WO2022122009A1 - Crystal forms of pyrrole derivative compound and preparation method therefor - Google Patents

Crystal forms of pyrrole derivative compound and preparation method therefor Download PDF

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WO2022122009A1
WO2022122009A1 PCT/CN2021/137015 CN2021137015W WO2022122009A1 WO 2022122009 A1 WO2022122009 A1 WO 2022122009A1 CN 2021137015 W CN2021137015 W CN 2021137015W WO 2022122009 A1 WO2022122009 A1 WO 2022122009A1
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crystal form
formula
compound
present
solid
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PCT/CN2021/137015
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French (fr)
Chinese (zh)
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鲁霞
陈智雄
张晓宇
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苏州晶云药物科技股份有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the invention relates to the field of chemical medicine, in particular to a crystal form of pyrrole derivative compounds and a preparation method thereof.
  • Orexin receptors include orexin type 1 receptor (OX1R) and orexin type 2 receptor (OX2R).
  • the type 1 receptor is a G protein-coupled receptor expressed in the hypothalamus, which is related to the feeding behavior of animals
  • the type 2 receptor also known as hypocretin receptor
  • hypocretin receptor is mainly distributed in the cerebral cortex, hypothalamus and some areas of the thalamus , involved in the regulation of sleep-wake behavior.
  • Studies have shown that mutations in genes encoding OX2 receptors are related to the onset and development of insomnia and depression.
  • Patent WO2011/050198A1 discloses the compound of formula (I), its synthesis and its use. The disclosed synthesis method needs to be purified by an Agilent HPLC column, and the yield is only 56%. Patent WO2017/156266A1 discloses the use of compounds of formula (I) in the treatment of depression.
  • the present invention provides three crystal forms A, crystal forms C and D of the compound of formula (I) and their preparation methods and uses.
  • the compound of formula (I) is dissolved in an alcoholic solvent, and after dissolving at -30-10° C., it is volatilized at -30-30° C. until a solid is precipitated to obtain crystal form C.
  • the compound represented by formula (I) [2-(4,6-dimethylpyrimidin-2-yl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]
  • the D-type crystal of pyrrol-5-yl]-[2-fluoro-6-(triazol-2-yl)phenyl]methanone, namely crystal form D, is characterized in that, using Cu-K ⁇ radiation, the The X-ray powder diffraction of Form D has characteristic peaks at 2 ⁇ values of 11.3° ⁇ 0.2°, 13.0° ⁇ 0.2° and 19.6° ⁇ 0.2°,
  • the compound of formula (I) is dissolved in ketones and esters solvents, dissolved at -30-10°C, and then volatilized at -30-30°C until a solid is precipitated to obtain crystal form D.
  • a pharmaceutical composition comprising the crystal form described in 1, 3, and 5 above and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition with OX2 receptor blocking activity comprising the crystal forms described in 1, 3, and 5 above as an active ingredient.
  • a clinical therapeutic drug for insomnia and depression comprising the crystal forms 1, 3, and 5 as an active ingredient.
  • the crystal form A, crystal form C and crystal form D of the compound of formula (I) provided by the present invention have the following advantages: There are advantages in at least one aspect of properties and processing performance, purification, preparation production, safety, etc., which provide a new and better choice for the preparation of pharmaceutical preparations containing the compound of formula (I), which is very important for drug development. Significance.
  • the X-ray powder diffraction of the crystal form A is at one or two or three places in the 2 ⁇ value of 11.5° ⁇ 0.2°, 14.9° ⁇ 0.2°, 19.7° ⁇ 0.2° There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form A has characteristic peaks at 2 ⁇ values of 11.5° ⁇ 0.2°, 14.9° ⁇ 0.2°, and 19.7° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form A has one or two or three 2 ⁇ values of 19.3° ⁇ 0.2°, 21.9° ⁇ 0.2°, and 23.6° ⁇ 0.2°. There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form A has characteristic peaks at 2 ⁇ values of 19.3° ⁇ 0.2°, 21.9° ⁇ 0.2°, and 23.6° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form A has 2 ⁇ values of 11.5° ⁇ 0.2°, 14.3° ⁇ 0.2°, 14.9° ⁇ 0.2°, 17.6° ⁇ 0.2°, 19.3° ⁇ 0.2°, 19.7° ⁇ 0.2°, 21.9° ⁇ 0.2°, 22.3° ⁇ 0.2°, 23.6° ⁇ 0.2° any 4, or 5, or 6, or 7, or 8, or 9 There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form A has 2 ⁇ values of 11.5° ⁇ 0.2°, 14.3° ⁇ 0.2°, 14.9° ⁇ 0.2°, 17.6° ⁇ 0.2°, 19.3° ⁇ There are characteristic peaks at 0.2°, 19.7° ⁇ 0.2°, 21.9° ⁇ 0.2°, 22.3° ⁇ 0.2°, and 23.6° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form A is shown in FIG. 1 .
  • the ketone solvent is 2-butanone
  • the ether solvent is ethylene glycol dimethyl ether
  • the alkane solvent is n-heptane.
  • the dissolution temperature is 20°C to 30°C.
  • the normal solvents include halogenated hydrocarbons, alcohols, cyclic ethers, acyclic ethers, ketones, esters and sulfoxide solvents, and the anti-solvents include alkanes, alcohols, esters and acyclic ethers solvent-like.
  • the halogenated hydrocarbon solvents include chloroform, dichloromethane and dibromomethane
  • the alcohol solvent is methanol
  • the cyclic ether solvents include tetrahydrofuran, 2-methyltetrahydrofuran and 1 ,4-dioxane
  • acyclic ether solvent is anisole
  • ketone solvent is acetone
  • ester solvent is ethyl formate
  • sulfoxide solvent is dimethyl sulfoxide
  • the solvent is n-heptane
  • the alcohol solvent is ethanol
  • the ester solvent is isopropyl acetate
  • the acyclic ether solvent is methyl cyclopentyl ether.
  • the temperature of the dissolving, dropping, stirring and precipitation is 5°C to 50°C, for example, 20°C to 30°C.
  • the normal solvents include halogenated hydrocarbons, alcohols, ketones, cyclic ethers, amides and alkyl nitrile solvents, and the anti-solvents include pure water, alkanes and acyclic ethers.
  • the halogenated hydrocarbon solvent is chloroform
  • the alcohol solvent is methanol
  • the ketone solvent is acetone
  • the cyclic ether solvent includes tetrahydrofuran and 1,4-dioxane
  • the amide solvent It is N,N-dimethylformamide
  • the alkyl nitrile solvent is acetonitrile
  • the alkane solvent is n-heptane
  • the acyclic ether solvent includes methyl tert-butyl ether and methyl cyclopentyl ether.
  • the temperature of dissolution, dropwise addition, stirring and precipitation is 20°C to 30°C.
  • the solvent system is a single or mixed solvent of alcohols, ketones, esters, ethers, pure water, alkyl nitriles, and alkanes.
  • alcohol solvents include isopropanol and trifluoroethanol
  • ketone solvents include acetone and methyl isobutyl ketone
  • ester solvents include ethyl acetate, isopropyl acetate Esters and n-butyl acetate
  • ether solvents include methyl tert-butyl ether, methyl cyclopentyl ether, tetrahydrofuran, 2-methyltetrahydrofuran and ethylene glycol dimethyl ether
  • alkyl nitrile solvents are acetonitrile
  • alkanes include n-heptane and cyclohexane.
  • the mixed solvent includes acetone/n-heptane, tetrahydrofuran/n-heptane, 2-methyltetrahydrofuran/n-heptane, acetonitrile/water, trifluoroethanol/water, tetrahydrofuran/water and Glycol dimethyl ether/cyclohexane.
  • the volume ratio of acetone/n-heptane is 1:3 ⁇ 1, for example, 1:2.
  • the volume ratio of tetrahydrofuran/n-heptane is 1:3-1, for example, 1:2.
  • the volume ratio of 2-methyltetrahydrofuran/n-heptane is 1:5-3, for example, 1:4.
  • the volume ratio of the acetonitrile/water is 2:1 ⁇ 2, for example, 1:1.
  • the volume ratio of the trifluoroethanol/water is 1:3 ⁇ 5, for example, 1:4.
  • the volume ratio of tetrahydrofuran/water is 1:0.5-2, for example 1:1.
  • the volume ratio of ethylene glycol dimethyl ether/cyclohexane is 1:0.5-2, such as 1:1.
  • the dissolution temperature is 40°C to 60°C, eg 50°C.
  • the crystallization temperature is -20°C to 5°C, eg -20°C.
  • the cooling rate is 0.05 ⁇ 1° C./min.
  • the volatilization temperature is 10°C to 50°C, for example, 20°C to 30°C.
  • the solvent system includes dichloromethane/ethyl acetate, methanol/water, tetrahydrofuran/water, ethylene glycol dimethyl ether/cyclohexane and dichloromethane/methyl isobutyl ketone.
  • the volume ratio of dichloromethane/ethyl acetate is 1:0.5-2, for example, 1:1.
  • the volume ratio of methanol/water is 1:0.5 ⁇ 2, for example, 1:1.
  • the volume ratio of acetonitrile/water is 1:1 ⁇ 3, for example, 1:2.
  • the volume ratio of the dichloromethane/methyl isobutyl ketone is 1:0.5-2, such as 1:1.
  • the alcoholic solvent includes ethanol and isopropanol.
  • the inorganic acid includes hydrochloric acid and sulfuric acid.
  • the alkaline aqueous solution includes an aqueous solution of potassium carbonate, sodium hydroxide and sodium bicarbonate.
  • the temperature of the dissolution, dropwise addition, stirring and precipitation is 20°C to 30°C.
  • the X-ray powder diffraction of the crystal form C has one or two or three 2 ⁇ values of 6.5° ⁇ 0.2°, 12.9° ⁇ 0.2°, and 26.1° ⁇ 0.2°. There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form C has characteristic peaks at 2 ⁇ values of 6.5° ⁇ 0.2°, 12.9° ⁇ 0.2°, and 26.1° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form C has one or two or three 2 ⁇ values of 8.0° ⁇ 0.2°, 19.6° ⁇ 0.2°, and 21.6° ⁇ 0.2°. There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form C has characteristic peaks at 2 ⁇ values of 8.0° ⁇ 0.2°, 19.6° ⁇ 0.2°, and 21.6° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form C has 2 ⁇ values of 6.5° ⁇ 0.2°, 8.0° ⁇ 0.2°, 9.9° ⁇ 0.2°, 10.8° ⁇ 0.2°, 12.9° ⁇ 0.2° 0.2°, 14.7° ⁇ 0.2°, 19.6° ⁇ 0.2°, 21.6° ⁇ 0.2°, 26.1° ⁇ 0.2° any 4, or 5, or 6, or 7, or 8, or 9 There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form C has 2 ⁇ values of 6.5° ⁇ 0.2°, 8.0° ⁇ 0.2°, 9.9° ⁇ 0.2°, 10.8° ⁇ 0.2°, 12.9° ⁇ 0.2° There are characteristic peaks at 0.2°, 14.7° ⁇ 0.2°, 19.6° ⁇ 0.2°, 21.6° ⁇ 0.2°, and 26.1° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form C is shown in FIG. 5 .
  • the compound of formula (I) is dissolved in an alcohol solvent, and volatilized under a certain temperature condition until a solid is precipitated to obtain crystal form C.
  • the alcohol solvent is methanol.
  • the volatilization temperature is -20°C to 30°C, for example, -20°C.
  • the X-ray powder diffraction of the crystal form D has one or two or three 2 ⁇ values of 6.5° ⁇ 0.2°, 7.1° ⁇ 0.2°, and 10.6° ⁇ 0.2°. There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form D has characteristic peaks at 2 ⁇ values of 6.5° ⁇ 0.2°, 7.1° ⁇ 0.2°, and 10.6° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form D has one or two or three 2 ⁇ values of 9.0° ⁇ 0.2°, 18.0° ⁇ 0.2°, and 21.4° ⁇ 0.2°. There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form D has characteristic peaks at 2 ⁇ values of 9.0° ⁇ 0.2°, 18.0° ⁇ 0.2°, and 21.4° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form D has 2 ⁇ values of 6.5° ⁇ 0.2°, 7.1° ⁇ 0.2°, 9.0° ⁇ 0.2°, 10.6° ⁇ 0.2°, 11.3° ⁇ 0.2°, 13.0° ⁇ 0.2°, 18.0° ⁇ 0.2°, 19.6° ⁇ 0.2°, 21.4° ⁇ 0.2° any 4, or 5, or 6, or 7, or 8, or 9 There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form D has 2 ⁇ values of 6.5° ⁇ 0.2°, 7.1° ⁇ 0.2°, 9.0° ⁇ 0.2°, 10.6° ⁇ 0.2°, 11.3° ⁇ There are characteristic peaks at 0.2°, 13.0° ⁇ 0.2°, 18.0° ⁇ 0.2°, 19.6° ⁇ 0.2°, and 21.4° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form D is shown in FIG. 9 .
  • the compound of formula (I) is dissolved in a ketone and ester solvent system, and volatilized under certain temperature conditions until a solid is precipitated to obtain crystal form D.
  • the ketone solvent is acetone
  • the ester solvent is ethyl formate.
  • the volatilization temperature is -30°C to 30°C, for example, -20°C.
  • said compound of formula (I) as starting material refers to its solid (crystalline or amorphous), semi-solid, wax or oil form.
  • the compound of formula (I) as starting material is in the form of a solid powder.
  • the "stirring" is accomplished by conventional methods in the art, such as magnetic stirring or mechanical stirring, and the stirring speed is 50-1800 rev/min, wherein the magnetic stirring is 200-1500 rev/min, preferably 300-1000 rev/min , the mechanical stirring is preferably 100 to 300 rpm.
  • the above crystals of the present invention can be used for the preparation of pharmaceutical compositions, which contain the above crystals of the present invention and a pharmaceutically acceptable carrier.
  • the above crystal of the present invention can be used to prepare a pharmaceutical composition having OX2 receptor blocking activity, which comprises the above crystal of the present invention as an active ingredient.
  • the above-mentioned crystal of the present invention can be used to prepare a therapeutic drug for insomnia or depression, which contains the above-mentioned crystal of the present invention as an active ingredient.
  • the present invention also provides a pharmaceutical composition comprising any one of the above-mentioned crystals of the present invention and a pharmaceutically acceptable carrier.
  • the present invention also provides a pharmaceutical composition with OX2 receptor blocking activity, which contains any one of the above-mentioned crystals of the present invention as an active ingredient.
  • the present invention provides a therapeutic drug for insomnia or depression, which contains any one of the above-mentioned crystals of the present invention as an active ingredient.
  • crystalline or “polymorphic form” means as evidenced by the characterization of the X-ray diffraction pattern shown.
  • X-ray diffraction patterns generally vary with the conditions of the instrument.
  • the relative intensities of X-ray diffraction patterns may also vary with experimental conditions, so the order of peak intensities cannot be used as the sole or decisive factor.
  • the relative intensities of the diffraction peaks in the X-ray diffraction pattern are related to the preferred orientation of the crystals, and the peak intensities shown here are illustrative and not for absolute comparison.
  • the experimental error of the peak angle is usually 5% or less, the error of these angles should also be taken into account, usually an error of ⁇ 0.2° is allowed.
  • the overall shift of the peak angle will be caused, and a certain shift is usually allowed.
  • the X-ray diffraction pattern of a crystal form in the present invention does not necessarily have to be exactly the same as the X-ray diffraction pattern in the examples mentioned here, and the "same X-ray diffraction pattern" mentioned herein does not mean absolutely identical, identical peak positions may differ by ⁇ 0.2° and some variability in peak intensity is allowed. Any crystalline form having the same or similar pattern as the characteristic peaks in these patterns is within the scope of the present invention.
  • Those skilled in the art can compare the patterns listed in the present invention with a pattern of an unknown crystal form to confirm whether the two sets of patterns reflect the same or different crystal forms.
  • the crystalline form of the present invention is pure, single, substantially free of admixture with any other crystalline form.
  • substantially free when used to refer to a new crystal form means that the crystal form contains less than 20% by weight of other crystal forms, especially less than 10% by weight of other crystal forms, and even less More than 5% (weight) of other crystal forms, more than 1% (weight) of other crystal forms.
  • the numerical values and numerical ranges mentioned in the present invention should not be narrowly construed as numerical values or numerical ranges themselves, and those skilled in the art should understand that they can be based on specific technical environments, without departing from the spirit and scope of the present invention. There are fluctuations around specific numerical values on the basis of principles. In the present invention, such a range of fluctuations that can be foreseen by those skilled in the art is often represented by the term "about”.
  • room temperature generally refers to 22°C to 28°C unless otherwise specified.
  • PSD particle size distribution
  • PLM Polarized Light Microscope
  • the X-ray powder diffraction patterns of the present invention were collected on Empyrean and X'Pert 3 X-ray powder diffractometers of Panalytical Corporation.
  • the method parameters of X-ray powder diffraction of the present invention are as follows:
  • the differential scanning calorimetry analysis diagram of the present invention is collected on the Q200 type and Discovery DSC 2500 type differential scanning calorimeter of TA company.
  • the method parameters of the differential scanning calorimetry analysis of the present invention are as follows:
  • thermogravimetric analysis diagram of the present invention is collected on the Discovery TGA 5500 type and Q5000 type thermogravimetric analyzer of TA company.
  • the method parameters of the thermogravimetric analysis of the present invention are as follows:
  • the hydrogen nuclear magnetic resonance spectrum data ( 1 H NMR) of the present invention was collected from a Bruker Avance II DMX 400M HZ nuclear magnetic resonance spectrometer. Weigh 1-5 mg of the sample, dissolve it with 0.5 mL of deuterated dimethyl sulfoxide, and prepare a solution of 2-10 mg/mL for testing.
  • the dynamic moisture adsorption diagram of the present invention is collected on the Intrinsic type and Intrinsic Plus type dynamic moisture adsorption instrument of SMS company.
  • the method parameters of the dynamic moisture adsorption test of the present invention are as follows:
  • Relative humidity gradient 10% (0%RH-90%RH-0%RH), 5% (90%RH-95%RH and 95%RH-90%RH)
  • the particle size distribution results described in the present invention were collected on Microtrac's Model S3500 laser particle size analyzer.
  • Microtrac S3500 is equipped with SDC (Sample Delivery Controller) sampling system.
  • SDC Sample Delivery Controller
  • This test adopts the wet method, and the test dispersion medium is Isopar G (containing 0.2% lecithin).
  • the method parameters of the described laser particle size analyzer are as follows:
  • Particle Size Distribution Volume Distribution Acquisition time: 10 seconds
  • Dispersion medium Isopar G
  • Granularity Coordinates Standard Collection times: 3 times
  • Transparency Transparent Residuals: enabled
  • Flow Rate 60%*
  • Ultrasonic power 30 watts
  • Ultrasound time Ultrasound 30s
  • the intrinsic dissolution rate data described in the present invention were collected on the Agilent 708DS type dissolution apparatus of Agilent. Described inherent dissolution test conditions are as follows:
  • the polarized light microscope photos described in the present invention were collected at room temperature by a Zeiss microscope Axio Scope.A1 equipped with an Axiocam 305 color camera and 5 ⁇ , 10 ⁇ , 20 ⁇ and 50 ⁇ objective lenses.
  • the starting material of compound (I) used in the following examples can be prepared according to the prior art, for example, according to the method described in WO2011/050198A1, but the starting crystal form is not a limitation for preparing the crystal form of the present invention.
  • the solids obtained in this example are all crystal form A.
  • the detailed test conditions involved in this example are shown in Table 3, the XRPD pattern of the solid obtained in Example 4 is shown in FIG. 1 , and the TGA, DSC, and 1 H NMR are shown in FIGS. 2 to 4 , respectively.
  • the sample is at about 11.5° ⁇ 0.2°, about 14.3° ⁇ 0.2°, about 14.9° ⁇ 0.2°, about 17.6° ⁇ 0.2°, about 18.2° ⁇ 0.2°, about 19.3° ⁇ 0.2°, about 19.7° ⁇ 0.2 °, about 21.9° ⁇ 0.2°, about 22.3° ⁇ 0.2°, about 23.6° ⁇ 0.2°, and about 26.9° ⁇ 0.2° have characteristic peaks.
  • the X-ray powder diffraction data of the sample of Example 4 are shown in Table 4.
  • Diffraction angle 2 ⁇ d value strength% 30.71 2.91 1.72 31.83 2.81 4.31 32.54 2.75 1.98 33.54 2.67 0.72 34.62 2.59 1.70 36.98 2.43 0.92 38.04 2.37 2.60
  • the solids obtained in this example are all crystal form A.
  • the detailed test conditions involved in this example are shown in Table 7, and the X-ray powder diffraction data of the sample of Example 25 are shown in Table 8.
  • the solids obtained in this example are all crystal form A.
  • the detailed test conditions involved in this example are shown in Table 9, and the X-ray powder diffraction data of the sample of Example 35 is shown in Table 10.
  • the solids obtained in this example are all crystal form A.
  • the detailed test conditions involved in this example are shown in Table 11, and the X-ray powder diffraction data of the sample of Example 37 is shown in Table 12.
  • Diffraction angle 2 ⁇ d value strength% 18.27 4.86 2.80 18.60 4.77 6.71 19.31 4.60 6.81 19.75 4.49 4.73 21.87 4.06 12.53 22.32 3.98 100.00 23.67 3.76 14.54 24.63 3.61 7.33 25.08 3.55 1.79 26.44 3.37 6.57 26.95 3.31 29.76 27.22 3.28 14.26 30.19 2.96 1.89 31.83 2.81 6.96 34.66 2.59 1.19 37.99 2.37 4.46
  • Example 39 Preparation of crystal form A (rapid evaporation method at room temperature)
  • Diffraction angle 2 ⁇ d value strength% 18.59 4.77 16.01 19.29 4.60 20.25 19.72 4.50 26.36 21.87 4.06 30.17 22.28 3.99 93.13 23.20 3.83 14.38 23.60 3.77 28.87 24.56 3.63 15.28 25.11 3.55 6.24 26.42 3.37 9.19 26.92 3.31 27.97 27.20 3.28 23.93 30.15 2.96 5.79 31.82 2.81 11.89 33.63 2.67 8.25 34.25 2.62 4.50 37.94 2.37 4.24
  • the sample is at about 6.5° ⁇ 0.2°, about 8.0° ⁇ 0.2°, about 9.9° ⁇ 0.2°, about 10.8° ⁇ 0.2°, about 12.9° ⁇ 0.2°, about 14.7° ⁇ 0.2°, about 16.1° ⁇ 0.2 °, about 17.5° ⁇ 0.2°, about 19.6° ⁇ 0.2°, about 21.6° ⁇ 0.2°, and about 26.1° ⁇ 0.2° have characteristic peaks. Its X-ray powder diffraction data are shown in Table 16.
  • Diffraction angle 2 ⁇ d value strength% 18.31 4.85 5.80 18.60 4.77 24.70 19.58 4.53 75.40 20.47 4.34 7.45 21.39 4.15 21.12 22.83 3.90 11.51 23.61 3.77 11.58 24.70 3.60 24.80 26.23 3.40 53.27 27.26 3.27 23.41 27.97 3.19 8.56 31.73 2.82 7.27
  • the XRPD pattern of the solid obtained in Example 45 is shown in FIG. 9 , and the TGA, DSC, and 1 H NMR are shown in FIGS. 10 to 12 , respectively.
  • the sample is at about 6.5° ⁇ 0.2°, about 7.1° ⁇ 0.2°, about 8.6° ⁇ 0.2°, about 9.0° ⁇ 0.2°, about 10.6° ⁇ 0.2°, about 11.3° ⁇ 0.2°, about 13.0° ⁇ 0.2 °, about 16.0° ⁇ 0.2°, about 18.0° ⁇ 0.2°, about 19.6° ⁇ 0.2°, and about 21.4° ⁇ 0.2° have characteristic peaks.
  • Its X-ray powder diffraction data are shown in Table 19.
  • the crystal form A, crystal form C and crystal form D of the present invention are respectively prepared into suspensions with FaSSIF (artificial intestinal fluid in fasting state) and pure water, and filtered after equilibration for 1 hour, 2 hours, 4 hours and 24 hours to obtain saturated solution.
  • the content of the sample in the saturated solution was determined by high performance liquid chromatography (HPLC).
  • HPLC high performance liquid chromatography
  • the test results are shown in Table 20, and the solubility curves are shown in Figures 13 to 14, respectively.
  • the test results show that the crystal form A, crystal form C and crystal form D of the present invention have good solubility in FaSSIF and pure water.
  • Example 51 Comparative study on hygroscopicity
  • Moisture gain is less than 15% but not less than 2%
  • wet weight gain is less than 2% but not less than 0.2%
  • wet weight gain is less than 0.2%

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Abstract

The present invention relates to crystal forms of a pyrrole derivative compound and a preparation method therefor. Provided are three crystal forms, crystal form A, crystal form C, and crystal form D, of a compound represented by formula (I), a preparation method therefor and a use thereof. The provided crystal form A, crystal form C, and crystal form D of the compound represented by formula (I) have advantages in at least one aspect among solubility, melting point, stability, dissolution, hygroscopicity, adhesion, fluidity, bioavailability and processability, purification, preparation production, safety, and so on. The present invention provides a new and better option for the preparation of pharmaceutical preparations containing the compound represented by formula (I), and is very important for drug development.

Description

吡咯类衍生化合物的晶型及其制备方法Crystal form of pyrrole derivative compound and preparation method thereof 技术领域technical field
本发明涉及化学医药领域，特别是涉及吡咯类衍生化合物的晶型及其制备方法。The invention relates to the field of chemical medicine, in particular to a crystal form of pyrrole derivative compounds and a preparation method thereof.
背景技术Background technique
食欲素(Orexin)受体包括食欲素1型受体(OX1R)与食欲素2型受体(OX2R)。其中，1型受体在下丘脑中表达的G蛋白偶联受体，以动物的进食行为有关，2型受体，也可称为hypocretin受体，主要分布于大脑皮层、下丘脑与丘脑部分区域，参与睡眠-觉醒行为的调节。研究显示，编码OX2受体相关基因的突变与失眠以及抑郁症的发病与发展有关，针对OX2受体阻断剂的研究，作为失眠以及抑郁症的治疗领域研究的一个全新的方向，成为制药领域研究的热点。Orexin receptors include orexin type 1 receptor (OX1R) and orexin type 2 receptor (OX2R). Among them, the type 1 receptor is a G protein-coupled receptor expressed in the hypothalamus, which is related to the feeding behavior of animals, and the type 2 receptor, also known as hypocretin receptor, is mainly distributed in the cerebral cortex, hypothalamus and some areas of the thalamus , involved in the regulation of sleep-wake behavior. Studies have shown that mutations in genes encoding OX2 receptors are related to the onset and development of insomnia and depression. Research on OX2 receptor blockers, as a new direction in the field of insomnia and depression treatment research, has become a new direction in the field of pharmaceuticals. research hotspot.
[2-(4,6-二甲基嘧啶-2-基)-1,3,3a,4,6,6a-六氢吡咯并[3,4-c]吡咯-5-基]-[2-氟-6-(三氮唑-2-基)苯基]甲酮是一种高选择性OX2受体阻断剂，临床上用于失眠以及抑郁症的治疗，其结构式如下所示：[2-(4,6-Dimethylpyrimidin-2-yl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl]-[2 -Fluoro-6-(triazol-2-yl)phenyl]methanone is a highly selective OX2 receptor blocker, clinically used for the treatment of insomnia and depression, its structural formula is as follows:
Figure PCTCN2021137015-appb-000001
Figure PCTCN2021137015-appb-000001
专利WO2011/050198A1公开了式(I)化合物，合成及使用方法，公开的合成方法需利用安捷伦HPLC色谱柱进行提纯，产率仅为56％。专利WO2017/156266A1公开了式(I)化合物在治疗抑郁症中的使用方法。Patent WO2011/050198A1 discloses the compound of formula (I), its synthesis and its use. The disclosed synthesis method needs to be purified by an Agilent HPLC column, and the yield is only 56%. Patent WO2017/156266A1 discloses the use of compounds of formula (I) in the treatment of depression.
上述制备方法过程繁琐、产率低，需开发更为简单且产率高的制备方法。而且目前，尚无有关式(I)化合物结晶形式以及结晶工艺的报道，有必要对该化合物晶体形态研究，以获得能够适用于工业生产的结晶形式以及结晶方法。The above-mentioned preparation method has complicated process and low yield, and a simpler preparation method with high yield needs to be developed. Moreover, at present, there is no report on the crystalline form and crystallization process of the compound of formula (I), and it is necessary to study the crystalline form of the compound to obtain a crystalline form and a crystallization method suitable for industrial production.
此外，同一药物的不同晶型在溶解度、熔点、密度、稳定性等方面有显著的差异，从而不同程度地影响药物的稳定性、均一性、生物利用度、疗效和安全性。因此，药物研发中进行全面系统的多晶型筛选，选择最适合开发的晶型，是不可忽视的重要研究内容之一。基于此，有必要对化合物(I)进行多晶型筛选，为药物的后续开发提供更多更好的选择。In addition, different crystal forms of the same drug have significant differences in solubility, melting point, density, stability, etc., thus affecting the stability, homogeneity, bioavailability, efficacy and safety of the drug to varying degrees. Therefore, it is one of the important research contents that can not be ignored to carry out comprehensive and systematic polymorph screening in drug research and development, and select the most suitable crystal form for development. Based on this, it is necessary to screen the polymorphic form of compound (I) to provide more and better choices for the subsequent development of the drug.
发明内容SUMMARY OF THE INVENTION
本发明提供了式(I)化合物的三种晶型A、晶型C、晶型D及其制备方法和用途。The present invention provides three crystal forms A, crystal forms C and D of the compound of formula (I) and their preparation methods and uses.
1.式(I)所示化合物[2-(4,6-二甲基嘧啶-2-基)-1,3,3a,4,6,6a-六氢吡咯并[3,4-c]吡咯-5-基]-[2-氟-6-(三氮唑-2-基)苯基]甲酮的A型晶体、即晶型A，其特征在于，使用Cu-Kα辐射，所述晶型A的X射线粉末衍射在2θ值为14.3°±0.2°,17.6°±0.2°和22.3°±0.2°处有特征峰，1. The compound represented by formula (I) [2-(4,6-dimethylpyrimidin-2-yl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c] A type crystal of pyrrol-5-yl]-[2-fluoro-6-(triazol-2-yl)phenyl]methanone, that is, crystal form A, characterized in that, using Cu-Kα radiation, the The X-ray powder diffraction of Form A has characteristic peaks at 2θ values of 14.3°±0.2°, 17.6°±0.2° and 22.3°±0.2°,
Figure PCTCN2021137015-appb-000002
Figure PCTCN2021137015-appb-000002
Figure PCTCN2021137015-appb-000003
Figure PCTCN2021137015-appb-000003
2.上述1中所述的晶型A的制备方法，其特征包括，2. the preparation method of the crystal form A described in the above-mentioned 1, is characterized in that,
(1)将式(I)化合物溶解于酮类、无环醚类溶剂中，室温条件下，置于烷烃类溶剂气氛下气液渗透一段时间，得到晶型A；或(1) dissolving the compound of formula (I) in a ketone, acyclic ether solvent, under room temperature conditions, place it in an alkane solvent atmosphere for a period of time to infiltrate gas and liquid to obtain crystal form A; or
(2)在5～50℃条件下，将式(I)化合物溶解于卤代烃类、醇类、环醚类、无环醚类、酮类、酯类、亚砜类溶剂中，加入烷烃类、醇类、酯类、无环醚类溶剂，搅拌至有固体析出，得到晶型A；或(2) Dissolve the compound of formula (I) in halogenated hydrocarbons, alcohols, cyclic ethers, acyclic ethers, ketones, esters and sulfoxide solvents at 5-50°C, add alkanes or
(3)在5～50℃条件下，将式(I)化合物溶解于卤代烃类、醇类、酮类、环醚类、酰胺类、烷基腈类溶剂中，搅拌状态下将其快速加入至纯水、烷烃类、无环醚类溶剂中，搅拌直至有固体析出，得到晶型A；或(3) Dissolve the compound of formula (I) in halogenated hydrocarbons, alcohols, ketones, cyclic ethers, amides, and alkyl nitrile solvents at 5 to 50 °C, and rapidly dissolve it under stirring. Add to pure water, alkanes, acyclic ether solvents, and stir until a solid is precipitated to obtain crystal form A; or
(4)将式(I)化合物溶解于酯类、酮类、烷基腈类、醇类、醚类、纯水、烷烃类的单一或者混合溶剂中，40～60℃下溶解后，置于-30～10℃下析出固体，得到晶型A；或(4) Dissolve the compound of formula (I) in a single or mixed solvent of esters, ketones, alkyl nitriles, alcohols, ethers, pure water, and alkanes, dissolve at 40-60 °C, and place it in a solvent. -30 ~ 10 ℃ to precipitate a solid to obtain crystal form A; or
(5)在5～50℃条件下，将式(I)化合物溶解于卤代烃类、酮类、醚类、纯水、醇类、酯类、烷烃类的混合溶剂体系中，5～50℃下挥发直至有固体析出，得到晶型A；或(5) Dissolve the compound of formula (I) in a mixed solvent system of halogenated hydrocarbons, ketones, ethers, pure water, alcohols, esters, and alkanes at 5 to 50 °C, 5 to 50 volatilize at ℃ until a solid is precipitated to obtain Form A; or
(6)在5～50℃条件下，将式(I)化合物加入到醇类溶剂中形成悬浮液。加入盐酸或硫酸的水溶液溶解。搅拌状态下向其中逐滴加入碳酸钾、氢氧化钠或碳酸氢钠的水溶液，直至有固体析出，得到晶型A。(6) The compound of formula (I) is added to an alcohol solvent under the condition of 5-50° C. to form a suspension. Add hydrochloric acid or sulfuric acid aqueous solution to dissolve. An aqueous solution of potassium carbonate, sodium hydroxide or sodium bicarbonate was added dropwise to it under stirring until a solid was precipitated, and crystal form A was obtained.
3.式(I)所示化合物[2-(4,6-二甲基嘧啶-2-基)-1,3,3a,4,6,6a-六氢吡咯并[3,4-c]吡咯-5-基]-[2-氟-6-(三氮唑-2-基)苯基]甲酮的C型晶体、即晶型C，其特征在于，使用Cu-Kα辐射，所述晶型C的X射线粉末衍射在2θ值为9.9°±0.2°,10.8°±0.2°和14.7°±0.2°处有特征峰，3. The compound represented by formula (I) [2-(4,6-dimethylpyrimidin-2-yl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c] The C-type crystal of pyrrol-5-yl]-[2-fluoro-6-(triazol-2-yl)phenyl]methanone, that is, crystal form C, characterized in that, using Cu-Kα radiation, the The X-ray powder diffraction of Form C has characteristic peaks at 2θ values of 9.9°±0.2°, 10.8°±0.2° and 14.7°±0.2°,
Figure PCTCN2021137015-appb-000004
Figure PCTCN2021137015-appb-000004
4.上述3中所述的晶型C的制备方法，其特征在于，4. the preparation method of crystal form C described in above-mentioned 3, is characterized in that,
将式(I)化合物溶解于醇类溶剂中，-30～10℃下溶解后，置于-30～30℃下挥发，直至固体析出，得到晶型C。The compound of formula (I) is dissolved in an alcoholic solvent, and after dissolving at -30-10° C., it is volatilized at -30-30° C. until a solid is precipitated to obtain crystal form C.
5.式(I)所示化合物[2-(4,6-二甲基嘧啶-2-基)-1,3,3a,4,6,6a-六氢吡咯并[3,4-c]吡咯-5-基]-[2-氟-6-(三氮唑-2-基)苯基]甲酮的D型晶体、即晶型D，其特征在于，使用Cu-Kα辐射，所述晶型D的X射线粉末衍射在2θ值为11.3°±0.2°,13.0°±0.2°和19.6°±0.2°处有特征峰，5. The compound represented by formula (I) [2-(4,6-dimethylpyrimidin-2-yl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c] The D-type crystal of pyrrol-5-yl]-[2-fluoro-6-(triazol-2-yl)phenyl]methanone, namely crystal form D, is characterized in that, using Cu-Kα radiation, the The X-ray powder diffraction of Form D has characteristic peaks at 2θ values of 11.3°±0.2°, 13.0°±0.2° and 19.6°±0.2°,
Figure PCTCN2021137015-appb-000005
Figure PCTCN2021137015-appb-000005
6.上述5中所述的晶型D的制备方法，其特征在于，6. the preparation method of the crystal form D described in the above-mentioned 5, is characterized in that,
将式(I)化合物溶解于酮类、酯类溶剂中，-30～10℃下溶解后，置于-30～30℃下挥发，直至固体析出，得到晶型D。The compound of formula (I) is dissolved in ketones and esters solvents, dissolved at -30-10°C, and then volatilized at -30-30°C until a solid is precipitated to obtain crystal form D.
7.药物组合物，其包含上述1,3,5所述晶型和制药学可接受的载体。7. A pharmaceutical composition comprising the crystal form described in 1, 3, and 5 above and a pharmaceutically acceptable carrier.
8.具有OX2受体阻断活性的药物组合物，其含有上述1,3,5所述晶型作为有效成分。8. A pharmaceutical composition with OX2 receptor blocking activity, comprising the crystal forms described in 1, 3, and 5 above as an active ingredient.
9.临床上失眠、抑郁症的治疗药，其含有1,3,5所述晶型作为有效成分。9. A clinical therapeutic drug for insomnia and depression, comprising the crystal forms 1, 3, and 5 as an active ingredient.
与现有技术相比，本发明提供的式(I)化合物晶型A、晶型C、晶型D，在溶解度、熔点、稳定性、溶出度、引湿性、黏附性、流动性、生物有效性以及加工性能、提纯作用、制剂生产、安全性等方面中的至少一方面上存在优势，为含式(I)化合物的药物制剂的制备提供了新的更好的选择，对于药物开发具有非常重要的意义。Compared with the prior art, the crystal form A, crystal form C and crystal form D of the compound of formula (I) provided by the present invention have the following advantages: There are advantages in at least one aspect of properties and processing performance, purification, preparation production, safety, etc., which provide a new and better choice for the preparation of pharmaceutical preparations containing the compound of formula (I), which is very important for drug development. Significance.
附图说明Description of drawings
图1晶型A的XRPD图Figure 1 XRPD pattern of Form A
图2晶型A的TGA曲线Figure 2 TGA curve of Form A
图3晶型A的DSC曲线Figure 3 DSC curve of Form A
图4晶型A的 1H NMR图谱 Figure 4 1 H NMR spectrum of Form A
图5晶型C的XRPD图Figure 5 XRPD pattern of Form C
图6晶型C的TGA曲线Figure 6 TGA curve of Form C
图7晶型C的DSC曲线Figure 7 DSC curve of Form C
图8晶型C的 1H NMR图谱 Figure 8 1 H NMR spectrum of Form C
图9晶型D的XRPD图Figure 9 XRPD pattern of Form D
图10晶型D的TGA曲线Figure 10 TGA curve of Form D
图11晶型D的DSC曲线Figure 11 DSC curve of Form D
图12晶型D的 1H NMR图谱 Figure 12 1 H NMR spectrum of Form D
图13不同晶型在FaSSIF中的溶解度对比图Fig. 13 Comparison of solubility of different crystal forms in FaSSIF
图14不同晶型在纯水中的溶解度对比图Figure 14 Comparison of solubility of different crystal forms in pure water
图15不同晶型在SGF中的溶出曲线Figure 15 Dissolution curves of different crystal forms in SGF
图16晶型A在25℃/60％相对湿度下稳定性测试XRPD对比图Figure 16. XRPD comparison chart of stability test of crystal form A at 25℃/60% relative humidity
图17晶型A在40℃/75％相对湿度下稳定性测试XRPD对比图Figure 17 XRPD comparison chart of stability test of crystal form A at 40°C/75% relative humidity
图18晶型C在25℃/60％相对湿度下稳定性测试XRPD对比图Figure 18. XRPD comparison chart of stability test of crystal form C at 25°C/60% relative humidity
图19晶型C在40℃/75％相对湿度下稳定性测试XRPD对比图Figure 19 XRPD comparison chart of stability test of crystal form C at 40°C/75% relative humidity
图20晶型D在25℃/60％相对湿度下稳定性测试XRPD对比图Figure 20 XRPD comparison chart of stability test of crystal form D at 25℃/60% relative humidity
图21晶型D在40℃/75％相对湿度下稳定性测试XRPD对比图Fig. 21 XRPD comparison chart of stability test of crystal form D at 40℃/75% relative humidity
图22晶型A的动态水分吸附图Figure 22 Dynamic moisture adsorption diagram of Form A
图23晶型A测试动态水分吸附脱附前后的XRPD对比图Fig. 23 Comparison of XRPD before and after dynamic moisture adsorption and desorption of crystal form A
图24晶型C的动态水分吸附图Figure 24 Dynamic moisture adsorption diagram of Form C
图25晶型C测试动态水分吸附脱附前后的XRPD对比图Fig. 25 Comparison of XRPD before and after dynamic moisture adsorption and desorption of crystal form C
图26晶型D的动态水分吸附图Figure 26 Dynamic moisture adsorption diagram of Form D
图27晶型D测试动态水分吸附脱附前后的XRPD对比图Fig. 27 Comparison of XRPD before and after dynamic moisture adsorption and desorption of crystal form D
图28晶型A的粒径分布图Figure 28 Particle size distribution of Form A
具体实施方式Detailed ways
式(I)所示化合物[2-(4,6-二甲基嘧啶-2-基)-1,3,3a,4,6,6a-六氢吡咯并[3,4-c]吡咯-5-基]-[2-氟-6-(三氮唑-2-基)苯基]甲酮的A型晶体、即晶型A，其特征在于，使用Cu-Kα辐射，所述晶型A的X射线粉末衍射在2θ值为14.3°±0.2°,17.6°±0.2°和22.3°±0.2°处有特征峰，The compound represented by formula (I) [2-(4,6-dimethylpyrimidin-2-yl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole- Form A crystal of 5-yl]-[2-fluoro-6-(triazol-2-yl)phenyl]methanone, namely crystal form A, characterized in that, using Cu-Kα radiation, the crystal form The X-ray powder diffraction of A has characteristic peaks at 2θ values of 14.3°±0.2°, 17.6°±0.2° and 22.3°±0.2°,
Figure PCTCN2021137015-appb-000006
Figure PCTCN2021137015-appb-000006
在本发明的一个实施方式中，所述晶型A的X射线粉末衍射在2θ值为11.5°±0.2°,14.9°±0.2°,19.7°±0.2°中的一处或两处或三处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form A is at one or two or three places in the 2θ value of 11.5°±0.2°, 14.9°±0.2°, 19.7°±0.2° There are characteristic peaks.
在本发明的一个实施方式中，所述晶型A的X射线粉末衍射在2θ值为11.5°±0.2°,14.9°±0.2°,19.7°±0.2°处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form A has characteristic peaks at 2θ values of 11.5°±0.2°, 14.9°±0.2°, and 19.7°±0.2°.
在本发明的一个实施方式中，所述晶型A的X射线粉末衍射在2θ值为19.3°±0.2°,21.9°±0.2°,23.6°±0.2°中的一处或两处或三处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form A has one or two or three 2θ values of 19.3°±0.2°, 21.9°±0.2°, and 23.6°±0.2°. There are characteristic peaks.
在本发明的一个实施方式中，所述晶型A的X射线粉末衍射在2θ值为19.3°±0.2°,21.9°±0.2°,23.6°±0.2°处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form A has characteristic peaks at 2θ values of 19.3°±0.2°, 21.9°±0.2°, and 23.6°±0.2°.
在本发明的一个实施方式中，所述晶型A的X射线粉末衍射在2θ值为11.5°±0.2°,14.3°±0.2°,14.9°±0.2°,17.6°±0.2°,19.3°±0.2°,19.7°±0.2°,21.9°±0.2°,22.3°±0.2°,23.6°±0.2°中的任意4处、或5处、或6处、或7处、或8处、或9处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form A has 2θ values of 11.5°±0.2°, 14.3°±0.2°, 14.9°±0.2°, 17.6°±0.2°, 19.3°± 0.2°, 19.7°±0.2°, 21.9°±0.2°, 22.3°±0.2°, 23.6°±0.2° any 4, or 5, or 6, or 7, or 8, or 9 There are characteristic peaks.
在本发明的一个实施方式中，所述晶型A的X射线粉末衍射在2θ值为11.5°±0.2°,14.3°±0.2°,14.9°±0.2°,17.6°±0.2°,19.3°±0.2°,19.7°±0.2°,21.9°±0.2°,22.3°±0.2°,23.6°±0.2°处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form A has 2θ values of 11.5°±0.2°, 14.3°±0.2°, 14.9°±0.2°, 17.6°±0.2°, 19.3°± There are characteristic peaks at 0.2°, 19.7°±0.2°, 21.9°±0.2°, 22.3°±0.2°, and 23.6°±0.2°.
在本发明的一个实施方式中，所述晶型A的X射线粉末衍射图如图1所示。In one embodiment of the present invention, the X-ray powder diffraction pattern of the crystal form A is shown in FIG. 1 .
所述晶型A的制备方法，其特征包括：The preparation method of described crystal form A is characterized by comprising:
(1)将式(I)化合物溶解于正溶剂中，置于反溶剂氛围下气液渗透一段时间，固体析出，得到晶型A。所述正溶剂包括酮类和醚类溶剂，所述反溶剂为烷烃类溶剂。(1) Dissolving the compound of formula (I) in a positive solvent, placing it in an anti-solvent atmosphere for gas-liquid permeation for a period of time, the solid is precipitated, and crystal form A is obtained. The positive solvent includes ketone and ether solvents, and the anti-solvent is an alkane solvent.
在本发明的一个实施方式中，所述酮类溶剂为2-丁酮，醚类溶剂为乙二醇二甲醚。In one embodiment of the present invention, the ketone solvent is 2-butanone, and the ether solvent is ethylene glycol dimethyl ether.
在本发明的一个实施方式中，所述烷烃类溶剂为正庚烷。In one embodiment of the present invention, the alkane solvent is n-heptane.
在本发明的一个实施方式中，所述溶解析出温度为20℃到30℃。In one embodiment of the present invention, the dissolution temperature is 20°C to 30°C.
(2)将式(I)化合物溶解于正溶剂中，搅拌状态下向其中逐滴加入反溶剂，直至有固体析出，得到晶型A。所述正溶剂包括卤代烃类、醇类、环醚类、无环醚类、酮类、酯类和亚砜类溶剂，所述反溶剂包括烷烃类、醇类、酯类和无环醚类溶剂。(2) Dissolving the compound of formula (I) in a positive solvent, adding an anti-solvent dropwise to it under stirring, until a solid is precipitated to obtain crystal form A. The normal solvents include halogenated hydrocarbons, alcohols, cyclic ethers, acyclic ethers, ketones, esters and sulfoxide solvents, and the anti-solvents include alkanes, alcohols, esters and acyclic ethers solvent-like.
在本发明的一个实施方式中，所述正溶剂中，卤代烃类溶剂包括氯仿、二氯甲烷和二溴甲烷，醇类溶剂为甲醇，环醚类溶剂包括四氢呋喃、2-甲基四氢呋喃和1,4-二氧六环，无环醚类溶剂为苯甲醚，酮类溶剂为丙酮，酯类溶剂为甲酸乙酯，亚砜类溶剂为二甲亚砜； 所述反溶剂中，烷烃类溶剂为正庚烷，醇类溶剂为乙醇，酯类溶剂为乙酸异丙酯，无环醚类溶剂为甲基环戊基醚。In one embodiment of the present invention, in the positive solvent, the halogenated hydrocarbon solvents include chloroform, dichloromethane and dibromomethane, the alcohol solvent is methanol, and the cyclic ether solvents include tetrahydrofuran, 2-methyltetrahydrofuran and 1 ,4-dioxane, acyclic ether solvent is anisole, ketone solvent is acetone, ester solvent is ethyl formate, sulfoxide solvent is dimethyl sulfoxide; The solvent is n-heptane, the alcohol solvent is ethanol, the ester solvent is isopropyl acetate, and the acyclic ether solvent is methyl cyclopentyl ether.
在本发明的一个实施方式中，所述溶解、滴加、搅拌和析出温度为5℃到50℃，例如20℃到30℃。In one embodiment of the present invention, the temperature of the dissolving, dropping, stirring and precipitation is 5°C to 50°C, for example, 20°C to 30°C.
(3)将式(I)化合物溶解于正溶剂中，搅拌状态下将其加入到反溶剂中，继续搅拌直至有固体析出，得到晶型A。所述正溶剂包括卤代烃类、醇类、酮类、环醚类、酰胺类和烷基腈类溶剂，所述反溶剂包括纯水、烷烃类和无环醚类溶剂。(3) Dissolving the compound of formula (I) in a positive solvent, adding it to an anti-solvent under stirring, and continuing to stir until a solid is precipitated to obtain crystal form A. The normal solvents include halogenated hydrocarbons, alcohols, ketones, cyclic ethers, amides and alkyl nitrile solvents, and the anti-solvents include pure water, alkanes and acyclic ethers.
在本发明的一个实施方式中，所述卤代烃类溶剂为氯仿，醇类溶剂为甲醇，酮类溶剂为丙酮，环醚类溶剂包括四氢呋喃和1,4-二氧六环，酰胺类溶剂为N,N-二甲基甲酰胺，烷基腈类溶剂为乙腈；所述烷烃类溶剂为正庚烷，无环醚类溶剂包括甲基叔丁基醚和甲基环戊基醚。In one embodiment of the present invention, the halogenated hydrocarbon solvent is chloroform, the alcohol solvent is methanol, the ketone solvent is acetone, the cyclic ether solvent includes tetrahydrofuran and 1,4-dioxane, and the amide solvent It is N,N-dimethylformamide, the alkyl nitrile solvent is acetonitrile; the alkane solvent is n-heptane, and the acyclic ether solvent includes methyl tert-butyl ether and methyl cyclopentyl ether.
在本发明的一个实施方式中，溶解、滴加、搅拌和析出温度为20℃到30℃。In one embodiment of the present invention, the temperature of dissolution, dropwise addition, stirring and precipitation is 20°C to 30°C.
(4)将式(I)化合物溶解于溶剂体系中，一定温度下达到溶解平衡后，降温至有固体析出，得到晶型A。所述溶剂体系为醇类、酮类、酯类、醚类、纯水、烷基腈类、烷烃类的单一或者混合溶剂。(4) Dissolving the compound of formula (I) in a solvent system, after reaching the dissolution equilibrium at a certain temperature, cooling down until a solid is precipitated to obtain crystal form A. The solvent system is a single or mixed solvent of alcohols, ketones, esters, ethers, pure water, alkyl nitriles, and alkanes.
在本发明的一个实施方式中，所述溶剂体系中，醇类溶剂包括异丙醇和三氟乙醇，酮类溶剂包括丙酮和甲基异丁基酮，酯类溶剂包括乙酸乙酯、乙酸异丙酯和乙酸正丁酯，醚类溶剂包括甲基叔丁基醚、甲基环戊基醚、四氢呋喃、2-甲基四氢呋喃和乙二醇二甲醚，烷基腈类溶剂为乙腈，烷烃类溶剂包括正庚烷和环己烷。In one embodiment of the present invention, in the solvent system, alcohol solvents include isopropanol and trifluoroethanol, ketone solvents include acetone and methyl isobutyl ketone, and ester solvents include ethyl acetate, isopropyl acetate Esters and n-butyl acetate, ether solvents include methyl tert-butyl ether, methyl cyclopentyl ether, tetrahydrofuran, 2-methyltetrahydrofuran and ethylene glycol dimethyl ether, alkyl nitrile solvents are acetonitrile, alkanes Solvents include n-heptane and cyclohexane.
在本发明的一个实施方式中，所述混合溶剂包括丙酮/正庚烷、四氢呋喃/正庚烷、2-甲基四氢呋喃/正庚烷、乙腈/水、三氟乙醇/水、四氢呋喃/水和乙二醇二甲醚/环己烷。In one embodiment of the present invention, the mixed solvent includes acetone/n-heptane, tetrahydrofuran/n-heptane, 2-methyltetrahydrofuran/n-heptane, acetonitrile/water, trifluoroethanol/water, tetrahydrofuran/water and Glycol dimethyl ether/cyclohexane.
在本发明的一个实施方式中，所述丙酮/正庚烷的体积比为1:3～1，例如1:2。In one embodiment of the present invention, the volume ratio of acetone/n-heptane is 1:3˜1, for example, 1:2.
在本发明的一个实施方式中，所述四氢呋喃/正庚烷的体积比为1:3～1，例如1:2。In one embodiment of the present invention, the volume ratio of tetrahydrofuran/n-heptane is 1:3-1, for example, 1:2.
在本发明的一个实施方式中，所述2-甲基四氢呋喃/正庚烷的体积比为1:5～3，例如1:4。In one embodiment of the present invention, the volume ratio of 2-methyltetrahydrofuran/n-heptane is 1:5-3, for example, 1:4.
在本发明的一个实施方式中，所述乙腈/水的体积比为2:1～2，例如1:1。In one embodiment of the present invention, the volume ratio of the acetonitrile/water is 2:1˜2, for example, 1:1.
在本发明的一个实施方式中，所述三氟乙醇/水的体积比为1:3～5，例如1:4。In one embodiment of the present invention, the volume ratio of the trifluoroethanol/water is 1:3˜5, for example, 1:4.
在本发明的一个实施方式中，所述四氢呋喃/水的体积比为1:0.5～2，例如1:1。In one embodiment of the present invention, the volume ratio of tetrahydrofuran/water is 1:0.5-2, for example 1:1.
在本发明的一个实施方式中，所述乙二醇二甲醚/环己烷的体积比为1:0.5～2，例如1:1。In one embodiment of the present invention, the volume ratio of ethylene glycol dimethyl ether/cyclohexane is 1:0.5-2, such as 1:1.
在本发明的一个实施方式中，所述溶解温度为40℃到60℃，例如50℃。In one embodiment of the present invention, the dissolution temperature is 40°C to 60°C, eg 50°C.
在本发明的一个实施方式中，所述析晶温度为-20℃到5℃，例如-20℃。In one embodiment of the present invention, the crystallization temperature is -20°C to 5°C, eg -20°C.
在本发明的一个实施方式中，所述降温速率为0.05～1℃/分钟。In one embodiment of the present invention, the cooling rate is 0.05˜1° C./min.
(5)将式(I)化合物溶解于混合溶剂体系中，一定温度条件下挥发，直至有固体析出，得到晶型A。(5) Dissolving the compound of formula (I) in a mixed solvent system, volatilizing under a certain temperature condition, until a solid is precipitated to obtain crystal form A.
在本发明的一个实施方式中，所述挥发温度为10℃到50℃，例如，20℃到30℃。In one embodiment of the present invention, the volatilization temperature is 10°C to 50°C, for example, 20°C to 30°C.
在本发明的一个实施方式中，所述溶剂体系包括二氯甲烷/乙酸乙酯、甲醇/水、四氢呋喃/水、乙二醇二甲醚/环己烷和二氯甲烷/甲基异丁基酮。In one embodiment of the present invention, the solvent system includes dichloromethane/ethyl acetate, methanol/water, tetrahydrofuran/water, ethylene glycol dimethyl ether/cyclohexane and dichloromethane/methyl isobutyl ketone.
在本发明的一个实施方式中，所述二氯甲烷/乙酸乙酯的体积比为1:0.5～2，例如1:1。In one embodiment of the present invention, the volume ratio of dichloromethane/ethyl acetate is 1:0.5-2, for example, 1:1.
在本发明的一个实施方式中，所述甲醇/水的体积比为1:0.5～2，例如1:1。In one embodiment of the present invention, the volume ratio of methanol/water is 1:0.5˜2, for example, 1:1.
在本发明的一个实施方式中，所述乙腈/水的体积比为1:1～3，例如1:2。In one embodiment of the present invention, the volume ratio of acetonitrile/water is 1:1˜3, for example, 1:2.
在本发明的一个实施方式中，所述二氯甲烷/甲基异丁基酮的体积比为1:0.5～2，例如1:1。In one embodiment of the present invention, the volume ratio of the dichloromethane/methyl isobutyl ketone is 1:0.5-2, such as 1:1.
(6)将式(I)化合物加入到醇类溶剂中形成悬浮液，加入无机酸的水溶液溶解。搅拌状态下向其中逐滴加入碱性水溶液，直至有固体析出，得到晶型A。(6) The compound of formula (I) is added to an alcohol solvent to form a suspension, and an aqueous solution of an inorganic acid is added to dissolve. The alkaline aqueous solution was added dropwise to it under stirring until a solid was precipitated, and the crystal form A was obtained.
在本发明的一个实施方式中，所述醇类溶剂包括乙醇和异丙醇。In one embodiment of the present invention, the alcoholic solvent includes ethanol and isopropanol.
在本发明的一个实施方式中，所述无机酸包括盐酸和硫酸。In one embodiment of the present invention, the inorganic acid includes hydrochloric acid and sulfuric acid.
在本发明的一个实施方式中，所述碱性水溶液包括碳酸钾、氢氧化钠和碳酸氢钠的水溶液。In one embodiment of the present invention, the alkaline aqueous solution includes an aqueous solution of potassium carbonate, sodium hydroxide and sodium bicarbonate.
在本发明的一个实施方式中，所述溶解、滴加、搅拌和析出温度为20℃到30℃。In one embodiment of the present invention, the temperature of the dissolution, dropwise addition, stirring and precipitation is 20°C to 30°C.
式(I)所示化合物[2-(4,6-二甲基嘧啶-2-基)-1,3,3a,4,6,6a-六氢吡咯并[3,4-c]吡咯-5-基]-[2-氟-6-(三氮唑-2-基)苯基]甲酮的C型晶体、即晶型C，其特征在于，使用Cu-Kα辐射，所述晶型C的X射线粉末衍射在2θ值为9.9°±0.2°,10.8°±0.2°和14.7°±0.2°处有特征峰，The compound represented by formula (I) [2-(4,6-dimethylpyrimidin-2-yl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole- C-type crystal of 5-yl]-[2-fluoro-6-(triazol-2-yl)phenyl]methanone, namely crystal form C, characterized in that, using Cu-Kα radiation, the crystal form The X-ray powder diffraction of C has characteristic peaks at 2θ values of 9.9°±0.2°, 10.8°±0.2° and 14.7°±0.2°,
Figure PCTCN2021137015-appb-000007
Figure PCTCN2021137015-appb-000007
在本发明的一个实施方式中，所述晶型C的X射线粉末衍射在2θ值为6.5°±0.2°,12.9°±0.2°,26.1°±0.2°中的一处或两处或三处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form C has one or two or three 2θ values of 6.5°±0.2°, 12.9°±0.2°, and 26.1°±0.2°. There are characteristic peaks.
在本发明的一个实施方式中，所述晶型C的X射线粉末衍射在2θ值为6.5°±0.2°,12.9°±0.2°,26.1°±0.2°处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form C has characteristic peaks at 2θ values of 6.5°±0.2°, 12.9°±0.2°, and 26.1°±0.2°.
在本发明的一个实施方式中，所述晶型C的X射线粉末衍射在2θ值为8.0°±0.2°,19.6°±0.2°,21.6°±0.2°中的一处或两处或三处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form C has one or two or three 2θ values of 8.0°±0.2°, 19.6°±0.2°, and 21.6°±0.2°. There are characteristic peaks.
在本发明的一个实施方式中，所述晶型C的X射线粉末衍射在2θ值为8.0°±0.2°,19.6°±0.2°,21.6°±0.2°处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form C has characteristic peaks at 2θ values of 8.0°±0.2°, 19.6°±0.2°, and 21.6°±0.2°.
在本发明的一个实施方式中，所述晶型C的X射线粉末衍射在2θ值为6.5°±0.2°,8.0°±0.2°,9.9°±0.2°,10.8°±0.2°,12.9°±0.2°,14.7°±0.2°,19.6°±0.2°,21.6°±0.2°,26.1°±0.2°中的任意4处、或5处、或6处、或7处、或8处、或9处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form C has 2θ values of 6.5°±0.2°, 8.0°±0.2°, 9.9°±0.2°, 10.8°±0.2°, 12.9°±0.2° 0.2°, 14.7°±0.2°, 19.6°±0.2°, 21.6°±0.2°, 26.1°±0.2° any 4, or 5, or 6, or 7, or 8, or 9 There are characteristic peaks.
在本发明的一个实施方式中，所述晶型C的X射线粉末衍射在2θ值为6.5°±0.2°,8.0°±0.2°,9.9°±0.2°,10.8°±0.2°,12.9°±0.2°,14.7°±0.2°,19.6°±0.2°,21.6°±0.2°,26.1°±0.2°处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form C has 2θ values of 6.5°±0.2°, 8.0°±0.2°, 9.9°±0.2°, 10.8°±0.2°, 12.9°±0.2° There are characteristic peaks at 0.2°, 14.7°±0.2°, 19.6°±0.2°, 21.6°±0.2°, and 26.1°±0.2°.
在本发明的一个实施方式中，所述晶型C的X射线粉末衍射图如图5所示。In one embodiment of the present invention, the X-ray powder diffraction pattern of the crystal form C is shown in FIG. 5 .
所述晶型C的制备方法，其特征在于：The preparation method of described crystal form C is characterized in that:
将式(I)化合物溶解于醇类溶剂中，一定温度条件下，挥发直至有固体析出，得到晶型C。The compound of formula (I) is dissolved in an alcohol solvent, and volatilized under a certain temperature condition until a solid is precipitated to obtain crystal form C.
在本发明的一个实施方式中，所述醇类溶剂为甲醇。In one embodiment of the present invention, the alcohol solvent is methanol.
在本发明的一个实施方式中，所述挥发温度为-20℃到30℃，例如，-20℃。In one embodiment of the present invention, the volatilization temperature is -20°C to 30°C, for example, -20°C.
式(I)所示化合物[2-(4,6-二甲基嘧啶-2-基)-1,3,3a,4,6,6a-六氢吡咯并[3,4-c]吡咯-5-基]-[2-氟-6-(三氮唑-2-基)苯基]甲酮的D型晶体、即晶型D，其特征在于，使用Cu-Kα辐射，所述晶型D的X射线粉末衍射在2θ值为11.3°±0.2°,13.0°±0.2°和19.6°±0.2°处有特征峰，The compound represented by formula (I) [2-(4,6-dimethylpyrimidin-2-yl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole- D-type crystal of 5-yl]-[2-fluoro-6-(triazol-2-yl)phenyl]methanone, namely crystal form D, characterized in that, using Cu-Kα radiation, the crystal form The X-ray powder diffraction of D has characteristic peaks at 2θ values of 11.3°±0.2°, 13.0°±0.2° and 19.6°±0.2°,
Figure PCTCN2021137015-appb-000008
Figure PCTCN2021137015-appb-000008
在本发明的一个实施方式中，所述晶型D的X射线粉末衍射在2θ值为6.5°±0.2°,7.1°±0.2°,10.6°±0.2°中的一处或两处或三处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form D has one or two or three 2θ values of 6.5°±0.2°, 7.1°±0.2°, and 10.6°±0.2°. There are characteristic peaks.
在本发明的一个实施方式中，所述晶型D的X射线粉末衍射在2θ值为6.5°±0.2°,7.1°±0.2°,10.6°±0.2°处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form D has characteristic peaks at 2θ values of 6.5°±0.2°, 7.1°±0.2°, and 10.6°±0.2°.
在本发明的一个实施方式中，所述晶型D的X射线粉末衍射在2θ值为9.0°±0.2°,18.0°±0.2°,21.4°±0.2°中的一处或两处或三处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form D has one or two or three 2θ values of 9.0°±0.2°, 18.0°±0.2°, and 21.4°±0.2°. There are characteristic peaks.
在本发明的一个实施方式中，所述晶型D的X射线粉末衍射在2θ值为9.0°±0.2°,18.0°±0.2°,21.4°±0.2°处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form D has characteristic peaks at 2θ values of 9.0°±0.2°, 18.0°±0.2°, and 21.4°±0.2°.
在本发明的一个实施方式中，所述晶型D的X射线粉末衍射在2θ值为6.5°±0.2°,7.1°±0.2°,9.0°±0.2°,10.6°±0.2°,11.3°±0.2°,13.0°±0.2°,18.0°±0.2°,19.6°±0.2°,21.4°±0.2°中的任意4处、或5处、或6处、或7处、或8处、或9处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form D has 2θ values of 6.5°±0.2°, 7.1°±0.2°, 9.0°±0.2°, 10.6°±0.2°, 11.3°± 0.2°, 13.0°±0.2°, 18.0°±0.2°, 19.6°±0.2°, 21.4°±0.2° any 4, or 5, or 6, or 7, or 8, or 9 There are characteristic peaks.
在本发明的一个实施方式中，所述晶型D的X射线粉末衍射在2θ值为6.5°±0.2°,7.1°±0.2°,9.0°±0.2°,10.6°±0.2°,11.3°±0.2°,13.0°±0.2°,18.0°±0.2°,19.6°±0.2°,21.4°±0.2°处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form D has 2θ values of 6.5°±0.2°, 7.1°±0.2°, 9.0°±0.2°, 10.6°±0.2°, 11.3°± There are characteristic peaks at 0.2°, 13.0°±0.2°, 18.0°±0.2°, 19.6°±0.2°, and 21.4°±0.2°.
在本发明的一个实施方式中，所述晶型D的X射线粉末衍射图如图9所示。In one embodiment of the present invention, the X-ray powder diffraction pattern of the crystal form D is shown in FIG. 9 .
所述晶型D的制备方法，其特征在于：The preparation method of described crystal form D, is characterized in that:
将式(I)化合物溶解于酮类、酯类溶剂体系中，一定温度条件下，挥发直至有固体析出，得到晶型D。The compound of formula (I) is dissolved in a ketone and ester solvent system, and volatilized under certain temperature conditions until a solid is precipitated to obtain crystal form D.
在本发明的一个实施方式中，所述酮类溶剂为丙酮。In one embodiment of the present invention, the ketone solvent is acetone.
在本发明的一个实施方式中，所述酯类溶剂为甲酸乙酯。In one embodiment of the present invention, the ester solvent is ethyl formate.
在本发明的一个实施方式中，所述挥发温度为-30℃到30℃，例如，-20℃。In one embodiment of the present invention, the volatilization temperature is -30°C to 30°C, for example, -20°C.
根据本发明，作为原料的所述式(I)化合物指其固体(晶体或无定形)、半固体、蜡或油形式。优选地，作为原料的式(I)化合物为固体粉末形式。所述“搅拌”，采用本领域的常规方法完成，例如磁力搅拌或机械搅拌，搅拌速度为50～1800转/分钟，其中，磁力搅拌200～1500转/分钟，优选为300～1000转/分钟，机械搅拌优选为100～300转/分钟。According to the present invention, said compound of formula (I) as starting material refers to its solid (crystalline or amorphous), semi-solid, wax or oil form. Preferably, the compound of formula (I) as starting material is in the form of a solid powder. The "stirring" is accomplished by conventional methods in the art, such as magnetic stirring or mechanical stirring, and the stirring speed is 50-1800 rev/min, wherein the magnetic stirring is 200-1500 rev/min, preferably 300-1000 rev/min , the mechanical stirring is preferably 100 to 300 rpm.
上述本发明的晶体可以用于制备药物组合物，在制备药物组合物时含有上述本发明的晶体和制药学可接受的载体。上述本发明的晶体可以用于制备具有OX2受体阻断活性的药物组合物，其包含上述本发明的晶体作为有效成分。上述本发明的晶体可以用于制备失眠或抑郁症的治疗药，其包含上述本发明的晶体作为有效成分。The above crystals of the present invention can be used for the preparation of pharmaceutical compositions, which contain the above crystals of the present invention and a pharmaceutically acceptable carrier. The above crystal of the present invention can be used to prepare a pharmaceutical composition having OX2 receptor blocking activity, which comprises the above crystal of the present invention as an active ingredient. The above-mentioned crystal of the present invention can be used to prepare a therapeutic drug for insomnia or depression, which contains the above-mentioned crystal of the present invention as an active ingredient.
本发明还提供药物组合物，其包含上述本发明的任意一种晶体和制药学可接受的载体。The present invention also provides a pharmaceutical composition comprising any one of the above-mentioned crystals of the present invention and a pharmaceutically acceptable carrier.
本发明还提供具有OX2受体阻断活性的药物组合物，其含有上述本发明的任意一种晶体作为有效成分。The present invention also provides a pharmaceutical composition with OX2 receptor blocking activity, which contains any one of the above-mentioned crystals of the present invention as an active ingredient.
本发明提供失眠或抑郁症的治疗药，其含有上述本发明的任意一种晶体作为有效成分。The present invention provides a therapeutic drug for insomnia or depression, which contains any one of the above-mentioned crystals of the present invention as an active ingredient.
本发明中，“晶体”或“多晶型”指的是被所示的X射线衍射图表征所证实的。本领域技术人员能够理解，这里所讨论的理化性质可以被表征，其中的实验误差取决于仪器的条件、样品的准备和样品的纯度。特别是，本领域技术人员公知，X射线衍射图通常会随着仪器的条件而有所改变。特别需要指出的是，X射线衍射图的相对强度也可能随着实验条件的变化而变化，所以峰强度的顺序不能作为唯一或决定性因素。事实上，X射线衍射图中衍射峰的相对强度与晶体的择优取向有关，本文所示的峰强度为说明性而非用于绝对比较。另外，峰角度的实验误差通常在5％或更少，这些角度的误差也应该被考虑进去，通常允许有±0.2°的误差。另外，由于样品厚度等实验因素的影响，会造成峰角度的整体偏移，通常允许一定的偏移。因而，本领域技术人员可以理解的是，本发明中一个晶型的X射线衍射图不必和这里所指的例子中的X射线衍射图完全一致，本文所述“X射线衍射图相同”并非指绝对相同，相同峰位置可相差±0.2°且峰强度允许一定可变性。任何具有和这些图谱中的特征峰相同或相似的图的晶型均属于本发明的范畴之内。本领域技术人员能够将本发明所列的图谱和一个未知晶型的图谱相比较，以证实这两组图谱反映的是相同还是不同的晶型。In the present invention, "crystalline" or "polymorphic form" means as evidenced by the characterization of the X-ray diffraction pattern shown. Those skilled in the art will appreciate that the physicochemical properties discussed herein can be characterized with experimental error depending on the conditions of the instrument, the preparation of the sample, and the purity of the sample. In particular, it is well known to those skilled in the art that X-ray diffraction patterns generally vary with the conditions of the instrument. In particular, it is important to point out that the relative intensities of X-ray diffraction patterns may also vary with experimental conditions, so the order of peak intensities cannot be used as the sole or decisive factor. In fact, the relative intensities of the diffraction peaks in the X-ray diffraction pattern are related to the preferred orientation of the crystals, and the peak intensities shown here are illustrative and not for absolute comparison. In addition, the experimental error of the peak angle is usually 5% or less, the error of these angles should also be taken into account, usually an error of ± 0.2° is allowed. In addition, due to the influence of experimental factors such as sample thickness, the overall shift of the peak angle will be caused, and a certain shift is usually allowed. Therefore, those skilled in the art can understand that the X-ray diffraction pattern of a crystal form in the present invention does not necessarily have to be exactly the same as the X-ray diffraction pattern in the examples mentioned here, and the "same X-ray diffraction pattern" mentioned herein does not mean Absolutely identical, identical peak positions may differ by ±0.2° and some variability in peak intensity is allowed. Any crystalline form having the same or similar pattern as the characteristic peaks in these patterns is within the scope of the present invention. Those skilled in the art can compare the patterns listed in the present invention with a pattern of an unknown crystal form to confirm whether the two sets of patterns reflect the same or different crystal forms.
在一些实施方案中，本发明的晶型是纯的、单一的，基本没有混合任何其他晶型。本发明中，“基本没有”当用来指新晶型时指这个晶型含有少于20％(重量)的其他晶型，尤其指少于10％(重量)的其他晶型，更指少于5％(重量)的其他晶型，更指少于1％(重量)的其他晶型。需要说明的是，本发明中提及的数值及数值范围不应被狭隘地理解为数值或数值范围本身，本领域技术人员应当理解其可以根据具体技术环境的不同，在不背离本发明精神和原则的基础上围绕具体数值有所浮动，本发明中，这种本领域技术人员可预见的浮动范围多以术语“约”来表示。In some embodiments, the crystalline form of the present invention is pure, single, substantially free of admixture with any other crystalline form. In the present invention, "substantially free" when used to refer to a new crystal form means that the crystal form contains less than 20% by weight of other crystal forms, especially less than 10% by weight of other crystal forms, and even less More than 5% (weight) of other crystal forms, more than 1% (weight) of other crystal forms. It should be noted that the numerical values and numerical ranges mentioned in the present invention should not be narrowly construed as numerical values or numerical ranges themselves, and those skilled in the art should understand that they can be based on specific technical environments, without departing from the spirit and scope of the present invention. There are fluctuations around specific numerical values on the basis of principles. In the present invention, such a range of fluctuations that can be foreseen by those skilled in the art is often represented by the term "about".
本发明说明书中记载的数值范围的上限值和下限值可以任意地组合。The upper limit value and the lower limit value of the numerical range described in the specification of the present invention can be arbitrarily combined.
实施例Example
以下将通过具体实施例进一步阐述本发明，但并不用于限制本发明的保护范围。本领域技术人员可在权利要求范围内对制备方法和使用仪器作出改进，这些改进也应视为本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。The following will further illustrate the present invention through specific examples, which are not intended to limit the protection scope of the present invention. Those skilled in the art can make improvements to the preparation method and using instruments within the scope of the claims, and these improvements should also be regarded as the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention should be subject to the appended claims.
本发明中“室温”如果没有特别说明，通常是指22℃到28℃。In the present invention, "room temperature" generally refers to 22°C to 28°C unless otherwise specified.
本发明中所用到的缩写的解释如下：The abbreviations used in the present invention are explained as follows:
XRPD：X射线粉末衍射XRPD: X-ray Powder Diffraction
DSC：差示扫描量热分析DSC: Differential Scanning Calorimetry
TGA：热重分析TGA: Thermogravimetric Analysis
1H NMR：核磁共振氢谱 1 H NMR: Hydrogen Nuclear Magnetic Resonance Spectroscopy
DVS：动态水分吸附DVS: Dynamic Moisture Sorption
PSD：粒径分布PSD: particle size distribution
PLM：偏光显微镜PLM: Polarized Light Microscope
HPLC：高效液相色谱HPLC: High Performance Liquid Chromatography
本发明所述的X射线粉末衍射图在Panalytical(帕纳科)公司的Empyrean型及X'Pert 3型X射线粉末衍射仪上采集。本发明所述的X射线粉末衍射的方法参数如下： The X-ray powder diffraction patterns of the present invention were collected on Empyrean and X'Pert 3 X-ray powder diffractometers of Panalytical Corporation. The method parameters of X-ray powder diffraction of the present invention are as follows:
X射线光源：Cu,KαX-ray light source: Cu, Kα
Figure PCTCN2021137015-appb-000009
1.54060；
Figure PCTCN2021137015-appb-000010
1.54443
Figure PCTCN2021137015-appb-000009
1.54060;
Figure PCTCN2021137015-appb-000010
1.54443
Kα2/Kα1强度比例：0.50Kα2/Kα1 intensity ratio: 0.50
电压：45千伏特(kV)Voltage: 45 kilovolts (kV)
电流：40毫安培(mA)Current: 40 milliamps (mA)
扫描范围：自3.0至40.0度(2θ角)Scanning range: from 3.0 to 40.0 degrees (2θ angle)
本发明所述的差示扫描量热分析图在TA公司的Q200型及Discovery DSC 2500型差示扫描量热仪上采集。本发明所述的差示扫描量热分析的方法参数如下：The differential scanning calorimetry analysis diagram of the present invention is collected on the Q200 type and Discovery DSC 2500 type differential scanning calorimeter of TA company. The method parameters of the differential scanning calorimetry analysis of the present invention are as follows:
扫描速率：10℃/分钟Scan rate: 10°C/min
保护气体：氮气Shielding gas: nitrogen
本发明所述的热重分析图在TA公司的Discovery TGA 5500型及Q5000型热重分析仪上采集。本发明所述的热重分析的方法参数如下：The thermogravimetric analysis diagram of the present invention is collected on the Discovery TGA 5500 type and Q5000 type thermogravimetric analyzer of TA company. The method parameters of the thermogravimetric analysis of the present invention are as follows:
扫描速率：10℃/分钟Scan rate: 10°C/min
保护气体：氮气Shielding gas: nitrogen
本发明所述的核磁共振氢谱数据( 1H NMR)采自于Bruker Avance II DMX 400M HZ核磁共振波谱仪。称量1-5mg样品，用0.5mL氘代二甲亚砜溶解，配制成2-10mg/mL的溶液进行测试。 The hydrogen nuclear magnetic resonance spectrum data ( 1 H NMR) of the present invention was collected from a Bruker Avance II DMX 400M HZ nuclear magnetic resonance spectrometer. Weigh 1-5 mg of the sample, dissolve it with 0.5 mL of deuterated dimethyl sulfoxide, and prepare a solution of 2-10 mg/mL for testing.
本发明所述的动态水分吸附图在SMS公司的Intrinsic型及Intrinsic Plus型动态水分吸附仪上采集。本发明所述的动态水分吸附测试的方法参数如下：The dynamic moisture adsorption diagram of the present invention is collected on the Intrinsic type and Intrinsic Plus type dynamic moisture adsorption instrument of SMS company. The method parameters of the dynamic moisture adsorption test of the present invention are as follows:
温度：25℃Temperature: 25℃
保护气体及流量：N 2，200毫升/分钟 Shielding gas and flow rate: N 2 , 200 ml/min
dm/dt：0.002％/分钟dm/dt: 0.002%/min
最小dm/dt平衡时间：10分钟Minimum dm/dt equilibration time: 10 minutes
最大平衡时间：180分钟Maximum Equilibration Time: 180 minutes
相对湿度范围：0％RH-95％RH-0％RHRelative humidity range: 0%RH-95%RH-0%RH
相对湿度梯度：10％(0％RH-90％RH-0％RH)、5％(90％RH-95％RH和95％RH-90％RH)Relative humidity gradient: 10% (0%RH-90%RH-0%RH), 5% (90%RH-95%RH and 95%RH-90%RH)
本发明中所述的粒径分布结果是在Microtrac公司的S3500型激光粒度分析仪上采集。Microtrac S3500配备SDC(Sample Delivery Controller)进样系统。本测试采用湿法，测试分散介质为Isopar G(含0.2％卵磷脂)。所述的激光粒度分析仪的方法参数如下：The particle size distribution results described in the present invention were collected on Microtrac's Model S3500 laser particle size analyzer. Microtrac S3500 is equipped with SDC (Sample Delivery Controller) sampling system. This test adopts the wet method, and the test dispersion medium is Isopar G (containing 0.2% lecithin). The method parameters of the described laser particle size analyzer are as follows:
粒度分布：体积分布Particle Size Distribution: Volume Distribution 采集时间：10秒Acquisition time: 10 seconds
分散介质：Isopar GDispersion medium: Isopar G 粒度坐标：标准Granularity Coordinates: Standard
采集次数：3次Collection times: 3 times 分散介质折射率：1.42Refractive index of dispersion medium: 1.42
透明度：透明Transparency: Transparent 残差：启用Residuals: enabled
颗粒折射率：1.59Grain Refractive Index: 1.59 流速：60％*Flow Rate: 60%*
颗粒形状：不规则Particle shape: irregular 过滤：启用filter: enabled
超声功率：30瓦Ultrasonic power: 30 watts 超声时间：超声30sUltrasound time: Ultrasound 30s
*：流速60％为65mL/s的60％*: Flow rate 60% is 60% of 65mL/s
本发明中所述的固有溶出速率数据是在Agilent公司的Agilent 708DS型溶出仪上采集。所述的固有溶出测试条件如下：The intrinsic dissolution rate data described in the present invention were collected on the Agilent 708DS type dissolution apparatus of Agilent. Described inherent dissolution test conditions are as follows:
溶出仪Dissolution Apparatus Agilent 708DSAgilent 708DS
方法method 桨法paddle method
介质medium pH 5.1醋酸盐缓冲液pH 5.1 acetate buffer
介质体积medium volume 900mL900mL
转速Rotating speed 100rpm100rpm
介质温度medium temperature 37℃37 ℃
取样点Sampling point 5,10,15,20,30,45,60,90,120min5,10,15,20,30,45,60,90,120min
补充介质supplementary medium NoNo
本发明中所述的偏光显微镜照片是通过蔡司显微镜Axio Scope.A1在室温条件下采集，显微镜配备Axiocam 305彩色相机以及5×、10×、20×和50×物镜。The polarized light microscope photos described in the present invention were collected at room temperature by a Zeiss microscope Axio Scope.A1 equipped with an Axiocam 305 color camera and 5×, 10×, 20× and 50× objective lenses.
下述实施例中所使用的化合物(I)起始物可根据现有技术制备得到，例如根据WO2011/050198A1所记载的方法制备获得，但起始晶型并非制备本发明晶型的限定条件。The starting material of compound (I) used in the following examples can be prepared according to the prior art, for example, according to the method described in WO2011/050198A1, but the starting crystal form is not a limitation for preparing the crystal form of the present invention.
实施例1～2：晶型A的制备(气液渗透法)Examples 1-2: Preparation of crystal form A (gas-liquid permeation method)
室温条件下称取适量的式(I)化合物固体置于3毫升的玻璃小瓶中，加入相应体积的正溶剂以溶解固体，使用0.45微米孔径的聚四氟乙烯滤膜将样品溶液过滤至新的3毫升玻璃小瓶中，敞口置于预盛有4毫升相应反溶剂的20毫升玻璃瓶中。封口后置于室温条件下气液渗透十天时间。固体析出，得到晶型A。本实施例中所涉详细试验条件如表1所示，实施例2样品的X射线粉末衍射数据如表2所示。Weigh an appropriate amount of the solid of the compound of formula (I) into a 3 ml glass vial at room temperature, add a corresponding volume of positive solvent to dissolve the solid, and use a 0.45-micron pore size polytetrafluoroethylene filter to filter the sample solution to a new 3 ml glass vials, open top in 20 ml glass vials prefilled with 4 ml of the corresponding anti-solvent. After sealing, it was placed at room temperature for gas-liquid permeation for ten days. A solid precipitated to obtain Form A. The detailed test conditions involved in this example are shown in Table 1, and the X-ray powder diffraction data of the sample of Example 2 is shown in Table 2.
表1Table 1
Figure PCTCN2021137015-appb-000011
Figure PCTCN2021137015-appb-000011
表2Table 2
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
8.798.79 10.0610.06 4.884.88
11.5311.53 7.687.68 11.5211.52
12.2112.21 7.257.25 3.583.58
13.3413.34 6.636.63 10.2610.26
14.3114.31 6.196.19 23.8923.89
14.8614.86 5.965.96 3.423.42
15.9115.91 5.575.57 1.351.35
17.5617.56 5.055.05 71.0271.02
18.2518.25 4.864.86 7.357.35
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
18.5918.59 4.774.77 6.416.41
19.2919.29 4.604.60 5.595.59
19.7319.73 4.504.50 13.2013.20
21.8421.84 4.074.07 16.5016.50
22.2722.27 3.993.99 100.00100.00
22.9622.96 3.873.87 2.532.53
23.5123.51 3.783.78 7.447.44
24.6124.61 3.623.62 7.357.35
26.4326.43 3.373.37 6.986.98
26.9026.90 3.313.31 33.6733.67
27.1827.18 3.283.28 12.5412.54
27.7627.76 3.213.21 1.581.58
30.1930.19 2.962.96 4.264.26
30.6930.69 2.912.91 3.023.02
31.7831.78 2.822.82 2.992.99
32.5232.52 2.752.75 1.991.99
33.3633.36 2.692.69 0.900.90
34.6034.60 2.592.59 1.561.56
35.3535.35 2.542.54 0.360.36
35.9135.91 2.502.50 1.521.52
37.0137.01 2.432.43 0.780.78
37.9537.95 2.372.37 7.917.91
实施例3～14：晶型A的制备(反溶剂添加法)Examples 3-14: Preparation of Crystal Form A (Anti-solvent Addition Method)
室温条件下称取适量的式(I)化合物固体置于3毫升的玻璃小瓶中，加入相应体积的正溶剂以溶解固体，使用0.45微米孔径的聚四氟乙烯滤膜将样品溶液过滤至20毫升玻璃小瓶中得到澄清溶液。随后在磁力搅拌(转速约为500转/分钟)下，往其中逐滴加入相应反溶剂，如有固体析出，则离心分离所得固体。若加入约10毫升反溶剂后仍无固体析出，则停止滴加反溶剂，将样品转移至5℃环境下磁力搅拌约两天时间；若无固体析出，则转移至-20℃环境下磁力搅拌约一天时间；若无固体析出，则转移至室温条件下挥发得到固体。Weigh an appropriate amount of the solid of the compound of formula (I) into a 3 ml glass vial at room temperature, add a corresponding volume of positive solvent to dissolve the solid, and use a 0.45-micron pore size polytetrafluoroethylene filter to filter the sample solution to 20 ml. A clear solution was obtained in a glass vial. Then, under magnetic stirring (the rotation speed is about 500 rpm), the corresponding anti-solvent is added dropwise thereto, and if a solid is precipitated, the obtained solid is centrifuged. If there is still no solid precipitation after adding about 10 ml of anti-solvent, stop adding the anti-solvent dropwise and transfer the sample to magnetic stirring at 5°C for about two days; if no solid is precipitated, transfer to -20°C under magnetic stirring About one day; if there is no solid precipitation, transfer to room temperature and volatilize to obtain solid.
经检测，本实施例所得固体均为晶型A。本实施例中所涉详细试验条件如表3所示，实施例4所得固体XRPD图如图1所示，TGA、DSC、 1H NMR分别如图2～4所示。该样品在约11.5°±0.2°、约14.3°±0.2°、约14.9°±0.2°、约17.6°±0.2°、约18.2°±0.2°、约19.3°±0.2°、约19.7°±0.2°、约21.9°±0.2°、约22.3°±0.2°、约23.6°±0.2°、约26.9°±0.2°有特征峰。实施例4样品的X射线粉末衍射数据如表4所示。 After testing, the solids obtained in this example are all crystal form A. The detailed test conditions involved in this example are shown in Table 3, the XRPD pattern of the solid obtained in Example 4 is shown in FIG. 1 , and the TGA, DSC, and 1 H NMR are shown in FIGS. 2 to 4 , respectively. The sample is at about 11.5°±0.2°, about 14.3°±0.2°, about 14.9°±0.2°, about 17.6°±0.2°, about 18.2°±0.2°, about 19.3°±0.2°, about 19.7°±0.2 °, about 21.9°±0.2°, about 22.3°±0.2°, about 23.6°±0.2°, and about 26.9°±0.2° have characteristic peaks. The X-ray powder diffraction data of the sample of Example 4 are shown in Table 4.
表3table 3
Figure PCTCN2021137015-appb-000012
Figure PCTCN2021137015-appb-000012
表4Table 4
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
8.808.80 10.0410.04 4.024.02
11.5311.53 7.687.68 19.7319.73
12.2012.20 7.257.25 9.369.36
13.3413.34 6.646.64 8.858.85
14.3014.30 6.196.19 56.5156.51
14.8714.87 5.965.96 22.8722.87
15.8715.87 5.595.59 1.031.03
17.5817.58 5.045.04 100.00100.00
18.2418.24 4.864.86 17.9917.99
18.6018.60 4.774.77 16.1116.11
19.2919.29 4.604.60 21.8721.87
19.7219.72 4.504.50 27.7527.75
21.8621.86 4.074.07 26.7226.72
22.2922.29 3.993.99 87.6887.68
23.2023.20 3.833.83 3.953.95
23.6323.63 3.773.77 19.4619.46
24.5724.57 3.623.62 14.1714.17
26.4126.41 3.383.38 7.957.95
26.9026.90 3.313.31 22.8722.87
27.2127.21 3.283.28 20.3020.30
30.2230.22 2.962.96 3.723.72
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
30.7130.71 2.912.91 1.721.72
31.8331.83 2.812.81 4.314.31
32.5432.54 2.752.75 1.981.98
33.5433.54 2.672.67 0.720.72
34.6234.62 2.592.59 1.701.70
36.9836.98 2.432.43 0.920.92
38.0438.04 2.372.37 2.602.60
实施例15～21：晶型A的制备(反向反溶剂添加法)Examples 15-21: Preparation of crystal form A (reverse anti-solvent addition method)
室温条件下称取适量的式(I)化合物固体置于3毫升的玻璃小瓶中，加入相应体积的正溶剂以溶解固体。在20毫升的玻璃小瓶中加入相应反溶剂(预先放置在-20℃平衡半小时)并磁力搅拌(转速约为500转/分钟)，随后使用0.45微米孔径的聚四氟乙烯滤膜将样品溶液快速过滤至20毫升玻璃小瓶中得到澄清溶液。将样品转移至5℃环境下磁力搅拌约两天时间；若无固体析出，则转移至-20℃环境下磁力搅拌约一天时间；若依旧无固体析出，则转移至室温条件下挥发得到固体。An appropriate amount of the solid of the compound of formula (I) was weighed into a 3 ml glass vial at room temperature, and a corresponding volume of positive solvent was added to dissolve the solid. Into a 20 ml glass vial, add the corresponding anti-solvent (preliminarily placed at -20 °C for half an hour) and stir magnetically (the rotation speed is about 500 rpm), and then use a 0.45-micron pore size polytetrafluoroethylene filter to filter the sample solution. A clear solution was obtained by quick filtration into a 20 mL glass vial. Transfer the sample to 5°C under magnetic stirring for about two days; if there is no solid precipitation, transfer it to -20°C under magnetic stirring for about one day; if there is still no solid precipitation, transfer to room temperature to volatilize to obtain a solid.
经检测，本实施例得到的固体均为晶型A。本实施例中所涉详细试验条件如表5所示。实施例19样品的X射线粉末衍射数据如表6所示。After testing, the solids obtained in this example are all crystal form A. The detailed test conditions involved in this example are shown in Table 5. The X-ray powder diffraction data of the sample of Example 19 are shown in Table 6.
表5table 5
Figure PCTCN2021137015-appb-000013
Figure PCTCN2021137015-appb-000013
表6Table 6
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
8.808.80 10.0410.04 3.993.99
11.5311.53 7.687.68 11.8711.87
12.2012.20 7.257.25 6.276.27
13.3613.36 6.636.63 6.256.25
14.3114.31 6.196.19 28.1828.18
14.8714.87 5.965.96 11.5411.54
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
15.8915.89 5.585.58 1.741.74
17.5817.58 5.045.04 98.6398.63
18.2518.25 4.864.86 18.2918.29
18.6018.60 4.774.77 13.7113.71
19.3019.30 4.604.60 10.5410.54
19.7419.74 4.504.50 14.6214.62
21.8621.86 4.074.07 22.3422.34
22.3022.30 3.993.99 100.00100.00
22.9822.98 3.873.87 4.044.04
23.2123.21 3.833.83 2.672.67
23.6423.64 3.763.76 10.3810.38
24.6024.60 3.623.62 10.8110.81
26.4326.43 3.373.37 6.396.39
26.9126.91 3.313.31 19.9219.92
27.2027.20 3.283.28 22.1722.17
30.1930.19 2.962.96 3.633.63
30.6630.66 2.922.92 2.222.22
31.8131.81 2.812.81 4.244.24
32.5132.51 2.752.75 2.482.48
33.3833.38 2.682.68 1.061.06
34.6134.61 2.592.59 1.551.55
35.3235.32 2.542.54 0.560.56
35.9235.92 2.502.50 1.211.21
37.9137.91 2.372.37 2.052.05
实施例22～30：晶型A的制备(快速降温法)Examples 22-30: Preparation of crystal form A (rapid cooling method)
室温条件下称取适量的式(I)化合物固体置于1.5毫升的玻璃小瓶中，加入1毫升体积的溶剂得到悬浊液。将该悬浊液在50℃条件下磁力搅拌(转速约为500转/分钟)约两小时后，使用0.45微米孔径的聚四氟乙烯滤膜将样品溶液趁热过滤至新的1.5毫升玻璃小瓶中，封口后于-20℃恒温静置约两天时间，固体析出。如无固体析出，则将样品转移至室温条件下快速挥发得到固体。An appropriate amount of the solid compound of formula (I) was weighed and placed in a 1.5 ml glass vial at room temperature, and a 1 ml volume of solvent was added to obtain a suspension. The suspension was magnetically stirred (about 500 rpm) at 50°C for about two hours, and then the sample solution was filtered hot into a new 1.5 ml glass vial using a 0.45-micron pore size polytetrafluoroethylene filter membrane. , after sealing at -20 ℃ constant temperature for about two days, solid precipitation. If there is no solid precipitation, transfer the sample to room temperature to quickly volatilize to obtain a solid.
经检测，本实施例得到的固体均为晶型A。本实施例中所涉详细试验条件如表7所示，实施例25样品的X射线粉末衍射数据如表8所示。After testing, the solids obtained in this example are all crystal form A. The detailed test conditions involved in this example are shown in Table 7, and the X-ray powder diffraction data of the sample of Example 25 are shown in Table 8.
表7Table 7
Figure PCTCN2021137015-appb-000014
Figure PCTCN2021137015-appb-000014
Figure PCTCN2021137015-appb-000015
Figure PCTCN2021137015-appb-000015
表8Table 8
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
8.808.80 10.0510.05 1.711.71
11.5311.53 7.687.68 6.796.79
12.2012.20 7.257.25 2.932.93
13.3413.34 6.646.64 6.206.20
14.3114.31 6.196.19 37.4537.45
14.8814.88 5.965.96 8.308.30
15.9215.92 5.575.57 1.541.54
17.5717.57 5.055.05 78.6278.62
18.2418.24 4.864.86 7.007.00
18.6018.60 4.774.77 8.248.24
19.3019.30 4.604.60 17.5417.54
19.7219.72 4.504.50 12.5112.51
21.8721.87 4.064.06 20.1820.18
22.2922.29 3.993.99 100.00100.00
22.9422.94 3.883.88 3.633.63
23.5323.53 3.783.78 21.8721.87
24.5824.58 3.623.62 5.855.85
26.4126.41 3.373.37 5.625.62
26.8926.89 3.323.32 24.0224.02
27.2027.20 3.283.28 24.9524.95
28.8928.89 3.093.09 0.680.68
30.1930.19 2.962.96 2.582.58
30.6830.68 2.912.91 2.082.08
31.7831.78 2.822.82 4.294.29
32.4532.45 2.762.76 3.703.70
33.5933.59 2.672.67 0.940.94
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
34.5734.57 2.592.59 1.181.18
37.0237.02 2.432.43 0.970.97
37.9737.97 2.372.37 17.7917.79
实施例31～35：晶型A的制备(缓慢降温-室温挥发法)Examples 31-35: Preparation of crystal form A (slow cooling-room temperature volatilization method)
室温条件下称取适量的式(I)化合物固体置于3毫升的玻璃小瓶中，加入相应体积的溶剂得到悬浊液。将该悬浊液在50℃条件下磁力搅拌(转速约为500转/分钟)约两小时后，使用0.45微米孔径的聚四氟乙烯滤膜将样品溶液趁热过滤至新的3毫升玻璃小瓶中，封口后以0.1℃每分钟的速率从50℃降温至5℃，而后于5℃恒温静置四天时间。样品溶清，转移至室温条件下快速挥发得到固体。An appropriate amount of the solid compound of formula (I) was weighed and placed in a 3 ml glass vial at room temperature, and a corresponding volume of solvent was added to obtain a suspension. The suspension was magnetically stirred (about 500 rpm) at 50°C for about two hours, and then the sample solution was filtered hot into a new 3 mL glass vial using a 0.45-micron pore size polytetrafluoroethylene filter. After sealing, the temperature was lowered from 50°C to 5°C at a rate of 0.1°C per minute, and then kept at a constant temperature of 5°C for four days. The sample dissolved and was transferred to room temperature and quickly evaporated to obtain a solid.
经检测，本实施例得到的固体均为晶型A。本实施例中所涉详细试验条件如表9所示，实施例35样品的X射线粉末衍射数据如表10所示。After testing, the solids obtained in this example are all crystal form A. The detailed test conditions involved in this example are shown in Table 9, and the X-ray powder diffraction data of the sample of Example 35 is shown in Table 10.
表9Table 9
实施例Example 固体质量(毫克)Solid mass (mg) 溶剂(体积比)Solvent (volume ratio) 体积(毫升)Volume (ml) 挥发时长(天)Evaporation time (days)
3131 16.016.0 乙酸正丁酯N-butyl acetate 2.02.0 1717
3232 15.315.3 乙腈/水(1:1)Acetonitrile/Water (1:1) 1.01.0 77
3333 15.415.4 三氟乙醇/水(1:4)Trifluoroethanol/water (1:4) 2.02.0 99
3434 15.815.8 四氢呋喃/水(1:1)Tetrahydrofuran/water (1:1) 1.01.0 77
3535 15.515.5 乙二醇二甲醚/环己烷(1:1)Glycol dimethyl ether/cyclohexane (1:1) 2.02.0 77
表10Table 10
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
8.798.79 10.0610.06 1.681.68
11.5311.53 7.687.68 11.5411.54
12.2112.21 7.257.25 5.145.14
13.3313.33 6.646.64 5.155.15
14.3014.30 6.196.19 19.0119.01
14.8814.88 5.955.95 7.727.72
15.8815.88 5.585.58 0.810.81
17.5817.58 5.055.05 54.2554.25
18.2518.25 4.864.86 20.6320.63
18.6018.60 4.774.77 12.1112.11
19.3019.30 4.604.60 10.1310.13
19.7219.72 4.504.50 10.5310.53
21.8521.85 4.074.07 18.8818.88
22.2622.26 3.993.99 100.00100.00
22.9422.94 3.883.88 2.832.83
23.5023.50 3.793.79 13.1813.18
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
23.6423.64 3.763.76 7.317.31
24.5724.57 3.623.62 12.3212.32
25.7125.71 3.473.47 0.830.83
26.4126.41 3.383.38 6.946.94
26.8826.88 3.323.32 16.1116.11
27.1827.18 3.283.28 20.0220.02
30.1830.18 2.962.96 4.004.00
30.6830.68 2.912.91 0.490.49
31.7931.79 2.812.81 5.545.54
32.4432.44 2.762.76 1.601.60
33.3333.33 2.692.69 1.601.60
34.5434.54 2.602.60 1.611.61
35.8835.88 2.502.50 1.211.21
37.0137.01 2.432.43 0.850.85
37.7137.71 2.392.39 3.473.47
37.9637.96 2.372.37 3.393.39
实施例36～38：晶型A的制备(室温缓慢挥发法)Examples 36-38: Preparation of crystal form A (slow evaporation method at room temperature)
室温条件下称取适量的式(I)化合物固体置于3毫升的玻璃小瓶中，加入2毫升体积的溶剂溶解固体。使用0.45微米孔径的聚四氟乙烯滤膜将样品溶液过滤至新的3毫升玻璃小瓶中。使用封口膜封口后于其上扎4个针孔，而后置于室温条件下缓慢挥发，直至有固体析出。An appropriate amount of the solid of the compound of formula (I) was weighed and placed in a 3-mL glass vial at room temperature, and a 2-mL volume of solvent was added to dissolve the solid. Filter the sample solution into a new 3 mL glass vial using a 0.45 micron pore size Teflon filter. After sealing with parafilm, 4 pinholes were made on it, and then it was slowly volatilized at room temperature until a solid was precipitated.
经检测，本实施例得到的固体均为晶型A。本实施例中所涉详细试验条件如表11所示，实施例37样品的X射线粉末衍射数据如表12所示。After testing, the solids obtained in this example are all crystal form A. The detailed test conditions involved in this example are shown in Table 11, and the X-ray powder diffraction data of the sample of Example 37 is shown in Table 12.
表11Table 11
实施例Example 固体质量(毫克)Solid mass (mg) 溶剂(体积比)Solvent (volume ratio) 挥发时长(天)Evaporation time (days)
3636 19.919.9 二氯甲烷/乙酸乙酯(1:1)Dichloromethane/ethyl acetate (1:1) 1616
3737 20.020.0 甲醇/水(1:1)Methanol/Water (1:1) 1010
3838 20.120.1 乙腈/水(1:2)Acetonitrile/Water (1:2) 1616
表12Table 12
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
11.5311.53 7.687.68 6.616.61
12.2312.23 7.247.24 4.244.24
13.3713.37 6.626.62 9.289.28
14.3314.33 6.186.18 17.7717.77
14.8814.88 5.955.95 10.5810.58
17.6117.61 5.045.04 75.1475.14
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
18.2718.27 4.864.86 2.802.80
18.6018.60 4.774.77 6.716.71
19.3119.31 4.604.60 6.816.81
19.7519.75 4.494.49 4.734.73
21.8721.87 4.064.06 12.5312.53
22.3222.32 3.983.98 100.00100.00
23.6723.67 3.763.76 14.5414.54
24.6324.63 3.613.61 7.337.33
25.0825.08 3.553.55 1.791.79
26.4426.44 3.373.37 6.576.57
26.9526.95 3.313.31 29.7629.76
27.2227.22 3.283.28 14.2614.26
30.1930.19 2.962.96 1.891.89
31.8331.83 2.812.81 6.966.96
34.6634.66 2.592.59 1.191.19
37.9937.99 2.372.37 4.464.46
实施例39：晶型A的制备(室温快速挥发法)Example 39: Preparation of crystal form A (rapid evaporation method at room temperature)
室温条件下称取15.1毫克的式(I)化合物固体置于1.5毫升的玻璃小瓶中，加入0.6毫升二氯甲烷/甲基异丁基酮(体积比1:1)的混合溶剂以得到澄清溶液。将该溶液在50℃条件下静置约两小时后，使用0.45微米孔径的聚四氟乙烯滤膜将样品溶液过滤至新的1.5毫升玻璃小瓶中，而后置于室温条件下快速挥发两天，得到晶型A。其X射线粉末衍射数据如表13所示。Weigh 15.1 mg of solid compound of formula (I) into a 1.5 ml glass vial at room temperature, add 0.6 ml of a mixed solvent of dichloromethane/methyl isobutyl ketone (volume ratio 1:1) to obtain a clear solution . After standing the solution at 50°C for about two hours, the sample solution was filtered into a new 1.5 ml glass vial using a 0.45-micron pore size polytetrafluoroethylene filter, and then placed at room temperature for rapid evaporation for two days. Form A was obtained. Its X-ray powder diffraction data are shown in Table 13.
表13Table 13
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
11.5311.53 7.687.68 4.044.04
12.2112.21 7.257.25 3.343.34
13.3413.34 6.646.64 6.586.58
14.3114.31 6.196.19 19.4119.41
14.8714.87 5.965.96 3.453.45
17.5817.58 5.055.05 46.8646.86
18.2518.25 4.864.86 4.124.12
18.5918.59 4.774.77 4.704.70
19.2919.29 4.604.60 5.045.04
19.7319.73 4.504.50 6.456.45
21.8521.85 4.074.07 8.758.75
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
22.3022.30 3.993.99 100.00100.00
22.9422.94 3.883.88 2.242.24
23.5423.54 3.783.78 9.019.01
24.6024.60 3.623.62 7.367.36
26.4226.42 3.373.37 4.194.19
26.9126.91 3.313.31 19.9519.95
27.2027.20 3.283.28 16.5216.52
30.1930.19 2.962.96 1.911.91
31.8231.82 2.812.81 1.551.55
32.5432.54 2.752.75 1.331.33
33.3833.38 2.682.68 0.900.90
34.6134.61 2.592.59 1.131.13
35.9135.91 2.502.50 0.750.75
37.9737.97 2.372.37 2.982.98
实施例40～42：晶型A的制备(pH转移法)Examples 40-42: Preparation of Form A (pH Transfer Method)
室温条件下称取适量的式(I)化合物固体置于3毫升的玻璃小瓶中，加入0.2毫升相应的溶剂以悬浮液。逐滴加入相应体积酸的水溶液后，使用0.45微米孔径的聚四氟乙烯滤膜将样品溶液过滤至新的3毫升玻璃小瓶中，而后加入相应体积的碱水溶液直至有固体析出，得到晶型A。本实施例中所涉详细试验条件如表14所示，实施例42样品的X射线粉末衍射数据如表15所示。An appropriate amount of the solid compound of formula (I) was weighed into a 3 ml glass vial at room temperature, and 0.2 ml of the corresponding solvent was added to suspend it. After the corresponding volume of acid aqueous solution was added dropwise, the sample solution was filtered into a new 3 ml glass vial using a 0.45-micron pore size polytetrafluoroethylene filter membrane, and then a corresponding volume of alkaline aqueous solution was added until a solid was precipitated to obtain crystal form A. . The detailed test conditions involved in this example are shown in Table 14, and the X-ray powder diffraction data of the sample of Example 42 are shown in Table 15.
表14Table 14
Figure PCTCN2021137015-appb-000016
Figure PCTCN2021137015-appb-000016
表15Table 15
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
11.5311.53 7.687.68 14.3214.32
12.2112.21 7.257.25 7.537.53
13.3613.36 6.636.63 6.386.38
14.2914.29 6.206.20 45.6045.60
14.8814.88 5.955.95 20.0220.02
17.5917.59 5.045.04 100.00100.00
18.2418.24 4.864.86 17.0417.04
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
18.5918.59 4.774.77 16.0116.01
19.2919.29 4.604.60 20.2520.25
19.7219.72 4.504.50 26.3626.36
21.8721.87 4.064.06 30.1730.17
22.2822.28 3.993.99 93.1393.13
23.2023.20 3.833.83 14.3814.38
23.6023.60 3.773.77 28.8728.87
24.5624.56 3.633.63 15.2815.28
25.1125.11 3.553.55 6.246.24
26.4226.42 3.373.37 9.199.19
26.9226.92 3.313.31 27.9727.97
27.2027.20 3.283.28 23.9323.93
30.1530.15 2.962.96 5.795.79
31.8231.82 2.812.81 11.8911.89
33.6333.63 2.672.67 8.258.25
34.2534.25 2.622.62 4.504.50
37.9437.94 2.372.37 4.244.24
实施例43：晶型C的制备(低温挥发法)Example 43: Preparation of crystal form C (low temperature volatilization method)
室温条件下称取15.6毫克的式(I)化合物固体置于3毫升的玻璃小瓶中，加入2.0毫升甲醇以得到澄清溶液。将该溶液在-20℃条件下静置约两小时后，使用0.45微米孔径的聚四氟乙烯滤膜将样品溶液过滤至新的3毫升玻璃小瓶中，然后敞口置于预盛有4毫升PEG400的20毫升玻璃瓶中。封口后置于-20℃条件下约8天时间，然后置于5℃条件下约20天时间，最后置于室温下约14天时间，直至固体析出，得到晶型C。其XRPD图如图5所示，TGA、DSC、 1H NMR分别如图6～8所示。该样品在约6.5°±0.2°、约8.0°±0.2°、约9.9°±0.2°、约10.8°±0.2°、约12.9°±0.2°、约14.7°±0.2°、约16.1°±0.2°、约17.5°±0.2°、约19.6°±0.2°、约21.6°±0.2°、约26.1°±0.2°有特征峰。其X射线粉末衍射数据如表16所示。 15.6 mg of solid compound of formula (I) was weighed into a 3 mL glass vial at room temperature and 2.0 mL of methanol was added to obtain a clear solution. After the solution was allowed to stand at -20°C for about two hours, the sample solution was filtered using a 0.45 micron pore size polytetrafluoroethylene filter into a new 3 ml glass vial, which was then placed in a prefilled 4 ml vial. PEG400 in a 20 ml glass vial. After sealing, it was placed at -20°C for about 8 days, then at 5°C for about 20 days, and finally at room temperature for about 14 days, until the solid was precipitated, and crystal form C was obtained. The XRPD pattern thereof is shown in FIG. 5 , and the TGA, DSC, and 1 H NMR are shown in FIGS. 6 to 8 , respectively. The sample is at about 6.5°±0.2°, about 8.0°±0.2°, about 9.9°±0.2°, about 10.8°±0.2°, about 12.9°±0.2°, about 14.7°±0.2°, about 16.1°±0.2 °, about 17.5°±0.2°, about 19.6°±0.2°, about 21.6°±0.2°, and about 26.1°±0.2° have characteristic peaks. Its X-ray powder diffraction data are shown in Table 16.
表16Table 16
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
6.486.48 13.6413.64 100.00100.00
8.028.02 11.0211.02 43.4343.43
9.869.86 8.978.97 36.5736.57
10.7610.76 8.228.22 86.8886.88
12.8712.87 6.886.88 24.9224.92
14.6814.68 6.046.04 9.479.47
15.3415.34 5.785.78 8.208.20
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
15.8315.83 5.605.60 24.1924.19
16.1116.11 5.505.50 46.1946.19
17.4717.47 5.085.08 47.2947.29
17.8817.88 4.964.96 11.6411.64
18.1618.16 4.894.89 6.236.23
19.5619.56 4.544.54 9.289.28
20.4920.49 4.334.33 5.235.23
20.8920.89 4.254.25 6.276.27
21.2221.22 4.194.19 5.765.76
21.6321.63 4.114.11 12.2912.29
22.6422.64 3.933.93 5.825.82
23.2623.26 3.823.82 3.793.79
23.7623.76 3.753.75 2.992.99
24.2624.26 3.673.67 4.564.56
25.0525.05 3.563.56 15.4215.42
25.3825.38 3.513.51 31.9231.92
26.1226.12 3.413.41 16.3516.35
26.9826.98 3.313.31 4.344.34
27.3527.35 3.263.26 3.873.87
28.4128.41 3.143.14 5.975.97
28.9228.92 3.093.09 2.972.97
实施例44：晶型C的制备(低温挥发法)Example 44: Preparation of crystal form C (low temperature volatilization method)
室温条件下称取50.4毫克的式(I)化合物固体置于3毫升的玻璃小瓶中，加入2.0毫升甲醇以得到澄清溶液。将该溶液在-20℃条件下静置约两小时后，使用0.45微米孔径的聚四氟乙烯滤膜将样品溶液过滤至新的3毫升玻璃小瓶中，然后敞口置于预盛有4毫升PEG400的20毫升玻璃瓶中。封口后置于-20℃条件下约4天时间，然后置于室温下约8天时间，直至固体析出，得到晶型C。其X射线粉末衍射数据如表17所示。50.4 mg of a solid compound of formula (I) was weighed into a 3 mL glass vial at room temperature, and 2.0 mL of methanol was added to obtain a clear solution. After the solution was allowed to stand at -20°C for about two hours, the sample solution was filtered using a 0.45 micron pore size polytetrafluoroethylene filter into a new 3 ml glass vial, which was then placed in a prefilled 4 ml vial. PEG400 in a 20 ml glass vial. After sealing, it was placed at -20°C for about 4 days, and then placed at room temperature for about 8 days, until the solid was precipitated, and crystal form C was obtained. Its X-ray powder diffraction data are shown in Table 17.
表17Table 17
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
6.486.48 13.6413.64 100.00100.00
8.018.01 11.0411.04 0.760.76
9.859.85 8.988.98 1.991.99
10.7510.75 8.238.23 4.144.14
12.9912.99 6.826.82 11.1911.19
14.6714.67 6.046.04 1.721.72
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
16.1016.10 5.505.50 0.580.58
17.4617.46 5.085.08 0.450.45
19.2819.28 4.604.60 1.141.14
19.5519.55 4.544.54 10.2010.20
21.6121.61 4.114.11 0.780.78
21.8221.82 4.074.07 1.351.35
25.3925.39 3.513.51 0.370.37
26.1926.19 3.403.40 2.552.55
28.0928.09 3.183.18 0.690.69
32.9032.90 2.722.72 0.240.24
34.6034.60 2.592.59 0.330.33
实施例45：晶型D的制备(低温挥发法)Example 45: Preparation of crystal form D (low temperature volatilization method)
室温条件下称取15.2毫克式(I)化合物固体置于3毫升的玻璃小瓶中，加入2.0毫升丙酮溶解得到澄清溶液。将该溶液在-20℃条件下静置约两小时后，使用0.45微米孔径的聚四氟乙烯滤膜将样品溶液过滤至新的3毫升玻璃小瓶中，然后敞口置于预盛有4毫升PEG400的20毫升玻璃瓶中。封口后置于-20℃条件下约8天时间，然后置于5℃条件下约20天时间，最后置于室温下约14天时间，直至固体析出，得到晶型D。其X射线粉末衍射数据如表18所示。At room temperature, 15.2 mg of the solid compound of formula (I) was weighed and placed in a 3 mL glass vial, and 2.0 mL of acetone was added to dissolve to obtain a clear solution. After the solution was allowed to stand at -20°C for about two hours, the sample solution was filtered using a 0.45 micron pore size polytetrafluoroethylene filter into a new 3 ml glass vial, which was then placed in a prefilled 4 ml vial. PEG400 in a 20 ml glass vial. After sealing, it was placed at -20°C for about 8 days, then at 5°C for about 20 days, and finally at room temperature for about 14 days, until the solid was precipitated, and crystal form D was obtained. Its X-ray powder diffraction data are shown in Table 18.
表18Table 18
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
6.496.49 13.6113.61 100.00100.00
7.087.08 12.4912.49 24.0024.00
8.548.54 10.3510.35 14.3114.31
9.049.04 9.789.78 23.0123.01
10.6410.64 8.318.31 45.5945.59
11.2511.25 7.867.86 65.2465.24
11.7211.72 7.557.55 11.3711.37
13.0213.02 6.806.80 90.0990.09
13.3813.38 6.626.62 41.6741.67
14.4714.47 6.126.12 9.619.61
15.5715.57 5.695.69 66.8066.80
15.7815.78 5.625.62 47.5247.52
16.0516.05 5.525.52 51.4351.43
17.1517.15 5.175.17 11.7511.75
18.0218.02 4.924.92 32.5332.53
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
18.3118.31 4.854.85 5.805.80
18.6018.60 4.774.77 24.7024.70
19.5819.58 4.534.53 75.4075.40
20.4720.47 4.344.34 7.457.45
21.3921.39 4.154.15 21.1221.12
22.8322.83 3.903.90 11.5111.51
23.6123.61 3.773.77 11.5811.58
24.7024.70 3.603.60 24.8024.80
26.2326.23 3.403.40 53.2753.27
27.2627.26 3.273.27 23.4123.41
27.9727.97 3.193.19 8.568.56
31.7331.73 2.822.82 7.277.27
实施例46：晶型D的制备(低温挥发法)Example 46: Preparation of crystal form D (low temperature volatilization method)
室温条件下称取15.2毫克式(I)化合物固体置于3毫升的玻璃小瓶中，加入2.0毫升甲酸乙酯溶解得到澄清溶液。将该溶液在-20℃条件下静置约两小时后，使用0.45微米孔径的聚四氟乙烯滤膜将样品溶液过滤至新的3毫升玻璃小瓶中，然后敞口置于预盛有4毫升PEG400的20毫升玻璃瓶中。封口后置于-20℃条件下约8天时间，然后置于5℃条件下约20天时间，最后置于室温下约14天时间，直至固体析出，得到晶型D。实施例45所得固体XRPD图如图9所示，TGA、DSC、 1H NMR分别如图10～12所示。该样品在约6.5°±0.2°、约7.1°±0.2°、约8.6°±0.2°、约9.0°±0.2°、约10.6°±0.2°、约11.3°±0.2°、约13.0°±0.2°、约16.0°±0.2°、约18.0°±0.2°、约19.6°±0.2°、约21.4°±0.2°有特征峰。其X射线粉末衍射数据如表19所示。 At room temperature, 15.2 mg of the solid compound of formula (I) was weighed into a 3 mL glass vial, and 2.0 mL of ethyl formate was added to dissolve to obtain a clear solution. After the solution was allowed to stand at -20°C for about two hours, the sample solution was filtered using a 0.45 micron pore size polytetrafluoroethylene filter into a new 3 ml glass vial, which was then placed in a prefilled 4 ml vial. PEG400 in a 20 ml glass vial. After sealing, it was placed at -20°C for about 8 days, then at 5°C for about 20 days, and finally at room temperature for about 14 days, until the solid was precipitated, and crystal form D was obtained. The XRPD pattern of the solid obtained in Example 45 is shown in FIG. 9 , and the TGA, DSC, and 1 H NMR are shown in FIGS. 10 to 12 , respectively. The sample is at about 6.5°±0.2°, about 7.1°±0.2°, about 8.6°±0.2°, about 9.0°±0.2°, about 10.6°±0.2°, about 11.3°±0.2°, about 13.0°±0.2 °, about 16.0°±0.2°, about 18.0°±0.2°, about 19.6°±0.2°, and about 21.4°±0.2° have characteristic peaks. Its X-ray powder diffraction data are shown in Table 19.
表19Table 19
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
6.496.49 13.6113.61 100.00100.00
7.087.08 12.4912.49 23.5423.54
8.608.60 10.2810.28 18.3718.37
9.039.03 9.809.80 22.3022.30
10.1510.15 8.718.71 8.288.28
10.6510.65 8.318.31 45.1745.17
11.2511.25 7.867.86 71.2471.24
11.7011.70 7.567.56 15.4315.43
13.0213.02 6.806.80 90.3590.35
13.3813.38 6.626.62 31.6931.69
14.0114.01 6.326.32 5.585.58
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
14.4214.42 6.146.14 12.0812.08
15.5415.54 5.705.70 62.2862.28
15.7715.77 5.625.62 39.6339.63
16.0416.04 5.535.53 38.8838.88
17.1217.12 5.185.18 10.2110.21
18.0218.02 4.924.92 30.5630.56
18.2918.29 4.854.85 4.334.33
18.6018.60 4.774.77 22.9722.97
19.5719.57 4.544.54 74.1474.14
20.4620.46 4.344.34 8.158.15
21.3821.38 4.164.16 21.8721.87
21.6321.63 4.114.11 8.488.48
22.0422.04 4.034.03 3.723.72
22.8322.83 3.903.90 11.9911.99
23.5723.57 3.783.78 11.9711.97
24.1824.18 3.683.68 4.214.21
24.6724.67 3.613.61 16.2716.27
25.6125.61 3.483.48 7.127.12
26.1826.18 3.403.40 31.2531.25
27.2527.25 3.273.27 18.5318.53
27.9527.95 3.193.19 7.447.44
28.5728.57 3.123.12 3.803.80
29.0829.08 3.073.07 2.942.94
30.3530.35 2.952.95 3.323.32
31.7631.76 2.822.82 6.736.73
33.1133.11 2.712.71 1.811.81
34.9434.94 2.572.57 3.573.57
37.7137.71 2.392.39 1.531.53
实施例47：晶型的溶解度Example 47: Solubility of Crystal Forms
将本发明晶型A、晶型C、晶型D用FaSSIF(空腹状态下人工肠液)和纯水分别配制成悬浊液，在1小时、2小时、4小时和24小时平衡后过滤，得到饱和溶液。通过高效液相色谱法(HPLC)测定饱和溶液中样品的含量。试验结果如表20所示，溶解度曲线分别如图13～14所示。试验结果显示，本发明晶型A、晶型C、晶型D在FaSSIF和纯水中具有较好的溶解度。The crystal form A, crystal form C and crystal form D of the present invention are respectively prepared into suspensions with FaSSIF (artificial intestinal fluid in fasting state) and pure water, and filtered after equilibration for 1 hour, 2 hours, 4 hours and 24 hours to obtain saturated solution. The content of the sample in the saturated solution was determined by high performance liquid chromatography (HPLC). The test results are shown in Table 20, and the solubility curves are shown in Figures 13 to 14, respectively. The test results show that the crystal form A, crystal form C and crystal form D of the present invention have good solubility in FaSSIF and pure water.
表20Table 20
Figure PCTCN2021137015-appb-000017
Figure PCTCN2021137015-appb-000017
实施例48：晶型的可压性Example 48: Compressibility of crystal forms
采用手动压片机进行压片，压片时，选择可以压制成圆柱体片剂的圆形平冲，分别加入一定量的本发明晶型A、晶型C，采用10kN压力压制成圆形片剂，放置于干燥器中24小时，待完全弹性复原后采用片剂硬度测定仪测试其径向破碎力(硬度，H)。采用游标卡尺测量片剂的直径(D)和厚度(L)，利用公式T＝2H/πDL计算出不同硬度下粉体的抗张强度。试验结果如表21所示。在一定的压力下，抗张强度越大的，表示其可压性越好。试验结果显示，本发明晶型A、晶型C具有较大的抗张强度，说明具有较优的可压性。Use a manual tablet press for tablet compression. When tableting, select a circular flat punch that can be compressed into a cylindrical tablet, add a certain amount of crystal form A and crystal form C of the present invention, and press 10 kN into a circular tablet. The tablet was placed in a desiccator for 24 hours, and its radial crushing force (hardness, H) was tested with a tablet hardness tester after complete elastic recovery. The diameter (D) and thickness (L) of the tablet were measured with a vernier caliper, and the tensile strength of the powder with different hardnesses was calculated using the formula T=2H/πDL. The test results are shown in Table 21. Under a certain pressure, the higher the tensile strength, the better the compressibility. The test results show that the crystal form A and the crystal form C of the present invention have larger tensile strength, indicating that they have better compressibility.
表21Table 21
晶型Crystal form 直径(mm)Diameter(mm) 厚度(mm)Thickness(mm) 硬度(N)Hardness (N) 抗张强度(MPa)Tensile strength (MPa)
晶型AForm A 6.026.02 2.662.66 16.0316.03 0.6380.638
晶型CForm C 6.046.04 2.702.70 8.058.05 0.3140.314
实施例49：晶型的累积溶出度Example 49: Cumulative Dissolution of Crystalline Forms
称取本发明晶型A、晶型C各约100mg，倒入圆形平冲，在5kN压力下持续1min，制成圆形片剂，取完整压片转移至溶出仪测试累积溶出度，试验结果如表22所示，溶出曲线如图15所示。试验结果显示，本发明晶型A、晶型C具有较快的累积溶出度。Weigh about 100 mg each of crystal form A and crystal form C of the present invention, pour into a circular flat punch, and continue for 1 min under a pressure of 5 kN to make round tablets. The results are shown in Table 22, and the dissolution profiles are shown in Figure 15. The test results show that the crystal form A and the crystal form C of the present invention have faster cumulative dissolution rates.
表22Table 22
Figure PCTCN2021137015-appb-000018
Figure PCTCN2021137015-appb-000018
Figure PCTCN2021137015-appb-000019
Figure PCTCN2021137015-appb-000019
实施例50：稳定性对比研究Example 50: Comparative stability study
称取本发明晶型A(起始纯度99.46％)、晶型D(起始纯度99.72％)各约15mg，分别敞口放置于25℃/60％RH和40℃/75％RH条件的稳定箱中，在1周、2周、4周和8周后取样测XRPD和HPLC。称取本发明晶型C(起始纯度99.22％)约15mg，敞口放置于25℃/60％RH条件的稳定箱中，在1周、2周、4周和8周后取样测XRPD和HPLC；另外称取本发明晶型C约15mg，敞口放置于40℃/75％RH条件的稳定箱中，在1周和2周后取样测XRPD和HPLC。试验结果如表23所示，晶型A的稳定性如图16～17所示，晶型C的稳定性如图18～19所示，晶型D的稳定性如图20～21所示。试验结果显示，本发明晶型A、晶型C、晶型D具有较好的物理稳定性。Weigh about 15 mg each of crystal form A (initial purity 99.46%) and crystal form D (initial purity 99.72%) of the present invention, and place them in the open under the conditions of 25°C/60%RH and 40°C/75%RH respectively. In the box, samples were taken for XRPD and HPLC after 1 week, 2 weeks, 4 weeks and 8 weeks. Weigh about 15 mg of the crystal form C of the present invention (initial purity 99.22%), open it and place it in a stable box under the condition of 25°C/60% RH, take samples after 1 week, 2 weeks, 4 weeks and 8 weeks to measure XRPD and HPLC; In addition, about 15 mg of the crystal form C of the present invention was weighed, and it was placed in a stable box under the condition of 40°C/75% RH, and samples were taken after 1 week and 2 weeks to measure XRPD and HPLC. The test results are shown in Table 23, the stability of Form A is shown in Figures 16-17, the stability of Form C is shown in Figures 18-19, and the stability of Form D is shown in Figures 20-21. The test results show that the crystal form A, crystal form C and crystal form D of the present invention have good physical stability.
表23Table 23
Figure PCTCN2021137015-appb-000020
Figure PCTCN2021137015-appb-000020
Figure PCTCN2021137015-appb-000021
Figure PCTCN2021137015-appb-000021
实施例51：引湿性对比研究Example 51: Comparative study on hygroscopicity
称取本发明晶型A、晶型C、晶型D和现有固体各约10mg进行动态水分吸附(DVS)测试，然后取样测XRPD。试验结果如表24所示，晶型A的DVS如图22所示，晶型A测试DVS前后的XRPD对比图如图23所示；晶型C的DVS如图24所示，晶型C测试DVS前后的XRPD对比图如图25所示；晶型D的DVS如图26所示，晶型D测试DVS前后的XRPD对比图如图27所示。试验结果显示，本发明晶型A、晶型C、晶型D具有较低的引湿性。About 10 mg each of crystal form A, crystal form C, crystal form D and existing solid of the present invention was weighed for dynamic moisture adsorption (DVS) test, and then sampled for XRPD measurement. The test results are shown in Table 24, the DVS of Form A is shown in Figure 22, and the XRPD comparison chart before and after the DVS test of Form A is shown in Figure 23; the DVS of Form C is shown in Figure 24, and the test of Form C is shown in Figure 23. The XRPD comparison chart before and after DVS is shown in Figure 25; the DVS of crystal form D is shown in Figure 26, and the XRPD comparison chart before and after the DVS test of crystal form D is shown in Figure 27. The test results show that the crystalline form A, the crystalline form C and the crystalline form D of the present invention have relatively low hygroscopicity.
表24Table 24
起始晶型starting crystal form 80％相对湿度的增重Weight gain at 80% relative humidity 引湿性hygroscopicity DVS测试后晶型Crystal form after DVS test
晶型AForm A 0.07460.0746 无或几乎无引湿性No or almost no hygroscopicity 晶型AForm A
晶型CForm C 0.89200.8920 略有引湿性slightly hygroscopic 晶型CForm C
晶型DForm D 0.49930.4993 略有引湿性slightly hygroscopic 晶型DForm D
关于引湿性特征描述与引湿性增重的界定(中国药典2015年版通则药物引湿性试验指导原则)：About hygroscopic characteristics description and definition of hygroscopic weight gain (Chinese Pharmacopoeia 2015 edition general rule drug hygroscopic test guidelines):
潮解：吸收足量水分形成液体Deliquescence: Absorbs sufficient water to form a liquid
极具引湿性：引湿增重不小于15％Extremely hygroscopic: wet weight gain is not less than 15%
有引湿性：引湿增重小于15％但不小于2％Moisture: Moisture gain is less than 15% but not less than 2%
略有引湿性：引湿增重小于2％但不小于0.2％Slightly hygroscopic: wet weight gain is less than 2% but not less than 0.2%
无或几乎无引湿性：引湿增重小于0.2％No or almost no hygroscopicity: wet weight gain is less than 0.2%
实施例52：晶习对比研究Example 52: Comparative study of crystal habit
称取本发明晶型A、晶型C、晶型D各约10mg，分别置于载玻片上，滴加少许真空硅油分散样品，然后盖上盖玻片，置于偏光显微镜下观察。本发明晶型A、晶型C、晶型D具有较优的晶习。Weigh about 10 mg each of crystal form A, crystal form C and crystal form D of the present invention, place them on a glass slide respectively, add a little vacuum silicone oil dropwise to disperse the samples, then cover with a cover glass and observe under a polarizing microscope. The crystal form A, crystal form C and crystal form D of the present invention have better crystal habits.
实施例53：粒径分布对比研究Example 53: Comparative Study of Particle Size Distribution
称取本发明晶型A约10-30mg，然后加入约5mL Isopar G(含有0.2％卵磷脂)，将待测样品充分混合均匀后加入SDC进样系统中，使遮光度达到合适范围，开始实验，超声30秒后进行粒径分布的测试。试验结果如表25所示，晶型A的粒径分布图如图28所示。试验结果显示，本发明晶型A具有较均匀的粒径分布。Weigh about 10-30 mg of crystal form A of the present invention, then add about 5 mL of Isopar G (containing 0.2% lecithin), fully mix the sample to be tested and add it into the SDC sampling system to make the shading degree reach an appropriate range, and start the experiment , the particle size distribution test was carried out after sonication for 30 seconds. The test results are shown in Table 25, and the particle size distribution diagram of Form A is shown in FIG. 28 . The test results show that the crystal form A of the present invention has a relatively uniform particle size distribution.
表25Table 25
晶型Crystal form 平均粒径(微米)Average particle size (microns) D10(微米)D10 (micron) D50(微米)D50 (micron) D90(微米)D90 (micron)
晶型AForm A 47.0547.05 15.0615.06 27.8327.83 43.6143.61
实施例54：黏附性对比研究Example 54: Adhesion Comparative Study
称取本发明晶型A、晶型C各约100mg，然后加入到6mm圆形平冲中，采用10kN的压力进行压片处理，压片后停留约半分钟，记录最后制成片剂的质量，并计算压制过程中的黏附量，试验结果如表26所示。试验结果显示，本发明晶型A、晶型C较不易黏附。Weigh about 100 mg each of crystal form A and crystal form C of the present invention, then add them to a 6mm circular flat punch, use a pressure of 10kN to perform tablet compression, stay for about half a minute after tableting, and record the final mass of the tablet. , and calculate the amount of adhesion during the pressing process. The test results are shown in Table 26. The test results show that the crystal form A and the crystal form C of the present invention are less likely to adhere.
表26Table 26
晶型Crystal form 压片前质量(毫克)Mass before tableting (mg) 压片后质量(毫克)Mass after compression (mg) 黏附量Adhesion
晶型AForm A 99.899.8 97.997.9 1.91.9
晶型CForm C 100.3100.3 98.198.1 2.22.2
上述实施例只为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。The above-mentioned embodiments are only intended to illustrate the technical concept and characteristics of the present invention, and the purpose is to enable those who are familiar with the art to understand the content of the present invention and implement accordingly, and cannot limit the protection scope of the present invention by this. All equivalent changes or modifications made according to the spirit of the present invention should be included within the protection scope of the present invention.

Claims (9)

  1. 式(I)所示化合物[2-(4,6-二甲基嘧啶-2-基)-1,3,3a,4,6,6a-六氢吡咯并[3,4-c]吡咯-5-基]-[2-氟-6-(三氮唑-2-基)苯基]甲酮的A型晶体、即晶型A，其特征在于，使用Cu-Kα辐射，所述晶型A的X射线粉末衍射在2θ值为14.3°±0.2°,17.6°±0.2°和22.3°±0.2°处有特征峰，The compound represented by formula (I) [2-(4,6-dimethylpyrimidin-2-yl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole- Form A crystal of 5-yl]-[2-fluoro-6-(triazol-2-yl)phenyl]methanone, namely crystal form A, characterized in that, using Cu-Kα radiation, the crystal form The X-ray powder diffraction of A has characteristic peaks at 2θ values of 14.3°±0.2°, 17.6°±0.2° and 22.3°±0.2°,
    Figure PCTCN2021137015-appb-100001
    Figure PCTCN2021137015-appb-100001
  2. 权利要求1中所述的晶型A的制备方法，其特征包括，The preparation method of crystal form A described in claim 1, is characterized in that,
    (1)将式(I)化合物溶解于酮类、无环醚类溶剂中，室温条件下，置于烷烃类溶剂气氛下气液渗透一段时间，得到晶型A；或(1) dissolving the compound of formula (I) in a ketone, acyclic ether solvent, under room temperature conditions, place it in an alkane solvent atmosphere for a period of time to infiltrate gas and liquid to obtain crystal form A; or
    (2)在5～50℃条件下，将式(I)化合物溶解于卤代烃类、醇类、环醚类、无环醚类、酮类、酯类、亚砜类溶剂中，加入烷烃类、醇类、酯类、无环醚类溶剂，搅拌至有固体析出，得到晶型A；或(2) Dissolve the compound of formula (I) in halogenated hydrocarbons, alcohols, cyclic ethers, acyclic ethers, ketones, esters and sulfoxide solvents at 5-50°C, add alkanes or
    (3)在5～50℃条件下，将式(I)化合物溶解于卤代烃类、醇类、酮类、环醚类、酰胺类、烷基腈类溶剂中，搅拌状态下将其快速加入至纯水、烷烃类、无环醚类溶剂中，搅拌直至有固体析出，得到晶型A；或(3) Dissolve the compound of formula (I) in halogenated hydrocarbons, alcohols, ketones, cyclic ethers, amides, and alkyl nitrile solvents at 5 to 50 °C, and quickly dissolve it under stirring. Add to pure water, alkanes, acyclic ether solvents, and stir until a solid is precipitated to obtain crystal form A; or
    (4)将式(I)化合物溶解于酯类、酮类、烷基腈类、醇类、醚类、纯水、烷烃类的单一或者混合溶剂中，40～60℃下溶解后，置于-30～10℃下析出固体，得到晶型A；或(4) Dissolve the compound of formula (I) in a single or mixed solvent of esters, ketones, alkyl nitriles, alcohols, ethers, pure water, and alkanes, dissolve at 40-60 °C, and place it in a solvent. -30 ~ 10 ℃ to precipitate a solid to obtain crystal form A; or
    (5)在5～50℃条件下，将式(I)化合物溶解于卤代烃类、酮类、醚类、纯水、醇类、酯类、烷烃类的混合溶剂体系中，5～50℃下挥发直至有固体析出，得到晶型A；或(5) Dissolve the compound of formula (I) in a mixed solvent system of halogenated hydrocarbons, ketones, ethers, pure water, alcohols, esters, and alkanes at 5 to 50 °C, 5 to 50 volatilize at ℃ until a solid is precipitated to obtain Form A; or
    (6)在5～50℃条件下，将式(I)化合物加入到醇类溶剂中形成悬浮液。加入盐酸或硫酸的水溶液溶解。搅拌状态下向其中逐滴加入碳酸钾、氢氧化钠或碳酸氢钠的水溶液，直至有固体析出，得到晶型A。(6) The compound of formula (I) is added to an alcohol solvent under the condition of 5-50° C. to form a suspension. Add hydrochloric acid or sulfuric acid aqueous solution to dissolve. An aqueous solution of potassium carbonate, sodium hydroxide or sodium bicarbonate was added dropwise to it under stirring until a solid was precipitated, and crystal form A was obtained.
  3. 式(I)所示化合物[2-(4,6-二甲基嘧啶-2-基)-1,3,3a,4,6,6a-六氢吡咯并[3,4-c]吡咯-5-基]-[2-氟-6-(三氮唑-2-基)苯基]甲酮的C型晶体、即晶型C，其特征在于，使用Cu-Kα辐射，所述晶型C的X射线粉末衍射在2θ值为9.9°±0.2°,10.8°±0.2°和14.7°±0.2°处有特征峰，The compound represented by formula (I) [2-(4,6-dimethylpyrimidin-2-yl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole- C-type crystal of 5-yl]-[2-fluoro-6-(triazol-2-yl)phenyl]methanone, namely crystal form C, characterized in that, using Cu-Kα radiation, the crystal form The X-ray powder diffraction of C has characteristic peaks at 2θ values of 9.9°±0.2°, 10.8°±0.2° and 14.7°±0.2°,
    Figure PCTCN2021137015-appb-100002
    Figure PCTCN2021137015-appb-100002
  4. 权利要求3中所述的晶型C的制备方法，其特征在于，The preparation method of crystal form C described in claim 3, is characterized in that,
    将式(I)化合物溶解于醇类溶剂中，-30～10℃下溶解后，置于-30～30℃下挥发，直至固体析出，得到晶型C。The compound of formula (I) is dissolved in an alcoholic solvent, and after dissolving at -30-10° C., it is volatilized at -30-30° C. until a solid is precipitated to obtain crystal form C.
  5. 式(I)所示化合物[2-(4,6-二甲基嘧啶-2-基)-1,3,3a,4,6,6a-六氢吡咯并[3,4-c]吡咯-5-基]-[2-氟-6-(三氮唑-2-基)苯基]甲酮的D型晶体、即晶型D，其特征在于，使用Cu-Kα辐射，所述晶型D的X射线粉末衍射在2θ值为11.3°±0.2°,13.0°±0.2°和19.6°±0.2°处有特征峰，The compound represented by formula (I) [2-(4,6-dimethylpyrimidin-2-yl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole- D-type crystal of 5-yl]-[2-fluoro-6-(triazol-2-yl)phenyl]methanone, namely crystal form D, characterized in that, using Cu-Kα radiation, the crystal form The X-ray powder diffraction of D has characteristic peaks at 2θ values of 11.3°±0.2°, 13.0°±0.2° and 19.6°±0.2°,
    Figure PCTCN2021137015-appb-100003
    Figure PCTCN2021137015-appb-100003
  6. 权利要求5中所述的晶型D的制备方法，其特征在于，The preparation method of crystal form D described in claim 5, is characterized in that,
    将式(I)化合物溶解于酮类、酯类溶剂中，-30～10℃下溶解后，置于-30～30℃下挥发，直至固体析出，得到晶型D。The compound of formula (I) is dissolved in ketones and esters solvents, dissolved at -30-10°C, and then volatilized at -30-30°C until a solid is precipitated to obtain crystal form D.
  7. 药物组合物，其包含权利要求1,3,5所述的晶型和制药学可接受的载体。A pharmaceutical composition comprising the crystal form of claims 1, 3, and 5 and a pharmaceutically acceptable carrier.
  8. 具有OX2受体阻断活性的药物组合物，其含有权利要求1,3,5所述的晶型作为有效成分。A pharmaceutical composition with OX2 receptor blocking activity, which contains the crystalline form of claims 1, 3, and 5 as an active ingredient.
  9. 失眠或抑郁症的治疗药，其含有权利要求1,3,5所述的晶型作为有效成分。A therapeutic drug for insomnia or depression, comprising the crystal form of claims 1, 3, and 5 as an active ingredient.
PCT/CN2021/137015 2020-12-11 2021-12-10 Crystal forms of pyrrole derivative compound and preparation method therefor WO2022122009A1 (en)

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