WO2023088457A1 - Solid form of benfotiamine derivative, and preparation method therefor and use thereof - Google Patents

Solid form of benfotiamine derivative, and preparation method therefor and use thereof Download PDF

Info

Publication number
WO2023088457A1
WO2023088457A1 PCT/CN2022/133152 CN2022133152W WO2023088457A1 WO 2023088457 A1 WO2023088457 A1 WO 2023088457A1 CN 2022133152 W CN2022133152 W CN 2022133152W WO 2023088457 A1 WO2023088457 A1 WO 2023088457A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
solvent
crystal form
solvents
Prior art date
Application number
PCT/CN2022/133152
Other languages
French (fr)
Chinese (zh)
Inventor
魏思源
张寰
Original Assignee
上海日馨医药科技股份有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 上海日馨医药科技股份有限公司 filed Critical 上海日馨医药科技股份有限公司
Publication of WO2023088457A1 publication Critical patent/WO2023088457A1/en

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6509—Six-membered rings
    • C07F9/6512—Six-membered rings having the nitrogen atoms in positions 1 and 3

Definitions

  • the present invention relates to (Z)-S-(2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamide)-5-(phosphonooxy)penta-2- Solid forms of en-3-yl) 2-fluorobenzenethiol esters (hereinafter referred to as "compounds of formula (I)"), processes for preparing said solid forms, pharmaceutical compositions comprising said solid forms, and The solid form is for use in the treatment of a disease.
  • Alzheimer's disease (commonly known as senile dementia, Alzheimer's disease, AD) is a progressive neurodegenerative disease with cognitive and behavioral disorders as the main clinical manifestations. Impairment of recognition ability and rapid decline of memory function.
  • the main pathophysiological features are the deposition of ⁇ -amyloid (A ⁇ ) in the brain to form senile plaques, the hyperphosphorylation of tau protein to form neurofibrillary tangles, the disturbance of brain glucose metabolism, and the loss of neurons/synapses. Due to the long course of the disease and poor self-care ability of patients, it brings serious mental and economic burdens to families and society. However, there is currently no drug that can prevent or delay the development of the disease in the world. The drugs currently on the market for the treatment of AD are only symptomatic drugs, which can only control or improve cognitive and functional symptoms for a period of time, but cannot prevent or delay the progression of the disease.
  • CN109111478A discloses a benfotiamine derivative and a preparation method thereof, whose inhibitory effect on A ⁇ 40 and A ⁇ 42 is significantly higher than that of benfotiamine.
  • One aspect of the present invention provides a compound of formula (I) shown below ((Z)-S-(2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamide )-5-(phosphonooxy)pent-2-en-3-yl)2-fluorobenzenethiol ester) in crystal form:
  • the preferred crystal form of the present invention has good stability, and the crystal form remains unchanged after storage under high temperature, high humidity or light conditions, which can meet the pharmaceutical requirements of production, transportation and storage.
  • the production process is stable, controllable and repeatable, and can Adapt to industrial production.
  • Another aspect of the present invention provides methods for preparing the crystals of the present invention, including but not limited to suspension stirring method, volatilization method, cooling method and gas-liquid infiltration method.
  • Another aspect of the present invention provides a pharmaceutical composition, which comprises any one or more crystalline forms of the present invention, and one or more pharmaceutically acceptable carriers.
  • Another aspect of the present invention provides the use of the crystalline form of the present invention in the preparation of a medicament for the prevention or treatment of vitamin B1 deficiency and metabolic-related disorders, psychiatric diseases and disorders, diabetes-related complications and/or neurodegenerative diseases .
  • Figure 1a is an X-ray powder diffraction (XRPD) pattern of an amorphous compound of formula (I).
  • Fig. 1b is the thermogravimetric analysis (TGA) figure of formula (I) compound amorphous
  • Fig. 1c is a differential scanning calorimetry (DSC) diagram of the amorphous compound of formula (I).
  • Fig. 1d is a hygroscopic analysis (DVS) diagram of the compound of formula (I) in an amorphous form.
  • Figure 2a is an X-ray powder diffraction pattern of Form A of the compound of formula (I).
  • Fig. 2b is a thermogravimetric analysis diagram of the crystal form A of the compound of formula (I).
  • Fig. 2c is a differential scanning calorimetry diagram of the crystal form A of the compound of formula (I).
  • Fig. 2d is a hygroscopicity analysis diagram of the crystal form A of the compound of formula (I).
  • Figure 3a is an X-ray powder diffraction pattern of Form B of the compound of formula (I).
  • Fig. 3b is a thermogravimetric analysis diagram of the crystal form B of the compound of formula (I).
  • Fig. 3c is a differential scanning calorimetry diagram of the crystal form B of the compound of formula (I).
  • Fig. 3d is a hygroscopicity analysis diagram of the crystal form B of the compound of formula (I).
  • Figure 4a is an X-ray powder diffraction pattern of Form C of the compound of formula (I).
  • Fig. 4b is a thermogravimetric analysis diagram of the crystal form C of the compound of formula (I).
  • Fig. 4c is a differential scanning calorimetry diagram of the crystal form C of the compound of formula (I).
  • Fig. 4d is a hygroscopicity analysis diagram of the crystal form C of the compound of formula (I).
  • Figure 5a is the X-ray powder diffraction pattern of the crystal form D of the compound of formula (I) prepared in Example 15.
  • Figure 5a-1 is the X-ray powder diffraction pattern of the crystal form D of the compound of formula (I) prepared in Example 18.
  • Figure 5a-2 is the X-ray powder diffraction pattern of the crystal form D of the compound of formula (I) prepared in Example 18-21.
  • Fig. 5b is a thermogravimetric analysis diagram of the crystal form D of the compound of formula (I).
  • Fig. 5c is a differential scanning calorimetry diagram of the crystal form D of the compound of formula (I).
  • Fig. 5d is a hygroscopicity analysis diagram of the crystal form D of the compound of formula (I).
  • Figure 6a is an X-ray powder diffraction pattern of Form E of the compound of formula (I).
  • Fig. 6b is a thermogravimetric analysis diagram of the crystal form E of the compound of formula (I).
  • Fig. 6c is a differential scanning calorimetry diagram of the crystal form E of the compound of formula (I).
  • Fig. 6d is a hygroscopicity analysis diagram of the crystal form E of the compound of formula (I).
  • Figure 7a is an X-ray powder diffraction pattern of Form F of the compound of formula (I).
  • Fig. 7b is a thermogravimetric analysis diagram of Form F of the compound of formula (I).
  • Fig. 7c is a differential scanning calorimetry diagram of Form F of the compound of formula (I).
  • Fig. 7d is a hygroscopicity analysis diagram of the crystal form F of the compound of formula (I).
  • Figure 8a is an X-ray powder diffraction pattern of Form G of the compound of formula (I).
  • Fig. 8b is a thermogravimetric analysis diagram of the crystal form G of the compound of formula (I).
  • Figure 8c is a differential scanning calorimetry diagram of Form G of the compound of formula (I).
  • Fig. 8d is a hygroscopicity analysis diagram of the crystal form G of the compound of formula (I).
  • Figure 9a is an X-ray powder diffraction pattern of Form H of the compound of formula (I).
  • Fig. 9b is a three-dimensional structure diagram of the crystal form H of the compound of formula (I).
  • Figure 10a is an X-ray powder diffraction pattern of Form I of the compound of formula (I).
  • Fig. 10b is a three-dimensional structure diagram of the crystal form I of the compound of formula (I).
  • Figure 11a is a comparison of the XRPD before and after the accelerated 15-day stability test of the compound of formula (I) (a represents the XRPD pattern before the test, and b represents the XRPD pattern after the test).
  • Figure 11b is an accelerated 15-day stability test XRPD comparison of compound crystal form A of formula (I) (wherein a represents the XRPD pattern before the start of the test, and b represents the XRPD pattern after the test).
  • Figure 11c is the XRPD comparison of the accelerated 15-day stability test of compound hydrate crystal form B of formula (I) (wherein a represents the XRPD pattern before the start of the test, and b represents the XRPD pattern after the test).
  • Figure 11d is the XRPD comparison of the accelerated 15-day stability test of compound crystal form C of formula (I) (wherein a represents the XRPD pattern before the start of the test, and b represents the XRPD pattern after the test).
  • Figure 11e is an accelerated 15-day stability test XRPD comparison of compound crystal form D of formula (I) (wherein a represents the XRPD pattern before the start of the test, and b represents the XRPD pattern after the test).
  • Figure 11f is the XRPD comparison of the accelerated 15-day stability test of the compound crystal form E of formula (I) (wherein a represents the XRPD pattern before the start of the test, and b represents the XRPD pattern after the test).
  • the word "about” means that one of ordinary skill in the art considers within an acceptable standard error of the stated value, such as ⁇ 0.05, ⁇ 0.1, ⁇ 0.2, ⁇ 0.3, ⁇ 1, ⁇ 2, or ⁇ 3 etc.
  • solid form includes all solid forms of the compounds of formula (I), such as crystalline or amorphous forms.
  • amorphous refers to any solid substance that is not ordered in three dimensions.
  • amorphous solids can be characterized by known techniques including XRPD crystallography, solid state nuclear magnetic resonance (ssNMR) spectroscopy, DSC, or some combination of these techniques. As explained below, amorphous solids give rise to diffuse XRPD patterns that typically include one or two broad peaks (ie, peaks with a base width of about 5° 2 ⁇ or greater).
  • crystalline form or “crystal” as used herein 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 refers to an experimentally observed diffraction pattern or parameters derived therefrom. XRPD patterns are usually characterized by peak positions (abscissa) and/or peak intensities (ordinate).
  • 2 ⁇ refers to the peak position in degrees based on the experimental setup of an X-ray diffraction experiment, and is generally a unit of abscissa in a diffraction pattern. If the reflections are diffracted when the incident beam forms an angle ⁇ with a certain lattice plane, the experimental setup requires recording the reflected beam at 2 ⁇ angles. It should be understood that references herein to specific 2 ⁇ values for particular crystalline forms are intended to represent 2 ⁇ values (expressed in degrees) as measured using the X-ray diffraction experimental conditions described herein. For example, as described herein, using Cu-K ⁇ (K ⁇ 1 1.540598 and K ⁇ 2 1.544426) as a radiation source.
  • DSC differential scanning calorimetry
  • the term "substantially the same" for X-ray diffraction peak positions means taking representative peak positions and intensity variations into account. For example, those skilled in the art will understand that peak position (2 ⁇ ) will show some variation, typically by as much as 0.1-0.2 degrees, and that the instrumentation used to measure diffraction will also show some variation. Additionally, those skilled in the art will appreciate that relative peak intensities will exhibit inter-instrument variation as well as variations due to degree of crystallinity, preferred orientation, prepared sample surface, and other factors known to those skilled in the art, and should be considered only for qualitative measurement. Similarly, as used herein, “substantially the same” with respect to a DSC profile is also intended to cover variations associated with these analytical techniques known to those skilled in the art. For example, differential scanning calorimetry profiles will typically have as much as ⁇ 0.2°C variation for well-defined peaks, and even greater (eg, as much as ⁇ 1°C) for broad peaks.
  • hydrocarbons as used herein preferably means hydrocarbons having 1-10 carbon atoms, including alkanes, halogenated alkanes, alkenes, alkynes and aromatics, specifically including but not limited to dichloro Methane, chloroform (chloroform), n-hexane, n-heptane, and toluene.
  • alcohols as used herein preferably means alcohols having 1-10 carbon atoms, including but not limited to methanol, ethanol, 1-propanol (n-propanol), 2-propanol (isopropanol alcohol), 1-butanol, 2-butanol and tert-butanol.
  • ether as used herein preferably means an ether having 2-6 carbon atoms, including chain ethers and cyclic ethers (such as furans (including tetrahydrofuran) and dioxane class), specifically including but not limited to diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, cyclopentyl methyl ether, anisole and dimethoxy ethane.
  • chain ethers and cyclic ethers such as furans (including tetrahydrofuran) and dioxane class
  • nitriles as used herein preferably means nitriles having 2-6 carbon atoms, including but not limited to acetonitrile and propionitrile.
  • ketone solvent preferably means a ketone having 2-6 carbon atoms, including but not limited to acetone, methyl ethyl ketone, methyl ethyl ketone, methyl isobutyl ketone and diethyl base ketones.
  • esters as used herein preferably means esters having 3-10 carbon atoms, including but not limited to ethyl acetate, propyl acetate, isopropyl acetate, ethyl isopropionate, dicarbonate methyl ester and butyl acetate.
  • the prepared salt or its crystalline form may be recovered by methods including decantation, centrifugation, evaporation, gravity filtration, suction filtration or any other technique for solid recovery under increased or reduced pressure.
  • the recovered solid can optionally be dried.
  • "Drying" in the present invention is carried out under reduced pressure (preferably vacuum) until the content of residual solvents is reduced to the limit given by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (“ICH”) guidelines within range.
  • the residual solvent content depends on the type of solvent, but does not exceed about 5000 ppm, or preferably about 4000 ppm, or more preferably about 3000 ppm.
  • the drying can be in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, etc. conduct.
  • the drying may be at atmospheric pressure or reduced pressure ( Preferably under vacuum) for any desired period of time (such as about 1, 2, 3, 5, 10, 15, 20, 24 hours or overnight) to achieve the desired result, provided the quality of the salt does not deteriorate.
  • the drying can be performed any desired number of times until the desired product quality is achieved.
  • the dried product can optionally be subjected to a comminution operation to produce the desired particle size. Grinding or micronization may be performed before drying of the product or after drying is complete. Techniques that can be used to reduce particle size include, but are not limited to, ball, roller, and hammer milling, and jet milling.
  • anhydrous crystal form as used herein preferably means a crystal form in which no water molecule is contained as a structural element.
  • the present invention provides the crystalline form A of the compound of formula (I), the XRPD pattern of the crystalline form A includes the crystal form A at about 11.9 ⁇ 0.2°, 12.3 ⁇ 0.2°, 12.7 ⁇ 0.2°, 18.5 ⁇ 0.2° , 18.8 ⁇ 0.2°, 25.5 ⁇ 0.2° and 26.2 ⁇ 0.2° diffraction angles (2 ⁇ ) at the characteristic peaks.
  • the present invention provides the crystalline form A of the compound of formula (I), the XRPD pattern of the crystalline form A includes the crystal form A at about 11.9 ⁇ 0.2°, 12.3 ⁇ 0.2°, 12.7 ⁇ 0.2°, 17.0 ⁇ 0.2° , 18.5 ⁇ 0.2°, 18.8 ⁇ 0.2°, 21.9 ⁇ 0.2°, 22.6 ⁇ 0.2°, 25.5 ⁇ 0.2°, 26.2 ⁇ 0.2° and 27.0 ⁇ 0.2° at diffraction angles (2 ⁇ ).
  • the XRPD pattern of the crystalline form A of the compound of formula (I) comprises a temperature range of about 11.7 ⁇ 0.2°, 11.9 ⁇ 0.2°, 12.3 ⁇ 0.2°, 12.7 ⁇ 0.2°, 13.3 ⁇ 0.2°, 14.8 ⁇ 0.2°, 16.0 ⁇ 0.2°, 17.0 ⁇ 0.2°, 17.3 ⁇ 0.2°, 17.5 ⁇ 0.2°, 18.5 ⁇ 0.2°, 18.8 ⁇ 0.2°, 19.6 ⁇ 0.2°, 21.9 ⁇ 0.2°, 22.6 ⁇ 0.2°, 23.0 ⁇ 0.2°, 24.9 ⁇ 0.2°, 25.5 ⁇ 0.2°, 26.2 ⁇ 0.2°, 26.4 ⁇ 0.2°, 27.0 ⁇ 0.2°, 28.8 ⁇ 0.2°, 30.3 ⁇ 0.2°, 32.4 ⁇ 0.2°, 34.8 ⁇ 0.2° and 36.8 Characteristic peaks at diffraction angles (2 ⁇ ) of ⁇ 0.2°.
  • the XRPD pattern of Form A of the compound of formula (I) includes characteristic peaks at substantially the same diffraction angle (2 ⁇ ) as shown in Figure 2a. In the most preferred embodiment, the XRPD pattern of Form A of the compound of formula (I) is substantially the same as that shown in Figure 2a.
  • the DSC spectrum of Form A of the compound of formula (I) of the present invention comprises endothermic peaks at about 92.6 ⁇ 0.2°C and about 144.0 ⁇ 0.2°C.
  • the DSC spectrum of Form A of the compound of formula (I) of the present invention comprises characteristic peaks at substantially the same temperature as shown in Figure 2c.
  • the DSC spectrum of Form A of the compound of formula (I) is substantially the same as that shown in Figure 2c.
  • the crystalline form A of the compound of formula (I) of the present invention has a weight loss of about 8.98% when heated to about 133 ⁇ 2° C. in thermogravimetric analysis.
  • the TGA pattern of Form A of the compound of formula (I) of the present invention is substantially the same as that shown in Figure 2b.
  • the crystal form A of the compound of formula (I) of the present invention is a solvate formed by the compound of formula (I) and nitromethane.
  • the present invention also provides a preparation method of Form A, which is a suspension stirring method, which comprises adding the compound of formula (I) into an organic solvent, stirring at 20-35°C, and then Filter to obtain Form A.
  • a suspension stirring method which comprises adding the compound of formula (I) into an organic solvent, stirring at 20-35°C, and then Filter to obtain Form A.
  • the organic solvent is nitromethane, or a mixed solvent of nitromethane and other organic solvents.
  • the other organic solvents are, for example, alcohols, hydrocarbons, ethers, esters, ketones or halogenated hydrocarbon solvents having 1-10 carbon atoms.
  • the alcohol solvent is, for example, isoamyl alcohol or methanol
  • the hydrocarbon solvent is, for example, n-hexane or n-heptane
  • the ether solvent is, for example, tetrahydrofuran or ether
  • the ester solvent is, for example, ethyl acetate or acetic acid Isopropyl ester
  • the ketone solvent is, for example, acetone, methyl ethyl ketone or methyl isobutyl ketone
  • the halogenated hydrocarbon solvent is, for example, methylene chloride.
  • the organic solvent is nitromethane or a mixed solvent of nitromethane and isoamyl alcohol. More preferably, the volume ratio of nitromethane to isoamyl alcohol in the mixed solvent is 1:1.
  • the stirring is performed at about 25°C.
  • the stirring is continued for about 24 hours.
  • the weight-to-volume ratio (mg/mL) of the compound of formula (I) to the organic solvent is (10-30):1, preferably about 20:1.
  • the present invention provides the crystalline form B of the compound of formula (I), the XRPD pattern of the crystalline form B comprises at about 6.2 ⁇ 0.2°, 12.5 ⁇ 0.2°, 16.0 ⁇ 0.2°, 18.8 ⁇ 0.2 °, 24.1 ⁇ 0.2°, 24.8 ⁇ 0.2° and 26.5 ⁇ 0.2° diffraction angles (2 ⁇ ) at the characteristic peaks.
  • the XRPD pattern of the crystalline form B of the compound of formula (I) comprises a temperature range of about 6.2 ⁇ 0.2°, 10.1 ⁇ 0.2°, 12.0 ⁇ 0.2°, 12.5 ⁇ 0.2°, 14.8 ⁇ 0.2°, 15.5 ⁇ 0.2°, 16.0 ⁇ 0.2°, 17.4 ⁇ 0.2°, 17.6 ⁇ 0.2°, 18.8 ⁇ 0.2°, 20.3 ⁇ 0.2°, 21.3 ⁇ 0.2°, 24.1 ⁇ 0.2°, 24.8 ⁇ 0.2°, 25.0 ⁇ 0.2°, 25.8 ⁇ 0.2°, 26.5 ⁇ 0.2°, 28.2 ⁇ 0.2°, 28.3 ⁇ 0.2°, 28.6 ⁇ 0.2°, 29.1 ⁇ 0.2°, 29.7 ⁇ 0.2°, 30.6 ⁇ 0.2° and 32.7 ⁇ 0.2° diffraction angles (2 ⁇ ) peak.
  • the XRPD pattern of Form B of the compound of formula (I) includes characteristic peaks at substantially the same diffraction angle (2 ⁇ ) as shown in Figure 3a. In the most preferred embodiment, the XRPD pattern of Form B of the compound of formula (I) is substantially the same as that shown in Figure 3a.
  • the DSC spectrum of Form B of the compound of formula (I) of the present invention comprises a characteristic peak at about 153.7 ⁇ 0.2°C.
  • the DSC profile of Form B of the compound of formula (I) of the present invention comprises characteristic peaks at substantially the same temperature as shown in Figure 3c.
  • the DSC spectrum of the crystalline form B of the compound of formula (I) is substantially the same as that shown in Figure 3c.
  • the crystalline form B of the compound of formula (I) of the present invention has a weight loss of about 1.52% when heated to about 71 ⁇ 2° C. There is a weight loss of 3.35% between 2°C.
  • the TGA pattern of Form B of the compound of formula (I) of the present invention is substantially the same as that shown in Figure 3b.
  • the crystal form B of the compound of formula (I) of the present invention is a hydrate.
  • the present invention also provides a preparation method of Form B, which includes but not limited to: suspension stirring method, volatilization method, cooling method and gas-liquid infiltration method.
  • the method is a suspension stirring method, which comprises adding the compound of formula (I) into a solvent, stirring at 20-80°C, and then filtering it to obtain Form B.
  • the solvent is selected from water, alcohol solvents having 1-10 carbon atoms (such as methanol, ethanol, isopropanol, isoamyl alcohol, etc.), ether solvents (such as diethyl ether, etc.), ketones solvents (such as acetone, methyl ethyl ketone, methyl isobutyl ketone, etc.), aromatic hydrocarbon solvents (such as toluene, etc.), halogenated hydrocarbon solvents (such as chloroform, etc.), or their mixed solvents.
  • alcohol solvents having 1-10 carbon atoms such as methanol, ethanol, isopropanol, isoamyl alcohol, etc.
  • ether solvents such as diethyl ether, etc.
  • ketones solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone, etc.
  • aromatic hydrocarbon solvents such as toluene, etc.
  • the solvent is one or more of water, isopropanol, ethanol, acetone and ether.
  • the solvent is a mixed solvent of ethanol and ether, wherein the volume ratio of ethanol and ether is preferably 1:1.
  • the solvent is a mixed solvent of ethanol and acetone, wherein the volume ratio of ethanol to acetone is preferably 1:1.
  • the solvent is water.
  • the stirring is performed at 20-60°C. More preferably, the stirring is performed at about 25°C or about 50°C.
  • said agitation is continued for about 24 hours.
  • the weight-to-volume ratio (mg/mL) of the compound of formula (I) to the solvent is (10-30):1, preferably about 20:1.
  • the volatilization method includes adding the compound of formula (I) into a solvent, mixing, and dissolving; volatilizing at 20° C. to 60° C. until solids are precipitated, and filtering to collect the solids.
  • the solvent in the volatilization method is selected from water and alcohol solvents (such as methanol, ethanol, isoamyl alcohol, etc.) with 1-10 carbon atoms, or their mixed solvents; preferably, The solvent is water or a mixed solvent of methanol and water (the volume ratio of methanol to water is preferably about 1:1).
  • alcohol solvents such as methanol, ethanol, isoamyl alcohol, etc.
  • the solvent is water or a mixed solvent of methanol and water (the volume ratio of methanol to water is preferably about 1:1).
  • the volatilization is performed at about 25°C or about 50°C.
  • the weight-to-volume ratio (mg/mL) of the compound of formula (I) to the solvent is (5-30):1, preferably about 10:1.
  • the cooling method comprises adding the compound of formula (I) into a solvent (preferably water), heating (preferably heating to 50-80°C, most preferably about 70°C) to completely dissolve the compound, Cool to crystallize and filter to collect the solid.
  • a solvent preferably water
  • heating preferably heating to 50-80°C, most preferably about 70°C
  • the weight-to-volume ratio (mg/mL) of the compound of formula (I) to the solvent is (5-30):1, preferably about 8:1.
  • the gas-liquid osmosis method comprises dissolving the compound of formula (I) in a good solvent in a first container, loading an anti-solvent into a second container, and placing the first container open in the second container. In the container, the second container was sealed and left to stand, and the precipitated solid was filtered to obtain crystals.
  • the good solvent in the gas-liquid infiltration method is a halogenated hydrocarbon solvent with 1-10 carbon atoms, such as chloroform, etc.;
  • the anti-solvent is a hydrocarbon with 5-10 carbon atoms Solvents, such as n-hexane, n-heptane, petroleum ether, etc.
  • the weight-to-volume ratio (mg/mL) of the compound of formula (I) to the good solvent is about (1-10):1.
  • the volume ratio of the good solvent to the anti-solvent is 1:(1-10).
  • said sealing and standing of the second container may be performed at room temperature.
  • the present invention provides crystalline form C of the compound of formula (I), the XRPD pattern of said crystalline form C comprises at about 10.8 ⁇ 0.2°, 14.3 ⁇ 0.2°, 16.9 ⁇ 0.2°, 18.0 ⁇ 0.2 The characteristic peaks at the diffraction angles (2 ⁇ ) of 18.5 ⁇ 0.2°, 24.8 ⁇ 0.2° and 25.3 ⁇ 0.2°.
  • the present invention provides crystalline form C of the compound of formula (I), the XRPD pattern of said crystalline form C comprises at about 10.8 ⁇ 0.2°, 12.7 ⁇ 0.2°, 14.0 ⁇ 0.2°, 14.3 ⁇ 0.2 °, 15.6 ⁇ 0.2°, 16.9 ⁇ 0.2°, 18.0 ⁇ 0.2°, 18.5 ⁇ 0.2°, 20.0 ⁇ 0.2°, 24.0 ⁇ 0.2°, 24.8 ⁇ 0.2°, 25.3 ⁇ 0.2° and 26.5 ⁇ 0.2° The characteristic peak at 2 ⁇ ).
  • the XRPD pattern of the crystalline form C of the compound of formula (I) comprises a temperature range of about 10.8 ⁇ 0.2°, 12.7 ⁇ 0.2°, 14.0 ⁇ 0.2°, 14.3 ⁇ 0.2°, 15.6 ⁇ 0.2°, 16.5 ⁇ 0.2°, 16.9 ⁇ 0.2°, 18.0 ⁇ 0.2°, 18.5 ⁇ 0.2°, 20.0 ⁇ 0.2°, 21.9 ⁇ 0.2°, 22.4 ⁇ 0.2°, 23.2 ⁇ 0.2°, 24.0 ⁇ 0.2°, 24.8 ⁇ 0.2°, 25.3 Characteristic peaks at diffraction angles (2 ⁇ ) of ⁇ 0.2°, 25.9 ⁇ 0.2°, 26.5 ⁇ 0.2°, 28.4 ⁇ 0.2°, 29.5 ⁇ 0.2° and 35.2 ⁇ 0.2°.
  • the XRPD pattern of Form C of the compound of formula (I) includes characteristic peaks at substantially the same diffraction angle (2 ⁇ ) as shown in Figure 4a. In the most preferred embodiment, the XRPD pattern of Form C of the compound of formula (I) is substantially the same as that shown in Figure 4a.
  • the DSC spectrum of Form C of the compound of formula (I) of the present invention comprises a characteristic peak at about 197.6 ⁇ 0.2°C.
  • the DSC spectrum of Form C of the compound of formula (I) of the present invention comprises characteristic peaks at substantially the same temperature as shown in Figure 4c.
  • the DSC spectrum of Form C of the compound of formula (I) is substantially the same as that shown in Figure 4c.
  • the TGA spectrum of Form C of the compound of formula (I) of the present invention is substantially the same as that shown in Figure 4b.
  • the crystal form C of the compound of formula (I) of the present invention is non-hydrate, non-solvate.
  • the present invention also provides a preparation method of Form C, which is a suspension stirring method, which comprises adding the compound of formula (I) into a solvent, stirring at 20-60°C, and then filtering it , to obtain crystals.
  • a suspension stirring method which comprises adding the compound of formula (I) into a solvent, stirring at 20-60°C, and then filtering it , to obtain crystals.
  • the solvent is a ketone solvent with 1-10 carbon atoms (such as acetone, methyl ethyl ketone, methyl isobutyl ketone, etc.), a nitrile solvent (such as acetonitrile, etc.), an ester solvent (such as ethyl acetate, isopropyl acetate, etc.), ether solvents (such as methyl tert-butyl ether, diethyl ether, tetrahydrofuran, etc.), alcohol solvents (such as methanol, ethanol, isoamyl alcohol, etc.), halogenated hydrocarbon solvents (such as dichloromethane or chloroform), or their mixed solvents.
  • a ketone solvent with 1-10 carbon atoms such as acetone, methyl ethyl ketone, methyl isobutyl ketone, etc.
  • a nitrile solvent such as acetonitrile, etc.
  • the solvent is acetone, or a mixed solvent of chloroform and isoamyl alcohol (the volume ratio is preferably 1:1).
  • the stirring is performed at 20-50°C. More preferably, the stirring is performed at about 25°C or about 50°C.
  • the stirring is continued for about 24 hours.
  • the weight-to-volume ratio (mg/mL) of the compound of formula (I) to the solvent is (10-30):1, preferably about 20:1.
  • the present invention provides the crystal form D of the compound of formula (I), the XRPD spectrum of the crystal form D comprises the temperature at about 9.0 ⁇ 0.2°, 11.4 ⁇ 0.2°, 16.7 ⁇ 0.2°, 18.6 ⁇ 0.2 °, 24.6 ⁇ 0.2°, 25.7 ⁇ 0.2° and 27.2 ⁇ 0.2° diffraction angles (2 ⁇ ) at the characteristic peaks.
  • the present invention provides the crystal form D of the compound of formula (I), and the XRPD pattern of the crystal form D includes the crystal form D at about 9.0 ⁇ 0.2°, 11.4 ⁇ 0.2°, 15.0 ⁇ 0.2°, 16.7 ⁇ 0.2 °, 18.6 ⁇ 0.2°, 19.6 ⁇ 0.2°, 24.6 ⁇ 0.2°, 25.7 ⁇ 0.2° and 27.2 ⁇ 0.2° diffraction angles (2 ⁇ ).
  • the present invention provides the crystal form D of the compound of formula (I), and the XRPD pattern of the crystal form D includes the crystal form D at about 9.0 ⁇ 0.2°, 11.4 ⁇ 0.2°, 15.0 ⁇ 0.2°, 16.7 ⁇ 0.2 Features at diffraction angles (2 ⁇ ) of °, 18.6 ⁇ 0.2°, 19.6 ⁇ 0.2°, 21.2 ⁇ 0.2°, 22.6 ⁇ 0.2°, 24.6 ⁇ 0.2°, 25.7 ⁇ 0.2°, 27.2 ⁇ 0.2° and 28.9 ⁇ 0.2° peak.
  • the XRPD pattern of the crystalline form D of the compound of formula (I) comprises a temperature range of about 9.0 ⁇ 0.2°, 11.4 ⁇ 0.2°, 15.0 ⁇ 0.2°, 16.7 ⁇ 0.2°, 17.6 ⁇ 0.2°, 18.6 ⁇ 0.2°, 19.6 ⁇ 0.2°, 20.0 ⁇ 0.2°, 21.2 ⁇ 0.2°, 21.8 ⁇ 0.2°, 22.6 ⁇ 0.2°, 24.6 ⁇ 0.2°, 25.7 ⁇ 0.2°, 26.7 ⁇ 0.2°, 27.2 ⁇ 0.2°, 28.9 Characteristic peaks at diffraction angles (2 ⁇ ) of ⁇ 0.2° and 31.5 ⁇ 0.2°.
  • the XRPD pattern of the crystalline form D of the compound of formula (I) includes characteristic peaks at substantially the same diffraction angle (2 ⁇ ) as shown in Figure 5a. In the most preferred embodiment, the XRPD pattern of Form D of the compound of formula (I) is substantially the same as that shown in Figure 5a.
  • the XRPD pattern of the crystalline form D of the compound of formula (I) includes characteristic peaks at substantially the same diffraction angle (2 ⁇ ) as shown in Figure 5a-1. In the most preferred embodiment, the XRPD pattern of the crystalline form D of the compound of formula (I) is substantially the same as that shown in Figure 5a-1.
  • the DSC spectrum of Form D of the compound of formula (I) of the present invention comprises a characteristic peak at about 163.6 ⁇ 0.2°C.
  • the DSC spectrum of Form D of the compound of formula (I) of the present invention comprises characteristic peaks at substantially the same temperature as shown in Figure 5c.
  • the DSC spectrum of the crystalline form D of the compound of formula (I) is substantially the same as that shown in Figure 5c.
  • the crystal form D of the compound of formula (I) of the present invention is a hydrate with a water content of 4.8%-5.7%.
  • the crystal form D of the compound of formula (I) of the present invention is a sesquihydrate.
  • the present invention also provides a preparation method of Form D, which includes but not limited to: suspension stirring method and volatilization method.
  • the method is a suspension stirring method, which comprises adding the compound of formula (I) into a solvent, stirring at 20-80°C, and then filtering it to obtain Form D.
  • the solvent is selected from water, alcoholic solvents having 1-10 carbon atoms (such as methanol, ethanol, isopropanol, isoamyl alcohol, etc.), halogenated hydrocarbon solvents (such as chloroform, etc.) , or their mixed solvents.
  • alcoholic solvents having 1-10 carbon atoms such as methanol, ethanol, isopropanol, isoamyl alcohol, etc.
  • halogenated hydrocarbon solvents such as chloroform, etc.
  • the solvent is ethanol; isoamyl alcohol; a mixed solvent of ethanol and water; or a mixed solvent of isoamyl alcohol and water.
  • the volume ratio of ethanol to water in the mixed solvent is 7:1. More preferably, the volume ratio of isoamyl alcohol to water in the mixed solvent is 7:1.
  • the stirring is performed at 20-60°C. More preferably, the stirring is performed at about 25°C or about 50°C.
  • the stirring is continued for about 24 hours.
  • the weight-to-volume ratio (mg/mL) of the compound of formula (I) to the solvent is (10-60):1, preferably about 20:1 or about 50:1.
  • the volatilization method includes adding the compound of formula (I) into a solvent, mixing, and dissolving; volatilizing at 20° C. to 60° C. until solids are precipitated, and filtering to collect the solids.
  • the solvent in the volatilization method is selected from water and ketone solvents (such as acetone or methyl ethyl ketone, etc.) with 1-10 carbon atoms, or their mixed solvents; preferably, the solvent is A mixed solvent of methyl ethyl ketone and water (the volume ratio of methyl ethyl ketone to water is preferably about 1:1).
  • said volatilization is performed at 25°C.
  • the weight-to-volume ratio (mg/mL) of the compound of formula (I) to the solvent is (5-30):1, preferably about 10:1.
  • the present invention provides the crystalline form E of the compound of formula (I), the XRPD spectrum of said crystalline form E comprises the temperature at about 9.3 ⁇ 0.2°, 11.9 ⁇ 0.2°, 12.6 ⁇ 0.2°, 14.4 ⁇ 0.2 The characteristic peaks at the diffraction angles (2 ⁇ ) of 17.2 ⁇ 0.2°, 18.9 ⁇ 0.2° and 24.9 ⁇ 0.2°.
  • the present invention provides the crystalline form E of the compound of formula (I), the XRPD pattern of the crystalline form E includes the crystal form E at about 9.3 ⁇ 0.2°, 11.9 ⁇ 0.2°, 12.6 ⁇ 0.2°, 13.2 ⁇ 0.2 °, 14.4 ⁇ 0.2°, 15.1 ⁇ 0.2°, 15.6 ⁇ 0.2°, 17.2 ⁇ 0.2°, 18.1 ⁇ 0.2°, 18.9 ⁇ 0.2°, 19.5 ⁇ 0.2°, 21.2 ⁇ 0.2°, 23.7 ⁇ 0.2°, 24.3 ⁇ 0.2 °, 24.9 ⁇ 0.2°, 26.3 ⁇ 0.2° and 27.0 ⁇ 0.2° diffraction angles (2 ⁇ ) at the characteristic peaks.
  • the XRPD pattern of the crystalline form E of the compound of formula (I) comprises a temperature range of about 9.3 ⁇ 0.2°, 10.4 ⁇ 0.2°, 11.9 ⁇ 0.2°, 12.6 ⁇ 0.2°, 13.2 ⁇ 0.2°, 14.4 ⁇ 0.2°, 15.1 ⁇ 0.2°, 15.6 ⁇ 0.2°, 16.9 ⁇ 0.2°, 17.2 ⁇ 0.2°, 18.1 ⁇ 0.2°, 18.6 ⁇ 0.2°, 18.9 ⁇ 0.2°, 19.5 ⁇ 0.2°, 21.2 ⁇ 0.2°, 21.6 ⁇ 0.2°, 22.0 ⁇ 0.2°, 23.7 ⁇ 0.2°, 24.3 ⁇ 0.2°, 24.9 ⁇ 0.2°, 25.2 ⁇ 0.2°, 26.0 ⁇ 0.2°, 26.3 ⁇ 0.2°, 27.0 ⁇ 0.2°, 28.1 ⁇ 0.2°, 31.5 Characteristic peaks at diffraction angles (2 ⁇ ) of ⁇ 0.2° and 34.2 ⁇ 0.2°.
  • the XRPD pattern of Form E of the compound of formula (I) includes characteristic peaks at substantially the same diffraction angle (2 ⁇ ) as shown in Figure 6a. In the most preferred embodiment, the XRPD pattern of Form E of the compound of formula (I) is substantially the same as that shown in Figure 6a.
  • the DSC spectrum of Form E of the compound of formula (I) of the present invention comprises a characteristic peak at about 201.8 ⁇ 0.2°C.
  • the DSC spectrum of Form E of the compound of formula (I) of the present invention comprises characteristic peaks at substantially the same temperature as shown in Figure 6c.
  • the DSC spectrum of Form E of the compound of formula (I) is substantially the same as that shown in Figure 6c.
  • the crystal form E of the compound of formula (I) of the present invention is non-hydrate, non-solvate.
  • the present invention also provides a preparation method of Form E, which is a suspension stirring method, which comprises adding the compound of formula (I) into an organic solvent, stirring at 40-60°C, and then Filter to obtain Form E.
  • a suspension stirring method which comprises adding the compound of formula (I) into an organic solvent, stirring at 40-60°C, and then Filter to obtain Form E.
  • the organic solvent is selected from nitromethane, or a mixed solvent of nitromethane and other organic solvents.
  • the other organic solvents are, for example, alcohols, ethers, esters, ketones or halogenated hydrocarbon solvents having 1-10 carbon atoms.
  • the alcohol solvent is, for example, isoamyl alcohol or methanol
  • the ether solvent is, for example, tetrahydrofuran or ether
  • the ester solvent is, for example, ethyl acetate
  • the ketone solvent is, for example, acetone, methyl ethyl ketone or methyl isobutyl base ketone
  • the halogenated hydrocarbon solvent is, for example, dichloromethane.
  • the stirring is performed at about 50°C.
  • the stirring is continued for about 24 hours.
  • the weight-to-volume ratio (mg/mL) of the compound of formula (I) to the organic solvent is (10-30):1, preferably about 20:1.
  • the present invention provides the crystalline form F of the compound of formula (I), the XRPD spectrum of the crystalline form F comprises the temperature at about 8.9 ⁇ 0.2°, 11.3 ⁇ 0.2°, 14.8 ⁇ 0.2°, 15.2 ⁇ 0.2 °, 16.1 ⁇ 0.2°, 16.4 ⁇ 0.2°, 17.8 ⁇ 0.2°, 18.6 ⁇ 0.2°, 19.4 ⁇ 0.2°, 20.8 ⁇ 0.2°, 21.3 ⁇ 0.2°, 24.8 ⁇ 0.2° and 27.4 ⁇ 0.2° The characteristic peak at 2 ⁇ ).
  • the XRPD pattern of Form F of the compound of formula (I) includes about 6.4 ⁇ 0.2°, 8.9 ⁇ 0.2°, 10.8 ⁇ 0.2°, 11.3 ⁇ 0.2°, 13.6 ⁇ 0.2°, 14.8 ⁇ 0.2° 0.2°, 15.2 ⁇ 0.2°, 15.7 ⁇ 0.2°, 16.1 ⁇ 0.2°, 16.4 ⁇ 0.2°, 17.0 ⁇ 0.2°, 17.8 ⁇ 0.2°, 18.6 ⁇ 0.2°, 19.4 ⁇ 0.2°, 19.9 ⁇ 0.2°, 20.8 ⁇ 0.2°, 21.3 ⁇ 0.2°, 21.8 ⁇ 0.2°, 22.5 ⁇ 0.2°, 23.4 ⁇ 0.2°, 23.9 ⁇ 0.2°, 24.8 ⁇ 0.2°, 27.4 ⁇ 0.2°, 28.1 ⁇ 0.2°, 28.7 ⁇ 0.2°, 30.1 ⁇ Peaks at diffraction angles (2 ⁇ ) of 0.2° and 32.6 ⁇ 0.2°.
  • the XRPD pattern of Form F of the compound of formula (I) includes characteristic peaks at substantially the same diffraction angle (2 ⁇ ) as shown in Figure 7a. In the most preferred embodiment, the XRPD pattern of Form F of the compound of formula (I) is substantially the same as that shown in Figure 7a.
  • the DSC spectrum of Form F of the compound of formula (I) of the present invention comprises a characteristic peak at about 153.9 ⁇ 0.2°C.
  • the DSC spectrum of Form F of the compound of formula (I) of the present invention comprises characteristic peaks at substantially the same temperature as shown in Figure 7c.
  • the DSC spectrum of Form F of the compound of formula (I) is substantially the same as that shown in Figure 7c.
  • the crystal form F of the compound of formula (I) of the present invention is a hydrate.
  • the present invention also provides a preparation method of Form F, which includes but not limited to: suspension stirring method and volatilization method.
  • the method is a suspension stirring method, which comprises adding the compound of formula (I) into a solvent, stirring at 20-80°C, and then filtering it to obtain Form F.
  • the solvent is selected from water, alcohol solvents having 1-10 carbon atoms (such as methanol, ethanol, isopropanol, isoamyl alcohol, etc.), ether solvents (such as diethyl ether, etc.), ketones solvents (such as methyl ethyl ketone, methyl isobutyl ketone, etc.), aromatic hydrocarbon solvents (such as toluene, etc.), halogenated hydrocarbon solvents (such as chloroform, etc.), or their mixed solvents.
  • alcohol solvents having 1-10 carbon atoms such as methanol, ethanol, isopropanol, isoamyl alcohol, etc.
  • ether solvents such as diethyl ether, etc.
  • ketones solvents such as methyl ethyl ketone, methyl isobutyl ketone, etc.
  • aromatic hydrocarbon solvents such as toluene, etc.
  • halogenated hydrocarbon solvents such as chloroform, etc
  • the solvent is chloroform or a mixed solvent of methanol and ethanol.
  • the volume ratio of methanol to ethanol in the mixed solvent is 1:1.
  • the stirring is performed at 20-60°C. More preferably, the stirring is performed at about 25°C or about 50°C.
  • the stirring is continued for about 24 hours.
  • the weight-to-volume ratio (mg/mL) of the compound of formula (I) to the solvent is (10-30):1, preferably about 20:1.
  • the volatilization method includes adding the compound of formula (I) into a solvent, mixing, and dissolving; volatilizing at 20° C. to 60° C. until solids are precipitated, and filtering to collect the solids.
  • the solvent in the volatilization method is selected from water and alcohol solvents (such as methanol, ethanol, isoamyl alcohol, etc.) with 1-10 carbon atoms, or their mixed solvents; preferably, The solvent is a mixed solvent of isoamyl alcohol and water (the volume ratio of isoamyl alcohol to water is preferably about 1:7).
  • alcohol solvents such as methanol, ethanol, isoamyl alcohol, etc.
  • the solvent is a mixed solvent of isoamyl alcohol and water (the volume ratio of isoamyl alcohol to water is preferably about 1:7).
  • said volatilization is carried out at 25°C or 50°C, more preferably at 50°C.
  • the weight-to-volume ratio (mg/mL) of the compound of formula (I) to the solvent is (5-30):1, preferably about 10:1.
  • the present invention provides the crystalline form G of the compound of formula (I), the XRPD pattern of the crystalline form G includes the crystal form G at about 7.0 ⁇ 0.2°, 12.2 ⁇ 0.2°, 12.6 ⁇ 0.2°, 15.4 ⁇ 0.2 °, 20.7 ⁇ 0.2°, 21.3 ⁇ 0.2° and 27.8 ⁇ 0.2° diffraction angles (2 ⁇ ) at the characteristic peaks.
  • the XRPD pattern of the crystalline form G of the compound of formula (I) comprises a temperature range of about 7.0 ⁇ 0.2°, 10.3 ⁇ 0.2°, 12.2 ⁇ 0.2°, 12.6 ⁇ 0.2°, 15.4 ⁇ 0.2°, 16.1 Peaks at diffraction angles (2 ⁇ ) of ⁇ 0.2°, 19.1 ⁇ 0.2°, 19.6 ⁇ 0.2°, 20.7 ⁇ 0.2°, 21.3 ⁇ 0.2°, 26.7 ⁇ 0.2°, 27.8 ⁇ 0.2° and 28.6 ⁇ 0.2°.
  • the XRPD pattern of Form G of the compound of formula (I) includes characteristic peaks at substantially the same diffraction angle (2 ⁇ ) as shown in Figure 8a. In the most preferred embodiment, the XRPD pattern of Form G of the compound of formula (I) is substantially the same as that shown in Figure 8a.
  • the DSC spectrum of Form G of the compound of formula (I) of the present invention comprises a characteristic peak at about 182.5 ⁇ 0.2°C.
  • the DSC spectrum of Form G of the compound of formula (I) of the present invention comprises characteristic peaks at substantially the same temperature as shown in Figure 8c.
  • the DSC spectrum of Form G of the compound of formula (I) is substantially the same as that shown in Figure 8c.
  • the crystal form G of the compound of formula (I) of the present invention is a solvate of methanol.
  • the present invention also provides a method for the preparation of Form G, which is a gas-liquid infiltration method, which comprises dissolving the compound of formula (I) in a good solvent in a first container, and injecting it into a second container The anti-solvent is charged, the first container is opened and placed in the second container, the second container is sealed and left standing, and the precipitated solid is filtered to obtain crystals.
  • a gas-liquid infiltration method which comprises dissolving the compound of formula (I) in a good solvent in a first container, and injecting it into a second container
  • the anti-solvent is charged, the first container is opened and placed in the second container, the second container is sealed and left standing, and the precipitated solid is filtered to obtain crystals.
  • the good solvent in the gas-liquid osmosis method is methanol; the anti-solvent is ethanol.
  • the weight-to-volume ratio (mg/mL) of the compound of formula (I) to the good solvent is about (1-10):1.
  • the volume ratio of the good solvent to the anti-solvent is 1:(1-10).
  • said sealing and standing of the second container may be performed at room temperature.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising Form A, Form B, Form C, Form D, Form E, Form F and Any one or more of the crystal forms G, and one or more pharmaceutically acceptable carriers.
  • the present invention provides crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E, crystalline form F and crystalline form G of the compound of formula (I) of the present invention for the preparation Use in medicines for preventing or treating vitamin B1 deficiency and metabolic-related disorders, mental diseases and disorders, diabetes-related complications and/or neurodegenerative diseases.
  • the present invention provides crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E, crystalline form F and crystalline form G of the compound of formula (I) of the present invention, which is used For the prevention or treatment of vitamin B1 deficiency and metabolic related disorders, psychiatric diseases and disorders, diabetes related complications and/or neurodegenerative diseases.
  • the present invention provides a method of preventing or treating vitamin B1 deficiency and metabolic related disorders, psychiatric diseases and disorders, diabetes related complications and/or neurodegenerative diseases comprising administering to an individual in need thereof ( Preferable mammal) administration of prophylactically or therapeutically effective amount of the compound of formula (I) of the present invention in crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, crystal form F and crystal form G any one or more of.
  • said neurodegenerative disease is selected from Alzheimer's disease, vascular dementia and mental disorders.
  • pharmaceutically acceptable carrier refers to a diluent, adjuvant, excipient or vehicle with which a therapeutic agent is administered, and which is within the scope of sound medical judgment suitable for contacting Human and/or other animal tissues without undue toxicity, irritation, allergic response or other problems or complications commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of this invention include, but are not limited to, sterile liquids such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. Physiological saline and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injections.
  • Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene glycol, water, ethanol etc.
  • the composition if desired, can also contain minor amounts of wetting agents, emulsifying agents, or pH buffering agents.
  • Oral formulations can contain standard carriers, such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).
  • compositions of the invention may act systemically and/or locally.
  • they can be administered by suitable routes, for example by injection, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or transdermal administration; or by oral, buccal, nasal, transmucosal, topical, It is administered as an ophthalmic preparation or by inhalation.
  • compositions of the present invention can be administered in suitable dosage forms.
  • the dosage forms can be solid preparations, semi-solid preparations, liquid preparations or gaseous preparations, specifically including but not limited to tablets, capsules, powders, granules, lozenges, hard candies, powders, sprays, creams, ointments elixirs, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, suspensions, elixirs, syrups.
  • the pharmaceutical composition of the present invention can be prepared by any method well known in the art, for example, by mixing, dissolving, granulating, sugar coating, milling, emulsifying, freeze-drying and other treatments.
  • terapéuticaally effective amount refers to the amount of a compound which, when administered, alleviates to some extent one or more symptoms of the condition being treated.
  • Dosage regimens may be adjusted to provide the optimum desired response. For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated and may comprise single or multiple doses. It is further understood that for any given individual, the specific dosing regimen will be adjusted over time according to the needs of the individual and the professional judgment of the person administering the composition or supervising the administration of the composition.
  • the amount of a compound of this invention administered will depend on the individual being treated, the severity of the disorder or condition, the rate of administration, disposition of the compound, and the judgment of the prescribing physician.
  • the effective dosage is about 0.0001 to about 50 mg per kg body weight per day, for example about 0.01 to about 10 mg/kg/day (single or divided administration). For a 70 kg human this would amount to about 0.007 mg/day to about 3500 mg/day, eg about 0.7 mg/day to about 700 mg/day.
  • Dosage levels up to the lower limit of the foregoing range may be sufficient in some cases, while in other cases larger doses may still be employed without causing any deleterious side effects, provided that the larger dose is first administered.
  • the dose is divided into several smaller doses to be administered throughout the day.
  • the content or amount of the compound of the present invention in the pharmaceutical composition can be about 0.01 mg to about 1000 mg, suitably 0.1-500 mg, preferably 0.5-300 mg, more preferably 1-150 mg, particularly preferably 1-50 mg, such as 1.5 mg, 2mg, 4mg, 10mg and 25mg etc.
  • treating means reversing, alleviating, inhibiting the disorder or condition to which such term applies or the progression of one or more symptoms of such disorder or condition, or Such a disorder or condition or one or more symptoms of such a disorder or condition is prevented.
  • “Individual” as used herein includes a human or non-human animal.
  • Exemplary human subjects include human subjects suffering from a disease (eg, a disease described herein) (referred to as a patient) or normal subjects.
  • Non-human animals in the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (e.g., sheep, dogs, , cats, cows, pigs, etc.).
  • X-ray powder diffraction (XRPD): Instrument model: Bruker D8advance, target: Cu K ⁇ (40kV, 40mA), distance from sample to detector: 30cm, scanning range: 3°-40° (2 ⁇ value), scanning step: 0.1 s.
  • Instrument model Rigaku Smart Lab 9KW, target: Cu K ⁇ (40kV, 100mA), distance from sample to detector: 30cm, scanning range: 3°-50° (2 ⁇ value), scanning step: 0.02°.
  • TGA Thermogravimetric analysis
  • DSC Differential scanning calorimetry
  • the compound of formula (I) was prepared according to the preparation method disclosed in Example 9 of CN109111478A.
  • Thiamine phosphate 1a (38g, 0.09mol) was dissolved in water (103g, 5.7mol), cooled to 0-5°C, and 30% sodium hydroxide solution (87.3g, 0.65mol) was added dropwise to adjust the pH value at Between 11 and 12, stir for 1.5 hours.
  • 2-Fluorobenzoyl chloride (19 g, 0.12 mol) was added dropwise at 0-5°C, and the pH value was controlled between 11-12 during the dropwise addition. After the dropwise addition, react at 5-10°C for 2h.
  • Concentrated hydrochloric acid 34 g, 0.33 mol was added dropwise to adjust the pH value between 3 and 4, and 50 mL of ethyl acetate was added and stirred for 16 hours.
  • Example 2 Preparation of Crystal Form A by Suspension and Stirring in a Single Solvent at Room Temperature
  • Example 2 Weigh 20mg of the compound of formula (I) prepared in Example 1, add it to a 3mL glass vial, add 1mL of a mixed solvent of nitromethane and isoamyl alcohol (volume ratio 1:1), and the obtained suspension Stir magnetically (500 rpm) at 25°C for about 24 hours, filter the suspension, and dry the solid part in a vacuum oven for 10 minutes.
  • the XRPD pattern of the obtained crystal form is substantially the same as the XRPD pattern in Example 2, indicating that the crystal form A is obtained.
  • Example 4 Preparation of crystal form B by suspending and stirring in a single solvent at room temperature
  • Example 2 Weigh 20mg of the compound of formula (I) prepared in Example 1, add it to a 3mL glass vial, add 1mL of a mixture of ethanol and acetone (volume ratio 1:1), and place the resulting suspension at 25°C Stir magnetically (500 rpm) for about 24 hours, filter the suspension, and dry the solid part in a vacuum oven for 10 minutes.
  • the XRPD pattern of the obtained crystal form is substantially the same as that in Example 4, indicating that the crystal form B was obtained.
  • Example 2 Weigh 20 mg of the compound of formula (I) prepared in Example 1, add it to a 3 mL glass vial, add 1 mL of water, stir the resulting suspension at 50° C. with magnetic force (500 rpm) for about 24 h, filter The suspension and the solid part were dried in a vacuum oven for 10 min.
  • the XRPD pattern of the obtained crystal form is substantially the same as that in Example 4, indicating that the crystal form B was obtained.
  • Example 2 Weigh 20mg of the compound of formula (I) prepared in Example 1, add it to a 3mL glass vial, add 1mL of a mixture of ethanol and ether (volume ratio 1:1), and place the resulting suspension at 50°C Stir magnetically (500 rpm) for about 24 hours, filter the suspension, and dry the solid part in a vacuum oven for 10 minutes.
  • the XRPD pattern of the obtained crystal form is substantially the same as that in Example 4, indicating that the crystal form B is obtained.
  • Embodiment 10 Preparation of crystal form B by cooling method
  • Example 12 Preparation of Form C by Suspension and Stirring in a Single Solvent at Room Temperature
  • Example 2 Weigh 20mg of the compound of formula (I) prepared in Example 1, add it to a 3mL glass vial, add 1mL of acetone, stir the resulting suspension at 50°C for about 24h with magnetic force (500 rpm), filter The suspension and the solid part were dried in a vacuum oven for 10 min.
  • the XRPD pattern of the obtained crystal form is substantially the same as that in Example 12, indicating that the crystal form C was obtained.
  • Example 2 Weigh 20 mg of the compound of formula (I) prepared in Example 1, add it to a 3 mL glass vial, add 1 mL of a mixed solution of chloroform and isoamyl alcohol (volume ratio 1:1), and dissolve the resulting suspension at 50 Stir magnetically (500 rpm) at °C for about 24 hours, filter the suspension, and dry the solid part in a vacuum oven for 10 minutes.
  • the XRPD pattern of the obtained crystal form is substantially the same as that in Example 12, indicating that the crystal form C was obtained.
  • Example 15 Preparation of crystal form D by suspending and stirring in a single solvent at room temperature
  • Example 1 Weigh 20mg of the compound of formula (I) prepared in Example 1, add it to a 3mL glass vial, add 1mL of ethanol and water mixture (volume ratio 7:1), and place the resulting suspension at 25°C under magnetic Stir (500 rpm) for about 24 hours, filter the suspension, and dry the solid part in a vacuum oven for 10 minutes.
  • the XRPD pattern of the obtained crystal form was substantially the same as that in Example 15, indicating that the crystal form D was obtained.
  • Example 17 Form D was prepared by volatilization and crystallization at room temperature
  • the obtained crystal form F was analyzed by TGA, and the obtained spectrum is shown in Fig. 7b.
  • Example 2 Take 20mg of the compound of formula (I) prepared in Example 1, stir it with 1mL of methanol and ethanol mixture (volume ratio 1:1) at 25°C for at least 24h, then filter the suspension, and store the solid part in a vacuum oven Dry in medium for 10min.
  • the XRPD pattern of the obtained crystalline form was substantially the same as that in Example 23, indicating that crystalline Form F was obtained.
  • Form I is a single crystal structure, the single crystal parameters are shown in the table below, and the three-dimensional structure is shown in Figure 10b.
  • Test example 2 Humidity test
  • a dynamic water adsorption instrument (DVS) was used to investigate the adsorption and analysis of the crystal form in the present application to moisture at a temperature of 25° C. and a relative humidity of 0 to 95%.
  • the evaluation was carried out according to the description of hygroscopic characteristics and the evaluation criteria of hygroscopic weight gain in "9103 Guiding Principles of Moisture-induced Drug Moisture” in the fourth part of the "Chinese Pharmacopoeia” in 2015 edition.
  • XRPD analysis was performed on the crystal form again to determine whether the crystal form changed.
  • the inner packaging is thermoplastic sealing of pharmaceutical low-density polyethylene bag
  • the outer packaging is thermoplastic sealing of polyester/aluminum/polyethylene pharmaceutical composite film
  • crystal form D of the compound of formula (I) was weighed as a sample to be tested, and the light experiment was carried out under the following light conditions, wherein the total illuminance was not lower than 2 ⁇ 106Lux ⁇ hr, and the near-ultraviolet energy was not lower than 200w ⁇ hr/m2.
  • inner packaging is thermoplastic sealing of pharmaceutical low-density polyethylene bag
  • outer packaging is thermoplastic sealing of polyester/aluminum/polyethylene pharmaceutical composite film

Abstract

The present invention relates to a solid form of a compound of formula (I) ((Z)-S-(2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)2-fluorobenzothioate), a preparation method therefor, a pharmaceutical composition containing same, and the use thereof in the treatment of a disease.

Description

苯磷硫胺衍生物的固体形式及其制备方法和用途Solid forms of benfotiamine derivatives and methods for their preparation and use 发明领域field of invention
本发明涉及(Z)-S-(2-(N–((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺)-5-(膦酰氧基)戊-2-烯-3-基)2-氟苯硫醇酯(在下文中称作“式(I)的化合物”)的固体形式、制备所述固体形式的方法、包含所述固体形式的药物组合物，以及所述固体形式用于治疗疾病的用途。The present invention relates to (Z)-S-(2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamide)-5-(phosphonooxy)penta-2- Solid forms of en-3-yl) 2-fluorobenzenethiol esters (hereinafter referred to as "compounds of formula (I)"), processes for preparing said solid forms, pharmaceutical compositions comprising said solid forms, and The solid form is for use in the treatment of a disease.
发明背景Background of the invention
阿尔茨海默病(俗称老年性痴呆，Alzheimer’s disease,AD)是一种以认知、行为失常为主要临床表现的进行性神经退行性疾病，是一种最常见的老年期痴呆，主要表现为识别能力障碍与记忆功能的迅速衰减。主要病理生理特征是脑内β-淀粉样蛋白(β-amyloid，Aβ)沉积形成老年斑、tau蛋白过度磷酸化形成神经纤维缠结、脑葡萄糖代谢障碍和神经元/突触丢失。由于病程长、患者生活自理能力差，给家庭、社会带来严重的精神和经济负担。但是，全球范围内目前没有能阻止或延缓疾病发展的药物，目前市场销售的治疗AD的药物仅为对症治疗药物，只能控制或改善认知和功能症状一段时间，不能阻止或延缓病情恶化。Alzheimer's disease (commonly known as senile dementia, Alzheimer's disease, AD) is a progressive neurodegenerative disease with cognitive and behavioral disorders as the main clinical manifestations. Impairment of recognition ability and rapid decline of memory function. The main pathophysiological features are the deposition of β-amyloid (Aβ) in the brain to form senile plaques, the hyperphosphorylation of tau protein to form neurofibrillary tangles, the disturbance of brain glucose metabolism, and the loss of neurons/synapses. Due to the long course of the disease and poor self-care ability of patients, it brings serious mental and economic burdens to families and society. However, there is currently no drug that can prevent or delay the development of the disease in the world. The drugs currently on the market for the treatment of AD are only symptomatic drugs, which can only control or improve cognitive and functional symptoms for a period of time, but cannot prevent or delay the progression of the disease.
研究表明，苯磷硫胺可以预防和治疗阿尔茨海默病。CN109111478A公开了一种苯磷硫胺衍生物及其制备方法，其对Aβ40和Aβ42的抑制效果明显高于苯磷硫胺。Research shows that benfotiamine can prevent and treat Alzheimer's disease. CN109111478A discloses a benfotiamine derivative and a preparation method thereof, whose inhibitory effect on Aβ40 and Aβ42 is significantly higher than that of benfotiamine.
发明概述Summary of the invention
本发明的一个方面提供如下所示的式(I)的化合物((Z)-S-(2-(N–((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺)-5-(膦酰氧基)戊-2-烯-3-基)2-氟苯硫醇酯)的晶体形式：One aspect of the present invention provides a compound of formula (I) shown below ((Z)-S-(2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamide )-5-(phosphonooxy)pent-2-en-3-yl)2-fluorobenzenethiol ester) in crystal form:
Figure PCTCN2022133152-appb-000001
Figure PCTCN2022133152-appb-000001
本发明的优选晶型稳定性良好，在高温、高湿或者光照条件下储存后晶体形式保持不变，能够满足生产、运输、储存的药用要求，生产工艺稳定、可控且可重复，能够适应于工业化生产。The preferred crystal form of the present invention has good stability, and the crystal form remains unchanged after storage under high temperature, high humidity or light conditions, which can meet the pharmaceutical requirements of production, transportation and storage. The production process is stable, controllable and repeatable, and can Adapt to industrial production.
本发明的另一方面提供制备本发明的晶体的方法，所述方法包括但不限于悬浮搅拌法、挥发法、冷却法和气液渗透法。Another aspect of the present invention provides methods for preparing the crystals of the present invention, including but not limited to suspension stirring method, volatilization method, cooling method and gas-liquid infiltration method.
本发明的另一方面提供药物组合物，其包含本发明中的任意一种或多种晶体形式，以及一种或多种药学上可接受的载体。Another aspect of the present invention provides a pharmaceutical composition, which comprises any one or more crystalline forms of the present invention, and one or more pharmaceutically acceptable carriers.
本发明的另一方面提供本发明的晶体形式在制备用于预防或治疗维生素B1缺乏症和代谢相关障碍、精神类疾病和紊乱、糖尿病相关并发症和/或神经退行性疾病的药物中的用途。Another aspect of the present invention provides the use of the crystalline form of the present invention in the preparation of a medicament for the prevention or treatment of vitamin B1 deficiency and metabolic-related disorders, psychiatric diseases and disorders, diabetes-related complications and/or neurodegenerative diseases .
附图简要说明Brief description of the drawings
图1a为式(I)化合物无定形的X射线粉末衍射(XRPD)图。Figure 1a is an X-ray powder diffraction (XRPD) pattern of an amorphous compound of formula (I).
图1b为式(I)化合物无定形的热重分析(TGA)图Fig. 1b is the thermogravimetric analysis (TGA) figure of formula (I) compound amorphous
图1c为式(I)化合物无定形的差示扫描量热分析(DSC)图。Fig. 1c is a differential scanning calorimetry (DSC) diagram of the amorphous compound of formula (I).
图1d为式(I)化合物无定形的引湿性分析(DVS)图。Fig. 1d is a hygroscopic analysis (DVS) diagram of the compound of formula (I) in an amorphous form.
图2a为式(I)化合物的晶型A的X射线粉末衍射图。Figure 2a is an X-ray powder diffraction pattern of Form A of the compound of formula (I).
图2b为式(I)化合物的晶型A的热重分析图。Fig. 2b is a thermogravimetric analysis diagram of the crystal form A of the compound of formula (I).
图2c为式(I)化合物的晶型A的差示扫描量热分析图。Fig. 2c is a differential scanning calorimetry diagram of the crystal form A of the compound of formula (I).
图2d为式(I)化合物的晶型A的引湿性分析图。Fig. 2d is a hygroscopicity analysis diagram of the crystal form A of the compound of formula (I).
图3a为式(I)化合物的晶型B的X射线粉末衍射图。Figure 3a is an X-ray powder diffraction pattern of Form B of the compound of formula (I).
图3b为式(I)化合物的晶型B的热重分析图。Fig. 3b is a thermogravimetric analysis diagram of the crystal form B of the compound of formula (I).
图3c为式(I)化合物的晶型B的差示扫描量热分析图。Fig. 3c is a differential scanning calorimetry diagram of the crystal form B of the compound of formula (I).
图3d为式(I)化合物的晶型B的引湿性分析图。Fig. 3d is a hygroscopicity analysis diagram of the crystal form B of the compound of formula (I).
图4a为式(I)化合物的晶型C的X射线粉末衍射图。Figure 4a is an X-ray powder diffraction pattern of Form C of the compound of formula (I).
图4b为式(I)化合物的晶型C的热重分析图。Fig. 4b is a thermogravimetric analysis diagram of the crystal form C of the compound of formula (I).
图4c为式(I)化合物的晶型C的差示扫描量热分析图。Fig. 4c is a differential scanning calorimetry diagram of the crystal form C of the compound of formula (I).
图4d为式(I)化合物的晶型C的引湿性分析图。Fig. 4d is a hygroscopicity analysis diagram of the crystal form C of the compound of formula (I).
图5a为实施例15中制备的式(I)化合物的晶型D的X射线粉末衍射图。Figure 5a is the X-ray powder diffraction pattern of the crystal form D of the compound of formula (I) prepared in Example 15.
图5a-1为实施例18中制备的式(I)化合物的晶型D的X射线粉末衍射图。Figure 5a-1 is the X-ray powder diffraction pattern of the crystal form D of the compound of formula (I) prepared in Example 18.
图5a-2为实施例18-21中制备的式(I)化合物的晶型D的X射线粉末衍射图。Figure 5a-2 is the X-ray powder diffraction pattern of the crystal form D of the compound of formula (I) prepared in Example 18-21.
图5b为式(I)化合物的晶型D的热重分析图。Fig. 5b is a thermogravimetric analysis diagram of the crystal form D of the compound of formula (I).
图5c为式(I)化合物的晶型D的差示扫描量热分析图。Fig. 5c is a differential scanning calorimetry diagram of the crystal form D of the compound of formula (I).
图5d为式(I)化合物的晶型D的引湿性分析图。Fig. 5d is a hygroscopicity analysis diagram of the crystal form D of the compound of formula (I).
图6a为式(I)化合物的晶型E的X射线粉末衍射图。Figure 6a is an X-ray powder diffraction pattern of Form E of the compound of formula (I).
图6b为式(I)化合物的晶型E的热重分析图。Fig. 6b is a thermogravimetric analysis diagram of the crystal form E of the compound of formula (I).
图6c为式(I)化合物的晶型E的差示扫描量热分析图。Fig. 6c is a differential scanning calorimetry diagram of the crystal form E of the compound of formula (I).
图6d为式(I)化合物的晶型E的引湿性分析图。Fig. 6d is a hygroscopicity analysis diagram of the crystal form E of the compound of formula (I).
图7a为式(I)化合物的晶型F的X射线粉末衍射图。Figure 7a is an X-ray powder diffraction pattern of Form F of the compound of formula (I).
图7b为式(I)化合物的晶型F的热重分析图。Fig. 7b is a thermogravimetric analysis diagram of Form F of the compound of formula (I).
图7c为式(I)化合物的晶型F的差示扫描量热分析图。Fig. 7c is a differential scanning calorimetry diagram of Form F of the compound of formula (I).
图7d为式(I)化合物的晶型F的引湿性分析图。Fig. 7d is a hygroscopicity analysis diagram of the crystal form F of the compound of formula (I).
图8a为式(I)化合物的晶型G的X射线粉末衍射图。Figure 8a is an X-ray powder diffraction pattern of Form G of the compound of formula (I).
图8b为式(I)化合物的晶型G的热重分析图。Fig. 8b is a thermogravimetric analysis diagram of the crystal form G of the compound of formula (I).
图8c为式(I)化合物的晶型G的差示扫描量热分析图。Figure 8c is a differential scanning calorimetry diagram of Form G of the compound of formula (I).
图8d为式(I)化合物的晶型G的引湿性分析图。Fig. 8d is a hygroscopicity analysis diagram of the crystal form G of the compound of formula (I).
图9a为式(I)化合物的晶型H的X射线粉末衍射图。Figure 9a is an X-ray powder diffraction pattern of Form H of the compound of formula (I).
图9b为式(I)化合物的晶型H的立体结构图。Fig. 9b is a three-dimensional structure diagram of the crystal form H of the compound of formula (I).
图10a为式(I)化合物的晶型I的X射线粉末衍射图。Figure 10a is an X-ray powder diffraction pattern of Form I of the compound of formula (I).
图10b为式(I)化合物的晶型I的立体结构图。Fig. 10b is a three-dimensional structure diagram of the crystal form I of the compound of formula (I).
图11a为式(I)化合物的无定形的加速15天稳定性测试前后的XRPD对比(其中a代表测试开始前的XRPD图，b代表测试结束后的XRPD图)。Figure 11a is a comparison of the XRPD before and after the accelerated 15-day stability test of the compound of formula (I) (a represents the XRPD pattern before the test, and b represents the XRPD pattern after the test).
图11b为式(I)化合物晶型A的加速15天稳定性测试XRPD对比(其中a代表测试开始前的XRPD图，b代表测试结束后的XRPD图)。Figure 11b is an accelerated 15-day stability test XRPD comparison of compound crystal form A of formula (I) (wherein a represents the XRPD pattern before the start of the test, and b represents the XRPD pattern after the test).
图11c为式(I)化合物水合物晶型B的加速15天稳定性测试XRPD对比(其中a代表测试开始前的XRPD图，b代表测试结束后的XRPD图)。Figure 11c is the XRPD comparison of the accelerated 15-day stability test of compound hydrate crystal form B of formula (I) (wherein a represents the XRPD pattern before the start of the test, and b represents the XRPD pattern after the test).
图11d为式(I)化合物晶型C的加速15天稳定性测试XRPD对比(其中a代表测试开始前的XRPD图，b代表测试结束后的XRPD图)。Figure 11d is the XRPD comparison of the accelerated 15-day stability test of compound crystal form C of formula (I) (wherein a represents the XRPD pattern before the start of the test, and b represents the XRPD pattern after the test).
图11e为式(I)化合物晶型D的加速15天稳定性测试XRPD对比(其中a代表测试开始前的XRPD图，b代表测试结束后的XRPD图)。Figure 11e is an accelerated 15-day stability test XRPD comparison of compound crystal form D of formula (I) (wherein a represents the XRPD pattern before the start of the test, and b represents the XRPD pattern after the test).
图11f为式(I)化合物晶型E的加速15天稳定性测试XRPD对比(其中a代表测试开始前的XRPD图，b代表测试结束后的XRPD图)。Figure 11f is the XRPD comparison of the accelerated 15-day stability test of the compound crystal form E of formula (I) (wherein a represents the XRPD pattern before the start of the test, and b represents the XRPD pattern after the test).
发明详述Detailed description of the invention
定义definition
除非在下文中另有定义，本文中所用的所有技术术语和科学术语的含义意图与本领域技术人员通常所理解的相同。提及本文中使用的技术意图指在本领域中通常所理解的技术，包括那些对本领域技术人员显而易见的技术的变化或等效技术的替换。虽然相信以下术语对于本领域技术人员很好理解，但仍然阐述以下定义以更好地解释本发明。Unless defined otherwise hereinafter, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. References to techniques used herein are intended to refer to techniques commonly understood in the art, including those variations of the techniques or substitutions of equivalent techniques that are obvious to those skilled in the art. While the following terms are believed to be well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.
如本文中所使用的术语“包括”、“包含”、“具有”、“含有”或“涉及”及其在本文中的其它变体形式为包含性的(inclusive)或开放式的，且不排除其它未列举的元素或方法步骤。As used herein, the terms "comprising", "comprising", "having", "containing" or "involving" and other variations thereof herein are inclusive or open-ended, and do not Other unlisted elements or method steps are excluded.
如本文中所使用的词语“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 word "about" means that one of ordinary skill in the art considers within an acceptable standard error of the stated value, such as ±0.05, ±0.1, ±0.2, ±0.3, ±1, ±2, or ±3 etc.
本发明所使用的术语“固体形式”包括式(I)的化合物的所有固态形式，例如晶体形式或无定形形 式。The term "solid form" as used in the present invention includes all solid forms of the compounds of formula (I), such as crystalline or amorphous forms.
如本文中所使用的术语“无定形”是指三维上无排序的任意固体物质。在一些情况中，无定形固体可通过已知技术表征，所述技术包括XRPD晶体学、固态核磁共振(ssNMR)波谱学、DSC或这些技术的一些组合。如以下所说明，无定形固体产生弥散的XRPD图谱，其通常包括一个或两个宽峰(即具有约5°2θ或更大的基宽的峰)。The term "amorphous" as used herein refers to any solid substance that is not ordered in three dimensions. In some cases, amorphous solids can be characterized by known techniques including XRPD crystallography, solid state nuclear magnetic resonance (ssNMR) spectroscopy, DSC, or some combination of these techniques. As explained below, amorphous solids give rise to diffuse XRPD patterns that typically include one or two broad peaks (ie, peaks with a base width of about 5° 2Θ or greater).
如本文中所使用的术语“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。The term "crystalline form" or "crystal" as used herein 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.
如本文中所使用的术语“X射线粉末衍射图谱(XRPD图谱)”是指实验观察的衍射图或源于其的参数。XRPD图谱通常由峰位(横坐标)和/或峰强度(纵坐标)表征。The term "X-ray powder diffraction pattern (XRPD pattern)" as used herein refers to an experimentally observed diffraction pattern or parameters derived therefrom. XRPD patterns are usually characterized by peak positions (abscissa) and/or peak intensities (ordinate).
如本文中所使用的术语“2θ”是指基于X射线衍射实验的实验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。如果当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体形式的特定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 PCTCN2022133152-appb-000002
1.540598和Kα2
Figure PCTCN2022133152-appb-000003
1.544426)作为辐射源。 The term "2Θ" as used herein refers to the peak position in degrees based on the experimental setup of an X-ray diffraction experiment, and is generally a unit of abscissa in a diffraction pattern. If the reflections are diffracted when the incident beam forms an angle θ with a certain lattice plane, the experimental setup requires recording the reflected beam at 2θ angles. It should be understood that references herein to specific 2Θ values for particular crystalline forms are intended to represent 2Θ values (expressed in degrees) as measured using the X-ray diffraction experimental conditions described herein. For example, as described herein, using Cu-Kα (Kα1
Figure PCTCN2022133152-appb-000002
1.540598 and Kα2
Figure PCTCN2022133152-appb-000003
1.544426) as a radiation source.
如本文中所使用的术语“差示扫描量热(DSC)图谱”是指在样品升温或恒温过程中，测量样品与参考物之间的温度差、热流差，以表征所有与热效应有关的物理变化和化学变化，得到样品的相变信息。本申请中的DSC图谱优选在TA DSC Q2000差示扫描量热仪上采集。As used herein, the term "differential scanning calorimetry (DSC) spectrum" refers to the measurement of the temperature difference and heat flow difference between the sample and the reference during the heating or constant temperature of the sample to characterize all the physical properties related to thermal effects. Changes and chemical changes to obtain phase transition information of the sample. The DSC collection of illustrative plates in this application is preferably collected on TA DSC Q2000 differential scanning calorimeter.
如本文中所使用的，对于X射线衍射峰位的术语“基本上相同”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0.1-0.2度，并且用于测量衍射的仪器也会显示一些变化。另外，本领域技术人员会理解相对峰强度会显示仪器间的变化以及由于结晶性程度、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的变化，并应将其看作仅为定性测量。相似地，如本文中所使用，对于DSC图谱的“基本上相同”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，对于边界清楚的峰，在差示扫描量热图谱通常会具有多达±0.2℃的变化，对于宽峰甚至更大(例如多达±1℃)。As used herein, the term "substantially the same" for X-ray diffraction peak positions means taking representative peak positions and intensity variations into account. For example, those skilled in the art will understand that peak position (2Θ) will show some variation, typically by as much as 0.1-0.2 degrees, and that the instrumentation used to measure diffraction will also show some variation. Additionally, those skilled in the art will appreciate that relative peak intensities will exhibit inter-instrument variation as well as variations due to degree of crystallinity, preferred orientation, prepared sample surface, and other factors known to those skilled in the art, and should be considered only for qualitative measurement. Similarly, as used herein, "substantially the same" with respect to a DSC profile is also intended to cover variations associated with these analytical techniques known to those skilled in the art. For example, differential scanning calorimetry profiles will typically have as much as ±0.2°C variation for well-defined peaks, and even greater (eg, as much as ±1°C) for broad peaks.
如本文中所使用的术语“烃类”优选意指具有1-10个碳原子的烃，其包括烷烃类、卤代烷烃类、烯烃类、炔烃类和芳烃类，具体包括但不限于二氯甲烷、三氯甲烷(氯仿)、正己烷、正庚烷和甲苯。The term "hydrocarbons" as used herein preferably means hydrocarbons having 1-10 carbon atoms, including alkanes, halogenated alkanes, alkenes, alkynes and aromatics, specifically including but not limited to dichloro Methane, chloroform (chloroform), n-hexane, n-heptane, and toluene.
如本文中所使用的术语“醇类”优选意指具有1-10个碳原子的醇，其包括但不限于甲醇、乙醇、1-丙醇(正丙醇)、2-丙醇(异丙醇)、1-丁醇、2-丁醇和叔丁醇。The term "alcohols" as used herein preferably means alcohols having 1-10 carbon atoms, including but not limited to methanol, ethanol, 1-propanol (n-propanol), 2-propanol (isopropanol alcohol), 1-butanol, 2-butanol and tert-butanol.
如本文中所使用的术语“醚类”优选意指具有2-6个碳原子的醚，其包括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***、二异丙基醚、甲基叔丁基醚、四氢呋喃、2-甲基四氢呋喃、二氧六环、环戊基甲醚、苯甲醚和二甲氧基乙烷。The term "ether" as used herein preferably means an ether having 2-6 carbon atoms, including chain ethers and cyclic ethers (such as furans (including tetrahydrofuran) and dioxane class), specifically including but not limited to diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, cyclopentyl methyl ether, anisole and dimethoxy ethane.
如本文中所使用的术语“腈类”优选意指具有2-6个碳原子的腈，其包括但不限于乙腈和丙腈。The term "nitriles" as used herein preferably means nitriles having 2-6 carbon atoms, including but not limited to acetonitrile and propionitrile.
如本文中所使用的术语“酮类溶剂”优选意指具有2-6个碳原子的酮，其包括但不限于丙酮、丁酮、甲基乙基酮、甲基异丁基酮和二乙基酮。As used herein, the term "ketone solvent" preferably means a ketone having 2-6 carbon atoms, including but not limited to acetone, methyl ethyl ketone, methyl ethyl ketone, methyl isobutyl ketone and diethyl base ketones.
如本文中所使用的术语“酯类”优选意指具有3-10个碳原子的酯，其包括但不限于乙酸乙酯、乙酸丙酯、乙酸异丙酯、异丙酸乙酯、碳酸二甲酯和乙酸丁酯。The term "esters" as used herein preferably means esters having 3-10 carbon atoms, including but not limited to ethyl acetate, propyl acetate, isopropyl acetate, ethyl isopropionate, dicarbonate methyl ester and butyl acetate.
如本文中所使用的数值范围(如“1-10个”)及其子范围(如“2-10个”、“2-6个”、“3-10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, "1-10") and subranges thereof (eg, "2-10", "2-6", "3-10") and the like encompass such numerical ranges Any of (eg, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) among.
可将制备的盐或其晶体形式通过包括倾析、离心、蒸发、重力过滤、抽滤或者在加压下或在减压下的任何其它用于固体回收的技术在内的方法进行回收。可将回收的固体任选地进行干燥。本发明中的“干燥”是在减压(优选真空)下进行直到残留溶剂的含量降低至International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use(“ICH”)指南所给出的限度的范围内。残留溶剂含量取决于溶剂的类型，但不超过约5000ppm、或优选约4000ppm、或更优选约3000ppm。所述干燥可以在盘式干燥器、真空烘箱、空气烘箱、锥形真空干燥器(cone vacuum dryer)、旋转式真空干燥器、流化床干燥器、旋转闪蒸干燥器、快速干燥器等中进行。所述干燥可以在低于约100℃、低于约80℃、低于约60℃、低于约50℃、低于约30℃的温度或任何其它合适的温度下，在大气压或减压(优选真空)下在能够实现期望的结果的任何期望的时间内(如约1、2、3、5、10、15、20、24小时或者过夜)进行，只要盐的品质不劣化。所述干燥可以进行任何期望的次数，直到实现所需的产物品质。干燥的产物可以任选地经历粉碎操作，以产生期望的粒度。可在产物的干燥前或干燥完成后进行研磨或微粉化。可用于减小粒度的技术包括但不限于球磨、辊磨和锤磨，以及喷射研磨(jet milling)。The prepared salt or its crystalline form may be recovered by methods including decantation, centrifugation, evaporation, gravity filtration, suction filtration or any other technique for solid recovery under increased or reduced pressure. The recovered solid can optionally be dried. "Drying" in the present invention is carried out under reduced pressure (preferably vacuum) until the content of residual solvents is reduced to the limit given by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use ("ICH") guidelines within range. The residual solvent content depends on the type of solvent, but does not exceed about 5000 ppm, or preferably about 4000 ppm, or more preferably about 3000 ppm. The drying can be in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, etc. conduct. The drying may be at atmospheric pressure or reduced pressure ( Preferably under vacuum) for any desired period of time (such as about 1, 2, 3, 5, 10, 15, 20, 24 hours or overnight) to achieve the desired result, provided the quality of the salt does not deteriorate. The drying can be performed any desired number of times until the desired product quality is achieved. The dried product can optionally be subjected to a comminution operation to produce the desired particle size. Grinding or micronization may be performed before drying of the product or after drying is complete. Techniques that can be used to reduce particle size include, but are not limited to, ball, roller, and hammer milling, and jet milling.
如本文中所使用的术语“无水晶型”优选意指其中不含有水分子作为结构要素的晶型。The term "anhydrous crystal form" as used herein preferably means a crystal form in which no water molecule is contained as a structural element.
晶型AForm A
在一个实施方案中，本发明提供式(I)的化合物的晶型A，所述晶型A的XRPD图谱包括在约11.9±0.2°、12.3±0.2°、12.7±0.2°、18.5±0.2°、18.8±0.2°、25.5±0.2°和26.2±0.2°的衍射角(2θ)处的特征峰。In one embodiment, the present invention provides the crystalline form A of the compound of formula (I), the XRPD pattern of the crystalline form A includes the crystal form A at about 11.9±0.2°, 12.3±0.2°, 12.7±0.2°, 18.5±0.2° , 18.8±0.2°, 25.5±0.2° and 26.2±0.2° diffraction angles (2θ) at the characteristic peaks.
在一个实施方案中，本发明提供式(I)的化合物的晶型A，所述晶型A的XRPD图谱包括在约11.9±0.2°、12.3±0.2°、12.7±0.2°、17.0±0.2°、18.5±0.2°、18.8±0.2°、21.9±0.2°、22.6±0.2°、25.5±0.2°、26.2±0.2°和27.0±0.2°的衍射角(2θ)处的特征峰。In one embodiment, the present invention provides the crystalline form A of the compound of formula (I), the XRPD pattern of the crystalline form A includes the crystal form A at about 11.9±0.2°, 12.3±0.2°, 12.7±0.2°, 17.0±0.2° , 18.5±0.2°, 18.8±0.2°, 21.9±0.2°, 22.6±0.2°, 25.5±0.2°, 26.2±0.2° and 27.0±0.2° at diffraction angles (2θ).
在优选实施方案中，所述式(I)的化合物的晶型A的XRPD图谱包括在约11.7±0.2°、11.9±0.2°、12.3±0.2°、12.7±0.2°、13.3±0.2°、14.8±0.2°、16.0±0.2°、17.0±0.2°、17.3±0.2°、17.5±0.2°、18.5±0.2°、18.8±0.2°、19.6±0.2°、21.9±0.2°、22.6±0.2°、23.0±0.2°、24.9±0.2°、25.5±0.2°、26.2±0.2°、26.4±0.2°、27.0±0.2°、28.8±0.2°、30.3±0.2°、32.4±0.2°、34.8±0.2°和36.8±0.2°的衍射角(2θ)处的特征峰。In a preferred embodiment, the XRPD pattern of the crystalline form A of the compound of formula (I) comprises a temperature range of about 11.7±0.2°, 11.9±0.2°, 12.3±0.2°, 12.7±0.2°, 13.3±0.2°, 14.8 ±0.2°, 16.0±0.2°, 17.0±0.2°, 17.3±0.2°, 17.5±0.2°, 18.5±0.2°, 18.8±0.2°, 19.6±0.2°, 21.9±0.2°, 22.6±0.2°, 23.0 ±0.2°, 24.9±0.2°, 25.5±0.2°, 26.2±0.2°, 26.4±0.2°, 27.0±0.2°, 28.8±0.2°, 30.3±0.2°, 32.4±0.2°, 34.8±0.2° and 36.8 Characteristic peaks at diffraction angles (2θ) of ±0.2°.
在更优选的实施方案中，所述式(I)的化合物的晶型A的XRPD图谱包括与图2a所示基本上相同的衍射角(2θ)处的特征峰。在最优选的实施方案中，所述式(I)的化合物的晶型A的XRPD图谱与图2a所示基本上相同。In a more preferred embodiment, the XRPD pattern of Form A of the compound of formula (I) includes characteristic peaks at substantially the same diffraction angle (2θ) as shown in Figure 2a. In the most preferred embodiment, the XRPD pattern of Form A of the compound of formula (I) is substantially the same as that shown in Figure 2a.
在优选的实施方案中，本发明的式(I)的化合物的晶型A的DSC图谱包括在约92.6±0.2℃和约144.0±0.2℃处的吸热峰。在更优选的实施方案中，本发明的式(I)的化合物的晶型A的DSC图谱包括与图2c所示基本上相同的温度处的特征峰。在最优选的实施方案中，所述式(I)的化合物的晶型A的DSC图谱与图2c所示基本上相同。In a preferred embodiment, the DSC spectrum of Form A of the compound of formula (I) of the present invention comprises endothermic peaks at about 92.6±0.2°C and about 144.0±0.2°C. In a more preferred embodiment, the DSC spectrum of Form A of the compound of formula (I) of the present invention comprises characteristic peaks at substantially the same temperature as shown in Figure 2c. In the most preferred embodiment, the DSC spectrum of Form A of the compound of formula (I) is substantially the same as that shown in Figure 2c.
在优选的实施方案中，在热重分析中，本发明的式(I)的化合物的晶型A在加热至约133±2℃时有约8.98％的失重。在更优选的实施方案中，本发明的式(I)的化合物的晶型A的TGA图谱与图2b所示基本上相同。In a preferred embodiment, the crystalline form A of the compound of formula (I) of the present invention has a weight loss of about 8.98% when heated to about 133±2° C. in thermogravimetric analysis. In a more preferred embodiment, the TGA pattern of Form A of the compound of formula (I) of the present invention is substantially the same as that shown in Figure 2b.
在优选的实施方案中，本方明的式(I)的化合物的晶型A为式(I)的化合物与硝基甲烷形成的溶剂合物。In a preferred embodiment, the crystal form A of the compound of formula (I) of the present invention is a solvate formed by the compound of formula (I) and nitromethane.
在一些实施方案中，本发明还提供晶型A的制备方法，所述方法为悬浮搅拌法，其包括将式(I)的化合物加入有机溶剂中，在20-35℃下搅拌，然后将其过滤，得到晶型A。In some embodiments, the present invention also provides a preparation method of Form A, which is a suspension stirring method, which comprises adding the compound of formula (I) into an organic solvent, stirring at 20-35°C, and then Filter to obtain Form A.
在优选的实施方案中，所述有机溶剂为硝基甲烷，或硝基甲烷与其它有机溶剂的混合溶剂。In a preferred embodiment, the organic solvent is nitromethane, or a mixed solvent of nitromethane and other organic solvents.
所述其它有机溶剂为例如具有1-10个碳原子的醇类、烃类、醚类、酯类、酮类或卤代烃类溶剂。所述醇类溶剂例如为异戊醇或甲醇，所述烃类溶剂例如为正己烷或正庚烷，所述醚类溶剂例如为四氢呋喃或***，所述酯类溶剂例如为乙酸乙酯或乙酸异丙酯，所述酮类溶剂例如为丙酮、甲乙酮或甲基异丁基酮，所述卤代烃类溶剂例如为二氯甲烷。The other organic solvents are, for example, alcohols, hydrocarbons, ethers, esters, ketones or halogenated hydrocarbon solvents having 1-10 carbon atoms. The alcohol solvent is, for example, isoamyl alcohol or methanol, the hydrocarbon solvent is, for example, n-hexane or n-heptane, the ether solvent is, for example, tetrahydrofuran or ether, and the ester solvent is, for example, ethyl acetate or acetic acid Isopropyl ester, the ketone solvent is, for example, acetone, methyl ethyl ketone or methyl isobutyl ketone, and the halogenated hydrocarbon solvent is, for example, methylene chloride.
优选地，所述有机溶剂为硝基甲烷或者硝基甲烷与异戊醇的混合溶剂。更优选地，所述混合溶剂中硝基甲烷与异戊醇体积比为1:1。Preferably, the organic solvent is nitromethane or a mixed solvent of nitromethane and isoamyl alcohol. More preferably, the volume ratio of nitromethane to isoamyl alcohol in the mixed solvent is 1:1.
优选地，所述搅拌在约25℃下进行。Preferably, the stirring is performed at about 25°C.
优选地，所述搅拌持续约24小时。Preferably, the stirring is continued for about 24 hours.
在一些实施方案中，所述式(I)的化合物与所述有机溶剂的重量体积比(mg/mL)为(10-30):1，优选为约20:1。In some embodiments, the weight-to-volume ratio (mg/mL) of the compound of formula (I) to the organic solvent is (10-30):1, preferably about 20:1.
晶型BForm B
在另一个实施方案中，本发明提供式(I)的化合物的晶型B，所述晶型B的XRPD图谱包括在约6.2±0.2°、12.5±0.2°、16.0±0.2°、18.8±0.2°、24.1±0.2°、24.8±0.2°和26.5±0.2°的衍射角(2θ)处的特征峰。In another embodiment, the present invention provides the crystalline form B of the compound of formula (I), the XRPD pattern of the crystalline form B comprises at about 6.2±0.2°, 12.5±0.2°, 16.0±0.2°, 18.8±0.2 °, 24.1±0.2°, 24.8±0.2° and 26.5±0.2° diffraction angles (2θ) at the characteristic peaks.
在优选实施方案中，所述式(I)的化合物的晶型B的XRPD图谱包括在约6.2±0.2°、10.1±0.2°、12.0±0.2°、12.5±0.2°、14.8±0.2°、15.5±0.2°、16.0±0.2°、17.4±0.2°、17.6±0.2°、18.8±0.2°、20.3±0.2°、21.3±0.2°、24.1±0.2°、24.8±0.2°、25.0±0.2°、25.8±0.2°、26.5±0.2°、28.2±0.2°、28.3±0.2°、28.6±0.2°、29.1±0.2°、29.7±0.2°、30.6±0.2°和32.7±0.2°衍射角(2θ)处的峰。In a preferred embodiment, the XRPD pattern of the crystalline form B of the compound of formula (I) comprises a temperature range of about 6.2±0.2°, 10.1±0.2°, 12.0±0.2°, 12.5±0.2°, 14.8±0.2°, 15.5 ±0.2°, 16.0±0.2°, 17.4±0.2°, 17.6±0.2°, 18.8±0.2°, 20.3±0.2°, 21.3±0.2°, 24.1±0.2°, 24.8±0.2°, 25.0±0.2°, 25.8 ±0.2°, 26.5±0.2°, 28.2±0.2°, 28.3±0.2°, 28.6±0.2°, 29.1±0.2°, 29.7±0.2°, 30.6±0.2° and 32.7±0.2° diffraction angles (2θ) peak.
在更优选的实施方案中，所述式(I)的化合物的晶型B的XRPD图谱包括与图3a所示基本上相同的衍射角(2θ)处的特征峰。在最优选的实施方案中，所述式(I)的化合物的晶型B的XRPD图谱与图3a所示基本上相同。In a more preferred embodiment, the XRPD pattern of Form B of the compound of formula (I) includes characteristic peaks at substantially the same diffraction angle (2θ) as shown in Figure 3a. In the most preferred embodiment, the XRPD pattern of Form B of the compound of formula (I) is substantially the same as that shown in Figure 3a.
在优选的实施方案中，本发明的式(I)的化合物的晶型B的DSC图谱包括在约153.7±0.2℃处的特征峰。在更优选的实施方案中，本发明的式(I)的化合物的晶型B的DSC图谱包括与图3c所示基 本上相同的温度处的特征峰。在最优选的实施方案中，所述式(I)的化合物的晶型B的DSC图谱与图3c所示基本上相同。In a preferred embodiment, the DSC spectrum of Form B of the compound of formula (I) of the present invention comprises a characteristic peak at about 153.7±0.2°C. In a more preferred embodiment, the DSC profile of Form B of the compound of formula (I) of the present invention comprises characteristic peaks at substantially the same temperature as shown in Figure 3c. In the most preferred embodiment, the DSC spectrum of the crystalline form B of the compound of formula (I) is substantially the same as that shown in Figure 3c.
在优选的实施方案中，在热重分析中，本发明的式(I)的化合物的晶型B在加热至约71±2℃时有约1.52％的失重，在71±2℃至135±2℃之间有3.35％的失重。在更优选的实施方案中，本发明的式(I)的化合物的晶型B的TGA图谱与图3b所示基本上相同。In a preferred embodiment, in thermogravimetric analysis, the crystalline form B of the compound of formula (I) of the present invention has a weight loss of about 1.52% when heated to about 71±2° C. There is a weight loss of 3.35% between 2°C. In a more preferred embodiment, the TGA pattern of Form B of the compound of formula (I) of the present invention is substantially the same as that shown in Figure 3b.
在优选的实施方案中，本方明的式(I)的化合物的晶型B为水合物。In a preferred embodiment, the crystal form B of the compound of formula (I) of the present invention is a hydrate.
在一些实施方案中，本发明还提供晶型B的制备方法，所述方法包括但不限于：悬浮搅拌法、挥发法、冷却法和气液渗透法。In some embodiments, the present invention also provides a preparation method of Form B, which includes but not limited to: suspension stirring method, volatilization method, cooling method and gas-liquid infiltration method.
在一些实施方案中，所述方法为悬浮搅拌法，其包括将式(I)的化合物加入溶剂中，在20-80℃下搅拌，然后将其过滤，得到晶型B。In some embodiments, the method is a suspension stirring method, which comprises adding the compound of formula (I) into a solvent, stirring at 20-80°C, and then filtering it to obtain Form B.
在一些实施方案中，所述溶剂选自水、具有1-10个碳原子的醇类溶剂(例如甲醇、乙醇、异丙醇、异戊醇等)、醚类溶剂(例如***等)、酮类溶剂(例如丙酮、甲乙酮、甲基异丁基酮等)、芳香烃类溶剂(例如甲苯等)、卤代烃类溶剂(例如氯仿等)，或者它们的混合溶剂。In some embodiments, the solvent is selected from water, alcohol solvents having 1-10 carbon atoms (such as methanol, ethanol, isopropanol, isoamyl alcohol, etc.), ether solvents (such as diethyl ether, etc.), ketones solvents (such as acetone, methyl ethyl ketone, methyl isobutyl ketone, etc.), aromatic hydrocarbon solvents (such as toluene, etc.), halogenated hydrocarbon solvents (such as chloroform, etc.), or their mixed solvents.
优选地，所述溶剂为水、异丙醇、乙醇、丙酮与***中的一种或多种。Preferably, the solvent is one or more of water, isopropanol, ethanol, acetone and ether.
任选地，所述溶剂为乙醇与***的混合溶剂，其中乙醇与***的体积比优选为1:1。Optionally, the solvent is a mixed solvent of ethanol and ether, wherein the volume ratio of ethanol and ether is preferably 1:1.
任选地，所述溶剂为乙醇与丙酮的混合溶剂，其中乙醇与丙酮的体积比优选为1:1。Optionally, the solvent is a mixed solvent of ethanol and acetone, wherein the volume ratio of ethanol to acetone is preferably 1:1.
任选地，所述溶剂为水。Optionally, the solvent is water.
优选地，所述搅拌在20-60℃下进行。更优选地，所述搅拌在约25℃或约50℃下进行。Preferably, the stirring is performed at 20-60°C. More preferably, the stirring is performed at about 25°C or about 50°C.
优选地，所述搅拌持续约24小时。Preferably, said agitation is continued for about 24 hours.
在优选的实施方案中，所述式(I)的化合物与所述溶剂的重量体积比(mg/mL)为(10-30):1，优选为约20:1。In a preferred embodiment, the weight-to-volume ratio (mg/mL) of the compound of formula (I) to the solvent is (10-30):1, preferably about 20:1.
在一些实施方案中，所述挥发法包括将式(I)的化合物加入至溶剂中，混匀，溶解；在20℃～60℃下挥发至有固体析出，过滤以收集固体。In some embodiments, the volatilization method includes adding the compound of formula (I) into a solvent, mixing, and dissolving; volatilizing at 20° C. to 60° C. until solids are precipitated, and filtering to collect the solids.
在优选的实施方案中，所述挥发法中的溶剂选自水和具有1-10个碳原子的醇类溶剂(例如甲醇、乙醇、异戊醇等)，或者它们的混合溶剂；优选地，所述溶剂为水或者甲醇与水的混合溶剂(甲醇与水的体积比优选为约1:1)。In a preferred embodiment, the solvent in the volatilization method is selected from water and alcohol solvents (such as methanol, ethanol, isoamyl alcohol, etc.) with 1-10 carbon atoms, or their mixed solvents; preferably, The solvent is water or a mixed solvent of methanol and water (the volume ratio of methanol to water is preferably about 1:1).
在优选的实施方案中，所述挥发在约25℃或约50℃下进行。In preferred embodiments, the volatilization is performed at about 25°C or about 50°C.
在优选的实施方案中，所述式(I)的化合物与所述溶剂的重量体积比(mg/mL)为(5-30):1，优选为约10:1。In a preferred embodiment, the weight-to-volume ratio (mg/mL) of the compound of formula (I) to the solvent is (5-30):1, preferably about 10:1.
在一些实施方案中，所述冷却法包括将式(I)的化合物加入至溶剂(优选为水)中，加热(优选加热至50-80℃，最优选约70℃)以使化合物完全溶解，冷却结晶，过滤以收集固体。In some embodiments, the cooling method comprises adding the compound of formula (I) into a solvent (preferably water), heating (preferably heating to 50-80°C, most preferably about 70°C) to completely dissolve the compound, Cool to crystallize and filter to collect the solid.
在优选的实施方案中，所述式(I)的化合物与所述溶剂的重量体积比(mg/mL)为(5-30):1，优选为约8:1。In a preferred embodiment, the weight-to-volume ratio (mg/mL) of the compound of formula (I) to the solvent is (5-30):1, preferably about 8:1.
在一些实施方案中，所述气液渗透法包括将式(I)的化合物在第一容器的良溶剂中溶解，向第二容器中装入反溶剂，将第一容器敞口放置于第二容器中，将第二容器密封并静置，将析出的固体过滤得到晶体。In some embodiments, the gas-liquid osmosis method comprises dissolving the compound of formula (I) in a good solvent in a first container, loading an anti-solvent into a second container, and placing the first container open in the second container. In the container, the second container was sealed and left to stand, and the precipitated solid was filtered to obtain crystals.
在优选的实施方案中，所述气液渗透法中的良溶剂为具有1-10个碳原子的卤代烃溶剂，例如氯仿等；所述反溶剂为具有5-10个碳原子的烃类溶剂，例如正己烷、正庚烷、石油醚等。In a preferred embodiment, the good solvent in the gas-liquid infiltration method is a halogenated hydrocarbon solvent with 1-10 carbon atoms, such as chloroform, etc.; the anti-solvent is a hydrocarbon with 5-10 carbon atoms Solvents, such as n-hexane, n-heptane, petroleum ether, etc.
在优选的实施方案中，所述式(I)的化合物与良溶剂的重量体积比(mg/mL)为约(1-10):1。在优选的实施方案中，所述良溶剂与反溶剂的体积比为1:(1-10)。在优选的实施方案中，所述将第二容器密封并静置可在室温下进行。In a preferred embodiment, the weight-to-volume ratio (mg/mL) of the compound of formula (I) to the good solvent is about (1-10):1. In a preferred embodiment, the volume ratio of the good solvent to the anti-solvent is 1:(1-10). In a preferred embodiment, said sealing and standing of the second container may be performed at room temperature.
晶型CForm C
在另一个实施方案中，本发明提供式(I)的化合物的晶型C，所述晶型C的XRPD图谱包括在约10.8±0.2°、14.3±0.2°、16.9±0.2°、18.0±0.2°、18.5±0.2°、24.8±0.2°和25.3±0.2°的衍射角(2θ)处的特征峰。In another embodiment, the present invention provides crystalline form C of the compound of formula (I), the XRPD pattern of said crystalline form C comprises at about 10.8±0.2°, 14.3±0.2°, 16.9±0.2°, 18.0±0.2 The characteristic peaks at the diffraction angles (2θ) of 18.5±0.2°, 24.8±0.2° and 25.3±0.2°.
在另一个实施方案中，本发明提供式(I)的化合物的晶型C，所述晶型C的XRPD图谱包括在约10.8±0.2°、12.7±0.2°、14.0±0.2°、14.3±0.2°、15.6±0.2°、16.9±0.2°、18.0±0.2°、18.5±0.2°、20.0±0.2°、24.0±0.2°、24.8±0.2°、25.3±0.2°和26.5±0.2°的衍射角(2θ)处的特征峰。In another embodiment, the present invention provides crystalline form C of the compound of formula (I), the XRPD pattern of said crystalline form C comprises at about 10.8±0.2°, 12.7±0.2°, 14.0±0.2°, 14.3±0.2 °, 15.6±0.2°, 16.9±0.2°, 18.0±0.2°, 18.5±0.2°, 20.0±0.2°, 24.0±0.2°, 24.8±0.2°, 25.3±0.2° and 26.5±0.2° The characteristic peak at 2θ).
在优选实施方案中，所述式(I)的化合物的晶型C的XRPD图谱包括在约10.8±0.2°、12.7±0.2°、14.0±0.2°、14.3±0.2°、15.6±0.2°、16.5±0.2°、16.9±0.2°、18.0±0.2°、18.5±0.2°、20.0±0.2°、21.9±0.2°、 22.4±0.2°、23.2±0.2°、24.0±0.2°、24.8±0.2°、25.3±0.2°、25.9±0.2°、26.5±0.2°、28.4±0.2°、29.5±0.2°和35.2±0.2°的衍射角(2θ)处的特征峰。In a preferred embodiment, the XRPD pattern of the crystalline form C of the compound of formula (I) comprises a temperature range of about 10.8±0.2°, 12.7±0.2°, 14.0±0.2°, 14.3±0.2°, 15.6±0.2°, 16.5 ±0.2°, 16.9±0.2°, 18.0±0.2°, 18.5±0.2°, 20.0±0.2°, 21.9±0.2°, 22.4±0.2°, 23.2±0.2°, 24.0±0.2°, 24.8±0.2°, 25.3 Characteristic peaks at diffraction angles (2θ) of ±0.2°, 25.9±0.2°, 26.5±0.2°, 28.4±0.2°, 29.5±0.2° and 35.2±0.2°.
在更优选的实施方案中，所述式(I)的化合物的晶型C的XRPD图谱包括与图4a所示基本上相同的衍射角(2θ)处的特征峰。在最优选的实施方案中，所述式(I)的化合物的晶型C的XRPD图谱与图4a所示基本上相同。In a more preferred embodiment, the XRPD pattern of Form C of the compound of formula (I) includes characteristic peaks at substantially the same diffraction angle (2θ) as shown in Figure 4a. In the most preferred embodiment, the XRPD pattern of Form C of the compound of formula (I) is substantially the same as that shown in Figure 4a.
在优选的实施方案中，本发明的式(I)的化合物的晶型C的DSC图谱包括在约197.6±0.2℃处的特征峰。在更优选的实施方案中，本发明的式(I)的化合物的晶型C的DSC图谱包括与图4c所示基本上相同的温度处的特征峰。在最优选的实施方案中，所述式(I)的化合物的晶型C的DSC图谱与图4c所示基本上相同。In a preferred embodiment, the DSC spectrum of Form C of the compound of formula (I) of the present invention comprises a characteristic peak at about 197.6±0.2°C. In a more preferred embodiment, the DSC spectrum of Form C of the compound of formula (I) of the present invention comprises characteristic peaks at substantially the same temperature as shown in Figure 4c. In the most preferred embodiment, the DSC spectrum of Form C of the compound of formula (I) is substantially the same as that shown in Figure 4c.
在优选的实施方案中，本发明的式(I)的化合物的晶型C的TGA图谱与图4b所示基本相同。In a preferred embodiment, the TGA spectrum of Form C of the compound of formula (I) of the present invention is substantially the same as that shown in Figure 4b.
在优选的实施方案中，本方明的式(I)的化合物的晶型C为非水合物、非溶剂合物。In a preferred embodiment, the crystal form C of the compound of formula (I) of the present invention is non-hydrate, non-solvate.
在一些实施方案中，本发明还提供晶型C的制备方法，所述方法为悬浮搅拌法，其包括将式(I)的化合物加入溶剂中，在20-60℃下搅拌，然后将其过滤，得到晶体。In some embodiments, the present invention also provides a preparation method of Form C, which is a suspension stirring method, which comprises adding the compound of formula (I) into a solvent, stirring at 20-60°C, and then filtering it , to obtain crystals.
在优选的实施方案中，所述溶剂为具有1-10个碳原子的酮类溶剂(例如丙酮、甲乙酮、甲基异丁基酮等)、腈类溶剂(例如乙腈等)、酯类溶剂(例如乙酸乙酯、乙酸异丙酯等)、醚类溶剂(例如甲基叔丁基醚、***、四氢呋喃等)、醇类溶剂(例如甲醇、乙醇、异戊醇等)、卤代烃类溶剂(例如二氯甲烷或氯仿)，或者它们的混合溶剂。In a preferred embodiment, the solvent is a ketone solvent with 1-10 carbon atoms (such as acetone, methyl ethyl ketone, methyl isobutyl ketone, etc.), a nitrile solvent (such as acetonitrile, etc.), an ester solvent ( Such as ethyl acetate, isopropyl acetate, etc.), ether solvents (such as methyl tert-butyl ether, diethyl ether, tetrahydrofuran, etc.), alcohol solvents (such as methanol, ethanol, isoamyl alcohol, etc.), halogenated hydrocarbon solvents (such as dichloromethane or chloroform), or their mixed solvents.
在优选的实施方案中，所述溶剂为丙酮，或者氯仿与异戊醇的混合溶剂(体积比优选为1:1)。In a preferred embodiment, the solvent is acetone, or a mixed solvent of chloroform and isoamyl alcohol (the volume ratio is preferably 1:1).
优选地，所述搅拌在20-50℃下进行。更优选地，所述搅拌在约25℃或约50℃下进行。Preferably, the stirring is performed at 20-50°C. More preferably, the stirring is performed at about 25°C or about 50°C.
优选地，所述搅拌持续约24小时。Preferably, the stirring is continued for about 24 hours.
在一些实施方案中，所述式(I)的化合物与所述溶剂的重量体积比(mg/mL)为(10-30):1，优选为约20:1。In some embodiments, the weight-to-volume ratio (mg/mL) of the compound of formula (I) to the solvent is (10-30):1, preferably about 20:1.
晶型DForm D
在另一个实施方案中，本发明提供式(I)的化合物的晶型D，所述晶型D的XRPD图谱包括在约9.0±0.2°、11.4±0.2°、16.7±0.2°、18.6±0.2°、24.6±0.2°、25.7±0.2°和27.2±0.2°的衍射角(2θ)处的特征峰。In another embodiment, the present invention provides the crystal form D of the compound of formula (I), the XRPD spectrum of the crystal form D comprises the temperature at about 9.0±0.2°, 11.4±0.2°, 16.7±0.2°, 18.6±0.2 °, 24.6±0.2°, 25.7±0.2° and 27.2±0.2° diffraction angles (2θ) at the characteristic peaks.
在优选的实施方案中，本发明提供式(I)的化合物的晶型D，所述晶型D的XRPD图谱包括在约9.0±0.2°、11.4±0.2°、15.0±0.2°、16.7±0.2°、18.6±0.2°、19.6±0.2°、24.6±0.2°、25.7±0.2°和27.2±0.2°的衍射角(2θ)处的特征峰。In a preferred embodiment, the present invention provides the crystal form D of the compound of formula (I), and the XRPD pattern of the crystal form D includes the crystal form D at about 9.0±0.2°, 11.4±0.2°, 15.0±0.2°, 16.7±0.2 °, 18.6±0.2°, 19.6±0.2°, 24.6±0.2°, 25.7±0.2° and 27.2±0.2° diffraction angles (2θ).
在优选的实施方案中，本发明提供式(I)的化合物的晶型D，所述晶型D的XRPD图谱包括在约9.0±0.2°、11.4±0.2°、15.0±0.2°、16.7±0.2°、18.6±0.2°、19.6±0.2°、21.2±0.2°、22.6±0.2°、24.6±0.2°、25.7±0.2°、27.2±0.2°和28.9±0.2°的衍射角(2θ)处的特征峰。In a preferred embodiment, the present invention provides the crystal form D of the compound of formula (I), and the XRPD pattern of the crystal form D includes the crystal form D at about 9.0±0.2°, 11.4±0.2°, 15.0±0.2°, 16.7±0.2 Features at diffraction angles (2θ) of °, 18.6±0.2°, 19.6±0.2°, 21.2±0.2°, 22.6±0.2°, 24.6±0.2°, 25.7±0.2°, 27.2±0.2° and 28.9±0.2° peak.
在优选实施方案中，所述式(I)的化合物的晶型D的XRPD图谱包括在约9.0±0.2°、11.4±0.2°、15.0±0.2°、16.7±0.2°、17.6±0.2°、18.6±0.2°、19.6±0.2°、20.0±0.2°、21.2±0.2°、21.8±0.2°、22.6±0.2°、24.6±0.2°、25.7±0.2°、26.7±0.2°、27.2±0.2°、28.9±0.2°和31.5±0.2°的衍射角(2θ)处的特征峰。In a preferred embodiment, the XRPD pattern of the crystalline form D of the compound of formula (I) comprises a temperature range of about 9.0±0.2°, 11.4±0.2°, 15.0±0.2°, 16.7±0.2°, 17.6±0.2°, 18.6 ±0.2°, 19.6±0.2°, 20.0±0.2°, 21.2±0.2°, 21.8±0.2°, 22.6±0.2°, 24.6±0.2°, 25.7±0.2°, 26.7±0.2°, 27.2±0.2°, 28.9 Characteristic peaks at diffraction angles (2θ) of ±0.2° and 31.5±0.2°.
在更优选的实施方案中，所述式(I)的化合物的晶型D的XRPD图谱包括与图5a所示基本上相同的衍射角(2θ)处的特征峰。在最优选的实施方案中，所述式(I)的化合物的晶型D的XRPD图谱与图5a所示基本上相同。In a more preferred embodiment, the XRPD pattern of the crystalline form D of the compound of formula (I) includes characteristic peaks at substantially the same diffraction angle (2θ) as shown in Figure 5a. In the most preferred embodiment, the XRPD pattern of Form D of the compound of formula (I) is substantially the same as that shown in Figure 5a.
在更优选的实施方案中，所述式(I)的化合物的晶型D的XRPD图谱包括与图5a-1所示基本上相同的衍射角(2θ)处的特征峰。在最优选的实施方案中，所述式(I)的化合物的晶型D的XRPD图谱与图5a-1所示基本上相同。In a more preferred embodiment, the XRPD pattern of the crystalline form D of the compound of formula (I) includes characteristic peaks at substantially the same diffraction angle (2θ) as shown in Figure 5a-1. In the most preferred embodiment, the XRPD pattern of the crystalline form D of the compound of formula (I) is substantially the same as that shown in Figure 5a-1.
在优选的实施方案中，本发明的式(I)的化合物的晶型D的DSC图谱包括在约163.6±0.2℃处的特征峰。在更优选的实施方案中，本发明的式(I)的化合物的晶型D的DSC图谱包括与图5c所示基本上相同的温度处的特征峰。在最优选的实施方案中，所述式(I)的化合物的晶型D的DSC图谱与图5c所示基本上相同。In a preferred embodiment, the DSC spectrum of Form D of the compound of formula (I) of the present invention comprises a characteristic peak at about 163.6±0.2°C. In a more preferred embodiment, the DSC spectrum of Form D of the compound of formula (I) of the present invention comprises characteristic peaks at substantially the same temperature as shown in Figure 5c. In the most preferred embodiment, the DSC spectrum of the crystalline form D of the compound of formula (I) is substantially the same as that shown in Figure 5c.
优选地，本方明的式(I)的化合物的晶型D为水合物，含水量为4.8％-5.7％。Preferably, the crystal form D of the compound of formula (I) of the present invention is a hydrate with a water content of 4.8%-5.7%.
更优选地，本方明的式(I)的化合物的晶型D为倍半水合物。More preferably, the crystal form D of the compound of formula (I) of the present invention is a sesquihydrate.
在一些实施方案中，本发明还提供晶型D的制备方法，所述方法包括但不限于：悬浮搅拌法和挥发法。In some embodiments, the present invention also provides a preparation method of Form D, which includes but not limited to: suspension stirring method and volatilization method.
在一些实施方案中，所述方法为悬浮搅拌法，其包括将式(I)的化合物加入溶剂中，在20-80℃下搅拌，然后将其过滤，得到晶型D。In some embodiments, the method is a suspension stirring method, which comprises adding the compound of formula (I) into a solvent, stirring at 20-80°C, and then filtering it to obtain Form D.
在一些实施方案中，所述溶剂选自水、具有1-10个碳原子的醇类溶剂(例如甲醇、乙醇、异丙醇、异戊醇等)、卤代烃类溶剂(例如氯仿等)，或者它们的混合溶剂。In some embodiments, the solvent is selected from water, alcoholic solvents having 1-10 carbon atoms (such as methanol, ethanol, isopropanol, isoamyl alcohol, etc.), halogenated hydrocarbon solvents (such as chloroform, etc.) , or their mixed solvents.
优选地，所述溶剂为乙醇；异戊醇；乙醇与水的混合溶剂；或者异戊醇与水的混合溶剂。Preferably, the solvent is ethanol; isoamyl alcohol; a mixed solvent of ethanol and water; or a mixed solvent of isoamyl alcohol and water.
更优选地，所述混合溶剂中乙醇与水的体积比为7:1。更优选地，所述混合溶剂中异戊醇与水的体积比为7:1。More preferably, the volume ratio of ethanol to water in the mixed solvent is 7:1. More preferably, the volume ratio of isoamyl alcohol to water in the mixed solvent is 7:1.
优选地，所述搅拌在20-60℃下进行。更优选地，所述搅拌在约25℃或约50℃下进行。Preferably, the stirring is performed at 20-60°C. More preferably, the stirring is performed at about 25°C or about 50°C.
优选地，所述搅拌持续约24小时。Preferably, the stirring is continued for about 24 hours.
在优选的实施方案中，所述式(I)的化合物与所述溶剂的重量体积比(mg/mL)为(10-60):1，优选为约20:1或者约50:1。In a preferred embodiment, the weight-to-volume ratio (mg/mL) of the compound of formula (I) to the solvent is (10-60):1, preferably about 20:1 or about 50:1.
在一些实施方案中，所述挥发法包括将式(I)的化合物加入至溶剂中，混匀，溶解；在20℃～60℃下挥发至有固体析出，过滤以收集固体。In some embodiments, the volatilization method includes adding the compound of formula (I) into a solvent, mixing, and dissolving; volatilizing at 20° C. to 60° C. until solids are precipitated, and filtering to collect the solids.
在优选的实施方案中，所述挥发法中的溶剂选自水和具有1-10个碳原子的酮类溶剂(例如丙酮或甲乙酮等)，或者它们的混合溶剂；优选地，所述溶剂为甲乙酮与水的混合溶剂(甲乙酮与水的体积比优选为约1:1)。In a preferred embodiment, the solvent in the volatilization method is selected from water and ketone solvents (such as acetone or methyl ethyl ketone, etc.) with 1-10 carbon atoms, or their mixed solvents; preferably, the solvent is A mixed solvent of methyl ethyl ketone and water (the volume ratio of methyl ethyl ketone to water is preferably about 1:1).
在优选的实施方案中，所述挥发在25℃下进行。In a preferred embodiment, said volatilization is performed at 25°C.
在优选的实施方案中，所述式(I)的化合物与所述溶剂的重量体积比(mg/mL)为(5-30):1，优选为约10:1。In a preferred embodiment, the weight-to-volume ratio (mg/mL) of the compound of formula (I) to the solvent is (5-30):1, preferably about 10:1.
晶型EForm E
在另一个实施方案中，本发明提供式(I)的化合物的晶型E，所述晶型E的XRPD图谱包括在约9.3±0.2°、11.9±0.2°、12.6±0.2°、14.4±0.2°、17.2±0.2°、18.9±0.2°和24.9±0.2°的衍射角(2θ)处的特征峰。In another embodiment, the present invention provides the crystalline form E of the compound of formula (I), the XRPD spectrum of said crystalline form E comprises the temperature at about 9.3±0.2°, 11.9±0.2°, 12.6±0.2°, 14.4±0.2 The characteristic peaks at the diffraction angles (2θ) of 17.2±0.2°, 18.9±0.2° and 24.9±0.2°.
在优选的实施方案中，本发明提供式(I)的化合物的晶型E，所述晶型E的XRPD图谱包括在约9.3±0.2°、11.9±0.2°、12.6±0.2°、13.2±0.2°、14.4±0.2°、15.1±0.2°、15.6±0.2°、17.2±0.2°、18.1±0.2°、18.9±0.2°、19.5±0.2°、21.2±0.2°、23.7±0.2°、24.3±0.2°、24.9±0.2°、26.3±0.2°和27.0±0.2°的衍射角(2θ)处的特征峰。In a preferred embodiment, the present invention provides the crystalline form E of the compound of formula (I), the XRPD pattern of the crystalline form E includes the crystal form E at about 9.3±0.2°, 11.9±0.2°, 12.6±0.2°, 13.2±0.2 °, 14.4±0.2°, 15.1±0.2°, 15.6±0.2°, 17.2±0.2°, 18.1±0.2°, 18.9±0.2°, 19.5±0.2°, 21.2±0.2°, 23.7±0.2°, 24.3±0.2 °, 24.9±0.2°, 26.3±0.2° and 27.0±0.2° diffraction angles (2θ) at the characteristic peaks.
在优选实施方案中，所述式(I)的化合物的晶型E的XRPD图谱包括在约9.3±0.2°、10.4±0.2°、11.9±0.2°、12.6±0.2°、13.2±0.2°、14.4±0.2°、15.1±0.2°、15.6±0.2°、16.9±0.2°、17.2±0.2°、18.1±0.2°、18.6±0.2°、18.9±0.2°、19.5±0.2°、21.2±0.2°、21.6±0.2°、22.0±0.2°、23.7±0.2°、24.3±0.2°、24.9±0.2°、25.2±0.2°、26.0±0.2°、26.3±0.2°、27.0±0.2°、28.1±0.2°、31.5±0.2°和34.2±0.2°的衍射角(2θ)处的特征峰。In a preferred embodiment, the XRPD pattern of the crystalline form E of the compound of formula (I) comprises a temperature range of about 9.3±0.2°, 10.4±0.2°, 11.9±0.2°, 12.6±0.2°, 13.2±0.2°, 14.4 ±0.2°, 15.1±0.2°, 15.6±0.2°, 16.9±0.2°, 17.2±0.2°, 18.1±0.2°, 18.6±0.2°, 18.9±0.2°, 19.5±0.2°, 21.2±0.2°, 21.6 ±0.2°, 22.0±0.2°, 23.7±0.2°, 24.3±0.2°, 24.9±0.2°, 25.2±0.2°, 26.0±0.2°, 26.3±0.2°, 27.0±0.2°, 28.1±0.2°, 31.5 Characteristic peaks at diffraction angles (2θ) of ±0.2° and 34.2±0.2°.
在更优选实施方案中，所述式(I)的化合物的晶型E的XRPD图谱包括与图6a所示基本上相同的衍射角(2θ)处的特征峰。在最优选的实施方案中，所述式(I)的化合物的晶型E的XRPD图谱与图6a所示基本上相同。In a more preferred embodiment, the XRPD pattern of Form E of the compound of formula (I) includes characteristic peaks at substantially the same diffraction angle (2θ) as shown in Figure 6a. In the most preferred embodiment, the XRPD pattern of Form E of the compound of formula (I) is substantially the same as that shown in Figure 6a.
在优选的实施方案中，本发明的式(I)的化合物的晶型E的DSC图谱包括在约201.8±0.2℃处的特征峰。在更优选的实施方案中，本发明的式(I)的化合物的晶型E的DSC图谱包括与图6c所示基本上相同的温度处的特征峰。在最优选的实施方案中，所述式(I)的化合物的晶型E的DSC图谱与图6c所示基本上相同。In a preferred embodiment, the DSC spectrum of Form E of the compound of formula (I) of the present invention comprises a characteristic peak at about 201.8±0.2°C. In a more preferred embodiment, the DSC spectrum of Form E of the compound of formula (I) of the present invention comprises characteristic peaks at substantially the same temperature as shown in Figure 6c. In the most preferred embodiment, the DSC spectrum of Form E of the compound of formula (I) is substantially the same as that shown in Figure 6c.
在优选的实施方案中，本方明的式(I)的化合物的晶型E为非水合物、非溶剂合物。In a preferred embodiment, the crystal form E of the compound of formula (I) of the present invention is non-hydrate, non-solvate.
在一些实施方案中，本发明还提供晶型E的制备方法，所述方法为悬浮搅拌法，其包括将式(I)的化合物加入有机溶剂中，在40-60℃下搅拌，然后将其过滤，得到晶型E。In some embodiments, the present invention also provides a preparation method of Form E, which is a suspension stirring method, which comprises adding the compound of formula (I) into an organic solvent, stirring at 40-60°C, and then Filter to obtain Form E.
在优选的实施方案中，所述有机溶剂选自硝基甲烷，或硝基甲烷与其它有机溶剂的混合溶剂。In a preferred embodiment, the organic solvent is selected from nitromethane, or a mixed solvent of nitromethane and other organic solvents.
所述其它有机溶剂为例如具有1-10个碳原子的醇类、醚类、酯类、酮类或卤代烃类溶剂。所述醇类溶剂例如为异戊醇或甲醇，所述醚类溶剂例如为四氢呋喃或***，所述酯类溶剂例如为乙酸乙酯，所述酮类溶剂例如为丙酮、甲乙酮或甲基异丁基酮，所述卤代烃类溶剂例如为二氯甲烷。The other organic solvents are, for example, alcohols, ethers, esters, ketones or halogenated hydrocarbon solvents having 1-10 carbon atoms. The alcohol solvent is, for example, isoamyl alcohol or methanol, the ether solvent is, for example, tetrahydrofuran or ether, the ester solvent is, for example, ethyl acetate, and the ketone solvent is, for example, acetone, methyl ethyl ketone or methyl isobutyl base ketone, the halogenated hydrocarbon solvent is, for example, dichloromethane.
优选地，所述搅拌在约50℃下进行。Preferably, the stirring is performed at about 50°C.
优选地，所述搅拌持续约24小时。Preferably, the stirring is continued for about 24 hours.
在一些实施方案中，所述式(I)的化合物与所述有机溶剂的重量体积比(mg/mL)为(10-30):1，优选为约20:1。In some embodiments, the weight-to-volume ratio (mg/mL) of the compound of formula (I) to the organic solvent is (10-30):1, preferably about 20:1.
晶型FForm F
在另一个实施方案中，本发明提供式(I)的化合物的晶型F，所述晶型F的XRPD图谱包括在约8.9±0.2°、11.3±0.2°、14.8±0.2°、15.2±0.2°、16.1±0.2°、16.4±0.2°、17.8±0.2°、18.6±0.2°、19.4±0.2°、20.8±0.2°、21.3±0.2°、24.8±0.2°和27.4±0.2°的衍射角(2θ)处的特征峰。In another embodiment, the present invention provides the crystalline form F of the compound of formula (I), the XRPD spectrum of the crystalline form F comprises the temperature at about 8.9±0.2°, 11.3±0.2°, 14.8±0.2°, 15.2±0.2 °, 16.1±0.2°, 16.4±0.2°, 17.8±0.2°, 18.6±0.2°, 19.4±0.2°, 20.8±0.2°, 21.3±0.2°, 24.8±0.2° and 27.4±0.2° The characteristic peak at 2θ).
在优选实施方案中，所述式(I)的化合物的晶型F的XRPD图谱包括约6.4±0.2°、8.9±0.2°、10.8±0.2°、11.3±0.2°、13.6±0.2°、14.8±0.2°、15.2±0.2°、15.7±0.2°、16.1±0.2°、16.4±0.2°、17.0±0.2°、17.8±0.2°、18.6±0.2°、19.4±0.2°、19.9±0.2°、20.8±0.2°、21.3±0.2°、21.8±0.2°、22.5±0.2°、23.4±0.2°、23.9±0.2°、24.8±0.2°、27.4±0.2°、28.1±0.2°、28.7±0.2°、30.1±0.2°和32.6±0.2°的衍射角(2θ)处的峰。In a preferred embodiment, the XRPD pattern of Form F of the compound of formula (I) includes about 6.4±0.2°, 8.9±0.2°, 10.8±0.2°, 11.3±0.2°, 13.6±0.2°, 14.8±0.2° 0.2°, 15.2±0.2°, 15.7±0.2°, 16.1±0.2°, 16.4±0.2°, 17.0±0.2°, 17.8±0.2°, 18.6±0.2°, 19.4±0.2°, 19.9±0.2°, 20.8± 0.2°, 21.3±0.2°, 21.8±0.2°, 22.5±0.2°, 23.4±0.2°, 23.9±0.2°, 24.8±0.2°, 27.4±0.2°, 28.1±0.2°, 28.7±0.2°, 30.1± Peaks at diffraction angles (2Θ) of 0.2° and 32.6±0.2°.
在更优选的实施方案中，所述式(I)的化合物的晶型F的XRPD图谱包括与图7a所示基本上相同的衍射角(2θ)处的特征峰。在最优选的实施方案中，所述式(I)的化合物的晶型F的XRPD图谱与图7a所示基本上相同。In a more preferred embodiment, the XRPD pattern of Form F of the compound of formula (I) includes characteristic peaks at substantially the same diffraction angle (2θ) as shown in Figure 7a. In the most preferred embodiment, the XRPD pattern of Form F of the compound of formula (I) is substantially the same as that shown in Figure 7a.
在优选的实施方案中，本发明的式(I)的化合物的晶型F的DSC图谱包括在约153.9±0.2℃处的特征峰。In a preferred embodiment, the DSC spectrum of Form F of the compound of formula (I) of the present invention comprises a characteristic peak at about 153.9±0.2°C.
在更优选的实施方案中，本发明的式(I)的化合物的晶型F的DSC图谱包括与图7c所示基本上相同的温度处的特征峰。在最优选的实施方案中，所述式(I)的化合物的晶型F的DSC图谱与图7c所示基本上相同。In a more preferred embodiment, the DSC spectrum of Form F of the compound of formula (I) of the present invention comprises characteristic peaks at substantially the same temperature as shown in Figure 7c. In the most preferred embodiment, the DSC spectrum of Form F of the compound of formula (I) is substantially the same as that shown in Figure 7c.
在优选的实施方案中，本方明的式(I)的化合物的晶型F为水合物。In a preferred embodiment, the crystal form F of the compound of formula (I) of the present invention is a hydrate.
在一些实施方案中，本发明还提供晶型F的制备方法，所述方法包括但不限于：悬浮搅拌法和挥发法。In some embodiments, the present invention also provides a preparation method of Form F, which includes but not limited to: suspension stirring method and volatilization method.
在一些实施方案中，所述方法为悬浮搅拌法，其包括将式(I)的化合物加入溶剂中，在20-80℃下搅拌，然后将其过滤，得到晶型F。In some embodiments, the method is a suspension stirring method, which comprises adding the compound of formula (I) into a solvent, stirring at 20-80°C, and then filtering it to obtain Form F.
在一些实施方案中，所述溶剂选自水、具有1-10个碳原子的醇类溶剂(例如甲醇、乙醇、异丙醇、异戊醇等)、醚类溶剂(例如***等)、酮类溶剂(例如甲乙酮、甲基异丁基酮等)、芳香烃类溶剂(例如甲苯等)、卤代烃类溶剂(例如氯仿等)，或者它们的混合溶剂。In some embodiments, the solvent is selected from water, alcohol solvents having 1-10 carbon atoms (such as methanol, ethanol, isopropanol, isoamyl alcohol, etc.), ether solvents (such as diethyl ether, etc.), ketones solvents (such as methyl ethyl ketone, methyl isobutyl ketone, etc.), aromatic hydrocarbon solvents (such as toluene, etc.), halogenated hydrocarbon solvents (such as chloroform, etc.), or their mixed solvents.
优选地，所述溶剂为氯仿或者甲醇与乙醇的混合溶剂。Preferably, the solvent is chloroform or a mixed solvent of methanol and ethanol.
更优选地，所述混合溶剂中甲醇与乙醇的体积比为1:1。More preferably, the volume ratio of methanol to ethanol in the mixed solvent is 1:1.
优选地，所述搅拌在20-60℃下进行。更优选地，所述搅拌在约25℃或约50℃下进行。Preferably, the stirring is performed at 20-60°C. More preferably, the stirring is performed at about 25°C or about 50°C.
优选地，所述搅拌持续约24小时。Preferably, the stirring is continued for about 24 hours.
在优选的实施方案中，所述式(I)的化合物与所述溶剂的重量体积比(mg/mL)为(10-30):1，优选为约20:1。In a preferred embodiment, the weight-to-volume ratio (mg/mL) of the compound of formula (I) to the solvent is (10-30):1, preferably about 20:1.
在一些实施方案中，所述挥发法包括将式(I)的化合物加入至溶剂中，混匀，溶解；在20℃～60℃下挥发至有固体析出，过滤以收集固体。In some embodiments, the volatilization method includes adding the compound of formula (I) into a solvent, mixing, and dissolving; volatilizing at 20° C. to 60° C. until solids are precipitated, and filtering to collect the solids.
在优选的实施方案中，所述挥发法中的溶剂选自水和具有1-10个碳原子的醇类溶剂(例如甲醇、乙醇、异戊醇等)，或者它们的混合溶剂；优选地，所述溶剂为异戊醇与水的混合溶剂(异戊醇与水的体积比优选为约1:7)。In a preferred embodiment, the solvent in the volatilization method is selected from water and alcohol solvents (such as methanol, ethanol, isoamyl alcohol, etc.) with 1-10 carbon atoms, or their mixed solvents; preferably, The solvent is a mixed solvent of isoamyl alcohol and water (the volume ratio of isoamyl alcohol to water is preferably about 1:7).
在优选的实施方案中，所述挥发在25℃或50℃下进行，更优选在50℃下进行。In a preferred embodiment, said volatilization is carried out at 25°C or 50°C, more preferably at 50°C.
在优选的实施方案中，所述式(I)的化合物与所述溶剂的重量体积比(mg/mL)为(5-30):1，优选为约10:1。In a preferred embodiment, the weight-to-volume ratio (mg/mL) of the compound of formula (I) to the solvent is (5-30):1, preferably about 10:1.
晶型GForm G
在另一个实施方案中，本发明提供式(I)的化合物的晶型G，所述晶型G的XRPD图谱包括在约7.0±0.2°、12.2±0.2°、12.6±0.2°、15.4±0.2°、20.7±0.2°、21.3±0.2°和27.8±0.2°的衍射角(2θ)处的特征峰。In another embodiment, the present invention provides the crystalline form G of the compound of formula (I), the XRPD pattern of the crystalline form G includes the crystal form G at about 7.0±0.2°, 12.2±0.2°, 12.6±0.2°, 15.4±0.2 °, 20.7±0.2°, 21.3±0.2° and 27.8±0.2° diffraction angles (2θ) at the characteristic peaks.
在优选实施方案中，所述式(I)的化合物的晶型G的XRPD图谱包括在约7.0±0.2°、10.3±0.2°、12.2±0.2°、12.6±0.2°、15.4±0.2°、16.1±0.2°、19.1±0.2°、19.6±0.2°、20.7±0.2°、21.3±0.2°、26.7±0.2°、27.8±0.2°和28.6±0.2°的衍射角(2θ)处的峰。In a preferred embodiment, the XRPD pattern of the crystalline form G of the compound of formula (I) comprises a temperature range of about 7.0±0.2°, 10.3±0.2°, 12.2±0.2°, 12.6±0.2°, 15.4±0.2°, 16.1 Peaks at diffraction angles (2θ) of ±0.2°, 19.1±0.2°, 19.6±0.2°, 20.7±0.2°, 21.3±0.2°, 26.7±0.2°, 27.8±0.2° and 28.6±0.2°.
在更优选的实施方案中，所述式(I)的化合物的晶型G的XRPD图谱包括与图8a所示基本上相同的衍射角(2θ)处的特征峰。在最优选的实施方案中，所述式(I)的化合物的晶型G的XRPD图谱与图8a所示基本上相同。In a more preferred embodiment, the XRPD pattern of Form G of the compound of formula (I) includes characteristic peaks at substantially the same diffraction angle (2θ) as shown in Figure 8a. In the most preferred embodiment, the XRPD pattern of Form G of the compound of formula (I) is substantially the same as that shown in Figure 8a.
在优选的实施方案中，本发明的式(I)的化合物的晶型G的DSC图谱包括在约182.5±0.2℃处的特征峰。In a preferred embodiment, the DSC spectrum of Form G of the compound of formula (I) of the present invention comprises a characteristic peak at about 182.5±0.2°C.
在更优选的实施方案中，本发明的式(I)的化合物的晶型G的DSC图谱包括与图8c所示基本上相同的温度处的特征峰。在最优选的实施方案中，所述式(I)的化合物的晶型G的DSC图谱与图8c所示基本上相同。In a more preferred embodiment, the DSC spectrum of Form G of the compound of formula (I) of the present invention comprises characteristic peaks at substantially the same temperature as shown in Figure 8c. In the most preferred embodiment, the DSC spectrum of Form G of the compound of formula (I) is substantially the same as that shown in Figure 8c.
在优选的实施方案中，本方明的式(I)的化合物的晶型G为甲醇的溶剂合物。In a preferred embodiment, the crystal form G of the compound of formula (I) of the present invention is a solvate of methanol.
在一些实施方案中，本发明还提供晶型G的制备方法，所述方法为气液渗透法，其包括将式(I)的化合物在第一容器的良溶剂中溶解，向第二容器中装入反溶剂，将第一容器敞口放置于第二容器中，将第二容器密封并静置，将析出的固体过滤得到晶体。In some embodiments, the present invention also provides a method for the preparation of Form G, which is a gas-liquid infiltration method, which comprises dissolving the compound of formula (I) in a good solvent in a first container, and injecting it into a second container The anti-solvent is charged, the first container is opened and placed in the second container, the second container is sealed and left standing, and the precipitated solid is filtered to obtain crystals.
在优选的实施方案中，所述气液渗透法中的良溶剂为甲醇；所述反溶剂为乙醇。In a preferred embodiment, the good solvent in the gas-liquid osmosis method is methanol; the anti-solvent is ethanol.
在优选的实施方案中，所述式(I)的化合物与良溶剂的重量体积比(mg/mL)为约(1-10):1。在优选的实施方案中，所述良溶剂与反溶剂的体积比为1:(1-10)。在优选的实施方案中，所述将第二容器密封并静置可在室温下进行。In a preferred embodiment, the weight-to-volume ratio (mg/mL) of the compound of formula (I) to the good solvent is about (1-10):1. In a preferred embodiment, the volume ratio of the good solvent to the anti-solvent is 1:(1-10). In a preferred embodiment, said sealing and standing of the second container may be performed at room temperature.
药物组合物和用途Pharmaceutical composition and use
在另一实施方案中，本发明提供药物组合物，其包含本发明的式(I)的化合物的晶型A、晶型B、晶型C、晶型D、晶型E、晶型F和晶型G中的任意一种或多种，以及一种或多种药学上可接受的载体。In another embodiment, the present invention provides a pharmaceutical composition comprising Form A, Form B, Form C, Form D, Form E, Form F and Any one or more of the crystal forms G, and one or more pharmaceutically acceptable carriers.
在另一实施方案中，本发明提供本发明的式(I)的化合物的晶型A、晶型B、晶型C、晶型D、晶型E、晶型F和晶型G在制备用于预防或治疗维生素B1缺乏症和代谢相关障碍、精神类疾病和紊乱、糖尿病相关并发症和/或神经退行性疾病的药物中的用途。In another embodiment, the present invention provides crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E, crystalline form F and crystalline form G of the compound of formula (I) of the present invention for the preparation Use in medicines for preventing or treating vitamin B1 deficiency and metabolic-related disorders, mental diseases and disorders, diabetes-related complications and/or neurodegenerative diseases.
在另一实施方案中，本发明提供本发明的式(I)的化合物的晶型A、晶型B、晶型C、晶型D、晶型E、晶型F和晶型G，其用于预防或治疗维生素B1缺乏症和代谢相关障碍、精神类疾病和紊乱、糖尿病相关并发症和/或神经退行性疾病。In another embodiment, the present invention provides crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E, crystalline form F and crystalline form G of the compound of formula (I) of the present invention, which is used For the prevention or treatment of vitamin B1 deficiency and metabolic related disorders, psychiatric diseases and disorders, diabetes related complications and/or neurodegenerative diseases.
在另一实施方案中，本发明提供预防或治疗维生素B1缺乏症和代谢相关障碍、精神类疾病和紊乱、糖尿病相关并发症和/或神经退行性疾病的方法，其包括向需要其的个体(优选哺乳动物)给药预防或治疗有效量的本发明的式(I)的化合物的晶型A、晶型B、晶型C、晶型D、晶型E、晶型F和晶型G中的任意一种或多种。In another embodiment, the present invention provides a method of preventing or treating vitamin B1 deficiency and metabolic related disorders, psychiatric diseases and disorders, diabetes related complications and/or neurodegenerative diseases comprising administering to an individual in need thereof ( Preferable mammal) administration of prophylactically or therapeutically effective amount of the compound of formula (I) of the present invention in crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, crystal form F and crystal form G any one or more of.
在优选实施方案中，所述神经退行性疾病选自阿尔兹海默症、血管性痴呆和精神障碍。In a preferred embodiment, said neurodegenerative disease is selected from Alzheimer's disease, vascular dementia and mental disorders.
如本文中所使用的术语“药学上可接受的载体”是指与治疗剂一同给药的稀释剂、辅剂、赋形剂或媒介物，并且其在合理的医学判断的范围内适于接触人类和/或其它动物的组织而没有过度的毒性、刺激、过敏反应或与合理的益处/风险比相应的其它问题或并发症。The term "pharmaceutically acceptable carrier" as used herein refers to a diluent, adjuvant, excipient or vehicle with which a therapeutic agent is administered, and which is within the scope of sound medical judgment suitable for contacting Human and/or other animal tissues without undue toxicity, irritation, allergic response or other problems or complications commensurate with a reasonable benefit/risk ratio.
在本发明的药物组合物中可使用的药学上可接受的载体包括但不限于无菌液体，例如水和油，包括那些石油、动物、植物或合成来源的油，例如花生油、大豆油、矿物油、芝麻油等。当所述药物组合物通过静脉内给药时，水是示例性载体。还可以使用生理盐水和葡萄糖及甘油水溶液作为液体载体，特别是用于注射液。适合的药物赋形剂包括淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽糖、白垩、硅胶、硬脂酸钠、单硬脂酸甘油酯、滑石、氯化钠、脱脂奶粉、甘油、丙二醇、水、乙醇等。所述组合物还可以视需要包含少量的湿润剂、乳化剂或pH缓冲剂。口服制剂可以包含标准载体，如药物级的甘露醇、乳糖、淀粉、硬脂酸镁、糖精钠、纤维素、碳酸镁等。适合的药学上可接受的载体的实例如在Remington’s Pharmaceutical Sciences(1990)中所述。Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of this invention include, but are not limited to, sterile liquids such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. Physiological saline and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injections. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene glycol, water, ethanol etc. The composition, if desired, can also contain minor amounts of wetting agents, emulsifying agents, or pH buffering agents. Oral formulations can contain standard carriers, such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).
本发明的组合物可以***地作用和/或局部地作用。为此目的，它们可以适合的途径给药，例如通过注射、静脉内、动脉内、皮下、腹膜内、肌内或经皮给药；或通过口服、含服、经鼻、透粘膜、局部、以眼用制剂的形式或通过吸入给药。The compositions of the invention may act systemically and/or locally. For this purpose, they can be administered by suitable routes, for example by injection, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or transdermal administration; or by oral, buccal, nasal, transmucosal, topical, It is administered as an ophthalmic preparation or by inhalation.
对于这些给药途径，可以适合的剂型给药本发明的组合物。For these routes of administration, the compositions of the present invention can be administered in suitable dosage forms.
所述剂型可为固体制剂、半固体制剂、液体制剂或气态制剂，具体包括但不限于片剂、胶囊剂、散剂、颗粒剂、锭剂、硬糖剂、散剂、喷雾剂、乳膏剂、软膏剂、栓剂、凝胶剂、糊剂、洗剂、软膏剂、水性混悬剂、可注射溶液剂、混悬剂、酏剂、糖浆剂。The dosage forms can be solid preparations, semi-solid preparations, liquid preparations or gaseous preparations, specifically including but not limited to tablets, capsules, powders, granules, lozenges, hard candies, powders, sprays, creams, ointments elixirs, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, suspensions, elixirs, syrups.
本发明所述的药物组合物可以通过本领域熟知的任何方法来制备，例如通过混合、溶解、制粒、糖包衣、碾磨、乳化、冻干等处理来制备。The pharmaceutical composition of the present invention can be prepared by any method well known in the art, for example, by mixing, dissolving, granulating, sugar coating, milling, emulsifying, freeze-drying and other treatments.
如本文中所使用的术语“治疗有效量”指被给药后会在一定程度上缓解所治疗病症的一或多种症状的化合物的量。The term "therapeutically effective amount" as used herein refers to the amount of a compound which, when administered, alleviates to some extent one or more symptoms of the condition being treated.
可调整给药方案以提供最佳所需响应。例如，可给药单次推注，可随时间给药数个分剂量，或可如治疗情况的急需所表明而按比例减少或增加剂量。要注意，剂量值可随要减轻的病况的类型及 严重性而变化，且可包括单次或多次剂量。要进一步理解，对于任何特定个体，具体的给药方案应根据个体需要及给药组合物或监督组合物的给药的人员的专业判断来随时间调整。Dosage regimens may be adjusted to provide the optimum desired response. For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated and may comprise single or multiple doses. It is further understood that for any given individual, the specific dosing regimen will be adjusted over time according to the needs of the individual and the professional judgment of the person administering the composition or supervising the administration of the composition.
所给药的本发明的化合物的量会取决于所治疗的个体、病症或病况的严重性、给药的速率、化合物的处置及处方医师的判断。一般而言，有效剂量在每日每kg体重约0.0001至约50mg，例如约0.01至约10mg/kg/日(单次或分次给药)。对70kg的人而言，这会合计为约0.007mg/日至约3500mg/日，例如约0.7mg/日至约700mg/日。在一些情况下，不高于前述范围的下限的剂量水平可以是足够的，而在其它情况下，仍可在不引起任何有害副作用的情况下采用较大剂量，条件是首先将所述较大剂量分成数个较小剂量以在一整天中给药。The amount of a compound of this invention administered will depend on the individual being treated, the severity of the disorder or condition, the rate of administration, disposition of the compound, and the judgment of the prescribing physician. Generally, the effective dosage is about 0.0001 to about 50 mg per kg body weight per day, for example about 0.01 to about 10 mg/kg/day (single or divided administration). For a 70 kg human this would amount to about 0.007 mg/day to about 3500 mg/day, eg about 0.7 mg/day to about 700 mg/day. Dosage levels up to the lower limit of the foregoing range may be sufficient in some cases, while in other cases larger doses may still be employed without causing any deleterious side effects, provided that the larger dose is first administered. The dose is divided into several smaller doses to be administered throughout the day.
本发明的化合物在药物组合物中的含量或用量可以是约0.01mg至约1000mg，适合地是0.1-500mg，优选0.5-300mg，更优选1-150mg，特别优选1-50mg，例如1.5mg、2mg、4mg、10mg和25mg等。The content or amount of the compound of the present invention in the pharmaceutical composition can be about 0.01 mg to about 1000 mg, suitably 0.1-500 mg, preferably 0.5-300 mg, more preferably 1-150 mg, particularly preferably 1-50 mg, such as 1.5 mg, 2mg, 4mg, 10mg and 25mg etc.
除非另外说明，否则如本文中所使用，术语“治疗(treating)”意指逆转、减轻、抑制这样的术语所应用的病症或病况或者这样的病症或病况的一或多种症状的进展，或预防这样的病症或病况或者这样的病症或病况的一或多种症状。As used herein, unless otherwise stated, the term "treating" means reversing, alleviating, inhibiting the disorder or condition to which such term applies or the progression of one or more symptoms of such disorder or condition, or Such a disorder or condition or one or more symptoms of such a disorder or condition is prevented.
如本文所使用的“个体”包括人或非人动物。示例性人个体包括患有疾病(例如本文所述的疾病)的人个体(称为患者)或正常个体。本发明中“非人动物”包括所有脊椎动物，例如非哺乳动物(例如鸟类、两栖动物、爬行动物)和哺乳动物，例如非人灵长类、家畜和/或驯化动物(例如绵羊、犬、猫、奶牛、猪等)。"Individual" as used herein includes a human or non-human animal. Exemplary human subjects include human subjects suffering from a disease (eg, a disease described herein) (referred to as a patient) or normal subjects. "Non-human animals" in the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (e.g., sheep, dogs, , cats, cows, pigs, etc.).
实施例Example
以下将结合实施例更详细地解释本发明，本发明的实施例仅用于说明本发明的技术方案，并非用于限定本发明的范围，本领域技术人员可进行一些非本质的改进和调整，仍属于本发明的保护范围。The present invention will be explained in more detail below in conjunction with the examples. The examples of the present invention are only used to illustrate the technical solutions of the present invention, and are not intended to limit the scope of the present invention. Those skilled in the art can carry out some non-essential improvements and adjustments, Still belong to the protection scope of the present invention.
实施例中所用仪器和测试条件如下：Apparatus and test conditions used in the embodiment are as follows:
X射线粉末衍射(XRPD)：仪器型号：Bruker D8advance，靶：Cu Kα(40kV，40mA)，样品到检测器距离：30cm，扫描范围：3°-40°(2θ值)，扫描步径：0.1s。X-ray powder diffraction (XRPD): Instrument model: Bruker D8advance, target: Cu Kα (40kV, 40mA), distance from sample to detector: 30cm, scanning range: 3°-40° (2θ value), scanning step: 0.1 s.
仪器型号：日本理学公司Smart Lab 9KW，靶：Cu Kα(40kV，100mA)，样品到检测器距离：30cm，扫描范围：3°-50°(2θ值)，扫描步长：0.02°。Instrument model: Rigaku Smart Lab 9KW, target: Cu Kα (40kV, 100mA), distance from sample to detector: 30cm, scanning range: 3°-50° (2θ value), scanning step: 0.02°.
热重分析(TGA)：仪器型号：TA Discovery TGA55，温度范围：25-400℃，扫描速率：10℃/min，吹扫气：60ml/min，保护气：40mL/min。Thermogravimetric analysis (TGA): Instrument model: TA Discovery TGA55, temperature range: 25-400°C, scan rate: 10°C/min, purge gas: 60ml/min, protective gas: 40mL/min.
差示扫描量热分析(DSC)：仪器型号：TA DSC Q2000，温度范围：20-210℃，扫描速率：10℃/min，氮气流速：20mL/min。Differential scanning calorimetry (DSC): Instrument model: TA DSC Q2000, temperature range: 20-210°C, scan rate: 10°C/min, nitrogen flow rate: 20mL/min.
DVS分析：仪器型号：SMS DVS Advantage，湿度范围：0～95％RH，温度：25℃。DVS Analysis: Instrument Model: SMS DVS Advantage, Humidity Range: 0-95% RH, Temperature: 25°C.
红外分析，仪器型号：Thermo Scientific Nicolet 6700，扫描范围：4000至400cm-1，分辨率：4cm-1。Infrared analysis, instrument model: Thermo Scientific Nicolet 6700, scanning range: 4000 to 400cm-1, resolution: 4cm-1.
实施例1Example 1
式(I)的化合物((Z)-S-(2-(N–((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺)-5-(膦酰氧基)戊-2-烯-3-基)2-氟苯硫醇酯)的制备Compound of formula (I) ((Z)-S-(2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamide)-5-(phosphonooxy) Preparation of pent-2-en-3-yl)2-fluorobenzenethiol ester)
Figure PCTCN2022133152-appb-000004
Figure PCTCN2022133152-appb-000004
根据CN109111478A实施例9中公开的制备方法来制备式(I)的化合物。The compound of formula (I) was prepared according to the preparation method disclosed in Example 9 of CN109111478A.
将磷酸硫胺1a(38g，0.09mol)溶解在水(103g，5.7mol)中，冷却至0～5℃，滴加30％的氢氧化钠溶液(87.3g，0.65mol)，调节pH值在11～12之间，搅拌1.5小时。0～5℃下滴加2-氟苯甲酰氯(19g，0.12mol)，在滴加过程中控制pH值在11～12之间。滴加完毕后5～10℃反应2h。滴加浓盐酸(34g，0.33mol)，调节pH值在3～4之间，加入50mL乙酸乙酯搅拌16小时。过滤，滤饼干 燥后溶解在甲醇中，快速蒸干，得到无定形形式的式(I)的化合物，其XRPD图谱如图1a所示，TGA图谱如图1b所示，DSC图谱如图1c所示。Thiamine phosphate 1a (38g, 0.09mol) was dissolved in water (103g, 5.7mol), cooled to 0-5°C, and 30% sodium hydroxide solution (87.3g, 0.65mol) was added dropwise to adjust the pH value at Between 11 and 12, stir for 1.5 hours. 2-Fluorobenzoyl chloride (19 g, 0.12 mol) was added dropwise at 0-5°C, and the pH value was controlled between 11-12 during the dropwise addition. After the dropwise addition, react at 5-10°C for 2h. Concentrated hydrochloric acid (34 g, 0.33 mol) was added dropwise to adjust the pH value between 3 and 4, and 50 mL of ethyl acetate was added and stirred for 16 hours. Filter, dissolve in methanol after the filter cake is dried, evaporate to dryness quickly, obtain the compound of the formula (I) of amorphous form, its XRPD collection of illustrative plates as shown in Figure 1a, TGA collection of illustrative plates as shown in Figure 1b, DSC collection of illustrative plates as shown in Figure 1c Show.
实施例2：室温单一溶剂悬浮搅拌法制备晶型AExample 2: Preparation of Crystal Form A by Suspension and Stirring in a Single Solvent at Room Temperature
称取20mg实施例1中制备的式(I)的化合物，将其加入至3mL玻璃小瓶中，加入1mL硝基甲烷，将得到的悬浮液于25℃下磁力搅拌(500转/分钟)约24h，过滤悬浮液，固体部分在真空干燥箱中干燥10min，将该晶型称作晶型A(类白色粉末)。Weigh 20 mg of the compound of formula (I) prepared in Example 1, add it to a 3 mL glass vial, add 1 mL of nitromethane, and magnetically stir the resulting suspension (500 rpm) at 25 ° C for about 24 h , the suspension was filtered, and the solid part was dried in a vacuum oven for 10 min. This crystal form was called Form A (off-white powder).
对所获得的晶型A进行XRPD分析，所得XRPD图谱如图2a所示，其特征峰位置如下表所示：XRPD analysis was performed on the obtained crystal form A, and the obtained XRPD pattern is shown in Figure 2a, and the positions of the characteristic peaks are shown in the table below:
2θ(°)2θ(°) 强度％strength%
11.711.7 23twenty three
11.911.9 4949
12.312.3 5858
12.712.7 100100
13.313.3 21twenty one
13.913.9 77
14.814.8 3131
15.115.1 88
16.016.0 2626
17.017.0 4040
17.317.3 1818
17.517.5 22twenty two
18.118.1 77
18.518.5 7474
18.818.8 4848
19.619.6 1212
20.320.3 77
20.920.9 77
21.921.9 3333
22.222.2 88
22.622.6 3232
23.023.0 1111
24.024.0 77
24.224.2 1010
24.924.9 1212
25.525.5 6363
26.226.2 4343
26.426.4 1818
27.027.0 3939
28.828.8 1212
29.329.3 66
30.330.3 1818
30.530.5 1010
31.831.8 77
32.432.4 2020
34.034.0 77
34.334.3 99
34.834.8 1212
36.836.8 1212
39.039.0 55
对所获得的晶型A进行TGA分析，所获得的图谱如图2b所示。由该分析可知，该晶型在约30℃开始缓慢脱溶剂，在约170℃分解。TGA analysis was performed on the obtained crystal form A, and the obtained spectrum is shown in Figure 2b. From the analysis, it can be seen that the crystal form begins to desolvate slowly at about 30°C and decomposes at about 170°C.
对所获得的晶型A进行DSC分析，所获得的图谱如图2c所示。由该分析可知，该晶型在约92.6℃和约144.0℃处具有吸热峰。DSC analysis was performed on the obtained crystal form A, and the obtained spectrum is shown in Figure 2c. From the analysis, it can be seen that the crystal form has endothermic peaks at about 92.6°C and about 144.0°C.
实施例3：室温混合溶剂悬浮搅拌法制备晶型AExample 3: Preparation of Crystalline Form A by Mixed Solvent Suspension and Stirring Method at Room Temperature
称取20mg实施例1中制备的式(I)的化合物，将其加入至3mL玻璃小瓶中，加入1mL硝基甲烷与异戊醇的混合溶剂(体积比1:1)，将得到的悬浮液于25℃下磁力搅拌(500转/分钟)约24h，过滤悬浮液，固体部分在真空干燥箱中干燥10min。所得晶型的XRPD图谱与实施例2中的XRPD图谱基本上相同，表明得到了晶型A。Weigh 20mg of the compound of formula (I) prepared in Example 1, add it to a 3mL glass vial, add 1mL of a mixed solvent of nitromethane and isoamyl alcohol (volume ratio 1:1), and the obtained suspension Stir magnetically (500 rpm) at 25°C for about 24 hours, filter the suspension, and dry the solid part in a vacuum oven for 10 minutes. The XRPD pattern of the obtained crystal form is substantially the same as the XRPD pattern in Example 2, indicating that the crystal form A is obtained.
实施例4：室温单一溶剂悬浮搅拌法制备晶型BExample 4: Preparation of crystal form B by suspending and stirring in a single solvent at room temperature
称取20mg实施例1中制备的式(I)的化合物，将其加入至3mL玻璃小瓶中，加入1mL异丙醇，将得到的悬浮液于25℃下磁力搅拌(500转/分钟)约24h，过滤悬浮液，固体部分在真空干燥箱中干燥10min，将该晶型称作晶型B(类白色粉末，片状晶体)。Weigh 20mg of the compound of formula (I) prepared in Example 1, add it to a 3mL glass vial, add 1mL of isopropanol, and stir the resulting suspension magnetically (500 rpm) at 25°C for about 24h , the suspension was filtered, and the solid part was dried in a vacuum oven for 10 min. This crystal form was called Form B (off-white powder, flaky crystal).
对所获得的晶型B进行XRPD分析，所得XRPD图谱如图3a所示，其特征峰位置如下表所示：XRPD analysis was performed on the obtained crystal form B, and the obtained XRPD pattern is shown in Figure 3a, and the positions of the characteristic peaks are shown in the table below:
2θ(°)2θ(°) 强度％strength%
6.26.2 100100
10.110.1 55
10.510.5 44
12.012.0 55
12.512.5 6969
14.814.8 55
15.515.5 55
16.016.0 2020
17.417.4 55
17.617.6 55
18.318.3 44
18.818.8 9898
19.719.7 44
20.020.0 44
20.320.3 77
21.321.3 66
22.322.3 44
22.722.7 44
22.922.9 44
24.124.1 1313
24.824.8 22twenty two
25.025.0 66
25.525.5 55
25.825.8 66
26.526.5 1616
26.926.9 44
28.228.2 66
28.328.3 77
28.628.6 77
29.129.1 77
29.729.7 77
30.630.6 88
30.930.9 44
31.531.5 33
32.032.0 33
32.732.7 88
37.337.3 33
38.238.2 44
38.338.3 44
39.239.2 44
对所获得的晶型B进行TGA分析，所获得的图谱如图3b所示。由该分析可知，该晶型B在约30℃开始缓慢脱溶剂，在约170℃分解。TGA analysis was performed on the obtained crystal form B, and the obtained spectrum is shown in Figure 3b. From the analysis, it can be seen that the crystal form B begins to desolvate slowly at about 30°C and decomposes at about 170°C.
对所获得的晶型B进行DSC分析，所获得的图谱如图3c所示。由该分析可知，该晶型在约153.7℃处具有吸热峰。DSC analysis was performed on the obtained crystal form B, and the obtained spectrum is shown in Figure 3c. From the analysis, it can be known that this crystal form has an endothermic peak at about 153.7°C.
实施例5：室温混合溶剂悬浮搅拌法制备晶型BExample 5: Preparation of Crystal Form B by Mixed Solvent Suspension and Stirring Method at Room Temperature
称取20mg实施例1中制备的式(I)的化合物，将其加入至3mL玻璃小瓶中，加入1mL乙醇与丙酮的混合液(体积比1:1)，将得到的悬浮液于25℃下磁力搅拌(500转/分钟)约24h，过滤悬浮液，固体部分在真空干燥箱中干燥10min。所得晶型的XRPD图谱与实施例4中的XRPD图谱基本上相同，表明得到了晶型B。Weigh 20mg of the compound of formula (I) prepared in Example 1, add it to a 3mL glass vial, add 1mL of a mixture of ethanol and acetone (volume ratio 1:1), and place the resulting suspension at 25°C Stir magnetically (500 rpm) for about 24 hours, filter the suspension, and dry the solid part in a vacuum oven for 10 minutes. The XRPD pattern of the obtained crystal form is substantially the same as that in Example 4, indicating that the crystal form B was obtained.
实施例6：高温单一溶剂悬浮搅拌法制备晶型BExample 6: Preparation of Crystal Form B by High Temperature Single Solvent Suspension and Stirring Method
称取20mg实施例1中制备的式(I)的化合物，将其加入至3mL玻璃小瓶中，加入1mL水，将得到的悬浮液于50℃下磁力搅拌(500转/分钟)约24h，过滤悬浮液，固体部分在真空干燥箱中干燥10min。所得晶型的XRPD图谱与实施例4中的XRPD图谱基本上相同，表明得到了晶型B。Weigh 20 mg of the compound of formula (I) prepared in Example 1, add it to a 3 mL glass vial, add 1 mL of water, stir the resulting suspension at 50° C. with magnetic force (500 rpm) for about 24 h, filter The suspension and the solid part were dried in a vacuum oven for 10 min. The XRPD pattern of the obtained crystal form is substantially the same as that in Example 4, indicating that the crystal form B was obtained.
实施例7：高温混合溶剂悬浮搅拌法制备晶型BExample 7: Preparation of Crystalline Form B by High-temperature Mixed Solvent Suspension and Stirring Method
称取20mg实施例1中制备的式(I)的化合物，将其加入至3mL玻璃小瓶中，加入1mL乙醇与***的混合液(体积比1:1)，将得到的悬浮液于50℃下磁力搅拌(500转/分钟)约24h，过滤悬浮液，固体部分在真空干燥箱中干燥10min。所得晶型的XRPD图谱与实施例4中的XRPD图谱基本上相同，表明得到了晶型B。Weigh 20mg of the compound of formula (I) prepared in Example 1, add it to a 3mL glass vial, add 1mL of a mixture of ethanol and ether (volume ratio 1:1), and place the resulting suspension at 50°C Stir magnetically (500 rpm) for about 24 hours, filter the suspension, and dry the solid part in a vacuum oven for 10 minutes. The XRPD pattern of the obtained crystal form is substantially the same as that in Example 4, indicating that the crystal form B is obtained.
实施例8：室温挥发法制备晶型BExample 8: Preparation of Form B by Room Temperature Volatility
称取10mg实施例1中制备的式(I)的化合物，将其加入至3mL玻璃小瓶中，加入1mL甲醇与水的混合液(体积比1:1)，混匀，溶解。在25℃缓慢挥发至有固体析出，收集固体。所得晶型的XRPD图谱与实施例4中的XRPD图谱基本上相同，表明得到了晶型B。Weigh 10 mg of the compound of formula (I) prepared in Example 1, add it into a 3 mL glass vial, add 1 mL of a mixture of methanol and water (volume ratio 1:1), mix and dissolve. Slowly evaporate at 25°C until a solid precipitates, and collect the solid. The XRPD pattern of the obtained crystal form is substantially the same as that in Example 4, indicating that the crystal form B was obtained.
实施例9：高温挥发法制备晶型BExample 9: Preparation of crystal form B by high temperature volatilization
称取10mg实施例1中制备的式(I)的化合物，将其加入至3mL玻璃小瓶中，加入1mL水中，混匀，溶解。在50℃缓慢挥发至有固体析出，收集固体。所得晶型的XRPD图谱与实施例4中的XRPD图谱基本上相同，表明得到了晶型B。Weigh 10 mg of the compound of formula (I) prepared in Example 1, add it into a 3 mL glass vial, add 1 mL of water, mix well, and dissolve. Slowly evaporate at 50°C until a solid precipitates out, and collect the solid. The XRPD pattern of the obtained crystal form is substantially the same as that in Example 4, indicating that the crystal form B was obtained.
实施例10：冷却法制备晶型BEmbodiment 10: Preparation of crystal form B by cooling method
称取25mg实施例1中制备的式(I)的化合物，将其加入至10mL玻璃小瓶中，加入3mL水，搅拌下加热至70℃，直至完全溶解，然后冷至4℃，直至固体析出，过滤收集、干燥固体。所得晶型的XRPD图谱与实施例4中的XRPD图谱基本上相同，表明得到了晶型B。Weigh 25mg of the compound of formula (I) prepared in Example 1, add it into a 10mL glass vial, add 3mL of water, heat to 70°C with stirring until completely dissolved, then cool to 4°C until solid precipitates, The solid was collected by filtration and dried. The XRPD pattern of the obtained crystal form is substantially the same as that in Example 4, indicating that the crystal form B was obtained.
实施例11：气液渗透法制备晶型BExample 11: Preparation of Form B by Gas-Liquid Infiltration
称取5mg实施例1中制备的式(I)的化合物，将其加入至盛有2mL氯仿(良溶剂)的小号玻璃瓶中。随后，将小号玻璃瓶放入置于已盛有4mL正己烷(反溶剂)的大号玻璃瓶中，将大号玻璃瓶密封。将析出的固体过滤、收集并干燥，得到固体。所得固体的XRPD图谱与实施例4中的XRPD图谱基本上相同，表明得到了晶型B。Weigh 5 mg of the compound of formula (I) prepared in Example 1, and add it into a small glass bottle filled with 2 mL of chloroform (good solvent). Subsequently, the small glass bottle was placed in a large glass bottle filled with 4 mL of n-hexane (anti-solvent), and the large glass bottle was sealed. The precipitated solid was filtered, collected and dried to give a solid. The XRPD pattern of the obtained solid was substantially the same as that in Example 4, indicating that Form B was obtained.
实施例12：室温单一溶剂悬浮搅拌法制备晶型CExample 12: Preparation of Form C by Suspension and Stirring in a Single Solvent at Room Temperature
称取20mg实施例1中制备的式(I)的化合物，将其加入至3mL玻璃小瓶中，加入1mL丙酮，将得到的悬浮液于25℃下磁力搅拌(500转/分钟)约24h，过滤悬浮液，固体部分在真空干燥箱中干燥10min，将该晶型称作晶型C。Weigh 20mg of the compound of formula (I) prepared in Example 1, add it to a 3mL glass vial, add 1mL of acetone, stir the resulting suspension at 25°C (500 rpm) for about 24h, filter The suspension and the solid part were dried in a vacuum oven for 10 minutes, and this crystal form was called crystal form C.
对所获得的晶型C进行XRPD分析，所得XRPD图谱如图4a所示，其特征峰位置如下表所示：XRPD analysis was performed on the obtained crystal form C, and the obtained XRPD pattern is shown in Figure 4a, and the positions of the characteristic peaks are shown in the table below:
2θ(°)2θ(°) 强度％strength%
10.810.8 4848
12.712.7 3232
13.613.6 1010
14.014.0 3232
14.314.3 7575
15.615.6 2525
16.516.5 1818
16.916.9 8080
18.018.0 8383
18.518.5 100100
20.020.0 2828
21.921.9 1111
22.422.4 1111
23.223.2 1717
24.024.0 2525
24.824.8 4141
25.025.0 1010
25.325.3 3737
25.625.6 88
25.925.9 1313
26.526.5 24twenty four
27.027.0 99
27.427.4 77
28.428.4 1717
29.329.3 1010
29.529.5 1212
33.233.2 1111
34.634.6 77
35.235.2 1313
35.535.5 1111
36.236.2 66
36.536.5 66
37.437.4 1111
37.937.9 77
39.239.2 77
39.639.6 66
对所获得的晶型C进行TGA分析，所获得的图谱如图4b所示。由该分析可知，该晶型不包含结晶溶剂，在约200℃分解，熔融前无转晶。TGA analysis was performed on the obtained crystal form C, and the obtained spectrum is shown in Figure 4b. From this analysis, it can be seen that this crystal form does not contain a crystallization solvent, decomposes at about 200°C, and has no crystal transformation before melting.
对所获得的晶型C进行DSC分析，所获得的图谱如图4c所示。由该分析可知，晶型C熔点为约197℃。DSC analysis was performed on the obtained crystalline form C, and the obtained spectrum is shown in Figure 4c. From this analysis, it can be seen that the melting point of Form C is about 197°C.
实施例13：高温单一溶剂悬浮搅拌法制备晶型CExample 13: Preparation of Crystalline Form C by High Temperature Single Solvent Suspension and Stirring Method
称取20mg实施例1中制备的式(I)的化合物，将其加入至3mL玻璃小瓶中，加入1mL丙酮，将得到的悬浮液于50℃下磁力搅拌(500转/分钟)约24h，过滤悬浮液，固体部分在真空干燥箱中干燥10min。所得晶型的XRPD图谱与实施例12中的XRPD图谱基本上相同，表明得到了晶型C。Weigh 20mg of the compound of formula (I) prepared in Example 1, add it to a 3mL glass vial, add 1mL of acetone, stir the resulting suspension at 50°C for about 24h with magnetic force (500 rpm), filter The suspension and the solid part were dried in a vacuum oven for 10 min. The XRPD pattern of the obtained crystal form is substantially the same as that in Example 12, indicating that the crystal form C was obtained.
实施例14：高温混合溶剂悬浮搅拌法制备晶型CExample 14: Preparation of Crystalline Form C by High-temperature Mixed Solvent Suspension and Stirring Method
称取20mg实施例1中制备的式(I)的化合物，将其加入至3mL玻璃小瓶中，加入1mL氯仿与异戊醇的混合液(体积比1:1)，将得到的悬浮液于50℃下磁力搅拌(500转/分钟)约24h，过滤悬浮液，固体部分在真空干燥箱中干燥10min。所得晶型的XRPD图谱与实施例12中的XRPD图谱基本上相同，表明得到了晶型C。Weigh 20 mg of the compound of formula (I) prepared in Example 1, add it to a 3 mL glass vial, add 1 mL of a mixed solution of chloroform and isoamyl alcohol (volume ratio 1:1), and dissolve the resulting suspension at 50 Stir magnetically (500 rpm) at °C for about 24 hours, filter the suspension, and dry the solid part in a vacuum oven for 10 minutes. The XRPD pattern of the obtained crystal form is substantially the same as that in Example 12, indicating that the crystal form C was obtained.
实施例15：常温单一溶剂悬浮搅拌法制备晶型DExample 15: Preparation of crystal form D by suspending and stirring in a single solvent at room temperature
称取20mg实施例1中制备的式(I)的化合物，将其加入至3mL玻璃小瓶中，加入1mL异戊醇，将得到的悬浮液于25℃下磁力搅拌(500转/分钟)约24h，过滤悬浮液，固体部分在真空干燥箱中干燥10min，将该晶型称作晶型D。Weigh 20 mg of the compound of formula (I) prepared in Example 1, add it to a 3 mL glass vial, add 1 mL of isoamyl alcohol, and magnetically stir the resulting suspension (500 rpm) at 25 ° C for about 24 h , the suspension was filtered, and the solid part was dried in a vacuum oven for 10 min. This crystal form was called crystal form D.
对所获得的晶型D进行XRPD分析，所得XRPD图谱如图5a所示，其特征峰位置如下表所示：XRPD analysis was carried out on the obtained crystal form D, and the obtained XRPD pattern is shown in Figure 5a, and the positions of the characteristic peaks are shown in the table below:
2θ(°)2θ(°) 强度％strength%
8.98.9 4242
11.411.4 3232
15.015.0 1111
16.616.6 1313
16.816.8 33
17.217.2 66
17.617.6 44
18.018.0 44
18.618.6 100100
19.219.2 33
19.519.5 1010
19.919.9 77
20.520.5 33
21.221.2 77
22.522.5 77
22.722.7 22
24.524.5 1717
24.624.6 1212
25.125.1 44
25.725.7 1111
25.925.9 33
26.426.4 66
27.127.1 1414
27.827.8 66
28.628.6 77
31.031.0 22
32.832.8 22
33.133.1 66
34.134.1 22
35.635.6 33
35.935.9 22
36.536.5 33
37.537.5 33
对所获得的晶型D进行TGA分析，所获得的图谱如图5b所示。由该分析可知，在135℃失重达4.84％。TGA analysis was performed on the obtained crystal form D, and the obtained spectrum is shown in Figure 5b. From this analysis, the weight loss at 135°C was 4.84%.
对所获得的晶型D进行DSC分析，所获得的图谱如图5c所示。由该分析可知，该晶型在约60℃开始缓慢脱水，在约170℃分解。DSC analysis was performed on the obtained crystal form D, and the obtained spectrum is shown in Figure 5c. From the analysis, it can be known that the crystal form slowly dehydrates at about 60°C and decomposes at about 170°C.
实施例16：常温混合溶剂悬浮搅拌法制备晶型DExample 16: Preparation of Crystal Form D by Suspension and Stirring in Mixed Solvents at Normal Temperature
称取20mg实施例1中制备的式(I)的化合物，将其加入至3mL玻璃小瓶中，加入1mL乙醇与水混合液(体积比7:1)，将得到的悬浮液于25℃下磁力搅拌(500转/分钟)约24h，过滤悬浮液，固体部分在真空干燥箱中干燥10min。所得晶型的XRPD图谱与实施例15中的XRPD图谱基本上相同，表明得到了晶型D。Weigh 20mg of the compound of formula (I) prepared in Example 1, add it to a 3mL glass vial, add 1mL of ethanol and water mixture (volume ratio 7:1), and place the resulting suspension at 25°C under magnetic Stir (500 rpm) for about 24 hours, filter the suspension, and dry the solid part in a vacuum oven for 10 minutes. The XRPD pattern of the obtained crystal form was substantially the same as that in Example 15, indicating that the crystal form D was obtained.
实施例17：常温挥发结晶制备晶型DExample 17: Form D was prepared by volatilization and crystallization at room temperature
称取10mg实施例1中制备的式(I)的化合物，将其加入至3mL玻璃小瓶中，加入1mL甲乙酮与水混合液(体积比1:1)，混匀，溶解。在25℃缓慢挥发至有固体析出，收集固体。所得晶型的XRPD图谱与实施例15中的XRPD图谱基本上相同，表明得到了晶型D。Weigh 10 mg of the compound of formula (I) prepared in Example 1, add it into a 3 mL glass vial, add 1 mL of methyl ethyl ketone and water mixture (volume ratio 1:1), mix and dissolve. Slowly evaporate at 25°C until a solid precipitates, and collect the solid. The XRPD pattern of the obtained crystal form was substantially the same as that in Example 15, indicating that the crystal form D was obtained.
实施例18：常温混合溶剂悬浮搅拌法制备晶型DExample 18: Preparation of Crystalline Form D by Mixed Solvent Suspension and Stirring Method at Normal Temperature
称取2.5kg式(I)的化合物，将其加入至反应釜中，加入50L乙醇与水混合液(体积比7:1)，将得到的悬浮液于25℃下机械搅拌(500转/分钟)约24h，过滤悬浮液，固体部分在真空干燥箱中干燥10h。所得晶型(批号RXXX-238-012-LB4)使用水分测量仪进行水分含量的测定，水分含量5.5％。Weigh 2.5kg of the compound of formula (I), add it to the reaction kettle, add 50L of ethanol and water mixed solution (volume ratio 7:1), and mechanically stir the obtained suspension at 25°C (500 rpm ) for about 24h, filter the suspension, and dry the solid part in a vacuum oven for 10h. The moisture content of the obtained crystal form (batch number RXXX-238-012-LB4) was measured using a moisture meter, and the moisture content was 5.5%.
对所得晶型进行XRPD分析，所得XRPD图谱如图5a-1所示，表明得到了晶型D。XRPD analysis was performed on the obtained crystal form, and the obtained XRPD pattern is shown in Figure 5a-1, indicating that crystal form D was obtained.
2θ(°)2θ(°) 强度％strength%
9.09.0 4343
11.411.4 100100
15.015.0 22twenty two
16.216.2 1212
16.716.7 24twenty four
17.617.6 2020
18.618.6 8181
19.619.6 2525
20.020.0 1616
20.620.6 1414
21.221.2 4040
21.821.8 1717
22.622.6 3131
24.624.6 3838
25.725.7 22twenty two
26.726.7 2020
27.227.2 3131
27.827.8 1313
28.928.9 2828
31.531.5 1717
32.232.2 1010
34.234.2 88
34.934.9 1010
37.737.7 99
实施例19：常温混合溶剂悬浮搅拌法制备晶型DExample 19: Preparation of Crystalline Form D by Mixed Solvent Suspension and Stirring Method at Normal Temperature
称取4.5kg式(I)的化合物，将其加入至反应釜中，加入90L乙醇与水混合液(体积比7:1)，将得到的悬浮液于25℃下机械搅拌(500转/分钟)约24h，过滤悬浮液，固体部分在真空干燥箱中干燥10h。所得晶型(批号RXXX-238-010-LB3)使用水分测量仪进行水分含量的测定，水分含量4.9％。Weigh 4.5kg of the compound of formula (I), add it to the reaction kettle, add 90L of ethanol and water mixed solution (volume ratio 7:1), and mechanically stir the obtained suspension at 25°C (500 rpm ) for about 24h, filter the suspension, and dry the solid part in a vacuum oven for 10h. The moisture content of the obtained crystal form (batch number RXXX-238-010-LB3) was measured using a moisture meter, and the moisture content was 4.9%.
对所得晶型进行XRPD分析，所得XRPD图谱如图5a-2所示，表明得到了晶型D。XRPD analysis was performed on the obtained crystal form, and the obtained XRPD pattern is shown in Figure 5a-2, indicating that crystal form D was obtained.
实施例20：常温混合溶剂悬浮搅拌法制备晶型DExample 20: Preparation of Crystalline Form D by Mixed Solvent Suspension and Stirring Method at Normal Temperature
称取5.0kg式(I)的化合物，将其加入至反应釜中，加入100L乙醇与水混合液(体积比7:1)，将得到的悬浮液于25℃下机械搅拌(500转/分钟)约24h，过滤悬浮液，固体部分在真空干燥箱中干燥10h。所得晶型(批号RXXX-238-012-LB3)使用水分测量仪进行水分含量的测定，水分含量5.1％。Weigh 5.0kg of the compound of formula (I), add it to the reaction kettle, add 100L of ethanol and water mixed solution (volume ratio 7:1), and mechanically stir the obtained suspension at 25°C (500 rpm ) for about 24h, filter the suspension, and dry the solid part in a vacuum oven for 10h. The moisture content of the obtained crystal form (batch number RXXX-238-012-LB3) was measured using a moisture meter, and the moisture content was 5.1%.
对所得晶型进行XRPD分析，所得XRPD图谱如图5a-2所示，表明得到了晶型D。XRPD analysis was performed on the obtained crystal form, and the obtained XRPD pattern is shown in Figure 5a-2, indicating that crystal form D was obtained.
实施例21：常温混合溶剂悬浮搅拌法制备晶型DExample 21: Preparation of Form D by Suspension and Stirring Method in Mixed Solvent at Room Temperature
称取2.5kg式(I)的化合物，将其加入至反应釜中，加入50L乙醇与水混合液(体积比7:1)，将得到的悬浮液于25℃下机械搅拌(500转/分钟)约24h，过滤悬浮液，固体部分在真空干燥箱中干燥10h。所得晶型(批号RXXX-238-010-LB4)使用水分测量仪进行水分含量的测定，水分含量5.2％。Weigh 2.5kg of the compound of formula (I), add it to the reaction kettle, add 50L of ethanol and water mixed solution (volume ratio 7:1), and mechanically stir the obtained suspension at 25°C (500 rpm ) for about 24h, filter the suspension, and dry the solid part in a vacuum oven for 10h. The moisture content of the obtained crystal form (batch number RXXX-238-010-LB4) was measured using a moisture meter, and the moisture content was 5.2%.
对所得晶型进行XRPD分析，所得XRPD图谱如图5a-2所示，表明得到了晶型D。XRPD analysis was performed on the obtained crystal form, and the obtained XRPD pattern is shown in Figure 5a-2, indicating that crystal form D was obtained.
实施例22：高温单一溶剂悬浮搅拌法制备晶型EExample 22: Preparation of Crystalline Form E by High Temperature Single Solvent Suspension and Stirring Method
称取20mg实施例1中制备的式(I)的化合物，将其加入至3mL玻璃小瓶中，加入1mL硝基甲烷，将得到的悬浮液于50℃下磁力搅拌(500转/分钟)约24h，过滤悬浮液，固体部分在真空干燥箱中干燥10min，将该晶型称作晶型E。Weigh 20mg of the compound of formula (I) prepared in Example 1, add it to a 3mL glass vial, add 1mL of nitromethane, and magnetically stir the resulting suspension (500 rpm) at 50°C for about 24h , the suspension was filtered, and the solid part was dried in a vacuum oven for 10 min. This crystal form was called crystal form E.
对所获得的晶型E进行XRPD分析，所得XRPD图谱如图6a所示，其特征峰位置如下表所示：XRPD analysis was performed on the obtained crystal form E, and the obtained XRPD pattern is shown in Figure 6a, and the positions of the characteristic peaks are shown in the table below:
2θ(°)2θ(°) 强度％strength%
9.39.3 41.241.2
10.410.4 1212
11.511.5 8.88.8
11.911.9 100100
12.612.6 6161
13.213.2 26.126.1
13.413.4 20.720.7
14.014.0 8.28.2
14.414.4 39.439.4
15.115.1 26.526.5
15.615.6 29.729.7
15.915.9 18.318.3
16.916.9 10.610.6
17.217.2 56.256.2
18.118.1 21.921.9
18.418.4 9.29.2
18.618.6 10.610.6
18.918.9 54.654.6
19.519.5 35.135.1
21.221.2 25.525.5
21.621.6 12.212.2
22.022.0 12.412.4
23.723.7 16.516.5
24.324.3 29.929.9
24.724.7 13.713.7
24.924.9 42.642.6
25.225.2 14.714.7
26.026.0 11.211.2
26.326.3 27.927.9
27.027.0 28.528.5
27.227.2 20.520.5
27.927.9 10.610.6
28.128.1 13.713.7
28.828.8 9.29.2
30.230.2 9.29.2
30.630.6 8.28.2
31.531.5 10.610.6
34.234.2 10.610.6
34.534.5 7.87.8
35.235.2 88
35.735.7 7.27.2
35.935.9 6.86.8
37.637.6 8.68.6
对所获得的晶型E进行TGA分析，所获得的图谱如图6b所示。由该分析可知，晶型E中不包含结晶溶剂。TGA analysis was performed on the obtained crystal form E, and the obtained spectrum is shown in Figure 6b. From this analysis, it can be known that Form E does not contain a crystallization solvent.
对所获得的晶型E进行DSC分析，所获得的图谱如图6c所示。DSC analysis was performed on the obtained crystal form E, and the obtained spectrum is shown in Figure 6c.
实施例23：高温单一溶剂悬浮搅拌法制备晶型FExample 23: Preparation of Form F by High Temperature Single Solvent Suspension and Stirring Method
称取20mg实施例1中制备的式(I)的化合物，将其加入至3mL玻璃小瓶中，加入1mL三氯甲烷，将得到的悬浮液于50℃下磁力搅拌(500转/分钟)约24h，过滤悬浮液，固体部分在真空干燥箱中干燥10min，将该晶型称作晶型F。Weigh 20mg of the compound of formula (I) prepared in Example 1, add it to a 3mL glass vial, add 1mL of chloroform, and magnetically stir the resulting suspension (500 rpm) at 50°C for about 24h , the suspension was filtered, and the solid part was dried in a vacuum oven for 10 min. This crystal form was called Form F.
对所获得的晶型F进行XRPD分析，所得XRPD图谱如图7a所示，其特征峰位置如下表所示：XRPD analysis was carried out on the obtained crystal form F, and the obtained XRPD pattern is shown in Figure 7a, and the positions of the characteristic peaks are shown in the table below:
2θ(°)2θ(°) 强度％strength%
6.46.4 1616
8.68.6 1515
8.98.9 5151
9.29.2 1111
10.810.8 1111
11.311.3 100100
13.613.6 1616
14.814.8 3232
15.215.2 24twenty four
15.715.7 1111
16.116.1 1919
16.416.4 3232
16.916.9 66
17.017.0 1111
17.817.8 3030
18.418.4 1919
18.618.6 5252
19.119.1 1212
19.419.4 2727
19.919.9 1818
20.620.6 1717
20.820.8 21twenty one
21.121.1 2525
21.321.3 3434
21.821.8 88
22.522.5 1111
22.722.7 77
23.423.4 1010
23.923.9 1212
24.624.6 1919
24.824.8 2929
27.427.4 1919
28.128.1 1111
28.728.7 1111
29.329.3 77
30.130.1 1111
30.630.6 1010
30.930.9 88
32.632.6 77
34.134.1 66
38.238.2 55
38.638.6 66
对所获得的晶型F进行TGA分析，所获得的图谱如图7b所示。The obtained crystal form F was analyzed by TGA, and the obtained spectrum is shown in Fig. 7b.
对所获得的晶型F进行DSC分析，所获得的图谱如图7c所示。DSC analysis was performed on the obtained crystalline form F, and the obtained spectrum is shown in Figure 7c.
实施例24：常温混合溶剂悬浮搅拌法制备晶型FExample 24: Preparation of Form F by Suspension and Stirring in Mixed Solvents at Normal Temperature
取20mg实施例1中制备的式(I)的化合物，在25℃条件下与1mL甲醇与乙醇混合液(体积比1:1)搅拌至少24h，随后，过滤悬浮液，固体部分在真空干燥箱中干燥10min。所得晶型的XRPD图谱与实施例23中的XRPD图谱基本上相同，表明得到了晶型F。Take 20mg of the compound of formula (I) prepared in Example 1, stir it with 1mL of methanol and ethanol mixture (volume ratio 1:1) at 25°C for at least 24h, then filter the suspension, and store the solid part in a vacuum oven Dry in medium for 10min. The XRPD pattern of the obtained crystalline form was substantially the same as that in Example 23, indicating that crystalline Form F was obtained.
实施例25：高温缓慢挥发法制备晶型FExample 25: Preparation of Form F by high temperature slow volatilization method
取10mg实施例1中制备的式(I)的化合物，加入1mL异戊醇与水的混合液(体积比1:7)，混匀，溶解。在50℃缓慢挥发至有固体析出，收集固体，经XRPD检测，所得晶型的XRPD图谱与实施例23中的XRPD图谱基本上相同，表明得到了晶型F。Take 10 mg of the compound of formula (I) prepared in Example 1, add 1 mL of a mixture of isoamyl alcohol and water (volume ratio 1:7), mix well, and dissolve. Slowly volatilized at 50°C until a solid precipitated, collected the solid, and detected it by XRPD. The XRPD pattern of the obtained crystal form was basically the same as that in Example 23, indicating that the crystal form F was obtained.
实施例26：晶型G的制备Example 26: Preparation of Form G
称取5mg实施例1中制备的式(I)的化合物，将其加入至盛有2mL甲醇(良溶剂)的小号玻璃瓶中。随后，将小号玻璃瓶放入置于已盛有4mL乙醇(反溶剂)的大号玻璃瓶中，将大号玻璃瓶密封。将析出的固体过滤、收集并干燥，得到固体。将该固体称作晶型G。Weigh 5 mg of the compound of formula (I) prepared in Example 1, and add it into a small glass bottle filled with 2 mL of methanol (good solvent). Subsequently, the small glass bottle was placed in a large glass bottle filled with 4 mL of ethanol (anti-solvent), and the large glass bottle was sealed. The precipitated solid was filtered, collected and dried to give a solid. This solid is referred to as Form G.
对所获得的晶型G进行XRPD分析，所得XRPD图谱如图8a所示，其特征峰位置如下表所示：XRPD analysis was performed on the obtained crystal form G, and the obtained XRPD pattern is shown in Figure 8a, and the positions of the characteristic peaks are shown in the table below:
2θ(°)2θ(°) 强度％strength%
7.07.0 1818
10.310.3 99
11.111.1 33
12.212.2 100100
12.612.6 2525
15.415.4 1414
16.116.1 1313
18.618.6 33
19.119.1 66
19.619.6 77
19.819.8 88
20.120.1 33
20.720.7 4848
21.321.3 22twenty two
21.621.6 44
22.022.0 44
23.323.3 33
24.124.1 33
25.225.2 44
26.726.7 1111
27.027.0 44
27.527.5 44
27.827.8 1414
28.228.2 55
28.628.6 88
31.031.0 33
33.233.2 33
33.633.6 33
33.933.9 44
36.036.0 44
37.137.1 22
37.837.8 33
38.238.2 22
38.538.5 44
对所获得的晶型G进行TGA分析，所获得的图谱如图8b所示。TGA analysis was performed on the obtained crystal form G, and the obtained spectrum is shown in Figure 8b.
对所获得的晶型G进行DSC分析，所获得的图谱如图8c所示。DSC analysis was performed on the obtained crystal form G, and the obtained spectrum is shown in Figure 8c.
实施例27：晶型H的制备和单晶结构Example 27: Preparation of Form H and Single Crystal Structure
取5mg实施例1中制备的式(I)的化合物，将其加入至盛有2mL甲醇溶剂(良溶剂)的小号玻璃瓶中。随后，将小号玻璃瓶放入装有4mL甲乙酮溶液(反溶剂)的大号玻璃瓶中，将大号玻璃瓶密封。将析出的固体过滤并收集，将该晶型称作晶型H，XRPD图谱如图9a所示。晶型H为单晶结构，单晶参数如下表中所示，立体结构如图9b所示。Take 5 mg of the compound of formula (I) prepared in Example 1, and add it into a small glass bottle filled with 2 mL of methanol solvent (good solvent). Subsequently, the small glass vial was placed into a large glass vial containing 4 mL of methyl ethyl ketone solution (anti-solvent), and the large glass vial was sealed. The precipitated solid was filtered and collected, and the crystal form was called Form H, and the XRPD pattern is shown in Figure 9a. Form H is a single crystal structure, the single crystal parameters are shown in the table below, and the three-dimensional structure is shown in Figure 9b.
实施例28：晶型I的制备和单晶结构Example 28: Preparation and single crystal structure of Form I
取10mg的实施例1中制备的式(I)的化合物，加入至3mL水中，搅拌下加热至70℃。将溶液趁热过滤，然后冷却至4℃，直至固体析出。固体沉淀后过滤收集、干燥固体，将该晶型称作晶型I，XRPD图谱如图10a所示。晶型I为单晶结构，单晶参数如下表中所示，立体结构如图10b所示。Take 10 mg of the compound of formula (I) prepared in Example 1, add it into 3 mL of water, and heat to 70° C. while stirring. The solution was filtered while hot, then cooled to 4°C until solids precipitated. After the solid precipitated, it was collected by filtration and dried, and the crystal form was called Form I, and the XRPD pattern is shown in Figure 10a. Form I is a single crystal structure, the single crystal parameters are shown in the table below, and the three-dimensional structure is shown in Figure 10b.
单晶H、I基本信息Single crystal H, I basic information
Figure PCTCN2022133152-appb-000005
Figure PCTCN2022133152-appb-000005
测试例test case
测试例1：稳定性试验Test Example 1: Stability Test
称取等重量的式(I)化合物无定形、晶型A、B、C、D、E(各10mg)，装入双层药用低密度聚乙烯袋中，然后放入到温度40℃±2℃，相对湿度75％±5％的恒温恒湿箱中，15天后取出做X-射线粉末衍射(XRPD)检测，结果见附图11a-11f。Weigh the amorphous, crystal form A, B, C, D, E (each 10mg) of formula (I) compound of equal weight, pack in double-layer pharmaceutical low-density polyethylene bag, put into temperature 40 ℃ ± In a constant temperature and humidity chamber at 2°C and a relative humidity of 75% ± 5%, take it out after 15 days for X-ray powder diffraction (XRPD) detection, the results are shown in Figures 11a-11f.
实验结果表明式(I)化合物的晶型B、晶型D、晶型E在40℃±2℃、75％±5％RH放置15天的条件下，XRPD峰型基本未发生变化，晶型稳定。The experimental results show that the crystal form B, crystal form D, and crystal form E of the compound of formula (I) are stored at 40°C±2°C, 75%±5%RH for 15 days, the XRPD peak shape basically does not change, and the crystal form Stablize.
测试例2：引湿性试验Test example 2: Humidity test
采用动态水吸附仪(DVS)考察本申请中的晶型在25℃的温度下，在0～95％相对湿度对水分的吸附与解析。依据《中国药典》2015年版四部中“9103药物引湿性指导原则”中引湿性特征描述与引湿性增重的评价标准进行评价。在引湿性试验后，再次对晶型进行XRPD分析，以判断晶型是否发生变化。A dynamic water adsorption instrument (DVS) was used to investigate the adsorption and analysis of the crystal form in the present application to moisture at a temperature of 25° C. and a relative humidity of 0 to 95%. The evaluation was carried out according to the description of hygroscopic characteristics and the evaluation criteria of hygroscopic weight gain in "9103 Guiding Principles of Moisture-induced Drug Moisture" in the fourth part of the "Chinese Pharmacopoeia" in 2015 edition. After the hygroscopicity test, XRPD analysis was performed on the crystal form again to determine whether the crystal form changed.
潮解deliquescence 吸收足够水分形成液体Absorb enough water to form a liquid
极具引湿性Very hygroscopic 引湿增重不小于15％Humidification weight gain is not less than 15%
有引湿性Hygroscopic 引湿增重小于15％但不小于2％Wetting weight gain is less than 15% but not less than 2%
略有引湿性slightly hygroscopic 引湿增重小于2％但不小于0.2％Humidity gain is less than 2% but not less than 0.2%
无或几乎无引湿性Little or no hygroscopicity 引湿增重小于0.2％Humidification weight gain is less than 0.2%
表1 水吸附与解析实验结果汇总Table 1 Summary of experimental results of water adsorption and desorption
Figure PCTCN2022133152-appb-000006
Figure PCTCN2022133152-appb-000006
Figure PCTCN2022133152-appb-000007
Figure PCTCN2022133152-appb-000007
测试例3：高温实验Test Example 3: High Temperature Experiment
称取适量式(I)化合物的晶型D作为待测样品，在以下高温条件下进行高温实验。结果表明，式(I)化合物的晶型D在高温条件下具有良好的耐高温性(热稳定性)。Weigh an appropriate amount of crystal form D of the compound of formula (I) as a sample to be tested, and perform a high temperature experiment under the following high temperature conditions. The results show that the crystal form D of the compound of formula (I) has good high temperature resistance (thermal stability) under high temperature conditions.
(1)在高温条件下(60℃，敞口)放置30天，分别在5天、10天、30天进行取样，观察样品性状变化，检测杂质、水分、晶型、式(I)化合物含量。(1) Place it under high temperature conditions (60°C, open) for 30 days, take samples at 5 days, 10 days, and 30 days respectively, observe the changes in the properties of the samples, and detect the content of impurities, moisture, crystal form, and the compound of formula (I) .
实验结果：各时间点外观、XRPD和红外检测结果均与0天结果一致；有关物质中已知杂质和未知杂质均未检出；含量检测结果在99.0％～100.6％范围内波动；水分检测结果在5.5％～5.6％范围内波动。Experimental results: the appearance, XRPD and infrared detection results at each time point were consistent with the results on day 0; the known and unknown impurities in the related substances were not detected; the content detection results fluctuated in the range of 99.0% to 100.6%; the moisture detection results It fluctuates within the range of 5.5% to 5.6%.
(2)在高温条件下(60℃，带包材，内包装为药用低密度聚乙烯袋热塑封，外包装为聚酯/铝/聚乙烯药用复合膜热塑封)放置30天，分别在5天、10天、30天进行取样，观察样品性状变化，检测杂质、水分、晶型、式(I)化合物含量。(2) Under high temperature conditions (60°C, with packaging materials, the inner packaging is thermoplastic sealing of pharmaceutical low-density polyethylene bag, and the outer packaging is thermoplastic sealing of polyester/aluminum/polyethylene pharmaceutical composite film) for 30 days, respectively Sampling was carried out at 5 days, 10 days, and 30 days, and the changes in the properties of the samples were observed, and the contents of impurities, moisture, crystal forms, and compounds of formula (I) were detected.
实验结果：各时间点外观、XRPD和红外检测结果均与0天结果一致；有关物质中已知杂质和未知杂质均未检出；含量检测结果在100.2％～101.7％范围内波动；水分检测结果在5.4％～5.6％范围内波动。Experimental results: the appearance, XRPD and infrared detection results at each time point were consistent with the results on day 0; the known and unknown impurities in the related substances were not detected; the content detection results fluctuated in the range of 100.2% to 101.7%; the moisture detection results It fluctuates within the range of 5.4% to 5.6%.
测试例4：高湿实验Test Example 4: High Humidity Experiment
称取适量式(I)化合物的晶型D作为待测样品，在以下高湿条件下进行高湿实验。结果表明，式(I)化合物的晶型D在高温条件下具有良好的耐高湿性。Weigh an appropriate amount of crystal form D of the compound of formula (I) as a sample to be tested, and perform a high humidity experiment under the following high humidity conditions. The results show that the crystal form D of the compound of formula (I) has good resistance to high humidity under high temperature conditions.
(1)在高湿条件下(92.5％RH，敞口)放置30天，分别在5天、10天、30天进行取样，观察样品性状变化，检测杂质、水分、晶型、式(I)化合物含量。(1) Place it under high humidity conditions (92.5% RH, open) for 30 days, take samples respectively at 5 days, 10 days, and 30 days, observe the changes in the properties of the samples, and detect impurities, moisture, crystal forms, formula (I) Compound content.
实验结果：各时间点外观、XRPD和红外检测结果均与0天结果一致。有关物质中已知杂质和未知杂质均未检出。含量检测结果在100.6％～101.9％范围内波动。水分检测结果在5.5％～5.7％范围内波动。Experimental results: The appearance, XRPD and infrared detection results at each time point are consistent with the results on day 0. The known impurities and unknown impurities in the related substances were not detected. The content detection results fluctuated in the range of 100.6% to 101.9%. The moisture test results fluctuated in the range of 5.5% to 5.7%.
(2)在高湿条件下(92.5％RH，带包材，内包装为药用低密度聚乙烯袋热塑封，外包装为聚酯/铝/聚乙烯药用复合膜热塑封)放置30天，分别在5天、10天、30天进行取样，观察样品性状变化，检测杂质、水分、晶型、式(I)化合物含量。(2) Under high humidity conditions (92.5% RH, with packaging materials, the inner packaging is thermoplastic sealing of pharmaceutical low-density polyethylene bag, and the outer packaging is thermoplastic sealing of polyester/aluminum/polyethylene pharmaceutical composite film) for 30 days , samples were taken at 5 days, 10 days, and 30 days respectively, and the changes in the properties of the samples were observed, and the contents of impurities, moisture, crystal forms, and compounds of formula (I) were detected.
实验结果：各时间点外观、XRPD和红外检测结果均与0天结果一致。有关物质中已知杂质和未知杂质均未检出。含量检测结果在100.6％～101.6％范围内波动。水分检测结果在5.6％范围内波动。Experimental results: The appearance, XRPD and infrared detection results at each time point are consistent with the results on day 0. The known impurities and unknown impurities in the related substances were not detected. The content detection results fluctuated in the range of 100.6% to 101.6%. Moisture test results fluctuated in the 5.6% range.
测试例5：光照实验Test Example 5: Lighting Experiment
称取适量式(I)化合物的晶型D作为待测样品，在以下光照条件下进行光照实验，其中总照度不低于2×106Lux·hr、近紫外能量不低于200w·hr/m2。An appropriate amount of crystal form D of the compound of formula (I) was weighed as a sample to be tested, and the light experiment was carried out under the following light conditions, wherein the total illuminance was not lower than 2×106Lux·hr, and the near-ultraviolet energy was not lower than 200w·hr/m2.
(1)在光照条件下(强白光+紫外，敞口)放置30天，分别在5天、10天、30天进行取样，观察样品性状变化，检测杂质、水分、晶型、式(I)化合物含量。(1) Place it under light conditions (strong white light+ultraviolet, open) for 30 days, and take samples at 5 days, 10 days, and 30 days respectively, observe the changes in the properties of the samples, and detect impurities, moisture, crystal forms, formula (I) Compound content.
实验结果：各时间点外观、XRPD和红外检测结果均与0天结果一致。有关物质中已知杂质和未知杂质均未检出。含量检测结果在100.1％～101.6％范围内波动。水分检测结果在5.5％～5.6％范围内波动。Experimental results: The appearance, XRPD and infrared detection results at each time point are consistent with the results on day 0. The known impurities and unknown impurities in the related substances were not detected. The content detection results fluctuated in the range of 100.1% to 101.6%. The moisture test results fluctuate in the range of 5.5% to 5.6%.
(2)在光照条件下(强白光+紫外，内包材，内包装为药用低密度聚乙烯袋热塑封)放置30天，分别在5天、10天、30天进行取样，观察样品性状变化，检测杂质、水分、晶型、式(I)化合物含量。(2) Place it under light conditions (strong white light + ultraviolet light, inner packaging material, inner packaging is a medicinal low-density polyethylene bag thermoplastic seal) for 30 days, take samples at 5 days, 10 days, and 30 days respectively, and observe the changes in the properties of the samples , detecting impurities, moisture, crystal form, and the content of the compound of formula (I).
实验结果：各时间点外观、XRPD和红外检测结果均与0天结果一致。有关物质中已知杂质和未知杂质均未检出。含量检测结果在100.3％～101.6％范围内波动。水分检测结果在5.4％～5.6％范围内波动。Experimental results: The appearance, XRPD and infrared detection results at each time point are consistent with the results on day 0. The known impurities and unknown impurities in the related substances were not detected. The content detection results fluctuated in the range of 100.3% to 101.6%. The moisture test results fluctuate in the range of 5.4% to 5.6%.
(3)在光照条件下(强白光+紫外，内外包材，内包装为药用低密度聚乙烯袋热塑封，外包装为聚酯/铝/聚乙烯药用复合膜热塑封)放置30天，分别在5天、10天、30天进行取样，观察样品性状变化，检测杂质、水分、晶型、式(I)化合物含量。(3) Under light conditions (strong white light + ultraviolet light, inner and outer packaging materials, inner packaging is thermoplastic sealing of pharmaceutical low-density polyethylene bag, outer packaging is thermoplastic sealing of polyester/aluminum/polyethylene pharmaceutical composite film) for 30 days , samples were taken at 5 days, 10 days, and 30 days respectively, and the changes in the properties of the samples were observed, and the contents of impurities, moisture, crystal forms, and compounds of formula (I) were detected.
实验结果：各时间点外观、XRPD和红外检测结果均与0天结果一致。有关物质中已知杂质和未知杂质均未检出。含量检测结果在100.5％～101.4％范围内波动。水分检测结果在5.4％～5.6％范围内波动。Experimental results: The appearance, XRPD and infrared detection results at each time point are consistent with the results on day 0. The known impurities and unknown impurities in the related substances were not detected. The content detection results fluctuated in the range of 100.5% to 101.4%. The moisture test results fluctuate in the range of 5.4% to 5.6%.
结果表明，式(I)化合物的晶型D在光照条件下具有良好的光稳定性，可保证晶型D在储存运输及服用时，不会因暴露于日光而产生光敏反应，也不需要为防止受光照影响而采取的特殊包装处理，保证药品的安全性和长期储存的有效性，同时降低成本。The results show that the crystal form D of the compound of formula (I) has good photostability under light conditions, which can ensure that the crystal form D will not produce photosensitivity reactions due to exposure to sunlight during storage, transportation and consumption, and does not need to The special packaging treatment adopted to prevent being affected by light ensures the safety of drugs and the effectiveness of long-term storage, while reducing costs.
除本文中描述的那些外，根据前述描述，本发明的各种修改对本领域技术人员而言会是显而易见的。这样的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。Various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also 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 (19)

  1. 式(I)的化合物的晶型A：Form A of the compound of formula (I):
    Figure PCTCN2022133152-appb-100001
    Figure PCTCN2022133152-appb-100001
    所述晶型A的XRPD图谱包括在约11.9±0.2°、12.3±0.2°、12.7±0.2°、18.5±0.2°、18.8±0.2°、25.5±0.2°和26.2±0.2°的衍射角(2θ)处的特征峰，优选包括在约11.9±0.2°、12.3±0.2°、12.7±0.2°、17.0±0.2°、18.5±0.2°、18.8±0.2°、21.9±0.2°、22.6±0.2°、25.5±0.2°、26.2±0.2°和27.0±0.2°的衍射角(2θ)处的特征峰，最优选包括在约11.7±0.2°、11.9±0.2°、12.3±0.2°、12.7±0.2°、13.3±0.2°、14.8±0.2°、16.0±0.2°、17.0±0.2°、17.3±0.2°、17.5±0.2°、18.5±0.2°、18.8±0.2°、19.6±0.2°、21.9±0.2°、22.6±0.2°、23.0±0.2°、24.9±0.2°、25.5±0.2°、26.2±0.2°、26.4±0.2°、27.0±0.2°、28.8±0.2°、30.3±0.2°、32.4±0.2°、34.8±0.2°和36.8±0.2°的衍射角(2θ)处的特征峰。The XRPD pattern of Form A includes diffraction angles (2θ ), preferably including characteristic peaks at about 11.9±0.2°, 12.3±0.2°, 12.7±0.2°, 17.0±0.2°, 18.5±0.2°, 18.8±0.2°, 21.9±0.2°, 22.6±0.2°, Characteristic peaks at diffraction angles (2θ) of 25.5±0.2°, 26.2±0.2° and 27.0±0.2°, most preferably included at about 11.7±0.2°, 11.9±0.2°, 12.3±0.2°, 12.7±0.2°, 13.3±0.2°, 14.8±0.2°, 16.0±0.2°, 17.0±0.2°, 17.3±0.2°, 17.5±0.2°, 18.5±0.2°, 18.8±0.2°, 19.6±0.2°, 21.9±0.2°, 22.6±0.2°, 23.0±0.2°, 24.9±0.2°, 25.5±0.2°, 26.2±0.2°, 26.4±0.2°, 27.0±0.2°, 28.8±0.2°, 30.3±0.2°, 32.4±0.2°, Characteristic peaks at diffraction angles (2θ) of 34.8±0.2° and 36.8±0.2°.
  2. 制备权利要求1的式(I)的化合物晶型A的方法，所述方法为悬浮搅拌法，其包括将式(I)的化合物加入有机溶剂中，在20-35℃下搅拌，然后将其过滤，得到晶型A；The method for preparing the compound crystal form A of the formula (I) of claim 1, the method is a suspension stirring method, which comprises adding the compound of the formula (I) into an organic solvent, stirring at 20-35 ° C, and then Filtration to obtain Form A;
    其中所述有机溶剂为硝基甲烷，或硝基甲烷与其它有机溶剂的混合溶剂；Wherein the organic solvent is nitromethane, or a mixed solvent of nitromethane and other organic solvents;
    所述其它有机溶剂为具有1-10个碳原子的醇类、烃类、醚类、酯类、酮类或卤代烃类溶剂。The other organic solvents are alcohols, hydrocarbons, ethers, esters, ketones or halogenated hydrocarbon solvents with 1-10 carbon atoms.
  3. 式(I)的化合物的晶型B：Form B of the compound of formula (I):
    Figure PCTCN2022133152-appb-100002
    Figure PCTCN2022133152-appb-100002
    所述晶型B的XRPD图谱包括在约6.2±0.2°、12.5±0.2°、16.0±0.2°、18.8±0.2°、24.1±0.2°、24.8±0.2°和26.5±0.2°的衍射角(2θ)处的特征峰，优选包括在约6.2±0.2°、10.1±0.2°、12.0±0.2°、12.5±0.2°、14.8±0.2°、15.5±0.2°、16.0±0.2°、17.4±0.2°、17.6±0.2°、18.8±0.2°、20.3±0.2°、21.3±0.2°、24.1±0.2°、24.8±0.2°、25.0±0.2°、25.8±0.2°、26.5±0.2°、28.2±0.2°、28.3±0.2°、28.6±0.2°、29.1±0.2°、29.7±0.2°、30.6±0.2°和32.7±0.2°衍射角(2θ)处的峰。The XRPD pattern of Form B includes diffraction angles (2θ ), preferably including characteristic peaks at about 6.2±0.2°, 10.1±0.2°, 12.0±0.2°, 12.5±0.2°, 14.8±0.2°, 15.5±0.2°, 16.0±0.2°, 17.4±0.2°, 17.6±0.2°, 18.8±0.2°, 20.3±0.2°, 21.3±0.2°, 24.1±0.2°, 24.8±0.2°, 25.0±0.2°, 25.8±0.2°, 26.5±0.2°, 28.2±0.2°, Peaks at 28.3±0.2°, 28.6±0.2°, 29.1±0.2°, 29.7±0.2°, 30.6±0.2° and 32.7±0.2° diffraction angles (2Θ).
  4. 制备权利要求3的式(I)的化合物的晶型B的方法，所述方法选自：悬浮搅拌法、挥发法、冷却法和气液渗透法；其中：The method for preparing the crystal form B of the compound of formula (I) of claim 3, said method is selected from: suspension stirring method, volatilization method, cooling method and gas-liquid infiltration method; wherein:
    所述悬浮搅拌法包括将式(I)的化合物加入溶剂中，在20-80℃下搅拌，然后将其过滤，得到晶型B；其中所述溶剂选自水、具有1-10个碳原子的醇类溶剂(例如甲醇、乙醇、异丙醇、异戊醇等)、醚类溶剂(例如***等)、酮类溶剂(例如丙酮、甲乙酮、甲基异丁基酮等)、芳香烃类溶剂(例如甲苯等)、卤代烃类溶剂(例如氯仿等)，或者它们的混合溶剂；The suspension stirring method comprises adding the compound of formula (I) into a solvent, stirring at 20-80° C., and then filtering it to obtain Form B; wherein the solvent is selected from water and has 1-10 carbon atoms Alcohol solvents (such as methanol, ethanol, isopropanol, isoamyl alcohol, etc.), ether solvents (such as ether, etc.), ketone solvents (such as acetone, methyl ethyl ketone, methyl isobutyl ketone, etc.), aromatic hydrocarbons Solvents (such as toluene, etc.), halogenated hydrocarbon solvents (such as chloroform, etc.), or their mixed solvents;
    所述挥发法包括将式(I)的化合物加入至溶剂中，混匀，溶解；在20℃～60℃下挥发至有固体析出，过滤以收集固体；其中所述溶剂为水或者甲醇与水的混合溶剂；The volatilization method includes adding the compound of formula (I) into a solvent, mixing, and dissolving; volatilizing at 20°C to 60°C until solids are precipitated, and filtering to collect the solids; wherein the solvent is water or methanol and water mixed solvent;
    所述冷却法包括将式(I)的化合物加入至溶剂(优选为水)中，加热以使化合物完全溶解，冷却结晶，过滤以收集固体；The cooling method includes adding the compound of formula (I) into a solvent (preferably water), heating to completely dissolve the compound, cooling to crystallize, and filtering to collect the solid;
    所述气液渗透法包括将式(I)的化合物在第一容器的良溶剂中溶解，向第二容器中装入反溶剂，将第一容器敞口放置于第二容器中，将第二容器密封并静置，将析出的固体过滤得到晶体；其中所 述良溶剂为具有1-10个碳原子的卤代烃溶剂，例如氯仿；所述反溶剂为具有5-10个碳原子的烃类溶剂，例如正己烷、正庚烷、石油醚。The gas-liquid infiltration method comprises dissolving the compound of formula (I) in a good solvent in a first container, loading an anti-solvent into a second container, placing the first container open in the second container, and dissolving the second container. The container is sealed and left standing, and the precipitated solid is filtered to obtain crystals; wherein the good solvent is a halogenated hydrocarbon solvent with 1-10 carbon atoms, such as chloroform; the anti-solvent is a hydrocarbon with 5-10 carbon atoms Solvents, such as n-hexane, n-heptane, petroleum ether.
  5. 式(I)的化合物的晶型C：Form C of the compound of formula (I):
    Figure PCTCN2022133152-appb-100003
    Figure PCTCN2022133152-appb-100003
    所述晶型C的XRPD图谱包括在约10.8±0.2°、14.3±0.2°、16.9±0.2°、18.0±0.2°、18.5±0.2°、24.8±0.2°和25.3±0.2°的衍射角(2θ)处的特征峰，优选包括在约10.8±0.2°、12.7±0.2°、14.0±0.2°、14.3±0.2°、15.6±0.2°、16.9±0.2°、18.0±0.2°、18.5±0.2°、20.0±0.2°、24.0±0.2°、24.8±0.2°、25.3±0.2°和26.5±0.2°的衍射角(2θ)处的特征峰，最优选包括在约10.8±0.2°、12.7±0.2°、14.0±0.2°、14.3±0.2°、15.6±0.2°、16.5±0.2°、16.9±0.2°、18.0±0.2°、18.5±0.2°、20.0±0.2°、21.9±0.2°、22.4±0.2°、23.2±0.2°、24.0±0.2°、24.8±0.2°、25.3±0.2°、25.9±0.2°、26.5±0.2°、28.4±0.2°、29.5±0.2°和35.2±0.2°的衍射角(2θ)处的特征峰。The XRPD pattern of Form C includes diffraction angles (2θ ), preferably including characteristic peaks at about 10.8±0.2°, 12.7±0.2°, 14.0±0.2°, 14.3±0.2°, 15.6±0.2°, 16.9±0.2°, 18.0±0.2°, 18.5±0.2°, Characteristic peaks at diffraction angles (2θ) of 20.0±0.2°, 24.0±0.2°, 24.8±0.2°, 25.3±0.2° and 26.5±0.2°, most preferably included at about 10.8±0.2°, 12.7±0.2°, 14.0±0.2°, 14.3±0.2°, 15.6±0.2°, 16.5±0.2°, 16.9±0.2°, 18.0±0.2°, 18.5±0.2°, 20.0±0.2°, 21.9±0.2°, 22.4±0.2°, Diffraction angles (2θ) of 23.2±0.2°, 24.0±0.2°, 24.8±0.2°, 25.3±0.2°, 25.9±0.2°, 26.5±0.2°, 28.4±0.2°, 29.5±0.2° and 35.2±0.2° characteristic peaks at .
  6. 制备权利要求5的式(I)的化合物的晶型C的方法，所述方法为悬浮搅拌法，其包括将式(I)的化合物加入溶剂中，在20-60℃下搅拌，然后将其过滤，得到晶体；其中所述溶剂为具有1-10个碳原子的酮类溶剂(例如丙酮、甲乙酮、甲基异丁基酮等)、腈类溶剂(例如乙腈等)、酯类溶剂(例如乙酸乙酯、乙酸异丙酯等)、醚类溶剂(例如甲基叔丁基醚、***、四氢呋喃等)、醇类溶剂(例如甲醇、乙醇、异戊醇等)、卤代烃类溶剂(例如二氯甲烷或氯仿)，或者它们的混合溶剂。The method for preparing the crystal form C of the compound of formula (I) according to claim 5, the method is a suspension stirring method, which comprises adding the compound of formula (I) into a solvent, stirring at 20-60°C, and then Filtration to obtain crystals; wherein the solvent is a ketone solvent (such as acetone, methyl ethyl ketone, methyl isobutyl ketone, etc.), a nitrile solvent (such as acetonitrile, etc.), an ester solvent (such as ethyl acetate, isopropyl acetate, etc.), ether solvents (such as methyl tert-butyl ether, diethyl ether, tetrahydrofuran, etc.), alcohol solvents (such as methanol, ethanol, isoamyl alcohol, etc.), halogenated hydrocarbon solvents ( such as dichloromethane or chloroform), or their mixed solvents.
  7. 式(I)的化合物的晶型D：Form D of the compound of formula (I):
    Figure PCTCN2022133152-appb-100004
    Figure PCTCN2022133152-appb-100004
    所述晶型D的XRPD图谱包括在约9.0±0.2°、11.4±0.2°、16.7±0.2°、18.6±0.2°、24.6±0.2°、25.7±0.2°和27.2±0.2°的衍射角(2θ)处的特征峰，优选包括在约9.0±0.2°、11.4±0.2°、15.0±0.2°、16.7±0.2°、18.6±0.2°、19.6±0.2°、24.6±0.2°、25.7±0.2°和27.2±0.2°的衍射角(2θ)处的特征峰，更优选包括在约9.0±0.2°、11.4±0.2°、15.0±0.2°、16.7±0.2°、18.6±0.2°、19.6±0.2°、21.2±0.2°、22.6±0.2°、24.6±0.2°、25.7±0.2°、27.2±0.2°和28.9±0.2°的衍射角(2θ)处的特征峰，最优选包括在约9.0±0.2°、11.4±0.2°、15.0±0.2°、16.7±0.2°、17.6±0.2°、18.6±0.2°、19.6±0.2°、20.0±0.2°、21.2±0.2°、21.8±0.2°、22.6±0.2°、24.6±0.2°、25.7±0.2°、26.7±0.2°、27.2±0.2°、28.9±0.2°和31.5±0.2°的衍射角(2θ)处的特征峰。The XRPD pattern of Form D includes diffraction angles (2θ ), preferably including characteristic peaks at about 9.0±0.2°, 11.4±0.2°, 15.0±0.2°, 16.7±0.2°, 18.6±0.2°, 19.6±0.2°, 24.6±0.2°, 25.7±0.2° and Characteristic peaks at a diffraction angle (2θ) of 27.2±0.2°, more preferably included at about 9.0±0.2°, 11.4±0.2°, 15.0±0.2°, 16.7±0.2°, 18.6±0.2°, 19.6±0.2°, Characteristic peaks at diffraction angles (2θ) of 21.2±0.2°, 22.6±0.2°, 24.6±0.2°, 25.7±0.2°, 27.2±0.2° and 28.9±0.2°, most preferably comprised at about 9.0±0.2°, 11.4±0.2°, 15.0±0.2°, 16.7±0.2°, 17.6±0.2°, 18.6±0.2°, 19.6±0.2°, 20.0±0.2°, 21.2±0.2°, 21.8±0.2°, 22.6±0.2°, Characteristic peaks at diffraction angles (2θ) of 24.6±0.2°, 25.7±0.2°, 26.7±0.2°, 27.2±0.2°, 28.9±0.2° and 31.5±0.2°.
  8. 权利要求7的式(I)的化合物的晶型D，其中所述式(I)的化合物的晶型D为水合物，含水量为4.8％-5.7％。The crystal form D of the compound of formula (I) according to claim 7, wherein the crystal form D of the compound of formula (I) is a hydrate with a water content of 4.8%-5.7%.
  9. 权利要求7或8的式(I)的化合物的晶型D，其中所述式(I)的化合物的晶型D为倍半水合物。The crystalline form D of the compound of formula (I) according to claim 7 or 8, wherein the crystalline form D of the compound of formula (I) is a sesquihydrate.
  10. 制备权利要求7-9中任一项的式(I)的化合物的晶型D的方法，所述方法选自：悬浮搅拌法和挥发法；其中A method for preparing the crystal form D of the compound of formula (I) according to any one of claims 7-9, said method being selected from: suspension stirring method and volatilization method; wherein
    所述悬浮搅拌法包括将式(I)的化合物加入溶剂中，在20-80℃下搅拌，然后将其过滤，得到晶型D；其中，所述溶剂选自水、具有1-10个碳原子的醇类溶剂(例如甲醇、乙醇、异丙醇、异戊醇等)、卤代烃类溶剂(例如氯仿等)，或者它们的混合溶剂；The suspension stirring method comprises adding the compound of formula (I) into a solvent, stirring at 20-80°C, and then filtering it to obtain the crystal form D; wherein, the solvent is selected from water and has 1-10 carbon Atomic alcoholic solvents (such as methanol, ethanol, isopropanol, isoamyl alcohol, etc.), halogenated hydrocarbon solvents (such as chloroform, etc.), or their mixed solvents;
    所述挥发法包括将式(I)的化合物加入至溶剂中，混匀，溶解；在20℃～60℃下挥发至有固体析出，过滤以收集固体；其中所述溶剂选自水和具有1-10个碳原子的酮类溶剂(例如丙酮或甲乙酮等)，或者它们的混合溶剂。The volatilization method includes adding the compound of formula (I) into a solvent, mixing, and dissolving; volatilize at 20°C to 60°C until solids are precipitated, and filter to collect the solids; wherein the solvent is selected from water and 1 - a ketone solvent having 10 carbon atoms (such as acetone, methyl ethyl ketone, etc.), or a mixed solvent thereof.
  11. 式(I)的化合物的晶型E：Form E of the compound of formula (I):
    Figure PCTCN2022133152-appb-100005
    Figure PCTCN2022133152-appb-100005
    所述晶型E的XRPD图谱包括在约9.3±0.2°、11.9±0.2°、12.6±0.2°、14.4±0.2°、17.2±0.2°、18.9±0.2°和24.9±0.2°的衍射角(2θ)处的特征峰，优选包括在约9.3±0.2°、11.9±0.2°、12.6±0.2°、13.2±0.2°、14.4±0.2°、15.1±0.2°、15.6±0.2°、17.2±0.2°、18.1±0.2°、18.9±0.2°、19.5±0.2°、21.2±0.2°、23.7±0.2°、24.3±0.2°、24.9±0.2°、26.3±0.2°和27.0±0.2°的衍射角(2θ)处的特征峰，最优选包括在约9.3±0.2°、10.4±0.2°、11.9±0.2°、12.6±0.2°、13.2±0.2°、14.4±0.2°、15.1±0.2°、15.6±0.2°、16.9±0.2°、17.2±0.2°、18.1±0.2°、18.6±0.2°、18.9±0.2°、19.5±0.2°、21.2±0.2°、21.6±0.2°、22.0±0.2°、23.7±0.2°、24.3±0.2°、24.9±0.2°、25.2±0.2°、26.0±0.2°、26.3±0.2°、27.0±0.2°、28.1±0.2°、31.5±0.2°和34.2±0.2°的衍射角(2θ)处的特征峰。The XRPD pattern of Form E includes diffraction angles (2θ ), preferably including characteristic peaks at about 9.3±0.2°, 11.9±0.2°, 12.6±0.2°, 13.2±0.2°, 14.4±0.2°, 15.1±0.2°, 15.6±0.2°, 17.2±0.2°, Diffraction angles (2θ) of 18.1±0.2°, 18.9±0.2°, 19.5±0.2°, 21.2±0.2°, 23.7±0.2°, 24.3±0.2°, 24.9±0.2°, 26.3±0.2° and 27.0±0.2° Characteristic peaks at, most preferably included at about 9.3±0.2°, 10.4±0.2°, 11.9±0.2°, 12.6±0.2°, 13.2±0.2°, 14.4±0.2°, 15.1±0.2°, 15.6±0.2°, 16.9±0.2°, 17.2±0.2°, 18.1±0.2°, 18.6±0.2°, 18.9±0.2°, 19.5±0.2°, 21.2±0.2°, 21.6±0.2°, 22.0±0.2°, 23.7±0.2°, Diffraction angles (2θ) of 24.3±0.2°, 24.9±0.2°, 25.2±0.2°, 26.0±0.2°, 26.3±0.2°, 27.0±0.2°, 28.1±0.2°, 31.5±0.2° and 34.2±0.2° characteristic peaks at .
  12. 制备权利要求11的式(I)的化合物的晶型E的方法，所述方法为悬浮搅拌法，其包括将式(I)的化合物加入有机溶剂中，在40-60℃下搅拌，然后将其过滤，得到晶型E；其中所述有机溶剂选自硝基甲烷，或硝基甲烷与其它有机溶剂的混合溶剂；The method for preparing the crystal form E of the compound of formula (I) according to claim 11, the method is a suspension stirring method, which comprises adding the compound of formula (I) into an organic solvent, stirring at 40-60°C, and then It is filtered to obtain crystal form E; wherein the organic solvent is selected from nitromethane, or a mixed solvent of nitromethane and other organic solvents;
    所述其它有机溶剂为具有1-10个碳原子的醇类、醚类、酯类、酮类或卤代烃类溶剂。The other organic solvents are alcohols, ethers, esters, ketones or halogenated hydrocarbon solvents with 1-10 carbon atoms.
  13. 式(I)的化合物的晶型F：Form F of the compound of formula (I):
    Figure PCTCN2022133152-appb-100006
    Figure PCTCN2022133152-appb-100006
    所述晶型F的XRPD图谱包括在约8.9±0.2°、11.3±0.2°、14.8±0.2°、15.2±0.2°、16.1±0.2°、16.4±0.2°、17.8±0.2°、18.6±0.2°、19.4±0.2°、20.8±0.2°、21.3±0.2°、24.8±0.2°和27.4±0.2°的衍射角(2θ)处的特征峰，优选包括约6.4±0.2°、8.9±0.2°、10.8±0.2°、11.3±0.2°、13.6±0.2°、14.8±0.2°、15.2±0.2°、15.7±0.2°、16.1±0.2°、16.4±0.2°、17.0±0.2°、17.8±0.2°、18.6±0.2°、19.4±0.2°、19.9±0.2°、20.8±0.2°、21.3±0.2°、21.8±0.2°、22.5±0.2°、23.4±0.2°、23.9±0.2°、24.8±0.2°、27.4±0.2°、28.1±0.2°、28.7±0.2°、30.1±0.2°和32.6±0.2°的衍射角(2θ)处的峰。The XRPD pattern of the crystalline form F includes at about 8.9±0.2°, 11.3±0.2°, 14.8±0.2°, 15.2±0.2°, 16.1±0.2°, 16.4±0.2°, 17.8±0.2°, 18.6±0.2° , 19.4±0.2°, 20.8±0.2°, 21.3±0.2°, 24.8±0.2° and 27.4±0.2° diffraction angles (2θ) at the characteristic peaks, preferably including about 6.4±0.2°, 8.9±0.2°, 10.8 ±0.2°, 11.3±0.2°, 13.6±0.2°, 14.8±0.2°, 15.2±0.2°, 15.7±0.2°, 16.1±0.2°, 16.4±0.2°, 17.0±0.2°, 17.8±0.2°, 18.6 ±0.2°, 19.4±0.2°, 19.9±0.2°, 20.8±0.2°, 21.3±0.2°, 21.8±0.2°, 22.5±0.2°, 23.4±0.2°, 23.9±0.2°, 24.8±0.2°, 27.4 Peaks at diffraction angles (2θ) of ±0.2°, 28.1±0.2°, 28.7±0.2°, 30.1±0.2° and 32.6±0.2°.
  14. 制备权利要求13的式(I)的化合物的晶型F的方法，所述方法选自：悬浮搅拌法和挥发法；其中：The method for preparing the crystal form F of the compound of formula (I) according to claim 13, said method being selected from: suspension stirring method and volatilization method; wherein:
    所述悬浮搅拌法包括将式(I)的化合物加入溶剂中，在20-80℃下搅拌，然后将其过滤，得到晶型F；其中所述溶剂选自水、具有1-10个碳原子的醇类溶剂(例如甲醇、乙醇、异丙醇、异戊醇等)、醚类溶剂(例如***等)、酮类溶剂(例如甲乙酮、甲基异丁基酮等)、芳香烃类溶剂(例如甲苯等)、卤代烃类溶剂(例如氯仿等)，或者它们的混合溶剂；The suspension stirring method comprises adding the compound of formula (I) into a solvent, stirring at 20-80° C., and then filtering it to obtain Form F; wherein the solvent is selected from water and has 1-10 carbon atoms Alcohol solvents (such as methanol, ethanol, isopropanol, isoamyl alcohol, etc.), ether solvents (such as ether, etc.), ketone solvents (such as methyl ethyl ketone, methyl isobutyl ketone, etc.), aromatic hydrocarbon solvents ( Such as toluene, etc.), halogenated hydrocarbon solvents (such as chloroform, etc.), or their mixed solvents;
    所述挥发法包括将式(I)的化合物加入至溶剂中，混匀，溶解；在20℃～60℃下挥发至有固体析出，过滤以收集固体；其中所述溶剂为异戊醇与水的混合溶剂。The volatilization method includes adding the compound of formula (I) into a solvent, mixing, and dissolving; volatilizing at 20°C to 60°C until solids are precipitated, and filtering to collect the solids; wherein the solvent is isoamyl alcohol and water mixed solvents.
  15. 式(I)的化合物的晶型G：Form G of the compound of formula (I):
    Figure PCTCN2022133152-appb-100007
    Figure PCTCN2022133152-appb-100007
    所述晶型G的XRPD图谱包括在约7.0±0.2°、12.2±0.2°、12.6±0.2°、15.4±0.2°、20.7±0.2°、21.3±0.2°和27.8±0.2°的衍射角(2θ)处的特征峰，优选包括在约7.0±0.2°、10.3±0.2°、12.2±0.2°、12.6±0.2°、15.4±0.2°、16.1±0.2°、19.1±0.2°、19.6±0.2°、20.7±0.2°、21.3±0.2°、26.7±0.2°、27.8±0.2°和28.6±0.2°的衍射角(2θ)处的峰。The XRPD pattern of Form G includes diffraction angles (2θ ), preferably including characteristic peaks at about 7.0±0.2°, 10.3±0.2°, 12.2±0.2°, 12.6±0.2°, 15.4±0.2°, 16.1±0.2°, 19.1±0.2°, 19.6±0.2°, Peaks at diffraction angles (2Θ) of 20.7±0.2°, 21.3±0.2°, 26.7±0.2°, 27.8±0.2° and 28.6±0.2°.
  16. 制备权利要求15的式(I)的化合物的晶型G的方法，所述方法为气液渗透法，其包括将式(I)的化合物在第一容器的良溶剂中溶解，向第二容器中装入反溶剂，将第一容器敞口放置于第二容器中，将第二容器密封并静置，将析出的固体过滤得到晶体；其中所述良溶剂为甲醇；所述反溶剂为乙醇。The method for preparing the crystal form G of the compound of formula (I) of claim 15, the method is a gas-liquid infiltration method, which comprises dissolving the compound of formula (I) in a good solvent in the first container, and injecting the compound into the second container Put the anti-solvent in the container, place the first container open in the second container, seal the second container and let it stand, filter the precipitated solid to obtain crystals; wherein the good solvent is methanol; the anti-solvent is ethanol .
  17. 药物组合物，其包含权利要求1、3、5、7-9、11、13和15中任一项的式(I)的化合物的晶型A、晶型B、晶型C、晶型D、晶型E、晶型F或晶型G，以及一种或多种药学上可接受的载体。A pharmaceutical composition comprising crystalline form A, crystalline form B, crystalline form C, and crystalline form D of the compound of formula (I) according to any one of claims 1, 3, 5, 7-9, 11, 13 and 15 , crystalline form E, crystalline form F or crystalline form G, and one or more pharmaceutically acceptable carriers.
  18. 权利要求1、3、5、7-9、11、13和15中任一项的式(I)的化合物的晶型A、晶型B、晶型C、晶型D、晶型E、晶型F或晶型G在制备用于预防或治疗维生素B1缺乏症和代谢相关障碍、精神类疾病和紊乱、糖尿病相关并发症和/或神经退行性疾病的药物中的用途。Crystal Form A, Crystal Form B, Crystal Form C, Crystal Form D, Crystal Form E, Crystal Form Use of form F or crystal form G in the preparation of drugs for preventing or treating vitamin B1 deficiency and metabolic-related disorders, mental diseases and disorders, diabetes-related complications and/or neurodegenerative diseases.
  19. 权利要求18的用途，其中所述神经退行性疾病选自阿尔兹海默症、血管性痴呆和精神障碍，优选为阿尔兹海默症。The use according to claim 18, wherein the neurodegenerative disease is selected from Alzheimer's disease, vascular dementia and mental disorders, preferably Alzheimer's disease.
PCT/CN2022/133152 2021-11-22 2022-11-21 Solid form of benfotiamine derivative, and preparation method therefor and use thereof WO2023088457A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202111391241.X 2021-11-22
CN202111391241 2021-11-22

Publications (1)

Publication Number Publication Date
WO2023088457A1 true WO2023088457A1 (en) 2023-05-25

Family

ID=86396272

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/133152 WO2023088457A1 (en) 2021-11-22 2022-11-21 Solid form of benfotiamine derivative, and preparation method therefor and use thereof

Country Status (1)

Country Link
WO (1) WO2023088457A1 (en)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1264580A (en) * 1969-09-18 1972-02-23
CN103113405A (en) * 2012-10-17 2013-05-22 上海日馨生物科技有限公司 Benfotiamine polymorphism body, preparation method and application thereof
WO2016079576A1 (en) * 2014-11-20 2016-05-26 Ashmi Life Sciences Private Limited A process for the preparation of a thiamine derivative and salt thereof
CN109111478A (en) * 2017-06-26 2019-01-01 上海日馨生物科技有限公司 Benfotiamine derivative, preparation method and its pharmaceutical composition
CN111233925A (en) * 2018-11-28 2020-06-05 上海日馨生物科技有限公司 Thiamine compound, preparation method and pharmaceutical composition thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1264580A (en) * 1969-09-18 1972-02-23
CN103113405A (en) * 2012-10-17 2013-05-22 上海日馨生物科技有限公司 Benfotiamine polymorphism body, preparation method and application thereof
WO2016079576A1 (en) * 2014-11-20 2016-05-26 Ashmi Life Sciences Private Limited A process for the preparation of a thiamine derivative and salt thereof
CN109111478A (en) * 2017-06-26 2019-01-01 上海日馨生物科技有限公司 Benfotiamine derivative, preparation method and its pharmaceutical composition
CN111233925A (en) * 2018-11-28 2020-06-05 上海日馨生物科技有限公司 Thiamine compound, preparation method and pharmaceutical composition thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
YANG SHIYING, JIAN ZHOU,LI ZHANG,YANG LYU,GUANHUA DU: "Present Situation and Progress of the Research for Polymorphic Chemical Drugs in China", HERALD OF MEDICINE, vol. 38, no. 2, 1 February 2019 (2019-02-01), pages 177 - 182, XP093068461, DOI: 10.3870/j.issn.1004-0781.2019.02.008 *

Similar Documents

Publication Publication Date Title
CN110922407B (en) Crystal forms of benzoylaminopyridine derivatives and uses thereof
US9550767B2 (en) Crystalline form of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride monohydrate
CN110577541B (en) Salts of benzoylaminopyridine derivatives and their use in medicine
CN110577538B (en) Salts of benzoylaminopyridine derivatives and their use in medicine
CN110577539B (en) Salts of benzoylaminopyridine derivatives and their use in medicine
CN110577540B (en) Salts of benzoylaminopyridine derivatives and their use in medicine
CN112079837B (en) Salts of dihydropyrimidine derivatives and their use in medicine
WO2023088457A1 (en) Solid form of benfotiamine derivative, and preparation method therefor and use thereof
WO2018149309A1 (en) Crystal form of 4-phenylthiazole derivative and preparation method thereof
CN113631542B (en) Solid form of aromatic compound and preparation method thereof
WO2021104257A1 (en) Crystalline form of acetylcholinesterase inhibitor and preparation method therefor and application thereof
AU2021231396A1 (en) Salts and polymorphic forms of 6-chloro-7-(4-(4-chlorobenzyl)piperazin-1-yl)-2-(1,3-dimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22894986

Country of ref document: EP

Kind code of ref document: A1