WO2021000687A1 - Preparation method for crystal form of pac-1 - Google Patents

Preparation method for crystal form of pac-1 Download PDF

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WO2021000687A1
WO2021000687A1 PCT/CN2020/094138 CN2020094138W WO2021000687A1 WO 2021000687 A1 WO2021000687 A1 WO 2021000687A1 CN 2020094138 W CN2020094138 W CN 2020094138W WO 2021000687 A1 WO2021000687 A1 WO 2021000687A1
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pac
crystal form
solvent
preparing
mixed solvent
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PCT/CN2020/094138
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French (fr)
Chinese (zh)
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王智民
刘晓谦
郭中原
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北京科佑爱科技有限责任公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention belongs to the technical field of medicinal chemistry, and specifically relates to a crystal form of PAC-1 and a preparation method thereof.
  • Cancer is a malignant disease with extremely high morbidity and mortality worldwide and relatively poor treatment effect.
  • anti-tumor drugs have become the largest therapeutic area in the drug market.
  • Currently commonly used anti-tumor drugs include cytotoxic drugs, hormone drugs, molecular targeted therapies, biological response modifiers, tumor differentiation inducers, Tumor angiogenesis inhibitors and drugs for adjuvant treatment of tumors.
  • Chinese Patent Publication CN101184491A and U.S. Patent Publication US2007/0049602A1 disclose to the public the first small molecule compound PAC-1 that directly activates procaspasse-3, and require protection of PAC-1 and PAC-1 derivative library compounds, including those with the ZZ formula, Related compounds of ZZ2, ZZ3, and ZZ4 formulas and their synthesis methods; at the same time, methods for selectively inducing apoptosis in cancer cells, methods for directly screening compounds that can modify procaspasse-3 molecules in vitro and in cells, and identification Or a method for judging the potential sensitivity of cancer cells to treatment with pro-caspase activating compounds, a screening method that can be applied to caspase by identifying elevated levels of pro-caspase in candidate cancer patients The method of the original activator treatment of the candidate is protected.
  • International patent WO2010/091382A1 protects PAC-1, non-neurotoxic compound S-PAC-1 and its analogs.
  • Cipheral Patent Publication CN104910100A discloses an amorphous PAC-1 named ZYS-1, which also mentions a PAC-1 needle crystal in the prior art, and its X-ray powder diffraction (XRPD) pattern is shown in the figure 2 shown.
  • ZYS-1 amorphous PAC-1
  • XRPD X-ray powder diffraction
  • the crystal form refers to the arrangement of molecules in the crystal lattice of a crystalline substance, and the difference between the crystal forms is essentially the difference in the microstructure of the unit cell.
  • Different crystal forms of the same compound may have significant differences in appearance, solubility, melting point, dissolution, bioavailability, etc., which affect the stability, bioavailability and efficacy of the drug. This phenomenon is manifested in oral solid preparations. Especially obvious. Drug polymorphism is one of the important factors affecting the quality and clinical efficacy of drugs, so it is particularly important to pay special attention to the analysis of crystal forms.
  • the purpose of the present invention is to provide a method for preparing PAC-1 crystal form A.
  • a method for preparing PAC-1 crystal form A using an anti-solvent addition method which comprises: dissolving a PAC-1 compound in a normal solvent, and then adding an anti-solvent dropwise, and collecting the obtained solid to obtain PAC-1 crystal Type A.
  • PAC-1 crystal form A is volatilized at room temperature.
  • a method for preparing PAC-1 crystal form A using a suspension stirring method which comprises: adding a solvent to the PAC-1 compound to obtain a suspension, stirring the suspension, and centrifuging the obtained solid to obtain PAC-1 crystal Type A.
  • the method for preparing PAC-1 crystal form A wherein the solvent is selected from a mixed solvent of acetone and water, a mixed solvent of tetrahydrofuran and water, n-propanol and water Mixed solvents, mixed solvents of dimethylformamide and water, mixed solvents of ethanol and water, mixed solvents of acetonitrile and water, mixed solvents of methyl isobutyl ketone and n-heptane, dioxane and n-heptane
  • the solvent is selected from a mixed solvent of acetone and water, a mixed solvent of tetrahydrofuran and water, n-propanol and water Mixed solvents, mixed solvents of dimethylformamide and water, mixed solvents of ethanol and water, mixed solvents of acetonitrile and water, mixed solvents of methyl isobutyl ketone and n-heptane, dioxane and n-heptane
  • a method for preparing PAC-1 crystal form A using a gas-liquid permeation method which comprises: dissolving the PAC-1 compound in a positive solvent to make a clear solution, and opening a container containing the clear solution Place it in a sealed container with an anti-solvent and let it stand still, and collect the precipitated solid to obtain PAC-1 crystal form A.
  • a method for preparing PAC-1 crystal form A using a gas-solid permeation method which comprises: placing an open container containing PAC-1 compound in a sealed container containing a positive solvent, standing still, and taking it out The solid obtained PAC-1 crystal form A.
  • a method for preparing PAC-1 crystal form A using a slow cooling method which comprises: dissolving the PAC-1 compound in a solvent, heating at 30-140°C, filtering the solution after it becomes clear, and removing the filtrate from Slowly lower the temperature from 30 ⁇ 140°C to 0 ⁇ 25°C, and keep it at 0 ⁇ 25°C for 0.1 ⁇ 10 days, then transfer the filtrate to -20 ⁇ -5°C for 0.1 ⁇ 10h, collect the obtained solid to obtain PAC-1 Form A.
  • a method for preparing PAC-1 crystal form A using a slow volatilization method which comprises: placing the PAC-1 compound in a container, and adding a solvent to dissolve the PAC-1 compound in the solvent to prepare a clear solution , Then slowly evaporate, and collect the resulting solid to obtain PAC-1 crystal form A.
  • a method for preparing PAC-1 crystal form A by using a polymer induction method which comprises: dissolving the PAC-1 compound in a positive solvent, adding the polymer, stirring and turning to volatilization, and collecting the resultant The solid obtained PAC-1 crystal form A.
  • a method for preparing PAC-1 crystal form A using a humidity induction method which comprises: placing a container containing PAC-1 compound in a desiccator with a humidity of 5-100%, and collecting it after 0.1-10 days The solid obtained PAC-1 crystal form A.
  • the method for preparing PAC-1 crystal form A according to item 32 which comprises: placing a container containing the PAC-1 compound in a desiccator with a humidity of 45% to 100%, and collecting the solid after 7 days PAC-1 crystal form A was obtained.
  • a method for preparing PAC-1 crystal form A by applying a grinding-to-crystal method which comprises: grinding the PAC-1 compound at 5-50° C. for 1 to 80 minutes to obtain PAC-1 crystal form A .
  • the preparation method of the PAC-1 crystal form A provided by the invention is simple, stable, and has strong operability, is suitable for industrial production, and the obtained PAC-1 crystal form A has high stability.
  • PAC-1 refers to a small molecule compound that can directly activate Procaspase-3, and its chemical name is 1-Piperazineacetic acid, 4-(phenylmethyl)-2 -[[2-hydroxy-3-(2-propen-1-yl)phenyl]methylene]((E)-N'-(3-allyl-2-hydroxybenzylidene)-2-(4 -Benzylpiperazin-1-yl)acethydrazine), with the structure shown in formula 1, which is believed to be able to selectively induce tumor cell apoptosis, and thus can be used as an antitumor drug.
  • Thermogravimetric Analysis refers to a thermal analysis technique that measures the relationship between the quality of the sample to be tested and the temperature change under program control temperature, and is used to study the thermal stability and composition of materials. TGA is a commonly used testing method in R&D and quality control. Thermogravimetric analysis is often used in combination with other analysis methods in actual material analysis to conduct comprehensive thermal analysis and analyze materials comprehensively and accurately. The curve recorded by the thermogravimetric analyzer is called the TGA curve.
  • Differential scanning calorimetry under the control of a temperature program, is a technique for measuring the heat flow rate of a sample relative to a reference with temperature or time.
  • the curve recorded by the differential scanning calorimeter is called the DSC curve.
  • W/g or mW/mg that is, the power per gram of sample
  • T or time t the abscissa.
  • Thermodynamic and kinetic parameters such as specific heat capacity, heat of reaction, heat of transition, phase diagram, reaction rate, crystallization rate, polymer crystallinity, sample purity, etc.
  • the method uses a wide temperature range (-175 ⁇ 725°C), high resolution, and small sample amount. It is suitable for the analysis of inorganic substances, organic compounds and drugs.
  • the PAC-1 crystal form of the present invention is named PAC-1 crystal form A, and its X-ray powder diffraction (XRPD) pattern is shown in FIG. 1.
  • XRPD X-ray powder diffraction
  • the PAC-1 crystal form A produced by the present invention is an amorphous type.
  • an anti-solvent addition method a suspension stirring method, a gas-liquid infiltration method, a gas-solid infiltration method, a slow cooling method, a slow volatilization method, a polymer induction method, a humidity induction method, and a grinding crystal conversion method can be used to prepare PAC-1 Form A.
  • the present invention uses the anti-solvent addition method to prepare PAC-1 crystal form A.
  • the anti-solvent addition method is to combine the positive solvent and the anti-solvent to reduce the solubility of the crystallized substance in the solvent.
  • the dissolved material to be crystallized is mixed with the anti-solvent around the transition temperature. Since the anti-solvent is combined with water, the solubility of the crystallized substance is reduced, so that the crystallized substance is precipitated, and the crystallized substance is obtained by filtration.
  • the method for preparing PAC-1 crystal form A using the anti-solvent addition method includes: dissolving the PAC-1 compound in a normal solvent, then adding the anti-solvent dropwise, and collecting the obtained solid to obtain PAC-1 Crystal form.
  • the anti-solvent addition method is used to prepare PAC-1 crystal form A, and the normal solvent is selected from methanol, acetone, tetrahydrofuran, dioxane, acetonitrile, ethanol, methyl ethyl ketone, and ethyl acetate. , 2-methyltetrahydrofuran, anisole, dichloromethane, toluene, acetone, dimethylacetamide, any one or a combination of any several, the anti-solvent is selected from water, n-heptane, cyclopentane Any one or a combination of any of the methyl ether.
  • the present invention applies the suspension stirring method to prepare PAC-1 crystal form A. Specifically, a solvent is added to the raw material sample to obtain a suspension, and the suspension is placed at room temperature or 25-100° C. and stirred for 0.1-10 days, and the obtained solid is collected by centrifugation to obtain PAC-1 crystal form A.
  • the suspension stirring method is used to prepare PAC-1 crystal form A, a solvent is added to the raw material sample to obtain a suspension, and the solvent is selected from ethanol, isopropanol, ethyl acetate, and methyl tert-butyl.
  • the obtained suspension is stirred at room temperature for 0.1 to 10 days, preferably for 6 days, and the obtained solid is collected by centrifugation to obtain PAC-1 crystal form A.
  • the solvent is a mixed solvent of methanol and water, and the volume ratio of the mixed solvent of methanol and water is methanol: water is 1:1.3 to 1:14; in any other mixed solvent, two solvents The volume ratio
  • the suspension stirring method is used to prepare PAC-1 crystal form A, and a solvent is added to the raw material sample to obtain a suspension.
  • the solvent is selected from a mixed solvent of dioxane and n-heptane, chloroform and n-heptane Alkane mixed solvent, isobutanol, isobutyl acetate, cyclopentyl methyl ether, methyl tert-butyl ether, acetone and n-heptane mixed solvent, isopropanol and n-heptane mixed solvent, acetonitrile and water Any one or a combination of any one of the mixed solvent of dioxane and water, or any combination of several, the suspension is placed at 50°C and stirred for 0.1-10 days, preferably 6 days, the resulting solid is collected by centrifugation and dried , Get PAC-1 crystal form A.
  • the present invention applies the gas-liquid permeation method to prepare PAC-1 crystal form A.
  • the raw material sample is dissolved in a positive solvent to make a clear solution, and the container with the clear solution is placed in a sealed container with an anti-solvent, and it is allowed to stand at room temperature to collect the precipitated solid to obtain PAC-1 crystal form A.
  • the gas-liquid permeation method is used to prepare PAC-1 crystal form A
  • the normal solvent is selected from ethanol, methyl ethyl ketone, 2-methyltetrahydrofuran, N-methylpyrrolidone, and n-propanol.
  • the anti-solvent is selected from any one of water and n-heptane.
  • the present invention uses gas-solid infiltration method to prepare PAC-1 crystal form A. Specifically, the container containing the raw material sample is placed in a sealed container containing a positive solvent, and left standing at room temperature, and the solid is taken out to obtain PAC-1 crystal form A.
  • the gas-solid permeation method is used to prepare PAC-1 crystal form A
  • the positive solvent is preferably ethanol and acetone.
  • the present invention uses a slow cooling method to prepare PAC-1 crystal form A.
  • the raw material sample is dissolved in a solvent, heated at 30-140°C, preferably 50°C, the heated solution becomes clear and filtered, and then the filtrate is slowly cooled to 0-25°C, preferably 5°C, and the cooling rate is controlled.
  • a slow cooling method is used to prepare PAC-1 crystal form A, and the solvent is selected from isopropanol, methyl tert-butyl ether, butyl acetate, a mixed solvent of alcohol and water, tetrahydrofuran and water Any one or a combination of any of the mixed solvent of, the mixed solvent of anisole and n-heptane, and the mixed solvent of acetonitrile and n-heptane.
  • the present invention applies the slow volatilization method to prepare PAC-1 crystal form A.
  • the raw material sample is placed in a container, and a solvent is added to dissolve it to prepare a clear solution, which is placed at room temperature to slowly volatilize, and the obtained solid is collected to obtain PAC-1 crystal form A.
  • a sealing film is used to seal the container containing the clear solution, and the sealing film has small holes.
  • a slow volatilization method is used to prepare PAC-1 crystal form A, and the solvent is selected from methanol, ethanol, ethyl acetate, acetone, methyl ethyl ketone, tetrahydrofuran, toluene, acetonitrile, and methylene chloride. , Chloroform, methyl tert-butyl ether, acetic acid or any combination of several.
  • the present invention uses a polymer induction method to prepare PAC-1 crystal form A. Specifically, a raw material sample is dissolved in a solvent, and a polymer is added. After stirring at room temperature for 0.1 to 12 hours, preferably after 2 hours, it is converted to volatilization, and the precipitated solid is collected to obtain PAC-1 crystal form A.
  • a polymer induction method is used to prepare PAC-1 crystal form A, and the polymer is selected from polyvinyl chloride, polyvinyl alcohol, polyvinyl acetate, methyl cellulose, and polyvinylpyrrolidone , Hydroxypropyl methylcellulose, etc.; the solvent is selected from any one or a combination of any of methanol, ethanol, acetone, and tetrahydrofuran.
  • the present invention uses the humidity induction method to prepare PAC-1 crystal form A. Specifically, the raw material sample is placed in a desiccator with a humidity of 45%-100%, and after 0.1-10 days, preferably 7 days later, the PAC-1 crystal form A is collected.
  • the humidity induction method is used to prepare PAC-1 crystal form A.
  • the container containing the raw material sample is sealed with a sealing film first, and the sealing film has small holes, and then the raw material sample The container is placed in a desiccator.
  • the present invention applies the grinding and crystal transformation method to prepare PAC-1 crystal form A. Specifically, the raw material sample is ground at 5-50° C. for 1-80 minutes to obtain PAC-1 crystal form A.
  • the anti-solvent addition method suspension stirring method, gas-liquid infiltration method, gas-solid infiltration method, slow cooling method, slow volatilization method, polymer induction method, humidity induction method, grinding and crystal conversion method of the present invention
  • the obtained PAC-1 crystal form A is dried.
  • Anti-solvent addition method Weigh about 20 mg of each sample into a 20-ml vial, dissolve it with a certain amount of positive solvent, add the corresponding anti-solvent in the table below to the clear solution dropwise, and stir while adding dropwise When a solid precipitated, the obtained solid was dried.
  • the solids finally obtained in the examples in Table 1 are respectively labeled as solids 1-1 to 1-14, and the precipitated solids are subjected to XRPD detection, and they are all crystal form A.
  • Suspension stirring method Weigh about 15 mg of each sample into a vial, add 0.3 ml of the solvents listed in the table below, and place the resulting suspension at room temperature and 50°C and stir for 6 days. Centrifuge to collect the solid and dry .
  • the solids finally obtained in the examples in Table 2 are marked as solids 2-1 to 2-27, and the obtained solids are subjected to XRPD detection, and they are all crystal form A.
  • Gas-liquid permeation method Weigh approximately 20 mg of each sample and dissolve it in a certain amount of solvent, place it in a 3 ml vial, take another 20 ml vial and add about 3 ml of anti-solvent to it, and open the 3 ml vial. The mouth is placed in a 20 ml vial, sealed and allowed to stand at room temperature, and the obtained solid is dried after the solid has separated out.
  • the solids finally obtained in the examples in Table 3 are marked as solids 3-1 to 3-12, and XRPD detection is performed, and they are all crystal form A.
  • Slow cooling method Weigh approximately 20 mg of each sample into a 3 ml vial, add 0.8 ml of the solvent in the table below, and place the sample in an oven at 50°C for 1 hour. If it becomes clear after heating and dissolving, then filter. The clear solution was cooled from 50°C to 5°C at a rate of 0.1°C/min, and kept at 5°C for 5 days, then the clear sample was transferred to -20°C, placed for 1 hour, and the obtained solid was collected and dried. The solids finally obtained in this example in Table 4 are marked as solids 4-1 to 4-7, and tested, and they are all crystal form A.
  • Polymer induction method Weigh about 20 mg of each sample into a vial, add about 2 mg of the polymer in the table below and 0.5 ml of solvent, stir at room temperature for 2 hours and then turn to volatilization, and collect after volatilization at room temperature A solid precipitated and dried.
  • the solids finally obtained in this example in Table 6 are marked as solids 6-1 to 6-6, and tested, and they are all crystal form A.
  • Humidity induction method Weigh 15 mg of sample into a vial, then seal 4 small holes with parafilm and place it in a desiccator corresponding to humidity. Collect the solid after 7 days and dry it. The solids finally obtained in this example in Table 7 are marked as solids 7-1 to 7-4, respectively, and tested, and crystal form A is obtained.
  • the X-ray powder diffraction pattern of PAC-1 crystal form A expressed by 2 ⁇ diffraction angles is 5.46 ⁇ 0.2°, 8.92 ⁇ 0.2°, 10.14 ⁇ 0.2°, 15.76 ⁇ 0.2°, 17.14 ⁇ 0.2°, 17.82 ⁇ 0.2° , 18.27 ⁇ 0.2°, 18.90 ⁇ 0.2°, 19.43 ⁇ 0.2°, 20.37 ⁇ 0.2°, 21.48 ⁇ 0.2°, 21.80 ⁇ 0.2° and 26.06 ⁇ 0.2° show characteristic peaks.
  • the X-ray powder diffraction pattern of PAC-1 crystal form A expressed in 2 ⁇ diffraction angles is 5.46 ⁇ 0.2°, 8.92 ⁇ 0.2°, 10.14 ⁇ 0.2°, 11.24 ⁇ 0.2°, 11.91 ⁇ 0.2°, 14.04 ⁇ 0.2° ⁇ 14.53 ⁇ 0.2° ⁇ 16.34 ⁇ 0.2° ⁇ 15.76 ⁇ 0.2° ⁇ 17.14 ⁇ 0.2° ⁇ 17.82 ⁇ 0.2° ⁇ 18.27 ⁇ 0.2° ⁇ 18.90 ⁇ 0.2° ⁇ 19.43 ⁇ 0.2° ⁇ 20.37 ⁇ 0.2° ⁇ 20.96 ⁇ 0.2° , 21.48 ⁇ 0.2°, 21.80 ⁇ 0.2°, 22.52 ⁇ 0.2°, 22.94 ⁇ 0.2°, 23.47 ⁇ 0.2°, 24.00 ⁇ 0.2°, 25.62 ⁇ 0.2°, 26.06 ⁇ 0.2°, 26.84 ⁇ 0.2°, 27.16 ⁇ 0.2° , 27.60 ⁇ 0.2°, 27.90 ⁇ 0.2°, 28.99 ⁇ 0.2°, 29.31 ⁇ 0.2°, 29.98 ⁇ 0.2°, 30.66 ⁇ 0.2°, 32.09 ⁇ 0.2°,
  • the measurement accuracy of the 2 ⁇ angle is ⁇ 0.2°, so each characteristic peak of the above-mentioned crystal form is within the range of the peak ⁇ 0.2° for its error tolerance.
  • FIG. 1 X-ray powder diffraction pattern of PAC-1 crystal form A of the present invention is shown in FIG. 1.
  • thermogravimetric analysis was performed on the PAC-1 crystal form A prepared in Examples 1-9.
  • the differential scanning calorimetry DSC curve of this crystal form shows a single dominant endotherm in the temperature range of 130°C to 140°C.
  • the melting point of the sample is 136.2°C
  • the peak endothermic peak is 137.3°C ⁇ 2°C
  • the peak area is- 94.54J/g.
  • the value of X-ray powder diffraction may be similar to the value of X-ray powder diffraction.
  • the value quoted by the differential scanning calorimetry technique cannot be interpreted as an absolute value.
  • the temperature measurement accuracy is ⁇ 2°C. Therefore, the endothermic peak of the above crystal form The peak value is within the range of ⁇ 2°C for its error tolerance.
  • the TGA curve of PAC-1 crystal form A shows that the crystal form A has a weight loss of about 2.03% at 120°C and has high thermal stability.
  • the present invention measured the solubility of PAC-1 crystal form A prepared in Examples 1-9.
  • PAC-1 crystal form A prepared in each example put an appropriate amount of about 20 mg of the PAC-1 crystal form A solid into the vial, and then divide into four steps (respectively 50, 50, 200, 700 ml) Shake after adding the corresponding solvent, and stop if the solid is dissolved.
  • the rough solubility of PAC-1 crystal form A prepared in Examples 1-9 at room temperature is shown in Table 10 below.

Abstract

The present invention provides a preparation method for a crystal form of PAC-1 . The crystal form A of PAC-1 provided in the present invention, by using CuKα radiation and an X-ray powder diffractogram represented with 2θ diffraction angles, shows characteristic peaks at 8.92 ± 0.2°, 17.14 ± 0.2°, 17.82 ± 0.2°, 18.90 ± 0.2°, 20.37 ± 0.2°, and 26.06 ± 0.2°. The crystal form A of PAC-1 of the present invention can be prepared by using an anti-solvent addition method, a suspension stirring method, a gas-liquid permeation method, a gas-solid permeation method, a slow cooling method, a slow volatilization method, a high polymer induction method, a humidity induction method or a grinding and recrystallization method. The crystal form A of PAC-1 of the present invention is suitable for industrial application in pharmacy. The crystal form has good solubility, and can improve the efficacy of a product. Moreover, the preparation process is simple and stable, has strong operability, and is suitable for industrial production. The crystal form has high stability.

Description

PAC-1晶型的制备方法Preparation method of PAC-1 crystal form 技术领域Technical field
本发明属于药物化学技术领域，具体涉及PAC-1的一种晶型及其制备方法。The invention belongs to the technical field of medicinal chemistry, and specifically relates to a crystal form of PAC-1 and a preparation method thereof.
背景技术Background technique
癌症是世界范围内发病率及死亡率极高、治疗效果相对较差的一种恶性疾病。在全球范围内，抗肿瘤药已成为用药市场的第一大治疗领域，目前常用的抗肿瘤药包括细胞毒类药物、激素药、分子靶向治疗药、生物反应调节剂、肿瘤分化诱导剂、肿瘤血管生成抑制剂以及辅助***的药物等。Cancer is a malignant disease with extremely high morbidity and mortality worldwide and relatively poor treatment effect. Globally, anti-tumor drugs have become the largest therapeutic area in the drug market. Currently commonly used anti-tumor drugs include cytotoxic drugs, hormone drugs, molecular targeted therapies, biological response modifiers, tumor differentiation inducers, Tumor angiogenesis inhibitors and drugs for adjuvant treatment of tumors.
美国伊利诺伊大学Quinn P.Peterson教授在对20000多种化合物进行体外筛选中，发现的第一个能够直接激活半胱天冬酶-3酶原(procaspasse-3)的小分子化合物，(E)-N’-(3-烯丙基-2-羟基苯亚甲基)-2-(4-苄基哌嗪-1-基)乙酰肼，命名为PAC-1，化学式为C 23H 28N 4O 2，结构如式1。研究证明，PAC-1能够选择性诱导肿瘤细胞发生凋亡，且其诱导凋亡作用与细胞内的procaspasse-3水平呈正相关，而正常细胞的procaspasse-3含量较低，对其杀伤能力就较小，具备了较好的选择性，主要用于治疗肺癌、乳腺癌、胃肠癌等恶性肿瘤。研究表明，其主要是通过螯合抑制锌离子，使半胱天冬酶-3酶原(procaspasse-3)自体活化为半胱天冬酶-3(caspase-3)，诱导细胞凋亡(Quinn P,et al.,J Mol Biol,2009,388(1):144-158.；Peterson Q P,etal.J Med Chem,2009,52(18):5721-5731.)，同时它对多种肿瘤细胞均具有诱导凋亡的作用。近期亦有研究显示，高浓度的PAC-1能够从内质网细胞凋亡途径诱导细胞凋亡，表现出独特细胞凋亡的作用特点(West DC,et al.Mol Pharm.2012,9(5):1425-1434)。 In the in vitro screening of more than 20,000 compounds, Professor Quinn P. Peterson of the University of Illinois in the United States discovered the first small molecule compound that can directly activate procaspasse-3. (E)- N'-(3-allyl-2-hydroxybenzylidene)-2-(4-benzylpiperazin-1-yl)acethydrazine, named PAC-1, chemical formula is C 23 H 28 N 4 O 2 , the structure is as formula 1. Studies have shown that PAC-1 can selectively induce tumor cell apoptosis, and its apoptosis-inducing effect is positively correlated with the level of procaspasse-3 in the cell, while the content of procaspasse-3 in normal cells is lower and its killing ability is better. It is small and has good selectivity. It is mainly used to treat malignant tumors such as lung cancer, breast cancer and gastrointestinal cancer. Studies have shown that it mainly inhibits zinc ions through chelation, autoactivates procaspasse-3 (procaspase-3) into caspase-3 (caspase-3), and induces apoptosis (Quinn P, et al., J Mol Biol, 2009, 388(1): 144-158.; Peterson QP, et al. J Med Chem, 2009, 52(18): 5721-5731.), at the same time it affects a variety of tumors The cells all have the effect of inducing apoptosis. Recent studies have also shown that high concentrations of PAC-1 can induce apoptosis from the endoplasmic reticulum cell apoptosis pathway, showing unique characteristics of apoptosis (West DC, et al. Mol Pharm. 2012, 9(5) ):1425-1434).
Figure PCTCN2020094138-appb-000001
Figure PCTCN2020094138-appb-000001
Figure PCTCN2020094138-appb-000002
Figure PCTCN2020094138-appb-000002
中国专利公开CN101184491A及美国专利公开US2007/0049602A1向大众公开第一个直接激活procaspasse-3的小分子化合物PAC-1，并要求保护PAC-1、PAC-1衍生物文库化合物，包括具有ZZ式、ZZ2式、ZZ3式、ZZ4式的相关化合物及其合成方法；同时对其在癌细胞中选择性诱导细胞凋亡的方法、体外及细胞内直接筛选能修饰procaspasse-3分子的化合物的方法、鉴定或判断癌细胞对于半胱天冬蛋白酶酶原活化化合物处理的潜在敏感性的方法、一种通过鉴定候选癌症患者体内半胱天冬酶原的升高水平来筛选可适用于半胱天冬酶原活化剂治疗的所述候选者的方法进行了保护。国际专利WO2010/091382A1对PAC-1、无神经毒性化合物S-PAC-1及其类似物进行保护。Chinese Patent Publication CN101184491A and U.S. Patent Publication US2007/0049602A1 disclose to the public the first small molecule compound PAC-1 that directly activates procaspasse-3, and require protection of PAC-1 and PAC-1 derivative library compounds, including those with the ZZ formula, Related compounds of ZZ2, ZZ3, and ZZ4 formulas and their synthesis methods; at the same time, methods for selectively inducing apoptosis in cancer cells, methods for directly screening compounds that can modify procaspasse-3 molecules in vitro and in cells, and identification Or a method for judging the potential sensitivity of cancer cells to treatment with pro-caspase activating compounds, a screening method that can be applied to caspase by identifying elevated levels of pro-caspase in candidate cancer patients The method of the original activator treatment of the candidate is protected. International patent WO2010/091382A1 protects PAC-1, non-neurotoxic compound S-PAC-1 and its analogs.
中国专利公开CN104910100A中公开了一种无定形的PAC-1，命名为ZYS-1，其中还提及现有技术中的一种PAC-1针晶，其X射线粉末衍射(XRPD)图谱如图2所示。Chinese Patent Publication CN104910100A discloses an amorphous PAC-1 named ZYS-1, which also mentions a PAC-1 needle crystal in the prior art, and its X-ray powder diffraction (XRPD) pattern is shown in the figure 2 shown.
晶型是指结晶物质晶格内分子的排列形式，晶型之间的差异实质上是晶胞微观结构上的差异。同一化合物的不同晶型在外观、溶解度、熔点、溶出度、生物有效性等方面可能会有显著不同，从而影响了药物的稳定性、生物利用度及疗效，该现象在口服固体制剂方面表现得尤为明显。药物多晶型现象是影响药品质量与临床疗效的重要因素之一，因此对晶型分析予以特别关注就显得尤为重要。The crystal form refers to the arrangement of molecules in the crystal lattice of a crystalline substance, and the difference between the crystal forms is essentially the difference in the microstructure of the unit cell. Different crystal forms of the same compound may have significant differences in appearance, solubility, melting point, dissolution, bioavailability, etc., which affect the stability, bioavailability and efficacy of the drug. This phenomenon is manifested in oral solid preparations. Especially obvious. Drug polymorphism is one of the important factors affecting the quality and clinical efficacy of drugs, so it is particularly important to pay special attention to the analysis of crystal forms.
发明内容Summary of the invention
本发明的目的是提供PAC-1晶型A的制备方法。The purpose of the present invention is to provide a method for preparing PAC-1 crystal form A.
本发明的技术方案如下：The technical scheme of the present invention is as follows:
1.一种应用反溶剂添加法制备PAC-1晶型A的方法，其中，其包括：将PAC-1化合物溶解在正溶剂中，再逐滴添加反溶剂，收集所得固体得到PAC-1晶型A。1. A method for preparing PAC-1 crystal form A using an anti-solvent addition method, which comprises: dissolving a PAC-1 compound in a normal solvent, and then adding an anti-solvent dropwise, and collecting the obtained solid to obtain PAC-1 crystal Type A.
2.根据项1所述的制备PAC-1晶型A的方法，其中，所述正溶剂选自甲醇、丙酮、四氢呋喃、二恶烷、乙腈、乙醇、甲基乙基酮、乙酸乙酯、2-甲基四氢呋喃、苯甲醚、二氯甲烷、甲苯、丙酮、二甲基乙酰胺中任意一种 或为任意几种的组合。2. The method for preparing PAC-1 crystal form A according to item 1, wherein the normal solvent is selected from methanol, acetone, tetrahydrofuran, dioxane, acetonitrile, ethanol, methyl ethyl ketone, ethyl acetate, Any one or a combination of 2-methyltetrahydrofuran, anisole, dichloromethane, toluene, acetone, and dimethylacetamide.
3.根据项1或2所述的制备PAC-1晶型A的方法，其中，所述反溶剂选自水、正庚烷、环戊基甲醚中的任意一种或为任意几种的组合。3. The method for preparing PAC-1 crystal form A according to item 1 or 2, wherein the anti-solvent is selected from any one or several of water, n-heptane and cyclopentyl methyl ether combination.
4.根据项1所述的制备PAC-1晶型A的方法，其中，在室温条件下析出固体制备所述PAC-1晶型A。4. The method for preparing PAC-1 crystal form A according to item 1, wherein a solid is precipitated at room temperature to prepare the PAC-1 crystal form A.
5.根据项1～3中任一项所述的制备PAC-1晶型A的方法，其中，5. The method for preparing PAC-1 crystal form A according to any one of items 1 to 3, wherein:
当所述正溶剂为甲苯，反溶剂为正庚烷时，在-20℃条件下析出固体得到PAC-1晶型A；或者When the normal solvent is toluene and the anti-solvent is n-heptane, a solid is precipitated at -20°C to obtain PAC-1 crystal form A; or
当所述正溶剂为丙酮或二甲基乙酰胺，反溶剂为环戊基甲醚时，在室温下挥发得到PAC-1晶型A。When the positive solvent is acetone or dimethylacetamide, and the anti-solvent is cyclopentyl methyl ether, PAC-1 crystal form A is volatilized at room temperature.
6.一种应用悬浮搅拌法制备PAC-1晶型A的方法，其中，其包括：在PAC-1化合物中加入溶剂得到悬浮液，搅拌所述悬浮液，离心收集所得固体得到PAC-1晶型A。6. A method for preparing PAC-1 crystal form A using a suspension stirring method, which comprises: adding a solvent to the PAC-1 compound to obtain a suspension, stirring the suspension, and centrifuging the obtained solid to obtain PAC-1 crystal Type A.
7.根据项6所述的制备PAC-1晶型A的方法，其中，所述溶剂选自乙醇、异丙醇、乙酸乙酯、甲基叔丁基醚、乙腈、水、甲醇与水的混合溶剂、丙酮与水的混合溶剂、四氢呋喃与水的混合溶剂、正丙醇与水的混合溶剂、二甲基甲酰胺与水的混合溶剂、乙醇与水的混合溶剂、乙腈与水的混合溶剂、甲基异丁基酮与正庚烷的混合溶剂、二恶烷与正庚烷的混合溶剂、氯仿与正庚烷的混合溶剂、异丁醇、乙酸异丁酯、环戊基甲醚、甲基叔丁基醚、丙酮与正庚烷的混合溶剂、异丙醇与正庚烷的混合溶剂、二恶烷与水的混合溶剂中的任意一种或为任意几种的组合。7. The method for preparing PAC-1 crystal form A according to item 6, wherein the solvent is selected from the group consisting of ethanol, isopropanol, ethyl acetate, methyl tert-butyl ether, acetonitrile, water, methanol and water Mixed solvent, mixed solvent of acetone and water, mixed solvent of tetrahydrofuran and water, mixed solvent of n-propanol and water, mixed solvent of dimethylformamide and water, mixed solvent of ethanol and water, mixed solvent of acetonitrile and water , Methyl isobutyl ketone and n-heptane mixed solvent, dioxane and n-heptane mixed solvent, chloroform and n-heptane mixed solvent, isobutanol, isobutyl acetate, cyclopentyl methyl ether, Any one or a combination of methyl tert-butyl ether, a mixed solvent of acetone and n-heptane, a mixed solvent of isopropanol and n-heptane, and a mixed solvent of dioxane and water.
8.根据项6或7所述的制备PAC-1晶型A的方法，其中，在25～100℃条件下搅拌所述悬浮液0.1～10天。8. The method for preparing PAC-1 crystal form A according to item 6 or 7, wherein the suspension is stirred at 25-100°C for 0.1-10 days.
9.根据项6～8中任一项所述的制备PAC-1晶型A的方法，其中，在室温或50℃下搅拌所述悬浮液6天。9. The method for preparing PAC-1 crystal form A according to any one of items 6 to 8, wherein the suspension is stirred at room temperature or 50°C for 6 days.
10.根据项7～9中任一项所述的制备PAC-1晶型A的方法，其中，所述溶剂为甲醇与水的混合溶剂，且所述甲醇与水的混合溶剂的体积比为甲醇：水为1:1.3～1:14。10. The method for preparing PAC-1 crystal form A according to any one of items 7 to 9, wherein the solvent is a mixed solvent of methanol and water, and the volume ratio of the mixed solvent of methanol and water is Methanol: water is 1:1.3 to 1:14.
11.根据项7～9中任一项所述的制备PAC-1晶型A的方法，其中，所述溶剂选自丙酮与水的混合溶剂、四氢呋喃与水的混合溶剂、正丙醇与水的 混合溶剂、二甲基甲酰胺与水的混合溶剂、乙醇与水的混合溶剂、乙腈与水的混合溶剂、甲基异丁基酮与正庚烷的混合溶剂、二恶烷与正庚烷的混合溶剂、氯仿与正庚烷的混合溶剂、丙酮与正庚烷的混合溶剂、异丙醇与正庚烷的混合溶剂、二噁烷与水的混合溶剂中的任一种混合溶剂时，用于形成混合溶剂的两种溶剂的体积比为1:1。11. The method for preparing PAC-1 crystal form A according to any one of items 7 to 9, wherein the solvent is selected from a mixed solvent of acetone and water, a mixed solvent of tetrahydrofuran and water, n-propanol and water Mixed solvents, mixed solvents of dimethylformamide and water, mixed solvents of ethanol and water, mixed solvents of acetonitrile and water, mixed solvents of methyl isobutyl ketone and n-heptane, dioxane and n-heptane When any one of the mixed solvent of the mixed solvent of chloroform and n-heptane, the mixed solvent of acetone and n-heptane, the mixed solvent of isopropanol and n-heptane, the mixed solvent of dioxane and water, The volume ratio of the two solvents used to form the mixed solvent is 1:1.
12.一种应用气液渗透法制备PAC-1晶型A的方法，其中，其包括：将PAC-1化合物溶解在正溶剂中，制成澄清溶液，并将装有澄清溶液的容器敞口放置在装有反溶剂的密封容器中静置，收集析出的固体得到PAC-1晶型A。12. A method for preparing PAC-1 crystal form A using a gas-liquid permeation method, which comprises: dissolving the PAC-1 compound in a positive solvent to make a clear solution, and opening a container containing the clear solution Place it in a sealed container with an anti-solvent and let it stand still, and collect the precipitated solid to obtain PAC-1 crystal form A.
13.根据项12所述的制备PAC-1晶型A的方法，其中，所述正溶剂选自乙醇、甲基乙基酮、2-甲基四氢呋喃、N-甲基吡咯烷酮、正丙醇、二噁烷、甲苯、乙酸异丙酯、二氯甲烷、丙酮、四氢呋喃、乙腈中的任意一种或为任意几种的组合。13. The method for preparing PAC-1 crystal form A according to item 12, wherein the normal solvent is selected from ethanol, methyl ethyl ketone, 2-methyltetrahydrofuran, N-methylpyrrolidone, n-propanol, Any one or a combination of any of dioxane, toluene, isopropyl acetate, dichloromethane, acetone, tetrahydrofuran, and acetonitrile.
14.根据项12或13所述的制备PAC-1晶型A的方法，其中，所述反溶剂选自水、正庚烷中的任意一种或为任意几种的组合。14. The method for preparing PAC-1 crystal form A according to item 12 or 13, wherein the anti-solvent is selected from any one of water and n-heptane or a combination of any of them.
15.根据项12～14中任一项所述的制备PAC-1晶型A的方法，其中，在室温下，将装有澄清溶液的容器敞口放置在装有反溶剂的密封装置中静置。15. The method for preparing PAC-1 crystal form A according to any one of items 12 to 14, wherein the container containing the clear solution is placed in a sealed device containing an anti-solvent at room temperature. Set.
16.一种应用气固渗透法制备PAC-1晶型A的方法，其中，其包括：将装有PAC-1化合物的敞口容器放置在装有正溶剂的密封容器中，静置，取出固体得到PAC-1晶型A。16. A method for preparing PAC-1 crystal form A using a gas-solid permeation method, which comprises: placing an open container containing PAC-1 compound in a sealed container containing a positive solvent, standing still, and taking it out The solid obtained PAC-1 crystal form A.
17.根据项16所述的制备PAC-1晶型A的方法，其中，所述正溶剂选自甲醇、乙醇、异丙醇、丙酮、乙腈、二氯甲烷、三氯甲烷、四氢呋喃、1，4-二氧六环、乙酸乙酯、甲苯、二甲基亚砜、N,N-二甲基甲酰胺中任意一种或为任意几种的组合。17. The method for preparing PAC-1 crystal form A according to item 16, wherein the normal solvent is selected from methanol, ethanol, isopropanol, acetone, acetonitrile, dichloromethane, chloroform, tetrahydrofuran, 1, Any one or a combination of 4-dioxane, ethyl acetate, toluene, dimethyl sulfoxide, N,N-dimethylformamide.
18.根据项16或17所述的制备PAC-1晶型A的方法，其中，将装有PAC-1化合物的敞口容器放置在装有正溶剂的密封容器中，在室温条件下静置。18. The method for preparing PAC-1 crystal form A according to item 16 or 17, wherein the open container filled with the PAC-1 compound is placed in a sealed container filled with a positive solvent and left standing at room temperature .
19.一种应用缓慢降温法制备PAC-1晶型A的方法，其中，其包括：将PAC-1化合物溶解在溶剂中，在30～140℃下加热，溶液变澄清后过滤，将 滤液从30～140℃缓慢降温至0～25℃，并在0～25℃恒温放置0.1～10天，随后将滤液转移至-20～-5℃条件，放置0.1～10h，收集所得固体得到PAC-1晶型A。19. A method for preparing PAC-1 crystal form A using a slow cooling method, which comprises: dissolving the PAC-1 compound in a solvent, heating at 30-140°C, filtering the solution after it becomes clear, and removing the filtrate from Slowly lower the temperature from 30～140℃ to 0～25℃, and keep it at 0～25℃ for 0.1～10 days, then transfer the filtrate to -20～-5℃ for 0.1～10h, collect the obtained solid to obtain PAC-1 Form A.
20.根据项19所述的制备PAC-1晶型A的方法，其中，其包括：将PAC-1化合物溶解在溶剂中，在50℃下加热，溶液变澄清后过滤，将滤液从50℃缓慢降温至5℃，并在5℃恒温放置5天，随后将滤液转移至-20℃，放置1h，收集所得固体得到PAC-1晶型A。20. The method for preparing PAC-1 crystal form A according to item 19, wherein it comprises: dissolving the PAC-1 compound in a solvent, heating at 50°C, filtering the solution after it becomes clear, and removing the filtrate from 50°C Slowly lower the temperature to 5°C, and keep it at 5°C for 5 days, then transfer the filtrate to -20°C, place for 1 hour, and collect the resulting solid to obtain PAC-1 crystal form A.
21.根据项19或20所述的制备PAC-1晶型A的方法，其中，所述缓慢降温的速率为0.1～20℃/分钟，优选0.1℃/分钟。21. The method for preparing PAC-1 crystal form A according to item 19 or 20, wherein the slow cooling rate is 0.1-20°C/min, preferably 0.1°C/min.
22.根据项19～21中任一项所述的制备PAC-1晶型A的方法，其中，所述缓慢降温的速率为0.1℃/分钟。22. The method for preparing PAC-1 crystal form A according to any one of items 19 to 21, wherein the slow cooling rate is 0.1° C./min.
23.根据项19～22中任一项所述的制备PAC-1晶型A的方法，其中，所述溶剂选自异丙醇、甲基叔丁基醚、乙酸丁酯、酒精与水的混合溶剂、四氢呋喃与水的混合溶剂、苯甲醚与正庚烷的混合溶剂、乙腈与正庚烷的混合溶剂中的任意一种或为任意几种的组合。23. The method for preparing PAC-1 crystal form A according to any one of items 19-22, wherein the solvent is selected from isopropanol, methyl tert-butyl ether, butyl acetate, alcohol and water Any one or a combination of a mixed solvent, a mixed solvent of tetrahydrofuran and water, a mixed solvent of anisole and n-heptane, and a mixed solvent of acetonitrile and n-heptane.
24.一种应用缓慢挥发法制备PAC-1晶型A的方法，其中，其包括：将PAC-1化合物置于容器中，并加入溶剂使PAC-1化合物溶解在溶剂中，配制成澄清溶液，随后缓慢挥发，收集所得固体得到PAC-1晶型A。24. A method for preparing PAC-1 crystal form A using a slow volatilization method, which comprises: placing the PAC-1 compound in a container, and adding a solvent to dissolve the PAC-1 compound in the solvent to prepare a clear solution , Then slowly evaporate, and collect the resulting solid to obtain PAC-1 crystal form A.
25.根据项24所述的制备PAC-1晶型A的方法，其中，所述溶剂选自甲醇、乙醇、乙酸乙酯、丙酮、甲基乙基酮、四氢呋喃、甲苯、乙腈、二氯甲烷、氯仿、甲基叔丁基醚、乙酸中的任意一种或为任意几种的组合。25. The method for preparing PAC-1 crystal form A according to item 24, wherein the solvent is selected from methanol, ethanol, ethyl acetate, acetone, methyl ethyl ketone, tetrahydrofuran, toluene, acetonitrile, dichloromethane , Chloroform, methyl tert-butyl ether, acetic acid or any combination of several.
26.根据项24或25所述的制备PAC-1晶型A的方法，其中，配制成澄清溶液后，在室温下缓慢挥发。26. The method for preparing PAC-1 crystal form A according to item 24 or 25, wherein after being prepared into a clear solution, it is slowly volatilized at room temperature.
27.根据项24～26中任一项所述的制备PAC-1晶型A的方法，其中，使用封口膜对装有PAC-1化合物的容器进行封口，且封口膜上有小孔。27. The method for preparing PAC-1 crystal form A according to any one of items 24 to 26, wherein the container containing the PAC-1 compound is sealed with a sealing film, and the sealing film has small holes.
28.一种应用高聚物诱导法制备PAC-1晶型A的方法，其中，其包括：将PAC-1化合物溶解在正溶剂中，并加入高聚物，搅拌后转为挥发，收集所得固体得到PAC-1晶型A。28. A method for preparing PAC-1 crystal form A by using a polymer induction method, which comprises: dissolving the PAC-1 compound in a positive solvent, adding the polymer, stirring and turning to volatilization, and collecting the resultant The solid obtained PAC-1 crystal form A.
29.根据项28所述的制备PAC-1晶型A的方法，其中，所述正溶剂选自甲醇、乙醇、丙酮、四氢呋喃中的任意一种或为任意几种的组合。29. The method for preparing PAC-1 crystal form A according to item 28, wherein the positive solvent is selected from any one or a combination of any of methanol, ethanol, acetone, and tetrahydrofuran.
30.根据项28或29所述的制备PAC-1晶型A的方法，其中，所述高聚物选自羟丙基甲基纤维素、聚乙烯吡咯烷酮、甲基纤维素、聚乙酸乙烯酯、聚乙烯醇、聚氯乙烯中的任意一种或为任意几种的组合。30. The method for preparing PAC-1 crystal form A according to item 28 or 29, wherein the high polymer is selected from hydroxypropyl methylcellulose, polyvinylpyrrolidone, methylcellulose, polyvinyl acetate Any one of, polyvinyl alcohol and polyvinyl chloride or a combination of any of them.
31.根据项28～30中任一项所述的制备PAC-1晶型A的方法，其中，在室温下搅拌后转为挥发。31. The method for preparing PAC-1 crystal form A according to any one of items 28 to 30, wherein the PAC-1 crystal form A is stirred at room temperature and then turned to volatilization.
32.一种应用湿度诱导法制备PAC-1晶型A的方法，其中，其包括：将装有PAC-1化合物的容器置于湿度为5～100％的干燥器中，0.1～10天后收集固体得到PAC-1晶型A。32. A method for preparing PAC-1 crystal form A using a humidity induction method, which comprises: placing a container containing PAC-1 compound in a desiccator with a humidity of 5-100%, and collecting it after 0.1-10 days The solid obtained PAC-1 crystal form A.
33.根据项32所述的制备PAC-1晶型A的方法，其中，其包括：将装有PAC-1化合物的容器置于湿度为45％～100％的干燥器中，7天后收集固体得到PAC-1晶型A。33. The method for preparing PAC-1 crystal form A according to item 32, which comprises: placing a container containing the PAC-1 compound in a desiccator with a humidity of 45% to 100%, and collecting the solid after 7 days PAC-1 crystal form A was obtained.
34.根据项32或33所述的制备PAC-1晶型A的方法，其中，使用封口膜对装有PAC-1化合物的容器进行封口，且封口膜上有小孔，然后再将装有PAC-1化合物的容器置于干燥器中。34. The method for preparing PAC-1 crystal form A according to item 32 or 33, wherein the container containing the PAC-1 compound is sealed with a sealing film, and the sealing film has small holes, and then the The container of PAC-1 compound is placed in a desiccator.
35.一种应用研磨转晶法制备PAC-1晶型A的方法，其中，其包括：将PAC-1化合物在5～50℃的条件下研磨1～80分钟，得到PAC-1晶型A。35. A method for preparing PAC-1 crystal form A by applying a grinding-to-crystal method, which comprises: grinding the PAC-1 compound at 5-50° C. for 1 to 80 minutes to obtain PAC-1 crystal form A .
发明的效果Effect of invention
本发明提供的PAC-1晶型A的制备方法简单、稳定、可操作性强，适合工业化生产，得到的PAC-1晶型A稳定性高。The preparation method of the PAC-1 crystal form A provided by the invention is simple, stable, and has strong operability, is suitable for industrial production, and the obtained PAC-1 crystal form A has high stability.
附图说明Description of the drawings
图1 PAC-1晶型A的X射线粉末衍射(XRPD)图谱Figure 1 X-ray powder diffraction (XRPD) pattern of PAC-1 crystal form A
图2 PAC-1晶型A的热重分析/差示扫描量热分析(TGA/DSC)图谱Figure 2 Thermogravimetric analysis/differential scanning calorimetry (TGA/DSC) spectrum of PAC-1 crystal form A
具体实施方式Detailed ways
在不与本说明书中的定义发生冲突的情况下，本说明书中的术语具有本领域技术人员通常理解的含义，但如有冲突，则以本说明书中的定义为准。As long as there is no conflict with the definition in this specification, the terms in this specification have the meaning commonly understood by those skilled in the art, but in case of conflict, the definition in this specification shall prevail.
PAC-1PAC-1
在本说明书中，PAC-1是指一种能够直接激活半胱天冬酶-3酶原 (Procaspase-3)的小分子化合物，其化学名称是1-Piperazineacetic acid,4-(phenylmethyl)-2-[[2-hydroxy-3-(2-propen-1-yl)phenyl]methylene]((E)-N’-(3-烯丙基-2-羟基苯亚甲基)-2-(4-苄基哌嗪-1-基)乙酰肼)，结构如式1，其被认为能够选择性诱导肿瘤细胞发生凋亡，因而能够作为抗肿瘤药物。In this specification, PAC-1 refers to a small molecule compound that can directly activate Procaspase-3, and its chemical name is 1-Piperazineacetic acid, 4-(phenylmethyl)-2 -[[2-hydroxy-3-(2-propen-1-yl)phenyl]methylene]((E)-N'-(3-allyl-2-hydroxybenzylidene)-2-(4 -Benzylpiperazin-1-yl)acethydrazine), with the structure shown in formula 1, which is believed to be able to selectively induce tumor cell apoptosis, and thus can be used as an antitumor drug.
Figure PCTCN2020094138-appb-000003
Figure PCTCN2020094138-appb-000003
热重分析Thermogravimetric analysis
热重分析(Thermogravimetric Analysis，TGA)是指在程序控制温度下测量待测样品的质量与温度变化关系的一种热分析技术，用来研究材料的热稳定性和组分。TGA在研发和质量控制方面都是比较常用的检测手段。热重分析在实际的材料分析中经常与其他分析方法联用，进行综合热分析，全面准确分析材料。热重分析仪记录到的曲线称TGA曲线。Thermogravimetric Analysis (TGA) refers to a thermal analysis technique that measures the relationship between the quality of the sample to be tested and the temperature change under program control temperature, and is used to study the thermal stability and composition of materials. TGA is a commonly used testing method in R&D and quality control. Thermogravimetric analysis is often used in combination with other analysis methods in actual material analysis to conduct comprehensive thermal analysis and analyze materials comprehensively and accurately. The curve recorded by the thermogravimetric analyzer is called the TGA curve.
差示扫描量热分析Differential scanning calorimetry
差示扫描量热分析(differential scanning calorimetry,DSC)，在温度程序控制下，测量试样相对于参比物的热流速率随温度或时间变化的一种技术。差示扫描量热仪记录到的曲线称DSC曲线，一般以W/g或mW/mg(即流向每克样品的功率)为纵坐标，以温度T或时间t为横坐标，可以测量多种热力学和动力学参数，例如比热容、反应热、转变热、相图、反应速率、结晶速率、高聚物结晶度、样品纯度等。该法使用温度范围宽(-175～725℃)、分辨率高、试样用量少。适用于无机物、有机化合物及药物分析。Differential scanning calorimetry (DSC), under the control of a temperature program, is a technique for measuring the heat flow rate of a sample relative to a reference with temperature or time. The curve recorded by the differential scanning calorimeter is called the DSC curve. Generally, W/g or mW/mg (that is, the power per gram of sample) is used as the ordinate, and the temperature T or time t is the abscissa. Various measurements can be made. Thermodynamic and kinetic parameters, such as specific heat capacity, heat of reaction, heat of transition, phase diagram, reaction rate, crystallization rate, polymer crystallinity, sample purity, etc. The method uses a wide temperature range (-175～725℃), high resolution, and small sample amount. It is suitable for the analysis of inorganic substances, organic compounds and drugs.
本发明的PAC-1晶型命名为PAC-1晶型A，其X射线粉末衍射(XRPD)图谱如图1所示。The PAC-1 crystal form of the present invention is named PAC-1 crystal form A, and its X-ray powder diffraction (XRPD) pattern is shown in FIG. 1.
在一个具体实施方式中，本发明所制得的PAC-1晶型A为无水晶型。In a specific embodiment, the PAC-1 crystal form A produced by the present invention is an amorphous type.
本发明中可采用反溶剂添加法、悬浮搅拌法、气液渗透法、气固渗透法、缓慢降温法、缓慢挥发法、高聚物诱导法、湿度诱导法、研磨转晶法制备 PAC-1晶型A。In the present invention, an anti-solvent addition method, a suspension stirring method, a gas-liquid infiltration method, a gas-solid infiltration method, a slow cooling method, a slow volatilization method, a polymer induction method, a humidity induction method, and a grinding crystal conversion method can be used to prepare PAC-1 Form A.
在一个具体实施方式中，本发明应用反溶剂添加法制备得到PAC-1晶型A。反溶剂添加法是将正溶剂与反溶剂结合使用，从而降低待结晶物在溶剂中的溶解性。被溶解的待结晶物是在转变温度附近与反溶剂混合的。由于反溶剂与水结合，降低了待结晶物的溶解性，从而使结晶物析出，过滤得到结晶物。具体的，本发明中，应用反溶剂添加法制备PAC-1晶型A的方法，包括：将PAC-1化合物溶解在正溶剂中，再逐滴添加反溶剂，收集所得固体，得到PAC-1晶型。In a specific embodiment, the present invention uses the anti-solvent addition method to prepare PAC-1 crystal form A. The anti-solvent addition method is to combine the positive solvent and the anti-solvent to reduce the solubility of the crystallized substance in the solvent. The dissolved material to be crystallized is mixed with the anti-solvent around the transition temperature. Since the anti-solvent is combined with water, the solubility of the crystallized substance is reduced, so that the crystallized substance is precipitated, and the crystallized substance is obtained by filtration. Specifically, in the present invention, the method for preparing PAC-1 crystal form A using the anti-solvent addition method includes: dissolving the PAC-1 compound in a normal solvent, then adding the anti-solvent dropwise, and collecting the obtained solid to obtain PAC-1 Crystal form.
在一个优选的实施方式中，应用反溶剂添加法制备PAC-1晶型A，所述正溶剂选自甲醇、丙酮、四氢呋喃、二噁烷、乙腈、乙醇、甲基乙基酮、乙酸乙酯、2-甲基四氢呋喃、苯甲醚、二氯甲烷、甲苯、丙酮、二甲基乙酰胺中任意一种或为任意几种的组合，所述反溶剂选自水、正庚烷、环戊基甲醚中的任意一种或为任意几种的组合。In a preferred embodiment, the anti-solvent addition method is used to prepare PAC-1 crystal form A, and the normal solvent is selected from methanol, acetone, tetrahydrofuran, dioxane, acetonitrile, ethanol, methyl ethyl ketone, and ethyl acetate. , 2-methyltetrahydrofuran, anisole, dichloromethane, toluene, acetone, dimethylacetamide, any one or a combination of any several, the anti-solvent is selected from water, n-heptane, cyclopentane Any one or a combination of any of the methyl ether.
在一个具体实施方式中，本发明应用悬浮搅拌法制备PAC-1晶型A。具体的，向原料样品中加入溶剂得到悬浮液，将所述悬浮液置于室温或25～100℃下搅拌0.1～10天后，离心收集所得固体，得到PAC-1晶型A。In a specific embodiment, the present invention applies the suspension stirring method to prepare PAC-1 crystal form A. Specifically, a solvent is added to the raw material sample to obtain a suspension, and the suspension is placed at room temperature or 25-100° C. and stirred for 0.1-10 days, and the obtained solid is collected by centrifugation to obtain PAC-1 crystal form A.
在一个优选的实施方式中，应用悬浮搅拌法制备PAC-1晶型A，在原料样品中加入溶剂得到悬浮液，所述溶剂选自乙醇、异丙醇、乙酸乙酯、甲基叔丁基醚、乙腈、水、甲醇与水的混合溶剂、丙酮与水的混合溶剂、四氢呋喃与水的混合溶剂、正丙醇与水的混合溶剂、二甲基甲酰胺与水的混合溶剂、乙醇与水的混合溶剂、乙腈与水的混合溶剂、甲基异丁基酮与正庚烷的混合溶剂、二噁烷与正庚烷的混合溶剂、氯仿与正庚烷的混合溶剂中任意一种或为任意几种的组合，将得到的悬浮液置于室温下搅拌0.1～10天，优选6天，离心收集所得固体，得到PAC-1晶型A。优选地，所述溶剂为甲醇与水的混合溶剂，且所述甲醇与水的混合溶剂的体积比为甲醇：水为1:1.3～1:14；其它任意一种混合溶剂中，两种溶剂的体积比均为1：1。In a preferred embodiment, the suspension stirring method is used to prepare PAC-1 crystal form A, a solvent is added to the raw material sample to obtain a suspension, and the solvent is selected from ethanol, isopropanol, ethyl acetate, and methyl tert-butyl. Ether, acetonitrile, water, mixed solvent of methanol and water, mixed solvent of acetone and water, mixed solvent of tetrahydrofuran and water, mixed solvent of n-propanol and water, mixed solvent of dimethylformamide and water, ethanol and water Any one of the mixed solvent, the mixed solvent of acetonitrile and water, the mixed solvent of methyl isobutyl ketone and n-heptane, the mixed solvent of dioxane and n-heptane, the mixed solvent of chloroform and n-heptane, or With any combination of several, the obtained suspension is stirred at room temperature for 0.1 to 10 days, preferably for 6 days, and the obtained solid is collected by centrifugation to obtain PAC-1 crystal form A. Preferably, the solvent is a mixed solvent of methanol and water, and the volume ratio of the mixed solvent of methanol and water is methanol: water is 1:1.3 to 1:14; in any other mixed solvent, two solvents The volume ratio is 1:1.
在一个优选的实施方式中，应用悬浮搅拌法制备PAC-1晶型A，在原料样品中加入溶剂得到悬浮液，所述溶剂选自二噁烷与正庚烷的混合溶剂、氯仿与正庚烷的混合溶剂、异丁醇、乙酸异丁酯、环戊基甲醚、甲基叔丁基醚、丙酮与正庚烷的混合溶剂、异丙醇与正庚烷的混合溶剂、乙腈与水的混合溶 剂、二噁烷与水的混合溶剂中任意一种或为任意几种的组合，将所述悬浮液置于50℃下搅拌0.1～10天，优选6天，离心收集所得固体并干燥，得到PAC-1晶型A。In a preferred embodiment, the suspension stirring method is used to prepare PAC-1 crystal form A, and a solvent is added to the raw material sample to obtain a suspension. The solvent is selected from a mixed solvent of dioxane and n-heptane, chloroform and n-heptane Alkane mixed solvent, isobutanol, isobutyl acetate, cyclopentyl methyl ether, methyl tert-butyl ether, acetone and n-heptane mixed solvent, isopropanol and n-heptane mixed solvent, acetonitrile and water Any one or a combination of any one of the mixed solvent of dioxane and water, or any combination of several, the suspension is placed at 50°C and stirred for 0.1-10 days, preferably 6 days, the resulting solid is collected by centrifugation and dried , Get PAC-1 crystal form A.
在一个具体实施方式中，本发明应用气液渗透法制备PAC-1晶型A。具体的，将原料样品溶解在正溶剂中，制成澄清溶液，并将装有澄清溶液的容器敞口放置在装有反溶剂的密封容器中，在室温下静置，收集析出的固体，得到PAC-1晶型A。In a specific embodiment, the present invention applies the gas-liquid permeation method to prepare PAC-1 crystal form A. Specifically, the raw material sample is dissolved in a positive solvent to make a clear solution, and the container with the clear solution is placed in a sealed container with an anti-solvent, and it is allowed to stand at room temperature to collect the precipitated solid to obtain PAC-1 crystal form A.
在一个优选的实施方式中，应用气液渗透法制备PAC-1晶型A，所述正溶剂选自乙醇、甲基乙基酮、2-甲基四氢呋喃、N-甲基吡咯烷酮、正丙醇、二噁烷、甲苯、乙酸异丙酯、二氯甲烷、丙酮、四氢呋喃、乙腈中任意一种或为任意几种的组合，所述反溶剂选自水和正庚烷中任意一种。In a preferred embodiment, the gas-liquid permeation method is used to prepare PAC-1 crystal form A, and the normal solvent is selected from ethanol, methyl ethyl ketone, 2-methyltetrahydrofuran, N-methylpyrrolidone, and n-propanol. , Dioxane, toluene, isopropyl acetate, dichloromethane, acetone, tetrahydrofuran, acetonitrile, any one or a combination of any of them, the anti-solvent is selected from any one of water and n-heptane.
在一个具体实施方式中，本发明应用气固渗透法制备得到PAC-1晶型A。具体的，将装有原料样品的容器放置在装有正溶剂的密封容器中，室温下静置，取出固体得到PAC-1晶型A。In a specific embodiment, the present invention uses gas-solid infiltration method to prepare PAC-1 crystal form A. Specifically, the container containing the raw material sample is placed in a sealed container containing a positive solvent, and left standing at room temperature, and the solid is taken out to obtain PAC-1 crystal form A.
在一个优选的实施方式中，应用气固渗透法制备PAC-1晶型A，所述正溶剂优选乙醇和丙酮。In a preferred embodiment, the gas-solid permeation method is used to prepare PAC-1 crystal form A, and the positive solvent is preferably ethanol and acetone.
在一个具体实施方式中，本发明应用缓慢降温法制备得到PAC-1晶型A。具体的，将原料样品溶解在溶剂中，在30～140℃下，优选50℃进行加热，经加热溶液变澄清后过滤，再将滤液缓慢降温至0～25℃，优选5℃，控制降温速率为0.1～20℃/分钟，优选0.1℃/分钟，并在该温度下恒温放置0.1～10天，优选5天，随后再将滤液转移至-20～-5℃，优选-20℃，放置1h，收集所得固体，得到PAC-1晶型A。In a specific embodiment, the present invention uses a slow cooling method to prepare PAC-1 crystal form A. Specifically, the raw material sample is dissolved in a solvent, heated at 30-140°C, preferably 50°C, the heated solution becomes clear and filtered, and then the filtrate is slowly cooled to 0-25°C, preferably 5°C, and the cooling rate is controlled. 0.1～20℃/min, preferably 0.1℃/min, and keep it at this temperature for 0.1～10 days, preferably 5 days, then transfer the filtrate to -20～-5℃, preferably -20℃, and leave it for 1h , Collect the obtained solid to obtain PAC-1 crystal form A.
在一个优选的实施方式中，应用缓慢降温法制备PAC-1晶型A，所述溶剂选自异丙醇、甲基叔丁基醚、乙酸丁酯、酒精与水的混合溶剂、四氢呋喃与水的混合溶剂、苯甲醚与正庚烷的混合溶剂、乙腈与正庚烷的混合溶剂中任意一种或为任意几种的组合。In a preferred embodiment, a slow cooling method is used to prepare PAC-1 crystal form A, and the solvent is selected from isopropanol, methyl tert-butyl ether, butyl acetate, a mixed solvent of alcohol and water, tetrahydrofuran and water Any one or a combination of any of the mixed solvent of, the mixed solvent of anisole and n-heptane, and the mixed solvent of acetonitrile and n-heptane.
在一个具体实施方式中，本发明应用缓慢挥发法制备PAC-1晶型A。具体的，将原料样品放置于容器中，加入溶剂使其溶解，配制成澄清溶液，置于室温下缓慢挥发，收集所得固体，得到PAC-1晶型A。在一个优选的实施方式中，使用封口膜对装有澄清溶液的容器进行封口，且封口膜上有小孔。In a specific embodiment, the present invention applies the slow volatilization method to prepare PAC-1 crystal form A. Specifically, the raw material sample is placed in a container, and a solvent is added to dissolve it to prepare a clear solution, which is placed at room temperature to slowly volatilize, and the obtained solid is collected to obtain PAC-1 crystal form A. In a preferred embodiment, a sealing film is used to seal the container containing the clear solution, and the sealing film has small holes.
在一个优选的实施方式中，应用缓慢挥发法制备PAC-1晶型A，所述溶剂选自甲醇、乙醇、乙酸乙酯、丙酮、甲基乙基酮、四氢呋喃、甲苯、乙腈、二氯甲烷、氯仿、甲基叔丁基醚、乙酸中任意一种或为任意几种的组合。In a preferred embodiment, a slow volatilization method is used to prepare PAC-1 crystal form A, and the solvent is selected from methanol, ethanol, ethyl acetate, acetone, methyl ethyl ketone, tetrahydrofuran, toluene, acetonitrile, and methylene chloride. , Chloroform, methyl tert-butyl ether, acetic acid or any combination of several.
在一个具体实施方式中，本发明应用高聚物诱导法制备PAC-1晶型A。具体的，将原料样品溶解在溶剂中，并加入高聚物，室温搅拌0.1～12小时后，优选2小时后转为挥发，收集析出的固体，得到PAC-1晶型A。In a specific embodiment, the present invention uses a polymer induction method to prepare PAC-1 crystal form A. Specifically, a raw material sample is dissolved in a solvent, and a polymer is added. After stirring at room temperature for 0.1 to 12 hours, preferably after 2 hours, it is converted to volatilization, and the precipitated solid is collected to obtain PAC-1 crystal form A.
在一个优选的实施方式中，应用高聚物诱导法制备PAC-1晶型A，所述高聚物选自聚氯乙烯、聚乙烯醇、聚乙酸乙烯酯、甲基纤维素、聚乙烯吡咯烷酮、羟丙基甲基纤维素等；所述溶剂选自甲醇、乙醇、丙酮、四氢呋喃中任意一种或为任意几种的组合。In a preferred embodiment, a polymer induction method is used to prepare PAC-1 crystal form A, and the polymer is selected from polyvinyl chloride, polyvinyl alcohol, polyvinyl acetate, methyl cellulose, and polyvinylpyrrolidone , Hydroxypropyl methylcellulose, etc.; the solvent is selected from any one or a combination of any of methanol, ethanol, acetone, and tetrahydrofuran.
在一个具体实施方式中，本发明应用湿度诱导法制备得到PAC-1晶型A。具体的，将原料样品置于湿度为45％～100％的干燥器中，0.1～10天后，优选7天后，收集得到PAC-1晶型A。In a specific embodiment, the present invention uses the humidity induction method to prepare PAC-1 crystal form A. Specifically, the raw material sample is placed in a desiccator with a humidity of 45%-100%, and after 0.1-10 days, preferably 7 days later, the PAC-1 crystal form A is collected.
在一个优选的实施方式中，应用湿度诱导法制备PAC-1晶型A，先使用封口膜对装有原料样品的容器进行封口，且封口膜上有小孔，然后再将装有原料样品的容器置于干燥器中。In a preferred embodiment, the humidity induction method is used to prepare PAC-1 crystal form A. The container containing the raw material sample is sealed with a sealing film first, and the sealing film has small holes, and then the raw material sample The container is placed in a desiccator.
在一个具体实施方式中，本发明应用研磨转晶法制备得到PAC-1晶型A。具体的，将原料样品在5～50℃的条件下研磨1～80分钟，得到PAC-1晶型A。In a specific embodiment, the present invention applies the grinding and crystal transformation method to prepare PAC-1 crystal form A. Specifically, the raw material sample is ground at 5-50° C. for 1-80 minutes to obtain PAC-1 crystal form A.
在一个具体实施方式中，本发明的反溶剂添加法、悬浮搅拌法、气液渗透法、气固渗透法、缓慢降温法、缓慢挥发法、高聚物诱导法、湿度诱导法、研磨转晶法制备PAC-1晶型A的方法中，得到的PAC-1晶型A后对其进行干燥。In a specific embodiment, the anti-solvent addition method, suspension stirring method, gas-liquid infiltration method, gas-solid infiltration method, slow cooling method, slow volatilization method, polymer induction method, humidity induction method, grinding and crystal conversion method of the present invention In the method of preparing PAC-1 crystal form A, the obtained PAC-1 crystal form A is dried.
实施例Example
以下列举的仅仅是本发明的若干个具体实施例。本发明不限于上述实施例，还可以有许多变形。本领域技术人员能从本发明公开的内容直接导出或联想到的所有变形，均应认为是本发明的保护范围。The following are only a few specific embodiments of the present invention. The present invention is not limited to the above-mentioned embodiments, and many modifications are possible. All modifications that can be directly derived or imagined by those skilled in the art from the disclosure of the present invention should be considered as the protection scope of the present invention.
实施例1Example 1
反溶剂添加法：称取约20毫克每份的样品于20毫升小瓶内，用一定量的正溶剂溶解后，向该澄清溶液中逐滴加入下表中对应的反溶剂，边滴加边搅拌至有固体析出，将所得固体干燥。表1中实施例最终得到的固体分别标记为固体1-1至1-14，将析出的固体进行XRPD检测，均为晶型A。Anti-solvent addition method: Weigh about 20 mg of each sample into a 20-ml vial, dissolve it with a certain amount of positive solvent, add the corresponding anti-solvent in the table below to the clear solution dropwise, and stir while adding dropwise When a solid precipitated, the obtained solid was dried. The solids finally obtained in the examples in Table 1 are respectively labeled as solids 1-1 to 1-14, and the precipitated solids are subjected to XRPD detection, and they are all crystal form A.
表1Table 1
Figure PCTCN2020094138-appb-000004
Figure PCTCN2020094138-appb-000004
注：*：-20℃固体析出得到；**：室温挥发得到。Note: *: Obtained by solid precipitation at -20°C; **: Obtained by volatilization at room temperature.
实施例2Example 2
悬浮搅拌法：称取约15毫克每份的样品至小瓶中，分别加入0.3毫升下表所列的溶剂，得到的悬浮液分别置于室温和50℃下搅拌6天后，离心收集得到固体并干燥。将表2中实施例最终得到的固体分别标记为固体2-1至2-27，将得到固体进行XRPD检测，均为晶型A。Suspension stirring method: Weigh about 15 mg of each sample into a vial, add 0.3 ml of the solvents listed in the table below, and place the resulting suspension at room temperature and 50°C and stir for 6 days. Centrifuge to collect the solid and dry . The solids finally obtained in the examples in Table 2 are marked as solids 2-1 to 2-27, and the obtained solids are subjected to XRPD detection, and they are all crystal form A.
表2Table 2
Figure PCTCN2020094138-appb-000005
Figure PCTCN2020094138-appb-000005
Figure PCTCN2020094138-appb-000006
Figure PCTCN2020094138-appb-000006
实施例3Example 3
气液渗透法：称取约20毫克每份的样品溶于一定量的溶剂中，置于3毫升小瓶中，另取20毫升小瓶并向其中加入约3毫升的反溶剂，将3毫升 小瓶敞口置于20毫升小瓶中，密闭并于室温下静置，待固体析出，将所得固体干燥。将表3中实施例最终得到的固体分别标记为固体3-1至3-12，进行XRPD检测，均为晶型A。Gas-liquid permeation method: Weigh approximately 20 mg of each sample and dissolve it in a certain amount of solvent, place it in a 3 ml vial, take another 20 ml vial and add about 3 ml of anti-solvent to it, and open the 3 ml vial. The mouth is placed in a 20 ml vial, sealed and allowed to stand at room temperature, and the obtained solid is dried after the solid has separated out. The solids finally obtained in the examples in Table 3 are marked as solids 3-1 to 3-12, and XRPD detection is performed, and they are all crystal form A.
表3table 3
Figure PCTCN2020094138-appb-000007
Figure PCTCN2020094138-appb-000007
实施例4Example 4
缓慢降温法：称取约20毫克每份的样品于3毫升小瓶中，分别加入0.8毫升下表中的溶剂，将样品置于50℃烘箱平衡1小时，若为加热溶解后变得清澈，则过滤。将澄清溶液从50℃降温至5℃，速率0.1℃/分钟，并在5℃恒温5天，随后将澄清样品转移至-20℃，放置1h，收集所得到的固体并干燥。将表4中本实施例最终得到的固体分别标记为固体4-1至4-7，进行测试，均为晶型A。Slow cooling method: Weigh approximately 20 mg of each sample into a 3 ml vial, add 0.8 ml of the solvent in the table below, and place the sample in an oven at 50°C for 1 hour. If it becomes clear after heating and dissolving, then filter. The clear solution was cooled from 50°C to 5°C at a rate of 0.1°C/min, and kept at 5°C for 5 days, then the clear sample was transferred to -20°C, placed for 1 hour, and the obtained solid was collected and dried. The solids finally obtained in this example in Table 4 are marked as solids 4-1 to 4-7, and tested, and they are all crystal form A.
表4Table 4
Figure PCTCN2020094138-appb-000008
Figure PCTCN2020094138-appb-000008
Figure PCTCN2020094138-appb-000009
Figure PCTCN2020094138-appb-000009
实施例5Example 5
缓慢挥发法：称取约20毫克每份的样品至小瓶中，分别加入1毫升下表中的溶剂，配制成澄清溶液，随后用封口膜扎4个小孔后置于室温下放置挥发，收集得到固体并干燥。将表5中本实施例最终得到的固体分别标记为固体5-1至5-12，并进行测试，均为晶型A。Slow volatilization method: Weigh about 20 mg of each sample into a vial, add 1 ml of the solvent in the table below to prepare a clear solution, then pierce 4 small holes with a parafilm and place it at room temperature to volatilize, and collect A solid is obtained and dried. The solids finally obtained in this example in Table 5 are marked as solids 5-1 to 5-12, and tested, and they are all crystal form A.
表5table 5
Figure PCTCN2020094138-appb-000010
Figure PCTCN2020094138-appb-000010
实施例6Example 6
高聚物诱导法：称取约20毫克每份的样品于小瓶中，加入约2毫克下表中的高聚物和0.5毫升溶剂，在室温下搅拌2小时后转为挥发，室温挥发后收集析出得固体并干燥。将表6中本实施例最终得到的固体分别标记为固体6-1至6-6，并进行测试，均为晶型A。Polymer induction method: Weigh about 20 mg of each sample into a vial, add about 2 mg of the polymer in the table below and 0.5 ml of solvent, stir at room temperature for 2 hours and then turn to volatilization, and collect after volatilization at room temperature A solid precipitated and dried. The solids finally obtained in this example in Table 6 are marked as solids 6-1 to 6-6, and tested, and they are all crystal form A.
表6Table 6
Figure PCTCN2020094138-appb-000011
Figure PCTCN2020094138-appb-000011
实施例7Example 7
湿度诱导法：称取15毫克样品置于小瓶中，随后用封口膜封扎4个小孔后置于对应湿度的干燥器中，7天后收集固体并干燥。将表7中本实施例最终得到的固体分别标记为固体7-1至7-4，进行测试，均得到晶型A。Humidity induction method: Weigh 15 mg of sample into a vial, then seal 4 small holes with parafilm and place it in a desiccator corresponding to humidity. Collect the solid after 7 days and dry it. The solids finally obtained in this example in Table 7 are marked as solids 7-1 to 7-4, respectively, and tested, and crystal form A is obtained.
表7Table 7
Figure PCTCN2020094138-appb-000012
Figure PCTCN2020094138-appb-000012
实施例8Example 8
气固渗透法Gas-solid infiltration
称取约15毫克每份的样品置于3毫升小瓶中，另取20毫升的小瓶并向其中加入约3毫升的对应溶剂，将3毫升小瓶敞口置于20毫升的小瓶中，密封并于室温下静置6～10天，收集固体并干燥。表8中本实施例最终得到的固体分别标记为固体8-1至8-9，进行测试，均得到晶型A。Weigh approximately 15 mg of each sample into a 3 ml vial, take another 20 ml vial and add about 3 ml of the corresponding solvent to it, place the 3 ml vial open in the 20 ml vial, seal and place Let stand for 6-10 days at room temperature, collect the solid and dry. The solids finally obtained in this example in Table 8 are marked as solids 8-1 to 8-9, respectively, and tested, and crystal form A is obtained.
表8Table 8
Figure PCTCN2020094138-appb-000013
Figure PCTCN2020094138-appb-000013
Figure PCTCN2020094138-appb-000014
Figure PCTCN2020094138-appb-000014
实施例9Example 9
研磨转晶法Grinding to crystal
称取50毫克样品置于研钵内，手动研磨约10分钟，加入10毫升相应溶剂，随后收集固体并干燥。表9中本实施例最终得到的固体分别标记为固体9-1至9-2，进行测试，均得到晶型A。Weigh 50 mg of sample into a mortar, manually grind for about 10 minutes, add 10 ml of the corresponding solvent, and then collect the solid and dry it. The solids finally obtained in this example in Table 9 are marked as solids 9-1 to 9-2, respectively, and tested, and crystal form A is obtained.
表9Table 9
Figure PCTCN2020094138-appb-000015
Figure PCTCN2020094138-appb-000015
实验例Experimental example
实验例1Experimental example 1
对于本发明中的实施例1～9所制备得到的PAC-1晶型A，分别使用XRERT-3X射线衍射仪和Empyream X射线衍射仪，在表10的测试条件下，得到的所有的PAC-1晶型A的以2θ衍射角表示的X射线粉末衍射图谱相同，其在8.92±0.2°、17.14±0.2°、17.82±0.2°、18.90±0.2°、20.37±0.2°和26.06±0.2°处显示特征峰。For the PAC-1 crystal form A prepared in Examples 1-9 of the present invention, XRERT-3 X-ray diffractometer and Empyream X-ray diffractometer were used respectively. Under the test conditions in Table 10, all PAC- 1 The X-ray powder diffraction patterns expressed by 2θ diffraction angles of Form A are the same, which are at 8.92±0.2°, 17.14±0.2°, 17.82±0.2°, 18.90±0.2°, 20.37±0.2° and 26.06±0.2° Display characteristic peaks.
表10Table 10
Figure PCTCN2020094138-appb-000016
Figure PCTCN2020094138-appb-000016
Figure PCTCN2020094138-appb-000017
Figure PCTCN2020094138-appb-000017
进一步地，PAC-1晶型A以2θ衍射角表示的X射线粉末衍射图谱在5.46±0.2°、8.92±0.2°、10.14±0.2°、15.76±0.2°、17.14±0.2°、17.82±0.2°、18.27±0.2°、18.90±0.2°、19.43±0.2°、20.37±0.2°、21.48±0.2°、21.80±0.2°和26.06±0.2°处显示特征峰。Furthermore, the X-ray powder diffraction pattern of PAC-1 crystal form A expressed by 2θ diffraction angles is 5.46±0.2°, 8.92±0.2°, 10.14±0.2°, 15.76±0.2°, 17.14±0.2°, 17.82±0.2° , 18.27±0.2°, 18.90±0.2°, 19.43±0.2°, 20.37±0.2°, 21.48±0.2°, 21.80±0.2° and 26.06±0.2° show characteristic peaks.
进一步地，PAC-1晶型A以2θ衍射角表示的X射线粉末衍射图谱在5.46±0.2°、8.92±0.2°、10.14±0.2°、11.24±0.2°、11.91±0.2°、14.04±0.2°、14.53±0.2°、16.34±0.2°、15.76±0.2°、17.14±0.2°、17.82±0.2°、18.27±0.2°、18.90±0.2°、19.43±0.2°、20.37±0.2°、20.96±0.2°、21.48±0.2°、21.80±0.2°、22.52±0.2°、22.94±0.2°、23.47±0.2°、24.00±0.2°、25.62±0.2°、26.06±0.2°、26.84±0.2°、27.16±0.2°、27.60±0.2°、27.90±0.2°、28.99±0.2°、29.31±0.2°、29.98±0.2°、30.66±0.2°、32.09±0.2°、32.35±0.2°、34.28±0.2°、36.09±0.2°、37.07±0.2°、37.93±0.2°和38.39±0.2°处显示特征峰。Furthermore, the X-ray powder diffraction pattern of PAC-1 crystal form A expressed in 2θ diffraction angles is 5.46±0.2°, 8.92±0.2°, 10.14±0.2°, 11.24±0.2°, 11.91±0.2°, 14.04±0.2° 、14.53±0.2°、16.34±0.2°、15.76±0.2°、17.14±0.2°、17.82±0.2°、18.27±0.2°、18.90±0.2°、19.43±0.2°、20.37±0.2°、20.96±0.2° , 21.48±0.2°, 21.80±0.2°, 22.52±0.2°, 22.94±0.2°, 23.47±0.2°, 24.00±0.2°, 25.62±0.2°, 26.06±0.2°, 26.84±0.2°, 27.16±0.2° , 27.60±0.2°, 27.90±0.2°, 28.99±0.2°, 29.31±0.2°, 29.98±0.2°, 30.66±0.2°, 32.09±0.2°, 32.35±0.2°, 34.28±0.2°, 36.09±0.2° , 37.07±0.2°, 37.93±0.2° and 38.39±0.2° show characteristic peaks.
进一步地，PAC-1晶型A的X射线粉末衍射图谱具有下列表11中所包含的数据：Further, the X-ray powder diffraction pattern of PAC-1 crystal form A has the data contained in Table 11 below:
表11Table 11
Figure PCTCN2020094138-appb-000018
Figure PCTCN2020094138-appb-000018
Figure PCTCN2020094138-appb-000019
Figure PCTCN2020094138-appb-000019
本发明中，2θ角的测定精度为±0.2°，因此上述晶型的每个特征峰值在峰值±0.2°范围内为其误差允许范围。In the present invention, the measurement accuracy of the 2θ angle is ±0.2°, so each characteristic peak of the above-mentioned crystal form is within the range of the peak ±0.2° for its error tolerance.
更进一步地，本发明的PAC-1晶型A的X射线粉末衍射图谱如图1所示。Furthermore, the X-ray powder diffraction pattern of PAC-1 crystal form A of the present invention is shown in FIG. 1.
实验例2Experimental example 2
使用热重分析仪，在下表12的测试条件下，对实施例1～9中制备得到的PAC-1晶型A进行热重分析。Using a thermogravimetric analyzer, under the test conditions of Table 12 below, thermogravimetric analysis was performed on the PAC-1 crystal form A prepared in Examples 1-9.
表12Table 12
Figure PCTCN2020094138-appb-000020
Figure PCTCN2020094138-appb-000020
Figure PCTCN2020094138-appb-000021
Figure PCTCN2020094138-appb-000021
使用差示扫描量热计，在上表12的测试条件下，对实施例1～9中制备得到的PAC-1晶型A进行差示扫描量热分析，测定晶型的吸热过程。Using a differential scanning calorimeter, under the test conditions of Table 12 above, the PAC-1 crystal form A prepared in Examples 1 to 9 was subjected to differential scanning calorimetry to determine the endothermic process of the crystal form.
根据上表9中的测量参数，本发明测得的实施例1～9中制备得到的PAC-1晶型A的TGA/DSC图谱均如图2所示。According to the measurement parameters in Table 9 above, the TGA/DSC spectra of the PAC-1 crystal form A prepared in Examples 1-9 of the present invention are all shown in FIG. 2.
该晶型的差示扫描量热分析DSC曲线在130℃到140℃的温度范围显示单一优势的吸热，样品的熔点为136.2℃，吸热峰峰值为137.3℃±2℃，峰面积为-94.54J/g。应当理解，与X射线粉末衍射数值可能有变差具有相似情况，差示扫描量热技术所引用的数值也不能解释为绝对值，温度测定精度为±2℃，因此上述晶型的吸热峰峰值在峰值±2℃范围内为其误差允许范围。The differential scanning calorimetry DSC curve of this crystal form shows a single dominant endotherm in the temperature range of 130°C to 140°C. The melting point of the sample is 136.2°C, the peak endothermic peak is 137.3°C±2°C, and the peak area is- 94.54J/g. It should be understood that the value of X-ray powder diffraction may be similar to the value of X-ray powder diffraction. The value quoted by the differential scanning calorimetry technique cannot be interpreted as an absolute value. The temperature measurement accuracy is ±2°C. Therefore, the endothermic peak of the above crystal form The peak value is within the range of ±2℃ for its error tolerance.
PAC-1晶型A的TGA曲线显示，该晶型A在120℃失重约2.03％，热稳定性高。The TGA curve of PAC-1 crystal form A shows that the crystal form A has a weight loss of about 2.03% at 120°C and has high thermal stability.
实验例3Experimental example 3
本发明测定了实施例1～9中制备得到的PAC-1晶型A的溶解度。对于每个实施例制备得到的PAC-1晶型A，分别将适量PAC-1晶型A的固体约20毫克置于小瓶中，再分四步(分别为50、50、200、700毫升)加入相应溶剂后震荡，若固体溶清则停止。实施例1～9制备得到的PAC-1晶型A在室温下的粗略溶解度均如下表10所示。The present invention measured the solubility of PAC-1 crystal form A prepared in Examples 1-9. For the PAC-1 crystal form A prepared in each example, put an appropriate amount of about 20 mg of the PAC-1 crystal form A solid into the vial, and then divide into four steps (respectively 50, 50, 200, 700 ml) Shake after adding the corresponding solvent, and stop if the solid is dissolved. The rough solubility of PAC-1 crystal form A prepared in Examples 1-9 at room temperature is shown in Table 10 below.
表10Table 10
Figure PCTCN2020094138-appb-000022
Figure PCTCN2020094138-appb-000022
Figure PCTCN2020094138-appb-000023
Figure PCTCN2020094138-appb-000023

Claims (35)

  1. 一种应用反溶剂添加法制备PAC-1晶型A的方法，其中，其包括：将PAC-1化合物溶解在正溶剂中，再逐滴添加反溶剂，收集所得固体得到PAC-1晶型A。A method for preparing PAC-1 crystal form A using an anti-solvent addition method, which comprises: dissolving PAC-1 compound in a positive solvent, and then adding an anti-solvent dropwise, and collecting the obtained solid to obtain PAC-1 crystal form A .
  2. 根据权利要求1所述的制备PAC-1晶型A的方法，其中，所述正溶剂选自甲醇、丙酮、四氢呋喃、二恶烷、乙腈、乙醇、甲基乙基酮、乙酸乙酯、2-甲基四氢呋喃、苯甲醚、二氯甲烷、甲苯、丙酮、二甲基乙酰胺中任意一种或为任意几种的组合。The method for preparing PAC-1 crystal form A according to claim 1, wherein the normal solvent is selected from methanol, acetone, tetrahydrofuran, dioxane, acetonitrile, ethanol, methyl ethyl ketone, ethyl acetate, 2 -Any one or a combination of any of methyltetrahydrofuran, anisole, dichloromethane, toluene, acetone, and dimethylacetamide.
  3. 根据权利要求1或2所述的制备PAC-1晶型A的方法，其中，所述反溶剂选自水、正庚烷、环戊基甲醚中的任意一种或为任意几种的组合。The method for preparing PAC-1 crystal form A according to claim 1 or 2, wherein the anti-solvent is selected from any one of water, n-heptane, cyclopentyl methyl ether or a combination of any several .
  4. 根据权利要求1所述的制备PAC-1晶型A的方法，其中，在室温条件下析出固体制备所述PAC-1晶型A。The method for preparing PAC-1 crystal form A according to claim 1, wherein a solid is precipitated at room temperature to prepare the PAC-1 crystal form A.
  5. 根据权利要求1～3中任一项所述的制备PAC-1晶型A的方法，其中，The method for preparing PAC-1 crystal form A according to any one of claims 1 to 3, wherein:
    当所述正溶剂为甲苯，反溶剂为正庚烷时，在-20℃条件下析出固体得到PAC-1晶型A；或者When the normal solvent is toluene and the anti-solvent is n-heptane, a solid is precipitated at -20°C to obtain PAC-1 crystal form A; or
    当所述正溶剂为丙酮或二甲基乙酰胺，反溶剂为环戊基甲醚时，在室温下挥发得到PAC-1晶型A。When the positive solvent is acetone or dimethylacetamide, and the anti-solvent is cyclopentyl methyl ether, PAC-1 crystal form A is volatilized at room temperature.
  6. 一种应用悬浮搅拌法制备PAC-1晶型A的方法，其中，其包括：在PAC-1化合物中加入溶剂得到悬浮液，搅拌所述悬浮液，离心收集所得固体得到PAC-1晶型A。A method for preparing PAC-1 crystal form A by using a suspension stirring method, which comprises: adding a solvent to a PAC-1 compound to obtain a suspension, stirring the suspension, and centrifuging the obtained solid to obtain PAC-1 crystal form A .
  7. 根据权利要求6所述的制备PAC-1晶型A的方法，其中，所述溶剂选自乙醇、异丙醇、乙酸乙酯、甲基叔丁基醚、乙腈、水、甲醇与水的混合溶剂、丙酮与水的混合溶剂、四氢呋喃与水的混合溶剂、正丙醇与水的混合溶剂、二甲基甲酰胺与水的混合溶剂、乙醇与水的混合溶剂、乙腈与水的混合溶剂、甲基异丁基酮与正庚烷的混合溶剂、二恶烷与正庚烷的混合溶剂、氯仿与正庚烷的混合溶剂、异丁醇、乙酸异丁酯、环戊基甲醚、甲基叔丁基醚、丙酮与正庚烷的混合溶剂、异丙醇与正庚烷的混合溶剂、二恶烷与水的混合溶剂中的任意一种或为任意几种的组合。The method for preparing PAC-1 crystal form A according to claim 6, wherein the solvent is selected from ethanol, isopropanol, ethyl acetate, methyl tert-butyl ether, acetonitrile, water, a mixture of methanol and water Solvent, acetone and water mixed solvent, tetrahydrofuran and water mixed solvent, n-propanol and water mixed solvent, dimethylformamide and water mixed solvent, ethanol and water mixed solvent, acetonitrile and water mixed solvent, Mixed solvent of methyl isobutyl ketone and n-heptane, mixed solvent of dioxane and n-heptane, mixed solvent of chloroform and n-heptane, isobutanol, isobutyl acetate, cyclopentyl methyl ether, methyl Any one or a combination of methyl tert-butyl ether, a mixed solvent of acetone and n-heptane, a mixed solvent of isopropanol and n-heptane, and a mixed solvent of dioxane and water.
  8. 根据权利要求6或7所述的制备PAC-1晶型A的方法，其中，在 25～100℃条件下搅拌所述悬浮液0.1～10天。The method for preparing PAC-1 crystal form A according to claim 6 or 7, wherein the suspension is stirred at 25-100°C for 0.1-10 days.
  9. 根据权利要求6～8中任一项所述的制备PAC-1晶型A的方法，其中，在室温或50℃下搅拌所述悬浮液6天。The method for preparing PAC-1 crystal form A according to any one of claims 6 to 8, wherein the suspension is stirred at room temperature or 50°C for 6 days.
  10. 根据权利要求7～9中任一项所述的制备PAC-1晶型A的方法，其中，所述溶剂为甲醇与水的混合溶剂，且所述甲醇与水的混合溶剂的体积比为甲醇：水为1:1.3～1:14。The method for preparing PAC-1 crystal form A according to any one of claims 7 to 9, wherein the solvent is a mixed solvent of methanol and water, and the volume ratio of the mixed solvent of methanol and water is methanol ：Water is 1:1.3～1:14.
  11. 根据权利要求7～9中任一项所述的制备PAC-1晶型A的方法，其中，所述溶剂选自丙酮与水的混合溶剂、四氢呋喃与水的混合溶剂、正丙醇与水的混合溶剂、二甲基甲酰胺与水的混合溶剂、乙醇与水的混合溶剂、乙腈与水的混合溶剂、甲基异丁基酮与正庚烷的混合溶剂、二恶烷与正庚烷的混合溶剂、氯仿与正庚烷的混合溶剂、丙酮与正庚烷的混合溶剂、异丙醇与正庚烷的混合溶剂、二噁烷与水的混合溶剂中的任一种混合溶剂时，用于形成混合溶剂的两种溶剂的体积比为1:1。The method for preparing PAC-1 crystal form A according to any one of claims 7-9, wherein the solvent is selected from a mixed solvent of acetone and water, a mixed solvent of tetrahydrofuran and water, a mixture of n-propanol and water Mixed solvent, mixed solvent of dimethylformamide and water, mixed solvent of ethanol and water, mixed solvent of acetonitrile and water, mixed solvent of methyl isobutyl ketone and n-heptane, mixed solvent of dioxane and n-heptane In the case of a mixed solvent, a mixed solvent of chloroform and n-heptane, a mixed solvent of acetone and n-heptane, a mixed solvent of isopropanol and n-heptane, a mixed solvent of dioxane and water, use The volume ratio of the two solvents to form the mixed solvent is 1:1.
  12. 一种应用气液渗透法制备PAC-1晶型A的方法，其中，其包括：将PAC-1化合物溶解在正溶剂中，制成澄清溶液，并将装有澄清溶液的容器敞口放置在装有反溶剂的密封容器中静置，收集析出的固体得到PAC-1晶型A。A method for preparing PAC-1 crystal form A by gas-liquid permeation method, which comprises: dissolving PAC-1 compound in a positive solvent to make a clear solution, and placing a container containing the clear solution in the open Place it in a sealed container with an anti-solvent and collect the precipitated solid to obtain PAC-1 crystal form A.
  13. 根据权利要求12所述的制备PAC-1晶型A的方法，其中，所述正溶剂选自乙醇、甲基乙基酮、2-甲基四氢呋喃、N-甲基吡咯烷酮、正丙醇、二噁烷、甲苯、乙酸异丙酯、二氯甲烷、丙酮、四氢呋喃、乙腈中的任意一种或为任意几种的组合。The method for preparing PAC-1 crystal form A according to claim 12, wherein the normal solvent is selected from the group consisting of ethanol, methyl ethyl ketone, 2-methyltetrahydrofuran, N-methylpyrrolidone, n-propanol, two Any one or a combination of oxane, toluene, isopropyl acetate, dichloromethane, acetone, tetrahydrofuran, and acetonitrile.
  14. 根据权利要求12或13所述的制备PAC-1晶型A的方法，其中，所述反溶剂选自水、正庚烷中的任意一种或为任意几种的组合。The method for preparing PAC-1 crystal form A according to claim 12 or 13, wherein the anti-solvent is selected from any one of water and n-heptane or a combination of any of them.
  15. 根据权利要求12～14中任一项所述的制备PAC-1晶型A的方法，其中，在室温下，将装有澄清溶液的容器敞口放置在装有反溶剂的密封装置中静置。The method for preparing PAC-1 crystal form A according to any one of claims 12 to 14, wherein at room temperature, the container containing the clear solution is placed open in a sealed device containing an anti-solvent and allowed to stand still .
  16. 一种应用气固渗透法制备PAC-1晶型A的方法，其中，其包括：将装有PAC-1化合物的敞口容器放置在装有正溶剂的密封容器中，静置，取出固体得到PAC-1晶型A。A method for preparing PAC-1 crystal form A by gas-solid permeation method, which comprises: placing an open container filled with PAC-1 compound in a sealed container filled with a positive solvent, standing still, and taking out the solid to obtain PAC-1 crystal form A.
  17. 根据权利要求16所述的制备PAC-1晶型A的方法，其中，所述正 溶剂选自甲醇、乙醇、异丙醇、丙酮、乙腈、二氯甲烷、三氯甲烷、四氢呋喃、1，4-二氧六环、乙酸乙酯、甲苯、二甲基亚砜、N,N-二甲基甲酰胺中任意一种或为任意几种的组合。The method for preparing PAC-1 crystal form A according to claim 16, wherein the positive solvent is selected from methanol, ethanol, isopropanol, acetone, acetonitrile, dichloromethane, chloroform, tetrahydrofuran, 1,4 -Any one or a combination of dioxane, ethyl acetate, toluene, dimethyl sulfoxide, N,N-dimethylformamide.
  18. 根据权利要求16或17所述的制备PAC-1晶型A的方法，其中，将装有PAC-1化合物的敞口容器放置在装有正溶剂的密封容器中，在室温条件下静置。The method for preparing PAC-1 crystal form A according to claim 16 or 17, wherein the open container filled with the PAC-1 compound is placed in a sealed container filled with a positive solvent and left standing at room temperature.
  19. 一种应用缓慢降温法制备PAC-1晶型A的方法，其中，其包括：将PAC-1化合物溶解在溶剂中，在30～140℃下加热，溶液变澄清后过滤，将滤液从30～140℃缓慢降温至0～25℃，并在0～25℃恒温放置0.1～10天，随后将滤液转移至-20～-5℃条件，放置0.1～10h，收集所得固体得到PAC-1晶型A。A method for preparing PAC-1 crystal form A using a slow cooling method, which comprises: dissolving the PAC-1 compound in a solvent, heating at 30-140°C, filtering the solution after the solution becomes clear, and removing the filtrate from 30 to Slowly lower the temperature from 140℃ to 0～25℃, and keep it at 0～25℃ for 0.1～10 days, then transfer the filtrate to -20～-5℃ for 0.1～10h, collect the solid obtained to obtain PAC-1 crystal form A.
  20. 根据权利要求19所述的制备PAC-1晶型A的方法，其中，其包括：将PAC-1化合物溶解在溶剂中，在50℃下加热，溶液变澄清后过滤，将滤液从50℃缓慢降温至5℃，并在5℃恒温放置5天，随后将滤液转移至-20℃，放置1h，收集所得固体得到PAC-1晶型A。The method for preparing PAC-1 crystal form A according to claim 19, wherein it comprises: dissolving the PAC-1 compound in a solvent, heating at 50°C, filtering the solution after the solution becomes clear, and slowly removing the filtrate from 50°C The temperature was lowered to 5°C and kept at a constant temperature of 5°C for 5 days, and then the filtrate was transferred to -20°C for 1 hour, and the resulting solid was collected to obtain PAC-1 crystal form A.
  21. 根据权利要求19或20所述的制备PAC-1晶型A的方法，其中，所述缓慢降温的速率为0.1～20℃/分钟，优选0.1℃/分钟。The method for preparing PAC-1 crystal form A according to claim 19 or 20, wherein the slow cooling rate is 0.1 to 20°C/min, preferably 0.1°C/min.
  22. 根据权利要求19～21中任一项所述的制备PAC-1晶型A的方法，其中，所述缓慢降温的速率为0.1℃/分钟。The method for preparing PAC-1 crystal form A according to any one of claims 19-21, wherein the rate of the slow cooling is 0.1° C./min.
  23. 根据权利要求19～22中任一项所述的制备PAC-1晶型A的方法，其中，所述溶剂选自异丙醇、甲基叔丁基醚、乙酸丁酯、酒精与水的混合溶剂、四氢呋喃与水的混合溶剂、苯甲醚与正庚烷的混合溶剂、乙腈与正庚烷的混合溶剂中的任意一种或为任意几种的组合。The method for preparing PAC-1 crystal form A according to any one of claims 19-22, wherein the solvent is selected from isopropyl alcohol, methyl tert-butyl ether, butyl acetate, a mixture of alcohol and water Any one or a combination of a solvent, a mixed solvent of tetrahydrofuran and water, a mixed solvent of anisole and n-heptane, and a mixed solvent of acetonitrile and n-heptane.
  24. 一种应用缓慢挥发法制备PAC-1晶型A的方法，其中，其包括：将PAC-1化合物置于容器中，并加入溶剂使PAC-1化合物溶解在溶剂中，配制成澄清溶液，随后缓慢挥发，收集所得固体得到PAC-1晶型A。A method for preparing PAC-1 crystal form A using the slow volatilization method, which comprises: placing the PAC-1 compound in a container and adding a solvent to dissolve the PAC-1 compound in the solvent to prepare a clear solution, and then Slowly evaporate, and collect the obtained solid to obtain PAC-1 crystal form A.
  25. 根据权利要求24所述的制备PAC-1晶型A的方法，其中，所述溶剂选自甲醇、乙醇、乙酸乙酯、丙酮、甲基乙基酮、四氢呋喃、甲苯、乙腈、二氯甲烷、氯仿、甲基叔丁基醚、乙酸中的任意一种或为任意几种的组合。The method for preparing PAC-1 crystal form A according to claim 24, wherein the solvent is selected from methanol, ethanol, ethyl acetate, acetone, methyl ethyl ketone, tetrahydrofuran, toluene, acetonitrile, dichloromethane, Any one or a combination of any of chloroform, methyl tert-butyl ether, and acetic acid.
  26. 根据权利要求24或25所述的制备PAC-1晶型A的方法，其中， 配制成澄清溶液后，在室温下缓慢挥发。The method for preparing PAC-1 crystal form A according to claim 24 or 25, wherein after being prepared into a clear solution, it is slowly volatilized at room temperature.
  27. 根据权利要求24～26中任一项所述的制备PAC-1晶型A的方法，其中，使用封口膜对装有PAC-1化合物的容器进行封口，且封口膜上有小孔。The method for preparing PAC-1 crystal form A according to any one of claims 24 to 26, wherein the container containing the PAC-1 compound is sealed with a sealing film, and the sealing film has small holes.
  28. 一种应用高聚物诱导法制备PAC-1晶型A的方法，其中，其包括：将PAC-1化合物溶解在正溶剂中，并加入高聚物，搅拌后转为挥发，收集所得固体得到PAC-1晶型A。A method for preparing PAC-1 crystal form A using a polymer induction method, which comprises: dissolving PAC-1 compound in a positive solvent, adding polymer, stirring and turning to volatilization, and collecting the obtained solid to obtain PAC-1 crystal form A.
  29. 根据权利要求28所述的制备PAC-1晶型A的方法，其中，所述正溶剂选自甲醇、乙醇、丙酮、四氢呋喃中的任意一种或为任意几种的组合。The method for preparing PAC-1 crystal form A according to claim 28, wherein the positive solvent is selected from any one or a combination of any of methanol, ethanol, acetone, and tetrahydrofuran.
  30. 根据权利要求28或29所述的制备PAC-1晶型A的方法，其中，所述高聚物选自羟丙基甲基纤维素、聚乙烯吡咯烷酮、甲基纤维素、聚乙酸乙烯酯、聚乙烯醇、聚氯乙烯中的任意一种或为任意几种的组合。The method for preparing PAC-1 crystal form A according to claim 28 or 29, wherein the high polymer is selected from hydroxypropyl methyl cellulose, polyvinylpyrrolidone, methyl cellulose, polyvinyl acetate, Any one of polyvinyl alcohol and polyvinyl chloride or a combination of any of them.
  31. 根据权利要求28～30中任一项所述的制备PAC-1晶型A的方法，其中，在室温下搅拌后转为挥发。The method for preparing PAC-1 crystal form A according to any one of claims 28 to 30, wherein the PAC-1 crystal form A is stirred at room temperature and then turned into volatilization.
  32. 一种应用湿度诱导法制备PAC-1晶型A的方法，其中，其包括：将装有PAC-1化合物的容器置于湿度为5～100％的干燥器中，0.1～10天后收集固体得到PAC-1晶型A。A method for preparing PAC-1 crystal form A using a humidity induction method, which comprises: placing a container containing PAC-1 compound in a desiccator with a humidity of 5-100%, and collecting the solid after 0.1-10 days PAC-1 crystal form A.
  33. 根据权利要求32所述的制备PAC-1晶型A的方法，其中，其包括：将装有PAC-1化合物的容器置于湿度为45％～100％的干燥器中，7天后收集固体得到PAC-1晶型A。The method for preparing PAC-1 crystal form A according to claim 32, wherein it comprises: placing the container containing the PAC-1 compound in a desiccator with a humidity of 45% to 100%, and collecting the solid after 7 days PAC-1 crystal form A.
  34. 根据权利要求32或33所述的制备PAC-1晶型A的方法，其中，使用封口膜对装有PAC-1化合物的容器进行封口，且封口膜上有小孔，然后再将装有PAC-1化合物的容器置于干燥器中。The method for preparing PAC-1 crystal form A according to claim 32 or 33, wherein the container containing the PAC-1 compound is sealed with a sealing film, and the sealing film has small holes, and then the PAC -1 The container of the compound is placed in a desiccator.
  35. 一种应用研磨转晶法制备PAC-1晶型A的方法，其中，其包括：将PAC-1化合物在5～50℃的条件下研磨1～80分钟，得到PAC-1晶型A。A method for preparing PAC-1 crystal form A by using a grinding-to-crystal method, which comprises: grinding the PAC-1 compound at 5-50° C. for 1 to 80 minutes to obtain PAC-1 crystal form A.
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