WO2017071375A1 - Crystal form of deuterated imidazolone compound, and preparation method and use therefor - Google Patents

Crystal form of deuterated imidazolone compound, and preparation method and use therefor Download PDF

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WO2017071375A1
WO2017071375A1 PCT/CN2016/095647 CN2016095647W WO2017071375A1 WO 2017071375 A1 WO2017071375 A1 WO 2017071375A1 CN 2016095647 W CN2016095647 W CN 2016095647W WO 2017071375 A1 WO2017071375 A1 WO 2017071375A1
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dimethyl
oxo
cyano
phenyl
trifluoromethyl
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PCT/CN2016/095647
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French (fr)
Chinese (zh)
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陈元伟
樊磊
匡通滔
耿熙
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成都海创药业有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/86—Oxygen and sulfur atoms, e.g. thiohydantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/72—Two oxygen atoms, e.g. hydantoin
    • 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 present invention relates to a crystalline form I of a deuterated imidazolidone compound, a process for its preparation and use.
  • Deuterated imidazolone compound——4- ⁇ 3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1- Imidazolidinyl ⁇ -2-fluoro-N-tridecanomethylbenzamide is a compound having the following chemical structure:
  • the present invention provides 4- ⁇ 3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl ⁇ -2-Fluoro-N-tridehypo-methylbenzamide, new crystal form I, the crystal form is stable and not easy to be oxidized; and the process of synthesizing crystal form is simple and can be amplified; the solubility in soft capsule content it is good.
  • the present invention provides a deuterated imidazolidinone compound, 4- ⁇ 3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2 Form I of -thio-1-imidazolidinyl ⁇ -2-fluoro-N-tridemethylolbenzamide, the X-ray powder diffraction of the crystal form, the 2 ⁇ diffraction angle is 12.3 ⁇ 0.2, 13.1 ⁇ 0.2 There are characteristic peaks at 15.0 ⁇ 0.2 and 17.5 ⁇ 0.2 degrees.
  • the 2 ⁇ diffraction angle is still 9.8 ⁇ 0.2, 13.5 ⁇ 0.2, 14.3 ⁇ 0.2, 16.7 ⁇ 0.2, 18.9 ⁇ 0.2, 21.1 ⁇ 0.2, 21.8 ⁇ 0.2, 22.8 ⁇ 0.2, and 24.4. There are characteristic peaks at ⁇ 0.2 degrees.
  • the relative intensity values of the characteristic peaks of the 2 ⁇ diffraction angle are:
  • the crystal form has an X-ray powder diffraction pattern substantially as shown in FIG. 1 or 2.
  • the crystalline form has a melting point of 192-209 °C.
  • the crystal form has a DSC pattern substantially as shown in FIG.
  • the present invention also provides a method of preparing the above Form I, comprising the steps of:
  • the crystallization of the step (2) is agitation cooling crystallization; or an anti-solvent is added, and the crystals are cooled by stirring.
  • the solvent is selected from any one of an alcohol, a nitrile, a halogenated hydrocarbon, an amide, a sulfoxide, a halogenated hydrocarbon, an aromatic hydrocarbon, an ester, an ether, a ketone, water, acetic acid or combination.
  • the solvent is selected from the group consisting of ethanol, isopropanol, n-butanol, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, toluene, xylene, and acetic acid Any one of ester, butyl acetate, tetrahydrofuran, acetone, methyl isopropyl ketone, methyl isobutyl ketone, water, acetic acid, or a combination thereof.
  • the solvent and 4- ⁇ 3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo- The volume ratio by weight of 2-thio-1-imidazolidinyl ⁇ -2-fluoro-N-tridecanomethylbenzamide is from 1 to 50:1 mL/g.
  • the temperature is from 0 ° C to the reflux temperature of the solvent.
  • the anti-solvent is water or a C5-C10 hydrocarbon solvent.
  • the crystallization temperature is -20 ° C to 100 ° C, and the preferred crystallization temperature is 3 ° C to room temperature.
  • the method for preparing the above Form I provided by the present invention further comprises:
  • step a) 4- ⁇ 3-[4-Cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl ⁇ a solution of 2-fluoro-N-tridecanomethylbenzamide in a solvent; and b) isolating 4- ⁇ 3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5 Form I of dimethyl-4-oxo-2-thio-1-imidazolidinyl ⁇ -2-fluoro-N-tris-methylbenzamide.
  • the providing solution in step a) comprises:
  • solvents include, but are not limited to, alcohols such as C2-C6 alcohols such as ethanol, 1-propanol, 2-propanol (isopropanol), 1-butanol, 2-butanol, tert-butyl An alcohol; or a nitrile such as acetonitrile or propionitrile; an amide such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone; a sulfoxide such as dimethyl Sulfoxide; halogenated hydrocarbons such as dichloromethane; aromatic hydrocarbons such as toluene, xylene; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, isopropyl acetate, isobutyl acetate, tert-butyl acetate Ester; ether, such as diethyl ether, diiso
  • the dissolution temperature can range from about 0 ° C to about the reflux temperature of the solvent, or less than about 150 ° C, less than about 130 ° C, less than about 100 ° C, less than about 70 ° C, less than about 40 ° C, less than about 20 ° C. , below about 0 ° C, or any other suitable temperature, as long as 4- ⁇ 3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo is obtained A clear solution of oxo-2-thio-1-imidazolidinyl ⁇ -2-fluoro-N-tridecanomethylbenzamide without affecting its mass.
  • the solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow) or any other suitable material to remove color, insoluble materials, improve clarity of the solution, and/or remove adsorbable Impurities on such materials.
  • the solution obtained above can be filtered to remove any insoluble particles.
  • the insoluble particles may be suitably removed by filtration, centrifugation, decantation, or any other suitable technique under pressure or under reduced pressure.
  • the solution can be filtered by passing it through paper, fiberglass, cloth or other membrane material, or a clarifying agent (e.g., or Hyflow) bed. Depending on the equipment used and the concentration and temperature of the solution, it may be necessary to preheat the filtration unit to avoid premature crystallization.
  • Step b) comprises isolating 4- ⁇ 3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo from the solution obtained in step a) Form I of 2-thio-1-imidazolidinyl ⁇ -2-fluoro-N-tridecanomethylbenzamide.
  • Form I of alkyl ⁇ -2-fluoro-N-tridemethylbenzamide comprises cooling, crash cooling, concentrated material, addition of anti-solvent, addition of seed crystals It is carried out by a method of inducing crystallization or evaporation or the like or a combination thereof. Stirring or other alternative methods such as shaking, agitation, etc. can also be used for the separation.
  • these crystals can be used as a seed crystal, and the form R1 can be separated in the presence of the seed crystal of the form R1 in the step (b). .
  • an antisolvent refers to 4- ⁇ 3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1 a liquid in which imidazolyl ⁇ -2-fluoro-N-tridecanomethylbenzamide is sparingly soluble or poorly soluble.
  • the quality of -2-fluoro-N-tridecanomethylbenzamide has no adverse effect and it can help the dissolved raw material to solidify or precipitate.
  • Suitable antisolvents which may be used include, but are not limited to, water; saturated or unsaturated linear or branched, cyclic or acyclic C1-C10 hydrocarbons such as hexane, heptane, cyclohexane or methyl Cyclohexane; an ether such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane or dimethoxyethane; or a mixture thereof.
  • Suitable separation temperatures can be less than about 100 ° C, less than about 80 ° C, less than about 60 ° C, less than about 40 ° C, less than about 20 ° C, less than about 10 ° C, less than about 5 ° C, below About 0 ° C, less than about -10 ° C, less than about -20 ° C, or any other suitable temperature.
  • 2-fluoro-N-tridehypo-methylbenzamide can be used for solids recovery by decantation, centrifugation, evaporation, gravity filtration, suction filtration or under pressure or under reduced pressure. Methods such as technology are recycled.
  • the recovered solid can optionally be dried. The drying may be in a tray dryer, a vacuum oven, an air oven, a cone vacuum dryer, a rotary vacuum dryer, a fluidized bed dryer, a rotary flash dryer, a quick dryer, and the like. get on.
  • the drying may be at atmospheric pressure or reduced pressure at a temperature below about 100 ° C, below about 80 ° C, below about 60 ° C, below about 50 ° C, below about 30 ° C, or at any other suitable temperature.
  • the drying can be carried out any desired number of times until the desired product quality is achieved.
  • the dried product can optionally undergo a size reduction operation to produce the desired particle size. Grinding or micronizing may be carried out before or after drying of the product. Techniques that can be used to reduce particle size include, but are not limited to, ball milling, roll milling and hammer milling, as well as jet milling.
  • the present invention also provides a pharmaceutical composition which is the above 4- ⁇ 3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo Form I prepared on the basis of the crystalline form I of the substituted 2-thio-1-imidazolidinyl ⁇ -2-fluoro-N-tris-methylbenzamide as an active ingredient together with a pharmaceutically acceptable adjuvant.
  • the present invention provides the above 4- ⁇ 3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2- Form I of thio-1-imidazolidinyl ⁇ -2-fluoro-N-tridemethylolbenzamide in the preparation of androgen receptor antagonists, or in the preparation of a disease associated with the treatment or/and prevention of androgen receptor activity The application of the drug.
  • the disease is selected from the group consisting of, but not limited to, hair loss, regenerative hair, acne, acne or prostate cancer.
  • the 2 ⁇ diffraction angle has characteristic peaks at 9.7 ⁇ 0.2, 14.5 ⁇ 0.2, 15.6 ⁇ 0.2, 16.9 ⁇ 0.2, and 25.5 ⁇ 0.2 degrees.
  • the relative intensity values of the characteristic peaks of the 2 ⁇ diffraction angle are:
  • the crystal form has an X-ray powder diffraction pattern substantially as shown in FIG. 4 or FIG.
  • the crystalline form has a melting point of 114-139 °C.
  • the crystal form has a DSC pattern substantially as shown in FIG.
  • the present invention also provides a method of preparing the above Form II, which comprises the steps of:
  • the crystallization of the step (2) is agitation cooling crystallization; or an anti-solvent is added, and the crystals are cooled by stirring.
  • the solvent and 4- ⁇ 3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo- The volume ratio by weight of 2-thio-1-imidazolidinyl ⁇ -2-fluoro-N-tridecanomethylbenzamide is from 2.5 to 10:1 mL/g.
  • the temperature is from 0 ° C to the reflux temperature of the solvent.
  • the anti-solvent is water or a C5-C10 hydrocarbon solvent.
  • the crystallization temperature is -20 ° C to 100 ° C, and the preferred crystallization temperature is 3 ° C to room temperature.
  • the method for preparing the above Form II provided by the present invention further comprises: a) providing 4- ⁇ 3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4- a solution of oxo-2-thio-1-imidazolidinyl ⁇ -2-fluoro-N-tridehypo-methylbenzamide in methanol or formic acid; and b) separation of 4- ⁇ 3-[4-cyano -3-(Trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl ⁇ -2-fluoro-N-tris-methylbenzene Form II of the amide.
  • the providing solution in step a) comprises:
  • step a when 4- ⁇ 3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazole is used.
  • a hydrate of alkyl ⁇ -2-fluoro-N-tridecanomethylbenzamide is used, before or after step a), it can be prepared by techniques known in the art such as distillation, heating, in a suitable solvent. The slurry or the like is subjected to a water reduction or removal step.
  • the dissolution temperature can range from about 0 ° C to about the reflux temperature of the solvent, or less than about 100 ° C, less than about 80 ° C, less than about 60 ° C, less than about 40 ° C, less than about 20 ° C, less than about 10 ° C. , or any other suitable temperature, as long as 4- ⁇ 3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio A clear solution of 1-Imidazolidinyl ⁇ -2-fluoro-N-tridecanomethylbenzamide without affecting its mass.
  • the solution may optionally be treated with carbon, calcined diatomaceous earth (Hyflow) or any other suitable material to remove color, insoluble materials, improve clarity of the solution, and/or remove sorbable materials. Impurities.
  • the solution obtained above can be filtered to remove any insoluble particles.
  • the insoluble particles may be suitably removed by filtration, centrifugation, decantation, or any other suitable technique under pressure or under reduced pressure.
  • the solution can be filtered by passing it through paper, fiberglass, cloth or other membrane material, or a clarifying agent (e.g., or Hyflow) bed. Depending on the equipment used and the concentration and temperature of the solution, it may be necessary to preheat the filtration unit to avoid premature crystallization.
  • Step b) comprises isolating 4- ⁇ 3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo from the solution obtained in step a) Form II of 2-thio-1-imidazolidinyl ⁇ -2-fluoro-N-tridecanomethylbenzamide.
  • the separation can be carried out by combining a suitable antisolvent with the solution obtained in step a).
  • antisolvent refers to 4- ⁇ 3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1- A liquid in which imidazolyl ⁇ -2-fluoro-N-tris-methylbenzamide is sparingly soluble or poorly soluble.
  • Suitable antisolvents which may be used include, but are not limited to, saturated or unsaturated linear or branched, cyclic or acyclic C1-C10 hydrocarbons such as hexane, heptane, cyclohexane or methyl rings.
  • Suitable separation temperatures can be less than about 100 ° C, less than about 80 ° C, less than about 60 ° C, less than about 40 ° C, less than about 20 ° C, less than about 10 ° C, less than about 5 ° C, below About 0 ° C, less than about -10 ° C, less than about -20 ° C, or any other suitable temperature.
  • Isolated 4- ⁇ 3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl ⁇ - Form II of 2-fluoro-N-tridehypo-methylbenzamide can be used by any technique for solids recovery including decantation, centrifugation, gravity filtration, suction filtration or under pressure or under reduced pressure. The method inside is recycled. The recovered solid can optionally be dried. The drying can be carried out in a tray dryer, a vacuum oven, an air oven, a conical vacuum dryer, a rotary vacuum dryer, a fluidized bed dryer, a rotary flash dryer, a quick dryer, and the like.
  • the drying may be at atmospheric pressure or reduced pressure at a temperature below about 100 ° C, below about 80 ° C, below about 60 ° C, below about 50 ° C, below about 30 ° C, or at any other suitable temperature.
  • the drying can be carried out any desired number of times until the desired product quality is achieved.
  • the dried product can optionally undergo a comminution operation to produce the desired particle size. Grinding or micronizing may be carried out before or after drying of the product. Techniques that can be used to reduce particle size include, but are not limited to, ball milling, roller and hammer milling, and jet milling.
  • the present invention also provides a pharmaceutical composition which is the above 4- ⁇ 3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo Form II prepared from -2-thio-1-imidazolidinyl ⁇ -2-fluoro-N-tris-methylbenzamide as an active ingredient, together with a pharmaceutically acceptable adjuvant.
  • the present invention also provides the above 4- ⁇ 3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio Form II of 1-Imidazolidinyl ⁇ -2-fluoro-N-tris-methylbenzamide in the preparation of androgen receptor antagonists, or in the preparation of a medicament for the treatment or/and prevention of androgen receptor activity-related diseases Application in .
  • the disease is selected from the group consisting of hair loss, regenerative hair, acne, acne or prostate cancer.
  • the inventors have repeated the compound obtained in the patent CN201280052853, which has an amorphous form.
  • the amorphous compound has an X-ray powder diffraction pattern substantially as shown in Fig. 7 or Fig. 8.
  • the present invention also provides a method of preparing the above amorphous compound, which comprises the steps of:
  • the solvent is selected from any one of an alcohol, a nitrile, a halogenated hydrocarbon, an amide, a sulfoxide, a halogenated hydrocarbon, an aromatic hydrocarbon, an ester, an ether, a ketone, water, acetic acid or combination.
  • the solvent is selected from the group consisting of methanol, ethanol, isopropanol, n-butanol, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, toluene, xylene, Either ethyl acetate, butyl acetate, tetrahydrofuran, acetone, methyl isopropyl ketone, methyl isobutyl ketone, water, acetic acid, or a combination thereof.
  • the solvent and 4- ⁇ 3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo- The volume ratio by weight of 2-thio-1-imidazolidinyl ⁇ -2-fluoro-N-tridecanomethylbenzamide is from 2.5 to 10:1 mL/g.
  • the temperature is from 0 ° C to the reflux temperature of the solvent.
  • the crystallization temperature is -20 ° C to 100 ° C, and the preferred crystallization temperature is 3 ° C to room temperature.
  • the rapid removal of the solvent means that at least 10 mL of the solvent is removed in 1 minute, and at least 1 g of 4- ⁇ 3-[4-cyano-3-(trifluoro) is dissolved in the solvent.
  • the solvent removal in the step (3) is carried out by rotary evaporation.
  • the rapid precipitation of the solid in the step (3) is carried out by adding an anti-solvent.
  • the anti-solvent is water or a C5-C10 hydrocarbon solvent.
  • the method for preparing the above amorphous compound provided by the present invention further comprises:
  • step a) 4- ⁇ 3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazole
  • a solution of an alkyl ⁇ -2-fluoro-N-tridehypo-methylbenzamide includes:
  • the dissolution temperature can range from about 0 ° C to about the reflux temperature of the solvent, or less than about 60 ° C, less than about 50 ° C, less than about 40 ° C, less than about 30 ° C, less than about 20 ° C, less than about 10 ° C. , or any other suitable temperature, as long as 4- ⁇ 3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio A clear solution of 1-Imidazolidinyl ⁇ -2-fluoro-N-tridecanomethylbenzamide without affecting its mass.
  • the solution may optionally be treated with carbon, calcined diatomaceous earth (Hyflow) or any other suitable material to remove color, insoluble materials, improve clarity of the solution, and/or remove sorbable materials. Impurities.
  • the solution obtained above can be filtered to remove any insoluble particles.
  • the insoluble particles may be suitably removed by filtration, centrifugation, decantation, or any other suitable technique under pressure or under reduced pressure.
  • the solution can be filtered by passing it through paper, fiberglass, cloth or other membrane material, or a clarifying agent (e.g., or Hyflow) bed. Depending on the equipment used and the concentration and temperature of the solution, it may be necessary to preheat the filtration unit to avoid premature crystallization.
  • Suitable solvents include any solvent which does not adversely affect the compound and which can dissolve the starting material to a useful extent.
  • solvents include, but are not limited to, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane or dimethoxyethane; ketones such as acetone, methyl ethyl ketone, methyl isobutyl Ketone or diethyl ketone; esters such as ethyl acetate, propyl acetate, isopropyl acetate or butyl acetate; alcohols such as methanol, ethanol, 1-propanol, 2-propanol (isopropanol), 2 -methoxyethanol, 1-butanol, 2-butanol, isobutanol, tert-butanol, 2-ethoxyethanol, diethylene glycol, 1-pentanol, 2-pentanol or 3-pentanol , neopentyl alcohol, tert-amyl alcohol, diethylene glycol monomethyl ether,
  • Step b) comprises isolating 4- ⁇ 3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo from the solution obtained in step a) Amorphous compound of 2-thio-1-imidazolidinyl ⁇ -2-fluoro-N-tridecanomethylbenzamide.
  • Amorphous compounds of alkyl ⁇ -2-fluoro-N-tris-methylbenzamide may involve removal of solvent, cooling, rapid cooling, concentration of material, evaporation, rapid Evaporation, simple evaporation, spin drying, spray drying, film drying, agitation suction filter drying, pressure suction filter drying, freeze drying, addition of anti-solvent, solvent extraction, and the like. Stirring or other alternative methods such as shaking, agitation, etc. can also be used for the separation.
  • the amorphous compound of -2-fluoro-N-tridecanomethylbenzamide may carry a certain amount of the occluded mother liquor and may have impurities above the desired level. If desired, the amorphous compound can be washed with a solvent or a solvent mixture to wash out the impurities.
  • the key to the preparation of the amorphous compound is to remove the solvent or precipitate the solid in a relatively short period of time to avoid the formation of a crystalline form of the compound, which can be obtained by a method for preparing an amorphous compound which is conventionally used in the art.
  • Suitable separation temperatures can be less than about 120 ° C, less than about 80 ° C, less than about 60 ° C, less than about 40 ° C, less than about 30 ° C, less than about 20 ° C, less than about 10 ° C, below About 0 ° C, less than about -10 ° C, less than about -40 ° C, or any other suitable temperature.
  • an antisolvent refers to 4- ⁇ 3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1 a liquid in which imidazolyl ⁇ -2-fluoro-N-tridecanomethylbenzamide is sparingly soluble or poorly soluble.
  • the inert anti-solvent has no adverse effect on the reaction and it can help the dissolved raw material to solidify or precipitate.
  • Suitable antisolvents which may be used include, but are not limited to, saturated or unsaturated linear or branched, cyclic or acyclic C1-C10 hydrocarbons such as heptane, cyclohexane or methylcyclohexane; Water; or any mixture thereof.
  • the recovered solid can optionally be dried.
  • the drying can be carried out in a tray dryer, a vacuum oven, an air oven, a conical vacuum dryer, a rotary vacuum dryer, a fluidized bed dryer, a rotary flash dryer, a quick dryer, and the like.
  • the drying may be at atmospheric pressure or reduced pressure at a temperature below about 100 ° C, below about 80 ° C, below about 60 ° C, below about 50 ° C, below about 30 ° C, or at any other suitable temperature.
  • the drying can be carried out any desired number of times until the desired product quality is achieved.
  • the dried product can optionally undergo a comminution operation to produce the desired particle size. Grinding or micronizing may be carried out before or after drying of the product. Techniques that can be used to reduce particle size include, but are not limited to, ball milling, roller or hammer milling, or jet milling.
  • the present invention also provides a deuterated imidazolidinone compound, 4- ⁇ 3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo- Amorphous compound of 2-thio-1-imidazolidinyl ⁇ -2-fluoro-N-tridemethylolbenzamide, the amorphous compound Is 4- ⁇ 3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl ⁇ 2-Fluoro-N-tridecanomethylbenzamide is used as a raw material, and is obtained by the above-mentioned method for preparing an amorphous compound or a method for preparing an amorphous compound conventionally used in the art.
  • the present invention also provides a pharmaceutical composition which is the above 4- ⁇ 3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo
  • An amorphous compound of substituted-2-thio-1-imidazolidin ⁇ -2-fluoro-N-tris-methylbenzamide is prepared as an active ingredient together with a pharmaceutically acceptable adjuvant.
  • the present invention also provides the above 4- ⁇ 3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio
  • the disease is selected from the group consisting of hair loss, regenerative hair, acne, acne or prostate cancer.
  • the hydrocarbon solvent of C5-C10 refers to a hydrocarbon solvent of C5, C6, C7, C8, C9, C10, that is, an alkane, an alkene, an alkyne, a cyclic hydrocarbon or an aromatic having 5 to 10 carbon atoms.
  • a hydrocarbon solvent such as n-hexane, cyclohexane, benzene, toluene or the like.
  • the stability test proves that the crystal form I of the invention has stable crystal form, good reproducibility and stable standing, and is superior to the existing amorphous substance and the newly discovered crystal form II, so that 4- ⁇ 3-[4- Cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl ⁇ -2-fluoro-N-triterpene
  • the benzamide bulk drug is more stable during storage.
  • the crystal form I of the invention has simple preparation process, low cost and broad market prospect.
  • Example 1 is a PXRD (X-ray powder diffraction) pattern of Form I obtained by the operation of Example 1.
  • Example 3 is a DSC chart of Form I obtained by the operation of Example 1.
  • Example 4 is a PXRD pattern of Form II obtained by the operation of Example 18.
  • Figure 5 is a PXRD pattern of Form II obtained by the operation of Example 19.
  • Figure 6 is a DSC chart of Form I obtained by the operation of Example 4.
  • Example 7 is a PXRD pattern of an amorphous compound obtained by the operation of Example 20.
  • Figure 8 is a PXRD pattern of the amorphous compound obtained by the operation of Example 21.
  • the crystal form I of the invention has stable crystal form, good reproducibility and stable standing, and is superior to the existing amorphous substance and the newly discovered crystal form II, so that 4- ⁇ 3-[4- Cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl ⁇ -2-fluoro-N-triterpene
  • the benzamide bulk drug is more stable during storage.
  • the crystal form I of the invention has simple preparation process, low cost and broad market prospect.

Abstract

Provided are crystal form I of a deuterated imidazolone——-4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl}-2-fluoro-N-trideuteromethyl benzamide compound, and a preparation method and use therefor. The crystal form I has a stable crystal form, good reproducibility, is stable in storage, and is superior to existing amorphous substances and crystal form II, such that a raw material drug of the 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl}-2-fluoro-N-trideuteromethyl benzamide has a more stable quality during storage. At the same time, the crystal form I has a simple preparation process, low cost and extensive market prospects.

Description

一种氘代咪唑酮化合物的晶型及其制备方法和用途Crystal form of deuterated imidazolidone compound, preparation method and use thereof 技术领域Technical field
本发明涉及氘代咪唑酮化合物晶型Ⅰ及其制备方法和用途。The present invention relates to a crystalline form I of a deuterated imidazolidone compound, a process for its preparation and use.
背景技术Background technique
氘代咪唑酮化合物——4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺是具有以下化学结构的化合物：Deuterated imidazolone compound——4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1- Imidazolidinyl}-2-fluoro-N-tridecanomethylbenzamide is a compound having the following chemical structure:
Figure PCTCN2016095647-appb-000001
Figure PCTCN2016095647-appb-000001
专利CN201280052853已公开了其制备方法和用途，但是目前，并没有关于其晶型的报道。对于同一种化合物来说，通常会有两种或多种不同的结晶状态，而不同的晶型在稳定性上均有所差异。探索出稳定性更好的晶型，有利于药物的存储及运输，保障了药效的稳定了。The preparation method and use thereof have been disclosed in the patent CN201280052853, but at present, there is no report on its crystal form. For the same compound, there are usually two or more different crystalline states, and different crystal forms differ in stability. Exploring a crystal form with better stability is conducive to the storage and transportation of drugs, and the stability of the drug is guaranteed.
因此，对于药物而言，探索得到药物的多种晶型，从中寻找到稳定性优异的晶型品种具有非常重要的意义。Therefore, for the drug, it is very important to explore a variety of crystal forms of the drug, and to find a crystal form with excellent stability.
发明内容Summary of the invention
本发明提供了4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺新晶型I，该晶型稳定性好不易被氧化；且合成晶型过程中操作简单，可放大生产；在软胶囊内容物中溶解度好。The present invention provides 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl }-2-Fluoro-N-tridehypo-methylbenzamide, new crystal form I, the crystal form is stable and not easy to be oxidized; and the process of synthesizing crystal form is simple and can be amplified; the solubility in soft capsule content it is good.
本发明提供了一种氘代咪唑酮化合物——4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺的晶型Ⅰ，该晶型的X射线粉末衍射中，2θ衍射角度在12.3±0.2、13.1±0.2、15.0±0.2和17.5±0.2度处有特征峰。The present invention provides a deuterated imidazolidinone compound, 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2 Form I of -thio-1-imidazolidinyl}-2-fluoro-N-tridemethylolbenzamide, the X-ray powder diffraction of the crystal form, the 2θ diffraction angle is 12.3 ± 0.2, 13.1 ± 0.2 There are characteristic peaks at 15.0±0.2 and 17.5±0.2 degrees.
进一步地，该晶型X射线粉末衍射中，2θ衍射角度还在9.8±0.2、13.5±0.2、14.3±0.2、16.7±0.2、18.9±0.2、21.1±0.2、21.8±0.2、22.8±0.2和24.4±0.2度处有特征峰。Further, in the X-ray powder diffraction, the 2θ diffraction angle is still 9.8±0.2, 13.5±0.2, 14.3±0.2, 16.7±0.2, 18.9±0.2, 21.1±0.2, 21.8±0.2, 22.8±0.2, and 24.4. There are characteristic peaks at ±0.2 degrees.
更进一步地，该晶型X射线粉末衍射中，2θ衍射角度特征峰的相对强度值为： Further, in the X-ray powder diffraction, the relative intensity values of the characteristic peaks of the 2θ diffraction angle are:
其中，该晶型具有基本如图1或图2所示的X射线粉末衍射图谱。Wherein, the crystal form has an X-ray powder diffraction pattern substantially as shown in FIG. 1 or 2.
其中，该晶型的熔点为192-209℃。Wherein, the crystalline form has a melting point of 192-209 °C.
其中，该晶型具有基本如图3所示的DSC图谱。Among them, the crystal form has a DSC pattern substantially as shown in FIG.
本发明还提供了一种制备上述晶型Ⅰ的方法，包括以下步骤：The present invention also provides a method of preparing the above Form I, comprising the steps of:
(1)将4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺溶解在溶剂中，所述溶剂不选自甲醇或甲酸中的任一种或其组合；(1) 4-{3-[4-Cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl }-2-fluoro-N-tridecanomethylbenzamide is dissolved in a solvent, the solvent not being selected from any one of methanol or formic acid or a combination thereof;
(2)结晶；(2) crystallization;
(3)分离出晶体，干燥即得。(3) The crystal is separated and dried.
进一步地，所述步骤(2)的结晶是搅拌冷却结晶；或加入抗溶剂，搅拌冷却结晶。Further, the crystallization of the step (2) is agitation cooling crystallization; or an anti-solvent is added, and the crystals are cooled by stirring.
进一步地，在步骤(1)中，所述溶剂选自醇、腈、卤代烃、酰胺、亚砜、卤代烃、芳烃、酯、醚、酮、水、乙酸中的任一种或其组合。Further, in the step (1), the solvent is selected from any one of an alcohol, a nitrile, a halogenated hydrocarbon, an amide, a sulfoxide, a halogenated hydrocarbon, an aromatic hydrocarbon, an ester, an ether, a ketone, water, acetic acid or combination.
进一步地，在步骤(1)中，所述溶剂选自乙醇、异丙醇、正丁醇、乙腈、N,N-二甲基甲酰胺、二甲基亚砜、甲苯、二甲苯、乙酸乙酯、乙酸丁酯、四氢呋喃、丙酮、甲基异丙基甲酮、甲基异丁基甲酮、水、乙酸中的任一种或其组合。Further, in the step (1), the solvent is selected from the group consisting of ethanol, isopropanol, n-butanol, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, toluene, xylene, and acetic acid Any one of ester, butyl acetate, tetrahydrofuran, acetone, methyl isopropyl ketone, methyl isobutyl ketone, water, acetic acid, or a combination thereof.
进一步地，在步骤(1)中，所述溶剂与4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺的体积重量比为1～50:1mL/g。Further, in the step (1), the solvent and 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo- The volume ratio by weight of 2-thio-1-imidazolidinyl}-2-fluoro-N-tridecanomethylbenzamide is from 1 to 50:1 mL/g.
进一步地，在步骤(1)的溶解过程中，温度为0℃至溶剂的回流温度。Further, in the dissolution process of the step (1), the temperature is from 0 ° C to the reflux temperature of the solvent.
进一步地，所述抗溶剂是水或C5-C10的烃类溶剂。Further, the anti-solvent is water or a C5-C10 hydrocarbon solvent.
进一步地，在步骤(2)中，析晶温度为-20℃-100℃，优选的析晶的温度为3℃至室温。Further, in the step (2), the crystallization temperature is -20 ° C to 100 ° C, and the preferred crystallization temperature is 3 ° C to room temperature.
本发明提供的制备上述晶型I的方法还包括：The method for preparing the above Form I provided by the present invention further comprises:
a)提供4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺在溶剂中的溶液；以及b)分离4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺的晶型I。步骤a)中的提供溶液包括：a) 4-{3-[4-Cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} a solution of 2-fluoro-N-tridecanomethylbenzamide in a solvent; and b) isolating 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5 Form I of dimethyl-4-oxo-2-thio-1-imidazolidinyl}-2-fluoro-N-tris-methylbenzamide. The providing solution in step a) comprises:
i)直接使用含有在4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺的合成过程中获得的4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺的反应混合物；或者i) Direct use of 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazole 4-{3-[4-Cyano-3-(trifluoromethyl)phenyl]-5,5- obtained during the synthesis of alkyl}-2-fluoro-N-tridecanomethylbenzamide a reaction mixture of dimethyl-4-oxo-2-thio-1-imidazolidinyl}-2-fluoro-N-tris-methylbenzamide; or
ii)将4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺溶解在溶剂中。 Ii) 4-{3-[4-Cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} 2-Fluoro-N-tridecanomethylbenzamide is dissolved in a solvent.
4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺的任何物理形式都可用于在步骤a)中提供4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺的溶液。任选地，当使用4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺的水合物时，在步骤a)之前或之后，可通过本领域中已知的技术例如蒸馏、加热、在合适的溶剂中制浆等来进行水减少或除去步骤。4-{3-[4-Cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl}-2- Any physical form of fluoro-N-tridehypo-methylbenzamide can be used to provide 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5 in step a) a solution of dimethyl-4-oxo-2-thio-1-imidazolidinyl}-2-fluoro-N-tridehypo-methylbenzamide. Optionally, when 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazole is used When a hydrate of alkyl}-2-fluoro-N-tridecanomethylbenzamide is used, before or after step a), it can be prepared by techniques known in the art such as distillation, heating, in a suitable solvent. A slurry or the like is used to carry out the water reduction or removal step.
在实施方案中，可将在4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺的合成过程中获得的4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺溶解在任何合适的溶剂中。此类合适的溶剂的实例包括但不限于：醇，例如C2-C6醇，例如乙醇、1-丙醇、2-丙醇(异丙醇)、1-丁醇、2-丁醇、叔丁醇；或腈，例如乙腈或丙腈；酰胺，例如N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基-2-吡咯烷酮；亚砜，例如二甲基亚砜；卤代烃，例如二氯甲烷；芳烃，例如甲苯、二甲苯；酯，例如乙酸乙酯、乙酸正丙酯、乙酸正丁酯、乙酸异丙酯、乙酸异丁酯、乙酸叔丁酯；醚，例如乙醚、二异丙基醚、甲基叔丁基醚、四氢呋喃、1,4-二噁烷、2-甲氧基乙醇、苯甲醚；酮，例如丙酮、乙基甲基酮、二乙基酮、甲基异丁基酮；水；或一种或多种这些溶剂的任意混合物。In an embodiment, 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5 obtained during the synthesis of imidazolidinyl}-2-fluoro-N-tridecanomethylbenzamide 5-Dimethyl-4-oxo-2-thio-1-imidazolidinyl}-2-fluoro-N-tridecanomethylbenzamide is dissolved in any suitable solvent. Examples of such suitable solvents include, but are not limited to, alcohols such as C2-C6 alcohols such as ethanol, 1-propanol, 2-propanol (isopropanol), 1-butanol, 2-butanol, tert-butyl An alcohol; or a nitrile such as acetonitrile or propionitrile; an amide such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone; a sulfoxide such as dimethyl Sulfoxide; halogenated hydrocarbons such as dichloromethane; aromatic hydrocarbons such as toluene, xylene; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, isopropyl acetate, isobutyl acetate, tert-butyl acetate Ester; ether, such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, anisole; ketone, such as acetone, ethyl methyl Ketone, diethyl ketone, methyl isobutyl ketone; water; or any mixture of one or more of these solvents.
溶解温度可为约0℃至约溶剂的回流温度，或者低于约150℃，低于约130℃，低于约100℃，低于约70℃，低于约40℃，低于约20℃，低于约0℃，或者任何其它合适的温度，只要获得4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺的澄清溶液而不影响其质量。可以任选地用碳、煅烧(flux-calcined)硅藻土(Hyflow)或任何其它合适的材料处理所述溶液，以除去颜色、不溶性材料，改善溶液的澄清度，和/或除去可吸附于此类材料上的杂质。任选地，可将上述获得的溶液过滤以除去任何不溶性颗粒。可以通过过滤、离心、倾析或者在加压下或在减压下的任何其它合适的技术来适当地除去所述不溶性颗粒。可通过使所述溶液通过纸、玻璃纤维、布或其它膜材料，或者澄清剂(例如或Hyflow)床对其进行过滤。取决于所使用的设备以及溶液的浓度和温度，可能需要预热过滤装置以避免过早结晶。The dissolution temperature can range from about 0 ° C to about the reflux temperature of the solvent, or less than about 150 ° C, less than about 130 ° C, less than about 100 ° C, less than about 70 ° C, less than about 40 ° C, less than about 20 ° C. , below about 0 ° C, or any other suitable temperature, as long as 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo is obtained A clear solution of oxo-2-thio-1-imidazolidinyl}-2-fluoro-N-tridecanomethylbenzamide without affecting its mass. The solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow) or any other suitable material to remove color, insoluble materials, improve clarity of the solution, and/or remove adsorbable Impurities on such materials. Optionally, the solution obtained above can be filtered to remove any insoluble particles. The insoluble particles may be suitably removed by filtration, centrifugation, decantation, or any other suitable technique under pressure or under reduced pressure. The solution can be filtered by passing it through paper, fiberglass, cloth or other membrane material, or a clarifying agent (e.g., or Hyflow) bed. Depending on the equipment used and the concentration and temperature of the solution, it may be necessary to preheat the filtration unit to avoid premature crystallization.
步骤b)包括从在步骤a)中获得的溶液中分离4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺的晶型I。步骤b)中的分离4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺的晶型I通过包括冷却、速冷(crash cooling)、浓缩物质、加入抗溶剂、加入晶种 以诱导结晶或蒸发等或其组合在内的方法进行。搅拌或其它替代方法例如振荡、搅动等也可以用于分离。或者，当形式R1的晶体存在于在步骤(a)中获得的溶液中时，这些晶体可以用作晶种，并且可以在步骤(b)中在此类形式R1的晶种存在下分离形式R1。Step b) comprises isolating 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo from the solution obtained in step a) Form I of 2-thio-1-imidazolidinyl}-2-fluoro-N-tridecanomethylbenzamide. Isolation of 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazole in step b) Form I of alkyl}-2-fluoro-N-tridemethylbenzamide comprises cooling, crash cooling, concentrated material, addition of anti-solvent, addition of seed crystals It is carried out by a method of inducing crystallization or evaporation or the like or a combination thereof. Stirring or other alternative methods such as shaking, agitation, etc. can also be used for the separation. Alternatively, when the crystal of the form R1 is present in the solution obtained in the step (a), these crystals can be used as a seed crystal, and the form R1 can be separated in the presence of the seed crystal of the form R1 in the step (b). .
任选地，可以通过将合适的抗溶剂与在步骤a)中获得的溶液组合来进行分离。如本文所用，抗溶剂是指4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺在其中微溶或难溶的液体。抗溶剂对4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺的质量没有不利的影响，并且它可以帮助溶解的原料凝固或沉淀。可使用的合适的抗溶剂包括但不限于：水；饱和或不饱和的直链或支链的、环状或非环状的C1-C10烃，例如己烷、庚烷、环己烷或甲基环己烷；醚，例如乙醚、二异丙基醚、四氢呋喃、二噁烷或二甲氧基乙烷；或其混合物。Optionally, the separation can be carried out by combining a suitable antisolvent with the solution obtained in step a). As used herein, an antisolvent refers to 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1 a liquid in which imidazolyl}-2-fluoro-N-tridecanomethylbenzamide is sparingly soluble or poorly soluble. Antisolvent for 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} The quality of -2-fluoro-N-tridecanomethylbenzamide has no adverse effect and it can help the dissolved raw material to solidify or precipitate. Suitable antisolvents which may be used include, but are not limited to, water; saturated or unsaturated linear or branched, cyclic or acyclic C1-C10 hydrocarbons such as hexane, heptane, cyclohexane or methyl Cyclohexane; an ether such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane or dimethoxyethane; or a mixture thereof.
合适的分离温度可为低于约100℃，低于约80℃，低于约60℃，低于约40℃，低于约20℃，低于约10℃，低于约5℃，低于约0℃，低于约-10℃，低于约-20℃，或者任何其它合适的温度。Suitable separation temperatures can be less than about 100 ° C, less than about 80 ° C, less than about 60 ° C, less than about 40 ° C, less than about 20 ° C, less than about 10 ° C, less than about 5 ° C, below About 0 ° C, less than about -10 ° C, less than about -20 ° C, or any other suitable temperature.
分离的4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺的晶型I可以通过包括倾析、离心、蒸发、重力过滤、抽滤或者在加压下或在减压下的任何其它用于固体回收的技术在内的方法进行回收。回收的固体可以任选地进行干燥。所述干燥可以在盘式干燥器、真空烘箱、空气烘箱、锥形真空干燥器(cone vacuum dryer)、旋转式真空干燥器、流化床干燥器、旋转闪蒸干燥器、快速干燥器等中进行。所述干燥可以在低于约100℃、低于约80℃、低于约60℃、低于约50℃、低于约30℃的温度或任何其它合适的温度下，在大气压或减压下进行，只要4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺的质量不劣化。所述干燥可以进行任何期望的次数，直到实现所需的产物质量。干燥的产物可以任选地经历粉碎(size reduction)操作，以产生期望的粒度。可在产物的干燥前或干燥完成后进行研磨或微粉化。可用于减小粒度的技术包括但不限于球磨、辊磨和锤磨，以及喷射研磨(jet milling)。Isolated 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl}- Form I of 2-fluoro-N-tridehypo-methylbenzamide can be used for solids recovery by decantation, centrifugation, evaporation, gravity filtration, suction filtration or under pressure or under reduced pressure. Methods such as technology are recycled. The recovered solid can optionally be dried. The drying may be in a tray dryer, a vacuum oven, an air oven, a cone vacuum dryer, a rotary vacuum dryer, a fluidized bed dryer, a rotary flash dryer, a quick dryer, and the like. get on. The drying may be at atmospheric pressure or reduced pressure at a temperature below about 100 ° C, below about 80 ° C, below about 60 ° C, below about 50 ° C, below about 30 ° C, or at any other suitable temperature. To proceed as long as 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} The quality of -2-fluoro-N-tridehypo-methylbenzamide does not deteriorate. The drying can be carried out any desired number of times until the desired product quality is achieved. The dried product can optionally undergo a size reduction operation to produce the desired particle size. Grinding or micronizing may be carried out before or after drying of the product. Techniques that can be used to reduce particle size include, but are not limited to, ball milling, roll milling and hammer milling, as well as jet milling.
本发明还提供了一种药物组合物，它是由上述的4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺的晶型Ⅰ作为活性成分，加上药学上可接受的辅料制备而成的制剂。The present invention also provides a pharmaceutical composition which is the above 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo Form I prepared on the basis of the crystalline form I of the substituted 2-thio-1-imidazolidinyl}-2-fluoro-N-tris-methylbenzamide as an active ingredient together with a pharmaceutically acceptable adjuvant.
进一步地，本发明提供了上述4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2- 硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺的晶型Ⅰ在制备雄性激素受体拮抗剂，或制备治疗或/和预防雄性激素受体活性相关疾病的药物中的应用。Further, the present invention provides the above 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2- Form I of thio-1-imidazolidinyl}-2-fluoro-N-tridemethylolbenzamide in the preparation of androgen receptor antagonists, or in the preparation of a disease associated with the treatment or/and prevention of androgen receptor activity The application of the drug.
其中，所述疾病选自但不局限于脱发、再生发、暗疮、青春痘或前列腺癌。Wherein the disease is selected from the group consisting of, but not limited to, hair loss, regenerative hair, acne, acne or prostate cancer.
除此之外，在对化合物4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺的晶型筛选中，发明人还发现了其晶型Ⅱ，该晶型的X射线粉末衍射中，2θ衍射角度在4.8±0.2、11.3±0.2和20.2±0.2度处有特征峰。In addition to the compound 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1 In the screening of the crystal form of imidazolidinyl}-2-fluoro-N-tridecylmethylbenzamide, the inventors have also found a crystal form II in which the X-ray powder diffraction has a 2θ diffraction angle of 4.8. There are characteristic peaks at ±0.2, 11.3±0.2 and 20.2±0.2 degrees.
进一步地，该晶型X射线粉末衍射中，2θ衍射角度还在9.7±0.2、14.5±0.2、15.6±0.2、16.9±0.2和25.5±0.2度处有特征峰。Further, in the X-ray powder diffraction, the 2θ diffraction angle has characteristic peaks at 9.7±0.2, 14.5±0.2, 15.6±0.2, 16.9±0.2, and 25.5±0.2 degrees.
进一步地，该晶型X射线粉末衍射中，2θ衍射角度特征峰的相对强度值为：Further, in the X-ray powder diffraction, the relative intensity values of the characteristic peaks of the 2θ diffraction angle are:
其中，该晶型具有基本如图4或图5所示的X射线粉末衍射图谱。Wherein, the crystal form has an X-ray powder diffraction pattern substantially as shown in FIG. 4 or FIG.
其中，该晶型的熔点为114-139℃。Wherein, the crystalline form has a melting point of 114-139 °C.
其中，该晶型具有基本如图6所示的DSC图谱。Among them, the crystal form has a DSC pattern substantially as shown in FIG.
本发明还提供了一种制备上述晶型Ⅱ的方法，它包括以下步骤：The present invention also provides a method of preparing the above Form II, which comprises the steps of:
(1)将4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺溶解在溶剂中，所述溶剂选自甲醇或甲酸中的任一种或其组合；(1) 4-{3-[4-Cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl }-2-Fluoro-N-tridehypo-methylbenzamide is dissolved in a solvent selected from any one or a combination of methanol or formic acid;
(2)结晶；(2) crystallization;
(3)分离出晶体，干燥即得。(3) The crystal is separated and dried.
进一步地，所述步骤(2)的结晶是搅拌冷却结晶；或加入抗溶剂，搅拌冷却结晶。Further, the crystallization of the step (2) is agitation cooling crystallization; or an anti-solvent is added, and the crystals are cooled by stirring.
进一步地，在步骤(1)中，所述溶剂与4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺的体积重量比为2.5～10:1mL/g。Further, in the step (1), the solvent and 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo- The volume ratio by weight of 2-thio-1-imidazolidinyl}-2-fluoro-N-tridecanomethylbenzamide is from 2.5 to 10:1 mL/g.
进一步地，在步骤(1)的溶解过程中，温度为0℃至溶剂的回流温度。Further, in the dissolution process of the step (1), the temperature is from 0 ° C to the reflux temperature of the solvent.
进一步地，所述抗溶剂是水或C5-C10的烃类溶剂。Further, the anti-solvent is water or a C5-C10 hydrocarbon solvent.
进一步地，在步骤(2)中，析晶温度为-20℃-100℃，优选的析晶的温度为3℃至室温。Further, in the step (2), the crystallization temperature is -20 ° C to 100 ° C, and the preferred crystallization temperature is 3 ° C to room temperature.
本发明提供的制备上述晶型Ⅱ的方法还包括：a)提供4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺在甲醇或甲酸中的溶液；以及b)分离4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺的晶型II。The method for preparing the above Form II provided by the present invention further comprises: a) providing 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4- a solution of oxo-2-thio-1-imidazolidinyl}-2-fluoro-N-tridehypo-methylbenzamide in methanol or formic acid; and b) separation of 4-{3-[4-cyano -3-(Trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl}-2-fluoro-N-tris-methylbenzene Form II of the amide.
步骤a)中的提供溶液包括：The providing solution in step a) comprises:
i)直接使用含有在4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑 烷基}-2-氟-N-三氘代甲基苯酰胺的合成过程中获得的4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺的反应混合物；或者i) Direct use of 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazole 4-{3-[4-Cyano-3-(trifluoromethyl)phenyl]-5,5- obtained during the synthesis of alkyl}-2-fluoro-N-tridecanomethylbenzamide a reaction mixture of dimethyl-4-oxo-2-thio-1-imidazolidinyl}-2-fluoro-N-tris-methylbenzamide; or
ii)将4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺溶解在甲醇或甲酸中。Ii) 4-{3-[4-Cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} 2-Fluoro-N-tridehypo-methylbenzamide is dissolved in methanol or formic acid.
4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺的任何物理形式都可以用于在步骤a)中提供4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺的溶液。任选地，当使用4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺的水合物时，在步骤a)之前或之后，可通过本领域中已知的技术例如蒸馏、加热、在合适的溶剂中制浆等进行水减少或除去步骤。4-{3-[4-Cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl}-2- Any physical form of fluoro-N-tridemethylolbenzamide can be used to provide 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5 in step a). A solution of 5-dimethyl-4-oxo-2-thio-1-imidazolidinyl}-2-fluoro-N-tridehypo-methylbenzamide. Optionally, when 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazole is used When a hydrate of alkyl}-2-fluoro-N-tridecanomethylbenzamide is used, before or after step a), it can be prepared by techniques known in the art such as distillation, heating, in a suitable solvent. The slurry or the like is subjected to a water reduction or removal step.
在实施方案中，可将在4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺的合成过程中获得的4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺溶解在甲醇或甲酸或其任意混合物中。In an embodiment, 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5 obtained during the synthesis of imidazolidinyl}-2-fluoro-N-tridecanomethylbenzamide 5-Dimethyl-4-oxo-2-thio-1-imidazolidinyl}-2-fluoro-N-tridehypo-methylbenzamide is dissolved in methanol or formic acid or any mixture thereof.
溶解温度可为约0℃至约溶剂的回流温度，或者低于约100℃，低于约80℃，低于约60℃，低于约40℃，低于约20℃，低于约10℃，或者任何其它合适的温度，只要获得4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺的澄清溶液而不影响其质量。可以任选地用碳、煅烧硅藻土(Hyflow)或任何其它合适的材料处理所述溶液，以除去颜色、不溶性材料，改善溶液的澄清度，和/或除去可吸附于此类材料上的杂质。任选地，可将上述获得的溶液过滤以除去任何不溶性颗粒。可以通过过滤、离心、倾析或者在加压下或在减压下的任何其它合适的技术来适当地除去所述不溶性颗粒。可通过使所述溶液通过纸、玻璃纤维、布或其它膜材料，或者澄清剂(例如或Hyflow)床对其进行过滤。取决于所使用的设备以及溶液的浓度和温度，可能需要预热过滤装置以避免过早结晶。The dissolution temperature can range from about 0 ° C to about the reflux temperature of the solvent, or less than about 100 ° C, less than about 80 ° C, less than about 60 ° C, less than about 40 ° C, less than about 20 ° C, less than about 10 ° C. , or any other suitable temperature, as long as 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio A clear solution of 1-Imidazolidinyl}-2-fluoro-N-tridecanomethylbenzamide without affecting its mass. The solution may optionally be treated with carbon, calcined diatomaceous earth (Hyflow) or any other suitable material to remove color, insoluble materials, improve clarity of the solution, and/or remove sorbable materials. Impurities. Optionally, the solution obtained above can be filtered to remove any insoluble particles. The insoluble particles may be suitably removed by filtration, centrifugation, decantation, or any other suitable technique under pressure or under reduced pressure. The solution can be filtered by passing it through paper, fiberglass, cloth or other membrane material, or a clarifying agent (e.g., or Hyflow) bed. Depending on the equipment used and the concentration and temperature of the solution, it may be necessary to preheat the filtration unit to avoid premature crystallization.
步骤b)包括从在步骤a)中获得的溶液中分离4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺的晶型II。步骤b)中的分离4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺的晶型II可以涉及包括冷却、浓缩物质、加入抗溶剂、加入晶种以诱导结晶等在内的方法。搅拌或其它替代方法例如振荡、搅动等也可以用于分离。Step b) comprises isolating 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo from the solution obtained in step a) Form II of 2-thio-1-imidazolidinyl}-2-fluoro-N-tridecanomethylbenzamide. Isolation of 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazole in step b) The crystal form II of the alkyl}-2-fluoro-N-tridecanomethylbenzamide may be involved in a method including cooling, concentrating a substance, adding an anti-solvent, adding a seed crystal to induce crystallization, and the like. Stirring or other alternative methods such as shaking, agitation, etc. can also be used for the separation.
任选地，可以通过将合适的抗溶剂与在步骤a)中获得的溶液组合来进行分离。如本 文所用，抗溶剂是指4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺在其中微溶或难溶的液体。抗溶剂对4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺的质量没有不利的影响，并且它可以帮助溶解的原料凝固或沉淀。可使用的合适的抗溶剂包括但不限于：饱和或不饱和的直链或支链的、环状或非环状的C1-C10烃，例如己烷、庚烷、环己烷或甲基环己烷；醚，例如乙醚、二异丙基醚、四氢呋喃、二噁烷或二甲氧基乙烷；或其任意混合物。Optionally, the separation can be carried out by combining a suitable antisolvent with the solution obtained in step a). Such as this As used herein, antisolvent refers to 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1- A liquid in which imidazolyl}-2-fluoro-N-tris-methylbenzamide is sparingly soluble or poorly soluble. Antisolvent for 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} The quality of -2-fluoro-N-tridecanomethylbenzamide has no adverse effect and it can help the dissolved raw material to solidify or precipitate. Suitable antisolvents which may be used include, but are not limited to, saturated or unsaturated linear or branched, cyclic or acyclic C1-C10 hydrocarbons such as hexane, heptane, cyclohexane or methyl rings. Hexane; an ether such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane or dimethoxyethane; or any mixture thereof.
合适的分离温度可为低于约100℃，低于约80℃，低于约60℃，低于约40℃，低于约20℃，低于约10℃，低于约5℃，低于约0℃，低于约-10℃，低于约-20℃，或者任何其它合适的温度。Suitable separation temperatures can be less than about 100 ° C, less than about 80 ° C, less than about 60 ° C, less than about 40 ° C, less than about 20 ° C, less than about 10 ° C, less than about 5 ° C, below About 0 ° C, less than about -10 ° C, less than about -20 ° C, or any other suitable temperature.
分离的4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺的晶型II可以通过包括倾析、离心、重力过滤、抽滤或者在加压下或在减压下的任何其它用于固体回收的技术在内的方法进行回收。回收的固体可以任选地进行干燥。所述干燥可以在盘式干燥器、真空烘箱、空气烘箱、锥形真空干燥器、旋转式真空干燥器、流化床干燥器、旋转闪蒸干燥器、快速干燥器等中进行。所述干燥可以在低于约100℃、低于约80℃、低于约60℃、低于约50℃、低于约30℃的温度或任何其它合适的温度下，在大气压或减压下进行，只要4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺的质量不劣化。所述干燥可以进行任何期望的次数，直到实现所需的产物质量。干燥的产物可以任选地经历粉碎操作，以产生期望的粒度。可在产物的干燥前或干燥完成后进行研磨或微粉化。可用于减小粒度的技术包括但不限于球磨、辊磨和锤磨，以及喷射研磨。Isolated 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl}- Form II of 2-fluoro-N-tridehypo-methylbenzamide can be used by any technique for solids recovery including decantation, centrifugation, gravity filtration, suction filtration or under pressure or under reduced pressure. The method inside is recycled. The recovered solid can optionally be dried. The drying can be carried out in a tray dryer, a vacuum oven, an air oven, a conical vacuum dryer, a rotary vacuum dryer, a fluidized bed dryer, a rotary flash dryer, a quick dryer, and the like. The drying may be at atmospheric pressure or reduced pressure at a temperature below about 100 ° C, below about 80 ° C, below about 60 ° C, below about 50 ° C, below about 30 ° C, or at any other suitable temperature. To proceed as long as 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} The quality of -2-fluoro-N-tridehypo-methylbenzamide does not deteriorate. The drying can be carried out any desired number of times until the desired product quality is achieved. The dried product can optionally undergo a comminution operation to produce the desired particle size. Grinding or micronizing may be carried out before or after drying of the product. Techniques that can be used to reduce particle size include, but are not limited to, ball milling, roller and hammer milling, and jet milling.
本发明还提供了一种药物组合物，它是由上述4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺的晶型Ⅱ作为活性成分，加上药学上可接受的辅料制备而成的制剂。The present invention also provides a pharmaceutical composition which is the above 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo Form II prepared from -2-thio-1-imidazolidinyl}-2-fluoro-N-tris-methylbenzamide as an active ingredient, together with a pharmaceutically acceptable adjuvant.
进一步地，本发明还提供了上述的4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺的晶型Ⅱ在制备雄性激素受体拮抗剂，或制备治疗或/和预防雄性激素受体活性相关疾病的药物中的应用。Further, the present invention also provides the above 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio Form II of 1-Imidazolidinyl}-2-fluoro-N-tris-methylbenzamide in the preparation of androgen receptor antagonists, or in the preparation of a medicament for the treatment or/and prevention of androgen receptor activity-related diseases Application in .
其中，所述疾病选自脱发、再生发、暗疮、青春痘或前列腺癌。Wherein the disease is selected from the group consisting of hair loss, regenerative hair, acne, acne or prostate cancer.
发明人重复专利CN201280052853得到的化合物，其晶型为无定形。其中，该无定形化合物具有基本如图7或图8所示的X射线粉末衍射图谱。 The inventors have repeated the compound obtained in the patent CN201280052853, which has an amorphous form. Wherein, the amorphous compound has an X-ray powder diffraction pattern substantially as shown in Fig. 7 or Fig. 8.
本发明还提供了一种制备上述无定形化合物的方法，它包括以下步骤：The present invention also provides a method of preparing the above amorphous compound, which comprises the steps of:
(1)将4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺溶解在溶剂中；(1) 4-{3-[4-Cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl }-2-Fluoro-N-tridehypo-methylbenzamide is dissolved in a solvent;
(2)冷却或不冷却；(2) cooling or not cooling;
(3)快速除去溶剂或快速析出固体并分离，即得。(3) Quickly remove the solvent or rapidly precipitate the solid and separate it.
进一步地，在步骤(1)中，所述溶剂选自醇、腈、卤代烃、酰胺、亚砜、卤代烃、芳烃、酯、醚、酮、水、乙酸中的任一种或其组合。Further, in the step (1), the solvent is selected from any one of an alcohol, a nitrile, a halogenated hydrocarbon, an amide, a sulfoxide, a halogenated hydrocarbon, an aromatic hydrocarbon, an ester, an ether, a ketone, water, acetic acid or combination.
进一步地，在步骤(1)中，所述溶剂选自甲醇、乙醇、异丙醇、正丁醇、乙腈、N,N-二甲基甲酰胺、二甲基亚砜、甲苯、二甲苯、乙酸乙酯、乙酸丁酯、四氢呋喃、丙酮、甲基异丙基甲酮、甲基异丁基甲酮、水、乙酸中的任一种或其组合。Further, in the step (1), the solvent is selected from the group consisting of methanol, ethanol, isopropanol, n-butanol, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, toluene, xylene, Either ethyl acetate, butyl acetate, tetrahydrofuran, acetone, methyl isopropyl ketone, methyl isobutyl ketone, water, acetic acid, or a combination thereof.
进一步地，在步骤(1)中，所述溶剂与4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺的体积重量比为2.5～10:1mL/g。Further, in the step (1), the solvent and 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo- The volume ratio by weight of 2-thio-1-imidazolidinyl}-2-fluoro-N-tridecanomethylbenzamide is from 2.5 to 10:1 mL/g.
进一步地，在步骤(1)的溶解过程中，温度为0℃至溶剂的回流温度。Further, in the dissolution process of the step (1), the temperature is from 0 ° C to the reflux temperature of the solvent.
进一步地，在步骤(2)中，析晶温度为-20℃-100℃，优选的析晶的温度为3℃至室温。Further, in the step (2), the crystallization temperature is -20 ° C to 100 ° C, and the preferred crystallization temperature is 3 ° C to room temperature.
进一步地，在步骤(3)中，所述快速除去溶剂指的是1分钟内至少除去10mL溶剂，所述溶剂中至少溶解有1g 4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺。Further, in the step (3), the rapid removal of the solvent means that at least 10 mL of the solvent is removed in 1 minute, and at least 1 g of 4-{3-[4-cyano-3-(trifluoro) is dissolved in the solvent. Methyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl}-2-fluoro-N-tridecanomethylbenzamide.
进一步地，所述步骤(3)的除去溶剂是通过旋转蒸发进行的。Further, the solvent removal in the step (3) is carried out by rotary evaporation.
进一步地，所述步骤(3)的快速析出固体是通过加入抗溶剂的进行的。Further, the rapid precipitation of the solid in the step (3) is carried out by adding an anti-solvent.
进一步地，所述抗溶剂是水或C5-C10的烃类溶剂。Further, the anti-solvent is water or a C5-C10 hydrocarbon solvent.
本发明提供的制备上述无定形化合物的方法还包括：The method for preparing the above amorphous compound provided by the present invention further comprises:
a)提供4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺在溶剂中的溶液；以及b)分离4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺的无定形化合物。a) 4-{3-[4-Cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} a solution of 2-fluoro-N-tridecanomethylbenzamide in a solvent; and b) isolating 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5 -Amorphous compound of dimethyl-4-oxo-2-thio-1-imidazolidinyl}-2-fluoro-N-tridecanomethylbenzamide.
步骤a)中的提供4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺的溶液包括：Provided in step a) 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazole A solution of an alkyl}-2-fluoro-N-tridehypo-methylbenzamide includes:
i)直接使用含有在4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺的合成过程中获得的4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺的反应混合物；或者 i) Direct use of 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazole 4-{3-[4-Cyano-3-(trifluoromethyl)phenyl]-5,5- obtained during the synthesis of alkyl}-2-fluoro-N-tridecanomethylbenzamide a reaction mixture of dimethyl-4-oxo-2-thio-1-imidazolidinyl}-2-fluoro-N-tris-methylbenzamide; or
ii)将4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺溶解在溶剂中。Ii) 4-{3-[4-Cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} 2-Fluoro-N-tridecanomethylbenzamide is dissolved in a solvent.
4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺的任何物理形式都可以用于在步骤a)中提供4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺的溶液。溶解温度可为约0℃至约溶剂的回流温度，或者低于约60℃，低于约50℃，低于约40℃，低于约30℃，低于约20℃，低于约10℃，或者任何其它合适的温度，只要获得4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺的澄清溶液而不影响其质量。可以任选地用碳、煅烧硅藻土(Hyflow)或任何其它合适的材料处理所述溶液，以除去颜色、不溶性材料，改善溶液的澄清度，和/或除去可吸附于此类材料上的杂质。任选地，可将上述获得的溶液过滤以除去任何不溶性颗粒。可以通过过滤、离心、倾析或者在加压下或在减压下的任何其它合适的技术来适当地除去所述不溶性颗粒。可通过使所述溶液通过纸、玻璃纤维、布或其它膜材料，或者澄清剂(例如或Hyflow)床对其进行过滤。取决于所使用的设备以及溶液的浓度和温度，可能需要预热过滤装置以避免过早结晶。4-{3-[4-Cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl}-2- Any physical form of fluoro-N-tridemethylolbenzamide can be used to provide 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5 in step a). A solution of 5-dimethyl-4-oxo-2-thio-1-imidazolidinyl}-2-fluoro-N-tridehypo-methylbenzamide. The dissolution temperature can range from about 0 ° C to about the reflux temperature of the solvent, or less than about 60 ° C, less than about 50 ° C, less than about 40 ° C, less than about 30 ° C, less than about 20 ° C, less than about 10 ° C. , or any other suitable temperature, as long as 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio A clear solution of 1-Imidazolidinyl}-2-fluoro-N-tridecanomethylbenzamide without affecting its mass. The solution may optionally be treated with carbon, calcined diatomaceous earth (Hyflow) or any other suitable material to remove color, insoluble materials, improve clarity of the solution, and/or remove sorbable materials. Impurities. Optionally, the solution obtained above can be filtered to remove any insoluble particles. The insoluble particles may be suitably removed by filtration, centrifugation, decantation, or any other suitable technique under pressure or under reduced pressure. The solution can be filtered by passing it through paper, fiberglass, cloth or other membrane material, or a clarifying agent (e.g., or Hyflow) bed. Depending on the equipment used and the concentration and temperature of the solution, it may be necessary to preheat the filtration unit to avoid premature crystallization.
在实施方案中，可将4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺溶解在任何合适的溶剂中。合适的溶剂包括对化合物没有不利的影响并且可以将原料溶解到有用的程度的任何溶剂。此类溶剂的实例包括但不限于：醚，例如乙醚、二异丙基醚、四氢呋喃、二噁烷或二甲氧基乙烷；酮，例如丙酮、甲基乙基酮、甲基异丁基酮或二乙基酮；酯，例如乙酸乙酯、乙酸丙酯、乙酸异丙酯或乙酸丁酯；醇，例如甲醇、乙醇、1-丙醇、2-丙醇(异丙醇)、2-甲氧基乙醇、1-丁醇、2-丁醇、异丁醇、叔丁醇、2-乙氧基乙醇、二乙二醇、1-戊醇、2-戊醇或3-戊醇、新戊醇、叔戊醇、二乙二醇单甲醚、环己醇、甘油或C1-C6醇；腈，例如乙腈或丙腈；酰胺，例如甲酰胺、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基-2-吡咯烷酮或六甲基磷酸三酰胺；亚砜，例如二甲基亚砜；卤代烃，例如二氯甲烷、氯仿、四氯化碳或氯苯；芳烃，例如甲苯；或其两种或更多种的任意混合物。In an embodiment, 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1- The imidazolidinyl}-2-fluoro-N-tridecanomethylbenzamide is dissolved in any suitable solvent. Suitable solvents include any solvent which does not adversely affect the compound and which can dissolve the starting material to a useful extent. Examples of such solvents include, but are not limited to, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane or dimethoxyethane; ketones such as acetone, methyl ethyl ketone, methyl isobutyl Ketone or diethyl ketone; esters such as ethyl acetate, propyl acetate, isopropyl acetate or butyl acetate; alcohols such as methanol, ethanol, 1-propanol, 2-propanol (isopropanol), 2 -methoxyethanol, 1-butanol, 2-butanol, isobutanol, tert-butanol, 2-ethoxyethanol, diethylene glycol, 1-pentanol, 2-pentanol or 3-pentanol , neopentyl alcohol, tert-amyl alcohol, diethylene glycol monomethyl ether, cyclohexanol, glycerol or C1-C6 alcohol; nitrile, such as acetonitrile or propionitrile; amide, such as formamide, N, N-dimethyl Amide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone or hexamethylphosphoric acid triamide; sulfoxides such as dimethyl sulfoxide; halogenated hydrocarbons such as dichloromethane, chloroform, tetra Carbon chloride or chlorobenzene; an aromatic hydrocarbon such as toluene; or any mixture of two or more thereof.
步骤b)包括从在步骤a)中获得的溶液中分离4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺的无定形化合物。步骤b)中的分离4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺的无定形化合物可以涉及包括除去溶剂、冷却、速冷、浓缩物质、蒸发、快速 蒸发、简单蒸发、旋转干燥、喷雾干燥、薄膜干燥、搅动吸滤器干燥、加压吸滤器干燥、冷冻干燥、加入抗溶剂、用溶剂萃取等在内的方法。搅拌或其它替代方法例如振荡、搅动等也可以用于分离。所分离的4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺的无定形化合物可能携带一定量的包藏的母液，并且可能具有高于期望水平的杂质。如果需要，可以用溶剂或溶剂混合物洗涤这种无定形化合物以洗出杂质。Step b) comprises isolating 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo from the solution obtained in step a) Amorphous compound of 2-thio-1-imidazolidinyl}-2-fluoro-N-tridecanomethylbenzamide. Isolation of 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazole in step b) Amorphous compounds of alkyl}-2-fluoro-N-tris-methylbenzamide may involve removal of solvent, cooling, rapid cooling, concentration of material, evaporation, rapid Evaporation, simple evaporation, spin drying, spray drying, film drying, agitation suction filter drying, pressure suction filter drying, freeze drying, addition of anti-solvent, solvent extraction, and the like. Stirring or other alternative methods such as shaking, agitation, etc. can also be used for the separation. Isolated 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} The amorphous compound of -2-fluoro-N-tridecanomethylbenzamide may carry a certain amount of the occluded mother liquor and may have impurities above the desired level. If desired, the amorphous compound can be washed with a solvent or a solvent mixture to wash out the impurities.
制备无定形化合物的关键在于在较短的时间内除去溶剂或是析出固体，以避免化合物形成晶型，可以通过本领域常用的制备无定形化合物的方法得到。The key to the preparation of the amorphous compound is to remove the solvent or precipitate the solid in a relatively short period of time to avoid the formation of a crystalline form of the compound, which can be obtained by a method for preparing an amorphous compound which is conventionally used in the art.
用旋转蒸发制备无定形化合物的关键在于，形成4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺在可溶溶剂中的溶液，低温(温度度不超过50℃)，以至少5毫升/分钟的速率去除溶剂，优选5-15毫升/分钟。The key to the preparation of amorphous compounds by rotary evaporation is the formation of 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2- A solution of thio-1-imidazolidinyl}-2-fluoro-N-tridehypo-methylbenzamide in a soluble solvent, at a low temperature (temperature not exceeding 50 ° C), at a rate of at least 5 ml/min The solvent is preferably 5-15 ml/min.
合适的分离温度可为低于约120℃，低于约80℃，低于约60℃，低于约40℃，低于约30℃，低于约20℃，低于约10℃，低于约0℃，低于约-10℃，低于约-40℃，或者任何其它合适的温度。Suitable separation temperatures can be less than about 120 ° C, less than about 80 ° C, less than about 60 ° C, less than about 40 ° C, less than about 30 ° C, less than about 20 ° C, less than about 10 ° C, below About 0 ° C, less than about -10 ° C, less than about -40 ° C, or any other suitable temperature.
任选地，可以通过将合适的抗溶剂与在步骤a)中获得的溶液组合来进行分离。如本文所用，抗溶剂是指4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺在其中微溶或难溶的液体。惰性抗溶剂对反应没有不利的影响，并且它可以帮助溶解的原料凝固或沉淀。可使用的合适的抗溶剂包括但不限于：饱和或不饱和的直链或支链的、环状或非环状的C1-C10烃，例如庚烷、环己烷或甲基环己烷；水；或其任意混合物。Optionally, the separation can be carried out by combining a suitable antisolvent with the solution obtained in step a). As used herein, an antisolvent refers to 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1 a liquid in which imidazolyl}-2-fluoro-N-tridecanomethylbenzamide is sparingly soluble or poorly soluble. The inert anti-solvent has no adverse effect on the reaction and it can help the dissolved raw material to solidify or precipitate. Suitable antisolvents which may be used include, but are not limited to, saturated or unsaturated linear or branched, cyclic or acyclic C1-C10 hydrocarbons such as heptane, cyclohexane or methylcyclohexane; Water; or any mixture thereof.
回收的固体可以任选地进行干燥。所述干燥可以在盘式干燥器、真空烘箱、空气烘箱、锥形真空干燥器、旋转式真空干燥器、流化床干燥器、旋转闪蒸干燥器、快速干燥器等中进行。所述干燥可以在低于约100℃、低于约80℃、低于约60℃、低于约50℃、低于约30℃的温度或任何其它合适的温度下，在大气压或减压下进行，只要4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺的质量不劣化。所述干燥可以进行任何期望的次数，直到实现所需的产物质量。干燥的产物可以任选地经历粉碎操作，以产生期望的粒度。可在产物的干燥前或干燥完成后进行研磨或微粉化。可用于减小粒度的技术包括但不限于球磨、辊磨或锤磨，或者喷射研磨。The recovered solid can optionally be dried. The drying can be carried out in a tray dryer, a vacuum oven, an air oven, a conical vacuum dryer, a rotary vacuum dryer, a fluidized bed dryer, a rotary flash dryer, a quick dryer, and the like. The drying may be at atmospheric pressure or reduced pressure at a temperature below about 100 ° C, below about 80 ° C, below about 60 ° C, below about 50 ° C, below about 30 ° C, or at any other suitable temperature. To proceed as long as 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} The quality of -2-fluoro-N-tridehypo-methylbenzamide does not deteriorate. The drying can be carried out any desired number of times until the desired product quality is achieved. The dried product can optionally undergo a comminution operation to produce the desired particle size. Grinding or micronizing may be carried out before or after drying of the product. Techniques that can be used to reduce particle size include, but are not limited to, ball milling, roller or hammer milling, or jet milling.
本发明还提供了一种氘代咪唑酮化合物——4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺的无定形化合物，该无定形化合 物是以4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺为原料，通过上述制备无定形化合物的方法制备得到的或是本领域常规的制备无定形化合物的方法得到的。The present invention also provides a deuterated imidazolidinone compound, 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo- Amorphous compound of 2-thio-1-imidazolidinyl}-2-fluoro-N-tridemethylolbenzamide, the amorphous compound Is 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} 2-Fluoro-N-tridecanomethylbenzamide is used as a raw material, and is obtained by the above-mentioned method for preparing an amorphous compound or a method for preparing an amorphous compound conventionally used in the art.
本发明还提供了一种药物组合物，它是由上述的4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺的无定形化合物作为活性成分，加上药学上可接受的辅料制备而成的制剂。The present invention also provides a pharmaceutical composition which is the above 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo An amorphous compound of substituted-2-thio-1-imidazolidin}-2-fluoro-N-tris-methylbenzamide is prepared as an active ingredient together with a pharmaceutically acceptable adjuvant.
进一步地，本发明还提供了上述的4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺的无定形化合物在制备雄性激素受体拮抗剂，或制备治疗或/和预防雄性激素受体活性相关疾病的药物中的应用。Further, the present invention also provides the above 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio An amorphous compound of 1-imidazolidinyl}-2-fluoro-N-tris-methylbenzamide in the preparation of androgen receptor antagonists or in the preparation of a medicament for the treatment or/and prevention of androgen receptor activity-related diseases Application in .
其中，所述疾病选自脱发、再生发、暗疮、青春痘或前列腺癌。Wherein the disease is selected from the group consisting of hair loss, regenerative hair, acne, acne or prostate cancer.
本发明中，C5-C10的烃类溶剂指的是C5、C6、C7、C8、C9、C10的烃类溶剂，即具有5-10个碳原子的烷烃、烯烃、炔烃、环烃或芳香烃溶剂，例如正己烷、环己烷、苯、甲苯等等。In the present invention, the hydrocarbon solvent of C5-C10 refers to a hydrocarbon solvent of C5, C6, C7, C8, C9, C10, that is, an alkane, an alkene, an alkyne, a cyclic hydrocarbon or an aromatic having 5 to 10 carbon atoms. A hydrocarbon solvent such as n-hexane, cyclohexane, benzene, toluene or the like.
稳定性试验证明，本发明的晶型Ⅰ，晶型稳定，重现性好，放置稳定，显著优于现有的无定形物以及新发现的晶型Ⅱ，使得4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺原料药在存储期内质量更稳定。同时，本发明的晶型Ⅰ，制备工艺简单，成本低，具有广阔的市场前景。The stability test proves that the crystal form I of the invention has stable crystal form, good reproducibility and stable standing, and is superior to the existing amorphous substance and the newly discovered crystal form II, so that 4-{3-[4- Cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl}-2-fluoro-N-triterpene The benzamide bulk drug is more stable during storage. At the same time, the crystal form I of the invention has simple preparation process, low cost and broad market prospect.
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。It is apparent that various other modifications, substitutions and changes can be made in the form of the above-described embodiments of the present invention.
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。The above content of the present invention will be further described in detail below by way of specific embodiments in the form of embodiments. However, the scope of the above-mentioned subject matter of the present invention should not be construed as being limited to the following examples. Any technique implemented based on the above description of the present invention is within the scope of the present invention.
附图说明DRAWINGS
图1为通过实施例1的操作获得的晶型I的PXRD(X射线粉末衍射)图形。1 is a PXRD (X-ray powder diffraction) pattern of Form I obtained by the operation of Example 1.
图2为通过实施例12的操作获得的晶型I的PXRD图形。2 is a PXRD pattern of Form I obtained by the operation of Example 12.
图3为通过实施例1的操作获得的晶型I的DSC图谱。3 is a DSC chart of Form I obtained by the operation of Example 1.
图4为通过实施例18的操作获得的晶型II的PXRD图形。4 is a PXRD pattern of Form II obtained by the operation of Example 18.
图5为通过实施例19的操作获得的晶型II的PXRD图形。Figure 5 is a PXRD pattern of Form II obtained by the operation of Example 19.
图6为通过实施例4的操作获得的晶型I的DSC图谱。Figure 6 is a DSC chart of Form I obtained by the operation of Example 4.
图7为通过实施例20的操作获得的无定形化合物的PXRD图形。 7 is a PXRD pattern of an amorphous compound obtained by the operation of Example 20.
图8为通过实施例21的操作获得的无定形化合物的PXRD图形。Figure 8 is a PXRD pattern of the amorphous compound obtained by the operation of Example 21.
具体实施方式detailed description
实施例1本发明晶型Ⅰ的制备Example 1 Preparation of Form I of the Invention
取1.0g 4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺固体，加10mL无水乙醇加热至70℃。加热至完全溶清后，继续搅拌10分钟，冷却至室温，再冰-水浴冷至3℃，搅拌10分钟过滤，滤饼用1mL冰无水乙醇淋洗，50℃真空干燥，得晶型I。Take 1.0 g of 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} 2-Fluoro-N-tridehypo-methylbenzamide solid, heated to 70 ° C with 10 mL of absolute ethanol. After heating to complete dissolution, stirring was continued for 10 minutes, cooled to room temperature, cooled to 3 ° C in an ice-water bath, stirred for 10 minutes, filtered, and the filter cake was rinsed with 1 mL of ice-free ethanol and dried under vacuum at 50 ° C to obtain crystal form I. .
实施例2本发明晶型Ⅰ的制备Example 2 Preparation of Form I of the Invention
取1.0g 4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺固体，加11mL混合溶剂(DMSO:乙酸异丙酯＝1:10)，搅拌至完全溶清，加15％食盐水萃洗两次，每次6mL。有机相用无水硫酸钠干燥，过滤，50℃旋出溶剂，得到油状物，加10mL异丙醇打浆，过夜，过滤。50℃真空干燥得到晶型I。Take 1.0 g of 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} -2-Fluoro-N-tridehypo-methylbenzamide solid, add 11mL mixed solvent (DMSO: isopropyl acetate = 1:10), stir until completely dissolved, add 15% brine to wash twice, each 6mL. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated and evaporated. Drying at 50 ° C in vacuo gave Form I.
实施例3本发明晶型Ⅰ的制备Example 3 Preparation of Form I of the Invention
取1.0g 4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺固体，加10mL乙腈，搅拌至完全溶清，滴加到装有30mL水的50mL单口瓶中，搅拌3小时，过滤，50℃真空干燥，得到晶型I。Take 1.0 g of 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} -2-Fluoro-N-tridehypo-methylbenzamide solid, add 10 mL of acetonitrile, stir until completely dissolved, add dropwise to a 50 mL single-mouth bottle containing 30 mL of water, stir for 3 hours, filter, and dry at 50 ° C under vacuum. Form I is obtained.
实施例4本发明晶型Ⅰ的制备Example 4 Preparation of Form I of the Invention
取1.0g 4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺固体，加20mL异丙醇加热至70℃。加热至完全溶清后，继续搅拌10分钟，冷却至室温，再冰-水浴冷至3℃，搅拌30分钟过滤，滤饼用1mL冰异丙醇淋洗，50℃真空干燥，得到晶型I。Take 1.0 g of 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} 2-Fluoro-N-tridehypo-methylbenzamide solid, heated to 70 ° C with 20 mL of isopropanol. After heating to complete dissolution, stirring was continued for 10 minutes, cooled to room temperature, cooled to 3 ° C in an ice-water bath, stirred for 30 minutes, filtered, and the filter cake was rinsed with 1 mL of ice-isopropanol and dried under vacuum at 50 ° C to obtain crystal form I. .
实施例5本发明晶型Ⅰ的制备Example 5 Preparation of Form I of the Invention
取1.0g 4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺固体，加10mL乙酸，室温搅拌30分钟至完全溶清，滴加20mL水，搅拌30分钟过滤，50℃真空干燥，得到晶型I。 Take 1.0 g of 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} 2-Fluoro-N-tridehypo-methylbenzamide solid, add 10 mL of acetic acid, stir at room temperature for 30 minutes to completely dissolve, add 20 mL of water dropwise, stir for 30 minutes, filter, and dry at 50 ° C under vacuum to obtain crystal form I.
实施例6本发明晶型Ⅰ的制备Example 6 Preparation of Form I of the Invention
取1.0g 4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺固体，加5mL乙酸乙酯，加热至50℃。加热至完全溶清后，继续搅拌10分钟，冰-水浴冷至5℃，搅拌3小时过滤，50℃真空干燥，得到晶型I。Take 1.0 g of 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} 2-Fluoro-N-tridehypo-methylbenzamide solid, 5 mL of ethyl acetate was added and heated to 50 °C. After heating to complete dissolution, stirring was continued for 10 minutes, ice-water bath was cooled to 5 ° C, stirred for 3 hours, filtered, and dried under vacuum at 50 ° C to obtain crystal form I.
实施例7本发明晶型Ⅰ的制备Example 7 Preparation of Form I of the Invention
取1.0g 4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺固体，加10mL乙酸丁酯，加热至70℃。加热至完全溶清后，继续搅拌10分钟，冰-水浴冷至3℃，搅拌10分钟过滤，50℃真空干燥，得到晶型I。Take 1.0 g of 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} 2-Fluoro-N-tridehypo-methylbenzamide solid, add 10 mL of butyl acetate, and heat to 70 °C. After heating to complete dissolution, stirring was continued for 10 minutes, and the mixture was cooled to 3 ° C in an ice-water bath, stirred for 10 minutes, and dried under vacuum at 50 ° C to obtain crystal form I.
实施例8本发明晶型Ⅰ的制备Example 8 Preparation of Form I of the Invention
取2.0g 4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺固体，加2.5mL四氢呋喃，加热至60℃。加热至完全溶清后，继续搅拌20分钟，冰-水浴冷至3℃，搅拌3小时过滤，50℃真空干燥，得到晶型I。Take 2.0 g of 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} 2-Fluoro-N-tridehypo-methylbenzamide solid, add 2.5 mL of tetrahydrofuran, and heat to 60 °C. After heating to complete dissolution, stirring was continued for 20 minutes, ice-water bath was cooled to 3 ° C, stirred for 3 hours, filtered, and dried under vacuum at 50 ° C to obtain crystal form I.
实施例9本发明晶型Ⅰ的制备Example 9 Preparation of Form I of the Invention
取2.0g 4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺固体，加10mL甲基异丙基甲酮，加热至50℃。加热至完全溶清后，继续搅拌20分钟，冰-水浴冷至3℃，搅拌30分钟过滤，50℃真空干燥，得到晶型I。Take 2.0 g of 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} 2-Fluoro-N-tridehypo-methylbenzamide solid, add 10 mL of methyl isopropyl ketone and heat to 50 °C. After heating to complete dissolution, stirring was continued for 20 minutes, ice-water bath was cooled to 3 ° C, stirred for 30 minutes, filtered, and dried under vacuum at 50 ° C to obtain crystal form I.
实施例10本发明晶型Ⅰ的制备Example 10 Preparation of Form I of the Invention
取1.0g 4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺固体，加50mL甲苯，加热至90℃。加热至完全溶清后，继续搅拌20分钟，冰-水浴冷至3℃，搅拌30分钟过滤，50℃真空干燥，得到晶型I。Take 1.0 g of 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} 2-Fluoro-N-tridehypo-methylbenzamide solid, add 50 mL of toluene, and heat to 90 °C. After heating to complete dissolution, stirring was continued for 20 minutes, ice-water bath was cooled to 3 ° C, stirred for 30 minutes, filtered, and dried under vacuum at 50 ° C to obtain crystal form I.
实施例11本发明晶型Ⅰ的制备Example 11 Preparation of Form I of the Invention
取1.0g 4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺固体，加10mL乙醇，加热至65℃。加热至完全溶清后，滴加20mL正庚烷，冰-水浴冷至3℃，搅拌20分钟过滤，50℃真空干燥，得到晶型I。Take 1.0 g of 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} 2-Fluoro-N-tridehypo-methylbenzamide solid, add 10 mL of ethanol, and heat to 65 °C. After heating to complete dissolution, 20 mL of n-heptane was added dropwise, cooled to 3 ° C in an ice-water bath, stirred for 20 minutes, and dried under vacuum at 50 ° C to obtain crystal form I.
实施例12本发明晶型Ⅰ的制备 Example 12 Preparation of Form I of the Invention
取1.0g 4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺固体，加20mL正丁醇，加热至90℃。加热至完全溶清后，继续搅拌20分钟，冰-水浴冷至3℃，搅拌15分钟过滤，50℃真空干燥，得到晶型I。Take 1.0 g of 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} 2-Fluoro-N-tridehypo-methylbenzamide solid, add 20 mL of n-butanol, and heat to 90 °C. After heating to complete dissolution, stirring was continued for 20 minutes, and the mixture was cooled to 3 ° C in an ice-water bath, stirred for 15 minutes, and dried under vacuum at 50 ° C to obtain crystal form I.
实施例13本发明晶型Ⅰ的制备Example 13 Preparation of Form I of the Invention
取1.0g 4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺固体，加50mL二甲苯，加热至100℃。加热至完全溶清后，继续搅拌20分钟，冰-水浴冷至3℃，搅拌15分钟过滤，50℃真空干燥，得到晶型I。Take 1.0 g of 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} 2-Fluoro-N-tridehypo-methylbenzamide solid, add 50 mL of xylene, and heat to 100 °C. After heating to complete dissolution, stirring was continued for 20 minutes, and the mixture was cooled to 3 ° C in an ice-water bath, stirred for 15 minutes, and dried under vacuum at 50 ° C to obtain crystal form I.
实施例14本发明晶型Ⅰ的制备Example 14 Preparation of Form I of the Invention
取1.0g 4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺固体，加25mL丙酮，25mL水，加热至50℃。加热至完全溶清后，继续搅拌10分钟，冰-水浴冷至3℃，搅拌1小时过滤，50℃真空干燥，得到晶型I。Take 1.0 g of 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} 2-Fluoro-N-tridehypo-methylbenzamide solid, add 25 mL of acetone, 25 mL of water, and heat to 50 °C. After heating to complete dissolution, stirring was continued for 10 minutes, and the mixture was cooled to 3 ° C in an ice-water bath, stirred for 1 hour, filtered, and dried under vacuum at 50 ° C to obtain crystal form I.
实施例15本发明晶型Ⅰ的制备Example 15 Preparation of Form I of the Invention
取1.0g 4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺固体，加5mLDMSO，室温搅拌30分钟至完全溶清，滴加20mL水，搅拌2小时过滤，50℃真空干燥，得到晶型I。Take 1.0 g of 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} 2-Fluoro-N-tridehypo-methylbenzamide solid, add 5 mL of DMSO, stir at room temperature for 30 minutes to completely dissolve, add 20 mL of water dropwise, stir for 2 hours, filter, and dry at 50 ° C under vacuum to obtain crystal form I.
实施例16本发明晶型Ⅰ的制备Example 16 Preparation of Form I of the Invention
取1.0g 4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺固体，加5mL甲基异丁基甲酮，加热至70℃。加热至完全溶清后，继续搅拌30分钟，冰-水浴冷至3℃，搅拌4小时过滤，50℃真空干燥，得到晶型I。Take 1.0 g of 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} 2-Fluoro-N-tridehypo-methylbenzamide solid, add 5 mL of methyl isobutyl ketone, and heat to 70 °C. After heating to complete dissolution, stirring was continued for 30 minutes, and the mixture was cooled to 3 ° C in an ice-water bath, stirred for 4 hours, and dried under vacuum at 50 ° C to obtain crystal form I.
实施例17本发明晶型Ⅰ的制备Example 17 Preparation of Form I of the Invention
取1.0g 4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺固体，加5mLDMF，室温搅拌30分钟至完全溶清，滴加20mL水，搅拌2小时过滤，50℃真空干燥，得到晶型I。Take 1.0 g of 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} 2-Fluoro-N-tridehypo-methylbenzamide solid, add 5 mL of DMF, stir at room temperature for 30 minutes to completely dissolve, add 20 mL of water dropwise, stir for 2 hours, filter, and dry at 50 ° C under vacuum to obtain crystal form I.
实施例18晶型Ⅱ的制备Example 18 Preparation of Form II
取1.0g 4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟 -N-三氘代甲基苯酰胺固体，加10mL无水甲醇加热至60℃。加热至完全溶清后，继续搅拌10分钟，冷却至室温，再冰-水浴冷至3℃，搅拌10分钟过滤，滤饼用1mL冰无水甲醇淋洗，50℃真空干燥，得晶型II。Take 1.0 g of 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} -2-fluoro -N-tridehypo-methylbenzamide solid, heated to 60 ° C with 10 mL of anhydrous methanol. After heating to complete dissolution, stirring was continued for 10 minutes, cooled to room temperature, cooled to 3 ° C in an ice-water bath, stirred for 10 minutes, filtered, and the filter cake was rinsed with 1 mL of ice-free methanol, and dried under vacuum at 50 ° C to obtain crystal form II. .
实施例19晶型Ⅱ的制备Example 19 Preparation of Form II
取2.0g 4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺固体，加5mL甲酸，加热至70℃。加热至完全溶清后，继续搅拌10分钟，冷却至室温，再冰-水浴冷至3℃，搅拌30分钟过滤，50℃真空干燥，得到晶型II。Take 2.0 g of 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} 2-Fluoro-N-tridehypo-methylbenzamide solid, add 5 mL of formic acid, and heat to 70 °C. After heating to complete dissolution, stirring was continued for 10 minutes, cooled to room temperature, cooled to 3 ° C in an ice-water bath, stirred for 30 minutes, filtered, and dried under vacuum at 50 ° C to give crystals.
实施例20无定形化合物的制备Example 20 Preparation of an amorphous compound
取1.0g 4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺固体，加10mL丙酮，超声至完全溶清。35℃旋干，去除溶剂的速率约为10mL/分钟，得无定形。Take 1.0 g of 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} 2-Fluoro-N-tridehypo-methylbenzamide solid, add 10 mL of acetone, and sonicate until completely dissolved. Spinning at 35 ° C, the rate of solvent removal was about 10 mL / min, resulting in amorphous.
实施例21无定形化合物的制备Example 21 Preparation of Amorphous Compounds
取2.0g 4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺固体，加5mL乙腈，加热至50℃。加热至完全溶清后，冰-水冷至室温，40℃旋干，得到无定形。Take 2.0 g of 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} 2-Fluoro-N-tridehypo-methylbenzamide solid, add 5 mL of acetonitrile and heat to 50 °C. After heating to complete dissolution, ice-water was cooled to room temperature, and dried at 40 ° C to obtain an amorphous shape.
以下通过实验例具体说明本发明的有益效果。The beneficial effects of the present invention will be specifically described below by way of experimental examples.
实验例1长期稳定性实验Experimental Example 1 Long-term stability experiment
取实施例1制备的4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺晶型Ⅰ、实施例18制备的4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺晶型Ⅱ和重复专利CN201280052853得到的无定形物，分别用铝塑复合膜袋进行封装，于40℃±2℃，相对湿度75％±5％的条件下，于1、3月、6月、9月、12月月末取样检测，结果如下表1所示。 4-{3-[4-Cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazole prepared in Example 1 Alkyl}-2-fluoro-N-tridehypo-methylbenzamide Form I, 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5 prepared in Example 18 , 5-dimethyl-4-oxo-2-thio-1-imidazolidinyl}-2-fluoro-N-tridehypo-methylbenzamide crystal form II and the amorphous material obtained by the repeated patent CN201280052853, They were packaged in aluminum-plastic composite film bags and sampled at 40 °C ± 2 °C, relative humidity of 75% ± 5% at the end of January, March, June, September, and December. The results are shown in Table 1 below. Shown.
表1晶型的长期稳定性实验结果(0-12月)Table 1 Long-term stability test results of crystal form (0-December)
Figure PCTCN2016095647-appb-000002
Figure PCTCN2016095647-appb-000002
由上述数据可以看出，4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺晶型I，晶型稳定，重现性好，放置稳定，使得4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺原料药在存储期内质量更稳定。此外，6月、9月和12月末用显微镜法进行晶型检查，结果本发明晶型Ⅰ无明显变化，而无定形物逐渐向固体颗粒状晶型转变。As can be seen from the above data, 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1- Imidazolidinyl}-2-fluoro-N-tridehypo-methylbenzamide crystal form I, stable in crystal form, good reproducibility, stable in standing, making 4-{3-[4-cyano-3-(three Fluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl}-2-fluoro-N-tridecylmethylbenzamide bulk drug in storage The quality is more stable during the period. Further, the crystal form examination was carried out by microscopy at the end of June, September, and December, and as a result, the crystal form I of the present invention showed no significant change, and the amorphous substance gradually changed to the solid granular crystal form.
综上所述，本发明的晶型Ⅰ，晶型稳定，重现性好，放置稳定，显著优于现有的无定形物以及新发现的晶型Ⅱ，使得4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺原料药在存储期内质量更稳定。同时，本发明的晶型Ⅰ，制备工艺简单，成本低，具有广阔的市场前景。 In summary, the crystal form I of the invention has stable crystal form, good reproducibility and stable standing, and is superior to the existing amorphous substance and the newly discovered crystal form II, so that 4-{3-[4- Cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl}-2-fluoro-N-triterpene The benzamide bulk drug is more stable during storage. At the same time, the crystal form I of the invention has simple preparation process, low cost and broad market prospect.

Claims (17)

  1. 一种氘代咪唑酮化合物——4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺的晶型Ⅰ，其特征在于：该晶型的X射线粉末衍射中，2θ衍射角度在12.3±0.2、13.1±0.2、15.0±0.2和17.5±0.2度处有特征峰。A deuterated imidazolidone compound, 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio- Form I of 1-imidazolidinyl}-2-fluoro-N-tridemethylolbenzamide characterized by a 2θ diffraction angle of 12.3±0.2, 13.1±0.2 in X-ray powder diffraction of the crystal form There are characteristic peaks at 15.0±0.2 and 17.5±0.2 degrees.
  2. 根据权利要求1所述的晶型Ⅰ，其特征在于：该晶型X射线粉末衍射中，2θ衍射角度还在9.8±0.2、13.5±0.2、14.3±0.2、16.7±0.2、18.9±0.2、21.1±0.2、21.8±0.2、22.8±0.2和24.4±0.2度处有特征峰。The crystal form I according to claim 1, wherein in the X-ray powder diffraction, the 2θ diffraction angle is still 9.8±0.2, 13.5±0.2, 14.3±0.2, 16.7±0.2, 18.9±0.2, 21.1. Characteristic peaks at ±0.2, 21.8±0.2, 22.8±0.2, and 24.4±0.2 degrees.
  3. 根据权利要求1或2所述的晶型Ⅰ，其特征在于：该晶型X射线粉末衍射中，2θ衍射角度特征峰的相对强度值为：The crystal form I according to claim 1 or 2, wherein in the X-ray powder diffraction, the relative intensity values of the characteristic peaks of the 2θ diffraction angle are:
    Figure PCTCN2016095647-appb-100001
    Figure PCTCN2016095647-appb-100001
  4. 根据权利要求1-3任一项所述的晶型Ⅰ，其特征在于：该晶型具有基本如图1或图2所示的X射线粉末衍射图谱。Form I according to any one of claims 1 to 3, characterized in that the crystal form has an X-ray powder diffraction pattern substantially as shown in Fig. 1 or Fig. 2.
  5. 根据权利要求1-4任一项所述的晶型Ⅰ，其特征在于：该晶型的熔点为192-209℃。The crystalline form I according to any one of claims 1 to 4, wherein the crystalline form has a melting point of from 192 to 209 °C.
  6. 根据权利要求1-5任一项所述的晶型Ⅰ，其特征在于：该晶型具有基本如图3所示的DSC图谱。Form I according to any one of claims 1 to 5, characterized in that the crystal form has a DSC pattern substantially as shown in FIG.
  7. 一种制备权利要求1-6任一项所述晶型Ⅰ的方法，其特征在于：它包括以下步骤：A method of preparing Form I according to any one of claims 1 to 6, characterized in that it comprises the steps of:
    (1)将4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟 -N-三氘代甲基苯酰胺溶解在溶剂中，所述溶剂不选自甲醇或甲酸中的任一种或其组合；(1) 4-{3-[4-Cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl }-2-Fluorine -N-tridehypo-methylbenzamide is dissolved in a solvent, the solvent not being selected from any one of methanol or formic acid or a combination thereof;
    (2)结晶；(2) crystallization;
    (3)分离出晶体，干燥即得。(3) The crystal is separated and dried.
  8. 根据权利要求7所述的方法，其特征在于：所述步骤(2)的结晶是搅拌冷却结晶；或加入抗溶剂，搅拌冷却结晶。The method according to claim 7, wherein the crystallization of the step (2) is agitation cooling crystallization; or an anti-solvent is added, and the crystals are cooled by stirring.
  9. 根据权利7或8所述的方法，其特征在于：在步骤(1)中，所述溶剂选自醇、腈、卤代烃、酰胺、亚砜、卤代烃、芳烃、酯、醚、酮、水、乙酸中的任一种或其组合。The method according to claim 7 or 8, wherein in the step (1), the solvent is selected from the group consisting of alcohols, nitriles, halogenated hydrocarbons, amides, sulfoxides, halogenated hydrocarbons, aromatic hydrocarbons, esters, ethers, ketones. Any one or combination of water, acetic acid.
  10. 根据权利7-9任一项所述的方法，其特征在于：在步骤(1)中，所述溶剂选自乙醇、异丙醇、正丁醇、乙腈、N,N-二甲基甲酰胺、二甲基亚砜、甲苯、二甲苯、乙酸乙酯、乙酸丁酯、四氢呋喃、丙酮、甲基异丙基甲酮、甲基异丁基甲酮、水、乙酸中的任一种或其组合。The method according to any one of claims 7-9, wherein in the step (1), the solvent is selected from the group consisting of ethanol, isopropanol, n-butanol, acetonitrile, N,N-dimethylformamide And dimethyl sulfoxide, toluene, xylene, ethyl acetate, butyl acetate, tetrahydrofuran, acetone, methyl isopropyl ketone, methyl isobutyl ketone, water, acetic acid, or a combination thereof.
  11. 根据权利要求7-10任一项所述的方法，其特征在于：在步骤(1)中，所述溶剂与4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺的体积重量比为1～50:1mL/g。The method according to any one of claims 7 to 10, wherein in the step (1), the solvent and 4-{3-[4-cyano-3-(trifluoromethyl)phenyl ]-5,5-Dimethyl-4-oxo-2-thio-1-imidazolidinyl}-2-fluoro-N-tridehypo-methylbenzamide in a volume-to-weight ratio of 1 to 50:1 mL /g.
  12. 根据权利要求7-11任一项所述的方法，其特征在于：在步骤(1)的溶解过程中，温度为0℃至溶剂的回流温度。A method according to any one of claims 7 to 11, wherein during the dissolution of the step (1), the temperature is from 0 ° C to the reflux temperature of the solvent.
  13. 根据权利要求8-12任一项所述的方法，其特征在于：所述抗溶剂是水或C5-C10的烃类溶剂。A method according to any one of claims 8 to 12, wherein the anti-solvent is water or a C5-C10 hydrocarbon solvent.
  14. 根据权利要求7-13任一项所述的方法，其特征在于：在步骤(2)中，所述析晶的温度为3℃至室温。The method according to any one of claims 7 to 13, characterized in that in the step (2), the temperature of the crystallization is from 3 ° C to room temperature.
  15. 一种药物组合物，其特征在于：它是由权利要求1-6任一项所述的4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺的晶型Ⅰ作为活性成分，加上药学上可接受的辅料制备而成的制剂。A pharmaceutical composition characterized in that it is 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5 according to any one of claims 1-6. Form I of dimethyl-4-oxo-2-thio-1-imidazolidinyl}-2-fluoro-N-tris-methylbenzamide as active ingredient plus pharmaceutically acceptable Preparation of excipients.
  16. 权利要求1-6任一项所述的4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺的晶型Ⅰ在制备雄性激素受体拮抗剂，或制备治疗或/和预防雄性激素受体活性相关疾病的药物中的应用。4-{3-[4-Cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfate according to any one of claims 1 to Form I of 1--1-imidazolidinyl}-2-fluoro-N-tris-methylbenzamide is used in the preparation of androgen receptor antagonists or in the preparation of a disease associated with the treatment and/or prevention of androgen receptor activity Application in medicine.
  17. 根据权利要求15所述的应用，其特征在于：所述疾病选自脱发、再生发、暗疮、青春痘或前列腺癌。 The use according to claim 15, characterized in that the disease is selected from the group consisting of hair loss, regenerative hair, acne, acne or prostate cancer.
PCT/CN2016/095647 2015-10-30 2016-08-17 Crystal form of deuterated imidazolone compound, and preparation method and use therefor WO2017071375A1 (en)

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WO2013087004A1 (en) * 2011-12-14 2013-06-20 Chen Yuanwei Imidazolidinedione compounds and their uses
CN104211683A (en) * 2013-05-29 2014-12-17 成都海创药业有限公司 Imidazoldione compound and use thereof
CN104341352A (en) * 2013-08-09 2015-02-11 南京衡杰生物科技有限公司 Diaryl hydantoin compound as androgen receptor antagonist and applications of diaryl hydantoin compound

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