TWI638810B - Crystal form i of deuterium labelled imidazolone compounds and preparation and use thereof - Google Patents

Abstract

The present invention discloses a deuterated imidazolone-4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo-2-thio 1-imidazolidinyl} -2-fluoro-N-trideuterated methylbenzamide compound, crystalline form I, and preparation method and application thereof. The crystalline form I of the present invention has stable crystalline form, good reproducibility, and stable placement, and is significantly superior to the existing amorphous form and newly discovered crystalline form II, making 4- {3- [4-cyano-3- ( Trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} -2-fluoro-N-trideuterated methylbenzidine drug substance Quality is more stable during storage. At the same time, the crystalline form I of the present invention has a simple preparation method, low cost, and broad market prospects.

Description

Crystalline form I of deuterated imidazolone compound, its preparation method and application

The present disclosure relates to a deuterated imidazolone compound crystal form I, and a preparation method and application thereof.

Deuterated imidazolone compound 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo-2-thio-1-imidazole Alkyl} -2-fluoro- N -trideuterated methylbenzidine is a compound having the following chemical structure:

Patent CN201280052853 has disclosed its preparation method and use, but at present, there is no report about its crystal form. For the same compound, there are usually two or more different crystalline states, and different crystal forms have different stability. Exploring a more stable crystalline form is conducive to the storage and transportation of the drug and ensures the stability of the drug effect.

Therefore, for drugs, it is of great significance to explore the multiple crystal forms of drugs and find crystal varieties with excellent stability from them.

An embodiment of the present disclosure provides a crystalline form I of a deuterated imidazolone compound, wherein the deuterated imidazolone compound is 4- {3- [4-cyano-3- (trifluoromethyl) phenyl]- 5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} -2-fluoro-N-trideuterated methylbenzidine, in the X-ray powder diffraction of this crystal form, 2θ diffraction angles have characteristic peaks at 12.3 ± 0.2, 13.1 ± 0.2, 15.0 ± 0.2, and 17.5 ± 0.2 degrees.

An embodiment of the present disclosure provides a method for preparing crystalline form I of a deuterated imidazolone compound, including the following steps: (1) 4- {3- [4-cyano-3- (trifluoromethyl) benzene Group] -5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} -2-fluoro-N-trideuterated methylbenzidine is dissolved in a solvent, and the solvent Not selected from any one or a combination of methanol or formic acid; (2) crystallization; and (3) crystals are separated and dried to obtain.

An embodiment of the present disclosure provides a pharmaceutical composition comprising 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo- Form I of 2-thio-1-imidazolidinyl} -2-fluoro-N-trideuterated methylbenzamide is prepared as an active ingredient and a pharmaceutically acceptable excipient.

According to an embodiment of the present disclosure, there is provided a use of the crystalline form I of a deuterated imidazolidone compound in preparing an androgen receptor antagonist, or preparing a medicament for treating or / and preventing diseases related to androgen receptor activity.

In order to make the above-mentioned objects, features, and advantages of the present invention more comprehensible, a preferred embodiment is given below in conjunction with the accompanying drawings for detailed description as follows.

FIG. 1 is a PXRD (X of the crystal form I obtained by the operation of Example 1 (Ray powder diffraction) pattern.

FIG. 2 is a PXRD pattern of the crystal form I obtained by the operation of Example 12. FIG.

FIG. 3 is a DSC spectrum of the crystal form I obtained by the operation of Example 1. FIG.

FIG. 4 is a PXRD pattern of the crystal form II obtained by the operation of Example 18. FIG.

FIG. 5 is a PXRD pattern of the crystal form II obtained by the operation of Example 19. FIG.

FIG. 6 is a DSC spectrum of the crystal form I obtained by the operation of Example 4. FIG.

FIG. 7 is a PXRD pattern of an amorphous compound obtained by the operation of Example 20. FIG.

Fig. 8 is a PXRD pattern of an amorphous compound obtained by the operation of Example 21.

The present invention provides 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl } -2-Fluoro- N -tri-deuterated methylbenzidine is a new crystalline form I, which has good stability and is not easy to be oxidized; and the process of synthesizing the crystalline form is simple and can be scaled up for production.

The present invention provides a deuterated imidazolone compound 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo-2-sulfide 1-imidazolidinyl} -2-fluoro-N-tri-deuterated methylbenzidine crystal form I, the X-ray powder diffraction of this 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.

Further, in this crystal form X-ray powder diffraction, a 2θ diffraction angle There are also characteristic peaks at 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 ± 0.2 degrees.

Furthermore, in the crystal form X-ray powder diffraction, the relative intensity value of the 2θ diffraction angle characteristic peak is: wherein the crystal form has an X-ray powder diffraction pattern substantially as shown in FIG. 1 or FIG. 2.

Wherein, the melting point of this crystal form is 192-209 ° C.

The crystal form has a DSC pattern substantially as shown in FIG. 3.

The present invention also provides a method for preparing the above-mentioned crystal form I, including the following steps: (1) 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-di Methyl-4-oxo-2-thio-1-imidazolidinyl} -2-fluoro-N-trideuterated methylbenzidine is dissolved in a solvent which is not selected from methanol or formic acid Any one or a combination thereof; (2) crystallization; (3) crystals are separated and dried to obtain.

Further, the crystallization in the step (2) is stirring and cooling the crystallization; or an anti-solvent is added and the crystallization is stirring and cooling.

Further, in step (1), the solvent is selected from any one of alcohols, nitriles, halogenated hydrocarbons, amidines, fluorenes, halogenated hydrocarbons, aromatic hydrocarbons, esters, ethers, ketones, water, acetic acid, or combination.

Further, in step (1), the solvent is selected from the group consisting of ethanol, isopropanol, n-butanol, acetonitrile, N, N-dimethylformamide, dimethylmethylene, toluene, xylene, and acetic acid. Ethyl acetate, butyl acetate, tetrahydrofuran, acetone, methyl isopropyl Any one of propyl ketone, methyl isobutyl ketone, water, acetic acid, or a combination thereof.

Further, in step (1), the solvent and 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo- The volume-weight ratio of 2-thio-1-imidazolidinyl} -2-fluoro-N-trideuterated methylbenzidine is 1 to 50: 1 mL / g.

Further, in the dissolution process of step (1), the temperature is from 0 ° C to the reflux temperature of the solvent.

Further, the anti-solvent is water or a C5-C10 hydrocarbon solvent.

Further, in step (2), 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-mentioned crystal form I provided by the present invention further includes: a) Provide 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} A solution of 2-fluoro-N-trideuterated methylbenzidine in a solvent; and b) separation of 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5, Form 5- of 5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} -2-fluoro-N-trideuterated methylbenzidine. The providing solution in step a) includes: i) Use directly containing 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-trideuterated methylbenzidine -A reaction mixture of dimethyl-4-oxo-2-thio-1-imidazolidinyl} -2-fluoro-N-trideuterated methylbenzidine; or ii) 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} -2-Fluoro-N-trideuterated methylbenzidine is dissolved in a solvent.

4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo Any physical form of the substituted 2-thio-1-imidazolidinyl} -2-fluoro-N-trideuterated methylbenzidine can be used to provide 4- {3- [4-cyanide in step a) 3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} -2-fluoro-N-trideuterated methyl A solution of amphetamine. Optionally, when 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo-2-thio-1-imidazole is used In the case of alkyl} -2-fluoro-N-trideuterated methylbenzidine hydrate, before or after step a), it may be performed by techniques known in the art such as distillation, heating, in a suitable solvent Water reduction or removal steps are performed by pulping and the like.

In an example, 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo-2-thio-1 -{3- [4-cyano-3- (trifluoromethyl) phenyl] -5 obtained during the synthesis of -imidazolidinyl} -2-fluoro-N-trideuterated methylbenzidine , 5-Dimethyl-4-oxo-2-thio-1-imidazolidinyl} -2-fluoro-N-trideuterated methylbenzidine 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 Alcohols; or nitriles, such as acetonitrile or propionitrile; amidines, such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone; fluorenes, such as Dimethyl sulfene; 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; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, anisole; ketones such as acetone, ethyl Methyl ketone, diethyl ketone, methyl isobutyl ketone; water; or any mixture of one or more of these solvents.

The dissolution temperature can be from about 0 ° C to about the reflux temperature of the solvent, or below about 150 ° C, below about 130 ° C, below about 100 ° C, below about 70 ° C, and below About 40 ° C, below about 20 ° C, below about 0 ° C, or any other suitable temperature, as long as 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5 is obtained, A clear solution of 5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} -2-fluoro-N-trideuterated methylbenzidine without affecting its quality. The solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow), or any other suitable material to remove color, insoluble materials, improve the 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 appropriately 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 a bed of paper, fiberglass, cloth, or other membrane material, or a clarifier (eg, or Hyflow). 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) includes separating 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo from the solution obtained in step a). Crystalline Form I of 2-thio-1-imidazolidinyl} -2-fluoro-N-trideuterated methylbenzidine. Isolation of 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo-2-thio-1-imidazole in step b) Alkyl} -2-fluoro-N-tri-deuterated methylbenzidine crystalline form I is obtained through the inclusion of The combination method is performed. Agitation or other alternative methods such as shaking, agitation, etc. can also be used for separation. Alternatively, when the crystals of the form R1 are present in the solution obtained in step (a), these crystals can be used as seed crystals, and the form R1 can be separated in the presence of a seed crystal of such a form R1 in step (b) .

Optionally, it can be obtained by combining a suitable antisolvent with step a). The obtained solutions were combined for separation. As used herein, antisolvent refers to 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo-2-thio-1 -Imidazolidinyl} -2-fluoro-N-trideuterated methylbenzamide liquid in which it is slightly or sparingly soluble. Antisolvent p- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} The quality of -2-fluoro-N-trideuterated methylbenzidine has no adverse effect, and it can help the solidified or precipitated dissolved raw materials. Suitable anti-solvents that can 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 formaldehyde Cyclohexane; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane or dimethoxyethane; or mixtures thereof.

Suitable separation temperatures can be below about 100 ° C, below about 80 ° C, below about 60 ° C, below about 40 ° C, below about 20 ° C, below about 10 ° C, below about 5 ° C, below About 0 ° C, below about -10 ° C, below 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 I of 2-fluoro-N-trideuterated methylbenzidine can be used for solid recovery by decantation, centrifugation, evaporation, gravity filtration, suction filtration, or any other under pressure or under reduced pressure. Technology including recycling. The recovered solid may optionally be dried. The drying can be performed 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, etc. get on. The drying may be at a temperature of less than about 100 ° C, less than about 80 ° C, less than about 60 ° C, less than about 50 ° C, less than about 30 ° C, or any other suitable temperature, at atmospheric pressure or reduced pressure. Proceed as long as 4- {3- [4- Cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} -2-fluoro-N-trideuterated methyl The quality of benzamidine does not deteriorate. The drying can be performed any desired number of times until the desired product quality is achieved. The dried product may optionally undergo a size reduction operation to produce the desired fineness. The product may be ground or micronized before or after drying. Techniques that can be used to reduce fineness include, but are not limited to, ball milling, roller milling, and hammer milling, as well as jet milling.

The present invention also provides a pharmaceutical composition, which is composed of the above 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo A formula prepared by using 2-thio-1-imidazolidinyl} -2-fluoro-N-trideuterated methylbenzamide as the active ingredient and a pharmaceutically acceptable excipient.

Further, the present invention provides the aforementioned 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo-2-thio-1 -Imidazolidinyl} -2-fluoro-N-tri-deuterated methylbenzidine, Form I in the preparation of androgen receptor antagonists, or in the preparation of drugs for the treatment and / or prevention of diseases related to androgen receptor activity Applications.

The disease is selected from, but not limited to, hair loss, recurrent hair, acne, acne, or prostate cancer.

In addition, the compound 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo-2-thio-1 -Imidazolidinyl} -2-fluoro-N-trideuterated methylbenzidine crystal form screening, the present invention provides its crystal form II, in the X-ray powder diffraction of this crystal form, the 2θ diffraction angle is 4.8 There are characteristic peaks at ± 0.2, 11.3 ± 0.2, and 20.2 ± 0.2 degrees.

Further, in this crystal form X-ray powder diffraction, a 2θ diffraction angle There are also 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.

Further, in the crystal form X-ray powder diffraction, the relative intensity value of the 2θ diffraction angle characteristic peak is: wherein the crystal form has an X-ray powder diffraction pattern substantially as shown in FIG. 4 or FIG. 5.

Wherein, the melting point of this crystal form is 114-139 ° C.

The crystal form has a DSC pattern substantially as shown in FIG. 6.

The present invention also provides a method for preparing the above-mentioned crystal form II, which comprises the following steps: (1) 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5- Dimethyl-4-oxo-2-thio-1-imidazolidinyl} -2-fluoro-N-trideuterated methylbenzidine is dissolved in a solvent selected from the group consisting of methanol or formic acid Any one or a combination thereof; (2) crystallization; (3) crystals are separated and dried to obtain.

Further, the crystallization in the step (2) is stirring and cooling the crystallization; or an anti-solvent is added and the crystallization is stirring and cooling.

Further, in step (1), the solvent and 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo- The volume-weight ratio of 2-thio-1-imidazolidinyl} -2-fluoro-N-trideuterated methylbenzidine is 2.5 to 10: 1 mL / g.

Further, in the dissolution process of step (1), the temperature is from 0 ° C to the reflux temperature of the solvent.

Further, the anti-solvent is water or a C5-C10 hydrocarbon solvent.

Further, in step (2), the crystallization temperature is -20 ° C-100 ° C, and the preferred crystallization temperature is 3 ° C to room temperature.

The method for preparing the above-mentioned crystal 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-trideuterated methylbenzidine 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-trideuterated methyl Form II of amphetamine.

The providing solution in step a) includes: i) Use directly containing 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-trideuterated methylbenzidine -A reaction mixture of dimethyl-4-oxo-2-thio-1-imidazolidinyl} -2-fluoro-N-trideuterated methylbenzidine; or ii) 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} -2-Fluoro-N-trideuterated methylbenzidine is dissolved in methanol or formic acid.

4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} -2- Any physical form of fluoro-N-trideuterated methylbenzidine can be used to provide 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5 in step a) , 5-Dimethyl-4-oxo-2-thio-1-imidazolidinyl} -2-fluoro-N-trideuterated methylbenzamide solution. Optionally, when 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo-2-thio-1-imidazole is used In the case of alkyl} -2-fluoro-N-trideuterated methylbenzidine hydrate, before or after step a), it may be performed by techniques known in the art such as distillation, heating, in a suitable solvent Water, etc. Reduce or remove steps.

In an example, 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo-2-thio-1 -{3- [4-cyano-3- (trifluoromethyl) phenyl] -5 obtained during the synthesis of -imidazolidinyl} -2-fluoro-N-trideuterated methylbenzidine , 5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} -2-fluoro-N-trideuterated methylbenzidine is dissolved in methanol or formic acid or any mixture thereof. .

The dissolution temperature may be 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, and 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-thioxo is obtained A clear solution of -1-imidazolidinyl} -2-fluoro-N-trideuterated methylbenzidine without affecting its quality. The solution may optionally be treated with carbon, diatomaceous earth (Hyflow), or any other suitable material to remove color, insoluble materials, improve the clarity of the solution, and / or remove materials that may be adsorbed on such materials Impurities. Optionally, the solution obtained above can be filtered to remove any insoluble particles. The insoluble particles may be appropriately 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 a bed of paper, fiberglass, cloth, or other membrane material, or a clarifier (eg, or Hyflow). 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) includes separating 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo from the solution obtained in step a). Form -2-thio-1-imidazolidinyl} -2-fluoro-N-trideuterated methylbenzamide. Isolation of 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo-2-thioxanthine in step b) The crystalline form II of 1-imidazolidinyl} -2-fluoro-N-trideuterated methylbenzidine may be a method including cooling, concentrating a substance, adding an antisolvent, adding a seed crystal to induce crystallization and the like. Agitation or other alternative methods such as shaking, agitation, etc. can also be used for separation.

Optionally, the separation can be performed by combining a suitable anti-solvent with the solution obtained in step a). As used herein, antisolvent refers to 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo-2-thio-1 -Imidazolidinyl} -2-fluoro-N-trideuterated methylbenzamide liquid in which it is slightly or sparingly soluble. Antisolvent p- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} The quality of -2-fluoro-N-trideuterated methylbenzidine has no adverse effect, and it can help the solidified or precipitated dissolved raw materials. Suitable anti-solvents that can be used include, but are not limited to, saturated or unsaturated straight or branched chain, cyclic or acyclic C1-C10 hydrocarbons, such as hexane, heptane, cyclohexane, or methylcyclo Hexane; an ether, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, or dimethoxyethane; or any mixture thereof.

Suitable separation temperatures can be below about 100 ° C, below about 80 ° C, below about 60 ° C, below about 40 ° C, below about 20 ° C, below about 10 ° C, below about 5 ° C, below About 0 ° C, below about -10 ° C, below 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-trideuterated methylbenzidine can be passed through any other technique for solids recovery including decantation, centrifugation, gravity filtration, suction filtration, or under pressure or pressure Recycling methods. The recovered solid may optionally be dried. The drying can be done in the pan Type dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, rotary flash dryer, fast dryer and so on. The drying may be at a temperature of less than about 100 ° C, less than about 80 ° C, less than about 60 ° C, less than about 50 ° C, less than about 30 ° C, or any other suitable temperature, at atmospheric pressure or reduced pressure. 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-trideuterated methylbenzidine does not deteriorate. The drying can be performed any desired number of times until the desired product quality is achieved. The dried product may optionally be subjected to a pulverization operation to produce the desired fineness. The product may be ground or micronized before or after drying. Techniques that can be used to reduce fineness include, but are not limited to, ball milling, roller milling, and hammer milling, as well as jet milling.

The invention also provides a pharmaceutical composition, which is composed of the 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo- A form prepared by using 2-thio-1-imidazolidinyl} -2-fluoro-N-trideuterated methylbenzidine as the active ingredient and a pharmaceutically acceptable excipient.

Further, the present invention also provides the aforementioned 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo-2-thioxanthine. -1-imidazolidinyl} -2-fluoro-N-tri-deuterated methylbenzidine crystal form II in the preparation of androgen receptor antagonists, or in the treatment and / or prevention of diseases related to androgen receptor activity Application in medicine.

Wherein, the disease is selected from the group consisting of hair loss, recurrent hair, acne, acne, or prostate cancer.

The compound obtained from the patent CN201280052853 has an amorphous form. Among them, the amorphous compound has a basic structure as shown in FIG. 7 or FIG. 8. X-ray powder diffraction pattern.

The present invention also provides a method for preparing the above-mentioned amorphous compound, which includes the following steps: (1) 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5- Dimethyl-4-oxo-2-thio-1-imidazolidinyl} -2-fluoro-N-trideuterated methylbenzidine is dissolved in a solvent; (2) with or without cooling; (3) ) Quickly remove the solvent or quickly precipitate a solid and separate, that is, obtained.

Further, in step (1), the solvent is selected from any one of alcohols, nitriles, halogenated hydrocarbons, amidines, fluorenes, halogenated hydrocarbons, aromatic hydrocarbons, esters, ethers, ketones, water, acetic acid, or combination.

Further, in step (1), the solvent is selected from the group consisting of methanol, ethanol, isopropanol, n-butanol, acetonitrile, N, N-dimethylformamide, dimethylmethane, toluene, and xylene. Or any combination thereof, ethyl acetate, butyl acetate, tetrahydrofuran, acetone, methyl isopropyl ketone, methyl isobutyl ketone, water, acetic acid, or a combination thereof.

Further, in step (1), the solvent and 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo- The volume-weight ratio of 2-thio-1-imidazolidinyl} -2-fluoro-N-trideuterated methylbenzidine is 2.5 to 10: 1 mL / g.

Further, in the dissolution process of step (1), the temperature is from 0 ° C to the reflux temperature of the solvent.

Further, in step (2), the crystallization temperature is -20 ° C to 100 ° C, and the preferred crystallization temperature is 3 ° C to room temperature.

Further, in step (3), the rapidly removing solvent means Is that at least 10 mL of solvent is removed within 1 minute, and at least 1 g of 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-4 is dissolved in the solvent -Oxo-2-thio-1-imidazolidinyl} -2-fluoro-N-trideuterated methylbenzamide.

Further, the solvent removal in the step (3) is performed by rotary evaporation.

Further, the rapid precipitation of solids in step (3) is performed by adding an anti-solvent.

Further, the anti-solvent is water or a C5-C10 hydrocarbon solvent.

The method for preparing the amorphous compound 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-trideuterated methylbenzidine in a solvent; and b) separation of 4- {3- [4-cyano- 3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} -2-fluoro-N-trideuterated methylphenylhydrazone Amorphous compound of amine.

Provide 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo-2-thio-1-imidazole in step a) Alkyl} -2-fluoro-N-trideuterated methylbenzidine solutions include: i) Direct use of a solution containing 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] 4- {3 obtained during the synthesis of -5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} -2-fluoro-N-trideuterated methylbenzidine -[4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} -2-fluoro-N- A reaction mixture of trideuterated methylbenzidine; or ii) 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl 4-oxo-2-thio-1-imidazolidinyl} -2-fluoro-N-trideuterated methylbenzamide is dissolved in a solvent.

4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} -2- Any physical form of fluoro-N-trideuterated methylbenzidine can be used to provide 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5 in step a) , 5-Dimethyl-4-oxo-2-thio-1-imidazolidinyl} -2-fluoro-N-trideuterated methylbenzamide solution. The dissolution temperature may be 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, and 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-thioxo is obtained A clear solution of -1-imidazolidinyl} -2-fluoro-N-trideuterated methylbenzidine without affecting its quality. The solution may optionally be treated with carbon, diatomaceous earth (Hyflow), or any other suitable material to remove color, insoluble materials, improve the clarity of the solution, and / or remove materials that may be adsorbed on such materials Impurities. Optionally, the solution obtained above can be filtered to remove any insoluble particles. The insoluble particles may be appropriately 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 a bed of paper, fiberglass, cloth, or other membrane material, or a clarifier (eg, or Hyflow). 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.

In an example, 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo-2-thio-1- Imidazolidinyl} -2-fluoro-N-trideuterated methylbenzamide is dissolved in any suitable solvent. Suitable solvents include any solvent that does not adversely affect the compound and can dissolve the raw materials to a useful degree. Agent. 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 Ketones or diethyl ketones; 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; nitriles, such as acetonitrile or propionitrile; ammonium, such as formamidine, N, N-dimethyl Methylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, or trimethylamine hexamethylphosphate; fluorene, such as dimethyl fluorene; halogenated hydrocarbons, such as dichloro Methane, chloroform, carbon tetrachloride or chlorobenzene; aromatic hydrocarbons, such as toluene; or any mixture of two or more thereof.

Step b) includes separating 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-trideuterated methylbenzidine. Isolation of 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo-2-thio-1-imidazole in step b) Alkyl} -2-fluoro-N-tri-deuterated methylbenzidine amorphous compounds may involve removing solvents, cooling, rapid cooling, concentrating substances, evaporation, rapid evaporation, simple evaporation, spin drying, spray drying, Film drying, agitated suction filter drying, pressure suction filter drying, freeze drying, anti-solvent addition, solvent extraction and other methods. Agitation or other alternative methods such as shaking, agitation, etc. can also be used for separation. Isolated 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} Amorphous compounds of 2-fluoro-N-tri-deuterated methylbenzidine may carry a certain amount of mother liquor in storage, and may have There are impurities higher than expected. If necessary, this amorphous compound can be washed with a solvent or a solvent mixture to wash out impurities.

The key to preparing an amorphous compound is to remove the solvent or precipitate a solid in a short period of time to avoid the compound from forming a crystalline form, which can be obtained by methods commonly used in the art for preparing amorphous compounds.

The key to preparing amorphous compounds by rotary evaporation is the formation of 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo-2- Solution of thio-1-imidazolidinyl} -2-fluoro-N-trideuterated methylbenzidine in a soluble solvent at low temperature (temperature not exceeding 50 ° C) and removed at a rate of at least 5 ml / min The solvent is preferably 5-15 ml / min.

Suitable separation temperatures can be below about 120 ° C, below about 80 ° C, below about 60 ° C, below about 40 ° C, below about 30 ° C, below about 20 ° C, below about 10 ° C, below About 0 ° C, below about -10 ° C, below about -40 ° C, or any other suitable temperature.

Optionally, the separation can be performed by combining a suitable anti-solvent with the solution obtained in step a). As used herein, antisolvent refers to 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo-2-thio-1 -Imidazolidinyl} -2-fluoro-N-trideuterated methylbenzamide liquid in which it is slightly or sparingly soluble. An inert anti-solvent has no adverse effect on the reaction, and it can help solidify or precipitate dissolved raw materials. Suitable anti-solvents that can be used include, but are not limited to, saturated or unsaturated straight or branched chain, cyclic or acyclic C1-C10 hydrocarbons, such as heptane, cyclohexane, or methylcyclohexane; Water; or any mixture thereof.

The recovered solid may optionally be dried. The drying can be performed in a tray dryer, a vacuum oven, an air oven, a cone vacuum dryer, a rotary Vacuum dryer, fluidized bed dryer, rotary flash dryer, fast dryer, etc. The drying may be at a temperature of less than about 100 ° C, less than about 80 ° C, less than about 60 ° C, less than about 50 ° C, less than about 30 ° C, or any other suitable temperature, at atmospheric pressure or reduced pressure. 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-trideuterated methylbenzidine does not deteriorate. The drying can be performed any desired number of times until the desired product quality is achieved. The dried product may optionally be subjected to a pulverization operation to produce the desired fineness. The product may be ground or micronized before or after drying. Techniques that can be used to reduce fineness include, but are not limited to, ball milling, roller milling, or hammer milling, or jet milling.

The present invention also provides a deuterated imidazolone compound 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo-2- Amorphous compound of thio-1-imidazolidinyl} -2-fluoro-N-trideuterated methylbenzidine, which is a 4- {3- [4-cyano-3- (tri Fluoromethyl) phenyl] -5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} -2-fluoro-N-trideuterated methylbenzidine as a raw material, Obtained by the above-mentioned method for preparing an amorphous compound or obtained by a conventional method for preparing an amorphous compound in the art.

The present invention also provides a pharmaceutical composition, which is composed of the above 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo A 2-thio-1-imidazolidinyl} -2-fluoro-N-trideuterated methylbenzidine amorphous compound as an active ingredient, and a preparation prepared by adding a pharmaceutically acceptable excipient.

Further, the present invention also provides the aforementioned 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo-2-thioxanthine. -1-imidazolidinyl} -2-fluoro-N-trideuterated methylbenzidine Receptor antagonist, or use in the preparation of a medicament for the treatment and / or prevention of diseases related to androgen receptor activity.

Wherein, the disease is selected from the group consisting of hair loss, recurrent hair, acne, acne, or prostate cancer.

In the present invention, C5-C10 hydrocarbon solvents refer to C5, C6, C7, C8, C9, C10 hydrocarbon solvents, that is, alkanes, olefins, alkynes, cyclic hydrocarbons or aromatics having 5 to 10 carbon atoms. Hydrocarbon solvents such as n-hexane, cyclohexane, benzene, toluene, and the like.

The stability test proves that the crystalline form I of the present invention has stable crystalline form, good reproducibility, stable placement, and is significantly better than the existing amorphous form and newly found crystalline form II, which makes 4- {3- [4-cyanide 3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} -2-fluoro-N-trideuterated methyl The quality of amphetamine drug substance is more stable during the storage period. At the same time, the crystalline form I of the present invention has a simple preparation method, low cost, and broad market prospects.

Obviously, according to the foregoing content of the present invention, in accordance with common technical knowledge and conventional means in the art, other various forms of modification, replacement, or alteration can be made without departing from the basic technical idea of the present invention.

Example 1 Preparation of Form I of the invention

Take 1.0 g of 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} -2-Fluoro-N-trideuterated methylbenzidine solid, add 10 mL of absolute ethanol and heat to 70 ° C. After heating to complete dissolution, stirring was continued for 10 minutes, cooled to room temperature, and then cooled to 3 ° C in an ice-water bath, and stirred for 10 minutes to filter. The filter cake was rinsed with 1 mL of ice absolute ethanol, and dried under vacuum at 50 ° C to obtain crystal form I. .

Example 2 Preparation of Form I of the invention

Take 1.0 g of 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} -2-Fluoro-N-tri-deuterated methylbenzidine solid, add 11 mL of mixed solvent (DMSO: isopropyl acetate = 1: 10), stir until completely dissolved, and extract and wash twice with 15% saline, 6mL each time. The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was spun off at 50 ° C. to obtain an oil, which was slurried with 10 mL of isopropanol, overnight, and filtered. Crystalline form I was obtained by vacuum drying at 50 ° C.

Example 3 Preparation of Form I of the invention

Take 1.0 g of 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} -2-Fluoro-N-tri-deuterated methylbenzidine solid, add 10 mL of acetonitrile, stir until completely dissolved, dropwise into a 50 mL single-necked bottle containing 30 mL of water, stir for 3 hours, filter, and vacuum dry at 50 ° C To obtain crystal form I.

Example 4 Preparation of Form I of the invention

Take 1.0 g of 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} -2-Fluoro-N-trideuterated methylbenzidine solid, add 20 mL of isopropanol and heat to 70 ° C. After heating to complete dissolution, continue to stir for 10 minutes, cool to room temperature, then cool to 3 ° C in an ice-water bath, stir for 30 minutes, and filter. The filter cake is rinsed with 1 mL of ice isopropanol, and dried at 50 ° C under vacuum to obtain a crystal form. I.

Example 5 Preparation of Form I of the invention

Take 1.0 g of 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} -2-Fluoro-N-trideuterated methylbenzidine 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 .

Example 6 Preparation of Form I of the invention

Take 1.0g of 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl 4-4-oxo-2-thio-1-imidazolidinyl} -2-fluoro-N-trideuterated methylbenzidine solid, 5 mL of ethyl acetate was added and heated to 50 ° C. After heating to complete dissolution, stirring was continued for 10 minutes, and the ice-water bath was cooled to 5 ° C, stirred for 3 hours, filtered, and dried at 50 ° C under vacuum to obtain crystal form I.

Example 7 Preparation of Form I of the invention

Take 1.0 g of 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} -2-Fluoro-N-trideuterated methylbenzidine solid, 10 mL of butyl acetate was added, and heated to 70 ° C. After heating to complete dissolution, stirring was continued for 10 minutes, and the ice-water bath was cooled to 3 ° C, stirred for 10 minutes, filtered, and dried at 50 ° C under vacuum to obtain crystal form I.

Example 8 Preparation of Form I of the invention

Take 2.0g of 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} -2-Fluoro-N-trideuterated methylbenzidine solid, 2.5 mL of tetrahydrofuran was added, and heated to 60 ° C. After heating to complete dissolution, stirring was continued for 20 minutes, and the ice-water bath was cooled to 3 ° C, stirred for 3 hours, filtered, and dried at 50 ° C under vacuum to obtain crystal form I.

Example 9 Preparation of Form I of the invention

Take 2.0g of 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} -2-fluoro-N-trideuterated methylbenzidine solid, 10 mL of methyl isopropyl ketone was added, and heated to 50 ° C. After heating to complete dissolution, stirring was continued for 20 minutes, and the ice-water bath was cooled to 3 ° C, stirred for 30 minutes, filtered, and dried at 50 ° C under vacuum to obtain crystal form I.

Example 10 Preparation of Form I of the invention

Take 1.0g of 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl Solid 4-oxo-2-thio-1-imidazolidinyl} -2-fluoro-N-trideuterated methylbenzidine, 50 mL of toluene was added, and the mixture was heated to 90 ° C. After heating to complete dissolution, stirring was continued for 20 minutes, and the ice-water bath was cooled to 3 ° C, stirred for 30 minutes, filtered, and dried at 50 ° C under vacuum to obtain crystal form I.

Example 11 Preparation of Form I of the invention

Take 1.0 g of 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} -2-Fluoro-N-trideuterated methylbenzidine solid, add 10 mL of ethanol, and heat to 65 ° C. After heating to complete dissolution, 20 mL of n-heptane was added dropwise, and the ice-water bath was cooled to 3 ° C, stirred for 20 minutes, filtered, and dried at 50 ° C under vacuum to obtain crystal form I.

Example 12 Preparation of Form I of the invention

Take 1.0 g of 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} -2-Fluoro-N-trideuterated methylbenzidine 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 ice-water bath was cooled to 3 ° C, stirred for 15 minutes, filtered, and dried at 50 ° C under vacuum to obtain crystal form I.

Example 13 Preparation of crystalline Form I of the present invention

Take 1.0 g of 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} -2-Fluoro-N-trideuterated methylbenzidine solid, 50 mL of xylene was added, and heated to 100 ° C. After heating to complete dissolution, stirring was continued for 20 minutes, and the ice-water bath was cooled to 3 ° C, stirred for 15 minutes, filtered, and dried at 50 ° C under vacuum to obtain crystal form I.

Example 14 Preparation of crystalline Form I of the present invention

Take 1.0g of 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl Solid 4-oxo-2-thio-1-imidazolidinyl} -2-fluoro-N-trideuterated methylbenzidine, 25 mL of acetone, 25 mL of water, and heated to 50 ° C. After heating to complete dissolution, stirring was continued for 10 minutes, and the ice-water bath was cooled to 3 ° C, stirred for 1 hour and filtered, and dried at 50 ° C under vacuum to obtain crystal form I.

Example 15 Preparation of Form I of the invention

Take 1.0 g of 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} Add -2-fluoro-N-trideuterated methylbenzidine 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 under vacuum at 50 ° C to obtain crystal form I.

Example 16 Preparation of Form I of the invention

Take 1.0 g of 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} -2-Fluoro-N-trideuterated methylbenzidine solid, 5 mL of methyl isobutyl ketone was added, and heated to 70 ° C. After heating to complete dissolution, stirring was continued for 30 minutes, and the ice-water bath was cooled to 3 ° C, stirred for 4 hours, filtered, and dried at 50 ° C under vacuum to obtain crystal form I.

Example 17 Preparation of Form I of the invention

Take 1.0 g of 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} Add -2-fluoro-N-trideuterated methylbenzidine 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 under vacuum at 50 ° C to obtain crystal form I.

Example 18 Preparation of Form 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-tri-deuterated methylbenzamide was solid, and 10 mL of anhydrous methanol was added to heat to 60 ° C. After heating until completely dissolved, continue Stir for 10 minutes, cool to room temperature, then cool to 3 ° C in an ice-water bath, stir for 10 minutes, and filter. The filter cake is rinsed with 1 mL of ice-free anhydrous methanol and dried at 50 ° C under vacuum to obtain crystal form II.

Example 19 Preparation of Form II

Take 2.0g of 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} -2-Fluoro-N-trideuterated methylbenzidine 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, and then cooled to 3 ° C in an ice-water bath, stirred for 30 minutes, filtered, and dried under vacuum at 50 ° C to obtain crystal form II.

Example 20 Preparation of amorphous compound

Take 1.0 g of 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} -2-Fluoro-N-trideuterated methylbenzidine solid, add 10 mL of acetone, and sonicate until completely dissolved. Spin-dry at 35 ° C and remove the solvent at a rate of about 10 mL / min to obtain amorphous.

Example 21 Preparation of amorphous compound

Take 2.0g of 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} -2-Fluoro-N-trideuterated methylbenzidine solid, 5 mL of acetonitrile was added, and heated to 50 ° C. After heating to complete dissolution, the mixture was cooled to room temperature with ice-water and spin-dried at 40 ° C to obtain an amorphous form.

The effect of the present invention will be specifically described below through experimental examples.

Experimental example 1 Long-term stability experiment

Take 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo-2-thio-1-imidazole prepared in Example 1 Alkyl} -2-fluoro-N-trideuterated methylbenzamide Form I, 4- {3- [4-cyano-3- (trifluoromethyl) phenyl]-prepared in Example 18 5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} -2-fluoro-N-trideuterated Toluidine form II and the amorphous material obtained from the patent CN201280052853 were packaged in aluminum-plastic composite film bags, respectively, at 40 ° C ± 2 ° C and relative humidity 75% ± 5% in January and March. Samples were taken at the end of June, June, September, and December. The results are shown in Table 1 below.

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-trideuterated methylbenzidine crystalline Form I, the crystal form is stable, the reproducibility is good, and the storage is stable, so that 4- {3- [4-cyano-3- ( Trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} -2-fluoro-N-trideuterated methylbenzidine drug substance Quality during storage more stable. In addition, crystalline form inspection was performed with a microscope method at the end of June, September, and December. As a result, the crystalline form I of the present invention did not change significantly, and the amorphous substance gradually changed to a solid granular crystalline form.

In summary, the crystalline form I of the present invention has stable crystalline form, good reproducibility, stable placement, and is significantly better than the existing amorphous form and newly discovered crystalline form II, which makes 4- {3- [4-cyanide 3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} -2-fluoro-N-trideuterated methyl The quality of amphetamine drug substance is more stable during the storage period. At the same time, the crystalline form I of the present invention has a simple preparation method, low cost, and broad market prospects.

Although the present invention has been disclosed above with several preferred embodiments, it is not intended to limit the present invention. Any person with ordinary knowledge in the technical field can make any changes without departing from the spirit and scope of the present invention. And retouching, so the scope of protection of the present invention shall be determined by the scope of the attached patent application.

Claims (15)

Form I of a deuterated imidazolone compound, wherein the deuterated imidazolone compound is 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl- 4-oxo-2-thio-1-imidazolidinyl} -2-fluoro-N-trideuterated methylbenzidine. In the X-ray powder diffraction of this crystal form, the 2θ diffraction angle is 12.3 ± 0.2, There are characteristic peaks at 13.1 ± 0.2, 15.0 ± 0.2, and 17.5 ± 0.2 degrees. According to the crystalline form I of the deuterated imidazolone compound described in item 1 of the scope of the patent application, in the X-ray powder diffraction of the crystalline form, the 2θ diffraction angle further includes 9.8 ± 0.2, 13.5 ± 0.2, 14.3 ± 0.2, 16.7 There are characteristic peaks at ± 0.2, 18.9 ± 0.2, 21.1 ± 0.2, 21.8 ± 0.2, 22.8 ± 0.2, and 24.4 ± 0.2 degrees. According to the crystalline form I of the deuterated imidazolone compound described in item 1 or 2 of the scope of the patent application, in the X-ray powder diffraction of the crystalline form, the relative intensity value of the 2θ diffraction angle characteristic peak is: The crystalline form I of the deuterated imidazolone compound according to item 3 of the scope of the patent application, wherein the crystalline form has an X-ray powder diffraction pattern shown in FIG. 1 or FIG. 2. The crystal form I of the deuterated imidazolidone compound as described in item 3 of the scope of the patent application, wherein the melting point of the crystal form is 192-209 ° C. The crystal form I of the deuterated imidazolidone compound as described in item 3 of the scope of the patent application, wherein the crystal form has a DSC spectrum shown in FIG. 3. A method for preparing crystal form I of a deuterated imidazolidone compound according to item 1, 2, 3, 4, 5, or 6 of the scope of patent application, comprising the following steps: (1) 4- {3- [4- Cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} -2-fluoro-N-trideuterated methyl Benzamidine is dissolved in a solvent which is not selected from any one of methanol or formic acid or a combination thereof, and the solvent is selected from ethanol, isopropanol, n-butanol, acetonitrile, N, N-dimethylformamide Any one of amidamine, dimethylmethylene, toluene, xylene, ethyl acetate, butyl acetate, tetrahydrofuran, acetone, methyl isopropyl ketone, methyl isobutyl ketone, water, acetic acid, or a combination thereof (2) Crystallization; (3) Crystals are separated and dried to obtain. According to the method for preparing crystalline form I of the deuterated imidazolone compound described in item 7 of the scope of the patent application, wherein the crystallization in step (2) is stirring and cooling crystallization, or adding an anti-solvent, stirring and cooling crystallization. The method for preparing crystalline form I of a deuterated imidazolone compound as described in item 7 of the scope of the patent application, wherein in step (1), the solvent and the 4- {3- [4-cyano-3- (tri Fluoromethyl) phenyl] -5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} -2-fluoro-N-trideuterated methylbenzidine The ratio is 1 ~ 50: 1mL / g. According to the method for preparing the crystalline form I of the deuterated imidazolidone compound according to item 7 in the scope of the patent application, in the dissolving process of step (1), the temperature is from 0 ° C. to a reflux temperature of one of the solvents. According to the method for preparing the deuterated imidazolone compound Form I as described in item 8 of the scope of the patent application, wherein the anti-solvent is water or a C5-C10 hydrocarbon solvent. According to the method for preparing the crystalline form I of the deuterated imidazolone compound described in item 7 of the scope of the patent application, wherein in step (2), the temperature of the separated crystal is 3 ° C to room temperature. A pharmaceutical composition comprising 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5 as described in claims 1, 2, 3, 4, 5, or 6 of the scope of patent application , 5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} -2-fluoro-N-trideuterated methylbenzamide, Form I as an active ingredient, and a pharmaceutical Prepared using acceptable excipients. A crystalline form I of a deuterated imidazolidone compound according to item 1, 2, 3, 4, 5, or 6 of the scope of the patent application is preparing an androgen receptor antagonist, or preparing and / or preventing androgen receptors Use in medicine for activity-related diseases. Use according to item 14 of the scope of patent application, wherein the disease is selected from the group consisting of hair loss, acne, acne, or prostate cancer.