WO2022037663A1 - Nouvelle forme cristalline d'un dérivé d'acide benzoïque et son procédé de préparation - Google Patents

Nouvelle forme cristalline d'un dérivé d'acide benzoïque et son procédé de préparation Download PDF

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WO2022037663A1
WO2022037663A1 PCT/CN2021/113682 CN2021113682W WO2022037663A1 WO 2022037663 A1 WO2022037663 A1 WO 2022037663A1 CN 2021113682 W CN2021113682 W CN 2021113682W WO 2022037663 A1 WO2022037663 A1 WO 2022037663A1
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crystal form
formula
compound
solid
temperature
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PCT/CN2021/113682
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Chinese (zh)
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鲁霞
薛文峰
张晓宇
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苏州晶云药物科技股份有限公司
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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
    • A61K31/415—1,2-Diazoles
    • A61K31/4162—1,2-Diazoles condensed with heterocyclic ring systems
    • 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
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered

Definitions

  • the invention relates to the field of chemical medicine, in particular to a new crystal form of a benzoic acid derivative and a preparation method thereof.
  • Farnesoid X receptor a member of the nuclear receptor superfamily, is an intracellular signaling protein that acts as a multifunctional transcriptional regulator to activate or inhibit target gene expression. It is highly expressed in tissues such as liver, intestine, adrenal gland and kidney, and regulates the production, binding and transport of bile acids. In addition, farnesoid X receptors can also reduce hepatic bile acids by regulating the expression of genes related to hepatic bile acid uptake and synthesis. Bile acids play an important role in liver inflammation and liver fibrosis. Research on farnesoid X receptor agonists has become the focus of attention in the field of metabolic disease research in recent years.
  • 4-(((8-Chloro-1,4-dihydro-1-methyl(1)benzopyran(4,3-C)pyrazol-3-yl)carbonyl)(phenylmethyl)amino ) methyl)-benzoic acid is a farnesoid X receptor agonist, which can be used for the treatment of non-alcoholic steatohepatitis (NASH), hepatobiliary dysfunction and diabetic nephropathy. Its structural formula is as follows:
  • Patent WO2015069666A1 discloses the synthesis method of the compound of formula (I), and discloses information such as the melting point and dehydration temperature of the compound Tris salt, meglumine salt and meglumine salt hydrate in the synthesis method, but does not involve the formula (I) Study on the crystal morphology and related properties of the compound in free state.
  • the present invention provides a new crystal form of the compound of formula (I) and its preparation method and use.
  • the present invention provides three crystal forms A, B and C of the compound of formula (I) and their preparation methods and uses.
  • the temperature of dissolving, dropping and stirring in method (1) is 20°C to 30°C
  • the cyclic ether is tetrahydrofuran, 1,4-dioxane, 2- Methyltetrahydrofuran, the alkyl nitrile is acetonitrile
  • the temperature of dissolving, dropping and stirring in the method (2) is 20°C to 30°C
  • the cyclic ether is tetrahydrofuran, 1,4-dioxane, 2 - methyltetrahydrofuran, the straight-chain alkane is n-pentane, n-hexane or n-heptane
  • the amide described in the method (3) is N-methylpyrrolidone
  • the cyclic ether is tetrahydrofuran
  • the alcohols are isopropanol
  • the acyclic ether is methyl tert-butyl ether
  • the temperature for dissolving and dropping is 20°C to 30°C
  • the temperature for standing is -20°C to 5°C
  • the cyclic ether is tetrahydrofuran
  • the sulfone is dimethyl sulfoxide
  • the amide is N-methylpyrrolidone, N,N-dimethylacetamide
  • the alkane is n-heptane, n-hexane, n-pentane
  • the alcohols are ethanol, methanol
  • the ketone is methyl isobutyl ketone
  • the ester is isopropyl acetate
  • the alkyl nitrile is acetonitrile
  • the halogenated hydrocarbon is dichloromethane
  • the aromatic hydrocarbon is toluene
  • method (2) The temperature of dissolving, dropping and stirring is 20°C to 30°C
  • the cyclic ether is tetrahydrofuran and 1,4-
  • the amides are N,N-dimethylacetamide, N-methylpyrrolidone, the alkanes are n-heptane, n-hexane, n-pentane, the alcohols are n-butanol, isopropanol, the The ketone is 2-butanone, the acyclic ether is methyl tert-butyl ether and anisole, the alkyl nitrile is acetonitrile, the halogenated hydrocarbon is chloroform, and the aromatic hydrocarbon is toluene; method (3) ), the sulfoxide is dimethyl sulfoxide, the amide is N-methylpyrrolidone, N,N-dimethylacetamide, the cyclic ether is tetrahydrofuran, the alcohols are methanol, ethanol, The ketone is acetone, the halogenated hydrocarbon is dichloromethane, the alkyl nitrile is aceton
  • the infiltration and volatilization temperature is 20 to 30°C, and the infiltration time is 3 to 15 days;
  • the volatilization temperature in the method (4) is 20°C to 30°C, and the ketones are acetone and 2-butanone.
  • the esters are ethyl acetate, the alcohols are methanol, the halogenated hydrocarbons are chloroform and dichloromethane, the ethers are tetrahydrofuran, 1,4-dioxane, 2-methyltetrahydrofuran, Cyclopentyl methyl ether, sulfoxide is dimethyl sulfoxide, and alkane is n-pentane; in method (5), the dissolution temperature is 50°C, the cooling temperature is -20°C to 5°C, and the volatilization temperature is is 20-30°C, the ketone is acetone, the cyclic ether is tetrahydrofuran, 2-methyltetrahydrofuran, the
  • the compound of formula (I) is dissolved in a cyclic ether at 5-50° C., and alkane is added until a solid is precipitated to obtain crystal form C.
  • a pharmaceutical composition comprising the crystal form A according to any one of the above 1 to 3, the crystal form B according to any one of the above 6 to 8, the crystal form C according to any one of the above 11 to 13, and a pharmaceutically acceptable composition. accepted vector.
  • a preventive or therapeutic drug for nonalcoholic steatohepatitis (NASH), hepatobiliary dysfunction, diabetic nephropathy and other diseases comprising the crystalline form A according to any one of the above 1 to 3, and the above 6 to 8.
  • NASH nonalcoholic steatohepatitis
  • hepatobiliary dysfunction hepatobiliary dysfunction
  • diabetic nephropathy diabetic nephropathy and other diseases
  • the new crystal form of the compound of formula (I) provided by the invention has the advantages of solubility, melting point, stability, dissolution, hygroscopicity, adhesion, fluidity, bioavailability and processing performance, purification, preparation.
  • advantages in at least one aspect of production, safety and the like which provide a new and better choice for the preparation of the pharmaceutical preparation of the compound of formula (I), which is of great significance for drug development.
  • crystal form A, crystal form B and crystal form C of the present invention are:
  • the crystal form B and crystal form C of the present invention have relatively high solubility.
  • SGF simulated artificial gastric fluid
  • FeSSIF artificial intestinal fluid in fasting state
  • FeSSIF artificial intestinal fluid in fed state
  • water the solubility of crystal form B and crystal form C are higher than other known crystal forms.
  • the compound of formula (I) is a poorly soluble drug belonging to BCS Class II.
  • higher solubility will directly improve the bioavailability of the drug, thereby improving the druggability and efficacy of the drug; in addition, the increase in solubility can reduce the dose of the drug while ensuring the efficacy of the drug, thereby reducing the drug's efficacy. side effects and improve the safety of medicines.
  • the crystal form A and the crystal form B of the present invention have good moisture absorption, and the moisture gain is less than 0.04% when the water absorption balance is reached under the condition of 25°C/80%RH, which is better than other known crystal forms. It can still maintain stable properties under wet conditions, and can maintain stability without specific humidity control conditions during production, storage and use, and can well meet the requirements of drug production and use.
  • the crystal form A of the present invention has good solution stability, can keep the crystal form stable at different temperatures and in different solvents, has good solution stability, meets the requirements of industrial production for the solid form of drugs, and has relatively high stability. high application value.
  • the currently reported crystal forms of the compound of formula (I) have few crystal forms available for industrial production and are difficult to develop in industry.
  • the inventors of the present invention solved the above problems through research and found a new crystal form suitable for development.
  • Compound 4-(((8-chloro-1,4-dihydro-1-methyl(1)benzopyran(4,3-C)pyrazol-3-yl)carbonyl) represented by formula (I) (Phenylmethyl)amino)methyl)-benzoic acid type A crystal, namely crystal form A, is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction of said crystal form A is at 25.2° ⁇ 0.2°, There are characteristic peaks at 22.1° ⁇ 0.2°, 17.8° ⁇ 0.2°,
  • the X-ray powder diffraction of the crystal form A has one or two or three 2 ⁇ values of 13.0° ⁇ 0.2°, 26.9° ⁇ 0.2°, and 19.1° ⁇ 0.2°. There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form A has characteristic peaks at 2 ⁇ values of 13.0° ⁇ 0.2°, 26.9° ⁇ 0.2°, and 19.1° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form A has 2 ⁇ values of 8.8 ⁇ 0.2°, 11.1° ⁇ 0.2°, and 20.3° ⁇ 0.2° at one or two or three places. Characteristic peaks.
  • the X-ray powder diffraction of the crystal form A has characteristic peaks at 2 ⁇ values of 8.8 ⁇ 0.2°, 11.1° ⁇ 0.2°, and 20.3° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form A has 2 ⁇ values of 8.8 ⁇ 0.2°, 11.1° ⁇ 0.2°, 13.0° ⁇ 0.2°, 17.8° ⁇ 0.2, 19.1° ⁇ 0.2° , 20.3° ⁇ 0.2°, 22.1° ⁇ 0.2°, 25.2° ⁇ 0.2°, 26.9° ⁇ 0.2°, any 4 places, or 5 places, or 6 places, or 7 places, or 8 places, or 9 places There are characteristic peaks.
  • the X-ray powder diffraction pattern of Form A is shown in FIG. 1 .
  • the preparation method of the crystal form A is characterized in that:
  • the compound of formula (I) is dissolved in a positive solvent, and an anti-solvent is added dropwise thereto under stirring until a solid is precipitated to obtain crystal form A.
  • the positive solvent is a cyclic ether
  • the anti-solvent is water or an alkyl nitrile
  • the cyclic ether is selected from tetrahydrofuran, 1,4-dioxane, 2-methyltetrahydrofuran, such as tetrahydrofuran, and the alkyl nitrile is acetonitrile.
  • the temperature for dissolving, mixing and stirring is 5-50°C, preferably 20-30°C.
  • the preparation method of the crystal form A is characterized in that:
  • the compound of formula (I) is dissolved in a positive solvent, rapidly added to an anti-solvent under stirring, and stirring is continued until a solid is precipitated to obtain crystal form A.
  • the positive solvent is a cyclic ether
  • the anti-solvent is a straight-chain alkane
  • the cyclic ether is selected from tetrahydrofuran, 1,4-dioxane, 2-methyltetrahydrofuran, such as 1,4-dioxane, and the linear alkane is n-pentane alkane, n-hexane or n-heptane, for example n-hexane.
  • the preparation method of the crystal form A is characterized in that:
  • the compound of formula (I) is dissolved in a positive solvent, and placed under an anti-solvent atmosphere for a period of time under the condition of room temperature, and the crystal form A is obtained.
  • the positive solvent is selected from amides and cyclic ethers
  • the anti-solvent is selected from alcohols, acyclic ethers, and halogenated hydrocarbons.
  • the amide is N-methylpyrrolidone
  • the cyclic ether is tetrahydrofuran
  • the alcohol is isopropanol
  • the acyclic ether is methyl tert-butyl ether
  • the halogenated Hydrocarbons are dichloromethane and chloroform.
  • the preparation method of the crystal form A is characterized in that:
  • the compound of formula (I) is dissolved in a single or mixed solvent system of an organic solvent, and is allowed to stand to volatilize under a certain temperature condition until a solid is precipitated to obtain the crystal form A.
  • the organic solvent is selected from single or mixed solvents of ketones, esters, alcohols, and halogenated hydrocarbons.
  • the ketones are acetone
  • the esters are ethyl acetate
  • the alcohols are methanol
  • the halogenated hydrocarbons are dichloromethane.
  • the mixed solvent is a mixed solvent of methanol and dichloromethane.
  • the volume ratio of methanol to dichloromethane is 1:2 to 2:1, for example, 1:1.
  • the volatilization temperature is 5°C to 50°C, for example, 20°C to 30°C.
  • the preparation method of the crystal form A is characterized in that:
  • the compound of formula (I) is dissolved in an organic solvent system, and after reaching a dissolution equilibrium under high temperature conditions, the temperature is rapidly cooled until a solid is precipitated to obtain crystal form A.
  • the organic solvent is a single or mixed solvent of ketones, esters, halogenated hydrocarbons, cyclic ethers, alkanes, and alcohols.
  • the ketones are acetone and butanone
  • the esters are ethyl acetate
  • the cyclic ethers are tetrahydrofuran
  • the alkanes are n-hexane
  • the alcohols are methanol
  • the The halogenated hydrocarbon is chloroform.
  • the mixed solvent is a mixed solvent of methanol/2-butanone, tetrahydrofuran/n-hexane, chloroform/ethyl acetate.
  • the volume ratio of the mixed solvent is 2:1 to 1:2, for example, 1:1.
  • the dissolution temperature is 40-60°C, for example, 50°C
  • the cooling crystallization temperature is -30-10°C, for example, -20-5°C.
  • the preparation method of the crystal form A is characterized in that:
  • the compound of formula (I) is dissolved in a single or mixed solvent system, a polymer is added, and under a certain temperature condition, it is left to volatilize until a solid is precipitated to obtain a crystal form A.
  • the solvent is selected from the group consisting of ketones, esters, alkyl nitriles, halogenated hydrocarbons, alcohols, cyclic ethers, alkanes and water.
  • the ketone is 2-butanone
  • the ester is methyl acetate and ethyl acetate
  • the alkyl nitrile is acetonitrile
  • the halogenated hydrocarbon is chloroform
  • the alcohol is ethanol
  • the cyclic ether is tetrahydrofuran
  • the alkane is n-pentane.
  • the mixed solvent is selected from acetonitrile/water, ethanol/water, tetrahydrofuran/n-pentane.
  • the volume ratio of the mixed solvent is 1:2 to 2:1, for example, 1:1.
  • the high polymer is selected from polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), polyvinyl chloride (PVC), polyvinyl acetate (PVAC), hypromellose (HPMC), methylcellulose (MC), caprolactone (PCL), polyethylene glycol (PEG), poly(methyl methacrylate) (PMMA), sodium alginate (SA) and hydroxyethyl cellulose singly or mixtures of HEC.
  • PVP polyvinylpyrrolidone
  • PVA polyvinyl alcohol
  • PVC polyvinyl chloride
  • PVAC polyvinyl acetate
  • HPMC hypromellose
  • MC methylcellulose
  • PCL caprolactone
  • PEG polyethylene glycol
  • PMMA poly(methyl methacrylate)
  • SA sodium alginate
  • hydroxyethyl cellulose singly or mixtures of HEC.
  • the mass ratio of the high polymer to the compound of formula (I) is 0.15:1 to 0.25:1.
  • the volatilization temperature is 5°C to 50°C, for example, 20°C to 30°C.
  • Compound 4-(((8-chloro-1,4-dihydro-1-methyl(1)benzopyran(4,3-C)pyrazol-3-yl)carbonyl) represented by formula (I) (Phenylmethyl)amino)methyl)-benzoic acid type B crystal, namely crystal form B, is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction of said crystal form B is at 23.5° ⁇ 0.2°, There are characteristic peaks at 8.6° ⁇ 0.2° and 14.9° ⁇ 0.2°,
  • the X-ray powder diffraction of the crystal form B has one or two or three 2 ⁇ values of 16.9° ⁇ 0.2°, 10.3° ⁇ 0.2°, and 21.4° ⁇ 0.2°. There are characteristic peaks.
  • the X-ray powder diffraction of the crystal B has characteristic peaks at 2 ⁇ values of 16.9° ⁇ 0.2°, 10.3° ⁇ 0.2°, and 21.4° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form B has one or two or three 2 ⁇ values of 15.6° ⁇ 0.2°, 20.7° ⁇ 0.2°, and 7.4° ⁇ 0.2°. There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form B has characteristic peaks at 2 ⁇ values of 15.6° ⁇ 0.2°, 20.7° ⁇ 0.2°, and 7.4° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form B has 2 ⁇ values of 7.4° ⁇ 0.2°, 8.6° ⁇ 0.2°, 10.3° ⁇ 0.2°, 14.9° ⁇ 0.2°, 15.6° ⁇ 0.2°, 16.9° ⁇ 0.2°, 20.7° ⁇ 0.2°, 21.4° ⁇ 0.2°, 23.5° ⁇ 0.2° any 4, or 5, or 6, or 7, or 8, or 9 There are characteristic peaks.
  • the X-ray powder diffraction pattern of the crystal form B is shown in FIG. 5 .
  • the preparation method of the crystal form B is characterized in that:
  • the compound of formula (I) is dissolved in a positive solvent, an anti-solvent is added dropwise to it under stirring, and the crystal form B is obtained by standing at low temperature and volatilizing at room temperature until a solid is precipitated.
  • the positive solvent is selected from cyclic ethers, sulfoxides, and amide solvents
  • the anti-solvent is selected from alkanes, alcohols, ketones, esters class, alkyl nitriles, halogenated hydrocarbons, aromatic hydrocarbons.
  • the cyclic ether is tetrahydrofuran
  • the sulfoxide is dimethyl sulfoxide
  • the amide is N-methylpyrrolidone, N,N-dimethylacetamide
  • the alkane is n-heptyl Alkane, n-hexane, n-pentane
  • the alcohols are ethanol, methanol
  • the ketones are methyl isobutyl ketone
  • the esters are isopropyl acetate
  • the alkyl nitrile is acetonitrile
  • the hydrocarbon is dichloromethane and the aromatic hydrocarbon is toluene.
  • the dropping temperature is 5-50°C, for example, 20-30°C
  • the standing temperature is -30-10°C, for example, -20-5°C.
  • the preparation method of the crystal form B is characterized in that:
  • the compound of formula (I) is dissolved in the positive solvent, rapidly added to the anti-solvent under stirring, and the stirring is continued until a solid is precipitated to obtain the crystal form B.
  • the positive solvent is selected from cyclic ethers, sulfoxides, and amides
  • the anti-solvent is selected from pure water, alkanes, alcohols, ketones, acyclic ethers, alkyl nitriles, halogenated Hydrocarbons, aromatic hydrocarbons.
  • the cyclic ether is tetrahydrofuran, 1,4-dioxane, and the sulfoxide is dimethyl sulfoxide.
  • the amides are N,N-dimethylacetamide, N-methylpyrrolidone, the alkanes are n-heptane, n-hexane, n-pentane, the alcohols are n-butanol, isopropanol, the The ketones are 2-butanone, the acyclic ethers are methyl tert-butyl ether and anisole, the alkyl nitrile is acetonitrile, the halogenated hydrocarbon is chloroform, and the aromatic hydrocarbon is toluene.
  • the temperature for dissolving, dropping and stirring is 5-50°C, for example, 20-30°C.
  • the preparation method of the crystal form B is characterized in that:
  • the compound of formula (I) is dissolved in a positive solvent, placed in an anti-solvent atmosphere for gas-liquid permeation for a period of time, directly crystallized, or openly volatilized to obtain crystal form B.
  • the positive solvent is selected from sulfoxides, amides, and cyclic ethers
  • the anti-solvent is selected from alcohols, ketones, halogenated hydrocarbons, alkyl nitriles, alkanes, aromatic hydrocarbons, esters, pure water.
  • the sulfoxide is dimethyl sulfoxide
  • the amide is N-methylpyrrolidone
  • the cyclic ether is tetrahydrofuran
  • the alcohol The ketones are methanol and ethanol, the ketones are acetone, the halogenated hydrocarbons are methylene chloride, the alkyl nitrile is acetonitrile, the alkane is n-heptane, the aromatic hydrocarbon is toluene, and the esters are Isopropyl acetate.
  • the penetration and volatilization temperature is 5-50°C, for example, 20-30°C.
  • the penetration time is 3 to 15 days.
  • the preparation method of the crystal form B is characterized in that:
  • the compound of formula (I) is dissolved in a single or mixed solvent system of an organic solvent, and the crystal form B is obtained by standing to volatilize under a certain temperature condition until a solid is precipitated.
  • the organic solvent is selected from single or mixed solvents of ketones, esters, alcohols, halogenated hydrocarbons, ethers, sulfoxides, and alkanes.
  • the ketones are acetone and 2-butanone
  • the esters are ethyl acetate
  • the alcohols are methanol
  • the halogenated hydrocarbons are chloroform and dichloromethane
  • the ether is tetrahydrofuran, 1,4-dioxane, 2-methyltetrahydrofuran, cyclopentyl methyl ether
  • the sulfoxide is dimethyl sulfoxide
  • the alkane is n-pentane.
  • the mixed solvent is a mixed solvent of methanol/tetrahydrofuran, tetrahydrofuran/n-pentane, cyclopentyl methyl ether/dichloromethane, chloroform/2-butanone.
  • the volume ratio of the mixed solvent is 1:2 ⁇ 2:1, for example, 1:1.
  • the volatilization temperature is 5°C to 50°C, for example, 20°C to 30°C.
  • the preparation method of the crystal form B is characterized in that:
  • the compound of formula (I) is dissolved in an organic solvent system, and after reaching the dissolution equilibrium under high temperature conditions, after cooling, volatilizing to solid precipitation to obtain crystal form B.
  • the organic solvent is a single or mixed solvent of ketones, halogenated hydrocarbons, cyclic ethers, and alkanes.
  • the ketone is acetone
  • the cyclic ether is tetrahydrofuran
  • the alkane is n-heptane
  • the halogenated hydrocarbon is chloroform
  • the mixed solvent is a mixed solvent of tetrahydrofuran/n-heptane.
  • the volume ratio of tetrahydrofuran/n-heptane is 2:1 to 1:2, for example, 1:1.
  • the dissolving temperature is 40-60°C, such as 50°C
  • the cooling precipitation temperature is -30-10°C, such as -20-5°C
  • the volatilization temperature is 5-50°C °C, for example, 20 to 30 °C.
  • the preparation method of the crystal form B is characterized in that:
  • the compound of formula (I) is added into a single or mixed solvent system, stirred at high temperature to reach a dissolution equilibrium, stirred at 20-30° C. for 2 days, and volatilized until a solid is precipitated to obtain crystal form B.
  • the solvent is selected from ketones, alkanes, cyclic ethers, halogenated hydrocarbons, sulfoxides, and aromatic hydrocarbons.
  • the ketone is methyl isobutyl ketone
  • the alkane is n-heptane
  • the cyclic ether is 1,4-dioxane
  • the halogenated hydrocarbon is tris Methyl chloride
  • the sulfoxide is dimethyl sulfoxide
  • the aromatic hydrocarbon is toluene.
  • the mixed solvent is 1,4-dioxane/n-heptane, dimethyl sulfoxide/toluene.
  • the volume ratio of 1,4-dioxane/n-heptane is 1:2 to 2:1, for example, 1:1.
  • the volume ratio of dimethyl sulfoxide/toluene is 1:8 to 1:10, such as 1:9.
  • the dissolution temperature is 65-75°C.
  • Compound 4-(((8-chloro-1,4-dihydro-1-methyl(1)benzopyran(4,3-C)pyrazol-3-yl)carbonyl) represented by formula (I) (Phenylmethyl)amino)methyl)-benzoic acid type C crystal, namely crystal form C, is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction of the crystal form C is at 11.1° ⁇ 0.2°, There are characteristic peaks at 22.4° ⁇ 0.2° and 16.8° ⁇ 0.2°,
  • the X-ray powder diffraction of the crystal form C has one or two or three 2 ⁇ values of 7.1° ⁇ 0.2°, 14.2° ⁇ 0.2°, and 15.2° ⁇ 0.2°. There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form C has characteristic peaks at 2 ⁇ values of 7.1° ⁇ 0.2°, 14.2° ⁇ 0.2°, and 15.2° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form C has one or two or three 2 ⁇ values of 28.8° ⁇ 0.2°, 13.8° ⁇ 0.2°, and 23.7° ⁇ 0.2°. There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form C has characteristic peaks at 2 ⁇ values of 28.8° ⁇ 0.2°, 13.8° ⁇ 0.2°, and 23.7° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form C has 2 ⁇ values of 7.1° ⁇ 0.2°, 11.1° ⁇ 0.2°, 13.8° ⁇ 0.2°, 14.2° ⁇ 0.2°, 15.2° ⁇ 0.2°, 16.8° ⁇ 0.2°, 22.4° ⁇ 0.2°, 23.7° ⁇ 0.2°, 28.8° ⁇ 0.2° any 4, or 5, or 6, or 7, or 8, or 9 There are characteristic peaks.
  • the X-ray powder diffraction pattern of the crystal form C is shown in FIG. 9 .
  • the preparation method of the crystal form C is characterized in that:
  • the compound of formula (I) is dissolved in a positive solvent, and an anti-solvent is added dropwise thereto until a solid is precipitated to obtain crystal form C.
  • the positive solvent is a cyclic ether
  • the anti-solvent is an alkane
  • the cyclic ether is tetrahydrofuran
  • the sulfoxide is dimethyl sulfoxide
  • the alkane is n-heptane
  • the temperature for dissolving, dropping and stirring is 5-50°C, for example, 20-30°C.
  • the compound of formula (I) and/or its salt as raw material refers to its solid (crystalline or amorphous), semi-solid, wax or oil form.
  • the compounds of formula (I) and/or their salts as starting materials are in the form of solid powders.
  • crystalline or “polymorphic form” means as evidenced by the characterization of the X-ray diffraction pattern shown.
  • X-ray diffraction patterns generally vary with the conditions of the instrument.
  • the relative intensities of X-ray diffraction patterns may also vary with experimental conditions, so the order of peak intensities cannot be used as the sole or decisive factor.
  • the relative intensities of the diffraction peaks in the XRPD pattern are related to the preferred orientation of the crystals, and the peak intensities shown here are illustrative rather than absolute comparisons.
  • the experimental error of the peak angle is usually 5% or less, and the error of these angles should also be taken into account, and an error of ⁇ 0.2° is usually allowed.
  • the overall shift of the peak angle will be caused, and a certain shift is usually allowed.
  • the X-ray diffraction pattern of a crystal form in the present invention does not necessarily have to be exactly the same as the X-ray diffraction pattern in the examples mentioned here, and the "same XRPD pattern" mentioned herein does not mean absolutely the same , the same peak position can differ by ⁇ 0.2° and the peak intensity allows some variability. Any crystalline form having the same or similar pattern as the characteristic peaks in these patterns is within the scope of the present invention. Those skilled in the art can compare the patterns listed in the present invention with a pattern of an unknown crystal form to confirm whether the two sets of patterns reflect the same or different crystal forms.
  • Form A, Form B, Form C of the present invention are pure, single, and substantially not mixed with any other crystalline form.
  • substantially free when used to refer to a new crystal form means that the crystal form contains less than 20% by weight of other crystal forms, especially less than 10% by weight of other crystal forms, and even less More than 5% (weight) of other crystal forms, more than 1% (weight) of other crystal forms.
  • the X-ray powder diffraction patterns of the present invention were collected on a PANalytical Empyrean or X'Pert 3 X-ray powder diffractometer.
  • the method parameters of X-ray powder diffraction of the present invention are as follows:
  • DSC Differential Scanning Calorimetry
  • thermogravimetric analysis (TGA) plots described in the present invention were collected on a TA Discovery 5500.
  • the method parameters of thermogravimetric analysis (TGA) of the present invention are as follows:
  • HPLC high performance liquid chromatography
  • PDA diode array detector
  • Chromatographic column Waters ACQUITY UPLC BEH C18, 50 ⁇ 2.1mm, 1.7 ⁇ m
  • the elution gradient is as follows:
  • the solids obtained in the above examples are all crystal form A
  • the X-ray powder diffraction patterns of the obtained solids are shown in FIG. 1
  • the X-ray powder diffraction data are shown in Table 1.
  • TGA, DSC, and 1 H NMR tests were performed on the above-mentioned crystal form A sample, and the obtained spectra are shown in Figures 2-4.
  • DSC data show that the melting point of the crystal form A sample is 205°C, the weight loss is 2.5% when heated by TGA at 160°C, and no solvent residue is found in the NMR.
  • the above characterization data show that Form A is an anhydrous form.
  • Example 6 the X-ray powder diffraction data of the obtained solid are shown in Table 7.
  • Nidufexor solid was added approximately 10 mg into a 3 mL glass vial, add the corresponding volume of solvent to dissolve the solid, and filter the sample solution into a new 3 mL glass vial using a 0.45-micron pore size teflon filter. Add about 2 mg of polymer mixture A or B, seal it with Parafilm, poke four small holes, and then leave it to evaporate at room temperature until solid precipitation.
  • Polymer Mixture A Polyvinylpyrrolidone (PVP), Polyvinyl Alcohol (PVA), Polyvinyl Chloride (PVC), Polyvinyl Acetate (PVAC), Hypromellose (HPMC), Methylcellulose ( MC) (equal mass mixing).
  • PVP Polyvinylpyrrolidone
  • PVA Polyvinyl Alcohol
  • PVC Polyvinyl Chloride
  • PVAC Polyvinyl Acetate
  • HPMC Hypromellose
  • MC Methylcellulose
  • Polymer Blend B polycaprolactone (PCL), polyethylene glycol (PEG), poly(methyl methacrylate) (PMMA) sodium alginate (SA) and hydroxyethyl cellulose (HEC) (equivalent mass mix).
  • PCL polycaprolactone
  • PEG polyethylene glycol
  • PMMA poly(methyl methacrylate)
  • SA sodium alginate
  • HEC hydroxyethyl cellulose
  • the solids obtained in the above examples are all crystal form B, the X-ray powder diffraction patterns of the obtained solids are shown in FIG. 5 , and the X-ray powder diffraction data are shown in Table 12.
  • TGA, DSC, and 1 H NMR data are shown in FIGS. 6 to 8 .
  • TGA showed a weight loss of 2.2% when heated to 170°C, and a weight loss of 1.3% when heated to 220°C; DSC showed that the melting point of Form B was 211°C; no solvent remained in NMR, indicating that Form B was an anhydrous crystal.
  • Example 13 The detailed test conditions involved in the above examples are shown in Table 13. After testing, the solids obtained in the above examples are all crystal form B. Taking Example 25 as an example, the X-ray powder diffraction data of the obtained solid are shown in Table 14.
  • Example 15 The detailed test conditions involved in the above examples are shown in Table 15. After testing, the solids obtained in the above examples are all crystal form B. Taking Example 39 as an example, the X-ray powder diffraction data of the obtained solid are shown in Table 16.
  • Example 21 The detailed test conditions involved in the above examples are shown in Table 21. After testing, the solids obtained in the above examples are all crystal form B. Taking Example 60 as an example, the X-ray powder diffraction data of the obtained solid are shown in Table 22.
  • Example 23 The detailed test conditions involved in the above examples are shown in Table 23. After testing, the solids obtained in the above examples are all crystal form B. Taking Example 74 as an example, the X-ray powder diffraction data of the obtained solid are shown in Table 24.
  • the solid obtained in this example is crystal form B.
  • Table 25 shows the X-ray powder diffraction data of the solid obtained in this example.
  • the solid obtained in this example is crystal form B.
  • Table 26 shows the X-ray powder diffraction data of the solid obtained in this example.
  • Example 27 The detailed test conditions involved in the above examples are shown in Table 27. After testing, the solids obtained in the above examples are all crystal form B. Taking Example 83 as an example, the X-ray powder diffraction data of the obtained solid are shown in Table 28.
  • the crystal form A, crystal form B and crystal form C of the present invention are respectively prepared into saturated solutions with SGF (simulated artificial gastric fluid), FaSSIF (artificial intestinal fluid in fasting state), FeSSIF (artificial intestinal fluid in fed state) and pure water, at 37 After equilibration at °C for 24 hours, the solution was filtered to obtain a saturated solution. The content of the sample in the saturated solution was determined by high performance liquid chromatography (HPLC), and the results are shown in Table 31.
  • SGF simulated artificial gastric fluid
  • FaSSIF artificial intestinal fluid in fasting state
  • FeSSIF artificial intestinal fluid in fed state
  • crystal form B increases the solubility of the compound of formula (I) by 33-180%
  • crystal form C increases the solubility of the compound of formula (I) by 30-250%.
  • the improvement of solubility will help the absorption and utilization of drugs in vivo, thereby achieving the purpose of improving bioavailability and efficacy. Therefore, selecting crystal form B and crystal form C as the pharmaceutical solid form of the compound of formula (I) will help the bioavailability of the compound of formula (I) in vivo, thereby improving the curative effect of the pharmaceutical preparation.
  • Form A Form B Form C 25°C/80%RH wet weight gain(%) 0.035 0.038 0.16 Changes in crystal form after DVS test constant constant constant
  • the crystal forms A, B and C of the present invention all have no or almost no hygroscopicity, and can still maintain stable properties under high humidity conditions. During use, it can maintain stability without specific humidity control conditions, and can well meet the requirements of drug production and use.
  • Moisture gain is less than 15% but not less than 2%
  • wet weight gain is less than 2% but not less than 0.2%
  • wet weight gain is less than 0.2%
  • the solids obtained in the above experiments are all crystal form A.
  • the X-ray powder diffraction patterns of the obtained solid are shown in FIGS. 19 to 24 .
  • the experimental results show that the crystal form A can keep the solid form unchanged at the test temperature and crystallization solvent, has good solution stability, meets the requirements of industrial production for the solid form of drugs, and has high application value.
  • Example 85 of the present invention place it in an oven at 80°C with a closed mouth, take samples to measure XRPD and HPLC 1 day later, and place it openly at 25°C/60% RH , 40°C/75%RH conditions, take samples to measure XRPD and HPLC after 2 weeks.
  • the experimental results showed that the crystal form and purity of Form A did not change significantly after being placed under the conditions of 25°C/60%RH and 40°C/75%RH.
  • the crystal form and purity did not change significantly after being placed under the condition of 40°C/75%RH.
  • the crystal form A of the present invention has good physical/chemical stability under the conditions of 25°C/60%RH and 40°C/75%RH, while the crystal forms B and C are at 80°C, 25°C/60%RH, 40°C/ It has good physical/chemical stability under the condition of 75%RH. During storage and use, it can maintain stability without specific temperature and humidity control conditions, and can well meet the requirements of drug storage and use.

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Abstract

L'invention concerne trois formes cristallines A, B et C d'un composé de formule (I), leur procédé de préparation et leur utilisation. Les formes cristallines A, B et C du composé de formule (I) ont une solubilité, point de fusion, stabilité, dissolution, hygroscopicité, adhérence, fluidité, efficacité biologique et performances de traitement, effet de purification, production de préparation, sécurité, etc, améliorés et peuvent fournir de meilleurs choix pour la préparation de médicament.
PCT/CN2021/113682 2020-08-21 2021-08-20 Nouvelle forme cristalline d'un dérivé d'acide benzoïque et son procédé de préparation WO2022037663A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105682656A (zh) * 2013-11-05 2016-06-15 诺华股份有限公司 调节法尼醇x受体的组合物和方法
CN109689050A (zh) * 2016-09-14 2019-04-26 诺华股份有限公司 Fxr激动剂的新方案

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105682656A (zh) * 2013-11-05 2016-06-15 诺华股份有限公司 调节法尼醇x受体的组合物和方法
CN109689050A (zh) * 2016-09-14 2019-04-26 诺华股份有限公司 Fxr激动剂的新方案

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHIANELLI DONATELLA, RUCKER PAUL V., ROLAND JASON, TULLY DAVID C., NELSON JOHN, LIU XIAODONG, BURSULAYA BADRY, HERNANDEZ ELOY D., : "Nidufexor (LMB763), a Novel FXR Modulator for the Treatment of Nonalcoholic Steatohepatitis", JOURNAL OF MEDICINAL CHEMISTRY, vol. 63, no. 8, 23 April 2020 (2020-04-23), US , pages 3868 - 3880, XP055820211, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.9b01621 *

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