TW201714878A - Crystal form I of deuterium labelled imidazolone compounds and preparation and use thereof - Google Patents
Crystal form I of deuterium labelled imidazolone compounds and preparation and use thereof Download PDFInfo
- Publication number
- TW201714878A TW201714878A TW105128872A TW105128872A TW201714878A TW 201714878 A TW201714878 A TW 201714878A TW 105128872 A TW105128872 A TW 105128872A TW 105128872 A TW105128872 A TW 105128872A TW 201714878 A TW201714878 A TW 201714878A
- Authority
- TW
- Taiwan
- Prior art keywords
- dimethyl
- oxo
- fluoro
- trifluoromethyl
- phenyl
- Prior art date
Links
Classifications
-
- 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
- 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
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
本揭露係有關於一種氘代咪唑酮化合物晶型I及其製備方法和用途。 The disclosure relates to a crystalline form I of a deuterated imidazolone compound, a preparation method thereof and use thereof.
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-三氘代甲基苯醯胺是具有以下化學結構的化合物：
專利CN201280052853已公開了其製備方法和用途，但是目前，並沒有關於其晶型的報導。對於同一種化合物來說，通常會有兩種或多種不同的結晶狀態，而不同的晶型在穩定性上均有所差異。探索出穩定性更好的晶型，有利於藥物的存儲及運輸，保障了藥效的穩定了。 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，對於藥物而言，探索得到藥物的多種晶型，從中尋找到穩定性優異的晶型品種具有非常重要的意義。 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.
本揭露之一實施例，提供一種氘代咪唑酮化合物之晶型I，其中該氘代咪唑酮化合物為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-三氘代甲基苯醯胺，該晶型之X射線粉末衍射中，2θ衍射角度在12.3±0.2、13.1±0.2、15.0±0.2和17.5±0.2度處有特徵峰。 In one embodiment of the present disclosure, there is provided a crystalline form I of a deuterated imidazolidone 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-tridecanomethylbenzamide, in X-ray powder diffraction of the crystal form, The 2θ diffraction angle has characteristic peaks at 12.3±0.2, 13.1±0.2, 15.0±0.2, and 17.5±0.2 degrees.
本揭露之一實施例，提供一種氘代咪唑酮化合物之晶型I之製備方法，包括以下步驟：(1)將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-三氘代甲基苯醯胺溶解在一溶劑中，該溶劑不選自甲醇或甲酸中之任一種或其組合；(2)結晶；以及(3)分離出晶體，乾燥即得。 An embodiment of the present disclosure provides a method for preparing a crystalline form I of a deuterated imidazolidone compound, comprising the steps of: (1) 4-{3-[4-cyano-3-(trifluoromethyl)benzene a group of -5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl}-2-fluoro-N-tridecylmethylphenylamine dissolved in a solvent, the solvent Not selected from any one or a combination of methanol or formic acid; (2) crystallization; and (3) crystals are isolated and dried.
本揭露之一實施例，提供一種藥物組合物，由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-三氘代甲基苯醯胺之晶型I作為一活性成分，以及一藥學上可接受之賦形劑所製備。 In one embodiment of the present disclosure, there is provided 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-tridecanomethylbenzamide is prepared as an active ingredient, together with a pharmaceutically acceptable excipient.
本揭露之一實施例，提供一種氘代咪唑酮化合物之晶型I在製備雄性激素受體拮抗劑，或製備治療或/和預防雄性激素受體活性相關疾病之藥物中之用途。 One embodiment of the present disclosure provides a use of a crystalline form I of a deuterated imidazolidone compound for the preparation of an androgen receptor antagonist, or a medicament for the treatment or prevention of a disease associated with androgen receptor activity.
為讓本發明之上述目的、特徵及優點能更明顯易懂，下文特舉一較佳實施例，並配合所附的圖式，作詳細說明如下。 The above described objects, features and advantages of the present invention will become more apparent and understood.
第1圖為通過實施例1的操作獲得的晶型I的PXRD(X 射線粉末衍射)圖形。 Fig. 1 is a PXRD (X) of Form I obtained by the operation of Example 1. Ray powder diffraction) pattern.
第2圖為通過實施例12的操作獲得的晶型I的PXRD圖形。 Fig. 2 is a PXRD pattern of Form I obtained by the operation of Example 12.
第3圖為通過實施例1的操作獲得的晶型I的DSC圖譜。 Fig. 3 is a DSC chart of Form I obtained by the operation of Example 1.
第4圖為通過實施例18的操作獲得的晶型II的PXRD圖形。 Fig. 4 is a PXRD pattern of Form II obtained by the operation of Example 18.
第5圖為通過實施例19的操作獲得的晶型II的PXRD圖形。 Fig. 5 is a PXRD pattern of Form II obtained by the operation of Example 19.
第6圖為通過實施例4的操作獲得的晶型I的DSC圖譜。 Fig. 6 is a DSC chart of Form I obtained by the operation of Example 4.
第7圖為通過實施例20的操作獲得的無定形化合物的PXRD圖形。 Fig. 7 is a PXRD pattern of the amorphous compound obtained by the operation of Example 20.
第8圖為通過實施例21的操作獲得的無定形化合物的PXRD圖形。 Fig. 8 is a PXRD pattern of the amorphous compound obtained by the operation of Example 21.
本發明提供了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-三氘代甲基苯醯胺新晶型I，該晶型穩定性好不易被氧化；且合成晶型過程中操作簡單，可放大生產。 The present invention provides 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl }-2-Fluoro- N -tris-methylbenzamide new crystal form I, the crystal form is stable and not easy to be oxidized; and the process of synthesizing the crystal form is simple and can be scaled up.
本發明提供了一種氘代咪唑酮化合物-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-三氘代甲基苯醯胺的晶型I，該晶型的X射線粉末衍射中，2θ衍射角度在12.3±0.2、13.1±0.2、15.0±0.2和17.5±0.2度處有特徵峰。 The present invention provides a deuterated imidazolone compound-4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfide Form I of the formula 1--1-imidazolidinyl}-2-fluoro-N-tridecanomethylbenzamide, the X-ray powder diffraction of the crystal form has a 2θ diffraction angle of 12.3±0.2, 13.1±0.2, There are characteristic peaks at 15.0 ± 0.2 and 17.5 ± 0.2 degrees.
進一步地，該晶型X射線粉末衍射中，2θ衍射角度 還在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度處有特徵峰。 Further, in the X-ray powder diffraction, the 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.
更進一步地，該晶型X射線粉末衍射中，2θ衍射角度特徵峰的相對強度值為：其中，該晶型具有基本如第1圖或第2圖所示的X射線粉末衍射圖譜。 Further, in the X-ray powder diffraction, the relative intensity value of the characteristic peak of the 2θ diffraction angle is: wherein the crystal form has an X-ray powder diffraction pattern substantially as shown in Fig. 1 or Fig. 2 .
其中，該晶型的熔點為192-209℃。 Wherein, the crystalline form has a melting point of 192-209 °C.
其中，該晶型具有基本如第3圖所示的DSC圖譜。 Among them, the crystal form has a DSC pattern substantially as shown in Fig. 3.
本發明還提供了一種製備上述晶型I的方法，包括以下步驟：(1)將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-三氘代甲基苯醯胺溶解在溶劑中，所述溶劑不選自甲醇或甲酸中的任一種或其組合；(2)結晶；(3)分離出晶體，乾燥即得。 The present invention also provides a process for the preparation of the above Form I, comprising the steps of: (1) 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-di Methyl-4-oxo-2-thio-1-imidazolidinyl}-2-fluoro-N-tridecanomethylbenzamide is dissolved in a solvent which is not selected from methanol or formic acid Any one or a combination thereof; (2) crystallization; (3) separating the crystals and drying.
進一步地，所述步驟(2)的結晶是攪拌冷卻結晶；或加入抗溶劑，攪拌冷卻結晶。 Further, the crystallization of the step (2) is agitation cooling crystallization; or an anti-solvent is added, and the crystals are cooled by stirring.
進一步地，在步驟(1)中，所述溶劑選自醇、腈、鹵代烴、醯胺、亞碸、鹵代烴、芳烴、酯、醚、酮、水、乙酸中的任一種或其組合。 Further, in the step (1), the solvent is selected from any one of an alcohol, a nitrile, a halogenated hydrocarbon, a guanamine, an anthracene, a halogenated hydrocarbon, an aromatic hydrocarbon, an ester, an ether, a ketone, water, acetic acid or combination.
進一步地，在步驟(1)中，所述溶劑選自乙醇、異丙醇、正丁醇、乙腈、N,N-二甲基甲醯胺、二甲基亞碸、甲苯、二甲苯、乙酸乙酯、乙酸丁酯、四氫呋喃、丙酮、甲基異 丙基甲酮、甲基異丁基甲酮、水、乙酸中的任一種或其組合。 Further, in the step (1), the solvent is selected from the group consisting of ethanol, isopropanol, n-butanol, acetonitrile, N,N-dimethylformamide, dimethyl hydrazine, toluene, xylene, and acetic acid. Ethyl ester, butyl acetate, tetrahydrofuran, acetone, methyl Any one or combination of propyl ketone, methyl isobutyl ketone, water, acetic acid.
進一步地，在步驟(1)中，所述溶劑與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-三氘代甲基苯醯胺的體積重量比為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.
進一步地，在步驟(1)的溶解過程中，溫度為0℃至溶劑的回流溫度。 Further, in the dissolution process of the step (1), the temperature is from 0 ° C to the reflux temperature of the solvent.
進一步地，所述抗溶劑是水或C5-C10的烴類溶劑。 Further, the anti-solvent is water or a C5-C10 hydrocarbon solvent.
進一步地，在步驟(2)中，析晶溫度為-20℃-100℃，優選的析晶的溫度為3℃至室溫。 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.
本發明提供的製備上述晶型I的方法還包括： 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-三氘代甲基苯醯胺在溶劑中的溶液；以及b)分離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-三氘代甲基苯醯胺的晶型I。步驟a)中的提供溶液包括： 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-三氘代甲基苯醯胺的合成過程中獲得的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-三氘代甲基苯醯胺的反應混合物；或者 ii)將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-三氘代甲基苯醯胺溶解在溶劑中。 The method for preparing the above Form I provided by the present invention further comprises: 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, Form I of 5-dimethyl-4-oxo-2-thio-1-imidazolidinyl}-2-fluoro-N-tridecanomethylbenzamide. The providing solution in step a) comprises: 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-tridecanomethylbenzamide; or 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-三氘代甲基苯醯胺的任何物理形式都可用於在步驟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-三氘代甲基苯醯胺的溶液。任選地，當使用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-三氘代甲基苯醯胺的水合物時，在步驟a)之前或之後，可通過本領域中已知的技術例如蒸餾、加熱、在合適的溶劑中製漿等來進行水減少或除去步驟。 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-tridecanomethylbenzamide 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-tridemethyl A solution of benzoguanamine. 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 subjected to techniques known in the art such as distillation, heating, in a suitable solvent. Pulping or the like is carried out to carry out a water reduction or removal step.
在實施例中，可將在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-三氘代甲基苯醯胺的合成過程中獲得的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-三氘代甲基苯醯胺溶解在任何合適的溶劑中。此類合適的溶劑的實例包括但不限於：醇，例如C2-C6醇，例如乙醇、1-丙醇、2-丙醇(異丙醇)、1-丁醇、2-丁醇、叔丁醇；或腈，例如乙腈或丙腈；醯胺，例如N,N-二甲基甲醯胺、N,N-二甲基乙醯胺、N-甲基-2-吡咯烷酮；亞碸，例如二甲基亞碸；鹵代烴，例如二氯甲烷；芳烴，例如甲苯、二甲苯；酯，例如乙酸乙酯、乙酸正丙酯、乙酸正丁酯、乙酸異丙酯、乙酸異丁酯、乙酸叔丁酯；醚，例如***、二異丙基醚、甲基叔丁基醚、四氫呋喃、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、甲基異丁基酮；水；或一種或多種這些溶劑的任意混合物。 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; a guanamine such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone; Dimethyl hydrazine; 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, B Methyl ketone, diethyl ketone, methyl isobutyl ketone; water; or any mixture of one or more of these solvents.
溶解溫度可為約0℃至約溶劑的回流溫度，或者低於約150℃，低於約130℃，低於約100℃，低於約70℃，低於 約40℃，低於約20℃，低於約0℃，或者任何其它合適的溫度，只要獲得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-三氘代甲基苯醯胺的澄清溶液而不影響其品質。可以任選地用碳、煆燒(flux-calcined)矽藻土(Hyflow)或任何其它合適的材料處理所述溶液，以除去顏色、不溶性材料，改善溶液的澄清度，和/或除去可吸附於此類材料上的雜質。任選地，可將上述獲得的溶液過濾以除去任何不溶性顆粒。可以通過過濾、離心、傾析或者在加壓下或在減壓下的任何其它合適的技術來適當地除去所述不溶性顆粒。可通過使所述溶液通過紙、玻璃纖維、布或其它膜材料，或者澄清劑(例如或Hyflow)床對其進行過濾。取決於所使用的設備以及溶液的濃度和溫度，可能需要預熱過濾裝置以避免過早結晶。 The dissolution temperature may 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, below About 40 ° C, less than about 20 ° C, less than 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-tridecanomethylbenzamide 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 clarity of the solution, and/or remove adsorbables. 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.
步驟b)包括從在步驟a)中獲得的溶液中分離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-三氘代甲基苯醯胺的晶型I。步驟b)中的分離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-三氘代甲基苯醯胺的晶型I通過包括冷卻、速冷(crash cooling)、濃縮物質、加入抗溶劑、加入晶種以誘導結晶或蒸發等或其組合在內的方法進行。攪拌或其它替代方法例如振盪、攪動等也可以用於分離。或者，當形式R1的晶體存在於在步驟(a)中獲得的溶液中時，這些晶體可以用作晶種，並且可以在步驟(b)中在此類形式R1的晶種存在下分離形式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-tridecanomethylbenzamide can include induction of cooling, crash cooling, concentration of material, addition of anti-solvent, addition of seed crystals to induce crystallization or evaporation, etc. The combination of the methods is carried out. 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). .
任選地，可以通過將合適的抗溶劑與在步驟a)中獲 得的溶液組合來進行分離。如本文所用，抗溶劑是指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-三氘代甲基苯醯胺在其中微溶或難溶的液體。抗溶劑對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-三氘代甲基苯醯胺的品質沒有不利的影響，並且它可以幫助溶解的原料凝固或沉澱。可使用的合適的抗溶劑包括但不限於：水；飽和或不飽和的直鏈或支鏈的、環狀或非環狀的C1-C10烴，例如己烷、庚烷、環己烷或甲基環己烷；醚，例如***、二異丙基醚、四氫呋喃、二噁烷或二甲氧基乙烷；或其混合物。 Optionally, by obtaining a suitable anti-solvent with the step a) The resulting solutions were combined for separation. 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-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, 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.
合適的分離溫度可為低於約100℃，低於約80℃，低於約60℃，低於約40℃，低於約20℃，低於約10℃，低於約5℃，低於約0℃，低於約-10℃，低於約-20℃，或者任何其它合適的溫度。 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.
分離的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-三氘代甲基苯醯胺的晶型I可以通過包括傾析、離心、蒸發、重力過濾、抽濾或者在加壓下或在減壓下的任何其它用於固體回收的技術在內的方法進行回收。回收的固體可以任選地進行乾燥。所述乾燥可以在盤式乾燥器、真空烘箱、空氣烘箱、錐形真空乾燥器(cone vacuum dryer)、旋轉式真空乾燥器、流化床乾燥器、旋轉閃蒸乾燥器、快速乾燥器等中進行。所述乾燥可以在低於約100℃、低於約80℃、低於約60℃、低於約50℃、低於約30℃的溫度或任何其它合適的溫度下，在大氣壓或減壓下進行，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-三氘代甲基苯醯胺的品質不劣化。所述乾燥可以進行任何期望的次數，直到實現所需的產物品質。乾燥的產物可以任選地經歷粉碎(size reduction)操作，以產生期望的細微性。可在產物的乾燥前或乾燥完成後進行研磨或微粉化。可用於減小細微性的技術包括但不限於球磨、輥磨和錘磨，以及噴射研磨(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-tridecanomethylbenzamide can be used for solids recovery by including decantation, centrifugation, evaporation, gravity filtration, suction filtration or under pressure or under reduced pressure. The method of recycling is carried out. 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. Carry out as long as 4-{3-[4- Cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl}-2-fluoro-N-triterpene The quality of the phenyl hydrazine is not deteriorated. 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 fineness. Grinding or micronizing may be carried out before or after drying of the product. Techniques that can be used to reduce fineness include, but are not limited to, ball milling, roll milling and hammer milling, as well as jet milling.
本發明還提供了一種藥物組合物，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-三氘代甲基苯醯胺的晶型I作為活性成分，加上藥學上可接受的輔料製備而成的製劑。 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 of 2-thio-1-imidazolidinyl}-2-fluoro-N-tris-methylbenzamide as an active ingredient, together with a pharmaceutically acceptable adjuvant.
進一步地，本發明提供了上述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-三氘代甲基苯醯胺的晶型I在製備雄性激素受體拮抗劑，或製備治療或/和預防雄性激素受體活性相關疾病的藥物中的應用。 Further, the present invention provides the above 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1 Form I of 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 Applications.
其中，所述疾病選自但不局限於脫髮、再生髮、暗瘡、青春痘或***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，在對化合物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-三氘代甲基苯醯胺的晶型篩選中，本發明提供了其晶型Ⅱ，該晶型的X射線粉末衍射中，2θ衍射角度在4.8±0.2、11.3±0.2和20.2±0.2度處有特徵峰。 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 the imidazolidinyl}-2-fluoro-N-tris-methylbenzamide, the present invention provides a crystalline form II in which the X-ray powder 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.
進一步地，該晶型X射線粉末衍射中，2θ衍射角度 還在9.7±0.2、14.5±0.2、15.6±0.2、16.9±0.2和25.5±0.2度處有特徵峰。 Further, in the X-ray powder diffraction, the 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.
進一步地，該晶型X射線粉末衍射中，2θ衍射角度特徵峰的相對強度值為：其中，該晶型具有基本如第4圖或第5圖所示的X射線粉末衍射圖譜。 Further, in the X-ray powder diffraction, the relative intensity value of the characteristic peak of the 2θ diffraction angle is: wherein the crystal form has an X-ray powder diffraction pattern substantially as shown in Fig. 4 or Fig. 5.
其中，該晶型的熔點為114-139℃。 Wherein, the crystalline form has a melting point of 114-139 °C.
其中，該晶型具有基本如第6圖所示的DSC圖譜。 Among them, the crystal form has a DSC pattern substantially as shown in Fig. 6.
本發明還提供了一種製備上述晶型Ⅱ的方法，它包括以下步驟：(1)將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-三氘代甲基苯醯胺溶解在溶劑中，所述溶劑選自甲醇或甲酸中的任一種或其組合；(2)結晶；(3)分離出晶體，乾燥即得。 The present invention also provides a process for the preparation of the above Form II, which comprises the steps of: (1) 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5- Dimethyl-4-oxo-2-thio-1-imidazolidinyl}-2-fluoro-N-tridecanomethylbenzamide dissolved in a solvent selected from methanol or formic acid Any one or a combination thereof; (2) crystallization; (3) separating the crystals and drying.
進一步地，所述步驟(2)的結晶是攪拌冷卻結晶；或加入抗溶劑，攪拌冷卻結晶。 Further, the crystallization of the step (2) is agitation cooling crystallization; or an anti-solvent is added, and the crystals are cooled by stirring.
進一步地，在步驟(1)中，所述溶劑與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-三氘代甲基苯醯胺的體積重量比為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.
進一步地，在步驟(1)的溶解過程中，溫度為0℃至溶劑的回流溫度。 Further, in the dissolution process of the step (1), the temperature is from 0 ° C to the reflux temperature of the solvent.
進一步地，所述抗溶劑是水或C5-C10的烴類溶劑。 Further, the anti-solvent is water or a C5-C10 hydrocarbon solvent.
進一步地，在步驟(2)中，析晶溫度為-20℃-100 ℃，優選的析晶的溫度為3℃至室溫。 Further, in the step (2), the crystallization temperature is -20 ° C - 100 At °C, the preferred crystallization temperature is from 3 ° C to room temperature.
本發明提供的製備上述晶型Ⅱ的方法還包括：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-三氘代甲基苯醯胺在甲醇或甲酸中的溶液；以及b)分離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-三氘代甲基苯醯胺的晶型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-tridecanomethylbenzamide in methanol or formic acid; and b) isolating 4-{3-[4-cyanide 3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl}-2-fluoro-N-tridemethyl Form II of benzoguanamine.
步驟a)中的提供溶液包括： 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-三氘代甲基苯醯胺的合成過程中獲得的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-三氘代甲基苯醯胺的反應混合物；或者 ii)將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-三氘代甲基苯醯胺溶解在甲醇或甲酸中。 The providing solution in step a) comprises: 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-tridecanomethylbenzamide; or Ii) 4-{3-[4-Cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} 2-Fluoro-N-tridecanomethylbenzamide 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-三氘代甲基苯醯胺的任何物理形式都可以用於在步驟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-三氘代甲基苯醯胺的溶液。任選地，當使用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-三氘代甲基苯醯胺的水合物時，在步驟a)之前或之後，可通過本領域中已知的技術例如蒸餾、加熱、在合適的溶劑中製漿等進行水 減少或除去步驟。 4-{3-[4-Cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl}-2- Any physical form of fluoro-N-tridecanomethylbenzamide 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-tridecanomethylbenzamide. 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 subjected to techniques known in the art such as distillation, heating, in a suitable solvent. Pulping, etc. Reduce or remove steps.
在實施例中，可將在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-三氘代甲基苯醯胺的合成過程中獲得的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-三氘代甲基苯醯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-tridecanomethylbenzamide is dissolved in methanol or formic acid or any mixture thereof. .
溶解溫度可為約0℃至約溶劑的回流溫度，或者低於約100℃，低於約80℃，低於約60℃，低於約40℃，低於約20℃，低於約10℃，或者任何其它合適的溫度，只要獲得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-三氘代甲基苯醯胺的澄清溶液而不影響其品質。可以任選地用碳、煆燒矽藻土(Hyflow)或任何其它合適的材料處理所述溶液，以除去顏色、不溶性材料，改善溶液的澄清度，和/或除去可吸附於此類材料上的雜質。任選地，可將上述獲得的溶液過濾以除去任何不溶性顆粒。可以通過過濾、離心、傾析或者在加壓下或在減壓下的任何其它合適的技術來適當地除去所述不溶性顆粒。可通過使所述溶液通過紙、玻璃纖維、布或其它膜材料，或者澄清劑(例如或Hyflow)床對其進行過濾。取決於所使用的設備以及溶液的濃度和溫度，可能需要預熱過濾裝置以避免過早結晶。 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 quality. The solution may optionally be treated with carbon, yttrium or any other suitable material to remove color, insoluble materials, improve clarity of the solution, and/or remove adsorbable on such 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.
步驟b)包括從在步驟a)中獲得的溶液中分離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-三氘代甲基苯醯胺的晶型II。步驟b)中的分離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-三氘代甲基苯醯胺的晶型II可以關於包括冷卻、濃縮物質、加入抗溶劑、加入晶種以誘導結晶等在內的方法。攪拌或其它替代方法例如振盪、攪動等也可以用於分離。 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 in step b) Form II of the 1--1-imidazolidinyl}-2-fluoro-N-tridecanomethylbenzamide can be used in connection with methods including cooling, concentration of a substance, addition of an anti-solvent, addition of 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.
任選地，可以通過將合適的抗溶劑與在步驟a)中獲得的溶液組合來進行分離。如本文所用，抗溶劑是指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-三氘代甲基苯醯胺在其中微溶或難溶的液體。抗溶劑對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-三氘代甲基苯醯胺的品質沒有不利的影響，並且它可以幫助溶解的原料凝固或沉澱。可使用的合適的抗溶劑包括但不限於：飽和或不飽和的直鏈或支鏈的、環狀或非環狀的C1-C10烴，例如己烷、庚烷、環己烷或甲基環己烷；醚，例如***、二異丙基醚、四氫呋喃、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). 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-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.
合適的分離溫度可為低於約100℃，低於約80℃，低於約60℃，低於約40℃，低於約20℃，低於約10℃，低於約5℃，低於約0℃，低於約-10℃，低於約-20℃，或者任何其它合適的溫度。 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.
分離的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-三氘代甲基苯醯胺的晶型II可以通過包括傾析、離心、重力過濾、抽濾或者在加壓下或在減壓下的任何其它用於固體回收的技術在內的方法進行回收。回收的固體可以任選地進行乾燥。所述乾燥可以在盤 式乾燥器、真空烘箱、空氣烘箱、錐形真空乾燥器、旋轉式真空乾燥器、流化床乾燥器、旋轉閃蒸乾燥器、快速乾燥器等中進行。所述乾燥可以在低於約100℃、低於約80℃、低於約60℃、低於約50℃、低於約30℃的溫度或任何其它合適的溫度下，在大氣壓或減壓下進行，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-三氘代甲基苯醯胺的品質不劣化。所述乾燥可以進行任何期望的次數，直到實現所需的產物品質。乾燥的產物可以任選地經歷粉碎操作，以產生期望的細微性。可在產物的乾燥前或乾燥完成後進行研磨或微粉化。可用於減小細微性的技術包括但不限於球磨、輥磨和錘磨，以及噴射研磨。 Isolated 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl}- Form II of 2-fluoro-N-tridemethylbenzamide can be used for any solid recovery by 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 on the tray Dryers, vacuum ovens, air ovens, conical vacuum dryers, rotary vacuum dryers, fluidized bed dryers, rotary flash dryers, quick dryers, 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-tris-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 fineness. Grinding or micronizing may be carried out before or after drying of the product. Techniques that can be used to reduce fineness include, but are not limited to, ball milling, roller and hammer milling, and jet milling.
本發明還提供了一種藥物組合物，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-三氘代甲基苯醯胺的晶型Ⅱ作為活性成分，加上藥學上可接受的輔料製備而成的製劑。 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 of 2-thio-1-imidazolidinyl}-2-fluoro-N-tris-methylbenzamide as an active ingredient, together with a pharmaceutically acceptable adjuvant.
進一步地，本發明還提供了上述的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-三氘代甲基苯醯胺的晶型Ⅱ在製備雄性激素受體拮抗劑，或製備治療或/和預防雄性激素受體活性相關疾病的藥物中的應用。 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 disease associated with the treatment and/or prevention of androgen receptor activity Application in medicine.
其中，所述疾病選自脫髮、再生髮、暗瘡、青春痘或***癌。 Wherein the disease is selected from the group consisting of hair loss, regenerative hair, acne, acne or prostate cancer.
專利CN201280052853得到的化合物，其晶型為無定形。其中，該無定形化合物具有基本如第7圖或第8圖所示的 X射線粉末衍射圖譜。 The compound obtained in the patent CN201280052853 has a crystalline form which is amorphous. Wherein the amorphous compound has substantially the same as shown in FIG. 7 or FIG. X-ray powder diffraction pattern.
本發明還提供了一種製備上述無定形化合物的方法，它包括以下步驟：(1)將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-三氘代甲基苯醯胺溶解在溶劑中；(2)冷卻或不冷卻；(3)快速除去溶劑或快速析出固體並分離，即得。 The present invention also provides a process for the preparation of the above amorphous compound, which comprises the steps of: (1) 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5- Dimethyl-4-oxo-2-thio-1-imidazolidinyl}-2-fluoro-N-tris-methylbenzamide is dissolved in a solvent; (2) cooled or not cooled; (3 ) Quickly remove the solvent or quickly precipitate the solid and separate it.
進一步地，在步驟(1)中，所述溶劑選自醇、腈、鹵代烴、醯胺、亞碸、鹵代烴、芳烴、酯、醚、酮、水、乙酸中的任一種或其組合。 Further, in the step (1), the solvent is selected from any one of an alcohol, a nitrile, a halogenated hydrocarbon, a guanamine, an anthracene, a halogenated hydrocarbon, an aromatic hydrocarbon, an ester, an ether, a ketone, water, acetic acid or combination.
進一步地，在步驟(1)中，所述溶劑選自甲醇、乙醇、異丙醇、正丁醇、乙腈、N,N-二甲基甲醯胺、二甲基亞碸、甲苯、二甲苯、乙酸乙酯、乙酸丁酯、四氫呋喃、丙酮、甲基異丙基甲酮、甲基異丁基甲酮、水、乙酸中的任一種或其組合。 Further, in the step (1), the solvent is selected from the group consisting of methanol, ethanol, isopropanol, n-butanol, acetonitrile, N,N-dimethylformamide, dimethyl hydrazine, toluene, xylene Either ethyl acetate, butyl acetate, tetrahydrofuran, acetone, methyl isopropyl ketone, methyl isobutyl ketone, water, acetic acid, or a combination thereof.
進一步地，在步驟(1)中，所述溶劑與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-三氘代甲基苯醯胺的體積重量比為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.
進一步地，在步驟(1)的溶解過程中，溫度為0℃至溶劑的回流溫度。 Further, in the dissolution process of the step (1), the temperature is from 0 ° C to the reflux temperature of the solvent.
進一步地，在步驟(2)中，析晶溫度為-20℃-100℃，優選的析晶的溫度為3℃至室溫。 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.
進一步地，在步驟(3)中，所述快速除去溶劑指 的是1分鐘內至少除去10mL溶劑，所述溶劑中至少溶解有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-三氘代甲基苯醯胺。 Further, in the step (3), the quick removal solvent refers to At least 10 mL of solvent was removed in 1 minute, and at least 1 g of 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4 was dissolved in the solvent. -Oxo-2-thio-1-imidazolidinyl}-2-fluoro-N-tridecanomethylbenzamide.
進一步地，所述步驟(3)的除去溶劑是通過旋轉蒸發進行的。 Further, the solvent removal in the step (3) is carried out by rotary evaporation.
進一步地，所述步驟(3)的快速析出固體是通過加入抗溶劑的進行的。 Further, the rapid precipitation of the solid in the step (3) is carried out by adding an anti-solvent.
進一步地，所述抗溶劑是水或C5-C10的烴類溶劑。 Further, the anti-solvent is water or a C5-C10 hydrocarbon solvent.
本發明提供的製備上述無定形化合物的方法還包括：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-三氘代甲基苯醯胺在溶劑中的溶液；以及b)分離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-三氘代甲基苯醯胺的無定形化合物。 The method for preparing the above 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-tridecanomethylbenzamide in a solvent; and b) isolating 4-{3-[4-cyano- 3-(Trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl}-2-fluoro-N-tris-methylphenylhydrazine An amorphous compound of an amine.
步驟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-三氘代甲基苯醯胺的溶液包括：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-三氘代甲基苯醯胺的合成過程中獲得的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-三氘代甲基苯醯胺的反應混合物；或者ii)將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-三氘代甲基苯醯胺溶解在溶劑中。 Provided in step a) 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazole A solution of alkyl}-2-fluoro-N-tridecanomethylbenzamide includes: i) used directly in 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-tridemethylbenzamide -[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl}-2-fluoro-N- a reaction mixture of trideuteromethylbenzamide; or 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-三氘代甲基苯醯胺的任何物理形式都可以用於在步驟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-三氘代甲基苯醯胺的溶液。溶解溫度可為約0℃至約溶劑的回流溫度，或者低於約60℃，低於約50℃，低於約40℃，低於約30℃，低於約20℃，低於約10℃，或者任何其它合適的溫度，只要獲得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-三氘代甲基苯醯胺的澄清溶液而不影響其品質。可以任選地用碳、煆燒矽藻土(Hyflow)或任何其它合適的材料處理所述溶液，以除去顏色、不溶性材料，改善溶液的澄清度，和/或除去可吸附於此類材料上的雜質。任選地，可將上述獲得的溶液過濾以除去任何不溶性顆粒。可以通過過濾、離心、傾析或者在加壓下或在減壓下的任何其它合適的技術來適當地除去所述不溶性顆粒。可通過使所述溶液通過紙、玻璃纖維、布或其它膜材料，或者澄清劑(例如或Hyflow)床對其進行過濾。取決於所使用的設備以及溶液的濃度和溫度，可能需要預熱過濾裝置以避免過早結晶。 4-{3-[4-Cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl}-2- Any physical form of fluoro-N-tridecanomethylbenzamide 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-tridecanomethylbenzamide. 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 quality. The solution may optionally be treated with carbon, yttrium or any other suitable material to remove color, insoluble materials, improve clarity of the solution, and/or remove adsorbable on such 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.
在實施例中，可將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-三氘代甲基苯醯胺溶解在任何合適的溶劑中。合適的溶劑包括對化合物沒有不利的影響並且可以將原料溶解到有用的程度的任何溶 劑。此類溶劑的實例包括但不限於：醚，例如***、二異丙基醚、四氫呋喃、二噁烷或二甲氧基乙烷；酮，例如丙酮、甲基乙基酮、甲基異丁基酮或二乙基酮；酯，例如乙酸乙酯、乙酸丙酯、乙酸異丙酯或乙酸丁酯；醇，例如甲醇、乙醇、1-丙醇、2-丙醇(異丙醇)、2-甲氧基乙醇、1-丁醇、2-丁醇、異丁醇、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、二乙二醇單甲醚、環己醇、甘油或C1-C6醇；腈，例如乙腈或丙腈；醯胺，例如甲醯胺、N,N-二甲基甲醯胺、N,N-二甲基乙醯胺、N-甲基-2-吡咯烷酮或六甲基磷酸三醯胺；亞碸，例如二甲基亞碸；鹵代烴，例如二氯甲烷、氯仿、四氯化碳或氯苯；芳烴，例如甲苯；或其兩種或更多種的任意混合物。 In an embodiment, 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1- The imidazolyl}-2-fluoro-N-tridecanomethylbenzamide is dissolved in any suitable solvent. Suitable solvents include those which do not adversely affect the compound and which dissolve the material to a useful extent. 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 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; guanamine, such as formamide, N, N-dimethyl Mercaptoamine, N,N-dimethylacetamide, N-methyl-2-pyrrolidone or tridecylamine hexamethylphosphate; anthracene, such as dimethyl hydrazine; halogenated hydrocarbon, such as dichloro Methane, chloroform, carbon tetrachloride or chlorobenzene; an aromatic hydrocarbon such as toluene; or any mixture of two or more thereof.
步驟b)包括從在步驟a)中獲得的溶液中分離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-三氘代甲基苯醯胺的無定形化合物。步驟b)中的分離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-三氘代甲基苯醯胺的無定形化合物可以涉及包括除去溶劑、冷卻、速冷、濃縮物質、蒸發、快速蒸發、簡單蒸發、旋轉乾燥、噴霧乾燥、薄膜乾燥、攪動吸濾器乾燥、加壓吸濾器乾燥、冷凍乾燥、加入抗溶劑、用溶劑萃取等在內的方法。攪拌或其它替代方法例如振盪、攪動等也可以用於分離。所分離的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-三氘代甲基苯醯胺的無定形化合物可能攜帶一定量的包藏的母液，並且可能具 有高於期望水準的雜質。如果需要，可以用溶劑或溶劑混合物洗滌這種無定形化合物以洗出雜質。 Step b) comprises isolating 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo from the solution obtained in step a) An 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-tridecanomethylbenzamide may be involved in solvent removal, cooling, rapid cooling, concentrated materials, evaporation, flash evaporation, simple evaporation, spin drying, spray drying, Drying of the film, drying of the aspirating suction filter, drying of the pressurized suction filter, freeze drying, addition of an anti-solvent, extraction with a solvent, 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} An amorphous compound of 2-fluoro-N-tris-methylbenzamide may carry a certain amount of the occluded mother liquor and may have There are 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.
製備無定形化合物的關鍵在於在較短的時間內除去溶劑或是析出固體，以避免化合物形成晶型，可以通過本領域常用的製備無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.
用旋轉蒸發製備無定形化合物的關鍵在於，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-三氘代甲基苯醯胺在可溶溶劑中的溶液，低溫(溫度不超過50℃)，以至少5毫升/分鐘的速率去除溶劑，優選5-15毫升/分鐘。 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-tridecanomethylbenzamide 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.
合適的分離溫度可為低於約120℃，低於約80℃，低於約60℃，低於約40℃，低於約30℃，低於約20℃，低於約10℃，低於約0℃，低於約-10℃，低於約-40℃，或者任何其它合適的溫度。 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.
任選地，可以通過將合適的抗溶劑與在步驟a)中獲得的溶液組合來進行分離。如本文所用，抗溶劑是指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-三氘代甲基苯醯胺在其中微溶或難溶的液體。惰性抗溶劑對反應沒有不利的影響，並且它可以幫助溶解的原料凝固或沉澱。可使用的合適的抗溶劑包括但不限於：飽和或不飽和的直鏈或支鏈的、環狀或非環狀的C1-C10烴，例如庚烷、環己烷或甲基環己烷；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-tris-methylbenzamide 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.
回收的固體可以任選地進行乾燥。所述乾燥可以在盤式乾燥器、真空烘箱、空氣烘箱、錐形真空乾燥器、旋轉 式真空乾燥器、流化床乾燥器、旋轉閃蒸乾燥器、快速乾燥器等中進行。所述乾燥可以在低於約100℃、低於約80℃、低於約60℃、低於約50℃、低於約30℃的溫度或任何其它合適的溫度下，在大氣壓或減壓下進行，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-三氘代甲基苯醯胺的品質不劣化。所述乾燥可以進行任何期望的次數，直到實現所需的產物品質。乾燥的產物可以任選地經歷粉碎操作，以產生期望的細微性。可在產物的乾燥前或乾燥完成後進行研磨或微粉化。可用於減小細微性的技術包括但不限於球磨、輥磨或錘磨，或者噴射研磨。 The recovered solid can optionally be dried. The drying can be in a tray dryer, a vacuum oven, an air oven, a conical vacuum dryer, a spin Vacuum dryers, fluidized bed dryers, rotary flash dryers, quick dryers, 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-tris-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 fineness. Grinding or micronizing may be carried out before or after drying of the product. Techniques that can be used to reduce fineness include, but are not limited to, ball milling, roller or hammer milling, or jet milling.
本發明還提供了一種氘代咪唑酮化合物-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-三氘代甲基苯醯胺的無定形化合物，該無定形化合物是以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-三氘代甲基苯醯胺為原料，通過上述製備無定形化合物的方法製備得到的或是本領域常規的製備無定形化合物的方法得到的。 The present invention also provides a deuterated imidazolone compound-4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2- An amorphous compound of thio-1-imidazolidinyl}-2-fluoro-N-tridecanomethylbenzamide, the amorphous compound being 4-{3-[4-cyano-3-(three Fluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl}-2-fluoro-N-tridecanomethylbenzamide as raw material, It is obtained by the above-mentioned method for preparing an amorphous compound or a method for preparing an amorphous compound which is conventional in the art.
本發明還提供了一種藥物組合物，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-三氘代甲基苯醯胺的無定形化合物作為活性成分，加上藥學上可接受的輔料製備而成的製劑。 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 2-thio-1-imidazolidinyl}-2-fluoro-N-tris-methylbenzamide as an active ingredient, together with a preparation prepared from a pharmaceutically acceptable adjuvant.
進一步地，本發明還提供了上述的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-三氘代甲基苯醯胺的無定形化合物在製備雄性激 素受體拮抗劑，或製備治療或/和預防雄性激素受體活性相關疾病的藥物中的應用。 Further, the present invention also provides the above 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio Amorphous compound of 1-imidazolidinyl}-2-fluoro-N-tridecanomethylbenzamide in preparation of male stimulating A receptor antagonist, or a medicament for the preparation of a medicament for treating or/and preventing a disease associated with androgen receptor activity.
其中，所述疾病選自脫髮、再生髮、暗瘡、青春痘或***癌。 Wherein the disease is selected from the group consisting of hair loss, regenerative hair, acne, acne or prostate cancer.
本發明中，C5-C10的烴類溶劑指的是C5、C6、C7、C8、C9、C10的烴類溶劑，即具有5-10個碳原子的烷烴、烯烴、炔烴、環烴或芳香烴溶劑，例如正己烷、環己烷、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.
穩定性試驗證明，本發明的晶型I，晶型穩定，重現性好，放置穩定，顯著優於現有的無定形物以及新發現的晶型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-三氘代甲基苯醯胺原料藥在存儲期內品質更穩定。同時，本發明的晶型I，製備方法簡單，成本低，具有廣闊的市場前景。 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-cyanide 3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl}-2-fluoro-N-tridemethyl The benzoguanamine API is more stable during storage. At the same time, the crystal form I of the invention has simple preparation method, low cost and broad market prospect.
顯然，根據本發明的上述內容，按照本領域的普通技術知識和慣用手段，在不脫離本發明上述基本技術思想前提下，還可以做出其它多種形式的修改、替換或變更。 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.
實施例1 本發明晶型I的製備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-三氘代甲基苯醯胺固體，加10mL無水乙醇加熱至70℃。加熱至完全溶清後，繼續攪拌10分鐘，冷卻至室溫，再冰-水浴冷至3℃，攪拌10分鐘過濾，濾餅用1mL冰無水乙醇淋洗，50℃真空乾燥，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-tridecanomethylbenzamide 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. .
實施例2 本發明晶型I的製備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-三氘代甲基苯醯胺固體，加11mL混合溶劑(DMSO：乙酸異丙酯=1：10)，攪拌至完全溶清，加15%食鹽水萃洗兩次，每次6mL。有機相用無水硫酸鈉乾燥，過濾，50℃旋出溶劑，得到油狀物，加10mL異丙醇打漿，過夜，過濾。50℃真空乾燥得到晶型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-tridecanomethylbenzamine solid, add 11 mL of mixed solvent (DMSO: isopropyl acetate = 1:10), stir until completely dissolved, add 15% saline solution and wash twice. 6mL each time. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated and evaporated. Drying at 50 ° C in vacuo gave Form I.
實施例3 本發明晶型I的製備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-三氘代甲基苯醯胺固體，加10mL乙腈，攪拌至完全溶清，滴加到裝有30mL水的50mL單口瓶中，攪拌3小時，過濾，50℃真空乾燥，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-tridecanomethylbenzamine solid, add 10mL acetonitrile, stir until completely dissolved, add dropwise to 50mL single-mouth bottle containing 30mL water, stir for 3 hours, filter, vacuum dry at 50 °C , crystal form I is obtained.
實施例4 本發明晶型I的製備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-三氘代甲基苯醯胺固體，加20mL異丙醇加熱至70℃。加熱至完全溶清後，繼續攪拌10分鐘，冷卻至室溫，再冰-水浴冷至3℃，攪拌30分鐘過濾，濾餅用1mL冰異丙醇淋洗，50℃真空乾燥，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-tridecanomethylbenzamide 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.
實施例5 本發明晶型I的製備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-三氘代甲基苯醯胺固體，加10mL乙酸，室溫攪拌30分鐘至完全溶清，滴加20mL水，攪拌30分鐘過濾，50℃真空乾燥，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-tridecanomethylbenzamine 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, vacuum dry at 50 ° C to obtain crystal form I .
實施例6 本發明晶型I的製備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-三氘代甲基苯醯胺固體，加5mL乙酸乙酯，加熱至50℃。加熱至完全溶清後，繼續攪拌10分鐘，冰-水浴冷至5℃，攪拌3小時過濾，50℃真空乾燥，得到晶型I。 Take 1.0g of 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl Base 4-oxo-2-thio-1-imidazolidinyl}-2-fluoro-N-tridecylmethylphenylguanamine 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.
實施例7 本發明晶型I的製備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-三氘代甲基苯醯胺固體，加10mL乙酸丁酯，加熱至70℃。加熱至完全溶清後，繼續攪拌10分鐘，冰-水浴冷至3℃，攪拌10分鐘過濾，50℃真空乾燥，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-tridecanomethylbenzamine 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.
實施例8 本發明晶型I的製備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-三氘代甲基苯醯胺固體，加2.5mL四氫呋喃，加熱至60℃。加熱至完全溶清後，繼續攪拌20分鐘，冰-水浴冷至3℃，攪拌3小時過濾，50℃真空乾燥，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-tridecanomethylbenzamine 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.
實施例9 本發明晶型I的製備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-三氘代甲基苯醯胺固體，加10mL甲基異丙基甲酮，加熱至50℃。加熱至完全溶清後，繼續攪拌20分鐘，冰-水浴冷至3℃，攪拌30分鐘過濾，50℃真空乾燥，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-tridecanomethylbenzamide 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.
實施例10 本發明晶型I的製備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-三氘代甲基苯醯胺固體，加50mL甲苯，加熱至90℃。加熱至完全溶清後，繼續攪拌20分鐘，冰-水浴冷至3℃，攪拌30分鐘過濾，50℃真空乾燥，得到晶型I。 Take 1.0g of 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl Base 4-oxo-2-thio-1-imidazolidinyl}-2-fluoro-N-tridecanomethylbenzamide solid, 50 mL of toluene was added and heated 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.
實施例11 本發明晶型I的製備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-三氘代甲基苯醯胺固體，加10mL乙醇，加熱至65℃。加熱至完全溶清後，滴加20mL正庚烷，冰-水浴冷至3℃，攪拌20分鐘過濾，50℃真空乾燥，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-trideuteromethylbenzamide 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.
實施例12 本發明晶型I的製備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-三氘代甲基苯醯胺固體，加20mL正丁醇，加熱至90℃。加熱至完全溶清後，繼續攪拌20分鐘，冰-水浴冷至3℃，攪拌15分鐘過濾，50℃真空乾燥，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-tridecanomethylbenzamine 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.
實施例13 本發明晶型I的製備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-三氘代甲基苯醯胺固體，加50mL二甲苯，加熱至100℃。加熱至完全溶清後，繼續攪拌20分鐘，冰-水浴冷至3℃，攪拌15分鐘過濾，50℃真空乾燥，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-tridecanomethylbenzamide 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.
實施例14 本發明晶型I的製備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-三氘代甲基苯醯胺固體，加25mL丙酮，25mL水，加熱至50℃。加熱至完全溶清後，繼續攪拌10分鐘，冰-水浴冷至3℃，攪拌1小時過濾，50℃真空乾燥，得到晶型I。 Take 1.0g of 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl Base 4-oxo-2-thio-1-imidazolidinyl}-2-fluoro-N-tridecanomethylbenzamide 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.
實施例15 本發明晶型I的製備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-三氘代甲基苯醯胺固體，加5mLDMSO，室溫攪拌30分鐘至完全溶清，滴加20mL水，攪拌2小時過濾，50℃真空乾燥，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-tridecanomethylbenzamine 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.
實施例16 本發明晶型I的製備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-三氘代甲基苯醯胺固體，加5mL甲基異丁基甲酮，加熱至70℃。加熱至完全溶清後，繼續攪拌30分鐘，冰-水浴冷至3℃，攪拌4小時過濾，50℃真空乾燥，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-tridecanomethylbenzamide 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.
實施例17 本發明晶型I的製備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-三氘代甲基苯醯胺固體，加5mLDMF，室溫攪拌30分鐘至完全溶清，滴加20mL水，攪拌2小時過濾，50℃真空乾燥，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-tridecanomethylbenzamine 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.
實施例18 晶型Ⅱ的製備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-三氘代甲基苯醯胺固體，加10mL無水甲醇加熱至60℃。加熱至完全溶清後，繼續 攪拌10分鐘，冷卻至室溫，再冰-水浴冷至3℃，攪拌10分鐘過濾，濾餅用1mL冰無水甲醇淋洗，50℃真空乾燥，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-tridecanomethylbenzamide solid, heated to 60 ° C with 10 mL of anhydrous methanol. After heating until completely dissolved, continue After stirring for 10 minutes, it was 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.
實施例19 晶型Ⅱ的製備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-三氘代甲基苯醯胺固體，加5mL甲酸，加熱至70℃。加熱至完全溶清後，繼續攪拌10分鐘，冷卻至室溫，再冰-水浴冷至3℃，攪拌30分鐘過濾，50℃真空乾燥，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-tridecanomethylbenzamine 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.
實施例20 無定形化合物的製備Example 20 Preparation of Amorphous Compounds
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-三氘代甲基苯醯胺固體，加10mL丙酮，超聲至完全溶清。35℃旋幹，去除溶劑的速率約為10mL/分鐘，得無定形。 Take 1.0 g of 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} -2-Fluoro-N-tridecanomethylbenzamine solid, add 10 mL of acetone, and ultrasonicate until completely dissolved. Spinning at 35 ° C, the rate of solvent removal was about 10 mL / min, resulting in amorphous.
實施例21 無定形化合物的製備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-三氘代甲基苯醯胺固體，加5mL乙腈，加熱至50℃。加熱至完全溶清後，冰-水冷至室溫，40℃旋幹，得到無定形。 Take 2.0 g of 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl} 2-Fluoro-N-tridecanomethylbenzamine 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.
以下通過實驗例具體說明本發明的功效。 The efficacy of the present invention will be specifically described below by way of experimental examples.
實驗例1 長期穩定性實驗Experimental Example 1 Long-term stability experiment
取實施例1製備的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-三氘代甲基苯醯胺晶型I、實施例18製備的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 甲基苯醯胺晶型Ⅱ和專利CN201280052853得到的無定形物，分別用鋁塑複合膜袋進行封裝，於40℃±2℃，相對濕度75%±5%的條件下，於1、3月、6月、9月、12月月末取樣檢測，結果如下表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-tridecanomethylbenzamide 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-trisole The amorphous form obtained from the methyl benzoguanamine crystal form II and the patent CN201280052853 is respectively packaged in an aluminum plastic composite film bag at 40 ° C ± 2 ° C, relative humidity of 75% ± 5%, in January and March. Samples were taken at the end of June, September, and December, and the results are shown in Table 1 below.
由上述資料可以看出，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-三氘代甲基苯醯胺晶型I，晶型穩定，重現性好，放置穩定，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-三氘代甲基苯醯胺原料藥在存儲期內品質 更穩定。此外，6月、9月和12月末用顯微鏡法進行晶型檢查，結果本發明晶型I無明顯變化，而無定形物逐漸向固體顆粒狀晶型轉變。 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-tridecanomethylbenzamide Methyl form I, stable in crystal form, good reproducibility and stable in standing, making 4-{3-[4-cyano-3-( Trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl}-2-fluoro-N-tris-methylbenzamide Quality during storage more stable. 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.
綜上所述，本發明的晶型I，晶型穩定，重現性好，放置穩定，顯著優於現有的無定形物以及新發現的晶型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-三氘代甲基苯醯胺原料藥在存儲期內品質更穩定。同時，本發明的晶型I，製備方法簡單，成本低，具有廣闊的市場前景。 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-cyanide 3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidinyl}-2-fluoro-N-tridemethyl The benzoguanamine API is more stable during storage. At the same time, the crystal form I of the invention has simple preparation method, low cost and broad market prospect.
雖然本發明已以數個較佳實施例揭露如上，然其並非用以限定本發明，任何所屬技術領域中具有通常知識者，在不脫離本發明之精神和範圍內，當可作任意之更動與潤飾，因此本發明之保護範圍當視後附之申請專利範圍所界定者為準。 While the invention has been described above in terms of several preferred embodiments, it is not intended to limit the scope of the present invention, and any one of ordinary skill in the art can make any changes without departing from the spirit and scope of the invention. And the scope of the present invention is defined by the scope of the appended claims.
Claims (17)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510726325 | 2015-10-30 | ||
| ??201510726325.2 | 2015-10-30 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| TW201714878A true TW201714878A (en) | 2017-05-01 |
| TWI638810B TWI638810B (en) | 2018-10-21 |
Family
ID=58184308
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TW105128872A TWI638810B (en) | 2015-10-30 | 2016-09-07 | Crystal form i of deuterium labelled imidazolone compounds and preparation and use thereof |
Country Status (3)
| Country | Link |
|---|---|
| CN (1) | CN106432090B (en) |
| TW (1) | TWI638810B (en) |
| WO (1) | WO2017071375A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20210290553A1 (en) * | 2018-05-14 | 2021-09-23 | Hinova Pharmaceuticals Inc. | Hc-1119 formulation, preparation method and use thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103159680A (en) * | 2011-12-14 | 2013-06-19 | 爱美尼迪药物有限公司 | Imidazole diketone compound and application thereof |
| CA2908326C (en) * | 2013-05-29 | 2017-09-12 | Hinova Pharmaceuticals Inc. | Imidazolidinedione compounds and their uses |
| 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 |
-
2016
- 2016-07-28 CN CN201610609034.XA patent/CN106432090B/en active Active
- 2016-08-17 WO PCT/CN2016/095647 patent/WO2017071375A1/en active Application Filing
- 2016-09-07 TW TW105128872A patent/TWI638810B/en active
Also Published As
| Publication number | Publication date |
|---|---|
| TWI638810B (en) | 2018-10-21 |
| CN106432090B (en) | 2019-08-20 |
| CN106432090A (en) | 2017-02-22 |
| WO2017071375A1 (en) | 2017-05-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US9701641B2 (en) | Enzalutamide polymorphic forms and its preparation | |
| WO2012066565A2 (en) | Asenapine maleate amorphous and crystalline form and process for preparation thereof | |
| JP2020530473A (en) | Polymorphs and co-crystals of Lokidustat | |
| JP2015536975A (en) | Polymorphic form of suvorexant | |
| WO2018184185A1 (en) | Ozanimod addition salt crystal, preparation method, pharmaceutical composition, and uses | |
| EP3461818A1 (en) | Polymorphic forms of nilotinib hydrochloride | |
| WO2016027243A1 (en) | Novel solid state forms of afatinib dimaleate | |
| WO2016088074A1 (en) | Process for the preparation of amorphous ibrutinib | |
| WO2018122780A1 (en) | Solid state forms of lenvatinib mesylate | |
| US9045473B2 (en) | Forms of Apixaban | |
| US20190300483A1 (en) | POLYMORPHS OF BETRlXABAN & ITS MALEATE SALT | |
| TW201617347A (en) | Form crystal of bisulfate of janus kinase (JAK) inhibitor and preparation method thereof | |
| TW201714878A (en) | Crystal form I of deuterium labelled imidazolone compounds and preparation and use thereof | |
| WO2018015974A1 (en) | Polymorphic forms and amorphous solid dispersion of selexipag | |
| EP3240575A1 (en) | Co-crystal of carfilzomib with maleic acid and process for the preparation of pure carfilzomib | |
| WO2012090221A1 (en) | Novel salts of imatinib | |
| US9212172B2 (en) | Preparation of crystalline bazedoxifene and its salts | |
| TWI708764B (en) | Crystalline form of androgen receptor inhibitor and a preparation method thereof | |
| CN117545755A (en) | Lanifibror crystal form and preparation method thereof | |
| WO2017115315A1 (en) | Solid forms of palbociclib | |
| WO2011139414A2 (en) | Dexlansoprazole polymorphic forms | |
| WO2017006227A1 (en) | Preparation process of amorphous daclatasvir dihydrochloride, amorphous solid dispersion thereof and preparation processes thereof | |
| CN104693200B (en) | A kind of crystal formation of moxifloxacin hydrochloride and preparation method thereof | |
| WO2005068453A2 (en) | Crystalline forms of rizatriptan benzoate | |
| WO2015166466A1 (en) | Crystalline form of saxagliptin acetate |