2,2,2-trifluoro-N-piperidin-4-ylacetamide

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 3 g (15.3 mmol) of 4-trifluoroacetamidopiperidine, 3 g (4.25 mL, 30.6 mmol) of triethylamine, 3 mL (45.9 mmol) of acrylonitrile in 10 mL of THF was stirred at room temperature for 17 hr. The solvent and volatile were evaporated under reduced pressure. The residue was dissolved in 20 mL of methanol and 4 mL of 30% NH4OH and the solution was refluxed for 5 hr. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel eluting first with 500 mL of dichloromethane, then 500 mL of 0.5% methanol/dichloromethane, followed by 1000 mL of 9:1:0.1 dichloromethane/methanol/ammonium hydroxide to give 0.7 g (30% yield) of the N-(2-cyanoethyl)-4-aminopiperidine. Step 4: Preparation of 6-(2-chlorophenyl)-2-(N-2-cyanoethylpiperidyl-4-amino)-pyrido[2,3-d]-pyrimidin-7-ol The solvent and volatile were evaporated under reduced pressure The residue was dissolved in 20 mL of methanol 4 mL of 30% NH4OH and the solution was refluxed for 5 hr The solvent was evaporated under reduced pressure the residue was purified by column chromatography on silica gel eluting first with 500 mL of dichloromethane

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 3 g (15.3 mmol) of 4-trifluoroacetamidopiperidine, 3 g (4.25 mL, 30.6 mmol) of triethylamine, 3 mL (45.9 mmol) of acrylonitrile in 10 mL of THF was stirred at room temperature for 17 hr. The solvent and volatile were evaporated under reduced pressure. The residue was dissolved in 20 mL of methanol and 4 mL of 30% NH4OH and the solution was refluxed for 5 hr. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel eluting first with 500 mL of dichloromethane, then 500 mL of 0.5% methanol/dichloromethane, followed by 1000 mL of 9:1:0.1 dichloromethane/methanol/ammonium hydroxide to give 0.7 g (30% yield) of the N-(2-cyanoethyl)-4-aminopiperidine. Step 4: Preparation of 6-(2-chlorophenyl)-2-(N-2-cyanoethylpiperidyl-4-amino)-pyrido[2,3-d]-pyrimidin-7-ol The solvent and volatile were evaporated under reduced pressure The residue was dissolved in 20 mL of methanol 4 mL of 30% NH4OH and the solution was refluxed for 5 hr The solvent was evaporated under reduced pressure the residue was purified by column chromatography on silica gel eluting first with 500 mL of dichloromethane

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 6-[(2,2-diphenylethyl)amino]-9-{(2R,3R,4S,5S)-5-[(ethylamino)carbonyl]-3,4-dihydroxytetrahydro-2-furanyl}-9H-purine-2-carboxylic acid (Preparation 39) (0.2 g, 0.38 mmol), 2,2,2-trifluoro-N-(4-piperidinyl)acetamide (83 mg, 0.42 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (81 mg, 0.42 mmol) in dichloromethane (5 ml) was stirred at room temperature for 48 hours and then heated under reflux for a further 96 hours. The solution was allowed to cool to room temperature and then solvent removed by evaporation under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol:concentrated aqueous ammonia (95:5:1, by volume) changing to dichloromethane:methanol:concentrated aqueous ammonia (80:20:1, by volume). After evaporation of appropriate fractions the target compound was obtained as a white solid, (43 mg, 18%). heated under reflux for a further 96 hours solvent removed by evaporation under reduced pressure The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane After evaporation of appropriate fractions the target compound was obtained as a white solid, (43 mg, 18%)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 6-[(2,2-diphenylethyl)amino]-9-{(2R,3R,4S,5S)-5-[(ethylamino)carbonyl]-3,4-dihydroxytetrahydro-2-furanyl}-9H-purine-2-carboxylic acid (Preparation 39) (0.2 g, 0.38 mmol), 2,2,2-trifluoro-N-(4-piperidinyl)acetamide (83 mg, 0.42 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (81 mg, 0.42 mmol) in dichloromethane (5 ml) was stirred at room temperature for 48 hours and then heated under reflux for a further 96 hours. The solution was allowed to cool to room temperature and then solvent removed by evaporation under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol:concentrated aqueous ammonia (95:5:1, by volume) changing to dichloromethane:methanol:concentrated aqueous ammonia (80:20:1, by volume). After evaporation of appropriate fractions the target compound was obtained as a white solid, (43 mg, 18%). heated under reflux for a further 96 hours solvent removed by evaporation under reduced pressure The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane After evaporation of appropriate fractions the target compound was obtained as a white solid, (43 mg, 18%)

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Using 4 g of 10% palladium-on-carbon (50% hydrous) as a catalyst, 11.431 g (39.927 mM) of N-(1-benzyl-piperidin-4-yl)trifluoroacetamide was hydrogenated in 100 ml of methanol at room temperature and atmospheric pressure until the starting compound had disappeared (i.e. for 2 hours). The catalyst in the reaction mixture was filtered off with the aid of celite and washed with methanol. The filtrate and washes were pooled and the solvent was distilled off under reduced pressure to provide crude N-(piperidin-4-yl)trifluoroacetamide. This crude product was not purified but used as it was in the next reaction. To a solution of the crude N-(piperidin-4-yl)trifluoroacetamide and 6.68 ml (47.9 mM) of triethylamine in tetrahydrofuran (50 ml)-methanol (20 ml) was added 9.59 g (43.9 mM) of di-tert-butyl dicarbonate dropwise at room temperature and the mixture was stirred at the prevailing temperature overnight. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) to provide the title compound. (i.e. for 2 hours) The catalyst in the reaction mixture was filtered off with the aid of celite washed with methanol the solvent was distilled off under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1-{1-[4-(5-Bromopentyloxy)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (2 g) and 4-trifluoroacetylaminopiperidine (2 g) are dissolved in dimethylformamide (40 ml), and thereto is added potassium carbonate (2 g) and the mixture is stirred overnight. The reaction mixture is poured into water, and the mixture is extracted with toluene/ethyl acetate (1:1), dried over magnesium sulfate, and purified by silica gel column chromatography (eluent; dichloromethane:methanol=50:1) to give 1-[1-{4-[5-(4-trifluoroacetylamino-1-piperidinyl)pentyloxy]benzoyl}-4-piperidinyl]-3,4-dihydrocarbostyril (2 g) as colorless oil. the mixture is extracted with toluene/ethyl acetate (1:1) dried over magnesium sulfate purified by silica gel column chromatography (eluent; dichloromethane:methanol=50:1)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 3 g (15.3 mmol) of 4-trifluoroacetamidopiperidine, 3 g (4.25 mL, 30.6 mmol) of triethylamine, 3 mL (45.9 mmol) of acrylonitrile in 10 mL of THF was stirred at room temperature for 17 hr. The solvent and volatile were evaporated under reduced pressure. The residue was dissolved in 20 mL of methanol and 4 mL of 30% NH4OH and the solution was refluxed for 5 hr. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel eluting first with 500 mL of dichloromethane, then 500 mL of 0.5% methanol/dichloromethane, followed by 1000 mL of 9:1:0.1 dichloromethane/methanol/ammonium hydroxide to give 0.7 g (30% yield) of the N-(2-cyanoethyl)-4-aminopiperidine. The solvent and volatile were evaporated under reduced pressure The residue was dissolved in 20 mL of methanol 4 mL of 30% NH4OH and the solution was refluxed for 5 hr The solvent was evaporated under reduced pressure the residue was purified by column chromatography on silica gel eluting first with 500 mL of dichloromethane

反応条件: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A 500 mL, three-necked round-bottomed flask under nitrogen was charged with 4 g of 10% Palladium on Carbon, and 100 mL of methanol. The suspension was cooled to 5° C. and 10 g of ammonium formate was added in one batch (evolution of gas was observed). A solution of 10 g (35 mmol) of the 4-trifluoroacetamido-1-benzylpiperidine in 100 mL of methanol was then added dropwise gradually. The resulting reaction mixture was refluxed for 2.5 hr. and then at room temperature overnight. The catalyst was filtered off through Celite under a blanket of nitrogen and washed with ethanol. The filtrate was concentrated under reduced pressure to give 6.9 g (quantitative yield) of a light yellow solid of the title compound. The resulting reaction mixture was refluxed for 2.5 hr at room temperature overnight The catalyst was filtered off through Celite under a blanket of nitrogen washed with ethanol The filtrate was concentrated under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1-{1-[4-(5-Bromopentyloxy)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (2 g) and 4-trifluoroacetylaminopiperidine (2 g) are dissolved in dimethylformamide (40 ml), and thereto is added potassium carbonate (2 g) and the mixture is stirred overnight. The reaction mixture is poured into water, and the mixture is extracted with toluene/ethyl acetate (1:1), dried over magnesium sulfate, and purified by silica gel column chromatography (eluent; dichloromethane: methanol=50:1) to give 1-[1-{4-[5-(4-trifluoroacetylamino-1-piperidinyl)pentyloxy]benzoyl}-4-piperidinyl]-3,4-dihydrocarbostyril (2 g) as colorless oil. the mixture is extracted with toluene/ethyl acetate (1:1) dried over magnesium sulfate purified by silica gel column chromatography (eluent; dichloromethane: methanol=50:1)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A suspension of 92 g of 1-benzyl 4-trifluoromethylcarbonylamino piperidine (X) and 9 g of wet 10% palladium on charcoal in 1000 ml of methanol is left under agitation for 8 days in a hydrogen atmosphere at room temperature. Then it is filtered, the filtrate is evaporated and the residue chromatographed on a silica column (M.P.L.C.). By eluting with pure methanol, 44 g of the expected product are obtained. Then it is filtered the filtrate is evaporated the residue chromatographed on a silica column (M.P.L.C.) By eluting with pure methanol, 44 g of the expected product are obtained