WO2017028762A1 - 一种萘环化合物的晶型 - Google Patents

一种萘环化合物的晶型 Download PDF

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WO2017028762A1
WO2017028762A1 PCT/CN2016/095150 CN2016095150W WO2017028762A1 WO 2017028762 A1 WO2017028762 A1 WO 2017028762A1 CN 2016095150 W CN2016095150 W CN 2016095150W WO 2017028762 A1 WO2017028762 A1 WO 2017028762A1
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ray powder
diffraction pattern
powder diffraction
degrees
crystal form
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PCT/CN2016/095150
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English (en)
French (fr)
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朱文民
刘地发
许国彬
区锦旺
樊玉平
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广东东阳光药业有限公司
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Priority to CN201680045765.4A priority Critical patent/CN108026043A/zh
Publication of WO2017028762A1 publication Critical patent/WO2017028762A1/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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms

Definitions

  • the invention relates to a crystal form of a naphthalene ring compound for treating gout and a preparation method thereof, and belongs to the field of medicinal chemistry.
  • the compound 2-[[3-(4-cyanophthalen-1-yl)pyridin-4-yl]thio]-2-methylpropionic acid also referred to as compound (1) in the present invention, is a urine
  • the acid salt anion transporter 1 inhibitor can be used for the treatment of hyperuricemia and gout, and its structure is as shown in formula (1):
  • the preparation methods, uses and the like of the compound (1) are disclosed in the patent applications WO2011159839 and WO2013067425, but information on the crystal form thereof is not disclosed.
  • the drug polymorph is a common phenomenon in drug development, it is an important factor affecting the quality of drugs.
  • Different crystal forms of the same drug may have significant differences in physical properties such as appearance, fluidity, solubility, storage stability, bioavailability, etc., and may have great differences, which may affect drug storage, application, stability, and efficacy. Different effects are produced; in order to obtain an effective crystalline form for the pharmaceutical preparation, it is necessary to conduct a comprehensive examination of the crystallization behavior of the drug to obtain a crystal form that satisfies the production requirements.
  • the present invention provides a novel crystal form of the compound (1) and a process for the preparation thereof.
  • crystalline form is used to describe the state of existence of a solid compound, and to describe a variety of parametric aggregates of ionic, atomic or molecular composition, symmetrical properties and periodic alignment within the crystal.
  • relative intensity means that the intensity of the first strong peak among a set of diffraction peaks belonging to a certain crystal form is defined as 100%, and other peaks are The ratio of the intensity to the intensity of the first strong peak.
  • the 2 ⁇ (also known as 2theta or diffraction peak) values in the X-ray powder diffraction pattern are all in degrees (°).
  • the term "diffraction peak" refers to a feature that would not be attributed to background noise by those skilled in the art.
  • the X-ray powder diffraction peak of the crystal form has an experimental error in the 2 ⁇ or diffraction peak of the X-ray powder diffraction pattern between one machine and another machine and between one sample and another sample.
  • the measurement of the 2 ⁇ or diffraction peak of the X-ray powder diffraction pattern may be slightly different.
  • the value of the experimental error or difference may be +/-0.2 units or +/-0.1 units or +/-0.05 units. Therefore, the value of the 2 ⁇ or diffraction peak cannot be regarded as absolute.
  • the differential scanning calorimetry curve (DSC) of the crystal form has experimental error.
  • the position and peak value of the endothermic peak may be slightly between one machine and another machine and between one sample and another sample.
  • the difference, the value of the experimental error or difference may be less than or equal to 5 ° C, or less than or equal to 4 ° C, or less than or equal to 3 ° C, or less than or equal to 2 ° C, or less than or equal to 1 ° C, so the peak position or peak of the DSC endothermic peak The value cannot be considered absolute.
  • thermogravimetric analysis (TGA) of the crystal form has experimental errors.
  • the difference between the weight loss temperature and the weight loss may be slightly different between one machine and another and between one sample and another sample.
  • the value of the difference may be about +/- 0.1 units, about +/- 0.05 units, or about +/- 0.01 units, so the values of the weight loss temperature and the amount of weight loss cannot be considered absolute.
  • Root temperature means a temperature of from about 15 ° C to 32 ° C or from about 20 ° C to 30 ° C or from about 23 ° C to 28 ° C or about 25 ° C.
  • good solvent may be a single solvent or a mixed solvent, meaning that the solubility of the sample in the single solvent or mixed solvent is greater than 1 g/L, or greater than 2 g/L, or greater than 3 g/L, or greater than 4 g/L, or greater than 5g/L, or greater than 6g/L, or greater than 7g/L, or greater than 8g/L, or greater than 9g/L, or greater than 10g/L, or greater than 15g/L, or greater than 20g/L, or greater than 30g/ L, or greater than 40 g/L, or greater than 50 g/L, or greater than 60 g/L, or greater than 70 g/L, or greater than 80 g/L, or greater than 100 g/L.
  • the solubility of the sample in the good solvent is greater than in the poor solvent; in some embodiments, the difference in solubility of the good and poor solvent to the sample is about 10%, 20%, 30%, 40%, 50 %, 60%, 70%, 80% or 90%; in some embodiments, the solubility of the good solvent to the sample is greater than the poor solvent, greater than 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90%.
  • the term “poor solvent” refers to a solvent that promotes the solution to an excessively saturated state or crystallization.
  • the sample has a solubility in a poor solvent of less than 0.001 g/L, or less than 0.01 g/L, or less than 0.1 g/L, or less than 0.2 g/L, or less than 0.3 g/L, or less than 0.4.
  • g/L or less than 0.5 g/L, or less than 0.6 g/L, or less than 0.8 g/L, or less than 1 g/L, or less than 2 g/L, or less than 3 g/L, or less than 4 g/L, or Less than 5 g/L, or less than 6 g/L, or less than 7 g/L, or less than 8 g/L, or less than 9 g/L, or less than 10 g/L.
  • Form 1 a new crystal form of the compound (1) by research, which is referred to as Form 1.
  • the crystal form 1 of the compound (1) has a characteristic that it has a diffraction peak at a position where the 2 ⁇ is 10.36, 13.89, 17.50, and 24.17 degrees in the X-ray powder diffraction pattern.
  • the X-ray powder diffraction pattern of Form 1 of Compound (1) has a diffraction peak at a position where 2 ⁇ is 10.36, 13.89, 17.51, 19.41, 22.46, 24.17 degrees.
  • the X-ray powder diffraction pattern of Form 1 of Compound (1) has diffraction peaks at positions of 2 ⁇ of 7.48, 10.36, 13.89, 17.51, 19.41, 20.62, 22.46, 24.17, 28.96, 29.39 degrees.
  • the X-ray powder diffraction pattern of Form 1 of Compound (1) has a diffraction peak at a position where 2 ⁇ is 10.38, 13.92, 17.54, 24.20, 28.15 degrees.
  • the X-ray powder diffraction pattern of Form 1 of Compound (1) has a diffraction peak at a position where 2 ⁇ is 10.38, 13.92, 17.54, 19.48, 20.65, 22.51, 24.20, 28.15 degrees.
  • the X-ray powder diffraction pattern of Form 1 of Compound (1) is 7.48, 10.36, 13.89, 14.94, 16.51, 17.51, 19.41, 20.62, 22.46, 24.17, 26.51, 28.96, 29.39 in 2 ⁇ .
  • the position of 34.85 degrees has a diffraction peak.
  • the X-ray powder diffraction pattern of Form 1 of Compound (1) is 2.48, 8.30, 10.36, 13.89, 14.94, 16.51, 17.51, 19.41, 20.62, 22.46, 24.17, 25.81, 26.51 in 2 ⁇ . 28.96, 29.39, 31.29, 32.4, 33.79, 34.85 degrees have diffraction peaks.
  • the X-ray powder diffraction pattern of Form 1 of Compound (1) is 2.48, 8.30, 10.36, 12.42, 13.89, 14.94, 15.29, 16.17, 16.51, 17.51, 18.58, 19.41, 20.62 in 2 ⁇ . 21.73, 22.46, 24.17, 25.36, 25.81, 26.51, 28.96, 29.39, 31.29, 32.4, 33.79, 34.85 degrees have diffraction peaks.
  • the X-ray powder diffraction pattern of Form 1 of Compound (1) is 2.48, 8.30, 10.36, 12.42, 13.89, 14.94, 15.29, 16.17, 16.51, 17.51, 18.58, 19.41, 20.62 in 2 ⁇ . 21.73, 22.46, 23.76, 24.17, 25.36, 25.81, 26.51, 28.96, 29.39, 30.19, 31.29, 32.0, 32.4, 33.79, 34.85 degrees have diffraction peaks.
  • the X-ray powder diffraction pattern of Form 1 of Compound (1) is shown in Figure 1, wherein the relative intensity of the peak at 2 ⁇ of 13.89 degrees is greater than 50%, or greater than 70%, or greater than 80. %, or greater than 90%, or greater than 99%.
  • the X-ray powder diffraction pattern of Form 1 of Compound (1) is shown in Figure 1.
  • the crystal form 1 of the compound (1) also has a characteristic that its differential scanning calorimetry curve (DSC) has an endothermic peak at 200 ° C to 220 ° C.
  • the differential scanning calorimetry curve (DSC) of Form 1 of Compound (1) has an endothermic peak at 205 °C - 215 °C.
  • the differential scanning calorimetry (DSC) of Form 1 of Compound (1) has an endothermic peak at 209 °C - 213 °C.
  • the differential scanning calorimetry (DSC) of Form 1 of Compound (1) has an endothermic peak at 210 ° C to 212 ° C, and an endothermic peak peak value. It is 212 °C.
  • the differential scanning calorimetry (DSC) of Form 1 of Compound (1) is shown in FIG.
  • the X-ray powder diffraction pattern of Form 1 of Compound (1) is shown in Figure 3.
  • the crystal form 1 of the present invention was studied, and it was found that the crystal form 1 is non-hygroscopic, has good performance in terms of stability and fluidity, is advantageous for storage, transfer, and operation in a production process, and can be used for preparing a pharmaceutical preparation.
  • the crystalline form 1 of the compound (1) or prepared into a salt may be mixed with a pharmaceutically acceptable adjuvant such as a filler, a binder, a disintegrating agent, or a lubricant to prepare various dosage forms such as a tablet.
  • a pharmaceutically acceptable adjuvant such as a filler, a binder, a disintegrating agent, or a lubricant to prepare various dosage forms such as a tablet.
  • the present invention provides a process for preparing Form 1 of the compound (1).
  • a method of preparing Form 1 comprises: compound (1) is mixed with a first solvent, stirred at a temperature, and then the solid is separated to obtain Form 1.
  • the first solvent is methyl tert-butyl ether, cyclohexane, n-heptane, diisopropyl ether or tetrahydrofuran; or the first solvent is methanol and methyl tert-butyl ether (MTBE), cyclohexane a mixed solvent of isopropyl acetate or n-heptane; or the first solvent is a mixed solvent of tetrahydrofuran and n-hexane or cyclohexane.
  • the temperature is from room temperature to the reflux temperature of the solvent.
  • the stirring time is from 0.5 hours to 6 hours.
  • compound (1) is mixed with methyl tert-butyl ether, cyclohexane, n-heptane, diisopropyl ether, or tetrahydrofuran, stirred at room temperature for 3 hours to 5 hours, and then the solid is separated to remove the solvent. Form 1 was obtained.
  • the compound (1) is stirred in a mixed solvent of methanol and MTBE, cyclohexane, isopropyl acetate, or n-heptane at a temperature for 1 hour to 5 hours, and the solid is separated to obtain a crystal form 1 .
  • a method for preparing Form 1 comprises: compound (1) is mixed with a second solvent, heated to completely dissolve, and then cooled to a temperature of -10 ° C to room temperature, crystallized, and the solid is separated to obtain a crystal.
  • Type 1 The second solvent is ethylene glycol dimethyl ether, methanol, ethanol, isopropanol, acetonitrile, acetone, water, toluene, or a combination thereof.
  • the second solvent is a mixed solvent of ethylene glycol dimethyl ether and methanol, acetone, water, or toluene.
  • the second solvent is a mixed solvent of water and methanol, or a mixed solvent of water and acetone.
  • the second solvent is methanol, ethanol, isopropanol or acetonitrile.
  • a method for preparing Form 1 comprises: dissolving compound (1) in ethylene glycol dimethyl ether, then mixing with a first poor solvent, stirring and crystallization, separating the solid to obtain Form 1;
  • a poor solvent is n-heptane or isopropyl acetate.
  • a method for preparing Form 1 comprises: dissolving Compound (1) in a third solvent, then adding a second poor solvent, and opening the solvent to dryness to obtain Form 1.
  • the third solvent is ethylene glycol dimethyl ether, methanol, ethanol, acetonitrile, ethyl acetate, isopropanol.
  • the second poor solvent is water, dichloromethane, methyl tert-butyl ether, toluene, acetonitrile, n-hexane, ethyl acetate, acetone, or isopropanol.
  • the third solvent is ethylene glycol dimethyl ether and the second poor solvent is water, dichloromethane, methyl tert-butyl ether, or toluene.
  • the third solvent is methanol and the second poor solvent is water, methyl tert-butyl ether, acetonitrile, dichloromethane, toluene, or acetone.
  • the third solvent is ethanol and the second poor solvent is water, toluene, n-hexane, dichloromethane, ethyl acetate, methyl tert-butyl ether, acetone, or isopropanol.
  • the third solvent is isopropyl The alcohol, the second poor solvent is dichloromethane, methyl tert-butyl ether, toluene, or n-hexane. In some embodiments, the third solvent is acetonitrile and the second poor solvent is water. In some embodiments, the third solvent is ethyl acetate and the second poor solvent is dichloromethane.
  • the present invention provides a novel crystalline form of Compound (1), referred to as Form 3.
  • the crystal form 3 of the compound (1) has the following characteristics: in the X-ray powder diffraction pattern, there are diffraction peaks at positions where 2 ⁇ is 10.41, 13.13, 13.89, 15.27, 16.58, 20.06, and 24.17 degrees.
  • the X-ray powder diffraction pattern of Form 3 of Compound (1) is diffracted at 2 ⁇ of 10.41, 13.13, 13.89, 15.27, 16.58, 17.57, 19.16, 20.06, 20.80, 22.31, 24.17 degrees. peak.
  • the X-ray powder diffraction pattern of Form 3 of Compound (1) is 9.54, 10.41, 10.88, 13.13, 13.89, 15.27, 16.58, 17.57, 19.16, 20.06, 20.80, 21.31, 22.31 in 2 ⁇ .
  • the position of 24.17 degrees has a diffraction peak.
  • the X-ray powder diffraction pattern of Form 3 of Compound (1) is 9.54, 10.41, 10.88, 13.13, 13.89, 15.27, 16.58, 17.57, 19.16, 20.06, 20.80, 21.31, 22.31 in 2 ⁇ . 24.17, 27.56, 28.34, 29.41, 31.35 degrees have diffraction peaks.
  • the X-ray powder diffraction pattern of Form 3 of Compound (1) is 2.89, 7.54, 9.54, 10.41, 10.88, 13.13, 13.89, 15.27, 16.58, 17.57, 19.16, 20.06, 20.80 in 2 ⁇ . 21.31, 22.31, 23.05, 23.73, 24.17, 26.32, 27.56, 28.34, 29.41, 31.35, 32.97 degrees have diffraction peaks.
  • the X-ray powder diffraction pattern of Form 3 of Compound (1) is shown in Figure 4, wherein the relative intensity of the peak at 2 ⁇ of 16.58 degrees is greater than 50%, or greater than 70%, or greater than 80. %, or greater than 90%, or greater than 99%.
  • the X-ray powder diffraction pattern of Form 3 of Compound (1) is shown in Figure 4.
  • the crystal form 3 of the present invention was studied, and it was found that the crystal form 3 is non-hygroscopic and has good performance in terms of fluidity, is advantageous for storage, transfer, and operation in a production process, and can be used for preparing a pharmaceutical preparation.
  • the crystal form 3 of the compound (1) or prepared into a salt may be mixed with a pharmaceutically acceptable adjuvant such as a filler, a binder, a disintegrator, or a lubricant to prepare various dosage forms such as a tablet.
  • a pharmaceutically acceptable adjuvant such as a filler, a binder, a disintegrator, or a lubricant to prepare various dosage forms such as a tablet.
  • the present invention provides a process for the preparation of the crystalline form 3 of the compound (1).
  • a method for preparing Form 3 comprises: dissolving Compound (1) in ethylene glycol dimethyl ether, then adding methyl tert-butyl ether, stirring for 3 hours to 6 hours, separating the solid, and removing the solvent to obtain Form 3.
  • a method for preparing Form 3 comprises: dissolving Compound (1) in ethyl acetate, then adding methyl tert-butyl ether, uniformly mixing, and then opening to volatilize the solvent to dryness to obtain Form 3.
  • a method for preparing the crystal form 3 comprises: mixing the compound (1) with chloroform or isopropanol, heating to form a solution, and then adding methyl tert-butyl ether dropwise; then stirring or cooling to a solid precipitate, stirring and decanting 0.1 After hours to 12 hours, the solid was separated and the solvent was removed to give the product of crystal.
  • the present invention provides a novel crystalline form of Compound (1), referred to as Form 4.
  • the crystal form 4 of the compound (1) has a characteristic that it has a diffraction peak at a position where the 2 ⁇ is 9.79, 13.20, 13.85, 15.94, 17.46, 20.32, 23.06, 28.68 degrees in the X-ray powder diffraction pattern.
  • the X-ray powder diffraction pattern of Form 4 of Compound (1) is 9.97, 11.35, 13.20, 13.85, 15.94, 17.46, 19.81, 20.32, 20.72, 21.66, 22.70, 23.06, 25.56 in 2 ⁇ .
  • the position of 28.68 degrees has a diffraction peak.
  • the X-ray powder diffraction pattern of Form 4 of Compound (1) is 9.97, 11.35, 13.20, 13.85, 15.94, 16.47, 17.07, 17.46, 19.81, 20.32, 20.72, 21.66, 22.70 in 2 ⁇ . 23.06, 24.03, 25.56, 27.91, 28.68, 29.64, 32.44 degrees have diffraction peaks.
  • the X-ray powder diffraction pattern of Form 4 of Compound (1) is 8.00, 9.79, 11.35, 12.05, 13.20, 13.85, 15.94, 16.47, 17.07, 17.46, 18.79, 19.81, 20.32 in 2 ⁇ . 20.72, 21.66, 22.12, 22.70, 23.06, 24.03, 24.50, 25.56, 27.91, 28.68, 29.64, 32.44, 35.22 degrees have diffraction peaks.
  • the X-ray powder diffraction pattern of Form 4 of Compound (1) is as shown in Figure 5, wherein the relative intensity of the peak at 2 ⁇ of 23.06 degrees is greater than 50%, or greater than 70%, or greater than 80. %, or greater than 90%, or greater than 99%.
  • the X-ray powder diffraction pattern of Form 4 of Compound (1) is shown in Figure 5.
  • the crystal form 4 of the compound (1) also has a characteristic that its differential scanning calorimetry curve (DSC) has an endothermic peak at about 200 ° C to 215 ° C.
  • the differential scanning calorimetry curve (DSC) of Form 4 of Compound (1) has an endothermic peak at about 202 °C to 213 °C.
  • the differential scanning calorimetry curve (DSC) of Form 4 of Compound (1) has an endothermic peak at about 203 ° C to 210 ° C and an endothermic peak peak value of 208 ° C.
  • the differential scanning calorimetry (DSC) of Form 4 of Compound (1) is shown in FIG.
  • the crystal form 4 of the present invention was investigated, and it was found that the crystal form 4 was not hygroscopic and had good performance in terms of fluidity, but the form 4 was changed to the form 1 after being left at room temperature for a certain period of time.
  • the crystalline form 4 of the compound (1) or prepared into a salt may be mixed with a pharmaceutically acceptable adjuvant such as a filler, a binder, a disintegrating agent, or a lubricant to prepare various dosage forms such as a tablet. Suitable dosage forms for agents, capsules, granules, etc., for the treatment of hyperuricemia or gout.
  • the present invention provides a process for the preparation of Form 4 of the compound (1).
  • a method for preparing Form 4 comprises: dissolving Compound (1) in ethyl acetate, then adding toluene, uniformly mixing, and then opening to volatilize the solvent to dryness to obtain Form 4.
  • a method for preparing Form 4 comprises: heating compound (1) in 2-methyltetrahydrofuran, and then adding n-hexane, cyclohexane, n-heptane or a combination solvent thereof at room temperature to precipitate a solid, and stirring and analyzing Crystals 0.5 to 8 hours, the solid is separated, the solvent is removed, and the crystal form 4 is obtained. Things.
  • the present invention provides a novel crystalline form of Compound (1), referred to as Form 5.
  • the crystal form 5 of the compound (1) has a characteristic that it has a diffraction peak at a position where the 2 ⁇ is 8.77, 17.55, 19.82, 23.74, 27.33, 35.48 degrees in the X-ray powder diffraction pattern.
  • the X-ray powder diffraction pattern of Form 5 of Compound (1) is 8.77, 11.09, 12.48, 15.38, 16.16, 17.55, 18.89, 19.82, 20.97, 22.22, 23.74, 27.33, 28.88 in 2 ⁇ .
  • the position of 35.48 degrees has a diffraction peak.
  • the X-ray powder diffraction pattern of Form 5 of Compound (1) is as shown in Figure 7, wherein the relative intensity of the peak at 17.5 degrees of 2 ⁇ is greater than 50%, or greater than 70%, or greater than 80. %, or greater than 90%, or greater than 99%.
  • the X-ray powder diffraction pattern of Form 5 of Compound (1) is shown in Figure 7.
  • the crystal form 5 of the compound (1) also has a characteristic that its differential scanning calorimetry curve (DSC) has an endothermic peak at about 130 ° C to 155 ° C.
  • the differential scanning calorimetry curve (DSC) of Form 5 of Compound (1) has an endothermic peak at about 132 °C to 150 °C.
  • the differential scanning calorimetry curve (DSC) of Form 5 of Compound (1) has an endothermic peak at about 132 ° C to 149 ° C and an endothermic peak peak value of 148.6 ° C.
  • the crystal form 5 of the present invention was studied, and it was found that the crystal form 5 is not hygroscopic, and has good properties in terms of stability, fluidity, etc., and is advantageous for storage, transfer, and operation in a production process, and can be used for preparing a pharmaceutical preparation.
  • the crystal form 5 of the compound (1) or after being prepared into a salt may be mixed with a pharmaceutically acceptable adjuvant such as a filler, a binder, a disintegrator, or a lubricant to prepare various dosage forms such as a tablet.
  • a pharmaceutically acceptable adjuvant such as a filler, a binder, a disintegrator, or a lubricant to prepare various dosage forms such as a tablet.
  • the present invention provides a process for producing the crystalline form 5 of the compound (1).
  • a method for preparing Form 5 comprises: compound (1) is dissolved in ethylene glycol dimethyl ether at 40 ° C - 60 ° C, then controlled temperature 30 ° C - 60 ° C, adding cyclohexane, plus After completion, the mixture was stirred at 10 ° C to 40 ° C for 4 hours to 6 hours, and the solid was separated, and the obtained solid was evaporated to give crystals.
  • a method for preparing Form 5 comprises: compound (1) is mixed with chloroform, heated to form a solution, and then cyclohexane is added dropwise at room temperature, a solid precipitates, and stirring is continued for 0.5 hours to 8 hours. The solid is then separated and the solvent is removed to give the crystalline form 5 product.
  • the present invention provides the crystalline form A of the monosodium salt and the monosodium salt of the compound (1).
  • the crystal form A of the monosodium salt of the compound (1) has the following characteristics: in the X-ray powder diffraction pattern, the 2 ⁇ is 10.15, 13.04, 15.42, 16.88, 20.07, 21.86, 24.62, 26.69, 31.11, 34.47 degrees. There are diffraction peaks at the location.
  • the X-ray powder diffraction pattern of Form A of the monosodium salt of Compound (1) is 10.15, 12.19, 13.04, 15.42, 15.64, 16.88, 18.67, 19.23, 20.07, 21.86, 22.93 in 2 ⁇ . 23.57, 24.62, 25.81, 26.69, 27.13, 28.72, 29.23, 31.11, the position of 34.47 degrees has a diffraction peak.
  • the X-ray powder diffraction pattern of Form A of the monosodium salt of Compound (1) is 2.10, 10.15, 12.19, 13.04, 15.42, 15.64, 16.88, 18.67, 19.23, 20.07, 20.91 in 2 ⁇ .
  • the X-ray powder diffraction pattern of Form A of the monosodium salt of Compound (1) is 5.15, 7.10, 10.15, 12.19, 13.04, 14.24, 15.42, 15.64, 16.88, 18.25, 18.67 in 2 ⁇ , 19.23, 20.07, 20.55, 20.91, 21.43, 21.86, 22.52, 22.93, 23.57, 24.62, 25.81, 26.69, 27.13, 27.63, 28.72, 29.23, 29.59, 31.11, 31.69, 32.00, 32.41, 32.97, 34.47, 39.05 degrees There are diffraction peaks.
  • the X-ray powder diffraction pattern of Form A of the monosodium salt of Compound (1) is shown in Figure 8, wherein the relative intensity of the peak at 2 ⁇ of 13.04 degrees is greater than 50%, or greater than 70%. , or greater than 80%, or greater than 90%, or greater than 99%.
  • the X-ray powder diffraction pattern of Form A of the monosodium salt of Compound (1) is shown in FIG.
  • Form A of the monosodium salt of the compound (1) also has the following characteristics: its differential scanning calorimetry curve (DSC) has an endothermic peak at 100 ° C - 125 ° C and a suction at 165 ° C - 195 ° C Hot peaks.
  • the differential scanning calorimetry (DSC) of Form A of the monosodium salt of Compound (1) has an endothermic peak at 105 ° C to 120 ° C and an endotherm at 170 ° C to 190 ° C. peak.
  • the differential scanning calorimetry (DSC) of Form A of the monosodium salt of Compound (1) has an endothermic peak at 110 ° C to 120 ° C, and the peak value of the endothermic peak is 120 ° C. It has an endothermic peak at 175 ° C - 190 ° C and an endothermic peak peak value of 186 ° C.
  • the differential scanning calorimetry (DSC) of Form A of the monosodium salt of Compound (1) is shown in FIG.
  • the crystal form A of the monosodium salt of the compound (1) of the present invention was investigated, and it was found that the crystal form A of the monosodium salt of the compound (1) has a good solubility in water, and the crystal form A does not absorb moisture, and is stable. It has good performance in terms of fluidity, etc. It is beneficial for storage, transfer, and operation in the production process, and can be used for preparing pharmaceutical preparations.
  • the crystalline form A of the monosodium salt of the compound (1) may be mixed with a pharmaceutically acceptable adjuvant such as a filler, a binder, a disintegrating agent, or a lubricant to prepare various dosage forms such as a tablet. Suitable dosage forms for capsules, granules, etc., for the treatment of hyperuricemia or gout.
  • the present invention provides a process for producing a crystalline form A of the monosodium salt of the compound (1).
  • a method for preparing the crystalline form A of the monosodium salt of the compound (1) comprises: dissolving the monosodium salt of the compound (1) in water, then entering the sodium chloride solid, stirring at room temperature for 3 hours to 15 hours, and then separating the solid The resulting solid was freed of residual solvent to give crystal form A, wherein the mass ratio of sodium chloride to water was not more than 20%. In some embodiments, wherein the mass ratio of sodium chloride to water is from 1% to 10%. In some embodiments, wherein the mass ratio of sodium chloride to water is from 1% to 5%. In some embodiments, wherein the mass ratio of sodium chloride to water is from 5% to 10%.
  • the present invention provides a novel crystalline form of the compound (1), referred to as Form 6.
  • the crystal form 6 of the compound (1) has the following characteristics: in the X-ray powder diffraction pattern, the position at 2 ⁇ is 13.84, 14.52, 16.01, 18.41, 18.82, 21.30, 22.00, 24.37, 25.36 degrees. There is a diffraction peak.
  • the X-ray powder diffraction pattern of Form 6 of Compound (1) is 10.30, 10.57, 13.84, 14.52, 16.01, 17.08, 17.45, 18.41, 18.82, 19.76, 20.12, 21.30, 22.00 in 2 ⁇ . 23.49, 24.37, 25.36, 32.49, 39.23 degrees have diffraction peaks.
  • the X-ray powder diffraction pattern of Form 6 of Compound (1) is shown in FIG.
  • Form 6 of Compound (1) also has the property that its differential scanning calorimetry curve (DSC) has an endothermic peak at 130 ° C - 150 ° C and an endothermic peak at 210 ° C - 220 ° C.
  • the differential scanning calorimetry curve (DSC) of Form 6 of Compound (1) has an endothermic peak at 135 °C - 145 °C and an endothermic peak at 215 °C - 219 °C.
  • the differential scanning calorimetry (DSC) of Form 6 of Compound (1) has an endothermic peak at 140 ° C - 145 ° C, and the peak value of endothermic peak is 144 ° C at 215 ° C. There is an endothermic peak at -219 ° C, and the peak value of the endothermic peak is 218 ° C.
  • the differential scanning calorimetry (DSC) of Form 6 of Compound (1) is shown in FIG.
  • Form 6 of Compound (1) also has the property that its thermogravimetric analysis curve (TGA) shows weight loss at 100 ° C - 150 ° C and a weight loss of about 8% - 10%.
  • the thermogravimetric analysis curve (TGA) of Form 6 of Compound (1) shows a weight loss at 100 ° C - 150 ° C with a weight loss of about 10%.
  • the thermogravimetric analysis curve (TGA) of Form 6 of Compound (1) is shown in FIG.
  • the crystal form 6 of the present invention is studied.
  • the crystal form 6 is non-hygroscopic, has good performance in terms of stability and fluidity, is advantageous for storage, transfer, and operation in a production process, and can be used for preparing a pharmaceutical preparation.
  • the crystalline form 6 of the compound (1) or prepared into a salt may be mixed with a pharmaceutically acceptable adjuvant such as a filler, a binder, a disintegrating agent, or a lubricant to prepare various dosage forms such as a tablet.
  • a pharmaceutically acceptable adjuvant such as a filler, a binder, a disintegrating agent, or a lubricant to prepare various dosage forms such as a tablet.
  • the present invention provides a process for producing the crystalline form 6 of the compound (1).
  • a method for preparing Form 6 comprises: compound (1) is mixed with glacial acetic acid, heated to reflux, and then water is added to the resulting mixture, the mixture is cooled to a solid precipitate, and the mixture is kept warm; the mixture is then cooled to room temperature. Stirring with heat; separating the solid and removing the solvent to give the product of Form 6.
  • the present invention provides a novel crystal form of the compound (1), which is referred to as Form 7.
  • the crystal form 7 of the compound (1) has the following characteristics: a diffraction peak at a position where the 2 ⁇ is 10.30, 13.83, 14.87, 16.06, 18.06, 19.76, 21.03, 23.02, 24.18, 25.25 degrees in the X-ray powder diffraction pattern. .
  • the X-ray powder diffraction pattern of Form 7 of Compound (1) is 8.25, 10.30, 13.83, 14.87, 16.06, 16.97, 18.06, 19.76, 20.31, 20.67, 21.03, 23.02, 24.18 in 2 ⁇ . 25.25, 28.43, 29.06, 31.66 degrees have diffraction peaks.
  • the X-ray powder diffraction pattern of Form 7 of Compound (1) is shown in Figure 13, wherein the relative intensity of the peak at 13.3 degrees of 2 ⁇ is greater than 50%, or greater than 70%, or greater than 80. %, or greater than 90%, or greater than 99%.
  • the X-ray powder diffraction pattern of Form 7 of Compound (1) is shown in FIG.
  • Form 7 of Compound (1) also has the property that its differential scanning calorimetry curve (DSC) has an endothermic peak at 215 °C - 225 °C.
  • the differential scanning calorimetry curve (DSC) of Form 7 of Compound (1) has an endothermic peak at 215 ° C to 219 ° C and an endothermic peak peak value of 217 ° C.
  • the differential scanning calorimetry (DSC) of Form 7 of Compound (1) is shown in FIG.
  • Form 7 of Compound (1) also has the property that its thermogravimetric analysis curve (TGA) shows weight loss at 100 ° C - 150 ° C and a weight loss of about 0.5% - 2%.
  • TGA thermogravimetric analysis curve
  • the thermogravimetric analysis curve (TGA) of Form 7 of Compound (1) shows weight loss from 100 ° C to 150 ° C with a weight loss of about 1.8%.
  • the thermogravimetric analysis curve (TGA) of Form 7 of Compound (1) is shown in FIG.
  • the crystal form 7 of the present invention was studied, and it was found that the crystal form 7 is non-hygroscopic, easy to be separated by filtration, has good performance in terms of stability, fluidity, etc., and is advantageous for storage, transfer, and operation in a production process, and can be used for preparing a drug. preparation.
  • the crystalline form 7 of the compound (1) or prepared into a salt may be mixed with a pharmaceutically acceptable adjuvant such as a filler, a binder, a disintegrating agent, or a lubricant to prepare various dosage forms such as a tablet.
  • a pharmaceutically acceptable adjuvant such as a filler, a binder, a disintegrating agent, or a lubricant to prepare various dosage forms such as a tablet.
  • the present invention provides a process for the preparation of the crystalline form 7 of the compound (1).
  • a method for preparing Form 7 comprises: compound (1) mixed with glacial acetic acid, heated to reflux; then adding water to the resulting mixture, cooling to room temperature or cooling to 0 ° C - 5 ° C, holding and stirring; separating solids and removing Solvent to give the crystalline form 7 product.
  • the present invention provides a novel crystalline form of the compound (1), which is referred to as Form 8.
  • the crystal form 8 of the compound (1) has the following characteristics: a diffraction peak at a position where the 2 ⁇ is 10.26, 13.83, 14.31, 19.08, 19.46, 20.14, 21.91, 23.87, 24.19, 29.10 degrees in the X-ray powder diffraction pattern. .
  • the X-ray powder diffraction pattern of Form 8 of Compound (1) is 7.52, 10.26, 13.83, 14.31, 15.01, 16.06, 16.91, 17.48, 18.61, 19.08, 19.46, 20.14, 21.91 in 2 ⁇ . There are diffraction peaks at 22.49, 23.87, 24.19, and 29.10 degrees.
  • the X-ray powder diffraction pattern of Form 8 of Compound (1) is shown in FIG.
  • Form 8 of Compound (1) also has the property that its differential scanning calorimetry curve (DSC) has an endothermic peak at 206 °C - 215 °C.
  • the differential scanning calorimetry curve (DSC) of Form 8 of Compound (1) has an endothermic peak at 207 °C to 212 °C and an endothermic peak peak value of 210.5 °C.
  • the differential scanning calorimetry (DSC) of Form 8 of Compound (1) is shown in FIG.
  • Form 8 of Compound (1) also has the property that its thermogravimetric analysis curve (TGA) shows weight loss at 100 ° C - 150 ° C and a weight loss of about 2.5% - 4.5%.
  • TGA thermogravimetric analysis curve
  • the thermogravimetric analysis curve (TGA) of Form 8 of Compound (1) shows weight loss at 100 ° C - 150 ° C with a weight loss of about 4%.
  • the thermogravimetric analysis curve (TGA) of Form 8 of Compound (1) is shown in FIG.
  • the crystal form 8 of the present invention was studied, and it was found that the crystal form 8 is not hygroscopic, has good properties in terms of fluidity and the like, is advantageous for storage, transfer, and operation in a production process, and can be used for preparing a pharmaceutical preparation.
  • the crystal form 8 of the compound (1) or after being prepared into a salt may be mixed with a pharmaceutically acceptable adjuvant such as a filler, a binder, a disintegrator, or a lubricant to prepare various dosage forms such as a tablet.
  • a pharmaceutically acceptable adjuvant such as a filler, a binder, a disintegrator, or a lubricant to prepare various dosage forms such as a tablet.
  • the present invention provides a process for the preparation of the crystalline form 8 of the compound (1).
  • a method for preparing Form 8 comprises: dissolving Compound (1) in chloroform, then adding n-heptane or cyclohexane or a mixture thereof, precipitating a solid, stirring and crystallization, and then separating the solid, removing the solvent to obtain a product of Form 8 .
  • the present invention provides a novel crystalline form of the compound (1), which is referred to as Form 9.
  • the crystal form 9 of the compound (1) has a characteristic that it has a diffraction peak at a position where the 2 ⁇ is 9.97, 12.66, 15.56, 16.54, 17.69, 18.31, 21.80, 25.14, 25.67 degrees in the X-ray powder diffraction pattern.
  • Form 9 of Compound (1) has an X-ray powder diffraction pattern at 2 ⁇ of 9.97, 12.66, 14.92, 15.56, 16.54, 17.69, 18.31, 19.19, 20.77, 21.80, 22.84, 25.14, 25.67, At 27.36, the position of 30.12 degrees has a diffraction peak.
  • the X-ray powder diffraction pattern of Form 9 of Compound (1) is 6.79, 9.97, 12.66, 13.54, 14.92, 15.56, 16.54, 17.32, 17.69, 18.31, 19.19, 19.79, 20.77 in 2 ⁇ . 21.80, 22.84, 24.27, 25.14, 25.67, 26.23, 27.36, 27.94, 28.60, 29.61, 30.12 degrees have diffraction peaks.
  • the X-ray powder diffraction pattern of Form 9 of Compound (1) is shown in Figure 19, wherein the relative intensity of the peak at 12.27 degrees of 2 ⁇ is greater than 50%, or greater than 70%, or greater than 80. %, or greater than 90%, or greater than 99%.
  • the X-ray powder diffraction pattern of Form 9 of Compound (1) is shown in FIG.
  • Form 9 of Compound (1) also has the property that its differential scanning calorimetry curve (DSC) has an endothermic peak at 155 °C - 175 °C.
  • the differential scanning calorimetry curve (DSC) of Form 9 of Compound (1) has an endothermic peak at 155 ° C to 170 ° C and an endothermic peak peak value of 165 ° C.
  • the differential scanning calorimetry curve (DSC) of Form 9 of Compound (1) is shown in FIG.
  • Form 9 of Compound (1) also has the property that its thermogravimetric analysis curve (TGA) shows weight loss at 100 ° C - 150 ° C and a weight loss of about 5% - 7%.
  • TGA thermogravimetric analysis curve
  • the thermogravimetric analysis curve (TGA) of Form 9 of Compound (1) shows weight loss from 100 ° C to 150 ° C with a weight loss of about 6.6%.
  • the thermogravimetric analysis curve (TGA) of Form 9 of Compound (1) is shown in FIG.
  • the crystal form 9 of the present invention was studied, and it was found that the crystal form 9 is non-hygroscopic and has good properties in terms of fluidity and the like, and is advantageous for storage, transfer, and operation in a production process, and can be used for preparing a pharmaceutical preparation.
  • the crystalline form 9 of the compound (1) or prepared into a salt may be mixed with a pharmaceutically acceptable adjuvant such as a filler, a binder, a disintegrating agent, or a lubricant to prepare various dosage forms such as a tablet.
  • a pharmaceutically acceptable adjuvant such as a filler, a binder, a disintegrating agent, or a lubricant to prepare various dosage forms such as a tablet.
  • the present invention provides a process for the preparation of the crystalline form 9 of the compound (1).
  • a method for preparing Form 9 comprises: dissolving compound (1) in N,N-dimethylformamide, adding methyl tert-butyl ether to a solid precipitate, and cooling to -5 ° C - 5 ° C to stir and crystallize. The solid is then separated and the solvent is removed to give the crystalline form 9 product.
  • the present invention provides a novel crystalline form of the compound (1), which is referred to as Form 10.
  • the crystal form 10 of the compound (1) has as Lower characteristics: There are diffraction peaks in the X-ray powder diffraction pattern at positions where 2 ⁇ is 10.38, 13.44, 13.95, 16.31, 17.62, 20.48, 22.50, 22.86, and 24.26 degrees.
  • the X-ray powder diffraction pattern of Form 10 of Compound (1) is 9.90, 10.38, 13.44, 13.95, 16.02, 16.31, 16.58, 16.96, 17.62, 20.48, 22.50, 22.86, 24.26 in 2 ⁇ .
  • the position of 32.20 degrees has a diffraction peak.
  • the X-ray powder diffraction pattern of Form 10 of Compound (1) is 2.49, 8.22, 9.90, 10.38, 11.17, 13.44, 13.95, 15.06, 16.02, 16.31, 16.58, 16.96, 17.62 in 2 ⁇ . 19.78, 20.48, 22.50, 22.86, 24.26, 25.79, 32.20 degrees have diffraction peaks.
  • the X-ray powder diffraction pattern of Form 10 of Compound (1) is shown in FIG.
  • Form 10 of Compound (1) also has the property that its differential scanning calorimetry curve (DSC) has an endothermic peak at 209 °C - 215 °C.
  • the differential scanning calorimetry curve (DSC) of Form 10 of Compound (1) has an endothermic peak at 209 °C to 212 °C and an endothermic peak peak value of 211.5 °C.
  • the differential scanning calorimetry (DSC) of Form 10 of Compound (1) is shown in FIG.
  • the crystal form 10 of the present invention was studied, and it was found that the crystal form 10 is not hygroscopic, has good performance in terms of stability, fluidity, etc., and is advantageous for storage, transfer, and operation in a production process, and can be used for preparing a pharmaceutical preparation.
  • the crystalline form 10 of the compound (1) or after being prepared into a salt may be mixed with a pharmaceutically acceptable auxiliary such as a filler, a binder, a disintegrating agent, or a lubricant to prepare various dosage forms such as a tablet.
  • a pharmaceutically acceptable auxiliary such as a filler, a binder, a disintegrating agent, or a lubricant to prepare various dosage forms such as a tablet.
  • the present invention provides a process for the preparation of the crystalline form 10 of the compound (1).
  • a method for preparing the crystalline form 10 comprises: mixing the compound (1) with tetrahydrofuran, isopropanol, dioxane or a combination thereof, heating to form a solution, and adding methyl tert-butyl ether and a ring to the solution at room temperature. Hexane, n-hexane, n-heptane, isopropyl acetate or a mixed solvent thereof until a solid precipitates, and the mixture is stirred at room temperature for 0.1 hour to 12 hours, and then the solid is separated to remove the solvent to obtain the product of the crystal form 10.
  • Fig. 1 shows an X-ray powder diffraction pattern of Form 1 of Compound (1).
  • FIG. 2 shows a differential scanning calorimetry chart (DSC) of Form 1 of Compound (1).
  • Figure 3 shows an X-ray powder diffraction pattern of Form 1 of Compound (1) in one embodiment.
  • Fig. 4 shows an X-ray powder diffraction pattern of Form 3 of Compound (1).
  • Fig. 5 shows an X-ray powder diffraction pattern of Form 4 of Compound (1).
  • Figure 6 shows a differential scanning calorimetry chart (DSC) of Form 4 of Compound (1).
  • Fig. 7 shows an X-ray powder diffraction pattern of Form 5 of Compound (1).
  • Figure 8 shows an X-ray powder diffraction pattern of Form A of the monosodium salt of Compound (1).
  • Figure 9 shows a differential scanning calorimetry chart (DSC) of Form A of the monosodium salt of Compound (1).
  • Figure 10 shows an X-ray powder diffraction pattern of Form 6 of Compound (1).
  • Figure 11 shows a differential scanning calorimetry chart (DSC) of Form 6 of Compound (1).
  • Fig. 12 is a graph showing the thermogravimetric analysis of Form 6 of Compound (1).
  • Figure 13 shows an X-ray powder diffraction pattern of Form 7 of Compound (1).
  • Figure 14 shows a differential scanning calorimetry chart (DSC) of Form 7 of Compound (1).
  • FIG. 15 shows a thermogravimetric analysis chart (TGA) of Form 7 of Compound (1).
  • Figure 16 shows an X-ray powder diffraction pattern of Form 8 of Compound (1).
  • Figure 17 shows a differential scanning calorimetry chart (DSC) of Form 8 of Compound (1).
  • Fig. 18 shows a thermogravimetric analysis chart (TGA) of the crystal form 8 of the compound (1).
  • Figure 19 shows an X-ray powder diffraction pattern of Form 9 of Compound (1).
  • Figure 20 shows a differential scanning calorimetry chart (DSC) of Form 9 of Compound (1).
  • FIG. 21 shows a thermogravimetric analysis chart (TGA) of Form 9 of Compound (1).
  • Figure 22 shows an X-ray powder diffraction pattern of Form 10 of Compound (1).
  • Figure 23 shows a differential scanning calorimetry chart (DSC) of Form 10 of Compound (1).
  • reagents used in the present invention are all commercially available or can be prepared by prior art methods or prepared by the methods described herein.
  • °C represents Celsius
  • g represents gram
  • mL milliliter
  • X-ray powder diffraction (XRPD) analysis was performed using an x'celerator detector equipped with a 2[theta] range of 120[deg.].
  • Real-time data was collected at a resolution of 0.01672 ⁇ using Cu-K ⁇ radiation starting at 2 ⁇ of 3°.
  • the tube voltage and amperage were set to 45 kV and 40 mA, respectively.
  • the anti-scatter slit is set to 6.6 mm and the divergence slit is 1 degree. A pattern of 3°-40° 2 ⁇ is displayed.
  • DSC Differential Scanning Calorimetry
  • the sample was placed in an aluminum DSC pan and the weight recorded accurately.
  • the disc is covered with a lid and then crimped.
  • the sample cell was equilibrated at 25 ° C and heated to a final temperature of 300 ° C at a rate of 10 ° C/min under a nitrogen purge.
  • Indium metal was used as a calibration standard.
  • the abscissa indicates the temperature (Temperature, ° C), and the ordinate indicates the heat flow (Heat Flow, W/g) released by the mass of the unit mass.
  • Thermogravimetric analysis was performed using a thermogravimetric analyzer Q500, and an appropriate amount of the sample was placed in a platinum sample pan and heated at a rate of 10 ° C/min under a nitrogen atmosphere at a temperature ranging from 25 ° C to 300 ° C.
  • the abscissa indicates temperature (°C) and the ordinate indicates mass percentage (%).
  • a mixed solution of methanol and methyl tert-butyl ether was replaced by 8 mL of a mixture of methanol cyclohexane, methanol isopropyl acetate and methanol n-heptane mixture in a volume ratio of 1:1, and the same operation was carried out to obtain crystal form 1 product.
  • a mixed solution of methanol and methyl tert-butyl ether was replaced with 6 mL of a mixture of tetrahydrofuran-n-hexane or tetrahydrofuran-cyclohexane in a volume ratio of 1:5, and the same operation was carried out to obtain a product of crystal form 1.
  • the methanol was replaced by acetone or ethylene glycol dimethyl ether, and the same operation was carried out to obtain a crystalline form 1 product.
  • the methanol 1 was replaced by ethanol, isopropanol or acetonitrile, and the same procedure was carried out to obtain the product of Form 1.
  • 0.1 g of the compound (1) was dissolved in 6 mL of ethanol under ultrasonic conditions, and then 6 mL of ethyl acetate was added thereto, and the mixture was stirred for 10 minutes, and no solid precipitated. Then, the solution was placed in the air at rest and the solvent was evaporated to dryness to obtain a dry powder of 0.1 g, which was confirmed to be crystal form 1.
  • 0.1 g of the compound (1) was dissolved in 8 mL of ethyl acetate under ultrasonic conditions, and 8 mL of methyl tert-butyl ether was added thereto, and the mixture was stirred at room temperature for 30 minutes, and no solid was precipitated. The solution was left to stand in the air at room temperature, and the solution was evaporated to dryness to obtain a dry powder of 0.1 g, which was confirmed to be crystal form 3.
  • n-hexane was replaced by cyclohexane or n-heptane, and the same product was obtained in the same manner.
  • the monosodium salt monosodium salt crystal form A of the obtained compound (1) was beaten with methyl tert-butyl ether, cyclohexane, n-hexane and isopropyl acetate at room temperature for 4 hours, and after filtration and drying, the crystal form was not observed. Change, still crystal form A.
  • n-heptane was replaced with isopropyl acetate, methyl tert-butyl ether, n-hexane or cyclohexane, and the same product was obtained in the same manner.
  • METHODS The samples were placed in a single-layer polyethylene bag (PE bag) and sealed in an aluminum foil bag. They were placed in an environment of 60 ° C and 75% relative humidity for 3 months, and samples were taken on Days 0 and 91, respectively.
  • PE bag polyethylene bag
  • aluminum foil bag The samples were placed in an environment of 60 ° C and 75% relative humidity for 3 months, and samples were taken on Days 0 and 91, respectively.
  • Crystal form of compound (1) 0 days Day 91 Crystal form 1 Crystal form 1 Crystal form 1 Crystal form 3 Crystal form 3 Crystal form 1 Form 4 Form 4 Crystal form 1 Form 5 Form 5 Form 5 Form 6 Form 6 Form 6 Form 7 Form 7 Form 8 Form 8 Crystal form 1 Form 9 Form 9 Crystal form 10 Crystal form 10 Monosodium salt crystal form A Monosodium salt crystal form A Monosodium salt crystal form A Monosodium salt crystal form A Monosodium salt crystal form A Monosodium salt crystal form A Monosodium salt crystal form A Monosodium salt crystal form A Monosodium salt crystal form A Monosodium salt crystal form A Monosodium salt crystal form A Monosodium salt crystal form A Monosodium salt crystal form A Monosodium salt crystal form A Monosodium salt crystal form A Monosodium salt crystal form A Monosodium salt crystal form A Monosodium salt crystal form A Monosodium salt crystal form A Monosodium salt crystal form A Monosodium salt crystal form A Monosodium salt crystal form A Monosodium salt crystal form A
  • crystal form 1, crystal form 5, crystal form 6, crystal form 7, crystal form 9, crystal form 10 and monosodium salt crystal form A are in the test strip.
  • the crystal form of the piece has no change and is relatively stable; while the crystal form 3, the crystal form 4, and the crystal form 8 have a crystal form transition and become the crystal form 1.

Abstract

本发明提供了一种萘环化合物的晶型，属于药物化学领域。所述晶型为晶型1，晶型2，晶型3，晶型4，晶型5，晶型6，晶型7，晶型8，晶型9，或晶型10，各种晶型具有不同的X-射线粉末衍射特征峰。所述晶型不吸湿，在稳定性或流动性等方面具有较好的性质，可以用于制备治疗高尿酸血症或者痛风的药物。本发明还提供了各种晶型的制备方法，通过不同的溶剂或操作方法，可以获得不同的晶型产物。

Description

一种萘环化合物的晶型 技术领域
本发明涉及一种用于治疗痛风的萘环化合物的晶型及其制备方法，属于药物化学领域。
背景技术
化合物2-[[3-(4-氰基萘-1-基)吡啶-4-基]硫代]-2-甲基丙酸，本发明中也称为化合物(1)，是一种尿酸盐阴离子转运体1抑制剂，可用于治疗高尿酸血症和痛风，其结构如式(1)所示：
Figure PCTCN2016095150-appb-000001
专利申请WO2011159839和WO2013067425公开了化合物(1)的制备方法、用途等，但未公开其晶型相关的信息。因药物多晶型是药品研发中的常见现象，是影响药品质量的重要因素。同一药物的不同晶型在外观、流动性、溶解度、储存稳定性、生物利用度等理化性质方面可能会有显著不同，可能存在极大差异，会对药物的储存转移、应用、稳定性、疗效等产生不同的影响；为了得到有效的利于药物制剂的晶型，需要对药物的结晶行为进行全面的考察，以得到满足生产要求的晶型。
发明内容
发明概述
本发明提供了化合物(1)的新晶型及其制备方法。
术语定义
术语“包含”或“包括”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。
术语“晶型”用来描述固体化合物的存在状态，描述晶体内部的离子、原子或分子组成、对称性质与周期排列规律的多种参量集合体。
术语“相对强度”是指将归属于某一晶型的一组衍射峰中的第一强峰的强度定义为100％时，其它峰的 强度与第一强峰的强度的比值。
在本发明的上下文中，X-射线粉末衍射图中的2θ(又称2theta或衍射峰)值均以度(°)为单位。
当提及图谱和/或图中数据，术语“衍射峰”是指本领域的技术人员不会归属于背景噪音的一个特征。
所述晶型的X-射线粉末衍射峰，其X-射线粉末衍射图谱的2θ或衍射峰的量度有实验误差，在一台机器和另一台机器之间以及一个样品和另一个样品之间，X-射线粉末衍射图谱的2θ或衍射峰的量度可能会略有差别，所述实验误差或差别的数值可能是+/-0.2个单位或+/-0.1个单位或+/-0.05个单位，因此所述2θ或衍射峰的数值不能视为绝对的。
所述晶型的差示扫描量热曲线(DSC)有实验误差，在一台机器和另一台机器之间以及一个样品和另一个样品之间，吸热峰的位置和峰值可能会略有差别，实验误差或差别的数值可能小于等于5℃，或小于等于4℃，或小于等于3℃，或小于等于2℃，或小于等于1℃，因此所述DSC吸热峰的峰位置或峰值的数值不能视为绝对的。
所述晶型的热重分析(TGA)有实验误差，在一台机器和另一台机器之间以及一个样品和另一个样品之间，失重温度和失重的量可能会略有差别，实验误差或差别的数值可能是大约+/-0.1个单位，大约+/-0.05个单位，或者大约+/-0.01个单位，因此所述失重温度和失重的量的数值不能视为绝对的。
在本发明上下文中，无论是否使用“大约”或“约”等字眼，所有在此公开了的数字均为近似值。每一个数字的数值有可能会出现1％，2％，或5％等差异。
“室温”是指温度在大约15℃-32℃或大约20℃-30℃或大约23℃-28℃或大约25℃。
术语“良溶剂”可以是单一溶剂或混合溶剂，指样品在该单一溶剂或混合溶剂中的溶解度大于1g/L,或大于2g/L,或大于3g/L,或大于4g/L,或大于5g/L,或大于6g/L,或大于7g/L,或大于8g/L,或大于9g/L,或大于10g/L,或大于15g/L,或大于20g/L,或大于30g/L,或大于40g/L,或大于50g/L,或大于60g/L,或大于70g/L,或大于80g/L,或大于100g/L。在一些实施方案中，样品在良溶剂中的溶解度比不良溶剂大；在一些实施方案中，良溶剂和不良溶剂对样品的溶解度之差大约为10％,20％,30％,40％,50％,60％,70％,80％或90％；在一些实施方案中，良溶剂对样品的溶解度比不良溶剂大，大于10％,20％,30％,40％,50％,60％,70％,80％或90％。
术语“不良溶剂”是指能促进溶液达到过度饱和状态或结晶的溶剂。在一些实施方案中，样品在不良溶剂中的溶解度小于0.001g/L,或小于0.01g/L,或小于0.1g/L,或小于0.2g/L,或小于0.3g/L,或小于0.4g/L,或小于0.5g/L,或小于0.6g/L,或小于0.8g/L,或小于1g/L,或小于2g/L,或小于3g/L,或小于4g/L,或小于5g/L,或小于6g/L,或小于7g/L,或小于8g/L,或小于9g/L,或小于10g/L。
发明详述
第一方面，发明人通过研究开发了化合物(1)的新晶型，称为晶型1。
化合物(1)的晶型1，具有如下特性：其X-射线粉末衍射图中在2θ为10.36,13.89,17.50,24.17度的位置有衍射峰。
一些实施方案中，化合物(1)的晶型1的X-射线粉末衍射图中在2θ为10.36,13.89,17.51,19.41,22.46,24.17度的位置有衍射峰。
一些实施方案中，化合物(1)的晶型1的X-射线粉末衍射图中在2θ为7.48,10.36,13.89,17.51,19.41,20.62,22.46,24.17,28.96,29.39度的位置有衍射峰。
一些实施方案中，化合物(1)的晶型1的X-射线粉末衍射图中在2θ为10.38,13.92,17.54,24.20,28.15度的位置有衍射峰。
一些实施方案中，化合物(1)的晶型1的X-射线粉末衍射图中在2θ为10.38,13.92,17.54,19.48,20.65,22.51,24.20,28.15度的位置有衍射峰。
一些实施方案中，化合物(1)的晶型1的X-射线粉末衍射图中在2θ为7.48,10.36,13.89,14.94,16.51,17.51,19.41,20.62,22.46,24.17,26.51,28.96,29.39,33.79,34.85度的位置有衍射峰。
一些实施方案中，化合物(1)的晶型1的X-射线粉末衍射图中在2θ为7.48,8.30,10.36,13.89,14.94,16.51,17.51,19.41,20.62,22.46,24.17,25.81,26.51,28.96,29.39,31.29,32.4,33.79,34.85度的位置有衍射峰。
一些实施方案中，化合物(1)的晶型1的X-射线粉末衍射图中在2θ为7.48,8.30,10.36,12.42,13.89,14.94,15.29,16.17,16.51,17.51,18.58,19.41,20.62,21.73,22.46,24.17,25.36,25.81,26.51,28.96,29.39,31.29,32.4,33.79,34.85度的位置有衍射峰。
一些实施方案中，化合物(1)的晶型1的X-射线粉末衍射图中在2θ为7.48,8.30,10.36,12.42,13.89,14.94,15.29,16.17,16.51,17.51,18.58,19.41,20.62,21.73,22.46,23.76,24.17,25.36,25.81,26.51,28.96,29.39,30.19,31.29,32.0,32.4,33.79,34.85度的位置有衍射峰。
一些实施方案中，化合物(1)的晶型1的X-射线粉末衍射图如图1所示，其中，在2θ为13.89度的峰的相对强度大于50％，或大于70％，或大于80％，或大于90％，或大于99％。
一些实施方案中，化合物(1)的晶型1的X-射线粉末衍射图如图1所示。
所述化合物(1)的晶型1，还具有如下特性：其差示扫描量热曲线(DSC)在200℃-220℃处具有吸热峰。在一具体实施方案中，化合物(1)的晶型1的差示扫描量热曲线(DSC)在205℃-215℃处具有吸热峰。在一具体实施方案中，化合物(1)的晶型1的差示扫描量热曲线(DSC)在209℃-213℃处具有吸热峰。在一具体实施方案中，化合物(1)的晶型1的差示扫描量热曲线(DSC)在210℃-212℃处具有吸热峰，吸热峰峰顶值 为212℃。在一些实施方案中，化合物(1)的晶型1的差示扫描量热曲线(DSC)如图2所示。
一个实施方案中，化合物(1)的晶型1的X-射线粉末衍射图如图3所示。
对本发明所述晶型1进行研究，发现晶型1不吸湿，在稳定性、流动性方面均具有良好的性能，有利于储存、转移、生产工艺中操作，可用于制备药物制剂。
所述化合物(1)的晶型1或制备成盐后可与药学上可接受的辅料，如填充剂，粘合剂，崩解剂，或润滑剂等混合，制备成各种剂型，如片剂，胶囊，颗粒剂等适合的剂型，用于治疗高尿酸血症或痛风等。
第二方面，本发明提供了制备所述化合物(1)的晶型1的方法。
一种制备晶型1的方法包括：化合物(1)与第一溶剂混合，在一定温度搅拌，然后分离固体，得到晶型1。所述第一溶剂为甲基叔丁基醚、环己烷、正庚烷、异丙醚、或四氢呋喃；或所述第一溶剂为甲醇与甲基叔丁基醚(MTBE)、环己烷、乙酸异丙酯、或正庚烷的混合溶剂；或所述第一溶剂为四氢呋喃与正己烷或环己烷的混合溶剂。所述温度为室温至溶剂的回流温度。所述搅拌的时间为0.5小时-6小时。
在一些实施方案中，化合物(1)与甲基叔丁基醚、环己烷、正庚烷、异丙醚、或四氢呋喃混合，在室温搅拌3小时-5小时，然后分离固体，除去溶剂，得到晶型1。
在一些实施方案中，化合物(1)在甲醇与MTBE、环己烷、乙酸异丙酯、或正庚烷的混合溶剂中，在一定温度搅拌1小时-5小时，分离固体，得到晶型1。
另一方面，一种制备晶型1的方法包括：化合物(1)与第二溶剂混合，加热使其完全溶解，然后降温至-10℃到室温的任意温度，析晶，分离固体，得到晶型1。所述第二溶剂为乙二醇二甲醚，甲醇，乙醇，异丙醇，乙腈，丙酮，水，甲苯，或其组合。
在一些实施方案中，所述第二溶剂为乙二醇二甲醚与甲醇、丙酮、水、或甲苯的混合溶剂。
在一些实施方案中，所述第二溶剂为水与甲醇的混合溶剂，或水与丙酮的混合溶剂。
在一些实施方案中，所述第二溶剂为甲醇，乙醇，异丙醇或乙腈。
另一方面，一种制备晶型1的方法包括：化合物(1)溶解于乙二醇二甲醚，然后与第一不良溶剂混合，搅拌析晶，分离固体，得到晶型1；所述第一不良溶剂为正庚烷或乙酸异丙酯。
另一方面，一种制备晶型1的方法包括：化合物(1)溶于第三溶剂中，然后加入第二不良溶剂，敞口使溶剂挥发至干，得到晶型1。所述第三溶剂为乙二醇二甲醚，甲醇，乙醇，乙腈，乙酸乙酯，异丙醇。所述第二不良溶剂为水，二氯甲烷，甲基叔丁基醚，甲苯，乙腈，正己烷，乙酸乙酯，丙酮，或异丙醇。
在一些实施方案中，所述第三溶剂为乙二醇二甲醚，所述第二不良溶剂为水，二氯甲烷，甲基叔丁基醚，或甲苯。在一些实施方案中，所述第三溶剂为甲醇，所述第二不良溶剂为水，甲基叔丁基醚，乙腈，二氯甲烷，甲苯，或丙酮。在一些实施方案中，所述第三溶剂为乙醇，所述第二不良溶剂为水，甲苯，正己烷，二氯甲烷，乙酸乙酯，甲基叔丁基醚，丙酮，或异丙醇。在一些实施方案中，所述第三溶剂为异丙 醇，所述第二不良溶剂为二氯甲烷，甲基叔丁基醚，甲苯，或正己烷。在一些实施方案中，所述第三溶剂为乙腈，所述第二不良溶剂为水。在一些实施方案中，所述第三溶剂为乙酸乙酯，所述第二不良溶剂为二氯甲烷。
第三方面，本发明提供了化合物(1)的新晶型，称为晶型3。
化合物(1)的晶型3，具有如下特性：其X-射线粉末衍射图中在2θ为10.41,13.13,13.89,15.27,16.58,20.06,24.17度的位置有衍射峰。
一些实施方案中，化合物(1)的晶型3的X-射线粉末衍射图中在2θ为10.41,13.13,13.89,15.27,16.58,17.57,19.16,20.06,20.80,22.31,24.17度的位置有衍射峰。
一些实施方案中，化合物(1)的晶型3的X-射线粉末衍射图中在2θ为9.54,10.41,10.88,13.13,13.89,15.27,16.58,17.57,19.16,20.06,20.80,21.31,22.31,23.73,24.17度的位置有衍射峰。
一些实施方案中，化合物(1)的晶型3的X-射线粉末衍射图中在2θ为9.54,10.41,10.88,13.13,13.89,15.27,16.58,17.57,19.16,20.06,20.80,21.31,22.31,24.17,27.56,28.34,29.41,31.35度的位置有衍射峰。
一些实施方案中，化合物(1)的晶型3的X-射线粉末衍射图中在2θ为6.89,7.54,9.54,10.41,10.88,13.13,13.89,15.27,16.58,17.57,19.16,20.06,20.80,21.31,22.31,23.05,23.73,24.17,26.32,27.56,28.34,29.41,31.35,32.97度的位置有衍射峰。
一些实施方案中，化合物(1)的晶型3的X-射线粉末衍射图如图4所示，其中，在2θ为16.58度的峰的相对强度大于50％，或大于70％，或大于80％，或大于90％，或大于99％。
一些实施方案中，化合物(1)的晶型3的X-射线粉末衍射图如图4所示。
对本发明所述晶型3进行研究，发现晶型3不吸湿，在流动性方面均具有良好的性能，有利于储存、转移、生产工艺中操作，可用于制备药物制剂。
所述化合物(1)的晶型3或制备成盐后可与药学上可接受的辅料，如填充剂，粘合剂，崩解剂，或润滑剂等混合，制备成各种剂型，如片剂，胶囊，颗粒剂等适合的剂型，用于治疗高尿酸血症或痛风等。
第四方面，本发明提供了所述化合物(1)的晶型3的制备方法。
一种制备晶型3的方法包括：化合物(1)溶于乙二醇二甲醚，然后加入甲基叔丁基醚，搅拌3小时-6小时，分离固体，除去溶剂，得到晶型3。
化合物(1)溶于乙二醇二甲醚时，可以采取加热或超声或其它有利于溶解的方法。
一种制备晶型3的方法包括：化合物(1)溶于乙酸乙酯，然后加入甲基叔丁基醚，混合均匀后敞口使溶剂挥发至干，得到晶型3。
一种制备晶型3的方法包括：化合物(1)与氯仿或异丙醇混合，加热，形成溶液，再滴加甲基叔丁基醚；然后搅拌或降温搅拌至固体析出，搅拌析晶0.1小时-12小时，分离固体，除去溶剂，得到晶型3产物。
第五方面，本发明提供了化合物(1)的新晶型，称为晶型4。
化合物(1)的晶型4，具有如下特性：其X-射线粉末衍射图中在2θ为9.79,13.20,13.85,15.94,17.46,20.32,23.06,28.68度的位置有衍射峰。
一些实施方案中，化合物(1)的晶型4的X-射线粉末衍射图中在2θ为9.79,11.35,13.20,13.85,15.94,17.46,19.81,20.32,20.72,21.66,22.70,23.06,25.56,28.68度的位置有衍射峰。
一些实施方案中，化合物(1)的晶型4的X-射线粉末衍射图中在2θ为9.79,11.35,13.20,13.85,15.94,16.47,17.07,17.46,19.81,20.32,20.72,21.66,22.70,23.06,24.03,25.56,27.91,28.68,29.64,32.44度的位置有衍射峰。
一些实施方案中，化合物(1)的晶型4的X-射线粉末衍射图中在2θ为8.00,9.79,11.35,12.05,13.20,13.85,15.94,16.47,17.07,17.46,18.79,19.81,20.32,20.72,21.66,22.12,22.70,23.06,24.03,24.50,25.56,27.91,28.68,29.64,32.44,35.22度的位置有衍射峰。
一些实施方案中，化合物(1)的晶型4的X-射线粉末衍射图如图5所示，其中，在2θ为23.06度的峰的相对强度大于50％，或大于70％，或大于80％，或大于90％，或大于99％。
一些实施方案中，化合物(1)的晶型4的X-射线粉末衍射图如图5所示。
所述化合物(1)的晶型4，还具有如下特性：其差示扫描量热曲线(DSC)在约200℃-215℃处具有吸热峰。在一具体实施方案中，化合物(1)的晶型4的差示扫描量热曲线(DSC)在约202℃-213℃处具有吸热峰。在一具体实施方案中，化合物(1)的晶型4的差示扫描量热曲线(DSC)在约203℃-210℃处具有吸热峰，吸热峰峰顶值为208℃。在一些实施方案中，化合物(1)的晶型4的差示扫描量热曲线(DSC)如图6所示。
对本发明所述晶型4进行研究，发现晶型4不吸湿，在流动性方面具有良好的性能，但晶型4在室温放置一定时间后向晶型1转变。所述化合物(1)的晶型4或制备成盐后可与药学上可接受的辅料，如填充剂，粘合剂，崩解剂，或润滑剂等混合，制备成各种剂型，如片剂，胶囊，颗粒剂等适合的剂型，用于治疗高尿酸血症或痛风等。
第六方面，本发明提供了所述化合物(1)的晶型4的制备方法。
一种制备晶型4的方法包括：化合物(1)溶于乙酸乙酯，然后加入甲苯，混合均匀后敞口使溶剂挥发至干，得到晶型4。
一种制备晶型4的方法包括：化合物(1)加热溶于2-甲基四氢呋喃中，然后在室温下滴加正己烷、环己烷、正庚烷或其组合溶剂，析出固体，搅拌析晶0.5小时-8小时，分离固体，除去溶剂，得到晶型4产 物。
第七方面，本发明提供了化合物(1)的新晶型，称为晶型5。
化合物(1)的晶型5，具有如下特性：其X-射线粉末衍射图中在2θ为8.77,17.55,19.82,23.74,27.33,35.48度的位置有衍射峰。
一些实施方案中，化合物(1)的晶型5的X-射线粉末衍射图中在2θ为8.77,11.09,12.48,15.38,16.16,17.55,18.89,19.82,20.97,22.22,23.74,27.33,28.88,35.48度的位置有衍射峰。
一些实施方案中，化合物(1)的晶型5的X-射线粉末衍射图如图7所示，其中，在2θ为17.55度的峰的相对强度大于50％，或大于70％，或大于80％，或大于90％，或大于99％。
一些实施方案中，化合物(1)的晶型5的X-射线粉末衍射图如图7所示。
所述化合物(1)的晶型5，还具有如下特性：其差示扫描量热曲线(DSC)在约130℃-155℃处具有吸热峰。在一具体实施方案中，化合物(1)的晶型5的差示扫描量热曲线(DSC)在约132℃-150℃处具有吸热峰。在一具体实施方案中，化合物(1)的晶型5的差示扫描量热曲线(DSC)在约132℃-149℃处具有吸热峰，吸热峰峰顶值为148.6℃。
对本发明所述晶型5进行研究，发现晶型5也不吸湿，在稳定性、流动性等方面均具有良好的性能，有利于储存、转移、生产工艺中操作，可用于制备药物制剂。
所述化合物(1)的晶型5或制备成盐后可与药学上可接受的辅料，如填充剂，粘合剂，崩解剂，或润滑剂等混合，制备成各种剂型，如片剂，胶囊，颗粒剂等适合的剂型，用于治疗高尿酸血症或痛风等。
第八方面，本发明提供了所述化合物(1)的晶型5的制备方法。
在一些实施方式中，一种制备晶型5的方法包括：化合物(1)在40℃-60℃溶于乙二醇二甲醚，然后控温30℃-60℃，加入环己烷，加毕，混合液在10℃-40℃搅拌4小时-6小时，分离固体，所得固体除去溶剂，得到晶型5。
在一些实施方式中，一种制备晶型5的方法包括：化合物(1)与氯仿混合，加热形成溶液，然后在室温下滴加环己烷，有固体析出，继续搅拌0.5小时-8小时，然后分离固体，除去溶剂，得到晶型5产物。
第九方面，本发明提供了所述化合物(1)的单钠盐、单钠盐的晶型A。所述化合物(1)的单钠盐的晶型A具有如下特性：其X-射线粉末衍射图中在2θ为10.15,13.04,15.42,16.88,20.07,21.86,24.62,26.69,31.11,34.47度的位置有衍射峰。
一些实施方案中，化合物(1)的单钠盐的晶型A的X-射线粉末衍射图中在2θ为10.15,12.19,13.04,15.42,15.64,16.88,18.67,19.23,20.07,21.86,22.93,23.57,24.62,25.81,26.69,27.13,28.72,29.23, 31.11,34.47度的位置有衍射峰。
一些实施方案中，化合物(1)的单钠盐的晶型A的X-射线粉末衍射图中在2θ为7.10,10.15,12.19,13.04,15.42,15.64,16.88,18.67,19.23,20.07,20.91,21.43,21.86,22.52,22.93,23.57,24.62,25.81,26.69,27.13,28.72,29.23,29.59,31.11,31.69,32.97,34.47度的位置有衍射峰。
一些实施方案中，化合物(1)的单钠盐的晶型A的X-射线粉末衍射图中在2θ为5.15,7.10,10.15,12.19,13.04,14.24,15.42,15.64,16.88,18.25,18.67,19.23,20.07,20.55,20.91,21.43,21.86,22.52,22.93,23.57,24.62,25.81,26.69,27.13,27.63,28.72,29.23,29.59,31.11,31.69,32.00,32.41,32.97,34.47,39.05度的位置有衍射峰。
一些实施方案中，化合物(1)的单钠盐的晶型A的X-射线粉末衍射图如图8所示，其中，在2θ为13.04度的峰的相对强度大于50％，或大于70％，或大于80％，或大于90％，或大于99％。
一些实施方案中，化合物(1)的单钠盐的晶型A的X-射线粉末衍射图如图8所示。
所述化合物(1)的单钠盐的晶型A，还具有如下特性：其差示扫描量热曲线(DSC)在100℃-125℃处具有吸热峰和165℃-195℃处有吸热峰。在一具体实施方案中，化合物(1)的单钠盐的晶型A的差示扫描量热曲线(DSC)在105℃-120℃处具有吸热峰和170℃-190℃处具有吸热峰。在一具体实施方案中，化合物(1)的单钠盐的晶型A的差示扫描量热曲线(DSC)在110℃-120℃处具有吸热峰，吸热峰峰顶值为120℃，在175℃-190℃处具有吸热峰，吸热峰峰顶值为186℃。在一些实施方案中，化合物(1)的单钠盐的晶型A的差示扫描量热曲线(DSC)如图9所示。
对本发明所述化合物(1)的单钠盐的晶型A进行研究，发现化合物(1)的单钠盐的晶型A在水中具有较好的溶解度，且晶型A不吸湿，在稳定性、流动性等方面均具有良好的性能，有利于储存、转移、生产工艺中操作，可用于制备药物制剂。
所述化合物(1)的单钠盐的晶型A可与药学上可接受的辅料，如填充剂，粘合剂，崩解剂，或润滑剂等混合，制备成各种剂型，如片剂，胶囊，颗粒剂等适合的剂型，用于治疗高尿酸血症或痛风等。
第十方面，本发明提供了所述化合物(1)的单钠盐的晶型A的制备方法。
一种制备化合物(1)的单钠盐的晶型A的方法包括：化合物(1)的单钠盐溶于水中，然后进入氯化钠固体，在室温搅拌3小时-15小时，然后分离固体，所得固体除去残余溶剂，得到晶型A，其中，氯化钠与水的质量比为不高于20％。在一些实施方式中，其中，氯化钠与水的质量比为1％-10％。在一些实施方式中，其中，氯化钠与水的质量比为1％-5％。在一些实施方式中，其中，氯化钠与水的质量比为5％-10％。
第十一方面，本发明提供了所述化合物(1)的新晶型，称为晶型6。所述化合物(1)的晶型6具有如下特性：其X-射线粉末衍射图中在2θ为13.84，14.52，16.01，18.41，18.82，21.30，22.00，24.37，25.36度的位 置有衍射峰。
一些实施方案中，化合物(1)的晶型6的X-射线粉末衍射图中在2θ为10.30,10.57,13.84,14.52,16.01,17.08,17.45,18.41,18.82,19.76,20.12,21.30,22.00,23.49,24.37,25.36,32.49,39.23度的位置有衍射峰。
一些实施方案中，化合物(1)的晶型6的X-射线粉末衍射图如图10所示。
化合物(1)的晶型6还具有如下特性：其差示扫描量热曲线(DSC)在130℃-150℃处具有吸热峰和210℃-220℃处有吸热峰。在一具体实施方案中，化合物(1)的晶型6的差示扫描量热曲线(DSC)在135℃-145℃处具有吸热峰和215℃-219℃处具有吸热峰。在一具体实施方案中，化合物(1)的晶型6的差示扫描量热曲线(DSC)在140℃-145℃处具有吸热峰，吸热峰峰顶值为144℃，在215℃-219℃处具有吸热峰，吸热峰峰顶值为218℃。在一具体实施方案中，化合物(1)的晶型6的差示扫描量热曲线(DSC)如图11所示。
化合物(1)的晶型6还具有如下特性：其热重分析曲线(TGA)显示在100℃-150℃有失重，失重量约为8％-10％。在一具体实施方案中，化合物(1)的晶型6的热重分析曲线(TGA)显示在100℃-150℃有失重，失重量约为10％。在一具体实施方案中，化合物(1)的晶型6的热重分析曲线(TGA)如图12所示。
对本发明所述晶型6进行研究，晶型6不吸湿，在稳定性和流动性等方面均具有良好的性能，有利于储存、转移、生产工艺中操作，可用于制备药物制剂。
所述化合物(1)的晶型6或制备成盐后可与药学上可接受的辅料，如填充剂，粘合剂，崩解剂，或润滑剂等混合，制备成各种剂型，如片剂，胶囊，颗粒剂等适合的剂型，用于治疗高尿酸血症或痛风等。
第十二方面，本发明提供了所述化合物(1)的晶型6的制备方法。
一种制备晶型6的方法包括：化合物(1)与冰醋酸混合，加热回流，然后向所得混合液加入水，将混合液降温至有固体析出，保温搅拌；然后将混合液降温至室温，保温搅拌；分离固体并除去溶剂，得到晶型6产物。
第十三方面，本发明提供了所述化合物(1)的新晶型，称为晶型7。所述化合物(1)的晶型7具有如下特性：其X-射线粉末衍射图中在2θ为10.30,13.83,14.87,16.06,18.06,19.76,21.03,23.02,24.18,25.25度的位置有衍射峰。
一些实施方案中，化合物(1)的晶型7的X-射线粉末衍射图中在2θ为8.25,10.30,13.83,14.87,16.06,16.97,18.06,19.76,20.31,20.67,21.03,23.02,24.18,25.25,28.43,29.06,31.66度的位置有衍射峰。
一些实施方案中，化合物(1)的晶型7的X-射线粉末衍射图如图13所示，其中，在2θ为13.83度的峰的相对强度大于50％，或大于70％，或大于80％，或大于90％，或大于99％。
一些实施方案中，化合物(1)的晶型7的X-射线粉末衍射图如图13所示。
化合物(1)的晶型7还具有如下特性：其差示扫描量热曲线(DSC)在215℃-225℃处具有吸热峰。在一具体实施方案中，化合物(1)的晶型7的差示扫描量热曲线(DSC)在215℃-219℃处具有吸热峰，吸热峰峰顶值为217℃。在一具体实施方案中，化合物(1)的晶型7的差示扫描量热曲线(DSC)如图14所示。
化合物(1)的晶型7还具有如下特性：其热重分析曲线(TGA)显示在100℃-150℃有失重，失重量约为0.5％-2％。在一具体实施方案中，化合物(1)的晶型7的热重分析曲线(TGA)显示在100℃-150℃有失重，失重量约为1.8％。在一具体实施方案中，化合物(1)的晶型7的热重分析曲线(TGA)如图15所示。
对本发明所述晶型7进行研究，发现晶型7不吸湿，易于过滤分离，在稳定性、流动性等方面均具有良好的性能，有利于储存、转移、生产工艺中操作，可用于制备药物制剂。
所述化合物(1)的晶型7或制备成盐后可与药学上可接受的辅料，如填充剂，粘合剂，崩解剂，或润滑剂等混合，制备成各种剂型，如片剂，胶囊，颗粒剂等适合的剂型，用于治疗高尿酸血症或痛风等。
第十四方面，本发明提供了所述化合物(1)的晶型7的制备方法。
一种制备晶型7的方法包括：化合物(1)与冰醋酸混合，加热回流；然后向所得混合液中加入水，降温至室温或者降温至0℃-5℃，保温搅拌；分离固体并除去溶剂，得到晶型7产物。
第十五方面，本发明提供了所述化合物(1)的新晶型，称为晶型8。所述化合物(1)的晶型8具有如下特性：其X-射线粉末衍射图中在2θ为10.26,13.83,14.31,19.08,19.46,20.14,21.91,23.87,24.19,29.10度的位置有衍射峰。
一些实施方案中，化合物(1)的晶型8的X-射线粉末衍射图中在2θ为7.52,10.26,13.83,14.31,15.01,16.06,16.91,17.48,18.61,19.08,19.46,20.14,21.91,22.49,23.87,24.19,29.10度的位置有衍射峰。
一些实施方案中，化合物(1)的晶型8的X-射线粉末衍射图如图16所示。
化合物(1)的晶型8还具有如下特性：其差示扫描量热曲线(DSC)在206℃-215℃处具有吸热峰。在一具体实施方案中，化合物(1)的晶型8的差示扫描量热曲线(DSC)在207℃-212℃处具有吸热峰，吸热峰峰顶值为210.5℃。在一具体实施方案中，化合物(1)的晶型8的差示扫描量热曲线(DSC)如图17所示。
化合物(1)的晶型8还具有如下特性：其热重分析曲线(TGA)显示在100℃-150℃有失重，失重量约为2.5％-4.5％。在一具体实施方案中，化合物(1)的晶型8的热重分析曲线(TGA)显示在100℃-150℃有失重，失重量约为4％。在一具体实施方案中，化合物(1)的晶型8的热重分析曲线(TGA)如图18所示。
对本发明所述晶型8进行研究，发现晶型8不吸湿，在流动性等方面均具有良好的性能，有利于储存、转移、生产工艺中操作，可用于制备药物制剂。
所述化合物(1)的晶型8或制备成盐后可与药学上可接受的辅料，如填充剂，粘合剂，崩解剂，或润滑剂等混合，制备成各种剂型，如片剂，胶囊，颗粒剂等适合的剂型，用于治疗高尿酸血症或痛风等。
第十六方面，本发明提供了所述化合物(1)的晶型8的制备方法。
一种制备晶型8的方法包括：化合物(1)溶于氯仿，然后加入正庚烷或环己烷或其混合物，析出固体，搅拌析晶，然后分离固体，除去溶剂，得到晶型8产物。
第十七方面，本发明提供了所述化合物(1)的新晶型，称为晶型9。所述化合物(1)的晶型9具有如下特性：其X-射线粉末衍射图中在2θ为9.97,12.66,15.56,16.54,17.69,18.31,21.80,25.14,25.67度的位置有衍射峰。
一些实施方案中，化合物(1)的晶型9的X-射线粉末衍射图中在2θ为9.97,12.66,14.92,15.56,16.54,17.69,18.31,19.19,20.77,21.80,22.84,25.14,25.67,27.36,30.12度的位置有衍射峰。
一些实施方案中，化合物(1)的晶型9的X-射线粉末衍射图中在2θ为6.79,9.97,12.66,13.54,14.92,15.56,16.54,17.32,17.69,18.31,19.19,19.79,20.77,21.80,22.84,24.27,25.14,25.67,26.23,27.36,27.94,28.60,29.61,30.12度的位置有衍射峰。
一些实施方案中，化合物(1)的晶型9的X-射线粉末衍射图如图19所示，其中，在2θ为12.66度的峰的相对强度大于50％，或大于70％，或大于80％，或大于90％，或大于99％。
一些实施方案中，化合物(1)的晶型9的X-射线粉末衍射图如图19所示。
化合物(1)的晶型9还具有如下特性：其差示扫描量热曲线(DSC)在155℃-175℃处具有吸热峰。在一具体实施方案中，化合物(1)的晶型9的差示扫描量热曲线(DSC)在155℃-170℃处具有吸热峰，吸热峰峰顶值为165℃。在一具体实施方案中，化合物(1)的晶型9的差示扫描量热曲线(DSC)如图20所示。
化合物(1)的晶型9还具有如下特性：其热重分析曲线(TGA)显示在100℃-150℃有失重，失重量约为5％-7％。在一具体实施方案中，化合物(1)的晶型9的热重分析曲线(TGA)显示在100℃-150℃有失重，失重量约为6.6％。在一具体实施方案中，化合物(1)的晶型9的热重分析曲线(TGA)如图21所示。
对本发明所述晶型9进行研究，发现晶型9不吸湿，在流动性等方面均具有良好的性能，有利于储存、转移、生产工艺中操作，可用于制备药物制剂。
所述化合物(1)的晶型9或制备成盐后可与药学上可接受的辅料，如填充剂，粘合剂，崩解剂，或润滑剂等混合，制备成各种剂型，如片剂，胶囊，颗粒剂等适合的剂型，用于治疗高尿酸血症或痛风等。
第十八方面，本发明提供了所述化合物(1)的晶型9的制备方法。
一种制备晶型9的方法包括：化合物(1)溶于N,N-二甲基甲酰胺中，加入甲基叔丁基醚至固体析出，降温至-5℃-5℃搅拌析晶，然后分离固体，除去溶剂，得到晶型9产物。
第十九方面，本发明提供了所述化合物(1)的新晶型，称为晶型10。所述化合物(1)的晶型10具有如 下特性：其X-射线粉末衍射图中在2θ为10.38,13.44,13.95,16.31,17.62,20.48,22.50,22.86,24.26度的位置有衍射峰。
一些实施方案中，化合物(1)的晶型10的X-射线粉末衍射图中在2θ为9.90,10.38,13.44,13.95,16.02,16.31,16.58,16.96,17.62,20.48,22.50,22.86,24.26,25.79,32.20度的位置有衍射峰。
一些实施方案中，化合物(1)的晶型10的X-射线粉末衍射图中在2θ为7.49,8.22,9.90,10.38,11.17,13.44,13.95,15.06,16.02,16.31,16.58,16.96,17.62,19.78,20.48,22.50,22.86,24.26,25.79,32.20度的位置有衍射峰。
一些实施方案中，化合物(1)的晶型10的X-射线粉末衍射图如图22所示。
化合物(1)的晶型10还具有如下特性：其差示扫描量热曲线(DSC)在209℃-215℃处具有吸热峰。在一具体实施方案中，化合物(1)的晶型10的差示扫描量热曲线(DSC)在209℃-212℃处具有吸热峰，吸热峰峰顶值为211.5℃。在一具体实施方案中，化合物(1)的晶型10的差示扫描量热曲线(DSC)如图23所示。
对本发明所述晶型10进行研究，发现晶型10不吸湿，在稳定性、流动性等方面均具有良好的性能，有利于储存、转移、生产工艺中操作，可用于制备药物制剂。
所述化合物(1)的晶型10或制备成盐后可与药学上可接受的辅料，如填充剂，粘合剂，崩解剂，或润滑剂等混合，制备成各种剂型，如片剂，胶囊，颗粒剂等适合的剂型，用于治疗高尿酸血症或痛风等。
第二十方面，本发明提供了所述化合物(1)的晶型10的制备方法。
一种制备晶型10的方法包括：化合物(1)与四氢呋喃、异丙醇、二氧六环或其组合溶剂混合，加热，形成溶液，室温下向溶液中加入甲基叔丁基醚、环己烷、正己烷、正庚烷、乙酸异丙酯或其混合溶剂至有固体析出，室温搅拌0.1小时-12小时，然后分离固体，除去溶剂，得到晶型10产物。
附图说明
图1示化合物(1)的晶型1的X-射线粉末衍射图。
图2示化合物(1)的晶型1的差示扫描量热曲线图(DSC)。
图3示一种实施方案中化合物(1)的晶型1的X-射线粉末衍射图。
图4示化合物(1)的晶型3的X-射线粉末衍射图。
图5示化合物(1)的晶型4的X-射线粉末衍射图。
图6示化合物(1)的晶型4的差示扫描量热曲线图(DSC)。
图7示化合物(1)的晶型5的X-射线粉末衍射图。
图8示化合物(1)的单钠盐的晶型A的X-射线粉末衍射图。
图9示化合物(1)的单钠盐的晶型A的差示扫描量热曲线图(DSC)。
图10示化合物(1)的晶型6的X-射线粉末衍射图。
图11示化合物(1)的晶型6的差示扫描量热曲线图(DSC)。
图12示化合物(1)的晶型6的热重分析曲线图。
图13示化合物(1)的晶型7的X-射线粉末衍射图。
图14示化合物(1)的晶型7的差示扫描量热曲线图(DSC)。
图15示化合物(1)的晶型7的热重分析曲线图(TGA)。
图16示化合物(1)的晶型8的X-射线粉末衍射图。
图17示化合物(1)的晶型8的差示扫描量热曲线图(DSC)。
图18示化合物(1)的晶型8的热重分析曲线图(TGA)。
图19示化合物(1)的晶型9的X-射线粉末衍射图。
图20示化合物(1)的晶型9的差示扫描量热曲线图(DSC)。
图21示化合物(1)的晶型9的热重分析曲线图(TGA)。
图22示化合物(1)的晶型10的X-射线粉末衍射图。
图23示化合物(1)的晶型10的差示扫描量热曲线图(DSC)。
具体实施方式
为了使本领域的技术人员更好地理解本发明的技术方案，下面进一步披露一些非限制实施例对本发明作进一步的详细说明。
本发明所使用的试剂均可以从市场上购得或者可以通过现有技术的方法制备或者通过本发明所描述的方法制备而得。
本发明中，℃表示摄氏度，g表示克，mL表示毫升。
仪器参数
除非参数中另行规定，以下所有分析都在室温下进行。
X-射线粉末衍射(XRPD)
使用配有具有120°的2θ范围的x'celerator检测器进行X-射线粉末衍射(XRPD)分析。使用Cu-Kα辐射在2θ为3°开始以0.01672θ分辨率收集实时数据。将管电压和安培数分别设定为45kV和40mA。防散射狭缝设定为6.6mm，发散狭缝为1度。显示3°-40°2θ的图案。取适量的晶型样品置于零背景样品架圆形凹槽处，用干净的载玻片轻压，得到一个平整的平面，并将零背景样品架固定，即得，将样品置于自动进样装置上，依次进样。使用硅参考标样进行仪器校准。在SSCI,Inc.根据cGMP规格收集实验XRPD图。在X-射线粉末衍射图中，纵坐标为用计数(counts)表示的衍射强度，横坐标为用度(°)表示的衍射角2θ。
差示扫描量热法(DSC)
使用TA Instruments差示扫描量热计Q2000进行差示扫描量热法(DSC)。将样品放入铝DSC盘中并精确记录重量。该盘用盖子覆盖，然后压接。将样品池在25℃下平衡并在氮气吹扫下以10℃/min的速率加热至300℃的最终温度。使用铟金属作为校准标样。在DSC图中，横坐标表示温度(Temperature,℃)，纵坐标表示单位质量的物质放出的热流量(Heat Flow,W/g)。
热重分析法(TGA)
使用热重分析仪Q500进行热重分析，将适量样品放置在铂样品盘中，在氮气氛下，以10℃/分钟速率升温，温度范围为25℃至300℃。在TGA图中，横坐标表示温度(Temperature,℃)，纵坐标表示质量百分数(Weight,％)。
实施例1
将化合物(1)0.3克加入到10mL甲基叔丁基醚中，室温搅拌打浆4小时；过滤，所得固体在50℃真空干燥至干，得到固体0.24g，检测固体，为晶型1，参见图1和图2。
用环己烷、正庚烷或异丙醚10mL替代甲基叔丁基醚，同样操作获得晶型1产物。
实施例2
将化合物(1)0.3克加入到3mL四氢呋喃中，室温搅拌打浆4小时；过滤，所得固体在50℃真空干燥至干，得到固体0.24g，检测，为晶型1。
实施例3
化合物(1)0.4克加入到8mL甲醇和甲基叔丁基醚的混合溶液(体积比1:1)中，50℃加热搅拌4小时；然后降温至10℃-20℃，过滤，所得固体在50℃真空干燥至干，得到固体0.35g，检测，为晶型1。
用体积比为1:1的甲醇环己烷混合液、甲醇乙酸异丙酯混合液、甲醇正庚烷混合液8mL替代甲醇和甲基叔丁基醚的混合溶液，同样操作，得到晶型1产物。
用体积比为1:5的四氢呋喃正己烷混合液或四氢呋喃环己烷混合液6mL替代甲醇和甲基叔丁基醚的混合溶液，同样操作，得到晶型1产物。
实施例4
化合物(1)0.5g中加入乙二醇二甲醚1mL和甲醇15mL，搅拌，升温至60℃搅拌澄清；然后降温至0℃，过滤，所得固体在50℃真空干燥，得到产物0.38g，经过检测，为晶型1。
以乙二醇二甲醚1mL和甲醇15mL，或乙二醇二甲醚3mL和丙酮20mL，或乙二醇二甲醚3mL和甲苯20mL替代乙二醇二甲醚1mL和甲醇15mL，同样操作，得到晶型1产物。
实施例5
化合物(1)0.5g中加入乙二醇二甲醚2mL，搅拌溶解；滴加正庚烷12mL，固体析出，室温搅拌4小时。过滤，所得固体在50℃真空干燥，得到晶型1产物0.37g。
以乙酸异丙酯替代正庚烷，同样操作，得到晶型1产物。
实施例6
化合物(1)4.0g中加入4mL水和40mL甲醇，加热回流至完全溶解；然后将混合液缓慢降温至5℃，搅拌2小时后过滤，所得固体在50℃真空干燥至干，得到晶型1产物3.1g。
以丙酮或乙二醇二甲醚替代甲醇，同样操作，得到晶型1产物。
实施例7
化合物(1)0.2g中加入甲醇5mL，加热回流至完全溶解；然后将溶液降温至0℃-5℃，析出固体，过滤，所得固体在50℃真空干燥至干，得到晶型1产物0.15g。
以乙醇，异丙醇或乙腈替代甲醇，同样操作，得到晶型1产物。
实施例8
将化合物(1)0.1g超声条件下溶于6mL乙醇中，然后加入6mL乙酸乙酯，搅拌10分钟，无固体析出。然后将溶液静止敞口置于空气中，溶剂挥发干后，得到干燥粉末0.1g，检测确认为晶型1。
实施例9
化合物(1)0.3g中加入10mL乙酸异丙酯，室温搅拌打浆4小时，过滤，所得固体在50℃真空干燥至干，得到粉末0.2g，经过检测确认，为图3所示的晶型1，参见图3。
以正己烷替代乙酸异丙酯，同样操作，得到晶型1产物。
实施例10
化合物(1)0.5g与2mL乙二醇二甲醚混合，室温搅拌溶解；滴加甲基叔丁基醚12mL，固体析出，室温搅拌4小时，然后过滤，所得固体在50℃真空干燥12小时，得到产物0.35g，经过检测，为晶型3，参见图4。
实施例11
化合物(1)0.3g加入至3mL氯仿中，搅拌，加热至回流，有少量固体不溶，趁热过滤；向所得滤液中滴加甲基叔丁基醚18mL，滴毕无固体析出。继续搅拌至固体开始析出，再搅拌6小时；然后过滤，所得固体50℃真空干燥12小时，得到晶型3产物0.2g。
实施例12
化合物(1)0.3g和3mL异丙醇混合，加热至85℃使固体溶解。停止加热，反应体系转移至室温下，向溶液中缓慢滴加甲基叔丁基醚18mL，滴毕无固体析出。冷却至0℃，搅拌1.5小时后有固体析出，继续搅拌6小时。然后过滤，所得固体50℃真空干燥12小时，得到晶型3产物0.2g。
实施例13
化合物(1)0.1g在超声条件下溶于8mL乙酸乙酯中，加入甲基叔丁基醚8mL，室温搅拌30分钟，无固体析出。将溶液室温敞口静置于空气中，溶液挥发至干，得到干燥粉末0.1g，经过检测确认为晶型3。
实施例14
化合物(1)0.1g在超声条件下溶于8mL乙酸乙酯中，加入甲苯8mL，室温搅拌30分钟，无固体析出。将溶液室温敞口静置于空气中，溶液挥发至干，得到干燥粉末0.11g，经过检测确认为晶型4，参见图5和图6。
实施例15
化合物(1)0.25g在40℃-60℃条件下溶于和3mL的2-甲基四氢呋喃中，然后将溶液降温至25℃-30℃；向溶液中滴加正己烷18mL，有固体析出，加毕继续搅拌6小时；然后过滤，所得固体在50℃真空干燥12小时，得到晶型4产物0.16g。
以环己烷或正庚烷替代正己烷，同样操作，也得到晶型4产物。
实施例16
化合物(1)0.5g加入至4mL乙二醇二甲醚中，室温搅拌不溶解，加热至40℃-60℃。固体溶解后，在30℃-60℃范围内滴加环已烷24mL至上述体系中，期间有固体析出，滴毕，在10℃-40℃继续搅拌4小时-6小时，过滤，所得固体在50℃真空干燥，得到干燥粉末0.4g，经过检测确认为晶型5，参见图7。
实施例17
化合物(1)0.3g加入至3mL氯仿中，加热，有部分固体不溶，趁热过滤；室温下向所得滤液中滴加环己烷18mL，滴加过程中即有固体析出；加毕，继续搅拌6小时；然后过滤，所得固体在50℃真空干燥12小时，得到晶型5产物0.17g。
实施例18
化合物(1)的单钠盐10g溶解在100mL水中，缓慢加入氯化钠固体5g，室温(25℃)搅拌，此过程有固体析出并逐渐增多，搅拌12h后过滤，所得固体在60℃真空干燥，得产物8.5g，检测为化合物(1)的单钠盐晶型A，参见图8和图9。
所得化合物(1)的单钠盐单钠盐晶型A以甲基叔丁基醚、环已烷、正已烷、乙酸异丙酯在室温打浆4小时，过滤干燥后检测，晶型未见变化，仍然为晶型A。
实施例19
化合物(1)2.0g和冰乙酸12mL混合，加热至回流，固体全部溶解。停止加热，向所形成的溶液中分批加入水3mL、5mL、3mL，体系仍然澄清。搅拌下缓慢降温，当温度为80℃时有少量固体析出，保温搅拌3小时。然后搅拌下降至室温，在室温搅拌析晶6小时，过滤，所得固体在50℃真空干燥12小时，得到产物1.6g，经过检测，为晶型6，参见图10，图11和图12。
实施例20
反应瓶中，加入化合物(1)2.0g，冰乙酸12mL，加热至回流，固体全部溶解。停止加热，向所形成的溶液中分批加入水3mL、5mL、3mL，体系仍然澄清。然后将反应瓶移至5℃冰水浴中搅拌，有固体析出；搅拌析晶6小时，过滤，所得固体在50℃真空干燥12小时，得产物1.6g，经过检测，为晶型7，参见图13，图14和图15。
实施例21
化合物(1)2.0g和冰乙酸12mL混合，加热至回流，固体全部溶解。停止加热，向所形成的溶液中分批加入水3mL、5mL、3mL，体系仍然澄清。然后将混合液在空气中搅拌降温至室温，有固体析出，搅拌析晶6小时，过滤，所得固体在50℃真空干燥12小时，得晶型7产物1.5g。
实施例22
化合物(1)0.3g和氯仿3mL混合，加热仍有少量固体不溶，趁热过滤得澄清溶液，向所得滤液中缓慢滴加正庚烷18mL，滴加过程中即有固体析出，加毕，继续搅拌6小时；过滤，所得固体在50℃真空干燥12小时，得到的产物0.15g，经过检测确认为晶型8，参见图16，图17和图18。
以正己烷替代正庚烷，同样操作，也得到晶型8产物。
实施例23
化合物(1)0.4g在室温下搅拌溶解于2mL N,N-二甲基甲酰胺中。向溶液中缓慢滴加甲基叔丁基醚20mL，无固体析出；降温至0℃，搅拌1小时有少量固体析出，补加甲基叔丁基醚6mL，再降温至-5℃搅拌3小时，过滤，所得固体在60℃真空干燥12小时，得到产物0.3g，经过检测确认为晶型9，参见图19，图20和图21。
实施例24
化合物(1)0.4g和四氢呋喃2mL混合，加热至40℃-50℃，固体完全溶解。将所得溶液降至室温， 缓慢滴加甲基叔丁基醚12mL，有固体析出，加毕继续搅拌6小时；过滤，所得固体在50℃真空干燥12小时，得到产物0.3g，经过检测确认为晶型10，参见图22和图23。
实施例25
化合物(1)0.3g和异丙醇3mL混合，加热至85℃，固体完全溶解。所得溶液转移至室温环境中，向其中缓慢滴加环己烷18mL，滴毕有固体析出，继续室温搅拌6小时；过滤，所得固体在50℃真空干燥12小时，得到晶型10产物，0.2g。
实施例26
化合物(1)0.4g和二氧六环4mL混合，加热至回流，固体全部溶解。所得溶液转移至室温环境中，向其中缓慢滴加正庚烷20mL，有固体析出，继续室温搅拌6小时；过滤，所得固体在50℃真空干燥12小时，得到晶型10产物0.3g。
以乙酸异丙酯、甲基叔丁基醚、正己烷、或环己烷替代正庚烷，同样操作，也得到晶型10产物。
实施例27
化合物(1)0.3g和二氧六环5mL混合，50℃-60℃加热至固体全部溶解。停止加热，在空气中将溶液搅拌降温至室温，搅拌析晶6小时；过滤，所得固体在50℃真空干燥12小时，得到晶型10产物0.2g。
实施例28稳定性测试
方法：样品置单层聚乙烯袋(PE袋)扎口，再置铝箔袋中密封；置于60℃相对湿度75％的环境放置3个月，分别在第0天和第91天取样检测。
结果：HPLC(高效液相色谱)检测样品纯度，发现纯度、杂质含量无变化，发现晶型变化如下表：
化合物(1)的晶型 0天 第91天
晶型1 晶型1 晶型1
晶型3 晶型3 晶型1
晶型4 晶型4 晶型1
晶型5 晶型5 晶型5
晶型6 晶型6 晶型6
晶型7 晶型7 晶型7
晶型8 晶型8 晶型1
晶型9 晶型9 晶型9
晶型10 晶型10 晶型10
单钠盐晶型A 单钠盐晶型A 单钠盐晶型A
根据检测结果可看出，晶型1，晶型5，晶型6，晶型7，晶型9，晶型10和单钠盐晶型A在测试条 件下晶型无变化，较为稳定；而晶型3，晶型4，晶型8出现了晶型转变，变为晶型1。
本发明的方法已经通过较佳实施例进行了描述，相关人员明显能在本发明内容、精神和范围内对本文所述的方法和应用进行改动或适当变更与组合，来实现和应用本发明技术。本领域技术人员可以借鉴本文内容，适当改进工艺参数实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明内。

Claims (30)

  1. 2-[[3-(4-氰基萘-1-基)吡啶-4-基]硫代]-2-甲基丙酸的一种晶型，所述晶型为晶型1，晶型3，晶型4，晶型5，晶型6，晶型7，晶型8，晶型9，或晶型10；其中，晶型1的X-射线粉末衍射图中在2θ为10.36,13.89,17.50,24.17度的位置有衍射峰；晶型3的X-射线粉末衍射图中在2θ为10.41,13.13,13.89,15.27,16.58,20.06,24.17度的位置有衍射峰；晶型4的X-射线粉末衍射图中在2θ为9.79,13.20,13.85,15.94,17.46,20.32,23.06,28.68度的位置有衍射峰；晶型5的X-射线粉末衍射图中在2θ为8.77,17.55,19.82,23.74,27.33,35.48度的位置有衍射峰；晶型6的X-射线粉末衍射图中在2θ为13.84,14.52,16.01,18.41,18.82,21.30,22.00,24.37,25.36度的位置有衍射峰；晶型7的X-射线粉末衍射图中在2θ为10.30,13.83,14.87,16.06,18.06,19.76,21.03,23.02,24.18,25.25度的位置有衍射峰；晶型8的X-射线粉末衍射图中在2θ为10.26,13.83,14.31,19.08,19.46,20.14,21.91,23.87,24.19,29.10度的位置有衍射峰；晶型9的X-射线粉末衍射图中在2θ为9.97,12.66,15.56,16.54,17.69,18.31,21.80,25.14,25.67度的位置有衍射峰；晶型10的X-射线粉末衍射图中在2θ为10.38,13.44,13.95,16.31,17.62,20.48,22.50,22.86,24.26度的位置有衍射峰。
  2. 权利要求1所述的晶型，其中，晶型1的X-射线粉末衍射图中在2θ为10.36,13.89,17.51,19.41,22.46,24.17度的位置有衍射峰，或晶型1的X-射线粉末衍射图中在2θ为7.48,10.36,13.89,17.51,19.41,20.62,22.46,24.17,28.96,29.39度的位置有衍射峰，或晶型1的X-射线粉末衍射图中在2θ为10.38,13.92,17.54,19.48,20.65,22.51,24.20,28.15度的位置有衍射峰；或晶型1的X-射线粉末衍射图中在2θ为7.48,10.36,13.89,14.94,16.51,17.51,19.41,20.62,22.46,24.17,26.51,28.96,29.39,33.79,34.85度的位置有衍射峰，或晶型1的X-射线粉末衍射图中在2θ为7.48,8.30,10.36,13.89,14.94,16.51,17.51,19.41,20.62,22.46,24.17,25.81,26.51,28.96,29.39,31.29,32.4,33.79,34.85度的位置有衍射峰，或晶型1的X-射线粉末衍射图中在2θ为7.48,8.30,10.36,12.42,13.89,14.94,15.29,16.17,16.51,17.51,18.58,19.41,20.62,21.73,22.46,24.17,25.36,25.81,26.51,28.96,29.39,31.29,32.4,33.79,34.85度的位置有衍射峰，或晶型1的X-射线粉末衍射图中在2θ为7.48,8.30,10.36,12.42,13.89,14.94,15.29,16.17,16.51,17.51,18.58,19.41,20.62,21.73,22.46,23.76,24.17,25.36,25.81,26.51,28.96,29.39,30.19,31.29,32.0,32.4,33.79,34.85度的位置有衍射峰，或晶型1的X-射线粉末衍射图如图1或图2所示。
  3. 权利要求1所述的晶型，其中，晶型1的差示扫描量热曲线在209℃-213℃处具有吸热峰。
  4. 权利要求1所述的晶型，其中，晶型3的X-射线粉末衍射图中在2θ为10.41,13.13,13.89,15.27,16.58,17.57,19.16,20.06,20.80,22.31,24.17度的位置有衍射峰，或晶型3的X-射线粉末衍射图中在2θ为9.54,10.41,10.88,13.13,13.89,15.27,16.58,17.57,19.16,20.06,20.80,21.31,22.31,23.73,24.17度的位置有衍射峰，或晶型3的X-射线粉末衍射图中在2θ为9.54,10.41,10.88,13.13,13.89,15.27,16.58,17.57,19.16,20.06,20.80,21.31,22.31,24.17,27.56,28.34,29.41,31.35度的位置有衍射峰，或晶型3 的X-射线粉末衍射图中在2θ为6.89,7.54,9.54,10.41,10.88,13.13,13.89,15.27,16.58,17.57,19.16,20.06,20.80,21.31,22.31,23.05,23.73,24.17,26.32,27.56,28.34,29.41,31.35,32.97度的位置有衍射峰，或晶型3的X-射线粉末衍射图如图4所示。
  5. 权利要求1所述的晶型，其中，晶型4的X-射线粉末衍射图中在2θ为9.79,11.35,13.20,13.85,15.94,17.46,19.81,20.32,20.72,21.66,22.70,23.06,25.56,28.68度的位置有衍射峰，或晶型4的X-射线粉末衍射图中在2θ为9.79,11.35,13.20,13.85,15.94,16.47,17.07,17.46,19.81,20.32,20.72,21.66,22.70,23.06,24.03,25.56,27.91,28.68,29.64,32.44度的位置有衍射峰，或晶型4的X-射线粉末衍射图中在2θ为8.00,9.79,11.35,12.05,13.20,13.85,15.94,16.47,17.07,17.46,18.79,19.81,20.32,20.72,21.66,22.12,22.70,23.06,24.03,24.50,25.56,27.91,28.68,29.64,32.44,35.22度的位置有衍射峰，或晶型4的X-射线粉末衍射图如图5所示。
  6. 权利要求1所述的晶型，其中，晶型4的差示扫描量热曲线在203℃-210℃处具有吸热峰。
  7. 权利要求1所述的晶型，其中，晶型5的X-射线粉末衍射图中在2θ为8.77,11.09,12.48,15.38,16.16,17.55,18.89,19.82,20.97,22.22,23.74,27.33,28.88,35.48度的位置有衍射峰。
  8. 一种制备权利要求1-3任一所述晶型1的方法，包括：2-[[3-(4-氰基萘-1-基)吡啶-4-基]硫代]-2-甲基丙酸与第一溶剂混合，在一定温度搅拌，然后分离固体，得到晶型1；所述第一溶剂为甲基叔丁基醚、环己烷、正庚烷、异丙醚、或四氢呋喃；或所述第一溶剂为甲醇与甲基叔丁基醚、环己烷、乙酸异丙酯、或正庚烷的混合溶剂；或所述第一溶剂为四氢呋喃与正己烷或环己烷的混合溶剂；所述温度为室温至溶剂的回流温度；或
    一种制备权利要求1-3任一所述晶型1的方法，包括：2-[[3-(4-氰基萘-1-基)吡啶-4-基]硫代]-2-甲基丙酸与第二溶剂混合，加热使其完全溶解，然后降温至-10℃到室温的任意温度，析晶，分离固体，得到晶型1；所述第二溶剂为乙二醇二甲醚，甲醇，乙醇，异丙醇，乙腈，丙酮，水，甲苯，或其组合；或
    一种制备权利要求1-3任一所述晶型1的方法，包括：2-[[3-(4-氰基萘-1-基)吡啶-4-基]硫代]-2-甲基丙酸溶解于乙二醇二甲醚，然后与第一不良溶剂混合，搅拌析晶，分离固体，得到晶型1；所述第一不良溶剂为正庚烷或乙酸异丙酯。
  9. 一种制备权利要求1或4所述晶型3的方法，包括：2-[[3-(4-氰基萘-1-基)吡啶-4-基]硫代]-2-甲基丙酸溶于乙二醇二甲醚，然后加入甲基叔丁基醚，搅拌3小时-6小时，分离固体，除去溶剂，得到晶型3。
  10. 一种制备权利要求1或5或6所述晶型4的方法，包括：化合物(1)加热溶于2-甲基四氢呋喃中，然后在室温下滴加正己烷、环己烷、正庚烷或其组合溶剂，析出固体，搅拌析晶0.5小时-8小时，分离固体， 除去溶剂，得到晶型4产物。
  11. 一种制备权利要求1或7所述晶型5的方法，包括：2-[[3-(4-氰基萘-1-基)吡啶-4-基]硫代]-2-甲基丙酸在40℃-60℃溶于乙二醇二甲醚，然后控温30℃-60℃，加入环己烷，加毕，混合液在10℃-40℃搅拌4小时-6小时，分离固体，所得固体除去溶剂，得到晶型5。
  12. 2-[[3-(4-氰基萘-1-基)吡啶-4-基]硫代]-2-甲基丙酸单钠盐的晶型，其X-射线粉末衍射图中在2θ为10.15,13.04,15.42,16.88,20.07,21.86,24.62,26.69,31.11,34.47度的位置有衍射峰。
  13. 权利要求12所述的晶型，其X-射线粉末衍射图中在2θ为10.15,12.19,13.04,15.42,15.64,16.88,18.67,19.23,20.07,21.86,22.93,23.57,24.62,25.81,26.69,27.13,28.72,29.23,31.11,34.47度的位置有衍射峰，或其X-射线粉末衍射图中在2θ为7.10,10.15,12.19,13.04,15.42,15.64,16.88,18.67,19.23,20.07,20.91,21.43,21.86,22.52,22.93,23.57,24.62,25.81,26.69,27.13,28.72,29.23,29.59,31.11,31.69,32.97,34.47度的位置有衍射峰，或其X-射线粉末衍射图中在2θ为5.15,7.10,10.15,12.19,13.04,14.24,15.42,15.64,16.88,18.25,18.67,19.23,20.07,20.55,20.91,21.43,21.86,22.52,22.93,23.57,24.62,25.81,26.69,27.13,27.63,28.72,29.23,29.59,31.11,31.69,32.00,32.41,32.97,34.47,39.05度的位置有衍射峰，或其X-射线粉末衍射图如图8所示。
  14. 权利要求12所述的2-[[3-(4-氰基萘-1-基)吡啶-4-基]硫代]-2-甲基丙酸单钠盐的晶型，其差示扫描量热曲线在110℃-120℃处具有吸热峰，吸热峰峰顶值为120℃，在175℃-190℃处具有吸热峰，吸热峰峰顶值为186℃。
  15. 一种制备权利要求12-14任一所述的晶型的方法，包括：2-[[3-(4-氰基萘-1-基)吡啶-4-基]硫代]-2-甲基丙酸的单钠盐与溶剂混合，搅拌3小时-5小时，分离固体，所得固体除去残余溶剂，得到晶体；所述溶剂为甲基叔丁基醚、环已烷、正已烷、或乙酸异丙酯。
  16. 权利要求1所述的晶型，其中，晶型6的X-射线粉末衍射图中在2θ为10.30,10.57,13.84,14.52,16.01,17.08,17.45,18.41,18.82,19.76,20.12,21.30,22.00,23.49,24.37,25.36,32.49,39.23度的位置有衍射峰；或者晶型6的X-射线粉末衍射图如图10所示。
  17. 权利要求1所述的晶型，其中，晶型6的差示扫描量热曲线在135℃-145℃处具有吸热峰和215℃-219℃处具有吸热峰。
  18. 一种制备权利要求1、16或17所述晶型6的方法，包括：2-[[3-(4-氰基萘-1-基)吡啶-4-基]硫代]-2-甲基丙酸与冰醋酸混合，加热回流，然后向所得混合液中加入水，将混合液降温至有固体析出，保温搅拌；然后将混合液降温至室温，保温搅拌；分离固体并除去溶剂，得到晶型6产物。
  19. 权利要求1所述的晶型，其中，晶型7的X-射线粉末衍射图中在2θ为8.25,10.30,13.83,14.87,16.06,16.97,18.06,19.76,20.31,20.67,21.03,23.02,24.18,25.25,28.43,29.06,31.66度的位置有衍射峰；或者晶型7的X-射线粉末衍射图如图13所示。
  20. 权利要求1所述的晶型，其中，晶型7的差示扫描量热曲线在215℃-219℃处具有吸热峰。
  21. 一种制备权利要求1、19或20所述的晶型7的方法，包括：2-[[3-(4-氰基萘-1-基)吡啶-4-基]硫代]-2-甲基丙酸与冰醋酸混合，加热回流，然后向所得混合液中加入水，降温至室温或0℃-5℃，保温搅拌；分离固体并除去溶剂，得到晶型7产物。
  22. 权利要求1所述的晶型，其中，晶型8的X-射线粉末衍射图中在2θ为7.52,10.26,13.83,14.31,15.01,16.06,16.91,17.48,18.61,19.08,19.46,20.14,21.91,22.49,23.87,24.19,29.10度的位置有衍射峰；或者晶型8的X-射线粉末衍射图如图16所示。
  23. 权利要求1所述的晶型，其中，晶型8的差示扫描量热曲线在207℃-212℃处具有吸热峰。
  24. 一种制备权利要求1、22或23所述的晶型8的方法，包括：2-[[3-(4-氰基萘-1-基)吡啶-4-基]硫代]-2-甲基丙酸溶于氯仿，然后加入正庚烷或环己烷或其混合物，析出固体，搅拌析晶，然后分离固体，除去溶剂，得到晶型8产物。
  25. 权利要求1所述的晶型，其中，晶型9的X-射线粉末衍射图中在2θ为9.97,12.66,14.92,15.56,16.54,17.69,18.31,19.19,20.77,21.80,22.84,25.14,25.67,27.36,30.12度的位置有衍射峰；或者晶型9的X-射线粉末衍射图中在2θ为6.79,9.97,12.66,13.54,14.92,15.56,16.54,17.32,17.69,18.31,19.19,19.79,20.77,21.80,22.84,24.27,25.14,25.67,26.23,27.36,27.94,28.60,29.61,30.12度的位置有衍射峰；或者晶型9的X-射线粉末衍射图如图19所示。
  26. 权利要求1所述的晶型，其中，晶型9的差示扫描量热曲线在155℃-170℃处具有吸热峰。
  27. 一种制备权利要求1、25或26所述的晶型9的方法，包括：2-[[3-(4-氰基萘-1-基)吡啶-4-基]硫代]-2-甲基丙酸溶于N,N-二甲基甲酰胺中，加入甲基叔丁基醚至固体析出，降温至-5℃-5℃搅拌析晶，然后分离固体，除去溶剂，得到晶型9产物。
  28. 权利要求1所述的晶型，其中，晶型10的X-射线粉末衍射图中在2θ为9.90,10.38,13.44,13.95,16.02,16.31,16.58,16.96,17.62,20.48,22.50,22.86,24.26,25.79,32.20度的位置有衍射峰；或者晶型10的X-射线粉末衍射图中在2θ为7.49,8.22,9.90,10.38,11.17,13.44,13.95,15.06,16.02,16.31,16.58,16.96,17.62,19.78,20.48,22.50,22.86,24.26,25.79,32.20度的位置有衍射峰；或者晶型10的X-射线粉末衍射图如图22所示。
  29. 权利要求1所述的晶型，其中，晶型10的差示扫描量热曲线在209℃-212℃处具有吸热峰。
  30. 一种制备权利要求1、28或29所述的晶型10的方法，包括：2-[[3-(4-氰基萘-1-基)吡啶-4-基]硫代]-2-甲基丙酸与四氢呋喃、异丙醇、二氧六环或其组合溶剂混合，加热，形成溶液，室温下向溶液中加入甲基叔丁基醚、环己烷、正己烷、正庚烷、乙酸异丙酯或其混合溶剂至有固体析出，室温搅拌0.1小时-12小时，然后分离固体，除去溶剂，得到晶型10产物。
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