WO2022121854A1 - 2-羟基-5-[2-(4-(三氟甲基苯基)乙基氨基)]苯甲酸晶型及其制备方法 - Google Patents

2-羟基-5-[2-(4-(三氟甲基苯基)乙基氨基)]苯甲酸晶型及其制备方法 Download PDF

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WO2022121854A1
WO2022121854A1 PCT/CN2021/135807 CN2021135807W WO2022121854A1 WO 2022121854 A1 WO2022121854 A1 WO 2022121854A1 CN 2021135807 W CN2021135807 W CN 2021135807W WO 2022121854 A1 WO2022121854 A1 WO 2022121854A1
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crystal form
crystal
crystallization
trifluoromethylphenyl
ethylamino
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PCT/CN2021/135807
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English (en)
French (fr)
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徐新良
张国庆
庄程翰
王磊
郭秉周
安春山
金京玉
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吉恩特药业株式会社
徐新良
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Application filed by 吉恩特药业株式会社, 徐新良 filed Critical 吉恩特药业株式会社
Priority to IL303409A priority Critical patent/IL303409A/en
Priority to CA3201367A priority patent/CA3201367A1/en
Priority to KR1020237022713A priority patent/KR20230117408A/ko
Priority to EP21902559.0A priority patent/EP4261202A1/en
Priority to US18/256,350 priority patent/US20240116853A1/en
Priority to JP2023534972A priority patent/JP2024500665A/ja
Priority to AU2021395052A priority patent/AU2021395052A1/en
Publication of WO2022121854A1 publication Critical patent/WO2022121854A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/52—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C229/54—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C229/64—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring the carbon skeleton being further substituted by singly-bound oxygen atoms
    • 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
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/38—Separation; Purification; Stabilisation; Use of additives
    • C07C227/40—Separation; Purification
    • C07C227/42—Crystallisation
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Definitions

  • the present invention requires a crystalline form of 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoic acid submitted in China on December 08, 2020 and its preparation method ”, the priority of the invention patent application with application number 202011443509.5, the entire content of which is incorporated herein by reference.
  • the invention belongs to the technical field of pharmaceutical crystal forms, in particular to crystal forms I and II of 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoic acid, and the two crystal forms of Preparation methods, and uses of the two crystal forms.
  • AD Alzheimer's disease
  • senile dementia is a degenerative disease of the central nervous system characterized by progressive cognitive impairment and memory impairment, and dementia is its most prominent psychiatric symptom. Since the etiology and pathogenesis of the disease are not yet clear, there is still no effective treatment for the cause.
  • drugs have been found to improve the memory ability, cognitive function, and delay aging of patients with Alzheimer's disease. etc. have a good effect.
  • the research and development of drugs for the treatment of senile dementia has attracted great attention from the medical community around the world.
  • Korea GNT Pharma Co., Ltd. has developed a compound that has a good effect on the treatment of Alzheimer's disease, Parkinson's disease and other neurological diseases.
  • the Chinese name is 2- Hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoic acid
  • the English name is 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoic acid
  • the structure is shown below.
  • the company's Chinese invention patent application CN 101874016 A discloses the compound and its preparation technology. Clinical trials have shown that the compound has a good inhibitory effect on Alzheimer's disease, but its appearance and microscopic morphology are not described.
  • the invention provides a kind of 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethyl) which is suitable for industrial production, and has the advantages of large crystal particles, complete structure, good fluidity and favorable preparation. Amino)] crystalline forms I and II of benzoic acid and preparation methods and medicinal uses thereof.
  • the present invention provides the crystal form I of 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoic acid, and its crystallographic parameters are as follows:
  • the X-ray powder diffraction pattern (XRPD) of the crystalline form I has characteristic peaks at 2 ⁇ values of 16.1 ⁇ 0.2°, 19.4 ⁇ 0.2°, 22.9 ⁇ 0.2°, 27.3 ⁇ 0.2° and 28.4 ⁇ 0.2°.
  • the XRPD values of the crystal form I are 6.9 ⁇ 0.2°, 13.6 ⁇ 0.2°, 20.5 ⁇ 0.2°, 21.9 ⁇ 0.2°, 22.6 ⁇ 0.2°, 25.1 ⁇ 0.2°, 25.7 ⁇ 0.2° and 34.3 At least one part of ⁇ 0.2° has a characteristic peak.
  • the XRPD of the crystal form I has 2 ⁇ values of 12.9 ⁇ 0.2°, 17.4 ⁇ 0.2°, 29.0 ⁇ 0.2°, 29.7 ⁇ 0.2°, 31.4 ⁇ 0.2°, 34.8 ⁇ 0.2°, 36.0 ⁇ 0.2°, At least one of 36.5 ⁇ 0.2° and 39.1 ⁇ 0.2° has characteristic peaks.
  • the differential scanning calorimetry (DSC) of the crystal form I has an endothermic peak at 249-252°C.
  • the morphology of the crystal form I is a random block, and the average particle size is 50 ⁇ m.
  • the present invention provides the crystal form II of 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoic acid, and its crystallographic parameters are as follows:
  • the X-ray powder diffraction pattern (XRPD) of the crystal form II has characteristic peaks at 2 ⁇ values of 6.8 ⁇ 0.2°, 13.5 ⁇ 0.2°, 27.2 ⁇ 0.2° and 28.3 ⁇ 0.2°.
  • the XRPD of the crystal form II has characteristic peaks at at least one of 2 ⁇ values of 16.0 ⁇ 0.2°, 20.4 ⁇ 0.2°, 22.4 ⁇ 0.2° and 34.2 ⁇ 0.2°.
  • the XRPD of the crystal form II is characterized by at least one of 2 ⁇ values of 19.3 ⁇ 0.2°, 22.7 ⁇ 0.2°, 23.1 ⁇ 0.2°, 24.5 ⁇ 0.2°, 25.0 ⁇ 0.2° and 26.0 ⁇ 0.2° peak.
  • the differential scanning calorimetry (DSC) of the crystal form II has an endothermic peak at 247-250°C.
  • the morphology of the crystal form II is a regular rod shape, and the average particle size is 18 ⁇ m.
  • a third aspect, the present invention provides the preparation method of above-mentioned crystal form I, it comprises the following steps:
  • the good solvent is selected from at least one of methanol, ethanol, isopropanol, tetrahydrofuran and dimethyl sulfoxide, preferably at least one of ethanol and isopropanol.
  • the dosage ratio of the crude product to the good solvent is 1 g: 5-300 mL.
  • the target temperature of the heating is 50-80°C.
  • the target temperature of the slow cooling and crystallization is 0°C or lower, and the cooling rate is 3°C/min or lower.
  • the ambient temperature for crystallization of the constant temperature volatile solvent is 10-30°C.
  • the target temperature of the temperature-raising evaporation solvent crystallization is above 80°C.
  • the anti-solvent used in the added anti-solvent crystallization is selected from at least one of water, acetonitrile, diethyl ether, acetone, petroleum ether, n-hexane and n-heptane, preferably water and petroleum ether.
  • volume ratio of the anti-solvent to the good solvent is 1-5:1, preferably 2:1.
  • the present invention provides a method for preparing the above-mentioned crystal form II, which comprises the following steps:
  • the good solvent is selected from at least one of methanol, ethanol and tetrahydrofuran, preferably at least one of methanol and ethanol.
  • the dosage ratio of the crude product to the good solvent is 1 g: 5-300 mL.
  • the target temperature of the heating is 50-80°C.
  • the target temperature of the rapid cooling and crystallization is below 0°C, and the cooling rate is above 5/min.
  • the present invention provides a pharmaceutical composition comprising the above-mentioned crystal form I and/or crystal form II, and at least one pharmaceutically acceptable carrier.
  • the present invention provides the use of the above-mentioned crystal form I and/or crystal form II in the preparation of a medicament for preventing and/or treating degenerative diseases of the central nervous system.
  • the central nervous system degenerative disease is selected from at least one of Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, preferably Alzheimer's disease .
  • crystal forms I and II of 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoic acid provided by the present invention and their preparation methods are that : 1) the process is simple, the cost is low, and the yield is as high as 90% or more; 2) the crystal forms I and II have high crystal purity, complete crystal form, good fluidity, convenient preparation, and have better apparent solubility than raw materials.
  • Fig. 1 is the XRPD spectrum of 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoic acid crystal form I prepared in Example 1, including the initial and three Spectra of samples after monthly stability test.
  • FIG. 3 is a SEM photograph of the crystalline form I of 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoic acid prepared in Example 1.
  • FIG. 3 is a SEM photograph of the crystalline form I of 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoic acid prepared in Example 1.
  • Figure 5 is the XRPD spectrum of the crystalline form II of 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoic acid prepared in Example 5, including the initial and three Spectra of samples after monthly stability test.
  • FIG. 6 is the DSC spectrum of 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoic acid crystal form II prepared in Example 5.
  • FIG. 6 is the DSC spectrum of 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoic acid crystal form II prepared in Example 5.
  • FIG. 7 is a SEM photograph of the crystalline form II of 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoic acid prepared in Example 5.
  • FIG. 7 is a SEM photograph of the crystalline form II of 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoic acid prepared in Example 5.
  • FIG. 8 is a particle size distribution diagram of crystal form II of 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoic acid prepared in Example 5.
  • FIG. 8 is a particle size distribution diagram of crystal form II of 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoic acid prepared in Example 5.
  • the present invention provides two crystal forms of 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoic acid, namely crystal form I and crystal form II.
  • the present invention provides preparation methods of the above two crystal forms.
  • the present invention provides a pharmaceutical composition comprising at least one of the above two crystal forms.
  • the present invention provides the pharmaceutical use of at least one of the above two crystal forms.
  • the crystal form I and crystal form II of the present invention can be characterized by methods such as X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), scanning electron microscope (SEM), etc. System, space group, unit cell parameters, number of molecules per cell and other parameters.
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • SEM scanning electron microscope
  • System space group, unit cell parameters, number of molecules per cell and other parameters.
  • the above-mentioned method can adopt parameter settings in routine operations in the field, and can be adjusted or changed as appropriate according to the specific physical and chemical properties of the substance to be tested.
  • the experimental conditions of X-ray powder diffraction are as follows: X-ray powder diffractometer (radiation source Cu-k ⁇ , ) test, scan the XRPD spectrum with a 2 ⁇ value of 3 to 40°.
  • the XRPD spectra of the crystal form I in Example 1 and the crystal form II in Example 2 are shown in FIG. 1 and FIG. 5 , respectively, and the XRPD data are shown in Table 1.
  • the crystal form I in Example 1 and the crystal form II in Example 2 were placed under the conditions of 40° C. and 60% relative humidity (RH) for three months and then subjected to powder diffraction test. The results were respectively As shown in Figures 1 and 5.
  • the experimental conditions for differential scanning calorimetry analysis are as follows: accurately weigh 3-10 mg of the sample and package it in an aluminum crucible, and heat it from 30 °C to 300 °C at a heating rate of 10 °C/min under nitrogen protection. °C, and record the relevant spectrum.
  • the DSC spectra of the crystal form I in Example 1 and the crystal form II in Example 2 are shown in Figure 2 and Figure 6 respectively.
  • the melting point of Form II is 248.77°C.
  • the SEM photographs of the crystal form I in Example 1 and the crystal form II in Example 2 are shown in FIG. 3 and FIG. 7 , respectively.
  • the morphology of the crystal form I of the present invention is roughly in the form of a random block, and the average particle size is about 50 ⁇ m, as shown in FIG. 4 .
  • the morphology of the crystal form II of the present invention is roughly in the shape of a regular rod, and the average particle size is about 18 ⁇ m, as shown in FIG. 8 .
  • the crystal form I of the present invention can be prepared by the following preparation method: adding crude 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoic acid into a good solvent (or called In the main solvent), stir and heat until the solid is completely dissolved, filter while hot, carry out slow cooling crystallization to the filtrate, constant temperature volatilizing solvent crystallization, heating evaporation solvent crystallization or adding anti-solvent crystallization to obtain crystal form I.
  • the good solvent for dissolving the crude 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoic acid can be either a solvent , it can also be a mixture of two or more solvents in any ratio, for example, it can be selected from at least one of methanol, ethanol, isopropanol, tetrahydrofuran and dimethyl sulfoxide.
  • the good solvent for dissolving crude 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoic acid can be selected from ethanol and At least one of isopropanol.
  • the target product can be obtained by various crystallization methods, such as slow cooling crystallization, constant temperature volatile solvent crystallization, heating evaporation solvent crystallization, adding anti-solvent crystallization and the like.
  • the crystal form I can be prepared by the method of slow cooling and crystallization.
  • the target temperature of the slow cooling and crystallization can be below 0 °C, that is, the crude product dissolved filtrate is slowly cooled to a temperature of 0 °C or lower, so as to form a supersaturated solution at a lower temperature, and then realize crystallization
  • the cooling rate of the slow cooling and crystallization can be below 3°C/min, that is, the temperature of the crude product solution filtrate is lowered to the target temperature at a rate of 3°C or slower per minute.
  • the crystalline form I can be prepared by the method of crystallization by evaporating the solvent at a constant temperature.
  • the ambient temperature for the crystallization of the constant temperature volatile solvent can be 10-30°C, that is, the temperature of the crude product dissolved filtrate is first lowered to an ambient temperature of 10-30°C, and then under the condition of constant ambient temperature, the solvent is evaporated by volatilizing the solvent. A supersaturated solution is formed, thereby achieving crystallization.
  • the crystal form I can be prepared by the method of crystallization by evaporating the solvent at elevated temperature.
  • the target temperature for the crystallization of the temperature-increasing evaporation solvent can be above 80°C, that is, the crude product solution filtrate is heated to a temperature of 80°C or higher, and a supersaturated solution is formed by evaporating the solvent, thereby realizing crystallization.
  • the elevated temperature evaporation solvent crystallization can be carried out under a certain degree of vacuum in order to speed up the solvent removal rate.
  • Form I can be prepared by adding an anti-solvent for crystallization.
  • the anti-solvent (or sub-solvent) can be either a solvent or a mixture of two or more solvents in any ratio, for example, it can be selected from water, acetonitrile, ether, acetone, petroleum ether, n-hexane and n-hexane At least one of heptane.
  • the dosage of the anti-solvent can be controlled, for example, the dosage ratio (eg, volume ratio) of the anti-solvent to the good solvent can be 1-5:1. In a more preferred embodiment of the invention, the amount ratio (eg, volume ratio) of anti-solvent to good solvent may be 2:1.
  • the crystal form II of the present invention can be prepared by the following preparation method: adding crude 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoic acid into a good solvent, stirring and heating until the solid is completely dissolved, filtered while hot, and the filtrate is rapidly cooled for crystallization or freeze-dried for crystallization to obtain crystal form II.
  • the good solvent for dissolving crude 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoic acid can also be a solvent , or a mixture of two or more solvents in any proportion, such as at least one selected from methanol, ethanol and tetrahydrofuran.
  • the good solvent for dissolving crude 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoic acid can be selected from methanol and At least one of ethanol.
  • the amount of good solvent used to dissolve crude 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoic acid can be controlled, such as
  • the dosage ratio of the crude product to the good solvent can be 1 g: 5-300 mL.
  • a good solvent for dissolving crude 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoic acid can be heated, for example, Heated to 50 ⁇ 80 °C.
  • the target product can be obtained by various crystallization methods, such as rapid cooling crystallization, freeze-drying crystallization, and the like.
  • the crystal form II can be prepared by the method of rapid cooling and crystallization.
  • the target temperature of the rapid cooling and crystallization can be below 0 °C; in addition, the cooling rate of the rapid cooling and crystallization can be more than 5 °C/min, that is, the temperature of the crude product dissolved filtrate is decreased by 5 °C or more per minute. to the target temperature at a rapid rate.
  • Form II can be prepared by lyophilization crystallization.
  • crystal form I and crystal form II may optionally include post-processing steps, such as filtration, drying, and the like.
  • Form I and Form II of 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoic acid of the present invention may be present in a pharmaceutical composition for administration.
  • pharmaceutical composition refers to a composition that can be used as a medicament, comprising a pharmaceutically active ingredient (API) (eg, Form I and Form II of the present invention) and optionally one or more pharmaceutically acceptable vector.
  • API pharmaceutically active ingredient
  • pharmaceutically acceptable carrier refers to pharmaceutical excipients that are compatible with active pharmaceutical ingredients and are harmless to subjects, including (but not limited to) diluents (or fillers), binders, disintegrants Agents, lubricants, wetting agents, thickeners, glidants, flavoring agents, olfactory agents, preservatives, antioxidants, pH adjusters, solvents, cosolvents, surfactants, etc.
  • a pharmaceutical composition may comprise Form I of the present invention.
  • a pharmaceutical composition may comprise Form II of the present invention.
  • a pharmaceutical composition may comprise both the crystal form I of the present invention and the crystal form II of the present invention, and the two crystal forms may be mixed in any ratio.
  • the above-mentioned pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier.
  • the present invention also provides the use of the above-mentioned crystal form I and/or crystal form II in the preparation of a medicament for preventing and/or treating degenerative diseases of the central nervous system.
  • AD Alzheimer's disease
  • PD Parkinson's disease
  • HD Huntington's disease
  • amyotrophic lateral sclerosis amyotrophic lateral sclerosis
  • the degenerative disease of the central nervous system may be selected from at least one of Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis.
  • the degenerative disease of the central nervous system may be Alzheimer's disease.
  • Example 1 Preparation and physicochemical identification of the crystal form I of the present invention.
  • Step 2 Slowly cool down and crystallize:
  • the above dissolving filtrate was lowered to -5°C at a cooling rate of 3°C/min. This process was accompanied by the precipitation of white precipitates, and kept at -5°C for 1 h until no more precipitates were formed, suction filtration, and drying.
  • the target product (95.6% yield).
  • Crystal stability test place a certain amount of samples at 40°C and 60% RH for three months to test the powder diffraction results, as shown in Figure 1. It can be seen from Figure 1 that after long-term storage, the diffraction characteristic peaks of the samples are consistent with the initial ones, indicating that the crystal form is stable and has not changed, and the crystal form I has long-term stability.
  • the particle size and distribution were tested by a particle size analyzer, and the average particle size was about 50 ⁇ m, as shown in Figure 4.
  • Example 2 Preparation and physicochemical identification of the crystal form I of the present invention.
  • Example 3 Preparation and physicochemical identification of the crystal form I of the present invention.
  • Step 2 Evaporate the solvent at high temperature for crystallization:
  • the above-mentioned dissolving filtrate was heated to 90°C, and the solvent was volatilized under a certain degree of vacuum (-0.12MPa). This process was accompanied by the precipitation of white precipitates, until the solvent volatilized completely and no more precipitates were formed, suction filtration, and drying.
  • the target product (98.1% yield).
  • Example 4 Preparation and physicochemical identification of the crystal form I of the present invention.
  • Example 5 Preparation and physicochemical identification of the crystal form II of the present invention.
  • the above-mentioned dissolving filtrate is reduced to 0 °C with the cooling rate of 8 °C/min, and this process is accompanied by the precipitation of white precipitate, and is incubated at 0 °C until no more precipitation is formed, suction filtration, and drying to obtain the target product ( The yield was 92.7%).
  • Crystal stability test place a certain amount of samples at 40° C. and 60% RH for three months, and test the powder diffraction results, as shown in FIG. 5 . It can be seen from Figure 5 that after long-term storage, the diffraction characteristic peaks of the sample are basically the same as the initial ones, indicating that the crystal form is relatively stable, and the crystal form II has a certain long-term stability.
  • the particle size and distribution of the particles were tested by a particle size analyzer, and the average particle size was about 18 ⁇ m, as shown in Figure 8.
  • Example 6 Preparation and physicochemical identification of the crystal form II of the present invention.
  • Step 2 Freeze drying and crystallization:
  • the above-mentioned dissolving filtrate was frozen at -40° C. to form a solid, put into a freeze dryer, and taken out after vacuum drying to obtain the target product (the yield was 99.7%).

Abstract

本发明属于药物晶型技术领域，具体涉及2-羟基-5-[2-(4-(三氟甲基苯基)乙基氨基)]苯甲酸晶型及其制备方法。晶型I为单斜晶系，Pc空间群，可以通过慢速降温、恒温挥发溶剂、升温蒸发溶剂或添加反溶剂的析晶方式获得。晶型II为三斜晶系，P1空间群，可以通过快速降温或冻干等析晶方式获得。本发明的两种晶型及其制法的优点在于：1)工艺简单，成本低廉，收率高达90％以上；2)晶型I和II的晶型纯度高、晶形完整、流动性好，便于制剂，特别是制备用于预防和/或治疗中枢神经系统退行性疾病的药物制剂，并且具有优于原料的表观溶解度。

Description

2-羟基-5-[2-(4-(三氟甲基苯基)乙基氨基)]苯甲酸晶型及其制备方法
相关申请的交叉引用
本发明要求2020年12月08日在中国提交的，名称为“2-羟基-5-[2-(4-(三氟甲基苯基)乙基氨基)]苯甲酸晶型及其制备方法”、申请号为202011443509.5的发明专利申请的优先权，通过引用的方式将该专利申请的全部内容并入本文。
技术领域
本发明属于药物晶型技术领域，具体涉及2-羟基-5-[2-(4-(三氟甲基苯基)乙基氨基)]苯甲酸的晶型I和II，两种晶型的制备方法，以及两种晶型的用途。
背景技术
老年痴呆症，即阿尔茨海默氏症(AD)，是一种以进行性认知障碍和记忆力损害为主的中枢神经系统退行性疾病，痴呆是其最突出的精神症状。由于该病的病因及发病机制尚未明了，目前仍缺乏特效的病因治疗方法，不过根据医药学家多年来的研究发现，有许多药物在改善老年痴呆患者的记忆能力、认知功能，以及延缓衰老等方面具有良好的作用。治疗老年痴呆药物的研发已引起世界各国医药界的高度重视，随着对于老年人神经生理、生化、药理等方面研究的不断深入，相关药物的开发研究也不断取得进展。
韩国GNT Pharma Co.,Ltd.(吉恩特药业株式会社)开发了一种对治疗阿尔兹海默氏症、帕金森氏症等神经性疾病有较好疗效的化合物，中文名称为2-羟基-5-[2-(4-(三氟甲基苯基)乙基氨基)]苯甲酸，英文名称为2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoic acid，结构如下所示。
Figure PCTCN2021135807-appb-000001
该公司的中国发明专利申请CN 101874016 A公开了该化合物及其制备技术，临床试验表明该化合物对阿尔兹海默氏症具有良好的抑制效果，但并未对其外观性状及微观形态进行描述。
发明内容
发明要解决的问题
本发明提供了一种适合工业化生产，且制得的晶体颗粒大、结构完整、流动性好、利于制剂的2-羟基-5-[2-(4-(三氟甲基苯基)乙基氨基)]苯甲酸的晶型I和II及其制备方法和医药用途。
用于解决问题的方案
本发明通过不同的工艺过程制备了一系列2-羟基-5-[2-(4-(三氟甲基苯基)乙基氨基)]苯甲酸产品，发现其固体呈现出两种较稳定的晶体形式，命名为晶型I和II。
第一方面，本发明提供了2-羟基-5-[2-(4-(三氟甲基苯基)乙基氨基)]苯甲酸的晶型I，其晶体学参数如下：
晶系：单斜晶系；
空间群：Pc；
晶胞参数：
Figure PCTCN2021135807-appb-000002
α＝90°，β＝98.7472°，γ＝90°；
单胞分子数：Z＝2。
此外，所述晶型I的X射线粉末衍射图(XRPD)在2θ值为16.1±0.2°、19.4±0.2°、22.9±0.2°、27.3±0.2°和28.4±0.2°处具有特征峰。
进一步地，所述晶型I的XRPD在2θ值为6.9±0.2°、13.6±0.2°、20.5±0.2°、21.9±0.2°、22.6±0.2°、25.1±0.2°、25.7±0.2°和34.3±0.2°的至少一处具有特征峰。
更进一步地，所述晶型I的XRPD在2θ值为12.9±0.2°、17.4±0.2°、29.0±0.2°、29.7±0.2°、31.4±0.2°、34.8±0.2°、36.0±0.2°、36.5±0.2°和39.1±0.2°的至少一处具有特征峰。
更进一步地，所述晶型I的XRPD如图1所示。
此外，所述晶型I的差式扫描量热分析图(DSC)在249～252℃处具有吸热峰。
进一步地，所述晶型I的DSC如图2所示。
此外，所述晶型I的形貌为无规则的块状，平均粒径为50μm。
第二方面，本发明提供了2-羟基-5-[2-(4-(三氟甲基苯基)乙基氨基)]苯甲酸的晶型II，其晶体学参数如下：
晶系：三斜晶系；
空间群：P1；
晶胞参数：
Figure PCTCN2021135807-appb-000003
α＝89.9804(7)°，β＝79.7108(12)°，γ＝80.6128(8)°；
单胞分子数：Z＝2。
此外，所述晶型II的X射线粉末衍射图(XRPD)在2θ值为6.8±0.2°、13.5±0.2°、27.2±0.2°和28.3±0.2°处具有特征峰。
进一步地，所述晶型II的XRPD在2θ值为16.0±0.2°、20.4±0.2°、22.4±0.2°和34.2±0.2°的至少一处具有特征峰。
更进一步地，所述晶型II的XRPD在2θ值为19.3±0.2°、22.7±0.2°、23.1±0.2°、24.5±0.2°、25.0±0.2°和26.0±0.2°的至少一处具有特征峰。
更进一步地，所述晶型II的XRPD如图5所示。
此外，所述晶型II的差示扫描量热分析图(DSC)在247～250℃处具有吸热峰。
进一步地，所述晶型II的DSC如图6所示。
此外，所述晶型II的形貌为规则的棒状，平均粒径为18μm。
第三方面，本发明提供了上述晶型I的制备方法，其包括下列步骤：
将2-羟基-5-[2-(4-(三氟甲基苯基)乙基氨基)]苯甲酸粗品加入到良溶剂中，搅拌并加热，直至固体完全溶解，趁热过滤，对滤液进行慢速降温析晶、恒温挥发溶剂析晶、升温蒸发溶剂析晶或添加反溶剂析晶，得到晶型I。
进一步地，所述良溶剂选自甲醇、乙醇、异丙醇、四氢呋喃和二甲基亚砜中的至少一种，优选乙醇和异丙醇中的至少一种。
进一步地，所述粗品与所述良溶剂的用量比为1g:5～300mL。
进一步地，所述加热的目标温度为50～80℃。
进一步地，所述慢速降温析晶的目标温度为0℃以下，降温速率为3℃/min以下。
进一步地，所述恒温挥发溶剂析晶的环境温度为10～30℃。
进一步地，所述升温蒸发溶剂析晶的目标温度为80℃以上。
进一步地，所述添加反溶剂析晶所使用的反溶剂选自水、乙腈、乙醚、丙酮、石油醚、正己烷和正庚烷中的至少一种，优选水和石油醚。
更进一步地，所述反溶剂与所述良溶剂的体积比为1～5:1，优选2:1。
第四方面，本发明提供了上述晶型II的制备方法，其包括下列步骤：
将2-羟基-5-[2-(4-(三氟甲基苯基)乙基氨基)]苯甲酸粗品加入到良溶剂中，搅拌并加热，直至固体完全溶解，趁热过滤，对滤液进行快速降温析晶或冻干析晶，得到晶型II。
进一步地，所述良溶剂选自甲醇、乙醇和四氢呋喃中的至少一种，优选甲醇和乙醇中的至少一种。
进一步地，所述粗品与所述良溶剂的用量比为1g:5～300mL。
进一步地，所述加热的目标温度为50～80℃。
进一步地，所述快速降温析晶的目标温度为0℃以下，降温速率为5/min以上。
第五方面，本发明提供了一种药物组合物，其包含上述晶型I和/或晶型II，以及至少一种药学上可接受的载体。
第六方面，本发明提供了上述晶型I和/或晶型II在制备用于预防和/或治疗中枢神经系统退行性疾病的药物中的用途。
进一步地，所述中枢神经系统退行性疾病选自阿尔茨海默氏症、帕金森氏症、亨廷顿氏症、肌萎缩性脊髓侧索硬化症中的至少一种，优选阿尔茨海默氏症。
发明的效果
本发明提供的2-羟基-5-[2-(4-(三氟甲基苯基)乙基氨基)]苯甲酸的两种晶型(晶型I和II)及其制备方法的优点在于：1)工艺简单，成本低廉，收率高达90％以上；2)晶型I和II的晶型纯度高、晶形完整、流动性好，便于制剂，并且具有优于原料的表观溶解度。
附图说明
图1为实施例1制备的2-羟基-5-[2-(4-(三氟甲基苯基)乙基氨基)]苯甲酸晶型I的XRPD谱图，其中包括初始时以及三个月稳定性试验后的样品谱图。
图2为实施例1制备的2-羟基-5-[2-(4-(三氟甲基苯基)乙基氨基)]苯甲酸晶型I的DSC谱图。
图3为实施例1制备的2-羟基-5-[2-(4-(三氟甲基苯基)乙基氨基)]苯甲酸晶型I的SEM照片。
图4为实施例1制备的2-羟基-5-[2-(4-(三氟甲基苯基)乙基氨基)]苯甲酸晶型I的粒径分布图。
图5为实施例5制备的2-羟基-5-[2-(4-(三氟甲基苯基)乙基氨基)]苯甲酸晶型II的XRPD谱图，其中包括初始时以及三个月稳定性试验后的样品谱图。
图6为实施例5制备的2-羟基-5-[2-(4-(三氟甲基苯基)乙基氨基)]苯甲酸晶型II的DSC谱图。
图7为实施例5制备的2-羟基-5-[2-(4-(三氟甲基苯基)乙基氨基)]苯甲酸晶型II的SEM照片。
图8为实施例5制备的2-羟基-5-[2-(4-(三氟甲基苯基)乙基氨基)]苯甲酸晶型II的粒径分布图。
图9为实施例1至实施例4制备的2-羟基-5-[2-(4-(三氟甲基苯基)乙基氨基)]苯甲酸晶型I的XRPD叠加谱图。
图10为实施例5至实施例6制备的2-羟基-5-[2-(4-(三氟甲基苯基)乙基氨基)]苯甲酸晶型II的XRPD叠加谱图。
具体实施方式
首先，本发明提供了2-羟基-5-[2-(4-(三氟甲基苯基)乙基氨基)]苯甲酸的两种晶型，即晶型I和晶型II。
其次，本发明提供了上述两种晶型的制备方法。
再次，本发明提供了一种药物组合物，其包含上述两种晶型中的至少一种。
最后，本发明提供了上述两种晶型中的至少一种的制药用途。
2-羟基-5-[2-(4-(三氟甲基苯基)乙基氨基)]苯甲酸的晶型I和II
本发明的晶型I和晶型II可以采用X射线粉末衍射(XRPD)、差示扫描量热分析(DSC)、扫描电子显微镜(SEM)等方法进行表征，并通过粉末多晶指标化获得晶系、空间群、晶胞参数、单胞分子数等参数结果。上述方法可以采用本领域常规操作中的参数设置，并且可以根据待测物质的具体理化性质酌情调整或变化。
X射线粉末衍射
在本发明中，X射线粉末衍射的实验条件如下所述：经X射线粉末衍射仪(辐射源Cu-kα，
Figure PCTCN2021135807-appb-000004
)测试，扫描2θ值为3～40°的XRPD谱图。实施例1中的晶型I和实施例2中的晶型II的XRPD谱图分别如图1和图5所示，XRPD数据如表1所示。为了测试晶型稳定性，将实施例1中的晶型I和实施例2中的 晶型II在40℃和60％相对湿度(RH)条件下放置三个月后进行粉末衍射测试，结果分别如图1和5所示。
表1.本发明的晶型I和II的XRPD数据
Figure PCTCN2021135807-appb-000005
差示扫描量热分析
在本发明中，差示扫描量热分析的实验条件如下所述：精确称量3～10mg样品并封装在铝坩埚里，在氮气保护下以10℃/分钟的升温速率从30℃加热到300℃，并记录相关谱图。实施例1中的晶型I和实施例2中的晶型II的DSC谱图分别如图2和图6所示，二者的升温熔融过程均比较明显，晶型I的熔点为251.89℃，晶型II的熔点为248.77℃。
扫描电子显微镜
实施例1中的晶型I和实施例2中的晶型II的SEM照片分别如图3和图7所示。本发明晶型I的形貌大致呈现为无规则的块状，平均粒径在50μm左右，如图4所示。本发明晶型II的形貌大致呈现为规则的棒状，平均粒径在18μm左右，如图8所示。
2-羟基-5-[2-(4-(三氟甲基苯基)乙基氨基)]苯甲酸的晶型I和II的制备方法
本发明的2-羟基-5-[2-(4-(三氟甲基苯基)乙基氨基)]苯甲酸晶型I和晶型II的制备方法通过对良溶剂和重结晶条件进行选择，最终确定以选自醇类(例如甲醇、乙醇、异丙醇等)、四氢呋喃和二甲基亚砜中的一种或多种的混合物为良溶剂，通过不同的析晶处理方法，得到相应的晶型I和II产品。
本发明的晶型I可以通过下列制备方法制得：将2-羟基-5-[2-(4-(三氟甲基苯基)乙基氨基)]苯甲酸粗品加入到良溶剂(或称主溶剂)中，搅拌并加热，直至固体完全溶解，趁热过滤，对滤液进行慢速降温析晶、恒温挥发溶剂析晶、升温蒸发溶剂析晶或添加反溶剂析晶，得到晶型I。
在本发明的一项实施方案中，用于溶解2-羟基-5-[2-(4-(三氟甲基苯基)乙基氨基)]苯甲酸粗品的良溶剂既可以是一种溶剂，也可以是两种以上溶剂的任意比例的混合物，例如可以选自甲醇、乙醇、异丙醇、四氢呋喃和二甲基亚砜中的至少一种。在本发明的一项优选实施方案中，用于溶解2-羟基-5-[2-(4-(三氟甲基苯基)乙基氨基)]苯甲酸粗品的良溶剂可以选自乙醇和异丙醇中的至少一种。
对于本发明的晶型I而言，可以通过多种析晶方式获得目标产品，例如慢速降温析晶、恒温挥发溶剂析晶、升温蒸发溶剂析晶、添加反溶剂析晶等。
在本发明的一项实施方案中，可以利用慢速降温析晶的方法制备晶型I。具体地，该慢速降温析晶的目标温度可以为0℃以下，即将粗品溶清滤液缓慢冷却至0℃或更低的温度，以便在较低的温度下形成过饱和溶液，进而实现析晶；另外，该慢速降温析晶的降温速率可以为3℃/min以下，即将粗品溶清滤液的温度以每分钟下降3℃或更慢的速率降至目标温度。
在本发明的另一项实施方案中，可以利用恒温挥发溶剂析晶的方法制备晶型I。具体地，该恒温挥发溶剂析晶的环境温度可以为10～30℃，即首先将粗品溶清滤液的温度降低至10～30℃的环境温度，然后在环境温度恒定的条件下，通过挥发溶剂形成过饱和溶液，进而实现析晶。
在本发明的另一项实施方案中，可以利用升温蒸发溶剂析晶的方法制备晶型I。具体地，该升温蒸发溶剂析晶的目标温度可以为80℃以上，即将粗品溶清滤液加热至80℃或更高的温度，通过蒸发溶剂形成过饱和溶液，进而实现析晶。在本发明的一项优选实施方案中，该升温蒸发溶剂析晶可以在一定真空度下进行，以便加快溶剂去除速率。
在本发明的另一项实施方案中，可以利用添加反溶剂析晶的方法制备晶型I。具体地，该反溶剂(或称次溶剂)既可以是一种溶剂，也可以是两种以上溶剂的任意比例的混合物，例如可以选自水、乙腈、乙醚、丙酮、石油醚、正己烷和正庚烷中的至少一种。在发明的一项优选实施方案中，可以控制反溶剂的用量，例如反溶剂与良溶剂的用量比(如体积比)可以为1～5:1。在发明的一项更优选实施方案中，反溶剂与良溶剂的用量比(如体积比)可以为2:1。
本发明的晶型II可以通过下列制备方法制得：将2-羟基-5-[2-(4-(三氟甲基苯基)乙基氨基)]苯甲酸粗品加入到良溶剂中，搅拌并加热，直至固体完全溶解，趁热过滤，对滤液进行快速降温析晶或冻干析晶，得到晶型II。
在本发明的一项实施方案中，用于溶解2-羟基-5-[2-(4-(三氟甲基苯基)乙基氨基)]苯甲酸粗品的良溶剂同样可以是一种溶剂，或者是两种以上溶剂的任意比例的混合物，例如可以选自甲醇、乙醇和四氢呋喃中的至少一种。在本发明的一项优选实施方案中，用于溶解2-羟基-5-[2-(4-(三氟甲基苯基)乙基氨基)]苯甲酸粗品的良溶剂可以选自甲醇和乙醇中的至少一种。
在本发明的一项实施方案中，可以控制用于溶解2-羟基-5-[2-(4-(三氟甲基苯基)乙基氨基)]苯甲酸粗品的良溶剂的用量，例如粗品与良溶剂的用量比可以为1g:5～300mL。
在本发明的一项实施方案中，可以对溶解2-羟基-5-[2-(4-(三氟甲基苯基)乙基氨基)]苯甲酸粗品的良溶剂进行加热处理，例如可以加热至50～80℃。
对于本发明的晶型II而言，可以通过多种析晶方式获得目标产品，例如快速降温析晶、冻干析晶等。
在本发明的一项实施方案中，可以利用快速降温析晶的方法制备晶型II。具体地，该快速降温析晶的目标温度可以为0℃以下；另外，该快速降温析晶的降温速率可以为5℃/min以上，即将粗品溶清滤液的温度以每分钟下降5℃或更快的速率降至目标温度。
在本发明的另一项实施方案中，可以利用冻干析晶的方法制备晶型II。
进一步地，上述晶型I和晶型II的制备方法可以任选地包括后处理步骤，例如过滤、干燥等。
药物组合物
本发明的2-羟基-5-[2-(4-(三氟甲基苯基)乙基氨基)]苯甲酸的晶型I和晶 型II可以存在于药物组合物中加以施用。术语“药物组合物”是指可以用作药物的组合物，其包含药物活性成分(API)(例如本发明的晶型I和晶型II)以及可选的一种或多种药学上可接受载体。术语“药学上可接受的载体”是指与药物活性成分相容并且对受试者无害的药用辅料，包括(但不限于)稀释剂(或称填充剂)、粘合剂、崩解剂、润滑剂、润湿剂、增稠剂、助流剂、矫味剂、矫嗅剂、防腐剂、抗氧化剂、pH调节剂、溶剂、助溶剂、表面活性剂等。
在本发明的一项实施方案中，一种药物组合物可以包含本发明的晶型I。
在本发明的另一项实施方案中，一种药物组合物可以包含本发明的晶型II。
在本发明的另一项实施方案中，一种药物组合物可以既包含本发明的晶型I，又包含本发明的晶型II，并且两种晶型可以按照任意比例混合。
在本发明的一项优选实施方案中，上述药物组合物还包含至少一种药学上可接受的载体。
医药用途
无论是上述2-羟基-5-[2-(4-(三氟甲基苯基)乙基氨基)]苯甲酸的晶型I或晶型II，还是上述包含晶型I和/或晶型II的药物组合物，都能够用于对抗中枢神经系统退行性疾病。因此，本发明还提供了上述晶型I和/或晶型II在制备用于预防和/或治疗中枢神经系统退行性疾病的药物中的用途。
术语“中枢神经系统退行性疾病”是指一组由慢性进行性的中枢神经组织退行性变性而产生的疾病的总称。这些疾病包括(但不限于)阿尔茨海默氏症(Alzheimer’s disease,AD)、帕金森氏症(Parkinson’s disease,PD)、亨廷顿氏症(Huntington’s disease,HD)和肌萎缩性脊髓侧索硬化症(amyotrophic lateral sclerosis,ALS)等。
在本发明的一项实施方案中，该中枢神经系统退行性疾病可以选自阿尔茨海默氏症、帕金森氏症、亨廷顿氏症、肌萎缩性脊髓侧索硬化症中的至少一种。
在本发明的一项优选实施方案中，该中枢神经系统退行性疾病可以为阿尔茨海默氏症。
以下将结合具体实施例来说明本发明的技术方案。本领域一般技术人员可以理解的是，下列实施例仅是为了进一步详细叙述本发明，而并不限制本发明的范围。除非另有限定，下列实施例中使用的药品、试剂、材料、仪器 等均可通过常规商业手段获得。
实施例1：本发明的晶型I的制备和理化鉴定。
步骤1：制备粗品溶清滤液
称取2-羟基-5-[2-(4-(三氟甲基苯基)乙基氨基)]苯甲酸粗品(100g)，置于1L烧瓶中，室温下加入乙醇(500mL)，搅拌下将体系升温至50℃，待溶清后，抽滤，除去杂质，得到粗品溶清滤液。
步骤2：缓慢降温析晶：
将上述溶清滤液以3℃/min的降温速率降至-5℃，这一过程伴随着白色沉淀物析出，于-5℃保持1h，直至不再有沉淀生成，抽滤，干燥，即得目标产品(收率为95.6％)。
经XRPD测试，其结果如图1所示，确定为晶型I。
晶型稳定性测试：将一定量样品于40℃、60％RH条件下放置三个月，测试其粉末衍射结果，如图1所示。由图1可知，长期放置后，样品的衍射特征峰与初始时一致，说明晶型稳定，未发生变化，晶型I具有长期稳定性。
经DSC测试，其熔融发生在249～252℃范围内，如图2所示。
取样，经SEM观察，其照片如图3所示，表现为无规则的大颗粒块体。
经粒度仪测试颗粒粒径及分布，平均粒度在50μm左右，如图4所示。
实施例2：本发明的晶型I的制备和理化鉴定。
步骤1：制备粗品溶清滤液
称取2-羟基-5-[2-(4-(三氟甲基苯基)乙基氨基)]苯甲酸粗品(80g)，置于1L烧瓶中，室温下加入异丙醇(560mL)，搅拌下将体系升温至80℃，待溶清后，抽滤，除去杂质，得到粗品溶清滤液。
步骤2：恒温挥发溶剂析晶：
将上述溶清滤液的温度降至30℃的环境温度，并在此恒定温度下自然挥发溶剂，这一过程伴随着白色沉淀物析出，直至溶剂挥发至不再有沉淀生成，抽滤，干燥，即得目标产品(收率为93.8％)。
经XRPD测试，判定其为晶型I，如图9所示。
实施例3：本发明的晶型I的制备和理化鉴定。
步骤1：制备粗品溶清滤液
称取2-羟基-5-[2-(4-(三氟甲基苯基)乙基氨基)]苯甲酸粗品(100g)，置于1L烧瓶中，室温下加入异丙醇(800mL)，搅拌下将体系升温至60℃，待溶 清后，抽滤，除去杂质，得到粗品溶清滤液。
步骤2：高温蒸发溶剂析晶：
将上述溶清滤液加热至90℃，在一定真空度下(-0.12MPa)挥发溶剂，这一过程伴随着白色沉淀物析出，直至溶剂挥发完全不再有沉淀生成，抽滤，干燥，即得目标产品(收率为98.1％)。
经XRPD测试，判定其为晶型I，如图9所示。
实施例4：本发明的晶型I的制备和理化鉴定。
步骤1：制备粗品溶清滤液
称取2-羟基-5-[2-(4-(三氟甲基苯基)乙基氨基)]苯甲酸粗品(50g)，置于1L烧瓶中，室温下加入乙醇(300mL)，搅拌下将体系升温至60℃，待溶清后，抽滤，除去杂质，得到粗品溶清滤液。
步骤2：添加反溶剂析晶：
将水(600mL)缓慢添加到上述溶清滤液中，这一过程伴随着白色沉淀物析出，抽滤，干燥，即得目标产品，(收率为94.2％)。
经XRPD测试，判定其为晶型I，如图9所示。
实施例5：本发明的晶型II的制备和理化鉴定。
步骤1：制备粗品溶清滤液
称取2-羟基-5-[2-(4-(三氟甲基苯基)乙基氨基)]苯甲酸粗品(80g)，置于1L烧瓶中，室温下加入甲醇(400mL)，搅拌下将体系升温至60℃，待溶清后，抽滤，除去杂质，得到粗品溶清滤液。
步骤2：快速降温析晶：
将上述溶清滤液以8℃/min的降温速率降至0℃，这一过程伴随着白色沉淀物析出，于0℃保温，直至不再有沉淀生成，抽滤，干燥，即得目标产品(收率为92.7％)。
经XRPD测试，其结果如图5所示，确定为晶型II。
晶型稳定性测试：将一定量样品于40℃、60％RH条件下放置三个月，测试其粉末衍射结果，如图5所示。由图5可知，长期放置后，样品的衍射特征峰与初始时基本一致，说明晶型比较稳定，晶型II具有一定的长期稳定性。
经DSC测试，其熔融发生在247～250℃范围内，如图6所示。
取样，经SEM观察，其照片如图7所示，表现为较规则的棒状颗粒体。
经粒度仪测试颗粒粒径及分布，平均粒度在18μm左右，如图8所示。
实施例6：本发明的晶型II的制备和理化鉴定。
步骤1：制备粗品溶清滤液
称取2-羟基-5-[2-(4-(三氟甲基苯基)乙基氨基)]苯甲酸粗品(100g)，置于1L烧瓶中，室温下加入乙醇(600mL)，搅拌下将体系升温至50℃，待溶清后，抽滤，除去杂质，得到粗品溶清滤液。
步骤2：冷冻干燥析晶：
将上述溶清滤液于-40℃冷冻成固体，放入冷冻干燥机，真空干燥后取出，即得目标产物(收率为99.7％)。
经XRPD测试，判定其为晶型II，如图10所示。
另外，利用HPLC测试原料粗品以及实施例1和实施例5制得的晶型I和晶型II的表观溶解度，结果表明本发明的晶型I和晶型II显示出较高的表观溶解度，如表2所示。
表2.本发明的晶型I和II与原料的表观溶解度比较结果
Figure PCTCN2021135807-appb-000006

Claims (10)

  1. 2-羟基-5-[2-(4-(三氟甲基苯基)乙基氨基)]苯甲酸的晶型I，其晶体学参数如下：晶系：单斜晶系；空间群：Pc；晶胞参数：
    Figure PCTCN2021135807-appb-100001
    Figure PCTCN2021135807-appb-100002
    α＝90°，β＝98.7472°，γ＝90°；单胞分子数：Z＝2。
  2. 根据权利要求1所述的晶型I，其特征在于，其X射线粉末衍射图在2θ值为16.1±0.2°、19.4±0.2°、22.9±0.2°、27.3±0.2°和28.4±0.2°处具有特征峰，优选其X射线粉末衍射图在2θ值为6.9±0.2°、13.6±0.2°、20.5±0.2°、21.9±0.2°、22.6±0.2°、25.1±0.2°、25.7±0.2°和34.3±0.2°的至少一处具有特征峰，更优选其X射线粉末衍射图在2θ值为12.9±0.2°、17.4±0.2°、29.0±0.2°、29.7±0.2°、31.4±0.2°、34.8±0.2°、36.0±0.2°、36.5±0.2°和39.1±0.2°的至少一处具有特征峰，最优选其X射线粉末衍射图如图1所示。
  3. 根据权利要求1或2所述的晶型I，其特征在于，其差示扫描量热分析图在249～252℃处具有吸热峰，优选其差示扫描量热分析图如图2所示。
  4. 2-羟基-5-[2-(4-(三氟甲基苯基)乙基氨基)]苯甲酸的晶型II，其晶体学参数如下：晶系：三斜晶系；空间群：P1；晶胞参数：
    Figure PCTCN2021135807-appb-100003
    Figure PCTCN2021135807-appb-100004
    α＝89.9804(7)°，β＝79.7108(12)°，γ＝80.6128(8)°；单胞分子数：Z＝2。
  5. 根据权利要求4所述的晶型II，其特征在于，其X射线粉末衍射图在2θ值为6.8±0.2°、13.5±0.2°、27.2±0.2°和28.3±0.2°处具有特征峰，优选其X射线粉末衍射图在2θ值为16.0±0.2°、20.4±0.2°、22.4±0.2°和34.2±0.2°的至少一处具有特征峰，更优选其X射线粉末衍射图在2θ值为19.3±0.2°、22.7±0.2°、23.1±0.2°、24.5±0.2°、25.0±0.2°和26.0±0.2°的至少一处具有特征峰，最优选其X射线粉末衍射图如图5所示。
  6. 根据权利要求4或5所述的晶型II，其特征在于，其差示扫描量热分析图在247～250℃处具有吸热峰，优选其差示扫描量热分析图如图6所示。
  7. 根据权利要求1至3中任一项所述的晶型I的制备方法，其包括下列步骤：
    将2-羟基-5-[2-(4-(三氟甲基苯基)乙基氨基)]苯甲酸粗品加入到良溶剂中，搅拌并加热，直至固体完全溶解，趁热过滤，对滤液进行慢速降温析晶、恒温挥发溶剂析晶、升温蒸发溶剂析晶或添加反溶剂析晶，得到晶型I。
  8. 根据权利要求4至6中任一项所述的晶型II的制备方法，其包括下列步骤：
    将2-羟基-5-[2-(4-(三氟甲基苯基)乙基氨基)]苯甲酸粗品加入到良溶剂中，搅拌并加热，直至固体完全溶解，趁热过滤，对滤液进行快速降温析晶或冻干析晶，得到晶型II。
  9. 一种药物组合物，其包含根据权利要求1至3中任一项所述的晶型I和/或根据权利要求4至6中任一项所述的晶型II，以及至少一种药学上可接受的载体。
  10. 根据权利要求1至3中任一项所述的晶型I和/或根据权利要求4至6中任一项所述的晶型II在制备用于预防和/或治疗中枢神经系统退行性疾病的药物中的用途。
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WU YU-LIANG, XIN LU, XIAO-LI CHEN, ZHANG XING-XIAN: "The synthesis of anti-Alzheimer's disease drug 2-hydroxy-5-2-n4-trifluoro methyl-phenyld-ethylamino -benzoic acid", CHINESE JOURNAL OF NEW DRUGS, vol. 21, no. 16, 30 August 2012 (2012-08-30), CN , pages 1930 - 1932, XP055941237, ISSN: 1003-3734 *

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US20240116853A1 (en) 2024-04-11
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