WO2018209667A1 - 多环杂环化合物的晶型、其制备方法、应用及组合物 - Google Patents

多环杂环化合物的晶型、其制备方法、应用及组合物 Download PDF

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WO2018209667A1
WO2018209667A1 PCT/CN2017/084995 CN2017084995W WO2018209667A1 WO 2018209667 A1 WO2018209667 A1 WO 2018209667A1 CN 2017084995 W CN2017084995 W CN 2017084995W WO 2018209667 A1 WO2018209667 A1 WO 2018209667A1
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compound
ethanol
crystal form
preparation
crystal
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PCT/CN2017/084995
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English (en)
French (fr)
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詹正云
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爱博新药研发(上海)有限公司
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Priority to PCT/CN2017/084995 priority Critical patent/WO2018209667A1/zh
Publication of WO2018209667A1 publication Critical patent/WO2018209667A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/765—Polymers containing oxygen
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to a crystalline form of a polycyclic heterocyclic compound, a process for its preparation, an application and a composition.
  • a polymorph of a chemical drug refers to a chemical drug that can exist in more than one crystal form. When it is crystallized, it is affected by various factors, and the bonding mode between molecules or molecules is changed, resulting in a molecule. Or atoms are arranged differently in the lattice space to form different crystal structures.
  • the molecular structure of the same chemical drug is the same, but crystals of different crystal forms may have significant differences in appearance, filterability, density, fluidity, solubility, dissolution rate, melting point (or initial melting temperature), etc. , which in turn affects drug stability, dissolution, bioavailability, and efficacy.
  • ZN2007 is a hepatitis C virus NS3/4A protease inhibitor. Studies have shown that the drug can competitively and strongly inhibit the activity of NS3/4A protease and block the replication of hepatitis C virus and RNA gene expression. This leads to a rapid decline in serum HCV-RNA levels and may allow for a shorter course of treatment. Rapid absorption after oral administration, half-life T 1/2 is about 2.76 hours.
  • R 2 may be nCH 3 CO 2 H, n ⁇ 5 or not.
  • R 2 When R 2 is not present, that is, when it is an unsolvate, its chemical name is (1S, 4R, 6S, 14S, 18R)-6,8-dihydro-[1,3]-dioxocyclopentene [4, 5-e]isoindole-7-carboxylic acid-14-tert-butoxyamido-4-cyclopropanesulfonylcarbonyl-2,15-dioxo-3,16-diaza-tricyclo[14.3 .0.0 4,6 ]19-carbon-7-en-18-yl ester having a molecular formula of C 36 H 47 N 5 O 11 S and a molecular weight of 757.86.
  • R 1 Li + , Na + , K + , Rb + , 1/2Be 2+ , 1/2Mg 2+ , 1/2Ca 2+ , 1/2Sr 2+ , 1/2Ba 2+ and their isotopes;
  • R 2 nH 2 O, n ⁇ 5 or not.
  • the technical problem to be solved by the present invention is to solve the problem that the existing protease inhibitor (ZN2007) has poor amorphous stability, poor absorption, and is not easy to be dispersed, combined, formulated and used, and the polycyclic heterocyclic compound is provided.
  • the different morphological forms, preparation methods, applications and compositions thereof have high purity, good stability and good absorption, and are crystalline powders, which are easy to disperse, combine, arrange and use for drugs;
  • the preparation method is simple and rapid, the preparation condition is mild, the yield is stable, the solvent used is environmentally friendly, the toxicity is extremely low, and the method is suitable for large-scale production.
  • the compound B (also referred to as the compound 12a) means a compound obtained by the following method.
  • Compound 11a (0.18 mmol) was dissolved in 10 mL of dry methylene chloride.
  • EtOAc EtOAc (EtOAc (EtOAc) HPLC-ELSD showed the reaction was complete.
  • the reaction solution was diluted with 20 mL of dichloromethane, washed with water and brine, and evaporated to dryness.
  • the obtained solid was dissolved in 10 mL of dry methylene chloride.
  • EtOAc (EtOAc, EtOAc.
  • the reaction solution was diluted with 20 mL of dichloromethane, washed successively with water, 1N hydrochloric acid and brine, and purified by column chromatography to afford the product 12a (ie Compound B, amorphous).
  • the structure of the compound 11a is as follows:
  • the room temperature refers to an ambient temperature of 10 ° C to 35 ° C.
  • the reagents and raw materials used in the present invention are commercially available.
  • the present invention provides a crystalline form I of Compound B represented by the following formula, which uses Cu-K ⁇ radiation, and an X-ray powder diffraction (XRPD) pattern expressed in terms of 2 ⁇ angle is 4.91 ⁇ 0.50°, 5.38 ⁇ 0.50°, Characteristic peaks at 5.87 ⁇ 0.50°, 7.90 ⁇ 0.50°, 10.32 ⁇ 0.50°, 11.69 ⁇ 0.50°, 15.04 ⁇ 0.50°, 17.94 ⁇ 0.50°, 18.66 ⁇ 0.50°, and 20.00 ⁇ 0.50°;
  • the X-ray powder diffraction (XRPD) pattern of the crystalline form I of the compound B in terms of 2 ⁇ angle is 4.91 ⁇ 0.20°, 5.38 ⁇ 0.20°, 5.87 ⁇ 0.20°, 7.90 ⁇ 0.20°, 10.32. Characteristic peaks at ⁇ 0.20°, 11.69 ⁇ 0.20°, 15.04 ⁇ 0.20°, 17.94 ⁇ 0.20°, 18.66 ⁇ 0.20°, and 20.00 ⁇ 0.20°. More preferably, the X-ray powder diffraction (XRPD) pattern of the compound B is substantially as shown in FIG.
  • the differential scanning calorimetry (DSC) pattern of Form I of Compound B has an endothermic peak at 163 ° C and another endothermic peak at about 180 ° C. More preferably, the differential scanning calorimetry (DSC) pattern of Form I of Compound B is substantially as shown in FIG.
  • thermogravimetric analysis (TGA) pattern of Form I of Compound B loses 3% by weight between 43 ° C and 173 ° C. More preferably, the thermogravimetric analysis (TGA) pattern of Form I of Compound B is substantially as shown in FIG.
  • the present invention also provides a process for the preparation of the crystalline form I of the compound B, which comprises the step of recrystallizing the compound B in ethyl acetate to obtain the crystalline form I of the compound B.
  • the volume-to-mass ratio of the ethyl acetate to the compound B may be from 3 mL/g to 20 mL/g, for example, 5 mL/g.
  • the recrystallization can be carried out in an air atmosphere.
  • the recrystallization may be a heat dissolution, a cooling precipitation.
  • the temperature of "heat dissolution” may be 50 to 70 ° C, for example, 60 ° C;
  • the temperature of the "cooling out” may be 10 to 30 ° C, for example, 20 ° C.
  • the recrystallization is carried out so that no solids are precipitated.
  • the compound B may be in any crystal form.
  • the present invention also provides a crystalline form II of Compound B represented by the following formula, which uses Cu-K ⁇ radiation, and has an X-ray powder diffraction (XRPD) pattern represented by a 2 ⁇ angle at 4.53 ⁇ 0.50°, 5.71 ⁇ 0.50°. Characteristic peaks at 8.48 ⁇ 0.50°, 9.05 ⁇ 0.50°, 10.45 ⁇ 0.50°, 13.50 ⁇ 0.50°, 16.43 ⁇ 0.50°, 16.9 ⁇ 0.50°, 19.86 ⁇ 0.50° and 20.63 ⁇ 0.50°;
  • the X-ray powder diffraction (XRPD) pattern of Form II of Compound B in terms of 2 ⁇ angle is 4.53 ⁇ 0.20°, 5.71 ⁇ 0.20°, 8.48 ⁇ 0.20°, 9.05 ⁇ 0.20°, 10.45. Characteristic peaks at ⁇ 0.20°, 13.50 ⁇ 0.20°, 16.43 ⁇ 0.20°, 16.9 ⁇ 0.20°, 19.86 ⁇ 0.20°, and 20.63 ⁇ 0.20°. More preferably, the X-ray powder diffraction (XRPD) pattern of Form II of Compound B is substantially as shown in FIG.
  • the differential scanning calorimetry (DSC) analysis pattern of Form II of Compound B has an endothermic peak at 175 °C. More preferably, the differential scanning calorimetry (DSC) pattern of Form II of Compound B is shown in FIG.
  • thermogravimetric analysis of Form II of Compound B loses 8.8% between 50 ° C and 195 ° C. More preferably, the thermogravimetric analysis (TGA) pattern of Form II of Compound B is substantially as shown in FIG.
  • the present invention also provides a process for preparing the crystalline form II of the compound B, which comprises the steps of: recrystallizing the compound B in ethanol to obtain the crystalline form II of the compound B.
  • the volume-to-mass ratio of the ethanol to the compound B may be from 5 mL/g to 20 mL/g, for example, 10 mL/g.
  • the recrystallization can be carried out in an air atmosphere.
  • the recrystallization may include an operation of dissolving the compound B by stirring or heating, followed by cooling, and precipitation of the crystal form II of the compound B.
  • the agitation temperature may be 10 to 35 ° C; the heating temperature may be 50 to 70 ° C, for example, 60 ° C; and the cooling temperature may be 10 to 30 ° C, for example, 20 ° C.
  • the recrystallization is carried out so that no solid precipitates.
  • the compound B may be in any crystal form.
  • the present invention also provides a crystalline form III of Compound B represented by the following formula, which uses Cu-K ⁇ radiation, and the X-ray powder diffraction (XRPD) pattern expressed in terms of 2 ⁇ angle is 5.80 ⁇ 0.50°, 9.12 ⁇ 0.50°. Characteristic peaks at 10.710° ⁇ 0.50°, 13.57 ⁇ 0.50°, 14.39 ⁇ 0.50°, 16.17 ⁇ 0.50°, 17.75 ⁇ 0.50°, 18.24 ⁇ 0.50°, 19.61 ⁇ 0.50°, and 20.92 ⁇ 0.50°;
  • the X-ray powder diffraction (XRPD) pattern of the crystalline form III of the compound B in terms of 2 ⁇ angle is 5.80 ⁇ 0.20°, 9.12 ⁇ 0.20°, 10.71 ⁇ 0.20°, 13.57 ⁇ 0.20°, There are characteristic peaks at 14.39 ⁇ 0.20°, 16.17 ⁇ 0.20°, 17.75 ⁇ 0.20°, 18.24 ⁇ 0.20°, 19.61 ⁇ 0.20°, and 20.92 ⁇ 0.20°. More preferably, the X-ray powder diffraction (XRPD) pattern of Form III of Compound B is substantially as shown in FIG.
  • the differential scanning calorimetry analysis of Form III of Compound B has an endothermic peak at 174 °C. More preferably, the differential scanning calorimetry (DSC) pattern of Form III of Compound B is substantially as shown in FIG.
  • thermogravimetric analysis (TGA) pattern of Form III of Compound B loses 5% between 41 ° C and 196 ° C. More preferably, the thermogravimetric analysis (TGA) pattern of Form III of Compound B is substantially as shown in FIG.
  • the present invention also provides a process for preparing the crystalline form III of the compound B, which comprises the steps of: recrystallizing the compound B in acetone to obtain the crystalline form III of the compound B.
  • the volume-to-mass ratio of the acetone to the compound B may be from 3 mL/g to 20 mL/g, for example, 10 mL/g.
  • the recrystallization can be carried out in an air atmosphere.
  • the recrystallization may be a precipitation of a volatile solvent.
  • the temperature at the time of "volatilization" may be 10 to 35 ° C, for example, 20 ° C.
  • the compound B is dissolved in acetone and the solution is filtered through a filter.
  • the compound B may be in any crystal form.
  • the present invention also provides a crystalline form IV of Compound B represented by the following formula, which uses Cu-K ⁇ radiation, and the X-ray powder diffraction (XRPD) pattern expressed in terms of 2 ⁇ angle is 5.36 ⁇ 0.50°, 7.85 ⁇ 0.50°. Characteristic peaks at 8.60 ⁇ 0.50°, 12.85 ⁇ 0.50°, 14.20 ⁇ 0.50°, 15.40 ⁇ 0.50°, 16.19 ⁇ 0.50°, 19.63 ⁇ 0.50°, 20.15 ⁇ 0.50°, and 21.09 ⁇ 0.50°;
  • the X-ray powder diffraction (XRPD) pattern of Form IV of Compound B in terms of 2 ⁇ angle is 5.36 ⁇ 0.20°, 7.85 ⁇ 0.20°, 8.60 ⁇ 0.20°, 12.85 ⁇ 0.20°, 14.20. Characteristic peaks at ⁇ 0.20°, 15.40 ⁇ 0.20°, 16.19 ⁇ 0.20°, 19.63 ⁇ 0.20°, 20.15 ⁇ 0.20°, and 21.09 ⁇ 0.20°. More preferably, the X-ray powder diffraction (XRPD) pattern of Form IV of Compound B is substantially as shown in FIG.
  • the differential scanning calorimetry (DSC) analysis of Form IV of Compound B has an endothermic peak at 174 °C. More preferably, the differential scanning calorimetry (DSC) pattern of Form IV of Compound B is shown in FIG.
  • thermogravimetric analysis (TGA) pattern of Form IV of Compound B loses 6% by weight between 23 ° C and 163 ° C. More preferably, the thermogravimetric analysis (TGA) pattern of Form IV of Compound B is substantially as shown in FIG.
  • the invention also provides a preparation method of the crystalline form IV of the compound B, which comprises the steps of: recrystallizing the compound B in acetone under an n-hexane atmosphere to obtain the crystalline form IV of the compound B. .
  • the volume-to-mass ratio of the acetone to the compound B may be from 3 mL/g to 20 mL/g, for example, 10 mL/g.
  • the recrystallization may be a volatile solvent precipitation.
  • the temperature at the time of "volatilization" may be 10 to 35 ° C, for example, 20 ° C.
  • the compound B is dissolved in acetone and the solution is filtered through a filter.
  • the compound B may be Any crystal form.
  • the unit cell parameter, space group and unit cell volume of the crystal form V of the compound B are measured by single crystal X-ray diffraction analysis, and the measurement wavelength is
  • the single crystal diffraction structure analysis chart (XRSD) of the crystal form V of the compound B is as shown in FIG.
  • the form V of the compound B may be a single crystal.
  • the invention also provides a preparation method of the crystalline form V of the compound B, which comprises the steps of: crystallizing the compound C in the crystal growth solution to obtain the crystal form V of the compound B;
  • the crystal solution is an aqueous solution containing ammonium acetate, acetic acid, acetonitrile and methanol;
  • the molar volume concentration of ammonium acetate may be 4 mmol/L
  • the volume concentration of the acetic acid may be 0.0004
  • the volume concentration of the acetonitrile may be 0.27
  • the volume concentration of the methanol may be 0.33.
  • the molar volume concentration is the volume ratio of the molar amount of the solute to the solution
  • the volume concentration is the volume ratio of the volume of the solute to the solution.
  • the crystal growth solution may be composed of the ammonium acetate, the acetic acid, the acetonitrile, the methanol, and the water.
  • the mass ratio of the compound C to the crystal solution may be 5 mg/mL to 15 mg/mL, for example, 8 mg/mL.
  • the crystal growth may be carried out in an air atmosphere.
  • the crystal may be dissolved and clarified, filtered, and left to volatilize.
  • the temperature of the crystal may be from 10 ° C to 35 ° C.
  • the crystal is grown to form a single crystal.
  • the post-treatment of the preparation method of the crystalline form V of the compound B may be: decanting the supernatant and drying.
  • the drying can be vacuum drying.
  • the drying temperature may be from 30 ° C to 90 ° C.
  • the drying time may be from 6 h to 48 h.
  • the present invention also provides a crystal growth solution which is an aqueous solution containing ammonium acetate, acetic acid, acetonitrile and methanol.
  • the ammonium acetate may have a molar volume concentration of 4 mmol/L
  • the acetic acid may have a volume concentration of 0.0004
  • the acetonitrile may have a volume concentration of 0.27
  • the methanol may have a volume concentration of 0.33.
  • the molar volume concentration is the volume ratio of the molar amount of the solute to the solution
  • the volume concentration is the volume ratio of the volume of the solute to the solution.
  • the crystal growth solution may be the ammonium acetate, the acetic acid, the acetonitrile, the Methanol and the water composition.
  • the X-ray powder diffraction pattern (XRPD) of the crystal form of the compound D expressed in terms of 2 ⁇ angle is 7.56 ⁇ 0.50°, 8.56 ⁇ 0.50°, 9.46 ⁇ 0.50°, 12.64 ⁇ Characteristic peaks at 0.50°, 13.39 ⁇ 0.50°, 14.28 ⁇ 0.50°, 15.95 ⁇ 0.50°, 17.59 ⁇ 0.50°, 18.84 ⁇ 0.50°, and 20.57 ⁇ 0.50°. More preferably, the X-ray powder diffraction (XRPD) pattern of the crystalline form of the compound D in terms of 2 ⁇ angle is 7.56 ⁇ 0.20°, 8.56 ⁇ 0.20°, 9.46 ⁇ 0.20°, 12.64 ⁇ 0.20°, 13.39 ⁇ 0.20.
  • the differential scanning calorimetry (DSC) analysis of the crystalline form of Compound D has an endothermic peak at 170 °C. More preferably, the differential scanning calorimetry (DSC) pattern of the crystalline form of the compound D is shown in FIG.
  • thermogravimetric analysis of the crystalline form of Compound D loses 3.7% between 52 ° C and 152 ° C. More preferably, the thermogravimetric analysis (TGA) pattern of the crystalline form of the compound D is substantially as shown in FIG.
  • the present invention also provides a method for preparing a crystalline form of the compound D, which comprises the steps of: recrystallizing the compound B in a mixed solvent of acetic acid/n-hexane to obtain a crystal form of the compound D;
  • the volume ratio of the acetic acid to the n-hexane may be 1:20.
  • the volume-to-mass ratio of the acetic acid/n-hexane mixed solvent to the compound B may be from 5 mL/g to 20 mL/g, for example, 10 mL/g.
  • the recrystallization can be carried out in an air atmosphere.
  • the recrystallization may be carried out by mixing the compound B with the acetic acid/n-hexane mixed solvent.
  • the recrystallization temperature may be from 10 ° C to 35 ° C.
  • the recrystallization is completed after the crystal form is completed; the recrystallization time may be from 12 h to 48 h, for example, 24 h.
  • the compound B may be in any crystal form.
  • the compound B and ethanol are preferably (0.8 to 1.2) g: (4 to 6) mL; more preferably 1 g: 5 mL.
  • the molar ratio of the sodium ethoxide to the compound B is preferably from 1.08:1 to 1.02:1, more preferably 1.05:1.
  • the amount of the ethanol may be a conventional amount in the art, which is based on at least complete dissolution of the sodium ethoxide.
  • the sodium ethoxide and ethanol are preferably used in an amount of (0.9 to 1) g: 50 mL, more preferably 0.942 g: 50 mL, in the ethanol solution of sodium ethoxide.
  • the methods and conditions of the reaction are conventional methods and conditions in the art.
  • the temperature of the reaction is preferably from 0 to 5 °C.
  • the reaction is generally carried out using an ice water bath method.
  • the end point of the reaction is completely based on the reaction, and the reaction is generally carried out until the reaction solution is clarified.
  • the present invention also provides another process for the preparation of the amorphous form of Compound C which comprises the steps of dissolving Compound C in water, drying, and obtaining.
  • the amount of the water used is a conventional amount in the art as long as the compound C can be dissolved.
  • the drying method can be a conventional method in the art as long as the moisture can be removed and the compound C is precipitated.
  • the drying temperature is preferably from 30 to 80 ° C, more preferably 55 ° C.
  • the present invention also provides an X-ray powder diffraction spectrum (XRPD) pattern of the amorphous form of Compound C as shown in Fig. 22, which has no characteristic peak in the 2 ⁇ spectrum.
  • XRPD X-ray powder diffraction spectrum
  • the present invention also provides other crystal forms of Compound C, which include Form A of Compound C, Form B of Compound C, Form C of Compound C, and Crystal of Compound C, and other crystal forms thereof.
  • Form D Form E of Compound C, Form G of Compound C, Form H of Compound C, Form I of Compound C, and Form J of Compound C.
  • the crystal form A of the compound C is irradiated with Cu-K ⁇ , and the X-ray powder diffraction (XRPD) pattern expressed by the angle of 2 ⁇ is 3.70 ⁇ 0.50°, 7.48 ⁇ 0.50°, 11.36 ⁇ 0.50°, 19.87. Characteristic peaks at ⁇ 0.50° and 25.60 ⁇ 0.50°.
  • the crystal form A of the compound C is irradiated with Cu-K ⁇ , preferably, the X-ray powder diffraction (XRPD) pattern expressed by the angle of 2 ⁇ is 3.70 ⁇ 0.20°, 7.48 ⁇ 0.20°, 11.36 ⁇ 0.20. Characteristic peaks at °, 19.87 ⁇ 0.20 ° and 25.60 ⁇ 0.20 °. Most preferably, the X-ray powder diffraction (XRPD) pattern of Form A of Compound C is substantially as shown in FIG.
  • the invention also provides a preparation method of the crystal form A of the compound C, which comprises the steps of: dissolving the compound C in dichloromethane to obtain a mixed liquid; adding diethyl ether to the mixed liquid to form a liquid phase layer After the ether was diffused to the mixed solution, a solid was precipitated, and the precipitated solid was collected to obtain.
  • the volume of the dichloromethane and the compound C is preferably 5 to 10 mL/g, more preferably 5 mL/g.
  • the amount of the ether should be above the amount of the dichloromethane.
  • the volume of the diethyl ether and the dichloromethane is preferably 2 or more.
  • the crystal form B of the compound C is Cu-K ⁇ radiation
  • the X-ray powder diffraction (XRPD) pattern expressed by the angle of 2 ⁇ is 4.4 ⁇ 0.50°, 5.32 ⁇ 0.50°, 6.38 ⁇ 0.50°, 8.69. Characteristic peaks at ⁇ 0.50°, 13.31 ⁇ 0.50°, 14.45 ⁇ 0.50°, 15.52 ⁇ 0.50°, 17.57 ⁇ 0.50°, and 21.11 ⁇ 0.50°.
  • the crystal form B of the compound C is irradiated with Cu-K ⁇
  • the X-ray powder diffraction (XRPD) pattern expressed by the angle of 2 ⁇ is 4.4 ⁇ 0.20°, 5.32 ⁇ 0.20°, 6.38 ⁇ 0.20. °, 8.69 ⁇ 0.20°, 13.31 ⁇ 0.20°, 14.45 ⁇ 0.20°, 15.52 ⁇ 0.20°, 17.57 ⁇ 0.20°
  • XRPD X-ray powder diffraction
  • the invention also provides a preparation method of the crystal form B of the compound C, which comprises the steps of: dissolving the amorphous form of the compound C in ethanol to obtain a mixed liquid; adding diethyl ether to the mixed liquid to form a liquid phase After the mixture is allowed to diffuse to the mixed solution, the solid is precipitated, and the precipitated solid is collected to obtain.
  • the volumetric mass of the ethanol and the compound C is preferably from 5 to 10 mL/g, more preferably 5 mL/g.
  • the amount of the ether should be above the amount of the ethanol.
  • the volume of the diethyl ether and the ethanol is preferably 2 or more.
  • the crystal form C of the compound C is a Cu-K ⁇ radiation
  • the X-ray powder diffraction (XRPD) pattern expressed by the angle of 2 ⁇ is 3.22 ⁇ 0.50°, 6.26 ⁇ 0.50°, 14.61 ⁇ 0.50°, 15.624. Characteristic peaks at ⁇ 0.50°, 18.82 ⁇ 0.50°, and 20.17 ⁇ 0.50°.
  • the crystal form C of the compound C is irradiated with Cu-K ⁇ , preferably, the X-ray powder diffraction (XRPD) pattern expressed by the angle of 2 ⁇ is 3.22 ⁇ 0.20°, 6.26 ⁇ 0.20°, 14.61 ⁇ 0.20. Characteristic peaks at °, 15.624 ⁇ 0.20 °, 18.82 ⁇ 0.20 °, and 20.17 ⁇ 0.20 °. Most preferably, the X-ray powder diffraction (XRPD) pattern of Form C of Compound C is substantially as shown in FIG.
  • the first method for preparing the crystalline form C of the compound C comprising the steps of: dissolving the compound C in a mixed solvent of tetrahydrofuran and n-hexane at 58-62 ° C to obtain a mixed solution; cooling, separating the solid, and collecting the precipitated Solid, that is.
  • the compound C is preferably dissolved in a mixed solvent of tetrahydrofuran and n-hexane at 60 °C.
  • the volume of the tetrahydrofuran and n-hexane is preferably from 1:1 to 1:1.2.
  • the volumetric mass of the mixed solvent of tetrahydrofuran and n-hexane and the compound of formula II is preferably from 5 to 10 mL/g, more preferably 6 mL/g.
  • the rate of temperature drop is preferably from 0.04 to 0.06 ° C/min.
  • the target temperature for the cooling is preferably 4 to 6 ° C, more preferably 5 ° C.
  • the second method for preparing the crystalline form C of the compound C comprises the steps of: dissolving the compound C in tetrahydrofuran to obtain a mixed solution; diffusing n-hexane into the mixed solution by gas diffusion, and collecting the precipitated solid, thereby obtaining .
  • the volumetric mass of the tetrahydrofuran and the compound C is preferably from 5 to 10 mL/g, more preferably 6 mL/g.
  • the amount of the n-hexane should be more than the amount of the tetrahydrofuran.
  • the volume of the n-hexane and the tetrahydrofuran is preferably from 5:1 to 10:1, more preferably 5:1.
  • the crystal form D of the compound C is Cu-K ⁇ radiation
  • the X-ray powder diffraction (XRPD) pattern expressed by 2 ⁇ angle is 2.02 ⁇ 0.50°, 4.769 ⁇ 0.50°, 5.677 ⁇ 0.50°
  • XRPD X-ray powder diffraction
  • the crystal form D of the compound C is irradiated with Cu-K ⁇
  • the X-ray powder diffraction (XRPD) pattern expressed by the angle of 2 ⁇ is 2.02 ⁇ 0.20°, 4.769 ⁇ 0.20°, 5.677 ⁇ 0.20. Characteristic peaks at °, 8.41 ⁇ 0.20 °, 11.04 ⁇ 0.20 °, 16.57 ⁇ 0.20 °, 18.25 ⁇ 0.20 °, 19.36 ⁇ 0.20 °, and 22.61 ⁇ 0.20 °.
  • the X-ray powder diffraction (XRPD) pattern of Form D of Compound C is substantially as shown in FIG.
  • the method for preparing the crystalline form D of the compound C comprising the steps of: dissolving the compound C in ethyl acetate to obtain a mixed solution; diffusing n-hexane into the mixed solution by gas diffusion, separating the solid, and collecting and depositing The solid, that is.
  • the volume of the ethyl acetate and the compound C is preferably 5 to 10 mL/g, more preferably 6 mL/g.
  • the amount of n-hexane used should be in the ethyl acetate The amount of use above.
  • the volume of the n-hexane and the ethyl acetate is preferably from 5:1 to 10:1, more preferably 5:1.
  • the crystal form E of the compound C is Cu-K ⁇ radiation
  • the X-ray powder diffraction (XRPD) pattern expressed by the angle of 2 ⁇ is 7.12 ⁇ 0.50°, 13.92 ⁇ 0.50°, 14.64 ⁇ 0.50°
  • XRPD X-ray powder diffraction
  • the crystal form E of the compound C is Cu-K ⁇ radiation
  • the X-ray powder diffraction (XRPD) pattern represented by the 2 ⁇ angle is 7.12 ⁇ 0.20°, 13.92 ⁇ 0.20°, 14.64 ⁇ 0.20. Characteristic peaks at °, 16.47 ⁇ 0.20 °, 18.86 ⁇ 0.20 °, 19.86 ⁇ 0.20 °, 20.78 ⁇ 0.20 °, 22.58 ⁇ 0.20 °, and 29.58 ⁇ 0.20 °.
  • the X-ray powder diffraction (XRPD) pattern of Form E of Compound C is substantially as shown in FIG.
  • the method for preparing the crystalline form E of the compound C comprising the steps of: dissolving the amorphous form of the compound C in ethanol to obtain a mixed solution; diffusing n-hexane into the mixed solution by gas diffusion, separating the solid, and collecting and depositing The solid, that is.
  • the volume of the ethanol and the compound C is preferably from 5 to 10 mL/g, more preferably 6 mL/g.
  • the amount of the n-hexane should be above the amount of the ethanol.
  • the volume of the n-hexane and the ethanol is preferably from 5:1 to 10:1, more preferably 5:1.
  • the X-ray powder diffraction (XRPD) pattern is at 7.59 ⁇ 0.50 °, 8.78 ⁇ 0.50 °, 13.33 ⁇ 0.50 °, 15.06 ⁇ 0.50 °, 16.31 ⁇ 0.50 °, 18.80 ⁇ 0.50 °, 20.28 ⁇ 0.50 °, 22.35 ⁇ 0.50 ° and There are characteristic peaks at 23.60 ⁇ 0.50 °.
  • the crystal form G of the compound C is irradiated with Cu-K ⁇ , preferably, the X-ray powder diffraction (XRPD) pattern expressed by the angle of 2 ⁇ is 7.59 ⁇ 0.20°, 8.78 ⁇ 0.20°, 13.33 ⁇ 0.20. Characteristic peaks at °, 15.06 ⁇ 0.20 °, 16.31 ⁇ 0.20 °, 18.80 ⁇ 0.20 °, 20.28 ⁇ 0.20 °, 22.35 ⁇ 0.20 °, and 23.60 ⁇ 0.20 °.
  • the crystalline form of the compound C The X-ray powder diffraction (XRPD) pattern of G is substantially as shown in FIG.
  • the preparation method 1 of the crystal form G of the compound C comprises the steps of dissolving the compound C in ethanol, stirring at 20 to 70 ° C for 1 to 8 hours, suction filtration, and drying.
  • the stirring is preferably carried out at 30 to 45 °C.
  • the agitation time is preferably 3 hours.
  • the compound B is mixed with ethanol to obtain a mixture; under stirring, an ethanol solution of sodium hydroxide is added to the mixture to react to clarification, and then to 20 ⁇ Stir at 70 ° C for 1-8 hours, filter by suction, and dry.
  • the mass volume of the compound B and the ethanol is preferably (0.8 to 1.2) g: (4 to 6) mL;
  • the molar ratio of the sodium hydroxide to the compound B is preferably from 1.20:1 to 1.00:1.
  • the amount of the sodium hydroxide and the ethanol is (0.5-1) g: 50 mL.
  • the temperature of the reaction is preferably from 0 to 25 °C.
  • the stirring is preferably carried out at 30 to 45 ° C after the reaction to the clarification.
  • the stirring time is preferably 3 hours after the reaction to the clarification operation.
  • the third method for producing the crystal form G of the compound C comprises the steps of dissolving the compound C in a mixed solvent of ethanol and n-hexane, evaporating the solvent at room temperature, depositing a solid, and collecting the precipitated solid.
  • the volume of the ethanol and the n-hexane is preferably 1:1.
  • the volumetric mass of the mixed solvent of ethanol and n-hexane and the compound C is preferably 5 to 10 mL/g, more preferably 6 mL/g.
  • the crystal form H of the compound C is a Cu-K ⁇ radiation
  • the X-ray powder diffraction (XRPD) pattern expressed by the angle of 2 ⁇ is 4.32 ⁇ 0.50°, 5.34 ⁇ 0.50°, 5.96 ⁇ 0.50°, 9.31 ⁇ 0.50°, 13.24 ⁇ 0.50°, 14.65 ⁇ 0.50°, 16.14 ⁇ 0.50°, 18.09 ⁇ 0.50° and There are characteristic peaks at 20.55 ⁇ 0.50°.
  • the crystal form H of the compound C is irradiated with Cu-K ⁇
  • the X-ray powder diffraction (XRPD) pattern expressed by the angle of 2 ⁇ is 4.32 ⁇ 0.20°, 5.34 ⁇ 0.20°, 5.96 ⁇ 0.20. Characteristic peaks at °, 9.31 ⁇ 0.20 °, 13.24 ⁇ 0.20 °, 14.65 ⁇ 0.20 °, 16.14 ⁇ 0.20 °, 18.09 ⁇ 0.20 °, and 20.55 ⁇ 0.20 °.
  • the X-ray powder diffraction (XRPD) pattern of Form H of Compound C is substantially as shown in FIG.
  • the method for preparing the crystalline form H of the compound C comprising the steps of: dissolving the compound C in ethanol to obtain a mixed solution; adding the mixed liquid drop to n-hexane under stirring to precipitate a solid, and collecting A solid is precipitated, that is, it is obtained.
  • the volumetric mass of the ethanol and the compound C is preferably from 5 to 8 mL/g, more preferably 6 mL/g.
  • the amount of the n-hexane should be above the amount of the ethanol.
  • the volume of the n-hexane and the ethanol is preferably from 30:1 to 40:1, more preferably 33:1.
  • the rate of the addition is preferably 0.1 mL/s.
  • the crystal form I of the compound C is a Cu-K ⁇ radiation
  • the X-ray powder diffraction (XRPD) pattern represented by the 2 ⁇ angle is 7.00 ⁇ 0.50°, 7.40 ⁇ 0.50°, 7.93 ⁇ 0.50°
  • XRPD X-ray powder diffraction
  • the crystalline form I of the compound C is irradiated with Cu-K ⁇ , preferably, the X-ray powder diffraction (XRPD) pattern expressed by the angle of 2 ⁇ is 7.00 ⁇ 0.20°, 7.40 ⁇ 0.20°, 7.93 ⁇ 0.20. Characteristic peaks at °, 14.09 ⁇ 0.20 °, 14.76 ⁇ 0.20 °, 18.89 ⁇ 0.20 °, 19.94 ⁇ 0.20 °, 20.78 ⁇ 0.20 °, and 22.35 ⁇ 0.20 °. Most preferably, the X-ray powder diffraction (XRPD) pattern of Form I of Compound C is substantially as shown in FIG.
  • a process for the preparation of Form I of Compound C which comprises the steps of: Compound C Dissolved in ethanol to obtain a mixed solution; the diethyl ether was diffused into the mixed solution by gas diffusion, a solid was precipitated, and the precipitated solid was collected to obtain.
  • the volume of the ethanol and the compound C is preferably 5 to 10 mL/g, more preferably 6 mL/g.
  • the amount of the diethyl ether should be above the amount of the ethanol.
  • the volume of the diethyl ether and the ethanol is preferably from 5:1 to 10:1, more preferably 5:1.
  • the crystal form J of the compound C is Cu-K ⁇ radiation
  • the X-ray powder diffraction (XRPD) pattern expressed by 2 ⁇ angle is 5.97 ⁇ 0.50°, 6.52 ⁇ 0.50°, 9.42 ⁇ 0.50°
  • Characteristic peaks at 11.03 ⁇ 0.50°, 11.63 ⁇ 0.50°, 15.59 ⁇ 0.50°, 16.61 ⁇ 0.50°, 19.91 ⁇ 0.50°, and 22.46 ⁇ 0.50°.
  • the crystal form J of the compound C is irradiated with Cu-K ⁇
  • the X-ray powder diffraction (XRPD) pattern expressed by the angle of 2 ⁇ is 5.97 ⁇ 0.20°, 6.52 ⁇ 0.20°, 9.42 ⁇ 0.20. Characteristic peaks at °, 11.03 ⁇ 0.20 °, 11.63 ⁇ 0.20 °, 15.59 ⁇ 0.20 °, 16.61 ⁇ 0.20 °, 19.91 ⁇ 0.20 °, and 22.46 ⁇ 0.20 °.
  • the X-ray powder diffraction (XRPD) pattern of Form J of Compound C is substantially as shown in FIG.
  • a process for preparing the crystalline form J of the compound C which comprises the steps of dissolving the compound C in a mixed system of ethyl acetate and water, and stirring at 0 to 30 ° C for 3 to 4 hours. , crystallization, suction filtration, that is.
  • the volume of the ethyl acetate and the compound C is preferably 5 to 10 mL/g, more preferably 6 mL/g.
  • the mixed system means "mixed solution which is not layered", and the amount of the water should be less than the maximum dissolved amount of water in ethyl acetate.
  • the volume of the water and the ethyl acetate is preferably from 1:10 to 1:40.
  • the crystal form J of the compound C optimally, the crystal form is a single crystal
  • the single crystal X-ray diffraction analysis the single crystal diffraction structure analysis (XRSD) pattern of the crystal form J of the compound C is shown in FIG.
  • the diffraction X-ray powder diffraction (XRPD) pattern of the crystal form J single crystal of Compound C is shown in Fig.
  • a method for preparing a single crystal of the crystal form J of the compound C which comprises the steps of dissolving the compound C in a mixed system of ethyl acetate and water at 10 to 30 ° C, After the solvent is slowly volatilized, the bulk crystals are precipitated, and the bulk crystals are collected to obtain a single crystal of the crystal form J of the compound C.
  • the volumetric mass of the ethyl acetate and the compound C is preferably from 5 to 100 mL/g.
  • the amount of the ethyl acetate may be a conventional amount in the art as long as the compound C can be completely dissolved.
  • the mixed system refers to a "non-layered mixed solution" which should be used in an amount less than the maximum dissolved amount of water in ethyl acetate.
  • the volume of the water and the ethyl acetate is preferably from 1:20 to 1:100.
  • the organic solvent which can be used for dissolving the compound C includes one or more of the following: methanol, ethanol, isopropanol, acetic acid, Acetonitrile, acetone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, N-methylpyrrolidone, dimethyl sulfoxide, dichloro Methane, toluene and N,N-dimethylacetamide.
  • ethanol is selected to dissolve Compound C.
  • the mixed system means that the amount of water used in the "non-layered mixed solution" should be less than the maximum dissolved amount of water in ethyl acetate.
  • the volume of the water and the ethyl acetate is preferably from 1:10 to 1:40.
  • the drying method and conditions can be conventional methods and conditions in the art, preferably The ground is vacuum dried.
  • the drying temperature is preferably from 50 to 60 °C.
  • solvent volatilization is a conventional meaning in the art, meaning that the solvent is free to volatilize.
  • the type of the compound C to be used is not limited.
  • the compound C as a raw material is preferably an amorphous substance of the compound C.
  • the compound B and ethanol are preferably (0.8 to 1.2) g: (4 to 6) mL; more preferably 1 g: 5 mL.
  • the molar ratio of the potassium t-butoxide to the compound B is preferably from 1.10:1 to 1.01:1, more preferably 1.05:1.
  • the amount of the ethanol may be a conventional amount in the art, which is based on at least complete dissolution of the potassium t-butoxide.
  • the potassium t-butoxide and ethanol are preferably used in an amount of (2.9 to 3.2) g: 50 mL, more preferably 3.1 g: 50 mL.
  • the methods and conditions of the reaction are conventional methods and conditions in the art.
  • the temperature of the reaction is preferably from 0 to 50 °C.
  • the reaction is generally carried out using an ice water bath method.
  • the end point of the reaction is completely based on the reaction, and the reaction is generally carried out until the reaction solution is clarified.
  • the compound B and ethanol are preferably (0.8 to 1.2) g: (12 to 18) mL; more preferably 1 g: 15 mL.
  • the molar ratio of the calcium hydroxide to the compound B is preferably from 0.55:1 to 0.5:1, more preferably from 0.52:1.
  • the amount of the glycerin may be a conventional amount in the art, which is based on at least complete dissolution of the calcium hydroxide.
  • the amount of the calcium hydroxide and glycerin is preferably (0.8 to 1.1) g: 10 mL, more preferably 0.9: 10 mL.
  • the methods and conditions of the reaction are conventional methods and conditions in the art.
  • the temperature of the reaction is preferably from 0 to 35 °C.
  • the reaction is generally carried out using an ice water bath method.
  • the end point of the reaction is completely based on the reaction, and the reaction is generally carried out until the reaction solution is clarified.
  • the ethanol is anhydrous ethanol.
  • the room temperature is a room temperature in the conventional sense of the art, and is generally 10 to 30 °C.
  • the shape and various crystal forms have high purity, good stability, good absorption, and are easily pulverized into a powder having a large surface area after drying, which is easy to configure and use the pharmaceutical composition.
  • the method for determining each product is as follows:
  • the X-ray diffraction pattern was acquired on a Sharp X-ray powder diffraction analyzer of the Dutch PANalytical Company at a wavelength of The 2 ⁇ value ranges from 0 to 40 degrees as measured by the K ⁇ line of the Cu target, and the reproducible range is 2 ⁇ ⁇ 0.50°.
  • DSC Differential Scanning Calorimetry
  • TGA Thermogravimetric analysis
  • Nuclear magnetic resonance spectroscopy was carried out on a Bruker Brucker 400 Hz nuclear magnetic resonance apparatus in Germany, and d 6 -DMSO was used as a solvent.
  • the positive progress is that the solvate and crystal form have high purity, good stability and good absorption. It is a crystalline powder, easy to disperse, combine, arrange and use.
  • the preparation method is simple and fast, the preparation conditions are mild, the yield is stable, the solvent is environmentally friendly, the toxicity is extremely low, and it is suitable for large-scale production.
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • FIG. 5 is a differential scanning calorimetry (DSC) analysis diagram of Form I of Compound B.
  • FIG. 6 is a thermogravimetric analysis (TGA) diagram of Form I of Compound B.
  • Figure 7 is an X-ray powder diffraction (XRPD) pattern of Form II of Compound B.
  • Figure 8 is a differential scanning calorimetry (DSC) analysis diagram of Form II of Compound B.
  • FIG. 9 is a thermogravimetric analysis (TGA) chart of Form II of Compound B.
  • Figure 10 is an X-ray powder diffraction (XRPD) pattern of Form III of Compound B.
  • Figure 11 is a differential scanning calorimetry (DSC) analysis diagram of Form III of Compound B.
  • Figure 12 is a thermogravimetric analysis (TGA) chart of Form III of Compound B.
  • Figure 13 is an X-ray powder diffraction (XRPD) pattern of Form IV of Compound B.
  • Figure 14 is a differential scanning calorimetry (DSC) analysis diagram of Form IV of Compound B.
  • FIG. 15 is a thermogravimetric analysis (TGA) chart of Form IV of Compound B.
  • Fig. 16 is a single crystal diffraction structure analysis (XRSD) diagram of the crystal form V of the compound B.
  • Figure 17 is an X-ray powder diffraction (XRPD) pattern of the crystalline form of Compound D.
  • Figure 18 is a differential scanning calorimetry (DSC) analysis diagram of the crystal form of Compound D.
  • Figure 19 is a thermogravimetric analysis (TGA) chart of the crystalline form of Compound D.
  • Figure 20 is a nuclear magnetic resonance spectrum (HNMR) spectrum of Compound C.
  • Figure 21 is a nuclear magnetic resonance spectrum (CNMR) spectrum of Compound C.
  • Figure 22 is an amorphous X-ray powder diffraction (XRPD) pattern of Compound C.
  • Figure 23 is a graph of amorphous differential scanning calorimetry (DSC) analysis of Compound C.
  • Figure 24 is an X-ray powder diffraction (XRPD) pattern of Form A of Compound C.
  • Figure 25 is a differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) chart of Form A of Compound C.
  • 26 is an X-ray powder diffraction (XRPD) pattern of Form B of Compound C.
  • DSC 29 is a differential scanning calorimetry (DSC) analysis chart of Form C of Compound C.
  • Figure 30 is an X-ray powder diffraction (XRPD) pattern of Form D of Compound C.
  • Figure 31 is a differential scanning calorimetry (DSC) analysis chart of Form D of Compound C.
  • Figure 32 is an X-ray powder diffraction (XRPD) pattern of Form E of Compound C.
  • Figure 33 is a differential scanning calorimetry (DSC) analysis chart of Form E of Compound C.
  • Figure 34 is an X-ray powder diffraction (XRPD) pattern of Form G of Compound C.
  • Figure 35 is a differential scanning calorimetry (DSC) analysis chart of Form G of Compound C.
  • TGA thermogravimetric analysis
  • Figure 37 is a thermogravimetric analysis (TGA) chart of Form C of Compound C after purging by N 2 gas at 25 ° C and relative humidity 0% RH.
  • TGA thermogravimetric analysis
  • Figure 38 is an X-ray powder diffraction (XRPD) pattern of Form H of Compound C.
  • Figure 39 is a differential scanning calorimetry (DSC) and thermogravimetric (TGA) resolution of Form H of Compound C.
  • XRPD 40 is an X-ray powder diffraction (XRPD) pattern of Form I of Compound C.
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • Figure 42 is an X-ray powder diffraction (XRPD) pattern of Form J of Compound C.
  • Figure 43 is a thermogravimetric analysis (TGA) chart of Form J of Compound C.
  • DSC differential scanning calorimetry
  • Figure 46 is a diffraction X-ray powder diffraction (XRPD) pattern of Form J single crystal of Compound C.
  • the X-ray diffraction pattern was acquired on a Sharp X-ray powder diffraction analyzer from the Dutch PANalytical Company at a wavelength of
  • the 2 ⁇ value ranges from 0 to 40 degrees as measured by the K ⁇ line of the Cu target, and the reproducible range is 2 ⁇ ⁇ 0.50°.
  • DSC Differential scanning calorimetry
  • Thermogravimetric analysis was collected on a TA instrument Q500 thermogravimetric analyzer in the United States with nitrogen protection.
  • Single crystal X-ray diffraction was collected on a Bruker APEX-II CCD in Bruker, Germany, and measured under the K ⁇ line of the Mo target, resolved using 'SHELXS-97 (Sheldrick, 2008)', and refined using 'SHELXL-2014 (Sheldrick, 2014).
  • the nuclear magnetic resonance spectrum was measured on a Bruker Brucker 400 Hz nuclear magnetic resonance apparatus in Germany, and d 6 -DMSO was used as a solvent.
  • the purity test of Compound B was carried out by high performance liquid chromatography (HPLC) on a Bruker Agilent 1260 (DAD detector) instrument.
  • HPLC high performance liquid chromatography
  • DAD detector D detector
  • the column was analyzed with octadecylsilane bonded silica as a filler.
  • Multi-organic solvent gradient elution Record the chromatogram to 2 times the retention time of the main component peak and calculate the purity according to the external standard method.
  • solubility is based on the provisions of the Pharmacopoeia 2015 edition of the four parts of the project x and the requirements of the fifteen (2) solubility: very soluble: means that the solute 1g (ml) can be small in the solvent Dissolved in 1mL; soluble: means that 1g (mL) of solute can be dissolved in solvent 1m to 10mL; Dissolved: means solute 1g (mL) can be dissolved in solvent 10mL to 30mL; slightly soluble: refers to solute 1g ( mL) can be dissolved in a solvent of 30mL to 100mL; slightly soluble: means that 1g (mL) of solute can be dissolved in 1000mL to 10000mL of solvent; insoluble: means that 1g (mL) of solute cannot be completely dissolved in 10000mL of solvent.
  • solubility in the following is consistent with this.
  • the compound used was prepared according to the method described in Example 40 of CN102140100B: Compound 11a (0.18 mmol) was dissolved in 10 mL of anhydrous methylene chloride, and EDCI (69.8 mg, 0.36 mmol, 2 eq.) was added. Stir at room temperature overnight. HPLC-ELSD showed the reaction was complete. The reaction solution was diluted with 20 mL of dichloromethane, washed with water and brine, and evaporated to dryness.
  • XRPD X-ray powder diffraction
  • Fig. 1 The X-ray powder diffraction (XRPD) of the solid of the compound B obtained by this method is shown in Fig. 1, and it is estimated that the solid described in CN102140100B is amorphous in the compound B, and the differential scanning calorimetry (DSC) chart is shown in Fig. 2. It is shown that there is an endothermic peak at 160 ° C, and a thermogravimetric analysis (TGA) chart is shown in FIG. 3 .
  • DSC differential scanning calorimetry
  • Solubility Test of Amorphous Samples of Compound B in Different Solvents Water, Ethanol, and A alcohol.
  • solvent temperature 25 ° C
  • the standard reference is stipulated in the 2015 edition of the Pharmacopoeia.
  • Test results insoluble in water; slightly soluble in ethanol; dissolved in methanol.
  • solvent temperature 50 ° C
  • the standard reference is stipulated in the 2015 edition of the Pharmacopoeia.
  • the amorphous sample solubility of Compound B also increases after the temperature rises.
  • the solid samples were mixed with water, SGF, FeSSIF and FaSSIF, respectively, and shaken in a 37 ° C oscillator. Samples were taken at 1 hour, 4 hours, and 24 hours, respectively, and centrifuged. Liquid samples were used for solubility detection and solid residual samples were tested by X-ray powder diffraction (XRPD).
  • BLQ- is below the detection limit, 0.002mg/mL.
  • the amorphous sample of Compound B was stored under normal temperature and light-proof conditions for 2 years, and was detected by X-ray powder diffraction (XRPD) without a characteristic peak and was an amorphous structure. After the HPLC determination, the main component did not change significantly.
  • XRPD X-ray powder diffraction
  • the amorphous sample of Compound B can be seen to be slightly hygroscopic from the wettability experimental data.
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • the crystalline form I of the compound B is slightly smaller than the amorphous wettability of the compound B.
  • the solid samples were mixed with water, SGF, FeSSIF and FaSSIF, respectively, and shaken in a 37 ° C oscillator. Samples were taken at 1 hour, 4 hours, and 24 hours, respectively, and centrifuged. The liquid sample is used for solubility detection, and the solid residual sample is subjected to X-ray powder diffraction pattern (XRPD) detection.
  • XRPD X-ray powder diffraction pattern
  • BLQ- is below the detection limit, 0.002mg/mL.
  • FaSSIF post-meal intestinal fluid
  • the crystalline form II of the compound B is slightly smaller than the amorphous wettability of the compound B.
  • the solid samples were mixed with water, SGF, FeSSIF and FaSSIF, respectively, and shaken in a 37 ° C oscillator. Samples were taken at 1 hour, 4 hours, and 24 hours, respectively, and centrifuged. Liquid samples were used for solubility detection and solid residual samples were tested by X-ray powder diffraction (XRPD).
  • BLQ- is below the detection limit, 0.002mg/mL.
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • the wettability of the crystalline form III of the compound B is slightly smaller than the amorphous wettability of the compound B.
  • the solid samples were mixed with water, SGF, FeSSIF and FaSSIF, respectively, and shaken in a 37 ° C oscillator. Samples were taken at 1 hour, 4 hours, and 24 hours, respectively, and centrifuged. Liquid samples were used for solubility detection and solid residual samples were tested by X-ray powder diffraction (XRPD).
  • BLQ- is below the detection limit, 0.002mg/mL.
  • FaSSIF post-meal intestinal fluid
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • Form IV of Compound B is slightly less than the amorphous wettability of the compound.
  • XRPD X-ray powder diffraction
  • BLQ- is below the detection limit, 0.002mg/mL.
  • Compound B was weighed and dissolved in 1 mL of the above-mentioned crystal growth solution, dissolved and clarified at 10-35 ° C, filtered, and allowed to stand at 10 - 35 ° C to volatilize under air to obtain. Then, the supernatant is decanted and dried under vacuum at 50 ° C to 60 ° C for 24 h to 48 h.
  • Compound D is slightly smaller than the amorphous wettability of Compound B.
  • the solid samples were mixed with water, SGF, FeSSIF and FaSSIF, respectively, and shaken in a 37 ° C oscillator. Samples were taken at 1 hour, 4 hours, and 24 hours, respectively, and centrifuged. Liquid samples were used for solubility detection and solid residual samples were tested by X-ray powder diffraction (XRPD).
  • BLQ- is below the detection limit, 0.002mg/mL.
  • the structure was identified and the obtained solid was characterized by nuclear magnetic resonance spectroscopy.
  • the instrument used was a Brucker-400 nuclear magnetic resonance spectrometer.
  • the nuclear magnetic resonance spectroscopy (HNMR) is shown in Fig. 20, and the nuclear magnetic resonance spectroscopy (CNMR) is shown in Fig. 21.
  • XRPD X-ray powder diffraction
  • Fig. 22 As the amorphous form of Compound C, its X-ray powder diffraction (XRPD) is shown in Fig. 22, and it can be seen that there is no characteristic peak in the 2 ⁇ spectrum, so that the product is determined to be amorphous.
  • DSC differential scanning calorimetry
  • Solubility test of amorphous samples of Compound C in different solvents water, ethanol and methanol.
  • solvent temperature 25 ° C
  • the standard reference to the 2015 edition of the Pharmacopoeia the results of the test: in the water Slightly soluble; soluble in ethanol; soluble in methanol.
  • the solvent temperature is 50 ° C, the standard reference 2015 edition of the Pharmacopoeia, the test results: soluble in water; very soluble in ethanol; very soluble in methanol.
  • the solubility of the amorphous sample of Compound C also increases after the temperature rises.
  • the solubility of the amorphous sample of Compound C is correspondingly increased as compared to the solubility of the amorphous sample of Compound B.
  • the stability of the amorphous substance of Compound C was examined.
  • the amorphous material of Compound C was stored for 2 years under the condition of being kept away from light at normal temperature, and was detected by X-ray powder diffraction (XRPD), and had no characteristic peak and was amorphous.
  • the main component did not change after high performance liquid chromatography (HPLC).
  • HPLC high performance liquid chromatography
  • a sample of Compound C was weighed 10.0 g, and 100 mL of dichloromethane was added to dissolve and clarify. 200 mL of diethyl ether was added to the upper layer of the solution to form a liquid phase layer, and diethyl ether was slowly diffused into the sample solution to precipitate a solid, and the precipitated solid was collected.
  • the X-ray powder diffraction (XRPD) pattern of the crystal form A of the compound C is shown in Fig. 24, and it can be seen from Fig. 24 that the X-ray powder diffraction (XRPD) spectrum of the crystal form A of the compound C is 3.70 °, 7.48 °. There are characteristic peaks at 11.36°, 19.87° and 25.60°.
  • a differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) pattern of Form A of Compound C is shown in Figure 25.
  • Solubility test of Form A of Compound C in different solvents water, ethanol and methanol.
  • solvent temperature 25 ° C
  • the standard reference to the 2015 edition of the Pharmacopoeia the results of the test: dissolved in water; soluble in ethanol; soluble in methanol.
  • the solvent temperature 50 ° C
  • the standard reference 2015 edition of the Pharmacopoeia the results of the test: soluble in water; soluble in ethanol; soluble in methanol.
  • the solubility of the Form A sample of Compound C also increased after the temperature was raised.
  • the solubility of the Form A sample of Compound C is correspondingly increased as compared with the solubility of the amorphous sample of Compound B, and the solubility of the Form A sample of Compound C is correspondingly reduced as compared with the solubility of the amorphous sample of Compound C.
  • the X-ray powder diffraction (XRPD) pattern of the crystal form B of the compound C is shown in Fig. 26.
  • the X-ray powder diffraction (XRPD) of the crystal form B of the compound C is 4.4 °, 5.32 in Fig. 2 .
  • a differential scanning calorimetry (DSC) chart of Form B of Compound C is shown in Figure 27.
  • Solubility test of Form B of Compound C in different solvents water, ethanol and methanol.
  • solvent temperature 25 ° C
  • the standard reference to the 2015 edition of the Pharmacopoeia the results of the test: dissolved in water; soluble in ethanol; soluble in methanol.
  • the solvent temperature 50 ° C
  • the standard reference 2015 edition of the Pharmacopoeia the results of the test: soluble in water; soluble in ethanol; soluble in methanol.
  • the solubility of the Form B sample of Compound C also increases after the temperature rises.
  • the solubility of the Form B sample of Compound C is correspondingly increased as compared with the solubility of the amorphous sample of Compound C, and the solubility of the Form B sample of Compound C is correspondingly reduced as compared with the solubility of the amorphous sample of Compound C.
  • the X-ray powder diffraction (XRPD) pattern of the crystal form C of the compound C is shown in Fig. 28.
  • the X-ray powder diffraction (XRPD) pattern of the crystal form C of the compound C is 3.22 °, 6.26 °. There are characteristic peaks at 14.61°, 15.624°, 18.82° and 20.17°.
  • a differential scanning calorimetry (DSC) chart of Form C of Compound C is shown in Figure 29.
  • Solubility test of Form C of Compound C in different solvents water, ethanol and methanol.
  • solvent temperature 25 ° C
  • the standard reference to the 2015 edition of the Pharmacopoeia the results of the test: dissolved in water; soluble in ethanol; soluble in methanol.
  • the solvent temperature 50 ° C
  • the standard reference 2015 edition of the Pharmacopoeia the results of the test: soluble in water; soluble in ethanol; soluble in methanol.
  • the solubility of the Form C sample of Compound C also increases after the temperature rises.
  • the solubility of the Form C sample of Compound C is correspondingly increased as compared with the solubility of the amorphous sample of Compound B, and the solubility of Form C of Compound C is correspondingly reduced as compared with the solubility of the amorphous sample of Compound C.
  • the X-ray powder diffraction (XRPD) pattern of the crystal form D of the compound C is shown in Fig. 30.
  • the X-ray powder diffraction (XRPD) pattern of the crystal form D of the compound C is 2.02°, 4.769°. Characteristic peaks at 5.677°, 8.41°, 11.04°, 16.57°, 18.25°, 19.36° and 22.61°.
  • a differential scanning calorimetry (DSC) chart of Form D of Compound C is shown in Figure 31.
  • Solubility test of Form D of Compound C in different solvents water, ethanol and methanol.
  • solvent temperature 25 ° C
  • the standard reference to the 2015 edition of the Pharmacopoeia the results of the test: dissolved in water; soluble in ethanol; soluble in methanol.
  • the solvent temperature 50 ° C
  • the standard reference 2015 edition of the Pharmacopoeia the results of the test: soluble in water; soluble in ethanol; soluble in methanol.
  • the solubility of the Form D sample of Compound C also increases after the temperature rises.
  • the solubility of the Form D sample of Compound C is correspondingly increased as compared with the solubility of the amorphous sample of Compound B, and the solubility of the Form D sample of Compound C is correspondingly reduced as compared with the solubility of the amorphous sample of Compound C.
  • the X-ray powder diffraction (XRPD) pattern of the crystal form E of the compound C is shown in Fig. 32.
  • the X-ray powder diffraction (XRPD) pattern of the crystal form E of the compound C is 7.12° and 13.92°. Characteristic peaks at 14.64°, 16.47°, 18.86°, 19.86°, 20.78°, 22.58°, and 29.58°.
  • a differential scanning calorimetry (DSC) chart of Form E of Compound C is shown in Figure 33.
  • Solubility test of Form E of Compound C in different solvents water, ethanol and methanol.
  • solvent temperature 25 ° C
  • the standard reference to the 2015 edition of the Pharmacopoeia the results of the test: dissolved in water; soluble in ethanol; soluble in methanol.
  • the solvent temperature 50 ° C
  • the standard reference 2015 edition of the Pharmacopoeia the results of the test: soluble in water; soluble in ethanol; soluble in methanol.
  • the solubility of the Form E sample of Compound C also increased after the temperature was raised.
  • the solubility of the Form E sample of Compound C is correspondingly increased as compared with the solubility of the amorphous sample of Compound B, and the solubility of the Form E sample of Compound C is correspondingly reduced as compared with the solubility of the amorphous sample of Compound C.
  • the X-ray powder diffraction (XRPD) pattern of the crystal form G of the compound C is shown in Fig. 34, and it can be seen from Fig. 14 that the crystal form G of the compound C has an X-ray powder diffraction (XRPD) pattern of 7.59 ° and 8.78 °. Characteristic peaks at 13.33°, 15.06°, 16.31°, 18.80°, 20.28°, 22.35°, and 23.60°.
  • a differential scanning calorimetry (DSC) chart of Form G of Compound C is shown in Figure 35.
  • thermogravimetric analysis (TGA) diagram of Form G of Compound C is shown in Figure 36
  • thermogravimetric analysis of Form C of Compound C after N 2 gas purge at 25 ° C and relative humidity 0% RH is shown in Figure 37.
  • 37 shows that the water content in the crystal form G of the compound C is 1.9%. From this value, it can be judged that the crystal form G of the compound C is a monohydrate.
  • the water of more than one theoretical amount of crystal water in Fig. 36 is adsorbed water.
  • Solubility test of Form G samples of Compound C in different solvents water, ethanol and methanol.
  • solvent temperature 25 ° C
  • the standard reference 2015 edition of the Pharmacopoeia the results of the test: dissolved in water; slightly soluble in ethanol; soluble in methanol.
  • the solvent temperature 50 ° C
  • the standard reference 2015 edition of the Pharmacopoeia the results of the test: soluble in water; dissolved in ethanol; soluble in methanol.
  • the solubility of the Form G sample of Compound C also increases after the temperature rises.
  • Crystal of compound C The solubility of the type G sample is increased correspondingly to the solubility of the amorphous sample of the compound B, and the solubility of the crystalline form G of the compound C is correspondingly reduced as compared with the solubility of the amorphous sample of the compound C.
  • the stability of the Form G sample of Compound C was examined.
  • the stability test conditions were: temperature 25 ° C, relative humidity 60%.
  • the test results are shown in the table below.
  • the crystal form G sample of the compound C of the present invention can be stably present for up to 24 months.
  • Form G sample of Compound C was slightly hygroscopic, the stability of the water content was not more than 5%, and remained stable at about 4%.
  • the crystal form G sample of Compound C was stable under other conditions of RH 95% for 30 days.
  • the high performance liquid chromatography (HPLC) method showed that the Form G sample of Compound C did not decompose and added impurities, and the related substances did not change; at a high temperature of 60 ° C It is stable for 30 days under conditions; stable for 5 days under strong light 4500Lx, degradation after 5 days; unstable under strong oxidation and acid conditions; stable under alkaline conditions.
  • the Form G sample of Compound C was cooled from 20 ° C to different temperatures (20 ° C, 40 ° C, 50 ° C and 60 ° C) in ethanol with different water content (anhydrous, 1% water and 5% water) and cooled to 20 °C (four times), no crystal transition was observed and was physically stable during this process.
  • the X-ray powder diffraction (XRPD) pattern of the crystal form H of the compound C is shown in Fig. 38.
  • the X-ray powder diffraction (XRPD) pattern of the crystal form H of the compound C is 4.32 °, 5.34 °. Characteristic peaks at 5.96°, 9.31°, 13.24°, 14.65°, 16.14°, 18.09° and 20.55°.
  • a differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) pattern of Form H of Compound C is shown in Figure 39.
  • Solubility test of Form H samples of Compound C in different solvents water, ethanol and methanol.
  • solvent temperature 25 ° C
  • the standard reference is stipulated in the 2015 edition of the Pharmacopoeia.
  • Test results slightly soluble in water; soluble in ethanol; soluble in methanol.
  • the solvent temperature is 50 ° C
  • the standard reference 2015 edition of the Pharmacopoeia the results of the test: soluble in water; soluble in ethanol; soluble in methanol.
  • the solubility of the Form H sample of Compound C also increases after the temperature rises.
  • the solubility of the Form H sample of Compound C is correspondingly increased as compared with the solubility of the amorphous sample of Compound B, and the solubility of Form H of Compound C is correspondingly reduced as compared with the solubility of the amorphous sample of Compound C.
  • the X-ray powder diffraction (XRPD) pattern of Form I of Compound C is shown in Figure 40.
  • the X-ray powder diffraction (XRPD) pattern of Form I of Compound C is 7.00 °, 7.40 °. Characteristic peaks at 7.93°, 14.09°, 14.76°, 18.89°, 19.94°, 20.78° and 22.35°.
  • a differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) pattern of Form I of Compound C is shown in Figure 41.
  • Solubility test of Form I samples of Compound C in different solvents water, ethanol and methanol.
  • solvent temperature 25 ° C
  • the standard reference 2015 edition of the Pharmacopoeia the results of the test: slightly soluble in water; soluble in ethanol; soluble in methanol.
  • the solvent temperature is 50 ° C
  • the standard reference 2015 edition of the Pharmacopoeia the results of the test: soluble in water; soluble in ethanol; soluble in methanol.
  • the solubility of the Form I sample of Compound C also increases after the temperature rises.
  • the solubility of the Form I sample of Compound C is correspondingly increased as compared with the solubility of the amorphous sample of Compound B, and the solubility of Form I of Compound C is correspondingly reduced as compared with the solubility of the amorphous sample of Compound C.
  • the X-ray powder diffraction (XRPD) pattern of the crystal form J of the compound C is shown in Fig. 42. As can be seen from Fig. 44, the X-ray powder diffraction (XRPD) pattern of the crystal form J of the compound C is 5.97 °, 6.52 °. Characteristic peaks at 9.42°, 11.03°, 11.63°, 15.59°, 16.61°, 19.91°, and 22.46°.
  • TGA thermogravimetric analysis
  • DSC differential scanning calorimetry
  • Solubility test of Form J samples of Compound C in different solvents water, ethanol and methanol.
  • solvent temperature 25 ° C
  • the standard reference 2015 edition of the Pharmacopoeia the results of the test: insoluble in water; soluble in ethanol; soluble in methanol.
  • the solvent temperature is 50 ° C
  • the standard reference 2015 edition of the Pharmacopoeia the results of the test: slightly soluble in water; soluble in ethanol; soluble in methanol.
  • the solubility of the Form J sample of Compound C also increases after the temperature rises.
  • the solubility of the Form J sample of Compound C is correspondingly increased as compared with the solubility of the amorphous sample of Compound B, and the solubility of the Form J of Compound C is correspondingly reduced as compared with the solubility of the amorphous sample of Compound C.
  • the stability of the Form J sample of Compound C was examined. The results showed that the crystal form J of compound C had a water absorption of 11.8% at 25 ° C and RH 80%; the crystal form J of compound C had a long-term open water content of 9%, and the dried water content was low. At 1%.
  • the amorphous sample of Compound E has a different moisture content under different humidity conditions, and the larger the moisture content of the environment, the larger the water content of the amorphous sample of Compound E.
  • the amorphous sample of Compound F has a different moisture content under different humidity conditions, and the amorphous sample of Compound F has a relatively large water content under different humidity environments.

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Abstract

本发明公开了一种多环杂环化合物的晶型、其制备方法、应用及组合物。本发明提供了一种如式所示的化合物的多晶型，该晶型的纯度高、稳定性好、吸收好，为结晶性粉末状，易于药物分散、组合、配置和使用；其制备方法简单、快捷，制备条件温和，收率稳定，使用溶剂环保，毒性极低，适合大规模生产。

Description

多环杂环化合物的晶型、其制备方法、应用及组合物 技术领域
本发明涉及一种多环杂环化合物的晶型、其制备方法、应用及组合物。
背景技术
化学药物的多晶型，是指能够以多于一种晶体形式存在的化学药物，在结晶时由于受到各种因素的影响，使其分子内或者分子之间的键合方式发生改变，致使分子或原子在晶格空间排列不同，形成不同的晶型结构。同一化学药物的分子结构相同，但晶型不同时，不同晶型的晶体在外观、可滤性、密度、流动性、溶解度、溶解速率、熔点(或初融温度)等方面可能会有显著不同，进而影响药物的稳定性、溶出度、生物利用度以及疗效。
该种现象在口服固型制剂方面表现得尤为明显，化学药物的多晶型现象是影响药物质量与临床疗效的重要因素之一。有些多晶型的化学药物由于形状或吸湿性而难于制成制剂。因此，确保药物活性成分的制造方法能够制得具有一致纯度水平的，且单一的晶型物，是药物研究过程中的重中之重。如果某一药物活性成分的制造方法，会制得含有不同程度的多晶型纯度的多晶型物，或者该制造方法不能控制多晶型之间的相互转换，那么会导致含有该活性成分的药物组合物中存在溶解和/或生物利用度方面的严重问题。
上世纪八十年代后期，由于仿制药的晶型不同而导致其溶解度和生物利用度都比原药差，以致于因无疗效造成事故之后，美国FDA对于药 物活性成份的形式、形状、粒度分布等方面的要求非常严格。
本品的化学结构通式如下式所示：
Figure PCTCN2017084995-appb-000001
ZN2007为丙型肝炎病毒NS3/4A蛋白酶抑制剂，研究表明该药进入动物肝细胞后，能竞争性、强有力地抑制NS3/4A蛋白酶的活性，阻断丙型肝炎病毒的复制和RNA基因表达，导致血清HCV-RNA水平快速下降，并有可能允许缩短疗程。口服后吸收迅速，半衰期T1/2约为2.76小时。
当R1＝H时，其化学结构通式如下式所示：
Figure PCTCN2017084995-appb-000002
其中R2可以为nCH3CO2H，n≤5或没有。
当R2没有时，即非溶剂化物时，其化学名为(1S，4R，6S，14S，18R)-6，8-二氢-[1，3]-二氧环戊烯并[4，5-e]异吲哚-7-羧酸-14-叔丁氧基酰胺基-4-环丙磺酰胺基羰基-2，15-二氧-3，16-二氮杂-三环[14.3.0.04，6]十九碳-7-烯-18-基酯，分子式为C36H47N5O11S，分子量为757.86。其可用于抑制丙型肝炎病毒蛋白酶，有效治疗丙型肝炎病毒感染。该化合物的专利申报情况如下：PCT申请，申请号WO2011/091757 A1；新加坡专利，P-No.182737(已授权)；美国专利，US 8653025 B2(已授权)；中国专利，CN 102140100 B(已授权)。该化合物的无定形、制备方法及药物活性可参见上述专利。
然而，当R1＝H时，经研究发现，该化合物(式I，R1＝H，R2不存在)的理化性质，例如稳定性和溶解度都较差，因此在实际应用方面有一定的局限性。
为了改善原料药的溶解性，制备出其盐的化合物形式，其化学结构通式如下式所示：
Figure PCTCN2017084995-appb-000003
其中R1＝Li+、Na+、K+、Rb+、1/2Be2+、1/2Mg2+、1/2Ca2+、1/2Sr2+、1/2Ba2+及其同位素；
R2＝nH2O，n≤5或没有。
其中当R1＝Na+，R2＝1H2O时，其化学名为：(1S，4R，6S，14S，18R)-6，8-二氢-[1，3]-二氧环戊烯并[4，5-e]异吲哚-7-羧酸-14-叔丁氧基酰胺基-4-环丙磺酰胺基羰基-2，15-二氧杂-三环[14.3.0.04，6]十九碳-7-烯-18-基酯钠盐一水合物。
发明内容
本发明所要解决的技术问题是为了解决现有蛋白酶抑制剂(ZN2007)的无定形稳定性差、吸收差，不易于药物分散、组合、配制和使用等缺点，而提供了该多环杂环化合物的不同晶型、其制备方法、应用及组合物，本发明公开的溶剂合物及晶型的纯度高、稳定性好、吸收好，为结晶性粉末状，易于药物分散、组合、配置和使用；其制备方法简单、快捷，制备条件温和，收率稳定，使用的溶剂环保，毒性极低，适合大规模生产。
本发明中，化合物B(也称为化合物12a)是指按照下述方法制得的化 合物：将化合物11a(0.18mmol)溶于10mL无水二氯甲烧中，加EDCI(69.8mg，0.36mmol，2eq.)，室温搅拌过夜。HPLC-ELSD显示反应完全。反应液用20mL二氯甲烷稀释后，依次用水、饱和食盐水洗涤后浓缩至干。将所得固体溶于10mL无水二氯甲烷中，加入DBU(61.0mg，0.40mmol)、环丙磺酰胺(0.36mmol)室温搅拌过夜。反应完全后，反应液用20mL二氯甲烷稀释，依次用水、1N盐酸、饱和食盐水洗涤，柱层析分离纯化，脱溶，得到所述的产物12a即可(即化合物B，无定形)。其中，化合物11a的结构如下所示：
Figure PCTCN2017084995-appb-000004
本发明中，所述的室温指环境温度，为10℃～35℃。
除上述化合物的制备方法以外，本发明所用试剂和原料均市售可得。
本发明提供了化合物B(式I，R1＝H，R2不存在)的其他晶型，所述化合物B的其他晶型包括化合物B的晶型I、化合物B的晶型II、化合物B的晶型III、化合物B的晶型IV、化合物B的晶型V。本发明还提供了化合物D(式I，R1＝H，R2＝CH3CO2H，即一乙酸溶剂合物)。
本发明提供了一种如下式所示的化合物B的晶型I，其使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射(XRPD)图在4.91±0.50°、5.38±0.50°、5.87±0.50°、7.90±0.50°、10.32±0.50°、11.69±0.50°、15.04±0.50°、17.94±0.50°、18.66±0.50°和20.00±0.50°处有特征峰；
Figure PCTCN2017084995-appb-000005
较佳地，所述的化合物B的晶型I的以2θ角度表示的X-射线粉末衍射(XRPD)图在4.91±0.20°、5.38±0.20°、5.87±0.20°、7.90±0.20°、10.32±0.20°、11.69±0.20°、15.04±0.20°、17.94±0.20°、18.66±0.20°和20.00±0.20°处有特征峰。更佳地，所述的化合物B的X射线粉末衍射(XRPD)图基本上如图4所示。
较佳地，所述的化合物B的晶型I的差示扫描量热法分析(DSC)图，在163℃处有吸热峰，另一吸热峰约在180℃。更佳地，所述的化合物B的晶型I的差示扫描量热法(DSC)图基本上如图5所示。
较佳地，所述的化合物B的晶型I的热重分析(TGA)图，在43℃至173℃之间失重3％。更佳地，所述的化合物B的晶型I的热重分析(TGA)图基本上如图6所示。
本发明还提供了一种所述的化合物B的晶型I的制备方法，其包括如下步骤：在乙酸乙酯中，将化合物B重结晶，得到化合物B的晶型I即可。
在制备所述的化合物B的晶型I的方法中，所述的乙酸乙酯与所述的化合物B的体积质量比可为3mL/g～20mL/g，例如5mL/g。
在制备所述的化合物B的晶型I的方法中，所述的重结晶可在空气氛围进行。
在制备所述的化合物B的晶型I的方法中，所述的重结晶可为加热溶解、冷却析出。所述的“加热溶解”的温度可为50～70℃，例如60℃； 所述的“冷却析出”的温度可为10～30℃，例如20℃。
在制备所述的化合物B的晶型I的方法中，所述的重结晶以不再有固体析出为止。
在制备所述的化合物B的晶型I的方法中，所述的化合物B可为任意的晶型。
本发明还提供了一种如下式所示的化合物B的晶型II，其使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射(XRPD)图在4.53±0.50°、5.71±0.50°、8.48±0.50°、9.05±0.50°、10.45±0.50°、13.50±0.50°、16.43±0.50°、16.9±0.50°、19.86±0.50°和20.63±0.50°处有特征峰；
Figure PCTCN2017084995-appb-000006
较佳地，所述的化合物B的晶型II的以2θ角度表示的X-射线粉末衍射(XRPD)图在4.53±0.20°、5.71±0.20°、8.48±0.20°、9.05±0.20°、10.45±0.20°、13.50±0.20°、16.43±0.20°、16.9±0.20°、19.86±0.20°和20.63±0.20°处有特征峰。更佳地，所述的化合物B的晶型II的X射线粉末衍射(XRPD)图基本上如图7所示。
较佳地，所述的化合物B的晶型II的差示扫描量热法(DSC)分析图在175℃处有吸热峰。更佳地，所述的化合物B的晶型II的差示扫描量热法(DSC)图基上如图8所示。
较佳地，所述的化合物B的晶型II的热重分析图在50℃至195℃之间失重8.8％。更佳地，所述的化合物B的晶型II的热重分析(TGA)图基本上如图9所示。
本发明还提供了一种所述的化合物B的晶型II的制备方法，其包括如下步骤：在乙醇中，将化合物B重结晶，得到化合物B的晶型II即可。
在制备所述的化合物B的晶型II的方法中，所述的乙醇与所述的化合物B的体积质量比可为5mL/g～20mL/g，例如10mL/g。
在制备所述的化合物B的晶型II的方法中，所述的重结晶可在空气氛围进行。
在制备所述的化合物B的晶型II的方法中，所述的重结晶可包括如下操作：搅拌或加热使化合物B溶解，而后冷却，并有所述的化合物B的晶型II析出。所述的搅拌的温度可为10～35℃；所述的加热的温度可为50～70℃，例如60℃；所述的冷却的温度可为10～30℃，例如20℃。
在制备所述的化合物B的晶型II的方法中，所述的重结晶以不再有固体析出为止。
在制备所述的化合物B的晶型II的方法中，所述的化合物B可为任意的晶型。
本发明还提供了一种如下式所示的化合物B的晶型III，其使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射(XRPD)图在5.80±0.50°、9.12±0.50°、10.710°±0.50°、13.57±0.50°、14.39±0.50°、16.17±0.50°、17.75±0.50°、18.24±0.50°、19.61±0.50°和20.92±0.50°处有特征峰；
Figure PCTCN2017084995-appb-000007
较佳地，所述的化合物B的晶型III的以2θ角度表示的X-射线粉末衍射(XRPD)图在5.80±0.20°、9.12±0.20°、10.71±0.20°、13.57±0.20°、 14.39±0.20°、16.17±0.20°、17.75±0.20°、18.24±0.20°、19.61±0.20°和20.92±0.20°处有特征峰。更佳地，所述的化合物B的晶型III的X射线粉末衍射(XRPD)图基本上如图10所示。
较佳地，所述的化合物B的晶型III的差示扫描量热法分析图在174℃处有吸热峰。更佳地，所述的化合物B的晶型III的差示扫描量热法(DSC)图基本上如图11所示。
较佳地，所述的化合物B的晶型III的热重分析(TGA)图在41℃至196℃之间失重5％。更佳地，所述的化合物B的晶型III的热重分析(TGA)图基本上如图12所示。
本发明还提供了一种所述化合物B的晶型III的制备方法，其包括如下步骤：在丙酮中，将化合物B重结晶，得到化合物B的晶型III即可。
在制备所述的化合物B的晶型III的方法中，所述的丙酮与所述的化合物B的体积质量比可为3mL/g～20mL/g，例如10mL/g。
在制备所述的化合物B的晶型III的方法中，所述的重结晶可在空气氛围进行。
在制备所述的化合物B的晶型III的方法中，所述的重结晶可为挥发溶剂析出。所述的“挥发”时的温度可为10～35℃，例如20℃。较佳地，挥发前，所述的化合物B溶于丙酮，并用滤膜过滤该溶液。
在制备所述的化合物B的晶型III的方法中，所述的化合物B可为任意的晶型。
本发明还提供了一种如下式所示的化合物B的晶型IV，其使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射(XRPD)图在5.36±0.50°、7.85±0.50°、8.60±0.50°、12.85±0.50°、14.20±0.50°、15.40±0.50°、16.19±0.50°、19.63±0.50°、20.15±0.50°和21.09±0.50°处有特征峰；
Figure PCTCN2017084995-appb-000008
较佳地，所述的化合物B的晶型IV的以2θ角度表示的X-射线粉末衍射(XRPD)图在5.36±0.20°、7.85±0.20°、8.60±0.20°、12.85±0.20°、14.20±0.20°、15.40±0.20°、16.19±0.20°、19.63±0.20°、20.15±0.20°和21.09±0.20°处有特征峰。更佳地，所述的化合物B的晶型IV的X射线粉末衍射(XRPD)图基本上如图13所示。
较佳地，所述的化合物B的晶型IV的差示扫描量热法(DSC)分析图在174℃处有吸热峰。更佳地，所述的化合物B的晶型IV的差示扫描量热法(DSC)图基上如图14所示。
较佳地，所述的化合物B的晶型IV的热重分析(TGA)图在23℃至163℃之间失重6％。更佳地，所述的化合物B的晶型IV的热重分析(TGA)图基本上如图15所示。
本发明还提供了一种所述的化合物B的晶型IV的制备方法，其包括如下步骤：在正己烷氛围中，在丙酮中，将化合物B重结晶，得到化合物B的晶型IV即可。
在制备所述的化合物B的晶型IV的方法中，所述的丙酮与所述的化合物B的体积质量比可为3mL/g～20mL/g，例如10mL/g。
在制备所述的化合物B的晶型IV的方法中，所述的重结晶可为挥发溶剂析出。所述的“挥发”时的温度可为10～35℃，例如20℃。较佳地，挥发前，所述的化合物B溶于丙酮，并用滤膜过滤该溶液。
在制备所述的化合物B的晶型IV的方法中，所述的化合物B可为 任意的晶型。
本发明还提供了一种所示的化合物B的晶型V，其晶胞参数为：
Figure PCTCN2017084995-appb-000009
α＝90°；
Figure PCTCN2017084995-appb-000010
β＝90°；
Figure PCTCN2017084995-appb-000011
γ＝90°；空间群为P21212；晶胞体积为
Figure PCTCN2017084995-appb-000012
Figure PCTCN2017084995-appb-000013
所述的化合物B的晶型V的晶胞参数、空间群和晶胞体积由单晶X衍射分析测得，测定波长为
Figure PCTCN2017084995-appb-000014
较佳地，所述的化合物B的晶型V的单晶衍射结构解析图(XRSD)如图16所示。
所述的化合物B的晶型V的存在形态可为单晶。
本发明还提供了一种所述的化合物B的晶型V的制备方法，其包括如下步骤：将化合物C在养晶溶液中养晶，得到化合物B的晶型V即可；所述的养晶溶液为含有醋酸铵、醋酸、乙腈和甲醇的水溶液；
Figure PCTCN2017084995-appb-000015
在制备所述的化合物B的晶型V的方法中，所述的养晶溶液中，所 述的醋酸铵的摩尔体积浓度可为4mmol/L、所述的乙酸的体积浓度可为0.0004、所述的乙腈的体积浓度可为0.27、所述的甲醇的体积浓度可为0.33。所述的摩尔体积浓度为溶质的摩尔量与溶液的体积比，所述的体积浓度为溶质的体积与溶液的体积比。
在制备所述的化合物B的晶型V的方法中，所述的养晶溶液可由所述的醋酸铵、所述的乙酸、所述的乙腈、所述的甲醇和所述的水组成。
在制备所述的化合物B的晶型V的方法中，所述的化合物C与所述的养晶溶液质量体积比可为5mg/mL～15mg/mL，例如8mg/mL。
在制备所述的化合物B的晶型V的方法中，所述的养晶可在空气氛围进行。
在制备所述的化合物B的晶型V的方法中，所述的养晶可为溶解澄清后，过滤，静置挥发。
在制备所述的化合物B的晶型V的方法中，所述的养晶的温度可为10℃～35℃。
在制备所述的化合物B的晶型V的方法中，所述的养晶以形成单晶为止。
所述的化合物B的晶型V的制备方法的后处理可为：倾出上清液，干燥。所述的干燥可为真空干燥。所述的干燥的温度可为30℃～90℃。所述的干燥的时间可为6h～48h。
本发明还提供了一种养晶溶液，其为含有醋酸铵、醋酸、乙腈和甲醇的水溶液。
所述的醋酸铵的摩尔体积浓度可为4mmol/L、所述的乙酸的体积浓度可为0.0004、所述的乙腈的体积浓度可为0.27、所述的甲醇的体积浓度可为0.33。所述的摩尔体积浓度为溶质的摩尔量与溶液的体积比，所述的体积浓度为溶质的体积与溶液的体积比。
所述的养晶溶液可由所述的醋酸铵、所述的乙酸、所述的乙腈、所 述的甲醇和所述的水组成。
本发明提供了一种如下式所示的化合物D(式I，R1＝H，R2＝CH3CO2H)即一乙酸溶剂合物；
Figure PCTCN2017084995-appb-000016
使用Cu-Kα辐射，较佳地，所述的化合物D的晶型以2θ角度表示的X-射线粉末衍射图(XRPD)在7.56±0.50°、8.56±0.50°、9.46±0.50°、12.64±0.50°、13.39±0.50°、14.28±0.50°、15.95±0.50°、17.59±0.50°、18.84±0.50°和20.57±0.50°处有特征峰。更佳地，所述的化合物D的晶型以2θ角度表示的X-射线粉末衍射(XRPD)图在7.56±0.20°、8.56±0.20°、9.46±0.20°、12.64±0.20°、13.39±0.20°、14.28±0.20°、15.95±0.20°、17.59±0.20°、18.84±0.20°和20.57±0.20°处有特征峰。最佳地，所述的化合物D的晶型的X射线粉末衍射(XRPD)图基本上如图17所示。
较佳地，所述的化合物D的晶型的差示扫描量热法(DSC)分析图在170℃处有吸热峰。更佳地，所述的化合物D的晶型的差示扫描量热法(DSC)图基上如图18所示。
较佳地，所述的化合物D的晶型的热重分析图在52℃至152℃之间失重3.7％。更佳地，所述的化合物D的晶型的热重分析(TGA)图基本上如图19所示。
本发明还提供了一种所述的化合物D的晶型的制备方法，其包括如下步骤：在乙酸/正己烷混合溶剂中，将化合物B重结晶，得到化合物D的晶型即可；
Figure PCTCN2017084995-appb-000017
在制备所述的化合物D的晶型的方法中，所述的乙酸/正己烷混合溶剂中，所述的乙酸与所述的正己烷的体积比可为1∶20。
在制备所述的化合物D的晶型的方法中，所述的乙酸/正己烷混合溶剂与所述的化合物B的体积质量比可为5mL/g～20mL/g，例如10mL/g。
在制备所述的化合物D的晶型的方法中，所述的重结晶可在空气氛围进行。
在制备所述的化合物D的晶型的方法中，所述的重结晶可为所述的化合物B与所述的乙酸/正己烷混合溶剂混合后，搅拌。
在制备所述的化合物D的晶型的方法中，所述的重结晶的温度可为10℃～35℃。
在制备所述的化合物D的晶型的方法中，所述的重结晶以晶型转化完毕为止；所述的重结晶的时间可为12h～48h，例如24h。
在所述的化合物D的晶型的制备方法中，所述的化合物B可为任意的晶型。
本发明还提供了一种化合物C(式I，R1＝Na+，R2＝nH2O，n≤5)的无定形的制备方法，其包括下述步骤：将化合物B与乙醇混合，得混合物；在搅拌状态下，将乙醇钠的乙醇溶液加入至所述混合物中，反应后浓缩至干，即得。
Figure PCTCN2017084995-appb-000018
其中，所述混合物中，化合物B和乙醇的配比较佳地为(0.8～1.2)g∶(4～6)mL；更佳地为1g∶5mL。
其中，所述乙醇钠与化合物B的摩尔比较佳地为1.08∶1～1.02∶1，更佳地为1.05∶1。所述乙醇钠的乙醇溶液中，所述乙醇的用量可为本领域常规用量，以至少完全溶解所述的乙醇钠为准。所述乙醇钠的乙醇溶液中，所述乙醇钠和乙醇的用量较佳地为(0.9～1)g∶50mL，更佳地为0.942g∶50mL。
其中，所述反应的方法和条件为本领域常规的方法和条件。所述反应的温度较佳地为0～5℃。所述反应一般采用冰水浴法进行。所述反应的终点以反应完全为准，一般反应至反应液澄清即可。
本发明还提供了化合物C的无定形物的另一种制备方法，其包括下述步骤：用水溶解化合物C，干燥，即得。
其中，所述的水的用量为本领域常规用量，只要能够溶解掉化合物C即可。
其中，所述干燥的方法可为本领域常规的方法，只要能去除水分并使化合物C析出即可。所述干燥的温度较佳地为30～80℃，更佳地为55℃。
本发明还提供了化合物C的无定形物的X射线粉末衍射光谱(XRPD)图基本如图22所示，其2θ谱中无特征峰。
本发明中，化合物C的晶型可以是化合物C(式I，R1＝Na+)的无水物晶型，或者是化合物C(式I，R1＝Na+，R2＝nH2O，n≠0时)的水合物晶型。
本发明还提供了化合物C的其他晶型及其制备方法，所述化合物C的其他晶型包括化合物C的晶型A、化合物C的晶型B、化合物C的晶型C、化合物C的晶型D、化合物C的晶型E、化合物C的晶型G、化合物C的晶型H、化合物C的晶型I、和化合物C的晶型J。
本发明中，所述化合物C的晶型A，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射(XRPD)图在3.70±0.50°、7.48±0.50°、11.36±0.50°、19.87±0.50°和25.60±0.50°处有特征峰。
其中，所述的化合物C的晶型A，使用Cu-Kα辐射，较佳地，以2θ角度表示的X-射线粉末衍射(XRPD)图在3.70±0.20°、7.48±0.20°、11.36±0.20°、19.87±0.20°和25.60±0.20°处有特征峰。最佳地，所述的化合物C的晶型A的X射线粉末衍射(XRPD)图基本上如图24所示。
本发明还提供了所述化合物C的晶型A的制备方法，其包括下述步骤：将化合物C溶解于二氯甲烷中，得混合液；在所述混合液上加入乙醚形成液相分层；至乙醚扩散至混合液后，析出固体，收集所析出固体，即得。
其中，所述二氯甲烷和化合物C体积质量比较佳地为5～10mL/g，更佳地为5mL/g。
其中，按本领域常识，所述的乙醚的用量应当在所述二氯甲烷的用量以上。所述乙醚和所述二氯甲烷的体积比较佳地在2以上。
本发明中，所述化合物C的晶型B，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射(XRPD)图在4.4±0.50°、5.32±0.50°、6.38±0.50°、8.69±0.50°、13.31±0.50°、14.45±0.50°、15.52±0.50°、17.57±0.50°和21.11±0.50°处有特征峰。
其中，所述的化合物C的晶型B，使用Cu-Kα辐射，较佳地，以2θ角度表示的X-射线粉末衍射(XRPD)图在4.4±0.20°、5.32±0.20°、6.38±0.20°、8.69±0.20°、13.31±0.20°、14.45±0.20°、15.52±0.20°、17.57±0.20° 和21.11±0.20°处有特征峰。最佳地，所述的化合物C的晶型B的X射线粉末衍射(XRPD)图基本上如图26所示。
本发明还提供了一种化合物C的晶型B的制备方法，其包括下述步骤：将化合物C的无定形溶解于乙醇中，得混合液；在所述混合液上加入乙醚形成液相分层；至乙醚扩散至混合液后，析出固体，收集所析出固体，即得。
其中，所述乙醇和化合物C的体积质量比较佳地为5～10mL/g，更佳地为5mL/g。
其中，按本领域常识，所述的乙醚的用量应当在所述乙醇的用量以上。所述乙醚和所述乙醇的体积比较佳地在2以上。
本发明中，所述化合物C的晶型C，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射(XRPD)图在3.22±0.50°、6.26±0.50°、14.61±0.50°、15.624±0.50°、18.82±0.50°和20.17±0.50°处有特征峰。
其中，所述的化合物C的晶型C，使用Cu-Kα辐射，较佳地，以2θ角度表示的X-射线粉末衍射(XRPD)图在3.22±0.20°、6.26±0.20°、14.61±0.20°、15.624±0.20°、18.82±0.20°和20.17±0.20°处有特征峰。最佳地，所述的化合物C的晶型C的X射线粉末衍射(XRPD)图基本上如图28所示。
所述化合物C的晶型C的制备方法一，其包括下述步骤：在58～62℃下将化合物C溶解于四氢呋喃与正己烷的混合溶剂，得混合液；降温，析出固体，收集所析出固体，即得。
其中，较佳地在60℃下将化合物C溶解于四氢呋喃与正己烷的混合溶剂。
其中，所述四氢呋喃与正己烷的混合溶剂中，所述四氢呋喃和正己烷的体积比较佳地为1∶1～1∶1.2。所述四氢呋喃与正己烷的混合溶剂和式II化合物的体积质量比较佳地为5～10mL/g，更佳地为6mL/g。
其中，所述降温的方法和条件可为本领域常规的方法和条件。所述降温的速率较佳地为0.04～0.06℃/min。所述降温的目标温度较佳地为4～6℃，更佳地为5℃。
所述化合物C的晶型C的制备方法二，其包括下述步骤：将化合物C溶解于四氢呋喃中，得混合液；通过气体扩散将正己烷扩散至混合液中，收集析出的固体，即得。
其中，所述四氢呋喃和化合物C的体积质量比较佳地为5～10mL/g，更佳地为6mL/g。
其中，按照本领域常识，所述正己烷的用量应当在所述四氢呋喃的用量以上。所述正己烷和所述四氢呋喃的体积比较佳地为5∶1～10∶1，更佳地为5∶1。
本发明中，所述的化合物C的晶型D，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射(XRPD)图在2.02±0.50°、4.769±0.50°、5.677±0.50°、8.41±0.50°、11.04±0.50°、16.57±0.50°、18.25±0.50°、19.36±0.50°和22.61±0.50°处有特征峰。
其中，所述的化合物C的晶型D，使用Cu-Kα辐射，较佳地，以2θ角度表示的X-射线粉末衍射(XRPD)图在2.02±0.20°、4.769±0.20°、5.677±0.20°、8.41±0.20°、11.04±0.20°、16.57±0.20°、18.25±0.20°、19.36±0.20°和22.61±0.20°处有特征峰。最佳地，所述的化合物C的晶型D的X射线粉末衍射(XRPD)图基本上如图30所示。
所述的化合物C的晶型D的制备方法，其包括下述步骤：将化合物C溶解于乙酸乙酯中，得混合液；通过气体扩散将正己烷扩散至混合液中，析出固体，收集析出的固体，即得。
其中，所述的乙酸乙酯和化合物C的体积质量比较佳地为5～10mL/g，更佳地为6mL/g。
其中，按照本领域常识，所述的正己烷的用量应当在所述乙酸乙酯 的用量以上。所述的正己烷和所述的乙酸乙酯的体积比较佳地为5∶1～10∶1，更佳地为5∶1。
本发明中，所述的化合物C的晶型E，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射(XRPD)图在7.12±0.50°、13.92±0.50°、14.64±0.50°、16.47±0.50°、18.86±0.50°、19.86±0.50°、20.78±0.50°、22.58±0.50°和29.58±0.50°处有特征峰。
其中，所述的化合物C的晶型E，使用Cu-Kα辐射，较佳地，以2θ角度表示的X-射线粉末衍射(XRPD)图在7.12±0.20°、13.92±0.20°、14.64±0.20°、16.47±0.20°、18.86±0.20°、19.86±0.20°、20.78±0.20°、22.58±0.20°和29.58±0.20°处有特征峰。最佳地，所述的化合物C的晶型E的X射线粉末衍射(XRPD)图基本上如图32所示。
所述化合物C的晶型E的制备方法，其包括下述步骤：将化合物C的无定形溶解于乙醇中，得混合液；通过气体扩散将正己烷扩散至混合液中，析出固体，收集析出的固体，即得。
其中，所述的乙醇和化合物C的体积质量比较佳地为5～10mL/g，更佳地为6mL/g。
其中，按照本领域常识，所述正己烷的用量应当在所述乙醇的用量以上。所述正己烷和所述乙醇的体积比较佳地为5∶1～10∶1，更佳地为5∶1。
本发明中，所述的化合物C(式I，R1＝Na+，n＝1，R2＝nH2O，n＝1)的晶型G，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射(XRPD)图在7.59±0.50°、8.78±0.50°、13.33±0.50°、15.06±0.50°、16.31±0.50°、18.80±0.50°、20.28±0.50°、22.35±0.50°和23.60±0.50°处有特征峰。
其中，所述的化合物C的晶型G，使用Cu-Kα辐射，较佳地，以2θ角度表示的X-射线粉末衍射(XRPD)图在7.59±0.20°、8.78±0.20°、13.33±0.20°、15.06±0.20°、16.31±0.20°、18.80±0.20°、20.28±0.20°、22.35±0.20°和23.60±0.20°处有特征峰。最佳地，所述的化合物C的晶型 G的X射线粉末衍射(XRPD)图基本上如图34所示。
所述化合物C的晶型G的制备方法一，其包括下述步骤：将化合物C溶解于乙醇中，于20～70℃下搅拌1～8小时，抽滤，干燥，即得。
其中，所述搅拌较佳地在30～45℃下进行。所述搅拌的时间较佳地为3小时。
所述化合物C的晶型G的制备方法二中，将化合物B与乙醇混合，得混合物；在搅拌状态下，将氢氧化钠的乙醇溶液加入至所述混合物中反应至澄清，再于20～70℃下搅拌1～8小时，抽滤，干燥，即得。
其中，所述混合物中，化合物B和乙醇的质量体积比较佳地为(0.8～1.2)g∶(4～6)mL；
其中，所述氢氧化钠与化合物B的摩尔比较佳地为1.20∶1～1.00∶1。
其中，所述氢氧化钠的乙醇溶液中，所述氢氧化钠和乙醇的用量为(0.5～1)g∶50mL。
其中，所述反应的温度较佳地为0～25℃。
其中，在反应至澄清后的操作后，所述搅拌较佳地在30～45℃下进行。在反应至澄清后的操作后，所述搅拌的时间较佳地为3小时。
所述化合物C的晶型G的制备方法三，其包括下述步骤：将化合物C溶解于乙醇和正己烷的混合溶剂中，于室温下挥发溶剂，析出固体，收集析出的固体，即得。
其中，所述乙醇和正己烷的混合溶剂中，所述乙醇和所述正己烷的体积比较佳地为1∶1。
其中，所述乙醇和正己烷的混合溶剂与化合物C的体积质量比较佳地为5～10mL/g，更佳地为6mL/g。
本发明中，所述的化合物C的晶型H，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射(XRPD)图在4.32±0.50°、5.34±0.50°、5.96±0.50°、9.31±0.50°、13.24±0.50°、14.65±0.50°、16.14±0.50°、18.09±0.50°和 20.55±0.50°处有特征峰。
其中，所述的化合物C的晶型H，使用Cu-Kα辐射，较佳地，以2θ角度表示的X-射线粉末衍射(XRPD)图在4.32±0.20°、5.34±0.20°、5.96±0.20°、9.31±0.20°、13.24±0.20°、14.65±0.20°、16.14±0.20°、18.09±0.20°和20.55±0.20°处有特征峰。最佳地，所述的化合物C的晶型H的X射线粉末衍射(XRPD)图基本上如图38所示。
所述化合物C的晶型H的制备方法，其包括下述步骤：将化合物C溶解于乙醇中，得混合液；在搅拌状态下将所述混合液滴加至正己烷中，析出固体，收集析出固体，即得。
其中，所述乙醇和化合物C的体积质量比较佳地为5～8mL/g，更佳地为6mL/g。
其中，按照本领域常识，所述正己烷的用量应当在所述乙醇的用量以上。所述正己烷和所述乙醇的体积比较佳地为30∶1～40∶1，更佳地为33∶1。
其中，所述滴加的方法和条件可为本领域常规的方法和条件。所述滴加的速度较佳地为0.1mL/s。
本发明中，所述的化合物C的晶型I，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射(XRPD)图在7.00±0.50°、7.40±0.50°、7.93±0.50°、14.09±0.50°、14.76±0.50°、18.89±0.50°、19.94±0.50°、20.78±0.50°和22.35±0.50°处有特征峰。
其中，所述的化合物C的晶型I，使用Cu-Kα辐射，较佳地，以2θ角度表示的X-射线粉末衍射(XRPD)图在7.00±0.20°、7.40±0.20°、7.93±0.20°、14.09±0.20°、14.76±0.20°、18.89±0.20°、19.94±0.20°、20.78±0.20°和22.35±0.20°处有特征峰。最佳地，所述的化合物C的晶型I的X射线粉末衍射(XRPD)图基本上如图40所示。
所述化合物C的晶型I的制备方法，其包括下述步骤：将化合物C 溶解于乙醇中，得混合液；通过气体扩散将乙醚扩散至混合液中，析出固体，收集析出的固体，即得。
其中，所述乙醇和化合物C的体积质量比较佳地为5～10mL/g，更佳地为6mL/g。
其中，按照本领域常识，所述乙醚的用量应当在所述乙醇的用量以上。所述乙醚和所述乙醇的体积比较佳地为5∶1～10∶1，更佳地为5∶1。
本发明中，所述的化合物C的晶型J，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射(XRPD)图在5.97±0.50°、6.52±0.50°、9.42±0.50°、11.03±0.50°、11.63±0.50°、15.59±0.50°、16.61±0.50°、19.91±0.50°和22.46±0.50°处有特征峰。
其中，所述的化合物C的晶型J，使用Cu-Kα辐射，较佳地，以2θ角度表示的X-射线粉末衍射(XRPD)图在5.97±0.20°、6.52±0.20°、9.42±0.20°、11.03±0.20°、11.63±0.20°、15.59±0.20°、16.61±0.20°、19.91±0.20°和22.46±0.20°处有特征峰。较佳地，所述的化合物C的晶型J的X射线粉末衍射(XRPD)图基本上如图42所示。
本发明中，还提供了所述化合物C的晶型J的制备方法，其包括下述步骤：将化合物C溶解于乙酸乙酯和水的混合体系中，于0～30℃下搅拌3～4h，析晶，抽滤，即得。
其中，所述乙酸乙酯和化合物C的体积质量比较佳地为5～10mL/g，更佳地为6mL/g。
其中，按本领域常识，所述混合体系是指“不分层的混合溶液”，所述水的用量应当小于水在乙酸乙酯中的最大溶解量。所述水和所述乙酸乙酯的体积比较佳地为1∶10～1∶40。
其中，所述化合物C的晶型J，最佳地，所述晶型为单晶，所述化合物C的晶型J的单晶晶胞参数为：
Figure PCTCN2017084995-appb-000019
α＝90°；
Figure PCTCN2017084995-appb-000020
β＝90°；
Figure PCTCN2017084995-appb-000021
γ＝90°；所述化合物C的晶型J单晶晶胞体积为
Figure PCTCN2017084995-appb-000022
所述化合物C的晶型的单晶晶胞参数和晶胞体积由测定波长为
Figure PCTCN2017084995-appb-000023
的单晶X衍射分析测得，化合物C的晶型J的单晶衍射结构解析(XRSD)图如图45所示。由化合物C的晶型J单晶衍射模拟X射线粉末衍射(XRPD)图如图46所示，其中在5.91±0.50°、6.01±0.50°、6.51±0.50°、8.94±0.50°、9.44±0.50°、11.66±0.50°、15.70±0.50°、21.04±0.50°和21.75±0.50°处有特征峰，与所述化合物C的晶型J的X射线粉末衍射(XRPD)图吻合。
本发明中，还提供了所述化合物C的晶型J的单晶制备方法，其包括下述步骤：将化合物C溶解于乙酸乙酯和水的混合体系中，于10～30℃下，待溶剂缓慢挥发后，析出块状晶体，收集块状晶体，即得化合物C的晶型J的单晶。
其中，所述乙酸乙酯和化合物C的体积质量比较佳地为5～100mL/g。
其中，所述乙酸乙酯的用量可为本领域常规用量，只要能够完全溶解化合物C即可。按本领域常识，所述混合体系是指“不分层的混合溶液”，所述水的用量应当小于水在乙酸乙酯中的最大溶解量。所述乙酸乙酯和水的混合体系中，所述水和所述乙酸乙酯的体积比较佳地为1∶20～1∶100。
本发明的发明人经大量研究发现，由于化合物C的特殊的物理性质，能用于溶解化合物C的有机溶剂包括下述物质中的一种或多种：甲醇、乙醇、异丙醇、乙酸、乙腈、丙酮、甲基异丁基酮、乙酸乙酯、乙酸异丙酯、四氢呋喃、2-甲基四氢呋喃、1，4-二氧六环、N-甲基吡咯烷酮、二甲亚砜、二氯甲烷、甲苯和N，N-二甲基乙酰胺。较佳地，选择乙醇溶解化合物C。
其中，按本领域常识，所述混合体系是指“不分层的混合溶液”所述水的用量应当小于水在乙酸乙酯中的最大溶解量。所述水和所述乙酸乙酯的体积比较佳地为1∶10～1∶40。
其中，所述干燥的方法和条件可为本领域常规的方法和条件，较佳 地为真空干燥。所述干燥的温度较佳地为50～60℃。
其中，所述溶剂挥发为本领域常规的含义，指的是溶剂自由挥发。
按照本领域常识，本发明中，在上述各化合物C的无定形物和化合物C的多晶型的制备方法中，所用的化合物C的晶型种类不限。在本发明的所述化合物C的晶型的制备方法中，作为原料的所述化合物C较佳地为化合物C的无定形物。
本发明还提供了一种化合物E(式I，R1＝K+，R2＝nH2O，n≤5)的无定形的制备方法，其包括下述步骤：将化合物B与乙醇混合，得混合物；在搅拌状态下，将叔丁醇钾的乙醇溶液加入至所述混合物中，反应后浓缩至干，即得。
Figure PCTCN2017084995-appb-000024
其中，所述混合物中，化合物B和乙醇的配比较佳地为(0.8～1.2)g∶(4～6)mL；更佳地为1g∶5mL。
其中，所述叔丁醇钾与化合物B的摩尔比较佳地为1.10∶1～1.01∶1，更佳地为1.05∶1。所述叔丁醇钾的乙醇溶液中，所述乙醇的用量可为本领域常规用量，以至少完全溶解所述的叔丁醇钾为准。所述叔丁醇钾的乙醇溶液中，所述叔丁醇钾和乙醇的用量较佳地为(2.9～3.2)g∶50mL，更佳地为3.1g∶50mL。
其中，所述反应的方法和条件为本领域常规的方法和条件。所述反应的温度较佳地为0～50℃。所述反应一般采用冰水浴法进行。所述反应的终点以反应完全为准，一般反应至反应液澄清即可。
本发明还提供了一种化合物F(式I，R1＝1/2Ca2+，R2＝nH2O，n≤5)的无定形的制备方法，其包括下述步骤：将化合物B与乙醇混合，得混合物；在搅拌状态下，将氢氧化钙的甘油溶液加入至所述混合物中，搅拌至溶解，加入石油醚，析出固体，过滤，干燥，即得。
Figure PCTCN2017084995-appb-000025
其中，所述混合物中，化合物B和乙醇的配比较佳地为(0.8～1.2)g∶(12～18)mL；更佳地为1g∶15mL。
其中，所述氢氧化钙与化合物B的摩尔比较佳地为0.55∶1～0.5∶1，更佳地为0.52∶1。所述氢氧化钙的甘油溶液中，所述甘油的用量可为本领域常规用量，以至少完全溶解所述的氢氧化钙为准。所述氢氧化钙的甘油溶液中，所述氢氧化钙和甘油的用量较佳地为(0.8～1.1)g∶10mL，更佳地为0.9∶10mL。
其中，所述反应的方法和条件为本领域常规的方法和条件。所述反应的温度较佳地为0～35℃。所述反应一般采用冰水浴法进行。所述反应的终点以反应完全为准，一般反应至反应液澄清即可。
本发明中，所述的乙醇均为无水乙醇。
本发明中，所述的室温为本领域常规意义上的室温温度，一般为10～30℃。
本发明的积极进步效果在于：
1、本发明的化合物B的无定形物和各种晶型；化合物(式I，R1＝Na+/K+/1/2Ca2+，R2＝nH2O，n≤5)的无定形物和各种晶型的纯度高，稳 定好，吸收好，干燥后易于粉碎成表面积大的粉末，易于药物组合物的配置和使用。
2、本发明的化合物B的无定形物和各种晶型；化合物(式I，R1＝Na+/K+/1/2Ca2+，R2＝nH2O，n≤5)的无定形物和各种晶型的制备方法简单、快捷，制备条件温和，收率稳定，使用溶剂环保，毒性极低，适合大规模生产
本发明还提供了如上所述的化合物B(式I，R1＝H，R2＝不存在)的无定形、化合物B的晶型I、化合物B的晶型II、化合物B的晶型III、化合物B的晶型IV、化合物B的晶型V、化合物D(式I，R1＝H，R2＝CH3CO2H，即一乙酸溶剂合物)、化合物C(式I，R1＝Na+，R2＝nH2O，n≤5)的无定形、化合物C的晶型A、化合物C的晶型B、化合物C的晶型C、化合物C的晶型D、化合物C的晶型E、化合物C的晶型G、化合物C的晶型H、化合物C的晶型I、化合物C的晶型J、化合物E(式I，R1＝K+，R2＝nH2O，n≤5)的无定形和化合物F(式I，R1＝1/2Ca2+，R2＝nH2O，n≤5)的无定形在制备治疗丙型肝炎病毒感染的药物中的应用。
本发明还提供了如上所述的化合物B(式I，R1＝H，R2＝不存在)的无定形、化合物B的晶型I、化合物B的晶型II、化合物B的晶型III、化合物B的晶型IV、化合物B的晶型V、化合物D(式I，R1＝H，R2＝CH3CO2H，即一乙酸溶剂合物)、化合物C(式I，R1＝Na+，R2＝nH2O，n≤5)的无定形、化合物C的晶型A、化合物C的晶型B、化合物C的晶型C、化合物C的晶型D、化合物C的晶型E、化合物C的晶型G、化合物C的晶型H、化合物C的晶型I、化合物C的晶型J、化合物E(式I，R1＝K+，R2＝nH2O，n≤5)的无定形和化合物(式I，R1＝1/2Ca2+，R2＝nH2O，n≤5)的无定形在制备NS3/4A蛋白酶抑制剂中的应用。
本发明还提供了一种药物组合物，其包含如上所述的本发明还提供了如上所述的化合物B(式I，R1＝H，R2＝不存在)的无定形、化合物B的 晶型I、化合物B的晶型II、化合物B的晶型III、化合物B的晶型IV、化合物B的晶型V、化合物D(式I，R1＝H，R2＝CH3CO2H，即一乙酸溶剂合物)、化合物C(式I，R1＝Na+，R2＝nH2O，n≤5)的无定形、括化合物C的晶型A、化合物C的晶型B、化合物C的晶型C、化合物C的晶型D、化合物C的晶型E、化合物C的晶型G、化合物C的晶型H、化合物C的晶型I、化合物C的晶型J、化合物E(式I，R1＝K+，R2＝nH2O，n≤5)的无定形、化合物F(式I，R1＝Ca2+，R2＝nH2O，n≤5)的无定形和可药用载体。所述的药用载体可为药剂领域常规的药用载体。
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明中，各产物的测定方法如下所述：
(1)、X射线衍射图是使用荷兰帕纳科公司的锐影X射线粉末衍射分析仪上采集，在波长为
Figure PCTCN2017084995-appb-000026
用Cu靶的Kα谱线下测定的，2θ值范围从0度至40度，可重现范围2θ±0.50°。
(2)、差示扫描量热法(DSC)在美国TA仪器Q200差示扫描量热仪上采集，氮气保护，升温速率：10℃/min。
(3)、热重分析(TGA)在美国TA仪器Q500热重分析仪上采集，氮气保护。
(4)、单晶X射线衍射在德国布鲁克Bruker APEX-II CCD上采集，Mo靶的Kα谱线下测定，采用′SHELXS-97(Sheldrick，2008)′解析，采用′SHELXL-2014(Sheldrick，2014)′精修。
(5)、核磁共振氢谱在德国布鲁克Brucker 400Hz核磁共振仪上测定，d6-DMSO作溶剂。
(6)、化合物B的纯度测试采用高效液相(HPLC)在美国布鲁克Agilent 1260(DAD检测器)仪上测定。
积极进步效果在于：溶剂合物及晶型的纯度高、稳定性好、吸收好， 为结晶性粉末状，易于药物分散、组合、配置和使用；制备方法简单、快捷，制备条件温和，收率稳定，使用溶剂环保，毒性极低，适合大规模生产。
附图说明
图1为化合物B的无定形的X射线粉末衍射(XRPD)图(为根据CN102140100B实施例40记载的制备方法制得的12a)。
图2为化合物B的无定形的差示扫描量热法(DSC)分析图(为根据CN102140100B实施例40记载的制备方法制得的12a)。
图3为化合物B的无定形的热重分析(TGA)图(为根据CN102140100B实施例40记载的制备方法制得的12a)。
图4为化合物B的晶型I的X射线粉末衍射(XRPD)图。
图5为化合物B的晶型I的差示扫描量热法(DSC)分析图。
图6为化合物B的晶型I的热重分析(TGA)图。
图7为化合物B的晶型II的X射线粉末衍射(XRPD)图。
图8为化合物B的晶型II的差示扫描量热法(DSC)分析图。
图9为化合物B的晶型II的热重分析(TGA)图。
图10为化合物B的晶型III的X射线粉末衍射(XRPD)图。
图11为化合物B的晶型III的差示扫描量热法(DSC)分析图。
图12为化合物B的晶型III的热重分析(TGA)图。
图13为化合物B的晶型IV的X射线粉末衍射(XRPD)图。
图14为化合物B的晶型IV的差示扫描量热法(DSC)分析图。
图15为化合物B的晶型IV的热重分析(TGA)图。
图16为化合物B的晶型V的单晶衍射结构解析(XRSD)图。
图17为化合物D的晶型的X射线粉末衍射(XRPD)图。
图18为化合物D的晶型的差示扫描量热法(DSC)分析图。
图19为化合物D的晶型的热重分析(TGA)图。
图20为化合物C的核磁共振氢谱(HNMR)谱图。
图21为化合物C的核磁共振氢谱(CNMR)谱图。
图22为化合物C的无定形的X射线粉末衍射(XRPD)图。
图23为化合物C的无定形的差示扫描量热法(DSC)分析图。
图24为化合物C的晶型A的X射线粉末衍射(XRPD)图。
图25为化合物C的晶型A的差示扫描量热法(DSC)和热重分析(TGA)图。
图26为化合物C的晶型B的X射线粉末衍射(XRPD)图。
图27为化合物C的晶型B的差示扫描量热法(DSC)和热重分析(TGA)图。
图28为化合物C的晶型C的X射线粉末衍射(XRPD)图。
图29为化合物C的晶型C的差示扫描量热法(DSC)分析图。
图30为化合物C的晶型D的X射线粉末衍射(XRPD)图。
图31为化合物C的晶型D的差示扫描量热法(DSC)分析图。
图32为化合物C的晶型E的X射线粉末衍射(XRPD)图。
图33为化合物C的晶型E的差示扫描量热法(DSC)分析图。
图34为化合物C的晶型G的X射线粉末衍射(XRPD)图。
图35为化合物C的晶型G的差示扫描量热法(DSC)分析图。
图36为化合物C的晶型G的热重分析(TGA)图。
图37为化合物C的晶型G在25℃和相对湿度0％RH条件下通过N2气吹扫后所测得的热重分析(TGA)图。
图38为化合物C的晶型H的X射线粉末衍射(XRPD)图。
图39为化合物C的晶型H的差示扫描量热法(DSC)和热重分(TGA)析图。
图40为化合物C的晶型I的X射线粉末衍射(XRPD)图。
图41为化合物C的晶型I的差示扫描量热法(DSC)和热重分析(TGA)图。
图42为化合物C的晶型J的X射线粉末衍射(XRPD)图。
图43为化合物C的晶型J的热重分析(TGA)图。
图44为化合物C的晶型J的差示扫描量热法(DSC)分析图。
图45为化合物C的晶型J的单晶衍射结构解析(XRSD)图。
图46为化合物C的晶型J单晶衍射模拟X射线粉末衍射(XRPD)图。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
本发明实施例中所使用的测定方法如下所述：
X射线衍射图是使用荷兰帕纳科公司的锐影X射线粉末衍射分析仪上采集，在波长为
Figure PCTCN2017084995-appb-000027
用Cu靶的Kα谱线下测定的，2θ值范围从0度至40度，可重现范围2θ±0.50°。
差示扫描量热法(DSC)在美国TA仪器Q200差示扫描量热仪上采集，氮气保护，升温速率：10℃/min。
热重分析(TGA)在美国TA仪器Q500热重分析仪上采集，氮气保护。
单晶X射线衍射在德国布鲁克BrukerAPEX-IICCD上采集，Mo靶的Kα谱线下测定，采用′SHELXS-97(Sheldrick，2008)′解析，采用′SHELXL-2014(Sheldrick，2014)′精修。
核磁共振氢谱在德国布鲁克Brucker 400Hz核磁共振仪上测定，d6-DMSO作溶剂。
化合物B的纯度测试采用高效液相(HPLC)在美国布鲁克Agilent 1260(DAD检测器)仪上测定，用十八烷基硅烷键合硅胶为充填剂的色谱柱进行分析，多元有机溶剂梯度洗脱，记录色谱图至主成分峰保留时间的2倍，按外标法计算纯度。
对于溶解度的界定按照参考《药典》2015年版四部凡例x项目与要求十五(2)溶解度的规定来进行：极易溶解：系指溶质1g(ml)能在溶剂小 于1mL中溶解；易溶：系指溶质1g(mL)能在溶剂1m至10mL中溶解；溶解：系指溶质1g(mL)能在溶剂10mL至30mL中溶解；略溶：系指溶质1g(mL)能在溶剂30mL至100mL中溶解；微溶：系指溶质1g(mL)能在溶剂1000mL至10000mL中溶解；不溶：系指溶质1g(mL)在溶剂10000mL中不能完全溶解。后文中对溶解度的界定均与此处一致。
本发明实施例中，所使用的化合物根据CN102140100B实施例40记载的方法制备：将化合物11a(0.18mmol)溶于10mL无水二氯甲烧中，加EDCI(69.8mg，0.36mmol，2eq.)，室温搅拌过夜。HPLC-ELSD显示反应完全。反应液用20mL二氯甲烷稀释后，依次用水、饱和食盐水洗涤后浓缩至干。将所得固体溶于10mL无水二氯甲烷中，加入DBU(61.0mg，0.40mmol)、RSO2NH2(0.36mmol，R＝环丙基)室温搅拌过夜。LC-MS显示反应完全。反应液用20mL二氯甲烷稀释后，依次用水、1N盐酸、饱和食盐水洗涤后浓缩制砂，柱层析分离纯化，得到产物12a即可(即式I，R1＝H，R2不存在的无定形)。其中，化合物11a的结构如下所示：
Figure PCTCN2017084995-appb-000028
该种方法所得化合物B固体的X射线粉末衍射(XRPD)如图1所示，据此推断CN102140100B记载的固体为化合物B为无定形，其差示扫描量热法(DSC)图如图2所示，在160℃处有吸热峰，热重分析(TGA)图如图3所示。
化合物B的无定形样品在不同溶剂中的溶解性试验：水、乙醇和甲 醇。溶剂温度为25℃时，标准参考2015版药典规定。测的结果：在水中不溶；在乙醇中微溶；在甲醇中溶解。溶剂温度为50℃时，标准参考2015版药典规定。测定结果：在水中微溶；在乙醇中溶解；在甲醇中极易溶解。化合物B的无定形样品溶解度在温度升高后也增大。
化合物B的无定形样品溶解性试验：以缓冲盐体系配置相应溶液，模拟人体胃液SGF(pH＝1.2)、空腹肠液FeSSIF(pH＝5.0)及餐后肠液FaSSIF(pH＝6.5)。将固体样品分别与水、SGF、FeSSIF及FaSSIF混匀，在37℃振荡器中震荡。分别在1小时、4小时、24小时取样，离心处理。液体样品用于溶解度检测，固体残留样品进行X射线粉末衍射(XRPD)检测。
化合物B的无定形样品溶解度试验结果：
Figure PCTCN2017084995-appb-000029
注：BLQ-低于检测限，0.002mg/mL。
固体残留样品进行X射线粉末衍射(XRPD)检测，没有特征峰，为无 定形结构。
化合物B的无定形样品在常温避光的条件下存储2年，经过X射线粉末衍射(XRPD)检测，没有特征峰，为无定形结构。经过在高效液相测定，主成分没有发生明显改变。
化合物B的无定形样品于40℃，湿度75％条件下放置一周，测定吸湿性。引湿性实验数据：
样品量(mg) 吸水量(mg) 增重百分率(％) 引湿性
622.9 8.2 1.3 略有引湿性
化合物B的无定形样品从引湿性实验数据可以看出略有引湿性。
实施例1化合物B的晶型I的制备
称量化合物B约10.0g溶于乙酸乙酯50mL，加热至60±10℃搅拌溶解后，冷却至20±10℃析出，过滤，干燥，得到白色固体。其X射线粉末衍射(XRPD)图如图4所示，其差示扫描量热法(DSC)图如图5所示，热重分析(TGA)图如图6所示。
化合物B的晶型I的X射线粉末衍射(XRPD)的特征衍射如表1所示：
表1 化合物B的晶型I的X射线粉末衍射(XRPD)的特征衍射
Figure PCTCN2017084995-appb-000030
Figure PCTCN2017084995-appb-000031
化合物B的晶型I样品于40℃，湿度75％条件下放置一周，测定吸湿性。引湿性实验数据：
样品量(mg) 吸水量(mg) 增重百分率(％) 引湿性
526.8 0.2 0.04 无或几乎无引湿性
化合物B的晶型I较化合物B的无定形的引湿性略微小。
化合物B的晶型I溶解性试验：以缓冲盐体系配置相应溶液，模拟人体胃液SGF(pH＝1.2)、空腹肠液FeSSIF(pH＝5.0)及餐后肠液FaSSIF(pH＝6.5)。将固体样品分别与水、SGF、FeSSIF及FaSSIF混匀，在37℃振荡器中震荡。分别在1小时、4小时、24小时取样，离心处理。液体样品用于溶解度检测，固体残留样品进行X射线粉末衍射图(XRPD)检测。
化合物B的晶型I溶解度试验结果：
Figure PCTCN2017084995-appb-000032
注：BLQ-低于检测限，0.002mg/mL。
化合物B的晶型I在餐后肠液FaSSIF(pH＝6.5)中较化合物B的无定形的溶解度略微减小，在水、模拟人体胃液SGF(pH＝1.2)和空腹肠液FeSSIF(pH＝5.0)的溶解度无明显差异。
实施例2化合物B的晶型II的制备
称量化合物B约10.0g的溶于乙醇100mL，10℃～35℃下搅拌使部分化合物B溶解并有新的晶体析出，而后加热溶液至60±10℃以充分溶解剩余的化合物B，但保留新析出的晶体作为晶种，之后冷却至20±10℃，过滤，干燥，得到白色固体。其X射线粉末衍射(XRPD)如图7所示，其差示扫描量热法(DSC)图如图8所示，热重分析(TGA)图如图9所示。
化合物B的晶型II的X射线粉末衍射(XRPD)的特征衍射如表2所示：
表2 化合物B的晶型II的X射线粉末衍射(XRPD)的特征衍射
Figure PCTCN2017084995-appb-000033
化合物B的晶型II样品于40℃，湿度75％条件下放置一周，测定 吸湿性。引湿性实验数据：
样品量(mg) 吸水量(mg) 增重百分率(％) 引湿性
166.2 -0.2 -0.12 无或几乎无引湿性
化合物B的晶型II较化合物B的无定形的引湿性略微小。
化合物B的晶型II溶解性试验：以缓冲盐体系配置相应溶液，模拟人体胃液SGF(pH＝.2)、空腹肠液FeSSIF(pH＝5.0)及餐后肠液FaSSIF(pH＝6.5)。将固体样品分别与水、SGF、FeSSIF及FaSSIF混匀，在37℃振荡器中震荡。分别在1小时、4小时、24小时取样，离心处理。液体样品用于溶解度检测，固体残留样品进行X射线粉末衍射(XRPD)检测。
化合物B的晶型II溶解度试验结果：
Figure PCTCN2017084995-appb-000034
注：BLQ-低于检测限，0.002mg/mL。
化合物B的晶型II在餐后肠液FaSSIF(pH＝6.5)中较化合物B的无定 形的溶解度略微减小，在水、模拟人体胃液SGF(pH＝1.2)和空腹肠液FeSSIF(pH＝5.0)的溶解度无明显差异。
实施例3化合物B的晶型III的制备
称量化合物B样品2g，溶于丙酮20mL，滤膜过滤，10℃～35℃条件下置于空气中将溶剂缓慢挥发，有新的晶体析出，过滤，干燥，得到类白色固体。其X射线粉末衍射(XRPD)如图10所示，其差示扫描量热法(DSC)图如图11所示，热重分析(TGA)图如图12所示。
化合物B的晶型III的X射线粉末衍射(XRPD)的特征衍射如表3所示：
表3 化合物B的晶型III的X射线粉末衍射(XRPD)的特征衍射
Figure PCTCN2017084995-appb-000035
化合物B的晶型III样品于40℃，湿度75％条件下放置一周，测定吸湿性。引湿性实验数据：
样品量(mg) 吸水量(mg) 增重百分率(％) 引湿性
466.8 -0.4 -0.08 无或几乎无引湿性
化合物B的晶型III的引湿性较化合物B的无定形的引湿性略微小。
化合物B的晶型III溶解性试验：以缓冲盐体系配置相应溶液，模拟人体胃液SGF(pH＝1.2)、空腹肠液FeSSIF(pH＝5.0)及餐后肠液FaSSIF(pH＝6.5)。将固体样品分别与水、SGF、FeSSIF及FaSSIF混匀，在37℃振荡器中震荡。分别在1小时、4小时、24小时取样，离心处理。液体样品用于溶解度检测，固体残留样品进行X射线粉末衍射(XRPD)检测。
化合物B的晶型III溶解度试验结果：
Figure PCTCN2017084995-appb-000036
注：BLQ-低于检测限，0.002mg/mL。
化合物B的晶型III在餐后肠液FaSSIF(pH＝6.5)中较化合物B的无定形的溶解度略微减小，在水、模拟人体胃液SGF(pH＝1.2)和空腹肠液FeSSIF(pH＝5.0)的溶解度无明显差异。
实施例4化合物B的晶型IV的制备
称量化合物B样品2g，溶于丙酮20mL，滤膜过滤，10℃～35℃条件下置于正己烷氛围中气相扩散，有新的晶体析出，过滤，干燥，得到类白色固体。其X射线粉末衍射(XRPD)如图13所示，其差示扫描量热法(DSC)图如图14所示，热重分析(TGA)图如图15所示。
化合物B的晶型IV的X射线粉末衍射(XRPD)的特征衍射如表4所示：
表4 化合物B的晶型IV的X射线粉末衍射(XRPD)的特征衍射
Figure PCTCN2017084995-appb-000037
化合物B的晶型IV样品于40℃，湿度75％条件下放置一周，测定吸湿性。引湿性实验数据：
样品量(mg) 吸水量(mg) 增重百分率(％) 引湿性
460.0 0.3 0.06 无或几乎无引湿性
化合物B的晶型IV较化合物的无定形的引湿性略微小。
化合物B的晶型IV溶解性试验：以缓冲盐体系配置相应溶液，模拟人体胃液SGF(pH＝1.2)、空腹肠液FeSSIF(pH＝5.0)及餐后肠液 FaSSIF(pH＝6.5)。将固体样品分别与水、SGF、FeSSIF及FaSSIF混匀，在37℃振荡器中震荡。分别在1小时、4小时、24小时取样，离心处理。液体样品用于溶解度检测，固体残留样品进行X射线粉末衍射(XRPD)检测。
化合物B的晶型IV溶解度试验结果：
Figure PCTCN2017084995-appb-000038
注：BLQ-低于检测限，0.002mg/mL。
化合物B的晶型IV的溶解度在餐后肠液FaSSIF(pH＝6.5)中较化合物B的无定形的溶解度略微减小，在水、模拟人体胃液SGF(pH＝1.2)和空腹肠液FeSSIF(pH＝5.0)的溶解度无明显差异。
实施例5化合物B的晶型V的制备
4mmol醋酸铵、0.4mL醋酸、270mL乙腈、330mL甲醇，溶解后加水定容至1L，制得养晶溶液。
称量化合物B约8mg溶于1mL的如上所述的养晶溶液中，10-35℃溶解澄清后，过滤，于空气下，于10-35℃静置挥发，即得。而后倾出上清液，50℃～60℃下真空干燥24h～48h。
其单晶衍射结构解析(XRSD)图如图16所示，其晶胞参数为：
Figure PCTCN2017084995-appb-000039
α＝90°；
Figure PCTCN2017084995-appb-000040
β＝90°；
Figure PCTCN2017084995-appb-000041
γ＝90°；空间群为P21212；晶胞体积为
Figure PCTCN2017084995-appb-000042
实施例6化合物D(式I，R1＝H，R2＝CH3CO2H时，即一乙酸溶剂合物)晶型的制备
称量化合物B样品约40g于样品瓶中，在10℃～35℃下，加入预先配制好的乙酸/正己烷(1∶20，v/v)的混合溶剂420mL，于空气下，悬浮搅拌24h收集固体，干燥，得到白色固体。其X射线粉末衍射(XRPD)如图17所示，其差示扫描量热法(DSC)图如图18所示，热重分析(TGA)图如图19所示。
所得固体经核磁共振氢谱表征，数据如下：1H-NMR(400Hz，d6-DMSO)11.97(s，1)，11.12(s，1)，8.99(s，1)，7.08-7.13(m，J＝7.9Hz，1)，6.68-6.81(m，J＝8.0Hz，1)，5.96-6.03(m，2)，5.58-5.65(q，J＝8.7Hz，1)，5.29(m，1)，5.04-5.09(t，J＝8.4Hz，1)，4.51-4.60(m，4)，4.41-4.514.29-4.35(m，1)，3.89-3.97(m，1)，3.68-3.72(m，1)，2.88-2.92(m，1)，2.60-2.63(m，1)，2.35-2.41(m，1)，2.25-2.30(m，2)，1.91(s，3)，1.69-1.70(m，2)，1.56-1.62(m，2)，1.33-1.39(m，5)，1.05-1.18(m，13)，0.97-1.01(m，2)。其中乙酸的特征峰为11.97(s，1)，1.91(s，3)，与化合物B的摩尔比例为1，由此推断制得了化合物D(式I，R1＝H，R2＝CH3CO2H时)，即一乙酸溶剂合物(式I，R1＝H，R2＝CH3CO2H时)。
化合物D的X射线粉末衍射(XRPD)的特征衍射如表5所示。
表5 化合物D的X射线粉末衍射(XRPD)的特征衍射
Figure PCTCN2017084995-appb-000043
化合物D的晶型样品于40℃，湿度75％条件下放置一周，测定吸湿性。引湿性实验数据：
样品量(mg) 吸水量(mg) 增重百分率(％) 引湿性
532.2 -0.5 -0.09 无或几乎无引湿性
化合物D较化合物B的无定形的引湿性略微小。
化合物D的晶型样品溶解性试验：以缓冲盐体系配置相应溶液，模拟人体胃液SGF(pH＝1.2)、空腹肠液FeSSIF(pH＝5.0)及餐后肠液FaSSIF(pH＝6.5)。将固体样品分别与水、SGF、FeSSIF及FaSSIF混匀，在37℃振荡器中震荡。分别在1小时、4小时、24小时取样，离心处理。液体样品用于溶解度检测，固体残留样品进行X射线粉末衍射(XRPD)检测。
化合物D的晶型样品溶解度试验结果：
Figure PCTCN2017084995-appb-000044
Figure PCTCN2017084995-appb-000045
注：BLQ-低于检测限，0.002mg/mL。
化合物D在餐后肠液FaSSIF(pH＝6.5)中较化合物B的无定形的溶解度减小，在水、模拟人体胃液SGF(pH＝1.2)和空腹肠液FeSSIF(pH＝5.0)的溶解度无明显差异或更小。
实施例7化合物C的无定形物的制备
称量化合物B 10.0g，加入至反应瓶中，加入无水乙醇50mL，开启搅拌，将乙醇钠0.942g(1.05eq)溶于50mL的无水乙醇中至澄清，反应瓶于10℃的冰水浴保温，将乙醇钠的乙醇溶液滴加至反应瓶中，待反应液澄清后，将其浓缩至干，得化合物C的无定形固体物。
结构鉴定，所得固体经核磁共振谱表征，所用仪器为Brucker-400核磁共振谱仪，核磁共振氢谱(HNMR)如图20所示，核磁共振氢谱(CNMR)如图21所示。核磁共振(NMR)测试数据如下：1HNMR(400MHz，DMSO-d6)δ7.81-7.83(d，1H)，6.85-6.88(m，2H，J＝7.9Hz)，6.71-6.80(m，1H，J＝7.9Hz)，5.98-6.03(m，2H)，5.43-5.48(t，1H，J＝10.0Hz)，5.26-5.32(m，2H)，4.54-4.55(m，4H)，4.38-4.44(m，1H)，4.12-4.15(m，2H)，3.85-3.90(m，1H)，2.56-2.60 (m，1H)，2.26-2.27(m，2H)，2.23(m，1H)1.98(m，1H)，1.83-1.85(m，1H)，1.66(m，2H)，1.51-1.54(m，2H)，1.32(m，5H)，1.18-1.21(m，9H)，1.07-1.09(m，1H)，0.75-0.78(m，2H)，0.60-0.64(m，2H)ppm；13C NMR(100MHz，DMSO-d6)δ174.05-174.12，172.07-172.16，170.70-170.81，155.63，153.76-153.88，147.08，141.88-141.95，131.71-132.30，129.59-129.79，129.40，117.56-118.18，115.62-115.72，108.32-108.41，101.75-101.79，78.24-78.85，74.38，59.49，53.25-53.36，52.19-52.24，51.67-52.0448.94-49.26，44.31，34.68-34.73，31.66，30.27，28.50，28.36-28.41，27.8026.75，25.55，22.34-22.39，20.94-21.12，4.60-4.78ppm。
由上述核磁共振数据可以看出，化合物C的结构与下式所示的结构相符。
Figure PCTCN2017084995-appb-000046
实施例7所制得的产物即为化合物C(式I，R1＝Na+，R2＝nH2O，n≤5)，也将其自拟代号为ZN2007Na。
化合物C的无定形物，其X射线粉末衍射(XRPD)如图22所示，可以看出，2θ谱中无特征峰，故确定该产物为无定形物。化合物C的无定形物的差示扫描量热法(DSC)分析图如图23所示。
化合物C的无定形样品在不同溶剂中的溶解性试验：水、乙醇和甲醇。溶剂温度为25℃时，标准参考2015版药典规定，测的结果：在水中 略溶；在乙醇中易溶；在甲醇中易溶。溶剂温度为50℃时，标准参考2015版药典规定，测的结果：在水中易溶；在乙醇中极易溶解；在甲醇中极易溶解。化合物C的无定形样品的溶解度在温度升高后也在增大。化合物C的无定形样品的溶解度较化合物B的无定形样品的溶解度相应增大。
化合物C的无定形物的稳定性进行考察。在常温避光的条件下存储2年的化合物C的无定形物，经过X射线粉末衍射(XRPD)检测，没有特征峰，为无定形。经过在高效液相(HPLC)测定，主成分没有发生改变。本发明的化合物C的无定形物能在长达24月的时间内保持稳定存在。
实施例8化合物C的晶型A的制备
称量化合物C样品10.0g，加入100mL二氯甲烷溶解澄清，在溶液上层加入200mL乙醚形成液相分层，让乙醚缓慢扩散至样品溶液中，析出固体，收集析出的固体。
化合物C的晶型A的X射线粉末衍射(XRPD)图如图24所示，从图24可以看出，化合物C的晶型A的X射线粉末衍射(XRPD)谱中在3.70°、7.48°、11.36°、19.87°和25.60°处有特征峰。化合物C的晶型A的差示扫描量热法(DSC)和热重分析(TGA)图见图25。
化合物C的晶型A样品在不同溶剂中的溶解性试验：水、乙醇和甲醇。溶剂温度为25℃时，标准参考2015版药典规定，测的结果：在水中溶解；在乙醇中易溶；在甲醇中易溶。溶剂温度为50℃时，标准参考2015版药典规定，测的结果：在水中易溶；在乙醇中易溶；在甲醇中易溶。化合物C的晶型A样品的溶解度在温度升高后也在增大。化合物C的晶型A样品的溶解度较化合物B的无定形样品的溶解度相应增大，化合物C的晶型A样品的溶解度较化合物C的无定形样品的溶解度相应减小。
实施例9化合物C的晶型B的制备
称量化合物C样品10.0g，用100mL乙醇溶解澄清，在溶液上层加入200mL乙醚形成液相分层，让乙醚缓慢扩散至样品溶液中，析出固体，收集析出的固体。
化合物C的晶型B的X射线粉末衍射(XRPD)图如图26所示，从图26可以看出，化合物C的晶型B的X射线粉末衍射(XRPD)图2中在4.4°、5.32°、6.38°、8.69°、13.31°、14.45°、15.52°、17.57°和21.11°处有特征峰。化合物C的晶型B的差示扫描量热法(DSC)图见图27。
化合物C的晶型B样品在不同溶剂中的溶解性试验：水、乙醇和甲醇。溶剂温度为25℃时，标准参考2015版药典规定，测的结果：在水中溶解；在乙醇中易溶；在甲醇中易溶。溶剂温度为50℃时，标准参考2015版药典规定，测的结果：在水中易溶；在乙醇中易溶；在甲醇中易溶。化合物C的晶型B样品的溶解度在温度升高后也在增大。化合物C的晶型B样品的溶解度较化合物C的无定形样品的溶解度相应增大，化合物C的晶型B样品的溶解度较化合物C的无定形样品的溶解度相应减小。
实施例10化合物C的晶型C的制备
称量化合物C样品10.0g，用100mL四氢呋喃溶解澄清，500mL正己烷液体通过气体扩散至样品溶液中，析出固体，收集析出的固体。
化合物C的晶型C的X射线粉末衍射(XRPD)图如图28所示，从图28可以看出，化合物C的晶型C的X射线粉末衍射(XRPD)图中在3.22°、6.26°、14.61°、15.624°、18.82°和20.17°处有特征峰。化合物C的晶型C的差示扫描量热法(DSC)图见图29。
化合物C的晶型C样品在不同溶剂中的溶解性试验：水、乙醇和甲醇。溶剂温度为25℃时，标准参考2015版药典规定，测的结果：在水中溶解；在乙醇中易溶；在甲醇中易溶。溶剂温度为50℃时，标准参考2015版药典规定，测的结果：在水中易溶；在乙醇中易溶；在甲醇中易溶。 化合物C的晶型C样品的溶解度在温度升高后也在增大。化合物C的晶型C样品的溶解度较化合物B的无定形样品的溶解度相应增大，化合物C的晶型C品的溶解度较化合物C的无定形样品的溶解度相应减小。
实施例11化合物C的晶型D的制备
称量化合物C样品10.0g，用100mL乙酸乙酯溶解澄清，500mL正己烷液体通过气体扩散至样品溶液中，析出固体，收集析出的固体。
化合物C的晶型D的X射线粉末衍射(XRPD)图如图30所示，从图30可以看出，化合物C的晶型D的X射线粉末衍射(XRPD)图中在2.02°、4.769°、5.677°、8.41°、11.04°、16.57°、18.25°、19.36°和22.61°处有特征峰。化合物C的晶型D的差示扫描量热法(DSC)图见图31。
化合物C的晶型D样品在不同溶剂中的溶解性试验：水、乙醇和甲醇。溶剂温度为25℃时，标准参考2015版药典规定，测的结果：在水中溶解；在乙醇中易溶；在甲醇中易溶。溶剂温度为50℃时，标准参考2015版药典规定，测的结果：在水中易溶；在乙醇中易溶；在甲醇中易溶。化合物C的晶型D样品的溶解度在温度升高后也在增大。化合物C的晶型D样品的溶解度较化合物B的无定形样品的溶解度相应增大，化合物C的晶型D样品的溶解度较化合物C的无定形样品的溶解度相应减小。
实施例12化合物C的晶型E的制备
称量化合物C样品10.0g，用100mL乙醇溶解澄清，500mL正己烷液体通过气体扩散至样品溶液中，析出固体，收集析出的固体。
化合物C的晶型E的X射线粉末衍射(XRPD)图如图32所示，从图32可以看出，化合物C的晶型E的X射线粉末衍射(XRPD)图中在7.12°、13.92°、14.64°、16.47°、18.86°、19.86°、20.78°、22.58°和29.58°处有特征峰。化合物C的晶型E的差示扫描量热法(DSC)图见图33。
化合物C的晶型E样品在不同溶剂中的溶解性试验：水、乙醇和甲醇。溶剂温度为25℃时，标准参考2015版药典规定，测的结果：在水中溶解；在乙醇中易溶；在甲醇中易溶。溶剂温度为50℃时，标准参考2015版药典规定，测的结果：在水中易溶；在乙醇中易溶；在甲醇中易溶。化合物C的晶型E样品的溶解度在温度升高后也在增大。化合物C的晶型E样品的溶解度较化合物B的无定形样品的溶解度相应增大，化合物C的晶型E样品的溶解度较化合物C的无定形样品的溶解度相应减小。
实施例13化合物C的晶型G的制备
称量化合物C样品10.0g，加入乙醇100mL，室温开启搅拌溶解，澄清后，升温至35℃，搅拌3h后有白色固体析出，抽滤，55℃真空干燥至恒重，得到产物。
化合物C的晶型G的X射线粉末衍射(XRPD)图如图34所示，从图14可以看出，化合物C的晶型G的X射线粉末衍射(XRPD)图中在7.59°、8.78°、13.33°、15.06°、16.31°、18.80°、20.28°、22.35°和23.60°处有特征峰。化合物C的晶型G的差示扫描量热法(DSC)图见图35。
化合物C的晶型G的热重分析(TGA)图见图36，化合物C的晶型G在25℃和相对湿度0％RH条件下通过N2气吹扫后所测得的热重分析(TGA)图见图37。图37显示，化合物C的晶型G中的水分为1.9％，通过这个数值，可以判定化合物C的晶型G为一水合物。图36中超过1个结晶水理论量的水为吸附水。
化合物C的晶型G样品在不同溶剂中的溶解性试验：水、乙醇和甲醇。溶剂温度为25℃时，标准参考2015版药典规定，测的结果：在水中溶解；在乙醇中微溶；在甲醇中易溶。溶剂温度为50℃时，标准参考2015版药典规定，测的结果：在水中易溶；在乙醇中溶解；在甲醇中易溶。化合物C的晶型G样品的溶解度在温度升高后也在增大。化合物C的晶 型G样品的溶解度较化合物B的无定形样品的溶解度相应增大，化合物C的晶型G品的溶解度较化合物C的无定形样品的溶解度相应减小。
化合物C的晶型G样品的稳定性进行考察。稳定性测试条件为：温度25℃，相对湿度60％。测试结果见下表。
考察时间 主成分含量(％) 水份(％)
0月 98.92 3.20
3月 99.11 4.11
6月 99.03 4.40
9月 99.15 4.00
12月 99.15 4.07
18月 99.12 4.26
24月 99.06 4.46
从表中数据可以看出，本发明的化合物C的晶型G样品能在长达24月的时间内保持稳定存在。
进一步的检测结果显示：化合物C的晶型G样品略有吸湿性，稳定性放置含水量不超过5％，在约4％保持稳定。化合物C的晶型G样品在RH95％的条件30天下其他性质稳定，高效液相色谱(HPLC)法显示化合物C的晶型G样品没有分解以及新增杂质，有关物质没有变化；在高温60℃条件下30天稳定；在强光4500Lx条件下5天稳定，5天后开始降解；在强氧化和酸条件下不稳定；在碱条件下较稳定。
化合物C的晶型G样品在不同含水量(无水，1％水和5％水)的乙醇中从20℃加热到不同温度(20℃，40℃，50℃和60℃)后冷却到20℃(四次)，没有观察到晶型转变，在此过程中物理稳定。
实施例14化合物C的晶型H的制备
称量化合物C样品10.0g，加入100mL乙醇使完全溶解；以0.1mL/s的速度加入搅拌状态下的3300mL正己烷中，析出固体，收集所得固体。
化合物C的晶型H的X射线粉末衍射(XRPD)图如图38所示，从图40可以看出，化合物C的晶型H的X射线粉末衍射(XRPD)图中在4.32°、5.34°、5.96°、9.31°、13.24°、14.65°、16.14°、18.09°和20.55°处有特征峰。化合物C的晶型H的差示扫描量热法(DSC)和热重分析(TGA)图见图39。
化合物C的晶型H样品在不同溶剂中的溶解性试验：水、乙醇和甲醇。溶剂温度为25℃时，标准参考2015版药典规定。测的结果：在水中略溶；在乙醇中易溶；在甲醇中易溶。溶剂温度为50℃时，标准参考2015版药典规定，测的结果：在水中易溶；在乙醇中易溶；在甲醇中易溶。化合物C的晶型H样品的溶解度在温度升高后也在增大。化合物C的晶型H样品的溶解度较化合物B的无定形样品的溶解度相应增大，化合物C的晶型H品的溶解度较化合物C的无定形样品的溶解度相应减小。
实施例15化合物C的晶型I的制备
称量化合物C样品10.0g，用100mL乙醇溶解澄清，用独立盛放的500mL乙醚液体，通过气体扩散至样品溶液中，析出固体，收集析出的固体。
化合物C的晶型I的X射线粉末衍射(XRPD)图如图40所示，从图42可以看出，化合物C的晶型I的X射线粉末衍射(XRPD)图中在7.00°、7.40°、7.93°、14.09°、14.76°、18.89°、19.94°、20.78°和22.35°处有特征峰。化合物C的晶型I的差示扫描量热法(DSC)和热重分析(TGA)图见图41。
化合物C的晶型I样品在不同溶剂中的溶解性试验：水、乙醇和甲醇。溶剂温度为25℃时，标准参考2015版药典规定，测的结果：在水中略溶；在乙醇中易溶；在甲醇中易溶。溶剂温度为50℃时，标准参考2015版药典规定，测的结果：在水中易溶；在乙醇中易溶；在甲醇中易溶。 化合物C的晶型I样品的溶解度在温度升高后也在增大。化合物C的晶型I样品的溶解度较化合物B的无定形样品的溶解度相应增大，化合物C的晶型I的溶解度较化合物C的无定形样品的溶解度相应减小。
实施例16化合物C的晶型J的制备
称量化合物C样品10.0g，加入乙酸乙酯100mL，加入水5mL，25℃下搅拌至澄清，然后降温至15℃，搅拌3h，析出白色固体，抽滤，得到产物。
化合物C的晶型J的X射线粉末衍射(XRPD)图如图42所示，从图44可以看出，化合物C的晶型J的X射线粉末衍射(XRPD)图中在5.97°、6.52°、9.42°、11.03°、11.63°、15.59°、16.61°、19.91°和22.46°处有特征峰。化合物C的晶型J的热重分析(TGA)图见图43，该产物的差示扫描量热法分析(DSC)图见图44。
化合物C的晶型J样品在不同溶剂中的溶解性试验：水、乙醇和甲醇。溶剂温度为25℃时，标准参考2015版药典规定，测的结果：在水中不溶；在乙醇中易溶；在甲醇中易溶。溶剂温度为50℃时，标准参考2015版药典规定，测的结果：在水中微溶；在乙醇中易溶；在甲醇中易溶。化合物C的晶型J样品的溶解度在温度升高后也在增大。化合物C的晶型J样品的溶解度较化合物B的无定形样品的溶解度相应增大，化合物C的晶型J品的溶解度较化合物C的无定形样品的溶解度相应减小。
化合物C的晶型J样品的稳定性进行考察。结果显示：化合物C的晶型J样品在25℃以及RH 80％的条件下，吸水量达到11.8％；化合物C的晶型J样品长期敞口放置含水量能达到9％，经过干燥含水量低于1％。
不同湿度下的稳定性：对化合物C的晶型J样品在25℃和40℃条件下的动态水分吸附(DVS)试验显示，样品在脱水过程中能够在45％-80％RH范围内稳定3小时。在低湿度下(RH 0％)，化合物C的晶型 J样品脱去水份，DVS试验后样品的结晶度降低。化合物C的晶型J样品在25℃以及RH60％条件下，或40℃以及RH75％条件下，放置2周后晶型没有发生变化，表明化合物C的晶型J样品在此条件下有良好的物理稳定性。样品在40℃以及RH75％条件下结晶度提高。
化合物C的晶型J样品溶解与晶型转变
称量化合物C的晶型J样品约90mg于20mL样品瓶中，分别向其中加入6mL水和SGF(模拟胃液)形成悬浊液。将悬浊液置于37℃的恒温箱中搅拌，分别于0.5h，1h，2h，4h，9h，12h过滤取澄清溶液进行高效液相色谱(HPLC)测试，同时取固体进行X射线粉末衍射(XRPD)测试。结果表明，随着在水中搅拌时间的增加，样品中无定形物含量增加，在水中的溶解度不断增大。而化合物C的晶型J样品在SGF(模拟胃液)中的溶解度低于仪器的最低检测限(0.002mg/mL)，不能检出，表明样品在SGF(模拟胃液)中逐渐转化为无定形。
实施例17化合物C的晶型J的单晶制备
称量化合物C样品10.0g，加入乙酸乙酯100mL和5mL水的混合体系，于10～30℃下待溶剂自由挥发后，收集析出固体，即得。纯度99.9％。
化合物C的晶型J的单晶衍射(XRSD)结构解析图见图45，通过测定波长为
Figure PCTCN2017084995-appb-000047
的单晶X衍射分析，该产物的晶胞参数为：
Figure PCTCN2017084995-appb-000048
α＝90°；
Figure PCTCN2017084995-appb-000049
β＝90°；
Figure PCTCN2017084995-appb-000050
γ＝90°；所述晶型L的晶胞体积为
Figure PCTCN2017084995-appb-000051
图46为由单晶数据的cif文件经过软件Mercury1.4模拟得到的XRPD谱图，从图48可以看出，该产物模拟的X射线粉末衍射光谱在5.91±0.50°、6.01±0.50°、6.51±0.50°、8.94±0.50°、9.44±0.50°、11.66±0.50°、15.70±0.50°、21.04±0.50°和21.75±0.50°处有特征峰；与图47相比较，主峰相似，确认这两个晶型都属于化合物C的晶型J，也可以说明化合物(式I)的化学立体构型与化合物C的晶型J的单晶衍射 (XRSD)结构解析图所示的化学立体构型一致。
实施例18化合物E(式I，R1＝K+，R2＝nH2O，n≤5)的无定形样品的制备
称量化合物B样品20.0g，加入乙醇100mL，冰水浴搅拌下，滴入叔丁醇钾3.1g溶于50mL乙醇配制的乙醇溶液，搅拌下溶液渐变澄清，浓缩除去乙醇，干燥，得产物。
化合物E的无定形物样品在不同的湿度环境下的稳定性试验，结果如下表所示。
水分(40℃、RH75％) 水分(2015版药典方法) 水分(25℃)
8.8％ 7.7％ 5.3％
化合物E的无定形物样品在不同的湿度环境下水分含量有差异，环境的水分含量越大，则化合物E的无定形样品的含水量越大。
实施例19化合物F(式I，R1＝1/2Ca2+，R2＝nH2O，n≤5)的无定形样品的制备
称量化合物B样品20.0g，加入乙醇300mL，浴搅拌下，滴入氢氧化钙1.0g溶于10mL甘油配制的甘油溶液，搅拌下溶液渐变澄清，浓缩除去乙醇，加入40mL的乙酸乙酯，搅拌溶解，加入150mL的石油醚，析出固体，搅拌，过滤，干燥，得产物。
化合物F的无定形物样品在不同的湿度环境下的稳定性试验，结果如下表所示。
水分(40℃、RH75％) 水分(2015版药典方法) 水分(25℃)
11.3％ 13.6％ 6.9％
化合物F的无定形样品在不同的湿度环境下水分含量有差异，则化合物F的无定形样品的在不同的湿度环境下含水量都比较大。

Claims (20)

  1. 一种如式I所示的大环状多环化合物：
    Figure PCTCN2017084995-appb-100001
    其中：
    R1选自：H、Li+、Na+、K+、Rb+、1/2Be2+、1/2Mg2+、1/2Ca2+、1/2Sr2+、1/2Ba2+及其同位素；
    R2不存在，或者选自：nCH3CO2H、nH2O，其中，n≤5。
  2. 一种如权利要求1所述的化合物其特征在于，所述化合物中R1是H，R2不存在时，形成化合物B，所述化合物B的晶型包括晶型I、晶型II、晶型III、晶型IV或晶型V；
    Figure PCTCN2017084995-appb-100002
    所述化合物B的晶型I使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射(XRPD)图在4.91±0.50°、5.37±0.50°、5.87±0.50°、7.90±0.50°、10.32±0.50°、11.69±0.50°、15.04±0.50°、17.94±0.50°、18.66±0.50°和 20.00±0.50°处有特征峰；
    所述化合物B的晶型II使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射(XRPD)图在4.53±0.50°、5.71±0.50°、8.48±0.50°、9.05±0.50°、10.45±0.50°、13.49±0.50°、16.43±0.50°、16.9±0.50°、19.86±0.50°和20.63±0.50°处有特征峰；
    所述化合物B的晶型III使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射(XRPD)图在5.80±0.50°、9.12±0.50°、10.71±0.50°、13.57±0.50°、14.39±0.50°、16.17±0.50°、17.75±0.50°、18.24±0.50°、19.61±0.50°和20.92±0.50°处有特征峰；
    所述化合物B的晶型IV使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射(XRPD)图在5.36±0.50°、7.85±0.50°、8.60±0.50°、12.85±0.50°、14.20±0.50°、15.40±0.50°、16.19±0.50°、19.63±0.50°、20.15±0.50°和21.09±0.50°处有特征峰；
    所述化合物B的晶型V为单晶，其晶胞参数为：
    Figure PCTCN2017084995-appb-100003
    α＝90°；
    Figure PCTCN2017084995-appb-100004
    β＝90°；
    Figure PCTCN2017084995-appb-100005
    γ＝90°；空间群为P21212；
    Figure PCTCN2017084995-appb-100006
  3. 一种如权利要求2所述的化合物B的晶型的制备方法，其特征在于，
    所述化合物B的晶型I的制备方法，其包括下述步骤：在乙酸乙酯中，将化合物B重结晶，得到化合物B的晶型I即可。
    所述化合物B的晶型II的制备方法，其包括下述步骤：在乙醇中，将化合物B重结晶，得到化合物B的晶型II即可。
    所述化合物B的晶型III的制备方法，其包括下述步骤：在丙酮中，将化合物B重结晶，得到化合物B的晶型III即可。
    所述化合物B的晶型IV的制备方法，其包括下述步骤：在丙酮中，将化合物B的溶液置于正己烷氛围气相扩散，得到化合物B的晶型IV 即可。
    所述化合物B的晶型V的制备方法，其包括下述步骤：在丙酮中，将化合物C在养晶溶液中养晶，得到化合物B的晶型V即可；所述的养晶溶液为含有醋酸铵、醋酸、乙腈和甲醇的水溶液；
    Figure PCTCN2017084995-appb-100007
  4. 一种如权利要求1所述的化合物，其特征在于，所述化合物中R1是H，R2是CH3CO2H，形成化合物D：
    Figure PCTCN2017084995-appb-100008
  5. 如权利要求4所述的化合物，其特征在于，其使用Cu-Kα辐射，以2θ角度表示的X射线粉末衍射(XRPD)图在7.56±0.50°、8.56±0.50°、9.46±0.50°、12.64±0.50°、13.39±0.50°、14.28±0.50°、15.95±0.50°、17.59±0.50°、18.84±0.50°和20.57±0.50°处有特征峰；
    和/或，所述化合物的差示扫描量热法(DSC)分析图在170℃处有吸热峰。
  6. 如权利要求4-5中任一项所述的化合物的制备方法，其特征在于，包括如下步骤：在乙酸/正己烷混合溶剂中，将化合物B或化合物C重结晶，得到化合物D即可；
    Figure PCTCN2017084995-appb-100009
  7. 如权利要求6所述的制备方法，其特征在于，所述的乙酸/正己烷混合溶剂中，所述的乙酸与所述的正己烷的体积比为1∶20；
    和/或，所述的乙酸/正己烷混合溶剂与所述的化合物B的体积质量比为5mL/g～20mL/g；
    和/或，所述的重结晶为化合物B与乙酸/正己烷混合溶剂混合后，搅拌；
    和/或，所述的重结晶的温度为10℃～35℃。
  8. 一种如权利要求1所述的化合物，其特征在于，所述化合物中R1是Na±，R2是nH2O，形成化合物C，其中，n≤5；
    Figure PCTCN2017084995-appb-100010
  9. 一种权利要求8中所述的化合物的制备方法，其特征在于，
    所述化合物C的无定形状态，其特征在于，所述无定形物的X射线粉末衍射(XRPD)光谱图中无特征峰。
    其包括下述步骤：将化合物B与乙醇混合，得混合物；在搅拌状态下，将乙醇钠或氢氧化钠的乙醇溶液加入至所述混合物中，反应后浓缩至干，即得化合物C；
    Figure PCTCN2017084995-appb-100011
    或者，其包括下述步骤：用水溶解化合物C，干燥，即得。
  10. 如权利要求9所述的制备方法，其特征在于，所述混合物中，化合物B和乙醇的配比为(0.8～1.2)g∶(4～6)mL；
    和/或，所述乙醇钠或氢氧化钠与化合物B的摩尔比为1.08∶1～1.02∶1；
    和/或，所述反应的温度为0～5℃；
    和/或，所述干燥的温度为30～80℃。
  11. 一种权利要求8中所述化合物C的晶型，其特征在于，所述化 合物C的晶型包括晶型A、晶型B、晶型C、晶型D、晶型E、晶型G、晶型H、晶型I或晶型J；
    所述化合物C的晶型A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射(XRPD)图在3.70±0.50°、7.48±0.50°、11.36±0.50°、19.87±0.50°和25.60±0.50°处有特征峰；
    所述化合物C的晶型B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射(XRPD)图在4.4±0.50°、5.32±0.50°、6.38±0.50°、8.69±0.50°、13.31±0.50°、14.45±0.50°、15.52±0.50°、17.57±0.50°和21.11±0.50°处有特征峰；
    所述化合物C的晶型C使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射(XRPD)图在3.22±0.50°、6.26±0.50°、14.61±0.50°、15.624±0.50°、18.82±0.50°和20.17±0.50°处有特征峰；
    所述化合物C的晶型D使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射(XRPD)图在2.02±0.50°、4.769±0.50°、5.677±0.50°、8.41±0.50°、11.04±0.50°、16.57±0.50°、18.25±0.50°、19.36±0.50°和22.61±0.50°处有特征峰；
    所述化合物C的晶型E使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射(XRPD)图在7.12±0.50°、13.92±0.50°、14.64±0.50°、16.47±0.50°、18.86±0.50°、19.86±0.50°、20.78±0.50°、22.58±0.50°和29.58±0.50°处有特征峰；
    所述化合物C的晶型G使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射(XRPD)图在7.59±0.50°、8.78±0.50°、13.33±0.50°、15.06±0.50°、16.31±0.50°、18.80±0.50°、20.28±0.50°、22.35±0.50°和23.60±0.50°处有特征峰，所述晶型G中，n为1；
    所述化合物C的晶型H使用Cu-Kα辐射，以2θ角度表示的X-射线 粉末衍射(XRPD)图在4.32±0.50°、5.34±0.50°、5.96±0.50°、9.31±0.50°、13.24±0.50°、14.65±0.50°、16.14±0.50°、18.09±0.50°和20.55±0.50°处有特征峰；
    所述化合物C的晶型I使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射(XRPD)图在7.00±0.50°、7.40±0.50°、7.93±0.50°、14.09±0.50°、14.76±0.50°、18.89±0.50°、19.94±0.50°、20.78±0.50°和22.35±0.50°处有特征峰；
    所述化合物C的晶型J使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射(XRPD)图在5.97±0.50°、6.52±0.50°、9.42±0.50°、11.03±0.50°、11.63±0.50°、15.59±0.50°、16.61±0.50°、19.91±0.50°和22.46±0.50°处有特征峰；所述晶型J中，n为1～5；
    较佳地，所述化合物C的晶型J为单晶，所述化合物C的晶型J单晶的晶胞参数为：
    Figure PCTCN2017084995-appb-100012
    α＝90°；
    Figure PCTCN2017084995-appb-100013
    β＝90°；
    Figure PCTCN2017084995-appb-100014
    γ＝90°；所述化合物C的晶型J单晶的晶胞体积为
    Figure PCTCN2017084995-appb-100015
    所述化合物C的晶型J的单晶晶胞参数和晶胞体积由测定波长为
    Figure PCTCN2017084995-appb-100016
    的单晶X衍射分析测得
  12. 一种权利要求11所述化合物的晶型的制备方法，其特征在于，
    所述化合物C的晶型A的制备方法，其包括下述步骤：将化合物C溶解于二氯甲烷中，得混合液；在所述混合液上加入乙醚形成液相分层；至乙醚扩散至混合液后，收集析出固体，即得；
    所述化合物C的晶型B的制备方法，其包括下述步骤：将化合物C溶解于乙醇中，得混合液；在所述混合液上加入乙醚形成液相分层；至乙醚扩散至混合液后，收集析出固体，即得；
    所述晶型C的制备方法一，其包括下述步骤：在58～62℃下将化合物C溶解于四氢呋喃与正己烷的混合溶剂，得混合液；降温，收集析出 固体，即得；
    所述化合物C的晶型C的制备方法二，其包括下述步骤：将化合物C溶解于四氢呋喃中，得混合液；通过气体扩散将正己烷扩散至混合液中，收集析出的固体，即得；
    所述化合物C的晶型D的制备方法，其包括下述步骤：将化合物C溶解于乙酸乙酯中，得混合液；通过气体扩散将正己烷扩散至混合液中，收集析出的固体，即得；
    所述化合物C的晶型E的制备方法，其包括下述步骤：将化合物C溶解于乙醇中，得混合液；通过气体扩散将正己烷扩散至混合液中，收集析出的固体，即得；
    所述化合物C的晶型G的制备方法一，其包括下述步骤：将化合物C溶解于乙醇中，于20～70℃下搅拌1～8小时，抽滤，干燥，即得；
    所述化合物C的晶型G的制备方法二，其包括下述步骤：将化合物B与乙醇混合，得混合物；在搅拌状态下，将氢氧化钠的乙醇溶液加入至所述混合物中反应至澄清，再于20～70℃下搅拌1～8小时，抽滤，干燥，即得；
    所述化合物C的晶型G的制备方法三，其包括下述步骤：将化合物C溶解于乙醇和正己烷的混合溶剂中，于室温下挥发溶剂，收集析出的固体，即得；
    所述化合物C的晶型H的制备方法，其包括下述步骤：将化合物C溶解于乙醇中，得混合液；在搅拌状态下将所述混合液滴加至正己烷中，收集析出固体，即得；
    所述化合物C的晶型I的制备方法，其包括下述步骤：将化合物C溶解于乙醇中，得混合液；通过气体扩散将乙醚扩散至混合液中，收集析出的固体，即得；
    所述化合物C的晶型J的制备方法一，其包括下述步骤：将化合物C溶解于乙酸乙酯和水的混合体系中，于0～30℃下搅拌3～4h，析晶，抽滤后即得；
    所述化合物C的晶型J的制备方法二，其包括下述步骤：将化合物C溶解于乙酸乙酯和水的混合体系中，于10～30℃下待溶剂挥发后收集析出固体，即得所述化合物C的晶型J的单晶。
  13. 如权利要求12所述的制备方法，其特征在于，所述化合物C的晶型A的制备方法中，所述二氯甲烷和化合物C的体积质量比为5～10mL/g；和/或，所述乙醚和所述二氯甲烷的体积比在2以上；
    所述化合物C的晶型B的制备方法中，所述乙醇和化合物C的体积质量比为5～10mL/g；和/或，所述乙醚和所述乙醇的体积比在2以上；
    所述化合物C的晶型C的制备方法一中，在60℃下将化合物C溶解于四氢呋喃与正己烷的混合溶剂；和/或，所述四氢呋喃与正己烷的混合溶剂中，所述四氢呋喃和正己烷的体积比为1∶1～1∶1.2；和/或，所述四氢呋喃与正己烷的混合溶剂和化合物C的体积质量比为5～10mL/g；和/或，所述降温的速率为0.04～0.06℃/min；所述降温的目标温度为4～6℃；
    所述化合物C的的晶型C的制备方法二中，所述四氢呋喃和化合物C的体积质量比为5～10mL/g；和/或，所述正己烷和所述四氢呋喃的体积比为5∶1～10∶1；
    所述化合物C的晶型D的制备方法中，所述乙酸乙酯和化合物C的体积质量比为5～10mL/g；和/或，所述正己烷和所述乙酸乙酯的体积比为5∶1～10∶1；
    所述化合物C的晶型E的制备方法中，所述乙醇和化合物C的体积质量比为5～10mL/g；和/或，所述正己烷和所述乙醇的体积比为5∶1～10∶1；
    所述化合物C的晶型G的制备方法一中，所述搅拌在30～45℃下进 行；和/或，所述搅拌的时间为3小时；
    所述化合物C的晶型G的制备方法二中，所述混合物中，化合物B和乙醇的质量体积比为(0.8～1.2)g∶(4～6)mL；和/或，所述氢氧化钠与化合物B的摩尔比为1.20∶1～1.00∶1；和/或，所述氢氧化钠的乙醇溶液中，所述氢氧化钠和乙醇的质量体积比为(0.5～1)g∶50mL；和/或，所述反应的温度为0～25℃；和/或，在反应至澄清后的操作后，所述搅拌在35℃下进行；和/或，在反应至澄清后的操作后，所述搅拌的时间为3小时；
    所述化合物C的晶型G的制备方法三中，所述乙醇和正己烷的混合溶剂中，所述乙醇和所述正己烷的体积比为1∶1；和/或，所述乙醇和正己烷的混合溶剂与化合物C的体积质量比为5～10mL/g；
    所述化合物C的晶型H的制备方法中，所述乙醇和化合物C的体积质量比为5～8mL/g；和/或，所述正己烷和所述乙醇的体积比为30∶1～40∶1；和/或，所述滴加的速度为0.1mL/s；
    所述化合物C的晶型I的制备方法中，所述乙醇和化合物C的体积质量比为5～10mL/g；和/或，所述乙醚和所述乙醇的体积比较佳地为5∶1～10∶1；
    所述化合物C的晶型J的制备方法一中，所述乙酸乙酯和式化合物C的体积质量比为5～10mL/g；和/或，所述水和所述乙酸乙酯的体积比为1∶10～1∶40；和/或，所述搅拌的温度为15℃；
    所述化合物C的晶型J的制备方法二中，所述乙酸乙酯和式化合物C的体积质量比为5～100mL/g；和/或，所述水和所述乙酸乙酯的体积比为1∶20～1∶100。
  14. 一种如权利要求1所述的化合物，其特征在于，R1是K+，R2＝nH2O，n≤5，形成化合物E；
    Figure PCTCN2017084995-appb-100017
  15. 一种权利要求14中所述的化合物的制备方法，其特征在于，其包括下述步骤：将化合物B与乙醇混合，得混合物；在搅拌状态下，将叔丁醇钾的乙醇溶液加入至所述混合物中，反应后浓缩至干，即得。
    Figure PCTCN2017084995-appb-100018
  16. 如权利要求15所述的制备方法，其特征在于，所述混合物中，化合物B和乙醇的配比为(0.8～1.2)g∶(4～6)mL；
    和/或，所述叔丁醇钾与化合物B的摩尔比为1.10∶1～1.01∶1；
    和/或，所述叔丁醇钾的乙醇溶液中，所述叔丁醇钾和乙醇的用量为(2.9～3.2)g∶50mL；
    和/或，所述反应的温度为0～50℃；
    和/或，所述干燥的温度为30～80℃。
  17. 一种如权利要求1所述的化合物，其特征在于，所述化合物中R1是1/2Ca2+，R2＝nH2O，n≤5，形成化合物F；
    Figure PCTCN2017084995-appb-100019
  18. 一种权利要求17中所述的化合物的制备方法，其特征在于，其包括下述步骤：将化合物B与乙醇混合，得混合物；在搅拌状态下，将氢氧化钙的甘油溶液加入至所述混合物中，搅拌至溶解，加入石油醚，析出固体，过滤，干燥，即得。
    Figure PCTCN2017084995-appb-100020
  19. 如权利要求18所述的制备方法，其特征在于，所述混合物中，化合物B和乙醇的配比为(0.8～1.2)g∶(12～18)mL；
    和/或，所述氢氧化钙与化合物B的摩尔比为0.55∶1～0.5∶1；
    和/或，所述反应的温度为0～35℃；
    和/或，所述干燥的温度为30～80℃。
  20. 如权利要求1所述的化合物在制备用于治疗丙型肝炎病毒感染的疾病的药物中的应用。
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CN102140100A (zh) * 2010-01-27 2011-08-03 爱博新药研发(上海)有限公司 高效抑制丙型肝炎病毒的多环化合物及其制备方法和用途
CN105859748A (zh) * 2015-02-05 2016-08-17 爱博新药研发(上海)有限公司 多环化合物钠盐及其多晶型、制备方法及应用

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* Cited by examiner, † Cited by third party
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CN102140100A (zh) * 2010-01-27 2011-08-03 爱博新药研发(上海)有限公司 高效抑制丙型肝炎病毒的多环化合物及其制备方法和用途
CN105859748A (zh) * 2015-02-05 2016-08-17 爱博新药研发(上海)有限公司 多环化合物钠盐及其多晶型、制备方法及应用

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