WO2022179636A1 - Formes cristallines d'agoniste du récepteur fxr - Google Patents

Formes cristallines d'agoniste du récepteur fxr Download PDF

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WO2022179636A1
WO2022179636A1 PCT/CN2022/078142 CN2022078142W WO2022179636A1 WO 2022179636 A1 WO2022179636 A1 WO 2022179636A1 CN 2022078142 W CN2022078142 W CN 2022078142W WO 2022179636 A1 WO2022179636 A1 WO 2022179636A1
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crystal form
ray powder
powder diffraction
diffraction pattern
radiation
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PCT/CN2022/078142
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Chinese (zh)
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刘斌
阳强
李继成
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轩竹生物科技股份有限公司
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Priority to CN202280012683.5A priority Critical patent/CN117043160A/zh
Publication of WO2022179636A1 publication Critical patent/WO2022179636A1/fr

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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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • 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
    • A61K31/439—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 the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present disclosure relates to a crystal form of a targeting FXR receptor agonist and a preparation method thereof, as well as a pharmaceutical composition comprising the crystal form, and the preparation of these crystal form compounds and compositions thereof for treatment and/or prevention Drug use in diseases mediated by FXR.
  • Farnesoid X receptor is a member of the ligand-activated transcription factor nuclear receptor family. Binding domain (LBD), amino-terminal ligand-independent transcriptional activation domain (AF1), carboxy-terminal ligand-dependent transcriptional activation domain (AF2) and foot chain domain. FXR can form a heterodimer with retinoid X receptor (RXR). When the ligand binds to the LBD region of FXR, the conformation of FXR can change, and the binding region of DNA binds to the FXR response element of the target gene promoter. Above (IR-1), co-repressors (such as NCOR) are released, and co-activators are recruited to play a role in transcriptional regulation.
  • LBD binding domain
  • AF1 amino-terminal ligand-independent transcriptional activation domain
  • AF2 carboxy-terminal ligand-dependent transcriptional activation domain
  • RXR retinoid X receptor
  • FXR is expressed in many organs and tissues, including adipose tissue, liver, gastrointestinal tract, kidney, etc., among which the liver is the most abundantly expressed.
  • FXR signaling pathway can regulate the expression of multiple downstream genes, such as BSEP, SHP, CYP7A1, FGFR4, OST ⁇ / ⁇ , SREBP-1C and other genes, and then regulate various metabolic pathways, such as: triglyceride, cholesterol, blood sugar and energy stability
  • Sexual metabolism of bile acid metabolism has the function of treating cancer, non-alcoholic fatty liver disease (NAFLD), metabolic disorders, inflammation and other diseases.
  • FXR regulates its metabolism by inhibiting the synthesis, binding and transport of bile acids, and is the main regulator of bile acid balance in the body.
  • Some natural cholic acid compounds can stimulate FXR, such as chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), lithocholic acid (LCA) and taurine and glycine conjugates of these cholic acids.
  • FXR agonists currently developed internationally can be mainly divided into two categories, one is steroids, represented by the obeticholic acid (OCA) of Intercept Company, which was released in May 2016.
  • LJN-452 developed by Novartis is in the clinical phase II research stage.
  • the indications are primary biliary cirrhosis, primary sclerosing cholangitis, and nonalcoholic steatohepatitis.
  • the structure is as follows:
  • WO2019007418A1 discloses a compound represented by formula (I) 2-((1S,4S,5R)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4- yl)methoxy)-2-azabicyclo[2.2.1]heptan-2-yl)benzo[d]thiazole-6-carboxylic acid, which has excellent FXR agonistic activity and liver microsomal stability, And higher security.
  • the present disclosure relates to the FXR agonist 2-((1S,4S,5R)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole- 4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-yl)benzo[d]thiazole-6-carboxylic acid crystal form I (referred to as crystal form I), crystal form Form II (referred to as crystal form II), crystal form III (referred to as crystal form III), crystal form IV (referred to as crystal form IV), crystal form V (referred to as crystal form V), crystal form VI (referred to as crystal form VI), crystal form VII (referred to as crystal form VII), crystal form VIII (referred to as crystal form VIII), and crystal form IX (referred to as crystal form IX).
  • the present disclosure also relates to preparation methods of the above crystal forms, pharmaceutical compositions comprising the above crystal forms, and applications of these crystal forms or compositions in the preparation of medicines for treating and/or preventing related diseases mediated by F
  • the crystal form is crystal form I, which uses Cu-K ⁇ radiation, expressed in 2 ⁇ angle, and the X-ray powder diffraction pattern is at 5.8 ⁇ 0.2°, 8.1 ⁇ 0.2°, 11.7 ⁇ 0.2°, 12.9 ⁇ 0.2°, 13.3° There are characteristic peaks at ⁇ 0.2°, 13.5 ⁇ 0.2°, 16.5 ⁇ 0.2°, 17.2 ⁇ 0.2°, 18.4 ⁇ 0.2°, 19.3 ⁇ 0.2°;
  • crystal form II which uses Cu-K ⁇ radiation, expressed in 2 ⁇ angle, and the X-ray powder diffraction pattern is at 8.9 ⁇ 0.2°, 13.3 ⁇ 0.2°, 20.4 ⁇ 0.2°, 22.4 ⁇ 0.2°, There are characteristic peaks at 24.4 ⁇ 0.2° and 26.5 ⁇ 0.2°;
  • crystal form III which uses Cu-K ⁇ radiation, expressed in 2 ⁇ angle, and the X-ray powder diffraction pattern is at 6.4 ⁇ 0.2°, 8.6 ⁇ 0.2°, 10.1 ⁇ 0.2°, 11.6 ⁇ 0.2°, There are characteristic peaks at 13.2 ⁇ 0.2°, 14.1 ⁇ 0.2°, 15.1 ⁇ 0.2°, 15.9 ⁇ 0.2°, 17.3 ⁇ 0.2°, 18.1 ⁇ 0.2°, 18.6 ⁇ 0.2°;
  • crystal form IV which uses Cu-K ⁇ radiation, expressed in 2 ⁇ angle, and the X-ray powder diffraction pattern is at 3.8 ⁇ 0.2°, 12.4 ⁇ 0.2°, 13.2 ⁇ 0.2°, 16.2 ⁇ 0.2°, There are characteristic peaks at 16.6 ⁇ 0.2°, 18.5 ⁇ 0.2°, 20.6 ⁇ 0.2°, 23.9 ⁇ 0.2°, 25.6 ⁇ 0.2°;
  • crystal form V which uses Cu-K ⁇ radiation, expressed in 2 ⁇ angle, and the X-ray powder diffraction pattern is at 8.8 ⁇ 0.2°, 10.4 ⁇ 0.2°, 12.9 ⁇ 0.2°, 16.0 ⁇ 0.2°, There are characteristic peaks at 16.7 ⁇ 0.2°, 17.2 ⁇ 0.2°, and 17.6 ⁇ 0.2°;
  • crystal form VI which uses Cu-K ⁇ radiation, expressed in 2 ⁇ angle, and the X-ray powder diffraction pattern is at 3.8 ⁇ 0.2°, 11.3 ⁇ 0.2°, 12.3 ⁇ 0.2°, 13.3 ⁇ 0.2°, There are characteristic peaks at 14.9 ⁇ 0.2°, 17.0 ⁇ 0.2°, 17.5 ⁇ 0.2°, 18.0 ⁇ 0.2°, 18.8 ⁇ 0.2°, 21.2 ⁇ 0.2°, 24.7 ⁇ 0.2°;
  • crystal form VII which uses Cu-K ⁇ radiation, expressed in 2 ⁇ angle, and the X-ray powder diffraction pattern is at 8.8 ⁇ 0.2°, 17.3 ⁇ 0.2°, 22.4 ⁇ 0.2°, 24.4 ⁇ 0.2°, There is a characteristic peak at 26.5 ⁇ 0.2°;
  • crystal form is crystal form VIII, which uses Cu-K ⁇ radiation, expressed in 2 ⁇ angle, and the X-ray powder diffraction pattern is at 13.2 ⁇ 0.2°, 13.7 ⁇ 0.2°, 15.8 ⁇ 0.2°, 16.4 ⁇ 0.2°, There are characteristic peaks at 17.3 ⁇ 0.2°, 19.3 ⁇ 0.2°, and 22.3 ⁇ 0.2°;
  • crystal form IX which uses Cu-K ⁇ radiation, expressed in 2 ⁇ angle, and the X-ray powder diffraction pattern is at 13.3 ⁇ 0.2°, 16.9 ⁇ 0.2°, 18.1 ⁇ 0.2°, 21.9 ⁇ 0.2°, There are characteristic peaks at 24.0 ⁇ 0.2°, 25.2 ⁇ 0.2°, and 26.2 ⁇ 0.2°.
  • the crystal form is crystal form I, which uses Cu-K ⁇ radiation, expressed in 2 ⁇ angle, and the X-ray powder diffraction pattern is at 5.8 ⁇ 0.2°, 8.1 ⁇ 0.2°, 11.7 ⁇ 0.2°, 12.9 ⁇ 0.2°, 13.3 ⁇ 0.2°, 13.5 ⁇ 0.2°, 16.1 ⁇ 0.2°, 16.5 ⁇ 0.2°, 17.2 ⁇ 0.2°, 18.4 ⁇ 0.2°, 19.3 ⁇ 0.2°, 20.7 ⁇ 0.2°, 21.9 ⁇ 0.2°, 24.8 ⁇ 0.2°, 25.2 There are characteristic peaks at ⁇ 0.2°;
  • the crystal form is crystal form III, which uses Cu-K ⁇ radiation, expressed in 2 ⁇ angle, and the X-ray powder diffraction pattern is at 6.4 ⁇ 0.2°, 8.6 ⁇ 0.2°, 10.1 ⁇ 0.2°, 11.6 ⁇ 0.2° , 13.2 ⁇ 0.2°, 14.1 ⁇ 0.2°, 15.1 ⁇ 0.2°, 15.9 ⁇ 0.2°, 16.9 ⁇ 0.2°, 17.3 ⁇ 0.2°, 18.1 ⁇ 0.2°, 18.6 ⁇ 0.2°, 20.2 ⁇ 0.2°, 20.7 ⁇ 0.2° , 22.6 ⁇ 0.2°, 23.6 ⁇ 0.2°, 25.7 ⁇ 0.2° have characteristic peaks;
  • crystal form IV which uses Cu-K ⁇ radiation, expressed in 2 ⁇ angle, and the X-ray powder diffraction pattern is at 3.8 ⁇ 0.2°, 10.9 ⁇ 0.2°, 11.4 ⁇ 0.2°, 12.4 ⁇ 0.2° , 13.2 ⁇ 0.2°, 13.8 ⁇ 0.2°, 14.8 ⁇ 0.2°, 16.2 ⁇ 0.2°, 16.6 ⁇ 0.2°, 17.0 ⁇ 0.2°, 17.7 ⁇ 0.2°, 18.5 ⁇ 0.2°, 20.6 ⁇ 0.2°, 23.9 ⁇ 0.2° , There are characteristic peaks at 25.6 ⁇ 0.2°;
  • crystal form V which uses Cu-K ⁇ radiation, expressed in 2 ⁇ angle, and the X-ray powder diffraction pattern is at 8.8 ⁇ 0.2°, 10.4 ⁇ 0.2°, 12.9 ⁇ 0.2°, 16.0 ⁇ 0.2° , 16.7 ⁇ 0.2°, 17.2 ⁇ 0.2°, 17.6 ⁇ 0.2°, 18.8 ⁇ 0.2°, 20.2 ⁇ 0.2°, 20.6 ⁇ 0.2°, 21.0 ⁇ 0.2°, 21.6 ⁇ 0.2°, 22.2 ⁇ 0.2°, 22.8 ⁇ 0.2° , 23.5 ⁇ 0.2°, 24.4 ⁇ 0.2°, 25.1 ⁇ 0.2°, 26.4 ⁇ 0.2° have characteristic peaks;
  • crystal form VI which uses Cu-K ⁇ radiation, expressed in 2 ⁇ angle, and the X-ray powder diffraction pattern is at 3.8 ⁇ 0.2°, 11.3 ⁇ 0.2°, 12.3 ⁇ 0.2°, 12.6 ⁇ 0.2° , 13.3 ⁇ 0.2°, 14.9 ⁇ 0.2°, 16.0 ⁇ 0.2°, 17.0 ⁇ 0.2°, 17.5 ⁇ 0.2°, 18.0 ⁇ 0.2°, 18.8 ⁇ 0.2°, 20.4 ⁇ 0.2°, 21.2 ⁇ 0.2°, 22.6 ⁇ 0.2° , 23.2 ⁇ 0.2°, 23.6 ⁇ 0.2°, 24.7 ⁇ 0.2°, 26.8 ⁇ 0.2°, 27.2 ⁇ 0.2°, 28.3 ⁇ 0.2° have characteristic peaks;
  • crystal form VII which uses Cu-K ⁇ radiation, expressed in 2 ⁇ angle, and the X-ray powder diffraction pattern is at 8.8 ⁇ 0.2°, 13.0 ⁇ 0.2°, 13.3 ⁇ 0.2°, 17.3 ⁇ 0.2°, There are characteristic peaks at 20.3 ⁇ 0.2°, 20.7 ⁇ 0.2°, 22.4 ⁇ 0.2°, 24.4 ⁇ 0.2°, 26.5 ⁇ 0.2°, 28.7 ⁇ 0.2°;
  • crystal form VIII which uses Cu-K ⁇ radiation, expressed in 2 ⁇ angle, and the X-ray powder diffraction pattern is at 5.9 ⁇ 0.2°, 8.1 ⁇ 0.2°, 13.2 ⁇ 0.2°, 13.7 ⁇ 0.2°, 15.8 ⁇ 0.2°, 16.4 ⁇ 0.2°, 17.3 ⁇ 0.2°, 18.4 ⁇ 0.2°, 19.3 ⁇ 0.2°, 20.4 ⁇ 0.2°, 22.3 ⁇ 0.2°, 24.6 ⁇ 0.2°, 25.3 ⁇ 0.2°, 27.1 ⁇ 0.2° There are characteristic peaks.
  • the crystalline form is Form I, which has an X-ray powder diffraction pattern obtained using Cu-K ⁇ radiation substantially as shown in FIG. 1 ;
  • crystal form II which has an X-ray powder diffraction pattern obtained using Cu-K ⁇ radiation substantially as shown in FIG. 13 ;
  • crystal form III which has an X-ray powder diffraction pattern obtained using Cu-K ⁇ radiation substantially as shown in FIG. 5;
  • Form IV which has an X-ray powder diffraction pattern obtained using Cu-K ⁇ radiation substantially as shown in Figure 15;
  • crystal form V which has an X-ray powder diffraction pattern obtained using Cu-K ⁇ radiation substantially as shown in FIG. 8;
  • crystal form VI which has an X-ray powder diffraction pattern obtained using Cu-K ⁇ radiation substantially as shown in Figure 10;
  • crystal form VII having an X-ray powder diffraction pattern obtained using Cu-K ⁇ radiation substantially as shown in Figure 17;
  • Form VIII having an X-ray powder diffraction pattern obtained using Cu-K ⁇ radiation substantially as shown in Figure 19;
  • the crystalline form is Form IX, which has an X-ray powder diffraction pattern obtained using Cu-K ⁇ radiation substantially as shown in FIG. 21 .
  • the crystal form is crystal form I, and its differential scanning calorimetry (DSC) analysis chart has an endothermic peak in the range of 175°C to 210°C; preferably, the maximum endothermic transition temperature is 192.88 ⁇ 5°C; more preferably , the crystal form I has a differential scanning calorimetry curve substantially as shown in Figure 2;
  • DSC differential scanning calorimetry
  • crystal form II which has a differential scanning calorimetry curve substantially as shown in Figure 14;
  • the crystal form is crystal form III, and its differential scanning calorimetry (DSC) analysis chart has an endothermic peak in the range of 180°C to 220°C; preferably, the maximum endothermic transition temperature is 205.82 ⁇ 5°C; more
  • the crystal form III has a differential scanning calorimetry curve substantially as shown in FIG. 6;
  • crystal form IV which has a differential scanning calorimetry curve substantially as shown in Figure 16;
  • the crystal form is crystal form V, and its differential scanning calorimetry (DSC) analysis chart has an endothermic peak in the range of 175°C to 200°C; preferably, the maximum endothermic transition temperature is 191.18 ⁇ 5°C; more
  • the crystal form V has a differential scanning calorimetry curve substantially as shown in FIG. 9;
  • the crystal form is crystal form VI, and its differential scanning calorimetry (DSC) analysis chart has an endothermic peak in the range of 100°C to 140°C; preferably, the maximum endothermic transition temperature is 114.88 ⁇ 5°C; more
  • the crystal form VI has a differential scanning calorimetry curve substantially as shown in FIG. 11 ;
  • the crystal form is crystal form VII, and its differential scanning calorimetry (DSC) analysis chart has an endothermic peak in the range of 175°C to 200°C; preferably, the maximum endothermic transition temperature is 190.7 ⁇ 5°C; more Preferably, the crystal form VII has a differential scanning calorimetry curve substantially as shown in FIG. 18 ;
  • the crystal form is crystal form VIII, and its differential scanning calorimetry (DSC) analysis chart has an endothermic peak in the range of 180°C to 210°C; preferably, the maximum endothermic transition temperature is 193.1 ⁇ 5°C; more
  • the crystalline form VIII has a differential scanning calorimetry curve substantially as shown in Figure 20;
  • the crystal form is crystal form IX, and its differential scanning calorimetry (DSC) analysis chart has an endothermic peak in the range of 160°C to 210°C; preferably, the maximum endothermic transition temperature is 188.9 ⁇ 5°C; more
  • the crystalline form IX has a differential scanning calorimetry curve substantially as shown in FIG. 22 .
  • the present disclosure also provides a method for preparing a crystal form of the compound of formula (I), comprising the following operations:
  • the compound of formula (I) is dissolved or suspended in an organic solvent or a mixed solvent of organic solvent and water, and the reaction is carried out at room temperature or heated to a certain temperature to obtain the crystal form of the compound of formula (I).
  • the organic solvent is selected from one of the following solvents or any combination between two or more solvents:
  • Alcohol solvent selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, tert-butanol, n-amyl alcohol, n-hexanol, ethylene glycol, propylene glycol, glycerol, Cyclopentyl alcohol, cyclopentyl alcohol, cyclohexanol, cyclohexyl alcohol, cyclohexyl alcohol, benzyl alcohol, phenylethyl alcohol or phenylpropanol;
  • nitrile solvents selected from acetonitrile or propionitrile
  • ester solvent selected from ethyl formate, methyl formate or ethyl acetate
  • ketone solvent selected from acetone, methyl ethyl ketone, isobutyl ketone or methyl isobutyl ketone;
  • alkane solvent selected from n-pentane, n-hexane, n-heptane or cyclohexane
  • the organic solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, dichloromethane, acetonitrile, ethyl formate, ethyl acetate, acetone, butyl alcohol Ketone, n-heptane, methyl tert-butyl ether, 1,4-dioxane, dimethyl sulfoxide, N-methylpyrrolidone, ethanol/isopropanol, ethanol/acetonitrile, dichloromethane/acetonitrile, acetone /butanone, dichloromethane/butanone, 1,4-dioxane/ethyl acetate.
  • the organic solvent is selected from ethanol/isopropanol, ethanol/acetonitrile, dichloromethane/acetonitrile, acetone/butanone, dichloromethane/butanone, or 1,4-dioxane/ A mixed solvent of ethyl acetate, and the volume ratio of the two single solvents in the mixed solvent is 1:3-3:1, such as 1:3, 1:2, 1:1, 2:1, 3:1, etc.
  • the volume ratio of organic solvent to water is selected from 1:5-5:1, such as 1:5, 1:4, 1:3, 1:5 2, 1:1, 2:1, 3:1, 3:2, 4:1, 4:3, 5:4, 5:2, 5:3, 5:1, etc.
  • the heating to a certain temperature refers to heating to 40-90°C, such as 50-90°C, 50-80°C, 50-60°C, 60-70°C, 40-70°C, 70°C -80°C, 70-75°C, 75-80°C, etc.
  • the crystallization is selected from room temperature crystallization.
  • the room temperature crystallization is selected from the group consisting of room temperature stirring crystallization and room temperature standing crystallization.
  • the separation is selected from atmospheric filtration or vacuum filtration.
  • the preparation process in the preparation method of the compound crystal form of the formula (I), can be optionally carried out under stirring conditions, wherein the stirring, the stirring mode is selected from mechanical stirring, Magnetic stirring; the preparation process includes a feeding process, a raw material dissolving process, a reaction generating process, and a crystallization process.
  • the drying is selected from natural drying at room temperature, natural drying in a fume hood, infrared lamp drying, oven drying, and vacuum dryer dry.
  • the drying temperature for drying under vacuum conditions is 30°C-100°C, such as 30°C-80°C, 30°C-70°C, 35°C-70°C, 40°C-65°C, 40°C-60°C, 40°C -50°C, 35°C-50°C, etc.
  • multiple dryings can be optionally performed at different temperatures.
  • the room temperature described in the present disclosure is the indoor temperature, which varies with the seasons, and is usually in the range of 10°C to 30°C.
  • the present disclosure also provides a method for preparing a crystal form of the compound of formula (I), comprising the following operations:
  • the compound of formula (I) is dissolved in an organic solvent or a mixed solvent of an organic solvent and water, heated to a certain temperature at room temperature, stirred, and then the second solvent is added or the reaction system is placed in the second solvent atmosphere to continue the reaction to obtain the formula (I) Crystal form of the compound.
  • the organic solvent is selected from one of the following solvents or any combination between two or more solvents:
  • Alcohol solvent selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, tert-butanol, n-amyl alcohol, n-hexanol, ethylene glycol, propylene glycol, glycerol, Cyclopentyl alcohol, cyclopentyl alcohol, cyclohexanol, cyclohexyl alcohol, cyclohexyl alcohol, benzyl alcohol, phenylethyl alcohol or phenylpropanol;
  • nitrile solvents selected from acetonitrile or propionitrile
  • ester solvent selected from ethyl formate, methyl formate or ethyl acetate
  • ketone solvent selected from acetone, methyl ethyl ketone, isobutyl ketone or methyl isobutyl ketone;
  • alkane solvent selected from n-pentane, n-hexane, n-heptane or cyclohexane
  • the organic solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, dichloromethane, acetonitrile, ethyl formate, ethyl acetate, acetone, butyl alcohol Ketone, n-heptane, methyl tert-butyl ether, 1,4-dioxane, dimethyl sulfoxide, N-methylpyrrolidone, ethanol/acetonitrile, dichloromethane/acetonitrile, acetone/butanone, dichloro Methane/butanone, 1,4-dioxane/ethyl acetate.
  • the organic solvent is selected from ethanol/isopropanol, ethanol/acetonitrile, dichloromethane/acetonitrile, acetone/butanone, dichloromethane/butanone, or 1,4-dioxane/ A mixed solvent of ethyl acetate, and the volume ratio of the two single solvents in the mixed solvent is 1:3-3:1, such as 1:3, 1:2, 1:1, 2:1, 3:1, etc.
  • the volume ratio of organic solvent to water is selected from 1:5-5:1, preferably 1:5-1:1 or 1:1-5: 1, such as 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 3:2, 4:1, 4:3, 5:4, 5:2 , 5:3, 5:1, etc.
  • the certain temperature refers to 40-90°C, such as 50-90°C, 50-80°C, 50-60°C, 60-70°C, 40-70°C, 70-80°C, 70-75°C, 75-80°C, etc.
  • the second solvent is selected from organic solvents or non-organic solvents
  • the organic solvent is selected from alkanes or ethers
  • the non-organic solvent is selected from water.
  • the second solvent is selected from water, diethyl ether, propyl ether, isopropyl ether, n-pentane, n-hexane, cyclohexane or n-heptane.
  • the crystallization is selected from room temperature crystallization.
  • the room temperature crystallization is selected from the group consisting of room temperature stirring crystallization and room temperature standing crystallization.
  • the separation is selected from atmospheric filtration or vacuum filtration.
  • the preparation process in the preparation method of the compound crystal form of the formula (I), can be optionally carried out under stirring conditions, wherein the stirring, the stirring mode is selected from mechanical stirring, Magnetic stirring; the preparation process includes a feeding process, a raw material dissolving process, a reaction generating process, and a crystallization process.
  • the drying is selected from natural drying at room temperature, natural drying in a fume hood, infrared lamp drying, oven drying, and vacuum dryer dry.
  • the drying temperature for drying under vacuum conditions is 30°C-100°C, such as 30°C-80°C, 30°C-70°C, 35°C-70°C, 40°C-65°C, 40°C-60°C, 40°C -50°C, 35°C-50°C, etc.
  • multiple dryings can be optionally performed at different temperatures.
  • the room temperature described in the present disclosure is the indoor temperature, which varies with the seasons, and is usually in the range of 10°C to 30°C.
  • the present disclosure provides a crystalline form I of the compound represented by formula (I), wherein, using Cu-K ⁇ radiation, expressed in 2 ⁇ angle, the X-ray powder diffraction pattern is at 5.8 ⁇ 0.2°, 8.1 ⁇ 0.2° , 11.7 ⁇ 0.2°, 12.9 ⁇ 0.2°, 13.3 ⁇ 0.2°, 13.5 ⁇ 0.2°, 16.5 ⁇ 0.2°, 17.2 ⁇ 0.2°, 18.4 ⁇ 0.2°, 19.3 ⁇ 0.2° have characteristic peaks,
  • the crystalline form I which is irradiated with Cu-K ⁇ , has an X-ray powder diffraction pattern at 5.8 ⁇ 0.2°, 8.1 ⁇ 0.2°, 11.7 ⁇ 0.2°, 12.9 ⁇ 0.2°, 13.3 ⁇ 0.2°, 13.5 ⁇ 0.2°, 16.1 ⁇ 0.2°, 16.5 ⁇ 0.2°, 17.2 ⁇ 0.2°, 18.4 ⁇ 0.2°, 19.3 ⁇ 0.2°, 20.7 ⁇ 0.2°, 21.9 ⁇ 0.2°, 24.8 There are characteristic peaks at ⁇ 0.2° and 25.2 ⁇ 0.2°.
  • the crystalline Form I has an X-ray powder diffraction pattern obtained using Cu-K ⁇ radiation substantially as shown in FIG. 1 .
  • the crystalline form I wherein, its differential scanning calorimetry (DSC) analysis pattern has an endothermic peak in the range of 175°C to 210°C.
  • DSC differential scanning calorimetry
  • the crystalline form I wherein, its differential scanning calorimetry (DSC) analysis pattern has a maximum endothermic transition peak at 192.88 ⁇ 5°C.
  • the Form I has a differential scanning calorimetry profile substantially as shown in FIG. 2 .
  • the Form I has a thermogravimetric analysis (TGA) curve substantially as shown in FIG. 3 .
  • TGA thermogravimetric analysis
  • the crystalline form I of the compound of formula (I), wherein its crystal structure is in substantially pure form is in substantially pure form.
  • the present disclosure also provides a method for preparing the crystal form I of the compound of formula (I), comprising the following operations:
  • the compound of formula (I) is dissolved or suspended in an organic solvent and reacted at room temperature or heated to a certain temperature to obtain crystal form I.
  • the organic solvent is selected from one of the following solvents or any combination between two or more solvents:
  • alcohol solvent selected from aliphatic alcohol, alicyclic alcohol and aromatic alcohol solvent
  • the aliphatic alcohol solvent is selected from methanol, ethanol, n-propanol, isopropanol, isobutanol, tert-butanol, normal Amyl alcohol, n-hexanol, ethylene glycol, propylene glycol or glycerol
  • the alicyclic alcohol solvent is selected from cyclopentanol, cyclopentyl alcohol, cyclohexanol, cyclohexyl alcohol or cyclohexanol
  • the class of solvent is selected from benzyl alcohol, phenethyl alcohol or phenylpropanol;
  • nitrile solvents selected from acetonitrile or propionitrile
  • Ester solvent selected from ethyl formate or methyl formate.
  • the organic solvent is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, acetonitrile, ethyl formate, dichloromethane, ethanol/ Isopropanol, ethanol/acetonitrile or dichloromethane/acetonitrile.
  • the organic solvent when the organic solvent is selected from a mixed solvent of ethanol/isopropanol, ethanol/acetonitrile or dichloromethane/acetonitrile, the mixed solvent in the mixed solvent
  • the volume ratio of the two single solvents is 1:3-3:1, such as 1:3, 1:2, 1:1, 2:1, 3:1, etc.
  • the organic solvent is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, acetonitrile, ethyl formate, ethanol/isopropanol, Ethanol/acetonitrile or dichloromethane/acetonitrile.
  • the heating to a certain temperature refers to heating to 50-80°C, such as 60-70°C, 70-80°C, 70-75°C, 75-80°C, and the like.
  • the method for preparing the crystal form I wherein, after the reaction is completed, the crystal form I is obtained through crystallization, separation and drying.
  • the crystallization is selected from room temperature crystallization.
  • the room temperature crystallization is selected from stirring crystallization at room temperature, and the room temperature standing crystallization; the separation is selected from atmospheric filtration or vacuum suction filtration.
  • the preparation process in the preparation method of the crystal form I, can be optionally carried out under stirring conditions, wherein the stirring, the stirring mode is selected from mechanical stirring and magnetic stirring;
  • the preparation process described above includes a feeding process, a raw material dissolving process, a reaction generating process, and a crystallization process.
  • the drying is selected from natural drying at room temperature, natural drying in a fume hood, infrared lamp drying, drying in an oven, and drying in a vacuum dryer.
  • the drying temperature for drying under vacuum conditions is 30°C-100°C, such as 30°C-80°C, such as 35°C-70°C, such as 40°C-65°C, such as 35°C-50°C; Select multiple dryings at different temperatures.
  • the room temperature described in the present disclosure is the indoor temperature, which varies with the seasons, and is usually in the range of 10°C to 30°C.
  • the present disclosure provides a crystal form II of the compound represented by formula (I), wherein, using Cu-K ⁇ radiation, expressed in 2 ⁇ angle, the X-ray powder diffraction pattern is at 8.9 ⁇ 0.2°, 13.3 ⁇ 0.2° °, 20.4 ⁇ 0.2°, 22.4 ⁇ 0.2°, 24.4 ⁇ 0.2°, 26.5 ⁇ 0.2° have characteristic peaks,
  • the crystalline Form II has an X-ray powder diffraction pattern obtained using Cu-K ⁇ radiation substantially as shown in FIG. 13 .
  • the crystalline Form II has a differential scanning calorimetry profile substantially as shown in FIG. 14 .
  • the present disclosure also provides a preparation method of the compound crystal form II of formula (I), comprising the following operations:
  • the compound of formula (I) is dissolved or suspended in an organic solvent and reacted at room temperature to obtain crystal form II.
  • the organic solvent is selected from one or both of acetone, butanone, n-butanol, methyl tert-butyl ether and n-heptane Any combination of solvents.
  • the organic solvent is selected from acetone/butanone, and the volume ratio of the two single solvents in the mixed solvent is 1:3-3:1, such as 1:3, 1:2, 1:1 , 2:1, 3:1, etc.
  • the room temperature is an indoor temperature, which varies with the seasons, and is usually in the range of 10°C to 30°C.
  • the present disclosure provides a crystal form III of the compound represented by formula (I), wherein, using Cu-K ⁇ radiation, expressed in 2 ⁇ angle, the X-ray powder diffraction pattern is at 6.4 ⁇ 0.2°, 8.6 ⁇ 0.2° °, 10.1 ⁇ 0.2°, 11.6 ⁇ 0.2°, 13.2 ⁇ 0.2°, 14.1 ⁇ 0.2°, 15.1 ⁇ 0.2°, 15.9 ⁇ 0.2°, 17.3 ⁇ 0.2°, 18.1 ⁇ 0.2°, 18.6 ⁇ 0.2° have characteristic peaks ,
  • the crystal form III using Cu-K ⁇ radiation, expressed in 2 ⁇ angle, has an X-ray powder diffraction pattern at 6.4 ⁇ 0.2°, 8.6 ⁇ 0.2°, 10.1 ⁇ 0.2°, 11.6 ⁇ 0.2 °, 13.2 ⁇ 0.2°, 14.1 ⁇ 0.2°, 15.1 ⁇ 0.2°, 15.9 ⁇ 0.2°, 16.9 ⁇ 0.2°, 17.3 ⁇ 0.2°, 18.1 ⁇ 0.2°, 18.6 ⁇ 0.2°, 20.2 ⁇ 0.2°, 20.7 ⁇ 0.2 There are characteristic peaks at °, 22.6 ⁇ 0.2°, 23.6 ⁇ 0.2°, and 25.7 ⁇ 0.2°.
  • the crystalline Form III has an X-ray powder diffraction pattern obtained using Cu-K ⁇ radiation substantially as shown in FIG. 5 .
  • the crystalline form III, wherein, its differential scanning calorimetry (DSC) analysis pattern has an endothermic peak in the range of 180°C to 220°C.
  • the crystalline form III, wherein the differential scanning calorimetry (DSC) analysis pattern has a maximum endothermic transition peak at 205.82 ⁇ 5°C.
  • the Form III has a differential scanning calorimetry profile substantially as shown in FIG. 6 .
  • the Form III has a thermogravimetric analysis (TGA) curve substantially as shown in FIG. 7 .
  • TGA thermogravimetric analysis
  • the present disclosure also provides a method for preparing the crystal form III of the compound of formula (I), comprising the following operations:
  • the compound of formula (I) is dissolved or suspended in a mixed solvent of organic solvent/water and reacted at room temperature to obtain crystal form III.
  • the organic solvent is selected from ethers, preferably 1,4-dioxane.
  • the volume ratio of organic solvent to water in the mixed solvent is selected from 1:5-1:1, such as 1:4, 1:4.5, 1:5, and the like.
  • the room temperature is an indoor temperature, which varies with the seasons, and is usually in the range of 10°C to 30°C.
  • the present disclosure provides a crystalline form IV of the compound represented by formula (I), wherein, using Cu-K ⁇ radiation, expressed in 2 ⁇ angle, the X-ray powder diffraction pattern is at 3.8 ⁇ 0.2°, 12.4 ⁇ 0.2° There are characteristic peaks at °, 13.2 ⁇ 0.2°, 16.2 ⁇ 0.2°, 16.6 ⁇ 0.2°, 18.5 ⁇ 0.2°, 20.6 ⁇ 0.2°, 23.9 ⁇ 0.2°, 25.6 ⁇ 0.2°,
  • the Form IV using Cu-K ⁇ radiation, has an X-ray powder diffraction pattern at 3.8 ⁇ 0.2°, 10.9 ⁇ 0.2°, 11.4 ⁇ 0.2°, 12.4 ⁇ 0.2°, expressed in 2 ⁇ angles. °, 13.2 ⁇ 0.2°, 13.8 ⁇ 0.2°, 14.8 ⁇ 0.2°, 16.2 ⁇ 0.2°, 16.6 ⁇ 0.2°, 17.0 ⁇ 0.2°, 17.7 ⁇ 0.2°, 18.5 ⁇ 0.2°, 20.6 ⁇ 0.2°, 23.9 ⁇ 0.2 There are characteristic peaks at 25.6 ⁇ 0.2°.
  • the crystalline Form IV has an X-ray powder diffraction pattern obtained using Cu-K ⁇ radiation substantially as shown in FIG. 15 .
  • the crystalline form IV has a differential scanning calorimetry profile substantially as shown in FIG. 16 .
  • the present disclosure also provides a preparation method of the compound crystal form IV of the formula (I), comprising the following operations:
  • the compound of formula (I) is dissolved or suspended in an organic solvent, stirred at room temperature, and then the second solvent is added or the reaction system is placed in the second solvent atmosphere to continue the reaction to obtain crystal form IV.
  • the organic solvent is N-methylpyrrolidone; the second solvent is water.
  • the room temperature is an indoor temperature, which varies with the seasons, and is usually in the range of 10°C to 30°C.
  • the present disclosure provides a crystal form V of the compound represented by formula (I), wherein, using Cu-K ⁇ radiation, expressed in 2 ⁇ angle, the X-ray powder diffraction pattern is at 8.8 ⁇ 0.2°, 10.4 ⁇ 0.2° There are characteristic peaks at °, 12.9 ⁇ 0.2°, 16.0 ⁇ 0.2°, 16.7 ⁇ 0.2°, 17.2 ⁇ 0.2°, 17.6 ⁇ 0.2°,
  • the crystal form V using Cu-K ⁇ radiation, expressed in 2 ⁇ angles, has an X-ray powder diffraction pattern at 8.8 ⁇ 0.2°, 10.4 ⁇ 0.2°, 12.9 ⁇ 0.2°, 16.0 ⁇ 0.2 °, 16.7 ⁇ 0.2°, 17.2 ⁇ 0.2°, 17.6 ⁇ 0.2°, 18.8 ⁇ 0.2°, 20.2 ⁇ 0.2°, 20.6 ⁇ 0.2°, 21.0 ⁇ 0.2°, 21.6 ⁇ 0.2°, 22.2 ⁇ 0.2°, 22.8 ⁇ 0.2 There are characteristic peaks at °, 23.5 ⁇ 0.2°, 24.4 ⁇ 0.2°, 25.1 ⁇ 0.2°, and 26.4 ⁇ 0.2°.
  • the crystalline Form V has an X-ray powder diffraction pattern obtained using Cu-K ⁇ radiation substantially as shown in FIG. 8 .
  • the crystalline form V, wherein, its differential scanning calorimetry (DSC) analysis pattern has an endothermic peak in the range of 175°C to 200°C.
  • the crystalline form V, wherein the differential scanning calorimetry (DSC) analysis pattern has a maximum endothermic transition peak at 191.18 ⁇ 5°C.
  • the Form V has a differential scanning calorimetry profile substantially as shown in FIG. 9 .
  • the Form V has a thermogravimetric analysis (TGA) curve substantially as shown in FIG. 9 .
  • TGA thermogravimetric analysis
  • the present disclosure also provides a preparation method of the compound crystal form V of the formula (I), comprising the following operations:
  • Compound (I) is added to an organic solvent, heated to a certain temperature, stirred, filtered while hot, a second organic solvent is added to the filtrate at a certain temperature, and the crystal form V is obtained by cooling.
  • the organic solvent is selected from one of the following solvents or any combination between two or more solvents:
  • ether solvent preferably diethyl ether or 1,4-dioxane
  • nitrile solvents preferably acetonitrile or propionitrile
  • Ester solvents preferably ethyl formate, ethyl acetate or methyl formate.
  • the organic solvent is selected from a mixed solvent of 1,4-dioxane/ethyl acetate.
  • the organic solvent is selected from a mixed solvent of 1,4-dioxane/ethyl acetate, and the volume ratio of 1,4-dioxane:ethyl acetate in the mixed solvent is 1 :3-3:1, such as 1:3, 1:2, 1:1, 2:1, 3:1, etc., preferably 1:2.
  • the second organic solvent is selected from alkanes, preferably n-pentane, n-hexane, cyclohexane or n-heptane.
  • the certain temperature is selected from 50-90°C, such as 70-80°C.
  • the second organic solvent can be added at one time or in portions.
  • the method for preparing the crystal form V wherein, after the reaction is completed, the crystal form V is obtained through crystallization, separation and drying.
  • the crystallization is selected from room temperature crystallization.
  • the room temperature crystallization is selected from stirring crystallization at room temperature, and the room temperature standing crystallization; the separation is selected from atmospheric filtration or vacuum suction filtration.
  • the preparation process in the preparation method of the crystal form V, can be optionally carried out under stirring conditions, wherein the stirring, the stirring mode is selected from mechanical stirring and magnetic stirring;
  • the preparation process described above includes a feeding process, a raw material dissolving process, a reaction generating process, and a crystallization process.
  • the drying is selected from natural drying at room temperature, natural drying in a fume hood, infrared lamp drying, oven drying, and vacuum dryer drying.
  • the drying temperature for drying under vacuum conditions is 30°C-70°C, such as 40°C-60°C, such as 40°C-50°C; during the drying process, multiple dryings can be optionally performed at different temperatures.
  • the room temperature described in the present disclosure is the indoor temperature, which varies with the seasons, and is usually in the range of 10°C to 30°C.
  • the present disclosure provides a crystalline form VI of the compound represented by formula (I), wherein, using Cu-K ⁇ radiation, expressed in 2 ⁇ angle, the X-ray powder diffraction pattern is at 3.8 ⁇ 0.2°, 11.3 ⁇ 0.2° °, 12.3 ⁇ 0.2°, 13.3 ⁇ 0.2°, 14.9 ⁇ 0.2°, 17.0 ⁇ 0.2°, 17.5 ⁇ 0.2°, 18.0 ⁇ 0.2°, 18.8 ⁇ 0.2°, 21.2 ⁇ 0.2°, 24.7 ⁇ 0.2° have characteristic peaks ,
  • the crystal form VI when using Cu-K ⁇ radiation, expressed in 2 ⁇ angle, has an X-ray powder diffraction pattern at 3.8 ⁇ 0.2°, 11.3 ⁇ 0.2°, 12.3 ⁇ 0.2°, 12.6 ⁇ 0.2°, 13.3 ⁇ 0.2°, 14.9 ⁇ 0.2°, 16.0 ⁇ 0.2°, 17.0 ⁇ 0.2°, 17.5 ⁇ 0.2°, 18.0 ⁇ 0.2°, 18.8 ⁇ 0.2°, 20.4 ⁇ 0.2°, 21.2 ⁇ 0.2°, 22.6 ⁇ There are characteristic peaks at 0.2°, 23.2 ⁇ 0.2°, 23.6 ⁇ 0.2°, 24.7 ⁇ 0.2°, 26.8 ⁇ 0.2°, 27.2 ⁇ 0.2°, and 28.3 ⁇ 0.2°.
  • the crystalline Form VI has an X-ray powder diffraction pattern obtained using Cu-K ⁇ radiation substantially as shown in FIG. 10 .
  • the crystalline form VI wherein the differential scanning calorimetry (DSC) analysis pattern has an endothermic peak in the range of 100°C to 130°C.
  • the crystalline form VI wherein the differential scanning calorimetry (DSC) analysis pattern has a maximum endothermic transition peak at 114.88 ⁇ 5°C.
  • the crystalline form VI, wherein the differential scanning calorimetry (DSC) analysis pattern also has an endothermic peak in the range of 160°C to 200°C.
  • the Form VI has a differential scanning calorimetry profile substantially as shown in FIG. 11 .
  • the crystal form VI is DMSO solvate, and the solvent content is 9%-13%.
  • the crystalline form VI is a solvate containing 1 molecule of DMSO.
  • the Form VI has a thermogravimetric analysis (TGA) curve substantially as shown in FIG. 11 .
  • TGA thermogravimetric analysis
  • the present disclosure also provides a method for preparing the crystal form VI of the compound of formula (I), comprising the following operations:
  • the compound of formula (I) is dissolved or suspended in a mixed solvent of DMSO/water, heated to a certain temperature to react, and crystal form VI is obtained after the reaction is completed.
  • the volume ratio of DMSO to water is selected from 1:1 to 5:1, eg, 2:1 to 3:1, eg, 2.5:1 (ie, 5:2).
  • the certain temperature is selected from 40°C-70°C, eg, 50°C-60°C.
  • the present disclosure provides a crystal form VII of the compound represented by formula (I), which uses Cu-K ⁇ radiation, expressed in 2 ⁇ angle, and has an X-ray powder diffraction pattern at 8.8 ⁇ 0.2°, 17.3 ⁇ 0.2° , 22.4 ⁇ 0.2°, 24.4 ⁇ 0.2°, 26.5 ⁇ 0.2° have characteristic peaks;
  • the crystal form VII when using Cu-K ⁇ radiation, expressed in 2 ⁇ angle, has an X-ray powder diffraction pattern at 8.8 ⁇ 0.2°, 13.0 ⁇ 0.2°, 13.3 ⁇ 0.2°, 17.3 ⁇ There are characteristic peaks at 0.2°, 20.3 ⁇ 0.2°, 20.7 ⁇ 0.2°, 22.4 ⁇ 0.2°, 24.4 ⁇ 0.2°, 26.5 ⁇ 0.2°, and 28.7 ⁇ 0.2°.
  • the Form VII has an X-ray powder diffraction pattern obtained using Cu-K ⁇ radiation substantially as shown in FIG. 17 .
  • the crystalline form VII, wherein, its differential scanning calorimetry (DSC) analysis pattern has an endothermic peak in the range of 175°C to 200°C.
  • the crystalline form VII, wherein the differential scanning calorimetry (DSC) analysis pattern has a maximum endothermic transition peak at 190.7 ⁇ 5°C.
  • the crystalline Form VII has a differential scanning calorimetry profile substantially as shown in FIG. 18 .
  • the crystalline Form VII has a thermogravimetric analysis (TGA) curve substantially as shown in FIG. 18 .
  • TGA thermogravimetric analysis
  • the present disclosure also provides a method for preparing a crystal form VII of the compound of formula (I), comprising the following operations:
  • the compound of formula (I) is dissolved or suspended in a mixed solvent of ethyl acetate and isopropanol, and reacted at room temperature to obtain crystal form VII of the compound of formula (I).
  • the volume ratio of the two in the mixed solvent of ethyl acetate and isopropanol is 1:1.
  • the preparation method of the crystal form VII wherein, after the reaction is completed, the crystal form VII is obtained through crystallization, separation and drying.
  • the room temperature described in the present disclosure is the indoor temperature, which varies with the seasons, and is usually in the range of 10°C to 30°C.
  • the present disclosure provides a crystal form VIII of the compound represented by formula (I), which uses Cu-K ⁇ radiation, expressed in 2 ⁇ angle, and has an X-ray powder diffraction pattern at 13.2 ⁇ 0.2°, 13.7 ⁇ 0.2° , 15.8 ⁇ 0.2°, 16.4 ⁇ 0.2°, 17.3 ⁇ 0.2°, 19.3 ⁇ 0.2°, 22.3 ⁇ 0.2° have characteristic peaks;
  • the crystalline Form VIII which is irradiated with Cu-K ⁇ , has an X-ray powder diffraction pattern at 5.9 ⁇ 0.2°, 8.1 ⁇ 0.2°, 13.2 ⁇ 0.2°, 13.7 ⁇ 0.2°, 15.8 ⁇ 0.2°, 16.4 ⁇ 0.2°, 17.3 ⁇ 0.2°, 18.4 ⁇ 0.2°, 19.3 ⁇ 0.2°, 20.4 ⁇ 0.2°, 22.3 ⁇ 0.2°, 24.6 ⁇ 0.2°, 25.3 ⁇ 0.2°, 27.1 There are characteristic peaks at ⁇ 0.2°.
  • the crystalline Form VIII has an X-ray powder diffraction pattern obtained using Cu-K ⁇ radiation substantially as shown in FIG. 19 .
  • the crystalline form VIII has an endothermic peak in the range of 180°C to 210°C in a differential scanning calorimetry (DSC) analysis pattern.
  • DSC differential scanning calorimetry
  • the crystalline form VIII has a maximum endothermic transition peak at 193.1 ⁇ 5°C in its differential scanning calorimetry (DSC) analysis.
  • the crystalline Form VIII has a differential scanning calorimetry profile substantially as shown in FIG. 20 .
  • the crystalline Form VIII has a thermogravimetric analysis (TGA) curve substantially as shown in FIG. 20 .
  • TGA thermogravimetric analysis
  • the present disclosure also provides a method for preparing a crystal form VIII of the compound of formula (I), comprising the following operations:
  • the compound of formula (I) is dissolved or suspended in an organic solvent or a mixed solvent of organic solvent and water, and the reaction is carried out at room temperature or heated to 50° C. to obtain crystal form VIII of the compound of formula (I).
  • the organic solvent is selected from a mixed solvent of isopropanol/n-heptane, a mixed solvent of acetone/ethyl formate, or a mixed solvent of water/isopropanol.
  • the volume ratio of the two solvents in the mixed solvent is 1:3-3:1, such as 1:3, 1:2, 1:1, 2:1, 3:1, etc., preferably 1:1.
  • the method for preparing the crystal form VIII wherein, after the reaction is completed, the crystal form VIII is obtained through crystallization, separation and drying.
  • the room temperature described in the present disclosure is the indoor temperature, which varies with the seasons, and is usually in the range of 10°C to 30°C.
  • the present disclosure provides a crystalline form IX of the compound represented by formula (I), which uses Cu-K ⁇ radiation, expressed in 2 ⁇ angle, and has an X-ray powder diffraction pattern at 13.3 ⁇ 0.2°, 16.9 ⁇ 0.2° , 18.1 ⁇ 0.2°, 21.9 ⁇ 0.2°, 24.0 ⁇ 0.2°, 25.2 ⁇ 0.2°, 26.2 ⁇ 0.2° have characteristic peaks,
  • the crystalline Form IX has an X-ray powder diffraction pattern obtained using Cu-K ⁇ radiation substantially as shown in FIG. 21 .
  • the crystalline Form IX has an endothermic peak in the range of 160°C to 210°C in a differential scanning calorimetry (DSC) analysis pattern.
  • DSC differential scanning calorimetry
  • the crystalline form IX has a maximum endothermic transition peak at 188.9 ⁇ 5°C in its differential scanning calorimetry (DSC) analysis.
  • the crystalline Form IX has a differential scanning calorimetry profile substantially as shown in FIG. 22 .
  • the crystalline Form IX has a thermogravimetric analysis (TGA) curve substantially as shown in FIG. 22 .
  • TGA thermogravimetric analysis
  • the present disclosure also provides a method for preparing a crystal form IX of the compound of formula (I), comprising the following operations:
  • the compound of formula (I) is dissolved or suspended in an organic solvent, and reacted at room temperature or heated to 50° C. to obtain crystal form IX of the compound of formula (I).
  • the organic solvent is selected from diethyl ether, ethyl acetate, or a mixed solvent of ethyl acetate/methyl tert-butyl ether.
  • the volume ratio of the two solvents in the mixed solvent is 1:3-3:1, such as 1:3, 1:2, 1:1, 2:1, 3:1, etc., preferably 1 :1.
  • the preparation method of the crystal form IX wherein, after the reaction is completed, the crystal form IX is obtained through crystallization, separation and drying.
  • the room temperature described in the present disclosure is the indoor temperature, which varies with the seasons, and is usually in the range of 10°C to 30°C.
  • the present disclosure also provides a pharmaceutical composition
  • a pharmaceutical composition comprising crystal form I, crystal form II, crystal form III, crystal form IV, crystal form V of the compound of formula (I) described in the present disclosure , Form VI, Form VII, Form VIII or Form IX, and optionally one or more pharmaceutically acceptable carriers and/or diluents.
  • a crystalline form eg, Form I, Form II, Form III, Form IV, Form V, Form VI, Form VII
  • a pharmaceutically acceptable carriers and/or diluents can be in any dosage form pharmaceutically acceptable.
  • Administration to patients in need thereof is by oral, parenteral, rectal or pulmonary administration.
  • conventional solid preparations such as tablets, capsules, pills, granules, etc., can be prepared; oral liquid preparations, such as oral solutions, oral suspensions, syrups, etc., can also be prepared.
  • injection solution When used for parenteral administration, it can be prepared into injection, including injection solution, sterile powder for injection and concentrated solution for injection.
  • injection solution When preparing the injection, it can be produced by the conventional methods in the existing pharmaceutical field.
  • no additives can be added, or suitable additives can be added according to the properties of the drug.
  • rectal administration it can be made into suppositories and the like.
  • pulmonary administration it can be made into inhalants or sprays.
  • the present disclosure also provides Form I, Form II, Form III, Form IV, Form V, Form VI, Form VII, Form VIII, Use of Form IX or a pharmaceutical composition of the present disclosure in the manufacture of a medicament for the treatment and/or prevention of a related disease mediated by FXR.
  • the present disclosure also provides a method of treating and/or preventing a related disease mediated by FXR in a mammal in need thereof, the method comprising administering to the mammal in need the treatment and/or prophylaxis An effective amount of Form I, Form II, Form III, Form IV, Form V, Form VI, Form VII, Form VIII, Form IX or Form IX of the compound of formula (I) described in this disclosure
  • An effective amount of Form I, Form II, Form III, Form IV, Form V, Form VI, Form VII, Form VIII, Form IX or Form IX of the compound of formula (I) described in this disclosure The pharmaceutical composition of the crystalline form.
  • the present disclosure also provides crystal form I, crystal form II, crystal form III, crystal form IV, crystal form V, crystal form VI, crystal form VII, crystal form of the compound of formula (I) Form VIII or Form IX for use in the treatment and/or prevention of related diseases mediated by FXR.
  • the FXR-mediated related diseases are selected from the group consisting of: atherosclerosis, bile acid disorders, primary sclerosing cholangitis, cholesterol stones, fibrosis-related diseases, fatty liver, cirrhosis, hepatitis, liver failure , cholestasis, gallstone disease, myocardial infarction, stroke, thrombosis, clinical complications of type I or II diabetes, hyperproliferative disease and inflammatory bowel disease.
  • the FXR-mediated related disease is selected from the group consisting of: alcoholic fatty liver, non-alcoholic fatty liver, primary biliary cirrhosis, primary biliary cirrhosis, chronic hepatitis, non-viral hepatitis, alcoholic steatohepatitis, nonalcoholic steatohepatitis, benign intrahepatic cholestasis, progressive familial intrahepatic cholestasis, drug-induced cholestasis, pregnancy cholestasis, cholestasis associated with parenteral nutrition, extrahepatic Cholestatic disorders, hypercholesterolemia, neonatal jaundice, kernicterus, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy and other observations of clinically significant long-term diabetes, hepatocellular carcinoma, colon adenoma , polyposis, colon adenocarcinoma, breast cancer, pancreatic cancer, esophageal
  • any combination between two or more solvents refers to a solvent formed by mixing the same or different types of solvents in an organic solvent according to a certain ratio.
  • Mixed solvents formed by the same kind of solvent including but not limited to the following specific examples: methanol/ethanol, methanol/isopropanol, methanol/ethanol/isopropanol, methanol/tert-butanol, methanol/cyclopentanol, methanol/benzyl alcohol , ethanol/isopropanol, ethanol/tert-butanol, ether/tetrahydrofuran, acetone/butanone, etc.
  • the mixed solvent formed by the different kinds of solvents includes but is not limited to the following mixed solvent systems: ethanol/acetonitrile, dichloromethane/acetonitrile, dichloromethane/acetone, dichloromethane/butanone, 1,4-dioxane Ring/ethyl acetate etc.
  • a therapeutically and/or prophylactically effective amount of Form I, Form II, Form III, Form IV, Form V, Form VI, Form VII, Form VIII or Form IX which can be used in pure form, or in the form of Form I, Form III, Form V, Form VI,
  • the pharmaceutical composition of Form VII, Form VIII or Form IX and one or more pharmaceutically acceptable excipients is administered.
  • a crystalline form (Form I-Form IX) of a compound of formula (I) described in this disclosure refers to treatment with a reasonable effect/risk ratio suitable for use in any medical treatment and/or prophylaxis A sufficient amount of the compound to obstruct. It should be recognized, however, that the total daily dosage of the crystalline forms (Form I-Form IX) of the compound of formula (I) and the pharmaceutical composition described in the present disclosure must be determined by the attending physician within the scope of sound medical judgment.
  • the particular therapeutically effective dosage level will depend upon a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the particular compound or crystalline form employed; specific composition; age, weight, general health, sex and diet of the patient; time of administration, route of administration and excretion rate of the specific compound or crystalline form employed; duration of treatment; Drugs used in combination or concomitantly in their crystalline forms; and similar factors well known in the medical field. For example, it is the practice in the art to start with a dose of the compound or a crystalline form below that required to obtain the desired therapeutic effect and gradually increase the dose until the desired effect is obtained.
  • the preparation method is easy to operate and suitable for industrial production
  • Fig. 1 is an X-ray powder diffraction (XRPD) pattern of the compound of formula (I) in crystal form I, where the ordinate represents the diffraction intensity and the abscissa represents the diffraction angle (2 ⁇ ).
  • XRPD X-ray powder diffraction
  • Figure 2 is a DSC analysis chart of the crystal form I of the compound of formula (I), the ordinate represents the heat flow (W/g), and the abscissa represents the temperature T (°C).
  • Fig. 3 is a TGA analysis chart of the crystal form I of the compound of formula (I), the ordinate represents the weight (%), and the abscissa represents the temperature T (°C).
  • Figure 4 is an X-ray powder diffraction (XRPD) pattern of the amorphous compound of formula (I), where the ordinate represents the diffraction intensity and the abscissa represents the diffraction angle (2 ⁇ ).
  • XRPD X-ray powder diffraction
  • Figure 5 is an X-ray powder diffraction (XRPD) pattern of the compound of formula (I) in crystal form III, where the ordinate represents the diffraction intensity and the abscissa represents the diffraction angle (2 ⁇ ).
  • XRPD X-ray powder diffraction
  • Fig. 6 is a DSC analysis chart of the compound of formula (I) in crystal form III, the ordinate represents the heat flow (W/g), and the abscissa represents the temperature T (°C).
  • Fig. 7 is a TGA analysis chart of the compound of formula (I) in crystal form III, the ordinate represents the weight (%), and the abscissa represents the temperature T (°C).
  • Fig. 8 is an X-ray powder diffraction (XRPD) pattern of the compound of formula (I) in crystal form V, where the ordinate represents the diffraction intensity and the abscissa represents the diffraction angle (2 ⁇ ).
  • XRPD X-ray powder diffraction
  • Fig. 9 is a TGA-DSC analysis diagram of the compound of formula (I) in crystal form V, the left ordinate represents weight (%), the right ordinate (outer side) represents heat flow (W/g), and the right ordinate (inner side) represents weight change rate (%/°C), and the abscissa represents temperature T (°C).
  • Fig. 10 is an X-ray powder diffraction (XRPD) pattern of the compound of formula (I) in crystal form VI, where the ordinate represents the diffraction intensity and the abscissa represents the diffraction angle (2 ⁇ ).
  • XRPD X-ray powder diffraction
  • Figure 11 is the TGA-DSC analysis diagram of the compound of formula (I) crystal form VI, the left ordinate represents weight (%), the right ordinate (outer side) represents heat flow (W/g), and the right ordinate (inner side) represents weight change rate (%/°C), and the abscissa represents temperature T (°C).
  • Figure 12 is the H 1 -NMR spectrum of the compound of formula (I) in crystal form VI.
  • Figure 13 is an X-ray powder diffraction (XRPD) pattern of the compound of formula (I) in crystal form II, where the ordinate represents the diffraction intensity and the abscissa represents the diffraction angle (2 ⁇ ).
  • XRPD X-ray powder diffraction
  • Fig. 14 is a DSC analysis chart of the compound of formula (I) in crystal form II, the ordinate represents the heat flow (W/g), and the abscissa represents the temperature T (°C).
  • Fig. 15 is an X-ray powder diffraction (XRPD) pattern of the compound of formula (I) in crystal form IV, where the ordinate represents the diffraction intensity and the abscissa represents the diffraction angle (2 ⁇ ).
  • XRPD X-ray powder diffraction
  • Fig. 16 is a DSC analysis chart of the compound of formula (I) in crystal form IV, the ordinate represents the heat flow (W/g), and the abscissa represents the temperature T (°C).
  • Figure 17 is an X-ray powder diffraction (XRPD) pattern of the compound of formula (I) in crystal form VII, the ordinate represents the diffraction intensity (intensity), and the abscissa represents the diffraction angle (2 ⁇ ).
  • XRPD X-ray powder diffraction
  • Figure 18 is a TGA-DSC analysis diagram of the compound of formula (I) crystal form VII, the left ordinate represents weight (%), the right ordinate represents heat flow (W/g), and the abscissa represents temperature T (°C).
  • Fig. 19 is an X-ray powder diffraction (XRPD) pattern of the compound of formula (I) in crystal form VIII, where the ordinate represents the diffraction intensity and the abscissa represents the diffraction angle (2 ⁇ ).
  • XRPD X-ray powder diffraction
  • Figure 20 is a TGA-DSC analysis chart of the compound of formula (I) crystal form VIII, the left ordinate represents weight (%), the right ordinate represents heat flow (W/g), and the abscissa represents temperature T (°C).
  • Figure 21 is an X-ray powder diffraction (XRPD) pattern of the compound of formula (I) in crystal form IX, where the ordinate represents the diffraction intensity and the abscissa represents the diffraction angle (2 ⁇ ).
  • XRPD X-ray powder diffraction
  • Figure 22 is a TGA-DSC analysis chart of the compound of formula (I) crystal form IX, the left ordinate represents weight (%), the right ordinate represents heat flow (W/g), and the abscissa represents temperature T (°C).
  • Preparation method 1 Weigh (I) compound (2.2g) and put it in a 50mL round-bottomed flask, add methanol (20mL), the solution is close to the clear solution, stir at about 10°C at room temperature, after half an hour, more solids are precipitated, continue After stirring, the suspension was suction filtered after 4 days to obtain a solid, which was dried under vacuum at 50°C for 8h. XRPD detection showed that the obtained solid was crystal form I.
  • Preparation method 2 Take six parts of the compound of formula (I) (50 mg) and place them in six 10 mL centrifuge tubes, respectively, add methanol (1 mL), ethanol (1 mL), isopropanol (1 mL), and acetonitrile to the centrifuge tubes. (1 mL), n-propanol (1 mL), and ethyl formate (1 mL), and stirred at room temperature. After 3 days, the suspension in 6 centrifuge tubes was suction filtered, and the obtained solid was naturally dried in a fume hood. Through XRPD detection, the obtained six solids are all crystal form I.
  • Preparation method four take the compound of formula (I) (18.5 g), add methanol (50 mL), heat to 70°C to 75°C and stir, after the reaction, cool to 15 to 25°C and keep stirring for 20 hours. After filtering, the filter cake was rinsed with methanol (15 mL*3). Vacuum drying at 40°C gave a solid (10.0 g). The obtained solid was crystalline form I by XRPD detection.
  • Preparation method 1 take a certain amount of four parts of the compound of formula (I), add them to a certain amount of sec-butanol, n-butanol, methyl tert-butyl ether or n-heptane, respectively, to form a suspension, stir for 72h, The solid was suction filtered and dried, and the obtained solid was detected by XRPD, and the obtained four solids were all in crystal form II.
  • the compound of formula (I) (36.7 mg) was weighed, ethyl acetate (1 mL) was added, heated to 50° C., stirred for 24 h, centrifuged, and vacuum-dried at room temperature. The obtained solid was detected as crystal form IX by XRPD.
  • the X-ray powder diffraction pattern of the compound of formula (I), Form I is shown in FIG. 1 .
  • the X-ray powder diffraction pattern of the compound of formula (I), Form II, is shown in FIG. 13 .
  • the X-ray powder diffraction pattern of the compound of formula (I), Form III, is shown in FIG. 5 .
  • the X-ray powder diffraction pattern of the compound of formula (I) Form IV is shown in FIG. 15 .
  • the X-ray powder diffraction pattern of the compound of formula (I) Form V is shown in FIG. 8 .
  • the X-ray powder diffraction pattern of the compound of formula (I), Form VI, is shown in FIG. 10 .
  • the X-ray powder diffraction pattern of the compound of formula (I) Form VII is shown in FIG. 17 .
  • the X-ray powder diffraction pattern of the compound of formula (I), Form VIII, is shown in FIG. 19 .
  • the X-ray powder diffraction pattern of the compound of formula (I) Form IX is shown in FIG. 21 .
  • Form I, Form II, Form III, Form IV, Form V, Form VI, Form VII, Form VII and Form VII of the compound of formula (I) were investigated by differential scanning calorimetry (DSC) Solid state thermal properties of Type IX.
  • Assay conditions Purge with nitrogen at 50 ml/min, collect data at a heating rate of 10°C/min between 25°C and 250°C, plot with endothermic peaks pointing down.
  • the differential scanning calorimetry analysis diagram of the crystal form I of the compound of formula (I) is shown in Figure 2; the differential scanning calorimetry analysis diagram of the crystal form II is shown in Figure 14; the differential scanning calorimetry analysis of the crystal form III
  • the calorimetric analysis diagram is shown in Figure 6; the differential scanning calorimetry analysis diagram of the crystal form IV is shown in Figure 16; the differential scanning calorimetry analysis diagram of the crystal form V is shown in Figure 9; the differential scanning calorimetry analysis of the crystal form VI is shown in Figure 9
  • the scanning calorimetry analysis diagram is shown in Figure 11; the differential scanning calorimetry analysis diagram of the crystal form VII is shown in Figure 18; the differential scanning calorimetry analysis diagram of the crystal form VIII is shown in Figure 20; The scanning calorimetry analysis is shown in Figure 22.
  • Test Conditions Purge with nitrogen at 60 ml/min, data collected at 10°C/min heating rate between room temperature and 300°C or 350°C. Measurement results: the TGA curve of the crystal form I of the compound of formula (I) is shown in Figure 3; the TGA curve of the crystal form III of the compound of formula (I) is shown in Figure 7; the TGA curve of the crystal form V is shown in Figure 9 The TGA curve of crystal form VI is shown in Figure 11; the TGA curve of crystal form VII is shown in Figure 18; the TGA curve of crystal form VIII is shown in Figure 20; the TGA curve of crystal form IX is shown in Figure 22.
  • Test article Form I of the compound of formula (I), prepared according to the method of the Preparation Example.
  • High temperature test place the test sample open for 30 days under the conditions of 40°C ⁇ 2°C and 60°C ⁇ 2°C, and take samples on the 5th, 10th and 30th days.
  • the test items include properties, related substances and XRD;
  • the test sample is sealed with EP tube plus sealing film and desiccant, and the outer coat is sealed with polyester/aluminum/polyethylene composite film.
  • 10 days, 30 days sampling, testing items include characters, related substances and XRD.
  • High-humidity test place the test sample under the conditions of 75%RH ⁇ 5%RH and 90%RH ⁇ 5%RH for 30 days, and take samples on the 5th, 10th, and 30th days.
  • the test items include traits, related substances and XRD; use EP tube with sealing film and desiccant for the test sample, and seal and package the polyester/aluminum/polyethylene drug packaging with composite film under the conditions of 75%RH ⁇ 5%RH, 90%RH ⁇ 5%RH
  • the samples were placed in the 5th, 10th, and 30th days, and the test items included characters, related substances and XRD.
  • Determination of related substances refer to the current version of Chinese Pharmacopoeia for determination by high performance liquid chromatography.
  • XRPD determination refer to the current version of the Chinese Pharmacopoeia X-ray diffraction method.
  • the crystal form I of the compound of formula (I) was placed open for 30 days under the conditions of 40°C ⁇ 2°C and 60°C ⁇ 2°C, the related substances increased slightly, and the properties and XRD did not change significantly; the crystal form I of the compound of formula (I) Under the conditions of 75%RH ⁇ 5%RH and 90%RH ⁇ 5%RH, the openings were placed for 30 days, and there was no significant change in each test item; the crystal form I of the compound of formula (I) was stored at 40°C ⁇ 2°C, 60°C ⁇ 2°C, 75%RH ⁇ 5%RH, 90%RH ⁇ 5%RH and sealed for 30 days, there is no obvious change in each inspection item.
  • the crystal form I of the compound of formula (I) of the present invention has good stability.
  • Test sample Form I of the compound of formula (I), prepared according to the method of the preparation example.
  • Determination of related substances refer to the current version of Chinese Pharmacopoeia by high performance liquid chromatography.
  • Moisture determination refer to the current version of the Chinese Pharmacopoeia for the first method of moisture determination method 2 Coulomb titration.
  • XRPD determination refer to the current version of the Chinese Pharmacopoeia X-ray diffraction method.
  • Table 2 shows the stability test results of the crystal form I of the compound of formula (I).
  • the crystal form I of the compound of formula (I) has good stability under the accelerated 30-day test conditions, and there is no obvious change in related substances, moisture and XRD.
  • Test sample the amorphous form of the compound of formula (I) was prepared according to the method in the prior art; the crystal form V and the crystal form VI of the compound of formula (I) were prepared according to the method of the preparation example.
  • High temperature test The compound crystal form V and crystal form VI of the formula (I) were sealed and placed for 10 days under the condition of 60 ° C, and sampling was carried out on the 10th day.
  • the test items included properties, content, moisture, related substances and XRD;
  • formula ( I) Compound amorphous and crystalline form V were left open for 10 days at 60°C, respectively, and sampling was performed on the 10th day for testing.
  • the testing items included properties, content, moisture, related substances and XRD.
  • High humidity test The compound of formula (I) crystal form V and crystal form VI are sealed and placed for 10 days under the condition of 25 °C RH 92.5%, and sampling is carried out on the 10th day.
  • the test items include properties, content, moisture, related substances and XRD;
  • the compound crystal form V and crystal form VI of the formula (I) are sealed and placed for 30 days under the condition of 40 ° C RH 75%, and sampling is carried out on the 30th day.
  • the test items include properties, content, moisture, related substances and XRD;
  • Amorphous and crystalline form V of the compound of formula (I) were left open for 10 days under the condition of 25° C. RH 92.5%, and sampling was carried out on the 10th day.
  • the test items included properties, content, moisture, related substances and XRD;
  • formula ( I) Compound amorphous and crystalline form V were left open for 30 days under the condition of 40°C RH75%, and sampling was carried out on the 30th day.
  • the test items included properties, content, moisture, related substances and XRD.
  • Illumination test put the compound of formula (I) in the form V and VI under illumination conditions and seal it, and take samples after satisfying the illumination (total illumination ⁇ 1.2 ⁇ 10 6 Lux ⁇ h, near-ultraviolet energy ⁇ 200w ⁇ h/m 2 ) Testing, the testing items include properties, content, moisture, related substances and XRD; the amorphous and crystalline forms V of the compound of formula (I) are placed under illumination conditions, and sampling is performed after satisfying the illumination (same as above), and the testing items include properties, content , moisture, related substances and XRD.
  • the sealing packaging is made of polyethylene bag + composite film bag.
  • Determination of related substances refer to the current version of Chinese Pharmacopoeia by high performance liquid chromatography.
  • Moisture determination refer to the current version of the Chinese Pharmacopoeia for the first method of moisture determination method 2 Coulomb titration.
  • XRPD determination refer to the current version of the Chinese Pharmacopoeia X-ray diffraction method.
  • Table 3 shows the stability test results of the crystal form V of the compound of formula (I).
  • Table 4 shows the stability test results of the crystal form VI of the compound of formula (I).
  • Table 5 shows the results of the stability test of the amorphous form of the compound of formula (I).
  • the crystal form VI of the compound of formula (I) was left open for 10 days under the condition of 60°C, and there was no significant change in each test item; under the condition of 92.5% RH, the water content increased slightly; under the condition of light, the total related The substance increased by 0.25%; however, when placed in the opening for 1 month under the condition of 40°C/RH75%, the crystal form changed and the stability was poor;
  • the amorphous compound of formula (I) was placed openly at a high temperature of 60°C, and there was no significant change in each test item; under light conditions, the total related substances increased slightly, and the moisture increased by 0.40%; placed under the condition of 92.5% RH with an opening After 10 days and 1 month under the condition of 40°C/RH75%, the moisture increases obviously, increasing by 0.79% and 0.69% respectively, and the stability is slightly worse.
  • crystal form I, crystal form V and crystal form VI of the compound of formula (I) were prepared according to the methods of the preparation examples.
  • Determination method Determination according to the current version of the Chinese Pharmacopoeia drug hygroscopicity test guidelines.
  • the crystalline form I, the crystalline form V and the crystalline form VI of the compound of formula (I) have no or almost no hygroscopicity, and the amorphous form of the compound of formula (I) has a slight hygroscopicity.
  • Test sample Form I of the compound of formula (I), prepared according to the method of the preparation example.
  • test sample The following properties were measured after treatment with universal pulverization.
  • Test instrument Baxter powder comprehensive characteristic tester
  • the fluidity of the crystal form can be characterized by the angle of repose parameter, which can indirectly measure the frictional force of the powder, and characterize the fluidity of the powder by reading the angle of repose. It is generally believed that the smaller the angle of repose, the better the fluidity. It can be seen from Table 7 that the crystal form I of the compound of formula (I) has better fluidity and is easy to formulate and industrially produce.
  • the mixed crystal forms containing crystal form I, crystal form VII and crystal form IX were placed in ethanol and acetonitrile systems respectively, and a competitive suspension experiment was carried out. Stir, separate and dry the solid, The obtained solid was examined by XRD.
  • Anhydrous Form I is thermodynamically more stable than Form VII and Form IX in the range of 10°C to 60°C.
  • the crystal form I was obtained after suspension and stirring in water/ethanol mixed solvents with different water contents and at different temperatures, which proves that the crystal form I is more stable.

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Abstract

La présente invention concerne les formes cristallines I, II, III, IV, V, VI, VII, VIII et IX d'un agoniste du récepteur FXR, l'acide 2-((1S,4S,5R)-5-((5-cyclopropyl-3-(2,6-dichlorophényl)isoxazol-4-yl)méthoxy)-2-azabicyclo [2.2.1]heptan-2-yl)benzo[d]thiazole-6-carboxylique, et un procédé de préparation s'y rapportant. Les formes cristallines ont les caractéristiques de pureté élevée, de moins de solvant résiduel, de solubilité élevée, de bonnes propriétés de désagrégation et de dissolution, de bonne stabilité et similaires, et les formes cristallines ont de bonnes propriétés, fluidité et compressibilité et sont pratiques pour la production, la détection, la préparation de formulations, le transport et le stockage ; le procédé de préparation est simple et pratique à mettre en œuvre et est approprié pour une production industrielle, et les formes cristallines peuvent être utilisées pour le traitement et/ou la prévention de maladies liées à médiation par FXR.
PCT/CN2022/078142 2021-02-27 2022-02-28 Formes cristallines d'agoniste du récepteur fxr WO2022179636A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019007418A1 (fr) * 2017-07-06 2019-01-10 山东轩竹医药科技有限公司 Agoniste du récepteur fxr
CN110177783A (zh) * 2016-08-23 2019-08-27 阿德利克斯股份有限公司 用于治疗代谢病状和病症的激素受体调节剂
WO2020033382A1 (fr) * 2018-08-08 2020-02-13 Inorbit Therapeutics Ab Composés utiles dans la modulation du récepteur farnésoïde x et leurs procédés de fabrication et d'utilisation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110177783A (zh) * 2016-08-23 2019-08-27 阿德利克斯股份有限公司 用于治疗代谢病状和病症的激素受体调节剂
WO2019007418A1 (fr) * 2017-07-06 2019-01-10 山东轩竹医药科技有限公司 Agoniste du récepteur fxr
WO2020033382A1 (fr) * 2018-08-08 2020-02-13 Inorbit Therapeutics Ab Composés utiles dans la modulation du récepteur farnésoïde x et leurs procédés de fabrication et d'utilisation

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