WO2022206879A1 - Crystal forms of sulfamoyl pyrrole amide compounds and preparation methods therefor - Google Patents

Crystal forms of sulfamoyl pyrrole amide compounds and preparation methods therefor Download PDF

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WO2022206879A1
WO2022206879A1 PCT/CN2022/084300 CN2022084300W WO2022206879A1 WO 2022206879 A1 WO2022206879 A1 WO 2022206879A1 CN 2022084300 W CN2022084300 W CN 2022084300W WO 2022206879 A1 WO2022206879 A1 WO 2022206879A1
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crystal form
formula
compound
crystal
present
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PCT/CN2022/084300
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Chinese (zh)
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鲁霞
陈智雄
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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/36—Oxygen or sulfur atoms

Definitions

  • the invention relates to the field of chemical medicine, in particular to a crystal form of a sulfamoyl pyrrole amide compound and a preparation method thereof.
  • Hepatitis B is caused by hepatitis B virus (HBV) infection.
  • HBV hepatitis B virus
  • the treatment of hepatitis B virus infection is mainly "functional treatment", which requires long-term or life-long medication to achieve “functional cure”, that is, the content of hepatitis B surface antigen (HBsAg) and HBV-DNA in serum is always maintained to an undetectable state, thereby improving residual liver damage or fibrosis and reducing the risk of hepatitis.
  • functional treatment which requires long-term or life-long medication to achieve “functional cure”
  • HBV is composed of two parts, the outer shell and the core part.
  • the core part includes the viral capsid composed of the core protein, the DNA polymerase and the viral pregenome (pgRNA) contained in it.
  • pgRNA viral pregenome
  • Hepatitis B virus capsid protein assembly regulator (CAM) can combine with core protein to interfere with the encapsidation process of pgRNA, thereby inhibiting the production of HBV in vivo.
  • CAMs are under clinical research. The CAM currently studied can be divided into two types: CAM-A and CAM-N.
  • CAM-A affects the structure of the core protein and prevents HBV from forming a capsid of normal structure and size;
  • CAM-N inhibits the inclusion process of viral DNA and pgRNA, thereby producing an empty capsid. Both CAMs can prevent normal viruses Formation of the capsid.
  • Pyrrole-2-carboxamide is a new type of CAM-N, the compound is currently in phase 2 clinical research for the treatment of hepatitis B, and its structural formula is as follows:
  • Patent WO2014/184350A1 discloses the compound of formula (I) and its synthesis process. Through column chromatography and multiple washing and purification processes, a small amount of the target product that meets the requirements is finally obtained. The preparation method is cumbersome and unfavorable for industrialized large-scale production. The patent does not mention relevant reports on the solid or crystalline form of the compound of formula (I).
  • crystallization process As the main method of chemical product purification, crystallization process has the advantages of simple operation, easy amplification, low cost, etc., and is a purification method widely used in chemical and pharmaceutical fields. In view of the complex preparation and purification process of the compound of formula (I) at present, and the difficulty of process amplification, it is necessary to find different crystalline forms of the compound of formula (I) to simplify the purification process of the final product in production and improve the purification efficiency.
  • the present invention provides two crystal forms A and B of the compound of formula (I) and their preparation methods and uses.
  • a pharmaceutical composition comprising the crystal of any one of 1 and 3 above and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition having CAM activity comprising the crystal of any one of 1 and 3 above as an active ingredient.
  • a preventive or therapeutic agent for hepatitis B virus infection comprising the crystal according to any one of 1 and 3 above as an active ingredient.
  • the crystalline forms A and B of the compounds of the formula (I) provided by the present invention are in solubility, melting point, stability, dissolution, hygroscopicity, adhesion, fluidity, bioavailability, processability, purification.
  • advantages in at least one aspect of action, preparation production, safety, etc. which provide a new and better choice for the preparation of pharmaceutical preparations containing the compound of formula (I), and are of great significance to drug development.
  • the compound represented by formula (I) N-(3-cyano-4-fluoro-phenyl)-1-methyl-4- ⁇ [(1S)-2,2,2-trifluoro-1-methyl-
  • the A-type crystal of ethyl]sulfamoyl ⁇ pyrrole-2-carboxamide, namely crystal form A is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction of the crystal form A has a 2 ⁇ value of 6.8° ⁇ There are characteristic peaks at 0.2°, 13.6° ⁇ 0.2° and 22.1° ⁇ 0.2°,
  • the X-ray powder diffraction of the crystal form A has one or two or three 2 ⁇ values of 11.7° ⁇ 0.2°, 17.1° ⁇ 0.2°, 20.5° ⁇ 0.2° There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form A has characteristic peaks at 2 ⁇ values of 11.7° ⁇ 0.2°, 17.1° ⁇ 0.2°, and 20.5° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form A has a 2 ⁇ value of 16.4° ⁇ 0.2°, 18.4 ⁇ 0.2°, 22.4° ⁇ 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 16.4° ⁇ 0.2°, 18.4° ⁇ 0.2° and 22.4° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form A has 2 ⁇ values of 6.8° ⁇ 0.2°, 11.7° ⁇ 0.2°, 13.6° ⁇ 0.2°, 16.4° ⁇ 0.2°, 17.1° ⁇ 0.2° Any 4, or 5, or 6, or 7, or 8, or 9 of 0.2°, 18.4° ⁇ 0.2°, 20.5° ⁇ 0.2°, 22.1° ⁇ 0.2°, 22.4° ⁇ 0.2° There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form A has 2 ⁇ values of 6.8° ⁇ 0.2°, 11.7° ⁇ 0.2°, 13.6° ⁇ 0.2°, 16.4° ⁇ 0.2°, 17.1° ⁇ 0.2° There are characteristic peaks at 0.2°, 18.4° ⁇ 0.2°, 20.5° ⁇ 0.2°, 22.1° ⁇ 0.2° and 22.4° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form A is shown in FIG. 1 .
  • the positive solvent includes ketones, cyclic ethers, alkyl nitrile or heteronitrogen-based solvents
  • the anti-solvent includes alkanes, alcohols or pure water.
  • the ketone solvent is acetone
  • the cyclic ether solvent is tetrahydrofuran.
  • the alkyl nitrile solvent is acetonitrile.
  • the hetero-nitrogen-based solvent is dimethyl sulfoxide.
  • the alkane solvent is n-hexane.
  • the alcoholic solvent is isopropanol.
  • the penetration time is 1 to 14 days, eg 7 days
  • the alcohol solvent is methanol.
  • the high temperature is 40°C to 60°C, for example 50°C.
  • the crystallization temperature is -20°C to 5°C.
  • the cooling rate is 0.05°C/min to 0.5°C/min, eg 0.1°C/min.
  • the positive solvent includes cyclic ethers, heteronitrogens or alkyl nitriles
  • the anti-solvent includes pure water, alkanes, aromatic hydrocarbons or halogenated hydrocarbons.
  • the cyclic ethers include tetrahydrofuran and 2-methyltetrahydrofuran, the heteronitrogens are dimethyl sulfoxide, and the alkyl nitriles are acetonitrile.
  • the alkanes are n-heptane
  • the aromatic hydrocarbons are toluene
  • the halogenated hydrocarbons include dichloromethane and chloroform.
  • the temperature of dissolving, adding, stirring and precipitation is 5°C to 50°C, preferably 20°C to 30°C.
  • the organic solvent includes single or mixed solvents of alcohols, ketones, esters, halogenated hydrocarbons, cyclic ethers or alkyl nitriles.
  • the alcohols include methanol, ethanol and isopropanol
  • the ketones include methyl isobutyl ketone and acetone
  • the esters include ethyl acetate and isopropyl acetate
  • the The halogenated hydrocarbons include methylene chloride and chloroform
  • the cyclic ethers include tetrahydrofuran, 2-methyltetrahydrofuran and 1,4-dioxane
  • the alkyl nitriles are acetonitrile.
  • the mixed solvent includes acetonitrile and ethanol, acetone and methyl tert-butyl ether, tetrahydrofuran and water, acetone and chloroform, tetrahydrofuran and methyl tert-butyl ether, acetonitrile and dichloromethane, Acetone and isopropanol, acetonitrile and methyl tert-butyl ether.
  • the volume ratio of acetonitrile and ethanol is 1:4.
  • the volume ratio of the acetone to methyl tert-butyl ether is 1:4.
  • the volume ratio of tetrahydrofuran and water is 1:4.
  • the volume ratio of the acetone and chloroform is 1:0.1-8.
  • the volume ratio of tetrahydrofuran and methyl tert-butyl ether is 1:0.1-8.
  • the volume ratio of the acetonitrile and dichloromethane is 1:0.1-8.
  • the volume ratio of the acetone and isopropanol is 1:0.1-18.
  • the volume ratio of the acetonitrile to methyl tert-butyl ether is 1:0.1-18.
  • the volatilization and precipitation temperature is 20°C to 30°C.
  • the X-ray powder diffraction of the crystal form B has one or two or three 2 ⁇ values of 11.5° ⁇ 0.2°, 13.6° ⁇ 0.2°, 20.5° ⁇ 0.2° There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form B has characteristic peaks at 2 ⁇ values of 11.5° ⁇ 0.2°, 13.6° ⁇ 0.2°, and 20.5° ⁇ 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°, 21.5° ⁇ 0.2°, 22.7° ⁇ 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°, 21.5° ⁇ 0.2°, and 22.7° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form B has 2 ⁇ values of 6.8° ⁇ 0.2°, 11.5° ⁇ 0.2°, 13.6° ⁇ 0.2°, 14.5° ⁇ 0.2°, 15.6° ⁇ 0.2° Any 4, or 5, or 6, or 7, or 8, or 9 of 0.2°, 20.5° ⁇ 0.2°, 21.5° ⁇ 0.2°, 22.7° ⁇ 0.2°, 23.2° ⁇ 0.2° There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form B has 2 ⁇ values of 6.8° ⁇ 0.2°, 11.5° ⁇ 0.2°, 13.6° ⁇ 0.2°, 14.5° ⁇ 0.2°, 15.6° ⁇ 0.2° There are characteristic peaks at 0.2°, 20.5° ⁇ 0.2°, 21.5° ⁇ 0.2°, 22.7° ⁇ 0.2° and 23.2° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form B is shown in FIG. 5 .
  • the ketone solvent is acetone
  • the volatilization and precipitation temperature is 20°C to 30°C.
  • the ketone solvent is acetone
  • the dissolution and precipitation temperature is 20°C to 30°C.
  • the penetration time is 1 to 4 weeks, eg 2 weeks.
  • said compound of formula (I) as starting material refers to its solid (crystalline or amorphous), semi-solid, wax or oil form.
  • the compound of formula (I) as starting material is in the form of a solid powder.
  • the "stirring" is accomplished by conventional methods in the art, such as magnetic stirring or mechanical stirring, and the stirring speed is 50-1800 rev/min, wherein the magnetic stirring is 200-1500 rev/min, preferably 300-1000 rev/min , the mechanical stirring is preferably 100 to 300 rpm.
  • the above crystals of the present invention can be used to prepare pharmaceutical compositions, which contain the above crystals of the present invention and a pharmaceutically acceptable carrier.
  • the above crystals of the present invention can be used to prepare a pharmaceutical composition with CAM activity, which comprises the above crystals of the present invention (forms A and B of the compound of formula (I)) as effective Element.
  • the above crystals of the present invention can be used to prepare a preventive or therapeutic drug for hepatitis B virus infection, which comprises the above-mentioned crystals of the present invention (formula (I) compound crystal form A, B) B) as an active ingredient.
  • the present invention also provides a pharmaceutical composition, which comprises any one of the above-mentioned crystals of the present invention (crystal forms A and B of the compound of formula (I)) and a pharmaceutically acceptable carrier.
  • the present invention also provides a pharmaceutical composition with CAM activity, which contains any one of the above-mentioned crystals of the present invention (crystal forms A and B of the compound of formula (I)) as an active ingredient.
  • the present invention provides a preventive or therapeutic drug for hepatitis B virus infection, which contains any one of the crystals of the present invention (forms A and B of the compound of formula (I)) as an active ingredient.
  • 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 X-ray diffraction pattern are related to the preferred orientation of the crystals, and the peak intensities shown here are illustrative and not for absolute comparison.
  • 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 X-ray diffraction pattern" mentioned herein does not mean absolutely identical, identical peak positions may differ by ⁇ 0.2° and some variability in peak intensity is allowed. 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.
  • the crystal forms A, B of the present invention are pure, single, and substantially not mixed with any other crystal forms.
  • 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 numerical values and numerical ranges mentioned in the present invention should not be narrowly construed as numerical values or numerical ranges themselves, and those skilled in the art should understand that they may vary according to specific technical environments, without departing from the spirit and scope of the present invention. There are fluctuations around specific numerical values on the basis of principles. In the present invention, such a range of fluctuations that can be foreseen by those skilled in the art is often represented by the term "about”.
  • room temperature generally refers to 22°C to 28°C unless otherwise specified.
  • the X-ray powder diffraction patterns of the present invention were collected on Empyrean and X'Pert 3 X-ray powder diffractometers of Panalytical Corporation.
  • the method parameters of X-ray powder diffraction of the present invention are as follows:
  • the differential scanning calorimetry analysis diagram of the present invention is collected on the Q200 type and Discovery DSC 2500 type differential scanning calorimeter of TA company.
  • the method parameters of the differential scanning calorimetry analysis of the present invention are as follows:
  • thermogravimetric analysis diagram of the present invention is collected on the Discovery TGA 5500 type and Q5000 type thermogravimetric analyzer of TA company.
  • the method parameters of the thermogravimetric analysis of the present invention are as follows:
  • the hydrogen nuclear magnetic resonance spectrum data ( 1 H NMR) of the present invention was collected from a Bruker Avance II DMX 400M HZ nuclear magnetic resonance spectrometer. Weigh 1-5 mg of the sample, dissolve it with 0.5 mL of deuterated dimethyl sulfoxide, and prepare a solution of 2-10 mg/mL for testing.
  • the obtained solid samples were tested by XRPD, TGA, DSC, and 1 H NMR.
  • the obtained XRPD, TGA, DSC, and 1 H NMR data are shown in Figures 1 to 4, respectively, and the X-ray powder diffraction data are shown in Table 1.
  • XRPD results showed that the obtained samples were at about 6.8° ⁇ 0.2°, about 11.7° ⁇ 0.2°, about 13.6° ⁇ 0.2°, about 16.4° ⁇ 0.2°, about 17.1° ⁇ 0.2°, about 18.4° ⁇ 0.2°, about 20.5°
  • TGA shows that the sample will lose about 1% weight when heated to 200°C.
  • DSC data show that the melting point of Form A is around 221°C. Based on the characterization data, it is speculated that Form A is an anhydrous crystal.
  • the sample was transferred to -20°C and left to stand for about 1 day, and no solid was precipitated.
  • the sample was transferred to room temperature and volatilized until the solid was precipitated, and crystal form A was obtained.
  • Table 11 The detailed test conditions involved in this example are shown in Table 11, and the X-ray powder diffraction data of the sample of Example 25 are shown in Table 12.
  • Example 30 Weigh 14.7 mg of the solid compound of formula (I) obtained in Preparation Example 1 into a 3.0-ml glass vial at room temperature, and place the open mouth in a 20-ml glass vial prefilled with 4 ml of acetone. After sealing, put it at room temperature for gas-solid permeation for two days to obtain a clear solution, which was volatilized at room temperature until the solid was precipitated to obtain crystal form B, whose X-ray powder diffraction data are shown in Table 15.
  • Example 31 Weigh 14.7 mg of the solid compound of formula (I) obtained in Preparation Example 1 into a 3.0 mL glass vial at room temperature, and add 0.5 mL of acetone to dissolve the solid. Filter the sample solution into a new 3 mL glass vial using a 0.45 micron pore size Teflon filter. After sealing with parafilm, four pinholes were pricked on it, and then slowly volatilized at room temperature until a solid was precipitated to obtain crystal form B, and its X-ray powder diffraction data are shown in Table 16.
  • the sample is at about 6.8° ⁇ 0.2°, about 11.5° ⁇ 0.2°, about 13.6° ⁇ 0.2°, about 14.5° ⁇ 0.2°, about 15.6° ⁇ 0.2°, about 20.5° ⁇ 0.2°, about 21.5° ⁇ 0.2°.
  • the crystal form A and crystal form B of the present invention are respectively added into SGF (simulated artificial gastric fluid), FaSSIF (artificial intestinal fluid in fasting state), FeSSIF (artificial intestinal fluid in satiety state) and pure water, and are prepared into a suspension liquid. After equilibration for 1 hour, 2 hours, 4 hours and 24 hours, filter to obtain a saturated solution. The content of the sample in the saturated solution was determined by high performance liquid chromatography (HPLC). The test results are shown in Table 18, and the solubility curves are shown in Figures 9 to 12, respectively. The test results show that the crystal form A and the crystal form B of the present invention have higher solubility in SGF, FaSSIF, FeSSIF and pure water.
  • 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%
  • crystal form A and crystal form B of the present invention were weighed, placed on glass slides respectively, a little vacuum silicone oil was added dropwise to disperse the samples, then covered with a cover glass and placed under a polarizing microscope for observation.
  • the crystal form A and the crystal form B of the present invention have better crystal habits.
  • crystal form A and crystal form B of the present invention have relatively uniform particle size distribution.

Abstract

Provided are crystal forms relating to sulfamoyl pyrrole amide compounds and preparation methods therefor. Specifically, two crystal forms A and B of compounds of formula (I) and preparation methods and uses therefor are provided. The provided crystal forms A and B of the compounds of formula (I) have advantages in at least one aspect regarding solubility, melting point, stability, dissolution, hygroscopicity, adhesion, fluidity, bioavailability, processability, purification effect, preparation production, safety, etc., provide a new and better choice for the preparation of pharmaceutical formulations comprising the compounds of formula (I), and are of great significance for drug development.

Description

氨磺酰基吡咯酰胺类化合物的晶型及其制备方法Crystal form of sulfamoyl pyrrole amide compounds and preparation method thereof 技术领域technical field
本发明涉及化学医药领域，特别是涉及氨磺酰基吡咯酰胺类化合物的晶型及其制备方法。The invention relates to the field of chemical medicine, in particular to a crystal form of a sulfamoyl pyrrole amide compound and a preparation method thereof.
背景技术Background technique
乙型肝炎，是由乙型肝炎病毒(HBV)感染所致，乙型肝炎病毒感染除了会导致恶心呕吐、黄疸、疲倦、茶色尿以及腹痛等急性症状外，多数感染者在急性感染症状消退后，会转为慢性肝炎，进而导致肝硬化以及肝癌等疾病的发生，严重威胁人类的健康。Hepatitis B is caused by hepatitis B virus (HBV) infection. In addition to acute symptoms such as nausea and vomiting, jaundice, fatigue, brown urine, and abdominal pain, most infected people experience symptoms after the acute infection subsides. , will turn into chronic hepatitis, and then lead to the occurrence of diseases such as liver cirrhosis and liver cancer, which seriously threatens human health.
目前，针对乙型肝炎病毒感染的治疗以“功能性治疗”为主，需要长期或者终生服药，以实现“功能性治愈”，即血清中的乙肝表面抗原(HBsAg)和HBV-DNA含量始终保持至无法检出的状态，进而改善残余肝损伤或纤维化，以降低罹患肝炎的风险。At present, the treatment of hepatitis B virus infection is mainly "functional treatment", which requires long-term or life-long medication to achieve "functional cure", that is, the content of hepatitis B surface antigen (HBsAg) and HBV-DNA in serum is always maintained to an undetectable state, thereby improving residual liver damage or fibrosis and reducing the risk of hepatitis.
HBV由外壳与核心部分两部分组成，核心部分包括由核心蛋白组成的病毒衣壳，以及其内所包含的DNA聚合酶以及病毒前基因组(pgRNA)。乙肝病毒衣壳蛋白装配调节剂(CAM)可以与核心蛋白结合，干扰pgRNA的衣壳化过程，进而抑制HBV在生物体内的生成，已有多种CAM处于临床研究中。目前研究的CAM可分为CAM-A与CAM-N两种。其中，CAM-A影响核心蛋白结构，使HBV无法形成正常结构与尺寸的衣壳；CAM-N抑制病毒DNA以及pgRNA的内含过程，进而产生空的衣壳，两种CAM均可阻止正常病毒衣壳的形成。HBV is composed of two parts, the outer shell and the core part. The core part includes the viral capsid composed of the core protein, the DNA polymerase and the viral pregenome (pgRNA) contained in it. Hepatitis B virus capsid protein assembly regulator (CAM) can combine with core protein to interfere with the encapsidation process of pgRNA, thereby inhibiting the production of HBV in vivo. Various CAMs are under clinical research. The CAM currently studied can be divided into two types: CAM-A and CAM-N. Among them, CAM-A affects the structure of the core protein and prevents HBV from forming a capsid of normal structure and size; CAM-N inhibits the inclusion process of viral DNA and pgRNA, thereby producing an empty capsid. Both CAMs can prevent normal viruses Formation of the capsid.
N-(3-氰基-4-氟-苯基)-1-甲基-4-{[(1S)-2,2,2-三氟-1-甲基-乙基]氨磺酰基}吡咯-2-羧酰胺是一种新型的CAM-N，该化合物针对乙型肝炎的治疗研究目前处于2期临床阶段，其结构式如下所示：N-(3-Cyano-4-fluoro-phenyl)-1-methyl-4-{[(1S)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl} Pyrrole-2-carboxamide is a new type of CAM-N, the compound is currently in phase 2 clinical research for the treatment of hepatitis B, and its structural formula is as follows:
Figure PCTCN2022084300-appb-000001
Figure PCTCN2022084300-appb-000001
专利WO2014/184350A1公开了式(I)化合物及其合成过程，通过柱层析以及多次洗涤、提纯过程，最终获得少量满足要求的目标产物。制备方法过程繁琐、不利于工业化大规模生产。该专利中未提及有关式(I)化合物固体形态或结晶形式的相关报道。Patent WO2014/184350A1 discloses the compound of formula (I) and its synthesis process. Through column chromatography and multiple washing and purification processes, a small amount of the target product that meets the requirements is finally obtained. The preparation method is cumbersome and unfavorable for industrialized large-scale production. The patent does not mention relevant reports on the solid or crystalline form of the compound of formula (I).
结晶过程作为化学产品提纯的主要方法，有操作简单、易于放大、成本低廉等优点，是化工以及制药领域广泛使用的提纯方法。针对目前式(I)化合物制备与提纯工艺复杂，较难工艺放大的问题，有必要寻找式(I)化合物的不同结晶形式，以简化生产中的终产物的提纯过程，提升提纯效率。As the main method of chemical product purification, crystallization process has the advantages of simple operation, easy amplification, low cost, etc., and is a purification method widely used in chemical and pharmaceutical fields. In view of the complex preparation and purification process of the compound of formula (I) at present, and the difficulty of process amplification, it is necessary to find different crystalline forms of the compound of formula (I) to simplify the purification process of the final product in production and improve the purification efficiency.
此外，同一药物的不同晶型在溶解度、熔点、密度、稳定性等方面有显著的差异，从而不同程度地影响药物的稳定性、均一性、生物利用度、疗效和安全性。因此，药物研发中进行全面系统的多晶型筛选，选择最适合开发的晶型，是不可忽视的重要研究内容之一。基于此，有必要对式(I)化合物进行多晶型筛选，为药物的后续开发提供更多更好的选择。In addition, different crystal forms of the same drug have significant differences in solubility, melting point, density, stability, etc., thus affecting the stability, homogeneity, bioavailability, efficacy and safety of the drug to varying degrees. Therefore, it is one of the important research contents that can not be ignored to carry out comprehensive and systematic polymorph screening in drug research and development, and select the most suitable crystal form for development. Based on this, it is necessary to screen the polymorphic form of the compound of formula (I) to provide more and better choices for the subsequent development of the drug.
发明内容SUMMARY OF THE INVENTION
本发明提供了式(I)化合物的两种晶型A、B及其制备方法和用途。The present invention provides two crystal forms A and B of the compound of formula (I) and their preparation methods and uses.
1.式(I)所示化合物N-(3-氰基-4-氟-苯基)-1-甲基-4-{[(1S)-2,2,2-三氟-1-甲基-乙基]氨磺酰基}吡咯-2-羧酰胺的A型晶体、即晶型A，其特征在于，使用Cu-Kα辐射，所述晶型A的X射线粉末衍射在2θ值为6.8°±0.2°、13.6°±0.2°和22.1°±0.2°处有特征峰，1. Compound N-(3-cyano-4-fluoro-phenyl)-1-methyl-4-{[(1S)-2,2,2-trifluoro-1-methyl represented by formula (I) Form A crystal of yl-ethyl]sulfamoyl}pyrrole-2-carboxamide, namely crystal form A, characterized in that, using Cu-Kα radiation, the X-ray powder diffraction of said crystal form A has a 2θ value of 6.8 There are characteristic peaks at °±0.2°, 13.6°±0.2° and 22.1°±0.2°,
Figure PCTCN2022084300-appb-000002
Figure PCTCN2022084300-appb-000002
2.上述1所述的晶型A的制备方法，其特征包括：2. the preparation method of above-mentioned 1 described crystal form A, is characterized in that:
(1)将式(I)化合物溶解于酮类、环醚类、烷基腈类或杂氮类溶剂中，将溶液敞口置于烷烃类、醇类或纯水溶剂气氛下进行气液渗透，1～7天后，固体析出，得到晶型A；或(1) Dissolve the compound of formula (I) in ketones, cyclic ethers, alkyl nitriles or hetero-nitrogen solvents, and place the solution open in an atmosphere of alkanes, alcohols or pure water solvent to carry out gas-liquid infiltration , after 1 to 7 days, the solid is precipitated to obtain crystal form A; or
(2)将式(I)化合物在40～60℃下溶解于醇类溶剂中，溶解后降温至固体析出，得到晶型A；或(2) dissolving the compound of formula (I) in an alcohol solvent at 40-60° C., and cooling down to solid precipitation after dissolving to obtain crystal form A; or
(3)将式(I)化合物溶解于环醚类、杂氮类或烷基腈类溶剂中，向其中逐滴加入纯水、烷烃类、芳烃类或卤代烃类反溶剂，固体析出，得到晶型A；或(3) dissolve the compound of formula (I) in cyclic ethers, heteronitrogens or alkyl nitrile solvents, add pure water, alkanes, aromatic hydrocarbons or halogenated hydrocarbons anti-solvent dropwise to it, the solids are separated out, to obtain Form A; or
(4)将式(I)化合物溶解于醇类、酮类、酯类、卤代烃类、环醚类或烷基腈类的单一或混合溶剂中，将溶液置于20～30℃下挥发，固体析出，得到晶型A。(4) Dissolve the compound of formula (I) in a single or mixed solvent of alcohols, ketones, esters, halogenated hydrocarbons, cyclic ethers or alkyl nitriles, and place the solution at 20 to 30 ° C to volatilize , the solid was precipitated, and the crystal form A was obtained.
3.式(I)所示化合物N-(3-氰基-4-氟-苯基)-1-甲基-4-{[(1S)-2,2,2-三氟-1-甲基-乙基]氨磺酰基}吡咯-2-羧酰胺的B型晶体、即晶型B，其特征在于，使用Cu-Kα辐射，所述晶型B的X射线粉末衍射在2θ值为6.8°±0.2°、14.5°±0.2°和23.2°±0.2°处有特征峰，3. Compound N-(3-cyano-4-fluoro-phenyl)-1-methyl-4-{[(1S)-2,2,2-trifluoro-1-methyl represented by formula (I) B-type crystal of yl-ethyl]sulfamoyl}pyrrole-2-carboxamide, namely crystal form B, characterized in that, using Cu-Kα radiation, the X-ray powder diffraction of said crystal form B has a 2θ value of 6.8 There are characteristic peaks at °±0.2°, 14.5°±0.2° and 23.2°±0.2°,
Figure PCTCN2022084300-appb-000003
Figure PCTCN2022084300-appb-000003
4.上述3所述的晶型B的制备方法，其特征包括：4. the preparation method of the crystal form B described in above-mentioned 3, is characterized in that:
(1)将式(I)化合物溶解于酮类溶剂中，将溶液置于20～30℃下挥发，固体析出，得到晶型B；或(1) Dissolving the compound of formula (I) in a ketone solvent, volatilizing the solution at 20-30° C., the solid is precipitated to obtain crystal form B; or
(2)将式(I)化合物溶解于酮类溶剂中，将溶液敞口置于纯水气氛下进行气液渗透，直至固体析出，得到晶型B。(2) Dissolving the compound of formula (I) in a ketone solvent, placing the solution open in a pure water atmosphere, and performing gas-liquid infiltration until the solid is precipitated to obtain crystal form B.
5.药物组合物，其包含上述1和3中任一项所述的晶体和制药学可接受的载体。5. A pharmaceutical composition comprising the crystal of any one of 1 and 3 above and a pharmaceutically acceptable carrier.
6.具有CAM活性的药物组合物，其含有上述1和3中任一项所述的晶体作为有效成分。6. A pharmaceutical composition having CAM activity, comprising the crystal of any one of 1 and 3 above as an active ingredient.
7.乙型肝炎病毒感染的预防药或治疗药，其含有上述1和3中任一项所述的晶体作为有效成分。7. A preventive or therapeutic agent for hepatitis B virus infection, comprising the crystal according to any one of 1 and 3 above as an active ingredient.
与现有技术相比，本发明提供的式(I)化合物晶型A、B，在溶解度、熔点、稳定性、 溶出度、引湿性、黏附性、流动性、生物有效性以及加工性能、提纯作用、制剂生产、安全性等方面中的至少一方面上存在优势，为含式(I)化合物的药物制剂的制备提供了新的更好的选择，对于药物开发具有非常重要的意义。Compared with the prior art, the crystalline forms A and B of the compounds of the formula (I) provided by the present invention are in solubility, melting point, stability, dissolution, hygroscopicity, adhesion, fluidity, bioavailability, processability, purification. There are advantages in at least one aspect of action, preparation production, safety, etc., which provide a new and better choice for the preparation of pharmaceutical preparations containing the compound of formula (I), and are of great significance to drug development.
附图说明Description of drawings
图1晶型A的XRPD图Figure 1 XRPD pattern of Form A
图2晶型A的TGA曲线Figure 2 TGA curve of Form A
图3晶型A的DSC曲线Figure 3 DSC curve of Form A
图4晶型A的 1H NMR图谱 Figure 4 1 H NMR spectrum of Form A
图5晶型B的XRPD图Figure 5 XRPD pattern of Form B
图6晶型B的TGA曲线Figure 6 TGA curve of Form B
图7晶型B的DSC曲线Figure 7 DSC curve of Form B
图8晶型B的 1H NMR图谱 Figure 8 1 H NMR spectrum of Form B
图9不同晶型在SGF中的溶解度对比图Fig. 9 Solubility comparison of different crystal forms in SGF
图10不同晶型在FaSSIF中的溶解度对比图Figure 10 Comparison of solubility of different crystal forms in FaSSIF
图11不同晶型在FeSSIF中的溶解度对比图Fig. 11 Comparison of solubility of different crystal forms in FeSSIF
图12不同晶型在纯水中的溶解度对比图Figure 12 Comparison of solubility of different crystal forms in pure water
图13晶型A压片前后的XRPD对比图Figure 13 XRPD comparison chart of Form A before and after tableting
图14晶型B压片前后的XRPD对比图Figure 14 XRPD comparison chart of Form B before and after compression
图15晶型A在25℃/60％相对湿度下稳定性测试XRPD对比图Figure 15. XRPD comparison chart of stability test of crystal form A at 25℃/60% relative humidity
图16晶型A在40℃/60％相对湿度下稳定性测试XRPD对比图Figure 16. XRPD comparison chart of stability test of crystal form A at 40°C/60% relative humidity
图17晶型B在25℃/60％相对湿度下稳定性测试XRPD对比图Fig. 17 XRPD comparison chart of stability test of crystal form B at 25℃/60% relative humidity
图18晶型B在40℃/60％相对湿度下稳定性测试XRPD对比图Figure 18 XRPD comparison chart of stability test of crystal form B at 40°C/60% relative humidity
图19晶型A的动态水分吸附图Figure 19 Dynamic moisture adsorption diagram of Form A
图20晶型A测试DVS前后的XRPD对比图Figure 20 Comparison of XRPD before and after DVS testing of Form A
图21晶型B的动态水分吸附图Figure 21 Dynamic moisture adsorption diagram of Form B
图22晶型B测试DVS前后的XRPD对比图Figure 22 Comparison of XRPD before and after DVS test for Form B
具体实施方式Detailed ways
式(I)所示化合物N-(3-氰基-4-氟-苯基)-1-甲基-4-{[(1S)-2,2,2-三氟-1-甲基-乙基]氨磺酰基}吡咯-2-羧酰胺的A型晶体、即晶型A，其特征在于，使用Cu-Kα辐射，所述晶型A的X射线粉末衍射在2θ值为6.8°±0.2°、13.6°±0.2°和22.1°±0.2°处有特征峰，The compound represented by formula (I) N-(3-cyano-4-fluoro-phenyl)-1-methyl-4-{[(1S)-2,2,2-trifluoro-1-methyl- The A-type crystal of ethyl]sulfamoyl}pyrrole-2-carboxamide, namely crystal form A, is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction of the crystal form A has a 2θ value of 6.8°± There are characteristic peaks at 0.2°, 13.6°±0.2° and 22.1°±0.2°,
Figure PCTCN2022084300-appb-000004
Figure PCTCN2022084300-appb-000004
在本发明的一个实施方式中，所述晶型A的X射线粉末衍射在2θ值为11.7°±0.2°、 17.1°±0.2°、20.5°±0.2°中的一处或两处或三处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form A has one or two or three 2θ values of 11.7°±0.2°, 17.1°±0.2°, 20.5°±0.2° There are characteristic peaks.
在本发明的一个实施方式中，所述晶型A的X射线粉末衍射在2θ值为11.7°±0.2°、17.1°±0.2°、20.5°±0.2°处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form A has characteristic peaks at 2θ values of 11.7°±0.2°, 17.1°±0.2°, and 20.5°±0.2°.
在本发明的一个实施方式中，所述晶型A的X射线粉末衍射在2θ值为16.4°±0.2°、18.4±0.2°、22.4°±0.2°中的一处或两处或三处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form A has a 2θ value of 16.4°±0.2°, 18.4±0.2°, 22.4°±0.2° at one or two or three places. Characteristic peaks.
在本发明的一个实施方式中，所述晶型A的X射线粉末衍射在2θ值为16.4°±0.2°、18.4±0.2°、22.4°±0.2°处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form A has characteristic peaks at 2θ values of 16.4°±0.2°, 18.4°±0.2° and 22.4°±0.2°.
在本发明的一个实施方式中，所述晶型A的X射线粉末衍射在2θ值为6.8°±0.2°、11.7°±0.2°、13.6°±0.2°、16.4°±0.2°、17.1°±0.2°、18.4°±0.2°、20.5°±0.2°、22.1°±0.2°、22.4°±0.2°中的任意4处、或5处、或6处、或7处、或8处、或9处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form A has 2θ values of 6.8°±0.2°, 11.7°±0.2°, 13.6°±0.2°, 16.4°±0.2°, 17.1°±0.2° Any 4, or 5, or 6, or 7, or 8, or 9 of 0.2°, 18.4°±0.2°, 20.5°±0.2°, 22.1°±0.2°, 22.4°±0.2° There are characteristic peaks.
在本发明的一个实施方式中，所述晶型A的X射线粉末衍射在2θ值为6.8°±0.2°、11.7°±0.2°、13.6°±0.2°、16.4°±0.2°、17.1°±0.2°、18.4°±0.2°、20.5°±0.2°、22.1°±0.2°和22.4°±0.2°处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form A has 2θ values of 6.8°±0.2°, 11.7°±0.2°, 13.6°±0.2°, 16.4°±0.2°, 17.1°±0.2° There are characteristic peaks at 0.2°, 18.4°±0.2°, 20.5°±0.2°, 22.1°±0.2° and 22.4°±0.2°.
在本发明的一个实施方式中，所述晶型A的X射线粉末衍射图如图1所示。In one embodiment of the present invention, the X-ray powder diffraction pattern of the crystal form A is shown in FIG. 1 .
(1)将式(I)化合物溶解于正溶剂中，将溶液敞口置于反溶剂气氛下进行气液渗透一段时间，固体析出，得到晶型A。所述正溶剂包括酮类、环醚类、烷基腈类或杂氮类溶剂，所述反溶剂包括烷烃类、醇类或纯水。(1) Dissolving the compound of formula (I) in a positive solvent, placing the solution open in an anti-solvent atmosphere to carry out gas-liquid infiltration for a period of time, the solid is precipitated, and crystal form A is obtained. The positive solvent includes ketones, cyclic ethers, alkyl nitrile or heteronitrogen-based solvents, and the anti-solvent includes alkanes, alcohols or pure water.
在本发明的一个实施方式中，所述酮类溶剂为丙酮。In one embodiment of the present invention, the ketone solvent is acetone.
在本发明的一个实施方式中，所述环醚类溶剂为四氢呋喃。In one embodiment of the present invention, the cyclic ether solvent is tetrahydrofuran.
在本发明的一个实施方式中，所述烷基腈类溶剂为乙腈。In one embodiment of the present invention, the alkyl nitrile solvent is acetonitrile.
在本发明的一个实施方式中，所述杂氮类溶剂为二甲基亚砜。In one embodiment of the present invention, the hetero-nitrogen-based solvent is dimethyl sulfoxide.
在本发明的一个实施方式中，所述烷烃类溶剂为正己烷。In one embodiment of the present invention, the alkane solvent is n-hexane.
在本发明的一个实施方式中，所述醇类溶剂为异丙醇。In one embodiment of the present invention, the alcoholic solvent is isopropanol.
在本发明的一个实施方式中，所述渗透时间为1至14天，例如7天In one embodiment of the invention, the penetration time is 1 to 14 days, eg 7 days
(2)将式(I)化合物溶解于醇类溶剂中，高温条件下达到溶解平衡，将溶液降温至有固体析出，得到晶型A。(2) Dissolving the compound of formula (I) in an alcohol solvent, reaching a dissolution equilibrium under high temperature conditions, cooling the solution until a solid is precipitated to obtain crystal form A.
在本发明的一个实施方式中，所述醇类溶剂为甲醇。In one embodiment of the present invention, the alcohol solvent is methanol.
在本发明的一个实施方式中，所述高温为40℃到60℃，例如为50℃。In one embodiment of the present invention, the high temperature is 40°C to 60°C, for example 50°C.
在本发明的一个实施方式中，所述析晶温度为-20℃到5℃。In one embodiment of the present invention, the crystallization temperature is -20°C to 5°C.
在本发明的一个实施方式中，所述降温速率为0.05℃/分钟到0.5℃/分钟，例如0.1℃/分钟。In one embodiment of the present invention, the cooling rate is 0.05°C/min to 0.5°C/min, eg 0.1°C/min.
(3)将式(I)化合物溶解于正溶剂中，过滤后向其中边搅拌边逐滴加入反溶剂，析出固体，得到晶型A。其中，所述正溶剂包括环醚类、杂氮类或烷基腈类，所述反溶剂包括纯水、烷烃类、芳烃类或卤代烃类。(3) Dissolving the compound of formula (I) in a positive solvent, after filtration, adding an anti-solvent dropwise to it while stirring, and precipitating a solid to obtain a crystal form A. Wherein, the positive solvent includes cyclic ethers, heteronitrogens or alkyl nitriles, and the anti-solvent includes pure water, alkanes, aromatic hydrocarbons or halogenated hydrocarbons.
在本发明的一个实施方式中，所述正溶剂中，环醚类包括四氢呋喃和2-甲基四氢呋喃，杂氮类为二甲基亚砜，烷基腈类为乙腈。In an embodiment of the present invention, in the positive solvent, the cyclic ethers include tetrahydrofuran and 2-methyltetrahydrofuran, the heteronitrogens are dimethyl sulfoxide, and the alkyl nitriles are acetonitrile.
在本发明的一个实施方式中，所述反溶剂中，烷烃类为正庚烷，芳烃类为甲苯，卤代烃类包括二氯甲烷和氯仿。In an embodiment of the present invention, in the anti-solvent, the alkanes are n-heptane, the aromatic hydrocarbons are toluene, and the halogenated hydrocarbons include dichloromethane and chloroform.
在本发明的一个实施方式中，所述溶解、添加、搅拌、析出温度为5℃到50℃，优选20℃到30℃。In one embodiment of the present invention, the temperature of dissolving, adding, stirring and precipitation is 5°C to 50°C, preferably 20°C to 30°C.
(4)将式(I)化合物溶解于有机溶剂中，将其挥发，得到晶型A。(4) Dissolving the compound of formula (I) in an organic solvent and volatilizing it to obtain crystal form A.
在本发明的一个实施方式中，所述有机溶剂包括醇类、酮类、酯类、卤代烃类、环醚类或烷基腈类的单一或混合溶剂。In one embodiment of the present invention, the organic solvent includes single or mixed solvents of alcohols, ketones, esters, halogenated hydrocarbons, cyclic ethers or alkyl nitriles.
在本发明的一个实施方式中，所述醇类包括甲醇、乙醇和异丙醇，所述酮类包括甲基异丁酮和丙酮，所述酯类包括乙酸乙酯和乙酸异丙酯，所述卤代烃类包括二氯甲烷和氯仿，所述环醚类包括四氢呋喃、2-甲基四氢呋喃和1,4-二氧六环，所述烷基腈类为乙腈。In one embodiment of the present invention, the alcohols include methanol, ethanol and isopropanol, the ketones include methyl isobutyl ketone and acetone, the esters include ethyl acetate and isopropyl acetate, and the The halogenated hydrocarbons include methylene chloride and chloroform, the cyclic ethers include tetrahydrofuran, 2-methyltetrahydrofuran and 1,4-dioxane, and the alkyl nitriles are acetonitrile.
在本发明的一个实施方式中，所述混合溶剂包括乙腈和乙醇、丙酮和甲基叔丁基醚、四氢呋喃和水、丙酮和氯仿、四氢呋喃和甲基叔丁基醚、乙腈和二氯甲烷、丙酮和异丙醇、乙腈和甲基叔丁基醚。In one embodiment of the present invention, the mixed solvent includes acetonitrile and ethanol, acetone and methyl tert-butyl ether, tetrahydrofuran and water, acetone and chloroform, tetrahydrofuran and methyl tert-butyl ether, acetonitrile and dichloromethane, Acetone and isopropanol, acetonitrile and methyl tert-butyl ether.
在本发明的一个实施方式中，所述乙腈和乙醇的体积比为1:4。In one embodiment of the present invention, the volume ratio of acetonitrile and ethanol is 1:4.
在本发明的一个实施方式中，所述丙酮和甲基叔丁基醚的体积比为1:4。In one embodiment of the present invention, the volume ratio of the acetone to methyl tert-butyl ether is 1:4.
在本发明的一个实施方式中，所述四氢呋喃和水的体积比为1:4。In one embodiment of the present invention, the volume ratio of tetrahydrofuran and water is 1:4.
在本发明的一个实施方式中，所述丙酮和氯仿的体积比为1:0.1～8。In one embodiment of the present invention, the volume ratio of the acetone and chloroform is 1:0.1-8.
在本发明的一个实施方式中，所述四氢呋喃和甲基叔丁基醚的体积比为1:0.1～8。In an embodiment of the present invention, the volume ratio of tetrahydrofuran and methyl tert-butyl ether is 1:0.1-8.
在本发明的一个实施方式中，所述乙腈和二氯甲烷的体积比为1:0.1～8。In one embodiment of the present invention, the volume ratio of the acetonitrile and dichloromethane is 1:0.1-8.
在本发明的一个实施方式中，所述丙酮和异丙醇的体积比为1:0.1～18。In one embodiment of the present invention, the volume ratio of the acetone and isopropanol is 1:0.1-18.
在本发明的一个实施方式中，所述乙腈和甲基叔丁基醚的体积比为1:0.1～18。In one embodiment of the present invention, the volume ratio of the acetonitrile to methyl tert-butyl ether is 1:0.1-18.
在本发明的一个实施方式中，所述挥发和析出温度为20℃到30℃。In one embodiment of the present invention, the volatilization and precipitation temperature is 20°C to 30°C.
式(I)所示N-(3-氰基-4-氟-苯基)-1-甲基-4-{[(1S)-2,2,2-三氟-1-甲基-乙基]氨磺酰基}吡咯-2-羧酰胺的B型晶体、即晶型B，其特征在于，使用Cu-Kα辐射，所述晶型B的X射线粉末衍射在2θ值为6.8°±0.2°、14.5°±0.2°和23.2°±0.2°处有特征峰，N-(3-cyano-4-fluoro-phenyl)-1-methyl-4-{[(1S)-2,2,2-trifluoro-1-methyl-ethyl represented by formula (I) B-type crystal of pyrrole-2-carboxamide, namely, crystal form B, characterized in that, using Cu-Kα radiation, the X-ray powder diffraction of crystal form B has a 2θ value of 6.8°±0.2 °, 14.5°±0.2° and 23.2°±0.2° have characteristic peaks,
Figure PCTCN2022084300-appb-000005
Figure PCTCN2022084300-appb-000005
在本发明的一个实施方式中，所述晶型B的X射线粉末衍射在2θ值为11.5°±0.2°、13.6°±0.2°、20.5°±0.2°中的一处或两处或三处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form B has one or two or three 2θ values of 11.5°±0.2°, 13.6°±0.2°, 20.5°±0.2° There are characteristic peaks.
在本发明的一个实施方式中，所述晶型B的X射线粉末衍射在2θ值为11.5°±0.2°、13.6°±0.2°、20.5°±0.2°处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form B has characteristic peaks at 2θ values of 11.5°±0.2°, 13.6°±0.2°, and 20.5°±0.2°.
在本发明的一个实施方式中，所述晶型B的X射线粉末衍射在2θ值为15.6°±0.2°、21.5°±0.2°、22.7°±0.2°中的一处或两处或三处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form B has one or two or three 2θ values of 15.6°±0.2°, 21.5°±0.2°, 22.7°±0.2° There are characteristic peaks.
在本发明的一个实施方式中，所述晶型B的X射线粉末衍射在2θ值为15.6°±0.2°、21.5°±0.2°、22.7°±0.2°处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form B has characteristic peaks at 2θ values of 15.6°±0.2°, 21.5°±0.2°, and 22.7°±0.2°.
在本发明的一个实施方式中，所述晶型B的X射线粉末衍射在2θ值为6.8°±0.2°、11.5°±0.2°、13.6°±0.2°、14.5°±0.2°、15.6°±0.2°、20.5°±0.2°、21.5°±0.2°、22.7°±0.2°、23.2°±0.2°中的任意4处、或5处、或6处、或7处、或8处、或9处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form B has 2θ values of 6.8°±0.2°, 11.5°±0.2°, 13.6°±0.2°, 14.5°±0.2°, 15.6°±0.2° Any 4, or 5, or 6, or 7, or 8, or 9 of 0.2°, 20.5°±0.2°, 21.5°±0.2°, 22.7°±0.2°, 23.2°±0.2° There are characteristic peaks.
在本发明的一个实施方式中，所述晶型B的X射线粉末衍射在2θ值为6.8°±0.2°、11.5°±0.2°、13.6°±0.2°、14.5°±0.2°、15.6°±0.2°、20.5°±0.2°、21.5°±0.2°、22.7°±0.2°和23.2°±0.2°处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form B has 2θ values of 6.8°±0.2°, 11.5°±0.2°, 13.6°±0.2°, 14.5°±0.2°, 15.6°±0.2° There are characteristic peaks at 0.2°, 20.5°±0.2°, 21.5°±0.2°, 22.7°±0.2° and 23.2°±0.2°.
在本发明的一个实施方式中，所述晶型B的X射线粉末衍射图如图5所示。In one embodiment of the present invention, the X-ray powder diffraction pattern of the crystal form B is shown in FIG. 5 .
所述的晶型B的制备方法，其特征包括：The preparation method of described crystal form B is characterized by comprising:
(1)将式(I)化合物溶解于酮类溶剂中，将其挥发，得到晶型B。(1) The compound of formula (I) is dissolved in a ketone solvent, and it is volatilized to obtain crystal form B.
在本发明的一个实施方式中，所述酮类溶剂为丙酮。In one embodiment of the present invention, the ketone solvent is acetone.
在本发明的一个实施方式中，所述挥发和析出温度为20℃到30℃。In one embodiment of the present invention, the volatilization and precipitation temperature is 20°C to 30°C.
(2)将式(I)化合物溶剂于酮类溶剂中，将澄清溶液置于纯水氛围下进行气液渗透一段时间，析出固体，得到晶型B。(2) The compound of formula (I) is dissolved in a ketone solvent, and the clear solution is placed in a pure water atmosphere to carry out gas-liquid infiltration for a period of time, and a solid is precipitated to obtain crystal form B.
在本发明的一个实施方式中，所述酮类溶剂为丙酮。In one embodiment of the present invention, the ketone solvent is acetone.
在本发明的一个实施方式中，所述溶解与析出温度为20℃到30℃。In one embodiment of the present invention, the dissolution and precipitation temperature is 20°C to 30°C.
在本发明的一个实施方式中，所述渗透时间为1至4周，例如2周。In one embodiment of the invention, the penetration time is 1 to 4 weeks, eg 2 weeks.
根据本发明，作为原料的所述式(I)化合物指其固体(晶体或无定形)、半固体、蜡或油形式。优选地，作为原料的式(I)化合物为固体粉末形式。所述“搅拌”，采用本领域的常规方法完成，例如磁力搅拌或机械搅拌，搅拌速度为50～1800转/分钟，其中，磁力搅拌200～1500转/分钟，优选为300～1000转/分钟，机械搅拌优选为100～300转/分钟。According to the present invention, said compound of formula (I) as starting material refers to its solid (crystalline or amorphous), semi-solid, wax or oil form. Preferably, the compound of formula (I) as starting material is in the form of a solid powder. The "stirring" is accomplished by conventional methods in the art, such as magnetic stirring or mechanical stirring, and the stirring speed is 50-1800 rev/min, wherein the magnetic stirring is 200-1500 rev/min, preferably 300-1000 rev/min , the mechanical stirring is preferably 100 to 300 rpm.
上述本发明的晶体(式(I)化合物晶型A、B)可以用于制备药物组合物，在制备药物组合物时含有上述本发明的晶体和制药学可接受的载体。上述本发明的晶体(式(I)化合物晶型A、B)可以用于制备具有CAM活性的药物组合物，其包含上述本发明的晶体(式(I)化合物晶型A、B)作为有效成分。上述本发明的晶体(式(I)化合物晶型A、B)可以用于制备乙型肝炎病毒感染的预防药或治疗药，其包含上述本发明的晶体(式(I)化合物晶型A、B)作为有效成分。The above crystals of the present invention (forms A and B of the compound of formula (I)) can be used to prepare pharmaceutical compositions, which contain the above crystals of the present invention and a pharmaceutically acceptable carrier. The above crystals of the present invention (forms A and B of the compound of formula (I)) can be used to prepare a pharmaceutical composition with CAM activity, which comprises the above crystals of the present invention (forms A and B of the compound of formula (I)) as effective Element. The above crystals of the present invention (formula (I) compound crystal forms A, B) can be used to prepare a preventive or therapeutic drug for hepatitis B virus infection, which comprises the above-mentioned crystals of the present invention (formula (I) compound crystal form A, B) B) as an active ingredient.
本发明还提供药物组合物，其包含上述本发明的任意一种晶体(式(I)化合物晶型A、B)和制药学可接受的载体。The present invention also provides a pharmaceutical composition, which comprises any one of the above-mentioned crystals of the present invention (crystal forms A and B of the compound of formula (I)) and a pharmaceutically acceptable carrier.
本发明还提供具有CAM活性的药物组合物，其含有上述本发明的任意一种晶体(式(I)化合物晶型A、B)作为有效成分。The present invention also provides a pharmaceutical composition with CAM activity, which contains any one of the above-mentioned crystals of the present invention (crystal forms A and B of the compound of formula (I)) as an active ingredient.
本发明提供乙型肝炎病毒感染的预防药或治疗药，其含有上述本发明的任意一种晶体(式(I)化合物晶型A、B)作为有效成分。The present invention provides a preventive or therapeutic drug for hepatitis B virus infection, which contains any one of the crystals of the present invention (forms A and B of the compound of formula (I)) as an active ingredient.
本发明中，“晶体”或“多晶型”指的是被所示的X射线衍射图表征所证实的。本领域技术人员能够理解，这里所讨论的理化性质可以被表征，其中的实验误差取决于仪器的条件、样品的准备和样品的纯度。特别是，本领域技术人员公知，X射线衍射图通常会随着仪器的条件而有所改变。特别需要指出的是，X射线衍射图的相对强度也可能随着实验条件的变化而变化，所以峰强度的顺序不能作为唯一或决定性因素。事实上，X射线衍射图中衍 射峰的相对强度与晶体的择优取向有关，本文所示的峰强度为说明性而非用于绝对比较。另外，峰角度的实验误差通常在5％或更少，这些角度的误差也应该被考虑进去，通常允许有±0.2°的误差。另外，由于样品厚度等实验因素的影响，会造成峰角度的整体偏移，通常允许一定的偏移。因而，本领域技术人员可以理解的是，本发明中一个晶型的X射线衍射图不必和这里所指的例子中的X射线衍射图完全一致，本文所述“X射线衍射图相同”并非指绝对相同，相同峰位置可相差±0.2°且峰强度允许一定可变性。任何具有和这些图谱中的特征峰相同或相似的图的晶型均属于本发明的范畴之内。本领域技术人员能够将本发明所列的图谱和一个未知晶型的图谱相比较，以证实这两组图谱反映的是相同还是不同的晶型。In the present invention, "crystalline" or "polymorphic form" means as evidenced by the characterization of the X-ray diffraction pattern shown. Those skilled in the art will appreciate that the physicochemical properties discussed herein can be characterized with experimental error depending on the conditions of the instrument, the preparation of the sample, and the purity of the sample. In particular, it is well known to those skilled in the art that X-ray diffraction patterns generally vary with the conditions of the instrument. In particular, it is important to point out that 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. In fact, the relative intensities of the diffraction peaks in the X-ray diffraction pattern are related to the preferred orientation of the crystals, and the peak intensities shown here are illustrative and not for absolute comparison. In addition, 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. In addition, due to the influence of experimental factors such as sample thickness, the overall shift of the peak angle will be caused, and a certain shift is usually allowed. Therefore, those skilled in the art can understand that 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 X-ray diffraction pattern" mentioned herein does not mean Absolutely identical, identical peak positions may differ by ±0.2° and some variability in peak intensity is allowed. 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.
在一些实施方案中，本发明的晶型A、B是纯的、单一的，基本没有混合任何其他晶型。本发明中，“基本没有”当用来指新晶型时指这个晶型含有少于20％(重量)的其他晶型，尤其指少于10％(重量)的其他晶型，更指少于5％(重量)的其他晶型，更指少于1％(重量)的其他晶型。需要说明的是，本发明中提及的数值及数值范围不应被狭隘地理解为数值或数值范围本身，本领域技术人员应当理解其可以根据具体技术环境的不同，在不背离本发明精神和原则的基础上围绕具体数值有所浮动，本发明中，这种本领域技术人员可预见的浮动范围多以术语“约”来表示。In some embodiments, the crystal forms A, B of the present invention are pure, single, and substantially not mixed with any other crystal forms. In the present invention, "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. It should be noted that the numerical values and numerical ranges mentioned in the present invention should not be narrowly construed as numerical values or numerical ranges themselves, and those skilled in the art should understand that they may vary according to specific technical environments, without departing from the spirit and scope of the present invention. There are fluctuations around specific numerical values on the basis of principles. In the present invention, such a range of fluctuations that can be foreseen by those skilled in the art is often represented by the term "about".
本发明说明书中记载的数值范围的上限值和下限值可以任意地组合。The upper limit value and the lower limit value of the numerical range described in the specification of the present invention can be arbitrarily combined.
实施例Example
以下将通过具体实施例进一步阐述本发明，但并不用于限制本发明的保护范围。本领域技术人员可在权利要求范围内对制备方法和使用仪器作出改进，这些改进也应视为本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。The following will further illustrate the present invention through specific examples, which are not intended to limit the protection scope of the present invention. Those skilled in the art can make improvements to the preparation method and using instruments within the scope of the claims, and these improvements should also be regarded as the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention should be subject to the appended claims.
本发明中“室温”如果没有特别说明，通常是指22℃到28℃。In the present invention, "room temperature" generally refers to 22°C to 28°C unless otherwise specified.
本发明中所用到的缩写的解释如下：The abbreviations used in the present invention are explained as follows:
XRPD：X射线粉末衍射XRPD: X-ray Powder Diffraction
DSC：差示扫描量热分析DSC: Differential Scanning Calorimetry
TGA：热重分析TGA: Thermogravimetric Analysis
1H NMR：核磁共振氢谱 1 H NMR: Hydrogen Nuclear Magnetic Resonance Spectroscopy
本发明所述的X射线粉末衍射图在Panalytical(帕纳科)公司的Empyrean型及X'Pert 3型X射线粉末衍射仪上采集。本发明所述的X射线粉末衍射的方法参数如下： The X-ray powder diffraction patterns of the present invention were collected on Empyrean and X'Pert 3 X-ray powder diffractometers of Panalytical Corporation. The method parameters of X-ray powder diffraction of the present invention are as follows:
X射线光源：Cu,KαX-ray light source: Cu, Kα
Figure PCTCN2022084300-appb-000006
1.54060；
Figure PCTCN2022084300-appb-000007
1.54443
Figure PCTCN2022084300-appb-000006
1.54060;
Figure PCTCN2022084300-appb-000007
1.54443
Kα2/Kα1强度比例：0.50Kα2/Kα1 intensity ratio: 0.50
电压：45千伏特(kV)Voltage: 45 kilovolts (kV)
电流：40毫安培(mA)Current: 40 milliamps (mA)
扫描范围：自3.0至40.0度(2θ角)Scanning range: from 3.0 to 40.0 degrees (2θ angle)
本发明所述的差示扫描量热分析图在TA公司的Q200型及Discovery DSC 2500型差示扫描量热仪上采集。本发明所述的差示扫描量热分析的方法参数如下：The differential scanning calorimetry analysis diagram of the present invention is collected on the Q200 type and Discovery DSC 2500 type differential scanning calorimeter of TA company. The method parameters of the differential scanning calorimetry analysis of the present invention are as follows:
扫描速率：10℃/分钟Scan rate: 10°C/min
保护气体：氮气Shielding gas: nitrogen
本发明所述的热重分析图在TA公司的Discovery TGA 5500型及Q5000型热重分析仪上采集。本发明所述的热重分析的方法参数如下：The thermogravimetric analysis diagram of the present invention is collected on the Discovery TGA 5500 type and Q5000 type thermogravimetric analyzer of TA company. The method parameters of the thermogravimetric analysis of the present invention are as follows:
扫描速率：10℃/分钟Scan rate: 10°C/min
保护气体：氮气Shielding gas: nitrogen
本发明所述的核磁共振氢谱数据( 1H NMR)采自于Bruker Avance II DMX 400M HZ核磁共振波谱仪。称量1-5mg样品，用0.5mL氘代二甲亚砜溶解，配制成2-10mg/mL的溶液进行测试。 The hydrogen nuclear magnetic resonance spectrum data ( 1 H NMR) of the present invention was collected from a Bruker Avance II DMX 400M HZ nuclear magnetic resonance spectrometer. Weigh 1-5 mg of the sample, dissolve it with 0.5 mL of deuterated dimethyl sulfoxide, and prepare a solution of 2-10 mg/mL for testing.
实施例1：晶型A的制备Example 1: Preparation of Form A
将约15g式(I)化合物固体用甲醇/水(2:1,100mL)打浆1小时，减压过滤，收集固体，45℃真空干燥2小时后得到粗品。所得粗品通过硅胶柱色谱法(二氯甲烷/甲醇＝30/1-20/1)纯化，收集产物点，减压浓缩至100mL，加入乙醇(100mL)，继续旋蒸至50mL，过滤、收集白色固体，室温真空干燥1小时后再45℃真空干燥5小时得到白色固体9.1g(式(I)化合物)。About 15 g of the solid compound of formula (I) was slurried with methanol/water (2:1, 100 mL) for 1 hour, filtered under reduced pressure, the solid was collected, and the crude product was obtained after vacuum drying at 45°C for 2 hours. The obtained crude product was purified by silica gel column chromatography (dichloromethane/methanol=30/1-20/1), the product points were collected, concentrated under reduced pressure to 100 mL, added ethanol (100 mL), continued to rotate to 50 mL, filtered and collected white The solid was vacuum-dried at room temperature for 1 hour and then vacuum-dried at 45° C. for 5 hours to obtain 9.1 g of a white solid (compound of formula (I)).
对所得固体样品进行XRPD、TGA、DSC、 1H NMR测试，所得XRPD、TGA、DSC、 1H NMR数据分别如图1～4所示，X射线粉末衍射数据如表1所示。XRPD结果显示所得样品在约6.8°±0.2°、约11.7°±0.2°、约13.6°±0.2°、约16.4°±0.2°、约17.1°±0.2°、约18.4°±0.2°、约20.5°±0.2°、约22.1°±0.2°、约22.4°±0.2°、约23.5°±0.2°和约28.1°±0.2°处有特征峰。 The obtained solid samples were tested by XRPD, TGA, DSC, and 1 H NMR. The obtained XRPD, TGA, DSC, and 1 H NMR data are shown in Figures 1 to 4, respectively, and the X-ray powder diffraction data are shown in Table 1. XRPD results showed that the obtained samples were at about 6.8°±0.2°, about 11.7°±0.2°, about 13.6°±0.2°, about 16.4°±0.2°, about 17.1°±0.2°, about 18.4°±0.2°, about 20.5° There are characteristic peaks at °±0.2°, about 22.1°±0.2°, about 22.4°±0.2°, about 23.5°±0.2° and about 28.1°±0.2°.
TGA显示将将样品加热到200℃失重约1％，DSC数据显示晶型A熔点在221℃附近，基于表征数据推测晶型A为无水晶型。TGA shows that the sample will lose about 1% weight when heated to 200°C. DSC data show that the melting point of Form A is around 221°C. Based on the characterization data, it is speculated that Form A is an anhydrous crystal.
表1Table 1
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
6.796.79 13.0213.02 20.0020.00
11.6911.69 7.577.57 7.757.75
13.6313.63 6.506.50 30.9330.93
16.3616.36 5.425.42 7.257.25
17.0317.03 5.215.21 9.779.77
18.3818.38 4.834.83 4.954.95
20.5120.51 4.334.33 13.4013.40
21.0021.00 4.234.23 1.921.92
22.0622.06 4.034.03 100.00100.00
22.4322.43 3.963.96 15.2215.22
23.0923.09 3.853.85 3.323.32
23.5223.52 3.783.78 4.764.76
24.2824.28 3.673.67 2.122.12
25.2725.27 3.523.52 1.491.49
28.1228.12 3.173.17 3.763.76
30.1330.13 2.972.97 0.880.88
30.6230.62 2.922.92 1.661.66
33.2233.22 2.702.70 1.091.09
33.8233.82 2.652.65 0.940.94
实施例2～7：晶型A的制备(气液渗透法)Examples 2-7: Preparation of crystal form A (gas-liquid permeation method)
室温条件下称取适量的制备例1得到的式(I)化合物固体置于3毫升的玻璃小瓶中，加入相应体积的正溶剂以溶解固体，使用0.45微米孔径的聚四氟乙烯滤膜将样品溶液过滤至新的3毫升玻璃小瓶中，敞口置于预盛有4毫升相应反溶剂的20毫升玻璃瓶中。封口后置于室温条件下气液渗透，直至有固体析出，得到晶型A。本实施例中所涉详细试验条件如表所示。其中，实施例3所得晶型A的X射线粉末衍射数据如表3所示。Weigh an appropriate amount of the solid compound of formula (I) obtained in Preparation Example 1 into a 3 ml glass vial at room temperature, add a corresponding volume of positive solvent to dissolve the solid, and use a 0.45-micron pore size polytetrafluoroethylene filter to filter the sample. The solution was filtered into a new 3 mL glass vial and placed open into a 20 mL glass vial prefilled with 4 mL of the corresponding antisolvent. After sealing, place it at room temperature for gas-liquid infiltration until a solid is precipitated, and crystal form A is obtained. The detailed test conditions involved in this example are shown in the table. Among them, the X-ray powder diffraction data of the crystal form A obtained in Example 3 is shown in Table 3.
表2Table 2
Figure PCTCN2022084300-appb-000008
Figure PCTCN2022084300-appb-000008
表3table 3
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
6.846.84 12.9212.92 75.7275.72
9.809.80 9.029.02 7.057.05
11.7311.73 7.547.54 11.5411.54
13.6813.68 6.486.48 100.00100.00
16.4216.42 5.405.40 37.1837.18
17.1417.14 5.175.17 80.2780.27
18.4218.42 4.824.82 11.6911.69
20.5520.55 4.324.32 50.3150.31
21.0521.05 4.224.22 23.7023.70
22.0922.09 4.024.02 96.0596.05
22.4622.46 3.963.96 16.7916.79
23.1523.15 3.843.84 25.7025.70
23.5523.55 3.783.78 8.148.14
24.3624.36 3.653.65 1.671.67
25.2825.28 3.523.52 2.432.43
28.1828.18 3.173.17 1.941.94
30.1730.17 2.962.96 5.415.41
30.6830.68 2.912.91 20.0520.05
33.2233.22 2.702.70 19.3719.37
33.9133.91 2.642.64 1.061.06
37.3837.38 2.412.41 6.106.10
39.4039.40 2.292.29 1.011.01
实施例8：晶型A的制备(缓慢降温法)Example 8: Preparation of crystal form A (slow cooling method)
室温条件下称取14.7毫克制备例1得到的式(I)化合物固体置于3毫升的玻璃小瓶中，加入0.5毫升甲醇得到悬浊液。将该悬浊液在50℃条件下磁力搅拌(转速约为1000转/分钟)约0.5小时后，使用0.45微米孔径的聚四氟乙烯滤膜将样品溶液趁热过滤至新的3毫升玻璃小瓶中，封口后以0.1℃每分钟的速率从50℃降温至5℃，5℃下静置约1天后无固体析出。将样品转移至-20℃条件下静置约1天时间，析出固体，得到晶型A，其X射线粉末衍射数据如表4所示。At room temperature, 14.7 mg of the solid compound of formula (I) obtained in Preparation Example 1 was weighed into a 3 mL glass vial, and 0.5 mL of methanol was added to obtain a suspension. The suspension was magnetically stirred (about 1000 rpm) at 50°C for about 0.5 hours, and the sample solution was filtered while hot using a 0.45-micron pore size polytetrafluoroethylene filter into a new 3-mL glass vial. After sealing, the temperature was lowered from 50°C to 5°C at a rate of 0.1°C per minute, and no solid was precipitated after standing at 5°C for about 1 day. The sample was transferred to -20°C and left to stand for about 1 day, and a solid was precipitated to obtain crystal form A. The X-ray powder diffraction data of which are shown in Table 4.
表4Table 4
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
6.856.85 12.9112.91 72.3872.38
11.7511.75 7.537.53 14.6714.67
13.6913.69 6.476.47 78.8978.89
16.4316.43 5.405.40 18.1618.16
17.1317.13 5.185.18 26.6926.69
18.1518.15 4.894.89 5.425.42
18.4418.44 4.814.81 8.418.41
18.5918.59 4.774.77 6.526.52
19.9019.90 4.464.46 7.317.31
20.5820.58 4.324.32 27.7827.78
21.0521.05 4.224.22 7.607.60
22.1122.11 4.024.02 100.00100.00
22.4922.49 3.953.95 17.4917.49
23.1623.16 3.843.84 8.398.39
23.5723.57 3.773.77 6.216.21
24.3724.37 3.653.65 11.4211.42
25.3825.38 3.513.51 4.064.06
26.2826.28 3.393.39 3.043.04
28.2128.21 3.163.16 12.5412.54
30.7230.72 2.912.91 3.743.74
33.2233.22 2.702.70 3.993.99
33.9133.91 2.642.64 2.822.82
实施例9～14：晶型A的制备(反溶剂添加法)Examples 9-14: Preparation of crystal form A (anti-solvent addition method)
室温条件下称取适量的制备例1得到的式(I)化合物固体置于5毫升的玻璃小瓶中，加入相应体积的正溶剂后，使用0.45微米孔径的聚四氟乙烯滤膜将样品溶液过滤至20毫升的玻璃小瓶中以得到澄清溶液。随后磁力搅拌(转速约为1000转/分钟)得到澄清溶液，并向其中逐滴加入相应反溶剂，如有固体析出，则离心分离得到晶型A。若加入约9毫升反溶剂后仍无固体析出，则停止滴加反溶剂，将样品转移至5℃环境下磁力搅拌约1天时间，固体析出，得到晶型A。若仍无固体析出，则将样品转移至-20℃搅拌约4天时间，固体析出，得到晶型A。本实施例中所涉详细试验条件如表5所示。其中，实施例9所得样品的X射线粉末衍射数据如表6所示。Weigh an appropriate amount of the solid compound of formula (I) obtained in Preparation Example 1 into a 5 ml glass vial at room temperature, add a corresponding volume of positive solvent, and filter the sample solution using a 0.45-micron pore size polytetrafluoroethylene filter membrane into a 20 mL glass vial to obtain a clear solution. Then magnetic stirring (rotation speed is about 1000 rpm) obtains a clear solution, and the corresponding anti-solvent is added dropwise to it, and if solid is precipitated, the crystal form A is obtained by centrifugation. If there is still no solid precipitation after adding about 9 ml of anti-solvent, stop the dropwise addition of the anti-solvent, transfer the sample to a 5°C environment with magnetic stirring for about 1 day, the solid is precipitated, and crystal form A is obtained. If there is still no solid precipitation, the sample is transferred to -20°C and stirred for about 4 days, the solid is precipitated, and crystal form A is obtained. The detailed test conditions involved in this example are shown in Table 5. The X-ray powder diffraction data of the sample obtained in Example 9 are shown in Table 6.
表5table 5
Figure PCTCN2022084300-appb-000009
Figure PCTCN2022084300-appb-000009
表6Table 6
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
6.816.81 12.9712.97 82.5682.56
9.709.70 9.129.12 5.555.55
11.7011.70 7.567.56 16.3116.31
13.6513.65 6.496.49 100.00100.00
16.3916.39 5.415.41 36.0236.02
17.0917.09 5.195.19 72.6472.64
18.0918.09 4.904.90 16.6916.69
18.5318.53 4.794.79 17.6917.69
19.8619.86 4.474.47 25.1725.17
20.5420.54 4.324.32 37.0937.09
21.0121.01 4.234.23 24.1924.19
22.0922.09 4.024.02 93.1493.14
23.1123.11 3.853.85 20.4420.44
24.3224.32 3.663.66 39.8639.86
25.3225.32 3.523.52 13.3913.39
26.2226.22 3.403.40 11.7611.76
28.1628.16 3.173.17 31.7231.72
30.6630.66 2.922.92 10.9010.90
33.1733.17 2.702.70 9.719.71
33.8733.87 2.652.65 6.506.50
实施例15～21：晶型A的制备(挥发法)Examples 15-21: Preparation of Crystal Form A (Volatilization Method)
室温条件下称取适量的制备例1得到的式(I)化合物固体置于3毫升的玻璃小瓶中，加入相应体积的溶剂以溶解固体。使用0.45微米孔径的聚四氟乙烯滤膜将样品溶液过滤至新的3毫升玻璃小瓶中。使用封口膜封口后于其上扎4个针孔，而后置于室温条件下缓慢挥发，得到晶型A。所涉详细试验条件如表7所示，实施例19样品的X射线粉末衍射数据如表8所示。An appropriate amount of the solid of the compound of formula (I) obtained in Preparation Example 1 was weighed and placed in a 3 ml glass vial at room temperature, and a corresponding volume of solvent was added to dissolve the solid. Filter the sample solution into a new 3 ml glass vial using a 0.45 micron pore size Teflon filter. After sealing with parafilm, 4 pinholes were pricked on it, and then slowly volatilized at room temperature to obtain crystal form A. The detailed test conditions involved are shown in Table 7, and the X-ray powder diffraction data of the sample of Example 19 is shown in Table 8.
表7Table 7
Figure PCTCN2022084300-appb-000010
Figure PCTCN2022084300-appb-000010
表8Table 8
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
6.826.82 12.9712.97 79.2879.28
9.779.77 9.069.06 6.746.74
11.7111.71 7.567.56 14.1014.10
13.6513.65 6.496.49 100.00100.00
16.3916.39 5.415.41 38.5638.56
17.1017.10 5.195.19 71.3471.34
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
18.0918.09 4.904.90 4.534.53
18.4018.40 4.824.82 10.5810.58
19.8319.83 4.484.48 6.906.90
20.5320.53 4.334.33 40.1340.13
21.0121.01 4.234.23 21.3221.32
22.0622.06 4.034.03 96.5696.56
22.4222.42 3.973.97 17.7417.74
23.1023.10 3.853.85 20.5020.50
23.5523.55 3.783.78 6.576.57
24.3124.31 3.663.66 14.9114.91
25.2925.29 3.523.52 4.634.63
26.2126.21 3.403.40 4.104.10
27.3127.31 3.273.27 1.421.42
28.1828.18 3.173.17 16.1816.18
29.0429.04 3.083.08 2.032.03
30.1430.14 2.972.97 3.433.43
30.6230.62 2.922.92 14.7414.74
32.0632.06 2.792.79 2.462.46
33.1533.15 2.702.70 14.8514.85
33.8133.81 2.652.65 4.664.66
34.9234.92 2.572.57 1.521.52
37.3337.33 2.412.41 4.184.18
实施例22～24：晶型A的制备(渗透-挥发法)Examples 22-24: Preparation of Form A (Infiltration-Volatilization Method)
室温条件下称取适量的制备例1得到的式(I)化合物固体置于3毫升的玻璃小瓶中，加入相应体积的正溶剂以溶解固体，使用0.45微米孔径的聚四氟乙烯滤膜将样品溶液过滤至新的3毫升玻璃小瓶中，敞口置于预盛有4毫升相应反溶剂的20毫升玻璃瓶中。封口后置于室温条件下气液渗透，六天后无固体析出，将样品转移至室温挥发，直至固体析出，得到晶型A。所涉详细试验条件如表9所示，实施例24样品的X射线粉末衍射数据如表10所示。Weigh an appropriate amount of the solid compound of formula (I) obtained in Preparation Example 1 into a 3 ml glass vial at room temperature, add a corresponding volume of positive solvent to dissolve the solid, and use a 0.45-micron pore size polytetrafluoroethylene filter to filter the sample. The solution was filtered into a new 3 mL glass vial and placed open into a 20 mL glass vial prefilled with 4 mL of the corresponding antisolvent. After sealing, it was placed at room temperature for gas-liquid infiltration, and no solid was precipitated after six days. The sample was transferred to room temperature to volatilize until the solid was precipitated to obtain crystal form A. The detailed test conditions involved are shown in Table 9, and the X-ray powder diffraction data of the sample of Example 24 is shown in Table 10.
表9Table 9
Figure PCTCN2022084300-appb-000011
Figure PCTCN2022084300-appb-000011
表10Table 10
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
6.786.78 12.9312.93 74.0574.05
9.739.73 9.049.04 7.127.12
11.6811.68 7.547.54 13.2113.21
13.6213.62 6.486.48 100.00100.00
16.3616.36 5.405.40 36.1236.12
17.0617.06 5.185.18 75.9275.92
18.0718.07 4.904.90 3.093.09
18.3818.38 4.814.81 9.249.24
19.7919.79 4.474.47 4.624.62
20.5120.51 4.324.32 35.8735.87
20.9720.97 4.224.22 21.1021.10
22.0622.06 4.024.02 71.7971.79
22.4422.44 3.953.95 13.6313.63
23.0723.07 3.853.85 19.5019.50
23.5123.51 3.773.77 5.545.54
24.2824.28 3.663.66 9.479.47
25.2725.27 3.523.52 3.873.87
26.2026.20 3.393.39 2.942.94
26.7926.79 3.323.32 1.001.00
28.1228.12 3.173.17 10.9410.94
29.0029.00 3.073.07 1.221.22
30.1030.10 2.962.96 3.003.00
30.5930.59 2.922.92 14.1414.14
32.0132.01 2.792.79 1.381.38
33.1233.12 2.702.70 13.1413.14
33.8133.81 2.652.65 2.342.34
37.2837.28 2.412.41 3.243.24
38.7438.74 2.322.32 0.170.17
实施例25～27：晶型A的制备(冷却-挥发法)Examples 25-27: Preparation of crystal form A (cooling-volatilization method)
室温条件下称取适量的制备例1得到的式(I)化合物固体置于3毫升的玻璃小瓶中，加入相应体积的溶剂得到悬浊液。将该悬浊液在50℃条件下磁力搅拌(转速约为1000转/ 分钟)约0.5小时后，使用0.45微米孔径的聚四氟乙烯滤膜将样品溶液趁热过滤至新的3毫升玻璃小瓶中，封口后以0.1℃每分钟的速率从50℃降温至5℃，5℃下静置约1天后无固体析出。将样品转移至-20℃条件下静置约1天时间，仍无固体析出，将样品转移至室温挥发，直至固体析出，得到晶型A。本实施例中所涉详细试验条件如表11所示，实施例25样品的X射线粉末衍射数据如表12所示。An appropriate amount of the solid compound of formula (I) obtained in Preparation Example 1 was weighed and placed in a 3 ml glass vial at room temperature, and a corresponding volume of solvent was added to obtain a suspension. After the suspension was magnetically stirred at 50°C (the rotation speed was about 1000 rpm) for about 0.5 hours, the sample solution was filtered hot into a new 3 ml glass vial using a 0.45-micron pore size polytetrafluoroethylene filter membrane. After sealing, the temperature was lowered from 50°C to 5°C at a rate of 0.1°C per minute, and no solid was precipitated after standing at 5°C for about 1 day. The sample was transferred to -20°C and left to stand for about 1 day, and no solid was precipitated. The sample was transferred to room temperature and volatilized until the solid was precipitated, and crystal form A was obtained. The detailed test conditions involved in this example are shown in Table 11, and the X-ray powder diffraction data of the sample of Example 25 are shown in Table 12.
表11Table 11
实施例Example 固体质量(毫克)Solid mass (mg) 溶剂(体积比)Solvent (volume ratio) 体积(毫升)Volume (ml)
2525 15.315.3 乙酸异丙酯isopropyl acetate 0.50.5
2626 15.515.5 乙腈/乙醇(1:4)Acetonitrile/ethanol (1:4) 0.50.5
2727 14.814.8 丙酮/甲基叔丁基醚(1:4)Acetone/Methyl tert-butyl ether (1:4) 0.50.5
表12Table 12
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
6.776.77 12.9312.93 69.4969.49
9.729.72 9.049.04 5.685.68
11.6811.68 7.547.54 13.6913.69
13.6213.62 6.476.47 90.3690.36
16.3516.35 5.405.40 33.8533.85
17.0617.06 5.185.18 63.1063.10
18.0718.07 4.894.89 6.196.19
18.3718.37 4.814.81 13.3313.33
19.8019.80 4.474.47 10.7610.76
20.5020.50 4.324.32 38.7638.76
20.9620.96 4.224.22 18.4218.42
22.0622.06 4.024.02 100.00100.00
22.4222.42 3.953.95 16.7216.72
23.0623.06 3.853.85 15.9415.94
23.5223.52 3.773.77 6.766.76
24.2724.27 3.663.66 20.0020.00
25.2825.28 3.513.51 6.056.05
26.1926.19 3.393.39 5.705.70
28.1228.12 3.173.17 21.8621.86
29.1329.13 3.063.06 0.740.74
30.1130.11 2.962.96 2.892.89
30.6030.60 2.922.92 12.7812.78
31.9931.99 2.792.79 2.322.32
33.1233.12 2.702.70 11.0611.06
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
33.8433.84 2.642.64 5.875.87
37.3237.32 2.412.41 2.742.74
实施例28～29：晶型A的制备(反溶剂-挥发法)Examples 28-29: Preparation of Form A (Anti-solvent-Volatilization Method)
室温条件下称取适量的制备例1得到的式(I)化合物固体置于5毫升的玻璃小瓶中，加入相应体积的正溶剂后，使用0.45微米孔径的聚四氟乙烯滤膜将样品溶液过滤至20毫升的玻璃小瓶中以得到澄清溶液。随后磁力搅拌(转速约为1000转/分钟)得到澄清溶液，并向其中逐滴加入相应反溶剂，加入约9毫升反溶剂后无固体析出，将样品转移至5℃环境下磁力搅拌约1天时间，无固体析出，将样品转移至-20℃搅拌约4天时间，仍无固体析出，将样品转移至室温挥发，直至固体析出，得到晶型A。本实施例中所涉详细试验条件如表13所示。实施28所得样品X射线粉末衍射数据如表14所示。Weigh an appropriate amount of the solid compound of formula (I) obtained in Preparation Example 1 into a 5 ml glass vial at room temperature, add a corresponding volume of positive solvent, and filter the sample solution using a 0.45-micron pore size polytetrafluoroethylene filter membrane into a 20 mL glass vial to obtain a clear solution. Then magnetic stirring (the rotation speed is about 1000 r/min) to obtain a clear solution, and the corresponding anti-solvent was added dropwise to it, no solid was precipitated after adding about 9 ml of anti-solvent, and the sample was transferred to 5 °C under magnetic stirring for about 1 day. Time, no solid precipitation, the sample was transferred to -20 ° C and stirred for about 4 days, still no solid precipitation, the sample was transferred to room temperature to volatilize until solid precipitation, obtaining crystal form A. The detailed test conditions involved in this example are shown in Table 13. The X-ray powder diffraction data of the samples obtained in Example 28 are shown in Table 14.
表13Table 13
Figure PCTCN2022084300-appb-000012
Figure PCTCN2022084300-appb-000012
表14Table 14
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
6.836.83 12.9312.93 73.0273.02
9.799.79 9.039.03 4.044.04
11.7211.72 7.557.55 12.0612.06
13.6713.67 6.486.48 100.00100.00
16.4016.40 5.415.41 25.4925.49
17.1217.12 5.185.18 42.3542.35
18.4118.41 4.824.82 8.418.41
20.5420.54 4.324.32 38.0338.03
21.0221.02 4.234.23 13.2613.26
22.0622.06 4.034.03 74.3674.36
22.4422.44 3.963.96 13.2813.28
23.1223.12 3.853.85 11.6811.68
23.5423.54 3.783.78 6.256.25
24.3224.32 3.663.66 1.031.03
25.2625.26 3.533.53 1.891.89
28.1228.12 3.173.17 1.511.51
30.1630.16 2.962.96 3.183.18
30.6330.63 2.922.92 9.719.71
33.1633.16 2.702.70 7.127.12
37.3437.34 2.412.41 2.672.67
实施例30～31：晶型B的制备(渗透-挥发法)Examples 30-31: Preparation of Crystal Form B (Infiltration-Volatilization Method)
实施例30：室温条件下称取14.7毫克制备例1得到的式(I)化合物固体置于3.0毫升的玻璃小瓶中，敞口置于预盛有4毫升丙酮的20毫升玻璃瓶中。封口后置于室温条件下气固渗透两天后得到澄清溶液，将该溶液置于室温挥发，直至固体析出，得到晶型B，其X射线粉末衍射数据如表15所示。Example 30: Weigh 14.7 mg of the solid compound of formula (I) obtained in Preparation Example 1 into a 3.0-ml glass vial at room temperature, and place the open mouth in a 20-ml glass vial prefilled with 4 ml of acetone. After sealing, put it at room temperature for gas-solid permeation for two days to obtain a clear solution, which was volatilized at room temperature until the solid was precipitated to obtain crystal form B, whose X-ray powder diffraction data are shown in Table 15.
表15Table 15
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
6.806.80 12.8912.89 32.5632.56
7.217.21 12.1812.18 15.8915.89
11.5211.52 7.657.65 4.174.17
12.1412.14 7.267.26 1.111.11
13.6313.63 6.476.47 7.307.30
14.4514.45 6.116.11 100.00100.00
15.5715.57 5.675.67 42.5642.56
15.8615.86 5.575.57 5.345.34
18.5218.52 4.784.78 2.062.06
19.0119.01 4.664.66 5.615.61
20.5720.57 4.314.31 4.294.29
21.5221.52 4.124.12 14.7514.75
21.7721.77 4.074.07 10.4210.42
22.6722.67 3.913.91 10.3310.33
23.2523.25 3.823.82 4.374.37
24.3424.34 3.653.65 0.960.96
29.3129.31 3.043.04 0.680.68
30.9830.98 2.882.88 1.451.45
32.0332.03 2.792.79 1.591.59
32.6932.69 2.732.73 2.472.47
34.6334.63 2.592.59 1.231.23
37.1737.17 2.422.42 1.161.16
实施例31：室温条件下称取14.7毫克制备例1得到的式(I)化合物固体置于3.0毫升的玻璃小瓶中，加入0.5毫升丙酮溶解固体。使用0.45微米孔径的聚四氟乙烯滤膜将样品溶液过滤至新的3毫升玻璃小瓶中。使用封口膜封口后于其上扎4个针孔，而后置于室温条件下缓慢挥发，直至有固体析出，得到晶型B，其X射线粉末衍射数据如表16所示。Example 31: Weigh 14.7 mg of the solid compound of formula (I) obtained in Preparation Example 1 into a 3.0 mL glass vial at room temperature, and add 0.5 mL of acetone to dissolve the solid. Filter the sample solution into a new 3 mL glass vial using a 0.45 micron pore size Teflon filter. After sealing with parafilm, four pinholes were pricked on it, and then slowly volatilized at room temperature until a solid was precipitated to obtain crystal form B, and its X-ray powder diffraction data are shown in Table 16.
表16Table 16
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
6.806.80 12.9012.90 45.8345.83
7.207.20 12.1912.19 16.7116.71
11.5611.56 7.627.62 6.706.70
12.1012.10 7.287.28 2.222.22
13.6413.64 6.476.47 10.0810.08
14.4514.45 6.116.11 100.00100.00
15.5815.58 5.675.67 42.5842.58
15.8815.88 5.575.57 5.795.79
17.7117.71 4.994.99 0.580.58
18.5818.58 4.764.76 2.952.95
19.0219.02 4.654.65 5.175.17
20.5220.52 4.324.32 7.787.78
21.5321.53 4.124.12 17.2217.22
21.7921.79 4.074.07 10.0410.04
22.6822.68 3.913.91 14.8914.89
23.2623.26 3.823.82 6.796.79
24.3824.38 3.643.64 2.372.37
25.1325.13 3.543.54 1.581.58
28.0328.03 3.183.18 0.540.54
29.3229.32 3.043.04 1.091.09
31.5131.51 2.842.84 2.092.09
32.0832.08 2.792.79 2.132.13
32.7332.73 2.732.73 3.743.74
34.1034.10 2.632.63 0.910.91
34.6534.65 2.592.59 1.761.76
37.1537.15 2.422.42 1.191.19
39.1339.13 2.302.30 0.890.89
实施例32：晶型B的制备(气液渗透法)Example 32: Preparation of crystal form B (gas-liquid permeation method)
室温条件下称取14.3毫克制备例1得到的式(I)化合物固体置于3.0毫升的玻璃小瓶中，加入0.5毫升丙酮以溶解固体，使用0.45微米孔径的聚四氟乙烯滤膜将样品溶液过滤至新的3毫升玻璃小瓶中，敞口置于预盛有4毫升纯水的20毫升玻璃瓶中。封口后置于室温条件下气液渗透，直至有固体析出，得到晶型B，其X射线粉末衍射数据如表17所示，衍射图如图5所示。该样品在约6.8°±0.2°、约11.5°±0.2°、约13.6°±0.2°、约14.5°±0.2°、约15.6°±0.2°、约20.5°±0.2°、约21.5°±0.2°、约22.7°±0.2°、约23.2°±0.2°、约24.4°±0.2°和约32.7°±0.2°处有特征峰。Weigh 14.3 mg of the solid compound of formula (I) obtained in Preparation Example 1 into a 3.0-mL glass vial at room temperature, add 0.5 mL of acetone to dissolve the solid, and filter the sample solution using a 0.45-micron pore size polytetrafluoroethylene filter membrane into a new 3 ml glass vial and place the open end in a 20 ml glass vial prefilled with 4 ml of purified water. After sealing, it was placed at room temperature for gas-liquid permeation until a solid was precipitated to obtain crystal form B, whose X-ray powder diffraction data are shown in Table 17, and the diffraction pattern is shown in Figure 5 . The sample is at about 6.8°±0.2°, about 11.5°±0.2°, about 13.6°±0.2°, about 14.5°±0.2°, about 15.6°±0.2°, about 20.5°±0.2°, about 21.5°±0.2 There are characteristic peaks at °, about 22.7° ± 0.2°, about 23.2° ± 0.2°, about 24.4° ± 0.2° and about 32.7° ± 0.2°.
表17Table 17
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
6.806.80 12.9412.94 100.00100.00
7.207.20 12.2212.22 6.766.76
11.5511.55 7.647.64 47.2147.21
12.1012.10 7.307.30 11.6611.66
13.6313.63 6.486.48 35.7035.70
14.4514.45 6.126.12 61.2761.27
15.5715.57 5.685.68 33.6733.67
15.8615.86 5.585.58 10.8510.85
17.7417.74 4.994.99 6.206.20
18.5518.55 4.774.77 4.534.53
18.8118.81 4.714.71 11.5111.51
20.5120.51 4.324.32 32.4632.46
21.5221.52 4.124.12 23.1223.12
21.7621.76 4.084.08 8.818.81
22.6722.67 3.923.92 42.3842.38
23.2223.22 3.833.83 75.8375.83
24.3624.36 3.653.65 20.3720.37
25.1425.14 3.543.54 2.542.54
25.6825.68 3.463.46 3.933.93
27.4527.45 3.253.25 1.101.10
29.3629.36 3.043.04 11.3611.36
31.1731.17 2.872.87 9.649.64
32.0232.02 2.792.79 6.176.17
32.6632.66 2.742.74 21.5121.51
34.5034.50 2.602.60 7.287.28
36.6736.67 2.452.45 2.602.60
39.0839.08 2.302.30 2.602.60
实施例33：晶型的溶解度Example 33: Solubility of Crystal Forms
将本发明晶型A和晶型B分别加入SGF(模拟人工胃液)、FaSSIF(空腹状态下人工肠液)、FeSSIF(饱食状态下人工肠液)和纯水中，配制成悬浊液，在1小时、2小时、4小时和24小时平衡后过滤，得到饱和溶液。通过高效液相色谱法(HPLC)测定饱和溶液中样品的含量。试验结果如表18所示，溶解度曲线分别如图9～12所示。试验结果表明，本发明晶型A和晶型B在SGF、FaSSIF、FeSSIF和纯水中具有较高的溶解度。The crystal form A and crystal form B of the present invention are respectively added into SGF (simulated artificial gastric fluid), FaSSIF (artificial intestinal fluid in fasting state), FeSSIF (artificial intestinal fluid in satiety state) and pure water, and are prepared into a suspension liquid. After equilibration for 1 hour, 2 hours, 4 hours and 24 hours, filter to obtain a saturated solution. The content of the sample in the saturated solution was determined by high performance liquid chromatography (HPLC). The test results are shown in Table 18, and the solubility curves are shown in Figures 9 to 12, respectively. The test results show that the crystal form A and the crystal form B of the present invention have higher solubility in SGF, FaSSIF, FeSSIF and pure water.
表18Table 18
Figure PCTCN2022084300-appb-000013
Figure PCTCN2022084300-appb-000013
实施例32：晶型的可压性Example 32: Compressibility of crystal forms
采用手动压片机进行压片，压片时，选择可以压制成圆柱体片剂的圆形平冲，分别加入一定量的本发明晶型A和晶型B，采用10kN压力压制成圆形片剂，采用片剂硬度测定仪测试其径向破碎力(硬度，H)。采用游标卡尺测量片剂的直径(D)和厚度(L)，利用公式T＝2H/πDL计算出不同硬度下粉体的抗张强度，试验结果如表19所示，晶型A压片后的XRPD如图13所示，晶型B压片后的XRPD如图14所示。在一定的压力下，抗张强度越大的，表示其可压性越好。本发明晶型A和晶型B具有较大的抗张强度，说明具有较优的可压性。Use a manual tablet press for tablet compression. When tableting, select a circular flat punch that can be compressed into cylindrical tablets, add a certain amount of crystal form A and crystal form B of the present invention, and press 10kN into circular tablets. The radial crushing force (hardness, H) was tested by a tablet hardness tester. Use vernier calipers to measure the diameter (D) and thickness (L) of the tablet, and use the formula T=2H/πDL to calculate the tensile strength of the powder with different hardnesses. The test results are shown in Table 19. The XRPD is shown in Figure 13, and the XRPD of Form B after tableting is shown in Figure 14. Under a certain pressure, the higher the tensile strength, the better the compressibility. The crystal form A and the crystal form B of the present invention have larger tensile strength, indicating that they have better compressibility.
表19Table 19
晶型Crystal form 直径(毫米)Diameter (mm) 厚度(毫米)Thickness (mm) 径向破碎力(牛)Radial crushing force (N) 抗张强度(兆帕)Tensile Strength (MPa)
晶型AForm A 6.086.08 2.462.46 48.3548.35 2.0592.059
晶型BForm B 6.086.08 2.522.52 55.9755.97 2.3272.327
实施例33：晶型的固有溶出速率Example 33: Intrinsic Dissolution Rate of Crystalline Form
称取本发明晶型A和晶型B各约100mg，倒入固有溶出模具，在5kN压力下持续1min，制成表面积0.5cm 2的薄片，取完整压片转移至溶出仪测试固有溶出速率，根据10～30min之间的测定点计算斜率，以mg/mL表示，根据斜率进一步计算固有溶出速率(Intrinsic dissolution rate,IDR)，以mg/min/cm 2表示。本发明晶型A和晶型B的具有较快的溶出速率。 Weigh about 100 mg of each of crystal form A and crystal form B of the present invention, pour into the inherent dissolution mold, continue for 1min under 5kN pressure, make thin slices with a surface area of 0.5cm 2 , take the complete tablet and transfer it to a dissolution apparatus to test the inherent dissolution rate, Calculate the slope according to the measurement point between 10 and 30 min, expressed in mg/mL, and further calculate the intrinsic dissolution rate (IDR) according to the slope, expressed in mg/min/cm 2 . The crystal form A and the crystal form B of the present invention have faster dissolution rates.
实施例34：稳定性对比研究Example 34: Comparative stability study
称取本发明晶型A(起始纯度为97.3％)和晶型B(起始纯度为97.3％)各约15mg，分别敞口放置于25℃/60％RH和40℃/75％RH条件的稳定箱中，在7天和14天后取样测XRPD和HPLC。试验结果如表20所示，晶型A的稳定性如图15～16所示，晶型B的稳定性如图17～18所示。试验结果显示，本发明晶型在25℃/60％RH和40℃/75％RH条件下具有较高的稳定性。Weigh about 15 mg each of crystal form A (initial purity of 97.3%) and crystal form B (initial purity of 97.3%) of the present invention, and place them in 25°C/60%RH and 40°C/75%RH conditions respectively. In the stability box, samples were taken for XRPD and HPLC after 7 and 14 days. The test results are shown in Table 20, the stability of Form A is shown in Figures 15-16, and the stability of Form B is shown in Figures 17-18. The test results show that the crystal form of the present invention has higher stability under the conditions of 25°C/60%RH and 40°C/75%RH.
表20Table 20
Figure PCTCN2022084300-appb-000014
Figure PCTCN2022084300-appb-000014
实施例35：引湿性对比研究Example 35: Comparative Study of Moisture Induction
称取本发明晶型A和晶型B各约10mg进行动态水分吸附(DVS)测试，然后取样测XRPD，试验结果如表21所示，晶型A的DVS如图19所示，晶型A测试DVS前后的XRPD叠图如图20所示，晶型B的DVS如图21所示，晶型B测试DVS前后的XRPD叠图如图22所示。试验结果显示，本发明晶型A和晶型B具有较低的引湿性。About 10 mg of each of crystal form A and crystal form B of the present invention was weighed for dynamic moisture adsorption (DVS) test, and then sampled to measure XRPD. The test results are shown in Table 21. The DVS of crystal form A is shown in Figure 19, and crystal form A The XRPD overlays before and after testing DVS are shown in Figure 20, the DVS of Form B is shown in Figure 21, and the XRPD overlays before and after DVS testing of Form B are shown in Figure 22. The test results show that the crystal form A and the crystal form B of the present invention have lower hygroscopicity.
表21Table 21
起始晶型starting crystal form 80％相对湿度的增重Weight gain at 80% relative humidity 引湿性hygroscopicity DVS测试后的晶型Crystal form after DVS test
晶型AForm A 0.12850.1285 无或几乎无引湿性No or almost no hygroscopicity 晶型AForm A
晶型BForm B 0.20440.2044 略有引湿性slightly hygroscopic 晶型BForm B
关于引湿性特征描述与引湿性增重的界定(中国药典2020年版四部药物引湿性试验指导原则)：Regarding the description of hygroscopicity characteristics and the definition of hygroscopicity weight gain (Guidelines for the hygroscopicity test of four drugs in the 2020 edition of the Chinese Pharmacopoeia):
潮解：吸收足量水分形成液体Deliquescence: Absorbs sufficient water to form a liquid
极具引湿性：引湿增重不小于15％Extremely hygroscopic: wet weight gain is not less than 15%
有引湿性：引湿增重小于15％但不小于2％Moisture: Moisture gain is less than 15% but not less than 2%
略有引湿性：引湿增重小于2％但不小于0.2％Slightly hygroscopic: wet weight gain is less than 2% but not less than 0.2%
无或几乎无引湿性：引湿增重小于0.2％No or almost no hygroscopicity: wet weight gain is less than 0.2%
实施例36：晶习对比研究Example 36: Crystal Habit Comparative Study
称取本发明晶型A和晶型B各约10mg，分别置于载玻片上，滴加少许真空硅油分散样品，然后盖上盖玻片，置于偏光显微镜下观察。本发明晶型A与晶型B具有较优的晶习。About 10 mg each of crystal form A and crystal form B of the present invention were weighed, placed on glass slides respectively, a little vacuum silicone oil was added dropwise to disperse the samples, then covered with a cover glass and placed under a polarizing microscope for observation. The crystal form A and the crystal form B of the present invention have better crystal habits.
实施例37：粒径分布对比研究Example 37: Comparative Study of Particle Size Distribution
称取本发明晶型A和晶型B各约10-30mg，然后加入约5mL Isopar G(含有0.2％卵磷脂)，将待测样品充分混合均匀后加入SDC进样系统中，使遮光度达到合适范围，开始实验，超声30秒后进行粒径分布的测试。本发明晶型A和晶型B具有较均匀的粒径分布。Weigh about 10-30 mg of crystal form A and crystal form B of the present invention, then add about 5 mL of Isopar G (containing 0.2% lecithin), fully mix the sample to be tested and add it into the SDC sampling system, so that the shading degree reaches In the suitable range, the experiment was started, and the particle size distribution test was carried out after sonication for 30 seconds. The crystal form A and the crystal form B of the present invention have relatively uniform particle size distribution.
实施例38：黏附性对比研究Example 38: Adhesion Comparative Study
称取本发明晶型A和晶型B各约100mg，然后加入到6mm圆形平冲中，采用10kN的压力进行压片处理，压片后停留约半分钟，记录最后压成片剂的质量，进而计算压制过程中黏附在圆形冲头的黏附量，试验结果如表22所示。试验结果显示，本发明晶型A和晶型B较不易黏附。Weigh about 100 mg each of crystal form A and crystal form B of the present invention, then add them into a 6mm circular flat punch, use a pressure of 10 kN to perform tablet compression, stay for about half a minute after tableting, and record the final mass of the tablet. , and then calculate the amount of adhesion on the round punch during the pressing process. The test results are shown in Table 22. The test results show that the crystal form A and the crystal form B of the present invention are less likely to adhere.
表22Table 22
晶型Crystal form 压片前质量(毫克)Mass before tableting (mg) 压片后质量(毫克)Mass after compression (mg) 黏附量(毫克)Adhesion (mg)
晶型AForm A 100.1100.1 96.896.8 3.33.3
晶型BForm B 100.2100.2 97.497.4 2.82.8
上述实施例只为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。The above-mentioned embodiments are only intended to illustrate the technical concept and characteristics of the present invention, and the purpose thereof is to enable those who are familiar with the art to understand the content of the present invention and implement them accordingly, and cannot limit the protection scope of the present invention. All equivalent changes or modifications made according to the spirit of the present invention should be included within the protection scope of the present invention.

Claims (7)

  1. 式(I)所示化合物N-(3-氰基-4-氟-苯基)-1-甲基-4-{[(1S)-2,2,2-三氟-1-甲基-乙基]氨磺酰基}吡咯-2-羧酰胺的A型晶体、即晶型A，其特征在于，使用Cu-Kα辐射，所述晶型A的X射线粉末衍射在2θ值为6.8°±0.2°、13.6°±0.2°和22.1°±0.2°处有特征峰，The compound represented by formula (I) N-(3-cyano-4-fluoro-phenyl)-1-methyl-4-{[(1S)-2,2,2-trifluoro-1-methyl- The A-type crystal of ethyl]sulfamoyl}pyrrole-2-carboxamide, namely crystal form A, is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction of the crystal form A has a 2θ value of 6.8°± There are characteristic peaks at 0.2°, 13.6°±0.2° and 22.1°±0.2°,
    Figure PCTCN2022084300-appb-100001
    Figure PCTCN2022084300-appb-100001
  2. 根据权利要求1所述的晶型A的制备方法，其特征包括：The preparation method of crystal form A according to claim 1, is characterized in that:
    (1)将式(I)化合物溶解于酮类、环醚类、烷基腈类或杂氮类溶剂中，将溶液敞口置于烷烃类、醇类或纯水溶剂气氛下进行气液渗透，1～7天后，固体析出，得到晶型A；或(1) Dissolve the compound of formula (I) in ketones, cyclic ethers, alkyl nitriles or hetero-nitrogen solvents, and place the solution open in an atmosphere of alkanes, alcohols or pure water solvent to carry out gas-liquid infiltration , after 1 to 7 days, the solid is precipitated to obtain crystal form A; or
    (2)将式(I)化合物在40～60℃下溶解于醇类溶剂中，溶解后降温至固体析出，得到晶型A；或(2) dissolving the compound of formula (I) in an alcohol solvent at 40-60° C., and cooling down to solid precipitation after dissolving to obtain crystal form A; or
    (3)将式(I)化合物溶解于环醚类、杂氮类或烷基腈类溶剂中，向其中逐滴加入纯水、烷烃类、芳烃类或卤代烃类反溶剂，固体析出，得到晶型A；或(3) dissolve the compound of formula (I) in cyclic ethers, heteronitrogens or alkyl nitrile solvents, add pure water, alkanes, aromatic hydrocarbons or halogenated hydrocarbons anti-solvent dropwise to it, the solids are separated out, to obtain Form A; or
    (4)将式(I)化合物溶解于醇类、酮类、酯类、卤代烃类、环醚类或烷基腈类的单一或混合溶剂中，将溶液置于20～30℃下挥发，固体析出，得到晶型A。(4) Dissolve the compound of formula (I) in a single or mixed solvent of alcohols, ketones, esters, halogenated hydrocarbons, cyclic ethers or alkyl nitriles, and place the solution at 20 to 30 ° C to volatilize , the solid was precipitated, and the crystal form A was obtained.
  3. 式(I)所示化合物N-(3-氰基-4-氟-苯基)-1-甲基-4-{[(1S)-2,2,2-三氟-1-甲基-乙基]氨磺酰基}吡咯-2-羧酰胺的B型晶体、即晶型B，其特征在于，使用Cu-Kα辐射，所述晶型F的X射线粉末衍射在2θ值为6.8°±0.2°、14.5°±0.2°和23.2°±0.2°处有特征峰，The compound represented by formula (I) N-(3-cyano-4-fluoro-phenyl)-1-methyl-4-{[(1S)-2,2,2-trifluoro-1-methyl- The B-type crystal of ethyl]sulfamoyl}pyrrole-2-carboxamide, namely crystal form B, is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction of crystal form F has a 2θ value of 6.8°± There are characteristic peaks at 0.2°, 14.5°±0.2° and 23.2°±0.2°,
    Figure PCTCN2022084300-appb-100002
    Figure PCTCN2022084300-appb-100002
  4. 根据权利要求3所述的晶型B的制备方法，其特征包括：The preparation method of crystal form B according to claim 3, is characterized in that:
    (1)将式(I)化合物溶解于酮类溶剂中，将溶液置于20～30℃下挥发，固体析出，得到晶型B；或(1) Dissolving the compound of formula (I) in a ketone solvent, volatilizing the solution at 20-30° C., the solid is precipitated to obtain crystal form B; or
    (2)将式(I)化合物溶解于酮类溶剂中，将溶液敞口置于纯水气氛下进行气液渗透，直至固体析出，得到晶型B。(2) Dissolving the compound of formula (I) in a ketone solvent, placing the solution open in a pure water atmosphere, and performing gas-liquid infiltration until the solid is precipitated to obtain crystal form B.
  5. 药物组合物，其包含权利要求1和3中任一项所述的晶体和制药学可接受的载体。A pharmaceutical composition comprising the crystal of any one of claims 1 and 3 and a pharmaceutically acceptable carrier.
  6. 具有CAM活性的药物组合物，其含有权利要求1和3中任一项所述的晶体作为有效成分。A pharmaceutical composition having CAM activity, which contains the crystal of any one of claims 1 and 3 as an active ingredient.
  7. 乙型肝炎病毒感染的预防药或治疗药，其含有权利要求1和3中任一项所述的晶体作为有效成分。A preventive or therapeutic agent for hepatitis B virus infection, comprising the crystal according to any one of claims 1 and 3 as an active ingredient.
PCT/CN2022/084300 2021-03-31 2022-03-31 Crystal forms of sulfamoyl pyrrole amide compounds and preparation methods therefor WO2022206879A1 (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105452220A (en) * 2013-05-17 2016-03-30 爱尔兰詹森科学公司 Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis b
WO2020016427A1 (en) * 2018-07-19 2020-01-23 Ospedale San Raffaele S.R.L. Inhibitors of hepatitis b virus
WO2020030781A1 (en) * 2018-08-10 2020-02-13 Ospedale San Raffaele S.R.L. Tricyclic inhibitors of hepatitis b virus

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105452220A (en) * 2013-05-17 2016-03-30 爱尔兰詹森科学公司 Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis b
WO2020016427A1 (en) * 2018-07-19 2020-01-23 Ospedale San Raffaele S.R.L. Inhibitors of hepatitis b virus
WO2020030781A1 (en) * 2018-08-10 2020-02-13 Ospedale San Raffaele S.R.L. Tricyclic inhibitors of hepatitis b virus

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