 0.20°, 8.96 ⁇ 0.20°, 10.53 ⁇ 0.20°, 12.30 ⁇ 0.20 °, 16.74 ⁇ 0.20°, 18.55 ⁇ 0.20°, 19.95 ⁇ 0.20° and 24.62 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned B crystal form has at least 9, 10 or 11 characteristic diffraction peaks at the following 2 ⁇ angles: 6.16 ⁇ 0.20°, 8.96 ⁇ 0.20° , 10.53 ⁇ 0.20°, 12.30 ⁇ 0.20°, 16.74 ⁇ 0.20°, 17.39 ⁇ 0.20°, 18.55 ⁇ 0.20°, 19.49 ⁇ 0.20°, 19.95 ⁇ 0.20°, 22.17 ⁇ 0.20°, 22.75 ⁇ 0.20° and 24.62 ⁇ 0.20° .
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 6.16 ⁇ 0.20°, 8.96 ⁇ 0.20°, 10.53 ⁇ 0.20°, 12.30 ⁇ 0.20 °, 16.74 ⁇ 0.20°, 17.39 ⁇ 0.20°, 18.55 ⁇ 0.20°, 19.49 ⁇ 0.20°, 19.95 ⁇ 0.20°, 22.17 ⁇ 0.20°, 22.75 ⁇ 0.20° and 24.62 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned B crystal form has at least 11, 12, 13, 14 or 15 characteristic diffraction peaks at the following 2 ⁇ angle: 6.16 ⁇ 0.20 °, 8.96 ⁇ 0.20°, 10.53 ⁇ 0.20°, 12.30 ⁇ 0.20°, 13.19 ⁇ 0.20°, 14.74 ⁇ 0.20°, 16.74 ⁇ 0.20°, 17.39 ⁇ 0.20°, 17.90 ⁇ 0.20°, 18.55 ⁇ 0.20°, 19.49 ⁇ 0.20 °, 19.95 ⁇ 0.20°, 21.55 ⁇ 0.20°, 22.17 ⁇ 0.20°, 22.75 ⁇ 0.20° and 24.62 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 6.16 ⁇ 0.20°, 8.96 ⁇ 0.20°, 10.53 ⁇ 0.20°, 12.30 ⁇ 0.20 °, 13.19 ⁇ 0.20°, 14.74 ⁇ 0.20°, 16.74 ⁇ 0.20°, 17.39 ⁇ 0.20°, 17.90 ⁇ 0.20°, 18.55 ⁇ 0.20°, 19.49 ⁇ 0.20°, 19.95 ⁇ 0.20°, 21.55 ⁇ 0.20°, 22.17 ⁇ 0.20 °, 22.75 ⁇ 0.20° and 24.62 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 3.16 ⁇ 0.20°, 6.16 ⁇ 0.20°, 8.96 ⁇ 0.20°, 10.53 ⁇ 0.20 °, 12.30 ⁇ 0.20°, 13.19 ⁇ 0.20°, 14.74 ⁇ 0.20°, 16.74 ⁇ 0.20°, 17.39 ⁇ 0.20°, 17.90 ⁇ 0.20°, 18.55 ⁇ 0.20°, 19.49 ⁇ 0.20°, 19.95 ⁇ 0.20°, 21.55 ⁇ 0.20
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 6.16 ⁇ 0.20°, 8.96 ⁇ 0.20°, 10.53 ⁇ 0.20°, and/or 3.16 ⁇ 0.20°, and/or 10.79 ⁇ 0.20°, and/or 12.30 ⁇ 0.20°, and/or 13.19 ⁇ 0.20°, and/or 14.74 ⁇ 0.20°, and/or 16.74 ⁇ 0.20°, and/or 17.39 ⁇ 0.20°, and/or 17.90 ⁇ 0.20°, and/or 18.55 ⁇ 0.20°, and/or 19.49 ⁇ 0.20°, and/or 19.95 ⁇ 0.20°, and/or 21.55 ⁇ 0.20°, and/or 22.17 ⁇ 0.20° , and/or 22.75 ⁇ 0.20°, and/or 24.62 ⁇ 0.20°, and/or 27.29 ⁇ 0.20°, and/or 28.05 ⁇ 0.20°, and/or 29.03 ⁇
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 3.16°, 6.16°, 8.96°, 10.53°, 10.79°, 12.30°, 13.19°, 14.74°, 16.74°, 17.39°, 17.90°, 18.55°, 19.49°, 19.95°, 21.55°, 22.17°, 22.75°, 24.62°, 27.29°, 28.05°, 29.03°, 32.55° and 34.15° .
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 6.16°, 8.96°, 10.53°, 10.79°, 12.30°, 13.19°, 14.74°, 16.74°, 17.39°, 17.90°, 18.55°, 19.49°, 19.95°, 21.55°, 22.17°, 22.75°, 24.62°, 27.29°, 28.05° and 29.03°.
  • the XRPD pattern of Cu K ⁇ radiation of the above-mentioned B crystal form is shown in Figure 2.
  • the differential scanning calorimetry (DSC) curve of the above-mentioned Form B shows an exothermic peak at 221.2°C ⁇ 3°C.
  • the DSC spectrum of the above crystal form B is shown in Figure 3.
  • thermogravimetric analysis (TGA) curve of the above-mentioned B crystal form has a weight loss of 3.85% at 150°C ⁇ 3°C.
  • the TGA spectrum of the above crystal form B is shown in Figure 4.
  • the present invention also provides a method for preparing the crystal form B of the compound of formula (I), which includes mixing the hydrochloride of the compound of formula (II) in solvents S1, S2 and S3, and then separating the solid.
  • the hydrochloride salt of the compound of formula (II) is amorphous. In one embodiment of the present invention, the hydrochloride salt of the compound of formula (II) is a compound of formula (I).
  • the method for preparing the crystal form of compound (I) B includes first mixing the hydrochloride of the compound of formula (II) in solvents S1 and S2, and then adding solvent S3.
  • the present invention also provides a method for preparing the crystal form B of the compound of formula (I),
  • the preparation method of the B crystal form includes the following steps:
  • the solvent S1 is selected from one or two mixture solvents of acetonitrile or acetone.
  • the solvent S2 is selected from water.
  • the solvent S3 is selected from a mixed solvent of acetone and ethyl acetate, acetonitrile or 1,4-dioxane.
  • the volume ratio of solvent S1 to solvent S2 is 5:1 to 1:5.
  • the present invention also provides a method for preparing the crystal form B of the compound of formula (I),
  • the preparation method of the B crystal form includes the following steps:
  • Solvent S1 is selected from one or two mixtures of acetonitrile or acetone;
  • Solvent S2 is selected from water;
  • Solvent S3 is selected from a mixed solvent of acetone and ethyl acetate, acetonitrile or 1,4-dioxane;
  • the volume ratio of solvent S1 to solvent S2 is 5:1 to 1:5.
  • the volume ratio of the above solvent S1 to solvent S2 is 5:1 to 1:1; preferably, the volume ratio of solvent S1 to solvent S2 is 5:1, 4:1, 3:1, 2:1 or 1:1; further preferably, the volume ratio of solvent S1 and solvent S2 is 5:1.
  • the above-mentioned solvent S1 is selected from acetone
  • the solvent S2 is selected from water
  • the volume ratio of acetone and water is 5:1, 4:1, 3:1, 2:1 or 1:1;
  • the volume ratio of acetone and water is 5:1.
  • the above-mentioned solvent S3 is selected from a mixed solvent of acetone and ethyl acetate, and the volume ratio of acetone and ethyl acetate is 1:1 to 1:3; preferably, acetone and ethyl acetate The volume ratio of acetone and ethyl acetate is 1:1, 1:1.5, 1:2 or 1:3; further preferably, the volume ratio of acetone and ethyl acetate is 1:1.5.
  • the above-mentioned solvent S1 is selected from acetone
  • solvent S2 is selected from water
  • solvent S3 is selected from a mixed solvent of acetone and ethyl acetate
  • the acetone water: a mixed solvent of acetone and ethyl acetate.
  • the volume ratios are 1 to 5:1:5 to 15 respectively
  • the preferred volume ratios of the mixed solvents of acetone:water:acetone and ethyl acetate are 5:1:5, 5:1:10, and 5:1:15 respectively.
  • the volume ratio of the mixed solvent of acetone and ethyl acetate is 5:1:5, 5:1: 10 or 5:1:15; the further preferred volume ratio of the mixed solvent of acetone and ethyl acetate is 5:1:15 respectively.
  • the mass volume ratio of the hydrochloride of the compound of formula (II) to the solvent S1 is 100 mg: 0.5 ⁇ 1 mL; preferably, the mass volume ratio of the hydrochloride of the compound of formula (II) to the solvent S1
  • the volume ratio is 100mg:0.5mL, 100mg:0.6mL, 100mg:0.7mL, 100mg:0.8mL, 100mg:0.9mL or 100mg:1mL; further preferably, the mass of the hydrochloride of the compound of formula (II) and the solvent S1
  • the volume ratio is 100mg:0.6mL.
  • the stirring temperature of step (b) is 15°C to 35°C; the stirring time is 5 minutes to 1 hour; preferably, the stirring temperature of step (b) is 15°C to 25°C; stirring The time is 5 to 10 minutes; further preferably, the stirring temperature of step (b) is 15°C ⁇ 25°C; stirring time is 5 minutes.
  • the stirring temperature of step (d) is 15°C to 35°C; the stirring time is 5 to 15 hours; preferably, the stirring temperature of step (d) is 15°C to 25°C; the stirring time for 12 hours.
  • the crystal of the compound of formula (I) is C crystal form
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the C crystal form has a characteristic diffraction peak at the following 2 ⁇ angle: 7.72 ⁇ 0.20°, 15.31 ⁇ 0.20° and 19.53 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned C crystal form has at least 6 or 7 characteristic diffraction peaks at the following 2 ⁇ angles: 7.72 ⁇ 0.20°, 14.67 ⁇ 0.20°, 15.31 ⁇ 0.20°, 16.66 ⁇ 0.20°, 18.76 ⁇ 0.20°, 19.53 ⁇ 0.20°, 22.67 ⁇ 0.20° and 24.28 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 7.72 ⁇ 0.20°, 14.67 ⁇ 0.20°, 15.31 ⁇ 0.20°, 16.66 ⁇ 0.20 °, 18.76 ⁇ 0.20°, 19.53 ⁇ 0.20°, 22.67 ⁇ 0.20° and 24.28 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned C crystal form has at least 9, 10 or 11 characteristic diffraction peaks at the following 2 ⁇ angles: 7.72 ⁇ 0.20°, 10.75 ⁇ 0.20° , 13.80 ⁇ 0.20°, 14.67 ⁇ 0.20°, 15.31 ⁇ 0.20°, 16.66 ⁇ 0.20°, 18.76 ⁇ 0.20°, 19.53 ⁇ 0.20°, 22.67 ⁇ 0.20°, 24.28 ⁇ 0.20°, 25.95 ⁇ 0.20° and 26.65 ⁇ 0.20° .
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 7.72 ⁇ 0.20°, 10.75 ⁇ 0.20°, 13.80 ⁇ 0.20°, 14.67 ⁇ 0.20 °, 15.31 ⁇ 0.20°, 16.66 ⁇ 0.20°, 18.76 ⁇ 0.20°, 19.53 ⁇ 0.20°, 22.67 ⁇ 0.20°, 24.28 ⁇ 0.20°, 25.95 ⁇ 0.20° and 26.65 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 7.72 ⁇ 0.20°, 15.31 ⁇ 0.20°, 19.53 ⁇ 0.20°, and/or 10.75 ⁇ 0.20°, and/or 13.80 ⁇ 0.20°, and/or 14.67 ⁇ 0.20°, and/or 16.66 ⁇ 0.20°, and/or 18.76 ⁇ 0.20°, and/or 22.67 ⁇ 0.20°, and/or 24.28 ⁇
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 7.72°, 10.75°, 13.80°, 14.67°, 15.31°, 16.66°, 18.76°, 19.53°, 22.67°, 24.28°, 25.95° and 26.65°.
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned C crystal form is shown in Figure 5.
  • the differential scanning calorimetry (DSC) curve of the above-mentioned C crystal form shows an exothermic peak at 227.5°C ⁇ 3°C.
  • thermogravimetric analysis (TGA) curve of the above-mentioned C crystal form loses 2.88% weight at 150.0°C ⁇ 3°C.
  • the TGA spectrum of the above crystal form C is shown in Figure 7.
  • the crystal of the compound of formula (I) is the D crystal form
  • the X-ray powder diffraction pattern of the Cu K ⁇ radiation of the D crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.93 ⁇ 0.20° and 11.82 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned D crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.93° and 11.82°.
  • the crystal of the compound of formula (I) is the E crystal form
  • the X-ray powder diffraction pattern of the Cu K ⁇ radiation of the E crystal form has at least 3 characteristic diffraction peaks at the following 2 ⁇ angle: 5.98 ⁇ 0.20°, 7.83 ⁇ 0.20°, 8.87 ⁇ 0.20° and 10.76 ⁇ 0.20°.
  • the E crystalline form of the compound of formula (I) is in the form of a hydrate.
  • the crystal of the compound of formula (I) is in the form of a hydrate
  • the hydrate is the E crystal form
  • the X-ray powder diffraction pattern of the Cu K ⁇ radiation of the E crystal form has at the following 2 ⁇ angle Characteristic diffraction peaks: 5.98 ⁇ 0.20°, 7.83 ⁇ 0.20°, 8.87 ⁇ 0.20° and 10.76 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned E crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.98°, 7.83°, 8.87° and 10.76°.
  • the X-ray powder diffraction pattern of the above-mentioned E crystal form is shown in Figure 9.
  • the crystal of the compound of formula (I) is the F crystal form
  • the X-ray powder diffraction pattern of the Cu K ⁇ radiation of the F crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.96 ⁇ 0.20°, 8.86 ⁇ 0.20°, 17.40 ⁇ 0.20°, 19.52 ⁇ 0.20° and 24.04 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned F crystal form has at least 6 or 7 characteristic diffraction peaks at the following 2 ⁇ angles: 5.96 ⁇ 0.20°, 8.86 ⁇ 0.20°, 10.82 ⁇ 0.20°, 13.32 ⁇ 0.20°, 17.40 ⁇ 0.20°, 19.52 ⁇ 0.20°, 24.04 ⁇ 0.20° and 24.74 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned F crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.96 ⁇ 0.20°, 8.86 ⁇ 0.20°, 10.82 ⁇ 0.20°, 13.32 ⁇ 0.20 °, 17.40 ⁇ 0.20°, 19.52 ⁇ 0.20°, 24.04 ⁇ 0.20° and 24.74 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned F crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.96 ⁇ 0.20°, 8.86 ⁇ 0.20°, 10.66 ⁇ 0.20°, 10.82 ⁇ 0.20 °, 11.94 ⁇ 0.20°, 13.32 ⁇ 0.20°, 14.86 ⁇ 0.20°, 17.40 ⁇ 0.20°, 17.96 ⁇ 0.20°, 18.72 ⁇ 0.20°, 19.52 ⁇ 0.20°, 21.66 ⁇ 0.20°, 24.04 ⁇ 0.20°, 24.74 ⁇ 0.20° and 26.56 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned F crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.96 ⁇ 0.20°, 8.86 ⁇ 0.20°, 17.40 ⁇ 0.20°, 19.52 ⁇ 0.20 °, 24.04 ⁇ 0.20°, and/or 10.66 ⁇ 0.20°, and/or 10.82 ⁇ 0.20°, and/or 11.06 ⁇ 0.20°, and/or 11.54 ⁇ 0.20°, and/or 11.94 ⁇ 0.20°, and/or 13.32 ⁇ 0.20°, and/or 14.86 ⁇ 0.20°, and/or 17.96 ⁇ 0.20°, and/or 18.72 ⁇ 0.20°, and/or 21.66 ⁇ 0.20°, and/or 23.68 ⁇ 0.20°, and/or 24.74 ⁇ 0.20°, and/or 26.56 ⁇ 0.20°, and/or 27.42 ⁇ 0.20°, and/or 30.78 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned F crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.96°, 8.86°, 10.66°, 10.82°, 11.06°, 11.54°, 11.94°, 13.32°, 14.86°, 17.40°, 17.96°, 18.72°, 19.52°, 21.66°, 23.68°, 24.04°, 24.74°, 26.56°, 27.42° and 30.78°.
  • the XRPD pattern of Cu K ⁇ radiation of the above-mentioned F crystal form is shown in Figure 11.
  • the peak position and relative intensity of the diffraction peak are shown in Table 16.
  • the present invention provides a crystalline composition
  • a crystalline composition comprising crystals of the compound of formula (II), wherein the crystals of the compound of formula (II) account for more than 50%, preferably more than 75%, by weight of the crystalline composition, More preferably, it is more than 90%, and even better, it is more than 95%.
  • Each of the crystalline compositions may also contain small amounts of other crystalline or non-crystalline forms of the compound of formula (II).
  • the present invention provides a crystalline composition
  • a crystalline composition comprising crystals of the compound of formula (I), wherein the crystals of the compound of formula (I) account for more than 50%, preferably more than 75%, by weight of the crystalline composition, More preferably, it is more than 90%, and even better, it is more than 95%.
  • Each of the crystalline compositions may also contain small amounts of other crystalline or non-crystalline forms of the compound of formula (I).
  • the present invention provides a pharmaceutical composition, which contains a therapeutically effective amount of the above-mentioned compound of formula (II) or its crystal, or a crystal composition of its crystal; the pharmaceutical composition may contain at least one pharmaceutically acceptable Acceptable carrier or other excipient.
  • the pharmaceutical compositions of the present application may further include one or more other therapeutic agents.
  • the present invention provides a pharmaceutical composition, which contains a therapeutically effective amount of the above-mentioned compound of formula (I) or its crystal, or a crystal composition of its crystal; the pharmaceutical composition may contain at least one pharmaceutically acceptable Acceptable carrier or other excipient.
  • the pharmaceutical compositions of the present application may further include one or more other therapeutic agents.
  • the present invention provides the above-mentioned compound of formula (II) or its crystal, the above-mentioned formula (I) or its crystal, the above-mentioned crystal composition, or the above-mentioned pharmaceutical composition for the preparation of treatment or prevention of diseases related to complement factor B. Applications in medicine.
  • the present invention provides the above-mentioned compound of formula (II) or its crystal, the above-mentioned compound of formula (I) or its crystal, the above-mentioned crystal composition, or the above-mentioned pharmaceutical composition for the treatment or prevention of diseases related to complement factor B. application.
  • the present invention provides a method for treating or preventing diseases related to complement factor B, which includes administering to a mammal in need a therapeutically effective amount of the above-mentioned compound of formula (II) or its crystal, the above-mentioned compound of formula (I) or Its crystal, the above-mentioned crystal composition, or the above-mentioned pharmaceutical composition.
  • the present invention provides the above-mentioned compound of formula (II) or crystal thereof, the above-mentioned compound of formula (I) or its crystal, the above-mentioned crystal composition, or the above-mentioned pharmaceutical composition for the treatment or prevention of diseases related to complement factor B. .
  • the mammal is a human.
  • the complement factor B-related disease is selected from the group consisting of inflammatory disorders and autoimmune diseases.
  • the compound of the present invention has obvious inhibitory activity on the activation of the human serum bypass pathway, and also has significant binding activity on human complement Factor B protein.
  • the crystal form and salt form of the compound of the present invention have simple preparation process, stable physical and chemical properties, good hygroscopicity, good pharmacokinetic properties (such as AUC, C max , T 1/2 ), easy preparation, and good use in prevention. And/or it has broad application prospects in the treatment of complement factor B-related drugs.
  • 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 those skilled in the art.
  • Well-known equivalents and preferred embodiments include, but are not limited to, the embodiments of the present invention.
  • room temperature in the present invention means 15°C to 35°C.
  • mammals include humans and domestic animals, such as laboratory mammals and household pets (such as cats, dogs, pigs, sheep, cattle, sheep, goats, horses, rabbits), and non-domesticated mammals, such as wild mammals.
  • composition refers to a formulation of a compound of the present application with a vehicle generally accepted in the art for delivering a biologically active compound to a mammal, such as a human. Such media include all pharmaceutically acceptable carriers for their use. Pharmaceutical compositions facilitate the administration of compounds to an organism.
  • terapéuticaally effective amount refers to a non-toxic amount of a drug or agent sufficient to achieve the desired effect.
  • the determination of the effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in individual cases can be determined by those skilled in the art based on routine experiments.
  • treating means administering a compound or formulation described herein to ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:
  • prevention means the administration of a compound or formulation described herein to prevent a disease or one or more symptoms associated with said disease, and includes preventing the occurrence of a disease or disease state in a mammal, in particular when Such mammals are susceptible to the disease state but have not yet been diagnosed as having the disease state.
  • pharmaceutically acceptable carriers refer to those carriers that are administered together with the active ingredients, have no obvious irritating effect on the organism, and do not impair the biological activity and performance of the active compound.
  • pharmaceutically acceptable carriers refer to those carriers that are administered together with the active ingredients, have no obvious irritating effect on the organism, and do not impair the biological activity and performance of the active compound.
  • the structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention involves the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art.
  • single crystal X-ray diffraction uses a Bruker D8 venture diffractometer to collect diffraction intensity data on the cultured single crystal.
  • the light source is CuK ⁇ radiation.
  • the scanning method is: After scanning and collecting relevant data, the direct method (Shelxs97) is further used to analyze the crystal structure, and the absolute configuration can be confirmed.
  • ACN represents acetonitrile
  • DMSO represents dimethyl sulfoxide.
  • N 2 nitrogen; RH: relative humidity; mL: milliliter; L: liter; min: minutes; °C: degrees Celsius; ⁇ m: micrometers; mm: millimeters; ⁇ L: microliters; moL/L: moles per liter; mg: milligrams ;s: seconds; nm: nanometers; MPa: megapascals; lux: lux; ⁇ w/cm 2 : microwatts per square centimeter; h: hours; Kg: kilograms; nM: nanomoles, rpm: rotational speed; XRPD represents X-rays Powder diffraction; DSC stands for differential scanning calorimetry; TGA stands for thermogravimetric analysis; 1 H NMR stands for hydrogen nuclear magnetic resonance spectroscopy.
  • the compounds of the present invention are named according to the conventional naming principles in this field or used Software nomenclature, commercially available compounds using supplier catalog names, all solvents used in this invention are commercially available.
  • Instrument model PANalytical X'Pert 3 type X-ray diffractometer.
  • Test method About 10mg sample is used for XRPD detection.
  • Step size 0.0263 degrees.
  • the acid-base molar ratio test in the experiment was performed by Agilent H-Class high performance liquid chromatography and ion chromatography.
  • the analysis conditions are shown in Tables 7 and 8.
  • RH gradient 10% (0%RH-90%RH, 90%RH-0%RH); 5% (90%RH-95%RH, 95%RH-90%RH).
  • Hygroscopicity evaluation classification absorb enough water to form liquid: deliquescence; ⁇ W% ⁇ 15%: extremely hygroscopic; 15% > ⁇ W% ⁇ 2%: yes Hygroscopicity; 2%> ⁇ W% ⁇ 0.2%: slightly hygroscopic; ⁇ W% ⁇ 0.2%: no or almost no hygroscopicity.
  • ⁇ W% represents the moisture absorption weight gain of the test product at 25 ⁇ 1°C and 80 ⁇ 2%RH.
  • Figure 1 is the XRPD pattern of the crystal form A of the compound of formula (II).
  • Figure 2 is the XRPD pattern of the crystal form B of the compound of formula (I).
  • Figure 3 is a DSC spectrum of compound B crystal form of formula (I).
  • Figure 4 is a TGA spectrum of the crystal form B of compound (I).
  • Figure 5 is the XRPD pattern of crystal form C of compound of formula (I).
  • Figure 6 is a DSC spectrum of crystal form C of compound of formula (I).
  • Figure 7 is a TGA spectrum of crystal form C of compound of formula (I).
  • Figure 8 is the XRPD pattern of the crystal form D of the compound of formula (I).
  • Figure 9 is the XRPD pattern of the hydrate crystal form E of the compound of formula (I).
  • Figure 10 is an ellipsoid diagram of the three-dimensional structure of a single crystal of the compound of formula (I).
  • Figure 11 is an XRPD simulation diagram of a single crystal of the compound of formula (I).
  • Benzylamine (194.62g) was slowly added to water (850mL) dissolved in acetic acid (103.88mL). The reaction system was cooled to 0-10°C, then 1,3-acetone dicarboxylic acid (265.36g) was slowly added in batches, and the reaction solution was allowed to react at 0°C for 0.5 hours. A solution of compound 10 (170 g) dissolved in dioxane (850 mL) was slowly added to the reaction system, the reaction solution was slowly returned to room temperature, and then reacted at 45°C for 12 hours.
  • Dissolve compound 11 (220g, 1eq) in acetonitrile (1700mL), then raise the temperature to 70°C and stir for 2 hours.
  • L-type dibenzoyl tartaric acid 200g, 0.8eq
  • the reaction solution is continued Stir at 70°C for 2 hours, then slowly return to 25°C and stir for 12 hours.
  • Add the filtered solid to 1000 mL of water, add 1 M NaOH aqueous solution with stirring to adjust the pH to 8, and then add ethyl acetate for extraction (2000 mL*2).
  • the organic phases were combined and washed with saturated brine (2000 mL*2).
  • N,N-dimethylformamide dimethyl acetal (59.81g) was added to a solution of compound 15 (99g) in methanol (1000mL), and the reaction solution was heated to 40°C and stirred for 16 hours. The reaction solution was directly concentrated under reduced pressure to obtain the residue. Ethyl acetate (1000 mL) was added to the residue, and then washed with water (500 mL) and saturated brine (500 mL) in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 16, which was used directly in the next step.
  • the amorphous hydrochloride of the compound of formula (II) prepared in Example 1 (0.4g) was dissolved in a mixed solvent of deionized water (1mL) and acetonitrile (3mL), and then a saturated sodium bicarbonate aqueous solution (70 ⁇ L) was slowly added , a solid precipitated, and the reaction system continued to stir at 20°C for 5 minutes. The solid is filtered and collected, and after drying, the crystal form A of the compound of formula (II) is obtained.
  • the amorphous form of the hydrochloride of the compound of formula (II) prepared in Example 1 was replaced with the crystal form of the compound of formula (I) B, the crystal form of the compound of formula (I) C, and the crystal form of the compound of formula (I) D. or the crystal form of compound E of formula (I) to obtain the crystal form of compound A of formula (II).
  • Method 1 Dissolve 100 mg of the amorphous hydrochloride of the compound of formula (II) prepared in Example 1 in a mixed solution of acetone (0.5 mL) and water (0.1 mL), stir for 5 minutes, and add acetone dropwise to the mixed solution. (0.6 mL) and ethyl acetate (0.9 mL), the reaction solution was stirred at room temperature for 12 hours, a solid precipitated, filtered, and the filter cake was dried to obtain the crystal form B of the compound of formula (I).
  • Method 2 Weigh approximately 20 mg of the amorphous hydrochloride of the compound of formula (II) prepared in Example 1 into a 20 ml glass vial, and add 1.0 mL of the corresponding solvent to completely dissolve the solid. Add anti-solvent dropwise to the clear solution while stirring until solid precipitates or the volume of anti-solvent added reaches 10 mL. Centrifuge and collect the solid for XRPD testing. The experimental results are shown in Table 9.
  • the three-dimensional structure ellipsoid diagram of the single crystal of the compound of formula (I) is shown in Figure 10, and the XRPD simulation diagram is shown in Figure 11.
  • the crystal structure data and parameters of the compound of formula (I) are shown in Tables 10 to 15, and the diffraction data of the XRPD simulation pattern are shown in Table 16.
  • ICH conditions the total visible light illumination reached 1,200,000 Lux ⁇ hrs, the total ultraviolet light When the illumination reaches 200W ⁇ hrs/m 2 ), place it in the open under visible light and ultraviolet light (samples in the shading control group are placed at the same time and wrapped in tin foil), and placed 1, 2 and 3 under 40°C/75%RH (open) conditions. months, placed at 25°C/60%RH (exposure) for 3 months. XRPD testing was performed on all stability samples to detect changes in crystal form.
  • the complement system alternative pathway kit is used to determine the inhibitory activity of the test compound against the complement alternative pathway in human serum.
  • the TR-FRET method was used to determine the binding activity of the test compound against human complement Factor B protein.
  • the binding activity of the test compounds to human complement Factor B protein is shown in Table 18.
  • hydrochloride salt of the compound of formula (II) in Example 1 has significant binding activity to human complement Factor B protein.
  • the compound of the present invention was prepared into a suspension with an aqueous solution of 0.5% MC (4000cP)/0.5% Tween 80. Rats were fasted overnight and then administered orally by gavage. The dosages were: 10mpk, 30mpk and 50mpk. Collect blood before and 0.25, 0.5, 1, 2, 4, 7, and 24 hours after administration, place it in a heparinized anticoagulant test tube, centrifuge at 7000 rpm (5204g), 4°C, separate plasma, and store at -80°C save. Eat 4 hours after dosing. The LC/MS/MS method was used to determine the content of the test compound in rat plasma after oral administration. Plasma samples were analyzed after pretreatment with precipitated proteins. Conclusion: Both the compounds and crystals of the present invention have good oral exposure, long half-life, and excellent pharmacokinetic properties.

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Abstract

Disclosed in the present invention are a crystal of a bridged heterocycle substituted benzoic acid derivative or a salt thereof, and a preparation method therefor. Specifically disclosed are a crystal of a compound of formula (II), a hydrochloride of a compound of formula (II) and a crystal thereof, and a preparation method therefor.

Description

一种桥杂环取代的苯酸衍生物或其盐的结晶及其制备方法Crystallization of a bridged heterocyclic substituted benzoic acid derivative or its salt and preparation method thereof
相关申请的交叉引用Cross-references to related applications
本申请要求于2022年07月20日向中国国家知识产权局提交的第202210861774.8号中国发明专利申请的优先权和权益，所述申请公开的全部内容通过引用整体并入本文中。This application claims the priority and rights of the Chinese invention patent application No. 202210861774.8 submitted to the State Intellectual Property Office of China on July 20, 2022. The entire disclosure of the application is incorporated herein by reference.
技术领域Technical field
本发明属于医药技术领域，涉及一种桥杂环取代的苯酸衍生物或其盐的结晶及其制备方法，具体涉及式(II)化合物的结晶、式(II)化合物盐酸盐及其结晶、及其制备方法。The invention belongs to the field of medical technology and relates to the crystallization of a bridged heterocyclic substituted benzoic acid derivative or its salt and its preparation method, specifically to the crystallization of the compound of formula (II), the hydrochloride of the compound of formula (II) and its crystallization , and preparation method thereof.
背景技术Background technique
补体系统是人体抵抗外源病原体、细菌和寄生虫等感染的重要的先天免疫组成，同时补体系统也是先天免疫与适应性免疫衔接的重要组成。补体由血浆蛋白组成，包括可溶性蛋白、膜结合性蛋白和补体受体，主要由肝脏或细胞表面表达的膜蛋白产生，在血浆，组织或细胞内发挥作用。补体系统主要通过三条通路激活：经典通路(classical pathway，CP)、凝集素通路(lectin pathway，LP)以及旁路通路(alternative pathway，AP)。The complement system is an important component of the body's innate immunity against infections such as foreign pathogens, bacteria, and parasites. The complement system is also an important component of the connection between innate immunity and adaptive immunity. Complement consists of plasma proteins, including soluble proteins, membrane-bound proteins and complement receptors. It is mainly produced by membrane proteins expressed in the liver or cell surface and plays a role in plasma, tissues or cells. The complement system is mainly activated through three pathways: the classical pathway (CP), the lectin pathway (LP), and the alternative pathway (AP).
健康个体的正常生理状态下，AP通路一直保持低水平的活化状态以随时监测外来病原体入侵状态。补体蛋白分布在凋亡细胞表面，补体激活受到严格的调节，仅仅用于清除凋亡的细胞，而不会进一步激活其他先天免疫或适应性免疫反应。在外来病原体感染的情况下，补体系统被全面激活，产生炎性反应，调理作用或吞噬作用等，破坏病原体并最终激活适应性免疫反应。补体的低效和过度刺激都可能对人体有害，并且与感染或非传染性疾病的易感性增加有关，比如自身免疫疾病，慢性炎症，血栓性微血管病，移植排斥和肿瘤等。Under normal physiological conditions of healthy individuals, the AP pathway always maintains a low-level activation state to monitor the invasion status of foreign pathogens at any time. Complement proteins are distributed on the surface of apoptotic cells, and complement activation is strictly regulated and is only used to clear apoptotic cells without further activating other innate or adaptive immune responses. In the case of infection by foreign pathogens, the complement system is fully activated, producing inflammatory responses, opsonization or phagocytosis, etc., destroying the pathogens and ultimately activating the adaptive immune response. Both complement inefficiency and overstimulation can be harmful and are associated with increased susceptibility to infections or non-communicable diseases, such as autoimmune diseases, chronic inflammation, thrombotic microangiopathies, transplant rejection and tumors.
补体因子B(Factor B)作用于AP通路，抑制Factor B活性能够阻止API通路激活，且不干扰CP和LP通路，能够避免因补体系统抑制增加感染风险。目前尚无小分子Factor B抑制剂上市，Novartis的factor B抑制剂LNP023处于临床III期研究阶段，用于PNH、IgAN、C3G等疾病的治疗。因此，有必要开发新型补体系统Factor B小分子抑制剂，增加临床研究和验证并用于补体异常导致的各种疾病的治疗，为未满足临床需求提供新的治疗手段。Complement factor B (Factor B) acts on the AP pathway. Inhibiting Factor B activity can prevent the activation of the API pathway without interfering with the CP and LP pathways, and can avoid increasing the risk of infection due to complement system inhibition. There are currently no small molecule Factor B inhibitors on the market. Novartis' factor B inhibitor LNP023 is in the clinical phase III research stage and is used for the treatment of PNH, IgAN, C3G and other diseases. Therefore, it is necessary to develop new small molecule inhibitors of the complement system Factor B, increase clinical research and verification, and use them in the treatment of various diseases caused by complement abnormalities to provide new treatment methods for unmet clinical needs.
发明内容Contents of the invention
一方面，本发明提供了式(II)化合物的结晶，
In one aspect, the invention provides crystallization of a compound of formula (II),
本发明所述式(II)化合物结晶可以是非溶剂合物的形式，也可以是溶剂合物的形式，例如水合物。The crystallization of the compound of formula (II) according to the present invention may be in the form of a non-solvate or a solvate, such as a hydrate.
本发明的一个实施方案中，式(II)化合物的结晶为A晶型，所述A晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.15±0.20°，9.28±0.20°和14.31±0.20°。In one embodiment of the present invention, the crystal of the compound of formula (II) is crystal form A, and the X-ray powder diffraction pattern of Cu Kα radiation of the crystal form A has a characteristic diffraction peak at the following 2θ angle: 7.15±0.20°, 9.28±0.20° and 14.31±0.20°.
本发明的一个实施方案中，上述A晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有至少3个或4个特征衍射峰：7.15±0.20°，9.28±0.20°，14.31±0.20°，19.52±0.20°和21.77±0.20°。 In one embodiment of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned A crystal form has at least 3 or 4 characteristic diffraction peaks at the following 2θ angles: 7.15±0.20°, 9.28±0.20°, 14.31± 0.20°, 19.52±0.20° and 21.77±0.20°.
本发明的一个实施方案中，上述A晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.15±0.20°，9.28±0.20°，14.31±0.20°，19.52±0.20°和21.77±0.20°。In one embodiment of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2θ angles: 7.15±0.20°, 9.28±0.20°, 14.31±0.20°, 19.52±0.20 ° and 21.77±0.20°.
本发明的一个实施方案中，上述A晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.15°，9.28°，14.31°，19.52°和21.77°。In one embodiment of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2θ angles: 7.15°, 9.28°, 14.31°, 19.52° and 21.77°.
本发明的一些实施方案中，上述A晶型的Cu Kα辐射的XRPD图谱如图1所示。In some embodiments of the present invention, the XRPD pattern of Cu Kα radiation of the above-mentioned crystal form A is shown in Figure 1.
本发明的一些实施方案中，上述A晶型的Cu Kα辐射的XRPD图谱中，衍射峰的峰位置及相对强度如表1-1所示：In some embodiments of the present invention, in the XRPD pattern of Cu Kα radiation of the above-mentioned crystal form A, the peak position and relative intensity of the diffraction peak are as shown in Table 1-1:
表1-1式(II)化合物A晶型的XRPD衍射数据
Table 1-1 XRPD diffraction data of compound A of formula (II)
本发明的一些实施方案中，上述A晶型的Cu Kα辐射的XRPD图谱中，衍射峰的峰位置及相对强度如表1所示：In some embodiments of the present invention, in the XRPD pattern of Cu Kα radiation of the above-mentioned crystal form A, the peak position and relative intensity of the diffraction peak are as shown in Table 1:
表1式(II)化合物A晶型的XRPD衍射数据
Table 1 XRPD diffraction data of crystal form A of compound (II)
另一方面，本发明还提供了式(II)化合物的盐酸盐，
On the other hand, the present invention also provides the hydrochloride salt of the compound of formula (II),
另一方面，本发明提供了式(II)化合物盐酸盐的结晶。In another aspect, the invention provides crystallization of the hydrochloride salt of the compound of formula (II).
本发明所述式(II)化合物盐酸盐的结晶可以是非溶剂合物的形式，也可以是溶剂合物的形式，例如水合物。The crystallization of the hydrochloride of the compound of formula (II) according to the present invention may be in the form of a non-solvate or in the form of a solvate, such as a hydrate.
另一方面，本发明提供了式(II-1)化合物，
In another aspect, the invention provides compounds of formula (II-1),
其中，in,
m选自0～2.5；m is selected from 0 to 2.5;
n选自0～2.5。n is selected from 0 to 2.5.
本发明的一些实施方案中，上述m选自0，0.5，0.6，0.7，0.8，0.9，1.0，1.1，1.2、1.3或2.0。In some embodiments of the present invention, the above m is selected from 0, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3 or 2.0.
本发明的一些实施方案中，上述m选自1.0或2.0。In some embodiments of the present invention, the above m is selected from 1.0 or 2.0.
本发明的一些实施方案中，上述m选自1.0。In some embodiments of the present invention, the above m is selected from 1.0.
本发明的一些实施方案中，上述n选自0，0.1，0.2，0.3，0.4，0.5，0.6，0.7，0.8，0.9，1.0，1.1，1.2，1.3，1.4，1.5，1.6，1.7，1.8，1.9，2.0，2.1，2.2，2.3，2.4或2.5。In some embodiments of the present invention, the above n is selected from 0, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4 or 2.5.
本发明的一些实施方案中，上述n选自0，1.0或2.0。In some embodiments of the present invention, the above n is selected from 0, 1.0 or 2.0.
本发明的一些实施方案中，上述n选自0。In some embodiments of the present invention, the above n is selected from 0.
本发明的一些实施方案中，上述式(II-1)化合物选自式(I)化合物，
In some embodiments of the present invention, the above-mentioned compound of formula (II-1) is selected from the group consisting of compounds of formula (I),
另一方面，本发明还提供了式(I)化合物的结晶，
On the other hand, the present invention also provides crystallization of the compound of formula (I),
本发明所述式(I)化合物的结晶可以是非溶剂合物的形式，也可以是溶剂合物的形式，例如水合物。 The crystallization of the compound of formula (I) according to the present invention may be in the form of a non-solvate or a solvate, such as a hydrate.
本发明的一个实施方案中，式(I)化合物的结晶为B晶型，所述B晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.16±0.20°，8.96±0.20°和10.53±0.20°。In one embodiment of the present invention, the crystal of the compound of formula (I) is crystal form B, and the X-ray powder diffraction pattern of Cu Kα radiation of the crystal form B has a characteristic diffraction peak at the following 2θ angle: 6.16±0.20°, 8.96±0.20° and 10.53±0.20°.
本发明的一个实施方案中，上述B晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.16±0.20°，8.96±0.20°，10.53±0.20°，18.55±0.20°和24.62±0.20°。In one embodiment of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2θ angles: 6.16±0.20°, 8.96±0.20°, 10.53±0.20°, 18.55±0.20 ° and 24.62±0.20°.
本发明的一个实施方案中，上述B晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有至少6个或7个特征衍射峰：6.16±0.20°，8.96±0.20°，10.53±0.20°，12.30±0.20°，16.74±0.20°，18.55±0.20°，19.95±0.20°和24.62±0.20°。In one embodiment of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned B crystal form has at least 6 or 7 characteristic diffraction peaks at the following 2θ angles: 6.16±0.20°, 8.96±0.20°, 10.53± 0.20°, 12.30±0.20°, 16.74±0.20°, 18.55±0.20°, 19.95±0.20° and 24.62±0.20°.
本发明的一个实施方案中，上述B晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.16±0.20°，8.96±0.20°，10.53±0.20°，12.30±0.20°，16.74±0.20°，18.55±0.20°，19.95±0.20°和24.62±0.20°。In one embodiment of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2θ angles: 6.16±0.20°, 8.96±0.20°, 10.53±0.20°, 12.30±0.20 °, 16.74±0.20°, 18.55±0.20°, 19.95±0.20° and 24.62±0.20°.
本发明的一个实施方案中，上述B晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有至少9个、10个或11个特征衍射峰：6.16±0.20°，8.96±0.20°，10.53±0.20°，12.30±0.20°，16.74±0.20°，17.39±0.20°，18.55±0.20°，19.49±0.20°，19.95±0.20°，22.17±0.20°，22.75±0.20°和24.62±0.20°。In one embodiment of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned B crystal form has at least 9, 10 or 11 characteristic diffraction peaks at the following 2θ angles: 6.16±0.20°, 8.96±0.20° , 10.53±0.20°, 12.30±0.20°, 16.74±0.20°, 17.39±0.20°, 18.55±0.20°, 19.49±0.20°, 19.95±0.20°, 22.17±0.20°, 22.75±0.20° and 24.62±0.20° .
本发明的一个实施方案中，上述B晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.16±0.20°，8.96±0.20°，10.53±0.20°，12.30±0.20°，16.74±0.20°，17.39±0.20°，18.55±0.20°，19.49±0.20°，19.95±0.20°，22.17±0.20°，22.75±0.20°和24.62±0.20°。In one embodiment of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2θ angles: 6.16±0.20°, 8.96±0.20°, 10.53±0.20°, 12.30±0.20 °, 16.74±0.20°, 17.39±0.20°, 18.55±0.20°, 19.49±0.20°, 19.95±0.20°, 22.17±0.20°, 22.75±0.20° and 24.62±0.20°.
本发明的一个实施方案中，上述B晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有至少11个、12个、13个、14个或15个特征衍射峰：6.16±0.20°，8.96±0.20°，10.53±0.20°，12.30±0.20°，13.19±0.20°，14.74±0.20°，16.74±0.20°，17.39±0.20°，17.90±0.20°，18.55±0.20°，19.49±0.20°，19.95±0.20°，21.55±0.20°，22.17±0.20°，22.75±0.20°和24.62±0.20°。In one embodiment of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned B crystal form has at least 11, 12, 13, 14 or 15 characteristic diffraction peaks at the following 2θ angle: 6.16±0.20 °, 8.96±0.20°, 10.53±0.20°, 12.30±0.20°, 13.19±0.20°, 14.74±0.20°, 16.74±0.20°, 17.39±0.20°, 17.90±0.20°, 18.55±0.20°, 19.49±0.20 °, 19.95±0.20°, 21.55±0.20°, 22.17±0.20°, 22.75±0.20° and 24.62±0.20°.
本发明的一个实施方案中，上述B晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.16±0.20°，8.96±0.20°，10.53±0.20°，12.30±0.20°，13.19±0.20°，14.74±0.20°，16.74±0.20°，17.39±0.20°，17.90±0.20°，18.55±0.20°，19.49±0.20°，19.95±0.20°，21.55±0.20°，22.17±0.20°，22.75±0.20°和24.62±0.20°。In one embodiment of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2θ angles: 6.16±0.20°, 8.96±0.20°, 10.53±0.20°, 12.30±0.20 °, 13.19±0.20°, 14.74±0.20°, 16.74±0.20°, 17.39±0.20°, 17.90±0.20°, 18.55±0.20°, 19.49±0.20°, 19.95±0.20°, 21.55±0.20°, 22.17±0.20 °, 22.75±0.20° and 24.62±0.20°.
本发明的一个实施方案中，上述B晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：3.16±0.20°，6.16±0.20°，8.96±0.20°，10.53±0.20°，12.30±0.20°，13.19±0.20°，14.74±0.20°，16.74±0.20°，17.39±0.20°，17.90±0.20°，18.55±0.20°，19.49±0.20°，19.95±0.20°，21.55±0.20°，22.17±0.20°，22.75±0.20°，24.62±0.20°，27.29±0.20°，28.05±0.20°，29.03±0.20°，32.55±0.20°和34.15±0.20°处有特征衍射峰。In one embodiment of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2θ angles: 3.16±0.20°, 6.16±0.20°, 8.96±0.20°, 10.53±0.20 °, 12.30±0.20°, 13.19±0.20°, 14.74±0.20°, 16.74±0.20°, 17.39±0.20°, 17.90±0.20°, 18.55±0.20°, 19.49±0.20°, 19.95±0.20°, 21.55±0.20 There are characteristic diffraction peaks at 22.17±0.20°, 22.75±0.20°, 24.62±0.20°, 27.29±0.20°, 28.05±0.20°, 29.03±0.20°, 32.55±0.20° and 34.15±0.20°.
本发明的一个实施方案中，上述B晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.16±0.20°，8.96±0.20°，10.53±0.20°，和/或3.16±0.20°，和/或10.79±0.20°，和/或12.30±0.20°，和/或13.19±0.20°，和/或14.74±0.20°，和/或16.74±0.20°，和/或17.39±0.20°，和/或17.90±0.20°，和/或18.55±0.20°，和/或19.49±0.20°，和/或19.95±0.20°，和/或21.55±0.20°，和/或22.17±0.20°，和/或22.75±0.20°，和/或24.62±0.20°，和/或27.29±0.20°，和/或28.05±0.20°，和/或29.03±0.20°，和/或32.55±0.20°，和/或34.15±0.20°处有特征衍射峰。In one embodiment of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2θ angles: 6.16±0.20°, 8.96±0.20°, 10.53±0.20°, and/or 3.16±0.20°, and/or 10.79±0.20°, and/or 12.30±0.20°, and/or 13.19±0.20°, and/or 14.74±0.20°, and/or 16.74±0.20°, and/or 17.39± 0.20°, and/or 17.90±0.20°, and/or 18.55±0.20°, and/or 19.49±0.20°, and/or 19.95±0.20°, and/or 21.55±0.20°, and/or 22.17±0.20° , and/or 22.75±0.20°, and/or 24.62±0.20°, and/or 27.29±0.20°, and/or 28.05±0.20°, and/or 29.03±0.20°, and/or 32.55±0.20°, and / Or there is a characteristic diffraction peak at 34.15±0.20°.
本发明的一个实施方案中，上述B晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：3.16°，6.16°，8.96°，10.53°，10.79°，12.30°，13.19°，14.74°，16.74°，17.39°，17.90°，18.55°，19.49°，19.95°，21.55°，22.17°，22.75°，24.62°，27.29°，28.05°，29.03°，32.55°和34.15°。In one embodiment of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2θ angles: 3.16°, 6.16°, 8.96°, 10.53°, 10.79°, 12.30°, 13.19°, 14.74°, 16.74°, 17.39°, 17.90°, 18.55°, 19.49°, 19.95°, 21.55°, 22.17°, 22.75°, 24.62°, 27.29°, 28.05°, 29.03°, 32.55° and 34.15° .
本发明的一个实施方案中，上述B晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.16°，8.96°，10.53°，10.79°，12.30°，13.19°，14.74°，16.74°，17.39°，17.90°，18.55°，19.49°，19.95°，21.55°，22.17°，22.75°，24.62°，27.29°，28.05°和29.03°。In one embodiment of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2θ angles: 6.16°, 8.96°, 10.53°, 10.79°, 12.30°, 13.19°, 14.74°, 16.74°, 17.39°, 17.90°, 18.55°, 19.49°, 19.95°, 21.55°, 22.17°, 22.75°, 24.62°, 27.29°, 28.05° and 29.03°.
本发明的一个实施方案中，上述B晶型的Cu Kα辐射的XRPD图谱如图2所示。In one embodiment of the present invention, the XRPD pattern of Cu Kα radiation of the above-mentioned B crystal form is shown in Figure 2.
本发明的一个实施方案中，上述B晶型的Cu Kα辐射的XRPD图谱中，衍射峰的峰位置及相对强度由表2-1所示： In one embodiment of the present invention, in the XRPD pattern of Cu Kα radiation of the above-mentioned B crystal form, the peak position and relative intensity of the diffraction peak are shown in Table 2-1:
表2-1式(I)化合物B晶型的XRPD衍射数据
Table 2-1 XRPD diffraction data of compound B crystal form of formula (I)
本发明的一个实施方案中，上述B晶型的Cu Kα辐射的XRPD图谱中，衍射峰的峰位置及相对强度由表2所示：In one embodiment of the present invention, in the XRPD pattern of Cu Kα radiation of the above-mentioned B crystal form, the peak position and relative intensity of the diffraction peak are shown in Table 2:
表2式(I)化合物B晶型的XRPD衍射数据

Table 2 XRPD diffraction data of compound B crystal form of formula (I)

本发明的一个实施方案中，上述B晶型的差示扫描量热(DSC)曲线显示在221.2℃±3℃处具有放热峰的峰值。In one embodiment of the present invention, the differential scanning calorimetry (DSC) curve of the above-mentioned Form B shows an exothermic peak at 221.2°C ± 3°C.
本发明的一个实施方案中，上述B晶型的DSC图谱如图3所示。In one embodiment of the present invention, the DSC spectrum of the above crystal form B is shown in Figure 3.
本发明的一个实施方案中，上述B晶型的热重分析(TGA)曲线在150℃±3℃时失重3.85％。In one embodiment of the present invention, the thermogravimetric analysis (TGA) curve of the above-mentioned B crystal form has a weight loss of 3.85% at 150°C ± 3°C.
本发明的一个实施方案中，上述B晶型的TGA图谱如图4所示。In one embodiment of the present invention, the TGA spectrum of the above crystal form B is shown in Figure 4.
另一方面，本发明还提供了式(I)化合物B晶型的制备方法，包括将式(II)化合物盐酸盐在溶剂S1、S2和S3中混合，后分离固体。On the other hand, the present invention also provides a method for preparing the crystal form B of the compound of formula (I), which includes mixing the hydrochloride of the compound of formula (II) in solvents S1, S2 and S3, and then separating the solid.
本发明的一个实施方案中，所述式(II)化合物盐酸盐为无定型。本发明的一个实施方案中，所述式(II)化合物盐酸盐为式(I)化合物。In one embodiment of the present invention, the hydrochloride salt of the compound of formula (II) is amorphous. In one embodiment of the present invention, the hydrochloride salt of the compound of formula (II) is a compound of formula (I).
本发明的一个实施方案中，所述(I)化合物B晶型的制备方法，包括将式(II)化合物盐酸盐先在溶剂S1和S2中混合，后加入溶剂S3。In one embodiment of the present invention, the method for preparing the crystal form of compound (I) B includes first mixing the hydrochloride of the compound of formula (II) in solvents S1 and S2, and then adding solvent S3.
另一方面，本发明还提供了式(I)化合物B晶型的制备方法，
On the other hand, the present invention also provides a method for preparing the crystal form B of the compound of formula (I),
其中，所述B晶型的制备方法包括如下步骤：Wherein, the preparation method of the B crystal form includes the following steps:
(a)15℃～70℃下将式(II)化合物盐酸盐无定型加入溶剂S1和溶剂S2中；(a) Add the amorphous hydrochloride salt of the compound of formula (II) to solvent S1 and solvent S2 at 15°C to 70°C;
(b)搅拌0.05～2小时；(b) Stir for 0.05 to 2 hours;
(c)15℃～35℃下再加入溶剂S3；(c) Add solvent S3 at 15°C to 35°C;
(d)搅拌1～16小时，析出固体；(d) Stir for 1 to 16 hours to precipitate solid;
(e)过滤，滤饼真空干燥。(e) Filter and vacuum dry the filter cake.
本发明的一个实施方案中，所述溶剂S1选自乙腈或丙酮中的一种或两种混合物溶剂。In one embodiment of the present invention, the solvent S1 is selected from one or two mixture solvents of acetonitrile or acetone.
本发明的一个实施方案中，所述溶剂S2选自水。 In one embodiment of the present invention, the solvent S2 is selected from water.
本发明的一个实施方案中，所述溶剂S3选自丙酮和乙酸乙酯的混合溶剂、乙腈或1,4-二氧六环。In one embodiment of the present invention, the solvent S3 is selected from a mixed solvent of acetone and ethyl acetate, acetonitrile or 1,4-dioxane.
本发明的一个实施方案中，所述溶剂S1和溶剂S2的体积比为5:1～1:5。In one embodiment of the present invention, the volume ratio of solvent S1 to solvent S2 is 5:1 to 1:5.
另一方面，本发明还提供了式(I)化合物B晶型的制备方法，
On the other hand, the present invention also provides a method for preparing the crystal form B of the compound of formula (I),
其中，所述B晶型的制备方法包括如下步骤：Wherein, the preparation method of the B crystal form includes the following steps:
(a)15℃～70℃下将式(II)化合物盐酸盐无定型加入溶剂S1和溶剂S2中；(a) Add the amorphous hydrochloride salt of the compound of formula (II) to solvent S1 and solvent S2 at 15°C to 70°C;
(b)搅拌0.05～2小时；(b) Stir for 0.05 to 2 hours;
(c)15℃～35℃下再加入溶剂S3；(c) Add solvent S3 at 15°C to 35°C;
(d)搅拌1～16小时，析出固体；(d) Stir for 1 to 16 hours to precipitate solid;
(e)过滤，滤饼真空干燥；(e) Filtration and vacuum drying of the filter cake;
其中，in,
溶剂S1选自乙腈或丙酮中的一种或两种混合物溶剂；Solvent S1 is selected from one or two mixtures of acetonitrile or acetone;
溶剂S2选自水；Solvent S2 is selected from water;
溶剂S3选自丙酮和乙酸乙酯的混合溶剂、乙腈或1,4-二氧六环；Solvent S3 is selected from a mixed solvent of acetone and ethyl acetate, acetonitrile or 1,4-dioxane;
溶剂S1和溶剂S2的体积比为5:1～1:5。The volume ratio of solvent S1 to solvent S2 is 5:1 to 1:5.
本发明的一些实施方案中，上述溶剂S1和溶剂S2的体积比为5:1～1:1；优选的，溶剂S1和溶剂S2的体积比为5:1、4:1、3:1、2:1或1:1；进一步优选的，溶剂S1和溶剂S2的体积比为5:1。In some embodiments of the present invention, the volume ratio of the above solvent S1 to solvent S2 is 5:1 to 1:1; preferably, the volume ratio of solvent S1 to solvent S2 is 5:1, 4:1, 3:1, 2:1 or 1:1; further preferably, the volume ratio of solvent S1 and solvent S2 is 5:1.
本发明的一些实施方案中，上述溶剂S1选自丙酮，溶剂S2选自水，所述丙酮和水的体积比为5:1、4:1、3:1、2:1或1:1；优选的，丙酮和水的体积比为5:1。In some embodiments of the present invention, the above-mentioned solvent S1 is selected from acetone, and the solvent S2 is selected from water, and the volume ratio of acetone and water is 5:1, 4:1, 3:1, 2:1 or 1:1; Preferably, the volume ratio of acetone and water is 5:1.
在本发明的一些实施方案中，上述溶剂S3选自丙酮和乙酸乙酯的混合溶剂，所述丙酮和乙酸乙酯的体积比为1:1～1:3；优选的，丙酮和乙酸乙酯的体积比为1:1、1:1.5、1:2或1:3；进一步优选的，丙酮和乙酸乙酯的体积比为1:1.5。In some embodiments of the present invention, the above-mentioned solvent S3 is selected from a mixed solvent of acetone and ethyl acetate, and the volume ratio of acetone and ethyl acetate is 1:1 to 1:3; preferably, acetone and ethyl acetate The volume ratio of acetone and ethyl acetate is 1:1, 1:1.5, 1:2 or 1:3; further preferably, the volume ratio of acetone and ethyl acetate is 1:1.5.
在本发明的一些实施方案中，上述溶剂S1选自丙酮，溶剂S2选自水，溶剂S3选自丙酮和乙酸乙酯的混合溶剂；所述丙酮：水：丙酮和乙酸乙酯的混合溶剂的体积比分别为1～5：1：5～15；优选的丙酮：水：丙酮和乙酸乙酯的混合溶剂的体积比分别为5：1：5、5：1：10、5：1：15、1：1：15、2：1：15、3：1：15、4：1：15、1：1：5、2：1：5、3：1：5、4：1：5、1：1：10、2：1：10、3：1：10或4：1：10；进一步优选的，丙酮和乙酸乙酯的混合溶剂的体积比分别为5：1：5、5：1：10或5：1：15；更进一步优选的丙酮和乙酸乙酯的混合溶剂的体积比分别为5：1：15。In some embodiments of the present invention, the above-mentioned solvent S1 is selected from acetone, solvent S2 is selected from water, and solvent S3 is selected from a mixed solvent of acetone and ethyl acetate; the acetone: water: a mixed solvent of acetone and ethyl acetate. The volume ratios are 1 to 5:1:5 to 15 respectively; the preferred volume ratios of the mixed solvents of acetone:water:acetone and ethyl acetate are 5:1:5, 5:1:10, and 5:1:15 respectively. , 1:1:15, 2:1:15, 3:1:15, 4:1:15, 1:1:5, 2:1:5, 3:1:5, 4:1:5, 1 : 1:10, 2:1:10, 3:1:10 or 4:1:10; further preferably, the volume ratio of the mixed solvent of acetone and ethyl acetate is 5:1:5, 5:1: 10 or 5:1:15; the further preferred volume ratio of the mixed solvent of acetone and ethyl acetate is 5:1:15 respectively.
在本发明的一些实施方案中，上述式(II)化合物的盐酸盐与溶剂S1的质量体积比为100mg：0.5～1mL；优选的，式(II)化合物的盐酸盐与溶剂S1的质量体积比为100mg：0.5mL、100mg：0.6mL、100mg：0.7mL、100mg：0.8mL、100mg：0.9mL或100mg：1mL；进一步优选的，式(II)化合物的盐酸盐与溶剂S1的质量体积比为100mg：0.6mL。In some embodiments of the present invention, the mass volume ratio of the hydrochloride of the compound of formula (II) to the solvent S1 is 100 mg: 0.5 ~ 1 mL; preferably, the mass volume ratio of the hydrochloride of the compound of formula (II) to the solvent S1 The volume ratio is 100mg:0.5mL, 100mg:0.6mL, 100mg:0.7mL, 100mg:0.8mL, 100mg:0.9mL or 100mg:1mL; further preferably, the mass of the hydrochloride of the compound of formula (II) and the solvent S1 The volume ratio is 100mg:0.6mL.
在本发明的一些实施方案中，步骤(b)的搅拌温度为15℃～35℃；搅拌时间为5分钟～1小时；优选的，步骤(b)的搅拌温度为15℃～25℃；搅拌时间为5～10分钟；进一步优选的，步骤(b)的搅拌温度为 15℃～25℃；搅拌时间为5分钟。In some embodiments of the present invention, the stirring temperature of step (b) is 15°C to 35°C; the stirring time is 5 minutes to 1 hour; preferably, the stirring temperature of step (b) is 15°C to 25°C; stirring The time is 5 to 10 minutes; further preferably, the stirring temperature of step (b) is 15℃～25℃; stirring time is 5 minutes.
在本发明的一些实施方案中，步骤(d)的搅拌温度为15℃～35℃；搅拌时间为5～15小时；优选的，步骤(d)的搅拌温度为15℃～25℃；搅拌时间为12小时。In some embodiments of the present invention, the stirring temperature of step (d) is 15°C to 35°C; the stirring time is 5 to 15 hours; preferably, the stirring temperature of step (d) is 15°C to 25°C; the stirring time for 12 hours.
本发明的一个实施方案中，式(I)化合物的结晶为C晶型，所述C晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.72±0.20°，15.31±0.20°和19.53±0.20°。In one embodiment of the present invention, the crystal of the compound of formula (I) is C crystal form, and the X-ray powder diffraction pattern of Cu Kα radiation of the C crystal form has a characteristic diffraction peak at the following 2θ angle: 7.72±0.20°, 15.31±0.20° and 19.53±0.20°.
本发明的一个实施方案中，上述C晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有至少6个或7个特征衍射峰：7.72±0.20°，14.67±0.20°，15.31±0.20°，16.66±0.20°，18.76±0.20°，19.53±0.20°，22.67±0.20°和24.28±0.20°。In one embodiment of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned C crystal form has at least 6 or 7 characteristic diffraction peaks at the following 2θ angles: 7.72±0.20°, 14.67±0.20°, 15.31± 0.20°, 16.66±0.20°, 18.76±0.20°, 19.53±0.20°, 22.67±0.20° and 24.28±0.20°.
本发明的一个实施方案中，上述C晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.72±0.20°，14.67±0.20°，15.31±0.20°，16.66±0.20°，18.76±0.20°，19.53±0.20°，22.67±0.20°和24.28±0.20°。In one embodiment of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2θ angles: 7.72±0.20°, 14.67±0.20°, 15.31±0.20°, 16.66±0.20 °, 18.76±0.20°, 19.53±0.20°, 22.67±0.20° and 24.28±0.20°.
本发明的一个实施方案中，上述C晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有至少9个、10个或11个特征衍射峰：7.72±0.20°，10.75±0.20°，13.80±0.20°，14.67±0.20°，15.31±0.20°，16.66±0.20°，18.76±0.20°，19.53±0.20°，22.67±0.20°，24.28±0.20°，25.95±0.20°和26.65±0.20°。In one embodiment of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned C crystal form has at least 9, 10 or 11 characteristic diffraction peaks at the following 2θ angles: 7.72±0.20°, 10.75±0.20° , 13.80±0.20°, 14.67±0.20°, 15.31±0.20°, 16.66±0.20°, 18.76±0.20°, 19.53±0.20°, 22.67±0.20°, 24.28±0.20°, 25.95±0.20° and 26.65±0.20° .
本发明的一个实施方案中，上述C晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.72±0.20°，10.75±0.20°，13.80±0.20°，14.67±0.20°，15.31±0.20°，16.66±0.20°，18.76±0.20°，19.53±0.20°，22.67±0.20°，24.28±0.20°，25.95±0.20°和26.65±0.20°。In one embodiment of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2θ angles: 7.72±0.20°, 10.75±0.20°, 13.80±0.20°, 14.67±0.20 °, 15.31±0.20°, 16.66±0.20°, 18.76±0.20°, 19.53±0.20°, 22.67±0.20°, 24.28±0.20°, 25.95±0.20° and 26.65±0.20°.
本发明的一个实施方案中，上述C晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.72±0.20°，15.31±0.20°，19.53±0.20°，和/或10.75±0.20°，和/或13.80±0.20°，和/或14.67±0.20°，和/或16.66±0.20°，和/或18.76±0.20°，和/或22.67±0.20°，和/或24.28±0.20°，和/或25.95±0.20°，和/或26.65±0.20°处有特征衍射峰。In one embodiment of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2θ angles: 7.72±0.20°, 15.31±0.20°, 19.53±0.20°, and/or 10.75±0.20°, and/or 13.80±0.20°, and/or 14.67±0.20°, and/or 16.66±0.20°, and/or 18.76±0.20°, and/or 22.67±0.20°, and/or 24.28± There are characteristic diffraction peaks at 0.20°, and/or 25.95±0.20°, and/or 26.65±0.20°.
本发明的一个实施方案中，上述C晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.72°，10.75°，13.80°，14.67°，15.31°，16.66°，18.76°，19.53°，22.67°，24.28°，25.95°和26.65°。In one embodiment of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2θ angles: 7.72°, 10.75°, 13.80°, 14.67°, 15.31°, 16.66°, 18.76°, 19.53°, 22.67°, 24.28°, 25.95° and 26.65°.
本发明的一些方案中，上述C晶型的Cu Kα辐射的X-射线粉末衍射图谱如图5所示。In some aspects of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned C crystal form is shown in Figure 5.
本发明的一些方案中，上述C晶型的Cu Kα辐射的XRPD图谱中，衍射峰的峰位置及相对强度由表3-1所示：In some solutions of the present invention, in the XRPD pattern of Cu Kα radiation of the above-mentioned C crystal form, the peak position and relative intensity of the diffraction peak are shown in Table 3-1:
表3-1式(I)化合物C晶型的XRPD衍射数据

Table 3-1 XRPD diffraction data of compound C crystal form of formula (I)

本发明的一些方案中，上述C晶型的Cu Kα辐射的XRPD图谱中，衍射峰的峰位置及相对强度由表3所示：In some solutions of the present invention, in the XRPD pattern of Cu Kα radiation of the above-mentioned C crystal form, the peak position and relative intensity of the diffraction peak are shown in Table 3:
表3式(I)化合物C晶型的XRPD衍射数据
Table 3 XRPD diffraction data of compound C crystal form of formula (I)
本发明的一些方案中，上述C晶型的差示扫描量热(DSC)曲线显示在227.5℃±3℃处具有放热峰的峰值。In some aspects of the present invention, the differential scanning calorimetry (DSC) curve of the above-mentioned C crystal form shows an exothermic peak at 227.5°C ± 3°C.
本发明的一些方案中，上述C晶型的DSC图谱如图6所示。In some aspects of the present invention, the DSC spectrum of the above crystal form C is shown in Figure 6.
本发明的一些方案中，上述C晶型的热重分析(TGA)曲线在150.0℃±3℃时失重2.88％。In some aspects of the present invention, the thermogravimetric analysis (TGA) curve of the above-mentioned C crystal form loses 2.88% weight at 150.0°C ± 3°C.
本发明的一些方案中，上述C晶型的TGA图谱如图7所示。In some aspects of the present invention, the TGA spectrum of the above crystal form C is shown in Figure 7.
本发明的一个实施方案中，式(I)化合物的结晶为D晶型，所述D晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.93±0.20°和11.82±0.20°。In one embodiment of the present invention, the crystal of the compound of formula (I) is the D crystal form, and the X-ray powder diffraction pattern of the Cu Kα radiation of the D crystal form has characteristic diffraction peaks at the following 2θ angles: 5.93±0.20° and 11.82±0.20°.
本发明的一个实施方案中，上述D晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.93°和11.82°。In one embodiment of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned D crystal form has characteristic diffraction peaks at the following 2θ angles: 5.93° and 11.82°.
本发明的一些方案中，上述D晶型的XRPD图谱如图8所示。In some aspects of the present invention, the XRPD pattern of the above-mentioned D crystal form is shown in Figure 8.
本发明的一些方案中，上述D晶型的Cu Kα辐射的XRPD图谱中，衍射峰的峰位置及相对强度由表4-1所示：In some solutions of the present invention, in the XRPD pattern of Cu Kα radiation of the above-mentioned D crystal form, the peak position and relative intensity of the diffraction peak are shown in Table 4-1:
表4-1式(I)化合物的D晶型的XRPD衍射数据
Table 4-1 XRPD diffraction data of the D crystal form of the compound of formula (I)
本发明的一些方案中，上述D晶型的Cu Kα辐射的XRPD图谱中，衍射峰的峰位置及相对强度由表4所示：In some solutions of the present invention, in the XRPD pattern of Cu Kα radiation of the above-mentioned D crystal form, the peak position and relative intensity of the diffraction peak are shown in Table 4:
表4式(I)化合物的D晶型的XRPD衍射数据
Table 4 XRPD diffraction data of the D crystal form of the compound of formula (I)
本发明的一个实施方案中，式(I)化合物的结晶为E晶型，所述E晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有至少3个特征衍射峰：5.98±0.20°，7.83±0.20°，8.87±0.20°和10.76±0.20°。In one embodiment of the present invention, the crystal of the compound of formula (I) is the E crystal form, and the X-ray powder diffraction pattern of the Cu Kα radiation of the E crystal form has at least 3 characteristic diffraction peaks at the following 2θ angle: 5.98± 0.20°, 7.83±0.20°, 8.87±0.20° and 10.76±0.20°.
本发明的一个实施方案中，所述式(I)化合物的E晶型为水合物形式。In one embodiment of the present invention, the E crystalline form of the compound of formula (I) is in the form of a hydrate.
本发明的一个实施方案中，式(I)化合物的结晶为水合物形式，所述水合物为E晶型，所述E晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.98±0.20°，7.83±0.20°，8.87±0.20°和10.76±0.20°。In one embodiment of the present invention, the crystal of the compound of formula (I) is in the form of a hydrate, the hydrate is the E crystal form, and the X-ray powder diffraction pattern of the Cu Kα radiation of the E crystal form has at the following 2θ angle Characteristic diffraction peaks: 5.98±0.20°, 7.83±0.20°, 8.87±0.20° and 10.76±0.20°.
本发明的一个实施方案中，上述E晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.98°，7.83°，8.87°和10.76°。In one embodiment of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned E crystal form has characteristic diffraction peaks at the following 2θ angles: 5.98°, 7.83°, 8.87° and 10.76°.
本发明的一个实施方案中，上述E晶型的X-射线粉末衍射图谱如图9所示。In one embodiment of the present invention, the X-ray powder diffraction pattern of the above-mentioned E crystal form is shown in Figure 9.
本发明的一个实施方案中，上述E晶型的Cu Kα辐射的XRPD图谱中，衍射峰的峰位置及相对强度由表5-1所示：In one embodiment of the present invention, in the XRPD pattern of Cu Kα radiation of the above-mentioned E crystal form, the peak position and relative intensity of the diffraction peak are shown in Table 5-1:
表5-1式(I)化合物的水合物的E晶型的XRPD衍射数据
Table 5-1 XRPD diffraction data of the E crystal form of the hydrate of the compound of formula (I)
本发明的一个实施方案中，上述E晶型的Cu Kα辐射的XRPD图谱中，衍射峰的峰位置及相对强度由表5所示：In one embodiment of the present invention, in the XRPD pattern of Cu Kα radiation of the above-mentioned E crystal form, the peak position and relative intensity of the diffraction peak are shown in Table 5:
表5式(I)化合物的水合物的E晶型的XRPD衍射数据
Table 5 XRPD diffraction data of the E crystal form of the hydrate of the compound of formula (I)
本发明的一个实施方案中，式(I)化合物的结晶为F晶型，所述F晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.96±0.20°、8.86±0.20°、17.40±0.20°、19.52±0.20°和24.04±0.20°。In one embodiment of the present invention, the crystal of the compound of formula (I) is the F crystal form, and the X-ray powder diffraction pattern of the Cu Kα radiation of the F crystal form has characteristic diffraction peaks at the following 2θ angles: 5.96±0.20°, 8.86±0.20°, 17.40±0.20°, 19.52±0.20° and 24.04±0.20°.
本发明的一个实施方案中，上述F晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有至少6个或7个特征衍射峰：5.96±0.20°、8.86±0.20°、10.82±0.20°、13.32±0.20°、17.40±0.20°、19.52±0.20°、24.04±0.20°和24.74±0.20°。In one embodiment of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned F crystal form has at least 6 or 7 characteristic diffraction peaks at the following 2θ angles: 5.96±0.20°, 8.86±0.20°, 10.82± 0.20°, 13.32±0.20°, 17.40±0.20°, 19.52±0.20°, 24.04±0.20° and 24.74±0.20°.
本发明的一个实施方案中，上述F晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.96±0.20°、8.86±0.20°、10.82±0.20°、13.32±0.20°、17.40±0.20°、19.52±0.20°、24.04±0.20°和24.74±0.20°。In one embodiment of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned F crystal form has characteristic diffraction peaks at the following 2θ angles: 5.96±0.20°, 8.86±0.20°, 10.82±0.20°, 13.32±0.20 °, 17.40±0.20°, 19.52±0.20°, 24.04±0.20° and 24.74±0.20°.
本发明的一个实施方案中，上述F晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.96±0.20°、8.86±0.20°、10.66±0.20°、10.82±0.20°、11.94±0.20°、13.32±0.20°、14.86±0.20°、17.40±0.20°、 17.96±0.20°、18.72±0.20°、19.52±0.20°、21.66±0.20°、24.04±0.20°、24.74±0.20°和26.56±0.20°。In one embodiment of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned F crystal form has characteristic diffraction peaks at the following 2θ angles: 5.96±0.20°, 8.86±0.20°, 10.66±0.20°, 10.82±0.20 °, 11.94±0.20°, 13.32±0.20°, 14.86±0.20°, 17.40±0.20°, 17.96±0.20°, 18.72±0.20°, 19.52±0.20°, 21.66±0.20°, 24.04±0.20°, 24.74±0.20° and 26.56±0.20°.
本发明的一个实施方案中，上述F晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.96±0.20°、8.86±0.20°、17.40±0.20°、19.52±0.20°、24.04±0.20°，和/或10.66±0.20°、和/或10.82±0.20°、和/或11.06±0.20°、和/或11.54±0.20°、和/或11.94±0.20°、和/或13.32±0.20°、和/或14.86±0.20°、和/或17.96±0.20°、和/或18.72±0.20°、和/或21.66±0.20°、和/或23.68±0.20°、和/或24.74±0.20°、和/或26.56±0.20°、和/或27.42±0.20°和/或30.78±0.20°。In one embodiment of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned F crystal form has characteristic diffraction peaks at the following 2θ angles: 5.96±0.20°, 8.86±0.20°, 17.40±0.20°, 19.52±0.20 °, 24.04±0.20°, and/or 10.66±0.20°, and/or 10.82±0.20°, and/or 11.06±0.20°, and/or 11.54±0.20°, and/or 11.94±0.20°, and/or 13.32±0.20°, and/or 14.86±0.20°, and/or 17.96±0.20°, and/or 18.72±0.20°, and/or 21.66±0.20°, and/or 23.68±0.20°, and/or 24.74± 0.20°, and/or 26.56±0.20°, and/or 27.42±0.20°, and/or 30.78±0.20°.
本发明的一个实施方案中，上述F晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.96°、8.86°、10.66°、10.82°、11.06°、11.54°、11.94°、13.32°、14.86°、17.40°、17.96°、18.72°、19.52°、21.66°、23.68°、24.04°、24.74°、26.56°、27.42°和30.78°。In one embodiment of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned F crystal form has characteristic diffraction peaks at the following 2θ angles: 5.96°, 8.86°, 10.66°, 10.82°, 11.06°, 11.54°, 11.94°, 13.32°, 14.86°, 17.40°, 17.96°, 18.72°, 19.52°, 21.66°, 23.68°, 24.04°, 24.74°, 26.56°, 27.42° and 30.78°.
本发明的一个实施方案中，上述F晶型的Cu Kα辐射的XRPD图谱如图11所示。In one embodiment of the present invention, the XRPD pattern of Cu Kα radiation of the above-mentioned F crystal form is shown in Figure 11.
本发明的一个实施方案中，上述F晶型的Cu Kα辐射的XRPD图谱中，衍射峰的峰位置及相对强度由表16-1所示：In one embodiment of the present invention, in the XRPD pattern of Cu Kα radiation of the above-mentioned F crystal form, the peak position and relative intensity of the diffraction peak are shown in Table 16-1:
表16-1式(I)化合物F晶型的XRPD模拟衍射数据
Table 16-1 XRPD simulated diffraction data of compound F crystal form of formula (I)
本发明的一个实施方案中，上述F晶型的Cu Kα辐射的XRPD图谱中，衍射峰的峰位置及相对强度由表16所示。In one embodiment of the present invention, in the XRPD pattern of Cu Kα radiation of the above-mentioned F crystal form, the peak position and relative intensity of the diffraction peak are shown in Table 16.
另一方面，本发明提供了一种包含式(II)化合物结晶的结晶组合物，其中所述式(II)化合物结晶占所述结晶组合物重量的50％以上，较好是75％以上，更好是90％以上，最好是95％以上。所述各结晶组合物中，还可能含有少量的式(II)化合物的其他结晶或非结晶形式。On the other hand, the present invention provides a crystalline composition comprising crystals of the compound of formula (II), wherein the crystals of the compound of formula (II) account for more than 50%, preferably more than 75%, by weight of the crystalline composition, More preferably, it is more than 90%, and even better, it is more than 95%. Each of the crystalline compositions may also contain small amounts of other crystalline or non-crystalline forms of the compound of formula (II).
另一方面，本发明提供了一种包含式(I)化合物结晶的结晶组合物，其中所述式(I)化合物结晶占所述结晶组合物重量的50％以上，较好是75％以上，更好是90％以上，最好是95％以上。所述各结晶组合物中，还可能含有少量的式(I)化合物的其他结晶或非结晶形式。On the other hand, the present invention provides a crystalline composition comprising crystals of the compound of formula (I), wherein the crystals of the compound of formula (I) account for more than 50%, preferably more than 75%, by weight of the crystalline composition, More preferably, it is more than 90%, and even better, it is more than 95%. Each of the crystalline compositions may also contain small amounts of other crystalline or non-crystalline forms of the compound of formula (I).
另一方面，本发明提供一种药物组合物，其包含治疗有效量的上述式(II)化合物或其结晶，或其结晶的结晶组合物；所述药物组合物可以包含至少一种药学上可接受的载体或其他赋形剂。此外，本申请的药物组合物可进一步包括一种或多种其它治疗剂。On the other hand, the present invention provides a pharmaceutical composition, which contains a therapeutically effective amount of the above-mentioned compound of formula (II) or its crystal, or a crystal composition of its crystal; the pharmaceutical composition may contain at least one pharmaceutically acceptable Acceptable carrier or other excipient. In addition, the pharmaceutical compositions of the present application may further include one or more other therapeutic agents.
另一方面，本发明提供一种药物组合物，其包含治疗有效量的上述式(I)化合物或其结晶，或其结晶的结晶组合物；所述药物组合物可以包含至少一种药学上可接受的载体或其他赋形剂。此外，本申请的药物组合物可进一步包括一种或多种其它治疗剂。On the other hand, the present invention provides a pharmaceutical composition, which contains a therapeutically effective amount of the above-mentioned compound of formula (I) or its crystal, or a crystal composition of its crystal; the pharmaceutical composition may contain at least one pharmaceutically acceptable Acceptable carrier or other excipient. In addition, the pharmaceutical compositions of the present application may further include one or more other therapeutic agents.
另一方面，本发明提供了上述式(II)化合物或其结晶、上述式(I)化合物或其结晶、上述结晶组合物、或上述药物组合物在制备治疗或预防与补体因子B相关疾病的药物中的应用。 On the other hand, the present invention provides the above-mentioned compound of formula (II) or its crystal, the above-mentioned formula (I) or its crystal, the above-mentioned crystal composition, or the above-mentioned pharmaceutical composition for the preparation of treatment or prevention of diseases related to complement factor B. Applications in medicine.
另一方面，本发明提供了上述式(II)化合物或其结晶、上述式(I)化合物或其结晶、上述结晶组合物、或上述药物组合物用于治疗或预防与补体因子B相关疾病的应用。On the other hand, the present invention provides the above-mentioned compound of formula (II) or its crystal, the above-mentioned compound of formula (I) or its crystal, the above-mentioned crystal composition, or the above-mentioned pharmaceutical composition for the treatment or prevention of diseases related to complement factor B. application.
另一方面，本发明提供了治疗或预防与补体因子B相关疾病的方法，其包括向有需要的哺乳动物给予治疗有效量的上述式(II)化合物或其结晶、上述式(I)化合物或其结晶、上述结晶组合物、或上述药物组合物。On the other hand, the present invention provides a method for treating or preventing diseases related to complement factor B, which includes administering to a mammal in need a therapeutically effective amount of the above-mentioned compound of formula (II) or its crystal, the above-mentioned compound of formula (I) or Its crystal, the above-mentioned crystal composition, or the above-mentioned pharmaceutical composition.
另一方面，本发明提供了用于治疗或预防与补体因子B相关疾病的上述式(II)化合物或其结晶、上述式(I)化合物或其结晶、上述结晶组合物、或上述药物组合物。On the other hand, the present invention provides the above-mentioned compound of formula (II) or crystal thereof, the above-mentioned compound of formula (I) or its crystal, the above-mentioned crystal composition, or the above-mentioned pharmaceutical composition for the treatment or prevention of diseases related to complement factor B. .
在本发明的一些实施方案中，所述哺乳动物为人类。In some embodiments of the invention, the mammal is a human.
本发明的一些实施方案中，所述补体因子B相关疾病选自炎性障碍和自身免疫性疾病。In some embodiments of the invention, the complement factor B-related disease is selected from the group consisting of inflammatory disorders and autoimmune diseases.
技术效果Technical effect
本发明化合物对人血清旁路通路激活抑制活性明显，且对人补体Factor B蛋白的结合活性也较显著。本发明化合物的晶型和盐型制备工艺简单，物理和化学性质稳定，引湿性良好，具有较好的药代动力学性质(例如AUC、Cmax、T1/2)，便于制剂，在预防和/或治疗补体因子B相关药物中的应用前景广阔。The compound of the present invention has obvious inhibitory activity on the activation of the human serum bypass pathway, and also has significant binding activity on human complement Factor B protein. The crystal form and salt form of the compound of the present invention have simple preparation process, stable physical and chemical properties, good hygroscopicity, good pharmacokinetic properties (such as AUC, C max , T 1/2 ), easy preparation, and good use in prevention. And/or it has broad application prospects in the treatment of complement factor B-related drugs.
定义和说明Definition and description
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 stated, the following terms and phrases used herein are intended to have the following meanings. A particular phrase or term should not be considered uncertain or unclear in the absence of a specific definition, but should be understood in its ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding trade name 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。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 those skilled in the art. Well-known equivalents and preferred embodiments include, but are not limited to, the embodiments 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 specific embodiments of the present invention are completed in a suitable solvent, and the solvent must be suitable for the chemical changes of the present invention and the required reagents and materials. In order to obtain the compounds of the present invention, those skilled in the art sometimes need to modify or select the synthesis steps or reaction procedures based on the existing embodiments.
除非另有说明，本发明化合物的差示扫描量热曲线中，向上表示放热(Exo Up)。Unless otherwise stated, in the differential scanning calorimetry curves of the compounds of the present invention, upward indicates exotherm (Exo Up).
除非另有说明，本发明中的室温表示15℃～35℃。Unless otherwise stated, room temperature in the present invention means 15°C to 35°C.
“哺乳动物”包括人和家畜如实验室哺乳动物与家庭宠物(例如猫、狗、猪、羊、牛、绵羊、山羊、马、家兔)，及非驯养哺乳动物，如野生哺乳动物等。"Mammals" include humans and domestic animals, such as laboratory mammals and household pets (such as cats, dogs, pigs, sheep, cattle, sheep, goats, horses, rabbits), and non-domesticated mammals, such as wild mammals.
术语“药物组合物”是指本申请化合物与本领域中通常接受的用于传递生物活性化合物至哺乳动物例如人的介质的制剂。所述介质包括所有供其使用的药物可接受的载体。药物组合物有利于化合物向生物体的给药。The term "pharmaceutical composition" refers to a formulation of a compound of the present application with a vehicle generally accepted in the art for delivering a biologically active compound to a mammal, such as a human. Such media include all pharmaceutically acceptable carriers for their use. Pharmaceutical compositions facilitate the administration of compounds to an organism.
术语“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。The term "therapeutically effective amount" refers to a non-toxic amount of a drug or agent sufficient to achieve the desired effect. The determination of the effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in individual cases can be determined by those skilled in the art based on routine experiments.
术语“治疗”意为将本申请所述化合物或制剂进行给药以改善或消除疾病或与所述疾病相关的一个或多个症状，且包括：The term "treating" means administering a compound or formulation described herein to ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:
(i)抑制疾病或疾病状态，即遏制其发展；(i) To inhibit a disease or disease state, that is, to arrest its progression;
(ii)缓解疾病或疾病状态，即使该疾病或疾病状态消退。(ii) Alleviation of a disease or condition, i.e. resolution of the disease or condition.
术语“预防”意为将本申请所述化合物或制剂进行给药以预防疾病或与所述疾病相关的一个或多个症状，且包括：预防疾病或疾病状态在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病状态，但尚未被诊断为已患有该疾病状态时。The term "prevention" means the administration of a compound or formulation described herein to prevent a disease or one or more symptoms associated with said disease, and includes preventing the occurrence of a disease or disease state in a mammal, in particular when Such mammals are susceptible to the disease state but have not yet been diagnosed as having the disease state.
本发明中，“药学上可接受的载体”是指与活性成份一同给药的、对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些载体。关于载体的其他信息，可以参考Remington:The Science  and Practice of Pharmacy,21st Ed.,Lippincott,Williams&Wilkins(2005)，该文献的内容通过引用的方式并入本文。In the present invention, "pharmaceutically acceptable carriers" refer to those carriers that are administered together with the active ingredients, have no obvious irritating effect on the organism, and do not impair the biological activity and performance of the active compound. For additional information about vectors, please refer to Remington:The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.
词语“包括(comprise)”或“包含(comprise)”及其英文变体例如comprises或comprising应理解为开放的、非排他性的意义，即“包括但不限于”。The words "comprise" or "comprise" and their English variants such as compris or comprising should be understood in an open, non-exclusive sense, that is, "including but not limited to."
下面会通过实施例具体描述本发明，这些实施例并不意味着对本发明的任何限制。The present invention will be described in detail through examples below. These examples do not mean any limitation to the present invention.
本发明的化合物可以通过本领域技术人员所熟知的常规方法来确认结构，如果本发明涉及化合物的绝对构型，则该绝对构型可以通过本领域常规技术手段予以确证。例如单晶X射线衍射法(SXRD)，把培养出的单晶用Bruker D8 venture衍射仪收集衍射强度数据，光源为CuKα辐射，扫描方式：扫描，收集相关数据后，进一步采用直接法(Shelxs97)解析晶体结构，便可以确证绝对构型。The structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention involves the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction (SXRD) uses a Bruker D8 venture diffractometer to collect diffraction intensity data on the cultured single crystal. The light source is CuKα radiation. The scanning method is: After scanning and collecting relevant data, the direct method (Shelxs97) is further used to analyze the crystal structure, and the absolute configuration can be confirmed.
本发明采用下述缩略词：ACN代表乙腈；DMSO代表二甲基亚砜。N2：氮气；RH：相对湿度；mL：毫升；L：升；min：分钟；℃：摄氏度；μm：微米；mm：毫米；μL：微升；moL/L：摩尔每升；mg：毫克；s：秒；nm：纳米；MPa：兆帕；lux：勒克斯；μw/cm2：微瓦每平方厘米；h:小时；Kg：千克；nM：纳摩尔，rpm：转速；XRPD代表X射线粉末衍射；DSC代表差示扫描量热分析；TGA代表热重分析；1H NMR代表核磁共振氢谱。The following abbreviations are used in the present invention: ACN represents acetonitrile; DMSO represents dimethyl sulfoxide. N 2 : nitrogen; RH: relative humidity; mL: milliliter; L: liter; min: minutes; ℃: degrees Celsius; μm: micrometers; mm: millimeters; μL: microliters; moL/L: moles per liter; mg: milligrams ;s: seconds; nm: nanometers; MPa: megapascals; lux: lux; μw/cm 2 : microwatts per square centimeter; h: hours; Kg: kilograms; nM: nanomoles, rpm: rotational speed; XRPD represents X-rays Powder diffraction; DSC stands for differential scanning calorimetry; TGA stands for thermogravimetric analysis; 1 H NMR stands for hydrogen nuclear magnetic resonance spectroscopy.
本发明化合物依据本领域常规命名原则或者使用软件命名，市售化合物采用供应商目录名称，本发明所使用的所有溶剂是市售可得的。The compounds of the present invention are named according to the conventional naming principles in this field or used Software nomenclature, commercially available compounds using supplier catalog names, all solvents used in this invention are commercially available.
本发明仪器及分析方法Instrument and analysis method of the present invention
(1)本发明X-射线粉末衍射(X-ray powder diffractometer,XRPD)方法(1) X-ray powder diffraction (X-ray powder diffractometer, XRPD) method of the present invention
仪器型号：PANalytical X'Pert3型X-射线衍射仪。Instrument model: PANalytical X'Pert 3 type X-ray diffractometer.
测试方法：大约10mg样品用于XRPD检测。Test method: About 10mg sample is used for XRPD detection.
详细的XRPD参数如下：The detailed XRPD parameters are as follows:
X射线类型：Cu,Kα。X-ray type: Cu, Kα.
1.540598；1.544426。 1.540598; 1.544426.
Kα2/Kα1强度比例：0.50。Kα2/Kα1 intensity ratio: 0.50.
电压：45仟伏特(kV)。Voltage: 45 kilovolts (kV).
电流：40毫安培(mA)。Current: 40 milliamps (mA).
发散狭缝：1/8度。Divergence slit: 1/8 degree.
扫描模式：连续。Scan mode: continuous.
扫描范围：自3.0至40.0度。Scanning range: from 3.0 to 40.0 degrees.
每步扫描时间：46.7秒。Scan time per step: 46.7 seconds.
步长：0.0263度。Step size: 0.0263 degrees.
(2)本发明差示扫描量热(Differential Scanning Calorimeter,DSC)方法和热重分析(Thermal Gravimetric Analyzer,TGA)方法(2) Differential Scanning Calorimeter (DSC) method and Thermogravimetric Analyzer (TGA) method of the present invention
仪器型号和参数见表6。The instrument model and parameters are shown in Table 6.
表6 DSC和TGA测试参数
Table 6 DSC and TGA test parameters
(3)高效液相色谱/离子色谱(HPLC/IC)仪器(3) High performance liquid chromatography/ion chromatography (HPLC/IC) instrument
试验中酸碱摩尔比测试是由Agilent H-Class高效液相色谱仪和离子色谱仪联用测试，分析条件如表7和表8所示。The acid-base molar ratio test in the experiment was performed by Agilent H-Class high performance liquid chromatography and ion chromatography. The analysis conditions are shown in Tables 7 and 8.
表7高效液相色谱测试条件
Table 7 High Performance Liquid Chromatography Test Conditions
表8离子色谱测试条件
Table 8 Ion chromatography test conditions
(4)动态水分吸附分析(Dynamic Vapor Sorption,DVS)方法(4)Dynamic Vapor Sorption (DVS) method
称取约10mg样品，使用SMS DVS intrinsic plus水分吸附仪进行检测，详细的仪器信息和参数如下：Weigh about 10 mg of the sample and use the SMS DVS intrinsic plus moisture adsorption meter for detection. The detailed instrument information and parameters are as follows:
温度：25℃；Temperature: 25℃;
样品量10-20mg；Sample size 10-20mg;
保护气体/流量：氮气，200mL/min；Protective gas/flow: nitrogen, 200mL/min;
dm/dt：0.002％/min；dm/dt: 0.002%/min;
最小dm/dt平衡时间：10min；Minimum dm/dt equilibrium time: 10min;
最大平衡时间：180min；Maximum balancing time: 180min;
RH范围：0％RH-95％RH；RH range: 0%RH-95%RH;
RH梯度：10％(0％RH-90％RH，90％RH-0％RH)；5％(90％RH-95％RH，95％RH-90％RH)。RH gradient: 10% (0%RH-90%RH, 90%RH-0%RH); 5% (90%RH-95%RH, 95%RH-90%RH).
引湿性评价分类：吸收足量水分形成液体：潮解；ΔW％≥15％：极具吸湿性；15％>ΔW％≥2％：有 吸湿性；2％>ΔW％≥0.2％：略有吸湿性；ΔW％<0.2％：无或几乎无吸湿性。ΔW％表示受试品在25±1℃、80±2％RH下的吸湿增重。Hygroscopicity evaluation classification: absorb enough water to form liquid: deliquescence; ΔW% ≥ 15%: extremely hygroscopic; 15% > ΔW% ≥ 2%: yes Hygroscopicity; 2%>ΔW%≥0.2%: slightly hygroscopic; ΔW%<0.2%: no or almost no hygroscopicity. ΔW% represents the moisture absorption weight gain of the test product at 25±1℃ and 80±2%RH.
附图说明Description of drawings
图1为式(II)化合物A晶型的XRPD图谱。Figure 1 is the XRPD pattern of the crystal form A of the compound of formula (II).
图2为式(I)化合物B晶型的XRPD图谱。Figure 2 is the XRPD pattern of the crystal form B of the compound of formula (I).
图3为式(I)化合物B晶型的DSC图谱。Figure 3 is a DSC spectrum of compound B crystal form of formula (I).
图4为式(I)化合物B晶型的TGA图谱。Figure 4 is a TGA spectrum of the crystal form B of compound (I).
图5为式(I)化合物C晶型的XRPD图谱。Figure 5 is the XRPD pattern of crystal form C of compound of formula (I).
图6为式(I)化合物C晶型的DSC图谱。Figure 6 is a DSC spectrum of crystal form C of compound of formula (I).
图7为式(I)化合物C晶型的TGA图谱。Figure 7 is a TGA spectrum of crystal form C of compound of formula (I).
图8为式(I)化合物D晶型的XRPD图谱。Figure 8 is the XRPD pattern of the crystal form D of the compound of formula (I).
图9为式(I)化合物的水合物E晶型的XRPD图谱。Figure 9 is the XRPD pattern of the hydrate crystal form E of the compound of formula (I).
图10为式(I)化合物单晶的立体结构椭球图。Figure 10 is an ellipsoid diagram of the three-dimensional structure of a single crystal of the compound of formula (I).
图11为式(I)化合物单晶的XRPD模拟图。Figure 11 is an XRPD simulation diagram of a single crystal of the compound of formula (I).
具体实施方式Detailed ways
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。The present invention is described in detail below through examples, which do not mean any adverse limitations to the present invention. The present invention has been described in detail herein, and its specific embodiments are also disclosed. For those skilled in the art, various changes and improvements can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention. will be obvious.
实施例1：式(II)化合物的盐酸盐的制备
Example 1: Preparation of hydrochloride salt of compound of formula (II)
第一步first step
在15℃，向化合物2(0.5g)的四氢呋喃(5mL)溶液中加入二碳酸二叔丁酯(812.33mg)和N,N-二异丙 基乙基胺(37.89mg)。反应液在15℃下搅拌1小时。反应液加入水(15mL)中，继续搅拌5分钟。分液，水相用乙酸乙酯(20mL*3)萃取。合并的有机层用饱和食盐水(20mL*2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。剩余物用硅胶柱层析法分离纯化(乙酸乙酯:石油醚＝0:1至1:10)，得到化合物3。To a solution of compound 2 (0.5 g) in tetrahydrofuran (5 mL) was added di-tert-butyl dicarbonate (812.33 mg) and N,N-diisopropyl dicarbonate at 15°C. Ethylamine (37.89 mg). The reaction solution was stirred at 15°C for 1 hour. The reaction solution was added to water (15 mL), and stirring was continued for 5 minutes. Separate the liquids, and extract the aqueous phase with ethyl acetate (20mL*3). The combined organic layers were washed with saturated brine (20 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0:1 to 1:10) to obtain compound 3.
1H NMR(400MHz,CDCl3)δppm 7.54-7.48(m,1H),6.90-6.84(m,1H),6.77-6.70(m,1H),6.50-6.43(m,1H),3.90-3.77(m,3H),2.70-2.55(m,3H),1.66-1.61(m,9H)；LC-MS:m/z＝206.1[M-56+H]+。 1 H NMR (400MHz, CDCl 3 ) δppm 7.54-7.48(m,1H),6.90-6.84(m,1H),6.77-6.70(m,1H),6.50-6.43(m,1H),3.90-3.77( m,3H), 2.70-2.55(m,3H), 1.66-1.61(m,9H); LC-MS: m/z=206.1[M-56+H] + .
第二步Step 2
在15℃下，向氮气保护的N-甲基-N-甲酰基苯胺(459.93mg)的二氯甲烷(2.7mL)溶液中缓慢滴加草酰氯(431.90mg)。加完后，反应液在15℃下搅拌12小时后，逐滴加入到-14℃的化合物3(0.684g)的二氯甲烷(2.8mL)溶液中。加完后反应液继续在-15℃下搅拌1.5小时。反应液倒入冰水(20mL)中，继续搅拌5分钟。水相用乙酸乙酯(20mL*3)萃取，合并的有机相用饱和食盐水(20mL*3)洗涤，无水硫酸钠干燥，过滤。滤液减压浓缩，剩余物用硅胶柱层析法分离纯化(乙酸乙酯:石油醚＝0:1至1:10)，得到化合物4。To a nitrogen-protected solution of N-methyl-N-formylanilide (459.93 mg) in dichloromethane (2.7 mL), oxalyl chloride (431.90 mg) was slowly added dropwise at 15°C. After the addition was completed, the reaction solution was stirred at 15°C for 12 hours, and then added dropwise to a solution of compound 3 (0.684g) in dichloromethane (2.8mL) at -14°C. After the addition was completed, the reaction solution was continued to stir at -15°C for 1.5 hours. The reaction solution was poured into ice water (20 mL), and stirring was continued for 5 minutes. The aqueous phase was extracted with ethyl acetate (20 mL*3), and the combined organic phases were washed with saturated brine (20 mL*3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate:petroleum ether=0:1 to 1:10) to obtain compound 4.
1H NMR(400MHz,DMSO-d6)δppm 10.61-10.41(m,1H),7.91-7.71(m,1H),7.38-7.21(m,1H),7.07-6.97(m,1H),3.97-3.93(m,3H),2.63-2.59(m,3H),1.60-1.58(m,9H)；LC-MS:m/z＝290.1[M+H]+。 1 H NMR (400MHz, DMSO-d 6 ) δppm 10.61-10.41(m,1H),7.91-7.71(m,1H),7.38-7.21(m,1H),7.07-6.97(m,1H),3.97- 3.93(m,3H), 2.63-2.59(m,3H), 1.60-1.58(m,9H); LC-MS: m/z=290.1[M+H] + .
第三步third step
在0℃下，向氮气保护的化合物4(5.24g)的四氢呋喃(20mL)和甲醇(20mL)溶液中缓慢加入硼氢化钠(1.71g)。加完后，反应液在15℃下搅拌0.5小时后，继续缓慢加入稀盐酸(0.5M,20mL)。加完后反应液继续搅拌20分钟。混合物用乙酸乙酯(60mL*3)萃取，合并的有机相用饱和食盐水(60mL*2)洗涤，无水硫酸钠干燥，过滤。滤液减压浓缩，剩余物用硅胶柱层析法分离纯化(乙酸乙酯:石油醚＝1:10至1:3)，得到化合物5。To a nitrogen-protected solution of compound 4 (5.24 g) in tetrahydrofuran (20 mL) and methanol (20 mL) at 0° C., sodium borohydride (1.71 g) was slowly added. After the addition was completed, the reaction solution was stirred at 15°C for 0.5 hours, and then continued to slowly add dilute hydrochloric acid (0.5M, 20mL). After the addition was completed, the reaction solution was continued to stir for 20 minutes. The mixture was extracted with ethyl acetate (60 mL*3), and the combined organic phases were washed with saturated brine (60 mL*2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:10 to 1:3) to obtain compound 5.
1H NMR(400MHz,CDCl3)δppm 7.59-7.50(m,1H),6.80-6.70(m,1H),6.66-6.60(m,1H),4.97-4.85(m,2H),3.96-3.86(m,3H),2.68-2.58(m,3H),1.65-1.63(m,9H)。 1 H NMR (400MHz, CDCl 3 ) δppm 7.59-7.50(m,1H),6.80-6.70(m,1H),6.66-6.60(m,1H),4.97-4.85(m,2H),3.96-3.86( m,3H),2.68-2.58(m,3H),1.65-1.63(m,9H).
第四步the fourth step
在15℃下，向氮气保护的化合物5(0.3g)的二氯甲烷(6.87mL)溶液中加入(氯亚甲基)二甲基氯化铵(197.71mg)。加完后，反应液在15℃下搅拌1小时。反应液降温至0℃，加入碳酸氢钠水溶液(5％，30mL)，二氯甲烷(20mL*3)萃取。合并的有机相用饱和食盐水(10mL*2)洗涤，无水硫酸钠干燥，过滤。滤液减压浓缩，得到化合物6。To a nitrogen-protected solution of compound 5 (0.3 g) in dichloromethane (6.87 mL) was added (chloromethylene)dimethylammonium chloride (197.71 mg) at 15°C. After the addition was completed, the reaction solution was stirred at 15°C for 1 hour. The reaction solution was cooled to 0°C, sodium bicarbonate aqueous solution (5%, 30mL) was added, and extracted with dichloromethane (20mL*3). The combined organic phases were washed with saturated brine (10 mL*2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain compound 6.
1H NMR(400MHz,DMSO-d6)δppm 7.73-7.61(m,1H),6.91-6.86(m,1H),6.82-6.75(m,1H),4.99-4.91(m,2H),3.89-3.82(m,3H),2.56-2.54(m,3H),1.60-1.57(m,9H)。 1 H NMR (400MHz, DMSO-d 6 ) δppm 7.73-7.61(m,1H),6.91-6.86(m,1H),6.82-6.75(m,1H),4.99-4.91(m,2H),3.89- 3.82(m,3H),2.56-2.54(m,3H),1.60-1.57(m,9H).
第五步the fifth step
在30℃时，氮气保护下，将镁屑(402.78g)加入到四氢呋喃(3000mL)中，慢慢加入化合物19(60g)，然后加入碘(3.0g)引发反应。反应液在30℃时，氮气保护下搅拌0.5小时。然后将剩余的化合物19(540.0g)逐滴加入到反应液中，滴加过程约2小时。滴加完成后，反应液在氮气氛围下在30℃下搅拌0.5小时，得到化合物8的四氢呋喃溶液(通过碘量法滴定测得浓度：0.66M)，直接用于下一步反应。At 30°C, under nitrogen protection, magnesium chips (402.78g) were added to tetrahydrofuran (3000mL), compound 19 (60g) was slowly added, and then iodine (3.0g) was added to initiate the reaction. The reaction solution was stirred under nitrogen protection for 0.5 hours at 30°C. Then the remaining compound 19 (540.0 g) was added dropwise to the reaction solution for about 2 hours. After the dropwise addition was completed, the reaction solution was stirred at 30°C for 0.5 hours under a nitrogen atmosphere to obtain a tetrahydrofuran solution of compound 8 (concentration measured by iodometric titration: 0.66M), which was directly used in the next reaction.
第六步Step 6
在-70℃下，将化合物8的四氢呋喃溶液(0.66M,2.01L)逐滴加入到溶有化合物7(200g)和溴化亚铜(17.30g)的甲苯(1000mL)溶液中，反应在氮气保护下进行，滴加时长3小时。滴加完毕，在-70℃下搅拌0.5小时。将反应液倒入冰水中(2000mL)，用稀盐酸(1M)调节pH到7，然后用乙酸乙酯(2000mL*2)萃取，合并有机相，并依次用饱和碳酸钾水溶液(500mL)、饱和氯化铵(500mL)和饱和的氯化钠(500mL)洗涤。有机相用无水硫酸钠干燥后减压浓缩得到粗品，再通过正庚烷(1000mL)，在10-15℃下打浆搅拌30分钟，过滤，收集滤饼得到化合物9。1H NMR(400MHz,CDCl3)δppm 8.07-7.94(m,2H),7.80-7.65(m,2H),4.93(t,J＝4.1Hz,1H),3.96-3.76(m,4H),3.05(t,J＝7.3Hz,2H),2.10(dt,J＝4.1,7.3Hz,2H)。 At -70°C, a solution of compound 8 in tetrahydrofuran (0.66M, 2.01L) was added dropwise to a solution of compound 7 (200g) and cuprous bromide (17.30g) in toluene (1000mL), and the reaction was carried out under nitrogen. Under protection, the dripping time is 3 hours. After the dropwise addition was completed, the mixture was stirred at -70°C for 0.5 hours. Pour the reaction solution into ice water (2000mL), adjust the pH to 7 with dilute hydrochloric acid (1M), then extract with ethyl acetate (2000mL*2), combine the organic phases, and use saturated aqueous potassium carbonate solution (500mL), saturated Wash with ammonium chloride (500 mL) and saturated sodium chloride (500 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product, which was then passed through n-heptane (1000 mL), beaten and stirred at 10-15°C for 30 minutes, filtered, and the filter cake was collected to obtain compound 9. 1 H NMR (400MHz, CDCl 3 ) δppm 8.07-7.94 (m, 2H), 7.80-7.65 (m, 2H), 4.93 (t, J = 4.1Hz, 1H), 3.96-3.76 (m, 4H), 3.05 (t, J=7.3Hz, 2H), 2.10 (dt, J=4.1, 7.3Hz, 2H).
第七步Step 7
将化合物9(264g)溶于水(150mL)和甲酸(1500mL)的混合溶剂中，反应液升温至40℃，并在该温度下搅拌2小时。降温至室温，将反应液缓慢加入到15％碳酸钾水溶液中(8L)，有固体析出，过滤，收集固体，并用水(500mL)洗涤滤饼，干燥滤饼得到化合物10。1H NMR(400MHz,CDCl3)δppm 9.92(s,1H),8.20-8.03(m,2H),7.95-7.68(m,2H),3.51-3.22(m,2H),3.09-2.88(m,2H)。Compound 9 (264 g) was dissolved in a mixed solvent of water (150 mL) and formic acid (1500 mL). The reaction solution was heated to 40°C and stirred at this temperature for 2 hours. Cool to room temperature, slowly add the reaction solution to 15% potassium carbonate aqueous solution (8L), solid precipitates, filter, collect the solid, wash the filter cake with water (500 mL), and dry the filter cake to obtain compound 10. 1 H NMR (400MHz, CDCl 3 ) δppm 9.92 (s, 1H), 8.20-8.03 (m, 2H), 7.95-7.68 (m, 2H), 3.51-3.22 (m, 2H), 3.09-2.88 (m, 2H).
第八步Step 8
将苄胺(194.62g)缓慢加入到溶有醋酸(103.88mL)的水(850mL)中。将反应体系降温至0-10℃，然后缓慢分批加入1,3-丙酮二羧酸(265.36g)，反应液在0℃下反应0.5小时。将溶有化合物10(170g)的二氧六环(850mL)溶液缓慢加入到反应体系中，将反应液缓慢恢复到室温，然后在45℃下反应12小时。反应液降至室温，然后加入乙酸乙酯萃取(500mL*2)，合并有机相，依次用饱和碳酸氢钠(500mL)和饱和氯化钠水溶液(500mL)洗涤，无水硫酸钠干燥后，滤液减压浓缩得到粗品。粗品在正庚烷和甲基叔丁基醚(1:1，500mL)混合溶剂中搅拌0.5小时，过滤并收集固体，得到化合物11。LC-MS:m/z＝317.1[M+H]+。Benzylamine (194.62g) was slowly added to water (850mL) dissolved in acetic acid (103.88mL). The reaction system was cooled to 0-10°C, then 1,3-acetone dicarboxylic acid (265.36g) was slowly added in batches, and the reaction solution was allowed to react at 0°C for 0.5 hours. A solution of compound 10 (170 g) dissolved in dioxane (850 mL) was slowly added to the reaction system, the reaction solution was slowly returned to room temperature, and then reacted at 45°C for 12 hours. The reaction solution was brought to room temperature, then ethyl acetate was added for extraction (500mL*2), the organic phases were combined, washed with saturated sodium bicarbonate (500mL) and saturated sodium chloride aqueous solution (500mL), and dried over anhydrous sodium sulfate. Concentrate under reduced pressure to obtain crude product. The crude product was stirred in a mixed solvent of n-heptane and methyl tert-butyl ether (1:1, 500 mL) for 0.5 hours, filtered and the solid was collected to obtain compound 11. LC-MS: m/z=317.1[M+H] + .
第九步Step 9
将化合物11(220g,1eq)溶于乙腈(1700mL)中，然后升温到70℃下搅拌2小时，在搅拌下慢慢加入L-型二苯甲酰基酒石酸(200g,0.8eq)，反应液继续在70℃下搅拌2小时，然后缓慢恢复到25℃，并搅拌12小时。过滤并收集固体，再用乙腈(400mL*2)洗涤滤饼。将过滤得到的固体加入到1000mL水中，搅拌下加入1M NaOH水溶液调节pH至8，然后加入乙酸乙酯萃取(2000mL*2)。合并有机相，并用饱和的食盐水(2000mL*2)洗涤，有机相用无水硫酸钠干燥，过滤后减压浓缩滤液得到化合物12(保留时间:2.175min，ee＝99.1％)。LC-MS:m/z＝317.1[M+H]+。SFC分析方法：色谱柱:Chiralpak AD 50×4.6mm I.D.,3μm，流动相:A:CO2，B:甲醇(0.05％二乙胺)，梯度B％：5％-40％。Dissolve compound 11 (220g, 1eq) in acetonitrile (1700mL), then raise the temperature to 70°C and stir for 2 hours. L-type dibenzoyl tartaric acid (200g, 0.8eq) is slowly added while stirring, and the reaction solution is continued Stir at 70°C for 2 hours, then slowly return to 25°C and stir for 12 hours. Filter and collect the solid, then wash the filter cake with acetonitrile (400mL*2). Add the filtered solid to 1000 mL of water, add 1 M NaOH aqueous solution with stirring to adjust the pH to 8, and then add ethyl acetate for extraction (2000 mL*2). The organic phases were combined and washed with saturated brine (2000 mL*2). The organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain compound 12 (retention time: 2.175 min, ee=99.1%). LC-MS: m/z=317.1[M+H] + . SFC analysis method: Chromatographic column: Chiralpak AD 50×4.6mm ID, 3μm, mobile phase: A: CO 2 , B: methanol (0.05% diethylamine), gradient B%: 5%-40%.
第十步Step 10
将化合物12(94g)溶于四氢呋喃(750mL)中，然后加入水(10.71mL)，氮气置换3次，降温至-40℃，并在该温度下缓慢滴加三仲丁基硼氢化锂(1M)。滴加完毕，在该温度下继续搅拌30分钟。向反应液中缓慢滴加双氧水(102.77mL,30％纯度)，控制温度在0℃以下。然后缓慢加入溶有亚硫酸钠(135g)的水(1000mL)溶液，并加入甲基叔丁基醚(500mL*2)萃取。有机相通过饱和食盐水(1000mL*2)洗涤，干燥后过滤，减压浓缩得到化合物13(保留时间:1.197min，ee＝96.9％)。LC-MS:m/z＝319.1[M+H]+。SFC分析方法：色谱柱:Chiralcel OJ 50×4.6mm I.D.,3μm，流动相:A:CO2，B:甲醇(0.05％二乙胺)，梯度B％：5％-40％。Compound 12 (94g) was dissolved in tetrahydrofuran (750mL), then water (10.71mL) was added, nitrogen was replaced three times, the temperature was cooled to -40°C, and tri-sec-butyllithium borohydride (1M) was slowly added dropwise at this temperature. ). After the dropwise addition is completed, stirring is continued at this temperature for 30 minutes. Slowly add hydrogen peroxide (102.77 mL, 30% purity) into the reaction solution, and control the temperature below 0°C. Then slowly add a solution of sodium sulfite (135g) in water (1000mL), and add methyl tert-butyl ether (500mL*2) for extraction. The organic phase was washed with saturated brine (1000 mL*2), dried, filtered, and concentrated under reduced pressure to obtain compound 13 (retention time: 1.197 min, ee=96.9%). LC-MS: m/z=319.1[M+H] + . SFC analysis method: Chromatographic column: Chiralcel OJ 50×4.6mm ID, 3μm, mobile phase: A: CO 2 , B: methanol (0.05% diethylamine), gradient B%: 5%-40%.
第十一步Step 11
将化合物13(7g)溶于N,N-二甲基甲酰胺(35mL)中，氮气置换3次，降温至0℃，然后加入叔丁醇钠(6.34g)，搅拌30min。降温至-10℃并在该温度下缓慢滴加硫酸二乙酯(6.78g)。滴加完毕，在该温度下继续搅拌2小时。将反应液加入到水(160mL)中，用柠檬酸固体调节pH＝5～6，加入乙酸乙酯(100mL)萃取。有机相依次用饱和碳酸钠水溶液(50mL)和食盐水(100mL)洗涤，干燥后过滤，滤液减压浓缩得到化合物14。LC-MS:m/z＝347.2[M+H]+。Compound 13 (7g) was dissolved in N,N-dimethylformamide (35 mL), replaced with nitrogen three times, cooled to 0°C, then sodium tert-butoxide (6.34g) was added, and stirred for 30 min. The temperature was lowered to -10°C and diethyl sulfate (6.78g) was slowly added dropwise at this temperature. After the dropwise addition is completed, stirring is continued at this temperature for 2 hours. The reaction solution was added to water (160 mL), the pH was adjusted to 5-6 with solid citric acid, and ethyl acetate (100 mL) was added for extraction. The organic phase was washed with saturated aqueous sodium carbonate solution (50 mL) and brine (100 mL) in sequence, dried and filtered, and the filtrate was concentrated under reduced pressure to obtain compound 14. LC-MS: m/z=347.2[M+H] + .
第十二步Step 12
在20℃下，向溶有化合物14(8g)的二甲基亚砜(40mL)溶液中加入碳酸钾(3.51g)，然后缓慢滴加双氧水(3.93g,30％纯度)。滴加完成后反应液升温至40℃，搅拌16小时。反应液降至室温后缓慢加入到冰水中(150mL)，在0℃下搅拌1小时。析出固体，过滤，滤饼干燥得到化合物15。LC-MS:m/z＝365.2[M+H]+。At 20°C, potassium carbonate (3.51g) was added to a solution of compound 14 (8g) dissolved in dimethyl sulfoxide (40mL), and then hydrogen peroxide (3.93g, 30% purity) was slowly added dropwise. After the dropwise addition was completed, the temperature of the reaction solution was raised to 40°C and stirred for 16 hours. After the reaction solution cooled to room temperature, it was slowly added to ice water (150 mL) and stirred at 0°C for 1 hour. The solid was precipitated, filtered, and the filter cake was dried to obtain compound 15. LC-MS: m/z=365.2[M+H] + .
第十三步Step 13
在室温下，往化合物15(99g)的甲醇(1000mL)溶液中，加入N,N-二甲基甲酰胺二甲基缩醛(59.81g)，反应液升温至40℃，搅拌16小时。反应液直接减压浓缩后得到剩余物。向剩余物中加入乙酸乙酯(1000mL)，然后依次用水(500mL)和饱和食盐水(500mL)洗涤，无水硫酸钠干燥，过滤后滤液浓缩得到化合物16直接用于下一步。LC-MS:m/z＝380.2[M+H]+。 At room temperature, N,N-dimethylformamide dimethyl acetal (59.81g) was added to a solution of compound 15 (99g) in methanol (1000mL), and the reaction solution was heated to 40°C and stirred for 16 hours. The reaction solution was directly concentrated under reduced pressure to obtain the residue. Ethyl acetate (1000 mL) was added to the residue, and then washed with water (500 mL) and saturated brine (500 mL) in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 16, which was used directly in the next step. LC-MS: m/z=380.2[M+H] + .
第十四步Step 14
在20℃下，氮气氛围下，向化合物16(4g)的甲醇(40mL)溶液中依次加入浓盐酸(1.18g,36％纯度)和湿钯碳(1g,10％含量)，氢气置换3次，反应液在50℃下搅拌1.5小时。反应液过滤，减压浓缩得到粗品化合物17直接用于下一步。LC-MS:m/z＝290.1[M+H]+。At 20°C, under a nitrogen atmosphere, concentrated hydrochloric acid (1.18g, 36% purity) and wet palladium on carbon (1g, 10% content) were sequentially added to a solution of compound 16 (4g) in methanol (40mL), and hydrogen was replaced three times. , the reaction solution was stirred at 50°C for 1.5 hours. The reaction solution was filtered and concentrated under reduced pressure to obtain crude compound 17, which was directly used in the next step. LC-MS: m/z=290.1[M+H] + .
第十五步Step 15
室温下向化合物17(3.6g)与化合物6(4.05g)的N,N-二甲基甲酰胺(40mL)混合溶液中加入碳酸铯(16.2g)和碘化钾(4.13g)，反应体系在15℃下反应16小时。将反应液缓慢加入200mL冰水中淬灭。水相用乙酸乙酯(400mL*2)萃取。合并有机相，无水硫酸钠干燥，过滤并减压浓缩。残留物经硅胶柱层析分离(二氯甲烷:甲醇＝10:1)纯化，得到化合物18，LC-MS:m/z＝563.4[M+H]+。Cesium carbonate (16.2g) and potassium iodide (4.13g) were added to a mixed solution of compound 17 (3.6g) and compound 6 (4.05g) in N,N-dimethylformamide (40mL) at room temperature, and the reaction system was at 15 React at ℃ for 16 hours. The reaction solution was slowly added to 200 mL of ice water to quench. The aqueous phase was extracted with ethyl acetate (400mL*2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain compound 18, LC-MS: m/z=563.4[M+H] + .
第十六步Step 16
在15℃氮气保护下，向化合物18(5g)的四氢呋喃(50mL)和甲醇(50mL)的混合溶液中加入氢氧化锂(1.5M,50mL)水溶液。反应液升温至50℃，搅拌16小时。反应液冷却至室温，用冰醋酸调节pH至6～7。混合物减压浓缩，得到粗品通过高效液相色谱法纯化(色谱柱:Phenomenex luna C18Μltra 250*80mm.,15μm；流动相：A：水(0.05％盐酸)，B：乙腈，方法：B：20％-50％，20min)，得到式(II)化合物盐酸盐的无定型。1H NMR(400MHz,DMSO-d6)δppm 13.23(brs,1H),11.26(s,1H),9.96(s,1H),8.24-7.96(m,4H),7.46(t,J＝2.8Hz,1H),6.86(s,1H),6.43(brs,1H),3.72(s,3H),3.70(brd,J＝3.5Hz,2H),3.18(brs,1H),3.06(brd,J＝2.0Hz,2H),2.42(s,3H),2.25-2.15(m,1H),2.12-1.86(m,6H),1.55-1.48(m,1H),1.11(t,J＝6.8Hz,3H)；LC-MS:m/z＝449.3[M+H]+。Under nitrogen protection at 15°C, an aqueous solution of lithium hydroxide (1.5 M, 50 mL) was added to a mixed solution of compound 18 (5 g) in tetrahydrofuran (50 mL) and methanol (50 mL). The reaction solution was heated to 50°C and stirred for 16 hours. The reaction solution was cooled to room temperature, and the pH was adjusted to 6-7 with glacial acetic acid. The mixture was concentrated under reduced pressure to obtain a crude product purified by high performance liquid chromatography (chromatographic column: Phenomenex luna C18Mltra 250*80mm., 15μm; mobile phase: A: water (0.05% hydrochloric acid), B: acetonitrile, method: B: 20% -50%, 20 min) to obtain the amorphous hydrochloride of the compound of formula (II). 1 H NMR (400MHz, DMSO-d 6 ) δppm 13.23 (brs, 1H), 11.26 (s, 1H), 9.96 (s, 1H), 8.24-7.96 (m, 4H), 7.46 (t, J＝2.8Hz ,1H),6.86(s,1H),6.43(brs,1H),3.72(s,3H),3.70(brd,J＝3.5Hz,2H),3.18(brs,1H),3.06(brd,J＝ 2.0Hz,2H),2.42(s,3H),2.25-2.15(m,1H),2.12-1.86(m,6H),1.55-1.48(m,1H),1.11(t,J＝6.8Hz,3H ); LC-MS: m/z=449.3[M+H] + .
实施例2：式(II)化合物A晶型的制备
Example 2: Preparation of crystal form A of compound of formula (II)
将实施例1制备得到的式(II)化合物盐酸盐的无定型(0.4g)溶于去离子水(1mL)和乙腈(3mL)混合溶剂中，然后缓慢加入饱和碳酸氢钠水溶液(70μL)，析出固体，反应体系继续在20℃下搅拌5分钟。过滤并收集固体，干燥后得到式(II)化合物A晶型。1H NMR(400MHz,DMSO-d6)δppm 10.81(brs,1H),7.96(d,J＝8.4Hz,2H),7.74(d,J＝8.4Hz,2H),7.26(t,J＝2.8Hz,1H),6.66(s,1H),6.53(brs,1H),3.72(s,3H),3.70(brd,J＝3.5Hz,2H),3.18(brs,1H),3.06(brd,J＝2.0Hz,2H),2.42(s,3H),2.25-2.15(m,1H),2.12-1.86(m,6H),1.55-1.48(m,1H),1.11(t,J＝6.8Hz,3H)。XRPD谱图如图1所示。The amorphous hydrochloride of the compound of formula (II) prepared in Example 1 (0.4g) was dissolved in a mixed solvent of deionized water (1mL) and acetonitrile (3mL), and then a saturated sodium bicarbonate aqueous solution (70μL) was slowly added , a solid precipitated, and the reaction system continued to stir at 20°C for 5 minutes. The solid is filtered and collected, and after drying, the crystal form A of the compound of formula (II) is obtained. 1 H NMR (400MHz, DMSO-d 6 ) δppm 10.81 (brs, 1H), 7.96 (d, J = 8.4Hz, 2H), 7.74 (d, J = 8.4Hz, 2H), 7.26 (t, J = 2.8 Hz,1H),6.66(s,1H),6.53(brs,1H),3.72(s,3H),3.70(brd,J＝3.5Hz,2H),3.18(brs,1H),3.06(brd,J ＝2.0Hz,2H),2.42(s,3H),2.25-2.15(m,1H),2.12-1.86(m,6H),1.55-1.48(m,1H),1.11(t,J＝6.8Hz, 3H). The XRPD spectrum is shown in Figure 1.
参考以上制备方法，将实施例1制备得到的式(II)化合物盐酸盐的无定型替换成式(I)化合物B晶型、式(I)化合物C晶型、式(I)化合物D晶型或式(I)化合物E晶型，得到式(II)化合物A晶型。Referring to the above preparation method, the amorphous form of the hydrochloride of the compound of formula (II) prepared in Example 1 was replaced with the crystal form of the compound of formula (I) B, the crystal form of the compound of formula (I) C, and the crystal form of the compound of formula (I) D. or the crystal form of compound E of formula (I) to obtain the crystal form of compound A of formula (II).
实施例3：式(I)化合物B晶型的制备
Example 3: Preparation of crystal form B of compound of formula (I)
方法一：将100mg实施例1制备得到的式(II)化合物的盐酸盐无定型溶于丙酮(0.5mL)和水(0.1mL)的混合溶液中搅拌5分钟，向混合溶液中滴加丙酮(0.6mL)和乙酸乙酯(0.9mL)的混合溶液，反应液室温搅拌12小时，析出固体，过滤，干燥滤饼后得到式(I)化合物B晶型。1H NMR(400MHz,DMSO-d6)δppm 13.36-13.07(m,1H),11.39-11.13(m,1H),10.22-9.95(m,1H),8.17-8.10(m,2H),8.03-7.96(m,1H),7.45-7.39(m,1H),6.84-6.76(m,1H),6.48-6.43(m,1H),4.07-3.93(m,4H),3.89-3.83(m,3H),3.65-3.56(m,1H),3.43-3.37(m,2H),3.35(br s,2H),2.92-2.64(m,1H),2.49-2.30(m,3H),2.09-1.98(m,3H),1.13(t,J＝6.8Hz,3H)；LC-MS:m/z＝449.3[M+H]+。Method 1: Dissolve 100 mg of the amorphous hydrochloride of the compound of formula (II) prepared in Example 1 in a mixed solution of acetone (0.5 mL) and water (0.1 mL), stir for 5 minutes, and add acetone dropwise to the mixed solution. (0.6 mL) and ethyl acetate (0.9 mL), the reaction solution was stirred at room temperature for 12 hours, a solid precipitated, filtered, and the filter cake was dried to obtain the crystal form B of the compound of formula (I). 1 H NMR (400MHz, DMSO-d 6 ) δppm 13.36-13.07(m,1H),11.39-11.13(m,1H),10.22-9.95(m,1H),8.17-8.10(m,2H),8.03- 7.96(m,1H),7.45-7.39(m,1H),6.84-6.76(m,1H),6.48-6.43(m,1H),4.07-3.93(m,4H),3.89-3.83(m,3H ),3.65-3.56(m,1H),3.43-3.37(m,2H),3.35(br s,2H),2.92-2.64(m,1H),2.49-2.30(m,3H),2.09-1.98( m, 3H), 1.13 (t, J = 6.8 Hz, 3H); LC-MS: m/z = 449.3 [M + H] + .
方法二：分别称取约20毫克的实施例1制备得到的式(II)化合物的盐酸盐无定型置于20毫升的玻璃小瓶中，加入1.0mL的相应的溶剂将固体完全溶解。向该澄清溶液中边搅拌边滴加反溶剂，直至有固体析出或反溶剂滴加体积达到10mL，离心，收集固体测试XRPD。实验结果如表9所示。Method 2: Weigh approximately 20 mg of the amorphous hydrochloride of the compound of formula (II) prepared in Example 1 into a 20 ml glass vial, and add 1.0 mL of the corresponding solvent to completely dissolve the solid. Add anti-solvent dropwise to the clear solution while stirring until solid precipitates or the volume of anti-solvent added reaches 10 mL. Centrifuge and collect the solid for XRPD testing. The experimental results are shown in Table 9.
表9 XRPD测试结果
Table 9 XRPD test results
HPLC/IC结果显示式(I)化合物B晶型为单盐酸盐，XRPD谱图如图2所示，DSC谱图如图3所示，TGA图谱如图4所示。The HPLC/IC results show that the crystal form B of compound of formula (I) is monohydrochloride. The XRPD spectrum is shown in Figure 2, the DSC spectrum is shown in Figure 3, and the TGA spectrum is shown in Figure 4.
实施例4：式(I)化合物C晶型的制备
Example 4: Preparation of crystal form C of compound of formula (I)
称取约20毫克的式(I)化合物B晶型，加入0.5mL乙腈，在室温下悬浮搅拌3天，离心，收集固体，得到式(I)化合物C晶型。HPLC/IC结果显示样品为单盐酸盐，XRPD谱图如图5所示，DSC谱图如图6所示，TGA图谱如图7所示。Weigh about 20 mg of the crystal form B of the compound of formula (I), add 0.5 mL of acetonitrile, suspend and stir at room temperature for 3 days, centrifuge, collect the solid, and obtain the crystal form C of the compound of the formula (I). The HPLC/IC results show that the sample is monohydrochloride. The XRPD spectrum is shown in Figure 5, the DSC spectrum is shown in Figure 6, and the TGA spectrum is shown in Figure 7.
实施例5：式(I)化合物D晶型的制备
Example 5: Preparation of crystal form D of compound of formula (I)
称取约20毫克的式(I)化合物B晶型，加入0.5mL异丙醇，在50℃下悬浮搅拌3天，离心，收集固体，得到式(I)化合物D晶型。HPLC/IC结果显示样品为单盐酸盐，XRPD谱图如图8所示。Weigh about 20 mg of the crystal form B of the compound of formula (I), add 0.5 mL of isopropyl alcohol, suspend and stir at 50°C for 3 days, centrifuge, collect the solid, and obtain the crystal form D of the compound of the formula (I). The HPLC/IC results show that the sample is monohydrochloride, and the XRPD spectrum is shown in Figure 8.
实施例6：式(I)化合物的水合物E晶型的制备
Example 6: Preparation of Hydrate E Crystal Form of Compound of Formula (I)
称取约20毫克的式(I)化合物B晶型，加入0.5mL乙醇，在室温下悬浮搅拌3天，转至5℃下搅拌1天，转至-20℃下再搅拌1天，转至室温敞口缓慢挥发得到固体，收集固体得到式(I)化合物的水合物E晶型。HPLC/IC结果显示样品为单盐酸盐，XRPD谱图如图9所示。Weigh about 20 mg of the crystal form B of the compound of formula (I), add 0.5 mL of ethanol, suspend and stir at room temperature for 3 days, transfer to 5°C and stir for 1 day, transfer to -20°C and stir for another 1 day, transfer to Slowly volatilize at room temperature to obtain a solid, which is collected to obtain the hydrate crystal form E of the compound of formula (I). The HPLC/IC results show that the sample is monohydrochloride, and the XRPD spectrum is shown in Figure 9.
实施例7：式(I)化合物单晶X射线衍射检测分析
Example 7: Single crystal X-ray diffraction detection and analysis of the compound of formula (I)
取式(II)化合物的盐酸盐无定型(10mg)溶解于乙腈/甲醇(0.6mL，体积比5:1)中，将样品溶液置于4mL半密封样品瓶中，在4℃下缓慢挥发。第二天得到无色针状晶体，该单晶为式(I)化合物晶型F。收集晶体，用Rigaku Oxford Diffraction XtaLAB Synergy four-circle diffractometer(HyPix-6000HE area detector)衍射仪收集衍射强度数据。单晶数据显示，单晶为式(I)化合物，可以确定式(I)化合物的绝对构型。式(I)化合物单晶的立体结构椭球图见附图10，XRPD模拟图见附图11。式(I)化合物的晶体结构数据和参数见表10～15，XRPD模拟图的衍射数据由表16所示。Dissolve the amorphous hydrochloride (10 mg) of the compound of formula (II) in acetonitrile/methanol (0.6 mL, volume ratio 5:1), place the sample solution in a 4 mL semi-sealed sample bottle, and slowly evaporate at 4°C. . Colorless needle-like crystals were obtained the next day, and this single crystal was Form F of the compound of formula (I). The crystals were collected and diffraction intensity data were collected using a Rigaku Oxford Diffraction XtaLAB Synergy four-circle diffractometer (HyPix-6000HE area detector). The single crystal data shows that the single crystal is a compound of formula (I), and the absolute configuration of the compound of formula (I) can be determined. The three-dimensional structure ellipsoid diagram of the single crystal of the compound of formula (I) is shown in Figure 10, and the XRPD simulation diagram is shown in Figure 11. The crystal structure data and parameters of the compound of formula (I) are shown in Tables 10 to 15, and the diffraction data of the XRPD simulation pattern are shown in Table 16.
表10式(I)化合物的单晶结构数据

Table 10 Single crystal structure data of compounds of formula (I)

表11式(I)化合物单晶的原子坐标(×104)和等价各向同性移位参数


Table 11 Atomic coordinates (×10 4 ) and equivalent isotropic shift parameters of the single crystal of the compound of formula (I)


表12式(I)化合物单晶的键长

Table 12 Bond lengths of single crystals of compounds of formula (I)

表13式(I)化合物单晶的键角(Angle/°)

Table 13 Bond angle (Angle/°) of compound single crystal of formula (I)

表14式(I)化合物单晶的扭转角度(Angle/°)


Table 14 Twist angle (Angle/°) of single crystal of compound of formula (I)


表15式(I)化合物单晶的氢键


注1：+X,1+Y,+Z；注2：+X,-1+Y,+Z。Table 15 Hydrogen bonds in single crystals of compounds of formula (I)


Note 1: +X,1+Y,+Z; Note 2: +X,-1+Y,+Z.
表16式(I)化合物单晶的XRPD模拟衍射数据
Table 16 XRPD simulated diffraction data of single crystal of compound of formula (I)
实施例8：式(I)化合物B晶型的固体稳定性试验Example 8: Solid stability test of crystal form B of compound of formula (I)
依据《原料药与制剂稳定性试验指导原则》(中国药典2020版四部通则9001)，为评估式(I)化合物B晶型的固体稳定性，对B晶型进行了影响因素(高温、高湿及光照)、40℃/75％RH及25℃/60％RH条件的稳定性考察。将B晶型分别在高温(60℃，敞口)、高湿(25℃/92.5％RH，敞口)条件下各放置30天，按照ICH条件(可见光总照度达到1200000Lux·hrs、紫外光总照度达到200W·hrs/m2)敞口放置在可见光及紫外光下(遮光对照组样品同时放置并用锡箔纸包裹)，在40℃/75％RH(敞口)条件下放置1、2和3个月，在25℃/60％RH(敞口)条件下放置3个月。对所有稳定性样品进行了XRPD测试，以检测晶型的变化。According to the "Guiding Principles for Stability Testing of Raw Materials and Preparations" (Chinese Pharmacopoeia 2020 Edition Four General Chapters 9001), in order to evaluate the solid stability of crystal form B of compound of formula (I), the influencing factors (high temperature, high humidity) of crystal form B were tested. and light), 40℃/75%RH and 25℃/60%RH conditions. The B crystal form was placed under high temperature (60℃, exposed) and high humidity (25℃/92.5%RH, exposed) conditions for 30 days respectively. According to ICH conditions (the total visible light illumination reached 1,200,000 Lux·hrs, the total ultraviolet light When the illumination reaches 200W·hrs/m 2 ), place it in the open under visible light and ultraviolet light (samples in the shading control group are placed at the same time and wrapped in tin foil), and placed 1, 2 and 3 under 40℃/75%RH (open) conditions. months, placed at 25℃/60%RH (exposure) for 3 months. XRPD testing was performed on all stability samples to detect changes in crystal form.
准确称取该晶型约10mg置于干燥洁净的玻璃瓶中，摊成薄薄一层，敞口放置于影响因素试验条件下和加速条件下。光照(可见光1200000Lux·hrs，紫外200W·hrs/m2)条件下放置的样品采用透明玻璃瓶，完全暴露，用于XRPD检测的样品单独放置。Accurately weigh about 10 mg of the crystal form and place it in a dry and clean glass bottle, spread it into a thin layer, and place it exposed under the influencing factors test conditions and accelerated conditions. The samples placed under illumination (visible light 1200000 Lux·hrs, ultraviolet 200W·hrs/m 2 ) conditions are in transparent glass bottles, which are completely exposed, and the samples used for XRPD detection are placed separately.
样品到时间点取出后，盖好盖子，使用封口膜密封，置于-20℃冰箱保存。配样时，将样品从冰箱取出，恢复至室温，加入25mL稀释液(乙腈/水，1:1，v/v)，使样品溶解，得浓度约为0.5mg/mL溶液，使用液相进行进样分析，检测结果与0天的初始检测结果进行比较，以检测晶型的化学稳定性。After the sample is taken out at the time point, cover it, seal it with a sealing film, and store it in a -20°C refrigerator. When preparing the sample, take the sample out of the refrigerator, return it to room temperature, add 25 mL of diluent (acetonitrile/water, 1:1, v/v) to dissolve the sample, and obtain a solution with a concentration of approximately 0.5 mg/mL. Use the liquid phase. Inject samples for analysis, and compare the test results with the initial test results on day 0 to detect the chemical stability of the crystal form.
结论：式(I)化合物B晶型在所有稳定性(高温，高湿，光照)条件下，晶型稳定且具有较好的化学稳定性。Conclusion: The crystal form of compound B of formula (I) is stable and has good chemical stability under all stability conditions (high temperature, high humidity, light).
实施例9：式(I)化合物B晶型的吸湿性研究Example 9: Study on hygroscopicity of crystal form B of compound of formula (I)
取式(I)化合物B晶型(约10mg)置于DVS样品盘内进行测试。实验结果显示，式(I)化合物B晶型在25℃/80％RH下略有引湿性。Take the crystal form B (about 10 mg) of compound of formula (I) and place it in the DVS sample tray for testing. Experimental results show that the crystal form B of compound of formula (I) is slightly hygroscopic at 25°C/80% RH.
生物测试数据Biological test data
实验例1：Wieslab补体旁路通路活化抑制(酶活测试)Experimental Example 1: Wieslab complement alternative pathway activation inhibition (enzyme activity test)
实验目的：Purpose:
通过补体系统旁路通路试剂盒，对待测化合物针对人血清中补体旁路通路的抑制活性的测定。 实验方案：pass The complement system alternative pathway kit is used to determine the inhibitory activity of the test compound against the complement alternative pathway in human serum. Experimental program:
用稀释液将血清进行稀释(1：23)。向稀释的血清中加入药物，8个浓度梯度，最高10mM或50mM，5倍梯度稀释。室温孵育15min。将化合物和血清混合物加入试剂盒提供的96孔板(100μL/孔)，在37度激活1小时。用洗涤缓冲液清洗三遍。加入试剂盒提供的检测抗体(100μL)在室温进行孵育30min。用洗涤缓冲液清洗三遍。加入底物(100μL)在室温进行孵育30min。酶标仪405nM处检测吸光度。Dilute the serum with diluent (1:23). Add the drug to the diluted serum in 8 concentration gradients, up to 10mM or 50mM, in 5-fold gradient dilutions. Incubate at room temperature for 15 minutes. Add the compound and serum mixture to the 96-well plate provided in the kit (100 μL/well) and activate at 37 degrees for 1 hour. Wash three times with wash buffer. Add the detection antibody (100 μL) provided by the kit and incubate at room temperature for 30 minutes. Wash three times with wash buffer. Add substrate (100 μL) and incubate at room temperature for 30 min. The absorbance was measured at 405nM with a microplate reader.
实验结果：Experimental results:
测试化合物对补体旁路通路抑制活性结果如表17所示。The results of the inhibitory activity of the test compounds on the complement alternative pathway are shown in Table 17.
表17本发明化合物对补体旁路通路抑制活性结果
Table 17 Results of the inhibitory activity of the compounds of the present invention on the complement alternative pathway
结论：实施例1式(II)化合物的盐酸盐对人血清旁路通路激活抑制活性明显。Conclusion: The hydrochloride salt of the compound of formula (II) in Example 1 has obvious inhibitory activity on the activation of the human serum alternative pathway.
实验例2：补体人Factor B蛋白结合测试(TR-FRET法)Experimental Example 2: Complement human Factor B protein binding test (TR-FRET method)
实验目的：Purpose:
利用TR-FRET方法，对待测化合物针对人补体Factor B蛋白的结合活性的测定。The TR-FRET method was used to determine the binding activity of the test compound against human complement Factor B protein.
实验方案：Experimental program:
将药物加入磷酸盐缓冲液PBS(pH 7.4)中，从10μM开始，4倍稀释，10个浓度。生物素化的Factor B(25nM)在不存在或存在不同浓度的测试化合物的情况下，添加Cy5标记的探针(75nM)和铕螯合物标记的链霉亲和素(Perkin Elmer#AD0060；0.225nM)后，在室温下孵育2小时。使用330nm作为激发波长和665nm作为发射波长，测量时间分辨荧光能量转移(TR-FRET)数据。Add the drug to phosphate buffered saline PBS (pH 7.4), starting from 10 μM, 4-fold dilution, and 10 concentrations. Biotinylated Factor B (25 nM) was added with Cy5-labeled probe (75 nM) and europium chelate-labeled streptavidin (Perkin Elmer #AD0060; 0.225nM), incubate at room temperature for 2 hours. Time-resolved fluorescence energy transfer (TR-FRET) data were measured using 330 nm as the excitation wavelength and 665 nm as the emission wavelength.
实验结果：Experimental results:
测试化合物对人补体Factor B蛋白的结合活性如表18所示。The binding activity of the test compounds to human complement Factor B protein is shown in Table 18.
表18本发明化合物对人补体Factor B蛋白结合测试结果
Table 18 Test results of binding of compounds of the present invention to human complement Factor B protein
结论：实施例1式(II)化合物的盐酸盐对人补体Factor B蛋白具有显著的结合活性。Conclusion: The hydrochloride salt of the compound of formula (II) in Example 1 has significant binding activity to human complement Factor B protein.
实验例3：大鼠药代动力学研究Experimental Example 3: Pharmacokinetic Study in Rats
实验目的：Purpose:
以雄性SD大鼠为受试动物，应用LC/MS/MS法测定大鼠口服灌胃给予本发明的化合物后不同时刻血浆中的药物浓度。研究本发明的化合物在大鼠体内的药代动力学行为，评价其药代动力学特征。Male SD rats were used as test animals, and the LC/MS/MS method was used to determine the drug concentration in the plasma of the rats at different times after oral administration of the compound of the present invention. Study the pharmacokinetic behavior of the compound of the present invention in rats and evaluate its pharmacokinetic characteristics.
试验方案：Test plan:
健康雄性大鼠200-300g，每组2只。Healthy male rats weighing 200-300g, 2 rats per group.
将本发明化合物，用0.5％MC(4000cP)/0.5％Tween 80的水溶液配制成混悬液。大鼠禁食一夜后口服灌胃给药，给药剂量：10mpk，30mpk和50mpk。于给药前及给药后0.25、0.5、1、2、4、7、24小时采血，置于肝素化抗凝试管中，7000rpm(5204g)、4℃下离心，分离血浆，于-80℃保存。给药后4小时进食。用LC/MS/MS法测定口服给药后大鼠血浆中的待测化合物含量。血浆样品经沉淀蛋白预处理后进行分析。结论：本发明化合物和结晶都具有较好的口服暴露量和较长的半衰期，药代动力学性质优良。 The compound of the present invention was prepared into a suspension with an aqueous solution of 0.5% MC (4000cP)/0.5% Tween 80. Rats were fasted overnight and then administered orally by gavage. The dosages were: 10mpk, 30mpk and 50mpk. Collect blood before and 0.25, 0.5, 1, 2, 4, 7, and 24 hours after administration, place it in a heparinized anticoagulant test tube, centrifuge at 7000 rpm (5204g), 4°C, separate plasma, and store at -80°C save. Eat 4 hours after dosing. The LC/MS/MS method was used to determine the content of the test compound in rat plasma after oral administration. Plasma samples were analyzed after pretreatment with precipitated proteins. Conclusion: Both the compounds and crystals of the present invention have good oral exposure, long half-life, and excellent pharmacokinetic properties.

Claims (10)

  1. 式(II)化合物的结晶，
    Crystallization of compounds of formula (II),
    其特征在于，所述结晶为A晶型，所述A晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.15±0.20°，9.28±0.20°和14.31±0.20°；It is characterized in that the crystal is crystal form A, and the X-ray powder diffraction pattern of Cu Kα radiation of the crystal form A has characteristic diffraction peaks at the following 2θ angles: 7.15±0.20°, 9.28±0.20° and 14.31±0.20. °;
    或者，所述A晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有至少3个或4个特征衍射峰：7.15±0.20°，9.28±0.20°，14.31±0.20°，19.52±0.20°和21.77±0.20°。Alternatively, the X-ray powder diffraction pattern of Cu Kα radiation of the A crystal form has at least 3 or 4 characteristic diffraction peaks at the following 2θ angles: 7.15±0.20°, 9.28±0.20°, 14.31±0.20°, 19.52± 0.20° and 21.77±0.20°.
  2. 一种式(II)化合物盐酸盐或其结晶，
    A hydrochloride salt of a compound of formula (II) or a crystal thereof,
    或者，一种式(II-1)化合物或其结晶，
    Alternatively, a compound of formula (II-1) or a crystal thereof,
    其中，in,
    m选自0～2.5；m is selected from 0 to 2.5;
    n选自0～2.5；n is selected from 0 to 2.5;
    或者，一种式(I)化合物或其结晶，
    Alternatively, a compound of formula (I) or crystals thereof,
  3. 如权利要求2所述的式(I)化合物的结晶为B晶型，其特征在于，所述B晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.16±0.20°，8.96±0.20°和10.53±0.20°；The crystal of the compound of formula (I) as claimed in claim 2 is crystal form B, characterized in that the X-ray powder diffraction pattern of Cu Kα radiation of the crystal form B has a characteristic diffraction peak at the following 2θ angle: 6.16± 0.20°, 8.96±0.20° and 10.53±0.20°;
    或者，所述B晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.16±0.20°，8.96±0.20°，10.53±0.20°，18.55±0.20°和24.62±0.20°；Alternatively, the X-ray powder diffraction pattern of Cu Kα radiation of the B crystal form has characteristic diffraction peaks at the following 2θ angles: 6.16±0.20°, 8.96±0.20°, 10.53±0.20°, 18.55±0.20° and 24.62±0.20 °;
    或者，所述B晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有至少6个或7个特征衍射峰：6.16±0.20°，8.96±0.20°，10.53±0.20°，12.30±0.20°，16.74±0.20°，18.55±0.20°，19.95±0.20°和24.62±0.20°；Alternatively, the X-ray powder diffraction pattern of Cu Kα radiation of the B crystal form has at least 6 or 7 characteristic diffraction peaks at the following 2θ angles: 6.16±0.20°, 8.96±0.20°, 10.53±0.20°, 12.30± 0.20°, 16.74±0.20°, 18.55±0.20°, 19.95±0.20° and 24.62±0.20°;
    或者，所述B晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.16±0.20°，8.96±0.20°，10.53±0.20°，12.30±0.20°，16.74±0.20°，18.55±0.20°，19.95±0.20°和24.62±0.20°；Alternatively, the X-ray powder diffraction pattern of Cu Kα radiation of the B crystal form has characteristic diffraction peaks at the following 2θ angles: 6.16±0.20°, 8.96±0.20°, 10.53±0.20°, 12.30±0.20°, 16.74±0.20 °, 18.55±0.20°, 19.95±0.20° and 24.62±0.20°;
    或者，所述B晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有至少9个、10个或11个特征衍射峰：6.16±0.20°，8.96±0.20°，10.53±0.20°，12.30±0.20°，16.74±0.20°，17.39±0.20°，18.55±0.20°，19.49±0.20°，19.95±0.20°，22.17±0.20°，22.75±0.20°和24.62±0.20°；Alternatively, the X-ray powder diffraction pattern of Cu Kα radiation of the B crystal form has at least 9, 10 or 11 characteristic diffraction peaks at the following 2θ angles: 6.16±0.20°, 8.96±0.20°, 10.53±0.20° , 12.30±0.20°, 16.74±0.20°, 17.39±0.20°, 18.55±0.20°, 19.49±0.20°, 19.95±0.20°, 22.17±0.20°, 22.75±0.20° and 24.62±0.20°;
    或者，所述B晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.16±0.20°，8.96±0.20°，10.53±0.20°，12.30±0.20°，16.74±0.20°，17.39±0.20°，18.55±0.20°，19.49±0.20°，19.95±0.20°，22.17±0.20°，22.75±0.20°和24.62±0.20°；Alternatively, the X-ray powder diffraction pattern of Cu Kα radiation of the B crystal form has characteristic diffraction peaks at the following 2θ angles: 6.16±0.20°, 8.96±0.20°, 10.53±0.20°, 12.30±0.20°, 16.74±0.20 °, 17.39±0.20°, 18.55±0.20°, 19.49±0.20°, 19.95±0.20°, 22.17±0.20°, 22.75±0.20° and 24.62±0.20°;
    或者，所述B晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有至少11个、12个、13个、14个或15个特征衍射峰：6.16±0.20°，8.96±0.20°，10.53±0.20°，12.30±0.20°，13.19±0.20°，14.74±0.20°，16.74±0.20°，17.39±0.20°，17.90±0.20°，18.55±0.20°，19.49±0.20°，19.95±0.20°，21.55±0.20°，22.17±0.20°，22.75±0.20°和24.62±0.20°；Alternatively, the X-ray powder diffraction pattern of Cu Kα radiation of the B crystal form has at least 11, 12, 13, 14 or 15 characteristic diffraction peaks at the following 2θ angles: 6.16±0.20°, 8.96±0.20 °, 10.53±0.20°, 12.30±0.20°, 13.19±0.20°, 14.74±0.20°, 16.74±0.20°, 17.39±0.20°, 17.90±0.20°, 18.55±0.20°, 19.49±0.20°, 19.95±0.20 °, 21.55±0.20°, 22.17±0.20°, 22.75±0.20° and 24.62±0.20°;
    或者，所述B晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.16±0.20°，8.96±0.20°，10.53±0.20°，和/或3.16±0.20°，和/或10.79±0.20°，和/或12.30±0.20°，和/或13.19±0.20°，和/或14.74±0.20°，和/或16.74±0.20°，和/或17.39±0.20°，和/或17.90±0.20°，和/或18.55±0.20°，和/或19.49±0.20°，和/或19.95±0.20°，和/或21.55±0.20°，和/或22.17±0.20°，和/或22.75±0.20°，和/或24.62±0.20°，和/或27.29±0.20°，和/或28.05±0.20°，和/或29.03±0.20°，和/或32.55±0.20°，和/或34.15±0.20°处有特征衍射峰；Alternatively, the X-ray powder diffraction pattern of Cu Kα radiation of the B crystal form has characteristic diffraction peaks at the following 2θ angles: 6.16±0.20°, 8.96±0.20°, 10.53±0.20°, and/or 3.16±0.20°, and/or 10.79±0.20°, and/or 12.30±0.20°, and/or 13.19±0.20°, and/or 14.74±0.20°, and/or 16.74±0.20°, and/or 17.39±0.20°, and/or or 17.90±0.20°, and/or 18.55±0.20°, and/or 19.49±0.20°, and/or 19.95±0.20°, and/or 21.55±0.20°, and/or 22.17±0.20°, and/or 22.75 ±0.20°, and/or 24.62±0.20°, and/or 27.29±0.20°, and/or 28.05±0.20°, and/or 29.03±0.20°, and/or 32.55±0.20°, and/or 34.15±0.20 There is a characteristic diffraction peak at °;
    或者，所述B晶型的Cu Kα辐射的XRPD图谱如图2所示。Alternatively, the XRPD pattern of Cu Kα radiation of the B crystal form is shown in Figure 2.
  4. 如权利要求2所述的式(I)化合物的结晶为C晶型，其特征在于，所述C晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.72±0.20°，15.31±0.20°和19.53±0.20°；The crystal of the compound of formula (I) as claimed in claim 2 is the C crystal form, characterized in that the X-ray powder diffraction pattern of the Cu Kα radiation of the C crystal form has a characteristic diffraction peak at the following 2θ angle: 7.72± 0.20°, 15.31±0.20° and 19.53±0.20°;
    或者，所述C晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有至少6个或7个特征衍射峰：7.72±0.20°，14.67±0.20°，15.31±0.20°，16.66±0.20°，18.76±0.20°，19.53±0.20°，22.67±0.20°和24.28±0.20°。Alternatively, the X-ray powder diffraction pattern of Cu Kα radiation of the C crystal form has at least 6 or 7 characteristic diffraction peaks at the following 2θ angles: 7.72±0.20°, 14.67±0.20°, 15.31±0.20°, 16.66± 0.20°, 18.76±0.20°, 19.53±0.20°, 22.67±0.20° and 24.28±0.20°.
  5. 如权利要求2所述的式(I)化合物的结晶为D晶型，其特征在于，所述D晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.93°和11.82°。The crystal of the compound of formula (I) as claimed in claim 2 is the D crystal form, wherein the X-ray powder diffraction pattern of the Cu Kα radiation of the D crystal form has a characteristic diffraction peak at the following 2θ angle: 5.93° and 11.82°.
  6. 如权利要求2所述的式(I)化合物的结晶为E晶型，其特征在于，所述E晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有至少3个特征衍射峰：5.98±0.20°，7.83±0.20°，8.87±0.20°和10.76±0.20°。 The crystal of the compound of formula (I) according to claim 2 is the E crystal form, wherein the X-ray powder diffraction pattern of the Cu Kα radiation of the E crystal form has at least 3 characteristic diffraction peaks at the following 2θ angles :5.98±0.20°, 7.83±0.20°, 8.87±0.20° and 10.76±0.20°.
  7. 如权利要求2所述的式(I)化合物的结晶为F晶型，其特征在于，所述F晶型的的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.96±0.20°、8.86±0.20°、17.40±0.20°、19.52±0.20°和24.04±0.20°；The crystal of the compound of formula (I) as claimed in claim 2 is the F crystal form, wherein the X-ray powder diffraction pattern of the Cu Kα radiation of the F crystal form has a characteristic diffraction peak at the following 2θ angle: 5.96 ±0.20°, 8.86±0.20°, 17.40±0.20°, 19.52±0.20° and 24.04±0.20°;
    或者，所述F晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有至少6个或7个特征衍射峰：5.96±0.20°、8.86±0.20°、10.82±0.20°、13.32±0.20°、17.40±0.20°、19.52±0.20°、24.04±0.20°和24.74±0.20°；Alternatively, the X-ray powder diffraction pattern of Cu Kα radiation of the F crystal form has at least 6 or 7 characteristic diffraction peaks at the following 2θ angles: 5.96±0.20°, 8.86±0.20°, 10.82±0.20°, 13.32± 0.20°, 17.40±0.20°, 19.52±0.20°, 24.04±0.20° and 24.74±0.20°;
    或者，所述F晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.96±0.20°、8.86±0.20°、17.40±0.20°、19.52±0.20°、24.04±0.20°，和/或10.66±0.20°、和/或10.82±0.20°、和/或11.06±0.20°、和/或11.54±0.20°、和/或11.94±0.20°、和/或13.32±0.20°、和/或14.86±0.20°、和/或17.96±0.20°、和/或18.72±0.20°、和/或21.66±0.20°、和/或23.68±0.20°、和/或24.74±0.20°、和/或26.56±0.20°、和/或27.42±0.20°和/或30.78±0.20°。Alternatively, the X-ray powder diffraction pattern of the Cu Kα radiation of the F crystal form has characteristic diffraction peaks at the following 2θ angles: 5.96±0.20°, 8.86±0.20°, 17.40±0.20°, 19.52±0.20°, 24.04±0.20 °, and/or 10.66±0.20°, and/or 10.82±0.20°, and/or 11.06±0.20°, and/or 11.54±0.20°, and/or 11.94±0.20°, and/or 13.32±0.20°, and/or 14.86±0.20°, and/or 17.96±0.20°, and/or 18.72±0.20°, and/or 21.66±0.20°, and/or 23.68±0.20°, and/or 24.74±0.20°, and/ Or 26.56±0.20°, and/or 27.42±0.20°, and/or 30.78±0.20°.
  8. 结晶组合物，所述包含如权利要求1-7中任意一项所述的式(II)化合物、式(II-1)化合物或式(I)化合物的结晶组合物，其中，权利要求1-7中任意一项所述的式(II)化合物、式(II-1)化合物或式(I)化合物的结晶占所述结晶组合物重量的50％以上，优选为80％以上，更优选为90％以上，最优选为95％以上。A crystalline composition comprising a compound of formula (II), a compound of formula (II-1) or a compound of formula (I) according to any one of claims 1-7, wherein claim 1- The crystal of the compound of formula (II), the compound of formula (II-1) or the compound of formula (I) described in any one of 7 accounts for more than 50% of the weight of the crystalline composition, preferably more than 80%, and more preferably 90% or more, most preferably 95% or more.
  9. 药物组合物，其包含治疗有效量的如权利要求1-7中任意一项所述的式(II)化合物的结晶、式(II-1)化合物或其结晶、式(I)化合物或其结晶、或包含治疗有效量的如权利要求8所述的结晶组合物。Pharmaceutical composition, which contains a therapeutically effective amount of a crystal of a compound of formula (II), a compound of formula (II-1) or a crystal thereof, a compound of formula (I) or a crystal thereof according to any one of claims 1-7 , or comprising a therapeutically effective amount of the crystalline composition of claim 8.
  10. 如权利要求1-7中任意一项所述的式(II)化合物的结晶、式(II-1)化合物或其结晶、式(I)化合物或其结晶、如权利要求8所述的结晶组合物、或者如权利要求9所述的药物组合物在预防或者治疗与补体因子B相关疾病中的用途，任选地，所述补体因子B相关疾病选自炎性障碍和自身免疫性疾病。 The crystal of the compound of formula (II) as claimed in any one of claims 1 to 7, the compound of formula (II-1) or its crystal, the compound of formula (I) or its crystal, the crystal combination as claimed in claim 8 or the use of the pharmaceutical composition according to claim 9 in preventing or treating diseases related to complement factor B, optionally, the diseases related to complement factor B are selected from the group consisting of inflammatory disorders and autoimmune diseases.
PCT/CN2023/108171 2022-07-20 2023-07-19 Crystal of bridged heterocycle substituted benzoic acid derivative or salt thereof, and preparation method therefor WO2024017299A1 (en)

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Publication number Priority date Publication date Assignee Title
CN109414441A (en) * 2016-06-27 2019-03-01 艾其林医药公司 The quinazoline and benzazolyl compounds for treating medical disorder
WO2022028527A1 (en) * 2020-08-07 2022-02-10 上海美悦生物科技发展有限公司 Complement factor b inhibitor, and pharmaceutical composition thereof, preparation method therefor and use thereof
WO2022143845A1 (en) * 2020-12-30 2022-07-07 江苏恒瑞医药股份有限公司 Nitrogen-containing bridged heterocyclic compound, preparation method therefor, and medical use thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109414441A (en) * 2016-06-27 2019-03-01 艾其林医药公司 The quinazoline and benzazolyl compounds for treating medical disorder
WO2022028527A1 (en) * 2020-08-07 2022-02-10 上海美悦生物科技发展有限公司 Complement factor b inhibitor, and pharmaceutical composition thereof, preparation method therefor and use thereof
WO2022143845A1 (en) * 2020-12-30 2022-07-07 江苏恒瑞医药股份有限公司 Nitrogen-containing bridged heterocyclic compound, preparation method therefor, and medical use thereof

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