WO2022052925A1 - Repotrectinib crystal form and preparation method therefor - Google Patents

Repotrectinib crystal form and preparation method therefor Download PDF

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WO2022052925A1
WO2022052925A1 PCT/CN2021/117042 CN2021117042W WO2022052925A1 WO 2022052925 A1 WO2022052925 A1 WO 2022052925A1 CN 2021117042 W CN2021117042 W CN 2021117042W WO 2022052925 A1 WO2022052925 A1 WO 2022052925A1
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crystal form
group
solvent
xrpd pattern
crystal
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PCT/CN2021/117042
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French (fr)
Chinese (zh)
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彭欢
闵思佳
张凤杰
张良
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上海希迈医药科技有限公司
上海创诺医药集团有限公司
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Publication of WO2022052925A1 publication Critical patent/WO2022052925A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to the field of medicinal chemistry, in particular to (7S,13R)-11 fluoro-7,14-dimethyl-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3
  • (7S,13R)-11 fluoro-7,14-dimethyl-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3 A new crystal form of -f][1,4,8,10]-benzoxatriazacyclotridecyn-4(5H)-one and its preparation method.
  • Loprotinib (TPX-0005) is a potent small-molecule multi-targeted kinase inhibitor that has been shown to inhibit wild-type and mutant ALA (anaplastic lymphoma kinase), wild-type and mutant ROS1 (pro-ROS1) Oncogene receptor tyrosine kinase), TRK family kinase (tropomyosin-related receptor tyrosine kinase), JAK2 of Janus family kinase, SRC (Src family protein tyrosine kinase (SFK)) and FAK (adhesion spot kinase) activity. It is the fourth-generation ALK inhibitor developed by TP Therapeutics.
  • TP Therapeutics announced that the FDA has granted orphan drug designation to its investigational new drug compound TPX-0005 for the treatment of NSCLC (non-small cell lung cancer) with ALK, ROS1 or NTRK oncogene rearrangements patient.
  • ALK inhibitor resistance mechanisms generally include the following: secondary resistance mutations in the ALK kinase domain, ALK fusion gene copy number amplification, activation of alternative and downstream pathways, epithelial-mesenchymal transition, etc.
  • the compact small-molecule structure of TPX-0005 enables it to bind to the central binding site inside ATP, and avoid steric hindrance caused by mutations outside the ATP binding site, that is, to avoid the interference of clinical drug resistance mutations.
  • Loprotinib (TPX-0005) has the chemical name of (7S,13R)-11fluoro-7,14-dimethyl-6,7,13,14-tetrahydro-1,15-vinylpyrazolo [4,3-f][1,4,8,10]-benzoxatriazacyclotridecyn-4(5H)-one, its molecular structure is as follows:
  • Patent WO2017007759 reports a crystalline form of the compound of formula (I) - Form 1, but does not publicly report any physical properties of this crystalline form that are of great significance to product development, such as stability, solubility, hygroscopicity, and powder properties. chemical properties.
  • the reported preparation method is concentrated crystallization, which has an unpredictable amplification effect, that is, it is difficult to control the particle size and crystal habit of crystals by using concentrated crystallization during the scale-up production process, resulting in inconsistencies between batches, which in turn affects subsequent preparations, etc. craft.
  • the above preparation method needs to use dichloromethane and methanol, which is carcinogenic to animals and has low environmental friendliness.
  • the purpose of the present invention is to provide a new crystal form of the compound of formula (I) that is easy to prepare and has high stability, so as to meet the needs of drug research and industrial production.
  • the first aspect of the present invention provides a crystal form of the compound of formula (I): the crystal form includes crystal form CM-I, crystal form CM-II, crystal form CM-III, crystal form CM-IV, crystal form Form CM-V, Form CM-VI, Form CM-VII and/or Form CM-VIII.
  • the crystal form is selected from the following group: crystal form CM-I, crystal form CM-II, crystal form CM-III;
  • the XRPD pattern of the crystal form CM-I includes 2 or more 2 ⁇ values selected from the following group: 7.7° ⁇ 0.2°, 8.9° ⁇ 0.2°, 11.3° ⁇ 0.2°, 15.5° ⁇ 0.2° , 17.8° ⁇ 0.2°;
  • the XRPD of the crystal form CM-II comprises 3 or more 2 ⁇ values selected from the group consisting of 10.7° ⁇ 0.2°, 12.4° ⁇ 0.2°, 19.1° ⁇ 0.2°, 22.8° ⁇ 0.2°;
  • the XRPD pattern of the crystalline form CM-III includes 3 or more 2 ⁇ values selected from the group consisting of 7.9° ⁇ 0.2°, 9.1° ⁇ 0.2°, 9.7° ⁇ 0.2°, 18.9° ⁇ 0.2°.
  • the crystal form is crystal form CM-I, wherein the XRPD pattern of the crystal form CM-I includes 2 or more (eg 2, 3, 4) 2 ⁇ values selected from the group consisting of: 7.7 ° ⁇ 0.2°, 8.9° ⁇ 0.2°, 11.3° ⁇ 0.2°, 15.5° ⁇ 0.2°, 17.8° ⁇ 0.2°.
  • the crystalline form is crystalline form CM-II, wherein the XRPD of the crystalline form CM-II includes 3 or more (eg 3, 4, 5) 2 ⁇ values selected from the following group: 10.7° ⁇ 0.2°, 12.4° ⁇ 0.2°, 19.1° ⁇ 0.2°, 22.8° ⁇ 0.2°.
  • the crystal form is crystal form CM-III, wherein the XRPD pattern of the crystal form CM-III includes 3 or more (eg 3, 4, 5) 2 ⁇ values selected from the group consisting of: 7.9 ° ⁇ 0.2°, 9.1° ⁇ 0.2°, 9.7° ⁇ 0.2°, 18.9° ⁇ 0.2°.
  • the crystalline form CM-I has one or more characteristics selected from the group consisting of:
  • the XRPD pattern of the crystal form CM-I includes 6 or more (eg 6, 7, 8, 9, 10) 2 ⁇ values selected from the following group: 3.9° ⁇ 0.2°, 7.7° ⁇ 0.2 °, 8.9° ⁇ 0.2°, 11.3° ⁇ 0.2°, 14.3° ⁇ 0.2°, 15.5° ⁇ 0.2°, 17.8° ⁇ 0.2°, 20.0° ⁇ 0.2°, 22.7° ⁇ 0.2°, 23.3° ⁇ 0.2°, 25.1° ⁇ 0.2°, 28.9° ⁇ 0.2°.
  • CM-I has an XRPD pattern basically as shown in Figure 1;
  • CM-I has a DSC diagram as shown in FIG. 3;
  • CM-I has a 1 H NMR spectrum substantially as shown in FIG. 4 .
  • the crystalline form CM-II has one or more characteristics selected from the group consisting of:
  • the XRPD pattern of the crystal form CM-II includes 6 or more (eg 6, 7, 8, 9, 10) 2 ⁇ values selected from the following group: 6.2° ⁇ 0.2°, 8.8° ⁇ 0.2 °, 10.7° ⁇ 0.2°, 12.4° ⁇ 0.2°, 16.4° ⁇ 0.2°, 17.0° ⁇ 0.2°, 17.5° ⁇ 0.2°, 19.1° ⁇ 0.2°, 20.2° ⁇ 0.2°, 21.4° ⁇ 0.2°, 22.3° ⁇ 0.2°, 22.8° ⁇ 0.2°, 24.5° ⁇ 0.2°, 26.8° ⁇ 0.2°, 27.0° ⁇ 0.2°, 27.5° ⁇ 0.2°.
  • CM-II has an XRPD pattern as basically shown in Figure 6;
  • CM-II has a TGA diagram as shown in FIG. 7 ;
  • CM-II has a DSC diagram as shown in FIG. 8;
  • CM-II has a 1 H NMR spectrum substantially as shown in FIG. 9 .
  • the crystalline form CM-III has one or more characteristics selected from the group consisting of:
  • the XRPD pattern of the crystal form CM-III includes 6 or more (eg 6, 7, 8, 9, 10) 2 ⁇ values selected from the following group: 6.5° ⁇ 0.2°, 7.9° ⁇ 0.2 °, 9.1° ⁇ 0.2°, 9.7° ⁇ 0.2°, 15.3° ⁇ 0.2°, 18.8° ⁇ 0.2°, 18.9° ⁇ 0.2°, 20.3° ⁇ 0.2°, 21.1° ⁇ 0.2°, 23.3° ⁇ 0.2°, 23.8° ⁇ 0.2°, 26.1° ⁇ 0.2°, 28.9° ⁇ 0.2°.
  • the crystal form CM-III has a DSC chart as shown in FIG. 15 ;
  • CM-III has a 1 H NMR spectrum substantially as shown in FIG. 16 .
  • the crystal form is crystal form CM-IV, wherein the XRPD pattern of the crystal form CM-IV includes 2 or more (eg 2, 3, 4) 2 ⁇ values selected from the group consisting of: 7.1 ° ⁇ 0.2°, 19.6° ⁇ 0.2°, 21.5° ⁇ 0.2°, 28.9° ⁇ 0.2°.
  • the crystalline form CM-IV has one or more characteristics selected from the group consisting of:
  • the XRPD pattern of the crystal form CM-IV includes 4 or more (such as 5, 6, 7, 8) 2 ⁇ values selected from the following group: 7.1° ⁇ 0.2°, 9.7° ⁇ 0.2°, 18.6° ⁇ 0.2°, 19.6° ⁇ 0.2°, 21.5° ⁇ 0.2°, 28.9° ⁇ 0.2°;
  • the crystal form CM-IV has an XRPD pattern substantially as shown in FIG. 18 .
  • the crystal form is crystal form CM-V, wherein the XRPD pattern of the crystal form CM-V includes 2 or more (eg 2, 3, 4) 2 ⁇ values selected from the following group: 6.9 ° ⁇ 0.2°, 9.4° ⁇ 0.2°, 21.0° ⁇ 0.2°, 21.5° ⁇ 0.2°, 28.1° ⁇ 0.2°.
  • the crystalline form CM-V has one or more characteristics selected from the group consisting of:
  • the XRPD pattern of the crystalline form CM-V includes 6 or more (such as 6, 7, 8, 9) 2 ⁇ values selected from the following group: 6.9° ⁇ 0.2°, 9.4° ⁇ 0.2°, 21.0° ⁇ 0.2°, 21.5° ⁇ 0.2°, 23.2° ⁇ 0.2°, 23.6° ⁇ 0.2°, 28.1° ⁇ 0.2°, 28.8° ⁇ 0.2°;
  • CM-V has an XRPD pattern substantially as shown in FIG. 19 .
  • the crystal form is crystal form CM-VI, wherein the XRPD pattern of the crystal form CM-VI includes 2 or more (eg 2, 3, 4) 2 ⁇ values selected from the group consisting of: 7.4 ° ⁇ 0.2°, 9.0° ⁇ 0.2°, 15.1° ⁇ 0.2°, 22.5° ⁇ 0.2°.
  • the crystalline form CM-VI has one or more characteristics selected from the group consisting of:
  • the XRPD pattern of the crystal form CM-VI includes 4 or more (such as 5, 6, 7, 8) 2 ⁇ values selected from the following group: 7.4° ⁇ 0.2°, 9.0° ⁇ 0.2°, 14.9° ⁇ 0.2°, 15.1° ⁇ 0.2°, 18.2° ⁇ 0.2°, 22.5° ⁇ 0.2°, 30.7° ⁇ 0.2°;
  • CM-VI has an XRPD pattern basically as shown in FIG. 20 .
  • the crystal form is crystal form CM-VII, wherein the XRPD pattern of the crystal form CM-VII includes 3 or more (eg 3, 4, 5) 2 ⁇ values selected from the following group: 8.4 ° ⁇ 0.2°, 13.6° ⁇ 0.2°, 15.3° ⁇ 0.2°, 16.8° ⁇ 0.2°, 18.9° ⁇ 0.2°, 23.0° ⁇ 0.2°.
  • the crystal form CM-VII has one or more features selected from the group consisting of:
  • the XRPD pattern of the crystal form CM-VII includes 6 or more (eg, 6, 7, 8, 9) 2 ⁇ values selected from the following group: 8.4° ⁇ 0.2°, 13.6° ⁇ 0.2° , 15.3° ⁇ 0.2°, 16.5° ⁇ 0.2°, 16.8° ⁇ 0.2°, 17.3° ⁇ 0.2°, 18.0° ⁇ 0.2°, 18.9° ⁇ 0.2°, 19.8° ⁇ 0.2°, 21.2° ⁇ 0.2°, 23.0 ° ⁇ 0.2°, 23.9° ⁇ 0.2°, 26.9° ⁇ 0.2°;
  • CM-VII has an XRPD pattern substantially as shown in Figure 21;
  • CM-VII has a TGA diagram substantially as shown in FIG. 22 .
  • the crystal form is crystal form CM-VIII, wherein the XRPD pattern of the crystal form CM-VIII includes 2 or more (eg 2, 3, 4) 2 ⁇ values selected from the group consisting of: 7.4 ° ⁇ 0.2°, 8.2° ⁇ 0.2°, 8.9° ⁇ 0.2°, 10.4° ⁇ 0.2°.
  • the crystalline form CM-VIII has one or more characteristics selected from the group consisting of:
  • the XRPD pattern of the crystal form CM-VIII includes 4 or more (eg 5, 6, 7) 2 ⁇ values selected from the following group: 7.4° ⁇ 0.2°, 8.2° ⁇ 0.2°, 8.9° ⁇ 0.2°, 10.4° ⁇ 0.2°, 16.3° ⁇ 0.2°, 18.3° ⁇ 0.2°, 25.2° ⁇ 0.2°;
  • CM-VIII has an XRPD pattern substantially as shown in FIG. 26 .
  • the second aspect of the present invention provides a method for preparing a crystal form as described in the first aspect, comprising the steps of: crystallizing the compound of formula (I) in an inert solvent, or crystallizing the compound of formula (I) in solid form
  • a treatment is performed to obtain the crystalline form, wherein the treatment includes one or more steps of the following group: stirring, heating, and placing under certain temperature and humidity conditions.
  • the preparation method includes the steps of: a) providing a solution of the raw material of the compound of formula (I) in a first solvent, adding a second solvent to the solution for crystallization, and collecting the precipitated solid to obtain the crystal form.
  • the step a) includes: dissolving the raw material of the compound of formula (I) in a first solvent, filtering, then adding a second solvent to the obtained filtrate for crystallization, and collecting the precipitated solid to obtain the crystal form.
  • the addition is dropwise or slow addition.
  • the crystallization comprises stirring crystallization or standing crystallization.
  • the preparation method comprises the steps of: b) providing a solution of the raw material of the compound of formula (I) in a first solvent, adding the solution to a second solvent for crystallization, and collecting the precipitated solid to obtain the crystal form.
  • the step b) comprises: dissolving the raw material of the compound of formula (I) in the first solvent, filtering, then adding the obtained filtrate to the second solvent for crystallization, and collecting the precipitated solid to obtain the crystal form.
  • the addition is dropwise or slow addition.
  • the crystallization comprises stirring crystallization or standing crystallization.
  • the preparation method includes the steps of: c) providing a solution or crystal slurry of the raw material of the compound of formula (I) in a first solvent, processing the solution or crystal slurry to obtain a solid, and collecting the obtained solid to obtain the crystal Type; wherein, the treatment includes stirring or volatilization.
  • the preparation method comprises the steps of: d) providing a solid form of the raw material of the compound of formula (I), and processing the solid form to obtain the crystal form; wherein, the solid form is a crystal form or an amorphous form,
  • the treatment includes one or more of the following steps: heating, placing under certain temperature and humidity conditions.
  • the first solvent includes alcohol-based solvents, ketone-based solvents, amide-based solvents, ester-based solvents, ether-based solvents, acid-based solvents, nitriles, water, or a combination thereof.
  • the alcoholic solvent is selected from the group consisting of methanol, ethanol, isopropanol, n-propanol, or a combination thereof.
  • the ketone solvent is selected from the group consisting of acetone, 2-butanone, N-methylpyrrolidone, or a combination thereof.
  • the amide solvent is selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, or a combination thereof.
  • the ester solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, or a combination thereof.
  • the ether solvent is selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, or a combination thereof.
  • the acid solvent is selected from the group consisting of formic acid, acetic acid, lactic acid, or a combination thereof.
  • the nitrile solvent is selected from the group consisting of acetonitrile.
  • the second solvent includes hydrocarbons, esters, water, or a combination thereof.
  • the hydrocarbon solvent is selected from the group consisting of chloroform, dichloromethane, nitromethane, n-heptane, cyclohexane, toluene, or a combination thereof.
  • the ester solvent is selected from the group consisting of butyl acetate, n-propyl acetate, or a combination thereof.
  • the solid is processed to obtain the crystal form, wherein the processing includes vacuum drying.
  • a third aspect of the present invention provides a pharmaceutical composition, the composition comprising:
  • the fourth aspect of the present invention provides the use of the pharmaceutical composition according to the third aspect to prepare a medicine for treating NSCLC patients with ALK, ROS1 or NTRK oncogene rearrangement.
  • the fifth aspect of the present invention provides the use of the crystal form according to the first aspect, the use includes: 1) preparing the compound of formula (I) or a salt thereof; 2) preparing for the treatment of carcinogenesis carrying ALK, ROS1 or NTRK Drugs for NSCLC patients with genetic rearrangements.
  • the fifth aspect of the present invention provides the use of the crystal form according to the first aspect, including: 1) preparing the compound of formula (I) or a salt thereof; 2) preparing the compound for the treatment of ALK, ROS1 or NTRK NSCLC patients with oncogene rearrangements.
  • the crystal form stability and mechanical stability of the present invention are good, thereby reducing the risk of crystal transformation during the preparation process, and reducing the risk of changes in the dissolution rate and bioavailability of the drug due to changes in the crystal form, which is conducive to crystallization and Crystal Form Control in Formulation Process.
  • the crystal form of the present invention has low hygroscopicity, does not require harsh packaging and storage conditions, and does not require special drying conditions in the preparation process, which simplifies the preparation and post-processing technology of the drug, is beneficial to industrial production, and significantly reduces the number of drugs.
  • the preparation method of the crystal form provided by the present invention is safe and reliable. At the same time, the operation is simple and easy, the cost is low, and the method is suitable for drug research and development and industrial production.
  • the crystal form provided by the present invention has good solubility and high bioavailability, and can reduce the dosage of the medicine while ensuring the curative effect of the medicine, thereby reducing the side effect of the medicine and improving the safety of the medicine.
  • Fig. 1 is the XRPD pattern of the crystal form CM-I of the present invention.
  • Figure 2 is a TGA diagram of the crystal form CM-I of the present invention.
  • Figure 3 is the DSC chart of the crystal form CM-I of the present invention.
  • Fig. 4 is the 1 H NMR spectrum of the crystal form CM-I of the present invention.
  • Fig. 5 is the XRPD comparison chart of the crystal form CM-I of the present invention placed at 25°C/60%RH and 40°C/75%RH for one month (from top to bottom in the figure, respectively placed at 40°C/75%RH, Figures after one month at 25°C/60% RH and before placement).
  • Fig. 6 is the XRPD pattern of the crystal form CM-II of the present invention.
  • Figure 7 is a TGA diagram of the crystal form CM-II of the present invention.
  • Figure 8 is the DSC chart of the crystal form CM-II of the present invention.
  • Fig. 9 is the 1 H NMR spectrum of the crystal form CM-II of the present invention.
  • Fig. 10 XRPD comparison chart of the crystal form CM-II of the present invention placed at 25°C/60%RH and 40°C/75%RH for one month (from top to bottom, respectively placed at 40°C/75%RH, 25°C/ 60% RH for one month and pictures before placement).
  • Figure 11 is the XRPD pattern of the crystal form CM-II of the present invention before and after milling (the upper figure is the XRPD pattern after milling, and the lower figure is the XRPD pattern before milling).
  • Figure 12 is a DVS diagram of the crystal form CM-II of the present invention.
  • Figure 13 is the XRPD pattern of the crystal form CM-III of the present invention.
  • Figure 14 is a TGA diagram of the crystal form CM-III of the present invention.
  • Figure 15 is the DSC chart of the crystal form CM-III of the present invention.
  • Figure 16 is the 1 H NMR spectrum of the crystal form CM-III of the present invention.
  • Figure 17 is the XRPD pattern of the crystal form CM-III of the present invention before and after milling (the upper figure is the XRPD pattern after milling, and the lower figure is the XRPD pattern before milling).
  • Figure 18 is the XRPD pattern of the crystal form CM-IV of the present invention.
  • Figure 19 is the XRPD pattern of the crystal form CM-V of the present invention.
  • Figure 20 is the XRPD pattern of the crystal form CM-VI of the present invention.
  • Figure 21 is the XRPD pattern of the crystal form CM-VII of the present invention.
  • Figure 22 is a TGA diagram of the crystal form CM-VII of the present invention.
  • Figure 23 is an XRPD pattern of the amorphous form of the present invention.
  • Figure 24 is the XRPD comparison chart of the crystal form CM-III of the present invention placed at 25°C/60%RH and 40°C/75%RH for one month (from top to bottom, placed at 40°C/75%RH, 25°C, respectively /60% RH for one month and pictures before placement).
  • Figure 25 is an XRPD pattern of Form 1 prepared according to the method in patent WO2017007759.
  • Figure 26 is the XRPD pattern of the crystal form CM-VIII of the present invention.
  • the XRPD pattern of the crystal form CM-I containing excipients of the present invention before and after tableting is the XRPD pattern of the crystal form CM-I containing excipients of the present invention before and after tableting (the upper picture is the XRPD pattern after tableting, and the lower picture is the XRPD pattern before tableting).
  • Figure 29 is the XRPD pattern of the crystal form CM-II containing excipients of the present invention before and after tabletting (the upper picture is the XRPD pattern after tabletting, and the lower picture is the XRPD pattern before tabletting).
  • Fig. 30 is the XRPD pattern of the crystal form CM-III containing excipients of the present invention before and after tabletting (the upper picture is the XRPD pattern after tabletting, and the lower picture is the XRPD pattern before tabletting).
  • the inventors of the present invention have surprisingly discovered a series of new crystal forms of the compound of formula (I) in the course of research. These crystal forms are simple to prepare, low cost, and have advantages in crystal form stability, solubility, moisture absorption, tableting stability, mechanical stability, formulation stability, process developability and powder processing performance. The optimization and development of drugs is of great significance.
  • the tablet is not sticky during tableting, so the tablet prepared from the crystal form of the present invention has excellent tableting stability.
  • raw material for the compound of formula (I) refers to the amorphous (form) and/or various crystalline forms (including the various crystalline and amorphous forms mentioned herein) of the compound of formula (I) , the crystalline form or amorphous form mentioned in various published or unpublished documents or patents, such as the compound form 1 of formula (I) prepared according to the method described in WO2017007759.
  • crystal form of the present invention refers to crystal form CM-I, crystal form CM-II, crystal form CM-III, crystal form CM-IV, crystal form CM-V, crystal form as described herein Form CM-VI, Form CM-VII and Form CM-VIII.
  • the method of adding the solvent or solution is direct pouring or uniform addition, and the like.
  • slow addition includes, but is not limited to, dropwise addition, slow addition along the container wall, and the like.
  • the solvents used in the present invention are all analytically pure, and the water content is about 0.1%.
  • the compounds of formula (I) used as raw materials in the examples were all purchased. All test methods of the present invention are general methods, and the test parameters are as follows:
  • X-ray powder diffractometer Bruker D2 Phaser X-ray powder diffractometer; radiation source Cu Generator kv: 30kv; Generator mA: 10mA; initial 2 ⁇ : 2.000°, scanning range: 2.0000-35.000°, scanning step size 0.02°, scanning speed 0.1s/step.
  • Thermogravimetric analysis (TGA) instrument TGA55 of TA company in the United States; heating rate: 10° C./min; nitrogen flow rate: 40 mL/min.
  • DSC Differential scanning calorimetry
  • Hydrogen nuclear magnetic resonance data ( 1 H NMR) were obtained from a Bruker Avance II DMX 400M HZ nuclear magnetic resonance spectrometer. 2 mg of the sample was weighed, dissolved in 0.6 mL of deuterated dimethyl sulfoxide, filtered, and the filtrate was added to a NMR tube for testing.
  • Dynamic Moisture Sorption (DVS) Instrument TA Q5000 SA from TA Company, USA; Temperature: 25°C; Nitrogen Flow Rate: 50mL/min; Mass Change per Unit Time: 0.002%/min; Relative Humidity Range: 0%RH ⁇ 90% RH.
  • Particle and powder characteristic analyzer FT-2000A/B of Ningbo Ruike Weiye Instrument Co., Ltd.
  • the drying method is a conventional drying method in the field.
  • drying in the embodiments of the present invention refers to vacuum drying or normal pressure drying in a conventional drying oven.
  • drying is performed for 0.1 to 50h or 1 to 30h.
  • compositions and methods of administration are provided.
  • the crystal form of the present invention or Loprotinib (amorphous) prepared from the crystal form of the present invention has an excellent therapeutic effect on NSCLC patients with ALK, ROS1 or NTRK oncogene rearrangements
  • the crystal form of the present invention Or Loprotinib (amorphous) prepared from the crystal form of the present invention and pharmaceutical compositions containing the crystal form of the present invention or Loprotinib (amorphous) prepared from the crystal form of the present invention as the main active ingredient can be used for the treatment of cancer patients or NSCLC patients with ALK, ROS1 or NTRK oncogene rearrangements.
  • the crystal form of the present invention or Loprotinib (amorphous form can be used to prepare and treat cancer patients (such as NSCLC patients carrying ALK, ROS1 or NTRK oncogene rearrangement) prepared from the crystal form of the present invention, the drug can Prepared by methods commonly used in the art.
  • the pharmaceutical composition of the present invention comprises the crystal form of the present invention or Loprotinib (amorphous) prepared from the crystal form of the present invention within a safe and effective amount, and a pharmaceutically acceptable excipient or carrier.
  • safe and effective amount refers to: the amount of the compound (or crystal form or amorphous form) is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1-2000 mg of the crystal form/dose of the present invention, more preferably, 10-200 mg of the crystal form/dose of the present invention.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to one or more compatible solid or liquid filler or gel substances which are suitable for human use and which must be of sufficient purity and sufficiently low toxicity. "Compatibility” as used herein means that the components of the composition can be blended with the active ingredients of the present invention and with each other without significantly reducing the efficacy of the active ingredients.
  • Examples of pharmaceutically acceptable carrier moieties include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid) , magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • the mode of administration of the polymorph or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active ingredient is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators such as quaternary amine compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostea
  • Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials well known in the art. They may contain opacifying agents, and the release of the active ingredient in such compositions may be in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric substances and waxes. If desired, the active ingredient may also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, and the like.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylform
  • compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • suspensions may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
  • suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
  • compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • Dosage forms of the polymorphs of the invention for topical administration include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
  • the crystalline form of the present invention or Loprotinib (amorphous) prepared from the crystalline form of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of the crystalline form of the present invention or Loprotinib (amorphous) prepared from the crystalline form of the present invention is suitable for mammals (such as humans) in need of treatment, wherein the dose at the time of administration
  • the daily dose is usually 1-2000 mg, preferably 20-500 mg.
  • the specific dosage should also take into account the route of administration, the patient's health and other factors, which are all within the skill of the skilled physician.
  • Form CM-I is stable for at least 30 days when left open at 25°C/60% RH.
  • Form CM-II and Form CM-III are stable for at least 30 days when placed open at 25°C/60%RH and 40°C/75%RH.
  • the crystal forms of crystal form CM-II and crystal form CM-III did not change before and after grinding, indicating that their mechanical stability is good, which can reduce the risk of crystal transformation caused by the crushing of raw materials during preparation processing.
  • Crystal form CM-I, crystal form CM-II and crystal form CM-III were mixed with excipients and then pressed into tablets, and the crystal forms did not change before and after tableting, indicating that they had good tableting stability.
  • Better crystal form stability can reduce the risk of changes in dissolution rate and bioavailability of drugs due to crystal form changes, and is conducive to crystal form control in crystallization and formulation processes, and is also of great benefit to product production and storage.
  • Crystal form CM-II has low hygroscopicity, and the weight gain is 0.12% from 40%RH to 80%RH.
  • the low hygroscopicity shows that the crystal form does not require strict packaging and storage conditions, and does not require special drying conditions during the preparation process, which simplifies the preparation and post-processing of the drug, is beneficial to industrial production, and significantly reduces the production, transportation and cost of drugs. storage costs.
  • the preparation method of the crystal form provided by the present invention is safer and more reliable. At the same time, the operation is simple and easy, the cost is low, and the method is suitable for drug research and development and industrial production.
  • the crystal forms provided by the present invention can be prepared by using low toxicity or non-toxic solvents, such as ethanol, acetic acid and water. At the same time, the preparation methods are all conventional crystallization methods that can be industrially produced. By controlling the process parameters, the particle size, crystal habit and crystal form can be controlled to obtain stable and high-quality products.
  • the crystal form provided by the present invention has good solubility, and the better solubility is beneficial to improve the absorption of the drug in the human body, improve the bioavailability, and make the drug exert a better therapeutic effect.
  • better solubility can reduce the dose of the drug while ensuring the efficacy of the drug, thereby reducing the side effect of the drug and improving the safety of the drug.
  • the crystal form provided by the present invention has better fluidity and is not sticky during tableting. It is beneficial to the transportation and transfer of drugs and the development of preparation technology.
  • the Form 1 was prepared as follows: 5.55 g of the compound of formula (I) was weighed and dissolved in ethyl acetate:dichloromethane:methanol (200:150:40), and the solution was concentrated to volume About 70 mL, a white solid was precipitated, filtered, and the white solid was the form 1 in the patent WO2017007759. The obtained solid was subjected to XRPD test, and its XRPD pattern is shown in Figure 25.
  • the obtained solid was tested by XRPD, and its X-ray powder diffraction data was shown in Table 1, and its XRPD pattern was shown in Figure 1; The weight loss is about 10.5%; DSC test is carried out on the obtained solid, there are 2 endothermic peaks at 60 ° C ⁇ 92 ° C, and 1 exothermic peak at 170 ° C ⁇ 185 ° C, the spectrum is shown in Figure 3;
  • Example 9 The crystal form CM-II obtained in Example 9 was placed in water and stirred at 5° C. for 1 day, and the obtained solid was the crystal form CM-I of the compound of formula (I). The obtained solid was tested by XRPD, and its X-ray powder diffraction data are shown in Table 6.
  • Example 11 The crystal form CM-IV obtained in Example 11 was placed in water and stirred at 5° C. for 1 day, and the obtained solid was the crystal form CM-I of the compound of formula (I). The obtained solid was subjected to XRPD test, and its X-ray powder diffraction data are shown in Table 7.
  • Example 10 The amorphous crystalline form obtained in Example 10 was placed in water and stirred at 5° C. for 1 day, and the obtained solid was the crystalline form CM-I of the compound of formula (I). The obtained solid was subjected to XRPD test, and its X-ray powder diffraction data are shown in Table 8.
  • Example 2 15 mg of the crystal form CM-I obtained in Example 1 was weighed, heated to 100° C. under nitrogen protection, and the obtained solid was the amorphous compound of formula (I). The obtained solid was tested by XRPD, and its XRPD pattern is shown in Figure 23.
  • Example 15 15 mg of the amorphous obtained in Example 15 was weighed, and it was placed openly under the condition of 25°C/92.5% RH for 2 weeks, and the obtained solid was crystal form CM-VIII.
  • the obtained solid was subjected to XRPD test, and its X-ray powder diffraction data is shown in Table 15, and its XRPD pattern is shown in Figure 26 .
  • the crystalline form CM-I and crystalline form CM-II prepared by the present invention were placed openly for 30 days under different conditions respectively, XRPD detection was performed on the crystalline form before and after placing, and the XRPD patterns of the crystalline form before and after being placed were compared. .
  • the specific results are shown in Table 16.
  • Example 9 of the present invention was taken to test its hygroscopicity by using a dynamic moisture absorption apparatus (DVS).
  • the DVS diagram is shown in Figure 12 .
  • XRPD test was performed on the solid before and after the DVS test, and its XRPD pattern is shown in Figure 27.
  • the overall test results are shown in Table 18.
  • the crystal form CM-II provided by the present invention has low moisture absorption; from the XRPD results, it can be seen that the crystal form does not change before and after the DVS test. It can be seen that the crystal form CM-II of the present invention has the ability to withstand high humidity environment.
  • solubility of the crystal form CM-I, the crystal form CM-II and the crystal form CM-III provided by the present invention are all higher than that of the form 1 in the patent WO2017007759, and have better solubility.
  • the tableting stability of crystal form CM-I, crystal form CM-II, crystal form CM-III and form 1 containing excipients in WO2017007759 was tested, and the pressure was 10 kN.
  • the formulation prescription is shown in Table 21.
  • the crystal form changes before and after tableting are shown in Table 22. Tableting It can be known from the tabletting data that the crystal form CM-I, crystal form CM-II and crystal form CM-III provided by the present invention have excellent tableting stability when they contain auxiliary materials. And there is no sticking phenomenon during tablet pressing.

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Abstract

Provided is a new crystal form of (7S,13R)-11fluoro-7,14-dimethyl-6,7,13,14-tetrahydro-1,15-vinyl-bridged pyrazolo[4,3-f][1,4,8,10]-benzoxatriazacyclotridecyne-4(5H)-one (formula I). In another aspect, provided is a method for preparing the foregoing crystal form. In comparison with the existing technology, the crystal form prepared in the present invention has high stability, low hygroscopicity, a simple and convenient preparation method, good solubility, and is suitable for subsequent formulation research and development and industrial production.

Description

一种洛普替尼晶型及其制备方法A kind of Loprotinib crystal form and preparation method thereof 技术领域technical field
本发明涉及药物化学领域，尤其涉及(7S,13R)-11氟-7,14-二甲基-6,7,13,14-四氢-1,15-乙烯桥吡唑并[4,3-f][1,4,8,10]-苯并氧杂三氮杂环十三炔-4(5H)-酮的新晶型及其制备方法。The present invention relates to the field of medicinal chemistry, in particular to (7S,13R)-11 fluoro-7,14-dimethyl-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3 A new crystal form of -f][1,4,8,10]-benzoxatriazacyclotridecyn-4(5H)-one and its preparation method.
背景技术Background technique
洛普替尼(TPX-0005)是一种强效的小分子多靶标激酶抑制剂，其显示出对抗野生型和突变型ALA(间变性淋巴瘤激酶)、野生型和突变型ROS1(ROS1原癌基因受体酪氨酸激酶)、TRK家族激酶(原肌球蛋白相关受体酪氨酸激酶)、Janus家族激酶的JAK2、SRC(Src家族蛋白酪氨酸激酶(SFK))和FAK(粘着斑激酶)的活性。它是TP Therapeutics公司研发的第四代ALK抑制剂。2017年6月28日，TP Therapeutics公司宣布FDA已经向其在研临床新药化合物TPX-0005颁发了孤儿药资格，用于治疗携带ALK、ROS1或NTRK致癌基因重排的NSCLC(非小细胞肺癌)患者。Loprotinib (TPX-0005) is a potent small-molecule multi-targeted kinase inhibitor that has been shown to inhibit wild-type and mutant ALA (anaplastic lymphoma kinase), wild-type and mutant ROS1 (pro-ROS1) Oncogene receptor tyrosine kinase), TRK family kinase (tropomyosin-related receptor tyrosine kinase), JAK2 of Janus family kinase, SRC (Src family protein tyrosine kinase (SFK)) and FAK (adhesion spot kinase) activity. It is the fourth-generation ALK inhibitor developed by TP Therapeutics. On June 28, 2017, TP Therapeutics announced that the FDA has granted orphan drug designation to its investigational new drug compound TPX-0005 for the treatment of NSCLC (non-small cell lung cancer) with ALK, ROS1 or NTRK oncogene rearrangements patient.
它拥有一种紧凑的三维大环分子结构，分子量为355.4，比现有的所有ALK和ROS1抑制剂分子量更小。众所周知，ALK抑制剂耐药性机制总体来说有以下几种：ALK激酶域继发性耐药突变、ALK融合基因拷贝数扩增、旁路和下游通路的激活、上皮间充质转化等。TPX-0005的紧凑的小分子结构使它在ATP内部与中心结合位点结合，并且避免ATP结合位点之外的突变造成的空间位阻，即避免临床耐药突变的干扰。洛普替尼(TPX-0005)的化学名称为(7S,13R)-11氟-7,14-二甲基-6,7,13,14-四氢-1,15-乙烯桥吡唑并[4,3-f][1,4,8,10]-苯并氧杂三氮杂环十三炔-4(5H)-酮，其分子结构式如下所示：It possesses a compact three-dimensional macrocyclic molecular structure with a molecular weight of 355.4, which is smaller than all existing ALK and ROS1 inhibitors. It is well known that ALK inhibitor resistance mechanisms generally include the following: secondary resistance mutations in the ALK kinase domain, ALK fusion gene copy number amplification, activation of alternative and downstream pathways, epithelial-mesenchymal transition, etc. The compact small-molecule structure of TPX-0005 enables it to bind to the central binding site inside ATP, and avoid steric hindrance caused by mutations outside the ATP binding site, that is, to avoid the interference of clinical drug resistance mutations. Loprotinib (TPX-0005) has the chemical name of (7S,13R)-11fluoro-7,14-dimethyl-6,7,13,14-tetrahydro-1,15-vinylpyrazolo [4,3-f][1,4,8,10]-benzoxatriazacyclotridecyn-4(5H)-one, its molecular structure is as follows:
Figure PCTCN2021117042-appb-000001
Figure PCTCN2021117042-appb-000001
专利WO2017007759报道了式(I)化合物的1个晶型——形态1，但未公开报道该晶型任何关于稳定性、溶解性、引湿性、粉体性能等一些对于产品开发具有重要意义的物理化学性质。而其报道的制备方法为浓缩析晶，具有不可预见的放大效应，即在放大生产过程中采用浓缩结晶很难控制晶体的粒度和晶习等，导致批次间的不一致，进而影响后续制剂等工艺。另外，上述制备方法中需要使用二氯甲烷和甲醇，对动物有致癌性，环境友好性低。Patent WO2017007759 reports a crystalline form of the compound of formula (I) - Form 1, but does not publicly report any physical properties of this crystalline form that are of great significance to product development, such as stability, solubility, hygroscopicity, and powder properties. chemical properties. The reported preparation method is concentrated crystallization, which has an unpredictable amplification effect, that is, it is difficult to control the particle size and crystal habit of crystals by using concentrated crystallization during the scale-up production process, resulting in inconsistencies between batches, which in turn affects subsequent preparations, etc. craft. In addition, the above preparation method needs to use dichloromethane and methanol, which is carcinogenic to animals and has low environmental friendliness.
对于药物研发而言，对多晶型的研究是一个至关重要的内容。晶型不同可造成药物的溶解度、稳定性和流动性等差异，从而影响药物的安全性和有效性，进而导致临床效果的不同。为了得到稳定的、适于药用的剂型，需要提供稳定性高、可工业化生产的晶型。因此，本领域仍需要开发一种在不同的温度、湿度以及研磨条件下稳定性好的晶型，以满足药物开发、制剂配方制备及工 业化生产的需要。For drug development, the study of polymorphism is a crucial content. Different crystal forms can cause differences in the solubility, stability and fluidity of drugs, thereby affecting the safety and effectiveness of drugs, and thus leading to different clinical effects. In order to obtain stable dosage forms suitable for pharmaceutical use, it is necessary to provide crystal forms with high stability and industrial production. Therefore, there is still a need to develop a crystal form with good stability under different temperature, humidity and grinding conditions in the art to meet the needs of drug development, formulation preparation and industrial production.
发明内容SUMMARY OF THE INVENTION
本发明的目的是提供易于制备、稳定性高的式(I)化合物的新晶型，以满足药物研究及工业化生产的需要。The purpose of the present invention is to provide a new crystal form of the compound of formula (I) that is easy to prepare and has high stability, so as to meet the needs of drug research and industrial production.
本发明的第一方面，提供了一种式(I)化合物的晶型：所述晶型包括晶型CM-I、晶型CM-II、晶型CM-III、晶型CM-IV、晶型CM-V、晶型CM-VI、晶型CM-VII和/或晶型CM-VIII。The first aspect of the present invention provides a crystal form of the compound of formula (I): the crystal form includes crystal form CM-I, crystal form CM-II, crystal form CM-III, crystal form CM-IV, crystal form Form CM-V, Form CM-VI, Form CM-VII and/or Form CM-VIII.
Figure PCTCN2021117042-appb-000002
Figure PCTCN2021117042-appb-000002
优选地，所述晶型选自下组：晶型CM-I、晶型CM-II、晶型CM-III；Preferably, the crystal form is selected from the following group: crystal form CM-I, crystal form CM-II, crystal form CM-III;
其中，所述晶型CM-I的XRPD图包括2个或2个以上选自下组的2θ值：7.7°±0.2°、8.9°±0.2°、11.3°±0.2°、15.5°±0.2°、17.8°±0.2°；Wherein, the XRPD pattern of the crystal form CM-I includes 2 or more 2θ values selected from the following group: 7.7°±0.2°, 8.9°±0.2°, 11.3°±0.2°, 15.5°±0.2° , 17.8°±0.2°;
所述晶型CM-II的XRPD包括3个或3个以上选自下组的2θ值：10.7°±0.2°、12.4°±0.2°、19.1°±0.2°、22.8°±0.2°；The XRPD of the crystal form CM-II comprises 3 or more 2θ values selected from the group consisting of 10.7°±0.2°, 12.4°±0.2°, 19.1°±0.2°, 22.8°±0.2°;
所述晶型CM-III的XRPD图包括3个或3个以上选自下组的2θ值：7.9°±0.2°、9.1°±0.2°、9.7°±0.2°、18.9°±0.2°。The XRPD pattern of the crystalline form CM-III includes 3 or more 2θ values selected from the group consisting of 7.9°±0.2°, 9.1°±0.2°, 9.7°±0.2°, 18.9°±0.2°.
优选地，所述晶型为晶型CM-I，其中所述晶型CM-I的XRPD图包括2个或2个以上(如2、3、4个)选自下组的2θ值：7.7°±0.2°、8.9°±0.2°、11.3°±0.2°、15.5°±0.2°、17.8°±0.2°。Preferably, the crystal form is crystal form CM-I, wherein the XRPD pattern of the crystal form CM-I includes 2 or more (eg 2, 3, 4) 2θ values selected from the group consisting of: 7.7 °±0.2°, 8.9°±0.2°, 11.3°±0.2°, 15.5°±0.2°, 17.8°±0.2°.
优选地，所述晶型为晶型CM-II，其中所述晶型CM-II的XRPD包括3个或3个以上(如3、4、5个)选自下组的2θ值：10.7°±0.2°、12.4°±0.2°、19.1°±0.2°、22.8°±0.2°。Preferably, the crystalline form is crystalline form CM-II, wherein the XRPD of the crystalline form CM-II includes 3 or more (eg 3, 4, 5) 2θ values selected from the following group: 10.7° ±0.2°, 12.4°±0.2°, 19.1°±0.2°, 22.8°±0.2°.
优选地，所述晶型为晶型CM-III，其中所述晶型CM-III的XRPD图包括3个或3个以上(如3、4、5个)选自下组的2θ值：7.9°±0.2°、9.1°±0.2°、9.7°±0.2°、18.9°±0.2°。Preferably, the crystal form is crystal form CM-III, wherein the XRPD pattern of the crystal form CM-III includes 3 or more (eg 3, 4, 5) 2θ values selected from the group consisting of: 7.9 °±0.2°, 9.1°±0.2°, 9.7°±0.2°, 18.9°±0.2°.
优选地，所述晶型CM-I具有选自下组的一个或多个特征：Preferably, the crystalline form CM-I has one or more characteristics selected from the group consisting of:
1)所述晶型CM-I的XRPD图包括6个或6个以上(如6、7、8、9、10个)选自下组的2θ值：3.9°±0.2°、7.7°±0.2°、8.9°±0.2°、11.3°±0.2°、14.3°±0.2°、15.5°±0.2°、17.8°±0.2°、20.0°±0.2°、22.7°±0.2°、23.3°±0.2°、25.1°±0.2°、28.9°±0.2°。1) The XRPD pattern of the crystal form CM-I includes 6 or more ( eg 6, 7, 8, 9, 10) 2θ values selected from the following group: 3.9°±0.2°, 7.7°±0.2 °, 8.9°±0.2°, 11.3°±0.2°, 14.3°±0.2°, 15.5°±0.2°, 17.8°±0.2°, 20.0°±0.2°, 22.7°±0.2°, 23.3°±0.2°, 25.1°±0.2°, 28.9°±0.2°.
2)所述晶型CM-I具有基本如图1所示的XRPD图；2) The crystal form CM-I has an XRPD pattern basically as shown in Figure 1;
3)所述晶型CM-I具有基本如图2所示的TGA图；3) The crystal form CM-I has a TGA diagram as shown in Figure 2;
4)所述晶型CM-I具有基本如图3所示的DSC图；4) The crystal form CM-I has a DSC diagram as shown in FIG. 3;
5)所述晶型CM-I具有基本如图4所示的 1H NMR图谱。 5) The crystalline form CM-I has a 1 H NMR spectrum substantially as shown in FIG. 4 .
优选地，所述晶型CM-II具有选自下组的一个或多个特征：Preferably, the crystalline form CM-II has one or more characteristics selected from the group consisting of:
1)所述晶型CM-II的XRPD图包括6个或6个以上(如6、7、8、9、10个)选自下组的2θ值： 6.2°±0.2°、8.8°±0.2°、10.7°±0.2°、12.4°±0.2°、16.4°±0.2°、17.0°±0.2°、17.5°±0.2°、19.1°±0.2°、20.2°±0.2°、21.4°±0.2°、22.3°±0.2°、22.8°±0.2°、24.5°±0.2°、26.8°±0.2°、27.0°±0.2°、27.5°±0.2°。1) The XRPD pattern of the crystal form CM-II includes 6 or more ( eg 6, 7, 8, 9, 10) 2θ values selected from the following group: 6.2°±0.2°, 8.8°±0.2 °, 10.7°±0.2°, 12.4°±0.2°, 16.4°±0.2°, 17.0°±0.2°, 17.5°±0.2°, 19.1°±0.2°, 20.2°±0.2°, 21.4°±0.2°, 22.3°±0.2°, 22.8°±0.2°, 24.5°±0.2°, 26.8°±0.2°, 27.0°±0.2°, 27.5°±0.2°.
2)所述晶型CM-II具有基本如图6所示的XRPD图；2) The crystal form CM-II has an XRPD pattern as basically shown in Figure 6;
3)所述晶型CM-II具有基本如图7所示的TGA图；3) The crystal form CM-II has a TGA diagram as shown in FIG. 7 ;
4)所述晶型CM-II具有基本如图8所示的DSC图；4) The crystal form CM-II has a DSC diagram as shown in FIG. 8;
5)所述晶型CM-II具有基本如图9所示的 1H NMR图谱。 5) The crystal form CM-II has a 1 H NMR spectrum substantially as shown in FIG. 9 .
优选地，所述晶型CM-III具有选自下组的一个或多个特征：Preferably, the crystalline form CM-III has one or more characteristics selected from the group consisting of:
1)所述晶型CM-III的XRPD图包括6个或6个以上(如6、7、8、9、10个)选自下组的2θ值：6.5°±0.2°、7.9°±0.2°、9.1°±0.2°、9.7°±0.2°、15.3°±0.2°、18.8°±0.2°、18.9°±0.2°、20.3°±0.2°、21.1°±0.2°、23.3°±0.2°、23.8°±0.2°、26.1°±0.2°、28.9°±0.2°。1) The XRPD pattern of the crystal form CM-III includes 6 or more ( eg 6, 7, 8, 9, 10) 2θ values selected from the following group: 6.5°±0.2°, 7.9°±0.2 °, 9.1°±0.2°, 9.7°±0.2°, 15.3°±0.2°, 18.8°±0.2°, 18.9°±0.2°, 20.3°±0.2°, 21.1°±0.2°, 23.3°±0.2°, 23.8°±0.2°, 26.1°±0.2°, 28.9°±0.2°.
2)所述晶型CM-III具有基本如图13所示的XRPD图；2) The crystal form CM-III has an XRPD pattern substantially as shown in Figure 13;
3)所述晶型CM-III具有基本如图14所示的TGA图；3) The crystal form CM-III has a TGA diagram as shown in Figure 14;
4)所述晶型CM-III具有基本如图15所示的DSC图；4) The crystal form CM-III has a DSC chart as shown in FIG. 15 ;
5)所述晶型CM-III具有基本如图16所示的 1H NMR图谱。 5) The crystal form CM-III has a 1 H NMR spectrum substantially as shown in FIG. 16 .
优选地，所述晶型为晶型CM-IV，其中所述晶型CM-IV的XRPD图包括2个或2个以上(如2、3、4个)选自下组的2θ值：7.1°±0.2°、19.6°±0.2°、21.5°±0.2°、28.9°±0.2°。Preferably, the crystal form is crystal form CM-IV, wherein the XRPD pattern of the crystal form CM-IV includes 2 or more (eg 2, 3, 4) 2θ values selected from the group consisting of: 7.1 °±0.2°, 19.6°±0.2°, 21.5°±0.2°, 28.9°±0.2°.
优选地，所述晶型CM-IV具有选自下组的一个或多个特征：Preferably, the crystalline form CM-IV has one or more characteristics selected from the group consisting of:
1)所述晶型CM-IV的XRPD图包括4个或4个以上(如5、6、7、8个)选自下组的2θ值：7.1°±0.2°、9.7°±0.2°、18.6°±0.2°、19.6°±0.2°、21.5°±0.2°、28.9°±0.2°；1) The XRPD pattern of the crystal form CM-IV includes 4 or more (such as 5, 6, 7, 8) 2θ values selected from the following group: 7.1°±0.2°, 9.7°±0.2°, 18.6°±0.2°, 19.6°±0.2°, 21.5°±0.2°, 28.9°±0.2°;
2)所述晶型CM-IV具有基本如图18所示的XRPD图。2) The crystal form CM-IV has an XRPD pattern substantially as shown in FIG. 18 .
优选地，所述晶型为晶型CM-V，其中所述晶型CM-V的XRPD图包括2个或2个以上(如2、3、4个)选自下组的2θ值：6.9°±0.2°、9.4°±0.2°、21.0°±0.2°、21.5°±0.2°、28.1°±0.2°。Preferably, the crystal form is crystal form CM-V, wherein the XRPD pattern of the crystal form CM-V includes 2 or more (eg 2, 3, 4) 2θ values selected from the following group: 6.9 °±0.2°, 9.4°±0.2°, 21.0°±0.2°, 21.5°±0.2°, 28.1°±0.2°.
优选地，所述晶型CM-V具有选自下组的一个或多个特征：Preferably, the crystalline form CM-V has one or more characteristics selected from the group consisting of:
1)所述晶型CM-V的XRPD图包括6个或6个以上(如6、7、8、9个)选自下组的2θ值：6.9°±0.2°、9.4°±0.2°、21.0°±0.2°、21.5°±0.2°、23.2°±0.2°、23.6°±0.2°、28.1°±0.2°、28.8°±0.2°；1) The XRPD pattern of the crystalline form CM-V includes 6 or more (such as 6, 7, 8, 9) 2θ values selected from the following group: 6.9°±0.2°, 9.4°±0.2°, 21.0°±0.2°, 21.5°±0.2°, 23.2°±0.2°, 23.6°±0.2°, 28.1°±0.2°, 28.8°±0.2°;
2)所述晶型CM-V具有基本如图19所示的XRPD图。2) The crystalline form CM-V has an XRPD pattern substantially as shown in FIG. 19 .
优选地，所述晶型为晶型CM-VI，其中所述晶型CM-VI的XRPD图包括2个或2个以上(如2、3、4个)选自下组的2θ值：7.4°±0.2°、9.0°±0.2°、15.1°±0.2°、22.5°±0.2°。Preferably, the crystal form is crystal form CM-VI, wherein the XRPD pattern of the crystal form CM-VI includes 2 or more (eg 2, 3, 4) 2θ values selected from the group consisting of: 7.4 °±0.2°, 9.0°±0.2°, 15.1°±0.2°, 22.5°±0.2°.
优选地，所述晶型CM-VI具有选自下组的一个或多个特征：Preferably, the crystalline form CM-VI has one or more characteristics selected from the group consisting of:
1)所述晶型CM-VI的XRPD图包括4个或4个以上(如5、6、7、8个)选自下组的2θ值：7.4°±0.2°、9.0°±0.2°、14.9°±0.2°、15.1°±0.2°、18.2°±0.2°、22.5°±0.2°、30.7°±0.2°；1) The XRPD pattern of the crystal form CM-VI includes 4 or more (such as 5, 6, 7, 8) 2θ values selected from the following group: 7.4°±0.2°, 9.0°±0.2°, 14.9°±0.2°, 15.1°±0.2°, 18.2°±0.2°, 22.5°±0.2°, 30.7°±0.2°;
2)所述晶型CM-VI具有基本如图20所示的XRPD图。2) The crystal form CM-VI has an XRPD pattern basically as shown in FIG. 20 .
优选地，所述晶型为晶型CM-VII，其中所述晶型CM-VII的XRPD图包括3个或3个以上(如3、4、5个)选自下组的2θ值：8.4°±0.2°、13.6°±0.2°、15.3°±0.2°、16.8°±0.2°、18.9°±0.2°、23.0°±0.2°。Preferably, the crystal form is crystal form CM-VII, wherein the XRPD pattern of the crystal form CM-VII includes 3 or more (eg 3, 4, 5) 2θ values selected from the following group: 8.4 °±0.2°, 13.6°±0.2°, 15.3°±0.2°, 16.8°±0.2°, 18.9°±0.2°, 23.0°±0.2°.
优选地，所述晶型CM-VII具有选自下组的一个或多个特征：Preferably, the crystal form CM-VII has one or more features selected from the group consisting of:
1)所述晶型CM-VII的XRPD图包括6个或6个以上(如、6、7、8、9个)选自下组的2θ值：8.4°±0.2°、13.6°±0.2°、15.3°±0.2°、16.5°±0.2°、16.8°±0.2°、17.3°±0.2°、18.0°±0.2°、18.9°±0.2°、19.8°±0.2°、21.2°±0.2°、23.0°±0.2°、23.9°±0.2°、26.9°±0.2°；1) The XRPD pattern of the crystal form CM-VII includes 6 or more (eg, 6, 7, 8, 9) 2θ values selected from the following group: 8.4°±0.2°, 13.6°±0.2° , 15.3°±0.2°, 16.5°±0.2°, 16.8°±0.2°, 17.3°±0.2°, 18.0°±0.2°, 18.9°±0.2°, 19.8°±0.2°, 21.2°±0.2°, 23.0 °±0.2°, 23.9°±0.2°, 26.9°±0.2°;
2)所述晶型CM-VII具有基本如图21所示的XRPD图；2) The crystal form CM-VII has an XRPD pattern substantially as shown in Figure 21;
3)所述晶型CM-VII具有基本如图22所示的TGA图。3) The crystal form CM-VII has a TGA diagram substantially as shown in FIG. 22 .
优选地，所述晶型为晶型CM-VIII，其中所述晶型CM-VIII的XRPD图包括2个或2个以上(如2、3、4个)选自下组的2θ值：7.4°±0.2°、8.2°±0.2°、8.9°±0.2°、10.4°±0.2°。Preferably, the crystal form is crystal form CM-VIII, wherein the XRPD pattern of the crystal form CM-VIII includes 2 or more (eg 2, 3, 4) 2θ values selected from the group consisting of: 7.4 °±0.2°, 8.2°±0.2°, 8.9°±0.2°, 10.4°±0.2°.
优选地，所述晶型CM-VIII具有选自下组的一个或多个特征：Preferably, the crystalline form CM-VIII has one or more characteristics selected from the group consisting of:
1)所述晶型CM-VIII的XRPD图包括4个或4个以上(如5、6、7个)选自下组的2θ值：7.4°±0.2°、8.2°±0.2°、8.9°±0.2°、10.4°±0.2°、16.3°±0.2°、18.3°±0.2°、25.2°±0.2°；1) The XRPD pattern of the crystal form CM-VIII includes 4 or more ( eg 5, 6, 7) 2θ values selected from the following group: 7.4°±0.2°, 8.2°±0.2°, 8.9° ±0.2°, 10.4°±0.2°, 16.3°±0.2°, 18.3°±0.2°, 25.2°±0.2°;
2)所述晶型CM-VIII具有基本如图26所示的XRPD图。2) The crystal form CM-VIII has an XRPD pattern substantially as shown in FIG. 26 .
本发明的第二方面，提供了一种如第一方面所述的晶型的制备方法，包括步骤：将式(I)化合物在惰性溶剂中析晶，或将式(I)化合物的固体形式进行处理，从而得到所述晶型，其中，所述处理包括下组中的一个或多个步骤：搅拌、加热、在一定的温度和湿度条件下放置。The second aspect of the present invention provides a method for preparing a crystal form as described in the first aspect, comprising the steps of: crystallizing the compound of formula (I) in an inert solvent, or crystallizing the compound of formula (I) in solid form A treatment is performed to obtain the crystalline form, wherein the treatment includes one or more steps of the following group: stirring, heating, and placing under certain temperature and humidity conditions.
优选地，所述制备方法包括步骤：a)提供式(I)化合物原料于第一溶剂中的溶液，向所述溶液中加入第二溶剂进行析晶，收集析出固体得到所述晶型。Preferably, the preparation method includes the steps of: a) providing a solution of the raw material of the compound of formula (I) in a first solvent, adding a second solvent to the solution for crystallization, and collecting the precipitated solid to obtain the crystal form.
优选地，所述步骤a)包括：将式(I)化合物原料溶解于第一溶剂中，过滤，然后将向得到的滤液中加入第二溶剂进行析晶，收集析出固体得到所述晶型。Preferably, the step a) includes: dissolving the raw material of the compound of formula (I) in a first solvent, filtering, then adding a second solvent to the obtained filtrate for crystallization, and collecting the precipitated solid to obtain the crystal form.
优选地，在步骤a)中，所述加入为滴加或缓慢加入。Preferably, in step a), the addition is dropwise or slow addition.
优选地，在步骤a)中，所述析晶包括搅拌析晶或静置析晶。Preferably, in step a), the crystallization comprises stirring crystallization or standing crystallization.
优选地，所述制备方法包括步骤：b)提供式(I)化合物原料于第一溶剂中的溶液，将所述溶液加入至第二溶剂中进行析晶，收集析出固体得到所述晶型。Preferably, the preparation method comprises the steps of: b) providing a solution of the raw material of the compound of formula (I) in a first solvent, adding the solution to a second solvent for crystallization, and collecting the precipitated solid to obtain the crystal form.
优选地，所述步骤b)包括：将式(I)化合物原料溶解于第一溶剂中，过滤，然后将得到的滤液加入第二溶剂进行析晶，收集析出固体得到所述晶型。Preferably, the step b) comprises: dissolving the raw material of the compound of formula (I) in the first solvent, filtering, then adding the obtained filtrate to the second solvent for crystallization, and collecting the precipitated solid to obtain the crystal form.
优选地，在步骤b)中，所述加入为滴加或缓慢加入。Preferably, in step b), the addition is dropwise or slow addition.
优选地，在步骤b)中，所述析晶包括搅拌析晶或静置析晶。Preferably, in step b), the crystallization comprises stirring crystallization or standing crystallization.
优选地，所述制备方法包括步骤：c)提供式(I)化合物原料于第一溶剂中的溶液或晶浆，对所述溶液或晶浆进行处理，得到固体，收集所得固体得到所述晶型；其中，所述的处理包括搅拌或挥发。Preferably, the preparation method includes the steps of: c) providing a solution or crystal slurry of the raw material of the compound of formula (I) in a first solvent, processing the solution or crystal slurry to obtain a solid, and collecting the obtained solid to obtain the crystal Type; wherein, the treatment includes stirring or volatilization.
优选地，所述制备方法包括步骤：d)提供式(I)化合物原料的固体形式，对所述固体形式进行处理，得到所述晶型；其中，所述固体形式为晶型或无定型，所述的处理包括下组中的一个或多个步骤：加热、在一定的温度和湿度条件下放置。Preferably, the preparation method comprises the steps of: d) providing a solid form of the raw material of the compound of formula (I), and processing the solid form to obtain the crystal form; wherein, the solid form is a crystal form or an amorphous form, The treatment includes one or more of the following steps: heating, placing under certain temperature and humidity conditions.
优选地，所述第一溶剂包括醇类溶剂、酮类溶剂、酰胺类溶剂、酯类溶剂、醚类溶剂、酸类溶剂、腈类、水，或其组合。Preferably, the first solvent includes alcohol-based solvents, ketone-based solvents, amide-based solvents, ester-based solvents, ether-based solvents, acid-based solvents, nitriles, water, or a combination thereof.
优选地，所述醇类溶剂选自下组：甲醇、乙醇、异丙醇、正丙醇，或其组合。Preferably, the alcoholic solvent is selected from the group consisting of methanol, ethanol, isopropanol, n-propanol, or a combination thereof.
优选地，所述酮类溶剂选自下组：丙酮、2-丁酮、N-甲基吡咯烷酮，或其组合。Preferably, the ketone solvent is selected from the group consisting of acetone, 2-butanone, N-methylpyrrolidone, or a combination thereof.
优选地，所述酰胺类溶剂选自下组：N,N-二甲基甲酰胺、N,N-二甲基乙酰胺，或其组合。Preferably, the amide solvent is selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, or a combination thereof.
优选地，所述酯类溶剂选自下组：乙酸乙酯、乙酸异丙酯，或其组合。Preferably, the ester solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, or a combination thereof.
优选地，所述醚类溶剂选自下组：四氢呋喃、2-甲基四氢呋喃、1,4-二氧六环，或其组合。Preferably, the ether solvent is selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, or a combination thereof.
优选地，所述酸类溶剂选自下组：甲酸、乙酸、乳酸，或其组合。Preferably, the acid solvent is selected from the group consisting of formic acid, acetic acid, lactic acid, or a combination thereof.
优选地，所述腈类溶剂选自下组：乙腈。Preferably, the nitrile solvent is selected from the group consisting of acetonitrile.
优选地，所述第二溶剂包括烃类、酯类、水，或其组合。Preferably, the second solvent includes hydrocarbons, esters, water, or a combination thereof.
优选地，所述烃类溶剂选自下组：氯仿、二氯甲烷、硝基甲烷、正庚烷、环己烷、甲苯，或其组合。Preferably, the hydrocarbon solvent is selected from the group consisting of chloroform, dichloromethane, nitromethane, n-heptane, cyclohexane, toluene, or a combination thereof.
优选地，所述酯类溶剂选自下组：乙酸丁酯、乙酸正丙酯，或其组合。Preferably, the ester solvent is selected from the group consisting of butyl acetate, n-propyl acetate, or a combination thereof.
所述步骤a)或所述步骤b)中，收集析出固体后，对固体进行处理，得到所述晶型，其中，所述处理包括真空干燥。In the step a) or the step b), after collecting the precipitated solid, the solid is processed to obtain the crystal form, wherein the processing includes vacuum drying.
本发明的第三方面，提供了一种药物组合物，所述组合物包括：A third aspect of the present invention provides a pharmaceutical composition, the composition comprising:
1)如第一方面所述的晶型；2)药学上可接受的载体。1) the crystalline form according to the first aspect; 2) a pharmaceutically acceptable carrier.
本发明的第四方面，提供了一种使用如第三方面所述的药物组合物制备用于治疗携带ALK、ROS1或NTRK致癌基因重排的NSCLC患者的药物的用途。The fourth aspect of the present invention provides the use of the pharmaceutical composition according to the third aspect to prepare a medicine for treating NSCLC patients with ALK, ROS1 or NTRK oncogene rearrangement.
本发明的第五方面，提供了如第一方面所述晶型的用途，所述用途包括：1)制备式(I)化合物或其盐；2)制备用于治疗携带ALK、ROS1或NTRK致癌基因重排的NSCLC患者的药物。The fifth aspect of the present invention provides the use of the crystal form according to the first aspect, the use includes: 1) preparing the compound of formula (I) or a salt thereof; 2) preparing for the treatment of carcinogenesis carrying ALK, ROS1 or NTRK Drugs for NSCLC patients with genetic rearrangements.
本发明的第五方面，提供了如第一方面所述的晶型的用途，包括：1)制备式(I)化合物或其盐；2)制备用于治疗用于治疗携带ALK、ROS1或NTRK致癌基因重排的NSCLC患者。The fifth aspect of the present invention provides the use of the crystal form according to the first aspect, including: 1) preparing the compound of formula (I) or a salt thereof; 2) preparing the compound for the treatment of ALK, ROS1 or NTRK NSCLC patients with oncogene rearrangements.
与现有技术相比，本发明的优点在于：Compared with the prior art, the advantages of the present invention are:
(1)本发明的晶型稳定性和机械稳定性好，从而降低制剂加工过程中的转晶风险，并减少药物由于晶型变化而导致溶出速率及生物利用度改变的风险，有利于结晶和制剂工艺中的晶型控制。(1) The crystal form stability and mechanical stability of the present invention are good, thereby reducing the risk of crystal transformation during the preparation process, and reducing the risk of changes in the dissolution rate and bioavailability of the drug due to changes in the crystal form, which is conducive to crystallization and Crystal Form Control in Formulation Process.
(2)本发明的晶型引湿性低，对包装和储存条件要求不苛刻，且在制备过程中无需特殊的干燥条件，简化了药物的制备和后处理工艺，利于工业化生产，显著降低了药物生产、运输和储存的成本。(2) The crystal form of the present invention has low hygroscopicity, does not require harsh packaging and storage conditions, and does not require special drying conditions in the preparation process, which simplifies the preparation and post-processing technology of the drug, is beneficial to industrial production, and significantly reduces the number of drugs. The cost of production, transportation and storage.
(3)本发明提供的晶型的制备方法安全可靠。同时操作简便易行，成本低廉，适用于药物研发和工业化生产中。(3) The preparation method of the crystal form provided by the present invention is safe and reliable. At the same time, the operation is simple and easy, the cost is low, and the method is suitable for drug research and development and industrial production.
(4)本发明提供的晶型溶解性好，生物利用度高，且能够在保证药物疗效的同时，降低药品的剂量，从而降低药品的副作用，提高药品的安全性。(4) The crystal form provided by the present invention has good solubility and high bioavailability, and can reduce the dosage of the medicine while ensuring the curative effect of the medicine, thereby reducing the side effect of the medicine and improving the safety of the medicine.
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described in the following (eg, the embodiments) can be combined with each other to constitute new or preferred technical solutions. Due to space limitations, it is not repeated here.
附图说明Description of drawings
图1是本发明晶型CM-I的XRPD图。Fig. 1 is the XRPD pattern of the crystal form CM-I of the present invention.
图2是本发明晶型CM-I的TGA图。Figure 2 is a TGA diagram of the crystal form CM-I of the present invention.
图3是本发明晶型CM-I的DSC图。Figure 3 is the DSC chart of the crystal form CM-I of the present invention.
图4是本发明晶型CM-I的 1H NMR谱图。 Fig. 4 is the 1 H NMR spectrum of the crystal form CM-I of the present invention.
图5是本发明晶型CM-I在25℃/60％RH和40℃/75％RH下放置一个月的XRPD对比图(图中由上至下分别为放置在40℃/75％RH、25℃/60％RH一个月后和放置前的图)。Fig. 5 is the XRPD comparison chart of the crystal form CM-I of the present invention placed at 25°C/60%RH and 40°C/75%RH for one month (from top to bottom in the figure, respectively placed at 40°C/75%RH, Figures after one month at 25°C/60% RH and before placement).
图6是本发明晶型CM-II的XRPD图。Fig. 6 is the XRPD pattern of the crystal form CM-II of the present invention.
图7是本发明晶型CM-II的TGA图。Figure 7 is a TGA diagram of the crystal form CM-II of the present invention.
图8是本发明晶型CM-II的DSC图。Figure 8 is the DSC chart of the crystal form CM-II of the present invention.
图9是本发明晶型CM-II的 1H NMR图谱。 Fig. 9 is the 1 H NMR spectrum of the crystal form CM-II of the present invention.
图10本发明晶型CM-II在25℃/60％RH和40℃/75％RH下放置一个月的XRPD对比图(由上至下分别为放置在40℃/75％RH、25℃/60％RH一个月和放置前的图)。Fig. 10 XRPD comparison chart of the crystal form CM-II of the present invention placed at 25°C/60%RH and 40°C/75%RH for one month (from top to bottom, respectively placed at 40°C/75%RH, 25°C/ 60% RH for one month and pictures before placement).
图11是本发明晶型CM-II碾磨前后的XRPD图(上图为碾磨后的XRPD图，下图为碾磨前的XRPD图)。Figure 11 is the XRPD pattern of the crystal form CM-II of the present invention before and after milling (the upper figure is the XRPD pattern after milling, and the lower figure is the XRPD pattern before milling).
图12是本发明晶型CM-II的DVS图。Figure 12 is a DVS diagram of the crystal form CM-II of the present invention.
图13是本发明晶型CM-III的XRPD图。Figure 13 is the XRPD pattern of the crystal form CM-III of the present invention.
图14是本发明晶型CM-III的TGA图。Figure 14 is a TGA diagram of the crystal form CM-III of the present invention.
图15是本发明晶型CM-III的DSC图。Figure 15 is the DSC chart of the crystal form CM-III of the present invention.
图16是本发明晶型CM-III的 1H NMR图谱。 Figure 16 is the 1 H NMR spectrum of the crystal form CM-III of the present invention.
图17是本发明晶型CM-III碾磨前后的XRPD图(上图为碾磨后的XRPD图，下图为碾磨前的XRPD图)。Figure 17 is the XRPD pattern of the crystal form CM-III of the present invention before and after milling (the upper figure is the XRPD pattern after milling, and the lower figure is the XRPD pattern before milling).
图18是本发明晶型CM-IV的XRPD图。Figure 18 is the XRPD pattern of the crystal form CM-IV of the present invention.
图19是本发明晶型CM-V的XRPD图。Figure 19 is the XRPD pattern of the crystal form CM-V of the present invention.
图20是本发明晶型CM-VI的XRPD图。Figure 20 is the XRPD pattern of the crystal form CM-VI of the present invention.
图21是本发明晶型CM-VII的XRPD图。Figure 21 is the XRPD pattern of the crystal form CM-VII of the present invention.
图22是本发明晶型CM-VII的TGA图。Figure 22 is a TGA diagram of the crystal form CM-VII of the present invention.
图23是本发明无定型的XRPD图。Figure 23 is an XRPD pattern of the amorphous form of the present invention.
图24是本发明晶型CM-III在25℃/60％RH和40℃/75％RH下放置一个月的XRPD对比图(由上至下分别为放置在40℃/75％RH、25℃/60％RH一个月和放置前的图)。Figure 24 is the XRPD comparison chart of the crystal form CM-III of the present invention placed at 25°C/60%RH and 40°C/75%RH for one month (from top to bottom, placed at 40°C/75%RH, 25°C, respectively /60% RH for one month and pictures before placement).
图25是按专利WO2017007759中方法制备的形态1的XRPD图。Figure 25 is an XRPD pattern of Form 1 prepared according to the method in patent WO2017007759.
图26是本发明晶型CM-VIII的XRPD图。Figure 26 is the XRPD pattern of the crystal form CM-VIII of the present invention.
图27是本发明晶型CM-II测试DVS前后的XRPD图(上图为测试后的XRPD图，下图为测试前的XRPD图)。27 is the XRPD pattern of the crystal form CM-II of the present invention before and after the DVS test (the upper picture is the XRPD pattern after the test, and the lower picture is the XRPD pattern before the test).
图28是本发明含辅料的晶型CM-I压片前后的XRPD图(上图为压片后的XRPD图，下图为压片前的XRPD图)。28 is the XRPD pattern of the crystal form CM-I containing excipients of the present invention before and after tableting (the upper picture is the XRPD pattern after tableting, and the lower picture is the XRPD pattern before tableting).
图29是本发明含辅料的晶型CM-II压片前后的XRPD图(上图为压片后的XRPD图，下图为压 片前的XRPD图)。Figure 29 is the XRPD pattern of the crystal form CM-II containing excipients of the present invention before and after tabletting (the upper picture is the XRPD pattern after tabletting, and the lower picture is the XRPD pattern before tabletting).
图30是本发明含辅料的晶型CM-III压片前后的XRPD图(上图为压片后的XRPD图，下图为压片前的XRPD图)。Fig. 30 is the XRPD pattern of the crystal form CM-III containing excipients of the present invention before and after tabletting (the upper picture is the XRPD pattern after tabletting, and the lower picture is the XRPD pattern before tabletting).
图31是本发明含辅料的WO2017007759中的形态1压片前后的XRPD图(上图为压片后的XRPD图，下图为压片前的XRPD图)。31 is the XRPD pattern of Form 1 in WO2017007759 containing excipients of the present invention before and after tableting (the upper picture is the XRPD pattern after tableting, and the lower picture is the XRPD pattern before tableting).
具体实施方式detailed description
本发明的发明人在研究过程中惊奇地发现了式(I)化合物的一系列新晶型。这些晶型制备简单，成本低廉，在晶型稳定性、溶解性、引湿性、压片稳定性、机械稳定性、制剂稳定性、工艺可开发性及粉体加工性能等方面存在优势，对该药物的优化和开发具有重要意义。并且在使用本发明的晶型以及药学上可接受的辅料制成片剂后，压片时不粘冲，因此本发明的晶型所制成的片剂具有优异的压片稳定性。The inventors of the present invention have surprisingly discovered a series of new crystal forms of the compound of formula (I) in the course of research. These crystal forms are simple to prepare, low cost, and have advantages in crystal form stability, solubility, moisture absorption, tableting stability, mechanical stability, formulation stability, process developability and powder processing performance. The optimization and development of drugs is of great significance. In addition, after using the crystal form of the present invention and pharmaceutically acceptable auxiliary materials to prepare a tablet, the tablet is not sticky during tableting, so the tablet prepared from the crystal form of the present invention has excellent tableting stability.
术语the term
在本文中，除非特别说明，各缩写均为本领域技术人员所理解的常规含义。Herein, unless otherwise specified, each abbreviation has the conventional meaning understood by those skilled in the art.
如本文所用，除非特别说明，术语“式(I)化合物原料”是指式(I)化合物的无定型(形)和/或各种晶型(包括本文提及的各种晶型和无定型、公开或未公开的各种文献或专利中提及的晶型或无定型，例如根据WO2017007759中记载的方法制备的式(I)化合物形态1。As used herein, unless otherwise specified, the term "raw material for the compound of formula (I)" refers to the amorphous (form) and/or various crystalline forms (including the various crystalline and amorphous forms mentioned herein) of the compound of formula (I) , the crystalline form or amorphous form mentioned in various published or unpublished documents or patents, such as the compound form 1 of formula (I) prepared according to the method described in WO2017007759.
如本文所用，“本发明的晶型”是指如本文中所述的晶型CM-I、晶型CM-II、晶型CM-III、晶型CM-IV、晶型CM-V、晶型CM-VI、晶型CM-VII和晶型CM-VIII。As used herein, "crystal form of the present invention" refers to crystal form CM-I, crystal form CM-II, crystal form CM-III, crystal form CM-IV, crystal form CM-V, crystal form as described herein Form CM-VI, Form CM-VII and Form CM-VIII.
如本文所用，除非特别说明，加入溶剂或溶液的方式为直接倒入或匀速加入等。As used herein, unless otherwise specified, the method of adding the solvent or solution is direct pouring or uniform addition, and the like.
如本文所用，“缓慢加入”的方式，包括但不限于：逐滴滴加，沿容器壁缓慢加入等。As used herein, the manner of "slow addition" includes, but is not limited to, dropwise addition, slow addition along the container wall, and the like.
通用方法general method
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。The present invention will be further described below in conjunction with specific embodiments. It should be understood that these examples are only used to illustrate the present invention and not to limit the scope of the present invention. In the following examples, the experimental methods without specific conditions are usually in accordance with conventional conditions or in accordance with the conditions suggested by the manufacturer. Percentages and parts are by weight unless otherwise indicated.
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described can be used in the methods of the present invention. Methods and materials for preferred embodiments described herein are provided for illustrative purposes only.
本发明中所用的溶剂均为分析纯，含水量约为0.1％。实施例中作为原料的式(I)化合物均通过购买。本发明所有的测试方法均为通用方法，测试参数如下：The solvents used in the present invention are all analytically pure, and the water content is about 0.1%. The compounds of formula (I) used as raw materials in the examples were all purchased. All test methods of the present invention are general methods, and the test parameters are as follows:
XRPD图测定方法：XRPD pattern determination method:
X-射线粉末衍射仪器：Bruker D2 Phaser X-射线粉末衍射仪；辐射源Cu
Figure PCTCN2021117042-appb-000003
发生器(Generator)kv：30kv；发生器(Generator)mA：10mA；起始的2θ：2.000°，扫描范围：2.0000～35.000°，扫描步长0.02°，扫描速度0.1s/step。 X-ray powder diffractometer: Bruker D2 Phaser X-ray powder diffractometer; radiation source Cu
Figure PCTCN2021117042-appb-000003
Generator kv: 30kv; Generator mA: 10mA; initial 2θ: 2.000°, scanning range: 2.0000-35.000°, scanning step size 0.02°, scanning speed 0.1s/step.
TGA图测定方法：TGA chart determination method:
热重分析法(TGA)仪器：美国TA公司的TGA55型；加热速率：10℃/min；氮气流速：40mL/min。Thermogravimetric analysis (TGA) instrument: TGA55 of TA company in the United States; heating rate: 10° C./min; nitrogen flow rate: 40 mL/min.
DSC图测定方法：DSC chart determination method:
差示扫描量热法(DSC)仪器：美国TA公司的TA Q2000型；加热速率：10℃/min，氮气流速：50mL/min。Differential scanning calorimetry (DSC) instrument: TA Q2000 type from TA company in the United States; heating rate: 10°C/min, nitrogen flow rate: 50mL/min.
核磁共振氢谱数据( 1H NMR)采自于Bruker Avance II DMX 400M HZ核磁共振波谱仪。称取2mg样品，溶于0.6mL氘代二甲亚砜中，过滤，滤液加入核磁管中进行测试。 Hydrogen nuclear magnetic resonance data ( 1 H NMR) were obtained from a Bruker Avance II DMX 400M HZ nuclear magnetic resonance spectrometer. 2 mg of the sample was weighed, dissolved in 0.6 mL of deuterated dimethyl sulfoxide, filtered, and the filtrate was added to a NMR tube for testing.
DVS图测定方法：DVS chart determination method:
动态水分吸附仪(DVS)仪器：美国TA公司的TA Q5000 SA型；温度：25℃；氮气流速：50mL/min；单位时间质量变化：0.002％/min；相对湿度范围：0％RH～90％RH。Dynamic Moisture Sorption (DVS) Instrument: TA Q5000 SA from TA Company, USA; Temperature: 25℃; Nitrogen Flow Rate: 50mL/min; Mass Change per Unit Time: 0.002%/min; Relative Humidity Range: 0%RH～90% RH.
堆密度测试：Bulk density test:
颗粒和粉末特性分析仪：宁波瑞柯伟业仪器有限公司的FT-2000A/B型。Particle and powder characteristic analyzer: FT-2000A/B of Ningbo Ruike Weiye Instrument Co., Ltd.
压片：Tablet:
单冲手动压片机，型号：ENERPAC，模具：φ6mm圆。Single punch manual tablet press, model: ENERPAC, mold: φ6mm circle.
在本发明中，除非特别说明，干燥所用的方法为本领域的常规干燥方法，例如在本发明的实施例中干燥是指在常规干燥用烘箱进行真空干燥或常压干燥。一般地，干燥0.1～50h或1～30h。In the present invention, unless otherwise specified, the drying method is a conventional drying method in the field. For example, drying in the embodiments of the present invention refers to vacuum drying or normal pressure drying in a conventional drying oven. Generally, drying is performed for 0.1 to 50h or 1 to 30h.
药物组合物和施用方法Pharmaceutical compositions and methods of administration
由于本发明的晶型或由本发明的晶型制得的洛普替尼(无定型)具有优异的对携带ALK、ROS1或NTRK致癌基因重排的NSCLC患者的治疗作用，因此本发明的晶型或由本发明的晶型制得的洛普替尼(无定型)以及含有本发明的晶型或由本发明的晶型制得的洛普替尼(无定型)为主要活性成分的药物组合物可用于治疗癌症患者或如携带ALK、ROS1或NTRK致癌基因重排的NSCLC患者。因此，本发明的晶型或由本发明的晶型制得的洛普替尼(无定型可以用于制备治疗癌症患者(如携带ALK、ROS1或NTRK致癌基因重排的NSCLC患者)，该药物可以通过本领域常用方法制得。Since the crystal form of the present invention or Loprotinib (amorphous) prepared from the crystal form of the present invention has an excellent therapeutic effect on NSCLC patients with ALK, ROS1 or NTRK oncogene rearrangements, the crystal form of the present invention Or Loprotinib (amorphous) prepared from the crystal form of the present invention and pharmaceutical compositions containing the crystal form of the present invention or Loprotinib (amorphous) prepared from the crystal form of the present invention as the main active ingredient can be used For the treatment of cancer patients or NSCLC patients with ALK, ROS1 or NTRK oncogene rearrangements. Therefore, the crystal form of the present invention or Loprotinib (amorphous form can be used to prepare and treat cancer patients (such as NSCLC patients carrying ALK, ROS1 or NTRK oncogene rearrangement) prepared from the crystal form of the present invention, the drug can Prepared by methods commonly used in the art.
本发明的药物组合物包含安全有效量范围内的本发明的晶型或由本发明晶型制得的洛普替尼(无定型)，及药学上可以接受的赋形剂或载体。The pharmaceutical composition of the present invention comprises the crystal form of the present invention or Loprotinib (amorphous) prepared from the crystal form of the present invention within a safe and effective amount, and a pharmaceutically acceptable excipient or carrier.
其中，“安全有效量”指的是：化合物(或晶型或无定型)的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明的晶型/剂，更佳地，含有10-200mg本发明的晶型/剂。较佳地，所述的“一剂”为一个胶囊或药片。Wherein, "safe and effective amount" refers to: the amount of the compound (or crystal form or amorphous form) is sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the crystal form/dose of the present invention, more preferably, 10-200 mg of the crystal form/dose of the present invention. Preferably, the "one dose" is a capsule or tablet.
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的活性成分以及它们之间相互掺和，而不明显降低活性成分的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、 多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如
Figure PCTCN2021117042-appb-000004
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。 "Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid filler or gel substances which are suitable for human use and which must be of sufficient purity and sufficiently low toxicity. "Compatibility" as used herein means that the components of the composition can be blended with the active ingredients of the present invention and with each other without significantly reducing the efficacy of the active ingredients. Examples of pharmaceutically acceptable carrier moieties include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid) , magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as
Figure PCTCN2021117042-appb-000004
), wetting agents (such as sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
本发明的多晶型物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。The mode of administration of the polymorph or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性成分与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active ingredient is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators such as quaternary amine compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostearate; (h) adsorbents such as kaolin; and (i) lubricants such as talc, hard Calcium fatty acid, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性成分的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性成分也可与上述赋形剂中的一种或多种形成微胶囊形式。Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials well known in the art. They may contain opacifying agents, and the release of the active ingredient in such compositions may be in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric substances and waxes. If desired, the active ingredient may also be in microencapsulated form with one or more of the above-mentioned excipients.
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性成分外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active ingredient, liquid dosage forms may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, and the like.
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。Besides these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
除了活性成分外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。In addition to the active ingredient, suspensions may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
用于局部给药的本发明的多晶型物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。Dosage forms of the polymorphs of the invention for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
本发明的晶型或由本发明的晶型制得的洛普替尼(无定型)可以单独给药，或者与其他药学上可接受的化合物联合给药。The crystalline form of the present invention or Loprotinib (amorphous) prepared from the crystalline form of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds.
使用药物组合物时，是将安全有效量的本发明的晶型或由本发明的晶型制得的洛普替尼(无定型)适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选20～500mg。当然，具体剂量还应考虑 给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。When using the pharmaceutical composition, a safe and effective amount of the crystalline form of the present invention or Loprotinib (amorphous) prepared from the crystalline form of the present invention is suitable for mammals (such as humans) in need of treatment, wherein the dose at the time of administration For a pharmaceutically effective dose, for a person with a body weight of 60 kg, the daily dose is usually 1-2000 mg, preferably 20-500 mg. Of course, the specific dosage should also take into account the route of administration, the patient's health and other factors, which are all within the skill of the skilled physician.
本发明的主要优点在于：The main advantages of the present invention are:
(1)晶型稳定性和机械稳定性好。晶型CM-I在25℃/60％RH下敞口放置至少可稳定性30天。晶型CM-II和晶型CM-III在25℃/60％RH和40℃/75％RH下敞口放置，至少可稳定性30天。晶型CM-II和晶型CM-III在研磨前后，晶型无变化，说明其机械稳定性较好，可降低制剂加工过程中对原料药粉碎带来的转晶风险。晶型CM-I、晶型CM-II和晶型CM-III与辅料一起混合后压片，压片前后晶型不变，说明其具有较好的压片稳定性。较好的晶型稳定性能够减少药物由于晶型变化而导致溶出速率及生物利用度改变的风险，且有利于结晶和制剂工艺中的晶型控制，对产品的生产和储存也是大有益处。(1) Good crystal stability and mechanical stability. Form CM-I is stable for at least 30 days when left open at 25°C/60% RH. Form CM-II and Form CM-III are stable for at least 30 days when placed open at 25°C/60%RH and 40°C/75%RH. The crystal forms of crystal form CM-II and crystal form CM-III did not change before and after grinding, indicating that their mechanical stability is good, which can reduce the risk of crystal transformation caused by the crushing of raw materials during preparation processing. Crystal form CM-I, crystal form CM-II and crystal form CM-III were mixed with excipients and then pressed into tablets, and the crystal forms did not change before and after tableting, indicating that they had good tableting stability. Better crystal form stability can reduce the risk of changes in dissolution rate and bioavailability of drugs due to crystal form changes, and is conducive to crystal form control in crystallization and formulation processes, and is also of great benefit to product production and storage.
(2)引湿性低。晶型CM-II引湿性低，40％RH～80％RH增重0.12％。低引湿性说明了该晶型对包装和储存条件要求不苛刻，且在制备过程中无需特殊的干燥条件，简化了药物的制备和后处理工艺，利于工业化生产，显著降低了药物生产、运输和储存的成本。(2) Low hygroscopicity. Crystal form CM-II has low hygroscopicity, and the weight gain is 0.12% from 40%RH to 80%RH. The low hygroscopicity shows that the crystal form does not require strict packaging and storage conditions, and does not require special drying conditions during the preparation process, which simplifies the preparation and post-processing of the drug, is beneficial to industrial production, and significantly reduces the production, transportation and cost of drugs. storage costs.
(3)与现有技术相比，本发明提供的晶型的制备方法更安全可靠。同时操作简便易行，成本低廉，适用于药物研发和工业化生产中。本发明提供的晶型可使用低毒或无毒的溶剂制备得到，如乙醇、乙酸和水等。同时制备方法均为常规的、可工业化生产的结晶方法，可通过控制工艺参数，进而控制粒度、晶习和晶型等，进而得到稳定高质量的产品。(3) Compared with the prior art, the preparation method of the crystal form provided by the present invention is safer and more reliable. At the same time, the operation is simple and easy, the cost is low, and the method is suitable for drug research and development and industrial production. The crystal forms provided by the present invention can be prepared by using low toxicity or non-toxic solvents, such as ethanol, acetic acid and water. At the same time, the preparation methods are all conventional crystallization methods that can be industrially produced. By controlling the process parameters, the particle size, crystal habit and crystal form can be controlled to obtain stable and high-quality products.
(4)与现有技术相比，本发明提供的晶型溶解性好，更好的溶解性有利于提高药物在人体内的吸收，提高生物利用度，使药物发挥更好的治疗作用。另外，更好的溶解性能够在保证药物疗效的同时，降低药品的剂量，从而降低药品的副作用，提高药品的安全性。(4) Compared with the prior art, the crystal form provided by the present invention has good solubility, and the better solubility is beneficial to improve the absorption of the drug in the human body, improve the bioavailability, and make the drug exert a better therapeutic effect. In addition, better solubility can reduce the dose of the drug while ensuring the efficacy of the drug, thereby reducing the side effect of the drug and improving the safety of the drug.
(5)与现有技术相比，本发明提供的晶型具有更好的流动性，并且压片时不黏冲。有利于药物的运输转移以及制剂工艺的开发。(5) Compared with the prior art, the crystal form provided by the present invention has better fluidity and is not sticky during tableting. It is beneficial to the transportation and transfer of drugs and the development of preparation technology.
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。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. Therefore, the protection scope of the patent of the present invention should be subject to the appended claims.
对比例1：专利WO2017007759中的形态1Comparative Example 1: Form 1 in Patent WO2017007759
根据专利WO2017007759中记载的方法，制备所述形态1如下：称取5.55g式(I)化合物溶于乙酸乙酯：二氯甲烷：甲醇(200:150:40)中，并将溶液浓缩至体积约为70mL，有白色固体析出，过滤，该白色固体即为专利WO2017007759中形态1，对所得固体进行XRPD测试，其XRPD图如图25所示。According to the method described in the patent WO2017007759, the Form 1 was prepared as follows: 5.55 g of the compound of formula (I) was weighed and dissolved in ethyl acetate:dichloromethane:methanol (200:150:40), and the solution was concentrated to volume About 70 mL, a white solid was precipitated, filtered, and the white solid was the form 1 in the patent WO2017007759. The obtained solid was subjected to XRPD test, and its XRPD pattern is shown in Figure 25.
实施例1：晶型CM-I的制备Example 1: Preparation of crystal form CM-I
称取500mg式(I)化合物在50℃下溶于27mL乙醇中，过滤。滤液在20℃下滴加至200mL水中，搅拌2h，过滤。湿滤饼在25℃下真空干燥24h，所得固体为式(I)化合物晶型CM-I。对得到的固体进行XRPD测试，其X-射线粉末衍射数据如表1所示，其XRPD图如图1所示；对所得固体进行TGA测试，其谱图如图2所示，25～100℃失重约10.5％；对所得固体进行DSC测试，60℃ ～92℃有2个吸热峰，170℃～185℃有1个放热峰，其谱图如图3所示；对所得固体进行1H NMR测试，其谱图如图4所示，核磁数据： 1H NMR(400MHz,DMSO-d 6)δ9.83(s,1H),8.81(d,J＝6.7Hz,1H),8.58(d,J＝7.6Hz,1H),8.04(s,1H),7.13(dd,J＝9.5,3.0Hz,1H),7.00(ddd,J＝10.9,8.5,3.8Hz,2H),6.36(d,J＝7.6Hz,1H),5.75–5.35(m,1H),4.49(t,J＝9.0Hz,1H),3.91(ddd,J＝12.1,8.1,3.7Hz,1H),3.14(dd,J＝11.5,8.6Hz,1H),2.50(s,6H),1.45(t,J＝6.8Hz,6H)。 500 mg of the compound of formula (I) was weighed and dissolved in 27 mL of ethanol at 50° C., and filtered. The filtrate was added dropwise to 200 mL of water at 20 °C, stirred for 2 h, and filtered. The wet filter cake was vacuum-dried at 25° C. for 24 h, and the obtained solid was the compound of formula (I) in crystal form CM-I. The obtained solid was tested by XRPD, and its X-ray powder diffraction data was shown in Table 1, and its XRPD pattern was shown in Figure 1; The weight loss is about 10.5%; DSC test is carried out on the obtained solid, there are 2 endothermic peaks at 60 ° C ~ 92 ° C, and 1 exothermic peak at 170 ° C ~ 185 ° C, the spectrum is shown in Figure 3; The obtained solid was subjected to 1H NMR test, its spectrum is shown in Figure 4, nuclear magnetic data: 1 H NMR (400MHz, DMSO-d 6 )δ9.83(s, 1H), 8.81(d, J=6.7Hz, 1H), 8.58(d , J＝7.6Hz, 1H), 8.04(s, 1H), 7.13(dd, J＝9.5, 3.0Hz, 1H), 7.00(ddd, J＝10.9, 8.5, 3.8Hz, 2H), 6.36(d, J=7.6Hz, 1H), 5.75–5.35 (m, 1H), 4.49 (t, J=9.0Hz, 1H), 3.91 (ddd, J=12.1, 8.1, 3.7Hz, 1H), 3.14 (dd, J =11.5,8.6Hz,1H),2.50(s,6H),1.45(t,J=6.8Hz,6H).
表1Table 1
2θ(°)2θ(°) 相对强度(％)Relative Strength(%) 2θ(°)2θ(°) 相对强度(％)Relative Strength(%)
3.83.8 1.11.1 20.020.0 2.92.9
7.77.7 8.88.8 22.722.7 1.41.4
8.98.9 100.0100.0 22.722.7 1.11.1
11.311.3 3.73.7 23.323.3 1.11.1
14.314.3 0.80.8 25.125.1 3.03.0
15.515.5 1.81.8 28.928.9 1.41.4
17.817.8 5.75.7      
实施例2：晶型CM-I的制备Example 2: Preparation of crystal form CM-I
称取9mg式(I)化合物在室温下溶于0.4mL甲酸/水(4:1,v/v)中，过滤。滤液在28℃下滴加至4mL水中，搅拌2h，过滤。固体在25℃下真空干燥24h，所得固体为式(I)化合物晶型CM-I。对得到的固体进行XRPD测试，其X-射线粉末衍射数据如表2所示。9 mg of the compound of formula (I) was weighed and dissolved in 0.4 mL of formic acid/water (4:1, v/v) at room temperature, and filtered. The filtrate was added dropwise to 4 mL of water at 28 °C, stirred for 2 h, and filtered. The solid was dried under vacuum at 25° C. for 24 h, and the obtained solid was the compound of formula (I) in crystal form CM-I. The obtained solid was tested by XRPD, and its X-ray powder diffraction data are shown in Table 2.
表2Table 2
2θ(°)2θ(°) 相对强度(％)Relative Strength(%) 2θ(°)2θ(°) 相对强度(％)Relative Strength(%)
3.73.7 1.91.9 17.617.6 4.24.2
7.57.5 11.411.4 20.020.0 3.23.2
8.78.7 100.0100.0 24.924.9 2.42.4
11.111.1 3.83.8 28.728.7 1.71.7
实施例3：晶型CM-I的制备Example 3: Preparation of crystal form CM-I
称取10mg式(I)化合物在室温下溶于0.5mL四氢呋喃中，过滤。在滤液中缓慢滴入1mL水，搅拌2h，过滤。固体在25℃下真空干燥24h，所得固体为式(I)化合物晶型CM-I。对得到的固体进行XRPD测试，其X-射线粉末衍射数据如表3所示。10 mg of the compound of formula (I) was weighed and dissolved in 0.5 mL of tetrahydrofuran at room temperature, and filtered. 1 mL of water was slowly dropped into the filtrate, stirred for 2 h, and filtered. The solid was dried under vacuum at 25° C. for 24 h, and the obtained solid was the compound of formula (I) in crystal form CM-I. The obtained solid was tested by XRPD, and its X-ray powder diffraction data are shown in Table 3.
表3table 3
2θ(°)2θ(°) 相对强度(％)Relative Strength(%) 2θ(°)2θ(°) 相对强度(％)Relative Strength(%)
7.67.6 8.08.0 15.315.3 2.32.3
8.78.7 100.0100.0 17.617.6 5.75.7
11.111.1 3.63.6 19.819.8 3.13.1
14.214.2 1.61.6 24.924.9 3.23.2
实施例4：晶型CM-I的制备Example 4: Preparation of crystal form CM-I
称取10mg式(I)化合物在室温下溶于0.5mL丙酮中，过滤。在滤液中缓慢滴入1mL水，搅拌2h，过滤。固体在25℃下真空干燥24h，所得固体为式(I)化合物晶型CM-I。对得到的固体进行XRPD测试，其X-射线粉末衍射数据如表4所示。10 mg of the compound of formula (I) was weighed and dissolved in 0.5 mL of acetone at room temperature, and filtered. 1 mL of water was slowly dropped into the filtrate, stirred for 2 h, and filtered. The solid was dried under vacuum at 25° C. for 24 h, and the obtained solid was the compound of formula (I) in crystal form CM-I. The obtained solid was tested by XRPD, and its X-ray powder diffraction data are shown in Table 4.
表4Table 4
2θ(°)2θ(°) 相对强度(％)Relative Strength(%) 2θ(°)2θ(°) 相对强度(％)Relative Strength(%)
7.57.5 4.44.4 17.617.6 4.04.0
8.78.7 100.0100.0 19.819.8 2.12.1
11.111.1 2.32.3 24.824.8 1.31.3
14.114.1 0.50.5 28.728.7 0.70.7
实施例5：晶型CM-I的制备Example 5: Preparation of crystal form CM-I
称取5mg式(I)化合物在室温下溶于5mL乙腈中，过滤。在滤液中23℃下敞口挥发，溶剂挥干，所得固体为式(I)化合物晶型CM-I。对得到的固体进行XRPD测试，其X-射线粉末衍射数据如表5所示。5 mg of the compound of formula (I) was weighed and dissolved in 5 mL of acetonitrile at room temperature, and filtered. The filtrate was evaporated openly at 23° C., the solvent was evaporated to dryness, and the obtained solid was the compound of formula (I) in crystal form CM-I. The obtained solid was subjected to XRPD test, and its X-ray powder diffraction data are shown in Table 5.
表5table 5
2θ(°)2θ(°) 相对强度(％)Relative Strength(%)
7.67.6 14.514.5
8.98.9 100.0100.0
15.315.3 3.03.0
实施例6：晶型CM-I的制备Example 6: Preparation of crystal form CM-I
将实施例9得到的晶型CM-II放置在水中，5℃下搅拌1天，所得固体为式(I)化合物晶型CM-I。对得到的固体进行XRPD测试，其X-射线粉末衍射数据如表6所示。The crystal form CM-II obtained in Example 9 was placed in water and stirred at 5° C. for 1 day, and the obtained solid was the crystal form CM-I of the compound of formula (I). The obtained solid was tested by XRPD, and its X-ray powder diffraction data are shown in Table 6.
表6Table 6
2θ(°)2θ(°) 相对强度(％)Relative Strength(%) 2θ(°)2θ(°) 相对强度(％)Relative Strength(%)
7.57.5 2.12.1 17.617.6 4.04.0
8.78.7 100.0100.0 19.819.8 1.91.9
11.111.1 2.12.1 28.728.7 1.01.0
实施例7：晶型CM-I的制备Example 7: Preparation of crystal form CM-I
将实施例11得到的晶型CM-IV放置在水中，5℃下搅拌1天，所得固体为式(I)化合物晶型CM-I。对得到的固体进行XRPD测试，其X-射线粉末衍射数据如表7所示。The crystal form CM-IV obtained in Example 11 was placed in water and stirred at 5° C. for 1 day, and the obtained solid was the crystal form CM-I of the compound of formula (I). The obtained solid was subjected to XRPD test, and its X-ray powder diffraction data are shown in Table 7.
表7Table 7
2θ(°)2θ(°) 相对强度(％)Relative Strength(%) 2θ(°)2θ(°) 相对强度(％)Relative Strength(%)
7.57.5 2.62.6 17.617.6 2.62.6
8.78.7 100.0100.0 19.819.8 1.21.2
11.111.1 1.41.4      
实施例8：晶型CM-I的制备Example 8: Preparation of crystal form CM-I
将实施例10得到的晶型无定型放置在水中，5℃下搅拌1天，所得固体为式(I)化合物晶型CM-I。对得到的固体进行XRPD测试，其X-射线粉末衍射数据如表8所示。The amorphous crystalline form obtained in Example 10 was placed in water and stirred at 5° C. for 1 day, and the obtained solid was the crystalline form CM-I of the compound of formula (I). The obtained solid was subjected to XRPD test, and its X-ray powder diffraction data are shown in Table 8.
表8Table 8
2θ(°)2θ(°) 相对强度(％)Relative Strength(%) 2θ(°)2θ(°) 相对强度(％)Relative Strength(%)
7.57.5 11.111.1 17.717.7 3.23.2
8.88.8 100.0100.0 19.819.8 1.41.4
11.111.1 3.23.2 22.722.7 0.70.7
14.214.2 0.90.9 24.924.9 1.11.1
15.315.3 1.11.1      
实施例9：晶型CM-II的制备Example 9: Preparation of crystal form CM-II
称取12mg实施1得到的晶型CM-I，在氮气保护下常压加热至200℃，所得固体为式(I)化合物晶型CM-II。对得到的固体进行XRPD测试，其X-射线粉末衍射数据如表9所示，其XRPD图如图6所示；对所得固体进行TGA测试，其谱图如图7所示，25～100℃失重约0.8％；对所得固体进行DSC测试，其谱图如图8所示；对所得固体进行 1H NMR测试，其谱图如图9所示，核磁数据： 1H NMR(400MHz,DMSO-d 6)δ9.82(d,J＝6.3Hz,1H),8.81(d,J＝6.7Hz,1H),8.58(d,J＝7.6Hz,1H),8.04(s,1H),7.13(dd,J＝9.5,3.0Hz,1H),7.06–6.91(m,2H),6.36(d,J＝7.6Hz,1H),5.60–5.48(m,1H),4.54–4.43(m,1H),3.91(ddd,J＝12.3,8.1,3.8Hz,1H),3.14(dd,J＝11.3,8.5Hz,1H),1.45(t,J＝6.9Hz,6H)。 12 mg of the crystal form CM-I obtained in Example 1 was weighed, and heated to 200° C. under normal pressure under nitrogen protection, and the obtained solid was the crystal form CM-II of the compound of formula (I). The obtained solid was tested by XRPD, and its X-ray powder diffraction data was shown in Table 9, and its XRPD pattern was shown in Figure 6; The weight loss is about 0.8%; the obtained solid is tested by DSC, and its spectrum is shown in Figure 8; the obtained solid is tested by 1 H NMR, and its spectrum is shown in Figure 9, nuclear magnetic data: 1 H NMR (400MHz, DMSO- d 6 )δ9.82(d,J=6.3Hz,1H),8.81(d,J=6.7Hz,1H),8.58(d,J=7.6Hz,1H),8.04(s,1H),7.13( dd, J=9.5, 3.0Hz, 1H), 7.06–6.91 (m, 2H), 6.36 (d, J=7.6Hz, 1H), 5.60–5.48 (m, 1H), 4.54–4.43 (m, 1H) , 3.91 (ddd, J=12.3, 8.1, 3.8 Hz, 1H), 3.14 (dd, J=11.3, 8.5 Hz, 1H), 1.45 (t, J=6.9 Hz, 6H).
表9Table 9
2θ(°)2θ(°) 相对强度(％)Relative Strength(%) 2θ(°)2θ(°) 相对强度(％)Relative Strength(%)
6.26.2 26.326.3 20.220.2 17.917.9
8.88.8 5.85.8 21.421.4 23.723.7
10.710.7 100.0100.0 22.322.3 19.019.0
12.412.4 37.437.4 22.822.8 49.349.3
16.416.4 6.76.7 24.524.5 13.613.6
17.017.0 16.916.9 26.826.8 9.89.8
17.517.5 10.310.3 27.027.0 8.78.7
19.119.1 75.075.0 27.527.5 8.08.0
实施例10：晶型CM-III的制备Example 10: Preparation of crystal form CM-III
称取8mg式(I)化合物在室温下溶于0.4mL乙酸中，过滤，将滤液在28℃下滴入4mL水中，搅拌2h，过滤。固体在25℃下真空干燥24h，所得固体为式(I)化合物晶型CM-III。对得到的固 体进行XRPD测试，其X-射线粉末衍射数据如表10所示，其XRPD图如图13所示；对所得固体进行TGA测试，其谱图如图14所示，25～100℃失重约8.6％；对所得固体进行DSC测试，60℃～92℃有2个吸热峰，170℃～185℃有1个放热峰，其谱图如图15所示；对所得固体进行1H NMR测试，其谱图如图16所示，核磁数据：1H NMR(400MHz,DMSO-d 6)δ9.81(d,J＝6.6Hz,1H),8.80(d,J＝6.7Hz,1H),8.58(d,J＝7.6Hz,1H),8.04(s,1H),7.13(dd,J＝9.5,3.1Hz,1H),7.08–6.91(m,2H),6.36(d,J＝7.6Hz,1H),5.61–5.45(m,1H),4.54–4.43(m,1H),3.90(ddd,J＝12.3,8.4,4.0Hz,1H),3.14(dd,J＝11.4,8.5Hz,1H),1.45(t,J＝7.0Hz,6H)。 8 mg of the compound of formula (I) was weighed and dissolved in 0.4 mL of acetic acid at room temperature, filtered, the filtrate was dropped into 4 mL of water at 28° C., stirred for 2 h, and filtered. The solid was dried under vacuum at 25° C. for 24 h, and the obtained solid was the crystalline form CM-III of the compound of formula (I). The obtained solid was tested by XRPD, and its X-ray powder diffraction data was shown in Table 10, and its XRPD pattern was shown in Figure 13; The weight loss is about 8.6%; the DSC test of the obtained solid shows that there are 2 endothermic peaks at 60 ° C ~ 92 ° C, and 1 exothermic peak at 170 ° C ~ 185 ° C, and its spectrum is shown in Figure 15; The obtained solid was subjected to 1H NMR test, its spectrum is shown in Figure 16, nuclear magnetic data: 1H NMR (400MHz, DMSO-d 6 ) δ9.81 (d, J=6.6Hz, 1H), 8.80 (d, J=6.7Hz, 1H) ,8.58(d,J=7.6Hz,1H),8.04(s,1H),7.13(dd,J=9.5,3.1Hz,1H),7.08–6.91(m,2H),6.36(d,J=7.6 Hz, 1H), 5.61–5.45 (m, 1H), 4.54–4.43 (m, 1H), 3.90 (ddd, J=12.3, 8.4, 4.0Hz, 1H), 3.14 (dd, J=11.4, 8.5Hz, 1H), 1.45 (t, J=7.0Hz, 6H).
表10Table 10
2θ(°)2θ(°) 相对强度(％)Relative Strength(%) 2θ(°)2θ(°) 相对强度(％)Relative Strength(%)
6.56.5 33.433.4 20.320.3 11.911.9
7.97.9 46.846.8 21.121.1 15.915.9
9.19.1 100.0100.0 23.323.3 12.212.2
9.79.7 40.840.8 23.823.8 10.310.3
15.315.3 8.48.4 26.126.1 5.75.7
18.818.8 25.225.2 28.928.9 6.16.1
18.918.9 29.129.1      
实施例11：晶型CM-IV的制备Example 11: Preparation of crystal form CM-IV
称取196mg式(I)化合物在室温下溶于8mL 95％乙醇中，过滤，将滤液滴入80mL水中，有固体析出。所得固体为式(I)化合物晶型CM-IV。对得到的固体进行XRPD测试，其X-射线粉末衍射数据如表11所示，其XRPD图如图18所示。196 mg of the compound of formula (I) was weighed and dissolved in 8 mL of 95% ethanol at room temperature, filtered, and the filtrate was dropped into 80 mL of water, and a solid was precipitated. The obtained solid is the crystalline form CM-IV of the compound of formula (I). The obtained solid was subjected to XRPD test, and its X-ray powder diffraction data is shown in Table 11, and its XRPD pattern is shown in Figure 18 .
表11Table 11
2θ(°)2θ(°) 相对强度(％)Relative Strength(%) 2θ(°)2θ(°) 相对强度(％)Relative Strength(%)
6.06.0 0.50.5 21.521.5 14.414.4
7.17.1 100.0100.0 22.922.9 0.60.6
7.87.8 0.60.6 23.923.9 0.30.3
9.79.7 0.80.8 24.524.5 0.20.2
12.612.6 0.40.4 25.625.6 0.20.2
18.618.6 0.90.9 28.928.9 5.55.5
19.619.6 1.51.5 30.030.0 0.40.4
21.021.0 0.50.5 31.531.5 0.40.4
实施例12：晶型CM-V的制备Example 12: Preparation of crystal form CM-V
称取12mg式(I)化合物在室温下溶于1mL1,4-二氧六环/水(1:1,v/v)中，过滤，将滤液放入10mL的玻璃小瓶中，缓慢加入3mL水，盖上瓶盖，在25℃下静置，直至有固体析出。所得固体为式(I)化合物晶型CM-V。对得到的固体进行XRPD测试，其X-射线粉末衍射数据如表12所示，其XRPD图如图19所示。Weigh 12 mg of the compound of formula (I) and dissolve it in 1 mL of 1,4-dioxane/water (1:1, v/v) at room temperature, filter, put the filtrate into a 10 mL glass vial, and slowly add 3 mL of water , cover the bottle, and let it stand at 25°C until a solid precipitates out. The obtained solid is the crystalline form CM-V of the compound of formula (I). The obtained solid was subjected to XRPD test, and its X-ray powder diffraction data is shown in Table 12, and its XRPD pattern is shown in Figure 19 .
表12Table 12
2θ(°)2θ(°) 相对强度(％)Relative Strength(%) 2θ(°)2θ(°) 相对强度(％)Relative Strength(%)
6.96.9 100.0100.0 23.623.6 1.71.7
7.67.6 1.11.1 25.625.6 0.50.5
9.49.4 1.71.7 28.128.1 2.92.9
19.319.3 0.90.9 28.828.8 1.81.8
21.021.0 8.18.1 30.830.8 0.70.7
21.521.5 3.23.2      
22.222.2 0.50.5      
23.223.2 1.51.5      
实施例13：晶型CM-VI的制备Example 13: Preparation of crystal form CM-VI
取20mg式(I)化合物在室温下溶于1mL甲酸中，过滤，将滤液放入10mL的玻璃小瓶中。沿瓶壁缓慢加入4mL水，盖上瓶盖，在25℃下静置，直至有固体析出。所得固体即为晶型CM-VI。对得到的固体进行XRPD测试，其X-射线粉末衍射数据如表13所示，其XRPD图如图20所示。Dissolve 20 mg of the compound of formula (I) in 1 mL of formic acid at room temperature, filter, and put the filtrate into a 10 mL glass vial. Slowly add 4 mL of water along the bottle wall, close the bottle cap, and let it stand at 25°C until a solid precipitates out. The obtained solid is crystal form CM-VI. The obtained solid was subjected to XRPD test, and its X-ray powder diffraction data is shown in Table 13, and its XRPD pattern is shown in Figure 20 .
表13Table 13
2θ(°)2θ(°) 相对强度(％)Relative Strength(%) 2θ(°)2θ(°) 相对强度(％)Relative Strength(%)
6.66.6 0.20.2 16.116.1 0.10.1
7.47.4 100.0100.0 18.218.2 0.90.9
9.09.0 7.67.6 22.522.5 3.53.5
9.69.6 0.20.2 22.822.8 0.40.4
13.613.6 0.10.1 30.430.4 0.10.1
14.914.9 1.71.7 30.730.7 0.80.8
15.115.1 5.15.1 32.432.4 0.10.1
实施例14：晶型CM-VII的制备Example 14: Preparation of crystal form CM-VII
取36mg式(I)化合物在室温下溶于0.2mL N,N-二甲基乙酰胺中，过滤，将滤液在28℃下滴入2mL乙酸丁酯中。继续搅拌，直至有固体析出。所得固体即为晶型CM-VII。对得到的固体进行XRPD测试，其X-射线粉末衍射数据如表14所示，其XRPD图如图21所示；对所得固体进行TGA测试，其谱图如图22所示。36 mg of the compound of formula (I) was dissolved in 0.2 mL of N,N-dimethylacetamide at room temperature, filtered, and the filtrate was added dropwise to 2 mL of butyl acetate at 28°C. Continue stirring until solids precipitate. The obtained solid is crystal form CM-VII. The obtained solid was subjected to XRPD test, and its X-ray powder diffraction data was shown in Table 14, and its XRPD pattern was shown in Figure 21; the obtained solid was subjected to TGA test, and its spectrum was shown in Figure 22.
表14Table 14
2θ(°)2θ(°) 相对强度(％)Relative Strength(%) 2θ(°)2θ(°) 相对强度(％)Relative Strength(%)
6.86.8 1.61.6 20.620.6 4.44.4
7.77.7 1.11.1 21.221.2 17.117.1
8.48.4 100.0100.0 21.621.6 5.15.1
9.49.4 2.02.0 22.122.1 4.94.9
10.610.6 2.02.0 22.622.6 7.17.1
11.811.8 4.14.1 23.023.0 14.114.1
12.912.9 1.51.5 23.523.5 3.93.9
13.313.3 2.72.7 23.923.9 10.310.3
13.613.6 6.76.7 24.824.8 9.19.1
13.913.9 4.44.4 25.425.4 2.42.4
14.214.2 3.13.1 25.725.7 7.77.7
14.514.5 2.22.2 26.926.9 11.611.6
15.315.3 15.515.5 28.028.0 2.82.8
16.516.5 7.57.5 28.528.5 4.74.7
16.816.8 30.430.4 29.029.0 6.66.6
17.317.3 8.08.0 29.629.6 6.76.7
18.018.0 12.012.0 30.730.7 3.73.7
18.918.9 41.541.5 31.031.0 3.33.3
19.819.8 6.96.9      
实施例15：无定型的制备Example 15: Preparation of Amorphous Forms
称取15mg实施1得到的晶型CM-I，在氮气保护下加热至100℃，所得固体为式(I)化合物无定型。对得到的固体进行XRPD测试，其XRPD图如图23所示。15 mg of the crystal form CM-I obtained in Example 1 was weighed, heated to 100° C. under nitrogen protection, and the obtained solid was the amorphous compound of formula (I). The obtained solid was tested by XRPD, and its XRPD pattern is shown in Figure 23.
实施例16：晶型CM-VIII的制备Example 16: Preparation of crystal form CM-VIII
称取15mg实施15得到的无定型，将其敞口放置在25℃/92.5％RH条件下2周，所得固体即为晶型CM-VIII。对得到的固体进行XRPD测试，其X-射线粉末衍射数据如表15所示，其XRPD图如图26所示。15 mg of the amorphous obtained in Example 15 was weighed, and it was placed openly under the condition of 25°C/92.5% RH for 2 weeks, and the obtained solid was crystal form CM-VIII. The obtained solid was subjected to XRPD test, and its X-ray powder diffraction data is shown in Table 15, and its XRPD pattern is shown in Figure 26 .
表15Table 15
2θ(°)2θ(°) 相对强度(％)Relative Strength(%) 2θ(°)2θ(°) 相对强度(％)Relative Strength(%)
7.47.4 9.99.9 16.316.3 3.73.7
8.28.2 100.0100.0 18.318.3 3.33.3
8.98.9 27.327.3 25.225.2 3.63.6
10.410.4 6.66.6      
测试例test case
测试例1：晶型稳定性Test Example 1: Crystal Form Stability
将本发明制备得到的晶型CM-I和晶型CM-II分别在不同的条件下敞口放置30天，对放置前后的晶型进行XRPD检测，并且对放置前后晶型的XRPD图进行对比。具体结果见表16。The crystalline form CM-I and crystalline form CM-II prepared by the present invention were placed openly for 30 days under different conditions respectively, XRPD detection was performed on the crystalline form before and after placing, and the XRPD patterns of the crystalline form before and after being placed were compared. . The specific results are shown in Table 16.
通过对比各图中放置前后的XRPD图可知，本发明提供的晶型CM-I、晶型CM-II、晶型CM-III在25℃/60％RH和40℃/75％RH条件下，敞口放置30天晶型不发生变化，表明本发明的晶型在不同的温度/湿度下有良好的稳定性。By comparing the XRPD patterns before and after placement in each figure, it can be seen that the crystal form CM-I, crystal form CM-II, and crystal form CM-III provided by the present invention under the conditions of 25°C/60%RH and 40°C/75%RH, The crystal form does not change after being left open for 30 days, which shows that the crystal form of the present invention has good stability under different temperature/humidity.
表16Table 16
Figure PCTCN2021117042-appb-000005
Figure PCTCN2021117042-appb-000005
测试例2：机械稳定性Test Example 2: Mechanical Stability
分别称取50mg晶型CM-II和晶型CM-III，于研钵中研磨10min，对研磨后的固体分别进行XRPD测试，研磨前后晶型XRPD对比图分别见图11和图17，研磨结果见表17。Weigh 50 mg of crystalline form CM-II and crystalline form CM-III respectively, grind them in a mortar for 10 min, and perform XRPD tests on the ground solids respectively. The XRPD comparison diagrams of the crystalline forms before and after grinding are shown in Figure 11 and Figure 17, respectively. The grinding results See Table 17.
通过对比各图中研磨前后的XRPD图可知，本发明提供的晶型CM-II和晶型CM-III在研磨前后晶型不发生变化，表明本发明提供的晶型CM-II和晶型CM-III具有良好的机械稳定性。By comparing the XRPD patterns before and after grinding in each figure, it can be seen that the crystal forms of CM-II and CM-III provided by the present invention do not change before and after grinding, indicating that the crystal forms CM-II and CM provided by the present invention do not change. -III has good mechanical stability.
表17Table 17
Figure PCTCN2021117042-appb-000006
Figure PCTCN2021117042-appb-000006
测试例3：引湿性Test Example 3: Humidity
取约20mg本发明中实施例9中得到的晶型CM-II采用动态水分吸附仪(DVS)测试其引湿性，其DVS图见图12。另外，对进行DVS测试前后的固体进行XRPD测试，其XRPD图见图27。总的测试结果见表18。About 20 mg of the crystal form CM-II obtained in Example 9 of the present invention was taken to test its hygroscopicity by using a dynamic moisture absorption apparatus (DVS). The DVS diagram is shown in Figure 12 . In addition, XRPD test was performed on the solid before and after the DVS test, and its XRPD pattern is shown in Figure 27. The overall test results are shown in Table 18.
由DVS测试结果可知，本发明提供的晶型CM-II具有较低的引湿性；由XRPD结果可知，晶型在测试DVS前后晶型不发生变化。可见，本发明晶型CM-II具有耐高湿度环境的能力。It can be seen from the DVS test results that the crystal form CM-II provided by the present invention has low moisture absorption; from the XRPD results, it can be seen that the crystal form does not change before and after the DVS test. It can be seen that the crystal form CM-II of the present invention has the ability to withstand high humidity environment.
表18Table 18
Figure PCTCN2021117042-appb-000007
Figure PCTCN2021117042-appb-000007
测试例4：溶解度Test Example 4: Solubility
分别取5mg本发明实施例1中制备的晶型CM-I，实施例9中制备的晶型CM-II、实施10中制备的晶型CM-III和对比例1晶型(根据专利WO2017007759中记载的方法制备的形态1)于37℃下的不同pH的溶剂中搅拌24小时，观察其溶解现象，并计算相应溶解度，具体数据见表19。Take 5 mg of the crystal form CM-I prepared in Example 1 of the present invention, the crystal form CM-II prepared in Example 9, the crystal form CM-III prepared in Example 10 and the crystal form of Comparative Example 1 (according to the patent WO2017007759) Form 1 prepared by the described method was stirred in solvents of different pH at 37°C for 24 hours, the dissolution phenomenon was observed, and the corresponding solubility was calculated. The specific data are shown in Table 19.
可见，本发明提供的晶型CM-I，晶型CM-II，晶型CM-III的溶解度均大于专利WO2017007759中的形态1，具有较好的溶解性。It can be seen that the solubility of the crystal form CM-I, the crystal form CM-II and the crystal form CM-III provided by the present invention are all higher than that of the form 1 in the patent WO2017007759, and have better solubility.
表19Table 19
Figure PCTCN2021117042-appb-000008
Figure PCTCN2021117042-appb-000008
测试例5：堆密度Test Example 5: Bulk Density
测试了晶型CM-I、晶型CM-III和WO2017007759中的形态1的堆密度，具体数据见表20。可见，本发明提供的晶型CM-I和晶型CM-III比WO2017007759中的形态1具有更好的流动性。The bulk density of crystal form CM-I, crystal form CM-III and Form 1 in WO2017007759 was tested, and the specific data are shown in Table 20. It can be seen that the crystal form CM-I and the crystal form CM-III provided by the present invention have better fluidity than the form 1 in WO2017007759.
表20Table 20
晶型Crystal form 松装密度(g/mL)Bulk density (g/mL) 振实密度(g/mL)Tap Density (g/mL) 豪斯那比Housenaby
形态1Form 1 0.220.22 0.350.35 1.591.59
晶型CM-IForm CM-I 0.280.28 0.330.33 1.181.18
晶型CM-IIIForm CM-III 0.270.27 0.330.33 1.221.22
测试例6：含辅料的压片稳定性Test Example 6: Tablet Stability with Excipients
测试了晶型CM-I、晶型CM-II、晶型CM-III和WO2017007759中的形态1含辅料的压片稳定性，压力10kN，制剂处方见表21。压片前后晶型变化情况见表22。压片由压片数据可知，本发明提 供的晶型CM-I、晶型CM-II和晶型CM-III在含辅料时，具有优异的压片稳定性。且压片时无黏冲现象。The tableting stability of crystal form CM-I, crystal form CM-II, crystal form CM-III and form 1 containing excipients in WO2017007759 was tested, and the pressure was 10 kN. The formulation prescription is shown in Table 21. The crystal form changes before and after tableting are shown in Table 22. Tableting It can be known from the tabletting data that the crystal form CM-I, crystal form CM-II and crystal form CM-III provided by the present invention have excellent tableting stability when they contain auxiliary materials. And there is no sticking phenomenon during tablet pressing.
表21Table 21
类别category mg/片mg/tablet ％(w/w)%(w/w)
本发明提供的晶型The crystal form provided by the present invention 30.030.0 30.030.0
微晶纤维素microcrystalline cellulose 50.050.0 50.050.0
羟丙基甲基纤维素Hydroxypropylmethylcellulose 9.09.0 9.09.0
预胶化淀粉pregelatinized starch 9.09.0 9.09.0
交联聚维酮Crospovidone 1.01.0 1.01.0
硬脂酸镁Magnesium stearate 1.01.0 1.01.0
表22Table 22
Figure PCTCN2021117042-appb-000009
Figure PCTCN2021117042-appb-000009
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。All documents mentioned herein are incorporated by reference in this application as if each document were individually incorporated by reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims (10)

  1. 一种如式(I)所示的化合物的晶型：A crystalline form of the compound represented by formula (I):
    Figure PCTCN2021117042-appb-100001
    Figure PCTCN2021117042-appb-100001
  2. 如权利要求1所述的晶型，其特征在于，所述晶型选自下组：晶型CM-I、晶型CM-II、晶型CM-III；The crystal form of claim 1, wherein the crystal form is selected from the group consisting of crystal form CM-I, crystal form CM-II, and crystal form CM-III;
    其中，所述晶型CM-I的XRPD图包括2个或2个以上选自下组的2θ值：7.7°±0.2°、8.9°±0.2°、11.3°±0.2°、15.5°±0.2°、17.8°±0.2°；Wherein, the XRPD pattern of the crystal form CM-I includes 2 or more 2θ values selected from the following group: 7.7°±0.2°, 8.9°±0.2°, 11.3°±0.2°, 15.5°±0.2° , 17.8°±0.2°;
    所述晶型CM-II的XRPD包括3个或3个以上选自下组的2θ值：10.7°±0.2°、12.4°±0.2°、19.1°±0.2°、22.8°±0.2°；The XRPD of the crystal form CM-II comprises 3 or more 2θ values selected from the group consisting of 10.7°±0.2°, 12.4°±0.2°, 19.1°±0.2°, 22.8°±0.2°;
    所述晶型CM-III的XRPD图包括3个或3个以上选自下组的2θ值：7.9°±0.2°、9.1°±0.2°、9.7°±0.2°、18.9°±0.2°。The XRPD pattern of the crystalline form CM-III includes 3 or more 2θ values selected from the group consisting of 7.9°±0.2°, 9.1°±0.2°, 9.7°±0.2°, 18.9°±0.2°.
  3. 如权利要求2所述的晶型，其特征在于，所述晶型CM-I具有选自下组的一个或多个特征：The crystal form of claim 2, wherein the crystal form CM-I has one or more features selected from the group consisting of:
    1)所述晶型CM-I的XRPD图包括6个或6个以上选自下组的2θ值：3.9°±0.2°、7.7°±0.2°、8.9°±0.2°、11.3°±0.2°、14.3°±0.2°、15.5°±0.2°、17.8°±0.2°、20.0°±0.2°、22.7°±0.2°、23.3°±0.2°、25.1°±0.2°、28.9°±0.2°；1) The XRPD pattern of the crystalline form CM-I includes 6 or more 2θ values selected from the following group: 3.9°±0.2°, 7.7°±0.2°, 8.9°±0.2°, 11.3°±0.2° , 14.3°±0.2°, 15.5°±0.2°, 17.8°±0.2°, 20.0°±0.2°, 22.7°±0.2°, 23.3°±0.2°, 25.1°±0.2°, 28.9°±0.2°;
    2)所述晶型CM-I具有基本如图1所示的XRPD图；2) The crystal form CM-I has an XRPD pattern basically as shown in Figure 1;
    3)所述晶型CM-I具有基本如图2所示的TGA图；3) The crystal form CM-I has a TGA diagram as shown in Figure 2;
    4)所述晶型CM-I具有基本如图3所示的DSC图；4) The crystal form CM-I has a DSC diagram as shown in FIG. 3;
    5)所述晶型CM-I具有基本如图4所示的 1H NMR图谱。 5) The crystalline form CM-I has a 1 H NMR spectrum substantially as shown in FIG. 4 .
  4. 如权利要求2所述的晶型，其特征在于，所述晶型CM-II具有选自下组的一个或多个特征：The crystal form of claim 2, wherein the crystal form CM-II has one or more features selected from the group consisting of:
    1)所述晶型CM-II的XRPD图包括6个或6个以上选自下组的2θ值：6.2°±0.2°、8.8°±0.2°、10.7°±0.2°、12.4°±0.2°、16.4°±0.2°、17.0°±0.2°、17.5°±0.2°、19.1°±0.2°、20.2°±0.2°、21.4°±0.2°、22.3°±0.2°、22.8°±0.2°、24.5°±0.2°、26.8°±0.2°、27.0°±0.2°、27.5°±0.2°；1) The XRPD pattern of the crystal form CM-II includes 6 or more 2θ values selected from the following group: 6.2°±0.2°, 8.8°±0.2°, 10.7°±0.2°, 12.4°±0.2° , 16.4°±0.2°, 17.0°±0.2°, 17.5°±0.2°, 19.1°±0.2°, 20.2°±0.2°, 21.4°±0.2°, 22.3°±0.2°, 22.8°±0.2°, 24.5 °±0.2°, 26.8°±0.2°, 27.0°±0.2°, 27.5°±0.2°;
    2)所述晶型CM-II具有基本如图6所示的XRPD图；2) The crystal form CM-II has an XRPD pattern as basically shown in Figure 6;
    3)所述晶型CM-II具有基本如图7所示的TGA图；3) The crystal form CM-II has a TGA diagram as shown in FIG. 7 ;
    4)所述晶型CM-II具有基本如图8所示的DSC图；4) The crystal form CM-II has a DSC diagram as shown in FIG. 8;
    5)所述晶型CM-II具有基本如图9所示的 1H NMR图谱。 5) The crystal form CM-II has a 1 H NMR spectrum substantially as shown in FIG. 9 .
  5. 如权利要求2所述的晶型，其特征在于，所述晶型CM-III具有选自下组的一个或多个特征：The crystal form of claim 2, wherein the crystal form CM-III has one or more features selected from the group consisting of:
    1)所述晶型CM-III的XRPD图包括6个或6个以上选自下组的2θ值：6.5°±0.2°、7.9°±0.2°、9.1°±0.2°、9.7°±0.2°、15.3°±0.2°、18.8°±0.2°、18.9°±0.2°、20.3°±0.2°、21.1°±0.2°、23.3°±0.2°、23.8°±0.2°、26.1°±0.2°、28.9°±0.2；1) The XRPD pattern of the crystal form CM-III includes 6 or more 2θ values selected from the following group: 6.5°±0.2°, 7.9°±0.2°, 9.1°±0.2°, 9.7°±0.2° , 15.3°±0.2°, 18.8°±0.2°, 18.9°±0.2°, 20.3°±0.2°, 21.1°±0.2°, 23.3°±0.2°, 23.8°±0.2°, 26.1°±0.2°, 28.9 °±0.2;
    2)所述晶型CM-III具有基本如图13所示的XRPD图；2) The crystal form CM-III has an XRPD pattern substantially as shown in Figure 13;
    3)所述晶型CM-III具有基本如图14所示的TGA图；3) The crystal form CM-III has a TGA diagram as shown in Figure 14;
    4)所述晶型CM-III具有基本如图15所示的DSC图；4) The crystal form CM-III has a DSC chart as shown in FIG. 15 ;
    5)所述晶型CM-III具有基本如图16所示的 1H NMR图谱。 5) The crystal form CM-III has a 1 H NMR spectrum substantially as shown in FIG. 16 .
  6. 一种如权利要求1-5中任一项所述的晶型的制备方法，其特征在于，A method for preparing a crystal form according to any one of claims 1-5, wherein,
    包括步骤：a)提供式(I)化合物原料于第一溶剂中的溶液，向所述溶液中加入第二溶剂进行析晶，收集析出固体得到所述晶型；It comprises the steps of: a) providing a solution of the raw material of the compound of formula (I) in a first solvent, adding a second solvent to the solution for crystallization, and collecting the precipitated solid to obtain the crystal form;
    或者，or,
    包括步骤：b)提供式(I)化合物原料于第一溶剂中的溶液，将所述溶液加入至第二溶剂中进行析晶，收集析出固体得到所述晶型；It comprises the steps of: b) providing a solution of the raw material of the compound of formula (I) in the first solvent, adding the solution to the second solvent for crystallization, and collecting the precipitated solid to obtain the crystal form;
    或者，or,
    包括步骤：c)提供式(I)化合物原料于第一溶剂中的溶液或晶浆，对所述溶液或晶浆进行处理，得到固体，收集所得固体得到所述晶型；其中，所述的处理包括搅拌或挥发；It comprises the steps of: c) providing a solution or crystal slurry of the raw material of the compound of formula (I) in a first solvent, processing the solution or crystal slurry to obtain a solid, and collecting the obtained solid to obtain the crystal form; wherein, the handling includes stirring or volatilization;
    或者，or,
    包括步骤：d)提供式(I)化合物原料的固体形式，对所述固体形式进行处理，得到所述晶型；其中，It comprises the steps of: d) providing a solid form of the raw material of the compound of formula (I), and processing the solid form to obtain the crystal form; wherein,
    所述固体形式为晶型或无定型，所述的处理包括下组中的一个或多个步骤：加热、在一定的温度和湿度条件下放置。The solid form is crystalline or amorphous, and the treatment includes one or more of the following steps: heating, placing under certain temperature and humidity conditions.
  7. 如权利要求6所述的制备方法，其特征在于，The preparation method of claim 6, wherein,
    所述第一溶剂包括醇类溶剂、酮类溶剂、酰胺类溶剂、酯类溶剂、醚类溶剂、酸类溶剂、腈类、水，或其组合，其中，The first solvent includes alcohol-based solvents, ketone-based solvents, amide-based solvents, ester-based solvents, ether-based solvents, acid-based solvents, nitriles, water, or a combination thereof, wherein,
    所述醇类溶剂选自下组：甲醇、乙醇、异丙醇、正丙醇，或其组合；The alcoholic solvent is selected from the group consisting of methanol, ethanol, isopropanol, n-propanol, or a combination thereof;
    所述酮类溶剂选自下组：丙酮、2-丁酮、N-甲基吡咯烷酮，或其组合；The ketone solvent is selected from the group consisting of acetone, 2-butanone, N-methylpyrrolidone, or a combination thereof;
    所述酰胺类溶剂选自下组：N,N-二甲基甲酰胺、N,N-二甲基乙酰胺，或其组合；The amide solvent is selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, or a combination thereof;
    所述酯类溶剂选自下组：乙酸乙酯、乙酸异丙酯，或其组合；Described ester solvent is selected from following group: ethyl acetate, isopropyl acetate, or its combination;
    所述醚类溶剂选自下组：四氢呋喃、2-甲基四氢呋喃，或其组合；The ether solvent is selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, or a combination thereof;
    所述酸类溶剂选自下组：甲酸、乙酸、乳酸，或其组合；The acid solvent is selected from the group consisting of formic acid, acetic acid, lactic acid, or a combination thereof;
    所述腈类溶剂选自下组：乙腈；The nitrile solvent is selected from the group consisting of acetonitrile;
    所述第二溶剂包括烃类、酯类、水，或其组合；the second solvent includes hydrocarbons, esters, water, or a combination thereof;
    所述烃类溶剂选自下组：氯仿、二氯甲烷、硝基甲烷、正庚烷、环己烷、甲苯，或其组合；The hydrocarbon solvent is selected from the group consisting of chloroform, dichloromethane, nitromethane, n-heptane, cyclohexane, toluene, or a combination thereof;
    所述酯类溶剂选自下组：乙酸丁酯、乙酸正丙酯，或其组合；The ester solvent is selected from the group consisting of butyl acetate, n-propyl acetate, or a combination thereof;
    所述步骤a)或所述步骤b)中，收集析出固体后，对固体进行处理，得到所述晶型，其中，所述处理包括真空干燥。In the step a) or the step b), after collecting the precipitated solid, the solid is processed to obtain the crystal form, wherein the processing includes vacuum drying.
  8. 一种药物组合物，其特征在于，所述组合物包括：A pharmaceutical composition, characterized in that the composition comprises:
    1)权利要求1-5中任一项所述的晶型；2)药学上可接受的载体。1) The crystal form of any one of claims 1-5; 2) a pharmaceutically acceptable carrier.
  9. 一种使用如权利要求8所述的药物组合物制备用于治疗携带ALK、ROS1或NTRK致癌基因重排 的NSCLC患者的药物的用途。A kind of use of the pharmaceutical composition as claimed in claim 8 to prepare a medicine for the treatment of NSCLC patients carrying ALK, ROS1 or NTRK oncogene rearrangement.
  10. 如权利要求1-5中任一项所述的晶型的用途，其特征在于，所述用途包括：1)制备式(I)化合物或其盐；2)制备用于治疗携带ALK、ROS1或NTRK致癌基因重排的NSCLC患者的药物。The use of the crystal form according to any one of claims 1-5, wherein the use comprises: 1) preparing a compound of formula (I) or a salt thereof; 2) preparing a compound for the treatment of ALK, ROS1 or Drugs for NSCLC patients with NTRK oncogene rearrangements.
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