4-甲硫基-3-(三氟甲基)苯胺

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 4-Methylsulfanyl-3-trifluoromethyl-phenylamine (828 mg; 4.00 mmol), 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (876 mg; 4.40 mmol) and sodium triacetoxyborohydride (2.52 g; 12.00 mmol) are suspended in dichloromethane (18 mL) and the resulting mixture is stirred for 1 day. The suspension is then diluted with dichloromethane (50 mL) and is washed with water (30 mL) and aq. sat. ammonium chloride (3×30 mL). The organic phase is dried over magnesium sulphate, filtered and concentrated under reduced pressure to deliver the desired product in the presence of remaining traces of solvent (1.8 g; 4.6 mmol). is washed with water (30 mL) and aq. sat. ammonium chloride (3×30 mL) The organic phase is dried over magnesium sulphate filtered concentrated under reduced pressure

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 4-Methylsulfanyl-3-trifluoromethyl-phenylamine (828 mg; 4.00 mmol), 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (876 mg; 4.40 mmol) and sodium triacetoxyborohydride (2.52 g; 12.00 mmol) are suspended in dichloromethane (18 mL) and the resulting mixture is stirred for 1 day. The suspension is then diluted with dichloromethane (50 mL) and is washed with water (30 mL) and aq. sat. ammonium chloride (3×30 mL). The organic phase is dried over magnesium sulphate, filtered and concentrated under reduced pressure to deliver the desired product in the presence of remaining traces of solvent (1.8 g; 4.6 mmol). is washed with water (30 mL) and aq. sat. ammonium chloride (3×30 mL) The organic phase is dried over magnesium sulphate filtered concentrated under reduced pressure

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 4-Methylsulfanyl-3-trifluoromethyl-phenylamine (414 mg; 2.00 mmol), 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (400 mg; 2.00 mmol) and sodium triacetoxyborohydride (1.27 g; 6.00 mmol) are suspended in dichloromethane (10 mL) and the resulting mixture is stirred for 2 days. The suspension is then diluted with dichloromethane (50 mL) and is washed with water (30 mL) and aq. sat. ammonium chloride (3×30 mL). The organic phase is dried over magnesium sulphate, filtered and concentrated under reduced pressure to deliver the desired intermediate. The crude intermediate is then dissolved in dichloromethane (5 mL) and trifluoroacetic acid is added (2.5 mL). After 90 minutes reaction time, the mixture is concentrated under reduced pressure and co-evaporated twice with dichloromethane (10 mL). The crude residue is then triturated with a 4N solution of hydrochloric acid in dioxane (5 mL) until a precipitate forms. The solid is filtered and dried under high vacuum to afford the desired product as hydrochloride (354 mg; 1.09 mmol). is washed with water (30 mL) and aq. sat. ammonium chloride (3×30 mL) The organic phase is dried over magnesium sulphate filtered concentrated under reduced pressure The crude intermediate is then dissolved in dichloromethane (5 mL) trifluoroacetic acid is added (2.5 mL) After 90 minutes reaction time the mixture is concentrated under reduced pressure The crude residue is then triturated with a 4N solution of hydrochloric acid in dioxane (5 mL) until a precipitate forms The solid is filtered dried under high vacuum

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 4-Methylsulfanyl-3-trifluoromethyl-phenylamine (414 mg; 2.00 mmol), 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (400 mg; 2.00 mmol) and sodium triacetoxyborohydride (1.27 g; 6.00 mmol) are suspended in dichloromethane (10 mL) and the resulting mixture is stirred for 2 days. The suspension is then diluted with dichloromethane (50 mL) and is washed with water (30 mL) and aq. sat. ammonium chloride (3×30 mL). The organic phase is dried over magnesium sulphate, filtered and concentrated under reduced pressure to deliver the desired intermediate. The crude intermediate is then dissolved in dichloromethane (5 mL) and trifluoroacetic acid is added (2.5 mL). After 90 minutes reaction time, the mixture is concentrated under reduced pressure and co-evaporated twice with dichloromethane (10 mL). The crude residue is then triturated with a 4N solution of hydrochloric acid in dioxane (5 mL) until a precipitate forms. The solid is filtered and dried under high vacuum to afford the desired product as hydrochloride (354 mg; 1.09 mmol). is washed with water (30 mL) and aq. sat. ammonium chloride (3×30 mL) The organic phase is dried over magnesium sulphate filtered concentrated under reduced pressure The crude intermediate is then dissolved in dichloromethane (5 mL) trifluoroacetic acid is added (2.5 mL) After 90 minutes reaction time the mixture is concentrated under reduced pressure The crude residue is then triturated with a 4N solution of hydrochloric acid in dioxane (5 mL) until a precipitate forms The solid is filtered dried under high vacuum

反应条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Compound 114.1 can be prepared by process “A”. To this end, 1.04 g of 4-methylsulfanyl-3-trifluoromethylphenylamine were dissolved in 25 ml of dry acetonitrile. This solution was added dropwise with stirring to a 20% solution, heated to 70° C., of phosgene in toluene, and then stirred at 80° C. for 2 h. The cooled reaction solution was concentrated under reduced pressure, and the residue was taken up with toluene and concentrated again under reduced pressure. Finally, the residue was dissolved in 25 ml of dry tetrahydrofuran and the solution was admixed with stirring with 0.88 g of tert-butyl 2-amino-2-methylpropionate hydrochloride. 1.05 ml of triethylamine were slowly added dropwise to the reaction mixture which was then stirred at room temperature for 4 h. The reaction mixture was admixed with water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and concentrated. tert-Butyl 2-methyl-2-[3-(4-methylsulfanyl-3-trifluoromethylphenyl)ureido]propionate (molecular weight 392.13 (C17H23F3N2O3S); retention time Rt=2.40 min. [B]; MS (ESI): 337.26 (MH+−C4H8)) was obtained. The urea was dissolved in 20 ml of tetrahydrofuran, admixed with 4.9 ml of concentrated hydrochloric acid and stirred at 80° C. for 2 h. The cooled reaction mixture was concentrated under reduced pressure and the residue was admixed with ethyl acetate and water. The organic phase was removed, washed with saturated sodium hydrogen-carbonate solution and then with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel with 96/4 dichloromethane/methanol. 21.2 g (90% yield) of 5,5-dimethyl-3-(4-methylsulfanyl-3-trifluoromethylphenyl)imidazolidin-2,4-dione 114.1 were obtained. Molecular weight 318.06 (C13H13F3N2O2S); retention time Rt=1.93 min. [B]; MS (ES−): 317.07 (M−H+). This solution was added dropwise The cooled reaction solution was concentrated under reduced pressure concentrated again under reduced pressure Finally, the residue was dissolved in 25 ml of dry tetrahydrofuran with stirring with 0.88 g of tert-butyl 2-amino-2-methylpropionate hydrochloride 1.05 ml of triethylamine were slowly added dropwise to the reaction mixture which was then stirred at room temperature for 4 h extracted with ethyl acetate The organic phase was dried over magnesium sulfate filtered concentrated

反应条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Compound 114.1 can be prepared by process “A”. To this end, 1.04 g of 4-methylsulfanyl-3-trifluoromethylphenylamine were dissolved in 25 ml of dry acetonitrile. This solution was added dropwise with stirring to a 20% solution, heated to 70° C., of phosgene in toluene, and then stirred at 80° C. for 2 h. The cooled reaction solution was concentrated under reduced pressure, and the residue was taken up with toluene and concentrated again under reduced pressure. Finally, the residue was dissolved in 25 ml of dry tetrahydrofuran and the solution was admixed with stirring with 0.88 g of tert-butyl 2-amino-2-methylpropionate hydrochloride. 1.05 ml of triethylamine were slowly added dropwise to the reaction mixture which was then stirred at room temperature for 4 h. The reaction mixture was admixed with water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and concentrated. tert-Butyl 2-methyl-2-[3-(4-methylsulfanyl-3-trifluoromethylphenyl)ureido]propionate (molecular weight 392.13 (C17H23F3N2O3S); retention time Rt=2.40 min. [B]; MS (ESI): 337.26 (MH+−C4H8)) was obtained. The urea was dissolved in 20 ml of tetrahydrofuran, admixed with 4.9 ml of concentrated hydrochloric acid and stirred at 80° C. for 2 h. The cooled reaction mixture was concentrated under reduced pressure and the residue was admixed with ethyl acetate and water. The organic phase was removed, washed with saturated sodium hydrogen-carbonate solution and then with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel with 96/4 dichloromethane/methanol. 21.2 g (90% yield) of 5,5-dimethyl-3-(4-methylsulfanyl-3-trifluoromethylphenyl)imidazolidin-2,4-dione 114.1 were obtained. Molecular weight 318.06 (C13H13F3N2O2S); retention time Rt=1.93 min. [B]; MS (ES−): 317.07 (M−H+). This solution was added dropwise The cooled reaction solution was concentrated under reduced pressure concentrated again under reduced pressure Finally, the residue was dissolved in 25 ml of dry tetrahydrofuran with stirring with 0.88 g of tert-butyl 2-amino-2-methylpropionate hydrochloride 1.05 ml of triethylamine were slowly added dropwise to the reaction mixture which was then stirred at room temperature for 4 h extracted with ethyl acetate The organic phase was dried over magnesium sulfate filtered concentrated

反应条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Compound 114.1 can be prepared by process “A”. To this end, 1.04 g of 4-methylsulfanyl-3-trifluoromethylphenylamine were dissolved in 25 ml of dry acetonitrile. This solution was added dropwise with stirring to a 20% solution, heated to 70° C., of phosgene in toluene, and then stirred at 80° C. for 2 h. The cooled reaction solution was concentrated under reduced pressure, and the residue was taken up with toluene and concentrated again under reduced pressure. Finally, the residue was dissolved in 25 ml of dry tetrahydrofuran and the solution was admixed with stirring with 0.88 g of tert-butyl 2-amino-2-methylpropionate hydrochloride. 1.05 ml of triethylamine were slowly added dropwise to the reaction mixture which was then stirred at room temperature for 4 h. The reaction mixture was admixed with water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and concentrated. tert-Butyl 2-methyl-2-[3-(4-methylsulfanyl-3-trifluoromethylphenyl)ureido]propionate (molecular weight 392.13 (C17H23F3N2O3S); retention time Rt=2.40 min. [B]; MS (ESI): 337.26 (MH+−C4H8)) was obtained. The urea was dissolved in 20 ml of tetrahydrofuran, admixed with 4.9 ml of concentrated hydrochloric acid and stirred at 80° C. for 2 h. The cooled reaction mixture was concentrated under reduced pressure and the residue was admixed with ethyl acetate and water. The organic phase was removed, washed with saturated sodium hydrogen-carbonate solution and then with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel with 96/4 dichloromethane/methanol. 21.2 g (90% yield) of 5,5-dimethyl-3-(4-methylsulfanyl-3-trifluoromethylphenyl)imidazolidin-2,4-dione 114.1 were obtained. Molecular weight 318.06 (C13H13F3N2O2S); retention time Rt=1.93 min. [B]; MS (ES−): 317.07 (M−H+). This solution was added dropwise The cooled reaction solution was concentrated under reduced pressure concentrated again under reduced pressure Finally, the residue was dissolved in 25 ml of dry tetrahydrofuran with stirring with 0.88 g of tert-butyl 2-amino-2-methylpropionate hydrochloride 1.05 ml of triethylamine were slowly added dropwise to the reaction mixture which was then stirred at room temperature for 4 h extracted with ethyl acetate The organic phase was dried over magnesium sulfate filtered concentrated

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 4-Methylsulfanyl-3-trifluoromethyl-phenylamine (828 mg; 4.00 mmol), 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (876 mg; 4.40 mmol) and sodium triacetoxyborohydride (2.52 g; 12.00 mmol) are suspended in dichloromethane (18 mL) and the resulting mixture is stirred for 1 day. The suspension is then diluted with dichloromethane (50 mL) and is washed with water (30 mL) and aq. sat. ammonium chloride (3×30 mL). The organic phase is dried over magnesium sulphate, filtered and concentrated under reduced pressure to deliver the desired product in the presence of remaining traces of solvent (1.8 g; 4.6 mmol). is washed with water (30 mL) and aq. sat. ammonium chloride (3×30 mL) The organic phase is dried over magnesium sulphate filtered concentrated under reduced pressure

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 4-Methylsulfanyl-3-trifluoromethyl-phenylamine (414 mg; 2.00 mmol), 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (400 mg; 2.00 mmol) and sodium triacetoxyborohydride (1.27 g; 6.00 mmol) are suspended in dichloromethane (10 mL) and the resulting mixture is stirred for 2 days. The suspension is then diluted with dichloromethane (50 mL) and is washed with water (30 mL) and aq. sat. ammonium chloride (3×30 mL). The organic phase is dried over magnesium sulphate, filtered and concentrated under reduced pressure to deliver the desired intermediate. The crude intermediate is then dissolved in dichloromethane (5 mL) and trifluoroacetic acid is added (2.5 mL). After 90 minutes reaction time, the mixture is concentrated under reduced pressure and co-evaporated twice with dichloromethane (10 mL). The crude residue is then triturated with a 4N solution of hydrochloric acid in dioxane (5 mL) until a precipitate forms. The solid is filtered and dried under high vacuum to afford the desired product as hydrochloride (354 mg; 1.09 mmol). is washed with water (30 mL) and aq. sat. ammonium chloride (3×30 mL) The organic phase is dried over magnesium sulphate filtered concentrated under reduced pressure The crude intermediate is then dissolved in dichloromethane (5 mL) trifluoroacetic acid is added (2.5 mL) After 90 minutes reaction time the mixture is concentrated under reduced pressure The crude residue is then triturated with a 4N solution of hydrochloric acid in dioxane (5 mL) until a precipitate forms The solid is filtered dried under high vacuum