WO2023241507A1 - Crystal form of alkynylpyridine compound and preparation method therefor - Google Patents

Crystal form of alkynylpyridine compound and preparation method therefor Download PDF

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WO2023241507A1
WO2023241507A1 PCT/CN2023/099660 CN2023099660W WO2023241507A1 WO 2023241507 A1 WO2023241507 A1 WO 2023241507A1 CN 2023099660 W CN2023099660 W CN 2023099660W WO 2023241507 A1 WO2023241507 A1 WO 2023241507A1
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reagent
solvent
crystal form
compound
preparation
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PCT/CN2023/099660
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French (fr)
Chinese (zh)
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郑晓平
江志赶
贺海鹰
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辰欣药业股份有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
    • C07D213/16—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing only one pyridine ring
    • C07D213/20—Quaternary compounds thereof
    • 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
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids

Definitions

  • the present invention relates to a crystal form of an alkynylpyridine compound and a preparation method thereof, in particular to a crystal form of a compound represented by formula (I) and a preparation method thereof.
  • Invasive fungal diseases are the most lethal type of fungal infections, and the morbidity and mortality are rising sharply.
  • the fungal cell wall is mainly composed of glucan, chitin and mannose protein.
  • Glycosylphosphatidylinositol egg-anchored protein (GPI-AP) is anchored on the cell membrane and cell wall, mediating the interaction between mannose protein and glucan.
  • Cross-linking has an important impact on fungal cell wall synthesis, adhesion and morphological transformation.
  • Gwt1 is a key acetylase in the GPI synthesis process and plays an important role in the formation of GPI precursors. Inhibiting Gwt1 activity blocks GPI-AP synthesis, and the fungal surface mannoprotein cannot be cross-linked to the cell wall, thereby destroying its ability to adhere to the host surface and cell wall integrity, thereby exerting an antifungal effect.
  • the invention provides the C crystal form of the compound of formula (I), which is characterized in that its X-ray powder diffraction pattern of Cu, K ⁇ radiation has characteristic diffraction peaks at the following 2 ⁇ angles: 3.9975 ⁇ 0.200°, 7.9169 ⁇ 0.200°, 19.9390 ⁇ 0.200°,
  • the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 3.9975 ⁇ 0.200°, 7.9169 ⁇ 0.200°, 15.8368 ⁇ 0.200°, 18.7250 ⁇ 0.200°, 19.9390 ⁇ 0.200°, 21.7115 ⁇ 0.200°, 23.0090 ⁇ 0.200°, 25.6600 ⁇ 0.200°.
  • the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 3.9975 ⁇ 0.200°, 7.9169 ⁇ 0.200°, 15.8368 ⁇ 0.200°, 18.7250 ⁇ 0.200°, 19.9390 ⁇ 0.200°, 20.3246 ⁇ 0.200°, 21.7115 ⁇ 0.200°, 23.0090 ⁇ 0.200°, 25.6600 ⁇ 0.200°.
  • the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 3.9975 ⁇ 0.200°, 7.9169 ⁇ 0.200°, 15.8368 ⁇ 0.200°, 18.7250 ⁇ 0.200°, 19.9390 ⁇ 0.200°, 20.8423 ⁇ 0.200°, 21.7115 ⁇ 0.200°, 22.3334 ⁇ 0.200°, 23.0090 ⁇ 0.200°, 24.0607 ⁇ 0.200°, 25.6600 ⁇ 0.200°, 27.1949 ⁇ 0.200°.
  • the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 3.9975 ⁇ 0.200°, 7.9169 ⁇ 0.200°, 10.7005 ⁇ 0.200°, 12.7114 ⁇ 0.200°, 15.8368 ⁇ 0.200°, 18.7250 ⁇ 0.200°, 19.9390 ⁇ 0.200°, 20.8423 ⁇ 0.200°, 21.7115 ⁇ 0.200°, 22.3334 ⁇ 0.200°, 23.0090 ⁇ 0.200°, 24.0607 ⁇ 0.200°, 25.6600 ⁇ 0.2 00°, 27.1949 ⁇ 0.200°, 28.9541 ⁇ 0.200°, 30.3507 ⁇ 0.200°.
  • the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 3.9975 ⁇ 0.200°, 7.9169 ⁇ 0.200°, 15.8368 ⁇ 0.200°, 18.7250 ⁇ 0.200°, 20.3246 ⁇ 0.200°, 21.7115 ⁇ 0.200°, 23.0090 ⁇ 0.200°, 25.6600 ⁇ 0.200°.
  • the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 3.9975 ⁇ 0.200°, 7.9169 ⁇ 0.200°, 12.7114 ⁇ 0.200°, 15.8368 ⁇ 0.200°, 18.7250 ⁇ 0.200°, 19.9390 ⁇ 0.200°, 22.3334 ⁇ 0.200°, 23.0090 ⁇ 0.200°.
  • the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 3.9975 ⁇ 0.200°, 7.9169 ⁇ 0.200°, 12.7114 ⁇ 0.200°, 15.8368 ⁇ 0.200°, 18.7250 ⁇ 0.200°, 19.9390 ⁇ 0.200°, 21.7115 ⁇ 0.200°, 22.3334 ⁇ 0.200°, 23.0090 ⁇ 0.200°, 25.6600 ⁇ 0.200°.
  • the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 3.9975 ⁇ 0.200°, 7.9169 ⁇ 0.200°, and/or 10.7005 ⁇ 0.200°, and/or 12.7114 ⁇ 0.200°, and/or 15.8368 ⁇ 0.200°, and/or 18.7250 ⁇ 0.200°, and/or 19.9390 ⁇ 0.200°, and/or 20.3246 ⁇ 0.200°, and/or 20.8423 ⁇ 0.200°, and/or 21.2448 ⁇ 0.200 °, and/or 21.7115 ⁇ 0.200°, and/or 22.3334 ⁇ 0.200°, and/or 23.0090 ⁇ 0.200°, and/or 23.8153 ⁇ 0.200°, and/or 24.0607 ⁇ 0.200°, and/or 25.0930 ⁇ 0.200°, and/or 25.6600 ⁇ 0.200°, and/or 27.1949 ⁇ 0.200°, and/or 28.9541 ⁇ 0.200
  • the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 4.00°, 7.92°, 10.70°, 12.71°, 15.84°, 18.72°, 19.94°, 20.32 °, 20.84°, 21.24°, 21.71°, 22.33°, 23.01°, 23.82°, 24.06°, 25.09°, 25.66°, 27.19°, 28.95°, 30.35°, 31.17°.
  • the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 3.9975°, 7.9169°, 10.7005°, 12.7114°, 15.8368°, 18.7250°, 19.9390°, 20.3246 °, 20.8423°, 21.2448°, 21.7115°, 22.3334°, 23.0090°, 23.8153°, 24.0607°, 25.0930°, 25.6600°, 27.1949°, 28.9541°, 30.3507°, 31.1749°.
  • the XRPD pattern of the above-mentioned crystal form C is basically as shown in Figure 1.
  • the differential scanning calorimetry curve of the above-mentioned C crystal form has an endothermic peak at 199.2 ⁇ 3°C.
  • the DSC pattern of the above-mentioned C crystal form is shown in Figure 2.
  • thermogravimetric analysis curve of the above-mentioned C crystal form has a weight loss of 2.28% at 150 ⁇ 3°C.
  • the TGA spectrum of the above crystal form C is shown in Figure 3.
  • the invention provides the D crystal form of the compound of formula (I), which is characterized in that its X-ray powder diffraction pattern of Cu, K ⁇ radiation has characteristic diffraction peaks at the following 2 ⁇ angles: 4.0789 ⁇ 0.200°, 8.1226 ⁇ 0.200°, 14.9322 ⁇ 0.200°, 18.2233 ⁇ 0.200°, 21.4231 ⁇ 0.200°,
  • the X-ray powder diffraction pattern of the above-mentioned D crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 4.0789 ⁇ 0.200°, 7.4609 ⁇ 0.200°, 8.1226 ⁇ 0.200°, 14.9322 ⁇ 0.200°, 18.2233 ⁇ 0.200°, 18.6712 ⁇ 0.200°, 21.4231 ⁇ 0.200°.
  • the X-ray powder diffraction pattern of the above-mentioned D crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 4.0789 ⁇ 0.200°, 7.4609 ⁇ 0.200°, 8.1226 ⁇ 0.200°, 12.1939 ⁇ 0.200°, 14.9322 ⁇ 0.200°, 18.2233 ⁇ 0.200°, 18.6712 ⁇ 0.200°, 21.4231 ⁇ 0.200°, 22.4812 ⁇ 0.200°, 26.2452 ⁇ 0.200°.
  • the X-ray powder diffraction pattern of the above-mentioned D crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 3.75°, 4.08°, 7.46°, 8.12°, 12.19°, 14.93°, 18.22°, 18.67 °, 19.38°, 21.42°, 22.48°, 26.25°.
  • the X-ray powder diffraction pattern of the above-mentioned D crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 3.7520°, 4.0789°, 7.4609°, 8.1226°, 12.1939°, 14.9322°, 18.2233°, 18.6712 °, 19.3838°, 21.4231°, 22.4812°, 26.2452°.
  • the XRPD pattern of the above-mentioned crystal form D is basically as shown in Figure 4.
  • the XRPD spectrum analysis data of the above-mentioned D crystal form is as shown in Table 2:
  • the invention also provides a preparation method of compound 1-6, which includes the following reaction steps:
  • Reagent 4A is selected from inorganic bases
  • Solvent 4B is selected from acyl solvents or mixed solvents of acyl solvents and water;
  • Reagent 4C is selected from inorganic bases
  • Reagent 4D is selected from palladium catalysts
  • Reagent 4E is selected from organophosphine ligands
  • Solvent 4F is selected from ester solvents.
  • Reagent 4A is selected from potassium fluoride
  • Solvent 4B is selected from DMF or a mixed solvent of DMF and water;
  • Reagent 4C is selected from cesium carbonate
  • Reagent 4D is selected from palladium acetate
  • Reagent 4E is selected from Xphos
  • Solvent 4F is selected from isopropyl acetate.
  • the preparation method of compound 1-6 wherein the volume ratio of DMF and water in the mixed solvent of solvent 4B is 5 to 8:1.
  • the preparation method of compound 1-6 wherein the molar ratio of reagent 4A to compound 1-5 is 4.0-6.0:1, and the molar ratio of compound 1-3 to compound 1-5 is 0.5 ⁇ 1.5:1, the molar ratio of reagent 4C to compound 1-5 is 3 ⁇ 5:1, the molar ratio of reagent 4D to compound 1-5 is 0.01 ⁇ 0.02:1, the molar ratio of reagent 4E to compound 1-5 It is 0.02 ⁇ 0.04:1.
  • the preparation method of compound 1-6 wherein the molar ratio of reagent 4A to compound 1-5 is 4.0 to 6.0:1.
  • the preparation method of compound 1-6 wherein the molar ratio of compound 1-3 to compound 1-5 is 0.5 to 1.5:1.
  • the molar ratio of reagent 4C to compound 1-5 is 3 to 5:1.
  • the molar ratio of reagent 4D to compound 1-5 is 0.01 to 0.02:1.
  • the molar ratio of reagent 4E to compound 1-5 is 0.02 to 0.04:1.
  • the preparation method of compound 1-6 wherein the molar ratio of reagent 4A to compound 1-5 is 5.0 to 5.5:1, and the molar ratio of compound 1-3 to compound 1-5 is 0.5 ⁇ 1:1, the molar ratio of reagent 4C to compound 1-5 is 3.5 ⁇ 4.5:1, the molar ratio of reagent 4D to compound 1-5 is 0.01 ⁇ 0.02:1, the molar ratio of reagent 4E to compound 1-5 It is 0.02 ⁇ 0.03:1.
  • the preparation method of compound 1-6, wherein the molar ratio of reagent 4A to compound 1-5 is 5.0 to 5.5:1.
  • the preparation method of compound 1-6 wherein the molar ratio of compound 1-3 to compound 1-5 is 0.5 to 1:1.
  • the molar ratio of reagent 4C to compound 1-5 is 3.5 to 4.5:1.
  • the molar ratio of reagent 4D to compound 1-5 is 0.01 to 0.02:1.
  • the preparation method of compound 1-6 wherein the molar ratio of reagent 4E to compound 1-5 is 0.02 to 0.03:1.
  • the preparation method of compound 1-6 wherein the reaction system temperature range of compound 1-5, reagent 4A, and solvent 4B is controlled to be 10-40°C, and the temperature range of the reaction system with compound 1-3, reagent 4B is controlled to be 10-40°C.
  • the reaction system temperature range of 4C, reagent 4D, reagent 4E, and solvent 4F is 60 to 100°C.
  • the preparation method of compound 1-6 wherein the temperature range of the reaction system of compound 1-5, reagent 4A, and solvent 4B is controlled to be 10 to 40°C.
  • the temperature range of the reaction system with compound 1-3, reagent 4C, reagent 4D, reagent 4E, and solvent 4F is controlled to be 60 to 100°C.
  • the preparation method of compound 1-6 wherein the reaction system temperature range of compound 1-5, reagent 4A, and solvent 4B is controlled to be 15-25°C, and the reaction system temperature range of compound 1-5, reagent 4A, and solvent 4B is controlled to be 15-25°C.
  • the reaction system temperature range of 4C, reagent 4D, reagent 4E, and solvent 4F is 75 to 85°C.
  • the preparation method of compound 1-6 wherein the reaction system temperature range of compound 1-5, reagent 4A, and solvent 4B is controlled to be 15-25°C.
  • the temperature range of the reaction system with compound 1-3, reagent 4C, reagent 4D, reagent 4E, and solvent 4F is controlled to be 75 to 85°C.
  • the preparation method of compound 1-6 includes controlling the reaction time of compound 1-5 with reagent 4A and solvent 4B to be 0.5 to 3 hours, and controlling the reaction time with compound 1-3, reagent 4C, The reaction time of reagent 4D, reagent 4E, and solvent 4F is 8 to 24 hours.
  • the preparation method of compound 1-6 wherein the reaction time with compound 1-3, reagent 4C, reagent 4D, reagent 4E, and solvent 4F is controlled to be 8 to 24 hours.
  • the preparation method of compound 1-6 includes controlling the reaction time of compound 1-5 with reagent 4A and solvent 4B to be 0.5 to 1.5 hours, and controlling the reaction time with compound 1-3, reagent 4C, The reaction time of reagent 4D, reagent 4E, and solvent 4F is 10 to 20 hours.
  • the preparation method of compound 1-6 wherein the reaction time with compound 1-3, reagent 4C, reagent 4D, reagent 4E, and solvent 4F is controlled to be 10 to 20 hours.
  • the preparation method of compound 1-6 includes the following reaction steps:
  • Reagent 3A is selected from metal catalysts
  • Solvent 3B is selected from nitrile solvents
  • Reagent 3C is selected from trimethylsilylacetylene
  • Reagent 3D is selected from palladium catalyst
  • Reagent 3E is selected from organic bases
  • Reagent 4A is selected from inorganic bases
  • Solvent 4B is selected from acyl solvents or mixed solvents of acyl solvents and water;
  • Reagent 4C is selected from inorganic bases
  • Reagent 4D is selected from palladium catalysts
  • Reagent 4E is selected from organophosphine ligands
  • Solvent 4F is selected from ester solvents.
  • Reagent 3A is selected from copper iodide
  • Solvent 3B is selected from acetonitrile
  • Reagent 3C is selected from trimethylsilylacetylene
  • Reagent 3D is selected from ditriphenylphosphine palladium chloride
  • Reagent 3E is selected from triethylamine
  • Reagent 4A is selected from potassium fluoride
  • Solvent 4B is selected from DMF or a mixed solvent of DMF and water;
  • Reagent 4C is selected from cesium carbonate
  • Reagent 4D is selected from palladium acetate
  • Reagent 4E is selected from Xphos
  • Solvent 4F is selected from isopropyl acetate.
  • the preparation method of compound 1-6 includes the following reaction steps:
  • Reagent 1A is selected from terephthalol
  • Solvent 1B is selected from DMF;
  • Reagent 1C is selected from potassium tert-butoxide
  • Solvent 2A is selected from anhydrous methylene chloride
  • Reagent 2B is selected from sulfoxide dichloride
  • Reagent 3A is selected from copper iodide
  • Solvent 3B is selected from acetonitrile
  • Reagent 3C is selected from trimethylsilylacetylene
  • Reagent 3D is selected from ditriphenylphosphine palladium chloride
  • Reagent 3E is selected from triethylamine
  • Reagent 4A is selected from potassium fluoride
  • Solvent 4B is selected from DMF or a mixed solvent of DMF and water;
  • Reagent 4C is selected from cesium carbonate
  • Reagent 4D is selected from palladium acetate
  • Reagent 4E is selected from Xphos
  • Solvent 4F is selected from isopropyl acetate.
  • the present invention also provides a preparation method of the compound of formula (I), which includes the following reaction steps:
  • Reagent 1A is selected from terephthalol
  • Solvent 1B is selected from DMF;
  • Reagent 1C is selected from potassium tert-butoxide
  • Solvent 2A is selected from anhydrous methylene chloride
  • Reagent 2B is selected from sulfoxide dichloride
  • Reagent 3A is selected from copper iodide
  • Solvent 3B is selected from acetonitrile
  • Reagent 3C is selected from trimethylsilylacetylene
  • Reagent 3D is selected from ditriphenylphosphine palladium chloride
  • Reagent 3E is selected from triethylamine
  • Reagent 4A is selected from potassium fluoride
  • Solvent 4B is selected from DMF or a mixed solvent of DMF and water;
  • Reagent 4C is selected from cesium carbonate
  • Reagent 4D is selected from palladium acetate
  • Reagent 4E is selected from Xphos
  • Solvent 4F is selected from isopropyl acetate
  • Solvent 5A is selected from anhydrous tetrahydrofuran
  • Reagent 5B is selected from sodium iodide.
  • the present invention also provides the use of the C crystal form and the D crystal form of the compound of formula (I) in the preparation of drugs related to the treatment of deep fungal infections.
  • the crystal form of the invention is stable, has good hygroscopicity, and has good prospects as a medicine, and the crystal form of the invention can effectively treat vaginal infections.
  • 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.
  • the relative intensities of diffraction peaks can change due to preferred orientation due to factors such as crystal morphology. Where there is an influence of preferred orientation, the peak intensity changes, but the diffraction peak position of the crystal form cannot be changed. Furthermore, there may be slight errors in the position of the peaks for any given crystalline form, as is also known in the art of crystallography. For example, due to changes in temperature, movement of the sample, or calibration of the instrument when analyzing the sample, the position of the peak may move, and the measurement error of the 2 ⁇ value is sometimes about ⁇ 0.2 degrees. Therefore, it is well known to those skilled in the art that when determining each crystal This error should be taken into account when constructing.
  • DSC measures the transition temperature when a crystal absorbs or releases heat due to a change in its crystal structure or melting of the crystal.
  • the thermal transition temperature and melting point errors are typically within about 5°C or 3°C.
  • DSC peak or melting point This refers to the DSC peak or melting point ⁇ 5°C or ⁇ 3°C.
  • DSC provides an auxiliary method to distinguish different crystal forms. Different crystalline forms can be identified based on their different transition temperature characteristics. It should be noted that for mixtures, the DSC peak or melting point may vary within a wider range. In addition, since the melting process of a substance is accompanied by decomposition, the melting temperature is related to the heating rate.
  • the TGA weight loss temperature may differ due to factors such as measuring instruments, measuring methods/conditions, etc. There may be an error in the weight loss temperature for any particular crystal form, which may be about ⁇ 5°C, and may be about ⁇ 3°C.
  • 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 D8venture 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.
  • Xphos represents 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl
  • DMF represents N,N-dimethylformamide
  • Test method About 10 ⁇ 20mg sample is used for XRPD detection.
  • Light tube voltage 45kV
  • light tube current 40mA
  • DSC Differential Scanning Calorimeter
  • Test method Take a sample ( ⁇ 1mg) and place it in a DSC aluminum pot for testing. Under N2 conditions, heat the sample from 25°C (room temperature) to 300°C (or 350°C) at a heating rate of 10°C/min.
  • TGA Thermal Gravimetric Analyzer
  • Test method Take a sample (2 ⁇ 5 mg) and place it in a TGA platinum pot for testing. Under N2 conditions, heat the sample from room temperature to 350°C or a weight loss of 20% at a heating rate of 10°C/min.
  • Test conditions Take a sample (10 ⁇ 20mg) and place it in the DVS sample tray for testing.
  • RH (%) range: 0-95%
  • Figure 1 is the XRPD spectrum of Cu-K ⁇ radiation of the crystal form C of the compound of formula (I);
  • Figure 2 is the DSC spectrum of the crystal form C of the compound of formula (I);
  • Figure 3 is the TGA spectrum of the crystal form C of the compound of formula (I);
  • Figure 4 is the XRPD spectrum of Cu-K ⁇ radiation of the crystal form D of the compound of formula (I);
  • Figure 5 is the DVS spectrum of the crystal form C of the compound of formula (I).
  • step 1
  • 2-Amino-5-iodopyridine (2.0Kg, 90.9mol) was dissolved in acetonitrile (20L), and copper iodide (86.6g, 0.45mol) and trimethylsilyl acetylene (1.16Kg, 11.8 mol), triethylamine (2.76Kg, 27.3mol) and diphenylphosphine palladium chloride (63.8g, 0.091mol).
  • the reaction mixture was stirred at 20°C for 1 hour. HPLC detected that the reaction was complete.
  • the reaction solution was directly concentrated under reduced pressure.
  • the filter cake is the hydrochloride of the compound of formula (I).
  • the filter cake was then slurried with a mixture of isopropyl alcohol (10L) and pure water (2.5L), filtered, and dried to obtain the C crystal form of the compound of formula (I) (700g, 47.1% yield).
  • the hygroscopic weight gain of the crystal form C of the compound of formula (I) at 25° C. and 80% RH is 0.42%, and it is slightly hygroscopic.
  • Test Example 1 In vivo efficacy study of compound C crystal form of formula (I) in candidemia model (VVC)
  • Microbial pathogen Candida albicans ATCC MYA-4788;
  • Inoculation level and route of inoculation 1.44E+05CFU/mouse, vaginal instillation infection;
  • vehicle vehicle
  • compound C crystal form 2, 6, 20mpk group of formula (I): oral administration of 1-aminobenzotriazole (ABT) 22 hours after infection, and intraperitoneal injection of the compound to be tested at 24 hours to start treatment .
  • ABT 1-aminobenzotriazole
  • mice in each group were infected, the vaginal tissue homogenates of the mice were taken for CFU counting.
  • a stable vaginal infection model can be established after mice are instilled with a certain dose of Candida albicans ATCC MYA-4788 through the vagina.
  • the bacterial load of vaginal tissue in the Vehicle group was 5.03 ⁇ 0.29 lg.
  • the bacterial load in vaginal tissue at doses of 20mpk, 6mpk, and 2mpk of compound C of formula (I) was reduced by 2.79 lg, 1.58 lg, and 0.68 lg respectively (P ⁇ 0.001, P ⁇ 0.05, P >0.05), and shows a certain dose-effect relationship.
  • the bactericidal effect of the crystal form C of the compound of formula (I) is very significant at a dose of 20mpk.
  • the crystal form of the present invention can effectively treat vaginal infection, and the crystal form C of compound of formula (I) has excellent medicinal efficacy.

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Abstract

Disclosed in the present invention are a crystal form of an alkynylpyridine compound and a preparation method therefor, specifically disclosed are a crystal form of a compound represented by formula (I) and a preparation method therefor.

Description

一种炔基吡啶类化合物的晶型及其制备方法Crystal form of alkynylpyridine compound and preparation method thereof
本发明主张如下优先权The present invention claims the following priority:
申请日：CN202210667399.3；申请号：2022年6月13日。Application date: CN202210667399.3; Application number: June 13, 2022.
技术领域Technical field
本发明涉及一种炔基吡啶类化合物的晶型及其制备方法，具体涉及式(I)所示化合物的晶型及其制备方法。The present invention relates to a crystal form of an alkynylpyridine compound and a preparation method thereof, in particular to a crystal form of a compound represented by formula (I) and a preparation method thereof.
背景技术Background technique
侵袭性真菌病(IFD)是真菌感染中致死率最高的一类，且发病率和死亡率呈急剧上升趋势。真菌细胞壁主要由葡聚糖、几丁质以及甘露糖蛋白组成，糖基磷脂酰肌醇卵锚定蛋白(GPI-AP)锚定于细胞膜及细胞壁上，介导甘露糖蛋白和葡聚糖进行交联，对于真菌的细胞壁合成、黏附及形态转换具有重要影响。其中，Gwt1是GPI合成过程中的关键乙酰化酶，对GPI前体形成具有重要作用。抑制Gwt1活性导致GPI-AP合成受阻，真菌表面甘露糖蛋白无法交联于细胞壁上，进而破坏其黏附宿主表面能力和细胞壁完整性，发挥抗真菌作用。Invasive fungal diseases (IFD) are the most lethal type of fungal infections, and the morbidity and mortality are rising sharply. The fungal cell wall is mainly composed of glucan, chitin and mannose protein. Glycosylphosphatidylinositol egg-anchored protein (GPI-AP) is anchored on the cell membrane and cell wall, mediating the interaction between mannose protein and glucan. Cross-linking has an important impact on fungal cell wall synthesis, adhesion and morphological transformation. Among them, Gwt1 is a key acetylase in the GPI synthesis process and plays an important role in the formation of GPI precursors. Inhibiting Gwt1 activity blocks GPI-AP synthesis, and the fungal surface mannoprotein cannot be cross-linked to the cell wall, thereby destroying its ability to adhere to the host surface and cell wall integrity, thereby exerting an antifungal effect.
发明内容Contents of the invention
本发明提供了式(I)化合物的C晶型，其特征在于其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：3.9975±0.200°，7.9169±0.200°，19.9390±0.200°，
The invention provides the C crystal form of the compound of formula (I), which is characterized in that its X-ray powder diffraction pattern of Cu, Kα radiation has characteristic diffraction peaks at the following 2θ angles: 3.9975±0.200°, 7.9169±0.200°, 19.9390± 0.200°,
在本发明的一些方案中，上述C晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：3.9975±0.200°，7.9169±0.200°，15.8368±0.200°，18.7250±0.200°，19.9390±0.200°，21.7115±0.200°，23.0090±0.200°，25.6600±0.200°。In some aspects of the invention, the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2θ angles: 3.9975±0.200°, 7.9169±0.200°, 15.8368±0.200°, 18.7250±0.200°, 19.9390± 0.200°, 21.7115±0.200°, 23.0090±0.200°, 25.6600±0.200°.
在本发明的一些方案中，上述C晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：3.9975±0.200°，7.9169±0.200°，15.8368±0.200°，18.7250±0.200°，19.9390±0.200°，20.3246±0.200°，21.7115±0.200°，23.0090±0.200°，25.6600±0.200°。In some aspects of the invention, the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2θ angles: 3.9975±0.200°, 7.9169±0.200°, 15.8368±0.200°, 18.7250±0.200°, 19.9390± 0.200°, 20.3246±0.200°, 21.7115±0.200°, 23.0090±0.200°, 25.6600±0.200°.
在本发明的一些方案中，上述C晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：3.9975±0.200°，7.9169±0.200°，15.8368±0.200°，18.7250±0.200°，19.9390±0.200°，20.8423±0.200°，21.7115±0.200°，22.3334±0.200°，23.0090±0.200°，24.0607±0.200°，25.6600±0.200°，27.1949±0.200°。In some aspects of the invention, the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2θ angles: 3.9975±0.200°, 7.9169±0.200°, 15.8368±0.200°, 18.7250±0.200°, 19.9390± 0.200°, 20.8423±0.200°, 21.7115±0.200°, 22.3334±0.200°, 23.0090±0.200°, 24.0607±0.200°, 25.6600±0.200°, 27.1949±0.200°.
在本发明的一些方案中，上述C晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：3.9975±0.200°，7.9169±0.200°，10.7005±0.200°，12.7114±0.200°，15.8368±0.200°，18.7250±0.200°，19.9390±0.200°，20.8423±0.200°，21.7115±0.200°，22.3334±0.200°，23.0090±0.200°，24.0607±0.200°，25.6600±0.200°，27.1949±0.200°，28.9541±0.200°，30.3507±0.200°。 In some aspects of the invention, the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2θ angles: 3.9975±0.200°, 7.9169±0.200°, 10.7005±0.200°, 12.7114±0.200°, 15.8368± 0.200°, 18.7250±0.200°, 19.9390±0.200°, 20.8423±0.200°, 21.7115±0.200°, 22.3334±0.200°, 23.0090±0.200°, 24.0607±0.200°, 25.6600±0.2 00°, 27.1949±0.200°, 28.9541± 0.200°, 30.3507±0.200°.
在本发明的一些方案中，上述C晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：3.9975±0.200°，7.9169±0.200°，15.8368±0.200°，18.7250±0.200°，20.3246±0.200°，21.7115±0.200°，23.0090±0.200°，25.6600±0.200°。In some aspects of the invention, the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2θ angles: 3.9975±0.200°, 7.9169±0.200°, 15.8368±0.200°, 18.7250±0.200°, 20.3246± 0.200°, 21.7115±0.200°, 23.0090±0.200°, 25.6600±0.200°.
在本发明的一些方案中，上述C晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：3.9975±0.200°，7.9169±0.200°，12.7114±0.200°，15.8368±0.200°，18.7250±0.200°，19.9390±0.200°，22.3334±0.200°，23.0090±0.200°。In some aspects of the invention, the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2θ angles: 3.9975±0.200°, 7.9169±0.200°, 12.7114±0.200°, 15.8368±0.200°, 18.7250± 0.200°, 19.9390±0.200°, 22.3334±0.200°, 23.0090±0.200°.
在本发明的一些方案中，上述C晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：3.9975±0.200°，7.9169±0.200°，12.7114±0.200°，15.8368±0.200°，18.7250±0.200°，19.9390±0.200°，21.7115±0.200°，22.3334±0.200°，23.0090±0.200°，25.6600±0.200°。In some aspects of the invention, the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2θ angles: 3.9975±0.200°, 7.9169±0.200°, 12.7114±0.200°, 15.8368±0.200°, 18.7250± 0.200°, 19.9390±0.200°, 21.7115±0.200°, 22.3334±0.200°, 23.0090±0.200°, 25.6600±0.200°.
在本发明的一些方案中，上述C晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：3.9975±0.200°，7.9169±0.200°，和/或10.7005±0.200°，和/或12.7114±0.200°，和/或15.8368±0.200°，和/或18.7250±0.200°，和/或19.9390±0.200°，和/或20.3246±0.200°，和/或20.8423±0.200°，和/或21.2448±0.200°，和/或21.7115±0.200°，和/或22.3334±0.200°，和/或23.0090±0.200°，和/或23.8153±0.200°，和/或24.0607±0.200°，和/或25.0930±0.200°，和/或25.6600±0.200°，和/或27.1949±0.200°，和/或28.9541±0.200°，和/或30.3507±0.200°，和/或31.1749±0.200°。In some aspects of the invention, the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2θ angles: 3.9975±0.200°, 7.9169±0.200°, and/or 10.7005±0.200°, and/or 12.7114 ±0.200°, and/or 15.8368±0.200°, and/or 18.7250±0.200°, and/or 19.9390±0.200°, and/or 20.3246±0.200°, and/or 20.8423±0.200°, and/or 21.2448±0.200 °, and/or 21.7115±0.200°, and/or 22.3334±0.200°, and/or 23.0090±0.200°, and/or 23.8153±0.200°, and/or 24.0607±0.200°, and/or 25.0930±0.200°, and/or 25.6600±0.200°, and/or 27.1949±0.200°, and/or 28.9541±0.200°, and/or 30.3507±0.200°, and/or 31.1749±0.200°.
在本发明的一些方案中，上述C晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.00°，7.92°，10.70°，12.71°，15.84°，18.72°，19.94°，20.32°，20.84°，21.24°，21.71°，22.33°，23.01°，23.82°，24.06°，25.09°，25.66°，27.19°，28.95°，30.35°，31.17°。In some aspects of the invention, the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2θ angles: 4.00°, 7.92°, 10.70°, 12.71°, 15.84°, 18.72°, 19.94°, 20.32 °, 20.84°, 21.24°, 21.71°, 22.33°, 23.01°, 23.82°, 24.06°, 25.09°, 25.66°, 27.19°, 28.95°, 30.35°, 31.17°.
在本发明的一些方案中，上述C晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：3.9975°，7.9169°，10.7005°，12.7114°，15.8368°，18.7250°，19.9390°，20.3246°，20.8423°，21.2448°，21.7115°，22.3334°，23.0090°，23.8153°，24.0607°，25.0930°，25.6600°，27.1949°，28.9541°，30.3507°，31.1749°。In some aspects of the invention, the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2θ angles: 3.9975°, 7.9169°, 10.7005°, 12.7114°, 15.8368°, 18.7250°, 19.9390°, 20.3246 °, 20.8423°, 21.2448°, 21.7115°, 22.3334°, 23.0090°, 23.8153°, 24.0607°, 25.0930°, 25.6600°, 27.1949°, 28.9541°, 30.3507°, 31.1749°.
在本发明的一些方案中，上述C晶型的XRPD图谱基本上如图1所示。In some aspects of the present invention, the XRPD pattern of the above-mentioned crystal form C is basically as shown in Figure 1.
在本发明的一些方案中，上述C晶型的XRPD图谱解析数据如表1所示：In some solutions of the present invention, the XRPD spectrum analysis data of the above-mentioned C crystal form is as shown in Table 1:
表1.C晶型的XRPD图谱解析数据

Table 1. XRPD spectrum analysis data of crystal form C

在本发明的一些方案中，上述C晶型的差示扫描量热曲线在199.2±3℃处具有吸热峰。In some aspects of the present invention, the differential scanning calorimetry curve of the above-mentioned C crystal form has an endothermic peak at 199.2±3°C.
在本发明的一些方案中，上述C晶型的DSC图谱如图2所示。In some aspects of the present invention, the DSC pattern of the above-mentioned C crystal form is shown in Figure 2.
在本发明的一些方案中，上述C晶型的热重分析曲线在150±3℃时失重达2.28％。In some aspects of the present invention, the thermogravimetric analysis curve of the above-mentioned C crystal form has a weight loss of 2.28% at 150±3°C.
在本发明的一些方案中，上述C晶型的TGA图谱如图3所示。In some aspects of the present invention, the TGA spectrum of the above crystal form C is shown in Figure 3.
本发明提供了式(I)化合物的D晶型，其特征在于其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：4.0789±0.200°，8.1226±0.200°，14.9322±0.200°，18.2233±0.200°，21.4231±0.200°，
The invention provides the D crystal form of the compound of formula (I), which is characterized in that its X-ray powder diffraction pattern of Cu, Kα radiation has characteristic diffraction peaks at the following 2θ angles: 4.0789±0.200°, 8.1226±0.200°, 14.9322± 0.200°, 18.2233±0.200°, 21.4231±0.200°,
在本发明的一些方案中，上述D晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.0789±0.200°，7.4609±0.200°，8.1226±0.200°，14.9322±0.200°，18.2233±0.200°，18.6712±0.200°，21.4231±0.200°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned D crystal form has characteristic diffraction peaks at the following 2θ angles: 4.0789±0.200°, 7.4609±0.200°, 8.1226±0.200°, 14.9322±0.200°, 18.2233± 0.200°, 18.6712±0.200°, 21.4231±0.200°.
在本发明的一些方案中，上述D晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.0789±0.200°，7.4609±0.200°，8.1226±0.200°，12.1939±0.200°，14.9322±0.200°，18.2233±0.200°，18.6712±0.200°，21.4231±0.200°，22.4812±0.200°，26.2452±0.200°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned D crystal form has characteristic diffraction peaks at the following 2θ angles: 4.0789±0.200°, 7.4609±0.200°, 8.1226±0.200°, 12.1939±0.200°, 14.9322± 0.200°, 18.2233±0.200°, 18.6712±0.200°, 21.4231±0.200°, 22.4812±0.200°, 26.2452±0.200°.
在本发明的一些方案中，上述D晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：3.75°，4.08°，7.46°，8.12°，12.19°，14.93°，18.22°，18.67°，19.38°，21.42°，22.48°，26.25°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned D crystal form has characteristic diffraction peaks at the following 2θ angles: 3.75°, 4.08°, 7.46°, 8.12°, 12.19°, 14.93°, 18.22°, 18.67 °, 19.38°, 21.42°, 22.48°, 26.25°.
在本发明的一些方案中，上述D晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：3.7520°，4.0789°，7.4609°，8.1226°，12.1939°，14.9322°，18.2233°，18.6712°，19.3838°，21.4231°，22.4812°，26.2452°。In some aspects of the invention, the X-ray powder diffraction pattern of the above-mentioned D crystal form has characteristic diffraction peaks at the following 2θ angles: 3.7520°, 4.0789°, 7.4609°, 8.1226°, 12.1939°, 14.9322°, 18.2233°, 18.6712 °, 19.3838°, 21.4231°, 22.4812°, 26.2452°.
在本发明的一些方案中，上述D晶型的XRPD图谱基本上如图4所示。In some aspects of the present invention, the XRPD pattern of the above-mentioned crystal form D is basically as shown in Figure 4.
在本发明的一些方案中，上述D晶型的XRPD图谱解析数据如表2所示：In some aspects of the present invention, the XRPD spectrum analysis data of the above-mentioned D crystal form is as shown in Table 2:
表2.D晶型的XRPD图谱解析数据

Table 2. XRPD spectrum analysis data of crystal form D

本发明还提供了化合物1-6的制备方法，其包括如下反应步骤：
The invention also provides a preparation method of compound 1-6, which includes the following reaction steps:
其中，in,
试剂4A选自无机碱；Reagent 4A is selected from inorganic bases;
溶剂4B选自酰类溶剂或酰类溶剂和水的混合溶剂；Solvent 4B is selected from acyl solvents or mixed solvents of acyl solvents and water;
试剂4C选自无机碱；Reagent 4C is selected from inorganic bases;
试剂4D选自钯催化剂；Reagent 4D is selected from palladium catalysts;
试剂4E选自有机膦配体；Reagent 4E is selected from organophosphine ligands;
溶剂4F选自酯类溶剂。Solvent 4F is selected from ester solvents.
在本发明的一些方案中，所述化合物1-6的制备方法，其中，In some aspects of the invention, the preparation method of compound 1-6, wherein,
试剂4A选自氟化钾；Reagent 4A is selected from potassium fluoride;
溶剂4B选自DMF或DMF和水的混合溶剂；Solvent 4B is selected from DMF or a mixed solvent of DMF and water;
试剂4C选自碳酸铯；Reagent 4C is selected from cesium carbonate;
试剂4D选自醋酸钯；Reagent 4D is selected from palladium acetate;
试剂4E选自Xphos；Reagent 4E is selected from Xphos;
溶剂4F选自醋酸异丙酯。Solvent 4F is selected from isopropyl acetate.
在本发明的一些方案中，所述化合物1-6的制备方法，其中，溶剂4B的混合溶剂中DMF和水的体积比为5～8:1。In some aspects of the present invention, the preparation method of compound 1-6, wherein the volume ratio of DMF and water in the mixed solvent of solvent 4B is 5 to 8:1.
在本发明的一些方案中，所述化合物1-6的制备方法，其中，化合物1-5先用试剂4A在溶剂4B中脱保护，再与化合物1-3经试剂4C、试剂4D、试剂4E催化在溶剂4F中偶联。In some aspects of the present invention, the preparation method of compound 1-6, wherein compound 1-5 is first deprotected with reagent 4A in solvent 4B, and then combined with compound 1-3 through reagent 4C, reagent 4D, reagent 4E Catalytic coupling was performed in solvent 4F.
在本发明的一些方案中，所述化合物1-6的制备方法，其中，试剂4A与化合物1-5的摩尔比为4.0～6.0:1，化合物1-3与化合物1-5的摩尔比为0.5～1.5:1，试剂4C与化合物1-5的摩尔比为3～5:1，试剂4D与化合物1-5的摩尔比为0.01～0.02:1，试剂4E与化合物1-5的摩尔比为0.02～0.04:1。In some aspects of the present invention, the preparation method of compound 1-6, wherein the molar ratio of reagent 4A to compound 1-5 is 4.0-6.0:1, and the molar ratio of compound 1-3 to compound 1-5 is 0.5～1.5:1, the molar ratio of reagent 4C to compound 1-5 is 3～5:1, the molar ratio of reagent 4D to compound 1-5 is 0.01～0.02:1, the molar ratio of reagent 4E to compound 1-5 It is 0.02~0.04:1.
在本发明的一些方案中，所述化合物1-6的制备方法，其中，试剂4A与化合物1-5的摩尔比为4.0～6.0:1。 In some aspects of the present invention, the preparation method of compound 1-6, wherein the molar ratio of reagent 4A to compound 1-5 is 4.0 to 6.0:1.
在本发明的一些方案中，所述化合物1-6的制备方法，其中，化合物1-3与化合物1-5的摩尔比为0.5～1.5:1。In some aspects of the present invention, the preparation method of compound 1-6, wherein the molar ratio of compound 1-3 to compound 1-5 is 0.5 to 1.5:1.
在本发明的一些方案中，所述化合物1-6的制备方法，其中，试剂4C与化合物1-5的摩尔比为3～5:1。In some aspects of the present invention, in the preparation method of compound 1-6, the molar ratio of reagent 4C to compound 1-5 is 3 to 5:1.
在本发明的一些方案中，所述化合物1-6的制备方法，其中，试剂4D与化合物1-5的摩尔比为0.01～0.02:1。In some aspects of the present invention, in the preparation method of compound 1-6, the molar ratio of reagent 4D to compound 1-5 is 0.01 to 0.02:1.
在本发明的一些方案中，所述化合物1-6的制备方法，其中，试剂4E与化合物1-5的摩尔比为0.02～0.04:1。In some aspects of the present invention, in the preparation method of compound 1-6, the molar ratio of reagent 4E to compound 1-5 is 0.02 to 0.04:1.
在本发明的一些方案中，所述化合物1-6的制备方法，其中，试剂4A与化合物1-5的摩尔比为5.0～5.5:1，化合物1-3与化合物1-5的摩尔比为0.5～1:1，试剂4C与化合物1-5的摩尔比为3.5～4.5:1，试剂4D与化合物1-5的摩尔比为0.01～0.02:1，试剂4E与化合物1-5的摩尔比为0.02～0.03:1。In some aspects of the present invention, the preparation method of compound 1-6, wherein the molar ratio of reagent 4A to compound 1-5 is 5.0 to 5.5:1, and the molar ratio of compound 1-3 to compound 1-5 is 0.5～1:1, the molar ratio of reagent 4C to compound 1-5 is 3.5～4.5:1, the molar ratio of reagent 4D to compound 1-5 is 0.01～0.02:1, the molar ratio of reagent 4E to compound 1-5 It is 0.02~0.03:1.
在本发明的一些方案中，所述化合物1-6的制备方法，其中，试剂4A与化合物1-5的摩尔比为5.0～5.5:1。In some aspects of the present invention, the preparation method of compound 1-6, wherein the molar ratio of reagent 4A to compound 1-5 is 5.0 to 5.5:1.
在本发明的一些方案中，所述化合物1-6的制备方法，其中，化合物1-3与化合物1-5的摩尔比为0.5～1:1。In some aspects of the present invention, the preparation method of compound 1-6, wherein the molar ratio of compound 1-3 to compound 1-5 is 0.5 to 1:1.
在本发明的一些方案中，所述化合物1-6的制备方法，其中，试剂4C与化合物1-5的摩尔比为3.5～4.5:1。In some aspects of the present invention, in the preparation method of compound 1-6, the molar ratio of reagent 4C to compound 1-5 is 3.5 to 4.5:1.
在本发明的一些方案中，所述化合物1-6的制备方法，其中，试剂4D与化合物1-5的摩尔比为0.01～0.02:1。In some aspects of the present invention, in the preparation method of compound 1-6, the molar ratio of reagent 4D to compound 1-5 is 0.01 to 0.02:1.
在本发明的一些方案中，所述化合物1-6的制备方法，其中，试剂4E与化合物1-5的摩尔比为0.02～0.03:1。In some aspects of the present invention, the preparation method of compound 1-6, wherein the molar ratio of reagent 4E to compound 1-5 is 0.02 to 0.03:1.
在本发明的一些方案中，所述化合物1-6的制备方法，其中，控制化合物1-5与试剂4A、溶剂4B的反应体系温度范围为10～40℃，控制与化合物1-3、试剂4C、试剂4D、试剂4E、溶剂4F的反应体系温度范围为60～100℃。In some aspects of the present invention, the preparation method of compound 1-6, wherein the reaction system temperature range of compound 1-5, reagent 4A, and solvent 4B is controlled to be 10-40°C, and the temperature range of the reaction system with compound 1-3, reagent 4B is controlled to be 10-40°C. The reaction system temperature range of 4C, reagent 4D, reagent 4E, and solvent 4F is 60 to 100°C.
在本发明的一些方案中，所述化合物1-6的制备方法，其中，控制化合物1-5与试剂4A、溶剂4B的反应体系温度范围为10～40℃。In some aspects of the present invention, the preparation method of compound 1-6, wherein the temperature range of the reaction system of compound 1-5, reagent 4A, and solvent 4B is controlled to be 10 to 40°C.
在本发明的一些方案中，所述化合物1-6的制备方法，其中，控制与化合物1-3、试剂4C、试剂4D、试剂4E、溶剂4F的反应体系温度范围为60～100℃。In some aspects of the present invention, in the preparation method of compound 1-6, the temperature range of the reaction system with compound 1-3, reagent 4C, reagent 4D, reagent 4E, and solvent 4F is controlled to be 60 to 100°C.
在本发明的一些方案中，所述化合物1-6的制备方法，其中，控制化合物1-5与试剂4A、溶剂4B的反应体系温度范围为15～25℃，控制与化合物1-3、试剂4C、试剂4D、试剂4E、溶剂4F的反应体系温度范围为75～85℃。In some aspects of the present invention, the preparation method of compound 1-6, wherein the reaction system temperature range of compound 1-5, reagent 4A, and solvent 4B is controlled to be 15-25°C, and the reaction system temperature range of compound 1-5, reagent 4A, and solvent 4B is controlled to be 15-25°C. The reaction system temperature range of 4C, reagent 4D, reagent 4E, and solvent 4F is 75 to 85°C.
在本发明的一些方案中，所述化合物1-6的制备方法，其中，控制化合物1-5与试剂4A、溶剂4B的反应体系温度范围为15～25℃。In some aspects of the present invention, the preparation method of compound 1-6, wherein the reaction system temperature range of compound 1-5, reagent 4A, and solvent 4B is controlled to be 15-25°C.
在本发明的一些方案中，所述化合物1-6的制备方法，其中，控制与化合物1-3、试剂4C、试剂4D、试剂4E、溶剂4F的反应体系温度范围为75～85℃。 In some aspects of the present invention, in the preparation method of compound 1-6, the temperature range of the reaction system with compound 1-3, reagent 4C, reagent 4D, reagent 4E, and solvent 4F is controlled to be 75 to 85°C.
在本发明的一些方案中，所述化合物1-6的制备方法，其中，控制化合物1-5与试剂4A、溶剂4B的反应时长为0.5～3小时，控制与化合物1-3、试剂4C、试剂4D、试剂4E、溶剂4F的反应时长为8～24小时。In some aspects of the invention, the preparation method of compound 1-6 includes controlling the reaction time of compound 1-5 with reagent 4A and solvent 4B to be 0.5 to 3 hours, and controlling the reaction time with compound 1-3, reagent 4C, The reaction time of reagent 4D, reagent 4E, and solvent 4F is 8 to 24 hours.
在本发明的一些方案中，所述化合物1-6的制备方法，其中，控制化合物1-5与试剂4A、溶剂4B的反应时长为0.5～3小时。In some aspects of the present invention, the preparation method of compound 1-6, wherein the reaction time of compound 1-5, reagent 4A, and solvent 4B is controlled to be 0.5 to 3 hours.
在本发明的一些方案中，所述化合物1-6的制备方法，其中，控制与化合物1-3、试剂4C、试剂4D、试剂4E、溶剂4F的反应时长为8～24小时。In some aspects of the present invention, the preparation method of compound 1-6, wherein the reaction time with compound 1-3, reagent 4C, reagent 4D, reagent 4E, and solvent 4F is controlled to be 8 to 24 hours.
在本发明的一些方案中，所述化合物1-6的制备方法，其中，控制化合物1-5与试剂4A、溶剂4B的反应时长为0.5～1.5小时，控制与化合物1-3、试剂4C、试剂4D、试剂4E、溶剂4F的反应时长为10～20小时。In some aspects of the invention, the preparation method of compound 1-6 includes controlling the reaction time of compound 1-5 with reagent 4A and solvent 4B to be 0.5 to 1.5 hours, and controlling the reaction time with compound 1-3, reagent 4C, The reaction time of reagent 4D, reagent 4E, and solvent 4F is 10 to 20 hours.
在本发明的一些方案中，所述化合物1-6的制备方法，其中，控制化合物1-5与试剂4A、溶剂4B的反应时长为0.5～1.5小时。In some aspects of the present invention, the preparation method of compound 1-6, wherein the reaction time of compound 1-5, reagent 4A, and solvent 4B is controlled to be 0.5 to 1.5 hours.
在本发明的一些方案中，所述化合物1-6的制备方法，其中，控制与化合物1-3、试剂4C、试剂4D、试剂4E、溶剂4F的反应时长为10～20小时。In some aspects of the present invention, the preparation method of compound 1-6, wherein the reaction time with compound 1-3, reagent 4C, reagent 4D, reagent 4E, and solvent 4F is controlled to be 10 to 20 hours.
在本发明的一些方案中，所述化合物1-6的制备方法，其包括如下反应步骤：
In some aspects of the present invention, the preparation method of compound 1-6 includes the following reaction steps:
其中，in,
试剂3A选自金属催化剂；Reagent 3A is selected from metal catalysts;
溶剂3B选自腈类溶剂；Solvent 3B is selected from nitrile solvents;
试剂3C选自三甲基硅乙炔；Reagent 3C is selected from trimethylsilylacetylene;
试剂3D选自钯催化剂；Reagent 3D is selected from palladium catalyst;
试剂3E选自有机碱；Reagent 3E is selected from organic bases;
试剂4A选自无机碱；Reagent 4A is selected from inorganic bases;
溶剂4B选自酰类溶剂或酰类溶剂和水的混合溶剂；Solvent 4B is selected from acyl solvents or mixed solvents of acyl solvents and water;
试剂4C选自无机碱；Reagent 4C is selected from inorganic bases;
试剂4D选自钯催化剂；Reagent 4D is selected from palladium catalysts;
试剂4E选自有机膦配体；Reagent 4E is selected from organophosphine ligands;
溶剂4F选自酯类溶剂。Solvent 4F is selected from ester solvents.
在本发明的一些方案中，所述化合物1-6的制备方法，其中，In some aspects of the invention, the preparation method of compound 1-6, wherein,
试剂3A选自碘化亚铜； Reagent 3A is selected from copper iodide;
溶剂3B选自乙腈；Solvent 3B is selected from acetonitrile;
试剂3C选自三甲基硅乙炔；Reagent 3C is selected from trimethylsilylacetylene;
试剂3D选自二三苯基膦氯化钯；Reagent 3D is selected from ditriphenylphosphine palladium chloride;
试剂3E选自三乙胺；Reagent 3E is selected from triethylamine;
试剂4A选自氟化钾；Reagent 4A is selected from potassium fluoride;
溶剂4B选自DMF或DMF和水的混合溶剂；Solvent 4B is selected from DMF or a mixed solvent of DMF and water;
试剂4C选自碳酸铯；Reagent 4C is selected from cesium carbonate;
试剂4D选自醋酸钯；Reagent 4D is selected from palladium acetate;
试剂4E选自Xphos；Reagent 4E is selected from Xphos;
溶剂4F选自醋酸异丙酯。Solvent 4F is selected from isopropyl acetate.
在本发明的一些方案中，所述化合物1-6的制备方法，其包括如下反应步骤：
In some aspects of the present invention, the preparation method of compound 1-6 includes the following reaction steps:
其中，in,
试剂1A选自对苯二甲醇；Reagent 1A is selected from terephthalol;
溶剂1B选自DMF；Solvent 1B is selected from DMF;
试剂1C选自叔丁醇钾；Reagent 1C is selected from potassium tert-butoxide;
溶剂2A选自无水二氯甲烷；Solvent 2A is selected from anhydrous methylene chloride;
试剂2B选自二氯亚砜；Reagent 2B is selected from sulfoxide dichloride;
试剂3A选自碘化亚铜；Reagent 3A is selected from copper iodide;
溶剂3B选自乙腈；Solvent 3B is selected from acetonitrile;
试剂3C选自三甲基硅乙炔；Reagent 3C is selected from trimethylsilylacetylene;
试剂3D选自二三苯基膦氯化钯；Reagent 3D is selected from ditriphenylphosphine palladium chloride;
试剂3E选自三乙胺；Reagent 3E is selected from triethylamine;
试剂4A选自氟化钾；Reagent 4A is selected from potassium fluoride;
溶剂4B选自DMF或DMF和水的混合溶剂；Solvent 4B is selected from DMF or a mixed solvent of DMF and water;
试剂4C选自碳酸铯；Reagent 4C is selected from cesium carbonate;
试剂4D选自醋酸钯； Reagent 4D is selected from palladium acetate;
试剂4E选自Xphos；Reagent 4E is selected from Xphos;
溶剂4F选自醋酸异丙酯。Solvent 4F is selected from isopropyl acetate.
本发明还提供了式(I)化合物的制备方法，其包括如下反应步骤：
The present invention also provides a preparation method of the compound of formula (I), which includes the following reaction steps:
其中，in,
试剂1A选自对苯二甲醇；Reagent 1A is selected from terephthalol;
溶剂1B选自DMF；Solvent 1B is selected from DMF;
试剂1C选自叔丁醇钾；Reagent 1C is selected from potassium tert-butoxide;
溶剂2A选自无水二氯甲烷；Solvent 2A is selected from anhydrous methylene chloride;
试剂2B选自二氯亚砜；Reagent 2B is selected from sulfoxide dichloride;
试剂3A选自碘化亚铜；Reagent 3A is selected from copper iodide;
溶剂3B选自乙腈；Solvent 3B is selected from acetonitrile;
试剂3C选自三甲基硅乙炔；Reagent 3C is selected from trimethylsilylacetylene;
试剂3D选自二三苯基膦氯化钯；Reagent 3D is selected from ditriphenylphosphine palladium chloride;
试剂3E选自三乙胺；Reagent 3E is selected from triethylamine;
试剂4A选自氟化钾；Reagent 4A is selected from potassium fluoride;
溶剂4B选自DMF或DMF和水的混合溶剂；Solvent 4B is selected from DMF or a mixed solvent of DMF and water;
试剂4C选自碳酸铯；Reagent 4C is selected from cesium carbonate;
试剂4D选自醋酸钯；Reagent 4D is selected from palladium acetate;
试剂4E选自Xphos；Reagent 4E is selected from Xphos;
溶剂4F选自醋酸异丙酯；Solvent 4F is selected from isopropyl acetate;
溶剂5A选自无水四氢呋喃； Solvent 5A is selected from anhydrous tetrahydrofuran;
试剂5B选自碘化钠。Reagent 5B is selected from sodium iodide.
本发明还提供了式(I)化合物的C晶型和D晶型在制备治疗与深部真菌感染相关药物中的应用。The present invention also provides the use of the C crystal form and the D crystal form of the compound of formula (I) in the preparation of drugs related to the treatment of deep fungal infections.
技术效果Technical effect
本发明晶型稳定，引湿性良好，成药前景佳，且本发明晶型可有效治疗***感染。The crystal form of the invention is stable, has good hygroscopicity, and has good prospects as a medicine, and the crystal form of the invention can effectively treat vaginal infections.
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.
需要说明的是，在制备药物晶型时，药物分子与溶剂分子在接触的过程中，外部条件与内部因素造成溶剂分子与化合物分子形成共晶而残留在固体物质中的情况很难避免，从而形成溶剂合物，具体包括化学计量类溶剂合物和非化学计量类溶剂合物。所述的溶剂合物均包括在本发明的范围内。It should be noted that when preparing drug crystal forms, during the contact process between drug molecules and solvent molecules, external conditions and internal factors cause the solvent molecules and compound molecules to form a eutectic and remain in the solid material. Therefore, it is difficult to avoid the situation. Solvates are formed, specifically including stoichiometric solvates and non-stoichiometric solvates. The solvates described are all included in the scope of the present invention.
对于任何给定的结晶形式而言，由于例如结晶形态等因素引起的优选取向，衍射峰的相对强度可以改变，这在结晶学领域中是公知的。存在优选取向影响的地方，峰强度是改变的，但是晶型的衍射峰位置是无法改变的。此外，对任何给定的晶型而言，峰的位置可能存在轻微误差，这在结晶学领域中也是公知的。例如，由于分析样品时温度的变化、样品的移动、或仪器的标定等，峰的位置可以移动，2θ值的测量误差有时约为±0.2度，因此，本领域技术人员公知在确定每种结晶结构时，应该将此误差考虑在内。For any given crystalline form, it is well known in the art of crystallography that the relative intensities of diffraction peaks can change due to preferred orientation due to factors such as crystal morphology. Where there is an influence of preferred orientation, the peak intensity changes, but the diffraction peak position of the crystal form cannot be changed. Furthermore, there may be slight errors in the position of the peaks for any given crystalline form, as is also known in the art of crystallography. For example, due to changes in temperature, movement of the sample, or calibration of the instrument when analyzing the sample, the position of the peak may move, and the measurement error of the 2θ value is sometimes about ±0.2 degrees. Therefore, it is well known to those skilled in the art that when determining each crystal This error should be taken into account when constructing.
DSC测定当结晶由于其结晶结构发生变化或结晶熔融而吸收或释放热时的转变温度。对于同种化合物的同种晶型，在连续的分析中，热转变温度和熔点误差典型的在约5℃或3℃之内，当我们说一个化合物具有一给定的DSC峰或熔点时，这是指该DSC峰或熔点±5℃或±3℃。DSC提供了一种辨别不同晶型的辅助方法。不同的结晶形态可根据其不同的转变温度特征而加以识别。需要指出的是对于混合物而言，其DSC峰或熔点可能会在更大的范围内变动。此外，由于在物质熔化的过程中伴有分解，因此熔化温度与升温速率相关。DSC measures the transition temperature when a crystal absorbs or releases heat due to a change in its crystal structure or melting of the crystal. For the same crystalline form of the same compound, in successive analyses, the thermal transition temperature and melting point errors are typically within about 5°C or 3°C. When we say that a compound has a given DSC peak or melting point, This refers to the DSC peak or melting point ±5°C or ±3°C. DSC provides an auxiliary method to distinguish different crystal forms. Different crystalline forms can be identified based on their different transition temperature characteristics. It should be noted that for mixtures, the DSC peak or melting point may vary within a wider range. In addition, since the melting process of a substance is accompanied by decomposition, the melting temperature is related to the heating rate.
对于同种晶型，TGA失重温度出现可能会因为测定仪器、测定方法/条件等因素而产生差异。对任何特定的晶型，失重温度可能存在误差，误差可以为约±5℃，可以为约±3℃。 For the same crystal form, the TGA weight loss temperature may differ due to factors such as measuring instruments, measuring methods/conditions, etc. There may be an error in the weight loss temperature for any particular crystal form, which may be about ±5°C, and may be about ±3°C.
除非另有规定，DSC谱图放热朝上。Unless otherwise specified, DSC spectra are exothermic upward.
本发明所使用的所有溶剂是市售的，无需进一步纯化即可使用。All solvents used in the present invention are commercially available and used without further purification.
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 D8venture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 D8venture 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.
本发明所使用的所有溶剂是市售的，无需进一步纯化即可使用。本发明采用如下缩略词：Xphos代表2-二环己基膦-2',4',6'-三异丙基联苯；DMF代表N,N-二甲基甲酰胺。All solvents used in the present invention are commercially available and used without further purification. The following abbreviations are used in the present invention: Xphos represents 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl; DMF represents N,N-dimethylformamide.
化合物依据本领域常规命名原则或者软件命名，市售化合物采用供应商目录名称。Compounds are named according to conventional naming principles in the field or For software naming, commercially available compounds adopt supplier catalog names.
本发明粉末X-射线衍射(X-ray powder diffractometer,XRPD)方法Powder X-ray diffraction (X-ray powder diffractometer, XRPD) method of the present invention
仪器型号：PANalytacal X’Pert3X-射线衍射仪Instrument model: PANalytacal X’Pert3X-ray diffractometer
测试方法：大约10～20mg样品用于XRPD检测。Test method: About 10~20mg sample is used for XRPD detection.
详细的XRPD参数如下：The detailed XRPD parameters are as follows:
光管：Cu,Kα, Light tube: Cu, Kα,
光管电压：45kV，光管电流：40mALight tube voltage: 45kV, light tube current: 40mA
发散狭缝：1/8°Divergence slit: 1/8°
扫描模式：连续Scan mode: continuous
扫描范围：3-40degScanning range: 3-40deg
扫描步长：0.0263degScan step size: 0.0263deg
每步扫描时间：46.7秒Scan time per step: 46.7 seconds
测试时间：～5minTest time: ~5min
本发明差热分析(Differential Scanning Calorimeter,DSC)方法Differential Scanning Calorimeter (DSC) method of the present invention
仪器型号：TA 2500差示扫描量热仪Instrument model: TA 2500 differential scanning calorimeter
测试方法：取样品(～1mg)置于DSC铝锅内进行测试，在N2条件下，以10℃/min的升温速率，加热样品从25℃(室温)到300℃(或350℃)。Test method: Take a sample (~1mg) and place it in a DSC aluminum pot for testing. Under N2 conditions, heat the sample from 25°C (room temperature) to 300°C (or 350°C) at a heating rate of 10°C/min.
本发明热重分析(Thermal Gravimetric Analyzer,TGA)方法Thermal Gravimetric Analyzer (TGA) method of the present invention
仪器型号：TA 5500热重分析仪Instrument model: TA 5500 thermogravimetric analyzer
测试方法：取样品(2～5mg)置于TGA铂金锅内进行测试，在N2条件下，以10℃/min的升温速率，加热样品从室温到350℃或失重20％。Test method: Take a sample (2~5 mg) and place it in a TGA platinum pot for testing. Under N2 conditions, heat the sample from room temperature to 350°C or a weight loss of 20% at a heating rate of 10°C/min.
本发明动态水分吸附分析(Dynamic Vapor Sorption,DVS)方法Dynamic moisture adsorption analysis (Dynamic Vapor Sorption, DVS) method of the present invention
仪器型号：SMS DVS Intrinsic Instrument model: SMS DVS Intrinsic
测试条件：取样品(10～20mg)置于DVS样品盘内进行测试。Test conditions: Take a sample (10~20mg) and place it in the DVS sample tray for testing.
详细的DVS参数如下：The detailed DVS parameters are as follows:
温度：25℃Temperature: 25℃
平衡：dm/dt＝0.002％/min(最短：10min，最长：180min)Balance: dm/dt=0.002%/min (minimum: 10min, maximum: 180min)
干燥：0％RH下干燥120minDrying: 120min at 0%RH
RH(％)范围：0-95％RH (%) range: 0-95%
RH(％)梯度：0％-95％RH (%) gradient: 0%-95%
引湿性评价分类如表3所示：The classification of hygroscopicity evaluation is shown in Table 3:
表3.引湿性评价分类

注：ΔW％表示受试品在25±1℃和80±2％RH下的吸湿增重。Table 3. Hygroscopicity evaluation classification

Note: ΔW% represents the moisture absorption weight gain of the test product at 25±1℃ and 80±2%RH.
附图说明Description of the drawings
图1为式(I)化合物C晶型的Cu-Kα辐射的XRPD谱图；Figure 1 is the XRPD spectrum of Cu-Kα radiation of the crystal form C of the compound of formula (I);
图2为式(I)化合物C晶型的DSC谱图；Figure 2 is the DSC spectrum of the crystal form C of the compound of formula (I);
图3为式(I)化合物C晶型的TGA谱图；Figure 3 is the TGA spectrum of the crystal form C of the compound of formula (I);
图4为式(I)化合物D晶型的Cu-Kα辐射的XRPD谱图；Figure 4 is the XRPD spectrum of Cu-Kα radiation of the crystal form D of the compound of formula (I);
图5为式(I)化合物C晶型的DVS谱图。Figure 5 is the DVS spectrum of the crystal form C 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(I)化合物C晶型的制备
Example 1: Preparation of crystal form C of compound of formula (I)
步骤1：step 1:
N2保护下，将2-氟吡啶(1.0Kg，10.3mol)和对苯二甲醇(2.13Kg，15.4mol)加入到DMF(10.0L)中，溶液冷却至0℃，分批加入叔丁醇钾(1.73Kg,15.4mol)，加料完毕，反应体系在20-35℃搅拌1小时，HPLC显示反应完成。反应液加入到冰水(20L)中，用正庚烷(10L×2)洗涤，水相用醋酸异丙酯(10L×2)萃取，有机相用10％氯化钠水溶液(10L)洗涤，无水硫酸钠干燥，过滤，滤液浓缩，得到化合物1-2(1.02Kg，收率46％)。1H NMR(400MHz,CDCl3)δ8.19(dd,J＝1.4,5.1Hz,1H),7.61(ddd,J＝2.0,6.8,8.5Hz,1H),7.52-7.45(m,2H),7.43-7.36(m,2H),6.91(ddd,J＝0.8,5.0,7.0Hz,1H),6.83(d,J＝8.3Hz,1H),5.39(s,2H),4.74-4.69(m,2H)。Under N2 protection, add 2-fluoropyridine (1.0Kg, 10.3mol) and terephthalol (2.13Kg, 15.4mol) to DMF (10.0L), cool the solution to 0°C, and add tert-butyl alcohol in batches Potassium (1.73Kg, 15.4mol), the addition is completed, the reaction system is stirred at 20-35°C for 1 hour, HPLC shows that the reaction is completed. The reaction solution was added to ice water (20L), washed with n-heptane (10L×2), the aqueous phase was extracted with isopropyl acetate (10L×2), and the organic phase was washed with 10% sodium chloride aqueous solution (10L). Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain compound 1-2 (1.02Kg, yield 46%). 1 H NMR (400MHz, CDCl 3 ) δ8.19 (dd, J＝1.4, 5.1Hz, 1H), 7.61 (ddd, J＝2.0, 6.8, 8.5Hz, 1H), 7.52-7.45 (m, 2H), 7.43-7.36(m,2H),6.91(ddd,J＝0.8,5.0,7.0Hz,1H),6.83(d,J＝8.3Hz,1H),5.39(s,2H),4.74-4.69(m, 2H).
步骤2：Step 2:
将化合物1-2(2.0Kg，9.29mol)加入到无水二氯甲烷(20.0L)中，溶液冷却至0℃，缓慢滴入二氯亚砜(1.01L，13.93mol)，滴加完毕，反应体系在15℃搅拌1小时，HPLC显示反应完成。反应液直接减压浓缩成固体，用正庚烷(15L)打浆，过滤，滤饼加入到乙酸乙酯(20L)中，用饱和碳酸氢钠调pH至7，分出有机相用10％氯化钠水溶液(10L)洗涤，无水硫酸钠干燥，过滤，滤液浓缩，得到化合物1-3(1.81Kg,收率为80.9％)。1H NMR(400MHz,CDCl3)δ8.20(dd,J＝1.3,5.0Hz,1H),7.61(ddd,J＝1.9,6.9,8.5Hz,1H),7.51-7.47(m,2H),7.42(d,J＝8.3Hz,2H),6.91(ddd,J＝0.8,5.1,7.0Hz,1H),6.84(d,J＝8.3Hz,1H),5.42(s,2H),4.62(s,2H)。Add compound 1-2 (2.0Kg, 9.29mol) to anhydrous dichloromethane (20.0L). The solution is cooled to 0°C, and thionyl chloride (1.01L, 13.93mol) is slowly added dropwise. The dropwise addition is completed. The reaction system was stirred at 15°C for 1 hour, and HPLC showed that the reaction was complete. The reaction solution was directly concentrated under reduced pressure to a solid, beaten with n-heptane (15L), and filtered. The filter cake was added to ethyl acetate (20L), and the pH was adjusted to 7 with saturated sodium bicarbonate. The organic phase was separated and treated with 10% chlorine. Wash with sodium chloride aqueous solution (10L), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain compound 1-3 (1.81Kg, yield 80.9%). 1 H NMR (400MHz, CDCl 3 ) δ8.20 (dd, J＝1.3, 5.0Hz, 1H), 7.61 (ddd, J＝1.9, 6.9, 8.5Hz, 1H), 7.51-7.47 (m, 2H), 7.42(d,J＝8.3Hz,2H),6.91(ddd,J＝0.8,5.1,7.0Hz,1H),6.84(d,J＝8.3Hz,1H),5.42(s,2H),4.62(s ,2H).
步骤3：Step 3:
2-氨基-5碘吡啶(2.0Kg，90.9mol)溶于乙腈(20L)中，在N2保护下加入碘化亚铜(86.6g，0.45mol)，三甲基硅乙炔(1.16Kg，11.8mol)，三乙胺(2.76Kg，27.3mol)和二三苯基膦氯化钯(63.8g，0.091mol)，反应混合液在20℃搅拌1小时，HPLC检测反应完全。反应液直接减压浓缩，粗品加入到乙酸乙酯(20L)中，用10％氯化钠水溶液(10L)洗涤，有机相用200-300目硅胶粉过滤，滤液浓缩得到化合物 1-5(1.59kg，收率：92％)。1H NMR(400MHz,CDCl3)δ＝8.22(d,J＝1.5Hz,1H),7.51(dd,J＝2.3,8.5Hz,1H),6.43(d,J＝8.5Hz,1H),4.71(s,2H),0.24(s,9H)。2-Amino-5-iodopyridine (2.0Kg, 90.9mol) was dissolved in acetonitrile (20L), and copper iodide (86.6g, 0.45mol) and trimethylsilyl acetylene (1.16Kg, 11.8 mol), triethylamine (2.76Kg, 27.3mol) and diphenylphosphine palladium chloride (63.8g, 0.091mol). The reaction mixture was stirred at 20°C for 1 hour. HPLC detected that the reaction was complete. The reaction solution was directly concentrated under reduced pressure. The crude product was added to ethyl acetate (20L), washed with 10% sodium chloride aqueous solution (10L), the organic phase was filtered with 200-300 mesh silica gel powder, and the filtrate was concentrated to obtain the compound. 1-5 (1.59kg, yield: 92%). 1 H NMR (400MHz, CDCl 3 ) δ = 8.22 (d, J = 1.5Hz, 1H), 7.51 (dd, J = 2.3, 8.5Hz, 1H), 6.43 (d, J = 8.5Hz, 1H), 4.71 (s,2H),0.24(s,9H).
步骤4：Step 4:
将化合物1-5(1.22kg,6.42mol)溶于DMF(5.0L)中，在20℃加入水(0.77kg,42.79mol)和氟化钾(1.98Kg，34.2mol)，搅拌1小时，将反应液加入到水(15L)和醋酸异丙酯(10L)的混合液中，过滤，分出水相用醋酸异丙酯(10.0L×2)萃取，合并所有醋酸异丙酯用10％氯化钠水溶液(10L)洗涤，有机相加入到反应釜中，N2保护下，加入化合物1-3(1.0kg,4.28mol)，碳酸铯(1.46Kg，4.49mol)，Xphos(81.6g，0.17mol)和醋酸钯(19.2g，0.09mol)，加料完毕，升温至80℃搅拌16小时。HPLC监测反应完全，加水(10L)淬灭反应，过滤，分出水层用醋酸异丙酯(10L)萃取，有机相再用10％食盐水(10L)洗涤，200-300目硅胶粉过滤，减压浓缩至少量溶剂，抽入叔戊醇(3L)置换出醋酸异丙酯，过滤，滤饼用正庚烷(5L)打浆，过滤，滤饼干燥得到化合物1-6(1.1Kg，收率：81.4％)。1H NMR(400MHz,CDCl3)δ＝8.23-8.18(m,2H),7.64-7.56(m,1H),7.51-7.41(m,5H),6.90(dd,J＝5.6,6.7Hz,1H),6.82(d,J＝8.3Hz,1H),6.45(d,J＝8.5Hz,1H),5.40(s,2H),4.58(s,2H),3.84(s,2H)。Dissolve compound 1-5 (1.22kg, 6.42mol) in DMF (5.0L), add water (0.77kg, 42.79mol) and potassium fluoride (1.98Kg, 34.2mol) at 20°C, and stir for 1 hour. The reaction solution was added to a mixture of water (15L) and isopropyl acetate (10L), filtered, and the aqueous phase was separated and extracted with isopropyl acetate (10.0L × 2). Combine all the isopropyl acetate and use 10% chlorine. Wash with sodium aqueous solution (10L), add the organic phase to the reaction kettle, and add compound 1-3 (1.0kg, 4.28mol), cesium carbonate (1.46Kg, 4.49mol), Xphos (81.6g, 0.17mol) under N2 protection. ) and palladium acetate (19.2g, 0.09mol), after the addition is completed, the temperature is raised to 80°C and stirred for 16 hours. HPLC monitors that the reaction is complete. Add water (10L) to quench the reaction. Filter. The aqueous layer is separated and extracted with isopropyl acetate (10L). The organic phase is washed with 10% brine (10L). Filter with 200-300 mesh silica gel powder. Concentrate to a small amount of solvent under pressure, pump in tert-amyl alcohol (3L) to replace isopropyl acetate, filter, beat the filter cake with n-heptane (5L), filter, and dry the filter cake to obtain compound 1-6 (1.1Kg, yield :81.4%). 1 H NMR (400MHz, CDCl 3 ) δ = 8.23-8.18 (m, 2H), 7.64-7.56 (m, 1H), 7.51-7.41 (m, 5H), 6.90 (dd, J = 5.6, 6.7Hz, 1H ), 6.82 (d, J = 8.3Hz, 1H), 6.45 (d, J = 8.5Hz, 1H), 5.40 (s, 2H), 4.58 (s, 2H), 3.84 (s, 2H).
步骤5：Step 5:
将化合物1-6(1.1kg，3.49mol)加入无水四氢呋喃(11.0L)中，N2保护下，加入碘化钠(0.78kg，5.23mol)和化合物1-7(1.8kg，6.98mol)，反应在25℃，搅拌16小时。加入0.5M碳酸钠水溶液(10L)，用醋酸异丙酯(10L×2)萃取，合并有机相用10％氯化钠水溶液(10L)洗涤，分出有机相，加入2M盐酸水溶液(22.0L)，搅拌10分钟分出有机相，水相继续搅拌1小时，加入4M氢氧化钠水溶液调pH至9，醋酸异丙酯(10L×2)洗涤，水相用4M盐酸水溶液调pH至4，有大量固体析出，搅拌30分钟过滤，滤饼加入到水(10L)中，搅拌下加入4M盐酸水溶液至溶解，搅拌1小时析出大量固体，过滤，滤饼为式(I)化合物盐酸盐。将式(I)化合物盐酸盐加入到水(10L)中，用4M氢氧化钠水溶液调pH至4，析出大量固体，搅拌30分钟，过滤，滤饼用纯水(10L)打浆，过滤，滤饼再用异丙醇(10L)和纯水(2.5L)的混合液打浆，过滤，干燥得到式(I)化合物的C晶型(700g，47.1％收率)。1H NMR(400MHz,CD3OD)δ＝8.22-8.10(m,2H),7.83-7.68(m,2H),7.47-7.37(m,4H),7.11-6.96(m,2H),6.88(d,J＝8.3Hz,1H),5.67(d,J＝8.3Hz,2H),5.34(s,2H),3.86(s,2H)。其XRPD谱图如图1所示，DSC谱图如图2所示，TGA谱图如图3所示。Compound 1-6 (1.1kg, 3.49mol) was added to anhydrous tetrahydrofuran (11.0L). Under N2 protection, sodium iodide (0.78kg, 5.23mol) and compound 1-7 (1.8kg, 6.98mol) were added. , the reaction was stirred at 25°C for 16 hours. Add 0.5M sodium carbonate aqueous solution (10L), extract with isopropyl acetate (10L×2), combine the organic phases and wash with 10% sodium chloride aqueous solution (10L), separate the organic phase, add 2M hydrochloric acid aqueous solution (22.0L) , stir for 10 minutes to separate the organic phase, continue stirring the aqueous phase for 1 hour, add 4M sodium hydroxide aqueous solution to adjust the pH to 9, wash with isopropyl acetate (10L×2), use 4M hydrochloric acid aqueous solution to adjust the pH to 4 for the aqueous phase. A large amount of solid precipitated. Stir for 30 minutes and filter. Add the filter cake to water (10L). Add 4M hydrochloric acid aqueous solution with stirring until dissolved. Stir for 1 hour to precipitate a large amount of solid. Filter. The filter cake is the hydrochloride of the compound of formula (I). Add the hydrochloride of the compound of formula (I) to water (10L), adjust the pH to 4 with 4M sodium hydroxide aqueous solution, precipitate a large amount of solid, stir for 30 minutes, filter, and beat the filter cake with pure water (10L) and filter. The filter cake was then slurried with a mixture of isopropyl alcohol (10L) and pure water (2.5L), filtered, and dried to obtain the C crystal form of the compound of formula (I) (700g, 47.1% yield). 1 H NMR (400MHz, CD 3 OD) δ = 8.22-8.10 (m, 2H), 7.83-7.68 (m, 2H), 7.47-7.37 (m, 4H), 7.11-6.96 (m, 2H), 6.88 ( d,J＝8.3Hz,1H),5.67(d,J＝8.3Hz,2H),5.34(s,2H),3.86(s,2H). The XRPD spectrum is shown in Figure 1, the DSC spectrum is shown in Figure 2, and the TGA spectrum is shown in Figure 3.
实施例2：式(I)化合物D晶型的制备Example 2: Preparation of crystal form D of compound of formula (I)
将式(I)化合物盐酸盐(15mg)加至20mL的小瓶内，用0.5mL的甲醇将固体完全溶解。向该澄清溶液中边搅拌(1000rpm)边滴加乙腈，直至有固体析出。分离析出的固体并进行XRPD测试，其XRPD谱图如图4所示。Add the hydrochloride salt of the compound of formula (I) (15 mg) into a 20 mL vial, and use 0.5 mL of methanol to completely dissolve the solid. Acetonitrile was added dropwise to the clear solution while stirring (1000 rpm) until solid precipitated. The precipitated solid was separated and tested by XRPD. Its XRPD spectrum is shown in Figure 4.
实施例3：式(I)化合物C晶型的吸湿性研究Example 3: Study on hygroscopicity of crystal form C of compound of formula (I)
实验材料：Experimental Materials:
SMS DVS Intrinsic动态水分吸附仪SMS DVS Intrinsic Dynamic Moisture Adsorption Meter
实验方法： experimental method:
取式(I)化合物C晶型10～15mg置于DVS样品盘内进行测试。Take 10 to 15 mg of the crystal form C of the compound of formula (I) and place it in the DVS sample tray for testing.
实验结果：Experimental results:
式(I)化合物C晶型的DVS谱图如图5所示，△W＝0.42％。The DVS spectrum of crystal form C of compound of formula (I) is shown in Figure 5, ΔW=0.42%.
实验结论：Experimental results:
式(I)化合物C晶型在25℃和80％RH下的吸湿增重为0.42％，略有吸湿性。The hygroscopic weight gain of the crystal form C of the compound of formula (I) at 25° C. and 80% RH is 0.42%, and it is slightly hygroscopic.
测试例1.式(I)化合物C晶型在念珠菌血症模型(VVC)的体内药效研究Test Example 1. In vivo efficacy study of compound C crystal form of formula (I) in candidemia model (VVC)
实验动物：雌性C3H/NeH小鼠，6～8周龄，19～21g，n＝10；Experimental animals: female C3H/NeH mice, 6 to 8 weeks old, 19 to 21 g, n=10;
微生物致病体：白色念珠菌(Candida albicans)ATCC MYA-4788；Microbial pathogen: Candida albicans ATCC MYA-4788;
接种水平、接种途径：1.44E+05CFU/小鼠，***滴注感染；Inoculation level and route of inoculation: 1.44E+05CFU/mouse, vaginal instillation infection;
治疗：溶媒(vehicle)组；式(I)化合物C晶型2、6、20mpk组：于感染后22h口服给药口服1-氨基苯并***(ABT)，24h腹腔注射待测试化合物开始治疗。Treatment: vehicle (vehicle) group; compound C crystal form 2, 6, 20mpk group of formula (I): oral administration of 1-aminobenzotriazole (ABT) 22 hours after infection, and intraperitoneal injection of the compound to be tested at 24 hours to start treatment .
观测指标：各组小鼠感染96h后，取小鼠的***组织匀浆进行CFU计数。Observation indicators: 96 hours after the mice in each group were infected, the vaginal tissue homogenates of the mice were taken for CFU counting.
实验结果：小鼠经***滴注一定接种剂量的白色念珠菌ATCC MYA-4788后可构建稳定的***感染模型。Vehicle组***组织的载菌量为5.03±0.29个lg。与Vehicle组相比，式(I)化合物C晶型20mpk、6mpk、2mpk剂量下的***组织载菌量分别降低2.79个lg，1.58个lg，0.68个lg(P<0.001，P<0.05，P＞0.05)，并呈现一定的量效关系。式(I)化合物C晶型20mpk剂量下杀菌效果非常显著。Experimental results: A stable vaginal infection model can be established after mice are instilled with a certain dose of Candida albicans ATCC MYA-4788 through the vagina. The bacterial load of vaginal tissue in the Vehicle group was 5.03±0.29 lg. Compared with the Vehicle group, the bacterial load in vaginal tissue at doses of 20mpk, 6mpk, and 2mpk of compound C of formula (I) was reduced by 2.79 lg, 1.58 lg, and 0.68 lg respectively (P<0.001, P<0.05, P >0.05), and shows a certain dose-effect relationship. The bactericidal effect of the crystal form C of the compound of formula (I) is very significant at a dose of 20mpk.
实验结论：本发明晶型可有效治疗***感染，式(I)化合物C晶型具有优异的药效。 Experimental conclusion: The crystal form of the present invention can effectively treat vaginal infection, and the crystal form C of compound of formula (I) has excellent medicinal efficacy.

Claims (20)

  1. 式(I)化合物的C晶型，其特征在于其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：3.9975±0.200°，7.9169±0.200°，19.939±0.200°，
    The C crystal form of the compound of formula (I) is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 3.9975±0.200°, 7.9169±0.200°, 19.939±0.200°,
  2. 根据权利要求1所述的C晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：3.9975±0.200°，7.9169±0.200°，15.8368±0.200°，18.7250±0.200°，19.9390±0.200°，21.7115±0.200°，23.0090±0.200°，25.6600±0.200°。According to the C crystal form of claim 1, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 3.9975±0.200°, 7.9169±0.200°, 15.8368±0.200°, 18.7250±0.200°, 19.9390±0.200 °, 21.7115±0.200°, 23.0090±0.200°, 25.6600±0.200°.
  3. 根据权利要求2所述的C晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：3.9975±0.200°，7.9169±0.200°，15.8368±0.200°，18.7250±0.200°，19.9390±0.200°，20.8423±0.200°，21.7115±0.200°，22.3334±0.200°，23.0090±0.200°，24.0607±0.200°，25.6600±0.200°，27.1949±0.200°。According to the C crystal form of claim 2, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 3.9975±0.200°, 7.9169±0.200°, 15.8368±0.200°, 18.7250±0.200°, 19.9390±0.200 °, 20.8423±0.200°, 21.7115±0.200°, 22.3334±0.200°, 23.0090±0.200°, 24.0607±0.200°, 25.6600±0.200°, 27.1949±0.200°.
  4. 根据权利要求3所述的C晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：3.9975°，7.9169°，10.7005°，12.7114°，15.8368°，18.7250°，19.9390°，20.3246°，20.8423°，21.2448°，21.7115°，22.3334°，23.0090°，23.8153°，24.0607°，25.0930°，25.6600°，27.1949°，28.9541°，30.3507°，31.1749°。According to the C crystal form of claim 3, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 3.9975°, 7.9169°, 10.7005°, 12.7114°, 15.8368°, 18.7250°, 19.9390°, 20.3246° , 20.8423°, 21.2448°, 21.7115°, 22.3334°, 23.0090°, 23.8153°, 24.0607°, 25.0930°, 25.6600°, 27.1949°, 28.9541°, 30.3507°, 31.1749°.
  5. 根据权利要求1～4任意一项所述的C晶型，其XRPD图谱基本上如图1所示。According to the C crystal form according to any one of claims 1 to 4, its XRPD pattern is basically as shown in Figure 1.
  6. 根据权利要求1～4任意一项所述的C晶型，其差示扫描量热曲线在199.2±3℃处具有吸热峰。According to the C crystal form according to any one of claims 1 to 4, its differential scanning calorimetry curve has an endothermic peak at 199.2±3°C.
  7. 根据权利要求6所述的C晶型，其DSC图谱如图2所示。According to the C crystal form of claim 6, its DSC pattern is shown in Figure 2.
  8. 根据权利要求1～4任意一项所述的C晶型，其热重分析曲线在150±3℃时失重达2.28％。According to the C crystal form according to any one of claims 1 to 4, the thermogravimetric analysis curve has a weight loss of 2.28% at 150±3°C.
  9. 根据权利要求8所述的C晶型，其TGA图谱如图3所示。According to the C crystal form of claim 8, its TGA spectrum is shown in Figure 3.
  10. 式(I)化合物的D晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.0789±0.200°，8.1226±0.200°，14.9322±0.200°，18.2233±0.200°，21.4231±0.200°，
    The X-ray powder diffraction pattern of the D crystal form of the compound of formula (I) has characteristic diffraction peaks at the following 2θ angles: 4.0789±0.200°, 8.1226±0.200°, 14.9322±0.200°, 18.2233±0.200°, 21.4231±0.200° ,
  11. 根据权利要求10所述的D晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.0789±0.200°，7.4609±0.200°，8.1226±0.200°，14.9322±0.200°，18.2233±0.200°，18.6712±0.200°，21.4231±0.200°。According to the D crystal form of claim 10, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 4.0789±0.200°, 7.4609±0.200°, 8.1226±0.200°, 14.9322±0.200°, 18.2233±0.200 °, 18.6712±0.200°, 21.4231±0.200°.
  12. 根据权利要求11所述的D晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.0789±0.200°，7.4609±0.200°，8.1226±0.200°，12.1939±0.200°，14.9322±0.200°，18.2233±0.200°，18.6712±0.200°，21.4231±0.200°，22.4812±0.200°，26.2452±0.200°。According to the D crystal form of claim 11, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 4.0789±0.200°, 7.4609±0.200°, 8.1226±0.200°, 12.1939±0.200°, 14.9322±0.200 °, 18.2233±0.200°, 18.6712±0.200°, 21.4231±0.200°, 22.4812±0.200°, 26.2452±0.200°.
  13. 根据权利要求12所述的D晶型，其XRPD图谱基本上如图4所示。According to the D crystal form of claim 12, its XRPD pattern is basically as shown in Figure 4.
  14. 化合物1-6的制备方法，其包括如下反应步骤：
    The preparation method of compound 1-6 includes the following reaction steps:
    其中，in,
    试剂4A选自无机碱；Reagent 4A is selected from inorganic bases;
    溶剂4B选自酰类溶剂或酰类溶剂和水的混合溶剂；Solvent 4B is selected from acyl solvents or mixed solvents of acyl solvents and water;
    试剂4C选自无机碱；Reagent 4C is selected from inorganic bases;
    试剂4D选自钯催化剂；Reagent 4D is selected from palladium catalysts;
    试剂4E选自有机膦配体；Reagent 4E is selected from organophosphine ligands;
    溶剂4F选自酯类溶剂。Solvent 4F is selected from ester solvents.
  15. 根据权利要求14所述的制备方法，其中，The preparation method according to claim 14, wherein,
    试剂4A选自氟化钾；Reagent 4A is selected from potassium fluoride;
    溶剂4B选自DMF或DMF和水的混合溶剂；Solvent 4B is selected from DMF or a mixed solvent of DMF and water;
    试剂4C选自碳酸铯；Reagent 4C is selected from cesium carbonate;
    试剂4D选自醋酸钯；Reagent 4D is selected from palladium acetate;
    试剂4E选自Xphos；Reagent 4E is selected from Xphos;
    溶剂4F选自醋酸异丙酯。Solvent 4F is selected from isopropyl acetate.
  16. 根据权利要求15所述的制备方法，其包括如下反应步骤：
    The preparation method according to claim 15, which includes the following reaction steps:
    其中，in,
    试剂3A选自金属催化剂；Reagent 3A is selected from metal catalysts;
    溶剂3B选自腈类溶剂；Solvent 3B is selected from nitrile solvents;
    试剂3C选自三甲基硅乙炔；Reagent 3C is selected from trimethylsilylacetylene;
    试剂3D选自钯催化剂；Reagent 3D is selected from palladium catalyst;
    试剂3E选自有机碱；Reagent 3E is selected from organic bases;
    试剂4A选自无机碱；Reagent 4A is selected from inorganic bases;
    溶剂4B选自酰类溶剂或酰类溶剂和水的混合溶剂；Solvent 4B is selected from acyl solvents or mixed solvents of acyl solvents and water;
    试剂4C选自无机碱； Reagent 4C is selected from inorganic bases;
    试剂4D选自钯催化剂；Reagent 4D is selected from palladium catalysts;
    试剂4E选自有机膦配体；Reagent 4E is selected from organophosphine ligands;
    溶剂4F选自酯类溶剂。Solvent 4F is selected from ester solvents.
  17. 根据权利要求16所述的制备方法，其中，The preparation method according to claim 16, wherein,
    试剂3A选自碘化亚铜；Reagent 3A is selected from copper iodide;
    溶剂3B选自乙腈；Solvent 3B is selected from acetonitrile;
    试剂3C选自三甲基硅乙炔；Reagent 3C is selected from trimethylsilylacetylene;
    试剂3D选自二三苯基膦氯化钯；Reagent 3D is selected from ditriphenylphosphine palladium chloride;
    试剂3E选自三乙胺；Reagent 3E is selected from triethylamine;
    试剂4A选自氟化钾；Reagent 4A is selected from potassium fluoride;
    溶剂4B选自DMF或DMF和水的混合溶剂；Solvent 4B is selected from DMF or a mixed solvent of DMF and water;
    试剂4C选自碳酸铯；Reagent 4C is selected from cesium carbonate;
    试剂4D选自醋酸钯；Reagent 4D is selected from palladium acetate;
    试剂4E选自Xphos；Reagent 4E is selected from Xphos;
    溶剂4F选自醋酸异丙酯。Solvent 4F is selected from isopropyl acetate.
  18. 根据权利要求16所述的制备方法，其包括如下反应步骤：
    The preparation method according to claim 16, which includes the following reaction steps:
    其中，in,
    试剂1A选自对苯二甲醇；Reagent 1A is selected from terephthalol;
    溶剂1B选自DMF；Solvent 1B is selected from DMF;
    试剂1C选自叔丁醇钾；Reagent 1C is selected from potassium tert-butoxide;
    溶剂2A选自无水二氯甲烷；Solvent 2A is selected from anhydrous methylene chloride;
    试剂2B选自二氯亚砜；Reagent 2B is selected from sulfoxide dichloride;
    试剂3A选自碘化亚铜；Reagent 3A is selected from copper iodide;
    溶剂3B选自乙腈；Solvent 3B is selected from acetonitrile;
    试剂3C选自三甲基硅乙炔；Reagent 3C is selected from trimethylsilylacetylene;
    试剂3D选自二三苯基膦氯化钯； Reagent 3D is selected from ditriphenylphosphine palladium chloride;
    试剂3E选自三乙胺；Reagent 3E is selected from triethylamine;
    试剂4A选自氟化钾；Reagent 4A is selected from potassium fluoride;
    溶剂4B选自DMF或DMF和水的混合溶剂；Solvent 4B is selected from DMF or a mixed solvent of DMF and water;
    试剂4C选自碳酸铯；Reagent 4C is selected from cesium carbonate;
    试剂4D选自醋酸钯；Reagent 4D is selected from palladium acetate;
    试剂4E选自Xphos；Reagent 4E is selected from Xphos;
    溶剂4F选自醋酸异丙酯。Solvent 4F is selected from isopropyl acetate.
  19. 式(I)化合物的制备方法，其包括如下反应步骤：
    The preparation method of the compound of formula (I) includes the following reaction steps:
    其中，in,
    试剂1A选自对苯二甲醇；Reagent 1A is selected from terephthalol;
    溶剂1B选自DMF；Solvent 1B is selected from DMF;
    试剂1C选自叔丁醇钾；Reagent 1C is selected from potassium tert-butoxide;
    溶剂2A选自无水二氯甲烷；Solvent 2A is selected from anhydrous methylene chloride;
    试剂2B选自二氯亚砜；Reagent 2B is selected from sulfoxide dichloride;
    试剂3A选自碘化亚铜；Reagent 3A is selected from copper iodide;
    溶剂3B选自乙腈；Solvent 3B is selected from acetonitrile;
    试剂3C选自三甲基硅乙炔；Reagent 3C is selected from trimethylsilylacetylene;
    试剂3D选自二三苯基膦氯化钯；Reagent 3D is selected from ditriphenylphosphine palladium chloride;
    试剂3E选自三乙胺；Reagent 3E is selected from triethylamine;
    试剂4A选自氟化钾；Reagent 4A is selected from potassium fluoride;
    溶剂4B选自DMF或DMF和水的混合溶剂； Solvent 4B is selected from DMF or a mixed solvent of DMF and water;
    试剂4C选自碳酸铯；Reagent 4C is selected from cesium carbonate;
    试剂4D选自醋酸钯；Reagent 4D is selected from palladium acetate;
    试剂4E选自Xphos；Reagent 4E is selected from Xphos;
    溶剂4F选自醋酸异丙酯；Solvent 4F is selected from isopropyl acetate;
    溶剂5A选自无水四氢呋喃；Solvent 5A is selected from anhydrous tetrahydrofuran;
    试剂5B选自碘化钠。Reagent 5B is selected from sodium iodide.
  20. 根据权利要求1～9任意一项所述的C晶型或权利要求10～13任意一项所述的D晶型在制备治疗与深部真菌感染相关药物中的应用。 Use of the C crystal form according to any one of claims 1 to 9 or the D crystal form according to any one of claims 10 to 13 in the preparation of drugs related to the treatment of deep fungal infections.
PCT/CN2023/099660 2022-06-13 2023-06-12 Crystal form of alkynylpyridine compound and preparation method therefor WO2023241507A1 (en)

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