WO2022089261A1 - Crystal form of pyrimidine derivative and preparation method therefor - Google Patents

Crystal form of pyrimidine derivative and preparation method therefor Download PDF

Info

Publication number
WO2022089261A1
WO2022089261A1 PCT/CN2021/124835 CN2021124835W WO2022089261A1 WO 2022089261 A1 WO2022089261 A1 WO 2022089261A1 CN 2021124835 W CN2021124835 W CN 2021124835W WO 2022089261 A1 WO2022089261 A1 WO 2022089261A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
crystal form
xrpd pattern
basically
Prior art date
Application number
PCT/CN2021/124835
Other languages
French (fr)
Chinese (zh)
Inventor
陈小新
张长宇
刘呈武
周光强
刘志强
刘卓伟
龙超峰
Original Assignee
广东众生睿创生物科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 广东众生睿创生物科技有限公司 filed Critical 广东众生睿创生物科技有限公司
Priority to CN202180070815.5A priority Critical patent/CN116323593A/en
Publication of WO2022089261A1 publication Critical patent/WO2022089261A1/en

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the invention belongs to the field of medicinal chemistry, and particularly relates to a series of crystal forms of pyrimidine derivatives and a preparation method thereof, as well as raw materials, pharmaceutical compositions and medicines containing the crystal forms.
  • Influenza is a major public health problem. According to WHO estimates, seasonal influenza causes approximately 3 to 5 million severe cases and 290,000 to 650,000 deaths related to respiratory diseases each year. Influenza imposes a heavy burden of death and hospitalization globally.
  • Influenza virus is a negative helix single-stranded RNA virus, and its replication does not involve the participation of RNA proofreading enzymes, so the frequency of mutation is much higher than that of other viruses, and it is easy to cause changes in surface antigens.
  • Influenza virus can be divided into three types: A, B, and C according to nucleoprotein (NP) and matrix protein (MP), among which influenza A has the strongest variability and has caused pandemics many times. Influenza is a serious public health safety event worldwide, but effective treatment drugs have been lacking.
  • M2 ion channel inhibitors are widely used in the treatment of influenza, which has induced the emergence of influenza drug-resistant strains. Since the outbreak of H1N1 in 2009, the resistance of influenza viruses to such drugs cannot be ignored and is no longer recommended.
  • the current anti-influenza virus drugs are mainly neuraminidase inhibitors (NAIS), such as oseltamivir (Tamiflu), which have obvious effects on influenza A virus. Resistant virus strains have emerged against aminoacidase inhibitors.
  • anti-influenza virus drugs with a new mechanism of action are urgently needed in clinical practice, which can support the use of single drugs for the treatment of influenza A, or can be used in combination with other anti-influenza virus drugs with other mechanisms of action that have been marketed for influenza A. Influenza prevention and treatment.
  • Patent WO2018041263 discloses a series of pyrimidine derivatives.
  • the in vitro activity data showed that some compounds showed a positive effect in the inhibition of influenza virus replication test, and in further animal tests, some compounds also showed a significant therapeutic effect on the influenza A virus H1N1 mouse infection model, among which the compound WX- The comprehensive performance of 216 (Example 4) is relatively outstanding, and it is considered to have a better prospect of finished medicine.
  • Patent WO2019170067 discloses a series of crystal forms, salt forms and crystal forms of salt forms of WX-216, the series of salt forms/crystal forms have good stability and production/clinical application prospects, and are large-scale production of raw materials and downstream processes of pharmaceutical products (eg, formulation processes) provide a variety of options for intermediates and/or APIs.
  • Patent WO2021012864 discloses the sodium salt of WX-216, the crystal form of this series of compounds shows good druggability (such as stability, fluidity, compressibility, etc.), providing a variety of raw material drug options for subsequent drug development.
  • Salt form screening and crystal form screening are one of the important links in drug development.
  • the physical and chemical properties of its free state, various salt forms and corresponding crystal forms are unknown, and further considerations based on its druggability , finding suitable salt forms and their corresponding dominant crystal forms, and providing a variety of intermediate products and/or API options for subsequent drug development is of great significance to drug development.
  • the purpose of the present invention is to provide hydrates or solvates of WX-216 free base, and for the first time disclose a series of crystal forms of hydrates or solvates of WX-216 free base.
  • Good druggability (stability, fluidity, compressibility, solubility, bioavailability, etc.) provides a variety of API options for subsequent drug development.
  • WX-216 is a pyrimidine derivative containing a carboxyl group.
  • WX-216 can exist in hydrate or solvate.
  • the number n can be 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5 and 4, that is, 1 molecule of WX-216 and n water molecules combine into a hydrate in a manner known in the art, which is a free hydrate known in the art The case where the base compound is hydrated.
  • the present invention also relates to a solvate of WX-216, the "solvent" in the solvate is an organic solvent, and the organic solvent includes but is not limited to methanol, ethanol, propanol, isopropanol, and acetone common in the art , butanone, acetonitrile, dichloromethane, chloroform, ethyl acetate, etc.
  • absorption peaks are not necessary diffraction peaks for characterizing this crystal form; more Specifically, the present invention follows the consensus on crystal form characterization in the art, and the selection of diffraction peaks comprehensively considers factors such as 2 ⁇ angle, absorption intensity (peak height), and grouping them according to stability and repeatability.
  • the present invention follows the consensus on the characterization of crystal forms in the art, and sets the fluctuation range of the endothermic peak and the starting point of the exothermic peak in the DSC spectrum to ⁇ 3 °C, and the TGA The fluctuation range of weight loss values in the spectrum was set to ⁇ 1%.
  • room temperature in the present invention refers to 25 ⁇ 5°C
  • thermogravimetric analysis curve (TGA) in the present invention does not show significant weight loss” refers to the weight loss ⁇ 1% before the detection end temperature.
  • the first object of the present invention is to provide a series of crystal forms of the compound of formula (I), and the series of crystal forms show good druggability.
  • n is selected from any value from 0 to 4.
  • n is selected from 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5 and 4.
  • the crystalline form I of the compound of formula (I) has diffraction peaks at 2 ⁇ of 8.4, 13.9, 15.0, 20.3, 23.4, 25.3, 25.7, 28.1, 29.4 ⁇ 0.2° in the XRPD pattern.
  • the XRPD pattern of the aforementioned compound of formula (I) in crystal form I is basically as shown in FIG. 1 .
  • the crystalline form I of the aforementioned compound of formula (I), its differential scanning calorimetry curve (DSC) has the onset of endothermic peaks at 126.1 ⁇ 3°C and 195.1 ⁇ 3°C.
  • the DSC spectrum of the crystalline form I of the compound of formula (I) is basically as shown in FIG. 2 .
  • thermogravimetric analysis curve loses 4.14 ⁇ 1% at 160°C and 0.46 ⁇ 1% at 210°C.
  • the TGA spectrum of the crystalline form I of the compound of formula (I) is basically as shown in FIG. 3 .
  • a preferred embodiment according to the present invention relates to the crystal form II of the aforementioned compound of formula (I), the structure of which is shown in (2):
  • the XRPD pattern also has diffraction peaks at 2 ⁇ of 10.2, 16.1, 17.4, 18.5, 23.4, 24.5, 26.2, 26.9, 27.8, 30.0, 31.0 ⁇ 0.2°.
  • the XRPD pattern of the crystalline form II of the compound of formula (I) is basically as shown in FIG. 5 .
  • the crystalline form II of the aforementioned compound of formula (I) has an onset of an endothermic peak at 164.0 ⁇ 3° C. in a differential scanning calorimetry curve (DSC).
  • the DSC spectrum of the crystalline form II of the compound of formula (I) is basically as shown in FIG. 6 .
  • thermogravimetric analysis curve TGA of which has a weight loss of 7.41 ⁇ 1% at 150°C;
  • the TGA spectrum of the crystalline form II of the aforementioned compound of formula (I) is basically as shown in FIG. 7 .
  • a preferred embodiment according to the present invention relates to the crystal form III of the compound of the aforementioned formula (I), whose structural formula is shown in the aforementioned (1);
  • crystal form III of the aforementioned compound of formula (I) also has diffraction peaks at 2 ⁇ of 4.8, 7.4, 16.5, 29.5 ⁇ 0.2° in the XRPD pattern.
  • the XRPD pattern of the crystalline form III of the compound of formula (I) is basically as shown in FIG. 9 .
  • the crystalline form III of the compound of the aforementioned formula (I), the differential scanning calorimetry curve (DSC) has the onset of the endothermic peak at 177.6 ⁇ 3°C and the onset of the endothermic peak at 209.77 ⁇ 3°C;
  • the DSC chart of the crystalline form III of the compound of formula (I) is basically as shown in FIG. 10 .
  • thermogravimetric analysis curve (TGA) of which is 1.62 ⁇ 1% weight loss at 90°C and 5.50 ⁇ 1% weight loss at 200°C;
  • the TGA spectrum of the crystalline form III of the compound of formula (I) is basically as shown in FIG. 11 .
  • a preferred embodiment according to the present invention relates to the crystalline form IV of the compound of formula (I), whose XRPD pattern has stable diffraction peaks at 2 ⁇ of 8.2, 8.7, 10.2, 16.9, 20.4 ⁇ 0.2° .
  • the crystalline form IV of the compound of formula (I) also has diffraction peaks at 2 ⁇ of 5.6, 7.2, 12.2, 14.3, 14.6, 15.5, 15.8, 18.8, 21.0, 21.8, 22.7 ⁇ 0.2°;
  • the crystalline form IV of the compound of the aforementioned formula (I), the diffraction peaks of its XRPD pattern are as shown in the following table:
  • the XRPD pattern of the crystalline form IV of the compound of formula (I) is basically as shown in FIG. 13 .
  • the crystalline form IV of the aforementioned compound of formula (I), its differential scanning calorimetry curve (DSC) has an onset of an endothermic peak at 125.0 ⁇ 3°C.
  • the DSC chart of the crystalline form IV of the compound of formula (I) is basically as shown in FIG. 14 .
  • thermogravimetric analysis curve (TGA) at 170°C loses 9.72 ⁇ 1% in weight.
  • the TGA spectrum of the crystalline form IV of the compound of formula (I) is basically as shown in FIG. 15 .
  • the crystalline form V of the compound of the formula (I) also has diffraction peaks at 2 ⁇ of 17.4, 20.4, 22.7, 24.8, 25.1, 25.9, 26.6, 27.6, 29.3, 30.4 ⁇ 0.2° in the XRPD pattern.
  • the XRPD pattern of the crystalline form V of the compound of formula (I) is basically as shown in FIG. 16 .
  • the crystalline form V of the aforementioned compound of formula (I) has an onset of an endothermic peak at 229.5 ⁇ 3° C. in a differential scanning calorimetry curve (DSC).
  • the DSC spectrum of the crystalline form V of the compound of formula (I) is basically as shown in FIG. 17 .
  • thermogravimetric analysis curve loses 71.02 ⁇ 1% at 125°C and 3.07 ⁇ 1% at 200°C.
  • the TGA spectrum of the crystalline form V of the compound of formula (I) is basically as shown in FIG. 18 .
  • crystal form VI of the aforementioned compound of formula (I) also has diffraction peaks at 2 ⁇ of 13.5, 25.4, 27.2, 30.3 ⁇ 0.2° in the XRPD pattern.
  • the XRPD pattern of the crystalline form VI of the compound of formula (I) is basically as shown in FIG. 20 .
  • the DSC spectrum of the crystalline form VI of the compound of formula (I) is basically as shown in FIG. 21 .
  • the TGA spectrum of the crystalline form VI of the compound of formula (I) is basically as shown in FIG. 22 .
  • the second object of the present invention is to provide the crystal form VII of the solvate of the compound of formula (II), which shows good druggability.
  • the aforementioned solvate of the compound of formula (II) is a methyl tert-butyl ether solvate of the compound of formula (II).
  • the aforementioned crystal form VII has an XRPD pattern with stable diffraction peaks at 2 ⁇ of 7.7, 8.9, 12.4, 14.7, 17.9, 18.4, 19.9, 20.6, 23.1, 23.6, 27.8, 28.7 ⁇ 0.2°.
  • its XRPD pattern also has diffraction peaks at 2 ⁇ of 5.9, 15.4, 16.1, 17.5, 19.0, 21.7, 24.5, 28.1, 30.8 ⁇ 0.2°.
  • the aforementioned crystal form VII, the diffraction peak situation of its XRPD pattern is as shown in the following table:
  • the XRPD pattern of the aforementioned crystal form VII is basically as shown in FIG. 23 .
  • the aforementioned crystal form VII has the onset of the endothermic peak at 161.8 ⁇ 3°C.
  • the aforementioned crystalline form VII, the DSC spectrum thereof is basically as shown in FIG. 24 .
  • the aforementioned crystal form VII, the TGA spectrum thereof is basically as shown in FIG. 25 .
  • the third object of the present invention is to provide a crystal form VIII of a solvate of the compound of formula (II) and a preparation method thereof.
  • the aforementioned solvate of the compound of formula (II) is an N-methylpyrrolidone solvate of the compound of formula (II).
  • the above-mentioned crystal form VIII its XRPD pattern has diffraction peaks that appear stably at 2 ⁇ of 7.8, 8.4, and 16.2 ⁇ 0.2°.
  • the XRPD pattern of the aforementioned crystal form VIII also has diffraction peaks at 2 ⁇ of 9.9, 13.7, 15.0, 16.9, 18.2, and 21.8 ⁇ 0.2°.
  • the XRPD pattern of the aforementioned crystal form VIII is basically as shown in FIG. 27 .
  • DSC differential scanning calorimetry curve
  • the aforementioned crystal form VIII the DSC spectrum of which is basically as shown in FIG. 28 .
  • thermogravimetric analysis curve loses 13.50 ⁇ 1% at 165°C.
  • the aforementioned crystal form VIII, the TGA spectrum thereof is basically as shown in FIG. 29 .
  • the fourth object of the present invention is to provide a metastable crystal form of the compound of formula (II) and a preparation method thereof.
  • the metastable crystal form IX of the compound of formula (II) has XRPD pattern with stable diffraction peaks at 2 ⁇ of 9.0, 10.5, 16.5, 19.6, 21.1, 22.8, 24.2 ⁇ 0.2°.
  • the crystalline form IX of the compound of formula (II), the XRPD pattern also has diffraction peaks at 2 ⁇ of 11.8, 17.5, 26.4, 27.5 ⁇ 0.2°.
  • the XRPD pattern of the crystalline form IX of the compound of formula (II) is basically as shown in FIG. 30 .
  • the fifth object of the present invention is to provide a bulk drug containing the compound WX-216 crystal form I to crystal form IX of the present invention or other hydrates and solvates of the compound WX-216 at least one of.
  • the API can be compound WX-216, or compound WX-216 and/or a hydrate of compound WX-216; more specifically , the API contains compound WX-216 crystal form I and/or compound WX-216 crystal form II and/or compound WX-216 crystal form III and/or compound WX-216 crystal form IV and/or compound WX-216-
  • the mass percentage of 216 crystal form V and/or compound WX-216 crystal form VI and/or compound WX-216 crystal form VII and/or compound WX-216 crystal form VIII and/or compound WX-216 crystal form IX is 0.01 ⁇ 99.99% of any value.
  • the API contains compound WX-216 crystal form I and/or compound WX-216 crystal form II and/or compound WX-216 crystal form III and/or compound WX-216 crystal form IV and/or compound
  • the mass percentage of WX-216 crystal form V and/or compound WX-216 crystal form VI and/or compound WX-216 crystal form VII and/or compound WX-216 crystal form VIII and/or compound WX-216 crystal form IX is Any value from 1.00 to 99.00%.
  • the sixth object of the present invention is to provide a pharmaceutical composition comprising pharmaceutically acceptable excipients and the aforementioned bulk drug.
  • the pharmaceutically acceptable adjuvants include, but are not limited to, at least one of fillers, binders, disintegrants, and lubricants.
  • the beneficial effects are finally reflected in the pharmaceutical composition; More specifically, the mass percentage of the aforementioned bulk drug contained in the pharmaceutical composition is any value ranging from 1.00 to 99.00%, and further, the mass percentage of the aforementioned bulk drug contained in the pharmaceutical composition is any value ranging from 5.00 to 95.00%. , and further, the mass percentage of the aforementioned raw materials contained in the pharmaceutical composition is any value of 10.00-90.00%.
  • the seventh object of the present invention is to provide a medicine, which comprises the above-mentioned compound WX-216 crystal form I to crystalline form IX or other hydrates, solvates of the above-mentioned compound WX-216, or the above-mentioned bulk drug or the above-mentioned at least one of the pharmaceutical compositions.
  • the eighth object of the present invention is to provide the above-mentioned compound WX-216 crystal form I to crystal form IX or other hydrates, solvates of the above-mentioned compound WX-216 or the above-mentioned raw materials or the above-mentioned pharmaceutical compositions in the preparation of influenza medicines applications in .
  • the compound WX-216 crystal form I to crystal form IX of the present invention and other hydrates and solvates of the compound WX-216 have certain drug prospects. If the crystal forms I to IX or other hydrates and solvates of the compound WX-216 exist in the aforementioned APIs and/or pharmaceutical compositions, it should be considered that the compound WX-216 provided by the present invention is used. Form I to Form IX or other hydrates and solvates of the compound WX-216.
  • the detection means may further include differential scanning calorimetry (DSC), infrared spectroscopy (IR), Raman spectroscopy (Raman), solid-state nuclear magnetic resonance ( SSNMR) and other methods and all other detection methods that individually or comprehensively can support the use of the crystal form I to crystal form IX of the compound WX-216 of the present invention or other hydrate and solvate forms of the compound WX-216,
  • DSC differential scanning calorimetry
  • IR infrared spectroscopy
  • Raman spectroscopy Raman spectroscopy
  • SSNMR solid-state nuclear magnetic resonance
  • the common methods of those skilled in the art can be used to remove the influences brought by such as pharmaceutical excipients, such as the subtractive atlas method and the like.
  • the present invention has the following advantages and beneficial effects:
  • a crystal form I of the compound of formula (I) and a preparation method thereof are disclosed, which is a hydrate of WX-216, and the crystal form has the characteristics of high stability and has considerable medicinal prospects;
  • a crystal form IV of the compound of formula (I) and a preparation method thereof are disclosed, which is the hydrate of WX-216, which provides large-scale production of bulk drugs and downstream processes (such as formulation processes) of pharmaceutical products. Selection of various intermediates and/or APIs;
  • a crystal form V of the compound of formula (I) and a preparation method thereof are disclosed, which is a hydrate of WX-216, which provides large-scale production of bulk drugs and downstream processes (such as formulation processes) of pharmaceutical products. Selection of various intermediates and/or APIs;
  • a crystal form VI of the compound of formula (I) and a preparation method thereof are disclosed for the first time, which is the hydrate of WX-216, which provides the large-scale production of raw materials and downstream processes (such as formulation processes) of pharmaceutical products. Selection of various intermediates and/or APIs;
  • composition comprising pharmaceutically acceptable excipients and the raw material drug of the present invention, which has the same properties as the compound WX-216 crystal form I to crystal form IX or all of the present invention.
  • the beneficial effects of the compound WX-216 or its hydrate and solvate are basically the same.
  • Figure 8 XRPD comparison chart of the crystalline form II of the compound of formula (I);
  • Figure 12 XRPD comparison chart of the compound of formula (I) Form III;
  • Exposure time 0.2 seconds
  • Light tube voltage and current 40KV, 40mA.
  • TA Discovery 2500 (TA, US);
  • Heating rate 10°C/min
  • Detection method The sample is accurately weighed and placed in a DSC Tzero sample pan, heated to 350 °C, and the nitrogen purge rate in the furnace is 50 mL/min.
  • Thermogravimetric analyzer TA Discovery 55 (TA, US);
  • Detection method The sample is placed in a balanced open aluminum sample pan and automatically weighed in a heating furnace. The sample was heated to 400°C at a rate of 10°C/min, the nitrogen purge rate at the sample was 60mL/min, and the nitrogen purge rate at the balance was 40mL/min.
  • Embodiment 1 The preparation method of compound WX-216
  • WX-216 was prepared with reference to the method disclosed in Example 4 of patent WO2018041263A1.
  • FIG. 8 A comparison of the XRPD spectra of the obtained crystal form II is shown in FIG. 8 .
  • FIG. 12 A comparison of the XRPD spectra of the obtained crystal form III is shown in FIG. 12 .
  • Embodiment 10 The preparation method of formula (I) compound crystal form V
  • crystal form I, crystal form II, crystal form III and crystal form VII were weighed and added to absolute ethanol, and saturated solutions were prepared at room temperature ( ⁇ 25°C), 40°C, and 60°C, respectively. Stir, and take solid samples for characterization when appropriate.
  • crystal form I and crystal form II are that they can be used as intermediate crystal forms to further prepare some other stable crystal forms described in the present invention.
  • Crystal form IV can be obtained by adding acetylacetone to crystal form I after stirring and crystallization for a long time. Those skilled in the art can understand that crystal form IV has high stability;
  • the crystal form V can be obtained by adding water to the crystal form I to suspend, then adding NMP to raise the temperature to 60°C, completely dissolving it, and placing the clear solution at 5°C for 20 hours after crystallization. Those skilled in the art can understand that the crystal form V has high stability;
  • Crystal form VI can be obtained by preparing a saturated solution (tetrahydrofuran/water) of crystal form I, adding the saturated solution dropwise to the water under stirring at room temperature, and obtaining after crystallization. Those skilled in the art can understand that crystal form VI has higher stability;
  • the crystal form VII can be prepared by adding methyl tert-butyl ether to the crystal form I to obtain a suspension, and the obtained suspension is placed at room temperature, suspended and stirred for 70 hours, and the obtained crystal is obtained, which can be understood by those skilled in the art. , the crystal form VII has high stability;
  • the crystal form VIII can be obtained by suspending the crystal form I in acetonitrile, adding NMP dropwise at 60°C, and cooling to room temperature for stirring and crystallization. Those skilled in the art can understand that the crystal form VIII has high stability;
  • the crystal form IX is an intermediate metastable crystal form. During the experiment, it was found that the crystal form IX can only exist in a wet state. If the suction filtration time is too long or drying, the crystal will be transformed into the crystal form I. It can be seen that the crystal form I has high stability.
  • the crystal form of the compound WX-216 of the present invention has at least one effect such as stability, which provides a variety of intermediates for the large-scale production of raw materials and downstream processes (such as formulation processes) of pharmaceutical products. Selection of product and/or drug substance.

Abstract

Provided are a crystal form of a pyrimidine derivative and a preparation method therefor. This series of crystal forms exhibit good druggability (such as stability) and provide a variety of active pharmaceutical ingredient options for subsequent drug development.

Description

一种嘧啶衍生物的晶型及其制备方法A kind of crystal form of pyrimidine derivative and preparation method thereof 技术领域technical field
本发明属于药物化学领域，特别涉及一系列嘧啶衍生物的晶型及其制备方法，及含有所述晶型的原料药、药物组合物及药物。The invention belongs to the field of medicinal chemistry, and particularly relates to a series of crystal forms of pyrimidine derivatives and a preparation method thereof, as well as raw materials, pharmaceutical compositions and medicines containing the crystal forms.
背景技术Background technique
流感是一个重大的公共卫生问题，据WHO估计，季节性流感每年约造成300万～500万例严重病例，29万～65万例与呼吸道疾病相关的死亡病例。流感给全球带来了沉重的死亡和住院负担。Influenza is a major public health problem. According to WHO estimates, seasonal influenza causes approximately 3 to 5 million severe cases and 290,000 to 650,000 deaths related to respiratory diseases each year. Influenza imposes a heavy burden of death and hospitalization globally.
流感病毒是负螺旋单链RNA病毒，其复制无RNA校正酶的参与，所以发生突变的频率远高于其他病毒，易于引起表面抗原的改变。流感病毒根据核蛋白(nucleoprotein,NP)和基质蛋白(matrixprotein,MP)可以分为甲、乙、丙三种，其中甲型流感变异性最强，曾多次引起大流行。流感是全球范围内严重的公共卫生安全事件，然而有效的治疗药物却一直缺乏。Influenza virus is a negative helix single-stranded RNA virus, and its replication does not involve the participation of RNA proofreading enzymes, so the frequency of mutation is much higher than that of other viruses, and it is easy to cause changes in surface antigens. Influenza virus can be divided into three types: A, B, and C according to nucleoprotein (NP) and matrix protein (MP), among which influenza A has the strongest variability and has caused pandemics many times. Influenza is a serious public health safety event worldwide, but effective treatment drugs have been lacking.
M2离子通道抑制剂因广泛用于流感的治疗，诱导了流感耐药株的出现，自2009年爆发H1N1后，流感病毒对此类药物的耐药性已经不可忽视，已不推荐使用。目前的抗流感病毒药物以神经氨酸酶抑制剂(neuraminidase inhibitors,NAIS)为主，如奥司他韦(达菲)，对于甲型流感病毒效果明显，但是经过临床观察发现，对于该类神经氨酸酶抑制剂已经出现了耐药的病毒株。M2 ion channel inhibitors are widely used in the treatment of influenza, which has induced the emergence of influenza drug-resistant strains. Since the outbreak of H1N1 in 2009, the resistance of influenza viruses to such drugs cannot be ignored and is no longer recommended. The current anti-influenza virus drugs are mainly neuraminidase inhibitors (NAIS), such as oseltamivir (Tamiflu), which have obvious effects on influenza A virus. Resistant virus strains have emerged against aminoacidase inhibitors.
在抗流感病毒领域，临床上亟需全新作用机制的抗流感病毒药物，能够支持单药使用治疗甲型流感，或者通过和已上市的其他作用机制的抗流感病毒药物联用，用于甲型流感的预防和治疗。In the field of anti-influenza virus, anti-influenza virus drugs with a new mechanism of action are urgently needed in clinical practice, which can support the use of single drugs for the treatment of influenza A, or can be used in combination with other anti-influenza virus drugs with other mechanisms of action that have been marketed for influenza A. Influenza prevention and treatment.
专利WO2018041263公开了一系列嘧啶衍生物。体外活性数据表明，部分化合物在抑制流感病毒复制试验中表现出积极效应，在进一步的动物试验中，部分化合物亦表现为对甲型流感病毒H1N1小鼠感染模型显著的治疗效果，其中化合物WX-216(实施例4)的综合表现相对突出，被认为具有较好的成药前景。Patent WO2018041263 discloses a series of pyrimidine derivatives. The in vitro activity data showed that some compounds showed a positive effect in the inhibition of influenza virus replication test, and in further animal tests, some compounds also showed a significant therapeutic effect on the influenza A virus H1N1 mouse infection model, among which the compound WX- The comprehensive performance of 216 (Example 4) is relatively outstanding, and it is considered to have a better prospect of finished medicine.
Figure PCTCN2021124835-appb-000001
Figure PCTCN2021124835-appb-000001
专利WO2019170067公开了WX-216的一系列晶型、盐型及盐型的晶型，该系列盐型/晶型具有较好稳定性及生产/临床上的应用前景，为原料药的规模化生产及制药产品的下游工艺(如制剂工艺)提供了多种中间产物和/或原料药的选择。Patent WO2019170067 discloses a series of crystal forms, salt forms and crystal forms of salt forms of WX-216, the series of salt forms/crystal forms have good stability and production/clinical application prospects, and are large-scale production of raw materials and downstream processes of pharmaceutical products (eg, formulation processes) provide a variety of options for intermediates and/or APIs.
专利WO2021012864公开了WX-216的钠盐，该系列化合物晶型表现为具有较好的成药性(如稳定性、流动性、可压性等)，为后续药品开发提供多种原料药选择。Patent WO2021012864 discloses the sodium salt of WX-216, the crystal form of this series of compounds shows good druggability (such as stability, fluidity, compressibility, etc.), providing a variety of raw material drug options for subsequent drug development.
盐型筛选和晶型筛选是药品开发的重要环节之一，对于特定的化合物，其游离态、各种盐型以及对应的晶型的理化性质的优劣均未可知，基于其成药性的进一步考虑，寻找合适的盐型及其对应的优势晶型，为后续药品开发提 供多种中间产物和/或原料药选择对药品开发意义重大。Salt form screening and crystal form screening are one of the important links in drug development. For a specific compound, the physical and chemical properties of its free state, various salt forms and corresponding crystal forms are unknown, and further considerations based on its druggability , finding suitable salt forms and their corresponding dominant crystal forms, and providing a variety of intermediate products and/or API options for subsequent drug development is of great significance to drug development.
发明内容SUMMARY OF THE INVENTION
本发明的目的在于提供WX-216游离碱的水合物或溶剂合物，并首次公开了一系列WX-216游离碱的水合物或溶剂合物的晶型，该系列化合物晶型表现为具有较好的成药性(稳定性、流动性、可压性、溶解度、生物利用度等)，为后续药品开发提供多种原料药的选择。The purpose of the present invention is to provide hydrates or solvates of WX-216 free base, and for the first time disclose a series of crystal forms of hydrates or solvates of WX-216 free base. Good druggability (stability, fluidity, compressibility, solubility, bioavailability, etc.) provides a variety of API options for subsequent drug development.
Figure PCTCN2021124835-appb-000002
Figure PCTCN2021124835-appb-000002
具体的，WX-216为含有羧基的嘧啶衍生物，本领域的技术人员可以理解，WX-216可以存在水合物或溶剂合物，进一步实验研究表明，WX-216的水合物，其中水分子个数n可为0、0.5、1、1.5、2、2.5、3、3.5和4，即1分子WX-216与n个水分子以本领域公知的方式结合成水合物，为本领域公知的游离碱化合物成水合物的情形。Specifically, WX-216 is a pyrimidine derivative containing a carboxyl group. Those skilled in the art can understand that WX-216 can exist in hydrate or solvate. The number n can be 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5 and 4, that is, 1 molecule of WX-216 and n water molecules combine into a hydrate in a manner known in the art, which is a free hydrate known in the art The case where the base compound is hydrated.
本发明还涉及WX-216的溶剂合物，所述溶剂合物中的“溶剂”为有机溶剂，所述有机溶剂包括但不限于本领域常见之甲醇、乙醇、丙醇、异丙醇、丙酮、丁酮、乙腈、二氯甲烷、三氯甲烷、乙酸乙酯等。The present invention also relates to a solvate of WX-216, the "solvent" in the solvate is an organic solvent, and the organic solvent includes but is not limited to methanol, ethanol, propanol, isopropanol, and acetone common in the art , butanone, acetonitrile, dichloromethane, chloroform, ethyl acetate, etc.
对于化合物晶型的表征，本领域的技术人员可以理解，对于特定化合物的特定晶型，由于在表征过程中受仪器设备、操作方法、样品纯度、人为因素等影响，其X-射线粉末衍射图谱(XRPD)中各衍射峰的2θ角在重复实验中会存在一定波动，该波动范围(误差范围)通常在±0.2°；另外，本领域的技术人员也可以理解，综合X-射线粉末衍射图谱各衍射峰的2θ角、吸收强度(峰高)等因素，衍射峰的稳定性及可重复性会受其影响；具体的，吸收强度越强、分离越好、2θ角越小的衍射峰，其具有越好的稳定性和可重复性，越可以用于表征该特定晶型；而对于2θ角较大和/或分离较差和/或相对强度较弱的衍射峰，其受到仪器设备、操作方法、样品纯度、人为因素等影响可能出现较大波动，也可能在重复实验中不能重复出现，因此对于本领域技术人员来说，此类吸收峰不是表征本晶型时必要的衍射峰；更具体的，本发明遵照本领域的对于晶型表征的共识，衍射峰的选择均综合考量了2θ角、吸收强度(峰高)等因素，并按照稳定性和可重复性进行分组。For the characterization of compound crystal forms, those skilled in the art can understand that for a specific crystal form of a specific compound, its X-ray powder diffraction pattern is affected by equipment, operation methods, sample purity, human factors, etc. during the characterization process. The 2θ angle of each diffraction peak in (XRPD) will fluctuate to a certain extent in repeated experiments, and the fluctuation range (error range) is usually ±0.2°; in addition, those skilled in the art can also understand that the comprehensive X-ray powder diffraction pattern The stability and repeatability of diffraction peaks will be affected by factors such as the 2θ angle, absorption intensity (peak height) and other factors of each diffraction peak; specifically, the stronger the absorption intensity, the better the separation, and the smaller the 2θ angle of the diffraction peak, The better stability and repeatability it has, the more it can be used to characterize the specific crystal form; and for diffraction peaks with larger 2θ angles and/or poor separation and/or weak relative intensities, they are subject to instrumentation, operation The influence of method, sample purity, human factors, etc. may fluctuate greatly, and may not be repeated in repeated experiments. Therefore, for those skilled in the art, such absorption peaks are not necessary diffraction peaks for characterizing this crystal form; more Specifically, the present invention follows the consensus on crystal form characterization in the art, and the selection of diffraction peaks comprehensively considers factors such as 2θ angle, absorption intensity (peak height), and grouping them according to stability and repeatability.
本领域的技术人员同样可以理解，对于样品的差示扫描量热曲线(DSC)和热重分析曲线(TGA)，其同批次和/或批间样品同样会受到来自仪器设备、检测条件、检测人员等影响而出现检测结果的波动，因此本发明遵照本领域的对于晶型表征的共识，将DSC图谱中吸热峰、放热峰起始点的波动范围设定为±3℃，将TGA图谱中失重数值的波动范围设定为±1％。Those skilled in the art can also understand that for the differential scanning calorimetry curve (DSC) and thermogravimetric analysis curve (TGA) of a sample, the same batch and/or between batches of samples will also be affected by equipment, detection conditions, The fluctuation of the detection results occurs due to the influence of the inspectors, etc. Therefore, the present invention follows the consensus on the characterization of crystal forms in the art, and sets the fluctuation range of the endothermic peak and the starting point of the exothermic peak in the DSC spectrum to ±3 °C, and the TGA The fluctuation range of weight loss values in the spectrum was set to ±1%.
如无特别说明，本发明中的“室温”指代25±5℃，本发明中的热重分析曲线(TGA)“未显示有明显失重”指代在检测终点温度前失重≤1％。Unless otherwise specified, the "room temperature" in the present invention refers to 25±5°C, and the thermogravimetric analysis curve (TGA) in the present invention "does not show significant weight loss" refers to the weight loss ≤1% before the detection end temperature.
本发明的第一个目的在于提供了式(I)化合物的一系列晶型，该系列晶型表现为具有较好的成药性。The first object of the present invention is to provide a series of crystal forms of the compound of formula (I), and the series of crystal forms show good druggability.
Figure PCTCN2021124835-appb-000003
Figure PCTCN2021124835-appb-000003
其中，n选自0～4中任意数值。Wherein, n is selected from any value from 0 to 4.
具体的，n选自0,0.5,1,1.5,2,2.5,3,3.5和4。Specifically, n is selected from 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5 and 4.
具体的，根据本发明的一种优选的实施方式涉及前述式(I)化合物的晶型I，其结构如(1)所示：Specifically, according to a preferred embodiment of the present invention, it relates to the crystal form I of the compound of formula (I), the structure of which is shown in (1):
Figure PCTCN2021124835-appb-000004
Figure PCTCN2021124835-appb-000004
其XRPD图谱在2θ为6.9,11.0,11.8,17.1,17.9,18.4,18.7,19.8,22.2,22.6,23.8,26.3,26.7,27.7±0.2°处具有稳定出现的衍射峰。Its XRPD pattern has stable diffraction peaks at 2θ of 6.9, 11.0, 11.8, 17.1, 17.9, 18.4, 18.7, 19.8, 22.2, 22.6, 23.8, 26.3, 26.7, 27.7±0.2°.
进一步地，前述式(I)化合物的晶型I，其XRPD图谱还在2θ为8.4,13.9,15.0,20.3,23.4,25.3,25.7,28.1,29.4±0.2°处具有衍射峰。Further, the crystalline form I of the compound of formula (I) has diffraction peaks at 2θ of 8.4, 13.9, 15.0, 20.3, 23.4, 25.3, 25.7, 28.1, 29.4±0.2° in the XRPD pattern.
进一步地，本发明的一些方案中，前述式(I)化合物的晶型I，其XRPD图谱的衍射峰如下表所示：Further, in some schemes of the present invention, the crystal form I of the compound of formula (I), the diffraction peaks of its XRPD pattern are shown in the following table:
编号Numbering 2θ(±0.2°)2θ(±0.2°) 峰高％Peak height% 编号Numbering 2θ(±0.2°)2θ(±0.2°) 峰高％Peak height%
11 6.96.9 15.215.2 1515 22.222.2 95.595.5
22 8.48.4 6.56.5 1616 22.622.6 56.756.7
33 11.011.0 100.0100.0 1717 23.423.4 6.46.4
44 11.811.8 43.443.4 1818 23.823.8 32.932.9
55 13.913.9 7.97.9 1919 25.325.3 3.63.6
66 15.015.0 4.84.8 2020 25.725.7 3.03.0
77 16.416.4 2.62.6 21twenty one 26.326.3 14.614.6
88 17.117.1 10.710.7 22twenty two 26.726.7 37.737.7
99 17.917.9 16.616.6 23twenty three 27.727.7 20.220.2
1010 18.418.4 15.015.0 24twenty four 28.128.1 3.13.1
1111 18.718.7 30.530.5 2525 29.429.4 6.76.7
1212 19.819.8 18.318.3 2626 29.829.8 2.02.0
1313 20.320.3 3.73.7 2727 30.730.7 3.53.5
1414 21.021.0 2.02.0         
进一步地，本发明的一些方案中，前述式(I)化合物的晶型I，其XRPD图谱基本如图1所示。Further, in some embodiments of the present invention, the XRPD pattern of the aforementioned compound of formula (I) in crystal form I is basically as shown in FIG. 1 .
前述式(I)化合物的晶型I，其差示扫描量热曲线(DSC)在126.1±3℃和195.1±3℃处具有吸热峰的起始点。The crystalline form I of the aforementioned compound of formula (I), its differential scanning calorimetry curve (DSC) has the onset of endothermic peaks at 126.1±3°C and 195.1±3°C.
进一步地，本发明的一些方案中，前述式(I)化合物的晶型I，其DSC图谱基本如图2所示。Further, in some embodiments of the present invention, the DSC spectrum of the crystalline form I of the compound of formula (I) is basically as shown in FIG. 2 .
前述式(I)化合物的晶型I，其热重分析曲线(TGA)在160℃时失重4.14±1％，在210℃时失重0.46±1％。For the crystalline form I of the compound of formula (I), its thermogravimetric analysis curve (TGA) loses 4.14±1% at 160°C and 0.46±1% at 210°C.
进一步地，本发明的一些方案中，前述式(I)化合物的晶型I，其TGA图谱基本如图3所示。Further, in some embodiments of the present invention, the TGA spectrum of the crystalline form I of the compound of formula (I) is basically as shown in FIG. 3 .
具体的，根据本发明的一种优选的实施方式涉及前述式(I)化合物的晶型II，其结构如(2)所示：Specifically, a preferred embodiment according to the present invention relates to the crystal form II of the aforementioned compound of formula (I), the structure of which is shown in (2):
Figure PCTCN2021124835-appb-000005
Figure PCTCN2021124835-appb-000005
其XRPD图谱在2θ为6.5,9.2,12.9,14.5,16.5,19.6,20.5,21.7±0.2°处具有稳定出现的衍射峰。Its XRPD pattern has stable diffraction peaks at 2θ of 6.5, 9.2, 12.9, 14.5, 16.5, 19.6, 20.5, 21.7±0.2°.
进一步地，前述式(I)化合物的晶型II，其XRPD图谱还在2θ为10.2,16.1,17.4,18.5,23.4,24.5,26.2,26.9,27.8,30.0,31.0±0.2°处具有衍射峰。Further, the crystal form II of the compound of the formula (I), the XRPD pattern also has diffraction peaks at 2θ of 10.2, 16.1, 17.4, 18.5, 23.4, 24.5, 26.2, 26.9, 27.8, 30.0, 31.0±0.2°.
进一步地，本发明的一些方案中，前述式(I)化合物的晶型II，其XRPD图谱的衍射峰情况如下表所示：Further, in some schemes of the present invention, the crystalline form II of the compound of formula (I), the diffraction peaks of its XRPD pattern are shown in the following table:
编号Numbering 2θ(±0.2°)2θ(±0.2°) 峰高％Peak height% 编号Numbering 2θ(±0.2°)2θ(±0.2°) 峰高％Peak height%
11 4.54.5 1.61.6 1212 20.520.5 10.010.0
22 6.56.5 100.0100.0 1313 21.721.7 14.914.9
33 9.29.2 38.238.2 1414 22.922.9 5.85.8
44 10.210.2 6.26.2 1515 23.423.4 9.09.0
55 12.912.9 1.31.3 1616 24.524.5 8.28.2
66 14.514.5 31.231.2 1717 25.425.4 2.62.6
77 16.116.1 6.36.3 1818 26.226.2 7.07.0
88 16.516.5 13.413.4 1919 26.926.9 4.24.2
99 17.417.4 6.16.1 2020 27.827.8 2.82.8
1010 18.518.5 9.29.2 21twenty one 30.030.0 3.73.7
1111 19.619.6 21.521.5 22twenty two 31.031.0 3.63.6
进一步地，本发明的一些方案中，前述式(I)化合物的晶型II，其XRPD图谱基本如图5所示。Further, in some embodiments of the present invention, the XRPD pattern of the crystalline form II of the compound of formula (I) is basically as shown in FIG. 5 .
前述式(I)化合物的晶型II，其差示扫描量热曲线(DSC)在164.0±3℃处具有吸热峰的起始点。The crystalline form II of the aforementioned compound of formula (I) has an onset of an endothermic peak at 164.0±3° C. in a differential scanning calorimetry curve (DSC).
进一步地，本发明的一些方案中，前述式(I)化合物的晶型II，其DSC图谱基本如图6所示。Further, in some embodiments of the present invention, the DSC spectrum of the crystalline form II of the compound of formula (I) is basically as shown in FIG. 6 .
前述式(I)化合物的晶型II，其热重分析曲线(TGA)在150℃时失重7.41±1％；The crystalline form II of the compound of the aforementioned formula (I), the thermogravimetric analysis curve (TGA) of which has a weight loss of 7.41±1% at 150°C;
进一步地，本发明的一些方案中，前述式(I)化合物的晶型II，其TGA图谱基本如图7所示。Further, in some embodiments of the present invention, the TGA spectrum of the crystalline form II of the aforementioned compound of formula (I) is basically as shown in FIG. 7 .
具体的，根据本发明的一种优选的实施方式涉及前述式(I)化合物的晶型III，其结构式如前述(1)所示；Specifically, a preferred embodiment according to the present invention relates to the crystal form III of the compound of the aforementioned formula (I), whose structural formula is shown in the aforementioned (1);
其XRPD图谱在2θ为3.7,6.4,8.2,9.5,9.8,11.1,14.8,18.5,22.1,23.6,25.8±0.2°处具有稳定出现的衍射峰。Its XRPD pattern has stable diffraction peaks at 2θ of 3.7, 6.4, 8.2, 9.5, 9.8, 11.1, 14.8, 18.5, 22.1, 23.6, 25.8±0.2°.
进一步地，前述式(I)化合物的晶型III，其XRPD图谱还在2θ为4.8,7.4,16.5,29.5±0.2°处具有衍射峰。Further, the crystal form III of the aforementioned compound of formula (I) also has diffraction peaks at 2θ of 4.8, 7.4, 16.5, 29.5±0.2° in the XRPD pattern.
进一步地，本发明的一些方案中，前述式(I)化合物的晶型III，其XRPD图谱的衍射峰情况如下表所示：Further, in some schemes of the present invention, the crystal form III of the compound of the aforementioned formula (I), the diffraction peaks of its XRPD pattern are shown in the following table:
编号Numbering 2θ(±0.2°)2θ(±0.2°) 峰高％Peak height% 编号Numbering 2θ(±0.2°)2θ(±0.2°) 峰高％ Peak height%
11 3.73.7 26.026.0 99 12.912.9 3.83.8
22 4.84.8 4.44.4 1010 14.814.8 100.0100.0
33 6.46.4 17.517.5 1111 16.516.5 8.08.0
44 7.47.4 4.54.5 1212 18.518.5 24.724.7
55 8.28.2 23.223.2 1313 22.122.1 14.414.4
66 9.59.5 13.113.1 1414 23.623.6 22.022.0
77 9.89.8 15.415.4 1515 25.825.8 20.720.7
88 11.111.1 49.149.1 1616 29.529.5 7.37.3
进一步地，本发明的一些方案中，前述式(I)化合物的晶型III，其XRPD图谱基本如图9所示。Further, in some embodiments of the present invention, the XRPD pattern of the crystalline form III of the compound of formula (I) is basically as shown in FIG. 9 .
前述式(I)化合物的晶型III，其差示扫描量热曲线(DSC)在177.6±3℃处具有吸热峰的起始点，在209.77±3℃处具有吸热峰的起始点；The crystalline form III of the compound of the aforementioned formula (I), the differential scanning calorimetry curve (DSC) has the onset of the endothermic peak at 177.6±3°C and the onset of the endothermic peak at 209.77±3°C;
进一步地，本发明的一些方案中，前述式(I)化合物的晶型III，其DSC图谱基本如图10所示。Further, in some embodiments of the present invention, the DSC chart of the crystalline form III of the compound of formula (I) is basically as shown in FIG. 10 .
前述式(I)化合物的晶型III，其热重分析曲线(TGA)在90℃时失重1.62±1％，在200℃时失重5.50±1％；The crystalline form III of the compound of the aforementioned formula (I), the thermogravimetric analysis curve (TGA) of which is 1.62±1% weight loss at 90°C and 5.50±1% weight loss at 200°C;
进一步地，本发明的一些方案中，前述式(I)化合物的晶型III，其TGA图谱基本如图11所示。Further, in some embodiments of the present invention, the TGA spectrum of the crystalline form III of the compound of formula (I) is basically as shown in FIG. 11 .
具体的，根据本发明的一种优选的实施方式涉及前述式(I)化合物的晶型IV，其XRPD图谱在2θ为8.2,8.7,10.2,16.9,20.4±0.2°处具有稳定出现的衍射峰。Specifically, a preferred embodiment according to the present invention relates to the crystalline form IV of the compound of formula (I), whose XRPD pattern has stable diffraction peaks at 2θ of 8.2, 8.7, 10.2, 16.9, 20.4±0.2° .
进一步地，前述式(I)化合物的晶型IV，其XRPD图谱还在2θ为5.6,7.2,12.2,14.3,14.6,15.5,15.8,18.8,21.0,21.8,22.7±0.2°处具有衍射峰；Further, the crystalline form IV of the compound of formula (I), the XRPD pattern also has diffraction peaks at 2θ of 5.6, 7.2, 12.2, 14.3, 14.6, 15.5, 15.8, 18.8, 21.0, 21.8, 22.7±0.2°;
进一步地，本发明的一些方案中，前述式(I)化合物的晶型IV，其XRPD图谱的衍射峰情况如下表所示：Further, in some schemes of the present invention, the crystalline form IV of the compound of the aforementioned formula (I), the diffraction peaks of its XRPD pattern are as shown in the following table:
编号Numbering 2θ(±0.2°)2θ(±0.2°) 峰高％Peak height% 编号Numbering 2θ(±0.2°)2θ(±0.2°) 峰高％ Peak height%
11 5.65.6 5.75.7 1010 15.815.8 5.05.0
22 7.27.2 7.87.8 1111 16.916.9 17.617.6
33 8.28.2 100.0100.0 1212 18.818.8 9.89.8
44 8.78.7 41.141.1 1313 20.420.4 15.215.2
55 10.210.2 20.720.7 1414 21.021.0 7.77.7
66 12.212.2 7.77.7 1515 21.821.8 4.14.1
77 14.314.3 5.55.5 1616 22.722.7 3.93.9
88 14.614.6 6.16.1 1717 25.025.0 2.82.8
99 15.515.5 5.85.8 1818 26.726.7 2.22.2
进一步地，本发明的一些方案中，前述式(I)化合物的晶型IV，其XRPD图谱基本如图13所示。Further, in some embodiments of the present invention, the XRPD pattern of the crystalline form IV of the compound of formula (I) is basically as shown in FIG. 13 .
前述式(I)化合物的晶型IV，其差示扫描量热曲线(DSC)在125.0±3℃处具有吸热峰的起始点。The crystalline form IV of the aforementioned compound of formula (I), its differential scanning calorimetry curve (DSC) has an onset of an endothermic peak at 125.0±3°C.
进一步地，本发明的一些方案中，前述式(I)化合物的晶型IV，其DSC图谱基本如图14所示。Further, in some embodiments of the present invention, the DSC chart of the crystalline form IV of the compound of formula (I) is basically as shown in FIG. 14 .
前述式(I)化合物的晶型IV，其热重分析曲线(TGA)在170℃时失重9.72±1％。For the crystalline form IV of the compound of formula (I), the thermogravimetric analysis curve (TGA) at 170°C loses 9.72±1% in weight.
进一步地，本发明的一些方案中，前述式(I)化合物的晶型IV，其TGA图谱基本如图15所示。Further, in some embodiments of the present invention, the TGA spectrum of the crystalline form IV of the compound of formula (I) is basically as shown in FIG. 15 .
具体的，根据本发明的一种优选的实施方式涉及前述式(I)化合物的晶型V，其结构式如前述(1)所示；Specifically, according to a preferred embodiment of the present invention, it relates to the crystalline form V of the compound of the aforementioned formula (I), whose structural formula is shown in the aforementioned (1);
其XRPD图谱在2θ为4.9,8.7,10.3,12.2,14.7,15.3,16.5,18.8,19.8,20.6,21.9,23.7,23.9,25.6,28.6,29.7±0.2°处具有稳定出现的衍射峰。Its XRPD pattern has stable diffraction peaks at 2θ of 4.9, 8.7, 10.3, 12.2, 14.7, 15.3, 16.5, 18.8, 19.8, 20.6, 21.9, 23.7, 23.9, 25.6, 28.6, 29.7±0.2°.
进一步地，前述式(I)化合物的晶型V，其XRPD图谱还在2θ为17.4,20.4,22.7,24.8,25.1,25.9,26.6,27.6,29.3,30.4±0.2°处具有衍射峰。Further, the crystalline form V of the compound of the formula (I) also has diffraction peaks at 2θ of 17.4, 20.4, 22.7, 24.8, 25.1, 25.9, 26.6, 27.6, 29.3, 30.4±0.2° in the XRPD pattern.
进一步地，本发明的一些方案中，前述式(I)化合物的晶型V，其XRPD图谱的衍射峰情况如下表所示：Further, in some schemes of the present invention, the crystal form V of the compound of the aforementioned formula (I), the diffraction peaks of its XRPD pattern are shown in the following table:
编号Numbering 2θ(±0.2°)2θ(±0.2°) 峰高％Peak height% 编号Numbering 2θ(±0.2°)2θ(±0.2°) 峰高％ Peak height%
11 4.94.9 14.514.5 1414 22.722.7 9.59.5
22 8.78.7 100.0100.0 1515 23.723.7 19.519.5
33 10.310.3 57.157.1 1616 23.923.9 15.715.7
44 12.212.2 25.425.4 1717 24.824.8 8.18.1
55 14.714.7 54.654.6 1818 25.125.1 5.55.5
66 15.315.3 53.253.2 1919 25.625.6 10.210.2
77 16.516.5 30.030.0 2020 25.925.9 4.44.4
88 17.417.4 5.55.5 21twenty one 26.626.6 8.78.7
99 18.818.8 63.963.9 22twenty two 27.627.6 8.68.6
1010 19.819.8 27.527.5 23twenty three 28.628.6 12.112.1
1111 20.420.4 8.78.7 24twenty four 29.329.3 8.28.2
1212 20.620.6 30.530.5 2525 29.729.7 11.311.3
1313 21.921.9 36.836.8 2626 30.430.4 8.88.8
进一步地，本发明的一些方案中，前述式(I)化合物的晶型V，其XRPD图谱基本如图16所示。Further, in some embodiments of the present invention, the XRPD pattern of the crystalline form V of the compound of formula (I) is basically as shown in FIG. 16 .
前述式(I)化合物的晶型V，其差示扫描量热曲线(DSC)在229.5±3℃处具有吸热峰的起始点。The crystalline form V of the aforementioned compound of formula (I) has an onset of an endothermic peak at 229.5±3° C. in a differential scanning calorimetry curve (DSC).
进一步地，本发明的一些方案中，前述式(I)化合物的晶型V，其DSC图谱基本如图17所示。Further, in some embodiments of the present invention, the DSC spectrum of the crystalline form V of the compound of formula (I) is basically as shown in FIG. 17 .
前述式(I)化合物的晶型V，其热重分析曲线(TGA)在125℃时失重71.02±1％，在200℃时失重3.07±1％。For the crystalline form V of the compound of formula (I), its thermogravimetric analysis curve (TGA) loses 71.02±1% at 125°C and 3.07±1% at 200°C.
进一步地，本发明的一些方案中，前述式(I)化合物的晶型V，其TGA图谱基本如图18所示。Further, in some embodiments of the present invention, the TGA spectrum of the crystalline form V of the compound of formula (I) is basically as shown in FIG. 18 .
具体的，根据本发明的一种优选的实施方式涉及前述式(I)化合物的晶型VI，其结构式如(3)所示：Specifically, according to a preferred embodiment of the present invention, it relates to the crystal form VI of the aforementioned compound of formula (I), and its structural formula is shown in (3):
Figure PCTCN2021124835-appb-000006
Figure PCTCN2021124835-appb-000006
其XRPD图谱在2θ为6.4,7.0,9.0,11.4,12.1,14.2,15.6,16.6,17.2,17.6,18.6,19.3,19.6,20.6,21.4,21.9,23.2, 24.9,26.4,29.6±0.2°处具有稳定出现的衍射峰。Its XRPD pattern at 2θ of 6.4, 7.0, 9.0, 11.4, 12.1, 14.2, 15.6, 16.6, 17.2, 17.6, 18.6, 19.3, 19.6, 20.6, 21.4, 21.9, 23.2, 24.9, 26.4, 29.6 ± 0.2° has Diffraction peaks appear stably.
进一步地，前述式(I)化合物的晶型VI，其XRPD图谱还在2θ为13.5,25.4,27.2,30.3±0.2°处具有衍射峰。Further, the crystal form VI of the aforementioned compound of formula (I) also has diffraction peaks at 2θ of 13.5, 25.4, 27.2, 30.3±0.2° in the XRPD pattern.
进一步地，本发明的一些方案中，前述式(I)化合物的晶型VI，其XRPD图谱的衍射峰情况如下表所示：Further, in some schemes of the present invention, the crystal form VI of the compound of the aforementioned formula (I), the diffraction peaks of its XRPD pattern are shown in the following table:
编号Numbering 2θ(±0.2°)2θ(±0.2°) 峰高％Peak height% 编号Numbering 2θ(±0.2°)2θ(±0.2°) 峰高％ Peak height%
11 6.46.4 19.119.1 1313 19.319.3 50.550.5
22 7.07.0 12.912.9 1414 19.619.6 100.0100.0
33 9.09.0 81.881.8 1515 20.620.6 12.212.2
44 11.411.4 18.918.9 1616 21.421.4 27.327.3
55 12.112.1 51.851.8 1717 21.921.9 28.828.8
66 13.513.5 6.16.1 1818 23.223.2 23.023.0
77 14.214.2 33.333.3 1919 24.924.9 78.278.2
88 15.615.6 12.912.9 2020 25.425.4 9.89.8
99 16.616.6 31.631.6 21twenty one 26.426.4 11.511.5
1010 17.217.2 24.024.0 22twenty two 27.227.2 9.39.3
1111 17.617.6 35.535.5 23twenty three 29.629.6 15.815.8
1212 18.618.6 48.948.9 24twenty four 30.330.3 9.59.5
进一步地，本发明的一些方案中，前述式(I)化合物的晶型VI，其XRPD图谱基本如图20所示。Further, in some embodiments of the present invention, the XRPD pattern of the crystalline form VI of the compound of formula (I) is basically as shown in FIG. 20 .
前述式(I)化合物的晶型VI，其差示扫描量热曲线(DSC)在78.5±3℃处具有吸热峰的起始点；The crystalline form VI of the compound of the aforementioned formula (I), the differential scanning calorimetry curve (DSC) of which has the onset of an endothermic peak at 78.5±3°C;
进一步地，本发明的一些方案中，前述式(I)化合物的晶型VI，其DSC图谱基本如图21所示。Further, in some embodiments of the present invention, the DSC spectrum of the crystalline form VI of the compound of formula (I) is basically as shown in FIG. 21 .
前述式(I)化合物的晶型VI，其热重分析曲线(TGA)在165℃时失重14.44±1％；The crystalline form VI of the compound of the formula (I), the thermogravimetric analysis curve (TGA) of which has a weight loss of 14.44±1% at 165°C;
进一步地，本发明的一些方案中，前述式(I)化合物的晶型VI，其TGA图谱基本如图22所示。Further, in some embodiments of the present invention, the TGA spectrum of the crystalline form VI of the compound of formula (I) is basically as shown in FIG. 22 .
本发明的第二个目的在于提供了式(II)化合物的溶剂合物的晶型VII，该晶型表现为具有较好的成药性。The second object of the present invention is to provide the crystal form VII of the solvate of the compound of formula (II), which shows good druggability.
Figure PCTCN2021124835-appb-000007
Figure PCTCN2021124835-appb-000007
具体的，前述式(II)化合物的溶剂合物是式(II)化合物的甲基叔丁基醚溶剂合物。Specifically, the aforementioned solvate of the compound of formula (II) is a methyl tert-butyl ether solvate of the compound of formula (II).
具体的，前述晶型VII，其XRPD图谱在2θ为7.7,8.9,12.4,14.7,17.9,18.4,19.9,20.6,23.1,23.6,27.8,28.7±0.2°处具有稳定出现的衍射峰。Specifically, the aforementioned crystal form VII has an XRPD pattern with stable diffraction peaks at 2θ of 7.7, 8.9, 12.4, 14.7, 17.9, 18.4, 19.9, 20.6, 23.1, 23.6, 27.8, 28.7±0.2°.
进一步地，前述晶型VII，其XRPD图谱还在2θ为5.9,15.4,16.1,17.5,19.0,21.7,24.5,28.1,30.8±0.2°处具有衍射峰。Further, in the aforementioned crystal form VII, its XRPD pattern also has diffraction peaks at 2θ of 5.9, 15.4, 16.1, 17.5, 19.0, 21.7, 24.5, 28.1, 30.8±0.2°.
进一步地，本发明的一些方案中，前述晶型VII，其XRPD图谱的衍射峰情况如下表所示：Further, in some schemes of the present invention, the aforementioned crystal form VII, the diffraction peak situation of its XRPD pattern is as shown in the following table:
编号Numbering 2θ(±0.2°)2θ(±0.2°) 峰高％Peak height% 编号Numbering 2θ(±0.2°)2θ(±0.2°) 峰高％Peak height%
11 5.95.9 6.26.2 1313 20.620.6 28.128.1
22 7.77.7 37.737.7 1414 21.721.7 8.78.7
33 8.98.9 100.0100.0 1515 23.123.1 28.828.8
44 12.412.4 81.081.0 1616 23.623.6 11.911.9
55 14.714.7 45.345.3 1717 24.524.5 7.87.8
66 15.415.4 7.47.4 1818 25.325.3 6.06.0
77 16.116.1 4.64.6 1919 25.825.8 1.81.8
88 17.517.5 9.79.7 2020 27.827.8 10.710.7
99 17.917.9 25.725.7 21twenty one 28.128.1 9.29.2
1010 18.418.4 22.322.3 22twenty two 28.728.7 11.511.5
1111 19.019.0 6.66.6 23twenty three 30.830.8 7.87.8
1212 19.919.9 15.115.1         
进一步地，本发明的一些方案中，前述晶型VII，其XRPD图谱基本如图23所示。Further, in some embodiments of the present invention, the XRPD pattern of the aforementioned crystal form VII is basically as shown in FIG. 23 .
前述晶型VII，其差示扫描量热曲线(DSC)在161.8±3℃处具有吸热峰的起始点。The aforementioned crystal form VII, its differential scanning calorimetry curve (DSC) has the onset of the endothermic peak at 161.8±3°C.
进一步地，本发明的一些方案中，前述晶型VII，其DSC图谱基本如图24所示。Further, in some embodiments of the present invention, the aforementioned crystalline form VII, the DSC spectrum thereof is basically as shown in FIG. 24 .
前述晶型VII，其热重分析曲线(TGA)在185℃时失重16.56±1％。The aforementioned crystal form VII, its thermogravimetric analysis curve (TGA) loses 16.56±1% at 185°C.
进一步地，本发明的一些方案中，前述晶型VII，其TGA图谱基本如图25所示。Further, in some embodiments of the present invention, the aforementioned crystal form VII, the TGA spectrum thereof is basically as shown in FIG. 25 .
本发明的第三个目的在于提供了式(II)化合物的溶剂合物的晶型VIII及其制备方法。The third object of the present invention is to provide a crystal form VIII of a solvate of the compound of formula (II) and a preparation method thereof.
具体的，前述式(II)化合物的溶剂合物是式(II)化合物的N-甲基吡咯烷酮溶剂合物。Specifically, the aforementioned solvate of the compound of formula (II) is an N-methylpyrrolidone solvate of the compound of formula (II).
具体的，前述晶型VIII，其XRPD图谱在2θ为7.8,8.4,16.2±0.2°处具有稳定出现的衍射峰。Specifically, the above-mentioned crystal form VIII, its XRPD pattern has diffraction peaks that appear stably at 2θ of 7.8, 8.4, and 16.2±0.2°.
进一步地，前述晶型VIII，其XRPD图谱还在2θ为9.9,13.7,15.0,16.9,18.2,21.8±0.2°处具有衍射峰。Further, the XRPD pattern of the aforementioned crystal form VIII also has diffraction peaks at 2θ of 9.9, 13.7, 15.0, 16.9, 18.2, and 21.8±0.2°.
进一步地，本发明的一些方案中，前述晶型VIII，其XRPD图谱的衍射峰情况如下表所示：Further, in some schemes of the present invention, the aforementioned crystal form VIII, the diffraction peaks of its XRPD pattern are as shown in the following table:
编号Numbering 2θ(±0.2°)2θ(±0.2°) 峰高％Peak height% 编号Numbering 2θ(±0.2°)2θ(±0.2°) 峰高％ Peak height%
11 7.87.8 100.0100.0 66 16.216.2 12.112.1
22 8.48.4 17.117.1 77 16.916.9 4.64.6
33 9.99.9 7.57.5 88 18.218.2 6.96.9
44 13.713.7 3.93.9 99 21.821.8 7.27.2
55 15.015.0 3.23.2         
进一步地，本发明的一些方案中，前述晶型VIII，其XRPD图谱基本如图27所示。Further, in some embodiments of the present invention, the XRPD pattern of the aforementioned crystal form VIII is basically as shown in FIG. 27 .
前述晶型VIII，其差示扫描量热曲线(DSC)在116.5±3℃处具有吸热峰的起始点，在171.6±3℃处具有吸热峰的起始点。For the aforementioned crystal form VIII, its differential scanning calorimetry curve (DSC) has an onset of an endothermic peak at 116.5±3°C and an onset of an endothermic peak at 171.6±3°C.
进一步地，本发明的一些方案中，前述晶型VIII，其DSC图谱基本如图28所示。Further, in some embodiments of the present invention, the aforementioned crystal form VIII, the DSC spectrum of which is basically as shown in FIG. 28 .
前述晶型VIII，其热重分析曲线(TGA)在165℃时失重13.50±1％。The aforementioned crystal form VIII, its thermogravimetric analysis curve (TGA) loses 13.50±1% at 165°C.
进一步地，本发明的一些方案中，前述晶型VIII，其TGA图谱基本如图29所示。Further, in some embodiments of the present invention, the aforementioned crystal form VIII, the TGA spectrum thereof is basically as shown in FIG. 29 .
本发明的第四个目的在于提供了一种式(II)化合物的亚稳态晶型及其制备方法。The fourth object of the present invention is to provide a metastable crystal form of the compound of formula (II) and a preparation method thereof.
具体的，前述式(II)化合物的亚稳态晶型IX，其XRPD图谱在2θ为9.0,10.5,16.5,19.6,21.1,22.8,24.2±0.2° 处具有稳定出现的衍射峰。Specifically, the metastable crystal form IX of the compound of formula (II) has XRPD pattern with stable diffraction peaks at 2θ of 9.0, 10.5, 16.5, 19.6, 21.1, 22.8, 24.2±0.2°.
进一步地，前述式(II)化合物的晶型IX，其XRPD图谱还在2θ为11.8,17.5,26.4,27.5±0.2°处具有衍射峰。Further, the crystalline form IX of the compound of formula (II), the XRPD pattern also has diffraction peaks at 2θ of 11.8, 17.5, 26.4, 27.5±0.2°.
进一步地，本发明的一些方案中，前述式(II)化合物的晶型IX，其XRPD图谱的衍射峰情况如下表所示：Further, in some schemes of the present invention, the crystalline form IX of the compound of formula (II), the diffraction peaks of its XRPD pattern are shown in the following table:
编号Numbering 2θ(±0.2°)2θ(±0.2°) 峰高％Peak height% 编号Numbering 2θ(±0.2°)2θ(±0.2°) 峰高％ Peak height%
11 9.09.0 15.115.1 77 21.121.1 25.725.7
22 10.510.5 19.419.4 88 22.822.8 37.337.3
33 11.811.8 8.58.5 99 24.224.2 36.736.7
44 16.516.5 33.833.8 1010 26.426.4 14.214.2
55 17.517.5 27.827.8 1111 27.527.5 15.215.2
66 19.619.6 100.0100.0         
进一步地，本发明的一些方案中，前述式(II)化合物的晶型IX，其XRPD图谱基本如图30所示。Further, in some embodiments of the present invention, the XRPD pattern of the crystalline form IX of the compound of formula (II) is basically as shown in FIG. 30 .
本发明的第五个目的在于提供了一种原料药，该原料药含有本发明所述化合物WX-216晶型I～晶型IX或所述化合物WX-216的其他水合物、溶剂合物中的至少一种。The fifth object of the present invention is to provide a bulk drug containing the compound WX-216 crystal form I to crystal form IX of the present invention or other hydrates and solvates of the compound WX-216 at least one of.
基于前述本发明所述化合物WX-216晶型I～晶型IX和所述化合物WX-216的其他水合物、溶剂合物的有益效果，含有所述晶型的原料药亦体现为与晶型基本一致的有益效果(如稳定性、水溶性等)，具体的，所述原料药可以是化合物WX-216，也可以是化合物WX-216和/或化合物WX-216的水合物；更具体的，所述原料药中含有化合物WX-216晶型I和/或化合物WX-216晶型II和/或化合物WX-216晶型III和/或化合物WX-216晶型IV和/或化合物WX-216晶型V和/或化合物WX-216晶型VI和/或化合物WX-216晶型VII和/或化合物WX-216晶型VIII和/或化合物WX-216晶型IX的质量百分数为0.01～99.99％的任意数值。进一步地，所述原料药中含有化合物WX-216晶型I和/或化合物WX-216晶型II和/或化合物WX-216晶型III和/或化合物WX-216晶型IV和/或化合物WX-216晶型V和/或化合物WX-216晶型VI和/或化合物WX-216晶型VII和/或化合物WX-216晶型VIII和/或化合物WX-216晶型IX的质量百分数为1.00～99.00％的任意数值。Based on the aforementioned beneficial effects of the compound WX-216 crystal form I to crystal form IX and other hydrates and solvates of the compound WX-216 of the present invention, the bulk drug containing the crystal form is also reflected in the same crystal form. Basically the same beneficial effects (such as stability, water solubility, etc.), specifically, the API can be compound WX-216, or compound WX-216 and/or a hydrate of compound WX-216; more specifically , the API contains compound WX-216 crystal form I and/or compound WX-216 crystal form II and/or compound WX-216 crystal form III and/or compound WX-216 crystal form IV and/or compound WX- The mass percentage of 216 crystal form V and/or compound WX-216 crystal form VI and/or compound WX-216 crystal form VII and/or compound WX-216 crystal form VIII and/or compound WX-216 crystal form IX is 0.01～ 99.99% of any value. Further, the API contains compound WX-216 crystal form I and/or compound WX-216 crystal form II and/or compound WX-216 crystal form III and/or compound WX-216 crystal form IV and/or compound The mass percentage of WX-216 crystal form V and/or compound WX-216 crystal form VI and/or compound WX-216 crystal form VII and/or compound WX-216 crystal form VIII and/or compound WX-216 crystal form IX is Any value from 1.00 to 99.00%.
本发明的第六个目的在于提供了一种药物组合物，所述药物组合物包括药学上可接受的辅料和前述原料药。具体的，所述药学上可接受的辅料包括但不限于填充剂、粘合剂、崩解剂、润滑剂中的至少一种。具体的，基于前述本发明所述化合物WX-216晶型I～晶型IX和所述化合物WX-216的其他水合物、溶剂合物的有益效果，其有益效果最终体现在药物组合物中；更具体的，所述药物组合物中含有前述原料药的质量百分数为1.00～99.00％的任意数值，进一步地，所述药物组合物中含有前述原料药的质量百分数为5.00～95.00％的任意数值，更进一步地，所述药物组合物中含有前述原料药的质量百分数为10.00～90.00％的任意数值。The sixth object of the present invention is to provide a pharmaceutical composition comprising pharmaceutically acceptable excipients and the aforementioned bulk drug. Specifically, the pharmaceutically acceptable adjuvants include, but are not limited to, at least one of fillers, binders, disintegrants, and lubricants. Specifically, based on the aforementioned beneficial effects of the compound WX-216 crystal forms I to IX of the present invention and other hydrates and solvates of the compound WX-216, the beneficial effects are finally reflected in the pharmaceutical composition; More specifically, the mass percentage of the aforementioned bulk drug contained in the pharmaceutical composition is any value ranging from 1.00 to 99.00%, and further, the mass percentage of the aforementioned bulk drug contained in the pharmaceutical composition is any value ranging from 5.00 to 95.00%. , and further, the mass percentage of the aforementioned raw materials contained in the pharmaceutical composition is any value of 10.00-90.00%.
本发明的第七个目的在于提供了一种药物，所述药物包括上述化合物WX-216晶型I～晶型IX或上述化合物WX-216的其他水合物、溶剂合物或上述原料药或上述药物组合物中的至少一种。The seventh object of the present invention is to provide a medicine, which comprises the above-mentioned compound WX-216 crystal form I to crystalline form IX or other hydrates, solvates of the above-mentioned compound WX-216, or the above-mentioned bulk drug or the above-mentioned at least one of the pharmaceutical compositions.
本发明的第八个目的在于提供了上述化合物WX-216晶型I～晶型IX或上述化合物WX-216的其他水合物、溶剂合物或上述原料药或上述药物组合物在制备治疗流感药物中的应用。The eighth object of the present invention is to provide the above-mentioned compound WX-216 crystal form I to crystal form IX or other hydrates, solvates of the above-mentioned compound WX-216 or the above-mentioned raw materials or the above-mentioned pharmaceutical compositions in the preparation of influenza medicines applications in .
综上可知，本发明化合物WX-216晶型I～晶型IX和所述化合物WX-216的其他水合物、溶剂合物具有一定的成药前景，因此，如果通过检测手段证明化合物WX-216的晶型I～晶型IX或所述化合物WX-216的其他水合物、溶剂合物在前述原料药和/或药物组合物中存在，则应被视为使用了本发明提供的化合物WX-216的晶型I～晶型IX或所述化合物WX-216的其他水合物、溶剂合物。所述检测手段除了前述提及的X-射线粉末衍射外，还可以进一步包括差示扫描量热法(DSC)，红外光谱法(IR)，拉曼光谱法(Raman)，固体核磁共振法(SSNMR)等方法及其他一切单 独或综合可以佐证使用了本发明所述化合物WX-216的晶型I～晶型IX或所述化合物WX-216的其他水合物、溶剂合物型的检测方法，并可以采用本领域技术人员常用方法去除诸如药物辅料等所带来的影响，如差减图谱法等。To sum up, the compound WX-216 crystal form I to crystal form IX of the present invention and other hydrates and solvates of the compound WX-216 have certain drug prospects. If the crystal forms I to IX or other hydrates and solvates of the compound WX-216 exist in the aforementioned APIs and/or pharmaceutical compositions, it should be considered that the compound WX-216 provided by the present invention is used. Form I to Form IX or other hydrates and solvates of the compound WX-216. In addition to the aforementioned X-ray powder diffraction, the detection means may further include differential scanning calorimetry (DSC), infrared spectroscopy (IR), Raman spectroscopy (Raman), solid-state nuclear magnetic resonance ( SSNMR) and other methods and all other detection methods that individually or comprehensively can support the use of the crystal form I to crystal form IX of the compound WX-216 of the present invention or other hydrate and solvate forms of the compound WX-216, In addition, the common methods of those skilled in the art can be used to remove the influences brought by such as pharmaceutical excipients, such as the subtractive atlas method and the like.
本发明相对于现有技术具有如下的优点及有益效果：Compared with the prior art, the present invention has the following advantages and beneficial effects:
1、首次公开了一种式(I)化合物的晶型I及其制备方法，其为WX-216的水合物，该晶型具有稳定性高的特点，具有相当的成药前景；1. For the first time, a crystal form I of the compound of formula (I) and a preparation method thereof are disclosed, which is a hydrate of WX-216, and the crystal form has the characteristics of high stability and has considerable medicinal prospects;
2、首次公开了一种式(I)化合物的晶型II及其制备方法，其为WX-216的水合物，该晶型具有稳定性高的特点，具有相当的成药前景；2. For the first time, a crystal form II of the compound of formula (I) and a preparation method thereof are disclosed, which is a hydrate of WX-216. This crystal form has the characteristics of high stability and has considerable drug prospects;
3、首次公开了一种式(I)化合物的晶型III及其制备方法，其为WX-216的水合物，该晶型具有稳定性高的特点，尤其在非水体系中，具有相当的成药前景；3. For the first time, a crystal form III of the compound of formula (I) and its preparation method are disclosed, which is a hydrate of WX-216. This crystal form has the characteristics of high stability, especially in non-aqueous systems, with considerable The prospect of finished medicine;
4、首次公开了一种式(I)化合物的晶型IV及其制备方法，其为WX-216的水合物，为原料药的规模化生产及制药产品的下游工艺(如制剂工艺)提供了多种中间产物和/或原料药的选择；4. For the first time, a crystal form IV of the compound of formula (I) and a preparation method thereof are disclosed, which is the hydrate of WX-216, which provides large-scale production of bulk drugs and downstream processes (such as formulation processes) of pharmaceutical products. Selection of various intermediates and/or APIs;
5、首次公开了一种式(I)化合物的晶型V及其制备方法，其为WX-216的水合物，为原料药的规模化生产及制药产品的下游工艺(如制剂工艺)提供了多种中间产物和/或原料药的选择；5. For the first time, a crystal form V of the compound of formula (I) and a preparation method thereof are disclosed, which is a hydrate of WX-216, which provides large-scale production of bulk drugs and downstream processes (such as formulation processes) of pharmaceutical products. Selection of various intermediates and/or APIs;
6、首次公开了一种式(I)化合物的晶型VI及其制备方法，其为WX-216的水合物，为原料药的规模化生产及制药产品的下游工艺(如制剂工艺)提供了多种中间产物和/或原料药的选择；6. A crystal form VI of the compound of formula (I) and a preparation method thereof are disclosed for the first time, which is the hydrate of WX-216, which provides the large-scale production of raw materials and downstream processes (such as formulation processes) of pharmaceutical products. Selection of various intermediates and/or APIs;
7、首次公开了一种式(II)化合物甲基叔丁基醚溶剂合物的晶型VII及其制备方法，该晶型具有稳定性高的特点，具有相当的成药前景；7. For the first time, a crystal form VII of the compound methyl tert-butyl ether solvate of the formula (II) and a preparation method thereof are disclosed, and the crystal form has the characteristics of high stability and has considerable medicinal prospects;
8、首次公开了一种式(II)化合物N-甲基吡咯烷酮溶剂合物的晶型VIII及其制备方法，为原料药的规模化生产及制药产品的下游工艺(如制剂工艺)提供了多种中间产物和/或原料药的选择；8. For the first time, a crystal form VIII of the compound N-methylpyrrolidone solvate of the formula (II) and its preparation method are disclosed, which provide many advantages for the large-scale production of raw materials and downstream processes (such as formulation processes) of pharmaceutical products. selection of intermediates and/or APIs;
9、首次公开了一种式(II)化合物的晶型IX及其制备方法，其为WX-216的亚稳态，为原料药的规模化生产及制药产品的下游工艺(如制剂工艺)提供了多种中间产物和/或原料药的选择。9. For the first time, a crystal form IX of the compound of formula (II) and its preparation method are disclosed, which is the metastable state of WX-216, which provides the large-scale production of raw materials and downstream processes (such as formulation processes) of pharmaceutical products. A variety of intermediate and/or drug substance options are available.
10、提供了一种原料药，该原料药含有本发明所述化合物WX-216晶型I～晶型IX或所述化合物WX-216的其他水合物、溶剂合物中的至少一种，所述原料药体现为与本发明所述化合物WX-216晶型I～晶型IX或所述化合物WX-216的其他水合物、溶剂合物基本一致的有益效果；10. Provides a bulk drug containing at least one of the compound WX-216 crystal form I to crystal form IX of the present invention or other hydrates and solvates of the compound WX-216, so Said API has basically the same beneficial effect as the compound WX-216 crystal form I to crystal form IX of the present invention or other hydrates and solvates of the compound WX-216;
11、提供了一种药物组合物，所述药物组合物包括药学上可接受的辅料和本发明所述原料药，其具有与本发明所述化合物WX-216晶型I～晶型IX或所述化合物WX-216或其水合物、溶剂合物基本一致的有益效果。11. Provided is a pharmaceutical composition comprising pharmaceutically acceptable excipients and the raw material drug of the present invention, which has the same properties as the compound WX-216 crystal form I to crystal form IX or all of the present invention. The beneficial effects of the compound WX-216 or its hydrate and solvate are basically the same.
附图说明Description of drawings
图1：式(I)化合物晶型I的XRPD谱图；Figure 1: XRPD spectrum of the compound of formula (I) crystal form I;
图2：式(I)化合物晶型I的DSC谱图；Figure 2: DSC spectrum of the compound of formula (I) crystal form I;
图3：式(I)化合物晶型I的TGA谱图；Figure 3: TGA spectrum of the compound of formula (I) crystal form I;
图4：式(I)化合物晶型I的XRPD比较图；Figure 4: XRPD comparison diagram of compound crystal form I of formula (I);
图5：式(I)化合物晶型II的XRPD谱图；Figure 5: XRPD spectrum of the compound of formula (I) crystal form II;
图6：式(I)化合物晶型II的DSC谱图；Figure 6: DSC spectrum of the compound of formula (I) in crystal form II;
图7：式(I)化合物晶型II的TGA谱图；Figure 7: TGA spectrum of the compound of formula (I) crystal form II;
图8：式(I)化合物晶型II的XRPD比较图；Figure 8: XRPD comparison chart of the crystalline form II of the compound of formula (I);
图9：式(I)化合物晶型III的XRPD谱图；Figure 9: XRPD spectrum of the compound of formula (I) crystal form III;
图10：式(I)化合物晶型III的DSC谱图；Figure 10: DSC spectrum of the compound of formula (I) in crystal form III;
图11：式(I)化合物晶型III的TGA谱图；Figure 11: TGA spectrum of the compound of formula (I) in crystal form III;
图12：式(I)化合物晶型III的XRPD比较图；Figure 12: XRPD comparison chart of the compound of formula (I) Form III;
图13：式(I)化合物晶型IV的XRPD谱图；Figure 13: XRPD spectrum of the compound of formula (I) crystal form IV;
图14：式(I)化合物晶型IV的DSC谱图；Figure 14: DSC spectrum of the compound of formula (I) crystal form IV;
图15：式(I)化合物晶型IV的TGA谱图；Figure 15: TGA spectrum of the compound of formula (I) crystal form IV;
图16：式(I)化合物晶型V的XRPD谱图；Figure 16: XRPD spectrum of the compound of formula (I) form V;
图17：式(I)化合物晶型V的DSC谱图；Figure 17: DSC spectrum of the compound of formula (I) form V;
图18：式(I)化合物晶型V的TGA谱图；Figure 18: TGA spectrum of the compound of formula (I) form V;
图19：式(I)化合物晶型V的XRPD比较图；Figure 19: XRPD comparison chart of the compound of formula (I) Form V;
图20：式(I)化合物晶型VI的XRPD谱图；Figure 20: XRPD spectrum of the compound of formula (I) in crystal form VI;
图21：式(I)化合物晶型VI的DSC谱图；Figure 21: DSC spectrum of the compound of formula (I) crystal form VI;
图22：式(I)化合物晶型VI的TGA谱图；Figure 22: TGA spectrum of the compound of formula (I) in crystal form VI;
图23：式(II)化合物晶型VII的XRPD谱图；Figure 23: XRPD spectrum of the compound of formula (II) crystal form VII;
图24：式(II)化合物晶型VII的DSC谱图；Figure 24: DSC spectrum of the compound of formula (II) crystal form VII;
图25：式(II)化合物晶型VII的TGA谱图；Figure 25: TGA spectrum of the compound of formula (II) crystal form VII;
图26：式(II)化合物晶型VII的XRPD比较图；Figure 26: XRPD comparison chart of the compound of formula (II) Form VII;
图27：式(II)化合物晶型VIII的XRPD谱图；Figure 27: XRPD spectrum of the compound of formula (II) Form VIII;
图28：式(II)化合物晶型VIII的DSC谱图；Figure 28: DSC spectrum of the compound of formula (II) crystal form VIII;
图29：式(II)化合物晶型VIII的TGA谱图；Figure 29: TGA spectrum of the compound of formula (II) crystal form VIII;
图30：式(II)化合物晶型IX的XRPD谱图。Figure 30: XRPD spectrum of the compound of formula (II), Form IX.
具体实施方式Detailed ways
下面结合实施例和附图对本发明作进一步详细的描述，但发明的实施方式不限于此。The present invention will be described in further detail below with reference to the embodiments and the accompanying drawings, but the embodiments of the invention are not limited thereto.
检测条件Detection conditions
X-射线粉末衍射X-ray powder diffraction
X-射线粉末衍射仪：Bruker D8 Advance；X-ray powder diffractometer: Bruker D8 Advance;
2θ扫描角度：从3°到45°；2θ scanning angle: from 3° to 45°;
扫描步长：0.02°；Scanning step size: 0.02°;
曝光时间：0.2秒；Exposure time: 0.2 seconds;
光管电压和电流：40KV、40mA。Light tube voltage and current: 40KV, 40mA.
差示扫描量热分析Differential Scanning Calorimetry
差示扫描量热分析仪：TA Discovery 2500(TA，US)；Differential scanning calorimetry analyzer: TA Discovery 2500 (TA, US);
加热速率：10℃/min；Heating rate: 10℃/min;
检测方法：样品经精确称重后置于DSC Tzero样品盘中，加热至350℃，炉内氮气吹扫速度为50mL/min。Detection method: The sample is accurately weighed and placed in a DSC Tzero sample pan, heated to 350 °C, and the nitrogen purge rate in the furnace is 50 mL/min.
热重分析Thermogravimetric Analysis
热重分析仪：TA Discovery 55(TA，US)；Thermogravimetric analyzer: TA Discovery 55 (TA, US);
检测方法：将样品置于已平衡的开口铝制样品盘中，在加热炉内自动称量。样品以10℃/min的速率加热至400℃，样品处氮气吹扫速度为60mL/min，天平处氮气吹扫速度为40mL/min。Detection method: The sample is placed in a balanced open aluminum sample pan and automatically weighed in a heating furnace. The sample was heated to 400°C at a rate of 10°C/min, the nitrogen purge rate at the sample was 60mL/min, and the nitrogen purge rate at the balance was 40mL/min.
实施例1 化合物WX-216的制备方法 Embodiment 1 The preparation method of compound WX-216
参考专利WO2018041263A1实施例4公开的方法制备得到WX-216。WX-216 was prepared with reference to the method disclosed in Example 4 of patent WO2018041263A1.
实施例2 式(I)化合物晶型I的制备方法Example 2 Preparation method of compound crystal form I of formula (I)
称取202.3mg采用实施例1方法制备得到的WX-216，加入2.5mL正庚烷中制备得到混悬液，将所得混悬液置于室温(～25℃)条件下混悬搅拌70h，将悬浮液离心分离，并在室温真空干燥，得到白色固体，为晶型I，所得晶型I的XRPD谱图如图1所示，DSC谱图如图2所示，TGA谱图如图3所示。Weigh 202.3 mg of WX-216 prepared by the method in Example 1, add it to 2.5 mL of n-heptane to prepare a suspension, and place the obtained suspension at room temperature (~25 °C) for 70 h. The suspension was centrifuged and dried under vacuum at room temperature to obtain a white solid, which was Form I. The XRPD spectrum of the obtained Form I was shown in Figure 1, the DSC spectrum was shown in Figure 2, and the TGA spectrum was shown in Figure 3. Show.
实施例3 式(I)化合物晶型I的制备方法Example 3 Preparation method of compound crystal form I of formula (I)
称取201.2mg采用实施例1方法制备得到的WX-216，加入2.5mL乙酰乙酸乙酯中制备得到混悬液，将所得混悬液置于室温(～25℃)条件下混悬搅拌70h，将悬浮液离心分离，并在室温真空干燥，得到白色固体，为晶型I。Weigh 201.2 mg of WX-216 prepared by the method in Example 1, add it to 2.5 mL of ethyl acetoacetate to prepare a suspension, and place the obtained suspension at room temperature (~25 °C) for 70 h. The suspension was centrifuged and dried in vacuo at room temperature to give a white solid as Form I.
所得晶型I的XRPD谱图的比较如图4所示。The comparison of the XRPD spectra of the obtained crystal form I is shown in FIG. 4 .
实施例4 式(I)化合物晶型II的制备方法Example 4 Preparation method of compound crystal form II of formula (I)
称取202.1mg采用实施例2方法制备得到的晶型I，加入1.0mL 1,4-二氧六环中制备得到混悬液，将所得混悬液置于室温(～25℃)条件下混悬搅拌70h，将悬浮液离心分离，并在室温真空干燥，得到白色固体，为晶型II，所得晶型II的XRPD谱图如图5所示，DSC谱图如图6所示，TGA谱图如图7所示。Weigh 202.1 mg of the crystal form I prepared by the method of Example 2, add 1.0 mL of 1,4-dioxane to prepare a suspension, and place the obtained suspension at room temperature (~25 ° C) under conditions of mixing The suspension was stirred for 70 h, the suspension was centrifuged, and dried under vacuum at room temperature to obtain a white solid, which was crystal form II. The XRPD spectrum of the obtained crystal form II is shown in Figure 5, the DSC spectrum is shown in Figure 6, and the TGA spectrum The diagram is shown in Figure 7.
实施例5 式(I)化合物晶型II的制备方法Example 5 Preparation method of compound crystal form II of formula (I)
称取101.0mg采用实施例2方法制备得到的晶型I，加入10.0mL甲苯则升温至90℃，无法完全溶解，降温至60℃进行悬浮打浆19h，将悬浮液离心分离，并在室温真空干燥，得到白色固体，为晶型II。Weigh 101.0 mg of the crystal form I prepared by the method in Example 2, add 10.0 mL of toluene, then heat up to 90 ° C, which cannot be completely dissolved, cool down to 60 ° C for suspending and beating for 19 hours, centrifuge the suspension, and vacuum dry at room temperature , a white solid was obtained, which was Form II.
所得晶型II的XRPD谱图的比较如图8所示。A comparison of the XRPD spectra of the obtained crystal form II is shown in FIG. 8 .
实施例6 式(I)化合物晶型III的制备方法Example 6 Preparation method of compound crystal form III of formula (I)
称取203.1mg采用实施例2方法制备得到的晶型I，加入2.5mL异丙醇中制备得到混悬液，将所得混悬液置于室温(～25℃)条件下混悬搅拌70h，将悬浮液离心分离，并在室温真空干燥，得到白色固体，为晶型III，所得晶型III的XRPD谱图如图9所示，DSC谱图如图10所示，TGA谱图如图11所示。Weigh 203.1 mg of the crystal form I prepared by the method in Example 2, add it to 2.5 mL of isopropanol to prepare a suspension, and place the obtained suspension at room temperature (~25 °C) for 70 h. The suspension was centrifuged and dried under vacuum at room temperature to obtain a white solid, which was crystal form III. The XRPD spectrum of the obtained crystal form III was shown in Figure 9, the DSC spectrum was shown in Figure 10, and the TGA spectrum was shown in Figure 11. Show.
实施例7 式(I)化合物晶型III的制备方法Example 7 Preparation method of compound crystal form III of formula (I)
称取102.5mg采用实施例2方法制备得到的晶型I，加入1.0mL正丙醇升温至60℃，完全溶解，将澄清溶液置于5℃下静置12h，将悬浮液离心分离，并在室温真空干燥，得到白色固体，为晶型III。Weigh 102.5 mg of the crystal form I prepared by the method in Example 2, add 1.0 mL of n-propanol and heat up to 60 ° C, completely dissolve, place the clear solution at 5 ° C and stand for 12 h, and centrifuge the suspension. Vacuum drying at room temperature gave a white solid as Form III.
所得晶型III的XRPD谱图的比较如图12所示。A comparison of the XRPD spectra of the obtained crystal form III is shown in FIG. 12 .
实施例8 式(I)化合物晶型IV的制备方法Example 8 Preparation method of compound crystal form IV of formula (I)
称取202.9mg采用实施例2方法制备得到的晶型I，加入2.5mL乙酰丙酮中制备得到混悬液，将所得混悬液置于室温(～25℃)条件下混悬搅拌70h，将悬浮液离心分离，并在室温真空干燥，得到白色固体，为晶型IV，所得 晶型IV的XRPD谱图如图13所示，DSC谱图如图14所示，TGA谱图如图15所示。Weigh 202.9 mg of the crystal form I prepared by the method in Example 2, add it to 2.5 mL of acetylacetone to prepare a suspension, place the obtained suspension at room temperature (~25°C) and suspend and stir for 70 hours. The liquid was centrifuged and dried under vacuum at room temperature to obtain a white solid, which was crystal form IV. The XRPD spectrum of the obtained crystal form IV is shown in Figure 13, the DSC spectrum is shown in Figure 14, and the TGA spectrum is shown in Figure 15 .
实施例9 式(I)化合物晶型V的制备方法Example 9 Preparation method of compound crystal form V of formula (I)
称取202.6mg采用实施例2方法制备得到的晶型I，悬浮于2mL水中，于60℃下滴加6mL NMP至固体完全溶解，随后冷却至室温搅拌，直至有固体析出，离心分离后室温真空干燥，得到白色固体，为晶型V，所得晶型V的XRPD谱图如图16所示，DSC谱图如图17所示，TGA谱图如图18所示。Weigh 202.6 mg of the crystal form I prepared by the method in Example 2, suspended in 2 mL of water, dropwise at 60°C with 6 mL of NMP until the solid is completely dissolved, then cooled to room temperature and stirred, until there is solid precipitation, after centrifugation, the room temperature vacuum After drying, a white solid is obtained, which is crystal form V. The XRPD spectrum of the obtained crystal form V is shown in FIG. 16 , the DSC spectrum is shown in FIG. 17 , and the TGA spectrum is shown in FIG. 18 .
实施例10 式(I)化合物晶型V的制备方法 Embodiment 10 The preparation method of formula (I) compound crystal form V
称取103.1mg采用实施例2方法制备得到的晶型I，加入0.5mL NMP升温至60℃，完全溶解，将澄清溶液置于5℃下静置20h，将悬浮液离心分离，并在室温真空干燥，得到白色固体，为晶型V。Weigh 103.1 mg of the crystal form I prepared by the method of Example 2, add 0.5 mL of NMP and heat up to 60 ° C, completely dissolve, place the clear solution at 5 ° C for 20 h, centrifuge the suspension, and vacuum at room temperature. Drying gave a white solid as Form V.
所得晶型V的XRPD谱图的比较如图19所示。A comparison of the XRPD spectra of the obtained Form V is shown in FIG. 19 .
实施例11 式(I)化合物晶型VI的制备方法Example 11 Preparation method of compound crystal form VI of formula (I)
称取1.0g采用实施例2方法制备得到的晶型I，配制饱和溶液(四氢呋喃/水)，于室温(～25℃)下将2.2mL的饱和溶液滴加至搅拌状态下的1.5mL水中，直至有固体析出，离心分离后室温真空干燥，得到类白色固体，为晶型VI，所得晶型VI的XRPD谱图如图20所示，DSC谱图如图21所示，TGA谱图如图22所示。Weigh 1.0 g of the crystal form I prepared by the method in Example 2, prepare a saturated solution (tetrahydrofuran/water), and add 2.2 mL of the saturated solution dropwise to 1.5 mL of water under stirring at room temperature (~25°C), Until there is solid precipitation, centrifuge and vacuum dry at room temperature to obtain an off-white solid, which is crystal form VI. The XRPD spectrum of the obtained crystal form VI is shown in Figure 20, the DSC spectrum is shown in Figure 21, and the TGA spectrum is shown in Figure 2 22 shown.
实施例12 式(II)化合物甲基叔丁基醚溶剂合物的晶型VII的制备方法Example 12 Preparation method of crystal form VII of compound methyl tert-butyl ether solvate of formula (II)
称取202.0mg采用实施例2方法制备得到的晶型I，加入2.5mL甲基叔丁基醚中制备得到混悬液，将所得混悬液置于室温(～25℃)条件下混悬搅拌70h，将悬浮液离心分离，并在室温真空干燥，得到类白色固体，为晶型VII，所得晶型VII的XRPD谱图如图23所示，DSC谱图如图24所示，TGA谱图如图25所示。Weigh 202.0 mg of the crystal form I prepared by the method in Example 2, add it to 2.5 mL of methyl tert-butyl ether to prepare a suspension, and place the obtained suspension at room temperature (~25°C) for suspension and stirring. 70h, the suspension was centrifuged and dried in vacuum at room temperature to obtain an off-white solid, which was crystal form VII. The XRPD spectrum of the obtained crystal form VII is shown in Figure 23, the DSC spectrum is shown in Figure 24, and the TGA spectrum As shown in Figure 25.
实施例13 式(II)化合物甲基叔丁基醚溶剂合物的晶型VII的制备方法Example 13 Preparation method of crystal form VII of compound methyl tert-butyl ether solvate of formula (II)
称取102.1mg采用实施例2方法制备得到的晶型I，悬浮于2mL乙醇中，于60℃下滴加0.2mL甲基叔丁基醚至固体完全溶解，随后冷却至室温搅拌，直至有固体析出，离心分离后室温真空干燥，得到类白色固体，为晶型VII。Weigh 102.1 mg of the crystal form I prepared by the method of Example 2, suspend in 2 mL of ethanol, add 0.2 mL of methyl tert-butyl ether dropwise at 60 ° C until the solid is completely dissolved, then cool to room temperature and stir until there is a solid Precipitation, centrifugation, and vacuum drying at room temperature to obtain an off-white solid, which is crystal form VII.
所得晶型VII的XRPD谱图的比较如图26所示。A comparison of the XRPD spectra of the obtained Form VII is shown in FIG. 26 .
实施例14 式(II)化合物N-甲基吡咯烷酮溶剂合物的晶型VIII的制备方法Example 14 Preparation method of crystal form VIII of compound N-methylpyrrolidone solvate of formula (II)
称取202.6mg采用实施例2方法制备得到的晶型I，悬浮于2mL乙腈中，于60℃下滴加6mL NMP至固体完全溶解，随后冷却至室温搅拌，直至有固体析出，离心分离后室温真空干燥，得到类白色固体，为晶型VIII，所得晶型VIII的XRPD谱图如图27所示，DSC谱图如图28所示，TGA谱图如图29所示。Weigh 202.6 mg of the crystal form I prepared by the method of Example 2, suspended in 2 mL of acetonitrile, dropwise at 60 ° C with 6 mL of NMP until the solid is completely dissolved, then cooled to room temperature and stirred, until there is solid precipitation, after centrifugation, the room temperature Dry in vacuo to obtain an off-white solid, which is crystal form VIII. The XRPD spectrum of the obtained crystal form VIII is shown in FIG. 27 , the DSC spectrum is shown in FIG. 28 , and the TGA spectrum is shown in FIG. 29 .
实施例15 式(II)化合物晶型IX的制备方法Example 15 Preparation method of compound crystal form IX of formula (II)
称取1.0g采用实施例2方法制备得到的晶型I，溶解于四氢呋喃配制饱和溶液，于室温(～25℃)下将0.6mL的饱和溶液滴加至搅拌状态下的1.5mL环己烷中，直至有固体析出，离心分离后室温真空干燥，得到类白色固体，为晶型IX，所得晶型IX的XRPD谱图如图30所示。Weigh 1.0 g of the crystal form I prepared by the method in Example 2, dissolve it in tetrahydrofuran to prepare a saturated solution, and add 0.6 mL of the saturated solution dropwise to 1.5 mL of cyclohexane under stirring at room temperature (~25 °C). , until there is solid precipitation, centrifugation and vacuum drying at room temperature to obtain an off-white solid, which is crystal form IX, and the XRPD spectrum of the obtained crystal form IX is shown in Figure 30.
实施例16 稳定性研究Example 16 Stability Study
称取一定量待测样品置于表面皿中，分别放置在高温(60℃)、高湿(25℃，92.5％RH)、光照(25℃，4500Lux)、加速条件(40℃，75％RH)下，于14天取样进行XRPD表征。Weigh a certain amount of samples to be tested and place them in a watch glass, and place them under high temperature (60°C), high humidity (25°C, 92.5%RH), light (25°C, 4500Lux), and accelerated conditions (40°C, 75%RH). ), samples were taken at 14 days for XRPD characterization.
分别对晶型I、晶型II、晶型III、晶型IV进行高温(60℃)、高湿(25℃，92.5％RH)、光照(25℃，4500Lux)、加速条件(40℃，75％RH)下的稳定性研究，结果如表1所示：Form I, Form II, Form III and Form IV were subjected to high temperature (60°C), high humidity (25°C, 92.5% RH), light (25°C, 4500Lux), and accelerated conditions (40°C, 75°C). Stability study under %RH), the results are shown in Table 1:
表1 稳定性研究结果(晶型)Table 1 Stability study results (crystal form)
Figure PCTCN2021124835-appb-000008
Figure PCTCN2021124835-appb-000008
表2 稳定性研究结果Table 2 Stability study results
Figure PCTCN2021124835-appb-000009
Figure PCTCN2021124835-appb-000009
Figure PCTCN2021124835-appb-000010
Figure PCTCN2021124835-appb-000010
*N.D.为未测*N.D. is not measured
结果显示晶型I、II、III、VII在稳定性研究的条件下不发生转晶；有关物质的检测结果显示晶型II和III在光照条件下不稳定，杂质增加明显。稳定性研究结果显示晶型I、II和晶型III在晶型和有关物质方面都相对稳定。The results show that crystal forms I, II, III and VII do not undergo crystal transformation under the conditions of stability research; the detection results of related substances show that crystal forms II and III are unstable under light conditions, and the impurities increase significantly. The results of the stability study showed that the crystal forms I, II and III were relatively stable in terms of crystal forms and related substances.
实施例17 竞争性悬浮实验Example 17 Competitive suspension experiment
分别称取一定量晶型I、晶型II、晶型III和晶型VII加入到无水乙醇中，分别在室温(～25℃)、40℃、60℃下配制饱和溶液，于不同温度下搅拌，适时取固体样品进行表征。A certain amount of crystal form I, crystal form II, crystal form III and crystal form VII were weighed and added to absolute ethanol, and saturated solutions were prepared at room temperature (~25°C), 40°C, and 60°C, respectively. Stir, and take solid samples for characterization when appropriate.
表3 竞争性悬浮实验结果Table 3 Competitive suspension test results
Figure PCTCN2021124835-appb-000011
Figure PCTCN2021124835-appb-000011
结果显示在室温(～25℃)至60℃范围内，晶型I和晶型II实验后都生成晶型III，晶型VII在60℃时生成晶型I，可知，晶型III在无水体系中比其它晶型具有更好的稳定性。The results show that in the range from room temperature (~25°C) to 60°C, both crystal form I and crystal form II form crystal form III after the experiment, and crystal form VII generates crystal form I at 60°C. The system has better stability than other crystal forms.
晶型I、晶型II的作用还在于可以作为中间体晶型，进一步制备部分本发明所述的其他稳定晶型；The function of crystal form I and crystal form II is that they can be used as intermediate crystal forms to further prepare some other stable crystal forms described in the present invention;
此外，发明人在实验过程中及进一步研究中还发现：In addition, the inventor also found in the course of experiments and further research:
晶型IV可通过在晶型I中加入乙酰丙酮中长时间搅拌、析晶后得到，本领域技术人员可以理解，晶型IV具有较高稳定性；Crystal form IV can be obtained by adding acetylacetone to crystal form I after stirring and crystallization for a long time. Those skilled in the art can understand that crystal form IV has high stability;
晶型V可通过在晶型I中加入水悬浮，后加入NMP升温至60℃，完全溶解，将澄清溶液置于5℃下静置20h析晶后得到，本领域技术人员可以理解，晶型V具有较高稳定性；The crystal form V can be obtained by adding water to the crystal form I to suspend, then adding NMP to raise the temperature to 60°C, completely dissolving it, and placing the clear solution at 5°C for 20 hours after crystallization. Those skilled in the art can understand that the crystal form V has high stability;
晶型VI可通过将晶型I，配制饱和溶液(四氢呋喃/水)，于室温下将饱和溶液滴加至搅拌状态下的水中，析晶后得到，本领域技术人员可以理解，晶型VI具有较高稳定性；Crystal form VI can be obtained by preparing a saturated solution (tetrahydrofuran/water) of crystal form I, adding the saturated solution dropwise to the water under stirring at room temperature, and obtaining after crystallization. Those skilled in the art can understand that crystal form VI has higher stability;
晶型VII可通过在晶型I中加入甲基叔丁基醚中制备得到混悬液，将所得混悬液置于室温条件下，混悬搅拌70h，析晶所得，本领域技术人员可以理解，晶型VII具有较高稳定性；The crystal form VII can be prepared by adding methyl tert-butyl ether to the crystal form I to obtain a suspension, and the obtained suspension is placed at room temperature, suspended and stirred for 70 hours, and the obtained crystal is obtained, which can be understood by those skilled in the art. , the crystal form VII has high stability;
晶型VIII可通过将晶型I，悬浮于乙腈中，于60℃下滴加NMP，冷却至室温搅拌析晶所得，本领域技术人员可以理解，晶型VIII具有较高稳定性；The crystal form VIII can be obtained by suspending the crystal form I in acetonitrile, adding NMP dropwise at 60°C, and cooling to room temperature for stirring and crystallization. Those skilled in the art can understand that the crystal form VIII has high stability;
晶型IX为中间态亚稳晶型，实验过程中发现，晶型IX仅能在湿品状态下存在，抽滤时间过长或干燥均会发生转晶，转为晶型I，可知晶型I具有较高的稳定性。The crystal form IX is an intermediate metastable crystal form. During the experiment, it was found that the crystal form IX can only exist in a wet state. If the suction filtration time is too long or drying, the crystal will be transformed into the crystal form I. It can be seen that the crystal form I has high stability.
综上可知，本发明所述的化合物WX-216的晶型具有稳定性等效果中的至少一种，为原料药的规模化生产及制药产品的下游工艺(如制剂工艺)提供了多种中间产物和/或原料药的选择。In summary, the crystal form of the compound WX-216 of the present invention has at least one effect such as stability, which provides a variety of intermediates for the large-scale production of raw materials and downstream processes (such as formulation processes) of pharmaceutical products. Selection of product and/or drug substance.
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。The above-mentioned embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited by the above-mentioned embodiments, and any other changes, modifications, substitutions, combinations, The simplification should be equivalent replacement manners, which are all included in the protection scope of the present invention.

Claims (30)

  1. 一种式(I)的化合物：A compound of formula (I):
    Figure PCTCN2021124835-appb-100001
    Figure PCTCN2021124835-appb-100001
    其中，n选自0～4中任意数值；具体的，n选自0,0.5,1,1.5,2,2.5,3,3.5或4。Wherein, n is selected from any value from 0 to 4; specifically, n is selected from 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5 or 4.
  2. 根据权利要求1所述式(I)化合物的晶型I，其结构式如(1)所示：According to the crystal form I of the compound of formula (I) according to claim 1, its structural formula is shown in (1):
    Figure PCTCN2021124835-appb-100002
    Figure PCTCN2021124835-appb-100002
    其特征在于，所述式(I)化合物的晶型I的XRPD图谱在2θ为6.9,11.0,11.8,17.1,17.9,18.4,18.7,19.8,22.2,22.6,23.8,26.3,26.7,27.7±0.2°处具有衍射峰；进一步地，所述式(I)化合物的晶型I的XRPD图谱还在2θ为8.4,13.9,15.0,20.3,23.4,25.3,25.7,28.1,29.4±0.2°处具有衍射峰；更进一步地，所述式(I)化合物的晶型I的XRPD图谱的衍射峰情况如下表所示：It is characterized in that the XRPD pattern of the crystal form I of the compound of formula (I) at 2θ is 6.9, 11.0, 11.8, 17.1, 17.9, 18.4, 18.7, 19.8, 22.2, 22.6, 23.8, 26.3, 26.7, 27.7±0.2 There are diffraction peaks at °; further, the XRPD pattern of the crystal form I of the compound of formula (I) also has diffraction at 2θ of 8.4, 13.9, 15.0, 20.3, 23.4, 25.3, 25.7, 28.1, 29.4±0.2° Peak; further, the diffraction peak situation of the XRPD pattern of the crystal form I of the compound of formula (I) is shown in the following table:
    编号Numbering 2θ(±0.2°)2θ(±0.2°) 编号Numbering 2θ(±0.2°)2θ(±0.2°) 11 6.96.9 1515 22.222.2 22 8.48.4 1616 22.622.6 33 11.011.0 1717 23.423.4 44 11.811.8 1818 23.823.8 55 13.913.9 1919 25.325.3 66 15.015.0 2020 25.725.7 77 16.416.4 21twenty one 26.326.3 88 17.117.1 22twenty two 26.726.7 99 17.917.9 23twenty three 27.727.7 1010 18.418.4 24twenty four 28.128.1 1111 18.718.7 2525 29.429.4
    1212 19.819.8 2626 29.829.8 1313 20.320.3 2727 30.730.7 1414 21.021.0      
    更进一步地，所述式(I)化合物的晶型I，其XRPD图谱基本如图1所示。Further, the XRPD pattern of the crystal form I of the compound of formula (I) is basically as shown in FIG. 1 .
  3. 根据权利要求2所述式(I)化合物的晶型I，其特征在于，所述式(I)化合物的晶型I的DSC图谱在126.1±3℃处具有吸热峰的起始点，在195.1±3℃处具有吸热峰的起始点；进一步地，所述式(I)化合物的晶型I的DSC图谱基本如图2所示。The crystalline form I of the compound of formula (I) according to claim 2, wherein the DSC spectrum of the crystalline form I of the compound of formula (I) has an onset of an endothermic peak at 126.1±3° C., at 195.1 The starting point of the endothermic peak is at ±3°C; further, the DSC spectrum of the crystal form I of the compound of formula (I) is basically as shown in FIG. 2 .
  4. 根据权利要求2所述式(I)化合物的晶型I，其特征在于，所述式(I)化合物的晶型I的TGA图谱在160℃时失重4.14±1％，在210℃时失重0.46±1％；进一步地，所述式(I)化合物的晶型I的TGA图谱基本如图3所示。The crystalline form I of the compound of formula (I) according to claim 2, wherein the TGA spectrum of the crystalline form I of the compound of formula (I) loses 4.14±1% in weight at 160°C, and loses 0.46% in weight at 210°C ±1%; further, the TGA spectrum of the crystal form I of the compound of formula (I) is basically as shown in FIG. 3 .
  5. 根据权利要求1所述的式(I)化合物的晶型II，其结构式如(2)所示：The crystal form II of the compound of formula (I) according to claim 1, its structural formula is shown in (2):
    Figure PCTCN2021124835-appb-100003
    Figure PCTCN2021124835-appb-100003
    其特征在于，所述式(I)化合物的晶型II的XRPD图谱在2θ为6.5,9.2,12.9,14.5,16.5,19.6,20.5,21.7±0.2°处具有衍射峰；进一步地，所述式(I)化合物的晶型II的XRPD图谱还在2θ为10.2,16.1,17.4,18.5,23.4,24.5,26.2,26.9,27.8,30.0,31.0±0.2°处具有衍射峰；更进一步地，所述式(I)化合物的晶型II的XRPD图谱的衍射峰情况如下表所示：It is characterized in that, the XRPD pattern of the crystal form II of the compound of formula (I) has diffraction peaks at 2θ of 6.5, 9.2, 12.9, 14.5, 16.5, 19.6, 20.5, 21.7±0.2°; further, the formula (I) The XRPD pattern of the crystal form II of the compound also has diffraction peaks at 2θ of 10.2, 16.1, 17.4, 18.5, 23.4, 24.5, 26.2, 26.9, 27.8, 30.0, 31.0±0.2°; further, the said The diffraction peaks of the XRPD pattern of the crystal form II of the compound of formula (I) are shown in the following table:
    编号Numbering 2θ(±0.2°)2θ(±0.2°) 编号Numbering 2θ(±0.2°)2θ(±0.2°) 11 4.54.5 1212 20.520.5 22 6.56.5 1313 21.721.7 33 9.29.2 1414 22.922.9 44 10.210.2 1515 23.423.4 55 12.912.9 1616 24.524.5 66 14.514.5 1717 25.425.4 77 16.116.1 1818 26.226.2 88 16.516.5 1919 26.926.9 99 17.417.4 2020 27.827.8 1010 18.518.5 21twenty one 30.030.0 1111 19.619.6 22twenty two 31.031.0
    更进一步地，所述式(I)化合物的晶型II，其XRPD图谱基本如图5所示。Further, the XRPD pattern of the crystal form II of the compound of formula (I) is basically as shown in FIG. 5 .
  6. 根据权利要求5所述式(I)化合物的晶型II，其特征在于，所述式(I)化合物的晶型II的DSC图谱在164.0±3℃处具有吸热峰的起始点；进一步地，所述式(I)化合物的晶型I的DSC图谱基本如图6所示。The crystalline form II of the compound of formula (I) according to claim 5, wherein the DSC spectrum of the crystalline form II of the compound of formula (I) has an onset of an endothermic peak at 164.0±3°C; further , the DSC spectrum of the crystal form I of the compound of formula (I) is basically as shown in FIG. 6 .
  7. 根据权利要求5所述式(I)化合物的晶型II，其特征在于，所述式(I)化合物的晶型II的TGA图谱在150℃时失重7.41±1％；进一步地，所述式(I)化合物的晶型II的TGA图谱基本如图7所示。The crystal form II of the compound of formula (I) according to claim 5, wherein the TGA spectrum of the crystal form II of the compound of formula (I) has a weight loss of 7.41±1% at 150°C; further, the formula The TGA spectrum of the crystal form II of the compound (I) is basically as shown in FIG. 7 .
  8. 根据权利要求1所述的式(I)化合物的晶型III，其结构式如(1)所示：The crystal form III of the compound of formula (I) according to claim 1, its structural formula is shown in (1):
    Figure PCTCN2021124835-appb-100004
    Figure PCTCN2021124835-appb-100004
    其特征在于，所述式(I)化合物的晶型III的XRPD图谱在2θ为3.7,6.4,8.2,9.5,9.8,11.1,14.8,18.5,22.1,23.6,25.8±0.2°处具有衍射峰；进一步地，所述式(I)化合物的晶型III的XRPD图谱还在2θ为4.8,7.4,16.5,29.5±0.2°处具有衍射峰；更进一步地，所述式(I)化合物的晶型III的XRPD图谱的衍射峰情况如下表所示：It is characterized in that, the XRPD pattern of the crystal form III of the compound of formula (I) has diffraction peaks at 2θ of 3.7, 6.4, 8.2, 9.5, 9.8, 11.1, 14.8, 18.5, 22.1, 23.6, 25.8±0.2°; Further, the XRPD pattern of the crystal form III of the compound of formula (I) also has diffraction peaks at 2θ of 4.8, 7.4, 16.5, 29.5±0.2°; further, the crystal form of the compound of formula (I) The diffraction peaks of the XRPD pattern of III are shown in the following table:
    编号Numbering 2θ(±0.2°)2θ(±0.2°) 编号Numbering 2θ(±0.2°)2θ(±0.2°) 11 3.73.7 99 12.912.9 22 4.84.8 1010 14.814.8 33 6.46.4 1111 16.516.5 44 7.47.4 1212 18.518.5 55 8.28.2 1313 22.122.1 66 9.59.5 1414 23.623.6 77 9.89.8 1515 25.825.8 88 11.111.1 1616 29.529.5
    更进一步地，所述式(I)化合物的晶型III，其XRPD图谱基本如图9所示。Further, the XRPD pattern of the crystal form III of the compound of formula (I) is basically as shown in FIG. 9 .
  9. 根据权利要求8所述式(I)化合物的晶型III，其特征在于，所述式(I)化合物的晶型III的DSC图谱在177.6±3℃处具有吸热峰的起始点，在209.77±3℃处具有吸热峰的起始点；进一步地，所述式(I)化合物的晶型III的DSC图谱基本如图10所示。The crystalline form III of the compound of formula (I) according to claim 8, wherein the DSC spectrum of the crystalline form III of the compound of formula (I) has an onset of an endothermic peak at 177.6±3°C and an onset of an endothermic peak at 209.77 The starting point of the endothermic peak is at ±3°C; further, the DSC spectrum of the crystal form III of the compound of formula (I) is basically as shown in FIG. 10 .
  10. 根据权利要求8所述式(I)化合物的晶型III，其特征在于，所述式(I)化合物的晶型III的TGA图谱在90℃时失重1.62±1％，在200℃时失重5.50±1％；进一步地，所述式(I)化合物的晶型III的TGA图谱基本如图11所示。The crystal form III of the compound of formula (I) according to claim 8, wherein the TGA spectrum of the crystal form III of the compound of formula (I) has a weight loss of 1.62±1% at 90° C. and a weight loss of 5.50 at 200° C. ±1%; further, the TGA spectrum of the crystal form III of the compound of formula (I) is basically as shown in FIG. 11 .
  11. 根据权利要求1所述的式(I)化合物的晶型IV，其特征在于，所述式(I)化合物的晶型IV的XRPD图谱在2θ为8.2,8.7,10.2,16.9,20.4±0.2°处具有衍射峰；进一步地，所述式(I)化合物的晶型IV的XRPD图谱还在2θ为5.6,7.2,12.2,14.3,14.6,15.5,15.8,18.8,21.0,21.8,22.7±0.2°处具有衍射峰；更进一步地，所述式(I)化合物的晶型IV的XRPD图谱的衍射峰情况如下表所示：The crystal form IV of the compound of formula (I) according to claim 1, wherein the XRPD pattern of the crystal form IV of the compound of formula (I) at 2θ is 8.2, 8.7, 10.2, 16.9, 20.4±0.2° There are diffraction peaks at; further, the XRPD pattern of the crystal form IV of the compound of formula (I) also has 2θ of 5.6, 7.2, 12.2, 14.3, 14.6, 15.5, 15.8, 18.8, 21.0, 21.8, 22.7±0.2° There are diffraction peaks at; further, the diffraction peaks of the XRPD pattern of the crystal form IV of the compound of formula (I) are shown in the following table:
    编号Numbering 2θ(±0.2°)2θ(±0.2°) 编号Numbering 2θ(±0.2°)2θ(±0.2°) 11 5.65.6 1010 15.815.8 22 7.27.2 1111 16.916.9 33 8.28.2 1212 18.818.8
    44 8.78.7 1313 20.420.4 55 10.210.2 1414 21.021.0 66 12.212.2 1515 21.821.8 77 14.314.3 1616 22.722.7 88 14.614.6 1717 25.025.0 99 15.515.5 1818 26.726.7
    更进一步地，所述式(I)化合物的晶型IV，其XRPD图谱基本如图13所示。Further, the XRPD pattern of the crystalline form IV of the compound of formula (I) is basically as shown in FIG. 13 .
  12. 根据权利要求11所述式(I)化合物的晶型IV，其特征在于，所述式(I)化合物的晶型IV的DSC图谱在125.0±3℃处具有吸热峰的起始点；进一步地，所述式(I)化合物的晶型IV的DSC图谱基本如图14所示。The crystalline form IV of the compound of formula (I) according to claim 11, wherein the DSC spectrum of the crystalline form IV of the compound of formula (I) has an onset of an endothermic peak at 125.0±3°C; further , the DSC spectrum of the crystal form IV of the compound of formula (I) is basically shown in FIG. 14 .
  13. 根据权利要求11所述式(I)化合物的晶型IV，其特征在于，所述式(I)化合物的晶型IV的TGA图谱在170℃时失重9.72±1％；进一步地，所述式(I)化合物的晶型IV的TGA图谱基本如图15所示。The crystalline form IV of the compound of formula (I) according to claim 11, wherein the TGA spectrum of the crystalline form IV of the compound of formula (I) has a weight loss of 9.72±1% at 170°C; further, the formula The TGA spectrum of the crystalline form IV of the compound (I) is basically as shown in FIG. 15 .
  14. 根据权利要求1所述的式(I)化合物的晶型V，其结构式如(1)所示：The crystal form V of the compound of formula (I) according to claim 1, its structural formula is shown in (1):
    Figure PCTCN2021124835-appb-100005
    Figure PCTCN2021124835-appb-100005
    其特征在于，所述式(I)化合物的晶型V的XRPD图谱在2θ为4.9,8.7,10.3,12.2,14.7,15.3,16.5,18.8,19.8,20.6,21.9,23.7,23.9,25.6,28.6,29.7±0.2°处具有衍射峰；进一步地，所述式(I)化合物的晶型V的XRPD图谱还在2θ为17.4,20.4,22.7,24.8,25.1,25.9,26.6,27.6,29.3,30.4±0.2°处具有衍射峰；更进一步地，所述式(I)化合物的晶型V的XRPD图谱的衍射峰情况如下表所示：It is characterized in that, the XRPD pattern of the crystal form V of the compound of formula (I) at 2θ is 4.9, 8.7, 10.3, 12.2, 14.7, 15.3, 16.5, 18.8, 19.8, 20.6, 21.9, 23.7, 23.9, 25.6, 28.6 , has a diffraction peak at 29.7±0.2°; further, the XRPD pattern of the crystal form V of the compound of formula (I) is also 2θ of 17.4, 20.4, 22.7, 24.8, 25.1, 25.9, 26.6, 27.6, 29.3, 30.4 There are diffraction peaks at ±0.2°; further, the diffraction peaks of the XRPD pattern of the crystal form V of the compound of formula (I) are shown in the following table:
    编号Numbering 2θ(±0.2°)2θ(±0.2°) 编号Numbering 2θ(±0.2°)2θ(±0.2°) 11 4.94.9 1414 22.722.7 22 8.78.7 1515 23.723.7 33 10.310.3 1616 23.923.9 44 12.212.2 1717 24.824.8 55 14.714.7 1818 25.125.1 66 15.315.3 1919 25.625.6 77 16.516.5 2020 25.925.9 88 17.417.4 21twenty one 26.626.6 99 18.818.8 22twenty two 27.627.6 1010 19.819.8 23twenty three 28.628.6 1111 20.420.4 24twenty four 29.329.3 1212 20.620.6 2525 29.729.7
    1313 21.921.9 2626 30.430.4
    更进一步地，所述式(I)化合物的晶型V，其XRPD图谱基本如图16所示。Further, the XRPD pattern of the crystalline form V of the compound of formula (I) is basically as shown in FIG. 16 .
  15. 根据权利要求14所述式(I)化合物的晶型V，其特征在于，所述式(I)化合物的晶型V的DSC图谱在229.5±3℃处具有吸热峰的起始点；进一步地，所述式(I)化合物的晶型V的DSC图谱基本如图17所示。The crystalline form V of the compound of formula (I) according to claim 14, wherein the DSC spectrum of the crystalline form V of the compound of formula (I) has an onset of an endothermic peak at 229.5±3°C; further , the DSC spectrum of the crystal form V of the compound of formula (I) is basically shown in FIG. 17 .
  16. 根据权利要求14所述式(I)化合物的晶型V，其特征在于，所述式(I)化合物的晶型V的TGA图谱在125℃时失重71.02±1％，在200℃时失重3.07±1％；进一步地，所述式(I)化合物的晶型V的TGA图谱基本如图18所示。The crystalline form V of the compound of formula (I) according to claim 14, wherein the TGA spectrum of the crystalline form V of the compound of formula (I) has a weight loss of 71.02±1% at 125°C and a weight loss of 3.07% at 200°C ±1%; further, the TGA spectrum of the crystal form V of the compound of formula (I) is basically as shown in FIG. 18 .
  17. 根据权利要求1所述的式(I)化合物的晶型VI，其结构式如(3)所示：The crystal form VI of the compound of formula (I) according to claim 1, its structural formula is shown in (3):
    Figure PCTCN2021124835-appb-100006
    Figure PCTCN2021124835-appb-100006
    其特征在于，所述式(I)化合物的晶型VI的XRPD图谱在2θ为6.4,7.0,9.0,11.4,12.1,14.2,15.6,16.6,17.2,17.6,18.6,19.3,19.6,20.6,21.4,21.9,23.2,24.9,26.4,29.6±0.2°处具有衍射峰；进一步地，所述式(I)化合物的晶型VI的XRPD图谱还在2θ为13.5,25.4,27.2,30.3±0.2°处具有衍射峰；更进一步地，所述式(I)化合物的晶型VI的XRPD图谱的衍射峰情况如下表所示：It is characterized in that, the XRPD pattern of the crystal form VI of the compound of formula (I) at 2θ is 6.4, 7.0, 9.0, 11.4, 12.1, 14.2, 15.6, 16.6, 17.2, 17.6, 18.6, 19.3, 19.6, 20.6, 21.4 , 21.9, 23.2, 24.9, 26.4, 29.6±0.2° have diffraction peaks; further, the XRPD pattern of the crystal form VI of the compound of formula (I) is also at 2θ of 13.5, 25.4, 27.2, 30.3±0.2° Has a diffraction peak; further, the diffraction peak situation of the XRPD pattern of the crystal form VI of the compound of formula (I) is shown in the following table:
    编号Numbering 2θ(±0.2°)2θ(±0.2°) 编号Numbering 2θ(±0.2°)2θ(±0.2°) 11 6.46.4 1313 19.319.3 22 7.07.0 1414 19.619.6 33 9.09.0 1515 20.620.6 44 11.411.4 1616 21.421.4 55 12.112.1 1717 21.921.9 66 13.513.5 1818 23.223.2 77 14.214.2 1919 24.924.9 88 15.615.6 2020 25.425.4 99 16.616.6 21twenty one 26.426.4 1010 17.217.2 22twenty two 27.227.2 1111 17.617.6 23twenty three 29.629.6 1212 18.618.6 24twenty four 30.330.3
    更进一步地，所述式(I)化合物的晶型VI，其XRPD图谱基本如图20所示。Further, the XRPD pattern of the crystalline form VI of the compound of formula (I) is basically as shown in FIG. 20 .
  18. 根据权利要求17所述式(I)化合物的晶型VI，其特征在于，所述式(I)化合物的晶型VI的DSC图谱在78.5±3℃处具有吸热峰的起始点；进一步地，所述式(I)化合物的晶型VI的DSC图谱基本如图21所示。The crystalline form VI of the compound of formula (I) according to claim 17, wherein the DSC spectrum of the crystalline form VI of the compound of formula (I) has an onset of an endothermic peak at 78.5±3°C; further , the DSC spectrum of the crystal form VI of the compound of formula (I) is basically as shown in FIG. 21 .
  19. 根据权利要求17所述式(I)化合物的晶型VI，其特征在于，所述式(I)化合物的晶型VI的TGA图谱在165℃ 时失重14.44±1％；进一步地，所述式(I)化合物的晶型VI的TGA图谱基本如图22所示。The crystal form VI of the compound of formula (I) according to claim 17, wherein the TGA spectrum of the crystal form VI of the compound of formula (I) has a weight loss of 14.44±1% at 165°C; further, the formula The TGA spectrum of the crystal form VI of the compound (I) is basically as shown in FIG. 22 .
  20. 一种式(II)化合物的溶剂合物的晶型VII，A crystalline form VII of a solvate of a compound of formula (II),
    Figure PCTCN2021124835-appb-100007
    Figure PCTCN2021124835-appb-100007
    具体的，前述式(II)化合物的溶剂合物是式(II)化合物的甲基叔丁基醚溶剂合物，Specifically, the solvate of the aforementioned compound of formula (II) is a methyl tert-butyl ether solvate of the compound of formula (II),
    其特征在于，所述晶型VII的XRPD图谱在2θ为7.7,8.9,12.4,14.7,17.9,18.4,19.9,20.6,23.1,23.6,27.8,28.7±0.2°处具有衍射峰；进一步地，所述晶型VII的XRPD图谱还在2θ为5.9,15.4,16.1,17.5,19.0,21.7,24.5,28.1,30.8±0.2°处具有衍射峰；更进一步地，所述晶型VII的XRPD图谱的衍射峰情况如下表所示：It is characterized in that, the XRPD pattern of the crystal form VII has diffraction peaks at 2θ of 7.7, 8.9, 12.4, 14.7, 17.9, 18.4, 19.9, 20.6, 23.1, 23.6, 27.8, 28.7±0.2°; further, the The XRPD pattern of the crystal form VII also has diffraction peaks at 2θ of 5.9, 15.4, 16.1, 17.5, 19.0, 21.7, 24.5, 28.1, 30.8±0.2°; further, the diffraction peaks of the XRPD pattern of the crystal form VII The peaks are shown in the table below:
    编号Numbering 2θ(±0.2°)2θ(±0.2°) 编号Numbering 2θ(±0.2°)2θ(±0.2°) 11 5.95.9 1313 20.620.6 22 7.77.7 1414 21.721.7 33 8.98.9 1515 23.123.1 44 12.412.4 1616 23.623.6 55 14.714.7 1717 24.524.5 66 15.415.4 1818 25.325.3 77 16.116.1 1919 25.825.8 88 17.517.5 2020 27.827.8 99 17.917.9 21twenty one 28.128.1 1010 18.418.4 22twenty two 28.728.7 1111 19.019.0 23twenty three 30.830.8 1212 19.919.9      
    更进一步地，所述晶型VII，其XRPD图谱基本如图23所示。Further, the XRPD pattern of the crystal form VII is basically as shown in FIG. 23 .
  21. 根据权利要求20所述的晶型VII，其特征在于，所述式(II)化合物的溶剂合物的晶型VII的DSC图谱在161.8±3℃处具有吸热峰的起始点；进一步地，所述式(II)化合物的溶剂合物的晶型VII的DSC图谱基本如图24所示。The crystal form VII according to claim 20, wherein the DSC spectrum of the crystal form VII of the solvate of the compound of formula (II) has an onset of an endothermic peak at 161.8±3°C; further, The DSC spectrum of the crystal form VII of the solvate of the compound of formula (II) is substantially as shown in FIG. 24 .
  22. 根据权利要求20所述的晶型VII，其特征在于，所述晶型VII的TGA图谱在185℃时失重16.56±1％；进一步地，所述晶型VII的TGA图谱基本如图25所示。The crystal form VII according to claim 20, wherein the TGA spectrum of the crystal form VII has a weight loss of 16.56±1% at 185°C; further, the TGA spectrum of the crystal form VII is basically as shown in FIG. 25 . .
  23. 一种式(II)化合物的溶剂合物的晶型VIII，A crystalline form VIII of a solvate of a compound of formula (II),
    Figure PCTCN2021124835-appb-100008
    Figure PCTCN2021124835-appb-100008
    具体的，前述式(II)化合物的溶剂合物是式(II)化合物的N-甲基吡咯烷酮溶剂合物，Specifically, the solvate of the aforementioned compound of formula (II) is an N-methylpyrrolidone solvate of the compound of formula (II),
    其特征在于，所述晶型VIII的XRPD图谱在2θ为7.8,8.4,16.2±0.2°处具有稳定出现的衍射峰；进一步地，所述晶型VIII的XRPD图谱还在2θ为9.9,13.7,15.0,16.9,18.2,21.8±0.2°处具有衍射峰；更进一步地，所述晶型VIII的XRPD图谱的衍射峰情况如下表所示：It is characterized in that, the XRPD pattern of the crystal form VIII has stable diffraction peaks at 2θ of 7.8, 8.4, 16.2±0.2°; further, the XRPD pattern of the crystal form VIII also has 2θ of 9.9, 13.7, There are diffraction peaks at 15.0, 16.9, 18.2, 21.8±0.2°; further, the diffraction peaks of the XRPD pattern of the crystal form VIII are shown in the following table:
    编号Numbering 2θ(±0.2°)2θ(±0.2°) 编号Numbering 2θ(±0.2°)2θ(±0.2°) 11 7.87.8 66 16.216.2 22 8.48.4 77 16.916.9 33 9.99.9 88 18.218.2 44 13.713.7 99 21.821.8 55 15.015.0      
    更进一步地，所述晶型VIII，其XRPD图谱基本如图27所示。Further, the XRPD pattern of the crystal form VIII is basically as shown in FIG. 27 .
  24. 根据权利要求23所述的晶型VIII，其特征在于，所述晶型VIII的DSC图谱在116.5±3℃处具有吸热峰的起始点，在171.6±3℃处具有吸热峰的起始点；进一步地，所述晶型VIII的DSC图谱基本如图28所示。The crystal form VIII according to claim 23, wherein the DSC pattern of the crystal form VIII has an endothermic peak starting point at 116.5±3°C and an endothermic peak starting point at 171.6±3°C ; Further, the DSC spectrum of the crystal form VIII is basically shown in Figure 28.
  25. 根据权利要求23所述的晶型VIII，其特征在于，所述晶型VIII的TGA图谱在165℃时失重13.50±1％；进一步地，所述晶型VIII的TGA图谱基本如图29所示。The crystal form VIII according to claim 23, wherein the TGA spectrum of the crystal form VIII has a weight loss of 13.50±1% at 165°C; further, the TGA spectrum of the crystal form VIII is basically as shown in FIG. 29 . .
  26. 一种包括WX-216和/或其水合物、溶剂合物的原料药，其特征在于，所述原料药包括如权利要求1-25任意一项所述晶型中的至少一种；A bulk drug comprising WX-216 and/or its hydrate and solvate, wherein the bulk drug comprises at least one of the crystal forms according to any one of claims 1-25;
    Figure PCTCN2021124835-appb-100009
    Figure PCTCN2021124835-appb-100009
  27. 一种药物组合物，其特征在于所述药物组合物包括药学上可接受的辅料和如权利要求26所述的原料药。A pharmaceutical composition, characterized in that the pharmaceutical composition comprises pharmaceutically acceptable excipients and the crude drug as claimed in claim 26.
  28. 根据权利要求27所述的一种药物组合物，其特征在于，所述药学上可接受的辅料包括填充剂、粘合剂、崩解剂、润滑剂中的至少一种。The pharmaceutical composition according to claim 27, wherein the pharmaceutically acceptable adjuvant comprises at least one of a filler, a binder, a disintegrant, and a lubricant.
  29. 一种药物，其特征在于，所述药物包括如权利要求1-25中任一项所述的晶型或如权利要求26所述的原料药或如权利要求27-28任一项所述的药物组合物中的至少一种。A medicine, characterized in that the medicine comprises the crystal form as claimed in any one of claims 1-25 or the bulk drug as claimed in claim 26 or the drug as claimed in any one of claims 27-28 at least one of the pharmaceutical compositions.
  30. 权利要求1-25中任一项所述的晶型或如权利要求26所述的原料药或如权利要求27-28任一项所述的药物组合物在制备治疗流感药物中的应用。Application of the crystal form according to any one of claims 1-25 or the raw material drug according to claim 26 or the pharmaceutical composition according to any one of claims 27-28 in the preparation of a medicine for treating influenza.
PCT/CN2021/124835 2020-10-29 2021-10-20 Crystal form of pyrimidine derivative and preparation method therefor WO2022089261A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202180070815.5A CN116323593A (en) 2020-10-29 2021-10-20 Crystal form of pyrimidine derivative and preparation method thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202011176731 2020-10-29
CN202011176731.3 2020-10-29

Publications (1)

Publication Number Publication Date
WO2022089261A1 true WO2022089261A1 (en) 2022-05-05

Family

ID=81381896

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/124835 WO2022089261A1 (en) 2020-10-29 2021-10-20 Crystal form of pyrimidine derivative and preparation method therefor

Country Status (2)

Country Link
CN (1) CN116323593A (en)
WO (1) WO2022089261A1 (en)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103492381A (en) * 2010-12-16 2014-01-01 沃泰克斯药物股份有限公司 Inhibitors of influenza viruses replication
WO2017133667A1 (en) * 2016-02-05 2017-08-10 Savira Pharmaceuticals Gmbh Pyrimidine and pyridine derivatives and use in treatment, amelioration or prevention of influenza thereof
WO2018041263A1 (en) * 2016-09-05 2018-03-08 广东众生药业股份有限公司 Anti-influenza virus pyrimidine derivative
WO2019170067A1 (en) * 2018-03-05 2019-09-12 广东众生睿创生物科技有限公司 Crystal form and salt form of pyridoimidazole compound and preparation method therefor
WO2021012864A1 (en) * 2019-07-22 2021-01-28 广东众生睿创生物科技有限公司 Dominant salt forms of pyrimidine derivatives, and crystal forms thereof
WO2021047437A1 (en) * 2019-09-10 2021-03-18 广东众生睿创生物科技有限公司 Pharmaceutical composition for treating viral influenza and preparation thereof

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103492381A (en) * 2010-12-16 2014-01-01 沃泰克斯药物股份有限公司 Inhibitors of influenza viruses replication
WO2017133667A1 (en) * 2016-02-05 2017-08-10 Savira Pharmaceuticals Gmbh Pyrimidine and pyridine derivatives and use in treatment, amelioration or prevention of influenza thereof
WO2018041263A1 (en) * 2016-09-05 2018-03-08 广东众生药业股份有限公司 Anti-influenza virus pyrimidine derivative
WO2019170067A1 (en) * 2018-03-05 2019-09-12 广东众生睿创生物科技有限公司 Crystal form and salt form of pyridoimidazole compound and preparation method therefor
WO2021012864A1 (en) * 2019-07-22 2021-01-28 广东众生睿创生物科技有限公司 Dominant salt forms of pyrimidine derivatives, and crystal forms thereof
WO2021047437A1 (en) * 2019-09-10 2021-03-18 广东众生睿创生物科技有限公司 Pharmaceutical composition for treating viral influenza and preparation thereof

Also Published As

Publication number Publication date
CN116323593A (en) 2023-06-23

Similar Documents

Publication Publication Date Title
WO2011095059A1 (en) Polymorphs of dasatinib, preparation methods and pharmaceutical compositions thereof
TWI675839B (en) Form crystal of bisulfate of janus kinase (jak) inhibitor and preparation method thereof
WO2019170067A1 (en) Crystal form and salt form of pyridoimidazole compound and preparation method therefor
MX2012010541A (en) Agomelatine hydrochloride hydrate and preparation thereof.
WO2018049632A1 (en) Crystal form of ozanimod, and preparation method and pharmaceutical composition thereof
WO2022223027A1 (en) Tolebrutinib crystal form, amorphous form, preparation method therefor and use thereof
TWI672305B (en) Form crystal of bisulfate of janus kinase (jak) inhibitor and preparation method thereof
WO2021129589A1 (en) New crystal form of kd-025 and preparation method therefor
CN117412749A (en) Tolebutinib salt and crystal form thereof, preparation method, pharmaceutical composition and application thereof
WO2016101867A1 (en) Α-crystal form of naproxen imatinib p-toluene sulfonate, preparation method thereof, and pharmaceutical composition containing same
WO2022089261A1 (en) Crystal form of pyrimidine derivative and preparation method therefor
WO2018072742A1 (en) Crystalline form of free base of imidazo isoindole derivative and preparation method therefor
TWI752553B (en) Dominant salt form and crystal form of pyrimidine derivatives
WO2017211325A1 (en) New crystal form of tenofovir alafenamide salt, preparation method and use thereof
CN108822054B (en) Oxydterol hydrochloride crystal form C and preparation method thereof
WO2021190337A1 (en) Salt form and crystal form of compound as smo inhibitor, and preparation method therefor
WO2016101868A1 (en) Β-crystalline form of naputinib tosylate, preparation method therefor and pharmaceutical composition containing same
WO2016050134A1 (en) L-proline compound of sodium-glucose cotransporter 2 inhibitor, and monohydrate and crystal of l-proline compound
US10815232B2 (en) Crystalline forms of viral-protein inhibitor drug VX-787, processes for preparation thereof and use thereof
WO2023185638A1 (en) Crystal form of quinoline derivative and preparation method therefor
AU2018298154A1 (en) Salt and polymorph of benzopyrimidinone compound and pharmaceutical composition and use thereof
WO2019242717A1 (en) Maleate salt of benzothiophene compound, crystalline form thereof, and use thereof
CN109096218B (en) Oxydterol hydrochloride crystal form A and preparation method thereof
WO2022166774A1 (en) Crystal form of 3-hydroxy-5-pregnane-20-one derivative, and preparation method therefor and use thereof
CN112225732B (en) Crystal form of pirone hydrochloride hydrate and preparation method thereof

Legal Events

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

Ref document number: 21884989

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205A DATED 28/09/2023)