WO2022089620A1 - New crystal forms of indole carboxamide compound and preparation method therefor - Google Patents

New crystal forms of indole carboxamide compound and preparation method therefor Download PDF

Info

Publication number
WO2022089620A1
WO2022089620A1 PCT/CN2021/127741 CN2021127741W WO2022089620A1 WO 2022089620 A1 WO2022089620 A1 WO 2022089620A1 CN 2021127741 W CN2021127741 W CN 2021127741W WO 2022089620 A1 WO2022089620 A1 WO 2022089620A1
Authority
WO
WIPO (PCT)
Prior art keywords
crystal form
formula
compound
solid
solvent
Prior art date
Application number
PCT/CN2021/127741
Other languages
French (fr)
Chinese (zh)
Inventor
鲁霞
陈智雄
张晓宇
Original Assignee
苏州晶云药物科技股份有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 苏州晶云药物科技股份有限公司 filed Critical 苏州晶云药物科技股份有限公司
Publication of WO2022089620A1 publication Critical patent/WO2022089620A1/en

Links

Images

Classifications

    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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 new crystal form of an indolylcarboxamide compound and a preparation method thereof.
  • B cells can secrete various antibodies to resist the invasion of foreign viruses or bacteria.
  • Bruton's nomine kinase (BTK) is mainly expressed in B cells and myeloid cells, and is widely distributed in the blood and lymphatic systems. It is a key kinase in the B cell antigen receptor (BCR) signaling pathway and can regulate the proliferation, differentiation and apoptosis of normal B cells.
  • BCR B cell antigen receptor
  • Malignant B cells require continuous activation of BTK to ensure rapid cancer cell growth. Therefore, inhibiting the activity of BTK can achieve the therapeutic effect of malignant tumors.
  • Formula (I) can selectively combine with BTK, reduce the degree of BTK activation, can effectively control the growth of malignant B cells, and has potential anti-tumor activity.
  • Formula (I) has certain therapeutic potential in chronic lymphocytic leukemia, mantle cell lymphoma and Waldenstrom's macroglobulinemia
  • Patent US20160115126A1 discloses the preparation method of the free base of formula (I) for the first time, the washing and purification process is complicated, and its solid form is not described. Therefore, it is necessary to carry out a complete polymorphic screening in order to obtain a simpler preparation and purification method.
  • Polymorphic forms of the same drug may change its physicochemical properties, such as solubility, dissolution rate, melting point and stability, which in turn may affect the effect of the drug in the human body. Therefore, it is necessary to carry out a comprehensive and systematic crystal form screening of formula (I) to develop a crystal form with good solubility and high stability, so as to provide more and better choices for the subsequent development of the drug.
  • the present invention provides preparation methods and uses of six crystal forms C, A, Y, V, AE and AA of the compound of formula (I).
  • the substances are polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, hydroxypropyl methylcellulose, methylcellulose, polycaprolactone, polyethylene glycol, polymethyl methacrylate, A single component or mixture of sodium alginate and hydroxyethyl cellulose; volatilize the above solution at 20°C to 30°C, and the solid is precipitated to obtain crystal form A; or
  • the compound of formula (I) is dissolved in an alcohol solvent, and the dissolution equilibrium is reached at 40° C. to 60° C., and the solution is cooled to solid precipitation to obtain crystal form AA.
  • a pharmaceutical composition comprising the crystal of any one of the above 1, 3, 5, 7, 9, 11 and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition having BTK inhibitory activity comprising the crystal according to any one of the above 1, 3, 5, 7, 9, and 11 as an active ingredient.
  • a preventive or therapeutic drug for chronic lymphocytic leukemia, mantle cell lymphoma and Waldenström's macroglobulinemia which contains the crystal described in any one of the above 1, 3, 5, 7, 9, and 11 as an active ingredient .
  • the crystalline form C, crystalline form A, crystalline form Y, crystalline form V, crystalline form AE and crystalline form AA of the compound of formula (I) provided by the invention are in solubility, melting point, stability, and dissolution rate.
  • hygroscopicity, adhesion, fluidity, bioavailability, and processing performance, purification, preparation production, safety, etc. have advantages in at least one aspect, providing for the preparation of this new type of BTK inhibitor pharmaceutical preparation. It is of great significance for drug development to develop new and better options.
  • Figure 32 Dynamic moisture adsorption and desorption of crystal form A
  • Figure 33 Dynamic moisture adsorption and desorption of crystal form C
  • Figure 36 Dynamic moisture adsorption and desorption of crystal form Y
  • the compound represented by formula (I) (S)-4-(3-(butyn-2-ylamide)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-
  • the C-type crystal of 7-formamide that is, crystal form C
  • the X-ray powder diffraction of the crystal form C has a 2 ⁇ value of 6.6° ⁇ 0.2°, 13.2° ⁇ 0.2°, There is a characteristic peak at 17.5° ⁇ 0.2°,
  • the X-ray powder diffraction of the crystal form C is at one or two or three places in the 2 ⁇ value of 23.2° ⁇ 0.2°, 24.2° ⁇ 0.2°, and 14.7° ⁇ 0.2° There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form C has characteristic peaks at 2 ⁇ values of 23.2° ⁇ 0.2°, 24.2° ⁇ 0.2°, and 14.7° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form C has one or two or three 2 ⁇ values of 18.9° ⁇ 0.2°, 21.9° ⁇ 0.2°, and 7.2° ⁇ 0.2°. There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form C has characteristic peaks at 2 ⁇ values of 18.9° ⁇ 0.2°, 21.9° ⁇ 0.2°, and 7.2° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form C has 2 ⁇ values of 6.6° ⁇ 0.2°, 13.2° ⁇ 0.2°, 17.5° ⁇ 0.2°, 23.2° ⁇ 0.2°, 24.2° ⁇ 0.2°, 14.7° ⁇ 0.2°, 18.9° ⁇ 0.2°, 21.9° ⁇ 0.2°, 7.2° ⁇ 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 6.6° ⁇ 0.2°, 13.2° ⁇ 0.2°, 17.5° ⁇ 0.2°, 23.2° ⁇ 0.2°, 24.2° ⁇ There are characteristic peaks at 0.2°, 14.7° ⁇ 0.2°, 18.9° ⁇ 0.2°, 21.9° ⁇ 0.2°, and 7.2° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form C is shown in FIG. 1 .
  • the alcoholic solvent includes methanol, ethanol, and isopropanol.
  • the hetero-nitrogen-based solvent is dimethyl sulfoxide.
  • the compound represented by formula (I) (S)-4-(3-(butyn-2-ylamide)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-
  • the A-type crystal of 7-formamide that is, the crystal form A
  • the X-ray powder diffraction of the crystal form A has a 2 ⁇ value of 7.1° ⁇ 0.2°, 14.3° ⁇ 0.2°, There is a characteristic peak at 8.3° ⁇ 0.2°,
  • the X-ray powder diffraction of the crystal form A is at one or two or three places in the 2 ⁇ value of 11.4° ⁇ 0.2°, 16.6° ⁇ 0.2°, 18.4° ⁇ 0.2° There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form A has characteristic peaks at 2 ⁇ values of 11.4° ⁇ 0.2°, 16.6° ⁇ 0.2°, and 18.4° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form A has 2 ⁇ values of 7.1° ⁇ 0.2°, 14.3° ⁇ 0.2°, 8.3° ⁇ 0.2°, 11.4° ⁇ 0.2°, 16.6° ⁇ 0.2°, 18.4° ⁇ 0.2° any 4 places, or 5 places, or 6 places have characteristic peaks.
  • the X-ray powder diffraction of the crystal form A has 2 ⁇ values of 7.1° ⁇ 0.2°, 14.3° ⁇ 0.2°, 8.3° ⁇ 0.2°, 11.4° ⁇ 0.2°, 16.6° ⁇ There are characteristic peaks at 0.2° and 18.4° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form A is shown in FIG. 2 .
  • the compound of formula (I) is dissolved in an organic solvent, the solution is added to a glass bottle containing a high polymer to volatilize, and a solid is precipitated to obtain crystal form A.
  • the organic solvent is selected from alcohols, ketones, ethers, halogenated hydrocarbons.
  • the high polymer is selected from the group consisting of polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, hydroxypropyl methylcellulose, methylcellulose, and polycaproic acid. At least one of ester, polyethylene glycol, polymethyl methacrylate, sodium alginate or hydroxyethyl cellulose.
  • the mass of the high polymer is 0.5% to 15% of the mass of the compound of formula (I).
  • the alcohols are ethanol
  • the ketones are acetone
  • the ethers are tetrahydrofuran
  • the halogenated hydrocarbons are dichloromethane, dibromomethane, and chloroform.
  • the dissolution and precipitation temperature is 20°C to 30°C.
  • the positive solvent includes alcohols, ketones, cyclic ethers, and esters
  • the anti-solvent includes pure water, linear ethers, and alkanes.
  • the dissolution and precipitation temperature is 20°C to 30°C.
  • the alcohols include ethanol and methanol
  • the ketones are acetone
  • the cyclic ethers include 1,4-dioxane and tetrahydrofuran
  • the esters are isopropyl acetate.
  • the linear ethers include methyl tert-butyl ether and cyclopentyl methyl ether, and the alkanes are n-heptane, n-hexane, and n-pentane.
  • the penetration time is 1 to 4 weeks, eg 2 weeks.
  • the organic solvent includes alcohols, ketones, ethers, esters, halogenated hydrocarbons, aromatic hydrocarbons, alkanes and mixtures thereof.
  • the alcohols are ethanol, isopropanol, methanol, the ketones are acetone, and the ethers are 2-methyltetrahydrofuran, tetrahydrofuran, 1,4-dioxane , methyl tert-butyl ether, cyclopentyl methyl ether, the esters are ethyl acetate, the halogenated hydrocarbons are chloroform, methylene chloride, the aromatic hydrocarbons are toluene, and the alkanes are n-heptyl alkyl.
  • the positive solvent includes alcohols, ketones, cyclic ethers, and esters.
  • the anti-solvents include ethers, aromatic hydrocarbons, and alkanes.
  • alcohols are ethanol
  • ketones are acetone
  • cyclic ethers include tetrahydrofuran and 2-methyltetrahydrofuran
  • esters are ethyl acetate
  • halogenated hydrocarbons are chloroform .
  • the ethers are methyl tert-butyl ether
  • the aromatic hydrocarbons are toluene
  • the alkanes are n-heptane.
  • the temperature of dissolving, adding and stirring is 5°C to 50°C, preferably 20°C to 30°C.
  • the alcohol is isopropanol
  • the ester is isopropyl acetate
  • the alkanes are n-heptane.
  • the temperature of dissolving, adding and stirring is 5°C to 50°C, preferably 20°C to 30°C.
  • the compound represented by formula (I) (S)-4-(3-(butyn-2-ylamide)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-
  • the Y-type crystal of 7-formamide that is, the crystal form Y
  • the Y-type crystal of 7-formamide is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction of the crystal form Y has a 2 ⁇ value of 14.0° ⁇ 0.2°, 7.0° ⁇ 0.2°, There is a characteristic peak at 17.5° ⁇ 0.2°,
  • the X-ray powder diffraction of the crystal form Y is at one or two or three locations in the 2 ⁇ value of 24.6° ⁇ 0.2°, 24.0° ⁇ 0.2°, and 21.7° ⁇ 0.2° There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form Y has characteristic peaks at 2 ⁇ values of 24.6° ⁇ 0.2°, 24.0° ⁇ 0.2°, and 21.7° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form Y is at one or two or three locations in the 2 ⁇ value of 27.2° ⁇ 0.2°, 21.0° ⁇ 0.2°, and 22.5° ⁇ 0.2° There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form Y has characteristic peaks at 2 ⁇ values of 27.2° ⁇ 0.2°, 21.0° ⁇ 0.2°, and 25.5° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form Y has 2 ⁇ values of 14.0° ⁇ 0.2°, 7.0° ⁇ 0.2°, 17.5° ⁇ 0.2°, 24.6° ⁇ 0.2°, 24.0° ⁇ 0.2°, 21.7° ⁇ 0.2°, 27.2° ⁇ 0.2°, 21.0° ⁇ 0.2°, 22.5° ⁇ 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 Y has 2 ⁇ values of 14.0° ⁇ 0.2°, 7.0° ⁇ 0.2°, 17.5° ⁇ 0.2°, 24.6° ⁇ 0.2°, 24.0° ⁇ There are characteristic peaks at 0.2°, 21.7° ⁇ 0.2°, 27.2° ⁇ 0.2°, 21.0° ⁇ 0.2°, and 22.5° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form Y is shown in FIG. 3 .
  • the alcoholic solvent is isopropanol.
  • the alcoholic solvent is isopropanol.
  • the compound represented by formula (I) (S)-4-(3-(butyn-2-ylamide)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-
  • the V-type crystal of 7-formamide that is, the crystal form V
  • the X-ray powder diffraction of the crystal form V has a 2 ⁇ value of 6.5° ⁇ 0.2°, 15.0° ⁇ 0.2°, There is a characteristic peak at 13.0° ⁇ 0.2°,
  • the X-ray powder diffraction of the crystal form V has one or two or three 2 ⁇ values of 16.3° ⁇ 0.2°, 24.4° ⁇ 0.2°, 17.1° ⁇ 0.2° There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form V has characteristic peaks at 2 ⁇ values of 16.3° ⁇ 0.2°, 24.4° ⁇ 0.2°, and 17.1° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form V has one or two or three 2 ⁇ values of 23.6° ⁇ 0.2°, 28.8° ⁇ 0.2°, and 22.9° ⁇ 0.2°. There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form V has characteristic peaks at 2 ⁇ values of 23.6° ⁇ 0.2°, 28.8° ⁇ 0.2°, and 22.9° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form V has 2 ⁇ values of 6.5° ⁇ 0.2°, 15.0° ⁇ 0.2°, 13.0° ⁇ 0.2°, 16.3° ⁇ 0.2°, 24.4° ⁇ 0.2°, 17.1° ⁇ 0.2°, 23.6° ⁇ 0.2°, 28.8° ⁇ 0.2°, 22.9° ⁇ 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 V has 2 ⁇ values of 6.5° ⁇ 0.2°, 15.0° ⁇ 0.2°, 13.0° ⁇ 0.2°, 16.3° ⁇ 0.2°, 24.4° ⁇ There are characteristic peaks at 0.2°, 17.1° ⁇ 0.2°, 23.6° ⁇ 0.2°, 28.8° ⁇ 0.2°, and 22.9° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form V is shown in FIG. 4 .
  • the preparation method of described crystal form V is characterized in that,
  • the cyclic ether solvent is tetrahydrofuran.
  • the mass of the high polymer is 0.5% to 15% of the mass of the formula (I).
  • the high polymer is selected from at least one of polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, hydroxypropyl methylcellulose or methylcellulose .
  • the precipitation temperature is 20°C to 30°C.
  • the alcohol solvent is methanol.
  • the high temperature is 40°C to 60°C, for example 50°C.
  • the crystallization temperature is -20°C to 5°C.
  • the cooling rate is 0.05°C/min to 0.5°C/min, eg 0.1°C/min.
  • the cooling is rapid cooling.
  • the alkyl nitrile solvent is acetonitrile.
  • the compound represented by formula (I) (S)-4-(3-(butyn-2-ylamide)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-
  • the AE-type crystal of 7-formamide that is, the crystalline form AE, is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction of the crystalline form AE has a 2 ⁇ value of 6.4° ⁇ 0.2°, 15.5° ⁇ 0.2°, There is a characteristic peak at 12.8° ⁇ 0.2°,
  • the X-ray powder diffraction of the crystal form AE has one or two or three 2 ⁇ values of 16.0° ⁇ 0.2°, 20.0° ⁇ 0.2°, and 21.0° ⁇ 0.2° There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form AE has characteristic peaks at 2 ⁇ values of 16.0° ⁇ 0.2°, 20.0° ⁇ 0.2°, and 21.0° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form AE has one or two or three 2 ⁇ values of 24.2° ⁇ 0.2°, 21.4° ⁇ 0.2°, and 16.4° ⁇ 0.2° There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form AE has characteristic peaks at 2 ⁇ values of 24.2° ⁇ 0.2°, 21.4° ⁇ 0.2°, and 16.4° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form AE has 2 ⁇ values of 6.4° ⁇ 0.2°, 15.5° ⁇ 0.2°, 12.8° ⁇ 0.2°, 16.0° ⁇ 0.2°, 20.0° ⁇ 0.2°, 21.0° ⁇ 0.2°, 24.2° ⁇ 0.2°, 21.4° ⁇ 0.2°, 16.4° ⁇ 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 crystalline form AE has 2 ⁇ values of 6.4° ⁇ 0.2°, 15.5° ⁇ 0.2°, 12.8° ⁇ 0.2°, 16.0° ⁇ 0.2°, 20.0° ⁇ There are characteristic peaks at 0.2°, 21.0° ⁇ 0.2°, 24.2° ⁇ 0.2°, 21.4° ⁇ 0.2°, and 16.4° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form AE is shown in FIG. 5 .
  • the hetero-nitrogen solvent is N,N-dimethylacetamide.
  • the mass of the high polymer is 0.5% to 5% of the mass of the formula (I).
  • the high polymer is selected from at least one of polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, hydroxypropyl methylcellulose or methylcellulose .
  • the alcoholic solvent is n-propanol.
  • the dissolution conditions are 40°C to 60°C, for example 50°C.
  • the crystallization temperature is -20°C to 5°C, eg -20°C.
  • the cooling is rapid cooling.
  • the alcoholic solvent is n-propanol.
  • the dissolution conditions are 40°C to 60°C, for example 50°C.
  • the cooling rate is 0.05°C/min to 0.5°C/min, eg 0.1°C/min.
  • the alcoholic solvent is n-propanol.
  • the compound represented by formula (I) (S)-4-(3-(butyn-2-ylamide)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-
  • the AA-type crystal of 7-formamide that is, the crystal form AA
  • the AA-type crystal of 7-formamide is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction of the crystal form AA has a 2 ⁇ value of 11.7° ⁇ 0.2°, 16.1° ⁇ 0.2°, There is a characteristic peak at 16.7° ⁇ 0.2°,
  • the X-ray powder diffraction of the crystal form AA has one or two or three 2 ⁇ values of 17.9° ⁇ 0.2°, 8.2° ⁇ 0.2°, and 8.9° ⁇ 0.2°. There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form AA has characteristic peaks at 2 ⁇ values of 17.9° ⁇ 0.2°, 8.2° ⁇ 0.2°, and 8.9° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form AA has characteristic peaks at 2 ⁇ values of 20.0° ⁇ 0.2°, 18.3° ⁇ 0.2°, and 23.4° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form AA has characteristic peaks at 2 ⁇ values of 20.0° ⁇ 0.2°, 18.3° ⁇ 0.2°, and 23.4° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form AA has 2 ⁇ values of 11.7° ⁇ 0.2°, 16.1° ⁇ 0.2°, 16.7° ⁇ 0.2°, 17.9° ⁇ 0.2°, 8.2° ⁇ 0.2°, 8.9° ⁇ 0.2°, 20.0° ⁇ 0.2°, 18.3° ⁇ 0.2°, 23.4° ⁇ 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 AA has 2 ⁇ values of 11.7° ⁇ 0.2°, 16.1° ⁇ 0.2°, 16.7° ⁇ 0.2°, 17.9° ⁇ 0.2°, 8.2° ⁇ There are characteristic peaks at 0.2°, 8.9° ⁇ 0.2°, 20.0° ⁇ 0.2°, 18.3° ⁇ 0.2°, and 23.4° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of crystal form AA is shown in FIG. 6 .
  • the preparation method of the crystal form AA is characterized in that,
  • the compound of formula (I) is dissolved in an alcoholic solvent at a high temperature, the solution is cooled down, and a solid is precipitated to obtain crystal form AA.
  • the dissolution conditions are 40°C to 60°C, for example 50°C.
  • the crystallization temperature is -20°C to 5°C, eg -20°C.
  • the cooling is rapid cooling.
  • the alcoholic solvent is isopropanol.
  • said formula (I) and/or its salts as raw materials refer to its solid (crystalline or amorphous), semi-solid, wax or oil form.
  • the compounds and/or their salts as raw materials are in the form of solid powders.
  • 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 preferably 300-1000 rev/min, and the mechanical stirring is preferably 100-100 300 rpm.
  • 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 XRPD pattern are related to the preferred orientation of the crystals, and the peak intensities shown here are illustrative rather than absolute comparisons.
  • the experimental error of the peak angle is usually 5% or less, and the error of these angles should also be taken into account, and an error of ⁇ 0.2° is usually 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 XRPD pattern" mentioned herein does not mean absolutely the same , the same peak position can differ by ⁇ 0.2° and the peak intensity allows some variability. 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.
  • Form C, Form A, Form Y, Form V, Form AE, Form AA of the present invention are pure, single, and substantially not mixed 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 crystal form C, crystal form A, crystal form Y, crystal form V, crystal form AE, crystal form AA of the formula (I) provided by the present invention are in solubility, melting point, stability, dissolution, wettability, adhesion, fluidity
  • Drug development is very important.
  • the new crystal form of the compound of formula (I) provided by the invention has the advantages of solubility, melting point, stability, dissolution, hygroscopicity, adhesion, fluidity, bioavailability, processability, purification, There are advantages in at least one aspect of preparation production, safety, etc., which provide a new and better choice for the preparation of pharmaceutical preparations of BTK inhibitors, and are of great significance for drug development.
  • room temperature generally refers to 22°C to 28°C unless otherwise specified.
  • the X-ray powder diffraction patterns of the present invention were collected on Empyrean and X'Pert3 ray powder diffractometers of PANalytacal.
  • the method parameters of X-ray powder diffraction of the present invention are as follows:
  • the differential scanning calorimetry analysis curve of the present invention is collected on the Q2000 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 curve 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:
  • UPLC high performance liquid chromatography
  • PDA diode array detector
  • Chromatographic column Waters Xbridge C18, 150 ⁇ 4.6mm, 5 ⁇ m
  • the elution gradient is as follows:
  • ion chromatography (IC) data is collected from ThermoFisher ICS-1100, and the IC method parameters of the test chloride ion content of the present invention are as follows:
  • Chromatographic column IonPac AS18Analytical Column (4 ⁇ 250mm)
  • 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)
  • 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 laser particle size analyzer are as follows:
  • the intrinsic dissolution rate data described in the present invention is collected on the Agilent 708DS type dissolution apparatus of Agilent Company. 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 US20160115126A1, but the starting crystal form is not a limitation for preparing the crystal form of the present invention.
  • Example 1 At room temperature, 15.2 mg of the solid compound of formula (I) was weighed and placed in a 3 mL glass vial, and the open mouth was placed in a 20 mL glass vial prefilled with 4 mL of ethanol. After sealing, it was placed at room temperature for gas-solid permeation for about 12 days, and the sample was dissolved and clear, and then the sample was transferred to room temperature for volatilization until a solid was precipitated, and crystal form C was obtained.
  • the X-ray powder diffraction data are shown in Table 1, and the diffraction pattern is shown in Figure 1.
  • the TGA data is shown in FIG. 7
  • the DSC data is shown in FIG. 8
  • the 1 H NMR data is shown in FIG. 9 .
  • Example 2 At room temperature, weigh 15.3 mg of the solid compound of formula (I) into a 3-mL glass vial, add 0.6 mL of isopropanol to dissolve the solid, and use a 0.45-micron pore size polytetrafluoroethylene filter to filter the sample. The solution was filtered into a new 3 ml glass vial, and the open mouth was placed in a fume hood to evaporate at room temperature, and a solid was precipitated to obtain crystal form C. Its X-ray powder diffraction data are shown in Table 2.
  • Examples 3-4 Under room temperature conditions, place an appropriate amount of the solid of the compound of formula (I) in a 1.5 ml glass vial, add a corresponding volume of solvent at 50°C to dissolve the solid, and use a 0.45-micron pore size polytetrafluoroethylene. The sample solution was filtered through a filter membrane, and then quickly placed at -20 °C to stand, the sample was clarified, and evaporated at room temperature until a solid was precipitated, and crystal form C was obtained. The detailed test conditions involved in this example are shown in Table 3.
  • Table 4 The detailed test conditions involved in this example are shown in Table 4, the X-ray powder diffraction data of the sample of Example 11 is shown in Table 5, and the diffraction pattern is shown in FIG. 2 .
  • the TGA data is shown in FIG. 10
  • the DSC data is shown in FIG. 11
  • the 1 H NMR data is shown in FIG. 12 .
  • Hybrid Polymer A Polyvinylpyrrolidone, Polyvinyl Alcohol, Polyvinyl Chloride, Polyvinyl Acetate, Hydroxypropyl Methyl Cellulose and Methyl Cellulose (mixed in equal mass)
  • Mixed polymer B polycaprolactone, polyethylene glycol, polymethyl methacrylate, sodium alginate and hydroxyethyl cellulose (mixed in equal mass)
  • Examples 19-29 Under room temperature conditions, weigh an appropriate amount of the solid of the compound of formula (I) and place it in a 1.5-ml glass vial, add a corresponding volume of solvent to dissolve the solid, and place the sample at 50 °C for 2 hours. The sample solution was filtered through a 0.45-micron pore size polytetrafluoroethylene filter into a new 1.5-ml glass vial, and the opening was placed in a fume hood to evaporate at room temperature, and a solid was precipitated. Form A was obtained. The detailed test conditions involved in this example are shown in Table 8, and the X-ray powder diffraction data of the sample of Example 19 is shown in Table 9.
  • Examples 30-31 Under room temperature conditions, place an appropriate amount of the solid of the compound of formula (I) in a 3 ml glass vial, add a corresponding volume of solvent to dissolve the solid, and filter through a 0.45-micron polytetrafluoroethylene membrane to obtain a clear solution, then The solution was placed in an atmosphere containing 4 ml of different solvents, and gas-liquid infiltration was carried out. After about 14 days, no solid was precipitated, and the solution was transferred to room temperature for volatilization, and a solid was precipitated to obtain crystal form A.
  • Table 10 The detailed test conditions involved in this example are shown in Table 10.
  • Examples 32 to 37 under room temperature conditions, place an appropriate amount of the solid compound of formula (I) in a 1.5 ml glass vial, add a corresponding volume of solvent to dissolve the solid, place it at 50°C to dissolve it, and use The sample solution was filtered through a polytetrafluoroethylene filter membrane with a pore size of 0.45 microns, and then the filtrate was quickly placed at -20°C for standing, and no solid was precipitated for about 1 to 3 days.
  • Table 11 The detailed test conditions involved in this example are shown in Table 11.
  • Examples 38-40 Under room temperature conditions, place an appropriate amount of the solid compound of formula (I) in a 5-mL glass vial, add a corresponding volume of positive solvent to obtain a clear solution, and place a 20-mL glass bottle containing an anti-solvent in advance. Equilibrate at -20°C for about 0.5 to 2 hours. The positive solvent solution containing the compound was filtered through a 0.45-micron polytetrafluoroethylene membrane to obtain a clear solution, and the filtrate was rapidly added to the pre-cooled anti-solvent. After the dropwise addition, there is no solid precipitation. Transfer the sample to 5 °C and stir for about 1 to 2 days. If there is still no solid, transfer it to -20 °C and stir for about 1 to 2 days. There is still no solid precipitation. Finally, it was placed in a fume hood to volatilize, and a solid was precipitated to obtain crystal form A. The detailed test conditions involved in this example are shown in Table 12.
  • the X-ray powder diffraction data of its samples are shown in Table 21.
  • the TGA data is shown in FIG. 20
  • the DSC data is shown in FIG. 21
  • the 1 H NMR data is shown in FIG. 22 .
  • Example 60 Preparation of crystal form AA (rapid cooling method)
  • Example 61 Preparation of crystal form G (rapid evaporation method)
  • Example 62 Preparation of crystal form G (rapid evaporation method)
  • Example 26 The detailed test conditions involved in this example are shown in Table 26, and the X-ray powder diffraction data of the sample of Example 63 are shown in Table 27.
  • the sample is at about 7.2° ⁇ 0.2°, about 6.4° ⁇ 0.2°, about 14.5° ⁇ 0.2°, about 19.4° ⁇ 0.2°, about 10.2° ⁇ 0.2°, about 12.9° ⁇ 0.2°, about 21.8° ⁇ 0.2
  • Example 66 Preparation of crystal form M (rapid evaporation method)
  • the sample is at about 7.1° ⁇ 0.2°, about 6.5° ⁇ 0.2°, about 14.3° ⁇ 0.2°, about 19.6° ⁇ 0.2°, about 10.2° ⁇ 0.2°, about 21.6° ⁇ 0.2°, about 13.0° ⁇ 0.2
  • the sample is at about 6.4° ⁇ 0.2°, about 19.4° ⁇ 0.2°, about 12.9° ⁇ 0.2°, about 7.2° ⁇ 0.2°, about 22.6° ⁇ 0.2°, about 17.1° ⁇ 0.2°, about 10.1° ⁇ 0.2
  • the sample is at about 7.0° ⁇ 0.2°, about 14.2° ⁇ 0.2°, about 6.5° ⁇ 0.2°, about 21.3° ⁇ 0.2°, about 19.7° ⁇ 0.2°, about 13.1° ⁇ 0.2°, about 10.2° ⁇ 0.2
  • the crystal form C/Y/A/V/AE of the present invention is respectively prepared into a suspension with SGF (simulated artificial gastric fluid), FaSSIF (artificial intestinal fluid in fasting state), FeSSIF (artificial intestinal fluid in satiation state) and pure water, After equilibration at room temperature for 1 hour, 2 hours, 4 hours and 24 hours, a saturated solution was obtained by filtration. The content of the sample in the saturated solution was determined by high performance liquid chromatography (HPLC). The experimental results are shown in Table 31, and the solubility curves are shown in Figures 23 to 26, respectively. The experimental results show that the crystal form C/Y/A/V/AE of the present invention has good solubility in SGF, FaSSIF, FeSSIF and pure water.
  • Example 70 Compressibility of crystal forms
  • the DVS of Form C is shown in Figure 33
  • the XRPD comparison chart of Form C before and after the DVS test is shown in Figure 34
  • the DVS of Form V is shown in Figure 35
  • the DVS of Form Y is shown in Figure 36
  • the XRPD comparison diagram of the crystal form Y before and after the DVS test is shown in Figure 37
  • the DVS of the crystal form AE is shown in Figure 38
  • the XRPD comparison diagram of the crystal form AE before and after the DVS test is shown in Figure 39.
  • the test results show that the crystalline form C/Y/A/V/AE of the present invention has lower 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%
  • the adhesion of the crystal form of the present invention is better than that of the solid S1 disclosed in the prior art.

Abstract

New crystal forms of an indole carboxamide compound and a preparation method therefor. Provided are preparation methods and uses for crystal form C, crystal form A, crystal form Y, crystal form V, crystal form AE, and crystal form AA of formula (I), the provided crystal form C, crystal form A, crystal form Y, crystal form V, crystal form AE, and crystal form AA of a compound of formula (I) are advantageous in at least one aspect among solubility, melting point, stability, dissolution, hygroscopicity, adhesiveness, flowability, bioavailability, as well as processability, a purification effect, production of a formulation, safety, etc., providing new, better choices for preparation of a pharmaceutical formulation containing a compound of formula (I), and having great significance for pharmaceutical development.

Description

吲哚基甲酰胺类化合物的新晶型及其制备方法New crystal forms of indolylcarboxamides and their preparation methods 技术领域technical field
本发明涉及化学医药领域，特别是涉及一种吲哚基甲酰胺类化合物的新晶型及其制备方法。The invention relates to the field of chemical medicine, in particular to a new crystal form of an indolylcarboxamide compound and a preparation method thereof.
背景技术Background technique
免疫细胞分为B细胞和T细胞，B细胞可以分泌各种抗体来抵抗外来病毒或细菌的入侵。布鲁顿诺氨酸激酶(BTK)主要在B细胞和髓细胞中表达，广泛分布在血液系统和淋巴系统。是B细胞抗原受体(BCR)信号通路中的关键激酶，能够调节正常B细胞的增殖、分化与凋亡。恶性B细胞需要BTK持续激活来保证癌细胞的快速生长。因此抑制BTK的活性，可以实现恶性肿瘤的治疗作用。(S)-4-(3-(丁炔-2-基酰胺)哌啶-1-基)-5-氟-2,3-二甲基-1H-吲哚-7-甲酰胺是一种口服活性、强效、选择性的BTK抑制剂，其结构式如下所示：Immune cells are divided into B cells and T cells. B cells can secrete various antibodies to resist the invasion of foreign viruses or bacteria. Bruton's nomine kinase (BTK) is mainly expressed in B cells and myeloid cells, and is widely distributed in the blood and lymphatic systems. It is a key kinase in the B cell antigen receptor (BCR) signaling pathway and can regulate the proliferation, differentiation and apoptosis of normal B cells. Malignant B cells require continuous activation of BTK to ensure rapid cancer cell growth. Therefore, inhibiting the activity of BTK can achieve the therapeutic effect of malignant tumors. (S)-4-(3-(Butyn-2-ylamide)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide is a Orally active, potent, and selective BTK inhibitor with the following structural formula:
Figure PCTCN2021127741-appb-000001
Figure PCTCN2021127741-appb-000001
式(I)可选择性地与BTK结合，降低了BTK激活的程度，能够有效地控制恶性B细胞的生长，具有潜在的抗肿瘤活性。式(I)在慢性淋巴细胞白血病，套细胞淋巴瘤和华氏巨球蛋白血症等方面具有一定的治疗潜力Formula (I) can selectively combine with BTK, reduce the degree of BTK activation, can effectively control the growth of malignant B cells, and has potential anti-tumor activity. Formula (I) has certain therapeutic potential in chronic lymphocytic leukemia, mantle cell lymphoma and Waldenstrom's macroglobulinemia
专利US20160115126A1中首次公开了式(I)的游离碱制备方法，洗涤提纯工艺复杂，并未说明其固体形式。因此，有必要展开完整的多晶型筛选，以期获得较为简便的制备和纯化方法。Patent US20160115126A1 discloses the preparation method of the free base of formula (I) for the first time, the washing and purification process is complicated, and its solid form is not described. Therefore, it is necessary to carry out a complete polymorphic screening in order to obtain a simpler preparation and purification method.
同一药物的多晶型可能会改变其物理化学性质，如溶解度、溶解速率、熔点和稳定性，进而可能会影响药物在人体内的作用效果。因此，有必要对式(I)进行全面系统的晶型筛选，开发出溶解度好、稳定性高的晶型，为药物的后续开发提供更多更好的选择。Polymorphic forms of the same drug may change its physicochemical properties, such as solubility, dissolution rate, melting point and stability, which in turn may affect the effect of the drug in the human body. Therefore, it is necessary to carry out a comprehensive and systematic crystal form screening of formula (I) to develop a crystal form with good solubility and high stability, so as 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)化合物的六种晶型C、A、Y、V、AE、AA制备方法和用途。The present invention provides preparation methods and uses of six crystal forms C, A, Y, V, AE and AA of the compound of formula (I).
1.式(I)所示化合物(S)-4-(3-(丁炔-2-基酰胺)哌啶-1-基)-5-氟-2,3-二甲基-1H-吲哚-7-甲酰胺的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6.6°±0.2°,13.2°±0.2°,17.5°±0.2°处有特征峰，1. Compound (S)-4-(3-(butyn-2-ylamide)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indium represented by formula (I) The C-type crystal of inole-7-carboxamide, that is, the crystal form C, is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction of the crystal form C has a 2θ value of 6.6°±0.2°, 13.2°±0.2 °, There are characteristic peaks at 17.5°±0.2°,
Figure PCTCN2021127741-appb-000002
Figure PCTCN2021127741-appb-000002
2.根据上述1中所述的晶型C的制备方法，其特征包括：2. according to the preparation method of crystal form C described in above-mentioned 1, it is characterized in that:
(1)将式(I)化合物溶解于醇类溶剂中，20℃至30℃挥发，固体析出，得到晶型C；或(1) Dissolving the compound of formula (I) in an alcoholic solvent, volatilizing at 20°C to 30°C, and precipitation of a solid to obtain crystal form C; or
(2)将式(I)化合物溶解于杂氮类溶剂中，将溶液快速加入至水中，固体析出，得到晶型C。(2) Dissolving the compound of formula (I) in an hetero-nitrogen-based solvent, adding the solution to water rapidly, the solid is precipitated, and crystal form C is obtained.
3.式(I)所示化合物(S)-4-(3-(丁炔-2-基酰胺)哌啶-1-基)-5-氟-2,3-二甲基-1H-吲哚-7-甲酰胺的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7.1±0.2°,14.3°±0.2°,8.3°±0.2°处有特征峰，3. Compound (S)-4-(3-(butyn-2-ylamide)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indium represented by formula (I) Form A crystal of inole-7-carboxamide, namely Form A, characterized in that, using Cu-Kα radiation, the X-ray powder diffraction of Form A has 2θ values of 7.1±0.2°, 14.3°±0.2° , there is a characteristic peak at 8.3°±0.2°,
Figure PCTCN2021127741-appb-000003
Figure PCTCN2021127741-appb-000003
4.根据上述3中所述的晶型A的制备方法，其特征包括：4. according to the preparation method of the crystal form A described in above-mentioned 3, it is characterized in that:
(1)将式(I)化合物溶解于醇类、酮类、醚类或卤代烃类溶剂中，向其中加入式(I)化合物质量的0.5％～5％的高聚物，该高聚物为聚乙烯吡咯烷酮、聚乙烯醇、聚氯乙烯、聚醋酸乙烯酯、羟丙基甲基纤维素、甲基纤维素、聚己酸内酯、聚乙二醇、聚甲基丙烯酸甲酯、海藻酸钠、羟乙基纤维素的单一成分或混合物；将上述溶液置于20℃至30℃下挥发，固体析出，得到晶型A；或(1) Dissolving the compound of formula (I) in alcohols, ketones, ethers or halogenated hydrocarbon solvents, and adding 0.5% to 5% of the mass of the compound of formula (I) to the polymer, the high polymer The substances are polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, hydroxypropyl methylcellulose, methylcellulose, polycaprolactone, polyethylene glycol, polymethyl methacrylate, A single component or mixture of sodium alginate and hydroxyethyl cellulose; volatilize the above solution at 20°C to 30°C, and the solid is precipitated to obtain crystal form A; or
(2)将式(I)化合物溶解于醇类、酮类、环醚类或酯类溶剂中，将溶液敞口置于纯水、直链醚类或烷烃类溶剂氛围下进行气液渗透，1～2周后，固体析出，得到晶型A；或(2) the compound of formula (I) is dissolved in alcohols, ketones, cyclic ethers or ester solvents, and the solution is placed openly in pure water, straight chain ethers or alkane solvent atmosphere to carry out gas-liquid infiltration, After 1 to 2 weeks, the solid is precipitated to obtain Form A; or
(3)将式(I)化合物的溶解于醇类、酮类、醚类、酯类、卤代烃类、芳香烃溶剂的单一溶剂或混合物中，20℃至30℃挥发，固体析出，得到晶型A；或(3) dissolving the compound of formula (I) in a single solvent or mixture of alcohols, ketones, ethers, esters, halogenated hydrocarbons, and aromatic hydrocarbon solvents, volatilizing at 20°C to 30°C, and the solid is precipitated to obtain Form A; or
(4)将式(I)化合物溶解于醇类、酮类、醚类或酯类溶剂中，向其中逐滴加入醚类、芳烃类或烷烃类反溶剂，固体析出，得到晶型A；或(4) dissolving the compound of formula (I) in alcohols, ketones, ethers or ester solvents, adding ethers, aromatic hydrocarbons or alkanes anti-solvent dropwise to it, solid precipitation to obtain crystal form A; or
(5)将式(I)化合物溶解于醇类或酯类溶剂中，将溶液快速加入至烷烃类反溶剂中，固体析出，得到晶型A。(5) Dissolving the compound of formula (I) in an alcohol or ester solvent, adding the solution to an alkane anti-solvent rapidly, the solid is precipitated, and crystal form A is obtained.
5.式(I)所示化合物(S)-4-(3-(丁炔-2-基酰胺)哌啶-1-基)-5-氟-2,3-二甲基-1H-吲哚-7-甲酰胺的Y型晶体、即晶型Y，其特征在于，使用Cu-Kα辐射，所述晶型Y的X射线粉末衍射在2θ值为14.0°±0.2°,7.0°±0.2°,17.5°±0.2°处有特征峰，5. Compound (S)-4-(3-(butyn-2-ylamide)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indium represented by formula (I) The Y-type crystal of inole-7-carboxamide, that is, the crystal form Y, is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction of the crystal form Y has a 2θ value of 14.0°±0.2°, 7.0°±0.2 °, There are characteristic peaks at 17.5°±0.2°,
Figure PCTCN2021127741-appb-000004
Figure PCTCN2021127741-appb-000004
6.根据上述5中所述的晶型Y的制备方法，其特征在于，6. according to the preparation method of crystal form Y described in above-mentioned 5, it is characterized in that,
(1)将上述3中所述晶型A，加入醇类溶剂中得到悬浊液，将其在20℃至30℃下超声30分钟，得到晶型Y；或(1) Add the crystal form A described in the above 3 into an alcohol solvent to obtain a suspension, and sonicate it at 20°C to 30°C for 30 minutes to obtain crystal form Y; or
(2)将上述3中所述晶型A，加入醇类溶剂中得到悬浊液，将其在20℃至30℃下悬浮搅拌1天至4天，分离固体，得到晶型Y。(2) Add the crystal form A described in the above 3 into an alcoholic solvent to obtain a suspension, which is suspended and stirred at 20°C to 30°C for 1 to 4 days, and the solid is separated to obtain crystal form Y.
7.式(I)所示化合物(S)-4-(3-(丁炔-2-基酰胺)哌啶-1-基)-5-氟-2,3-二甲基-1H-吲哚-7-甲酰胺的V型晶体、即晶型V，其特征在于，使用Cu-Kα辐射，所述晶型V的X射线粉末衍射在2θ值为6.5°±0.2°,15.0°±0.2°,13.0°±0.2°处有特征峰，7. Compound (S)-4-(3-(butyn-2-ylamide)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indium represented by formula (I) The V-type crystal of indole-7-carboxamide, that is, the crystal form V, is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction of the crystal form V has a 2θ value of 6.5°±0.2°, 15.0°±0.2 °, there are characteristic peaks at 13.0°±0.2°,
Figure PCTCN2021127741-appb-000005
Figure PCTCN2021127741-appb-000005
8.根据上述7中所述的晶型V的制备方法，其特征包括：8. according to the preparation method of crystal form V described in above-mentioned 7, it is characterized in that:
(1)将式(I)化合物溶解于环醚类溶剂中，将溶液挥发，固体析出，得到晶型V；或(1) Dissolving the compound of formula (I) in a cyclic ether solvent, volatilizing the solution, and precipitating a solid to obtain crystal form V; or
(2)将式(I)化合物溶解于醇类溶剂中，向溶液中加入式(I)化合物质量的0.5％～15％的高聚物，该高聚物为聚乙烯吡咯烷酮、聚乙烯醇、聚氯乙烯、聚醋酸乙烯酯、羟丙基甲基纤维素与甲基纤维素的单一成分或混合物；将该溶液挥发，固体析出，得到晶型V；或(2) Dissolving the compound of formula (I) in an alcohol solvent, adding a high polymer of 0.5% to 15% of the mass of the compound of formula (I) to the solution, the high polymer is polyvinylpyrrolidone, polyvinyl alcohol, A single component or mixture of polyvinyl chloride, polyvinyl acetate, hydroxypropyl methylcellulose and methylcellulose; the solution is volatilized, and the solid is precipitated to obtain crystal form V; or
(3)将式(I)化合物溶解于烷基腈类溶剂中，高温条件下达到溶解平衡，将溶液降温至有固体析出，得到晶型V。(3) Dissolving the compound of formula (I) in an alkyl nitrile solvent, reaching a dissolution equilibrium under high temperature conditions, cooling the solution until a solid is precipitated to obtain crystal form V.
9.式(I)所示化合物(S)-4-(3-(丁炔-2-基酰胺)哌啶-1-基)-5-氟-2,3-二甲基-1H-吲哚-7-甲酰胺的AE型晶体、即晶型AE，其特征在于，使用Cu-Kα辐射，所述晶型AE的X射线粉末衍射在2θ值为6.4°±0.2°,15.5°±0.2°,12.8°±0.2°处有特征峰，9. Compound (S)-4-(3-(butyn-2-ylamide)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indium represented by formula (I) The AE-type crystal of inole-7-carboxamide, that is, the crystalline form AE, is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction of the crystalline form AE has a 2θ value of 6.4°±0.2°, 15.5°±0.2 °, There are characteristic peaks at 12.8°±0.2°,
Figure PCTCN2021127741-appb-000006
Figure PCTCN2021127741-appb-000006
10.根据上述9中所述的晶型AE的制备方法，其特征包括：10. according to the preparation method of the crystal form AE described in above-mentioned 9, it is characterized in that:
(1)将式(I)化合物溶解于杂氮类溶剂中，将溶液快速加入至纯水中，固体析出，得到晶型AE；或(1) dissolving the compound of formula (I) in the hetero-nitrogen solvent, adding the solution to pure water quickly, the solid is precipitated to obtain crystal form AE; or
(2)将式(I)化合物溶解于醇类溶剂中，在溶液中加入式(I)化合物质量的0.5％～15％的高聚物，该高聚物为聚乙烯吡咯烷酮、聚乙烯醇、聚氯乙烯、聚醋酸乙烯酯、羟丙基甲基纤维素、甲基纤维素的单一或混合物；将该溶液转移至20℃至30℃下挥发，固体析出，得到晶型AE；或(2) Dissolving the compound of formula (I) in an alcohol solvent, adding a high polymer of 0.5% to 15% of the mass of the compound of formula (I) to the solution, the high polymer is polyvinylpyrrolidone, polyvinyl alcohol, Single or mixture of polyvinyl chloride, polyvinyl acetate, hydroxypropyl methyl cellulose, methyl cellulose; transfer the solution to 20°C to 30°C to volatilize, and the solid is precipitated to obtain crystal form AE; or
(3)将式(I)化合物的溶解于醇类溶剂中，40℃至60℃下溶解平衡，将溶液转移至5℃至-25℃条件下静置，固体析出，得到晶型AE；或(3) dissolving the compound of formula (I) in an alcohol solvent, dissolving equilibrium at 40°C to 60°C, transferring the solution to stand at 5°C to -25°C, and solid precipitation to obtain crystal form AE; or
(4)将式(I)化合物的溶解于醇类溶剂中，将溶液转移至20℃至30℃挥发，固体析出，得到晶型AE。(4) Dissolve the compound of formula (I) in an alcohol solvent, transfer the solution to 20°C to 30°C to volatilize, and precipitate a solid to obtain crystal form AE.
11.式(I)所示化合物(S)-4-(3-(丁炔-2-基酰胺)哌啶-1-基)-5-氟-2,3-二甲基-1H-吲哚-7-甲酰胺的AA型晶体、即晶型AA，其特征在于，使用Cu-Kα辐射，所述晶型AA的X射线粉末衍射在2θ值为11.7°±0.2°,16.1°±0.2°,16.7°±0.2°处有特征峰，11. Compound (S)-4-(3-(butyn-2-ylamide)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indium represented by formula (I) The AA-type crystal of inole-7-carboxamide, that is, the crystalline form AA, is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction of the crystalline form AA has 2θ values of 11.7°±0.2°, 16.1°±0.2 °, There are characteristic peaks at 16.7°±0.2°,
Figure PCTCN2021127741-appb-000007
Figure PCTCN2021127741-appb-000007
12.根据上述11中所述的晶型AA的制备方法，其特征在于，12. According to the preparation method of crystal form AA described in the above 11, it is characterized in that,
将式(I)化合物的溶解于醇类溶剂中，40℃至60℃下达到溶解平衡，将溶液降温至固体析出，得到晶型AA。The compound of formula (I) is dissolved in an alcohol solvent, and the dissolution equilibrium is reached at 40° C. to 60° C., and the solution is cooled to solid precipitation to obtain crystal form AA.
13.药物组合物，其包含上述1、3、5、7、9、11中任一项所述的晶体和制药学可接受的载体。13. A pharmaceutical composition comprising the crystal of any one of the above 1, 3, 5, 7, 9, 11 and a pharmaceutically acceptable carrier.
14.具有BTK抑制活性的药物组合物，其含有上述1、3、5、7、9、11中任一项所述的晶体作为有效成分。14. A pharmaceutical composition having BTK inhibitory activity, comprising the crystal according to any one of the above 1, 3, 5, 7, 9, and 11 as an active ingredient.
15.慢性淋巴细胞白血病，套细胞淋巴瘤和华氏巨球蛋白血症的预防药或治疗药，其含有 上述1、3、5、7、9、11中任一项所述的晶体作为有效成分。15. A preventive or therapeutic drug for chronic lymphocytic leukemia, mantle cell lymphoma and Waldenström's macroglobulinemia, which contains the crystal described in any one of the above 1, 3, 5, 7, 9, and 11 as an active ingredient .
与现有技术相比，发明提供的式(I)化合物的晶型C、晶型A、晶型Y、晶型V、晶型AE和晶型AA，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，为这种新型的BTK抑制剂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 crystalline form C, crystalline form A, crystalline form Y, crystalline form V, crystalline form AE and crystalline form AA of the compound of formula (I) provided by the invention are in solubility, melting point, stability, and dissolution rate. , hygroscopicity, adhesion, fluidity, bioavailability, and processing performance, purification, preparation production, safety, etc. have advantages in at least one aspect, providing for the preparation of this new type of BTK inhibitor pharmaceutical preparation. It is of great significance for drug development to develop new and better options.
附图说明Description of drawings
图1晶型C的XRPD图Figure 1 XRPD pattern of Form C
图2晶型A的XRPD图Figure 2 XRPD pattern of Form A
图3晶型Y的XRPD图Figure 3 XRPD pattern of Form Y
图4晶型V的XRPD图Figure 4 XRPD pattern of Form V
图5晶型AE的XRPD图Figure 5 XRPD pattern of Form AE
图6晶型AA的XRPD图Figure 6 XRPD pattern of Form AA
图7晶型C的TGA曲线Figure 7 TGA curve of Form C
图8晶型C的DSC曲线Figure 8 DSC curve of Form C
图9晶型C的 1H NMR图 Figure 9 1 H NMR of Form C
图10晶型A的TGA曲线Figure 10 TGA curve of Form A
图11晶型A的DSC曲线Figure 11 DSC curve of Form A
图12晶型A的 1H NMR图 Figure 12 1 H NMR chart of Form A
图13晶型Y的XRPD图Figure 13 XRPD pattern of Form Y
图14晶型Y的TGA曲线Figure 14 TGA curve of Form Y
图15晶型Y的DSC曲线Figure 15 DSC curve of crystal form Y
图16晶型Y的 1H NMR图 Figure 16 1 H NMR of Form Y
图17晶型V的TGA曲线Figure 17 TGA curve of Form V
图18晶型V的DSC曲线Figure 18 DSC curve of Form V
图19晶型V的 1H NMR图 Figure 19 1 H NMR of Form V
图20晶型AE的TGA曲线Figure 20 TGA curve of crystal form AE
图21晶型AE的DSC曲线Figure 21 DSC curve of crystal form AE
图22晶型AE的 1H NMR图 Figure 22 1 H NMR of Form AE
图23不同晶型水中溶解度对比图Figure 23 Comparison of solubility in water of different crystal forms
图24不同晶型SGF中溶解度对比图Figure 24. Comparison of solubility in different crystal forms of SGF
图25不同晶型FaSSIF中溶解度对比图Figure 25 Comparison of solubility in different crystal forms of FaSSIF
图26不同晶型FeSSIF中溶解度对比图Figure 26 Comparison of solubility in FeSSIF of different crystal forms
图27晶型C在25℃/60％相对湿度下稳定性测试XRPD对比图Fig. 27 XRPD comparison chart of stability test of crystal form C at 25℃/60% relative humidity
图28晶型C在40℃/75％相对湿度下稳定性测试XRPD对比图Figure 28 XRPD comparison chart of stability test of crystal form C at 40°C/75% relative humidity
图29晶型V在25℃/60％相对湿度下稳定性测试XRPD对比图Figure 29 XRPD comparison chart of the stability test of crystal form V at 25℃/60% relative humidity
图30晶型Y在25℃/60％相对湿度下稳定性测试XRPD对比图Figure 30 XRPD comparison chart of stability test of crystal form Y at 25℃/60% relative humidity
图31晶型Y在40℃/75％相对湿度下稳定性测试XRPD对比图Figure 31 XRPD comparison chart of the stability test of crystal form Y at 40°C/75% relative humidity
图32晶型A的动态水分吸附脱附图Figure 32. Figure 32 Dynamic moisture adsorption and desorption of crystal form A
图33晶型C的动态水分吸附脱附图Figure 33. Figure 33 Dynamic moisture adsorption and desorption of crystal form C
图34晶型C测试动态水分吸附脱附前后的XRPD对比图Fig. 34 Comparison of XRPD before and after dynamic moisture adsorption and desorption of crystal form C
图35晶型V的动态水分吸附脱附图Figure 35. Figure 35 Dynamic moisture adsorption and desorption of crystal form V
图36晶型Y的动态水分吸附脱附图Figure 36. Figure 36 Dynamic moisture adsorption and desorption of crystal form Y
图37晶型Y测试动态水分吸附脱附前后的XRPD对比图Fig. 37 Comparison of XRPD before and after dynamic moisture adsorption and desorption of crystal form Y
图38晶型AE的动态水分吸附脱附图Figure 38 Figure 38 Dynamic moisture adsorption and desorption of crystal form AE
图39晶型AE测试动态水分吸附脱附前后的XRPD对比图Fig. 39 Comparison of XRPD before and after dynamic moisture adsorption and desorption of crystal form AE
具体实施方式Detailed ways
式(I)所示化合物(S)-4-(3-(丁炔-2-基酰胺)哌啶-1-基)-5-氟-2,3-二甲基-1H-吲哚-7-甲酰胺的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6.6°±0.2°,13.2°±0.2°,17.5°±0.2°处有特征峰，The compound represented by formula (I) (S)-4-(3-(butyn-2-ylamide)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole- The C-type crystal of 7-formamide, that is, crystal form C, is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction of the crystal form C has a 2θ value of 6.6°±0.2°, 13.2°±0.2°, There is a characteristic peak at 17.5°±0.2°,
Figure PCTCN2021127741-appb-000008
Figure PCTCN2021127741-appb-000008
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23.2°±0.2°,24.2°±0.2°,14.7°±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 C is at one or two or three places in the 2θ value of 23.2°±0.2°, 24.2°±0.2°, and 14.7°±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23.2°±0.2°,24.2°±0.2°,14.7°±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 23.2°±0.2°, 24.2°±0.2°, and 14.7°±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18.9°±0.2°,21.9°±0.2°,7.2°±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 18.9°±0.2°, 21.9°±0.2°, and 7.2°±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18.9°±0.2°,21.9°±0.2°,7.2°±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 18.9°±0.2°, 21.9°±0.2°, and 7.2°±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6.6°±0.2°,13.2°±0.2°,17.5°±0.2°,23.2°±0.2°,24.2°±0.2°,14.7°±0.2°,18.9°±0.2°,21.9°±0.2°,7.2°±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 6.6°±0.2°, 13.2°±0.2°, 17.5°±0.2°, 23.2°±0.2°, 24.2°± 0.2°, 14.7°±0.2°, 18.9°±0.2°, 21.9°±0.2°, 7.2°±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6.6°±0.2°,13.2°±0.2°,17.5°±0.2°,23.2°±0.2°,24.2°±0.2°,14.7°±0.2°,18.9°±0.2°,21.9°±0.2°,7.2°±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 6.6°±0.2°, 13.2°±0.2°, 17.5°±0.2°, 23.2°±0.2°, 24.2°± There are characteristic peaks at 0.2°, 14.7°±0.2°, 18.9°±0.2°, 21.9°±0.2°, and 7.2°±0.2°.
在本发明的一个实施方式中，晶型C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 Form C is shown in FIG. 1 .
所述晶型C的制备方法，其特征包括：The preparation method of described crystal form C is characterized by comprising:
(1)将式(I)化合物溶解于醇类溶剂中，20℃至30℃挥发，固体析出，得到晶型C。(1) The compound of formula (I) is dissolved in an alcohol solvent, volatilized at 20°C to 30°C, and a solid is precipitated to obtain crystal form C.
在本发明的一个实施方式中，所述醇类溶剂包括甲醇、乙醇、异丙醇。In one embodiment of the present invention, the alcoholic solvent includes methanol, ethanol, and isopropanol.
(2)将式(I)化合物溶解于杂氮类溶剂中，将溶液快速加入至水中，固体析出，即得晶型C。(2) Dissolving the compound of formula (I) in an hetero-nitrogen solvent, adding the solution to water rapidly, and precipitation of a solid, crystalline form C is obtained.
在本发明的一个实施方式中，所述杂氮类溶剂为二甲基亚砜。In one embodiment of the present invention, the hetero-nitrogen-based solvent is dimethyl sulfoxide.
式(I)所示化合物(S)-4-(3-(丁炔-2-基酰胺)哌啶-1-基)-5-氟-2,3-二甲基-1H-吲哚-7-甲酰胺的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7.1°±0.2°,14.3°±0.2°,8.3°±0.2°处有特征峰，The compound represented by formula (I) (S)-4-(3-(butyn-2-ylamide)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole- The A-type crystal of 7-formamide, that is, the crystal form A, is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction of the crystal form A has a 2θ value of 7.1°±0.2°, 14.3°±0.2°, There is a characteristic peak at 8.3°±0.2°,
Figure PCTCN2021127741-appb-000009
Figure PCTCN2021127741-appb-000009
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11.4°±0.2°,16.6°±0.2°,18.4°±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 A is at one or two or three places in the 2θ value of 11.4°±0.2°, 16.6°±0.2°, 18.4°±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11.4°±0.2°,16.6°±0.2°,18.4°±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 11.4°±0.2°, 16.6°±0.2°, and 18.4°±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7.1°±0.2°,14.3°±0.2°,8.3°±0.2°,11.4°±0.2°,16.6°±0.2°,18.4°±0.2°中的任意4处、或5处、或6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 7.1°±0.2°, 14.3°±0.2°, 8.3°±0.2°, 11.4°±0.2°, 16.6°± 0.2°, 18.4°±0.2° any 4 places, or 5 places, or 6 places have 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7.1°±0.2°,14.3°±0.2°,8.3°±0.2°,11.4°±0.2°,16.6°±0.2°,18.4°±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 7.1°±0.2°, 14.3°±0.2°, 8.3°±0.2°, 11.4°±0.2°, 16.6°± There are characteristic peaks at 0.2° and 18.4°±0.2°.
在本发明的一个实施方式中，晶型A的X射线粉末衍射图如图2所示。In one embodiment of the present invention, the X-ray powder diffraction pattern of Form A is shown in FIG. 2 .
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)式(I)化合物溶解于有机溶剂中，将溶液加至装有高聚物的玻璃瓶中挥发，固体析出，即得晶型A。所述有机溶剂选自醇类、酮类、醚类、卤代烃类。(1) The compound of formula (I) is dissolved in an organic solvent, the solution is added to a glass bottle containing a high polymer to volatilize, and a solid is precipitated to obtain crystal form A. The organic solvent is selected from alcohols, ketones, ethers, halogenated hydrocarbons.
在本发明的一个实施方式中，所述高聚物选自聚乙烯吡咯烷酮、聚乙烯醇、聚氯乙烯、聚醋酸乙烯酯、羟丙基甲基纤维素、甲基纤维素、聚己酸内酯、聚乙二醇、聚甲基丙烯酸甲酯、海藻酸钠或羟乙基纤维素中的至少一种。In one embodiment of the present invention, the high polymer is selected from the group consisting of polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, hydroxypropyl methylcellulose, methylcellulose, and polycaproic acid. At least one of ester, polyethylene glycol, polymethyl methacrylate, sodium alginate or hydroxyethyl cellulose.
在本发明的一个实施方式中，所述高聚物的质量为式(I)化合物质量的0.5％～15％。In one embodiment of the present invention, the mass of the high polymer is 0.5% to 15% of the mass of the compound of formula (I).
在本发明的一个实施方式中，所述醇类为乙醇，所述酮类为丙酮；所述醚类为四氢呋喃，所述卤代烃类为二氯甲烷、二溴甲烷、氯仿。In one embodiment of the present invention, the alcohols are ethanol, the ketones are acetone; the ethers are tetrahydrofuran, and the halogenated hydrocarbons are dichloromethane, dibromomethane, and chloroform.
在本发明的一个实施方式中，所述溶解与析出温度为20℃到30℃。In one embodiment of the present invention, the dissolution and precipitation temperature is 20°C to 30°C.
(2)将式(I)化合物溶解于正溶剂中，将澄清溶液置于反溶剂氛围下进行气液渗透一段时间，析出固体，即得晶型A。所述正溶剂包括醇类、酮类、环醚类、酯类，所述反溶剂包括纯水、直链醚类、烷烃类。(2) Dissolving the compound of formula (I) in a positive solvent, placing the clear solution in an anti-solvent atmosphere for a period of time to carry out gas-liquid permeation, and precipitating a solid to obtain crystal form A. The positive solvent includes alcohols, ketones, cyclic ethers, and esters, and the anti-solvent includes pure water, linear ethers, and alkanes.
在本发明的一个实施方式中，所述溶解与析出温度为20℃至30℃。In one embodiment of the present invention, the dissolution and precipitation temperature is 20°C to 30°C.
在本发明的一个实施方式中，所述正溶剂中，醇类包括乙醇、甲醇，酮类为丙酮，环醚类包括1,4-二氧六环、四氢呋喃，酯类为乙酸异丙酯。In one embodiment of the present invention, in the positive solvent, the alcohols include ethanol and methanol, the ketones are acetone, the cyclic ethers include 1,4-dioxane and tetrahydrofuran, and the esters are isopropyl acetate.
在本发明的一个实施方式中，所述反溶剂中，直链醚类包括甲基叔丁基醚、环戊基甲醚，烷烃类为正庚烷、正己烷、正戊烷。In one embodiment of the present invention, in the anti-solvent, the linear ethers include methyl tert-butyl ether and cyclopentyl methyl ether, and the alkanes are n-heptane, n-hexane, and n-pentane.
在本发明的一个实施方式中，所述渗透时间为1至4周，例如2周。In one embodiment of the invention, the penetration time is 1 to 4 weeks, eg 2 weeks.
(3)将式(I)化合物溶解于有机溶剂中，将其挥发，得到晶型A。(3) Dissolving the compound of formula (I) in an organic solvent and volatilizing it to obtain crystal form A.
在本发明的一个实施方式中，所述有机溶剂包括醇类、酮类、醚类、酯类、卤代烃类、芳香烃、烷烃类及其混合物。In one embodiment of the present invention, the organic solvent includes alcohols, ketones, ethers, esters, halogenated hydrocarbons, aromatic hydrocarbons, alkanes and mixtures thereof.
在本发明的一个实施方式中，所述醇类为乙醇、异丙醇、甲醇，所述酮类为丙酮，所述醚类为2-甲基四氢呋喃、四氢呋喃、1,4-二氧六环、甲基叔丁基醚、环戊基甲醚，所述酯类为乙酸乙酯，所述卤代烃类为氯仿、二氯甲烷，所述芳香烃为甲苯，所述烷烃类为正庚烷。In one embodiment of the present invention, the alcohols are ethanol, isopropanol, methanol, the ketones are acetone, and the ethers are 2-methyltetrahydrofuran, tetrahydrofuran, 1,4-dioxane , methyl tert-butyl ether, cyclopentyl methyl ether, the esters are ethyl acetate, the halogenated hydrocarbons are chloroform, methylene chloride, the aromatic hydrocarbons are toluene, and the alkanes are n-heptyl alkyl.
(4)将式(I)化合物溶解于正溶剂中，过滤后向其中边搅拌边逐滴加入反溶剂，析出固体，即得晶型A。其中，所述正溶剂包括醇类、酮类、环醚类、酯类。所述反溶剂包括醚类、芳烃类、烷烃类。(4) Dissolving the compound of formula (I) in a positive solvent, after filtration, adding an anti-solvent dropwise to it while stirring, and precipitating a solid to obtain crystal form A. Wherein, the positive solvent includes alcohols, ketones, cyclic ethers, and esters. The anti-solvents include ethers, aromatic hydrocarbons, and alkanes.
在本发明的一个实施方式中，所述正溶剂中，醇类为乙醇，酮类为丙酮，环醚类包括四氢呋喃、2-甲基四氢呋喃，酯类为乙酸乙酯，卤代烃类为氯仿。In one embodiment of the present invention, in the positive solvent, alcohols are ethanol, ketones are acetone, cyclic ethers include tetrahydrofuran and 2-methyltetrahydrofuran, esters are ethyl acetate, and halogenated hydrocarbons are chloroform .
在本发明的一个实施方式中，所述反溶剂中，醚类为甲基叔丁基醚，芳烃类为甲苯，烷烃类为正庚烷。In one embodiment of the present invention, in the anti-solvent, the ethers are methyl tert-butyl ether, the aromatic hydrocarbons are toluene, and the alkanes are n-heptane.
在本发明的一个实施方式中，所述溶解、添加、搅拌温度为5℃到50℃，优选20℃到30℃。In one embodiment of the present invention, the temperature of dissolving, adding and stirring is 5°C to 50°C, preferably 20°C to 30°C.
(5)将式(I)化合物溶解于正溶剂中，将其快速加入至搅拌的反溶剂中，析出固体即得晶型A。其中所述正溶剂包括醇类、酯类，所述反溶剂为烷烃类。(5) Dissolving the compound of formula (I) in a positive solvent, quickly adding it to a stirring anti-solvent, and precipitating a solid to obtain crystal form A. The positive solvent includes alcohols and esters, and the anti-solvent is alkane.
在本发明的一个实施方式中，所述醇类为异丙醇，所述酯类为乙酸异丙酯。In one embodiment of the present invention, the alcohol is isopropanol, and the ester is isopropyl acetate.
在本发明的一个实施方式中，所述烷烃类为正庚烷。In one embodiment of the present invention, the alkanes are n-heptane.
在本发明的一个实施方式中，所述溶解、添加、搅拌温度为5℃到50℃，优选20℃到30℃。In one embodiment of the present invention, the temperature of dissolving, adding and stirring is 5°C to 50°C, preferably 20°C to 30°C.
式(I)所示化合物(S)-4-(3-(丁炔-2-基酰胺)哌啶-1-基)-5-氟-2,3-二甲基-1H-吲哚-7-甲酰胺的Y型晶体、即晶型Y，其特征在于，使用Cu-Kα辐射，所述晶型Y的X射线粉末衍射在2θ值为14.0°±0.2°,7.0°±0.2°,17.5°±0.2°处有特征峰，The compound represented by formula (I) (S)-4-(3-(butyn-2-ylamide)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole- The Y-type crystal of 7-formamide, that is, the crystal form Y, is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction of the crystal form Y has a 2θ value of 14.0°±0.2°, 7.0°±0.2°, There is a characteristic peak at 17.5°±0.2°,
Figure PCTCN2021127741-appb-000010
Figure PCTCN2021127741-appb-000010
在本发明的一个实施方式中，所述晶型Y的X射线粉末衍射在2θ值为24.6°±0.2°,24.0°±0.2°,21.7°±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 Y is at one or two or three locations in the 2θ value of 24.6°±0.2°, 24.0°±0.2°, and 21.7°±0.2° There are characteristic peaks.
在本发明的一个实施方式中，所述晶型Y的X射线粉末衍射在2θ值为24.6°±0.2°,24.0°±0.2°,21.7°±0.2°处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form Y has characteristic peaks at 2θ values of 24.6°±0.2°, 24.0°±0.2°, and 21.7°±0.2°.
在本发明的一个实施方式中，所述晶型Y的X射线粉末衍射在2θ值为27.2°±0.2°,21.0°±0.2°,22.5°±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 Y is at one or two or three locations in the 2θ value of 27.2°±0.2°, 21.0°±0.2°, and 22.5°±0.2° There are characteristic peaks.
在本发明的一个实施方式中，所述晶型Y的X射线粉末衍射在2θ值为27.2°±0.2°,21.0°±0.2°,25.5°±0.2°处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form Y has characteristic peaks at 2θ values of 27.2°±0.2°, 21.0°±0.2°, and 25.5°±0.2°.
在本发明的一个实施方式中，所述晶型Y的X射线粉末衍射在2θ值为14.0°±0.2°,7.0°±0.2°,17.5°±0.2°,24.6°±0.2°,24.0°±0.2°,21.7°±0.2°,27.2°±0.2°,21.0°±0.2°,22.5°±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 Y has 2θ values of 14.0°±0.2°, 7.0°±0.2°, 17.5°±0.2°, 24.6°±0.2°, 24.0°± 0.2°, 21.7°±0.2°, 27.2°±0.2°, 21.0°±0.2°, 22.5°±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Y的X射线粉末衍射在2θ值为14.0°±0.2°,7.0°±0.2°,17.5°±0.2°,24.6°±0.2°,24.0°±0.2°,21.7°±0.2°,27.2°±0.2°,21.0°±0.2°,22.5°±0.2°处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form Y has 2θ values of 14.0°±0.2°, 7.0°±0.2°, 17.5°±0.2°, 24.6°±0.2°, 24.0°± There are characteristic peaks at 0.2°, 21.7°±0.2°, 27.2°±0.2°, 21.0°±0.2°, and 22.5°±0.2°.
在本发明的一个实施方式中，晶型Y的X射线粉末衍射图如图3所示。In one embodiment of the present invention, the X-ray powder diffraction pattern of the crystal form Y is shown in FIG. 3 .
所述晶型Y的制备方法，其特征在于，The preparation method of described crystal form Y is characterized in that,
(1)在晶型A固体中，加入醇类溶剂，使其得到悬浊液，将其在20℃至30℃条件下超声30分钟，分离固体得到晶型Y。(1) Add an alcohol solvent to the solid of crystal form A to obtain a suspension, which is sonicated at 20°C to 30°C for 30 minutes to separate the solid to obtain crystal form Y.
在本发明的一个实施方式中，所述醇类溶剂为异丙醇。In one embodiment of the present invention, the alcoholic solvent is isopropanol.
(2)在晶型A固体中，加入醇类溶剂，使其得到悬浊液，将其在20℃至30℃条件下悬浮搅拌1～3天，分离固体得到晶型Y。(2) Add an alcohol solvent to the solid of crystal form A to obtain a suspension, which is suspended and stirred at 20°C to 30°C for 1 to 3 days, and the solid is separated to obtain crystal form Y.
在本发明的一个实施方式中，所述醇类溶剂为异丙醇。In one embodiment of the present invention, the alcoholic solvent is isopropanol.
式(I)所示化合物(S)-4-(3-(丁炔-2-基酰胺)哌啶-1-基)-5-氟-2,3-二甲基-1H-吲哚-7-甲酰胺的V型晶体、即晶型V，其特征在于，使用Cu-Kα辐射，所述晶型V的X射线粉末衍射在2θ值为6.5°±0.2°,15.0°±0.2°,13.0°±0.2°处有特征峰，The compound represented by formula (I) (S)-4-(3-(butyn-2-ylamide)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole- The V-type crystal of 7-formamide, that is, the crystal form V, is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction of the crystal form V has a 2θ value of 6.5°±0.2°, 15.0°±0.2°, There is a characteristic peak at 13.0°±0.2°,
Figure PCTCN2021127741-appb-000011
Figure PCTCN2021127741-appb-000011
在本发明的一个实施方式中，所述晶型V的X射线粉末衍射在2θ值为16.3°±0.2°,24.4°±0.2°,17.1°±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 V has one or two or three 2θ values of 16.3°±0.2°, 24.4°±0.2°, 17.1°±0.2° There are characteristic peaks.
在本发明的一个实施方式中，所述晶型V的X射线粉末衍射在2θ值为16.3°±0.2°,24.4°±0.2°,17.1°±0.2°处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form V has characteristic peaks at 2θ values of 16.3°±0.2°, 24.4°±0.2°, and 17.1°±0.2°.
在本发明的一个实施方式中，所述晶型V的X射线粉末衍射在2θ值为23.6°±0.2°,28.8°±0.2°,22.9°±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 V has one or two or three 2θ values of 23.6°±0.2°, 28.8°±0.2°, and 22.9°±0.2°. There are characteristic peaks.
在本发明的一个实施方式中，所述晶型V的X射线粉末衍射在2θ值为23.6°±0.2°,28.8°±0.2°,22.9°±0.2°处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form V has characteristic peaks at 2θ values of 23.6°±0.2°, 28.8°±0.2°, and 22.9°±0.2°.
在本发明的一个实施方式中，所述晶型V的X射线粉末衍射在2θ值为6.5°±0.2°,15.0°±0.2°,13.0°±0.2°,16.3°±0.2°,24.4°±0.2°,17.1°±0.2°,23.6°±0.2°,28.8°±0.2°,22.9°±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 V has 2θ values of 6.5°±0.2°, 15.0°±0.2°, 13.0°±0.2°, 16.3°±0.2°, 24.4°± 0.2°, 17.1°±0.2°, 23.6°±0.2°, 28.8°±0.2°, 22.9°±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V的X射线粉末衍射在2θ值为6.5°±0.2°,15.0°±0.2°,13.0°±0.2°,16.3°±0.2°,24.4°±0.2°,17.1°±0.2°,23.6°±0.2°,28.8°±0.2°,22.9°±0.2°处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form V has 2θ values of 6.5°±0.2°, 15.0°±0.2°, 13.0°±0.2°, 16.3°±0.2°, 24.4°± There are characteristic peaks at 0.2°, 17.1°±0.2°, 23.6°±0.2°, 28.8°±0.2°, and 22.9°±0.2°.
在本发明的一个实施方式中，所述晶型V的X射线粉末衍射图如图4所示。In one embodiment of the present invention, the X-ray powder diffraction pattern of the crystal form V is shown in FIG. 4 .
所述晶型V的制备方法，其特征在于，The preparation method of described crystal form V, is characterized in that,
(1)将式(I)化合物溶解于环醚类溶剂中，将溶液挥发，固体析出，即得晶型V。(1) The compound of formula (I) is dissolved in a cyclic ether solvent, the solution is volatilized, and the solid is precipitated to obtain crystal form V.
在本发明的一个实施方式中，所述环醚类溶剂为四氢呋喃。In one embodiment of the present invention, the cyclic ether solvent is tetrahydrofuran.
(2)将式(I)化合物溶解于醇类溶剂中，向溶液中加入高聚物，将溶液挥发，析出固体，即得晶型V。(2) Dissolving the compound of formula (I) in an alcohol solvent, adding a high polymer to the solution, volatilizing the solution, and precipitating a solid, the crystal form V is obtained.
在本发明的一个实施方式中，所述高聚物的质量为式(I)质量的0.5％～15％。In one embodiment of the present invention, the mass of the high polymer is 0.5% to 15% of the mass of the formula (I).
在本发明的一个实施方式中，所述高聚物选自聚乙烯吡咯烷酮、聚乙烯醇、聚氯乙烯、聚醋酸乙烯酯、羟丙基甲基纤维素或甲基纤维素中的至少一种。In one embodiment of the present invention, the high polymer is selected from at least one of polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, hydroxypropyl methylcellulose or methylcellulose .
在本发明的一个实施方式中，所述析出温度为20℃到30℃。In one embodiment of the present invention, the precipitation temperature is 20°C to 30°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.
(3)将式(I)化合物溶解于烷基腈类溶剂中，高温条件下达到溶解平衡，将溶液降温至有固体析出，得到晶型V。(3) Dissolving the compound of formula (I) in an alkyl nitrile solvent, reaching a dissolution equilibrium under high temperature conditions, cooling the solution until a solid is precipitated to obtain crystal form V.
在本发明的一个实施方式中，所述高温为40℃到60℃，例如为50℃。In one embodiment of the present invention, the high temperature is 40°C to 60°C, for example 50°C.
在本发明的一个实施方式中，析晶温度为-20℃到5℃。In one embodiment of the present invention, the crystallization temperature is -20°C to 5°C.
在本发明的一个实施方式中，降温速率为0.05℃/分钟到0.5℃/分钟，例如0.1℃/分钟。In one embodiment of the present invention, the cooling rate is 0.05°C/min to 0.5°C/min, eg 0.1°C/min.
在本发明的一个实施方式中，所述降温为快速降温。In one embodiment of the present invention, the cooling is rapid cooling.
在本发明的一个实施方式中，所述烷基腈类溶剂为乙腈。In one embodiment of the present invention, the alkyl nitrile solvent is acetonitrile.
式(I)所示化合物(S)-4-(3-(丁炔-2-基酰胺)哌啶-1-基)-5-氟-2,3-二甲基-1H-吲哚-7-甲酰胺的AE型晶体、即晶型AE，其特征在于，使用Cu-Kα辐射，所述晶型AE的X射线粉末衍射在2θ值为6.4°±0.2°,15.5°±0.2°,12.8°±0.2°处有特征峰，The compound represented by formula (I) (S)-4-(3-(butyn-2-ylamide)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole- The AE-type crystal of 7-formamide, that is, the crystalline form AE, is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction of the crystalline form AE has a 2θ value of 6.4°±0.2°, 15.5°±0.2°, There is a characteristic peak at 12.8°±0.2°,
Figure PCTCN2021127741-appb-000012
Figure PCTCN2021127741-appb-000012
在本发明的一个实施方式中，所述晶型AE的X射线粉末衍射在2θ值为16.0°±0.2°,20.0°±0.2°,21.0°±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 AE has one or two or three 2θ values of 16.0°±0.2°, 20.0°±0.2°, and 21.0°±0.2° There are characteristic peaks.
在本发明的一个实施方式中，所述晶型AE的X射线粉末衍射在2θ值为16.0°±0.2°,20.0°±0.2°,21.0°±0.2°处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form AE has characteristic peaks at 2θ values of 16.0°±0.2°, 20.0°±0.2°, and 21.0°±0.2°.
在本发明的一个实施方式中，所述晶型AE的X射线粉末衍射在2θ值为24.2°±0.2°,21.4°±0.2°,16.4°±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 AE has one or two or three 2θ values of 24.2°±0.2°, 21.4°±0.2°, and 16.4°±0.2° There are characteristic peaks.
在本发明的一个实施方式中，所述晶型AE的X射线粉末衍射在2θ值为24.2°±0.2°,21.4°±0.2°,16.4°±0.2°处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form AE has characteristic peaks at 2θ values of 24.2°±0.2°, 21.4°±0.2°, and 16.4°±0.2°.
在本发明的一个实施方式中，所述晶型AE的X射线粉末衍射在2θ值为6.4°±0.2°,15.5°±0.2°,12.8°±0.2°,16.0°±0.2°,20.0°±0.2°,21.0°±0.2°,24.2°±0.2°,21.4°±0.2°,16.4°±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 crystalline form AE has 2θ values of 6.4°±0.2°, 15.5°±0.2°, 12.8°±0.2°, 16.0°±0.2°, 20.0°± 0.2°, 21.0°±0.2°, 24.2°±0.2°, 21.4°±0.2°, 16.4°±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AE的X射线粉末衍射在2θ值为6.4°±0.2°,15.5°±0.2°,12.8°±0.2°,16.0°±0.2°,20.0°±0.2°,21.0°±0.2°,24.2°±0.2°,21.4°±0.2°,16.4°±0.2°处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystalline form AE has 2θ values of 6.4°±0.2°, 15.5°±0.2°, 12.8°±0.2°, 16.0°±0.2°, 20.0°± There are characteristic peaks at 0.2°, 21.0°±0.2°, 24.2°±0.2°, 21.4°±0.2°, and 16.4°±0.2°.
在本发明的一个实施方式中，晶型AE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 AE is shown in FIG. 5 .
所述晶型AE的制备方法，其特征包括：The preparation method of described crystal form AE is characterized by comprising:
(1)将式(I)化合物溶解于杂氮类溶剂中，将溶液快速加入至纯水中，固体析出，即得晶型AE。(1) Dissolving the compound of formula (I) in an hetero-nitrogen solvent, quickly adding the solution to pure water, the solid is precipitated to obtain crystal form AE.
在本发明的一个实施方式中，所述杂氮类溶剂为N,N-二甲基乙酰胺。In one embodiment of the present invention, the hetero-nitrogen solvent is N,N-dimethylacetamide.
(2)将式(I)化合物溶解于醇类溶剂中，向溶液中加入高聚物，20℃至30℃下挥发，固体析出，得到晶型AE。(2) Dissolving the compound of formula (I) in an alcohol solvent, adding a high polymer to the solution, volatilizing at 20°C to 30°C, and precipitation of a solid to obtain crystal form AE.
在本发明的一个实施方式中，所述高聚物的质量为式(I)质量的0.5％～5％。In one embodiment of the present invention, the mass of the high polymer is 0.5% to 5% of the mass of the formula (I).
在本发明的一个实施方式中，所述高聚物选自聚乙烯吡咯烷酮、聚乙烯醇、聚氯乙烯、 聚醋酸乙烯酯、羟丙基甲基纤维素或甲基纤维素中的至少一种。In one embodiment of the present invention, the high polymer is selected from at least one of polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, hydroxypropyl methylcellulose or methylcellulose .
在本发明的一个实施方式中，所述醇类溶剂为正丙醇。In one embodiment of the present invention, the alcoholic solvent is n-propanol.
(3)将式(I)化合物的溶解于醇类溶剂中，将溶液降温，析出固体，即得到晶型AE。(3) Dissolving the compound of formula (I) in an alcohol solvent, cooling the solution, and precipitating a solid, the crystal form AE is obtained.
在本发明的一个实施方式中，所述溶解条件为40℃至60℃，例如50℃。In one embodiment of the present invention, the dissolution conditions are 40°C to 60°C, for example 50°C.
在本发明的一个实施方式中，所述析晶温度为-20℃至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，所述降温为快速降温。In one embodiment of the present invention, the cooling is rapid cooling.
在本发明的一个实施方式中，所述醇类溶剂为正丙醇。In one embodiment of the present invention, the alcoholic solvent is n-propanol.
(4)将式(I)化合物的溶解于醇类溶剂中，将溶液降温至-20℃，静置约1～3天未有固体析出，转移至20℃至30℃下挥发，固体析出，即得晶型AE。(4) dissolving the compound of formula (I) in an alcoholic solvent, cooling the solution to -20°C, standing for about 1 to 3 days without solid precipitation, transferring to 20°C to 30°C to volatilize, solid precipitation, That is, the crystal form AE is obtained.
在本发明的一个实施方式中，所述溶解条件为40℃至60℃，例如50℃。In one embodiment of the present invention, the dissolution conditions are 40°C to 60°C, for example 50°C.
在本发明的一个实施方式中，降温速率为0.05℃/分钟到0.5℃/分钟，例如0.1℃/分钟。In one embodiment of the present invention, the cooling rate is 0.05°C/min to 0.5°C/min, eg 0.1°C/min.
在本发明的一个实施方式中，所述醇类溶剂为正丙醇。In one embodiment of the present invention, the alcoholic solvent is n-propanol.
式(I)所示化合物(S)-4-(3-(丁炔-2-基酰胺)哌啶-1-基)-5-氟-2,3-二甲基-1H-吲哚-7-甲酰胺的AA型晶体、即晶型AA，其特征在于，使用Cu-Kα辐射，所述晶型AA的X射线粉末衍射在2θ值为11.7°±0.2°,16.1°±0.2°,16.7°±0.2°处有特征峰，The compound represented by formula (I) (S)-4-(3-(butyn-2-ylamide)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole- The AA-type crystal of 7-formamide, that is, the crystal form AA, is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction of the crystal form AA has a 2θ value of 11.7°±0.2°, 16.1°±0.2°, There is a characteristic peak at 16.7°±0.2°,
Figure PCTCN2021127741-appb-000013
Figure PCTCN2021127741-appb-000013
在本发明的一个实施方式中，所述晶型AA的X射线粉末衍射在2θ值为17.9°±0.2°,8.2°±0.2°,8.9°±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 AA has one or two or three 2θ values of 17.9°±0.2°, 8.2°±0.2°, and 8.9°±0.2°. There are characteristic peaks.
在本发明的一个实施方式中，所述晶型AA的X射线粉末衍射在2θ值为17.9°±0.2°,8.2°±0.2°,8.9°±0.2°处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form AA has characteristic peaks at 2θ values of 17.9°±0.2°, 8.2°±0.2°, and 8.9°±0.2°.
在本发明的一个实施方式中，所述晶型AA的X射线粉末衍射在2θ值为20.0°±0.2°,18.3°±0.2°,23.4°±0.2°处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form AA has characteristic peaks at 2θ values of 20.0°±0.2°, 18.3°±0.2°, and 23.4°±0.2°.
在本发明的一个实施方式中，所述晶型AA的X射线粉末衍射在2θ值为20.0°±0.2°,18.3°±0.2°,23.4°±0.2°处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form AA has characteristic peaks at 2θ values of 20.0°±0.2°, 18.3°±0.2°, and 23.4°±0.2°.
在本发明的一个实施方式中，所述晶型AA的X射线粉末衍射在2θ值为11.7°±0.2°,16.1°±0.2°,16.7°±0.2°,17.9°±0.2°,8.2°±0.2°,8.9°±0.2°,20.0°±0.2°,18.3°±0.2°,23.4°±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 AA has 2θ values of 11.7°±0.2°, 16.1°±0.2°, 16.7°±0.2°, 17.9°±0.2°, 8.2°± 0.2°, 8.9°±0.2°, 20.0°±0.2°, 18.3°±0.2°, 23.4°±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AA的X射线粉末衍射在2θ值为11.7°±0.2°,16.1°±0.2°,16.7°±0.2°,17.9°±0.2°,8.2°±0.2°,8.9°±0.2°,20.0°±0.2°,18.3°±0.2°,23.4°±0.2°处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form AA has 2θ values of 11.7°±0.2°, 16.1°±0.2°, 16.7°±0.2°, 17.9°±0.2°, 8.2°± There are characteristic peaks at 0.2°, 8.9°±0.2°, 20.0°±0.2°, 18.3°±0.2°, and 23.4°±0.2°.
在本发明的一个实施方式中，晶型AA的X射线粉末衍射图如图6所示。In one embodiment of the present invention, the X-ray powder diffraction pattern of crystal form AA is shown in FIG. 6 .
所述晶型AA的制备方法，其特征在于，The preparation method of the crystal form AA is characterized in that,
将式(I)化合物在高温下溶于醇类溶剂中，将溶液降温，析出固体，即得到晶型AA。The compound of formula (I) is dissolved in an alcoholic solvent at a high temperature, the solution is cooled down, and a solid is precipitated to obtain crystal form AA.
在本发明的一个实施方式中，所述溶解条件为40℃至60℃，例如50℃。In one embodiment of the present invention, the dissolution conditions are 40°C to 60°C, for example 50°C.
在本发明的一个实施方式中，所述析晶温度为-20℃至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，所述降温为快速降温。In one embodiment of the present invention, the cooling is rapid cooling.
在本发明的一个实施方式中，所述醇类溶剂为异丙醇。In one embodiment of the present invention, the alcoholic solvent is isopropanol.
根据本发明，作为原料的所述式(I)和/或其盐指其固体(晶体或无定形)、半固体、蜡或油形式。优选地，作为原料的化合物和/或其盐为固体粉末形式。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 formula (I) and/or its salts as raw materials refer to its solid (crystalline or amorphous), semi-solid, wax or oil form. Preferably, the compounds and/or their salts as raw materials are in the form of solid powders. 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 preferably 300-1000 rev/min, and the mechanical stirring is preferably 100-100 300 rpm.
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，XRPD图谱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“XRPD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 XRPD pattern are related to the preferred orientation of the crystals, and the peak intensities shown here are illustrative rather than absolute comparisons. In addition, the experimental error of the peak angle is usually 5% or less, and the error of these angles should also be taken into account, and an error of ±0.2° is usually 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 XRPD pattern" mentioned herein does not mean absolutely the same , the same peak position can differ by ±0.2° and the peak intensity allows some variability. 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C，晶型A，晶型Y，晶型V，晶型AE，晶型AA，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。In some embodiments, Form C, Form A, Form Y, Form V, Form AE, Form AA of the present invention are pure, single, and substantially not mixed 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.
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。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".
本发明提供的式(I)晶型C，晶型A，晶型Y，晶型V，晶型AE，晶型AA，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。The crystal form C, crystal form A, crystal form Y, crystal form V, crystal form AE, crystal form AA of the formula (I) provided by the present invention are in solubility, melting point, stability, dissolution, wettability, adhesion, fluidity There are advantages in at least one aspect of properties, bioavailability, processing performance, purification, preparation production, safety, etc., providing a new and better choice for the preparation of pharmaceutical preparations containing the compound of formula (I). Drug development is very important.
与现有技术相比，发明提供的式(I)化合物的新晶型，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BTK抑制剂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 new crystal form of the compound of formula (I) provided by the invention has the advantages of solubility, melting point, stability, dissolution, hygroscopicity, adhesion, fluidity, bioavailability, processability, purification, There are advantages in at least one aspect of preparation production, safety, etc., which provide a new and better choice for the preparation of pharmaceutical preparations of BTK inhibitors, and are of great significance for drug development.
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℃至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
UPLC：超高效液相色谱UPLC: Ultra High Performance Liquid Chromatography
1H NMR：液态氢谱核磁 1 H NMR: Liquid Hydrogen Spectroscopy
本发明所述的X射线粉末衍射图在PANalytacal(帕纳科)公司的Empyrean型及X’Pert3型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'Pert3 ray powder diffractometers of PANalytacal. 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
Kα1
Figure PCTCN2021127741-appb-000014
1.540598；Kα2
Figure PCTCN2021127741-appb-000015
1.544426 Kα1
Figure PCTCN2021127741-appb-000014
1.540598; Kα2
Figure PCTCN2021127741-appb-000015
1.544426
Kα2/Kα1强度比例：0.50Kα2/Kα1 intensity ratio: 0.50
电压：45仟伏特(kV)Voltage: 45 thousand volts (kV)
电流：40毫安培(mA)Current: 40 milliamps (mA)
扫描范围：自3.0至40.0度Scanning range: from 3.0 to 40.0 degrees
本发明所述的差示扫描量热分析曲线在TA公司的Q2000型及Discovery DSC 2500型差式扫描量热仪上采集。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 curve of the present invention is collected on the Q2000 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℃/minScan rate: 10°C/min
保护气体：氮气Shielding gas: nitrogen
本发明所述的热重分析曲线在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 curve 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℃/minScan rate: 10°C/min
保护气体：氮气Shielding gas: nitrogen
本发明中高效液相色谱(UPLC)数据采自于Waters H Class，所用检测器为二极管阵列检测器(PDA)。本发明所述的测试纯度和溶解度的UPLC方法参数如下：In the present invention, high performance liquid chromatography (UPLC) data is collected from Waters H Class, and the detector used is a diode array detector (PDA). The UPLC method parameters of test purity and solubility of the present invention are as follows:
1、色谱柱：Waters Xbridge C18,150×4.6mm,5μm1. Chromatographic column: Waters Xbridge C18, 150×4.6mm, 5μm
2、流动相：A：0.05％TFA水溶液2. Mobile phase: A: 0.05% TFA aqueous solution
B：0.05％TFA乙腈溶液B: 0.05% TFA in acetonitrile
洗脱梯度如下：The elution gradient is as follows:
Time(min)Time(min) ％B%B
0.00.0 5.05.0
3.03.0 40.040.0
3.53.5 90.090.0
3.83.8 90.090.0
3.93.9 5.05.0
5.05.0 5.05.0
3、流速：0.5mL/min3. Flow rate: 0.5mL/min
4、进样量：1μl4. Injection volume: 1μl
5、检测波长：254nm5. Detection wavelength: 254nm
6、柱温：30℃6. Column temperature: 30℃
7、稀释剂：Acetonitrile/H 2O 1:1 7. Thinner: Acetonitrile/H 2 O 1:1
本发明中离子色谱(IC)数据采自于ThermoFisher ICS-1100，本发明所述的测试氯离子含量的IC方法参数如下：In the present invention, ion chromatography (IC) data is collected from ThermoFisher ICS-1100, and the IC method parameters of the test chloride ion content of the present invention are as follows:
1、色谱柱：IonPac AS18Analytical Column(4×250mm)1. Chromatographic column: IonPac AS18Analytical Column (4×250mm)
2、流动相：25mM氢氧化钠水溶液2. Mobile phase: 25mM aqueous sodium hydroxide solution
3、流速：1.0mL/min3. Flow rate: 1.0mL/min
4、进样量：25μl4. Injection volume: 25μl
6、柱温：35℃6. Column temperature: 35℃
7、样品室温度：35℃7. Sample room temperature: 35℃
8、电流：80mA8. Current: 80mA
7、运行时间：7min7. Running time: 7min
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 Protective gas and flow: 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。The particle size distribution results described in the present invention were collected on Microtrac's Model S3500 laser particle size analyzer.
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：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 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30秒Ultrasound time: Ultrasound for 30 seconds
*：流速60％为65毫升/s的60％*: 60% of flow rate 60% of 65 ml/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 is collected on the Agilent 708DS type dissolution apparatus of Agilent Company. Described inherent dissolution test conditions are as follows:
溶出仪Dissolution Apparatus Agilent 708DSAgilent 708DS
方法method 浆法pulp method
介质medium pH 6.8磷酸盐缓冲液pH 6.8 Phosphate Buffer
介质体积medium volume 900毫升900ml
转速 Rotating speed 100转/分100 rpm
介质温度medium temperature 37℃37 ℃
取样点Sampling point 1,2,3,4,5,10,15,20,25,30分钟1,2,3,4,5,10,15,20,25,30 minutes
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US20160115126A1中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 US20160115126A1, but the starting crystal form is not a limitation for preparing the crystal form of the present invention.
实施例1～4：晶型C的制备(挥发法)Examples 1-4: Preparation of Crystal Form C (Volatilization Method)
实施例1：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，敞口置于预盛有4毫升乙醇的20毫升玻璃瓶中。封口后置于室温条件下气固渗透约12天，样品溶清，之后将样品转移至室温下敞口挥发，直至有固体析出，得到晶型C。其X射线粉末衍射数据如表1所示，衍射图如图1所示。TGA数据如图7所示，DSC数据如图8所示， 1H NMR数据如图9所示。 Example 1: At room temperature, 15.2 mg of the solid compound of formula (I) was weighed and placed in a 3 mL glass vial, and the open mouth was placed in a 20 mL glass vial prefilled with 4 mL of ethanol. After sealing, it was placed at room temperature for gas-solid permeation for about 12 days, and the sample was dissolved and clear, and then the sample was transferred to room temperature for volatilization until a solid was precipitated, and crystal form C was obtained. The X-ray powder diffraction data are shown in Table 1, and the diffraction pattern is shown in Figure 1. The TGA data is shown in FIG. 7 , the DSC data is shown in FIG. 8 , and the 1 H NMR data is shown in FIG. 9 .
表1Table 1
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
6.636.63 13.3413.34 100.00100.00
7.187.18 12.3212.32 5.935.93
9.439.43 9.379.37 4.464.46
9.949.94 8.898.89 2.502.50
13.2613.26 6.686.68 65.9865.98
13.5213.52 6.556.55 6.096.09
14.3514.35 6.176.17 6.016.01
14.5414.54 6.096.09 4.794.79
14.7914.79 5.995.99 8.008.00
16.0716.07 5.515.51 3.633.63
17.5917.59 5.045.04 9.779.77
18.0418.04 4.924.92 3.383.38
18.2418.24 4.864.86 3.233.23
18.9318.93 4.694.69 6.656.65
19.3619.36 4.594.59 3.553.55
19.9219.92 4.464.46 4.114.11
20.5120.51 4.334.33 3.803.80
20.7120.71 4.294.29 3.793.79
21.4621.46 4.144.14 3.993.99
21.9121.91 4.064.06 6.586.58
22.4522.45 3.963.96 3.273.27
23.2823.28 3.823.82 10.0210.02
24.2424.24 3.673.67 8.398.39
24.7624.76 3.603.60 2.562.56
26.1326.13 3.413.41 4.644.64
26.3926.39 3.383.38 4.114.11
27.1827.18 3.283.28 3.003.00
27.6027.60 3.233.23 2.382.38
30.0830.08 2.972.97 1.321.32
32.4132.41 2.762.76 0.700.70
36.5336.53 2.462.46 1.071.07
37.3037.30 2.412.41 1.451.45
实施例2：室温条件下，称取15.3毫克式(I)化合物固体置于3毫升的玻璃小瓶中，加入0.6毫升异丙醇以溶解固体，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，敞口置于通风橱室温挥发，析出固体，得到晶型C。其X射线粉末衍射数据如表2所示。Example 2: At room temperature, weigh 15.3 mg of the solid compound of formula (I) into a 3-mL glass vial, add 0.6 mL of isopropanol to dissolve the solid, and use a 0.45-micron pore size polytetrafluoroethylene filter to filter the sample. The solution was filtered into a new 3 ml glass vial, and the open mouth was placed in a fume hood to evaporate at room temperature, and a solid was precipitated to obtain crystal form C. Its X-ray powder diffraction data are shown in Table 2.
表2Table 2
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
3.273.27 27.0127.01 46.7146.71
6.576.57 13.4513.45 100.00100.00
7.147.14 12.3912.39 17.3017.30
8.468.46 10.4510.45 7.547.54
9.419.41 9.409.40 8.418.41
10.2510.25 8.638.63 11.6811.68
13.2113.21 6.706.70 96.4296.42
13.4613.46 6.586.58 20.0220.02
14.3114.31 6.196.19 19.3519.35
14.7414.74 6.016.01 24.3524.35
16.0216.02 5.535.53 12.3212.32
17.5317.53 5.065.06 16.5716.57
18.1318.13 4.894.89 6.416.41
18.8818.88 4.704.70 13.9913.99
19.4619.46 4.564.56 10.3610.36
20.6720.67 4.304.30 8.078.07
21.8521.85 4.074.07 11.5211.52
23.2923.29 3.823.82 13.6413.64
24.1924.19 3.683.68 14.9214.92
26.1126.11 3.413.41 11.1511.15
实施例3～4：室温条件下，将适量式(I)化合物固体置于1.5毫升的玻璃小瓶中，加入相应体积的溶剂在50℃条件下以溶解固体，使用0.45微米孔径的聚四氟乙烯滤膜将样品溶液过滤，之后迅速置于-20℃静置，样品澄清，转至室温挥发，直至析出固体，得到晶型C。本实施例中所涉详细试验条件如表3所示。Examples 3-4: Under room temperature conditions, place an appropriate amount of the solid of the compound of formula (I) in a 1.5 ml glass vial, add a corresponding volume of solvent at 50°C to dissolve the solid, and use a 0.45-micron pore size polytetrafluoroethylene. The sample solution was filtered through a filter membrane, and then quickly placed at -20 °C to stand, the sample was clarified, and evaporated at room temperature until a solid was precipitated, and crystal form C was obtained. The detailed test conditions involved in this example are shown in Table 3.
表3table 3
实施例Example 固体质量(毫克)Solid mass (mg) 溶剂solvent 体积(毫升)Volume (ml)
33 15.315.3 甲醇methanol 0.40.4
44 15.115.1 乙醇Ethanol 0.40.4
实施例5：晶型C的制备(反反溶剂添加法)Example 5: Preparation of Form C (Anti-Anti-Solvent Addition Method)
室温条件下，将适量式(I)化合物固体置于5毫升的玻璃小瓶中，加入0.6毫升二甲基亚砜溶解固体，预先将装有4毫升纯水的20毫升玻璃瓶置于5℃条件下预冷，采用0.45微米聚四氟乙烯膜过滤含有化合物的溶液，得到澄清溶液，将其过滤至预冷的纯水中。固体析 出，得到晶型C。At room temperature, place an appropriate amount of the solid compound of formula (I) into a 5-mL glass vial, add 0.6 mL of dimethyl sulfoxide to dissolve the solid, and place a 20-mL glass vial containing 4 mL of pure water at 5°C in advance. Under pre-cooling, the solution containing the compound was filtered through a 0.45-micron polytetrafluoroethylene membrane to obtain a clear solution, which was filtered into pre-cooled pure water. A solid precipitated to obtain Form C.
实施例6～11：晶型A的制备(高聚物诱导法)Examples 6-11: Preparation of crystal form A (polymer induction method)
室温条件下，称取适量式(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另一3毫升玻璃小瓶中，加入约2毫克混合高聚物以诱导式(I)化合物结晶。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挥发，直至有固体析出，得到晶型A。At room temperature, an appropriate amount of the solid compound of formula (I) was weighed into a 3 ml glass vial, and a corresponding volume of solvent was added to dissolve the solid. The sample solution was filtered using a 0.45 micron pore size polytetrafluoroethylene filter into another 3 ml glass vial and about 2 mg of the mixed polymer was added to induce crystallization of the compound of formula (I). After sealing with parafilm, 4 pinholes were pricked on it, and then volatilized at room temperature until a solid was precipitated, and crystal form A was obtained.
本实施例中所涉详细试验条件如表4所示，实施例11样品的X射线粉末衍射数据如表5所示，衍射图如图2所示。TGA数据如图10所示，DSC数据如图11所示， 1H NMR数据如图12所示。 The detailed test conditions involved in this example are shown in Table 4, the X-ray powder diffraction data of the sample of Example 11 is shown in Table 5, and the diffraction pattern is shown in FIG. 2 . The TGA data is shown in FIG. 10 , the DSC data is shown in FIG. 11 , and the 1 H NMR data is shown in FIG. 12 .
表4Table 4
Figure PCTCN2021127741-appb-000016
Figure PCTCN2021127741-appb-000016
混合高聚物A：聚乙烯吡咯烷酮，聚乙烯醇，聚氯乙烯，聚醋酸乙烯酯，羟丙基甲基纤维素和甲基纤维素(等质量混合)Hybrid Polymer A: Polyvinylpyrrolidone, Polyvinyl Alcohol, Polyvinyl Chloride, Polyvinyl Acetate, Hydroxypropyl Methyl Cellulose and Methyl Cellulose (mixed in equal mass)
混合高聚物B：聚己酸内酯，聚乙二醇，聚甲基丙烯酸甲酯，海藻酸钠和羟乙基纤维素(等质量混合)Mixed polymer B: polycaprolactone, polyethylene glycol, polymethyl methacrylate, sodium alginate and hydroxyethyl cellulose (mixed in equal mass)
表5table 5
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
7.097.09 12.4712.47 100.00100.00
8.268.26 10.7010.70 53.1753.17
8.428.42 10.5110.51 48.1748.17
9.149.14 9.679.67 18.2718.27
10.5710.57 8.378.37 10.2710.27
11.4411.44 7.737.73 17.2317.23
12.9912.99 6.826.82 6.936.93
14.2714.27 6.206.20 69.3269.32
16.6416.64 5.335.33 5.775.77
18.3818.38 4.834.83 12.7412.74
19.7919.79 4.494.49 15.2815.28
21.4821.48 4.144.14 21.1721.17
21.8921.89 4.064.06 19.6919.69
23.8023.80 3.743.74 4.264.26
25.5325.53 3.493.49 15.5615.56
29.2829.28 3.053.05 2.472.47
实施例12-～18：晶型A的制备(气液渗透法)Examples 12-18: Preparation of Crystal Form A (Gas-Liquid Permeation Method)
室温条件下，将适量式(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以溶解固体，采用0.45微米聚四氟乙烯膜过滤得到澄清溶液，之后将该溶液置于盛有4毫升不同溶剂气氛中，进行气液渗透，1～4周后，固体析出，得到晶型A。本实施例中所涉详细试验条件如表6所示，实施例12样品的X射线粉末衍射数据如表7所示。Under room temperature conditions, an appropriate amount of the solid compound of formula (I) was placed in a 3 ml glass vial, a corresponding volume of solvent was added to dissolve the solid, a 0.45-micron polytetrafluoroethylene membrane was used to filter to obtain a clear solution, and then the solution was placed in a In an atmosphere of 4 ml of different solvents, gas-liquid infiltration was performed, and after 1 to 4 weeks, the solid was precipitated to obtain crystal form A. The detailed test conditions involved in this example are shown in Table 6, and the X-ray powder diffraction data of the sample of Example 12 is shown in Table 7.
表6Table 6
Figure PCTCN2021127741-appb-000017
Figure PCTCN2021127741-appb-000017
表7Table 7
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
5.395.39 16.3916.39 0.410.41
7.097.09 12.4712.47 100.00100.00
8.258.25 10.7210.72 12.3712.37
9.089.08 9.749.74 0.760.76
11.5311.53 7.677.67 1.651.65
12.7812.78 6.936.93 0.480.48
14.0714.07 6.306.30 3.253.25
14.3814.38 6.166.16 43.8443.84
15.0015.00 5.905.90 1.891.89
16.4116.41 5.405.40 0.560.56
16.7016.70 5.315.31 0.340.34
17.6817.68 5.025.02 0.750.75
18.1118.11 4.904.90 0.590.59
18.5618.56 4.784.78 1.991.99
19.1619.16 4.634.63 0.530.53
19.9719.97 4.454.45 1.091.09
20.6820.68 4.294.29 0.880.88
21.2821.28 4.174.17 1.181.18
21.7421.74 4.094.09 5.135.13
22.1822.18 4.014.01 4.124.12
23.3423.34 3.813.81 0.530.53
24.0824.08 3.703.70 1.041.04
25.5725.57 3.483.48 0.260.26
28.4028.40 3.143.14 0.210.21
29.2029.20 3.063.06 0.440.44
29.5129.51 3.033.03 0.650.65
30.8330.83 2.902.90 0.090.09
31.8731.87 2.812.81 0.100.10
37.0737.07 2.422.42 0.190.19
实施例19～40：晶型A的制备(挥发法)Examples 19-40: Preparation of Crystal Form A (Volatilization Method)
实施例19～29：室温条件下，称取适量式(I)化合物固体置于1.5毫升的玻璃小瓶中，加入相应体积的溶剂以溶解固体，将样品置于50℃条件下平衡2小时，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，敞口置于通风橱室温挥发，析出固体。得到晶型A。本实施例中所涉详细试验条件如表8所示，实施例19样品的X射线粉末衍射数据如表9所示。Examples 19-29: Under room temperature conditions, weigh an appropriate amount of the solid of the compound of formula (I) and place it in a 1.5-ml glass vial, add a corresponding volume of solvent to dissolve the solid, and place the sample at 50 °C for 2 hours. The sample solution was filtered through a 0.45-micron pore size polytetrafluoroethylene filter into a new 1.5-ml glass vial, and the opening was placed in a fume hood to evaporate at room temperature, and a solid was precipitated. Form A was obtained. The detailed test conditions involved in this example are shown in Table 8, and the X-ray powder diffraction data of the sample of Example 19 is shown in Table 9.
实施例30～31：室温条件下，将适量式(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以溶解固体，采用0.45微米聚四氟乙烯膜过滤得到澄清溶液，之后将该溶液置于盛有4毫升不同溶剂气氛中，进行气液渗透，约14天后，无固体析出，转移至室温挥发，析出固体，得到晶型A。本实施例中所涉详细试验条件如表10所示。Examples 30-31: Under room temperature conditions, place an appropriate amount of the solid of the compound of formula (I) in a 3 ml glass vial, add a corresponding volume of solvent to dissolve the solid, and filter through a 0.45-micron polytetrafluoroethylene membrane to obtain a clear solution, then The solution was placed in an atmosphere containing 4 ml of different solvents, and gas-liquid infiltration was carried out. After about 14 days, no solid was precipitated, and the solution was transferred to room temperature for volatilization, and a solid was precipitated to obtain crystal form A. The detailed test conditions involved in this example are shown in Table 10.
实施例32～37：室温条件下，将适量式(I)化合物固体置于1.5毫升的玻璃小瓶中，加入相应体积的溶剂以溶解固体，将其置于50℃条件下使其溶清，使用0.45微米孔径的聚四氟乙烯滤膜将样品溶液过滤，之后将滤液迅速置于-20℃静置，约1～3天未有固体析出，转移至室温挥发，得到晶型A。本实施例中所涉详细试验条件如表11所示。Examples 32 to 37: under room temperature conditions, place an appropriate amount of the solid compound of formula (I) in a 1.5 ml glass vial, add a corresponding volume of solvent to dissolve the solid, place it at 50°C to dissolve it, and use The sample solution was filtered through a polytetrafluoroethylene filter membrane with a pore size of 0.45 microns, and then the filtrate was quickly placed at -20°C for standing, and no solid was precipitated for about 1 to 3 days. The detailed test conditions involved in this example are shown in Table 11.
实施例38～40：室温条件下，将适量式(I)化合物固体置于5毫升的玻璃小瓶中，加入 相应体积的正溶剂以得到澄清溶液，预先将装有反溶剂的20毫升玻璃瓶置于-20℃条件下平衡约0.5小时～2小时。将含有化合物的正溶剂溶液，采用0.45微米聚四氟乙烯膜过滤得到澄清溶液，将滤液迅速加入至预冷的反溶剂中。滴加完成后无固体析出，将样品转移至5℃条件下搅拌约1～2天，仍无固体则转移至-20℃搅拌约1～2天，依旧无固体析出。最后置于通风橱挥发，析出固体，得到晶型A。本实施例中所涉详细试验条件如表12所示。Examples 38-40: Under room temperature conditions, place an appropriate amount of the solid compound of formula (I) in a 5-mL glass vial, add a corresponding volume of positive solvent to obtain a clear solution, and place a 20-mL glass bottle containing an anti-solvent in advance. Equilibrate at -20°C for about 0.5 to 2 hours. The positive solvent solution containing the compound was filtered through a 0.45-micron polytetrafluoroethylene membrane to obtain a clear solution, and the filtrate was rapidly added to the pre-cooled anti-solvent. After the dropwise addition, there is no solid precipitation. Transfer the sample to 5 °C and stir for about 1 to 2 days. If there is still no solid, transfer it to -20 °C and stir for about 1 to 2 days. There is still no solid precipitation. Finally, it was placed in a fume hood to volatilize, and a solid was precipitated to obtain crystal form A. The detailed test conditions involved in this example are shown in Table 12.
表8Table 8
实施例Example 固体质量(毫克)Solid mass (mg) 溶剂solvent 体积(毫升)Volume (ml)
1919 14.814.8 乙酸乙酯Ethyl acetate 1.01.0
2020 15.115.1 丙酮acetone 0.50.5
21twenty one 14.914.9 异丙醇isopropyl alcohol 0.60.6
22twenty two 15.015.0 二甲基四氢呋喃Dimethyltetrahydrofuran 0.60.6
23twenty three 15.315.3 氯仿Chloroform 1.01.0
24twenty four 2.12.1 1.4二氧六环1.4 Dioxane 0.050.05
2525 2.12.1 丙酮acetone 0.050.05
2626 2.32.3 四氢呋喃tetrahydrofuran 0.050.05
2727 2.02.0 正庚烷n-heptane 1.01.0
2828 2.22.2 甲苯Toluene 1.01.0
2929 2.12.1 二氯甲烷Dichloromethane 1.01.0
表9Table 9
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
6.446.44 13.7413.74 100.00100.00
7.097.09 12.4612.46 96.2996.29
8.318.31 10.6510.65 11.9511.95
10.5610.56 8.388.38 29.0029.00
11.3711.37 7.787.78 6.936.93
12.9312.93 6.856.85 18.2418.24
14.3214.32 6.196.19 72.0472.04
16.7516.75 5.295.29 12.2712.27
18.4118.41 4.824.82 9.909.90
19.4919.49 4.554.55 69.9769.97
21.5421.54 4.134.13 23.2523.25
23.1723.17 3.843.84 17.6817.68
29.9429.94 2.982.98 2.222.22
表10Table 10
Figure PCTCN2021127741-appb-000018
Figure PCTCN2021127741-appb-000018
Figure PCTCN2021127741-appb-000019
Figure PCTCN2021127741-appb-000019
表11Table 11
实施例Example 固体质量(毫克)Solid mass (mg) 溶剂solvent 体积(毫升)Volume (ml)
3232 15.015.0 丙酮acetone 0.50.5
3333 15.115.1 四氢呋喃tetrahydrofuran 0.30.3
3434 15.115.1 乙酸乙酯Ethyl acetate 0.50.5
3535 15.115.1 2-甲基四氢呋喃2-Methyltetrahydrofuran 0.50.5
3636 15.015.0 氯仿Chloroform 0.50.5
3737 15.115.1 二氯甲烷Dichloromethane 0.50.5
表12Table 12
Figure PCTCN2021127741-appb-000020
Figure PCTCN2021127741-appb-000020
实施例41～47：晶型A的制备(反溶剂添加法)Examples 41-47: Preparation of Form A (Anti-solvent Addition Method)
室温条件下，将适量式(I)化合物固体置于5毫升的玻璃小瓶中，加入相应体积的正溶剂溶解，采用0.45微米聚四氟乙烯膜过滤得到澄清溶液。随后磁力搅拌(转速约为1000转/分钟)澄清溶液，并向其中逐滴加入相应反溶剂，固体析出，即得到晶型A。本实施例中所涉详细试验条件如表13所示At room temperature, an appropriate amount of the solid compound of formula (I) was placed in a 5 ml glass vial, a corresponding volume of positive solvent was added to dissolve, and a 0.45-micron polytetrafluoroethylene membrane was used to filter to obtain a clear solution. Then magnetic stirring (rotation speed is about 1000 r/min) to clarify the solution, and the corresponding anti-solvent is added dropwise to it, the solid is precipitated, and the crystal form A is obtained. The detailed test conditions involved in this example are shown in Table 13
表13Table 13
Figure PCTCN2021127741-appb-000021
Figure PCTCN2021127741-appb-000021
实施例48～49：晶型A的制备(反反溶剂添加法)Examples 48-49: Preparation of Form A (Anti-Anti-Solvent Addition Method)
室温条件下，将适量式(I)化合物固体置于5毫升的玻璃小瓶中，加入相应体积的正溶剂以得到澄清溶液，预先将装有反溶剂的20毫升玻璃瓶置于-20℃条件下平衡一段时间。将含有化合物的正溶剂溶液，采用0.45微米聚四氟乙烯膜过滤得到澄清溶液，将滤液迅速加入至预冷的反溶剂中，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。At room temperature, place an appropriate amount of the solid compound of formula (I) in a 5-mL glass vial, add a corresponding volume of positive solvent to obtain a clear solution, and place the 20-mL glass vial with anti-solvent at -20°C in advance. Balance for a while. The positive solvent solution containing the compound was filtered through a 0.45-micron polytetrafluoroethylene membrane to obtain a clear solution, and the filtrate was rapidly added to the pre-cooled anti-solvent, and the solid was precipitated to obtain crystal form A. The detailed test conditions involved in this example are shown in Table 14.
表14Table 14
Figure PCTCN2021127741-appb-000022
Figure PCTCN2021127741-appb-000022
实施例50：晶型Y的制备(悬浮搅拌法)Example 50: Preparation of crystal form Y (suspension stirring method)
将14.9毫克晶型A固体置于1.5毫升的玻璃小瓶中，加入0.5毫升的异丙醇得到悬浊液，将该悬浊液在室温下以1000转/分钟的速度悬浮搅拌3天，分离固体得到晶型Y。其样品X射线粉末衍射数据如表15所示，衍射图如图3所示。14.9 mg of crystal form A solid was placed in a 1.5 ml glass vial, 0.5 ml of isopropanol was added to obtain a suspension, the suspension was suspended and stirred at room temperature at a speed of 1000 rpm for 3 days, and the solid was separated. Form Y was obtained. The X-ray powder diffraction data of the sample is shown in Table 15, and the diffraction pattern is shown in Figure 3.
表15Table 15
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
3.523.52 25.1225.12 100.00100.00
6.976.97 12.6812.68 38.3038.30
13.4113.41 6.606.60 5.135.13
13.9813.98 6.336.33 43.2543.25
14.9414.94 5.935.93 8.218.21
15.4815.48 5.725.72 12.1312.13
17.5117.51 5.075.07 10.0110.01
19.2519.25 4.614.61 7.317.31
20.9720.97 4.244.24 6.046.04
21.6821.68 4.104.10 11.1111.11
22.4922.49 3.953.95 5.345.34
22.9522.95 3.873.87 11.0111.01
23.5923.59 3.773.77 9.359.35
24.0124.01 3.713.71 15.3315.33
24.6124.61 3.623.62 22.5122.51
25.3125.31 3.523.52 11.6411.64
26.0926.09 3.423.42 17.0917.09
27.2027.20 3.283.28 6.766.76
28.0928.09 3.183.18 3.553.55
28.9828.98 3.083.08 4.614.61
30.1530.15 2.962.96 4.734.73
35.4435.44 2.532.53 3.263.26
实施例51：晶型Y的制备(超声法)Example 51: Preparation of Crystal Form Y (Ultrasonic Method)
将30.0毫克晶型A固体置于3毫升的玻璃小瓶中，加入0.5毫升的异丙醇得到悬浊液，将该悬浊液在室温下超声30分钟，分离固体得到晶型Y。其样品X射线粉末衍射数据如表16所示，衍射图如图13所示。TGA数据如图14所示，DSC数据如图15所示， 1H NMR数据如图16所示。 30.0 mg of crystal form A solid was placed in a 3 ml glass vial, 0.5 ml of isopropanol was added to obtain a suspension, the suspension was sonicated at room temperature for 30 minutes, and the solid was separated to obtain crystal form Y. The X-ray powder diffraction data of the sample is shown in Table 16, and the diffraction pattern is shown in Figure 13. The TGA data is shown in FIG. 14 , the DSC data is shown in FIG. 15 , and the 1 H NMR data is shown in FIG. 16 .
表16Table 16
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
3.513.51 25.1825.18 16.6516.65
6.986.98 12.6712.67 88.0988.09
11.9511.95 7.417.41 0.450.45
13.9813.98 6.346.34 100.00100.00
17.5017.50 5.075.07 21.5621.56
19.2419.24 4.614.61 1.901.90
19.8819.88 4.474.47 2.472.47
20.4020.40 4.354.35 1.491.49
20.9520.95 4.244.24 3.563.56
21.6721.67 4.104.10 2.922.92
22.4422.44 3.963.96 2.622.62
23.0023.00 3.873.87 1.201.20
23.5823.58 3.773.77 2.022.02
23.9923.99 3.713.71 6.976.97
24.6024.60 3.623.62 6.146.14
25.5925.59 3.483.48 3.133.13
26.0626.06 3.423.42 2.212.21
27.1927.19 3.283.28 3.873.87
28.1828.18 3.173.17 6.196.19
28.8928.89 3.093.09 1.551.55
31.8031.80 2.812.81 1.541.54
34.8634.86 2.572.57 0.770.77
35.4235.42 2.532.53 5.195.19
实施例52：晶型V的制备(快速挥发法)Example 52: Preparation of crystal form V (rapid evaporation method)
室温条件下，将15.4毫克式(I)化合物固体置于1.5毫升玻璃小瓶中，加入0.2毫升四氢呋喃溶解固体，将其放50℃条件下平衡，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毫升的玻璃小瓶中，将澄清溶液敞口置于通风橱室温挥发，直至析出固体，得到晶型V。其X射线粉末衍射数据如表17所示，其衍射图如图4所示。TGA数据如图17所示，DSC数据如图18所示， 1H NMR数据如图19所示。 At room temperature, 15.4 mg of the solid compound of formula (I) was placed in a 1.5 ml glass vial, 0.2 ml of tetrahydrofuran was added to dissolve the solid, and it was equilibrated at 50 °C. The solution was filtered into a new 1.5 ml glass vial, and the clear solution was left open in a fume hood to evaporate at room temperature until a solid was precipitated to obtain Form V. Its X-ray powder diffraction data are shown in Table 17, and its diffraction pattern is shown in Figure 4 . The TGA data is shown in FIG. 17 , the DSC data is shown in FIG. 18 , and the 1 H NMR data is shown in FIG. 19 .
表17Table 17
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
3.233.23 27.3527.35 40.2040.20
6.466.46 13.6813.68 100.00100.00
9.419.41 9.409.40 4.354.35
9.719.71 9.119.11 4.674.67
12.1012.10 7.327.32 2.972.97
13.0013.00 6.816.81 40.8340.83
13.3813.38 6.626.62 7.537.53
15.0415.04 5.895.89 28.7028.70
15.7315.73 5.635.63 9.049.04
16.2916.29 5.445.44 24.1124.11
17.0517.05 5.205.20 15.6115.61
17.8917.89 4.964.96 4.034.03
18.8318.83 4.714.71 8.378.37
20.1020.10 4.424.42 7.677.67
21.0121.01 4.234.23 15.1515.15
22.8722.87 3.893.89 15.5115.51
23.5923.59 3.773.77 18.4918.49
24.0624.06 3.703.70 39.1139.11
24.4424.44 3.643.64 30.0930.09
24.9324.93 3.573.57 24.2624.26
25.5525.55 3.493.49 12.6812.68
25.8025.80 3.453.45 9.149.14
26.2726.27 3.393.39 8.468.46
26.6826.68 3.343.34 9.309.30
26.9926.99 3.303.30 6.366.36
28.7728.77 3.103.10 16.4316.43
29.4929.49 3.033.03 10.9310.93
29.7929.79 3.003.00 5.855.85
30.7430.74 2.912.91 3.033.03
32.7332.73 2.742.74 1.751.75
36.3736.37 2.472.47 2.082.08
38.0738.07 2.362.36 2.042.04
39.3439.34 2.292.29 2.012.01
实施例53：晶型V的制备(高聚物诱导法)Example 53: Preparation of crystal form V (polymer induction method)
室温条件下，称取14.9毫克式(I)化合物固体置于3毫升的玻璃小瓶中，加入0.2毫升甲醇以溶解固体，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，加入约2毫克混合高聚物(聚己酸内酯，聚乙二醇，聚甲基丙烯酸甲酯，海藻酸钠和羟乙基纤维素等质量混合)以诱导式(I)化合物结晶。使用封口膜封口后于其上扎4个针孔，置于室温条件下挥发，直至固体析出，得到晶型V。本实施例中所涉详细试验条件如表18所示。At room temperature, weigh 14.9 mg of the solid compound of formula (I) into a 3-mL glass vial, add 0.2 mL of methanol 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 vial, add about 2 mg of mixed polymer (polycaprolactone, polyethylene glycol, polymethyl methacrylate, sodium alginate and hydroxyethyl cellulose, etc.) to induce formula (I ) compound crystals. After sealing with a parafilm, 4 pinholes were pricked on it, and it was volatilized at room temperature until the solid was precipitated, and the crystal form V was obtained. The detailed test conditions involved in this example are shown in Table 18.
表18Table 18
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
3.253.25 27.1827.18 63.7663.76
4.604.60 19.2219.22 28.5728.57
6.466.46 13.6813.68 100.00100.00
9.449.44 9.379.37 6.036.03
12.9912.99 6.826.82 28.3528.35
13.3513.35 6.636.63 4.954.95
15.0715.07 5.885.88 34.9334.93
15.7715.77 5.625.62 9.039.03
16.2616.26 5.455.45 13.2313.23
17.0817.08 5.195.19 12.5812.58
17.9017.90 4.954.95 3.093.09
18.9718.97 4.684.68 11.6311.63
20.1420.14 4.414.41 2.932.93
21.1121.11 4.214.21 10.8110.81
22.9122.91 3.883.88 8.368.36
23.2223.22 3.833.83 6.556.55
23.6123.61 3.773.77 10.1510.15
24.0624.06 3.703.70 10.7010.70
24.4624.46 3.643.64 13.6913.69
24.9824.98 3.563.56 6.976.97
25.6025.60 3.483.48 6.676.67
25.8525.85 3.443.44 10.0410.04
26.3426.34 3.383.38 6.916.91
28.8128.81 3.103.10 6.456.45
29.4929.49 3.033.03 2.832.83
29.7829.78 3.003.00 3.573.57
实施例54：晶型V的制备(缓慢降温-挥发法)Example 54: Preparation of Crystal Form V (Slow Cooling-Volatilization Method)
室温条件下，称取14.9毫克适量式(I)化合物固体置于1.5毫升的玻璃小瓶中，加入0.5毫升乙腈得到悬浊液。将该悬浊液在50℃条件下磁力搅拌(转速约为1000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，将澄清滤液封口后以0.1℃每分钟的速率从50℃降温至5℃，之后5℃恒温静置约两天时间，无固体析出，将样品转移至-20℃条件下静置，依旧无固体析出，将其转移至室温下挥发至固体析出，得到晶型V。其X射线粉末衍射数据如表19所示。At room temperature, 14.9 mg of the solid compound of formula (I) was weighed in an appropriate amount and placed in a 1.5 ml glass vial, and 0.5 ml of acetonitrile was added to obtain a suspension. After the suspension was magnetically stirred at 50°C (the rotation speed was about 1000 rpm) for about two hours, 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 the clarified filtrate, 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 about two days, no solid was precipitated, and the sample was transferred to -20°C. No solid was precipitated, and it was transferred to room temperature and volatilized until solid was precipitated to obtain crystal form V. 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%
6.466.46 13.6813.68 100.00100.00
9.729.72 9.109.10 2.582.58
11.7111.71 7.567.56 0.300.30
12.9812.98 6.826.82 36.4936.49
14.9114.91 5.945.94 2.812.81
15.7615.76 5.625.62 1.581.58
16.2516.25 5.455.45 11.6911.69
17.1217.12 5.185.18 2.012.01
18.5318.53 4.794.79 1.001.00
19.0519.05 4.664.66 0.670.67
19.5519.55 4.544.54 0.570.57
20.2520.25 4.384.38 1.741.74
20.6320.63 4.314.31 0.700.70
21.1821.18 4.204.20 1.621.62
22.4722.47 3.963.96 1.551.55
23.0723.07 3.853.85 2.552.55
23.2923.29 3.823.82 2.692.69
23.5423.54 3.783.78 3.593.59
24.3224.32 3.663.66 6.626.62
25.3125.31 3.523.52 1.431.43
26.1826.18 3.403.40 3.953.95
26.6026.60 3.353.35 1.131.13
27.0427.04 3.303.30 0.900.90
27.8227.82 3.213.21 0.630.63
28.3428.34 3.153.15 0.750.75
28.9028.90 3.093.09 2.262.26
29.3929.39 3.043.04 1.361.36
30.0630.06 2.972.97 0.300.30
31.4131.41 2.852.85 0.340.34
32.6832.68 2.742.74 0.440.44
34.4434.44 2.602.60 0.020.02
35.2635.26 2.552.55 0.490.49
35.8935.89 2.502.50 0.500.50
36.2636.26 2.482.48 1.051.05
37.4437.44 2.402.40 0.480.48
39.7339.73 2.272.27 0.820.82
实施例55：晶型V的制备(快速降温法)Example 55: Preparation of crystal form V (rapid cooling method)
室温条件下，将15.1毫克式(I)化合物溶解于0.5毫升的乙腈中，置于50℃条件下使其溶清，使用0.45微米孔径的聚四氟乙烯滤膜将样品溶液过滤，之后迅速置于-20℃静置，固体析出，得到晶型V。At room temperature, 15.1 mg of the compound of formula (I) was dissolved in 0.5 ml of acetonitrile, placed at 50 °C to dissolve it, and the sample solution was filtered using a 0.45-micron pore size polytetrafluoroethylene filter, and then quickly placed. After standing at -20°C, the solid was precipitated, and the crystal form V was obtained.
实施例56：晶型AE的制备(反反溶剂添加法)Example 56: Preparation of crystal form AE (anti-anti-solvent addition method)
室温条件下，将15.2毫克式(I)化合物溶解于0.4毫升二甲基乙酰胺中溶清，预先将装有4毫升纯水的反溶剂置于5℃条件下预冷，使用0.45微米孔径的聚四氟乙烯滤膜将含有化 合物的溶液过滤至纯水中，得到悬浊液，离心分离，室温晾干得到晶型AE。其样品X射线粉末衍射数据如表20所示，衍射图如图5所示。At room temperature, 15.2 mg of the compound of formula (I) was dissolved in 0.4 ml of dimethylacetamide, and the anti-solvent filled with 4 ml of pure water was pre-cooled at 5 °C, and a 0.45-micron pore size was used. The solution containing the compound was filtered through a polytetrafluoroethylene filter into pure water to obtain a suspension, which was centrifuged and air-dried at room temperature to obtain crystal form AE. The X-ray powder diffraction data of the sample is shown in Table 20, and the diffraction pattern is shown in Figure 5.
表20Table 20
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
6.386.38 13.8513.85 100.00100.00
9.419.41 9.409.40 4.394.39
12.8112.81 6.916.91 40.9740.97
14.5114.51 6.106.10 2.102.10
15.4415.44 5.745.74 17.4117.41
16.0316.03 5.535.53 22.6622.66
16.4416.44 5.395.39 3.203.20
17.9917.99 4.934.93 2.472.47
18.6318.63 4.764.76 4.064.06
19.2519.25 4.614.61 5.455.45
19.9819.98 4.444.44 12.7212.72
20.9920.99 4.234.23 6.416.41
21.4121.41 4.154.15 5.425.42
22.1122.11 4.024.02 4.944.94
22.8822.88 3.893.89 5.535.53
24.1724.17 3.683.68 12.9612.96
24.9824.98 3.563.56 3.093.09
25.8125.81 3.453.45 9.239.23
26.1726.17 3.413.41 3.073.07
27.0627.06 3.293.29 4.344.34
29.0529.05 3.073.07 6.156.15
30.0630.06 2.972.97 1.921.92
30.6930.69 2.912.91 4.054.05
32.1932.19 2.782.78 3.303.30
32.9632.96 2.722.72 1.671.67
35.6635.66 2.522.52 1.071.07
39.1139.11 2.302.30 2.612.61
实施例57：晶型AE的制备(高聚物诱导法)Example 57: Preparation of crystal form AE (polymer induction 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0.4毫升 的正丙醇以溶解固体，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，加入约2毫克混合高聚物(聚乙烯吡咯烷酮，聚乙烯醇，聚氯乙烯，聚醋酸乙烯酯，羟丙基甲基纤维素和甲基纤维素等质量混合)以诱导式(I)化合物结晶。使用封口膜封口后于其上扎4个针孔，转移至室温条件挥发，直至有固体析出，得到晶型AE。其样品X射线粉末衍射数据如表21所示。TGA数据如图20所示，DSC数据如图21所示， 1H NMR数据如图22所示。 At room temperature, weigh 15.2 mg of the solid compound of formula (I) into a 3-mL glass vial, add 0.4 mL of n-propanol to dissolve the solid, and use a 0.45-micron pore size polytetrafluoroethylene filter to filter the sample solution to In a new 3 ml glass vial, add about 2 mg of mixed polymer (polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, hydroxypropyl methylcellulose, and methylcellulose, etc. mass mix) Crystallization of the compound of formula (I) was induced. After sealing with parafilm, 4 pinholes were pricked on it, transferred to room temperature to volatilize until solids were precipitated, and crystal form AE was obtained. The X-ray powder diffraction data of its samples are shown in Table 21. The TGA data is shown in FIG. 20 , the DSC data is shown in FIG. 21 , and the 1 H NMR data is shown in FIG. 22 .
表21Table 21
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
3.233.23 27.3927.39 96.3396.33
6.396.39 13.8413.84 100.00100.00
9.439.43 9.389.38 12.2912.29
12.3312.33 7.187.18 2.582.58
12.8012.80 6.926.92 38.3438.34
14.4314.43 6.146.14 7.097.09
15.4515.45 5.735.73 44.9644.96
16.0316.03 5.535.53 24.2524.25
16.4316.43 5.395.39 8.388.38
17.1917.19 5.165.16 2.752.75
17.9517.95 4.944.94 5.435.43
18.0618.06 4.914.91 6.086.08
18.6518.65 4.764.76 15.1815.18
18.9218.92 4.694.69 8.338.33
19.2519.25 4.614.61 9.539.53
19.7119.71 4.504.50 9.179.17
20.0020.00 4.444.44 20.2320.23
21.0221.02 4.234.23 12.5012.50
21.4221.42 4.154.15 8.908.90
22.1322.13 4.024.02 11.5411.54
22.3722.37 3.983.98 13.3013.30
22.8022.80 3.903.90 11.0011.00
23.6823.68 3.763.76 8.078.07
24.1624.16 3.683.68 30.3130.31
24.3524.35 3.663.66 18.8518.85
24.6424.64 3.613.61 8.648.64
25.0325.03 3.563.56 9.419.41
25.4425.44 3.503.50 8.548.54
25.8125.81 3.453.45 13.4213.42
26.0426.04 3.423.42 12.5112.51
26.7026.70 3.343.34 6.166.16
27.0627.06 3.293.29 8.058.05
27.3827.38 3.263.26 5.165.16
28.2228.22 3.163.16 3.683.68
28.5228.52 3.133.13 2.032.03
29.0329.03 3.083.08 7.617.61
30.0430.04 2.972.97 3.343.34
30.6030.60 2.922.92 6.176.17
30.8330.83 2.902.90 7.397.39
31.5331.53 2.842.84 2.982.98
32.1632.16 2.782.78 4.244.24
33.5333.53 2.672.67 0.930.93
34.7934.79 2.582.58 0.700.70
35.5735.57 2.522.52 0.920.92
36.4636.46 2.462.46 1.091.09
37.5837.58 2.392.39 1.561.56
38.0538.05 2.372.37 1.761.76
38.6438.64 2.332.33 1.551.55
39.1039.10 2.302.30 5.505.50
实施例58：晶型AE的制备(快速降温法)Example 58: Preparation of crystal form AE (rapid cooling method)
室温条件下，将15.1毫克式(I)化合物加入0.5毫升正丙醇，50℃条件下使其溶解，使用0.45微米孔径的聚四氟乙烯滤膜将样品溶液过滤，之后迅速置于-20℃静置，固体析出，得到晶型AE。其样品X射线粉末衍射数据如表22所示。At room temperature, 15.1 mg of the compound of formula (I) was added to 0.5 ml of n-propanol, dissolved at 50 °C, and the sample solution was filtered using a 0.45-micron pore size polytetrafluoroethylene filter, and then quickly placed at -20 °C After standing, the solid was precipitated to obtain crystal form AE. The X-ray powder diffraction data of its samples are shown in Table 22.
表22Table 22
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
3.223.22 27.4327.43 21.4621.46
6.396.39 13.8413.84 3.353.35
9.419.41 9.409.40 100.00100.00
12.8112.81 6.916.91 0.680.68
13.5913.59 6.516.51 48.0448.04
14.4414.44 6.136.13 0.500.50
15.4515.45 5.745.74 1.721.72
16.0316.03 5.535.53 4.474.47
16.4316.43 5.395.39 1.991.99
17.1717.17 5.165.16 23.4823.48
18.0018.00 4.934.93 1.541.54
18.7618.76 4.734.73 0.460.46
19.2719.27 4.614.61 0.890.89
19.9919.99 4.444.44 0.460.46
20.9920.99 4.234.23 0.560.56
21.4121.41 4.154.15 2.422.42
22.1422.14 4.014.01 3.023.02
22.8122.81 3.903.90 1.311.31
24.1824.18 3.683.68 5.295.29
24.3524.35 3.653.65 1.041.04
24.6224.62 3.623.62 0.900.90
25.0025.00 3.563.56 1.671.67
25.4925.49 3.493.49 0.710.71
25.8125.81 3.453.45 0.740.74
26.0326.03 3.423.42 10.0710.07
26.7026.70 3.343.34 5.885.88
27.0727.07 3.293.29 2.692.69
27.3927.39 3.263.26 3.303.30
28.2528.25 3.163.16 4.654.65
29.0529.05 3.073.07 8.418.41
30.0530.05 2.972.97 2.682.68
30.6930.69 2.912.91 1.741.74
31.0731.07 2.882.88 3.853.85
31.5231.52 2.842.84 1.051.05
32.1732.17 2.782.78 0.610.61
33.0033.00 2.712.71 1.101.10
35.7535.75 2.512.51 0.730.73
39.1139.11 2.302.30 1.651.65
39.4739.47 2.282.28 1.611.61
实施例59：晶型AE的制备(缓慢降温-挥发法)Example 59: Preparation of crystal form AE (slow cooling-volatilization method)
室温条件下，称取15.0毫克适量式(I)化合物固体置于1.5毫升的玻璃小瓶中，加入0.5毫升乙腈得到悬浊液。将该悬浊液在50℃条件下磁力搅拌(转速约为1000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，将澄清滤液封口后以0.1℃每分钟的速率从50℃降温至5℃，之后5℃恒温静置约两天时间，无固体析出，将样品转移至-20℃条件下静置，依旧无固体析出，将其转移至室温下挥发至固体析出，得到晶型AE。At room temperature, weigh 15.0 mg of an appropriate amount of the solid compound of formula (I) into a 1.5-mL glass vial, and add 0.5 mL of acetonitrile to obtain a suspension. After the suspension was magnetically stirred at 50°C (the rotation speed was about 1000 rpm) for about two hours, 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 the clarified filtrate, 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 about two days, no solid was precipitated, and the sample was transferred to -20°C. No solid was precipitated, and it was transferred to room temperature and volatilized until solid was precipitated to obtain crystal form AE.
实施例60：晶型AA的制备(快速降温法)Example 60: Preparation of crystal form AA (rapid cooling method)
室温条件下，将15.2毫克式(I)化合物溶解于0.5毫升异丙醇中50℃条件下使其溶解，使用0.45微米孔径的聚四氟乙烯滤膜将样品溶液过滤，之后迅速置于-20℃静置，固体析出，得到晶型AA。其样品X射线粉末衍射数据如表23所示，衍射图如图6所示。At room temperature, 15.2 mg of the compound of formula (I) was dissolved in 0.5 ml of isopropanol at 50° C. The sample solution was filtered using a 0.45-micron pore size polytetrafluoroethylene filter, and then quickly placed in -20 After standing at °C, the solid was precipitated to obtain crystal form AA. The X-ray powder diffraction data of the sample is shown in Table 23, and the diffraction pattern is shown in Figure 6.
表23Table 23
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
8.208.20 10.7910.79 9.819.81
8.898.89 9.949.94 8.888.88
9.729.72 9.109.10 0.810.81
11.6511.65 7.607.60 100.00100.00
12.3312.33 7.187.18 5.105.10
12.7712.77 6.936.93 4.904.90
13.3813.38 6.626.62 1.361.36
16.0716.07 5.515.51 18.7918.79
16.7216.72 5.305.30 15.8515.85
17.2717.27 5.135.13 3.963.96
17.8817.88 4.964.96 11.7611.76
18.2718.27 4.864.86 5.025.02
18.5318.53 4.794.79 5.675.67
19.2619.26 4.614.61 1.961.96
20.0420.04 4.434.43 5.475.47
20.6920.69 4.294.29 2.072.07
21.3321.33 4.174.17 1.811.81
22.7922.79 3.903.90 2.602.60
23.3923.39 3.803.80 4.894.89
24.2424.24 3.673.67 1.991.99
24.4924.49 3.633.63 4.174.17
24.7724.77 3.593.59 5.345.34
25.2725.27 3.523.52 2.302.30
25.8225.82 3.453.45 2.352.35
26.4126.41 3.383.38 3.423.42
26.9726.97 3.303.30 1.001.00
27.6027.60 3.233.23 1.641.64
实施例61：晶型G的制备(快速挥发法)Example 61: Preparation of crystal form G (rapid evaporation method)
室温条件下，将2.2毫克式(I)化合物置于1.5毫升玻璃小瓶中，加入1.0mL乙酸异丙酯得到澄清溶液，将该溶液置于室温下挥发，直至析出固体，得到晶型G。其X射线粉末衍射数据如表24所示。该样品在约6.5°±0.2°、约19.6°±0.2°、约10.6°±0.2°、约5.3°±0.2°、约13.0°±0.2°、约8.5°±0.2°、约16.8°±0.2°、约23.2°±0.2°和约21.7°±0.2°处有特征峰。At room temperature, 2.2 mg of the compound of formula (I) was placed in a 1.5 mL glass vial, and 1.0 mL of isopropyl acetate was added to obtain a clear solution. The solution was evaporated at room temperature until a solid was precipitated to obtain Form G. Its X-ray powder diffraction data are shown in Table 24. The sample is at about 6.5°±0.2°, about 19.6°±0.2°, about 10.6°±0.2°, about 5.3°±0.2°, about 13.0°±0.2°, about 8.5°±0.2°, about 16.8°±0.2 There are characteristic peaks at about 23.2°±0.2° and about 21.7°±0.2°.
表24Table 24
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
5.305.30 16.6916.69 16.1916.19
6.496.49 13.6213.62 100.00100.00
8.488.48 10.4310.43 6.596.59
10.5910.59 8.358.35 17.5817.58
11.2411.24 7.877.87 3.573.57
13.0113.01 6.806.80 12.4512.45
14.1414.14 6.266.26 2.902.90
15.9515.95 5.565.56 2.112.11
16.8516.85 5.265.26 6.546.54
19.5819.58 4.534.53 42.1642.16
21.6621.66 4.104.10 3.963.96
23.1823.18 3.843.84 5.405.40
25.0825.08 3.553.55 2.152.15
实施例62：晶型G的制备(快速挥发法)Example 62: Preparation of crystal form G (rapid evaporation method)
室温条件下，将15.0毫克式(I)化合物置于3毫升玻璃小瓶中，将其敞口置于装有4毫升环己酮的溶剂中，将该溶液置于室温下挥发，直至析出固体，得到晶型G。其X射线粉末衍射数据如表25所示。该样品在约6.6°±0.2°、约19.9°±0.2°、约10.7°±0.2°、约17.1°±0.2°、约13.2°±0.2°、约5.3°±0.2°、约23.6°±0.2°、约8.4°±0.2°和约14.1°±0.2°处有特征峰。At room temperature, 15.0 mg of the compound of formula (I) was placed in a 3-mL glass vial, and the opening was placed in a solvent containing 4 mL of cyclohexanone, and the solution was placed at room temperature to volatilize until a solid was precipitated, Form G was obtained. Its X-ray powder diffraction data are shown in Table 25. The sample is at about 6.6°±0.2°, about 19.9°±0.2°, about 10.7°±0.2°, about 17.1°±0.2°, about 13.2°±0.2°, about 5.3°±0.2°, about 23.6°±0.2 There are characteristic peaks at about 8.4°±0.2° and about 14.1°±0.2°.
表25Table 25
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
5.325.32 16.6016.60 14.7414.74
6.596.59 13.4113.41 100.00100.00
7.077.07 12.5012.50 7.197.19
8.408.40 10.5310.53 7.287.28
10.7510.75 8.238.23 39.6339.63
11.3011.30 7.837.83 5.235.23
12.4712.47 7.107.10 2.502.50
13.2313.23 6.696.69 15.1715.17
14.1314.13 6.276.27 6.716.71
16.1016.10 5.505.50 3.433.43
17.1017.10 5.195.19 15.4115.41
18.2418.24 4.864.86 5.005.00
19.5019.50 4.554.55 15.7915.79
19.9219.92 4.464.46 59.3059.30
22.0222.02 4.044.04 6.736.73
23.6423.64 3.763.76 7.797.79
25.4625.46 3.503.50 4.804.80
28.2928.29 3.153.15 1.471.47
30.4130.41 2.942.94 1.471.47
37.1737.17 2.422.42 0.450.45
38.4538.45 2.342.34 0.760.76
实施例63～65：晶型M的制备(气液渗透-快速挥发法)Examples 63-65: Preparation of crystal form M (gas-liquid permeation-rapid volatilization method)
室温条件下，称取适量式(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约12天，样品澄清，将其转移至室温条件下敞口挥发，直至有固体析出，得到晶型M。本实施例中所涉详细试验条件如表26所示，实施例63样品的X射线粉末衍射数据如表27所示。该样品在约7.2°±0.2°、约6.4°±0.2°、约14.5°±0.2°、约19.4°±0.2°、约10.2°±0.2°、约12.9°±0.2°、约21.8°±0.2°、约22.8°±0.2°、约10.9°±0.2°、约17.1°±0.2°和约16.4°±0.2°处有特征峰。At room temperature, weigh an appropriate amount of the solid of the compound of formula (I) and place it in a 3-mL glass vial, add a corresponding volume of positive solvent to dissolve the solid, and filter the sample solution to a new size using a 0.45-micron pore size polytetrafluoroethylene filter membrane. 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 about 12 days, and the sample was clarified. It was transferred to room temperature and volatilized in the open until a solid was precipitated to obtain crystal form M. The detailed test conditions involved in this example are shown in Table 26, and the X-ray powder diffraction data of the sample of Example 63 are shown in Table 27. The sample is at about 7.2°±0.2°, about 6.4°±0.2°, about 14.5°±0.2°, about 19.4°±0.2°, about 10.2°±0.2°, about 12.9°±0.2°, about 21.8°±0.2 There are characteristic peaks at °, about 22.8° ± 0.2°, about 10.9° ± 0.2°, about 17.1° ± 0.2° and about 16.4° ± 0.2°.
表26Table 26
Figure PCTCN2021127741-appb-000023
Figure PCTCN2021127741-appb-000023
Figure PCTCN2021127741-appb-000024
Figure PCTCN2021127741-appb-000024
表27Table 27
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
5.115.11 17.2917.29 1.601.60
5.545.54 15.9415.94 1.081.08
6.446.44 13.7213.72 77.3477.34
7.207.20 12.2712.27 100.00100.00
8.368.36 10.5710.57 5.285.28
10.2310.23 8.658.65 13.7913.79
10.9010.90 8.118.11 5.365.36
11.6811.68 7.587.58 1.151.15
12.9212.92 6.856.85 11.1711.17
14.4714.47 6.126.12 44.0944.09
16.3716.37 5.415.41 3.973.97
17.0917.09 5.195.19 5.015.01
19.4419.44 4.574.57 26.7926.79
20.5620.56 4.324.32 2.612.61
21.8021.80 4.084.08 9.369.36
22.7622.76 3.913.91 6.036.03
24.0824.08 3.703.70 1.691.69
29.2629.26 3.053.05 1.161.16
实施例66：晶型M的制备(快速挥发法)Example 66: Preparation of crystal form M (rapid evaporation method)
室温条件下，称取15.0毫克式(I)化合物固体置于1.5毫升的玻璃小瓶中，加入0.5毫升乙酸异丙酯在50℃条件下使其溶解，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，敞口置于室温下挥发，直至析出固体，得到晶型M。其样品X射线粉末衍射数据如表28所示。该样品在约7.1°±0.2°、约6.5°±0.2°、约14.3°±0.2°、约19.6°±0.2°、约10.2°±0.2°、约21.6°±0.2°、约13.0°±0.2°、约22.8°±0.2°、约11.1°±0.2°、约16.4°±0.2°和约17.3°±0.2°处有特征峰。At room temperature, weigh 15.0 mg of the solid compound of formula (I) into a 1.5-mL glass vial, add 0.5 mL of isopropyl acetate to dissolve it at 50°C, and use a 0.45-micron pore size polytetrafluoroethylene filter membrane. The sample solution was filtered into a new 1.5 ml glass vial, left open to volatilize at room temperature until a solid was precipitated, and crystal form M was obtained. The X-ray powder diffraction data of its samples are shown in Table 28. The sample is at about 7.1°±0.2°, about 6.5°±0.2°, about 14.3°±0.2°, about 19.6°±0.2°, about 10.2°±0.2°, about 21.6°±0.2°, about 13.0°±0.2 There are characteristic peaks at °, about 22.8° ± 0.2°, about 11.1° ± 0.2°, about 16.4° ± 0.2° and about 17.3° ± 0.2°.
表28Table 28
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
6.506.50 13.6113.61 79.2879.28
7.127.12 12.4212.42 100.00100.00
8.448.44 10.4810.48 8.158.15
10.1810.18 8.698.69 18.6518.65
11.0611.06 8.008.00 6.656.65
13.0313.03 6.806.80 10.3010.30
14.2914.29 6.206.20 47.1347.13
16.3916.39 5.415.41 4.264.26
17.3417.34 5.115.11 3.113.11
19.6119.61 4.534.53 32.7332.73
20.4720.47 4.344.34 7.067.06
21.5521.55 4.124.12 13.1313.13
22.8322.83 3.903.90 7.547.54
实施例67：晶型M的制备(反反溶剂添加-快速挥发法)Example 67: Preparation of Crystal Form M (Anti-Anti-Solvent Addition-Fast Evaporation Method)
室温条件下，将15.5毫克式(I)化合物溶解于0.4毫升乙醇中溶清，预先将装有4毫升异丙醚的反溶剂置于5℃条件下预冷，使用0.45微米孔径的聚四氟乙烯滤膜将其过滤至反溶剂中，无固体析出，将样品转移至5℃条件下，仍无固体析出，转移至-20℃环境下，无固体析出。转移至室温下挥发，直至析出固体，得到晶型M。其样品X射线粉末衍射数据如表29所示。该样品在约6.4°±0.2°、约19.4°±0.2°、约12.9°±0.2°、约7.2°±0.2°、约22.6°±0.2°、约17.1°±0.2°、约10.1°±0.2°、约11.0°±0.2°、约16.2°±0.2°、约14.4°±0.2°和约21.6°±0.2°处有特征峰。At room temperature, 15.5 mg of the compound of formula (I) was dissolved in 0.4 ml of ethanol, and the anti-solvent containing 4 ml of isopropyl ether was pre-cooled at 5 °C, using 0.45 micron pore size polytetrafluoroethylene. It was filtered into the anti-solvent with an ethylene filter, and no solid was precipitated. The sample was transferred to 5 °C, and there was still no solid precipitation. When it was transferred to -20 °C, no solid was precipitated. It was transferred to room temperature and volatilized until a solid was precipitated to obtain crystal form M. The X-ray powder diffraction data of its samples are shown in Table 29. The sample is at about 6.4°±0.2°, about 19.4°±0.2°, about 12.9°±0.2°, about 7.2°±0.2°, about 22.6°±0.2°, about 17.1°±0.2°, about 10.1°±0.2 There are characteristic peaks at °, about 11.0° ± 0.2°, about 16.2° ± 0.2°, about 14.4° ± 0.2° and about 21.6° ± 0.2°.
表29Table 29
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
5.625.62 15.7415.74 0.560.56
6.426.42 13.7613.76 100.00100.00
7.177.17 12.3412.34 6.186.18
10.1310.13 8.748.74 5.545.54
10.9510.95 8.088.08 3.603.60
11.2511.25 7.867.86 0.480.48
12.8712.87 6.886.88 15.7915.79
14.3714.37 6.176.17 2.292.29
16.2216.22 5.465.46 2.522.52
17.1017.10 5.195.19 5.755.75
18.6418.64 4.764.76 0.310.31
19.3519.35 4.594.59 40.9240.92
20.3420.34 4.374.37 1.111.11
21.6221.62 4.114.11 0.700.70
22.0322.03 4.044.04 0.660.66
22.5622.56 3.943.94 5.865.86
23.4623.46 3.793.79 1.771.77
24.4424.44 3.643.64 0.150.15
25.9325.93 3.443.44 0.280.28
29.0429.04 3.083.08 0.430.43
29.9729.97 2.982.98 0.520.52
35.6635.66 2.522.52 0.380.38
36.6136.61 2.452.45 0.150.15
39.3039.30 2.292.29 0.150.15
实施例68：晶型M的制备(高温快速挥发法)Example 68: Preparation of crystal form M (high temperature rapid volatilization method)
室温条件下，将15.0毫克式(I)化合物在加入0.5毫升甲基异丁酮80℃条件下使其溶解，使用0.45微米孔径的聚四氟乙烯滤膜过滤，将澄清滤液转移至80℃条件挥发，直至析出固体，得到晶型M。其样品X射线粉末衍射数据如30所示。该样品在约7.0°±0.2°、约14.2°±0.2°、约6.5°±0.2°、约21.3°±0.2°、约19.7°±0.2°、约13.1°±0.2°、约10.2°±0.2°、约22.9°±0.2°、约16.5°±0.2°、约11.1°±0.2°和约17.4°±0.2°处有特征峰。At room temperature, 15.0 mg of the compound of formula (I) was dissolved by adding 0.5 ml of methyl isobutyl ketone at 80 °C, filtered with a 0.45-micron pore size polytetrafluoroethylene filter, and the clear filtrate was transferred to 80 °C. Volatilize until a solid is precipitated to obtain crystal form M. Its sample X-ray powder diffraction data are shown in 30. The sample is at about 7.0°±0.2°, about 14.2°±0.2°, about 6.5°±0.2°, about 21.3°±0.2°, about 19.7°±0.2°, about 13.1°±0.2°, about 10.2°±0.2 There are characteristic peaks at °, about 22.9° ± 0.2°, about 16.5° ± 0.2°, about 11.1° ± 0.2° and about 17.4° ± 0.2°.
表30Table 30
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
5.035.03 17.5517.55 1.371.37
5.605.60 15.7915.79 1.021.02
6.536.53 13.5413.54 30.0630.06
7.057.05 12.5512.55 100.00100.00
8.468.46 10.4510.45 1.471.47
10.2410.24 8.648.64 3.163.16
11.0911.09 7.987.98 1.471.47
11.5911.59 7.637.63 0.720.72
13.0913.09 6.766.76 4.304.30
14.1614.16 6.256.25 45.5045.50
16.4716.47 5.385.38 1.641.64
17.4017.40 5.105.10 1.031.03
19.7019.70 4.514.51 12.6012.60
21.3421.34 4.164.16 13.0713.07
22.9322.93 3.883.88 1.961.96
23.7523.75 3.753.75 0.410.41
25.6725.67 3.473.47 0.130.13
26.3826.38 3.383.38 0.170.17
28.5828.58 3.123.12 0.600.60
实施例69：晶型的溶解度Example 69: Solubility of Crystal Forms
将本发明晶型C/Y/A/V/AE用SGF(模拟人工胃液)、FaSSIF(空腹状态下人工肠液)、FeSSIF(饱食状态下人工肠液)和纯水分别配制成悬浊液，在室温条件下平衡1小时、2小时、4小时和24小时后过滤，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。实验结果如表31所示，溶解度曲线分别如图23～26所示。实验结果显示，本发明晶型C/Y/A/V/AE在SGF、FaSSIF、FeSSIF和纯水中均具有较好的溶解度。The crystal form C/Y/A/V/AE of the present invention is respectively prepared into a suspension with SGF (simulated artificial gastric fluid), FaSSIF (artificial intestinal fluid in fasting state), FeSSIF (artificial intestinal fluid in satiation state) and pure water, After equilibration at room temperature for 1 hour, 2 hours, 4 hours and 24 hours, a saturated solution was obtained by filtration. The content of the sample in the saturated solution was determined by high performance liquid chromatography (HPLC). The experimental results are shown in Table 31, and the solubility curves are shown in Figures 23 to 26, respectively. The experimental results show that the crystal form C/Y/A/V/AE of the present invention has good solubility in SGF, FaSSIF, FeSSIF and pure water.
表31Table 31
Figure PCTCN2021127741-appb-000025
Figure PCTCN2021127741-appb-000025
实施例70：晶型的可压性Example 70: 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和现有技术中披露固体S1，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。在一定的压力下，抗张强度越大的，表示其可压性越好。结果表明，本发明晶型较现有技术中披露固体S1的抗张强度更大，具有更优的可压性。Use a manual tablet press to perform tablet compression. When tableting, select a circular flat punch that can be compressed into a cylindrical tablet, add a certain amount of the crystal form of the present invention and the solid S1 disclosed in the prior art, and press 10 kN to make a tablet. The round tablets were placed in a desiccator for 24 hours, and after complete elastic recovery, the radial crushing force (hardness, H) was tested by a tablet hardness tester. The diameter (D) and thickness (L) of the tablet were measured with a vernier caliper, and the tensile strength of the powder with different hardness was calculated using the formula T=2H/πDL. Under a certain pressure, the higher the tensile strength, the better the compressibility. The results show that the crystal form of the present invention has higher tensile strength and better compressibility than the solid S1 disclosed in the prior art.
实施例71：晶型的固有溶出速率Example 71: Intrinsic Dissolution Rate of Crystalline Form
称取本发明晶型和现有技术中披露固体S1各约100毫克，倒入固有溶出模具，在5kN压力下持续1分钟，制成表面积0.5cm 2的薄片，取完整压片转移至溶出仪测试固有溶出速率，溶出条件如表32所示，根据10～30分钟之间的测定点计算斜率，以毫克/毫升表示，根据斜率进一步计算固有溶出速率(Intrinsic dissolution rate,IDR)，以毫克/分钟/cm 2表示。结果表明，本发明晶型的溶出速率较现有技术中披露固体S1更快。 Weigh about 100 mg each of the crystal form of the present invention and the solid S1 disclosed in the prior art, pour into the inherent dissolution mold, and continue for 1 minute under the pressure of 5kN to make a sheet with a surface area of 0.5cm 2 , take the complete tablet and transfer it to the dissolution apparatus Test the intrinsic dissolution rate, and the dissolution conditions are shown in Table 32. Calculate the slope according to the measurement point between 10 and 30 minutes, expressed in mg/ml, and further calculate the intrinsic dissolution rate (IDR) according to the slope, in mg/ml expressed in minutes/cm 2 . The results show that the dissolution rate of the crystal form of the present invention is faster than that of the solid S1 disclosed in the prior art.
表32Table 32
溶出仪Dissolution Apparatus CSE-051 Agilent 708DSCSE-051 Agilent 708DS
方法method 浆法pulp method
介质medium pH 6.8磷酸盐缓冲液pH 6.8 Phosphate Buffer
介质体积medium volume 900毫升900ml
转速 Rotating speed 100转/分100 rpm
介质温度medium temperature 37℃37 ℃
取样点Sampling point 1,2,3,4,5,10,15,20,25,30min1,2,3,4,5,10,15,20,25,30min
补充介质supplementary medium NoNo
实施例72：稳定性对比研究Example 72: Comparative stability study
称取本发明晶型C(起始纯度99.49％)、晶型Y(起始纯度99.66％)、晶型V(起始纯度99.53％)各约15毫克，敞口放置于25℃/60％RH条件或40℃/75％RH条件的稳定箱中，在7天后取样测XRPD与HPLC。实验结果如表33所示，晶型C的稳定性如图27～28所示，晶型V的稳定性如图29所示，晶型Y的稳定性如图30～31所示。试验结果显示，本发明晶型C/Y/V在25℃/60％RH、40℃/75％RH条件下具有较好的物理/化学稳定性。Weigh about 15 mg each of crystal form C (initial purity 99.49%), crystal form Y (initial purity 99.66%) and crystal form V (initial purity 99.53%) of the present invention, and place them in an open position at 25°C/60% RH conditions or 40°C/75%RH conditions in a stable box, samples were taken after 7 days for XRPD and HPLC. The experimental results are shown in Table 33, the stability of Form C is shown in Figures 27-28, the stability of Form V is shown in Figure 29, and the stability of Form Y is shown in Figures 30-31. The test results show that the crystal form C/Y/V of the present invention has good physical/chemical stability under the conditions of 25°C/60%RH and 40°C/75%RH.
表33Table 33
Figure PCTCN2021127741-appb-000026
Figure PCTCN2021127741-appb-000026
实施例73：引湿性对比研究Example 73: Comparative Study on Moisture Induction
称取本发明晶型C/Y/A/V/AE各约10毫克进行动态水分吸附(DVS)测试，然后取样测XRPD，实验结果如表34所示，晶型A的DVS如图32所示，晶型C的DVS如图33所示，晶型C测试DVS前后的XRPD对比图如图34所示，晶型V的DVS如图35所示，晶型Y的DVS如图36所示，晶型Y测试DVS前后的XRPD对比图如图37所示，晶型AE的DVS 如图38所示，晶型AE测试DVS前后的XRPD对比图如图39所示。试验结果显示，本发明晶型C/Y/A/V/AE具有较低的引湿性。Weigh about 10 mg each of crystal form C/Y/A/V/AE of the present invention to carry out dynamic moisture adsorption (DVS) test, then sample and measure XRPD, the experimental results are shown in Table 34, and the DVS of crystal form A is shown in Figure 32. The DVS of Form C is shown in Figure 33, the XRPD comparison chart of Form C before and after the DVS test is shown in Figure 34, the DVS of Form V is shown in Figure 35, and the DVS of Form Y is shown in Figure 36 , the XRPD comparison diagram of the crystal form Y before and after the DVS test is shown in Figure 37, the DVS of the crystal form AE is shown in Figure 38, and the XRPD comparison diagram of the crystal form AE before and after the DVS test is shown in Figure 39. The test results show that the crystalline form C/Y/A/V/AE of the present invention has lower hygroscopicity.
表34Table 34
晶型Crystal form 80％相对湿度的增重Weight gain at 80% relative humidity 引湿性hygroscopicity
晶型CForm C 0.22620.2262 略有引湿性slightly hygroscopic
晶型YForm Y 0.69350.6935 略有引湿性slightly hygroscopic
晶型AForm A 2.85482.8548 有引湿性hygroscopic
晶型VForm V 0.12220.1222 无或几乎无引湿性No or almost no hygroscopicity
晶型AEForm AE 0.21630.2163 略有引湿性slightly hygroscopic
关于引湿性特征描述与引湿性增重的界定(中国药典2010年版附录XIX J药物引湿性试验指导原则)：About the description of hygroscopicity characteristics and the definition of hygroscopicity weight gain (Chinese Pharmacopoeia 2010 Edition Appendix XIX J Guidelines for the hygroscopicity test of drugs):
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74：晶习对比研究Example 74: Crystal Habit Comparative Study
称取本发明晶型C/V/AE各约10毫克，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。晶型V的PLM图如图40所示，晶型C的PLM图如图41所示，晶型AE的PLM图如图42所示。实验结果显示，本发明晶型C/V/AE具有较优的晶习。Weigh about 10 mg of each of the crystal forms C/V/AE of the present invention, place them on glass slides, add a little vacuum silicone oil dropwise to disperse the samples, cover with a cover glass, and observe under a polarizing microscope. The PLM diagram of crystal form V is shown in FIG. 40 , the PLM diagram of crystal form C is shown in FIG. 41 , and the PLM diagram of crystal form AE is shown in FIG. 42 . The experimental results show that the crystal form C/V/AE of the present invention has a better crystal habit.
实施例75：粒径分布对比研究Example 75: Comparative Study of Particle Size Distribution
称取本发明晶型C/V各约10-30毫克，然后加入约5毫升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35所示，晶型V的粒径分布图如图43所示，晶型C的粒径分布图如图44所示。实验结果显示，本发明晶型C/V具有较均匀的粒径分布。Weigh about 10-30 mg of each of the crystal forms C/V 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, so that the shading degree reaches 0.2%. Appropriate range, start the experiment, and test the particle size distribution after sonicating for 30 seconds. The test results are shown in Table 35, the particle size distribution diagram of crystal form V is shown in Figure 43, and the particle size distribution diagram of crystal form C is shown in Figure 44 shown. The experimental results show that the crystal form C/V of the present invention has a relatively uniform particle size distribution.
表35Table 35
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CForm C 31.1931.19 10.8810.88 23.9323.93 54.6654.66
晶型VForm V 13.2513.25 2.562.56 6.916.91 18.0618.06
实施例76：黏附性对比研究Example 76: Adhesion Comparative Study
称取本发明晶型和现有技术中披露固体S1各约30毫克，然后加入到8毫米圆形平冲中，采用10kN的压力进行压片处理，压片后停留约半分钟，称量冲头吸附的粉末量。采用该方法连续压制两次后，记录冲头累积的最终黏附量、压制过程中的最高黏附量和平均黏附量。Weigh about 30 mg of each of the crystal form of the present invention and the solid S1 disclosed in the prior art, then add it to an 8 mm round flat punch, use a pressure of 10 kN to perform tableting treatment, stay for about half a minute after tableting, and weigh the punch. The amount of powder absorbed by the head. After two consecutive pressings using this method, the final sticking amount accumulated by the punch, the highest sticking amount and the average sticking amount during the pressing process were recorded.
本发明晶型的黏附性优于现有技术中披露固体S1。The adhesion of the crystal form of the present invention is better than that of the solid S1 disclosed in the prior art.
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 skilled in the art to understand the content of the present invention and implement them accordingly, and cannot limit the protection scope of the present invention. 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 (15)

  1. 式(I)所示化合物(S)-4-(3-(丁炔-2-基酰胺)哌啶-1-基)-5-氟-2,3-二甲基-1H-吲哚-7-甲酰胺的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6.6°±0.2°,13.2°±0.2°,17.5°±0.2°处有特征峰，The compound represented by formula (I) (S)-4-(3-(butyn-2-ylamide)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole- The C-type crystal of 7-formamide, that is, crystal form C, is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction of the crystal form C has a 2θ value of 6.6°±0.2°, 13.2°±0.2°, There is a characteristic peak at 17.5°±0.2°,
    Figure PCTCN2021127741-appb-100001
    Figure PCTCN2021127741-appb-100001
  2. 根据权利要求1中所述的晶型C的制备方法，其特征包括：According to the preparation method of crystal form C described in claim 1, it is characterized in that:
    (1)将式(I)化合物溶解于醇类溶剂中，20℃至30℃挥发，固体析出，得到晶型C；或(1) Dissolving the compound of formula (I) in an alcoholic solvent, volatilizing at 20°C to 30°C, and precipitation of a solid to obtain crystal form C; or
    (2)将式(I)化合物溶解于杂氮类溶剂中，将溶液快速加入至水中，固体析出，得到晶型C。(2) Dissolving the compound of formula (I) in an hetero-nitrogen-based solvent, adding the solution to water rapidly, the solid is precipitated, and crystal form C is obtained.
  3. 式(I)所示化合物(S)-4-(3-(丁炔-2-基酰胺)哌啶-1-基)-5-氟-2,3-二甲基-1H-吲哚-7-甲酰胺的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7.1±0.2°,14.3°±0.2°,8.3°±0.2°处有特征峰，The compound represented by formula (I) (S)-4-(3-(butyn-2-ylamide)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole- The A-type crystal of 7-carboxamide, that is, the crystal form A, is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction of the crystal form A has 2θ values of 7.1±0.2°, 14.3°±0.2°, 8.3 There are characteristic peaks at °±0.2°,
    Figure PCTCN2021127741-appb-100002
    Figure PCTCN2021127741-appb-100002
  4. 根据权利要求3中所述的晶型A的制备方法，其特征包括：According to the preparation method of crystal form A described in claim 3, it is characterized in that:
    (1)将式(I)化合物溶解于醇类、酮类、醚类或卤代烃类溶剂中，向其中加入式(I)化合物质量的0.5％～5％的高聚物，该高聚物为聚乙烯吡咯烷酮、聚乙烯醇、聚氯乙烯、聚醋酸乙烯酯、羟丙基甲基纤维素、甲基纤维素、聚己酸内酯、聚乙二醇、聚甲基丙烯酸甲酯、海藻酸钠、羟乙基纤维素的单一成分或混合物；将上述溶液置于20℃至30℃下挥发，固体析出，得到晶型A；或(1) Dissolving the compound of formula (I) in alcohols, ketones, ethers or halogenated hydrocarbon solvents, and adding 0.5% to 5% of the mass of the compound of formula (I) to the polymer, the high polymer The substances are polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, hydroxypropyl methylcellulose, methylcellulose, polycaprolactone, polyethylene glycol, polymethyl methacrylate, A single component or mixture of sodium alginate and hydroxyethyl cellulose; volatilize the above solution at 20°C to 30°C, and the solid is precipitated to obtain crystal form A; or
    (2)将式(I)化合物溶解于醇类、酮类、环醚类或酯类溶剂中，将溶液敞口置于纯水、直链醚类或烷烃类溶剂氛围下进行气液渗透，1～2周后，固体析出，得到晶型A；或(2) the compound of formula (I) is dissolved in alcohols, ketones, cyclic ethers or ester solvents, and the solution is placed openly in pure water, straight chain ethers or alkane solvent atmosphere to carry out gas-liquid infiltration, After 1 to 2 weeks, the solid is precipitated to obtain Form A; or
    (3)将式(I)化合物的溶解于醇类、酮类、醚类、酯类、卤代烃类、芳香烃溶剂的单一溶剂或混合物中，20℃至30℃挥发，固体析出，得到晶型A；或(3) dissolving the compound of formula (I) in a single solvent or mixture of alcohols, ketones, ethers, esters, halogenated hydrocarbons, and aromatic hydrocarbon solvents, volatilizing at 20°C to 30°C, and the solid is precipitated to obtain Form A; or
    (4)将式(I)化合物溶解于醇类、酮类、醚类或酯类溶剂中，向其中逐滴加入醚类、芳烃类或烷烃类反溶剂，固体析出，得到晶型A；或(4) dissolving the compound of formula (I) in alcohols, ketones, ethers or ester solvents, adding ethers, aromatic hydrocarbons or alkanes anti-solvent dropwise to it, solid precipitation to obtain crystal form A; or
    (5)将式(I)化合物溶解于醇类或酯类溶剂中，将溶液快速加入至烷烃类反溶剂中，固体析出，得到晶型A。(5) Dissolving the compound of formula (I) in an alcohol or ester solvent, adding the solution to an alkane anti-solvent rapidly, the solid is precipitated, and crystal form A is obtained.
  5. 式(I)所示化合物(S)-4-(3-(丁炔-2-基酰胺)哌啶-1-基)-5-氟-2,3-二甲基-1H-吲哚-7-甲酰胺的Y型晶体、即晶型Y，其特征在于，使用Cu-Kα辐射，所述晶型Y的X射线粉末衍射在2θ值为14.0°±0.2°,7.0°±0.2°,17.5°±0.2°处有特征峰，The compound represented by formula (I) (S)-4-(3-(butyn-2-ylamide)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole- The Y-type crystal of 7-formamide, that is, the crystal form Y, is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction of the crystal form Y has a 2θ value of 14.0°±0.2°, 7.0°±0.2°, There is a characteristic peak at 17.5°±0.2°,
    Figure PCTCN2021127741-appb-100003
    Figure PCTCN2021127741-appb-100003
  6. 根据权利要求5中所述的晶型Y的制备方法，其特征在于，according to the preparation method of crystal form Y described in claim 5, is characterized in that,
    (1)将权利要求3中所述晶型A，加入醇类溶剂中得到悬浊液，将其在20℃至30℃下超声30分钟，得到晶型Y；或(1) adding the crystal form A described in claim 3 to an alcohol solvent to obtain a suspension, and sonicating it for 30 minutes at 20°C to 30°C to obtain crystal form Y; or
    (2)将权利要求3中所述晶型A，加入醇类溶剂中得到悬浊液，将其在20℃至30℃下悬浮搅拌1天至4天，分离固体，得到晶型Y。(2) Add the crystal form A described in claim 3 into an alcoholic solvent to obtain a suspension, which is suspended and stirred at 20°C to 30°C for 1 to 4 days, and the solid is separated to obtain crystal form Y.
  7. 式(I)所示化合物(S)-4-(3-(丁炔-2-基酰胺)哌啶-1-基)-5-氟-2,3-二甲基-1H-吲哚-7-甲酰胺的V型晶体、即晶型V，其特征在于，使用Cu-Kα辐射，所述晶型V的X射线粉末衍射在2θ值为6.5°±0.2°,15.0°±0.2°,13.0°±0.2°处有特征峰，The compound represented by formula (I) (S)-4-(3-(butyn-2-ylamide)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole- The V-type crystal of 7-formamide, that is, the crystal form V, is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction of the crystal form V has a 2θ value of 6.5°±0.2°, 15.0°±0.2°, There is a characteristic peak at 13.0°±0.2°,
    Figure PCTCN2021127741-appb-100004
    Figure PCTCN2021127741-appb-100004
  8. 根据权利要求7中所述的晶型V的制备方法，其特征包括：According to the preparation method of crystal form V described in claim 7, it is characterized in that:
    (1)将式(I)化合物溶解于环醚类溶剂中，将溶液挥发，固体析出，得到晶型V；或(1) Dissolving the compound of formula (I) in a cyclic ether solvent, volatilizing the solution, and precipitating a solid to obtain crystal form V; or
    (2)将式(I)化合物溶解于醇类溶剂中，向溶液中加入式(I)化合物质量的0.5％～15％的高聚物，该高聚物为聚乙烯吡咯烷酮、聚乙烯醇、聚氯乙烯、聚醋酸乙烯酯、羟丙基甲基纤维素与甲基纤维素的单一成分或混合物；将该溶液挥发，固体析出，得到晶型V；或(2) Dissolving the compound of formula (I) in an alcohol solvent, adding a high polymer of 0.5% to 15% of the mass of the compound of formula (I) to the solution, the high polymer is polyvinylpyrrolidone, polyvinyl alcohol, A single component or mixture of polyvinyl chloride, polyvinyl acetate, hydroxypropyl methylcellulose and methylcellulose; the solution is volatilized, and the solid is precipitated to obtain crystal form V; or
    (3)将式(I)化合物溶解于烷基腈类溶剂中，高温条件下达到溶解平衡，将溶液降温至有固体析出，得到晶型V。(3) Dissolving the compound of formula (I) in an alkyl nitrile solvent, reaching a dissolution equilibrium under high temperature conditions, cooling the solution until a solid is precipitated to obtain crystal form V.
  9. 式(I)所示化合物(S)-4-(3-(丁炔-2-基酰胺)哌啶-1-基)-5-氟-2,3-二甲基-1H-吲哚-7-甲酰胺的AE型晶体、即晶型AE，其特征在于，使用Cu-Kα辐射，所述晶型AE的X射线粉末衍射在2θ值为6.4°±0.2°,15.5°±0.2°,12.8°±0.2°处有特征峰，The compound represented by formula (I) (S)-4-(3-(butyn-2-ylamide)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole- The AE-type crystal of 7-formamide, that is, the crystalline form AE, is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction of the crystalline form AE has a 2θ value of 6.4°±0.2°, 15.5°±0.2°, There is a characteristic peak at 12.8°±0.2°,
    Figure PCTCN2021127741-appb-100005
    Figure PCTCN2021127741-appb-100005
  10. 根据权利要求9中所述的晶型AE的制备方法，其特征包括：According to the preparation method of crystal form AE described in claim 9, it is characterized in that:
    (1)将式(I)化合物溶解于杂氮类溶剂中，将溶液快速加入至纯水中，固体析出，得到晶型AE；或(1) dissolving the compound of formula (I) in the hetero-nitrogen solvent, adding the solution to pure water quickly, the solid is precipitated to obtain crystal form AE; or
    (2)将式(I)化合物溶解于醇类溶剂中，在溶液中加入式(I)化合物质量的0.5％～15％的高聚物，该高聚物为聚乙烯吡咯烷酮、聚乙烯醇、聚氯乙烯、聚醋酸乙烯酯、羟丙基甲基纤维素、甲基纤维素的单一或混合物；将该溶液转移至20℃至30℃下挥发，固体析出，得到晶型AE；或(2) Dissolving the compound of formula (I) in an alcohol solvent, adding a high polymer of 0.5% to 15% of the mass of the compound of formula (I) to the solution, the high polymer is polyvinylpyrrolidone, polyvinyl alcohol, Single or mixture of polyvinyl chloride, polyvinyl acetate, hydroxypropyl methyl cellulose, methyl cellulose; transfer the solution to 20°C to 30°C to volatilize, and the solid is precipitated to obtain crystal form AE; or
    (3)将式(I)化合物的溶解于醇类溶剂中，40℃至60℃下溶解平衡，将溶液转移至5℃至-25℃条件下静置，固体析出，得到晶型AE；或(3) dissolving the compound of formula (I) in an alcohol solvent, dissolving equilibrium at 40°C to 60°C, transferring the solution to stand at 5°C to -25°C, and solid precipitation to obtain crystal form AE; or
    (4)将式(I)化合物的溶解于醇类溶剂中，将溶液转移至20℃至30℃挥发，固体析出，得到晶型AE。(4) Dissolve the compound of formula (I) in an alcohol solvent, transfer the solution to 20°C to 30°C to volatilize, and precipitate a solid to obtain crystal form AE.
  11. 式(I)所示化合物(S)-4-(3-(丁炔-2-基酰胺)哌啶-1-基)-5-氟-2,3-二甲基-1H-吲哚-7-甲酰胺的AA型晶体、即晶型AA，其特征在于，使用Cu-Kα辐射，所述晶型AA的X射线粉末衍射在2θ值为11.7°±0.2°,16.1°±0.2°,16.7°±0.2°处有特征峰，The compound represented by formula (I) (S)-4-(3-(butyn-2-ylamide)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole- The AA-type crystal of 7-formamide, that is, the crystal form AA, is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction of the crystal form AA has a 2θ value of 11.7°±0.2°, 16.1°±0.2°, There is a characteristic peak at 16.7°±0.2°,
    Figure PCTCN2021127741-appb-100006
    Figure PCTCN2021127741-appb-100006
  12. 根据权利要求11中所述的晶型AA的制备方法，其特征在于，According to the preparation method of crystal form AA described in claim 11, it is characterized in that,
    将式(I)化合物的溶解于醇类溶剂中，40℃至60℃下达到溶解平衡，将溶液降温至固体析出，得到晶型AA。The compound of formula (I) is dissolved in an alcohol solvent, and the dissolution equilibrium is reached at 40° C. to 60° C., and the solution is cooled to solid precipitation to obtain crystal form AA.
  13. 药物组合物，其包含上述1、3、5、7、9、11中任一项所述的晶体和制药学可接受的载体。A pharmaceutical composition comprising the crystal described in any one of the above 1, 3, 5, 7, 9, 11 and a pharmaceutically acceptable carrier.
  14. 具有BTK抑制活性的药物组合物，其含有上述1、3、5、7、9、11中任一项所述的晶体作为有效成分。A pharmaceutical composition having BTK inhibitory activity, which contains the crystal described in any one of the above 1, 3, 5, 7, 9, and 11 as an active ingredient.
  15. 慢性淋巴细胞白血病，套细胞淋巴瘤和华氏巨球蛋白血症的预防药或治疗药，其含有上述1、3、5、7、9、11中任一项所述的晶体作为有效成分。A preventive or therapeutic drug for chronic lymphocytic leukemia, mantle cell lymphoma and Waldenstrom's macroglobulinemia, which contains the crystal described in any one of the above 1, 3, 5, 7, 9, and 11 as an active ingredient.
PCT/CN2021/127741 2020-10-30 2021-10-30 New crystal forms of indole carboxamide compound and preparation method therefor WO2022089620A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202011184955 2020-10-30
CN202011184955.9 2020-10-30

Publications (1)

Publication Number Publication Date
WO2022089620A1 true WO2022089620A1 (en) 2022-05-05

Family

ID=81383595

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/127741 WO2022089620A1 (en) 2020-10-30 2021-10-30 New crystal forms of indole carboxamide compound and preparation method therefor

Country Status (1)

Country Link
WO (1) WO2022089620A1 (en)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016065226A1 (en) * 2014-10-24 2016-04-28 Bristol-Myers Squibb Company Indole carboxamides compounds useful as kinase inhobitors
WO2018045157A1 (en) * 2016-09-02 2018-03-08 Bristol-Myers Squibb Company Process for preparing indole carboxamide compounds

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016065226A1 (en) * 2014-10-24 2016-04-28 Bristol-Myers Squibb Company Indole carboxamides compounds useful as kinase inhobitors
WO2018045157A1 (en) * 2016-09-02 2018-03-08 Bristol-Myers Squibb Company Process for preparing indole carboxamide compounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
WATTERSON SCOTT H., LIU QINGJIE, BEAUDOIN BERTRAND MYRA, BATT DOUGLAS G., LI LING, PATTOLI MARK A., SKALA STACEY, CHENG LIHONG, OB: "Discovery of Branebrutinib (BMS-986195): A Strategy for Identifying a Highly Potent and Selective Covalent Inhibitor Providing Rapid in Vivo Inactivation of Bruton’s Tyrosine Kinase (BTK)", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 62, no. 7, 11 April 2019 (2019-04-11), US , pages 3228 - 3250, XP055781288, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.9b00167 *

Similar Documents

Publication Publication Date Title
WO2019052133A1 (en) Crystal form of gsk1278863 and preparation method and pharmaceutical use thereof
US11066384B2 (en) Crystalline forms of ARN-509, preparation method and use thereof
US11117876B2 (en) Crystalline form of ozanimod hydrochloride, and processes for preparation thereof
WO2019019959A1 (en) Crystal form of monosuccinate of ribociclib and preparation method and use thereof
WO2017193914A1 (en) Crystal forms of crisaborole in free form and preparation method and use thereof
WO2022121670A1 (en) Crystal form of tolebrutinib, preparation method therefor and use thereof
WO2022257845A1 (en) Crystal form of tolebrutinib, preparation method therefor and use thereof
WO2018103726A1 (en) Crystal form of bromodomain protein inhibitor drug, preparation method and use thereof
US20220002306A1 (en) Crystal form of upadacitinib and preparation method and use thereof
WO2022089620A1 (en) New crystal forms of indole carboxamide compound and preparation method therefor
WO2023280132A1 (en) Crystal form of oxodihydroimidazopyridine compound and preparation method therefor
WO2019205812A1 (en) New crystal form of acalabrutinib, preparation method therefor and use thereof
WO2021249367A1 (en) New crystal form of p-toluenesulfonate salt of diazabicyclic compound and preparation method therefor
WO2020057622A1 (en) Cabozantinib malate crystal form, preparation method therefor and use thereof
WO2022105792A1 (en) New crystal forms of quinazolinone derivative and preparation method therefor
WO2022122009A1 (en) Crystal forms of pyrrole derivative compound and preparation method therefor
WO2019149262A1 (en) Crystal form of sb-939, preparation method and use thereof
WO2019105359A1 (en) Crystal form of acalabrutinib, preparation method therefor and application thereof
WO2021218948A1 (en) Crystal forms of sulfonamide compound and preparation method therefor
WO2022007752A1 (en) New crystal form of benzamide compound and dihydrochloride thereof, and preparation method therefor
WO2022206879A1 (en) Crystal forms of sulfamoyl pyrrole amide compounds and preparation methods therefor
WO2023109939A1 (en) Crystal form of pyridine derivative and preparation method therefor
WO2023025268A1 (en) Crystal forms of pyridazine carboxamide compound and preparation method thereof
WO2022206937A1 (en) New crystal form of hydrochloride of pyrazole-substituted nicotinamide compound and preparation method therefor
WO2019148789A1 (en) Crystal form of ap26113 and preparation method therefor

Legal Events

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

Ref document number: 21885346

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21885346

Country of ref document: EP

Kind code of ref document: A1