WO2023025271A1 - Crystal form of pyrazine derivative and preparation method therefor - Google Patents

Crystal form of pyrazine derivative and preparation method therefor Download PDF

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Publication number
WO2023025271A1
WO2023025271A1 PCT/CN2022/115011 CN2022115011W WO2023025271A1 WO 2023025271 A1 WO2023025271 A1 WO 2023025271A1 CN 2022115011 W CN2022115011 W CN 2022115011W WO 2023025271 A1 WO2023025271 A1 WO 2023025271A1
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Prior art keywords
compound
crystal form
room temperature
diffraction
solvent
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PCT/CN2022/115011
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French (fr)
Chinese (zh)
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郑骏浩
胡海文
许旭华
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杭州中美华东制药有限公司
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Priority to CN202280058327.7A priority Critical patent/CN117881665A/en
Publication of WO2023025271A1 publication Critical patent/WO2023025271A1/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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms

Definitions

  • the present invention relates to pyrazine derivatives, especially crystals of compound 3,6-diamino-2,5-bis ⁇ N-[(1R)-1-carboxy-2-hydroxyethyl]carbamoyl ⁇ pyrazine type and its preparation method.
  • MB-102 3,6-Diamino-2,5-bis ⁇ N-[(1R)-1-carboxy-2-hydroxyethyl]carbamoyl ⁇ pyrazine, also known as "MB-102", is a Fluorescent compounds with excellent photophysical properties and other chemical and physical properties. The compound is known for use in the monitoring of renal function as disclosed in patents US 8,155,000, US 8,664,392, US 8,697,033, US 8,722,685, US 8,778,309, US 9,005,581, US 9,114,160, US 9,283,288, US 9,376,399 and US 9,480,687. MB-102 is being developed as a fluorescer for real-time glomerular filtration rate (GFR) assays.
  • GFR glomerular filtration rate
  • the clearance rate of MB-102 in the patient's blood stream can be measured in real time through the skin, so as to convert the glomerular filtration rate of the patient.
  • the crystal structure of pharmaceutical active ingredients often affects the chemical stability of the drug. Different crystallization conditions and storage conditions may lead to changes in the crystal structure of the compound, sometimes accompanied by the production of other crystal forms.
  • the bioavailability of different crystal forms of the same drug may also be different; in addition, its stability, fluidity, and compressibility may also be different. These physical and chemical properties have a certain impact on the application of the drug, thereby affecting the drug. curative effect.
  • a first aspect of the present invention provides 3,6-diamino-2,5-bis ⁇ N-[(1R)-1-carboxy-2-hydroxyethyl]carbamoyl ⁇ pyrazine (hereinafter referred to as "the compound I") crystal form:
  • the crystal form can simultaneously meet the reproducibility and controllability of the crystallization process in the industrial production process, as well as the pharmaceutical requirements of production, transportation and storage.
  • the second aspect of the present invention provides a method for preparing the crystal forms A to G.
  • the third aspect of the present invention provides the compound I in the form of the crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E, crystalline form F or crystalline form G.
  • the fourth aspect of the present invention provides a pharmaceutical composition, which comprises an effective amount of any one selected from the crystal forms A to G and one or more pharmaceutically acceptable carriers.
  • the fifth aspect of the present invention provides any one of the crystal forms A to G or the pharmaceutical composition for monitoring renal function, wherein the renal function detection is GFR monitoring, especially real-time GFR detection.
  • the sixth aspect of the present invention provides any one of the crystal forms A to G or the use of the pharmaceutical composition in the preparation of a drug for renal function monitoring, wherein the renal function detection is GFR monitoring, especially Real-time GFR detection.
  • the seventh aspect of the present invention provides a method for monitoring renal function in an individual, the method comprising administering to the individual an effective amount of any one of the crystal forms A to G or the pharmaceutical composition, wherein the The aforementioned renal function test is GFR monitoring, especially real-time GFR testing.
  • the eighth aspect of the present invention provides a method of purifying Compound I, said method comprising allowing Compound I to form a solvate from a suitable solvent.
  • Fig. 1 shows the X-ray powder diffraction (XRPD) pattern of the crystal form A of Compound I prepared in Method 1 of Example 1.
  • TGA thermogravimetric analysis
  • DSC differential scanning calorimetry
  • Fig. 3 shows the NMR spectrum of the crystal form A of compound I prepared in method 1 of Example 1.
  • Fig. 4 shows (a) dynamic moisture adsorption (DVS) curve of crystalline form A of compound I prepared in method 1 of Example 1, and (b) XRPD patterns before and after DVS test.
  • DVD dynamic moisture adsorption
  • Fig. 5 shows the polarized light microscopy (PLM) image of the crystal form A of compound I prepared in method 1 of Example 1.
  • FIG. 6 shows the XRPD pattern of Form B of Compound I prepared in Example 2.
  • FIG. 7 is the TGA and DSC spectra of the crystal form B of compound I prepared in Example 2.
  • FIG. 8 is the NMR spectrum of the crystal form B of compound I prepared in Example 2.
  • Figure 9 shows (a) DVS curve of Form B of Compound I prepared in Example 2, and (b) XRPD patterns before and after DVS test.
  • FIG. 10 shows the PLM image of Form B of Compound I prepared in Example 2.
  • Fig. 11 shows the XRPD pattern of the crystal form C of compound I prepared in method 1 of Example 3.
  • Fig. 12 shows the TGA and DSC spectra of the crystal form C of compound I prepared in method 1 of Example 3.
  • Fig. 13 shows the NMR spectrum of the crystal form C of compound I prepared in method 1 of Example 3.
  • Figure 14 shows (a) DVS curve of Form C of Compound I prepared in Method 1 of Example 3, and (b) XRPD patterns before and after DVS test.
  • Figure 15 shows the PLM image of Form C of Compound I prepared in Method 1 of Example 3.
  • Fig. 16 shows the XRPD pattern of the crystal form D of compound I prepared in method 1 of Example 4.
  • Fig. 17 shows the TGA and DSC spectra of the crystal form D of compound I prepared in method 1 of Example 4.
  • Fig. 18 shows the NMR spectrum of the crystal form D of compound I prepared in method 1 of Example 4.
  • FIG. 19 shows the XRPD pattern of Form E of Compound I prepared in Example 5.
  • FIG. 20 shows the TGA and DSC spectra of Form E of Compound I prepared in Example 5.
  • FIG. 21 shows the NMR spectrum of Form E of Compound I prepared in Example 5.
  • FIG. 22 shows the XRPD pattern of Form F of Compound I prepared in Example 6.
  • FIG. 24 shows the NMR spectrum of Form F of Compound I prepared in Example 6.
  • FIG. 25 shows the XRPD pattern of Form G of Compound I prepared in Example 7.
  • FIG. 26 shows the TGA and DSC spectra of Form G of Compound I prepared in Example 7.
  • FIG. 27 shows the NMR spectrum of Form G of Compound I prepared in Example 7.
  • Figure 28 shows a comparison of XRPD patterns of different crystal forms of Compound I.
  • Figure 29 shows the XRPD pattern of the stability of Form A of Compound 1.
  • Figure 30 shows the XRPD pattern of the stability of Form B of Compound 1.
  • Figure 31 shows the XRPD pattern of the stability of Form C of Compound 1.
  • the term "about" used when describing XRPD diffraction angles means that those of ordinary skill in the art believe that within an acceptable standard error of the stated value, for example ⁇ 0.05, ⁇ 0.1, ⁇ 0.2, ⁇ 0.3 , ⁇ 1, ⁇ 2 or ⁇ 3, etc.
  • the term "optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that description includes that said event or circumstance occurs and that it does not.
  • crystalline form or “crystal” refers to any solid material that exhibits a three-dimensional order, as opposed to amorphous solid material, which produces a characteristic XRPD pattern with well-defined peaks.
  • X-ray powder diffraction pattern or "XRPD pattern” refers to an experimentally observed diffraction pattern or a parameter, data or value derived therefrom. XRPD patterns are usually characterized by peak positions (abscissa) and/or peak intensities (ordinate).
  • the term "diffraction angle" or “2 ⁇ ” refers to the peak position expressed in degrees (°) based on the setup in an X-ray diffraction experiment, and is usually the unit of abscissa in a diffraction pattern. If reflections are diffracted when the incident beam forms an angle ⁇ with a lattice plane, the experimental setup requires recording the reflected beam at 2 ⁇ angles. It should be understood that reference herein to a particular 2 ⁇ value for a particular crystalline form is intended to represent the 2 ⁇ value (expressed in degrees) measured using the X-ray diffraction experimental conditions described herein. For example, as described herein, using Cu-K ⁇ (K ⁇ 1 : 1.5406) monochromatic radiation.
  • the XRPD pattern herein is preferably collected on a Bruker D8 Advance (Bruker, GER) X-ray powder diffraction analyzer, and the transmission mode is preferably collected on a Bruker D8 Advance (Bruker, GER) X-ray powder diffraction analyzer.
  • the terms "substantially the same” or “substantially as shown in Figure X" for X-ray diffraction peaks mean that representative peak positions and intensity variations are taken into consideration. For example, those skilled in the art will understand that peak position (2 ⁇ ) will show some variation, typically by as much as 0.1 to 0.2 degrees, and that the instrumentation used to measure diffraction will also cause some variation. In addition, those skilled in the art will appreciate that relative peak intensities will vary due to instrument-to-instrument variation, as well as the degree of crystallinity, preferred orientation, prepared sample surface, and other factors known to those skilled in the art.
  • the NMR spectra in the present application are preferably collected on a Bruker AVANCE-III (Bruker, GER) NMR instrument, unless otherwise specified, using DMSO-d6 as a solvent.
  • Polarized light microscopy data in the application is preferably collected by a Motic BA310Met (Motic, CN) polarized light microscope.
  • the term “good solvent” means a solvent in which Compound I can dissolve or have a relatively higher solubility.
  • the term “anti-solvent” means a solvent in which Compound I is insoluble or substantially insoluble or has relatively lower solubility.
  • the terms “good solvent” and “anti-solvent” may also be relative terms, and do not represent the absolute solubility of Compound I therein.
  • the same solvent can act as a good solvent in some cases and as an anti-solvent in other cases.
  • water or toluene can be used as a good solvent in some cases, such as when used alone to dissolve compound I, but can be used as an anti-solvent in some cases, such as when used in combination with DMF.
  • alkanes means alkanes having 1 to 10, preferably 5 to 8 carbon atoms, including but not limited to pentane, n-hexane, n-heptane and isooctane.
  • alcohols means alcohols with 1 to 10, preferably 1 to 4 carbon atoms, especially alkanols with 1 to 4 carbon atoms, including but not limited to methanol, ethanol , n-propanol, isopropanol, n-butanol, sec-butanol and tert-butanol.
  • ether means an ether having 2 to 6 carbon atoms, which includes chain ethers and cyclic ethers (such as furans (including tetrahydrofurans) and dioxanes) , including but not limited to diethyl ether, isopropyl ether, methyl tert-butyl ether, ethylene glycol methyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran and dioxane (preferably 1,4- dioxane).
  • chain ethers and cyclic ethers such as furans (including tetrahydrofurans) and dioxanes
  • ketones means ketones having 2 to 6 carbon atoms, including but not limited to acetone, methyl ethyl ketone, methyl ethyl ketone, and 4-methyl-2-pentanone.
  • esters means esters having 3 to 10 carbon atoms, including but not limited to ethyl acetate, propyl acetate, isopropyl acetate, ethyl formate, and butyl formate.
  • room temperature refers to 20°C ⁇ 5°C.
  • the present invention provides Form A, Form B, Form C, Form D, Form E, Form F and Form G of Compound I.
  • the XRPD pattern of Form A of Compound 1 exhibits at least two, at least three, at least four, at least five, or at least six diffraction angles 2 ⁇ (°) at maximum intensity.
  • the XRPD pattern of Form A of Compound I includes diffraction at diffraction angles (2 ⁇ ) of about 6.7 ⁇ 0.2°, 18.2 ⁇ 0.2°, 27.4 ⁇ 0.2°, and/or 28.2 ⁇ 0.2° peak.
  • the XRPD pattern of the crystal form A further includes diffraction at a diffraction angle (2 ⁇ ) of about 16.9 ⁇ 0.2°, 20.2 ⁇ 0.2°, 20.7 ⁇ 0.2°, 21.0 ⁇ 0.2° and/or 21.8 ⁇ 0.2° peak.
  • the XRPD pattern of the crystalline form A also includes a temperature at about 14.0 ⁇ 0.2°, 15.1 ⁇ 0.2°, 17.3 ⁇ 0.2°, 19.1 ⁇ 0.2°, 19.7 ⁇ 0.2°, 20.5 ⁇ 0.2°, 22.4 ⁇ 0.2° , 23.1 ⁇ 0.2°, 24.4 ⁇ 0.2°, 24.8 ⁇ 0.2°, 26.9 ⁇ 0.2°, 28.5 ⁇ 0.2°, 29.2 ⁇ 0.2°, 30.6 ⁇ 0.2°, 30.8 ⁇ 0.2°, 32.8 ⁇ 0.2°, 33.5 ⁇ 0.2° , 34.2 ⁇ 0.2°, 41.2 ⁇ 0.2° and/or 43.5 ⁇ 0.2° diffraction angles (2 ⁇ ) of the diffraction peaks.
  • the XRPD pattern of the crystalline form A is substantially as shown in FIG. 1 , more preferably as shown in FIG. 1 .
  • the onset temperature of the endothermic peak of the crystalline form A is about 185 ⁇ 5°C, preferably about 185 ⁇ 2°C.
  • the DSC spectrum of the crystal form A is substantially as shown in Figure 2, more preferably as shown in Figure 2.
  • the crystal form A loses about 1.54% in weight during heating to about 100 ⁇ 5°C (preferably about 100 ⁇ 2°C), and may Decomposition started, as measured using TGA.
  • the TGA spectrum of the crystal form A is basically as shown in Figure 2, more preferably as shown in Figure 2.
  • the NMR spectrum of the crystalline form A is substantially as shown in FIG. 3 , preferably as shown in FIG. 3 .
  • the NMR spectrum shows no obvious organic solvent characteristic peaks.
  • the Form A is not a solvate, more preferably an anhydrate.
  • the PLM image of Form A is substantially as shown in FIG. 5 , preferably as shown in FIG. 5 .
  • the crystalline form A is tabular particles, the particle size of which is generally less than about 20 ⁇ m.
  • the XRPD pattern of Form B of Compound I exhibits at least two, at least three, at least four, at least five, or at least six diffraction angles 2 ⁇ (°) at maximum intensity.
  • the XRPD pattern of Form B of Compound 1 includes diffraction at diffraction angles (2 ⁇ ) of about 6.9 ⁇ 0.2°, 9.5 ⁇ 0.2°, 10.0 ⁇ 0.2°, and/or 19.1 ⁇ 0.2° peak.
  • the XRPD pattern of the crystal form B further includes diffraction peaks at diffraction angles (2 ⁇ ) of about 6.7 ⁇ 0.2°, 17.2 ⁇ 0.2°, 18.3 ⁇ 0.2° and/or 21.0 ⁇ 0.2°.
  • the XRPD pattern of the crystalline form B also includes a temperature of , 26.9 ⁇ 0.2°, 27.3 ⁇ 0.2°, 27.5 ⁇ 0.2°, 28.1 ⁇ 0.2°, 29.5 ⁇ 0.2°, 31.1 ⁇ 0.2° and/or 35.1 ⁇ 0.2° diffraction angle (2 ⁇ ) of the diffraction peaks.
  • the XRPD pattern of the crystalline form B is substantially as shown in FIG. 6 , more preferably as shown in FIG. 6 .
  • the crystalline form B has two endothermic peaks, the onset temperatures of which are about 72 ⁇ 5°C and about 212 ⁇ 5°C, preferably about 72 ⁇ 2°C and about 212 ⁇ 2°C.
  • the crystal form B also has an exothermic peak with an onset temperature of about 215°C ⁇ 5°C, preferably about 215°C ⁇ 2°C.
  • the DSC spectrum of the crystal form B is substantially as shown in FIG. 7 , more preferably as shown in FIG. 7 .
  • the crystal form B loses about 3.82% in weight during heating to about 130 ⁇ 5°C (preferably about 130 ⁇ 2°C), and may Decomposition started to occur as measured using TGA.
  • the TGA spectrum of the crystal form B is substantially as shown in FIG. 7 , more preferably as shown in FIG. 7 .
  • the NMR spectrum of the crystal form B is substantially as shown in FIG. 8 , preferably as shown in FIG. 8 .
  • the Form B is a monohydrate.
  • the PLM image of the Form B is substantially as shown in FIG. 10 , preferably as shown in FIG. 10 .
  • the crystal form B is tabular particles, the particle size of which is generally less than about 20 ⁇ m.
  • the XRPD pattern of Form C of Compound I exhibits at least two, at least three, at least four, at least five, or at least six diffraction angles 2 ⁇ (°) at maximum intensity.
  • the XRPD pattern of Form C of Compound 1 includes diffraction angles at about 6.8 ⁇ 0.2°, 15.1 ⁇ 0.2°, 21.4 ⁇ 0.2°, 22.0 ⁇ 0.2°, and/or 27.6 ⁇ 0.2° ( Diffraction peaks at 2 ⁇ ).
  • the XRPD pattern of the crystalline form C further includes diffraction peaks at diffraction angles (2 ⁇ ) of about 20.6 ⁇ 0.2°, 21.2 ⁇ 0.2°, 26.7 ⁇ 0.2° and/or 28.7 ⁇ 0.2°.
  • the XRPD pattern of the crystalline form C also includes a range at about 13.6 ⁇ 0.2°, 14.7 ⁇ 0.2°, 16.2 ⁇ 0.2°, 18.0 ⁇ 0.2°, 19.1 ⁇ 0.2°, 20.0 ⁇ 0.2°, 22.7 ⁇ 0.2°, 23.3 ⁇ 0.2°, 25.0 ⁇ 0.2°, 27.1 ⁇ 0.2°, 28.0 ⁇ 0.2°, 30.2 ⁇ 0.2°, 31.5 ⁇ 0.2°, 31.9 ⁇ 0.2°, 34.6 ⁇ 0.2°, 34.8 ⁇ 0.2°, 38.8 ⁇ 0.2°, Diffraction peaks at diffraction angles (2 ⁇ ) of 40.0 ⁇ 0.2° and/or 41.9 ⁇ 0.2°.
  • the XRPD pattern of the crystalline form C is substantially as shown in FIG. 11 , more preferably as shown in FIG. 11 .
  • the DSC spectrum of the crystalline form C is substantially as shown in FIG. 12 , preferably as shown in FIG. 12 .
  • the crystalline form C has no obvious heat flow signal before heating to the decomposition temperature, and the baseline shifts obviously after about 210 ⁇ 5°C (preferably about 210 ⁇ 2°C).
  • the crystal form C loses about 0.95% in weight during heating to about 100 ⁇ 5°C (preferably about 100 ⁇ 2°C), and may Decomposition occurred as measured using TGA.
  • the TGA spectrum of the crystal form C is substantially as shown in FIG. 12 , more preferably as shown in FIG. 12 .
  • the NMR spectrum of Form C is substantially as shown in Figure 13, preferably as shown in Figure 13.
  • the Form C is not a solvate, more preferably an anhydrate.
  • the PLM image of Form C is substantially as shown in FIG. 15 , preferably as shown in FIG. 15 .
  • the crystal form C is agglomerated in a spherical shape, and the particle size is generally less than about 20 ⁇ m.
  • the XRPD pattern of Form D of Compound I exhibits at least two, at least three, at least four, at least five, or at least six diffraction angles 2 ⁇ (°) at maximum intensity.
  • the XRPD pattern of Form D of Compound I includes diffraction at diffraction angles (2 ⁇ ) of about 9.6 ⁇ 0.2°, 17.0 ⁇ 0.2°, 19.9 ⁇ 0.2°, and/or 26.0 ⁇ 0.2° peak.
  • the XRPD pattern of the crystalline form D further includes a temperature range of about 4.4 ⁇ 0.2°, 13.4 ⁇ 0.2°, 20.2 ⁇ 0.2°, 23.3 ⁇ 0.2°, 25.1 ⁇ 0.2°, 28.4 ⁇ 0.2° and/or 29.2 ⁇ 0.2°
  • the XRPD pattern of the crystalline form D also includes an , 24.1 ⁇ 0.2°, 24.9 ⁇ 0.2°, 27.8 ⁇ 0.2°, 30.0 ⁇ 0.2°, 31.6 ⁇ 0.2°, 32.2 ⁇ 0.2°, 32.6 ⁇ 0.2°, 32.8 ⁇ 0.2°, 34.0 ⁇ 0.2°, 36.5 ⁇ 0.2° , 37.5 ⁇ 0.2°, 37.7 ⁇ 0.2° and/or 40.1 ⁇ 0.2° diffraction angle (2 ⁇ ) of the diffraction peaks.
  • the XRPD pattern of the crystalline form D is substantially as shown in FIG. 16 , more preferably as shown in FIG. 16 .
  • the crystalline form D loses about 3.9% of its weight during heating to about 110 ⁇ 5°C (preferably about 110 ⁇ 2°C), and loses about 18.3% of its weight during heating from about 110 to about 200 ⁇ 5°C. %, decomposition may start after about 200 ⁇ 5°C, preferably about 200 ⁇ 2°C, as measured using TGA.
  • the TGA spectrum of the crystal form D is substantially as shown in FIG. 17 , more preferably as shown in FIG. 17 .
  • the crystal form D has an endothermic signal corresponding to the first order weight loss of the TGA when heated to about 100 ⁇ 5°C (preferably about 100 ⁇ 2°C), and when heated to about 168 ⁇ 5°C (preferably about 168 ⁇ 2°C) has an endothermic peak corresponding to the second order weight loss of the TGA.
  • the DSC spectrum of the crystal form D is substantially as shown in FIG. 17 , more preferably as shown in FIG. 17 .
  • the NMR spectrum of the crystalline form D is substantially as shown in FIG. 18 , preferably as shown in FIG. 18 .
  • the Form D is a solvate with DMSO, wherein the stoichiometric ratio of Compound I to the DMSO is about 1:1.
  • the XRPD pattern of Form E of Compound I exhibits at least two, at least three, at least four, at least five, or at least six diffraction angles 2 ⁇ (°) at maximum intensity.
  • the XRPD pattern of Form E of Compound I includes diffraction angles at about 4.2 ⁇ 0.2°, 9.6 ⁇ 0.2°, 12.8 ⁇ 0.2°, 19.1 ⁇ 0.2°, and/or 27.2 ⁇ 0.2° ( Diffraction peaks at 2 ⁇ ).
  • the XRPD pattern of the crystalline form E further includes diffraction peaks at diffraction angles (2 ⁇ ) of about 25.3 ⁇ 0.2°, 25.7 ⁇ 0.2°, 28.8 ⁇ 0.2° and/or 35.7 ⁇ 0.2°.
  • the XRPD pattern of the crystalline form E also includes a temperature at about 12.1 ⁇ 0.2°, 17.0 ⁇ 0.2°, 17.4 ⁇ 0.2°, 17.9 ⁇ 0.2°, 19.4 ⁇ 0.2°, 20.2 ⁇ 0.2°, 21.3 ⁇ 0.2° , 21.7 ⁇ 0.2°, 21.9 ⁇ 0.2°, 23.2 ⁇ 0.2°, 26.7 ⁇ 0.2°, 27.9 ⁇ 0.2°, 29.9 ⁇ 0.2°, 30.1 ⁇ 0.2°, 31.4 ⁇ 0.2°, 32.1 ⁇ 0.2°, 35.0 ⁇ 0.2° and/or diffraction peaks at a diffraction angle (2 ⁇ ) of 39.0 ⁇ 0.2°.
  • the XRPD pattern of the crystalline form E is substantially as shown in Figure 19, more preferably as shown in Figure 19;
  • the crystalline form E loses about 3.3% of its weight during heating to about 100 ⁇ 5°C (preferably about 100 ⁇ 2°C), and loses about 21.0% of its weight during heating from about 100 to about 180 ⁇ 5°C. %, decomposition may start at about 210 ⁇ 5°C, preferably about 210 ⁇ 2°C, as measured using TGA.
  • the TGA spectrum of the crystal form E is substantially as shown in FIG. 20 , more preferably as shown in FIG. 20 .
  • the onset temperature of the endothermic peak of the crystalline form E is about 177°C ⁇ 5°C, preferably about 177 ⁇ 2°C.
  • the endothermic peak corresponds to the weight loss of the TGA.
  • the DSC spectrum of the crystal form E is substantially as shown in FIG. 20 , more preferably as shown in FIG. 20 .
  • the NMR spectrum of the crystalline form E is substantially as shown in Figure 21, preferably as shown in Figure 21.
  • the Form E is a solvate with NMP, wherein the stoichiometric ratio of Compound I to the NMP is about 1:1.
  • the XRPD pattern of Form F of Compound I exhibits at least two, at least three, at least four, at least five, or at least six diffraction angles 2 ⁇ (°) at maximum intensity.
  • the XRPD pattern of Form F of Compound I includes diffraction angles at about 5.3 ⁇ 0.2°, 7.0 ⁇ 0.2°, 9.5 ⁇ 0.2°, 19.1 ⁇ 0.2°, and/or 21.7 ⁇ 0.2° ( Diffraction peaks at 2 ⁇ ).
  • the XRPD pattern of the crystalline form F further includes diffraction at a diffraction angle (2 ⁇ ) of about 10.0 ⁇ 0.2°, 17.2 ⁇ 0.2°, 18.5 ⁇ 0.2°, 20.4 ⁇ 0.2° and/or 21.0 ⁇ 0.2° peak.
  • the XRPD pattern of the crystalline form F also includes a temperature at about 10.8 ⁇ 0.2°, 14.0 ⁇ 0.2°, 14.4 ⁇ 0.2°, 15.0 ⁇ 0.2°, 15.5 ⁇ 0.2°, 15.9 ⁇ 0.2°, 16.5 ⁇ 0.2° , 17.5 ⁇ 0.2°, 18.8 ⁇ 0.2°, 19.6 ⁇ 0.2°, 20.2 ⁇ 0.2°, 22.1 ⁇ 0.2°, 22.4 ⁇ 0.2°, 22.8 ⁇ 0.2°, 24.6 ⁇ 0.2°, 26.8 ⁇ 0.2°, 27.2 ⁇ 0.2° , 27.5 ⁇ 0.2°, 28.1 ⁇ 0.2°, 28.5 ⁇ 0.2°, 29.0 ⁇ 0.2°, 29.5 ⁇ 0.2°, 29.8 ⁇ 0.2°, 31.1 ⁇ 0.2°, 32.6 ⁇ 0.2°, 33.0 ⁇ 0.2°, 35.1 ⁇ 0.2° , 35.9 ⁇ 0.2°, 37.4 ⁇ 0.2°, 38.9 ⁇ 0.2° and/or 40.9 ⁇ 0.2° diffraction angles (2 ⁇ ) of the diffraction peaks.
  • the XRPD pattern of the crystalline form F is substantially as shown in FIG. 22 , more preferably as shown in FIG. 22 .
  • the crystalline Form F loses about 1.6% of its weight during heating to about 60 ⁇ 5°C (preferably about 60 ⁇ 2°C), and loses about 13.9% of its weight during heating from about 60 to about 150 ⁇ 5°C. %, decomposition may start at about 200°C ⁇ 5°C (preferably about 200 ⁇ 2°C), as measured using TGA.
  • the TGA spectrum of the crystal form F is substantially as shown in FIG. 23 , more preferably as shown in FIG. 23 .
  • the crystalline form F has an endothermic peak with an onset temperature of about 131 ⁇ 5°C, preferably about 131 ⁇ 2°C.
  • the endothermic peak corresponds to desolvation.
  • the DSC spectrum of the crystalline form F is substantially as shown in FIG. 23 , more preferably as shown in FIG. 23 .
  • the NMR spectrum of Form F is substantially as shown in Figure 24, more preferably as shown in Figure 24.
  • the Form F is a solvate with DMF, wherein the stoichiometric ratio of Compound I to the DMF is about 1:1.
  • the XRPD pattern of Form G of Compound I exhibits at least two, at least three, at least four, at least five, or at least six diffraction angles 2 ⁇ (°) at maximum intensity.
  • the XRPD pattern of Form G of Compound I comprises diffraction angles at about 12.1 ⁇ 0.2°, 20.8 ⁇ 0.2°, 23.6 ⁇ 0.2°, 24.6 ⁇ 0.2° and/or 29.1 ⁇ 0.2° ( Diffraction peaks at 2 ⁇ ).
  • the XRPD pattern of the crystalline form G further includes diffraction angles at about 15.7 ⁇ 0.2°, 21.1 ⁇ 0.2°, 23.0 ⁇ 0.2°, 23.4 ⁇ 0.2°, 28.2 ⁇ 0.2° and/or 33.0 ⁇ 0.2° ( Diffraction peaks at 2 ⁇ ).
  • the XRPD pattern of the crystalline form G also includes an , 22.9 ⁇ 0.2°, 23.9 ⁇ 0.2°, 24.4 ⁇ 0.2°, 25.5 ⁇ 0.2°, 25.9 ⁇ 0.2°, 26.1 ⁇ 0.2°, 27.0 ⁇ 0.2°, 27.5 ⁇ 0.2°, 27.7 ⁇ 0.2°, 28.0 ⁇ 0.2° , 31.2 ⁇ 0.2°, 33.3 ⁇ 0.2°, 33.5 ⁇ 0.2°, 35.7 ⁇ 0.2°, 35.9 ⁇ 0.2°, 36.3 ⁇ 0.2°, 36.6 ⁇ 0.2°, 37.5 ⁇ 0.2°, 40.5 ⁇ 0.2°, 41.3 ⁇ 0.2° and/or diffraction peaks at a diffraction angle (2 ⁇ ) of 42.9 ⁇ 0.2°.
  • the XRPD pattern of Form G is substantially as shown in Figure 25, more preferably as shown in Figure 25.
  • the crystalline Form G loses about 2.0% of its weight during heating to about 50 ⁇ 5°C (preferably about 50 ⁇ 2°C), and loses about 12.7% of its weight during heating from about 50 to about 100 ⁇ 5°C. %, decomposition may start at about 180 ⁇ 5°C, preferably about 180 ⁇ 2°C, as measured using TGA.
  • the TGA spectrum of the crystal form G is substantially as shown in FIG. 26 , more preferably as shown in FIG. 26 .
  • the crystalline form G has endothermic peaks with onset temperatures of about 78.6 ⁇ 5°C (about 78.6 ⁇ 2°C) and about 84.8 ⁇ 5°C (preferably about 84.8 ⁇ 2°C), respectively.
  • the endothermic peak corresponds to the weight loss of the TGA.
  • the DSC spectrum of the crystal form G is substantially as shown in FIG. 26 , more preferably as shown in FIG. 26 .
  • the NMR spectrum of Form G is substantially as shown in Figure 27, preferably as shown in Figure 27.
  • the Form G is a trihydrate.
  • the present invention provides a process for the preparation of a crystalline free form of Compound I, said process comprising:
  • Dissolving Compound I in different solvents by adding an acid or base to adjust the pH, adding a base or acid to precipitate a solid, then performing solid-liquid separation, and drying the obtained solid to obtain the crystalline Compound I; or
  • One crystal form of compound I in free form is converted into another crystal form by crystal transformation.
  • the method for crystal transformation includes: heating or suspension in a suitable solvent for crystal transformation.
  • Said solvents include, but are not limited to, water, alcohols (such as alkanols having 1-4 carbon atoms), chlorinated alkanes, ketones, ethers, cyclic ethers, esters, alkanes, cycloalkanes, Benzene, amides, sulfoxides or mixtures thereof, preferably selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, acetonitrile, acetone, methyl ethyl ketone, tetrahydrofuran, dioxane, N,N- Dimethylformamide, dimethyl sulfoxide, ethyl acetate, dichloromethane, trichloroethane, carbon tetrachloride, n-heptane, n-hexane, isooctane, pentane, cyclohexane, cyclopentane Al
  • the present invention provides a method for preparing the crystalline form A, the method comprising:
  • a1) providing a suspension of Compound I in a suitable solvent, preferably the content of Compound I in said suspension is about 1-200 mg/ml;
  • the suitable solvent is selected from DMF, DMSO, methanol, ethanol, n-propanol, isopropanol, acetone, 4-methyl-2-pentanone, ethyl acetate, isopropyl acetate Esters, ethyl formate, butyl formate, n-heptane, cyclohexane, dioxane, diethyl ether, methyl tert-butyl ether, ethylene glycol methyl ether, ethylene glycol dimethyl ether, water, acetonitrile, toluene , dichloromethane, chloroform, tetrahydrofuran and mixtures thereof.
  • the stirring at room temperature in step a2), lasts for about 3-7 days.
  • the stirring at room temperature in a pilot experiment, the stirring at room temperature lasts for about 7 days; in scale-up production, the stirring at room temperature lasts for about 3 days.
  • the present invention provides a method for preparing the crystalline form A, the method comprising:
  • step b2) adding an appropriate acid to the filtrate obtained in step b1), to precipitate a solid to obtain the crystal form A;
  • the good solvent is water, isopropyl ether, n-heptane or toluene, more preferably water.
  • the base is ethanolamine.
  • the acid is hydrochloric acid, sulfuric acid or phosphoric acid.
  • the present invention provides a method for preparing the crystalline form B, the method comprising:
  • Dissolving compound I in a suitable good solvent then adding an anti-solvent dropwise to precipitate a solid, performing solid-liquid separation (for example, by centrifugation), and drying the obtained solid to obtain the crystal form B.
  • the method comprises:
  • the good solvent includes, but is not limited to, DMF.
  • the anti-solvent includes, but is not limited to, toluene.
  • the heating is to about 50°C ⁇ 2°C.
  • the stirring at room temperature is continued for about 1 day.
  • the drying is vacuum drying at room temperature.
  • the present invention provides a method for preparing the crystalline form C, the method comprising:
  • the method comprises:
  • said compound I is said crystalline form E.
  • the heating is to a temperature of about 40 to 60°C, more preferably about 50°C ⁇ 2°C.
  • said stirring at room temperature lasts for about 1 day.
  • the present invention provides a method for preparing the crystalline form C, the method comprising: at a temperature of about 10 to 60°C (eg, about 40 to 60°C, preferably about 50°C ⁇ 2°C) Stir the suspension of the crystal form E in an appropriate solvent for a sufficient time, then perform solid-liquid separation, and dry the obtained solid to obtain the crystal form C.
  • the suitable solvents include, but are not limited to, DMF, water, acetone, dichloromethane, toluene, chloroform, acetonitrile, and mixtures thereof.
  • the content of the crystalline form E in the suspension is about 1-200 mg/ml.
  • the method comprises:
  • said compound I is said crystalline form E.
  • the heating is to a temperature of about 40 to 60°C, more preferably about 50°C ⁇ 2°C.
  • said stirring at room temperature lasts for about 1 day.
  • the method comprises:
  • said compound I is said crystalline form E.
  • said suspension lasts for about 1 day.
  • the present invention provides a method for preparing the crystalline form C, the method comprising:
  • Compound I was added to a mixed solvent of DMSO and isopropanol and suspended at room temperature, filtered and dried to obtain the crystalline form C.
  • said suspension lasts for about 7 days.
  • the present invention provides a method for preparing the crystalline form D, the method comprising:
  • Compound I was dissolved in a suitable good solvent (including but not limited to DMSO), then an anti-solvent (including but not limited to chloroform) was added until solids were precipitated, solid-liquid separation was performed, and the resulting solids were dried to obtain the crystal Type D.
  • a suitable good solvent including but not limited to DMSO
  • an anti-solvent including but not limited to chloroform
  • the method comprises:
  • Compound I is mixed with DMSO, heated to dissolve and then cooled to room temperature, anti-solvent is added, stirred at room temperature for a sufficient time, solid-liquid separation (for example, by centrifugation), and then the obtained solid is dried to obtain the crystal form D.
  • the anti-solvent includes but not limited to chloroform.
  • the heating is to about 50°C ⁇ 2°C; and/or
  • the stirring at room temperature continues for about 1 day
  • the present invention provides a method for preparing the crystalline form D, the method comprising:
  • the anti-solvent includes but not limited to water.
  • the good solvent includes but not limited to DMSO.
  • the method comprises:
  • the anti-solvent includes but not limited to water.
  • the heating is to about 50°C, such as about 50°C ⁇ 2°C.
  • the cooling is down to about -15°C ⁇ 2°C.
  • the present invention provides a method for preparing the crystalline form E, the method comprising:
  • Dissolve compound I in a suitable good solvent including but not limited to NMP
  • an anti-solvent including but not limited to chloroform, toluene or a mixture thereof
  • the method comprises:
  • Compound I is mixed with NMP, cooled to room temperature after heating to dissolve, then adding an anti-solvent (including but not limited to chloroform, toluene or a mixture thereof), stirring at room temperature for a sufficient time, and then performing solid-liquid separation (for example, by centrifugation), The resulting solid was dried to obtain Form E as described.
  • an anti-solvent including but not limited to chloroform, toluene or a mixture thereof
  • the heating is to about 50°C ⁇ 2°C.
  • said stirring at room temperature lasts for about 1 day.
  • the present invention provides a method for preparing the crystalline form F, the method comprising:
  • Compound I was dissolved in an appropriate good solvent (such as but not limited to DMF), and then an anti-solvent (including but not limited to toluene) was added until solids were precipitated, followed by solid-liquid separation to obtain the Form F.
  • an appropriate good solvent such as but not limited to DMF
  • an anti-solvent including but not limited to toluene
  • the method comprises:
  • Compound I was mixed with DMF, heated to dissolve and cooled to room temperature, anti-solvent (including but not limited to toluene) was added, stirred at room temperature for a sufficient time, and then solid-liquid separation (for example, by centrifugation) was performed, and the obtained solid was dried to obtain the obtained Said crystal form F.
  • anti-solvent including but not limited to toluene
  • the heating is to about 50°C ⁇ 2°C.
  • said stirring at room temperature lasts for about 1 day.
  • the present invention also provides a method for preparing the crystalline form G, the method comprising:
  • the method comprises:
  • Compound I is added into an appropriate solvent, stirred at low temperature for a sufficient time, and then subjected to solid-liquid separation (for example, by centrifugation), and the resulting solid is dried at room temperature to obtain the crystalline form G.
  • said compound I is said crystal form B.
  • the suitable solvent includes, but is not limited to, ethanol, water or a mixture thereof.
  • the content of Compound I in said suspension is about 1-200 mg/ml.
  • the low temperature is about 5 to 30°C, more preferably about 10°C ⁇ 2°C.
  • said stirring at low temperature lasts for about 2 days.
  • the drying at room temperature is vacuum drying at room temperature.
  • the present invention provides said compound I in the form of said crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E, crystalline form F or crystalline form G.
  • the present invention provides a pharmaceutical composition, which comprises an effective amount of the selected from the crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, crystal form F and crystal form G Any one and one or more pharmaceutically acceptable carriers.
  • the present invention provides any one of the crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E, crystalline form F and crystalline form G or the pharmaceutical composition, which For renal function monitoring, wherein the renal function detection is GFR monitoring, especially real-time GFR detection.
  • the present invention provides any one of the crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E, crystalline form F and crystalline form G or the pharmaceutical composition in the preparation Use in a medicament ("tracer") for renal function monitoring, wherein said renal function test is GFR monitoring, in particular real-time GFR testing.
  • the present invention provides a method for monitoring renal function in an individual, the method comprising administering to the individual an effective amount of the crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E. Any one of the crystal forms F and G or the pharmaceutical composition, wherein the renal function detection is GFR monitoring, especially real-time GFR detection.
  • the crystalline forms A to G or the pharmaceutical composition or drug can be administered by various routes, including but not limited to oral, parenteral, transdermal, subcutaneous, enteral or intravenous administration.
  • the present invention also provides a method of purifying Compound I, said method comprising forming a solvate of Compound I from a suitable solvent.
  • suitable solvents include, but are not limited to, DMSO, NMP, and DMF.
  • the solvate is Form D, Form E, or Form F described above.
  • Anhydrous crystal forms A and C and monohydrate crystal form B can maintain stable crystal forms under high temperature, high humidity and light conditions.
  • Crystal form A has obvious advantages in stability under conditions such as light, high temperature, high humidity and competitive floating, and can meet the medicinal requirements of production, transportation, and storage.
  • the production process is stable, repeatable, and controllable, and can adapt to industrialization Production.
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • 1H NMR nuclear magnetic resonance
  • PLM polarized light microscope analysis
  • Samples were analyzed with an X-ray powder diffractometer Bruker D8 Advance (Bruker, GER).
  • the scanning 2 ⁇ range is from 3° to 45° (Cu-K ⁇ (K ⁇ 1 : 1.5406)), the scan step size is 0.02°, and the exposure time is 0.12 seconds.
  • the light tube voltage and current of the test sample are 40kV and 40mA respectively, and the sample disk is a zero background sample disk.
  • thermogravimetric analyzer TA Discovery 55 (TA, US) was used. 2 to 5 mg of sample is placed in a balanced open aluminum sample pan and automatically weighed in a TGA heating furnace. The sample is heated to the final temperature at a rate of 10°C/min, the nitrogen purging rate at the sample is 60ml/min, and the nitrogen purging rate at the balance is 40ml/min.
  • a differential scanning calorimeter TA Discovery 2500 (TA, US) was used. 1-2 mg of sample was accurately weighed and placed in a perforated DSC Tzero sample pan, heated to the final temperature at a rate of 10°C/min, and the nitrogen purging rate in the furnace was 50ml/min.
  • Polarizing microscope Motic BA310Met (Motic, CN) was used. Place a small amount of sample on a glass slide, and select a suitable lens to observe the shape of the sample.
  • Dynamic moisture sorption-desorption analysis was performed using DVS Intrinsic (SMS, UK).
  • the test adopts the gradient mode, the humidity change is 50%-95%-0%-50%, the humidity change of each gradient is 10% within the range of 0% to 90%, and the gradient end point is judged by the dm/dt method. dm/dt is less than 0.002% and maintained for 10 minutes as the end point of the gradient.
  • XRPD analysis is performed on the sample to confirm whether the solid form has changed.
  • Embodiment 1 the preparation of crystal form A
  • Form A loses 1.54% of its weight when heated to 100°C, and may decompose at around 200°C.
  • the NMR spectrum of Form A is shown in FIG. 3 .
  • the NMR results showed that the peak positions and integration results of each peak of the crystal form A were consistent with the reference spectrum, and no obvious organic solvent characteristic peaks were seen.
  • Form A has a weight gain of 0.42% at 95% humidity and a weight loss of 0.82% at 0% humidity, which is consistent with the TGA weight loss, indicating that Form A has very low hygroscopicity.
  • the XRPD results in Figure 4 show that the crystalline form of the sample after the DVS test did not change.
  • the PLM image of Form A is shown in Figure 5.
  • the PLM image shows that A is flake-like particles, and the particle size is generally less than 20 ⁇ m.
  • Form A is an anhydrous substance with good crystallinity and low hygroscopicity.
  • the XRPD pattern of the crystal form A of compound I obtained by method 2 is basically shown in FIG. 1 .
  • Embodiment 2 the preparation of crystal form B
  • Form B loses 3.82% of its weight when heated to 130°C, and may decompose at around 200°C.
  • Form B has two endothermic peaks at 72°C and 212°C after heating, and an exothermic peak at 215°C.
  • the NMR spectrum of Form B is shown in FIG. 8 .
  • NMR results showed that the peak positions and integration results of each peak of Form B were consistent with the reference spectrum, and the characteristic peak of DMF could be seen at 2.5–3.0ppm.
  • the ratio of compound I to DMF is 1:0.02
  • the ratio of DMF to TGA weight loss is small (theoretical weight loss is 0.37%).
  • the DVS spectrum of Form B is shown in FIG. 9 .
  • the weight gain of Form B was 3.15% at 95% humidity, indicating that Form B has a certain hygroscopicity; the weight loss was 4.10% at 0% humidity, which was consistent with the TGA weight loss.
  • the XRPD results in Figure 9 show that the crystalline form of the sample after the DVS test did not change.
  • the PLM image of the crystal form B is shown in Figure 10: the crystal form B is a plate-shaped particle, and the particle size is generally less than 20 ⁇ m.
  • crystal form B is a monohydrate with certain crystallinity and certain hygroscopicity.
  • Embodiment 3 the preparation of crystal form C
  • Form C loses only 0.95% of its weight when heated to 100°C, and may decompose at around 200°C.
  • Form C has no obvious heat flow signal before heating to the decomposition temperature, and the baseline shifts significantly after 210°C.
  • the NMR spectrum of Form C is shown in Figure 13.
  • the NMR results show that the peak positions and integration results of each peak of the crystal form C are consistent with the reference spectrum, and the absorption peak of DMF can be seen at 2.5-3.0ppm.
  • Form C has a weight gain of 2.58% at 95% humidity and a weight loss of 1.03% at 0% humidity, which is consistent with the TGA weight loss, indicating that Form C has certain hygroscopicity.
  • the XRPD results in Figure 14 show that the crystalline form of the sample after the DVS test did not change.
  • Form C is agglomerated into a spherical shape, and the particle size is generally less than 20 ⁇ m.
  • the crystal form C is an anhydrous substance with certain crystallinity and has certain hygroscopicity.
  • Form E prepared according to the method in Example 5 below was added to 1 ml of acetonitrile, stirred at 50° C. for 1 day, centrifuged, and the obtained solid was vacuum-dried at room temperature to obtain Form C.
  • Form E prepared according to the method in Example 5 below was added to a mixed solvent of 0.1 ml of water and 0.40 ml of acetone, suspended at room temperature for 1 day, then filtered, and the resulting solid was dried to obtain Form C.
  • the XRPD patterns of Form C obtained according to methods 2, 3 and 4 are basically shown in FIG. 11 .
  • Embodiment 4 the preparation of crystal form D
  • Form D loses 3.9% of its weight when heated to 110°C, loses 18.3% of its weight during the process from 110 to 200°C, and may decompose after 200°C.
  • Form D has an endothermic signal corresponding to the first-order weight loss of TGA when heated to 100°C, and an endothermic peak corresponding to the second-order weight loss at around 168°C.
  • the NMR spectrum of Form D is shown in Figure 18.
  • the NMR results showed that the peak positions and integration results of each peak of the crystal form D were consistent with the reference spectrum, the structure of the compound did not change, and the solvent peak of DMSO could be seen at 2.5-3.0ppm.
  • the ratio of compound I to DMSO is 1:1.2, which is consistent with the weight loss of TGA (theoretical weight loss is 20.12%).
  • crystal form D is a DMSO solvate in which the stoichiometric ratio of compound 1 and DMSO is 1:1.
  • the XRPD pattern of Form D obtained according to Method 2 is substantially as shown in FIG. 16 .
  • Embodiment 5 the preparation of crystal form E
  • Form E is a solid with certain crystallinity.
  • the TGA results show that the crystal form E loses 3.3% of its weight when heated to 100°C, loses 21.0% of its weight when heated from 100 to 180°C, and may decompose at around 210°C.
  • Form E has no obvious signal when heated to 140°C, but has an endothermic peak corresponding to TGA weight loss at around 177°C.
  • NMR results show that the peak positions and integration results of each peak of Form E are consistent with the reference spectrum, and the structure of the compound has not changed.
  • the solvent peaks of NMP can be seen at 1.9, 2.2, 2.7 and 3.3ppm, and can be seen at 2.3 and 7.13-7.27ppm.
  • Solvent peak for toluene Calculated according to the integral result, the ratio of compound I to NMP is 1:1.1, which is consistent with the weight loss of TGA (theoretical weight loss is 23.67%); the ratio of compound I to toluene is 1:0.07.
  • crystal form E is an NMP solvate in which the stoichiometric ratio of compound I to NMP is 1:1.
  • Embodiment 6 the preparation of crystal form F
  • Form F loses 1.6% in weight when heated to 60°C, loses 13.9% in the process from 60 to 150°C, and may decompose at around 200°C.
  • Form F has an endothermic peak corresponding to desolvation at around 131°C.
  • NMR results of Form F are shown in Figure 24. NMR results show that the peak positions and integration results of each peak of crystal form F are consistent with the reference collection, the compound structure does not change, and the solvent peak of DMF can be seen at 2.5-3.0ppm and 7.95ppm. According to the integral calculation, the ratio of the compound to DMF is 1:0.9, which is close to the weight loss of TGA (theoretical weight loss is 16.4%).
  • Form F is a DMF solvate in which the stoichiometric ratio of Compound I to DMF is 1:1.
  • Embodiment 7 the preparation of crystal form G
  • Form B 20mg of Form B was added to 2ml of water, stirred at 10°C for 2 days, centrifuged, and the resulting solid was vacuum-dried at room temperature to obtain Form G, whose XRPD pattern is shown in Figure 25.
  • Form G loses 2.0% of its weight in the process of heating to 50°C, loses 12.7% in the process of heating from 50 to 100°C, and may decompose at around 180°C.
  • Form G has endothermic peaks corresponding to TGA weight loss at around 78.6°C and 84.8°C.
  • the NMR spectrum of Form G is shown in Figure 27.
  • the NMR results showed that the peak positions and integration results of each peak of Form G were consistent with the reference spectrum, the structure of the compound did not change, and no obvious solvent peak was seen.
  • Form G is a trihydrate.
  • the laboratory-level scale-up preparation of the target crystal form is carried out, and the preparation process is shown in Table 2 below.
  • XRPD XRPD, DSC, TGA, NMR, DVS, PLM, etc. were used to characterize the crystal form A obtained by the scale-up preparation process.
  • XRPD is basically as shown in Figure 1, and the result shows that Form A is a solid with good crystallinity.
  • the TGA results showed that Form A lost 1.54% of its weight when heated to 100°C, and may decompose at around 200°C.
  • DSC results showed that Form A had an endothermic peak at 185°C.
  • the NMR results showed that the peak positions and integration results of each peak of the crystal form A were consistent with the reference spectrum, and no obvious organic solvent characteristic peaks were seen.
  • the DVS results showed that Form A gained 0.42% in weight at 95% humidity, and lost 0.82% at 0% humidity, which was consistent with the TGA weight loss, indicating that Form A had very low hygroscopicity.
  • XRPD results showed that the samples after DVS testing were not No crystal form change occurred.
  • the PLM image shows that the crystal form A is a plate-shaped particle, and the particle size is generally less than 20 ⁇ m. It can be seen that Form A is an anhydrous substance with good crystallinity and low hygroscopicity. Overall, Form A has good crystallinity, low hygroscopicity, and good particle size, which is conducive to drying, storage and transportation.
  • XRPD XRPD, DSC, TGA, NMR, DVS, PLM, etc. were used to characterize the crystal form B obtained by the scale-up preparation process.
  • XRPD is basically as shown in Figure 6, and the result shows that Form B is a solid with certain crystallinity.
  • the TGA results showed that Form B lost 3.82% of its weight when heated to 130°C, and it may decompose at around 200°C.
  • DSC results show that Form B has two endothermic peaks at 72°C and 212°C after heating, and an exothermic peak at 215°C. Combining with TGA, it begins to lose weight at this temperature, which may correspond to the melting of compound I with decomposition process.
  • the NMR results showed that the peak positions and integration results of each peak in B were consistent with the reference spectrum, and the characteristic peak of DMF could be seen at 2.5–3.0ppm. According to the calculation of the integral results, the ratio of compound I to DMF is 1:0.02, and the ratio of DMF to TGA weight loss is small (theoretical weight loss is 0.37%).
  • the DVS results show that the crystal form B has a weight gain of 3.15% at 95% humidity, indicating that the crystal form B has a certain hygroscopicity; the weight loss at 0% humidity is 4.10%, which is consistent with the TGA weight loss; the XRPD results show that the samples after the DVS test did not A crystal form change occurs.
  • the PLM image shows that the crystal form B is a plate-shaped particle, and the particle size is generally less than 20 ⁇ m. It can be seen that crystal form B is a monohydrate with certain crystallinity and certain hygroscopicity.
  • XRPD XRPD, DSC, TGA, NMR, DVS, PLM, etc. were used to characterize the crystal form C obtained by the scale-up preparation process.
  • XRPD is basically as shown in Figure 11, and the results show that Form C is a solid with certain crystallinity.
  • TGA results show that the crystal form C loses only 0.95% of its weight when heated to 100°C, and may decompose at around 200°C.
  • DSC results show that the crystal form C has no obvious heat flow signal before heating to the decomposition temperature, and the baseline shifts significantly after 210°C. Combined with the obvious weight loss of TGA at this temperature, there may be a heat flow signal corresponding to the decomposition of compound I.
  • the NMR results show that the peak positions and integration results of each peak of the crystal form C are consistent with the reference spectrum, and the absorption peak of DMF can be seen at 2.5-3.0ppm. According to the integral calculation, the ratio of compound to DMF is 1:0.09, which is close to the weight loss of TGA (theoretical weight loss is 1.7%).
  • the DVS results showed that Form C gained 2.58% in weight at 95% humidity, and lost 1.03% at 0% humidity, which was consistent with the TGA weight loss, indicating that Form C had a certain hygroscopicity; XRPD results showed that the samples after DVS testing did not A crystal form change occurs.
  • the PLM image shows that the crystal form C is agglomerated into a spherical shape, and the particle size is generally less than 20 ⁇ m. It can be seen that the crystal form C is an anhydrous substance with certain crystallinity and has certain hygroscopicity.
  • the crystal forms A, B, and C obtained by the scale-up preparation process are consistent with those obtained from the small test, indicating that the preparation process can be stably scaled up.
  • Embodiment 9 Stability study of crystal form
  • the water activity experiments of the hydrate crystal form B were carried out at 10°C, 25°C and 60°C, respectively. It was found that in ethanol at 10°C, 25°C and 60°C, the crystal form of Form B did not change after being suspended for two days; At 60°C, when the solvent is ethanol/water (1:1 v/v) or pure water, the crystal form B is transformed into crystal form A after being suspended for two days.
  • a total of 7 crystal forms were obtained in the crystal form screening, including two anhydrates (crystal forms A and C), two hydrates (crystal forms B and G) and three solvates (crystal forms D, E and F ).
  • the characterization results of the seven crystal forms are summarized in Table 6 below.
  • Embodiment 13 HPLC determination result of different crystal forms
  • FaSSIF is a simulated intestinal fluid in a fasting state, which is prepared as follows: (1) Weigh 0.042g sodium hydroxide, 0.3438g sodium dihydrogen phosphate and 0.6186g sodium chloride, add 90mL of purified water and mix well, then wash with 1N hydrochloric acid or 1N Adjust the pH to 6.5 with sodium hydroxide, and dilute to 100mL with purified water; (2) Take 50mL of the buffer solution prepared in (1) above, add 0.224g of FaSSIF/FeSSIF/FaSSGF commercially available powder (Biorelevant.com) , stir until dissolved, and then dilute to 100 mL with the buffer prepared in (1). Place the prepared buffer solution at room temperature, and observe that the buffer solution is slightly milky white after standing for two hours, and it can be used immediately.
  • FeSSIF is a simulated intestinal juice in a fed state, which is prepared as follows: (1) Weigh 0.404g sodium hydroxide, 0.865g glacial acetic acid and 1.1874g sodium chloride, add 90mL of pure water and mix well, then oxidize with 1N hydrochloric acid or 1N hydroxide Adjust the pH to 5.0 with sodium, and dilute to 100 mL with purified water; (2) Take 50 mL of the buffer solution prepared in (1) above, add 1.12 g of FaSSIF/FeSSIF/FaSSGF commercially available powder (Biorelevant.com), and stir Until dissolved, then dilute to 100mL with the buffer solution prepared in (1). Place the prepared buffer solution at room temperature, and observe that the buffer solution is a transparent liquid after standing for two hours, and it can be used immediately.
  • SGF FaSSGF
  • the crystalline form A has no crystal form change during the solubility test, and has good solubility in FaSSIF, FeSSIF and FaSSGF, so it can have a considerable dissolution advantage in the prepared preparation, which is conducive to the application process. Dissolution and bioavailability under different biological media conditions.

Abstract

A crystal form of a pyrazine derivative and a preparation method therefor, specifically relating to a crystal form, in particular crystal forms A-G of 3,6-diamino-2,5-bis{N-[(1R)-1-carboxyl-2-hydroxyethyl]carbamoyl}pyrazine (compound I), and a preparation method therefor. Anhydrous crystal forms A and C and monohydrate crystal form B have good stability, especially crystal form A has obvious advantages under the conditions of illumination, high temperature and high humidity. Provided is a method for purifying compound I, comprising forming compound I into a solvate from an appropriate solvent (such as DMSO, NMP and DMF).

Description

吡嗪类衍生物的晶型及其制备方法Crystal form of pyrazine derivatives and preparation method thereof 技术领域technical field
本发明涉及吡嗪类衍生物、特别是化合物3,6-二氨基-2,5-双{N-[(1R)-1-羧基-2-羟基乙基]氨基甲酰基}吡嗪的晶型及其制备方法。The present invention relates to pyrazine derivatives, especially crystals of compound 3,6-diamino-2,5-bis{N-[(1R)-1-carboxy-2-hydroxyethyl]carbamoyl}pyrazine type and its preparation method.
背景技术Background technique
3,6-二氨基-2,5-双{N-[(1R)-1-羧基-2-羟基乙基]氨基甲酰基}吡嗪，也称做“MB-102”，是一种具有优异的光物理性质和其他化学和物理特性的荧光化合物。如专利US 8,155,000、US 8,664,392、US 8,697,033、US 8,722,685、US 8,778,309、US 9,005,581、US 9,114,160、US 9,283,288、US 9,376,399和US 9,480,687所公开的，该化合物已知用于肾功能监测。MB-102正在被开发作为用于实时肾小球滤过率(GFR)测定的荧光剂。当在434nm激发时，它在556nm处发出强荧光信号。目前人体临床研究正在进行中。值得注意的是，可以经皮实时测量在患者血流中MB-102的清除速率，从而换算得到患者的肾小球滤过率。3,6-Diamino-2,5-bis{N-[(1R)-1-carboxy-2-hydroxyethyl]carbamoyl}pyrazine, also known as "MB-102", is a Fluorescent compounds with excellent photophysical properties and other chemical and physical properties. The compound is known for use in the monitoring of renal function as disclosed in patents US 8,155,000, US 8,664,392, US 8,697,033, US 8,722,685, US 8,778,309, US 9,005,581, US 9,114,160, US 9,283,288, US 9,376,399 and US 9,480,687. MB-102 is being developed as a fluorescer for real-time glomerular filtration rate (GFR) assays. It emits a strong fluorescent signal at 556nm when excited at 434nm. Human clinical research is currently in progress. It is worth noting that the clearance rate of MB-102 in the patient's blood stream can be measured in real time through the skin, so as to convert the glomerular filtration rate of the patient.
药用活性成分的晶型结构往往影响到药物的化学稳定性。结晶条件及储存条件的不同有可能导致化合物的晶型结构的变化，有时还会伴随着产生其他形态的晶型。同一种药物的不同晶型的生物利用度也可能会存在差别；另外，其稳定性、流动性、可压缩性也可能会不同，这些理化性质对药物的应用产生一定的影响，从而影响药物的疗效。The crystal structure of pharmaceutical active ingredients often affects the chemical stability of the drug. Different crystallization conditions and storage conditions may lead to changes in the crystal structure of the compound, sometimes accompanied by the production of other crystal forms. The bioavailability of different crystal forms of the same drug may also be different; in addition, its stability, fluidity, and compressibility may also be different. These physical and chemical properties have a certain impact on the application of the drug, thereby affecting the drug. curative effect.
尚未发现公开3,6-二氨基-2,5-双{N-[(1R)-1-羧基-2-羟基乙基]氨基甲酰基}吡嗪的具体晶型的报道。为了满足3,6-二氨基-2,5-双{N-[(1R)-1-羧基-2-羟基乙基]氨基甲酰基}吡嗪制剂开发所选用的原料形态，同时满足工业化生产过程中结晶工艺的重现性和可控性，满足生产、运输、储存的药用要求，需要开发新的3,6-二氨基-2,5-双{N-[(1R)-1-羧基-2-羟基乙基]氨基甲酰基}吡嗪晶型及相应的适用于工业化生产的制备方法。No report disclosing a specific crystal form of 3,6-diamino-2,5-bis{N-[(1R)-1-carboxy-2-hydroxyethyl]carbamoyl}pyrazine has been found yet. In order to meet the requirements of the selected raw material form for the development of 3,6-diamino-2,5-bis{N-[(1R)-1-carboxy-2-hydroxyethyl]carbamoyl}pyrazine preparations, and to meet the needs of industrial production The reproducibility and controllability of the crystallization process in the process to meet the pharmaceutical requirements of production, transportation and storage requires the development of new 3,6-diamino-2,5-bis{N-[(1R)-1- Carboxy-2-hydroxyethyl]carbamoyl}pyrazine crystal form and a corresponding preparation method suitable for industrial production.
发明内容Contents of the invention
本发明的第一方面提供3,6-二氨基-2,5-双{N-[(1R)-1-羧基-2-羟基乙基]氨基甲酰基}吡嗪(在下文中称作“化合物I”)的晶型：A first aspect of the present invention provides 3,6-diamino-2,5-bis{N-[(1R)-1-carboxy-2-hydroxyethyl]carbamoyl}pyrazine (hereinafter referred to as "the compound I") crystal form:
Figure PCTCN2022115011-appb-000001
Figure PCTCN2022115011-appb-000001
包括晶型A、晶型B、晶型C、晶型D、晶型E、晶型F和晶型G。所述晶型能同时满足工业化生产过程中结晶工艺的重现性和可控性，以及生产、运输、储存的药用要求等。Including crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E, crystalline form F and crystalline form G. The crystal form can simultaneously meet the reproducibility and controllability of the crystallization process in the industrial production process, as well as the pharmaceutical requirements of production, transportation and storage.
本发明的第二方面提供所述晶型A至G的制备方法。The second aspect of the present invention provides a method for preparing the crystal forms A to G.
本发明的第三方面提供所述化合物I，其为所述晶型A、晶型B、晶型C、晶型D、晶型E、晶型F或晶型G的形式。The third aspect of the present invention provides the compound I in the form of the crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E, crystalline form F or crystalline form G.
本发明的第四方面提供药物组合物，其包含有效量的选自所述晶型A至G中的任一种以及一种或多种药学上可接受的载体。The fourth aspect of the present invention provides a pharmaceutical composition, which comprises an effective amount of any one selected from the crystal forms A to G and one or more pharmaceutically acceptable carriers.
本发明的第五方面提供所述晶型A至G中的任一种或所述药物组合物，其用于肾功能监测，其中所述肾功能检测是GFR监测，特别是实时GFR检测。The fifth aspect of the present invention provides any one of the crystal forms A to G or the pharmaceutical composition for monitoring renal function, wherein the renal function detection is GFR monitoring, especially real-time GFR detection.
本发明的第六方面提供所述晶型A至G中的任一种或所述药物组合物在制备用于肾功能监测的药物中的用途，其中所述肾功能检测是GFR监测，特别是实时GFR检测。The sixth aspect of the present invention provides any one of the crystal forms A to G or the use of the pharmaceutical composition in the preparation of a drug for renal function monitoring, wherein the renal function detection is GFR monitoring, especially Real-time GFR detection.
本发明的第七方面提供用于个体的肾功能监测的方法，所述方法包括向所述个体施用有效量的所述晶型A至G中的任一种或所述药物组合物，其中所述肾功能检测是GFR监测，特别是实时GFR检测。The seventh aspect of the present invention provides a method for monitoring renal function in an individual, the method comprising administering to the individual an effective amount of any one of the crystal forms A to G or the pharmaceutical composition, wherein the The aforementioned renal function test is GFR monitoring, especially real-time GFR testing.
本发明的第八方面提供纯化化合物I的方法，所述方法包括使化合物I从适当的溶剂中形成溶剂合物。The eighth aspect of the present invention provides a method of purifying Compound I, said method comprising allowing Compound I to form a solvate from a suitable solvent.
附图说明Description of drawings
图1显示实施例1方法1中制备的化合物I的晶型A的X射线粉末衍 射(XRPD)图谱。Fig. 1 shows the X-ray powder diffraction (XRPD) pattern of the crystal form A of Compound I prepared in Method 1 of Example 1.
图2显示实施例1方法1中制备的化合物I的晶型A的热重量分析(TGA)图谱和差示扫描量热(DSC)图谱。2 shows the thermogravimetric analysis (TGA) spectrum and differential scanning calorimetry (DSC) spectrum of the crystal form A of compound I prepared in method 1 of Example 1.
图3显示实施例1方法1中制备的化合物I的晶型A的NMR图谱。Fig. 3 shows the NMR spectrum of the crystal form A of compound I prepared in method 1 of Example 1.
图4显示实施例1方法1中制备的化合物I的晶型A的(a)动态水分吸附(DVS)曲线，以及(b)DVS测试前后的XRPD图谱。Fig. 4 shows (a) dynamic moisture adsorption (DVS) curve of crystalline form A of compound I prepared in method 1 of Example 1, and (b) XRPD patterns before and after DVS test.
图5显示实施例1方法1中制备的化合物I的晶型A的偏光显微镜分析(PLM)图像。Fig. 5 shows the polarized light microscopy (PLM) image of the crystal form A of compound I prepared in method 1 of Example 1.
图6显示实施例2中制备的化合物I的晶型B的XRPD图谱。FIG. 6 shows the XRPD pattern of Form B of Compound I prepared in Example 2.
图7实施例2中制备的化合物I的晶型B的TGA和DSC图谱。FIG. 7 is the TGA and DSC spectra of the crystal form B of compound I prepared in Example 2.
图8实施例2中制备的化合物I的晶型B的NMR图谱。FIG. 8 is the NMR spectrum of the crystal form B of compound I prepared in Example 2.
图9显示实施例2中制备的化合物I的晶型B的(a)DVS曲线，以及(b)DVS测试前后的XRPD图谱。Figure 9 shows (a) DVS curve of Form B of Compound I prepared in Example 2, and (b) XRPD patterns before and after DVS test.
图10显示实施例2中制备的化合物I的晶型B的PLM图像。FIG. 10 shows the PLM image of Form B of Compound I prepared in Example 2.
图11显示实施例3方法1中制备的化合物I的晶型C的XRPD图谱。Fig. 11 shows the XRPD pattern of the crystal form C of compound I prepared in method 1 of Example 3.
图12显示实施例3方法1中制备的化合物I的晶型C的TGA和DSC图谱。Fig. 12 shows the TGA and DSC spectra of the crystal form C of compound I prepared in method 1 of Example 3.
图13显示实施例3方法1中制备的化合物I的晶型C的NMR图谱。Fig. 13 shows the NMR spectrum of the crystal form C of compound I prepared in method 1 of Example 3.
图14显示实施例3方法1中制备的化合物I的晶型C的(a)DVS曲线，以及(b)DVS测试前后的XRPD图谱。Figure 14 shows (a) DVS curve of Form C of Compound I prepared in Method 1 of Example 3, and (b) XRPD patterns before and after DVS test.
图15显示实施例3方法1中制备的化合物I的晶型C的PLM图像。Figure 15 shows the PLM image of Form C of Compound I prepared in Method 1 of Example 3.
图16显示实施例4方法1中制备的化合物I的晶型D的XRPD图谱。Fig. 16 shows the XRPD pattern of the crystal form D of compound I prepared in method 1 of Example 4.
图17显示实施例4方法1中制备的化合物I的晶型D的TGA和DSC图谱。Fig. 17 shows the TGA and DSC spectra of the crystal form D of compound I prepared in method 1 of Example 4.
图18显示实施例4方法1中制备的化合物I的晶型D的NMR图谱。Fig. 18 shows the NMR spectrum of the crystal form D of compound I prepared in method 1 of Example 4.
图19显示实施例5中制备的化合物I的晶型E的XRPD图谱。FIG. 19 shows the XRPD pattern of Form E of Compound I prepared in Example 5.
图20显示实施例5中制备的化合物I的晶型E的TGA和DSC图谱。FIG. 20 shows the TGA and DSC spectra of Form E of Compound I prepared in Example 5.
图21显示实施例5中制备的化合物I的晶型E的NMR图谱。FIG. 21 shows the NMR spectrum of Form E of Compound I prepared in Example 5.
图22显示实施例6中制备的化合物I的晶型F的XRPD图谱。FIG. 22 shows the XRPD pattern of Form F of Compound I prepared in Example 6.
图23显示实施例6中制备的化合物I的晶型F的DSC和TGA图谱。23 shows the DSC and TGA spectra of Form F of Compound I prepared in Example 6.
图24显示实施例6中制备的化合物I的晶型F的NMR图谱。FIG. 24 shows the NMR spectrum of Form F of Compound I prepared in Example 6.
图25显示实施例7中制备的化合物I的晶型G的XRPD图谱。FIG. 25 shows the XRPD pattern of Form G of Compound I prepared in Example 7.
图26显示实施例7中制备的化合物I的晶型G的TGA和DSC图谱。FIG. 26 shows the TGA and DSC spectra of Form G of Compound I prepared in Example 7.
图27显示实施例7中制备的化合物I的晶型G的NMR图谱。FIG. 27 shows the NMR spectrum of Form G of Compound I prepared in Example 7.
图28显示化合物I的不同晶型的XRPD图谱的对比图。Figure 28 shows a comparison of XRPD patterns of different crystal forms of Compound I.
图29显示化合物I的晶型A的稳定性的XRPD图谱。Figure 29 shows the XRPD pattern of the stability of Form A of Compound 1.
图30显示化合物I的晶型B的稳定性的XRPD图谱。Figure 30 shows the XRPD pattern of the stability of Form B of Compound 1.
图31显示化合物I的晶型C的稳定性的XRPD图谱。Figure 31 shows the XRPD pattern of the stability of Form C of Compound 1.
具体实施方式Detailed ways
以下对本发明进一步解释说明，应理解，所述用语旨在描述目的，而非限制本发明。The present invention is further explained below, and it should be understood that the terminology is intended to describe rather than limit the present invention.
定义definition
除非另有说明，本文使用的所有技术术语和科学术语均具有与本发明所属领域技术人员通常所理解的相同的含义。若存在矛盾，则以本文中的定义为准。当以范围、优选范围或者优选的数值上限及优选的数值下限的形式表述某个量、浓度或其他值或参数时，应当理解相当于具体揭示了通过将任意一对范围上限或优选数值与任意范围下限或优选数值结合起来的任何范围。除非另有说明，本文所列出的数值范围旨在包括范围的端点和该范围内的所有整数和分数(小数)。Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of conflict, the definitions herein shall prevail. When an amount, concentration or other value or parameter is expressed in the form of a range, a preferred range, or a preferred upper numerical limit and a preferred lower numerical limit, it is Any range where the lower limit of the range or combination of preferred values. Unless otherwise indicated, the numerical ranges set forth herein are intended to include the range endpoints and all integers and fractions (decimals) within the range.
术语“约”当与数值变量并用时，通常指该变量的数值和该变量的所有数值在实验误差内(例如对于平均值95％的置信区间内)或在指定数值的±20％、±10％、±5％或±2％的范围内。The term "about" when used in conjunction with a numerical variable generally means that the value of the variable and all values of the variable are within experimental error (e.g., within a 95% confidence interval for the mean) or within ±20%, ±10% of the stated value. %, ±5% or ±2%.
如本文中，在描述XRPD衍射角时所使用的术语“约”是指本领域的普通技术人员认为在所述值的可接受的标准误差内，例如±0.05、±0.1、±0.2、±0.3、±1、±2或±3等。As used herein, the term "about" used when describing XRPD diffraction angles means that those of ordinary skill in the art believe that within an acceptable standard error of the stated value, for example ±0.05, ±0.1, ±0.2, ±0.3 , ±1, ±2 or ±3, etc.
术语“包含”或与其同义的类似表述“包括”、“含有”和“具有”等是开放性的，不排除额外的未列举的元素、步骤或成分。表述“由……组成”排除未指明的任何元素、步骤或成分。术语“基本上由……组成”指范围限制在指定的元素、步骤或成分，加上任选存在的不会实质上影响所要求保护的主题的基本和新的特征的元素、步骤或成分。应当理解，术语“包含”、“包括”及类似术语涵盖术语“基本上由……组成”和“由……组成”。The term "comprising" or its synonymous similar expressions "comprising", "containing" and "having", etc. are open-ended and do not exclude additional unrecited elements, steps or components. The expression "consisting of" excludes any element, step or ingredient not specified. The term "consisting essentially of" means limiting the scope to the specified elements, steps or ingredients, plus the optional presence of elements, steps or ingredients that do not materially affect the basic and novel characteristics of the claimed subject matter. It should be understood that the terms "comprising", "including" and similar terms encompass the terms "consisting essentially of" and "consisting of".
本文所使用的术语“任选”或“任选地”是指随后描述的事件或情况可能发生或可能不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。As used herein, the term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that description includes that said event or circumstance occurs and that it does not.
除非另有说明，本文的百分比、份数等都按重量计。Unless otherwise indicated, percentages, parts, etc. herein are by weight.
如本文中所使用，术语“晶型”或“晶体”是指呈现三维排序的任意固体物质，与无定形固体物质相反，其产生具有边界清楚的峰的特征性XRPD图谱。As used herein, the term "crystalline form" or "crystal" refers to any solid material that exhibits a three-dimensional order, as opposed to amorphous solid material, which produces a characteristic XRPD pattern with well-defined peaks.
如本文中所使用，术语“X射线粉末衍射图谱”或“XRPD图谱”是指实验观察的衍射图或源于其的参数、数据或值。XRPD图谱通常由峰位(横坐标)和/或峰强度(纵坐标)表征。As used herein, the term "X-ray powder diffraction pattern" or "XRPD pattern" refers to an experimentally observed diffraction pattern or a parameter, data or value derived therefrom. XRPD patterns are usually characterized by peak positions (abscissa) and/or peak intensities (ordinate).
如本文中所使用，术语“衍射角”或“2θ”是指基于X射线衍射实验中设置的以度数(°)表示的峰位，并且通常是在衍射图谱中的横坐标单位。如果入射束与某晶格面形成θ角时反射被衍射，则实验设置需要以2θ角记录反射束。应当理解，在本文中提到的特定晶型的特定2θ值意图表示使用本文所述的X射线衍射实验条件所测量的2θ值(以度数表示)。例如，如本文所述，使用Cu-Kα(Kα1
Figure PCTCN2022115011-appb-000002
：1.5406)单色辐射。本文中的XRPD图谱优选在Bruker D8Advance(Bruker，GER)X射线粉末衍射分析仪上采集，透射模式优选在Bruker D8Advance(Bruker，GER)X射线粉末衍射分析仪上采集。 As used herein, the term "diffraction angle" or "2Θ" refers to the peak position expressed in degrees (°) based on the setup in an X-ray diffraction experiment, and is usually the unit of abscissa in a diffraction pattern. If reflections are diffracted when the incident beam forms an angle θ with a lattice plane, the experimental setup requires recording the reflected beam at 2θ angles. It should be understood that reference herein to a particular 2Θ value for a particular crystalline form is intended to represent the 2Θ value (expressed in degrees) measured using the X-ray diffraction experimental conditions described herein. For example, as described herein, using Cu-Kα (Kα1
Figure PCTCN2022115011-appb-000002
: 1.5406) monochromatic radiation. The XRPD pattern herein is preferably collected on a Bruker D8 Advance (Bruker, GER) X-ray powder diffraction analyzer, and the transmission mode is preferably collected on a Bruker D8 Advance (Bruker, GER) X-ray powder diffraction analyzer.
如本文中所使用，对于X射线衍射峰的术语“基本上相同”或“基本上如图×所示”意指将代表性峰位和强度变化考虑在内。例如，本领域技术人员会理解峰位(2θ)会显示一些变化，通常多达0.1至0.2度，并且用于测量衍射的仪器也会导致一些变化。另外，本领域技术人员会理解相对峰强度会因仪器间的差异以及结晶性程度、择优取向、制备的样品表面以及本领域技术人员已知的其它因素而出现变化。As used herein, the terms "substantially the same" or "substantially as shown in Figure X" for X-ray diffraction peaks mean that representative peak positions and intensity variations are taken into consideration. For example, those skilled in the art will understand that peak position (2Θ) will show some variation, typically by as much as 0.1 to 0.2 degrees, and that the instrumentation used to measure diffraction will also cause some variation. In addition, those skilled in the art will appreciate that relative peak intensities will vary due to instrument-to-instrument variation, as well as the degree of crystallinity, preferred orientation, prepared sample surface, and other factors known to those skilled in the art.
类似地，如本文中所使用，对于DSC图谱和TGA图谱所述的“基本上如图×所示”也意图涵盖本领域技术人员已知的与这些分析技术有关的变化。例如，对于DSC图谱中边界清楚的峰，通常会具有多达±0.2℃的变化，对于宽峰甚至更大(例如多达±1℃)。Similarly, as used herein, reference to "substantially as shown in Figure X" for DSC and TGA spectra is also intended to cover variations associated with these analytical techniques known to those skilled in the art. For example, well-defined peaks in a DSC profile will typically have variations of as much as ±0.2°C, and even larger (eg, as much as ±1°C) for broad peaks.
本申请中的核磁谱图优选在Bruker AVANCE-III(Bruker,GER)核磁共振仪上采集，除非另外说明，以DMSO-d6作为溶剂。The NMR spectra in the present application are preferably collected on a Bruker AVANCE-III (Bruker, GER) NMR instrument, unless otherwise specified, using DMSO-d6 as a solvent.
本申请中的偏光显微数据优选通过Motic BA310Met(Motic，CN)偏 光显微镜进行采集。Polarized light microscopy data in the application is preferably collected by a Motic BA310Met (Motic, CN) polarized light microscope.
如本文中所使用，术语“良溶剂”意指在其中化合物I能够溶解或具有相对更高的溶解度的溶剂。如本文中所使用，术语“反溶剂”意指在其中化合物I不溶或基本上不溶或者具有相对更低的溶解度的溶剂。在本文中，术语“良溶剂”和“反溶剂”也可以是相对而言的，不表示化合物I在其中的绝对溶解性。同一溶剂在某些情况下可以作为良溶剂，在其他情况下可以作为反溶剂。例如，水或甲苯在某些情况下，例如在单独用来溶解化合物I时，可以作为良溶剂，但在某些情况下，例如在与DMF配合使用时，可以作为反溶剂。As used herein, the term "good solvent" means a solvent in which Compound I can dissolve or have a relatively higher solubility. As used herein, the term "anti-solvent" means a solvent in which Compound I is insoluble or substantially insoluble or has relatively lower solubility. Herein, the terms "good solvent" and "anti-solvent" may also be relative terms, and do not represent the absolute solubility of Compound I therein. The same solvent can act as a good solvent in some cases and as an anti-solvent in other cases. For example, water or toluene can be used as a good solvent in some cases, such as when used alone to dissolve compound I, but can be used as an anti-solvent in some cases, such as when used in combination with DMF.
如本文中所使用，术语“烷烃类”意指具有1至10个、优选5至8个碳原子的烷烃，包括但不限于戊烷、正己烷、正庚烷和异辛烷。As used herein, the term "alkanes" means alkanes having 1 to 10, preferably 5 to 8 carbon atoms, including but not limited to pentane, n-hexane, n-heptane and isooctane.
如本文中所使用，术语“醇类”意指具有1至10个、优选1至4个碳原子的醇，特别是具有1-4个碳原子的链烷醇，包括但不限于甲醇、乙醇、正丙醇、异丙醇、正丁醇、仲丁醇和叔丁醇。As used herein, the term "alcohols" means alcohols with 1 to 10, preferably 1 to 4 carbon atoms, especially alkanols with 1 to 4 carbon atoms, including but not limited to methanol, ethanol , n-propanol, isopropanol, n-butanol, sec-butanol and tert-butanol.
如本文中所使用，术语“醚类”意指具有2至6个碳原子的醚，其包括链状醚类和环状醚类(例如呋喃类(包括四氢呋喃类)和二氧六环类)，具体包括但不限于***、异丙醚、甲基叔丁基醚、乙二醇甲醚、乙二醇二甲醚、四氢呋喃、2-甲基四氢呋喃和二氧六环(优选1,4-二氧六环)。As used herein, the term "ether" means an ether having 2 to 6 carbon atoms, which includes chain ethers and cyclic ethers (such as furans (including tetrahydrofurans) and dioxanes) , including but not limited to diethyl ether, isopropyl ether, methyl tert-butyl ether, ethylene glycol methyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran and dioxane (preferably 1,4- dioxane).
如本文中所使用，术语“酮类”意指具有2至6个碳原子的酮，包括但不限于丙酮、丁酮、甲乙酮和4-甲基-2-戊酮。As used herein, the term "ketones" means ketones having 2 to 6 carbon atoms, including but not limited to acetone, methyl ethyl ketone, methyl ethyl ketone, and 4-methyl-2-pentanone.
如本文中所使用，术语“酯类”意指具有3至10个碳原子的酯，包括但不限于乙酸乙酯、乙酸丙酯、乙酸异丙酯、甲酸乙酯和甲酸丁酯。As used herein, the term "esters" means esters having 3 to 10 carbon atoms, including but not limited to ethyl acetate, propyl acetate, isopropyl acetate, ethyl formate, and butyl formate.
如本文中所使用的数值范围(如“1至10个”)及其子范围(如“2至10个”、“2至6个”、“3至10个”)等涵盖所述数值范围中的任意个(例如1个、2个、3个、4个、5个、6个、7个、8个、9个或10个)。As used herein, numerical ranges (eg, "1 to 10") and subranges thereof (eg, "2 to 10", "2 to 6", "3 to 10") and the like encompass such numerical ranges Any of (eg, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) among.
如本文中所使用，术语“室温”是指20℃±5℃。As used herein, the term "room temperature" refers to 20°C ± 5°C.
化合物I的晶型Crystalline Form of Compound I
在第一方面，本发明提供化合物I的晶型A、晶型B、晶型C、晶型D、晶型E、晶型F和晶型G。In a first aspect, the present invention provides Form A, Form B, Form C, Form D, Form E, Form F and Form G of Compound I.
晶型AForm A
在一些实施方案中，所述化合物I的晶型A的XRPD图谱以最大强度 显示至少两个、至少三个、至少四个、至少五个或至少六个衍射角2θ(°)。In some embodiments, the XRPD pattern of Form A of Compound 1 exhibits at least two, at least three, at least four, at least five, or at least six diffraction angles 2θ (°) at maximum intensity.
在一些实施方案中，所述化合物I的晶型A的XRPD图谱包括在约6.7±0.2°、18.2±0.2°、27.4±0.2°和/或28.2±0.2°的衍射角(2θ)处的衍射峰。优选地，所述晶型A的XRPD图谱还包括在约16.9±0.2°、20.2±0.2°、20.7±0.2°、21.0±0.2°和/或21.8±0.2°的衍射角(2θ)处的衍射峰。更优选地，所述晶型A的XRPD图谱还包括在约14.0±0.2°、15.1±0.2°、17.3±0.2°、19.1±0.2°、19.7±0.2°、20.5±0.2°、22.4±0.2°、23.1±0.2°、24.4±0.2°、24.8±0.2°、26.9±0.2°、28.5±0.2°、29.2±0.2°、30.6±0.2°、30.8±0.2°、32.8±0.2°、33.5±0.2°、34.2±0.2°、41.2±0.2°和/或43.5±0.2°的衍射角(2θ)处的衍射峰。In some embodiments, the XRPD pattern of Form A of Compound I includes diffraction at diffraction angles (2θ) of about 6.7±0.2°, 18.2±0.2°, 27.4±0.2°, and/or 28.2±0.2° peak. Preferably, the XRPD pattern of the crystal form A further includes diffraction at a diffraction angle (2θ) of about 16.9±0.2°, 20.2±0.2°, 20.7±0.2°, 21.0±0.2° and/or 21.8±0.2° peak. More preferably, the XRPD pattern of the crystalline form A also includes a temperature at about 14.0±0.2°, 15.1±0.2°, 17.3±0.2°, 19.1±0.2°, 19.7±0.2°, 20.5±0.2°, 22.4±0.2° , 23.1±0.2°, 24.4±0.2°, 24.8±0.2°, 26.9±0.2°, 28.5±0.2°, 29.2±0.2°, 30.6±0.2°, 30.8±0.2°, 32.8±0.2°, 33.5±0.2° , 34.2±0.2°, 41.2±0.2° and/or 43.5±0.2° diffraction angles (2θ) of the diffraction peaks.
在一些优选的实施方案中，所述晶型A的XRPD图谱基本上如图1所示，更优选如图1所示。In some preferred embodiments, the XRPD pattern of the crystalline form A is substantially as shown in FIG. 1 , more preferably as shown in FIG. 1 .
在一些实施方案中，所述晶型A的吸热峰的起始温度为约185±5℃，优选为约185±2℃。优选地，所述晶型A的DSC图谱基本上如图2所示，更优选如图2所示。In some embodiments, the onset temperature of the endothermic peak of the crystalline form A is about 185±5°C, preferably about 185±2°C. Preferably, the DSC spectrum of the crystal form A is substantially as shown in Figure 2, more preferably as shown in Figure 2.
在一些实施方案中，所述晶型A在加热至约100±5℃(优选约100±2℃)的过程中失重约1.54％，在约200±5℃(优选约200±2℃)可能开始分解，如使用TGA所测得的。优选地，所述晶型A的TGA图谱基本上如图2所示，更优选如图2所示。In some embodiments, the crystal form A loses about 1.54% in weight during heating to about 100±5°C (preferably about 100±2°C), and may Decomposition started, as measured using TGA. Preferably, the TGA spectrum of the crystal form A is basically as shown in Figure 2, more preferably as shown in Figure 2.
在一些实施方案中，所述晶型A的NMR图谱基本上如图3所示，优选如图3所示。所述NMR图谱显示未见明显的有机溶剂特征峰。In some embodiments, the NMR spectrum of the crystalline form A is substantially as shown in FIG. 3 , preferably as shown in FIG. 3 . The NMR spectrum shows no obvious organic solvent characteristic peaks.
在一些实施方案中，所述晶型A不是溶剂合物，更优选地为无水物。In some embodiments, the Form A is not a solvate, more preferably an anhydrate.
在一些实施方案中，所述晶型A的PLM图像基本上如图5所示，优选如图5所示。所述晶型A为片状颗粒，其粒径一般小于约20μm。In some embodiments, the PLM image of Form A is substantially as shown in FIG. 5 , preferably as shown in FIG. 5 . The crystalline form A is tabular particles, the particle size of which is generally less than about 20 μm.
晶型BForm B
在一些实施方案中，所述化合物I的晶型B的XRPD图谱以最大强度显示至少两个、至少三个、至少四个、至少五个或至少六个衍射角2θ(°)。In some embodiments, the XRPD pattern of Form B of Compound I exhibits at least two, at least three, at least four, at least five, or at least six diffraction angles 2θ (°) at maximum intensity.
在一些实施方案中，所述化合物I的晶型B的XRPD图谱包括在约6.9±0.2°、9.5±0.2°、10.0±0.2°和/或19.1±0.2°的衍射角(2θ)处的衍射峰。优选地，所述晶型B的XRPD图谱还包括在约6.7±0.2°、17.2±0.2°、18.3±0.2°和/或21.0±0.2°的衍射角(2θ)处的衍射峰。更优选地，所述晶型B的XRPD图 谱还包括在约14.0±0.2°、15.9±0.2°、20.2±0.2°、21.3±0.2°、21.7±0.2°、22.1±0.2°、24.6±0.2°、26.9±0.2°、27.3±0.2°、27.5±0.2°、28.1±0.2°、29.5±0.2°、31.1±0.2°和/或35.1±0.2°的衍射角(2θ)处的衍射峰。In some embodiments, the XRPD pattern of Form B of Compound 1 includes diffraction at diffraction angles (2θ) of about 6.9±0.2°, 9.5±0.2°, 10.0±0.2°, and/or 19.1±0.2° peak. Preferably, the XRPD pattern of the crystal form B further includes diffraction peaks at diffraction angles (2θ) of about 6.7±0.2°, 17.2±0.2°, 18.3±0.2° and/or 21.0±0.2°. More preferably, the XRPD pattern of the crystalline form B also includes a temperature of , 26.9±0.2°, 27.3±0.2°, 27.5±0.2°, 28.1±0.2°, 29.5±0.2°, 31.1±0.2° and/or 35.1±0.2° diffraction angle (2θ) of the diffraction peaks.
在一些优选的实施方案中，所述晶型B的XRPD图谱基本上如图6所示，更优选如图6所示。In some preferred embodiments, the XRPD pattern of the crystalline form B is substantially as shown in FIG. 6 , more preferably as shown in FIG. 6 .
在一些实施方案中，所述晶型B具有两个吸热峰，其起始温度分别为约72±5℃和约212±5℃，优选为约72±2℃和约212±2℃。在一些实施方案中，所述晶型B还具有一个放热峰，其起始温度为约215℃±5℃，优选为约215℃±2℃。优选地，所述晶型B的DSC图谱基本上如图7所示，更优选如图7所示。In some embodiments, the crystalline form B has two endothermic peaks, the onset temperatures of which are about 72±5°C and about 212±5°C, preferably about 72±2°C and about 212±2°C. In some embodiments, the crystal form B also has an exothermic peak with an onset temperature of about 215°C±5°C, preferably about 215°C±2°C. Preferably, the DSC spectrum of the crystal form B is substantially as shown in FIG. 7 , more preferably as shown in FIG. 7 .
在一些实施方案中，所述晶型B在加热至约130±5℃(优选约130±2℃)的过程中失重约3.82％，在约200±5℃(优选约200±2℃)可能开始发生分解，如使用TGA所测得的。优选地，所述晶型B的TGA图谱基本上如图7所示，更优选如图7所示。In some embodiments, the crystal form B loses about 3.82% in weight during heating to about 130±5°C (preferably about 130±2°C), and may Decomposition started to occur as measured using TGA. Preferably, the TGA spectrum of the crystal form B is substantially as shown in FIG. 7 , more preferably as shown in FIG. 7 .
在一些实施方案中，所述的晶型B的NMR图谱基本上如图8所示，优选如图8所示。In some embodiments, the NMR spectrum of the crystal form B is substantially as shown in FIG. 8 , preferably as shown in FIG. 8 .
在一些实施方案中，所述晶型B为一水合物。In some embodiments, the Form B is a monohydrate.
在一些实施方案中，所述晶型B的PLM图像基本上如图10所示，优选如图10所示。所述晶型B为片状颗粒，其粒径一般小于约20μm。In some embodiments, the PLM image of the Form B is substantially as shown in FIG. 10 , preferably as shown in FIG. 10 . The crystal form B is tabular particles, the particle size of which is generally less than about 20 μm.
晶型CForm C
在一些实施方案中，所述化合物I的晶型C的XRPD图谱以最大强度显示至少两个、至少三个、至少四个、至少五个或至少六个衍射角2θ(°)。In some embodiments, the XRPD pattern of Form C of Compound I exhibits at least two, at least three, at least four, at least five, or at least six diffraction angles 2θ (°) at maximum intensity.
在一些实施方案中，所述化合物I的晶型C的XRPD图谱包括在约6.8±0.2°、15.1±0.2°、21.4±0.2°、22.0±0.2°和/或27.6±0.2°的衍射角(2θ)处的衍射峰。优选地，所述晶型C的XRPD图谱还包括在约20.6±0.2°、21.2±0.2°、26.7±0.2°和/或28.7±0.2°的衍射角(2θ)处的衍射峰。优选地，所述晶型C的XRPD图谱还包括在约13.6±0.2°、14.7±0.2°、16.2±0.2°、18.0±0.2°、19.1±0.2°、20.0±0.2°、22.7±0.2°、23.3±0.2°、25.0±0.2°、27.1±0.2°、28.0±0.2°、30.2±0.2°、31.5±0.2°、31.9±0.2°、34.6±0.2°、34.8±0.2°、38.8±0.2°、40.0±0.2°和/或41.9±0.2°的衍射角(2θ)处的衍射峰。In some embodiments, the XRPD pattern of Form C of Compound 1 includes diffraction angles at about 6.8±0.2°, 15.1±0.2°, 21.4±0.2°, 22.0±0.2°, and/or 27.6±0.2° ( Diffraction peaks at 2θ). Preferably, the XRPD pattern of the crystalline form C further includes diffraction peaks at diffraction angles (2θ) of about 20.6±0.2°, 21.2±0.2°, 26.7±0.2° and/or 28.7±0.2°. Preferably, the XRPD pattern of the crystalline form C also includes a range at about 13.6±0.2°, 14.7±0.2°, 16.2±0.2°, 18.0±0.2°, 19.1±0.2°, 20.0±0.2°, 22.7±0.2°, 23.3±0.2°, 25.0±0.2°, 27.1±0.2°, 28.0±0.2°, 30.2±0.2°, 31.5±0.2°, 31.9±0.2°, 34.6±0.2°, 34.8±0.2°, 38.8±0.2°, Diffraction peaks at diffraction angles (2θ) of 40.0±0.2° and/or 41.9±0.2°.
在一些优选的实施方案中，所述晶型C的XRPD图谱基本上如图11所示，更优选地如图11所示。In some preferred embodiments, the XRPD pattern of the crystalline form C is substantially as shown in FIG. 11 , more preferably as shown in FIG. 11 .
在一些实施方案中，所述晶型C的DSC图谱基本上如图12所示，优选如12所示。所述晶型C在加热到分解温度之前没有明显的热流信号，在约210±5℃(优选约210±2℃)后基线发生明显偏移。In some embodiments, the DSC spectrum of the crystalline form C is substantially as shown in FIG. 12 , preferably as shown in FIG. 12 . The crystalline form C has no obvious heat flow signal before heating to the decomposition temperature, and the baseline shifts obviously after about 210±5°C (preferably about 210±2°C).
在一些实施方案中，所述晶型C在加热至约100±5℃(优选约100±2℃)的过程中失重约0.95％，在约200±5℃(优选约200±2℃)可能发生分解，如使用TGA所测得的。优选地，所述晶型C的TGA图谱基本上如图12所示，更优选地如图12所示。In some embodiments, the crystal form C loses about 0.95% in weight during heating to about 100±5°C (preferably about 100±2°C), and may Decomposition occurred as measured using TGA. Preferably, the TGA spectrum of the crystal form C is substantially as shown in FIG. 12 , more preferably as shown in FIG. 12 .
在一些实施方案中，所述晶型C的NMR图谱基本上如图13所示，优选如图13所示。In some embodiments, the NMR spectrum of Form C is substantially as shown in Figure 13, preferably as shown in Figure 13.
在一些实施方案中，所述晶型C不是溶剂合物，更优选地为无水物。In some embodiments, the Form C is not a solvate, more preferably an anhydrate.
在一些实施方案中，所述晶型C的PLM图像基本上如图15所示，优选如图15所示。所述晶型C团聚为球形，粒径一般小于约20μm。In some embodiments, the PLM image of Form C is substantially as shown in FIG. 15 , preferably as shown in FIG. 15 . The crystal form C is agglomerated in a spherical shape, and the particle size is generally less than about 20 μm.
晶型DForm D
在一些实施方案中，所述化合物I的晶型D的XRPD图谱以最大强度显示至少两个、至少三个、至少四个、至少五个或至少六个衍射角2θ(°)。In some embodiments, the XRPD pattern of Form D of Compound I exhibits at least two, at least three, at least four, at least five, or at least six diffraction angles 2θ (°) at maximum intensity.
在一些实施方案中，所述化合物I的晶型D的XRPD图谱包括在约9.6±0.2°、17.0±0.2°、19.9±0.2°和/或26.0±0.2°的衍射角(2θ)处的衍射峰。优选地，所述晶型D的XRPD图谱还包括在约4.4±0.2°、13.4±0.2°、20.2±0.2°、23.3±0.2°、25.1±0.2°、28.4±0.2°和/或29.2±0.2°的衍射角(2θ)处的衍射峰。更优选地，所述晶型D的XRPD图谱还包括在约12.3±0.2°、15.9±0.2°、19.0±0.2°、20.9±0.2°、21.4±0.2°、21.8±0.2°、22.6±0.2°、24.1±0.2°、24.9±0.2°、27.8±0.2°、30.0±0.2°、31.6±0.2°、32.2±0.2°、32.6±0.2°、32.8±0.2°、34.0±0.2°、36.5±0.2°、37.5±0.2°、37.7±0.2°和/或40.1±0.2°衍射角(2θ)处的衍射峰。In some embodiments, the XRPD pattern of Form D of Compound I includes diffraction at diffraction angles (2θ) of about 9.6±0.2°, 17.0±0.2°, 19.9±0.2°, and/or 26.0±0.2° peak. Preferably, the XRPD pattern of the crystalline form D further includes a temperature range of about 4.4±0.2°, 13.4±0.2°, 20.2±0.2°, 23.3±0.2°, 25.1±0.2°, 28.4±0.2° and/or 29.2±0.2° The diffraction peak at the diffraction angle (2θ) of °. More preferably, the XRPD pattern of the crystalline form D also includes an , 24.1±0.2°, 24.9±0.2°, 27.8±0.2°, 30.0±0.2°, 31.6±0.2°, 32.2±0.2°, 32.6±0.2°, 32.8±0.2°, 34.0±0.2°, 36.5±0.2° , 37.5±0.2°, 37.7±0.2° and/or 40.1±0.2° diffraction angle (2θ) of the diffraction peaks.
在一些优选的实施方案中，所述晶型D的XRPD图谱基本上如图16所示，更优选如图16所示。In some preferred embodiments, the XRPD pattern of the crystalline form D is substantially as shown in FIG. 16 , more preferably as shown in FIG. 16 .
在一些实施方案中，所述晶型D在加热至约110±5℃(优选约110±2℃)的过程中失重约3.9％，在约110至约200±5℃的过程中失重约18.3％，在约200±5℃(优选约200±2℃)后可能开始分解，如使用TGA所测得 的。优选地，所述晶型D的TGA图谱基本上如图17所示，更优选如图17所示。In some embodiments, the crystalline form D loses about 3.9% of its weight during heating to about 110±5°C (preferably about 110±2°C), and loses about 18.3% of its weight during heating from about 110 to about 200±5°C. %, decomposition may start after about 200±5°C, preferably about 200±2°C, as measured using TGA. Preferably, the TGA spectrum of the crystal form D is substantially as shown in FIG. 17 , more preferably as shown in FIG. 17 .
在一些实施方案中，所述晶型D在加热至约100±5℃(优选约100±2℃)有对应所述TGA的第一阶失重的吸热信号，在加热至约168±5℃(优选约168±2℃)有对应所述TGA的第二阶失重的吸热峰。优选地，所述晶型D的DSC图谱基本上如图17所示，更优选如图17所示。In some embodiments, the crystal form D has an endothermic signal corresponding to the first order weight loss of the TGA when heated to about 100±5°C (preferably about 100±2°C), and when heated to about 168±5°C (preferably about 168±2°C) has an endothermic peak corresponding to the second order weight loss of the TGA. Preferably, the DSC spectrum of the crystal form D is substantially as shown in FIG. 17 , more preferably as shown in FIG. 17 .
在一些实施方案中，所述晶型D的NMR图谱基本上如图18所示，优选如图18所示。In some embodiments, the NMR spectrum of the crystalline form D is substantially as shown in FIG. 18 , preferably as shown in FIG. 18 .
在一些实施方案中，所述晶型D为具有DMSO的溶剂合物，其中化合物I与所述DMSO的化学计量比为约1:1。In some embodiments, the Form D is a solvate with DMSO, wherein the stoichiometric ratio of Compound I to the DMSO is about 1:1.
晶型EForm E
在一些实施方案中，所述化合物I的晶型E的XRPD图谱以最大强度显示至少两个、至少三个、至少四个、至少五个或至少六个衍射角2θ(°)。In some embodiments, the XRPD pattern of Form E of Compound I exhibits at least two, at least three, at least four, at least five, or at least six diffraction angles 2θ (°) at maximum intensity.
在一些实施方案中，所述化合物I的晶型E的XRPD图谱包括在约4.2±0.2°、9.6±0.2°、12.8±0.2°、19.1±0.2°和/或27.2±0.2°的衍射角(2θ)处的衍射峰。优选地，所述晶型E的XRPD图谱还包括在约25.3±0.2°、25.7±0.2°、28.8±0.2°和/或35.7±0.2°的衍射角(2θ)处的衍射峰。更优选地，所述晶型E的XRPD图谱还包括在约12.1±0.2°、17.0±0.2°、17.4±0.2°、17.9±0.2°、19.4±0.2°、20.2±0.2°、21.3±0.2°、21.7±0.2°、21.9±0.2°、23.2±0.2°、26.7±0.2°、27.9±0.2°、29.9±0.2°、30.1±0.2°、31.4±0.2°、32.1±0.2°、35.0±0.2°和/或39.0±0.2°的衍射角(2θ)处的衍射峰。In some embodiments, the XRPD pattern of Form E of Compound I includes diffraction angles at about 4.2±0.2°, 9.6±0.2°, 12.8±0.2°, 19.1±0.2°, and/or 27.2±0.2° ( Diffraction peaks at 2θ). Preferably, the XRPD pattern of the crystalline form E further includes diffraction peaks at diffraction angles (2θ) of about 25.3±0.2°, 25.7±0.2°, 28.8±0.2° and/or 35.7±0.2°. More preferably, the XRPD pattern of the crystalline form E also includes a temperature at about 12.1±0.2°, 17.0±0.2°, 17.4±0.2°, 17.9±0.2°, 19.4±0.2°, 20.2±0.2°, 21.3±0.2° , 21.7±0.2°, 21.9±0.2°, 23.2±0.2°, 26.7±0.2°, 27.9±0.2°, 29.9±0.2°, 30.1±0.2°, 31.4±0.2°, 32.1±0.2°, 35.0±0.2° and/or diffraction peaks at a diffraction angle (2θ) of 39.0±0.2°.
在一些优选的实施方案中，所述晶型E的XRPD图谱基本上如图19所示，更优选地如图19所示；In some preferred embodiments, the XRPD pattern of the crystalline form E is substantially as shown in Figure 19, more preferably as shown in Figure 19;
在一些实施方案中，所述晶型E在加热至约100±5℃(优选约100±2℃)的过程中失重约3.3％，在约100至约180±5℃的过程中失重约21.0％，在约210±5℃(优选约210±2℃)可能开始分解，如使用TGA所测得的。优选地，所述晶型E的TGA图谱基本上如图20所示，更优选如图20所示。In some embodiments, the crystalline form E loses about 3.3% of its weight during heating to about 100±5°C (preferably about 100±2°C), and loses about 21.0% of its weight during heating from about 100 to about 180±5°C. %, decomposition may start at about 210±5°C, preferably about 210±2°C, as measured using TGA. Preferably, the TGA spectrum of the crystal form E is substantially as shown in FIG. 20 , more preferably as shown in FIG. 20 .
在一些实施方案中，所述晶型E的吸热峰的起始温度为约177℃±5℃，优选约177±2℃。所述吸热峰对应所述TGA的失重。优选地，所述晶型E 的DSC图谱基本上如图20所示，更优选如图20所示。In some embodiments, the onset temperature of the endothermic peak of the crystalline form E is about 177°C±5°C, preferably about 177±2°C. The endothermic peak corresponds to the weight loss of the TGA. Preferably, the DSC spectrum of the crystal form E is substantially as shown in FIG. 20 , more preferably as shown in FIG. 20 .
在一些实施方案中，所述晶型E的NMR图谱基本上如图21所示，优选如图21所示。In some embodiments, the NMR spectrum of the crystalline form E is substantially as shown in Figure 21, preferably as shown in Figure 21.
在一些实施方案中，所述晶型E为具有NMP的溶剂合物，其中化合物I与所述NMP的化学计量比为约1:1。In some embodiments, the Form E is a solvate with NMP, wherein the stoichiometric ratio of Compound I to the NMP is about 1:1.
晶型FForm F
在一些实施方案中，所述化合物I的晶型F的XRPD图谱以最大强度显示至少两个、至少三个、至少四个、至少五个或至少六个衍射角2θ(°)。In some embodiments, the XRPD pattern of Form F of Compound I exhibits at least two, at least three, at least four, at least five, or at least six diffraction angles 2θ (°) at maximum intensity.
在一些实施方案中，所述化合物I的晶型F的XRPD图谱包括在约5.3±0.2°、7.0±0.2°、9.5±0.2°、19.1±0.2°和/或21.7±0.2°的衍射角(2θ)处的衍射峰。优选地，所述晶型F的XRPD图谱还包括在约10.0±0.2°、17.2±0.2°、18.5±0.2°、20.4±0.2°和/或21.0±0.2°的衍射角(2θ)处的衍射峰。更优选地，所述晶型F的XRPD图谱还包括在约10.8±0.2°、14.0±0.2°、14.4±0.2°、15.0±0.2°、15.5±0.2°、15.9±0.2°、16.5±0.2°、17.5±0.2°、18.8±0.2°、19.6±0.2°、20.2±0.2°、22.1±0.2°、22.4±0.2°、22.8±0.2°、24.6±0.2°、26.8±0.2°、27.2±0.2°、27.5±0.2°、28.1±0.2°、28.5±0.2°、29.0±0.2°、29.5±0.2°、29.8±0.2°、31.1±0.2°、32.6±0.2°、33.0±0.2°、35.1±0.2°、35.9±0.2°、37.4±0.2°、38.9±0.2°和/或40.9±0.2°的衍射角(2θ)处的衍射峰。In some embodiments, the XRPD pattern of Form F of Compound I includes diffraction angles at about 5.3±0.2°, 7.0±0.2°, 9.5±0.2°, 19.1±0.2°, and/or 21.7±0.2° ( Diffraction peaks at 2θ). Preferably, the XRPD pattern of the crystalline form F further includes diffraction at a diffraction angle (2θ) of about 10.0±0.2°, 17.2±0.2°, 18.5±0.2°, 20.4±0.2° and/or 21.0±0.2° peak. More preferably, the XRPD pattern of the crystalline form F also includes a temperature at about 10.8±0.2°, 14.0±0.2°, 14.4±0.2°, 15.0±0.2°, 15.5±0.2°, 15.9±0.2°, 16.5±0.2° , 17.5±0.2°, 18.8±0.2°, 19.6±0.2°, 20.2±0.2°, 22.1±0.2°, 22.4±0.2°, 22.8±0.2°, 24.6±0.2°, 26.8±0.2°, 27.2±0.2° , 27.5±0.2°, 28.1±0.2°, 28.5±0.2°, 29.0±0.2°, 29.5±0.2°, 29.8±0.2°, 31.1±0.2°, 32.6±0.2°, 33.0±0.2°, 35.1±0.2° , 35.9±0.2°, 37.4±0.2°, 38.9±0.2° and/or 40.9±0.2° diffraction angles (2θ) of the diffraction peaks.
在一些优选的实施方案中，所述晶型F的XRPD图谱基本上如图22所示，更优选地如图22所示。In some preferred embodiments, the XRPD pattern of the crystalline form F is substantially as shown in FIG. 22 , more preferably as shown in FIG. 22 .
在一些实施方案中，所述晶型F在加热至约60±5℃(优选约60±2℃)的过程中失重约1.6％，在约60至约150±5℃的过程中失重约13.9％，在约200℃±5℃(优选约200±2℃)可能开始分解，如使用TGA所测得的。优选地，所述晶型F的TGA图谱基本上如图23所示，更优选如图23所示。In some embodiments, the crystalline Form F loses about 1.6% of its weight during heating to about 60±5°C (preferably about 60±2°C), and loses about 13.9% of its weight during heating from about 60 to about 150±5°C. %, decomposition may start at about 200°C±5°C (preferably about 200±2°C), as measured using TGA. Preferably, the TGA spectrum of the crystal form F is substantially as shown in FIG. 23 , more preferably as shown in FIG. 23 .
在一些实施方案中，所述晶型F具有起始温度为约131℃±5℃，优选为约131±2℃的吸热峰。所述吸热峰对应脱溶剂。优选地，所述晶型F的DSC图谱基本上如图23所示，更优选如图23所示。In some embodiments, the crystalline form F has an endothermic peak with an onset temperature of about 131±5°C, preferably about 131±2°C. The endothermic peak corresponds to desolvation. Preferably, the DSC spectrum of the crystalline form F is substantially as shown in FIG. 23 , more preferably as shown in FIG. 23 .
在一些实施方案中，所述晶型F的NMR图谱基本上如图24所示，更优选如图24所示。In some embodiments, the NMR spectrum of Form F is substantially as shown in Figure 24, more preferably as shown in Figure 24.
在一些实施方案中，所述晶型F为具有DMF的溶剂合物，其中化合物I与所述DMF的化学计量比为约1:1。In some embodiments, the Form F is a solvate with DMF, wherein the stoichiometric ratio of Compound I to the DMF is about 1:1.
晶型GForm G
在一些实施方案中，所述化合物I的晶型G的XRPD图谱以最大强度显示至少两个、至少三个、至少四个、至少五个或至少六个衍射角2θ(°)。In some embodiments, the XRPD pattern of Form G of Compound I exhibits at least two, at least three, at least four, at least five, or at least six diffraction angles 2θ (°) at maximum intensity.
在一些实施方案中，所述化合物I的晶型G的XRPD图谱包括在约12.1±0.2°、20.8±0.2°、23.6±0.2°、24.6±0.2°和/或29.1±0.2°的衍射角(2θ)处的衍射峰。优选地，所述晶型G的XRPD图谱还包括在约15.7±0.2°、21.1±0.2°、23.0±0.2°、23.4±0.2°、28.2±0.2°和/或33.0±0.2°的衍射角(2θ)处的衍射峰。更优选地，所述晶型G的XRPD图谱还包括在约8.1±0.2°、12.9±0.2°、13.3±0.2°、16.3±0.2°、16.8±0.2°、18.2±0.2°、22.2±0.2°、22.9±0.2°、23.9±0.2°、24.4±0.2°、25.5±0.2°、25.9±0.2°、26.1±0.2°、27.0±0.2°、27.5±0.2°、27.7±0.2°、28.0±0.2°、31.2±0.2°、33.3±0.2°、33.5±0.2°、35.7±0.2°、35.9±0.2°、36.3±0.2°、36.6±0.2°、37.5±0.2°、40.5±0.2°、41.3±0.2°和/或42.9±0.2°的衍射角(2θ)处的衍射峰。In some embodiments, the XRPD pattern of Form G of Compound I comprises diffraction angles at about 12.1±0.2°, 20.8±0.2°, 23.6±0.2°, 24.6±0.2° and/or 29.1±0.2° ( Diffraction peaks at 2θ). Preferably, the XRPD pattern of the crystalline form G further includes diffraction angles at about 15.7±0.2°, 21.1±0.2°, 23.0±0.2°, 23.4±0.2°, 28.2±0.2° and/or 33.0±0.2° ( Diffraction peaks at 2θ). More preferably, the XRPD pattern of the crystalline form G also includes an , 22.9±0.2°, 23.9±0.2°, 24.4±0.2°, 25.5±0.2°, 25.9±0.2°, 26.1±0.2°, 27.0±0.2°, 27.5±0.2°, 27.7±0.2°, 28.0±0.2° , 31.2±0.2°, 33.3±0.2°, 33.5±0.2°, 35.7±0.2°, 35.9±0.2°, 36.3±0.2°, 36.6±0.2°, 37.5±0.2°, 40.5±0.2°, 41.3±0.2° and/or diffraction peaks at a diffraction angle (2θ) of 42.9±0.2°.
在一些优选的实施方案中，所述晶型G的XRPD图谱基本上如图25所示，更优选地如图25所示。In some preferred embodiments, the XRPD pattern of Form G is substantially as shown in Figure 25, more preferably as shown in Figure 25.
在一些实施方案中，所述晶型G在加热至约50±5℃(优选约50±2℃)的过程中失重约2.0％，在约50至约100±5℃的过程中失重约12.7％，在约180±5℃(优选约180±2℃)可能开始分解，如使用TGA所测得的。优选地，所述晶型G的TGA图谱基本上如图26所示，更优选如图26所示。In some embodiments, the crystalline Form G loses about 2.0% of its weight during heating to about 50±5°C (preferably about 50±2°C), and loses about 12.7% of its weight during heating from about 50 to about 100±5°C. %, decomposition may start at about 180±5°C, preferably about 180±2°C, as measured using TGA. Preferably, the TGA spectrum of the crystal form G is substantially as shown in FIG. 26 , more preferably as shown in FIG. 26 .
在一些实施方案中，所述晶型G具有起始温度分别为约78.6±5℃(约78.6±2℃)和约84.8±5℃(优选约84.8±2℃)的吸热峰。所述吸热峰对应所述TGA的失重。优选地，所述晶型G的DSC图谱基本上如图26所示，更优选如图26所示。In some embodiments, the crystalline form G has endothermic peaks with onset temperatures of about 78.6±5°C (about 78.6±2°C) and about 84.8±5°C (preferably about 84.8±2°C), respectively. The endothermic peak corresponds to the weight loss of the TGA. Preferably, the DSC spectrum of the crystal form G is substantially as shown in FIG. 26 , more preferably as shown in FIG. 26 .
在一些实施方案中，所述晶型G的NMR图谱基本上如图27所示，优选如图27所示。In some embodiments, the NMR spectrum of Form G is substantially as shown in Figure 27, preferably as shown in Figure 27.
在一些实施方案中，所述晶型G为三水合物。In some embodiments, the Form G is a trihydrate.
化合物I的晶型的制备Preparation of the Crystalline Form of Compound I
在第二方面，本发明提供用于制备结晶型的游离态形式的化合物I的方法，所述方法包括：In a second aspect, the present invention provides a process for the preparation of a crystalline free form of Compound I, said process comprising:
将化合物I在溶剂中悬浮液搅拌一段时间，然后过滤和干燥所得的固体，得到所述结晶型化合物I；或者Stirring a suspension of Compound I in a solvent for a period of time, then filtering and drying the resulting solid to obtain the crystalline Compound I; or
将化合物I完全溶解在一定量的良溶剂中，然后添加反溶剂至有固体析出，过滤和干燥所得的固体，得到所述结晶型化合物I；或者Completely dissolving Compound I in a certain amount of good solvent, then adding an anti-solvent until a solid precipitates, filtering and drying the resulting solid, to obtain the crystalline Compound I; or
将化合物I在反溶剂中加热，然后添加良溶剂至溶液澄清，冷却析晶后过滤干燥所得的固体，得到所述结晶型化合物I；或者heating compound I in an anti-solvent, then adding a good solvent until the solution is clear, cooling and crystallizing, and filtering and drying the resulting solid to obtain the crystalline compound I; or
通过加入酸或碱调节pH将化合物I溶解在不同的溶剂中，通过加入碱或酸析出固体，然后进行固液分离，干燥所得的固体，得到所述结晶型化合物I；或者Dissolving Compound I in different solvents by adding an acid or base to adjust the pH, adding a base or acid to precipitate a solid, then performing solid-liquid separation, and drying the obtained solid to obtain the crystalline Compound I; or
通过晶型转化将游离态形式的化合物I的一种晶型转化为另外一种晶型。晶型转化的方法包括：加热或在合适的溶剂中混悬液转晶的方法。One crystal form of compound I in free form is converted into another crystal form by crystal transformation. The method for crystal transformation includes: heating or suspension in a suitable solvent for crystal transformation.
所述溶剂包括但不限于水、醇类(例如具有1-4个碳原子的链烷醇)、氯代烷烃、酮类、醚类、环醚类、酯类、烷烃类、环烷烃类、苯类、酰胺类、亚砜类或其混合物，优选地选自甲醇、乙醇、正丙醇、异丙醇、正丁醇、乙腈、丙酮、甲乙酮、四氢呋喃、二氧六环、N,N-二甲基甲酰胺、二甲基亚砜、乙酸乙酯、二氯甲烷、三氯乙烷、四氯化碳、正庚烷、正己烷、异辛烷、戊烷、环己烷、环戊烷、***、甲基叔丁基醚、异丙醚、苯、甲苯、二甲苯及其混合物；超临界流体如二氧化碳液体、离子液体，以及高分子溶液等。Said solvents include, but are not limited to, water, alcohols (such as alkanols having 1-4 carbon atoms), chlorinated alkanes, ketones, ethers, cyclic ethers, esters, alkanes, cycloalkanes, Benzene, amides, sulfoxides or mixtures thereof, preferably selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, acetonitrile, acetone, methyl ethyl ketone, tetrahydrofuran, dioxane, N,N- Dimethylformamide, dimethyl sulfoxide, ethyl acetate, dichloromethane, trichloroethane, carbon tetrachloride, n-heptane, n-hexane, isooctane, pentane, cyclohexane, cyclopentane Alkanes, diethyl ether, methyl tert-butyl ether, isopropyl ether, benzene, toluene, xylene and their mixtures; supercritical fluids such as carbon dioxide liquid, ionic liquid, and polymer solutions, etc.
晶型A的制备Preparation of Form A
在一些实施方案中，本发明提供用于制备所述晶型A的方法，所述方法包括：In some embodiments, the present invention provides a method for preparing the crystalline form A, the method comprising:
a1)提供化合物I在适当的溶剂中的悬浮液，优选地化合物I在所述悬浮液中的含量为约1-200mg/ml；a1) providing a suspension of Compound I in a suitable solvent, preferably the content of Compound I in said suspension is about 1-200 mg/ml;
a2)在室温下搅拌所述悬浮液足够的时间，然后进行固液分离(例如通过离心)，干燥所得的固体，得到所述晶型A。a2) Stir the suspension at room temperature for a sufficient time, then perform solid-liquid separation (for example, by centrifugation), and dry the resulting solid to obtain the crystalline form A.
在一些优选的实施方案中，所述适当的溶剂选自DMF、DMSO、甲醇、乙醇、正丙醇、异丙醇、丙酮、4-甲基-2-戊酮、乙酸乙酯、乙酸异丙酯、甲酸乙酯、甲酸丁酯、正庚烷、环己烷、二氧六环、***、甲基叔丁基醚、乙 二醇甲醚、乙二醇二甲醚、水、乙腈、甲苯、二氯甲烷、氯仿、四氢呋喃及其混合物。In some preferred embodiments, the suitable solvent is selected from DMF, DMSO, methanol, ethanol, n-propanol, isopropanol, acetone, 4-methyl-2-pentanone, ethyl acetate, isopropyl acetate Esters, ethyl formate, butyl formate, n-heptane, cyclohexane, dioxane, diethyl ether, methyl tert-butyl ether, ethylene glycol methyl ether, ethylene glycol dimethyl ether, water, acetonitrile, toluene , dichloromethane, chloroform, tetrahydrofuran and mixtures thereof.
在一些优选的实施方案中，在步骤a2)中，所述在室温下搅拌持续约3-7天。例如，在小试实验中，所述在室温下搅拌持续约7天；在放大生产中，所述在室温下搅拌持续约3天。In some preferred embodiments, in step a2), the stirring at room temperature lasts for about 3-7 days. For example, in a pilot experiment, the stirring at room temperature lasts for about 7 days; in scale-up production, the stirring at room temperature lasts for about 3 days.
在另一些实施方案中，本发明提供用于制备所述晶型A的方法，所述方法包括：In other embodiments, the present invention provides a method for preparing the crystalline form A, the method comprising:
b1)将化合物I加入良溶剂中，然后加入适当的碱，在固体溶清后过滤；b1) adding compound I to a good solvent, then adding an appropriate base, and filtering after the solid dissolves;
b2)向步骤b1)中得到滤液中加入适当的酸，析出固体，得到所述晶型A；b2) adding an appropriate acid to the filtrate obtained in step b1), to precipitate a solid to obtain the crystal form A;
在一些优选的实施方案中，所述良溶剂为水、异丙醚、正庚烷或甲苯，更优选水。In some preferred embodiments, the good solvent is water, isopropyl ether, n-heptane or toluene, more preferably water.
在一些优选的实施方案中，所述碱为乙醇胺。In some preferred embodiments, the base is ethanolamine.
在一些优选的实施方案中，所述酸为盐酸、硫酸或磷酸。In some preferred embodiments, the acid is hydrochloric acid, sulfuric acid or phosphoric acid.
晶型B的制备Preparation of Form B
在一些实施方案中，本发明提供用于制备所述晶型B的方法，所述方法包括：In some embodiments, the present invention provides a method for preparing the crystalline form B, the method comprising:
将化合物I溶解在适当的良溶剂中，然后滴加反溶剂以析出固体，进行固液分离(例如通过离心)，干燥所得的固体，得到所述晶型B。Dissolving compound I in a suitable good solvent, then adding an anti-solvent dropwise to precipitate a solid, performing solid-liquid separation (for example, by centrifugation), and drying the obtained solid to obtain the crystal form B.
在一些优选的实施方案中，所述方法包括：In some preferred embodiments, the method comprises:
将化合物I与良溶剂混合，加热溶解后降温至室温，然后加入反溶剂，在室温下搅拌足够的时间，然后离心，干燥所得的固体，得到所述晶型B。Mix compound I with a good solvent, heat to dissolve and then cool down to room temperature, then add anti-solvent, stir at room temperature for a sufficient time, then centrifuge, and dry the obtained solid to obtain the crystal form B.
在一些优选的实施方案中，所述良溶剂包括但不限于DMF。In some preferred embodiments, the good solvent includes, but is not limited to, DMF.
在一些优选的实施方案中，所述反溶剂包括但不限于甲苯。In some preferred embodiments, the anti-solvent includes, but is not limited to, toluene.
在一些优选的实施方案中，所述加热是加热至约50℃±2℃。In some preferred embodiments, the heating is to about 50°C ± 2°C.
在一些优选的实施方案中，所述在室温下搅拌持续约1天。In some preferred embodiments, the stirring at room temperature is continued for about 1 day.
在一些优选的实施方案中，所述干燥为在室温下真空干燥。In some preferred embodiments, the drying is vacuum drying at room temperature.
晶型C的制备Preparation of Form C
在一些实施方案中，本发明提供用于制备所述晶型C的方法，所述方 法包括：In some embodiments, the present invention provides a method for preparing the crystalline form C, the method comprising:
搅拌化合物I在DMSO和异丙醇的混合溶剂中悬浮液足够的时间，然后进行固液分离(例如通过离心)，干燥所得的固体，得到所述晶型C。Stir the suspension of Compound I in a mixed solvent of DMSO and isopropanol for a sufficient time, then perform solid-liquid separation (for example, by centrifugation), and dry the obtained solid to obtain the crystalline form C.
在一些优选的实施方案中，所述方法包括：In some preferred embodiments, the method comprises:
将化合物I与DMF混合，加热溶解后降温至室温，然后加入氯仿并在室温下搅拌所得的悬浮液足够的时间，进行固液分离(例如通过离心)，干燥所得的固体，得到所述晶型C。Mix compound I with DMF, heat to dissolve and then cool down to room temperature, then add chloroform and stir the resulting suspension at room temperature for a sufficient time, perform solid-liquid separation (for example, by centrifugation), and dry the resulting solid to obtain the crystal form c.
优选地，所述化合物I是所述晶型E。Preferably, said compound I is said crystalline form E.
优选地，所述加热是加热至约40至60℃的温度，更优选约50℃±2℃。Preferably, the heating is to a temperature of about 40 to 60°C, more preferably about 50°C ± 2°C.
优选地，所述在室温下搅拌持续约1天。Preferably, said stirring at room temperature lasts for about 1 day.
在另一些实施方案中，本发明提供用于制备所述晶型C的方法，所述方法包括：在约10至60℃(例如约40至60℃，优选约50℃±2℃)的温度下，搅拌所述晶型E在适当的溶剂中悬浮液足够的时间，然后进行固液分离，干燥所得的固体，得到所述晶型C。在一些优选的实施方案中，所述适当的溶剂包括但不限于DMF、水、丙酮、二氯甲烷、甲苯、氯仿、乙腈及其混合物。在一些优选的实施方案中，所述晶型E在所述悬浮液中的含量为约1-200mg/ml。In other embodiments, the present invention provides a method for preparing the crystalline form C, the method comprising: at a temperature of about 10 to 60°C (eg, about 40 to 60°C, preferably about 50°C±2°C) Stir the suspension of the crystal form E in an appropriate solvent for a sufficient time, then perform solid-liquid separation, and dry the obtained solid to obtain the crystal form C. In some preferred embodiments, the suitable solvents include, but are not limited to, DMF, water, acetone, dichloromethane, toluene, chloroform, acetonitrile, and mixtures thereof. In some preferred embodiments, the content of the crystalline form E in the suspension is about 1-200 mg/ml.
在一些优选的实施方案中，所述方法包括：In some preferred embodiments, the method comprises:
提供化合物I在乙腈中的悬浮液并在加热下搅拌足够的时间，然后进行固液分离，在室温下干燥所得的固体，得到所述晶型C。Provide a suspension of compound I in acetonitrile and stir under heating for a sufficient time, then perform solid-liquid separation, and dry the obtained solid at room temperature to obtain the crystal form C.
优选地，所述化合物I是所述晶型E。Preferably, said compound I is said crystalline form E.
优选地，所述加热是加热至约40至60℃的温度，更优选约50℃±2℃。Preferably, the heating is to a temperature of about 40 to 60°C, more preferably about 50°C ± 2°C.
优选地，所述在室温下搅拌持续约1天。Preferably, said stirring at room temperature lasts for about 1 day.
在另一些优选的实施方案中，所述方法包括：In other preferred embodiments, the method comprises:
将化合物I加入到丙酮和水的混合溶剂中并在室温下悬浮足够的时间，过滤并干燥所得的固体，得到所述晶型C。Compound I was added to a mixed solvent of acetone and water and suspended at room temperature for a sufficient time, the resulting solid was filtered and dried to obtain the crystal form C.
优选地，所述化合物I是所述晶型E。Preferably, said compound I is said crystalline form E.
优选地，所述悬浮持续约1天。Preferably, said suspension lasts for about 1 day.
在另一些实施方案中，本发明提供用于制备所述晶型C的方法，所述方法包括：In other embodiments, the present invention provides a method for preparing the crystalline form C, the method comprising:
将化合物I加入到DMSO和异丙醇的混合溶剂中并在室温下悬浮，过 滤并干燥所得的固体，得到所述晶型C。Compound I was added to a mixed solvent of DMSO and isopropanol and suspended at room temperature, filtered and dried to obtain the crystalline form C.
优选地，所述悬浮持续约7天。Preferably, said suspension lasts for about 7 days.
晶型D的制备Preparation of Form D
在一些实施方案中，本发明提供用于制备所述晶型D的方法，所述方法包括：In some embodiments, the present invention provides a method for preparing the crystalline form D, the method comprising:
将化合物I中溶于适当的良溶剂(包括但不限于DMSO)中，然后加入反溶剂(包括但不限于氯仿)至有固体析出，进行固液分离，然后干燥所得的固体，得到所述晶型D。Compound I was dissolved in a suitable good solvent (including but not limited to DMSO), then an anti-solvent (including but not limited to chloroform) was added until solids were precipitated, solid-liquid separation was performed, and the resulting solids were dried to obtain the crystal Type D.
在一些优选的此类实施方案中，所述方法包括：In some preferred such embodiments, the method comprises:
将化合物I与DMSO混合，加热溶解后降温至室温，加入反溶剂，在室温下搅拌足够的时间，进行固液分离(例如通过离心)，然后干燥所得的固体，得到所述晶型D。Compound I is mixed with DMSO, heated to dissolve and then cooled to room temperature, anti-solvent is added, stirred at room temperature for a sufficient time, solid-liquid separation (for example, by centrifugation), and then the obtained solid is dried to obtain the crystal form D.
优选地，所述反溶剂包括但不限于氯仿。Preferably, the anti-solvent includes but not limited to chloroform.
优选地，所述加热为加热至约50℃±2℃；和/或Preferably, the heating is to about 50°C±2°C; and/or
优选地，所述在室温下搅拌持续约1天Preferably, the stirring at room temperature continues for about 1 day
在一些实施方案中，本发明提供用于制备所述晶型D的方法，所述方法包括：In some embodiments, the present invention provides a method for preparing the crystalline form D, the method comprising:
将化合物I加入适当的反溶剂中，然后加入适当的良溶剂，加热溶解后降温析出固体，进行固液分离，在室温下干燥所得的固体，得到所述晶型D。Compound I was added to an appropriate anti-solvent, and then an appropriate good solvent was added. After heating and dissolving, the temperature was lowered to precipitate a solid. Solid-liquid separation was performed, and the obtained solid was dried at room temperature to obtain the crystal form D.
优选地，所述反溶剂包括但不限于水。Preferably, the anti-solvent includes but not limited to water.
优选地，所述良溶剂包括但不限于DMSO。Preferably, the good solvent includes but not limited to DMSO.
在一些优选的此类实施方案中，所述方法包括：In some preferred such embodiments, the method comprises:
将化合物I加入反溶剂中，然后加入DMSO，加热溶解后降温析出固体，进行固液分离(例如通过离心)，在室温下干燥所得的固体，得到所述晶型D。Add compound I to the anti-solvent, then add DMSO, heat to dissolve, then cool down to precipitate a solid, perform solid-liquid separation (for example, by centrifugation), and dry the obtained solid at room temperature to obtain the crystal form D.
优选地，所述反溶剂包括但不限于水。Preferably, the anti-solvent includes but not limited to water.
优选地，所述加热是加热至约50℃，例如约50℃±2℃。Preferably, the heating is to about 50°C, such as about 50°C±2°C.
优选地，所述降温是降温至约-15℃±2℃。Preferably, the cooling is down to about -15°C±2°C.
晶型E的制备Preparation of Form E
在一些实施方案中，本发明提供用于制备所述晶型E的方法，所述方法包括：In some embodiments, the present invention provides a method for preparing the crystalline form E, the method comprising:
将化合物I溶于适当的良溶剂(包括但不限于NMP)，然后加入反溶剂(包括但不限于氯仿、甲苯或其混合物)至有固体析出，进行固液分离，然后干燥所得的固体，得到所述晶型E。Dissolve compound I in a suitable good solvent (including but not limited to NMP), then add an anti-solvent (including but not limited to chloroform, toluene or a mixture thereof) until a solid is precipitated, perform solid-liquid separation, and then dry the resulting solid to obtain The crystal form E.
在一些优选的实施方案中，所述方法包括：In some preferred embodiments, the method comprises:
将化合物I与NMP混合，加热溶解后降温至室温，然后加入反溶剂(包括但不限于氯仿、甲苯或其混合物)，在室温下搅拌足够的时间，然后进行固液分离(例如通过离心)，干燥所得的固体，得到所述晶型E。Compound I is mixed with NMP, cooled to room temperature after heating to dissolve, then adding an anti-solvent (including but not limited to chloroform, toluene or a mixture thereof), stirring at room temperature for a sufficient time, and then performing solid-liquid separation (for example, by centrifugation), The resulting solid was dried to obtain Form E as described.
优选地，所述加热是加热至约50℃±2℃。Preferably, the heating is to about 50°C±2°C.
优选地，所述在室温下搅拌持续约1天。Preferably, said stirring at room temperature lasts for about 1 day.
晶型F的制备Preparation of Form F
在一些实施方案中，本发明提供用于制备所述晶型F的方法，所述方法包括：In some embodiments, the present invention provides a method for preparing the crystalline form F, the method comprising:
将化合物I溶于适当的良溶剂(例如但不限于DMF)，然后加入反溶剂(包括但不限于甲苯)至有固体析出，然后进行固液分离，得到所述晶型F。Compound I was dissolved in an appropriate good solvent (such as but not limited to DMF), and then an anti-solvent (including but not limited to toluene) was added until solids were precipitated, followed by solid-liquid separation to obtain the Form F.
在一些优选的实施方案中，所述方法包括：In some preferred embodiments, the method comprises:
将化合物I与DMF混合，加热溶解后降温室温，加入反溶剂(包括但不限于甲苯)，在室温下搅拌足够的时间，然后进行固液分离(例如通过离心)，干燥所得的固体，得到所述晶型F。Compound I was mixed with DMF, heated to dissolve and cooled to room temperature, anti-solvent (including but not limited to toluene) was added, stirred at room temperature for a sufficient time, and then solid-liquid separation (for example, by centrifugation) was performed, and the obtained solid was dried to obtain the obtained Said crystal form F.
优选地，所述加热为加热至约50℃±2℃。Preferably, the heating is to about 50°C±2°C.
优选地，所述在室温下搅拌持续约1天。Preferably, said stirring at room temperature lasts for about 1 day.
晶型G的制备Preparation of Form G
在一些实施方案中，本发明还提供用于制备所述晶型G的方法，所述方法包括：In some embodiments, the present invention also provides a method for preparing the crystalline form G, the method comprising:
将化合物I悬浮在适当的溶剂(包括但不限于乙醇、水或其混合物)中，在低温下搅拌悬浮液至完全转化成所述晶型G，然后进行固液分离，干燥所得的固体，得到所述晶型G。Suspend compound I in an appropriate solvent (including but not limited to ethanol, water or a mixture thereof), stir the suspension at low temperature until it is completely converted into the crystal form G, then perform solid-liquid separation, and dry the resulting solid to obtain The crystal form G.
在一些优选的实施方案中，所述方法包括：In some preferred embodiments, the method comprises:
将化合物I加入适当的溶剂中，在低温下搅拌足够的时间，然后进行固液分离(例如通过离心)，在室温下干燥所得的固体，得到所述晶型G。Compound I is added into an appropriate solvent, stirred at low temperature for a sufficient time, and then subjected to solid-liquid separation (for example, by centrifugation), and the resulting solid is dried at room temperature to obtain the crystalline form G.
优选地，所述化合物I是所述晶型B。Preferably, said compound I is said crystal form B.
优选地，所述适当的溶剂包括但不限于乙醇、水或其混合物。Preferably, the suitable solvent includes, but is not limited to, ethanol, water or a mixture thereof.
优选地，化合物I在所述悬浮液中的含量为约1-200mg/ml。Preferably, the content of Compound I in said suspension is about 1-200 mg/ml.
优选地，所述低温是约5至30℃，更优选是约10℃±2℃。Preferably, the low temperature is about 5 to 30°C, more preferably about 10°C ± 2°C.
优选地，所述在低温下搅拌持续约2天。Preferably, said stirring at low temperature lasts for about 2 days.
优选地，所述在室温下干燥是在室温下真空干燥。Preferably, the drying at room temperature is vacuum drying at room temperature.
在第三方面，本发明提供所述化合物I，其为所述晶型A、晶型B、晶型C、晶型D、晶型E、晶型F或晶型G的形式。In a third aspect, the present invention provides said compound I in the form of said crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E, crystalline form F or crystalline form G.
在第四方面，本发明提供药物组合物，其包含有效量的选自所述晶型A、晶型B、晶型C、晶型D、晶型E、晶型F和晶型G中的任一种以及一种或多种药学上可接受的载体。In the fourth aspect, the present invention provides a pharmaceutical composition, which comprises an effective amount of the selected from the crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, crystal form F and crystal form G Any one and one or more pharmaceutically acceptable carriers.
在第五方面，本发明提供所述晶型A、晶型B、晶型C、晶型D、晶型E、晶型F和晶型G中的任一种或所述药物组合物，其用于肾功能监测，其中所述肾功能检测是GFR监测，特别是实时GFR检测。In the fifth aspect, the present invention provides any one of the crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E, crystalline form F and crystalline form G or the pharmaceutical composition, which For renal function monitoring, wherein the renal function detection is GFR monitoring, especially real-time GFR detection.
在第六方面，本发明提供所述晶型A、晶型B、晶型C、晶型D、晶型E、晶型F和晶型G中的任一种或所述药物组合物在制备用于肾功能监测的药物(“示踪剂”)中的用途，其中所述肾功能检测是GFR监测，特别是实时GFR检测。In the sixth aspect, the present invention provides any one of the crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E, crystalline form F and crystalline form G or the pharmaceutical composition in the preparation Use in a medicament ("tracer") for renal function monitoring, wherein said renal function test is GFR monitoring, in particular real-time GFR testing.
在第七方面，本发明提供用于个体的肾功能监测的方法，所述方法包括向所述个体施用有效量的所述晶型A、晶型B、晶型C、晶型D、晶型E、晶型F和晶型G中的任一种或所述药物组合物，其中所述肾功能检测是GFR监测，特别是实时GFR检测。In a seventh aspect, the present invention provides a method for monitoring renal function in an individual, the method comprising administering to the individual an effective amount of the crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E. Any one of the crystal forms F and G or the pharmaceutical composition, wherein the renal function detection is GFR monitoring, especially real-time GFR detection.
所述晶型A至G或者所述药物组合物或药物可以通过多种途径施用，包括但不限于口服、肠胃外、透皮、皮下、肠内或静脉内施用。The crystalline forms A to G or the pharmaceutical composition or drug can be administered by various routes, including but not limited to oral, parenteral, transdermal, subcutaneous, enteral or intravenous administration.
在第八方面，本发明还提供纯化化合物I的方法，所述方法包括使化合物I从适当的溶剂中形成溶剂合物。所述溶剂包括但不限于DMSO、NMP和DMF。在一些实施方案中，所述溶剂合物为上文所述的晶型D、晶型E 或晶型F。In an eighth aspect, the present invention also provides a method of purifying Compound I, said method comprising forming a solvate of Compound I from a suitable solvent. Such solvents include, but are not limited to, DMSO, NMP, and DMF. In some embodiments, the solvate is Form D, Form E, or Form F described above.
本发明的有益效果Beneficial effects of the present invention
本发明的晶型的优势在于：The advantage of the crystal form of the present invention is:
1.无水物晶型A和C及一水合物晶型B在高温、高湿和光照条件下都能保持晶型稳定。1. Anhydrous crystal forms A and C and monohydrate crystal form B can maintain stable crystal forms under high temperature, high humidity and light conditions.
2.晶型A在光照、高温、高湿和竞争性漂浮等条件下稳定性具有明显优势，能够满足生产、运输、储存的药用要求，生产工艺稳定、可重复、可控，能够适应工业化生产。2. Crystal form A has obvious advantages in stability under conditions such as light, high temperature, high humidity and competitive floating, and can meet the medicinal requirements of production, transportation, and storage. The production process is stable, repeatable, and controllable, and can adapt to industrialization Production.
3.化合物I会与DMSO、NMP、DMF等溶剂形成溶剂合物，具有进一步提纯作用，从而提供一种有效的精制手段。3. Compound I will form a solvate with solvents such as DMSO, NMP, DMF, etc., which has further purification effect, thereby providing an effective means of refining.
实施例Example
以下将参考附图，结合具体实施例对本发明做进一步阐述，其目的仅在于举例说明以便更好地理解本发明，但并意图限制本发明的范围。The present invention will be further described below in conjunction with specific embodiments with reference to the accompanying drawings, the purpose of which is only to illustrate for a better understanding of the present invention, but is not intended to limit the scope of the present invention.
方法和材料Methods and materials
通过X射线粉末衍射(XRPD)、差示扫描量热法(DSC)、热重量分析法(TGA)、核磁共振( 1H NMR)波谱和偏光显微镜分析(PLM)对实施例制备的各晶型进行表征。 Each crystal form prepared by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetic resonance ( 1H NMR) spectrum and polarized light microscope analysis (PLM) To characterize.
1H NMR 1H NMR
将若干毫克固体样品溶解于二甲基亚砜-d6中，在Bruker AVANCE-III(Bruker,GER)上进行核磁分析。Several milligrams of solid samples were dissolved in DMSO-d6 for NMR analysis on a Bruker AVANCE-III (Bruker, GER).
XRPDXRPD
将样品用X射线粉末衍射仪Bruker D8Advance(Bruker，GER)进行分析。扫描2θ范围为3°到45°(Cu-Kα(Kα1
Figure PCTCN2022115011-appb-000003
：1.5406))，扫描步长为0.02°，曝光时间为0.12秒。测试样品时光管电压和电流分别为40kV和40mA，样品盘为零背景样品盘。 Samples were analyzed with an X-ray powder diffractometer Bruker D8 Advance (Bruker, GER). The scanning 2θ range is from 3° to 45° (Cu-Kα(Kα1
Figure PCTCN2022115011-appb-000003
: 1.5406)), the scan step size is 0.02°, and the exposure time is 0.12 seconds. The light tube voltage and current of the test sample are 40kV and 40mA respectively, and the sample disk is a zero background sample disk.
TGATGA
采用热重分析仪TA Discovery 55(TA，US)。将2至5mg样品置于已平衡的开口铝制样品盘中，在TGA加热炉内自动称量。样品以10℃/min的速率加热至最终温度，样品处氮气吹扫速度为60ml/min，天平处氮气吹 扫速度为40ml/min。A thermogravimetric analyzer TA Discovery 55 (TA, US) was used. 2 to 5 mg of sample is placed in a balanced open aluminum sample pan and automatically weighed in a TGA heating furnace. The sample is heated to the final temperature at a rate of 10°C/min, the nitrogen purging rate at the sample is 60ml/min, and the nitrogen purging rate at the balance is 40ml/min.
DSCDSC
采用差示扫描量热分析仪TA Discovery 2500(TA，US)。将1-2mg样品经精确称重后置于扎孔的DSC Tzero样品盘中，以10℃/min的速率加热至最终温度，炉内氮气吹扫速度为50ml/min。A differential scanning calorimeter TA Discovery 2500 (TA, US) was used. 1-2 mg of sample was accurately weighed and placed in a perforated DSC Tzero sample pan, heated to the final temperature at a rate of 10°C/min, and the nitrogen purging rate in the furnace was 50ml/min.
PLMPLM
采用偏光显微镜Motic BA310Met(Motic，CN)。将少量样品放置在载玻片上，选择合适的镜头观察样品形貌。Polarizing microscope Motic BA310Met (Motic, CN) was used. Place a small amount of sample on a glass slide, and select a suitable lens to observe the shape of the sample.
动态水分吸脱附分析(DVS)Dynamic Moisture Sorption and Desorption Analysis (DVS)
采用DVS Intrinsic(SMS，UK)进行动态水分吸脱附分析。测试采用梯度模式，湿度变化为50％—95％—0％—50％，在0％至90％范围内每个梯度的湿度变化量为10％，梯度终点采用dm/dt方式进行判断，以dm/dt小于0.002％并维持10分钟为梯度终点。测试完成后，对样品进行XRPD分析，以确认固体形态是否发生变化。Dynamic moisture sorption-desorption analysis was performed using DVS Intrinsic (SMS, UK). The test adopts the gradient mode, the humidity change is 50%-95%-0%-50%, the humidity change of each gradient is 10% within the range of 0% to 90%, and the gradient end point is judged by the dm/dt method. dm/dt is less than 0.002% and maintained for 10 minutes as the end point of the gradient. After the test is complete, XRPD analysis is performed on the sample to confirm whether the solid form has changed.
高效液相色谱(HPLC)High performance liquid chromatography (HPLC)
采用高效液相色谱仪Aglient 1260，测试条件如下表1所示。A high performance liquid chromatograph Agilent 1260 was used, and the test conditions were shown in Table 1 below.
表1Table 1
Figure PCTCN2022115011-appb-000004
Figure PCTCN2022115011-appb-000004
化合物ICompound I
化合物I参考WO 2019/084475A1实施例12所述的方法获得，而且除 非另有明确说明，在本文的上下文中提到的化合物I是以所获得的产物的形式。Compound I is obtained by referring to the method described in Example 12 of WO 2019/084475A1, and unless otherwise specified, the compound I mentioned in the context of this article is in the form of the obtained product.
实施例1：晶型A的制备Embodiment 1: the preparation of crystal form A
方法1：method 1:
将19.4mg的化合物I加入到2ml甲醇中，在室温下搅拌7天后离心，室温真空干燥所得的固体，得到晶型A，其XRPD图谱如图1所示。19.4 mg of Compound I was added to 2 ml of methanol, stirred at room temperature for 7 days, centrifuged, and the resulting solid was vacuum-dried at room temperature to obtain Form A, whose XRPD pattern is shown in FIG. 1 .
晶型A的TGA图谱如图2所示：晶型A在加热至100℃的过程中失重1.54％，在200℃左右可能发生分解。The TGA spectrum of Form A is shown in Figure 2: Form A loses 1.54% of its weight when heated to 100°C, and may decompose at around 200°C.
晶型A的DSC图谱如图2所示，在185℃有吸热峰。The DSC spectrum of Form A is shown in Figure 2, and there is an endothermic peak at 185°C.
晶型A的NMR图谱如图3所示。NMR结果显示晶型A各个峰的峰位置和积分结果与参考图谱一致，未见明显有机溶剂特征峰。The NMR spectrum of Form A is shown in FIG. 3 . The NMR results showed that the peak positions and integration results of each peak of the crystal form A were consistent with the reference spectrum, and no obvious organic solvent characteristic peaks were seen.
晶型A的DVS图谱如图4所示：晶型A在95％湿度下增重0.42％，在0％湿度下失重0.82％，与TGA失重相符，表明晶型A具有很低的引湿性。图4的XRPD结果显示DVS测试后的样品并未发生晶型改变。The DVS spectrum of Form A is shown in Figure 4: Form A has a weight gain of 0.42% at 95% humidity and a weight loss of 0.82% at 0% humidity, which is consistent with the TGA weight loss, indicating that Form A has very low hygroscopicity. The XRPD results in Figure 4 show that the crystalline form of the sample after the DVS test did not change.
晶型A的PLM图像如图5所示。PLM图像显示A为片状颗粒，粒径一般小于20μm。The PLM image of Form A is shown in Figure 5. The PLM image shows that A is flake-like particles, and the particle size is generally less than 20 μm.
可以看出，晶型A为结晶性良好的无水物，具有很低的引湿性。It can be seen that Form A is an anhydrous substance with good crystallinity and low hygroscopicity.
方法2：Method 2:
称取18.6mg样品，加入1ml水中并在室温下搅拌，然后加入3mg乙醇胺(200mg/ml，15uL)，固体基本溶清。过滤取清液，加入50uL HCl(1M)，5min后有固体析出，10min后离心，将所得的固体室温真空干燥，得到晶型A。Weigh 18.6mg of sample, add 1ml of water and stir at room temperature, then add 3mg of ethanolamine (200mg/ml, 15uL), and the solid basically dissolves. The clear liquid was collected by filtration, and 50uL HCl (1M) was added. After 5 minutes, a solid was precipitated, centrifuged after 10 minutes, and the resulting solid was vacuum-dried at room temperature to obtain Form A.
方法2获得的化合物I的晶型A的XRPD图谱基本上如图1所示。The XRPD pattern of the crystal form A of compound I obtained by method 2 is basically shown in FIG. 1 .
实施例2：晶型B的制备Embodiment 2: the preparation of crystal form B
将20mg的化合物I与1ml的DMF混合，在50℃下加热澄清后降至室温，加入8ml甲苯。室温搅拌1天后离心，室温真空干燥所得的固体，得到晶型B，其XRPD图谱如图6所示。20mg of compound I was mixed with 1ml of DMF, heated at 50°C for clarification, then cooled to room temperature, and 8ml of toluene was added. After stirring at room temperature for 1 day, centrifuge, and vacuum-dry the obtained solid at room temperature to obtain Form B, the XRPD pattern of which is shown in FIG. 6 .
晶型B的TGA图谱如图7所示：晶型B在加热至130℃的过程中失 重3.82％，在200℃左右可能发生分解。The TGA spectrum of Form B is shown in Figure 7: Form B loses 3.82% of its weight when heated to 130°C, and may decompose at around 200°C.
晶型B的DSC图谱如图7所示：晶型B在加热后在72℃和212℃两个吸热峰，在215℃有一个放热峰。The DSC spectrum of Form B is shown in Figure 7: Form B has two endothermic peaks at 72°C and 212°C after heating, and an exothermic peak at 215°C.
晶型B的NMR图谱如图8所示。NMR结果显示晶型B各个峰的峰位置和积分结果与参考图谱一致，在2.5–3.0ppm可见DMF的特征峰。根据积分结果计算，化合物I与DMF的比例为1:0.02，该比例的DMF占TGA失重量较小(理论失重量为0.37％)。The NMR spectrum of Form B is shown in FIG. 8 . NMR results showed that the peak positions and integration results of each peak of Form B were consistent with the reference spectrum, and the characteristic peak of DMF could be seen at 2.5–3.0ppm. According to the calculation of the integral results, the ratio of compound I to DMF is 1:0.02, and the ratio of DMF to TGA weight loss is small (theoretical weight loss is 0.37%).
晶型B的DVS图谱如图9所示。晶型B在95％湿度下增重3.15％，表明晶型B具有一定的引湿性；在0％湿度下失重4.10％，与TGA失重相符。图9的XRPD结果显示DVS测试后的样品并未发生晶型改变。The DVS spectrum of Form B is shown in FIG. 9 . The weight gain of Form B was 3.15% at 95% humidity, indicating that Form B has a certain hygroscopicity; the weight loss was 4.10% at 0% humidity, which was consistent with the TGA weight loss. The XRPD results in Figure 9 show that the crystalline form of the sample after the DVS test did not change.
晶型B的PLM图像如图10所示：晶型B为片状颗粒，粒径一般小于20μm。The PLM image of the crystal form B is shown in Figure 10: the crystal form B is a plate-shaped particle, and the particle size is generally less than 20 μm.
可以看出，晶型B为有一定结晶性的一水合物，有一定的引湿性。It can be seen that crystal form B is a monohydrate with certain crystallinity and certain hygroscopicity.
实施例3：晶型C的制备Embodiment 3: the preparation of crystal form C
方法1： Method 1 :
将20mg的晶型E(根据下文实施例5的方法制备)与1ml的DMF混合，在50℃下加热澄清后降至室温，加入8ml氯仿。室温搅拌1天后离心，室温真空干燥得到晶型C，其XRPD图谱如图11所示。Mix 20 mg of Form E (prepared according to the method in Example 5 below) with 1 ml of DMF, heat at 50° C. for clarification, then cool down to room temperature, and add 8 ml of chloroform. Stir at room temperature for 1 day, centrifuge, and vacuum dry at room temperature to obtain Form C, whose XRPD pattern is shown in FIG. 11 .
晶型C的TGA图谱如图12所示：晶型C在加热至100℃的过程中仅失重0.95％，在200℃左右可能发生分解。The TGA spectrum of Form C is shown in Figure 12: Form C loses only 0.95% of its weight when heated to 100°C, and may decompose at around 200°C.
晶型C的DSC图谱如图12所示：晶型C在加热到分解温度之前没有明显的热流信号，在210℃后基线发生明显偏移。The DSC spectrum of Form C is shown in Figure 12: Form C has no obvious heat flow signal before heating to the decomposition temperature, and the baseline shifts significantly after 210°C.
晶型C的NMR图谱如图13所示。NMR结果显示晶型C各个峰的峰位置和积分结果与参考图谱一致，在2.5-3.0ppm处可见DMF的吸收峰。The NMR spectrum of Form C is shown in Figure 13. The NMR results show that the peak positions and integration results of each peak of the crystal form C are consistent with the reference spectrum, and the absorption peak of DMF can be seen at 2.5-3.0ppm.
晶型C的DVS图谱如图14所示：晶型C在95％湿度下增重2.58％，在0％湿度下失重1.03％，与TGA失重相符，表明晶型C具有一定的引湿性。图14的XRPD结果显示DVS测试后的样品并未发生晶型改变。The DVS spectrum of Form C is shown in Figure 14: Form C has a weight gain of 2.58% at 95% humidity and a weight loss of 1.03% at 0% humidity, which is consistent with the TGA weight loss, indicating that Form C has certain hygroscopicity. The XRPD results in Figure 14 show that the crystalline form of the sample after the DVS test did not change.
晶型C的PLM图像如图15所示：晶型C团聚为球形，粒径一般小于20μm。The PLM image of Form C is shown in Figure 15: Form C is agglomerated into a spherical shape, and the particle size is generally less than 20 μm.
可以看出，晶型C为有一定结晶性的无水物，具有一定的引湿性。It can be seen that the crystal form C is an anhydrous substance with certain crystallinity and has certain hygroscopicity.
方法2： Method 2 :
将19.4mg的晶型E(根据下文实施例5的方法制备)加入到1ml乙腈中，在50℃下搅拌1天后离心，室温真空干燥所得的固体，得到晶型C。19.4 mg of Form E (prepared according to the method in Example 5 below) was added to 1 ml of acetonitrile, stirred at 50° C. for 1 day, centrifuged, and the obtained solid was vacuum-dried at room temperature to obtain Form C.
方法3： Method 3 :
将20.0mg的晶型E(根据下文实施例5的方法制备)加入到0.1ml水与0.40ml丙酮的混合溶剂中，室温悬浮1天，然后过滤，干燥所得的固体，得到晶型C。20.0 mg of Form E (prepared according to the method in Example 5 below) was added to a mixed solvent of 0.1 ml of water and 0.40 ml of acetone, suspended at room temperature for 1 day, then filtered, and the resulting solid was dried to obtain Form C.
方法4： Method 4 :
将20.2mg的化合物I加入到0.2ml DMSO与0.80ml异丙醇的混合溶剂中，室温悬浮7天，然后过滤，干燥所得的固体，得到晶型C。20.2 mg of compound I was added to a mixed solvent of 0.2 ml DMSO and 0.80 ml isopropanol, suspended at room temperature for 7 days, then filtered, and the resulting solid was dried to obtain Form C.
根据方法2、3和4获得的晶型C的XRPD图谱基本上如图11所示。The XRPD patterns of Form C obtained according to methods 2, 3 and 4 are basically shown in FIG. 11 .
实施例4:晶型D的制备Embodiment 4: the preparation of crystal form D
方法1： Method 1 :
将20mg的化合物I与1ml的DMSO混合，在50℃下加热澄清后降至室温，加入8ml氯仿，室温搅拌1天后离心，室温真空干燥所得的固体，得到晶型D，其XRPD图谱如图16所示。Mix 20mg of compound I with 1ml of DMSO, heat at 50°C for clarification, then cool down to room temperature, add 8ml of chloroform, stir at room temperature for 1 day, centrifuge, and dry the resulting solid in vacuum at room temperature to obtain crystal form D, whose XRPD pattern is shown in Figure 16 shown.
晶型D的TGA图谱如图17所示：晶型D在加热至110℃的过程中失重3.9％，在110至200℃的过程中失重18.3％，在200℃后可能发生分解。The TGA spectrum of Form D is shown in Figure 17: Form D loses 3.9% of its weight when heated to 110°C, loses 18.3% of its weight during the process from 110 to 200°C, and may decompose after 200°C.
晶型D的DSC图谱如图17所示：晶型D在加热至100℃有对应TGA第一阶失重的吸热信号，在168℃左右有与第二阶失重对应的吸热峰。The DSC spectrum of Form D is shown in Figure 17: Form D has an endothermic signal corresponding to the first-order weight loss of TGA when heated to 100°C, and an endothermic peak corresponding to the second-order weight loss at around 168°C.
晶型D的NMR图谱如图18所示。NMR结果显示晶型D各个峰的峰位置和积分结果与参考图谱一致，化合物结构没有发生变化，在2.5-3.0ppm可见DMSO的溶剂峰。根据积分结果计算，化合物I与DMSO的比例为1:1.2，该比例与TGA的失重量相符(理论失重量为20.12％)。The NMR spectrum of Form D is shown in Figure 18. The NMR results showed that the peak positions and integration results of each peak of the crystal form D were consistent with the reference spectrum, the structure of the compound did not change, and the solvent peak of DMSO could be seen at 2.5-3.0ppm. Calculated according to the integral result, the ratio of compound I to DMSO is 1:1.2, which is consistent with the weight loss of TGA (theoretical weight loss is 20.12%).
可以看出，晶型D为化合物1和DMSO的化学计量比是1:1的DMSO溶剂合物。It can be seen that the crystal form D is a DMSO solvate in which the stoichiometric ratio of compound 1 and DMSO is 1:1.
方法2： Method 2 :
将19.4mg的化合物I加入到1ml水中，然后加入DMSO，在50℃加热使其溶解，然后降温至-15℃以析出固体，离心，室温真空干燥所得的固 体，得到晶型D。Add 19.4 mg of compound I to 1 ml of water, then add DMSO, heat at 50°C to dissolve, then cool down to -15°C to precipitate a solid, centrifuge, and vacuum-dry the obtained solid at room temperature to obtain crystal form D.
根据方法2获得的晶型D的XRPD图谱基本上如图16所示。The XRPD pattern of Form D obtained according to Method 2 is substantially as shown in FIG. 16 .
实施例5:晶型E的制备Embodiment 5: the preparation of crystal form E
将20mg的化合物I与1ml的NMP混合，在50℃下加热澄清后降至室温，然后加入8ml甲苯，室温搅拌1天后离心，室温真空干燥所得的固体，得到晶型E，其XRPD图谱如图19所示。Mix 20mg of compound I with 1ml of NMP, heat at 50°C for clarification, then cool down to room temperature, then add 8ml of toluene, stir at room temperature for 1 day, centrifuge, and dry the resulting solid in vacuum at room temperature to obtain crystal form E, whose XRPD pattern is shown in the figure 19.
晶型E的TGA图谱如图20所示：晶型E为有一定结晶性的固体。TGA结果显示晶型E在加热至100℃的过程中失重3.3％，在100至180℃的过程中失重21.0％，在210℃左右可能发生分解。The TGA spectrum of Form E is shown in Figure 20: Form E is a solid with certain crystallinity. The TGA results show that the crystal form E loses 3.3% of its weight when heated to 100°C, loses 21.0% of its weight when heated from 100 to 180°C, and may decompose at around 210°C.
晶型E的DSC图谱如图20所示：晶型E在加热至140℃没有明显信号，在177℃左右有对应TGA失重的吸热峰。The DSC spectrum of Form E is shown in Figure 20: Form E has no obvious signal when heated to 140°C, but has an endothermic peak corresponding to TGA weight loss at around 177°C.
晶型E的NMR图谱如图21所示。NMR结果显示晶型E各个峰的峰位置和积分结果与参考图谱一致，化合物结构没有发生变化，在1.9、2.2、2.7和3.3ppm处可见NMP的溶剂峰，在2.3和7.13-7.27ppm处可见甲苯的溶剂峰。根据积分结果计算，化合物I与NMP的比例为1:1.1，该比例与TGA的失重量相符(理论失重量为23.67％)；化合物I与甲苯的比例为1:0.07。The NMR spectrum of Form E is shown in Figure 21. NMR results show that the peak positions and integration results of each peak of Form E are consistent with the reference spectrum, and the structure of the compound has not changed. The solvent peaks of NMP can be seen at 1.9, 2.2, 2.7 and 3.3ppm, and can be seen at 2.3 and 7.13-7.27ppm. Solvent peak for toluene. Calculated according to the integral result, the ratio of compound I to NMP is 1:1.1, which is consistent with the weight loss of TGA (theoretical weight loss is 23.67%); the ratio of compound I to toluene is 1:0.07.
可以看出，晶型E为化合物I与NMP的化学计量比是1:1的NMP溶剂合物。It can be seen that the crystal form E is an NMP solvate in which the stoichiometric ratio of compound I to NMP is 1:1.
实施例6:晶型F的制备Embodiment 6: the preparation of crystal form F
将20mg的化合物I与1ml的DMF混合，在50℃下加热澄清后降至室温，然后加入8ml甲苯，室温搅拌1天后离心，得到晶型F，其XRPD图谱如图22所示。Mix 20 mg of compound I with 1 ml of DMF, heat at 50°C for clarification, then cool down to room temperature, then add 8 ml of toluene, stir at room temperature for 1 day and then centrifuge to obtain Form F, whose XRPD pattern is shown in Figure 22.
晶型F的TGA图谱如图23所示：晶型F在加热至60℃的过程中失重1.6％，在60至150℃的过程中失重13.9％，在200℃左右可能发生分解。The TGA spectrum of Form F is shown in Figure 23: Form F loses 1.6% in weight when heated to 60°C, loses 13.9% in the process from 60 to 150°C, and may decompose at around 200°C.
晶型F的DSC图谱如图23所示：晶型F在131℃左右有对应脱溶剂的吸热峰。The DSC spectrum of Form F is shown in Figure 23: Form F has an endothermic peak corresponding to desolvation at around 131°C.
晶型F的NMR图谱如图24所示。NMR结果显示晶型F各个峰的峰 位置和积分结果与参考图谱一致，化合物结构没有发生变化，在2.5-3.0ppm和7.95ppm可见DMF的溶剂峰。根据积分结果计算，化合物与DMF的比例为1:0.9，该比例与TGA的失重量接近(理论失重量为16.4％)。The NMR spectrum of Form F is shown in Figure 24. NMR results show that the peak positions and integration results of each peak of crystal form F are consistent with the reference collection, the compound structure does not change, and the solvent peak of DMF can be seen at 2.5-3.0ppm and 7.95ppm. According to the integral calculation, the ratio of the compound to DMF is 1:0.9, which is close to the weight loss of TGA (theoretical weight loss is 16.4%).
可以看出，晶型F为化合物I与DMF的化学计量比是1:1的DMF溶剂合物。It can be seen that Form F is a DMF solvate in which the stoichiometric ratio of Compound I to DMF is 1:1.
实施例7:晶型G的制备Embodiment 7: the preparation of crystal form G
将20mg的晶型B加入到2ml水中，在10℃下搅拌2天后离心，室温真空干燥所得的固体，得到晶型G，其XRPD图谱如图25所示。20mg of Form B was added to 2ml of water, stirred at 10°C for 2 days, centrifuged, and the resulting solid was vacuum-dried at room temperature to obtain Form G, whose XRPD pattern is shown in Figure 25.
晶型G的TGA图谱如图26所示：晶型G在加热至50℃的过程中失重2.0％，在50至100℃的过程中失重12.7％，在180℃左右可能发生分解。The TGA spectrum of Form G is shown in Figure 26: Form G loses 2.0% of its weight in the process of heating to 50°C, loses 12.7% in the process of heating from 50 to 100°C, and may decompose at around 180°C.
晶型G的DSC图谱如图26所示：晶型G在78.6℃和84.8℃左右有对应TGA失重的吸热峰。The DSC spectrum of Form G is shown in Figure 26: Form G has endothermic peaks corresponding to TGA weight loss at around 78.6°C and 84.8°C.
晶型G的NMR图谱如图27所示。NMR结果显示晶型G各个峰的峰位置和积分结果与参考图谱一致，化合物结构没有发生变化，未见明显溶剂峰。The NMR spectrum of Form G is shown in Figure 27. The NMR results showed that the peak positions and integration results of each peak of Form G were consistent with the reference spectrum, the structure of the compound did not change, and no obvious solvent peak was seen.
可以看出，晶型G为三水合物。It can be seen that Form G is a trihydrate.
实施例8：晶型A、B和C的放大制备Example 8: Scaled-up preparation of Forms A, B and C
对目标晶型进行实验室级别的放大制备，制备过程如下表2所示。The laboratory-level scale-up preparation of the target crystal form is carried out, and the preparation process is shown in Table 2 below.
表2Table 2
Figure PCTCN2022115011-appb-000005
Figure PCTCN2022115011-appb-000005
Figure PCTCN2022115011-appb-000006
Figure PCTCN2022115011-appb-000006
对放大制备工艺获得的晶型A进行XRPD、DSC、TGA、NMR、DVS、PLM等表征。XRPD基本上如图1所示，结果显示晶型A为结晶性良好的固体。TGA结果显示晶型A在加热至100℃的过程中失重1.54％，在200℃左右可能发生分解。DSC结果显示晶型A在185℃有吸热峰。NMR结果显示晶型A各个峰的峰位置和积分结果与参考图谱一致，未见明显有机溶剂特征峰。DVS结果显示晶型A在95％湿度下增重0.42％，在0％湿度下失重0.82％，与TGA失重相符，表明晶型A具有很低的引湿性，XRPD结果显示DVS测试后的样品并未发生晶型改变。PLM图像显示晶型A为片状颗粒，粒径一般小于20μm。可以看出，晶型A为结晶性良好的无水物，具有很低的引湿性。总体而言，晶型A具有很好的结晶性、低引湿性、较好的颗粒度，有利于干燥、储存和运输。XRPD, DSC, TGA, NMR, DVS, PLM, etc. were used to characterize the crystal form A obtained by the scale-up preparation process. XRPD is basically as shown in Figure 1, and the result shows that Form A is a solid with good crystallinity. The TGA results showed that Form A lost 1.54% of its weight when heated to 100°C, and may decompose at around 200°C. DSC results showed that Form A had an endothermic peak at 185°C. The NMR results showed that the peak positions and integration results of each peak of the crystal form A were consistent with the reference spectrum, and no obvious organic solvent characteristic peaks were seen. The DVS results showed that Form A gained 0.42% in weight at 95% humidity, and lost 0.82% at 0% humidity, which was consistent with the TGA weight loss, indicating that Form A had very low hygroscopicity. XRPD results showed that the samples after DVS testing were not No crystal form change occurred. The PLM image shows that the crystal form A is a plate-shaped particle, and the particle size is generally less than 20 μm. It can be seen that Form A is an anhydrous substance with good crystallinity and low hygroscopicity. Overall, Form A has good crystallinity, low hygroscopicity, and good particle size, which is conducive to drying, storage and transportation.
对放大制备工艺获得的晶型B进行XRPD、DSC、TGA、NMR、DVS、PLM等表征。XRPD基本上如图6所示，结果显示晶型B为有一定结晶性的固体。TGA结果显示晶型B在加热至130℃的过程中失重3.82％，在200℃左右可能发生分解。DSC结果显示晶型B在加热后在72℃和212℃有两个吸热峰，在215℃有一个放热峰，结合TGA在此温度下开始失重，可能对应化合物I熔融伴随分解过程。NMR结果显示进行B各个峰的峰位置和积分结果与参考图谱一致，在2.5–3.0ppm处可见DMF的特征峰。根据积分结果计算，化合物I与DMF的比例为1:0.02，该比例的DMF占TGA失重量较小(理论失重量为0.37％)。DVS结果显示晶型B在95％湿度下增重3.15％，表明晶型B具有一定的引湿性；在0％湿度下失重4.10％，与TGA失重相符；XRPD结果显示DVS测试后的样品并未发生晶型改变。PLM图像显示晶型B为片状颗粒，粒径一般小于20μm。可以看出，晶型B为有一定结晶性的一水合物，有一定的引湿性。XRPD, DSC, TGA, NMR, DVS, PLM, etc. were used to characterize the crystal form B obtained by the scale-up preparation process. XRPD is basically as shown in Figure 6, and the result shows that Form B is a solid with certain crystallinity. The TGA results showed that Form B lost 3.82% of its weight when heated to 130°C, and it may decompose at around 200°C. DSC results show that Form B has two endothermic peaks at 72°C and 212°C after heating, and an exothermic peak at 215°C. Combining with TGA, it begins to lose weight at this temperature, which may correspond to the melting of compound I with decomposition process. The NMR results showed that the peak positions and integration results of each peak in B were consistent with the reference spectrum, and the characteristic peak of DMF could be seen at 2.5–3.0ppm. According to the calculation of the integral results, the ratio of compound I to DMF is 1:0.02, and the ratio of DMF to TGA weight loss is small (theoretical weight loss is 0.37%). The DVS results show that the crystal form B has a weight gain of 3.15% at 95% humidity, indicating that the crystal form B has a certain hygroscopicity; the weight loss at 0% humidity is 4.10%, which is consistent with the TGA weight loss; the XRPD results show that the samples after the DVS test did not A crystal form change occurs. The PLM image shows that the crystal form B is a plate-shaped particle, and the particle size is generally less than 20 μm. It can be seen that crystal form B is a monohydrate with certain crystallinity and certain hygroscopicity.
对放大制备工艺获得的晶型C进行XRPD、DSC、TGA、NMR、DVS、PLM等表征。XRPD基本上如图11所示，结果显示晶型C为有一定结晶性 的固体。TGA结果显示晶型C在加热至100℃的过程中仅失重0.95％，在200℃左右可能发生分解。DSC结果显示晶型C在加热到分解温度之前没有明显的热流信号，在210℃后基线发生明显偏移，结合TGA在此温度下有明显失重，可能有对应化合物I分解的热流信号。NMR结果显示晶型C各个峰的峰位置和积分结果与参考图谱一致，在2.5-3.0ppm处可见DMF的吸收峰。根据积分结果计算，化合物与DMF的比例为1:0.09，该比例与TGA的失重量相近(理论失重量为1.7％)。DVS结果显示晶型C在95％湿度下增重2.58％，在0％湿度下失重1.03％，与TGA失重相符，表明晶型C具有一定的引湿性；XRPD结果显示DVS测试后的样品并未发生晶型改变。PLM图像显示晶型C团聚为球形，粒径一般小于20μm。可以看出，晶型C为有一定结晶性的无水物，具有一定的引湿性。XRPD, DSC, TGA, NMR, DVS, PLM, etc. were used to characterize the crystal form C obtained by the scale-up preparation process. XRPD is basically as shown in Figure 11, and the results show that Form C is a solid with certain crystallinity. TGA results show that the crystal form C loses only 0.95% of its weight when heated to 100°C, and may decompose at around 200°C. DSC results show that the crystal form C has no obvious heat flow signal before heating to the decomposition temperature, and the baseline shifts significantly after 210°C. Combined with the obvious weight loss of TGA at this temperature, there may be a heat flow signal corresponding to the decomposition of compound I. The NMR results show that the peak positions and integration results of each peak of the crystal form C are consistent with the reference spectrum, and the absorption peak of DMF can be seen at 2.5-3.0ppm. According to the integral calculation, the ratio of compound to DMF is 1:0.09, which is close to the weight loss of TGA (theoretical weight loss is 1.7%). The DVS results showed that Form C gained 2.58% in weight at 95% humidity, and lost 1.03% at 0% humidity, which was consistent with the TGA weight loss, indicating that Form C had a certain hygroscopicity; XRPD results showed that the samples after DVS testing did not A crystal form change occurs. The PLM image shows that the crystal form C is agglomerated into a spherical shape, and the particle size is generally less than 20 μm. It can be seen that the crystal form C is an anhydrous substance with certain crystallinity and has certain hygroscopicity.
综上，放大制备工艺获得的晶型A、B和C与小试保持一致性，说明制备工艺能稳定地进行放大生产。In summary, the crystal forms A, B, and C obtained by the scale-up preparation process are consistent with those obtained from the small test, indicating that the preparation process can be stably scaled up.
实施例9：晶型的稳定性研究Embodiment 9: Stability study of crystal form
对晶型A、B和C进行高温(60℃)、高湿(25℃，92.5％RH)、光照(25℃，4500Lux)条件下的稳定性研究，分别于7天和15天取样进行XRPD表征。根据图29-图31的XRPD图谱，结果显示三种晶型在高温、高湿、光照条件下15天均稳定，没有发生晶型转变。Stability studies were carried out on crystal forms A, B and C under conditions of high temperature (60°C), high humidity (25°C, 92.5% RH) and light (25°C, 4500Lux), and samples were taken for XRPD at 7 days and 15 days respectively characterization. According to the XRPD patterns in Figures 29-31, the results show that the three crystal forms are stable for 15 days under high temperature, high humidity, and light conditions, and no crystal form transformation occurs.
表3table 3
Figure PCTCN2022115011-appb-000007
Figure PCTCN2022115011-appb-000007
实施例10：竞争性悬浮的晶型稳定性研究Example 10: Study on crystal form stability of competitive suspension
分别在10℃、25℃和60℃下在无水体系中进行晶型A和C的竞争性悬浮实验，结果如下表4所示。发现在10℃和25℃下悬浮两周后，所得固体仍为晶型A和C的混合物；在60℃下悬浮两周后晶型C有转变为晶型A的趋势。Competitive suspension experiments of Forms A and C were carried out in anhydrous systems at 10°C, 25°C and 60°C, respectively, and the results are shown in Table 4 below. It was found that after two weeks of suspension at 10°C and 25°C, the obtained solid was still a mixture of crystal forms A and C; after two weeks of suspension at 60°C, crystal form C tended to transform into crystal form A.
表4Table 4
实验编号experiment number 温度(℃)temperature(℃) 悬浮5天suspension for 5 days 悬浮8天Suspension for 8 days 悬浮14天Suspension for 14 days
11 1010 晶型A+CCrystal form A+C 晶型A+CCrystal form A+C 晶型A+CCrystal form A+C
22 2525 晶型A+CCrystal form A+C 晶型A+CCrystal form A+C 晶型A+CCrystal form A+C
33 6060 晶型A+CCrystal form A+C 晶型A+CCrystal form A+C 晶型A+CCrystal form A+C
实施例11：水活度实验的晶型稳定性研究Example 11: Study on crystal form stability in water activity experiment
分别在10℃、25℃和60℃下进行水合物晶型B的水活度实验。发现在10℃、25℃和60℃的乙醇中，晶型B悬浮两天后未发生晶型变化；在10℃和25℃下，在溶剂为乙醇/水(1:1v/v)或纯水时，晶型B悬浮两天后转变为晶型G；在60℃下，在溶剂为乙醇/水(1:1v/v)或纯水时，晶型B悬浮两天后转变为晶型A。The water activity experiments of the hydrate crystal form B were carried out at 10°C, 25°C and 60°C, respectively. It was found that in ethanol at 10°C, 25°C and 60°C, the crystal form of Form B did not change after being suspended for two days; At 60°C, when the solvent is ethanol/water (1:1 v/v) or pure water, the crystal form B is transformed into crystal form A after being suspended for two days.
表5table 5
Figure PCTCN2022115011-appb-000008
Figure PCTCN2022115011-appb-000008
Figure PCTCN2022115011-appb-000009
Figure PCTCN2022115011-appb-000009
实施例12：不同晶型表征结果汇总Example 12: Summary of Characterization Results of Different Crystal Forms
在晶型筛选中共得到7种晶型，包括两个无水物(晶型A和C)，两个水合物(晶型B和G)和三个溶剂合物(晶型D、E和F)。7种晶型的表征结果汇总见下表6。A total of 7 crystal forms were obtained in the crystal form screening, including two anhydrates (crystal forms A and C), two hydrates (crystal forms B and G) and three solvates (crystal forms D, E and F ). The characterization results of the seven crystal forms are summarized in Table 6 below.
表6Table 6
Figure PCTCN2022115011-appb-000010
Figure PCTCN2022115011-appb-000010
实施例13：不同晶型的HPLC测定结果Embodiment 13: HPLC determination result of different crystal forms
所制备的7种晶型的化学纯度均较佳，尤其是溶剂合物的形成(晶型D、E、F)起到了对化合物I的提纯和精制的作用，具有实际的应用价值。The chemical purity of the prepared 7 crystal forms are all good, especially the formation of solvates (crystal forms D, E, F) play a role in the purification and refinement of compound I, which has practical application value.
表7Table 7
Figure PCTCN2022115011-appb-000011
Figure PCTCN2022115011-appb-000011
实施例14：稳定性研究Example 14: Stability Study
在高温(60℃)、高湿(25℃，92.5％RH)和光照(25℃，4500Lux)条件下，对晶型A进行稳定性研究，其中在第7天和第16天取样测定XRPD图谱。结果如下表8所示。Under the conditions of high temperature (60°C), high humidity (25°C, 92.5% RH) and light (25°C, 4500Lux), the stability of Form A was studied, and XRPD patterns were measured on the 7th and 16th days . The results are shown in Table 8 below.
表8Table 8
Figure PCTCN2022115011-appb-000012
Figure PCTCN2022115011-appb-000012
实施例15：在生物媒介中的溶解度试验Example 15: Solubility Test in Biological Media
FaSSIF是空腹状态下模拟肠液，其如下制备：(1)称量0.042g氢氧化钠、0.3438g磷酸二氢钠和0.6186g氯化钠，加入90mL纯净水并混合均匀，然后用1N盐酸或者1N氢氧化钠调节pH＝6.5，用纯净水定容至100mL；(2)取50mL在上述(1)中配制好的缓冲液，加入0.224g的FaSSIF/FeSSIF/FaSSGF市售粉末(Biorelevant.com)，搅拌直至溶解，然后用 在(1)中配制好的缓冲液定容至100mL。将配制的缓冲液放置室温，静置两小时后观察缓冲液为轻微的乳白色，即可使用。FaSSIF is a simulated intestinal fluid in a fasting state, which is prepared as follows: (1) Weigh 0.042g sodium hydroxide, 0.3438g sodium dihydrogen phosphate and 0.6186g sodium chloride, add 90mL of purified water and mix well, then wash with 1N hydrochloric acid or 1N Adjust the pH to 6.5 with sodium hydroxide, and dilute to 100mL with purified water; (2) Take 50mL of the buffer solution prepared in (1) above, add 0.224g of FaSSIF/FeSSIF/FaSSGF commercially available powder (Biorelevant.com) , stir until dissolved, and then dilute to 100 mL with the buffer prepared in (1). Place the prepared buffer solution at room temperature, and observe that the buffer solution is slightly milky white after standing for two hours, and it can be used immediately.
FeSSIF是进食状态下模拟肠液，其如下制备：(1)称量0.404g氢氧化钠、0.865g冰醋酸和1.1874g氯化钠，加入90mL纯净水并混合均匀，然后用1N盐酸或者1N氢氧化钠调节pH＝5.0，用纯净水定容至100mL；(2)取50mL在上述(1)中配制好的缓冲液，加入1.12g的FaSSIF/FeSSIF/FaSSGF市售粉末(Biorelevant.com)，搅拌直至溶解，然后用在(1)中配制好的缓冲液定容至100mL。将配制的缓冲液放置室温，静置两小时后观察缓冲液为透明液体，即可使用。FeSSIF is a simulated intestinal juice in a fed state, which is prepared as follows: (1) Weigh 0.404g sodium hydroxide, 0.865g glacial acetic acid and 1.1874g sodium chloride, add 90mL of pure water and mix well, then oxidize with 1N hydrochloric acid or 1N hydroxide Adjust the pH to 5.0 with sodium, and dilute to 100 mL with purified water; (2) Take 50 mL of the buffer solution prepared in (1) above, add 1.12 g of FaSSIF/FeSSIF/FaSSGF commercially available powder (Biorelevant.com), and stir Until dissolved, then dilute to 100mL with the buffer solution prepared in (1). Place the prepared buffer solution at room temperature, and observe that the buffer solution is a transparent liquid after standing for two hours, and it can be used immediately.
FaSSGF(SGF)是模拟胃液，其如下制备：(1)称量0.2g氯化钠，加入90mL纯净水并混合均匀，然后用1N盐酸调节pH＝1.8，用纯净水定容至100mL，静置至室温；(2)取50mL在上述(1)中配置好的缓冲液，加入0.006g的FaSSIF/FeSSIF/FaSSGF市售粉末(Biorelevant.com)，搅拌直至溶解，用在(1)中配制好的缓冲液定容至100mL。将配制的缓冲液放置室温，静置两小时后观察缓冲液为透明液体，即可使用。FaSSGF (SGF) is simulated gastric juice, which is prepared as follows: (1) Weigh 0.2g of sodium chloride, add 90mL of pure water and mix well, then adjust pH=1.8 with 1N hydrochloric acid, dilute to 100mL with pure water, let stand to room temperature; (2) Take 50mL of the buffer prepared in the above (1), add 0.006g of FaSSIF/FeSSIF/FaSSGF commercially available powder (Biorelevant.com), stir until dissolved, and use the prepared in (1) The buffer was adjusted to 100mL. Place the prepared buffer solution at room temperature, and observe that the buffer solution is a transparent liquid after standing for two hours, and it can be used immediately.
测定晶型A在FaSSIF、FeSSIF和FaSSGF这三种生物媒介中的溶解度。结果如下表9所示。The solubility of Form A in three biological media, FaSSIF, FeSSIF and FaSSGF, was determined. The results are shown in Table 9 below.
表9Table 9
Figure PCTCN2022115011-appb-000013
Figure PCTCN2022115011-appb-000013
结果显示，晶型A在溶解度测试过程中没有发生晶型变化，在FaSSIF、FeSSIF和FaSSGF中均具有较好的溶解度，因而可在制备的制剂中具备相当的溶出优势，有利于在施用过程中在不同的生物媒介条件下的溶出和生物利用。The results show that the crystalline form A has no crystal form change during the solubility test, and has good solubility in FaSSIF, FeSSIF and FaSSGF, so it can have a considerable dissolution advantage in the prepared preparation, which is conducive to the application process. Dissolution and bioavailability under different biological media conditions.
除本文中描述的那些外，根据前述描述，本发明的多种修改也意图落入所附权利要求书的范围内。本申请中所引用的各参考文献(包括所有专利、专利申请、期刊文章、书籍及任何其它公开)均以其整体援引加入本文。From the foregoing description, modifications of the invention in addition to those described herein are intended to fall within the scope of the appended claims. Each reference cited in this application, including all patents, patent applications, journal articles, books, and any other publications, is hereby incorporated by reference in its entirety.

Claims (17)

  1. 化合物I的晶型A，Form A of Compound I,
    Figure PCTCN2022115011-appb-100001
    Figure PCTCN2022115011-appb-100001
    其特征在于所述晶型A的X-射线粉末衍射(XRPD)图谱包括在约6.7±0.2°、18.2±0.2°、27.4±0.2°和/或28.2±0.2°的衍射角(2θ)处的衍射峰，优选还包括在约16.9±0.2°、20.2±0.2°、20.7±0.2°、21.0±0.2°和/或21.8±0.2°的衍射角(2θ)处的衍射峰，更优选还包括在约14.0±0.2°、15.1±0.2°、17.3±0.2°、19.1±0.2°、19.7±0.2°、20.5±0.2°、22.4±0.2°、23.1±0.2°、24.4±0.2°、24.8±0.2°、26.9±0.2°、28.5±0.2°、29.2±0.2°、30.6±0.2°、30.8±0.2°、32.8±0.2°、33.5±0.2°、34.2±0.2°、41.2±0.2°和/或43.5±0.2°的衍射角(2θ)处的衍射峰；It is characterized in that the X-ray powder diffraction (XRPD) pattern of the crystal form A includes diffraction angles (2θ) at about 6.7±0.2°, 18.2±0.2°, 27.4±0.2° and/or 28.2±0.2° Diffraction peaks, preferably also include diffraction peaks at diffraction angles (2θ) at about 16.9±0.2°, 20.2±0.2°, 20.7±0.2°, 21.0±0.2° and/or 21.8±0.2°, more preferably also include diffraction peaks at Approx. 14.0±0.2°, 15.1±0.2°, 17.3±0.2°, 19.1±0.2°, 19.7±0.2°, 20.5±0.2°, 22.4±0.2°, 23.1±0.2°, 24.4±0.2°, 24.8±0.2° , 26.9±0.2°, 28.5±0.2°, 29.2±0.2°, 30.6±0.2°, 30.8±0.2°, 32.8±0.2°, 33.5±0.2°, 34.2±0.2°, 41.2±0.2° and/or 43.5± The diffraction peak at the diffraction angle (2θ) of 0.2°;
    进一步优选地，所述晶型A的XRPD图谱基本上如图1所示，更进一步优选如图1所示；Further preferably, the XRPD pattern of the crystalline form A is basically as shown in Figure 1, more preferably as shown in Figure 1;
    更进一步优选地，所述晶型A不是溶剂合物，更优选地为无水物。Even more preferably, the crystal form A is not a solvate, more preferably an anhydrate.
  2. 化合物I的晶型B，Form B of Compound I,
    Figure PCTCN2022115011-appb-100002
    Figure PCTCN2022115011-appb-100002
    其特征在于所述晶型B的XRPD图谱包括在约6.9±0.2°、9.5±0.2°、10.0±0.2°和/或19.1±0.2°的衍射角(2θ)处的衍射峰，优选还包括在约6.7±0.2°、17.2±0.2°、18.3±0.2°、20.4±0.2°和/或21.0±0.2°的衍射角(2θ)处的衍射峰，更优选还包括在约14.0±0.2°、15.9±0.2°、20.2±0.2°、21.3±0.2°、21.7±0.2°、22.1±0.2°、24.6±0.2°、26.9±0.2°、27.3±0.2°、27.5±0.2°、28.1±0.2°、29.5±0.2°、 31.1±0.2°和/或35.1±0.2°的衍射角(2θ)处的衍射峰；It is characterized in that the XRPD pattern of the crystal form B includes diffraction peaks at diffraction angles (2θ) of about 6.9±0.2°, 9.5±0.2°, 10.0±0.2° and/or 19.1±0.2°, and preferably also includes diffraction peaks at Diffraction peaks at diffraction angles (2θ) of about 6.7±0.2°, 17.2±0.2°, 18.3±0.2°, 20.4±0.2° and/or 21.0±0.2°, more preferably at about 14.0±0.2°, 15.9 ±0.2°, 20.2±0.2°, 21.3±0.2°, 21.7±0.2°, 22.1±0.2°, 24.6±0.2°, 26.9±0.2°, 27.3±0.2°, 27.5±0.2°, 28.1±0.2°, 29.5 Diffraction peaks at diffraction angles (2θ) of ±0.2°, 31.1±0.2° and/or 35.1±0.2°;
    进一步优选地，所述晶型B的XRPD图谱基本上如图6所示，更进一步优选如图6所示；Further preferably, the XRPD pattern of the crystal form B is basically as shown in Figure 6, and more preferably as shown in Figure 6;
    更进一步优选地，所述晶型B为一水合物。Still further preferably, the crystal form B is a monohydrate.
  3. 化合物I的晶型C，Form C of Compound I,
    Figure PCTCN2022115011-appb-100003
    Figure PCTCN2022115011-appb-100003
    其特征在于所述晶型C的XRPD图谱包括在约6.8±0.2°、15.1±0.2°、21.4±0.2°、22.0±0.2°和/或27.6±0.2°的衍射角(2θ)处的衍射峰，优选还包括在约20.6±0.2°、21.2±0.2°、26.7±0.2°和/或28.7±0.2°的衍射角(2θ)处的衍射峰，优选还包括在约13.6±0.2°、14.7±0.2°、16.2±0.2°、18.0±0.2°、19.1±0.2°、20.0±0.2°、22.7±0.2°、23.3±0.2°、25.0±0.2°、27.1±0.2°、28.0±0.2°、30.2±0.2°、31.5±0.2°、31.9±0.2°、34.6±0.2°、34.8±0.2°、38.8±0.2°、40.0±0.2°和/或41.9±0.2°的衍射角(2θ)处的衍射峰；It is characterized in that the XRPD pattern of the crystal form C includes diffraction peaks at diffraction angles (2θ) of about 6.8±0.2°, 15.1±0.2°, 21.4±0.2°, 22.0±0.2° and/or 27.6±0.2° , preferably also include diffraction peaks at about 20.6±0.2°, 21.2±0.2°, 26.7±0.2° and/or 28.7±0.2° at diffraction angles (2θ), preferably also include diffraction peaks at about 13.6±0.2°, 14.7±0.2° 0.2°, 16.2±0.2°, 18.0±0.2°, 19.1±0.2°, 20.0±0.2°, 22.7±0.2°, 23.3±0.2°, 25.0±0.2°, 27.1±0.2°, 28.0±0.2°, 30.2± Diffraction peaks at diffraction angles (2θ) of 0.2°, 31.5±0.2°, 31.9±0.2°, 34.6±0.2°, 34.8±0.2°, 38.8±0.2°, 40.0±0.2° and/or 41.9±0.2°;
    进一步优选地，所述晶型C的XRPD图谱基本上如图11所示，更进一步优选地如图11所示；Further preferably, the XRPD spectrum of the crystalline form C is basically as shown in Figure 11, more preferably as shown in Figure 11;
    更进一步优选地，所述晶型C不是溶剂合物，更优选地为无水物。Even more preferably, the crystal form C is not a solvate, more preferably an anhydrate.
  4. 化合物I的晶型D，Form D of compound I,
    Figure PCTCN2022115011-appb-100004
    Figure PCTCN2022115011-appb-100004
    其特征在于所述晶型D的XRPD图谱包括在约9.6±0.2°、17.0±0.2°、19.9±0.2°和/或26.0±0.2°的衍射角(2θ)处的衍射峰，优选还包括在约4.4±0.2°、 13.4±0.2°、20.2±0.2°、23.3±0.2°、25.1±0.2°、28.4±0.2°和/或29.2±0.2°的衍射角(2θ)处的衍射峰，更优选还包括在约12.3±0.2°、15.9±0.2°、19.0±0.2°、20.9±0.2°、21.4±0.2°、21.8±0.2°、22.6±0.2°、24.1±0.2°、24.9±0.2°、27.8±0.2°、30.0±0.2°、31.6±0.2°、32.2±0.2°、32.6±0.2°、32.8±0.2°、34.0±0.2°、36.5±0.2°、37.5±0.2°、37.7±0.2°和/或40.1±0.2°衍射角(2θ)处的衍射峰；It is characterized in that the XRPD pattern of the crystal form D includes diffraction peaks at diffraction angles (2θ) of about 9.6±0.2°, 17.0±0.2°, 19.9±0.2° and/or 26.0±0.2°, preferably also includes diffraction peaks at Diffraction peaks at diffraction angles (2θ) of about 4.4±0.2°, 13.4±0.2°, 20.2±0.2°, 23.3±0.2°, 25.1±0.2°, 28.4±0.2° and/or 29.2±0.2°, more preferably Also included at approx. ±0.2°, 30.0±0.2°, 31.6±0.2°, 32.2±0.2°, 32.6±0.2°, 32.8±0.2°, 34.0±0.2°, 36.5±0.2°, 37.5±0.2°, 37.7±0.2° and/or Or the diffraction peak at 40.1±0.2°diffraction angle (2θ);
    进一步优选地，所述晶型D的XRPD图谱基本上如图16所示，更进一步优选地如图16所示；Further preferably, the XRPD pattern of the crystal form D is basically as shown in Figure 16, and even more preferably as shown in Figure 16;
    更进一步优选地，所述晶型D为具有DMSO的溶剂合物，其中化合物I与所述DMSO的化学计量比为约1:1。Even more preferably, the crystal form D is a solvate with DMSO, wherein the stoichiometric ratio of Compound I to the DMSO is about 1:1.
  5. 化合物I的晶型E，Form E of Compound I,
    Figure PCTCN2022115011-appb-100005
    Figure PCTCN2022115011-appb-100005
    其特征在于所述晶型E的XRPD图谱包括在约4.2±0.2°、9.6±0.2°、12.8±0.2°、19.1±0.2°和/或27.2±0.2°的衍射角(2θ)处的衍射峰，优选还包括在约25.3±0.2°、25.7±0.2°、28.8±0.2°和/或35.7±0.2°的衍射角(2θ)处的衍射峰，更优选还包括在约12.1±0.2°、17.0±0.2°、17.4±0.2°、17.9±0.2°、19.4±0.2°、20.2±0.2°、21.3±0.2°、21.7±0.2°、21.9±0.2°、23.2±0.2°、26.7±0.2°、27.9±0.2°、29.9±0.2°、30.1±0.2°、31.4±0.2°、32.1±0.2°、35.0±0.2°和/或39.0±0.2°的衍射角(2θ)处的衍射峰；It is characterized in that the XRPD pattern of the crystal form E includes diffraction peaks at diffraction angles (2θ) of about 4.2±0.2°, 9.6±0.2°, 12.8±0.2°, 19.1±0.2° and/or 27.2±0.2° , preferably also include diffraction peaks at about 25.3±0.2°, 25.7±0.2°, 28.8±0.2° and/or 35.7±0.2° at diffraction angles (2θ), more preferably at about 12.1±0.2°, 17.0 ±0.2°, 17.4±0.2°, 17.9±0.2°, 19.4±0.2°, 20.2±0.2°, 21.3±0.2°, 21.7±0.2°, 21.9±0.2°, 23.2±0.2°, 26.7±0.2°, 27.9 Diffraction peaks at diffraction angles (2θ) of ±0.2°, 29.9±0.2°, 30.1±0.2°, 31.4±0.2°, 32.1±0.2°, 35.0±0.2° and/or 39.0±0.2°;
    进一步优选地，所述晶型E的XRPD图谱基本上如图19所示，更进一步优选地如图19所示；Further preferably, the XRPD pattern of the crystal form E is basically as shown in Figure 19, and even more preferably as shown in Figure 19;
    更进一步优选地，所述晶型E为具有NMP的溶剂合物，其中化合物I与所述NMP的化学计量比为约1:1。Even more preferably, the crystal form E is a solvate with NMP, wherein the stoichiometric ratio of Compound I to the NMP is about 1:1.
  6. 化合物I的晶型F，Form F of compound I,
    Figure PCTCN2022115011-appb-100006
    Figure PCTCN2022115011-appb-100006
    其特征在于所述晶型F的XRPD图谱包括在约5.3±0.2°、7.0±0.2°、9.5±0.2°、19.1±0.2°和/或21.7±0.2°的衍射角(2θ)处的衍射峰，优选还包括在约10.0±0.2°、17.2±0.2°、18.5±0.2°、20.4±0.2°和/或21.0±0.2°的衍射角(2θ)处的衍射峰，更优选还包括在约10.8±0.2°、14.0±0.2°、14.4±0.2°、15.0±0.2°、15.5±0.2°、15.9±0.2°、16.5±0.2°、17.5±0.2°、18.8±0.2°、19.6±0.2°、20.2±0.2°、22.1±0.2°、22.4±0.2°、22.8±0.2°、24.6±0.2°、26.8±0.2°、27.2±0.2°、27.5±0.2°、28.1±0.2°、28.5±0.2°、29.0±0.2°、29.5±0.2°、29.8±0.2°、31.1±0.2°、32.6±0.2°、33.0±0.2°、35.1±0.2°、35.9±0.2°、37.4±0.2°、38.9±0.2°和/或40.9±0.2°的衍射角(2θ)处的衍射峰；It is characterized in that the XRPD spectrum of the crystal form F includes diffraction peaks at diffraction angles (2θ) of about 5.3±0.2°, 7.0±0.2°, 9.5±0.2°, 19.1±0.2° and/or 21.7±0.2° , preferably also include diffraction peaks at diffraction angles (2θ) of about 10.0±0.2°, 17.2±0.2°, 18.5±0.2°, 20.4±0.2° and/or 21.0±0.2°, more preferably at about 10.8 ±0.2°, 14.0±0.2°, 14.4±0.2°, 15.0±0.2°, 15.5±0.2°, 15.9±0.2°, 16.5±0.2°, 17.5±0.2°, 18.8±0.2°, 19.6±0.2°, 20.2 ±0.2°, 22.1±0.2°, 22.4±0.2°, 22.8±0.2°, 24.6±0.2°, 26.8±0.2°, 27.2±0.2°, 27.5±0.2°, 28.1±0.2°, 28.5±0.2°, 29.0 ±0.2°, 29.5±0.2°, 29.8±0.2°, 31.1±0.2°, 32.6±0.2°, 33.0±0.2°, 35.1±0.2°, 35.9±0.2°, 37.4±0.2°, 38.9±0.2° and/or Or the diffraction peak at the diffraction angle (2θ) of 40.9±0.2°;
    进一步优选地，所述晶型F的XRPD图谱基本上如图22所示，更进一步优选地如图22所示；Further preferably, the XRPD spectrum of the crystalline form F is basically as shown in Figure 22, even more preferably as shown in Figure 22;
    更进一步优选地，所述晶型F为具有DMF的溶剂合物，其中化合物I与所述DMF的化学计量比为约1:1。Even more preferably, the crystalline form F is a solvate with DMF, wherein the stoichiometric ratio of Compound I to the DMF is about 1:1.
  7. 化合物I的晶型G，Form G of Compound I,
    Figure PCTCN2022115011-appb-100007
    Figure PCTCN2022115011-appb-100007
    其特征在于所述晶型G的XRPD图谱包括在约12.1±0.2°、20.8±0.2°、23.6±0.2°、24.6±0.2°和/或29.1±0.2°的衍射角(2θ)处的衍射峰，优选还包括在约15.7±0.2°、21.1±0.2°、23.0±0.2°、23.4±0.2°、28.2±0.2°和/或33.0±0.2°的衍射角(2θ)处的衍射峰，更优选还包括在约8.1±0.2°、12.9±0.2°、13.3±0.2°、16.3±0.2°、16.8±0.2°、18.2±0.2°、22.2±0.2°、22.9±0.2°、23.9±0.2°、24.4±0.2°、 25.5±0.2°、25.9±0.2°、26.1±0.2°、27.0±0.2°、27.5±0.2°、27.7±0.2°、28.0±0.2°、31.2±0.2°、33.3±0.2°、33.5±0.2°、35.7±0.2°、35.9±0.2°、36.3±0.2°、36.6±0.2°、37.5±0.2°、40.5±0.2°、41.3±0.2°和/或42.9±0.2°的衍射角(2θ)处的衍射峰；It is characterized in that the XRPD pattern of the crystal form G includes diffraction peaks at diffraction angles (2θ) of about 12.1±0.2°, 20.8±0.2°, 23.6±0.2°, 24.6±0.2° and/or 29.1±0.2° , preferably also comprising diffraction peaks at diffraction angles (2θ) of about 15.7±0.2°, 21.1±0.2°, 23.0±0.2°, 23.4±0.2°, 28.2±0.2° and/or 33.0±0.2°, more preferably Also included at about 8.1±0.2°, 12.9±0.2°, 13.3±0.2°, 16.3±0.2°, 16.8±0.2°, 18.2±0.2°, 22.2±0.2°, 22.9±0.2°, 23.9±0.2°, 24.4 ±0.2°, 25.5±0.2°, 25.9±0.2°, 26.1±0.2°, 27.0±0.2°, 27.5±0.2°, 27.7±0.2°, 28.0±0.2°, 31.2±0.2°, 33.3±0.2°, 33.5 Diffraction angles (2θ ) at the diffraction peak;
    优选地，所述晶型G的XRPD图谱基本上如图25所示，更进一步优选地如图25所示；Preferably, the XRPD spectrum of the crystalline form G is basically as shown in Figure 25, more preferably as shown in Figure 25;
    更进一步优选地，所述晶型G为三水合物。Still further preferably, the crystal form G is a trihydrate.
  8. 制备如权利要求1所述的晶型A的方法，其特征在于，The method for preparing the crystal form A as claimed in claim 1, characterized in that,
    所述方法包括：The methods include:
    a1)提供化合物I在适当的溶剂中的悬浮液，优选地化合物I在所述悬浮液中的含量为约1-200mg/ml；a1) providing a suspension of Compound I in a suitable solvent, preferably the content of Compound I in said suspension is about 1-200 mg/ml;
    a2)在室温下搅拌所述悬浮液足够的时间，然后进行固液分离，干燥所得的固体，得到所述晶型A；a2) stirring the suspension at room temperature for a sufficient time, then performing solid-liquid separation, and drying the obtained solid to obtain the crystal form A;
    优选地，其中所述适当的溶剂选自DMF、DMSO、甲醇、乙醇、正丙醇、异丙醇、丙酮、4-甲基-2-戊酮、乙酸乙酯、乙酸异丙酯、甲酸乙酯、甲酸丁酯、正庚烷、环己烷、二氧六环、***、甲基叔丁基醚、乙二醇甲醚、乙二醇二甲醚、水、乙腈、甲苯、二氯甲烷、氯仿、四氢呋喃及其混合物；和/或Preferably, wherein said suitable solvent is selected from DMF, DMSO, methanol, ethanol, n-propanol, isopropanol, acetone, 4-methyl-2-pentanone, ethyl acetate, isopropyl acetate, ethyl formate Esters, butyl formate, n-heptane, cyclohexane, dioxane, diethyl ether, methyl tert-butyl ether, ethylene glycol methyl ether, ethylene glycol dimethyl ether, water, acetonitrile, toluene, dichloromethane , chloroform, tetrahydrofuran and mixtures thereof; and/or
    优选地，其中在步骤a2)中，所述在室温下搅拌持续约3-7天；或者Preferably, wherein in step a2), the stirring at room temperature lasts for about 3-7 days; or
    所述方法包括：The methods include:
    b1)将化合物I加入良溶剂中，然后加入适当的碱，在固体溶清后过滤；b1) adding compound I to a good solvent, then adding an appropriate base, and filtering after the solid dissolves;
    b2)向步骤b1)中得到滤液中加入适当的酸，析出固体，得到所述晶型A；b2) adding an appropriate acid to the filtrate obtained in step b1), to precipitate a solid to obtain the crystal form A;
    优选地，其中所述良溶剂为水、异丙醚、正庚烷或甲苯；和/或Preferably, wherein said good solvent is water, isopropyl ether, n-heptane or toluene; and/or
    优选地，其中所述碱为乙醇胺；和/或Preferably, wherein the base is ethanolamine; and/or
    优选地，其中所述酸为盐酸、硫酸或磷酸。Preferably, wherein the acid is hydrochloric acid, sulfuric acid or phosphoric acid.
  9. 制备如权利要求2所述的晶型B的方法，其特征在于所述方法包括：The method for preparing the crystal form B as claimed in claim 2, characterized in that the method comprises:
    将化合物I与良溶剂混合，加热溶解后降温至室温，然后加入反溶剂，在室温下搅拌足够的时间，然后进行固液分离，干燥所得的固体，得到所述晶型B；Mix compound I with a good solvent, heat to dissolve, then cool down to room temperature, then add an anti-solvent, stir at room temperature for a sufficient time, then perform solid-liquid separation, and dry the obtained solid to obtain the crystal form B;
    优选地，其中所述良溶剂为DMF；和/或Preferably, wherein the good solvent is DMF; and/or
    优选地，其中所述反溶剂为甲苯；和/或Preferably, wherein the anti-solvent is toluene; and/or
    优选地，其中所述加热是加热至约50℃±2℃；和/或Preferably, wherein the heating is to about 50°C ± 2°C; and/or
    优选地，其中所述在室温下搅拌持续约1天；和/或Preferably, wherein said stirring at room temperature lasts for about 1 day; and/or
    优选地，其中所述干燥为在室温下真空干燥。Preferably, the drying is vacuum drying at room temperature.
  10. 制备如权利要求3所述的晶型C的方法，其特征在于，The method for preparing the crystal form C as claimed in claim 3, is characterized in that,
    所述方法包括：The methods include:
    将化合物I与DMF混合，加热溶解后降温至室温，然后加入氯仿并在室温下搅拌所得的悬浮液足够的时间，进行固液分离，干燥所得的固体，得到所述晶型C；Mix compound I with DMF, heat to dissolve, then cool down to room temperature, then add chloroform and stir the resulting suspension at room temperature for a sufficient time, perform solid-liquid separation, and dry the resulting solid to obtain the crystal form C;
    优选地，其中所述化合物I是如权利要求5所述的晶型E；Preferably, wherein said compound I is the crystal form E as claimed in claim 5;
    优选地，其中所述加热是加热至约40至60℃的温度，更优选约50℃±2℃；和/或Preferably, wherein said heating is to a temperature of about 40 to 60°C, more preferably about 50°C±2°C; and/or
    优选地，其中所述在室温下搅拌持续约1天；或者Preferably, wherein said stirring at room temperature lasts for about 1 day; or
    所述方法包括：The methods include:
    提供化合物I在乙腈中的悬浮液并在加热下搅拌足够的时间，然后进行固液分离，在室温下干燥所得的固体，得到所述晶型C；Provide a suspension of Compound I in acetonitrile and stir under heating for a sufficient time, then perform solid-liquid separation, and dry the resulting solid at room temperature to obtain the crystal form C;
    优选地，其中所述化合物I是如权利要求5所述的晶型E；Preferably, wherein said compound I is the crystal form E as claimed in claim 5;
    优选地，其中所述加热是加热至约40至60℃的温度，更优选约50℃±2℃；和/或Preferably, wherein said heating is to a temperature of about 40 to 60°C, more preferably about 50°C±2°C; and/or
    优选地，其中所述在室温下搅拌持续约1天；或者Preferably, wherein said stirring at room temperature lasts for about 1 day; or
    所述方法包括：The methods include:
    将化合物I加入到丙酮和水的混合溶剂中并在室温下悬浮足够的时间，过滤并干燥所得的固体，得到所述晶型C；Add compound I to a mixed solvent of acetone and water and suspend at room temperature for a sufficient time, filter and dry the resulting solid to obtain the crystal form C;
    优选地，其中所述化合物I是所述晶型E；和/或Preferably, wherein said compound I is said crystal form E; and/or
    优选地，其中所述悬浮持续约1天；Preferably, wherein said suspension lasts for about 1 day;
    或者or
    所述方法包括：The methods include:
    将化合物I加入到DMSO和异丙醇的混合溶剂中并在室温下悬浮足够的时间，过滤并干燥所得的固体，得到所述晶型C；Add compound I to a mixed solvent of DMSO and isopropanol and suspend at room temperature for a sufficient time, filter and dry the resulting solid to obtain the crystal form C;
    优选地，其中所述悬浮持续约7天。Preferably, wherein said suspension lasts for about 7 days.
  11. 制备如权利要求4所述的晶型D的方法，其特征在于，The method for preparing the crystal form D as claimed in claim 4, is characterized in that,
    所述方法包括：The methods include:
    将化合物I与DMSO混合，加热溶解后降温至室温，加入反溶剂，在室温下搅拌足够的时间，进行固液分离，然后干燥所得的固体，得到所述晶型D；Mix compound I with DMSO, heat to dissolve, then cool down to room temperature, add anti-solvent, stir at room temperature for a sufficient time, perform solid-liquid separation, and then dry the obtained solid to obtain the crystal form D;
    优选地，其中所述反溶剂为氯仿；和/或Preferably, wherein the anti-solvent is chloroform; and/or
    优选地，其中所述加热为加热至约50℃±2℃；和/或Preferably, wherein the heating is heating to about 50°C±2°C; and/or
    优选地，其中所述在室温下搅拌持续约1天；或者Preferably, wherein said stirring at room temperature lasts for about 1 day; or
    所述方法包括：The methods include:
    将化合物I加入反溶剂中，然后加入DMSO，加热溶解后降温析出固体，进行固液分离，在室温下干燥所得的固体，得到所述晶型D；Add compound I to the anti-solvent, then add DMSO, heat to dissolve, then cool down to precipitate a solid, perform solid-liquid separation, and dry the obtained solid at room temperature to obtain the crystal form D;
    优选地，其中所述反溶剂为水；和/或Preferably, wherein the anti-solvent is water; and/or
    优选地，其中所述加热是加热至约50℃±2℃；和/或Preferably, wherein the heating is to about 50°C ± 2°C; and/or
    优选地，其中所述降温是降温至约-15℃±2℃。Preferably, the temperature reduction is to reduce the temperature to about -15°C±2°C.
  12. 制备如权利要求5所述的晶型E的方法，其特征在于所述方法包括：The method for preparing the crystal form E as claimed in claim 5, characterized in that the method comprises:
    将化合物I与NMP混合，加热溶解后降温至室温，然后加入反溶剂，在室温下搅拌足够的时间，然后进行固液分离，干燥所得的固体，得到所述晶型E；Mix compound I with NMP, heat to dissolve, then cool down to room temperature, then add anti-solvent, stir at room temperature for a sufficient time, then perform solid-liquid separation, and dry the obtained solid to obtain the crystal form E;
    优选地，其中所述反溶剂选自氯仿、甲苯及其混合物；和/或Preferably, wherein the anti-solvent is selected from chloroform, toluene and mixtures thereof; and/or
    优选地，其中所述加热是加热至约50℃±2℃；和/或Preferably, wherein the heating is to about 50°C ± 2°C; and/or
    优选地，其中所述在室温下搅拌持续约1天。Preferably, wherein said stirring at room temperature lasts for about 1 day.
  13. 制备如权利要求6所述的晶型F的方法，其特征在于所述方法包括：The method for preparing the crystal form F as claimed in claim 6, characterized in that the method comprises:
    将化合物I与DMF混合，加热溶解后降温至室温，然后加入反溶剂，在室温下搅拌足够的时间，然后进行固液分离，干燥所得的固体，得到所述晶型F；Mix compound I with DMF, heat to dissolve, then cool down to room temperature, then add anti-solvent, stir at room temperature for a sufficient time, then perform solid-liquid separation, and dry the obtained solid to obtain the crystal form F;
    优选地，其中所述反溶剂为甲苯；和/或Preferably, wherein the anti-solvent is toluene; and/or
    优选地，其中所述加热为加热至约50℃±2℃；和/或Preferably, wherein the heating is heating to about 50°C±2°C; and/or
    优选地，其中所述在室温下搅拌持续约1天。Preferably, wherein said stirring at room temperature lasts for about 1 day.
  14. 制备如权利要求7所述的晶型G的方法，其特征在于所述方法包括：The method for preparing the crystal form G as claimed in claim 7, characterized in that the method comprises:
    将化合物I加入适当的溶剂中，在低温下搅拌足够的时间，然后进行固液分离，在室温下干燥所得的固体，得到所述晶型G；Add compound I into an appropriate solvent, stir at low temperature for a sufficient time, then separate solid from liquid, and dry the obtained solid at room temperature to obtain the crystal form G;
    优选地，其中所述化合物I是如权利要求2所述的晶型B；Preferably, wherein said compound I is the crystal form B as claimed in claim 2;
    优选地，其中所述适当的溶剂选自乙醇、水及其混合物；和/或Preferably, wherein said suitable solvent is selected from ethanol, water and mixtures thereof; and/or
    优选地，化合物I在所述悬浮液中的含量为约1-200 mg/ml；Preferably, the content of Compound I in said suspension is about 1-200 mg/ml;
    优选地，其中所述低温是约5至30℃的温度，更优选是约10℃±2℃；和/或Preferably, wherein said low temperature is a temperature of about 5 to 30°C, more preferably about 10°C ± 2°C; and/or
    优选地，其中所述在低温下搅拌持续约2天；和/或Preferably, wherein said stirring at low temperature lasts for about 2 days; and/or
    优选地，其中所述在室温下干燥是在室温下真空干燥。Preferably, wherein said drying at room temperature is vacuum drying at room temperature.
  15. 药物组合物，其包含有效量的选自如权利要求1所述的化合物I的晶型A、如权利要求2所述的化合物I的晶型B、如权利要求3所述的化合物I的晶型C、如权利要求4所述的化合物I的晶型D、如权利要求5所述的化合物I的晶型E、如权利要求6所述的化合物I的晶型F和如权利要求7所述的化合物I的晶型G中的任一种，以及A pharmaceutical composition comprising an effective amount selected from the crystal form A of compound I as claimed in claim 1, the crystal form B of compound I as claimed in claim 2, and the crystal form of compound I as claimed in claim 3 C, the crystal form D of compound I as claimed in claim 4, the crystal form E of compound I as claimed in claim 5, the crystal form F of compound I as claimed in claim 6, and the crystal form F of compound I as claimed in claim 7 Any of the crystal forms G of Compound I, and
    一种或多种药学上可接受的载体。One or more pharmaceutically acceptable carriers.
  16. 如权利要求1所述的化合物I的晶型A、如权利要求2所述的化合物I的晶型B、如权利要求3所述的化合物I的晶型C、如权利要求4所述的化合物I的晶型D、如权利要求5所述的化合物I的晶型E、如权利要求6所述的化合物I的晶型F、如权利要求7所述的化合物I的晶型G、或如权利要求15所述的药物组合物在制备用于肾功能监测的药物中的用途，其中所述肾功能检测是GFR监测，特别是实时GFR检测。The crystal form A of compound I as claimed in claim 1, the crystal form B of compound I as claimed in claim 2, the crystal form C of compound I as claimed in claim 3, the compound as claimed in claim 4 The crystal form D of I, the crystal form E of compound I as claimed in claim 5, the crystal form F of compound I as claimed in claim 6, the crystal form G of compound I as claimed in claim 7, or as The use of the pharmaceutical composition according to claim 15 in the preparation of a medicament for renal function monitoring, wherein the renal function detection is GFR monitoring, especially real-time GFR detection.
  17. 纯化化合物I的方法，A method of purifying compound I,
    Figure PCTCN2022115011-appb-100008
    Figure PCTCN2022115011-appb-100008
    其特征在于所述方法包括使化合物I从适当的溶剂中形成溶剂合物，其中所述溶剂优选为DMSO、NMP或DMF；It is characterized in that the method comprises forming a solvate of compound I from a suitable solvent, wherein said solvent is preferably DMSO, NMP or DMF;
    其中优选地，所述溶剂合物为如权利要求4所述的化合物I的晶型D、如权利要求5所述的化合物I的晶型E、或如权利要求6所述的化合物I的晶型F。Wherein preferably, the solvate is the crystal form D of compound I as claimed in claim 4, the crystal form E of compound I as claimed in claim 5, or the crystal form E of compound I as claimed in claim 6 Type F.
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