benzyl N-piperidin-4-ylcarbamate

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of piperidin-4-yl-carbamic acid benzyl ester (15 g, 58.4 mmol, crude product from Boc-deprotection step) in dimethylformamide (60 mL) at 23° C. was added potassium carbonate (12.1 g, 87.6 mmol, 1.5 equiv), potassium iodide (4.85 g, 29.2 mmol, 0.5 equiv) and (3-bromo-propyl)-carbamic acid tert-butyl ester (13.9 g, 58.4 mmol, 1 equiv). The resulting mixture was warmed to 60° C. (oil bath). After 90 min at 60° C. the reaction mixture was cooled to 23° C. then partitioned between ethyl acetate and water (100 mL each). The organic layer was separated, washed with saturated brine solution (150 mL), dried (MgSO4), filtered and concentrated. The product was purified using an Isco CombiFlash automated chromatography system. The residue was loaded onto a 330 g silica gel column as a solution in dichloromethane (25 mL) then eluted with 2 M ammonia in methanol in dichloromethane (0-12.5% 2 M ammonia in methanol linear gradient over 12 column volumes at a flow rate of 100 mL/min) to give 16.9 g (43.2 mmol, 74% over 3 steps) of the title compound as a clear After 90 min at 60° C. the reaction mixture was cooled to 23° C. then partitioned between ethyl acetate and water (100 mL each) The organic layer was separated washed with saturated brine solution (150 mL) dried (MgSO4) filtered concentrated The product was purified then eluted with 2 M ammonia in methanol in dichloromethane (0-12.5% 2 M ammonia in methanol linear gradient over 12 column volumes at a flow rate of 100 mL/min)

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

実験手順: To a solution of 4-benzyloxycarbonylamino-piperidine-1-carboxylic acid tert-butyl ester (20.4 g, crude from previous step) in dichloromethane (100 mL) at 23° C. was added trifluoroacetic acid (40 mL). After stirring for 45 min the reaction mixture was concentrated. The residue was dissolved in water (100 mL) then basified to pH 11 via addition of solid potassium carbonate. The resulting solution was extracted with dichloromethane (2×150 mL). The organic extracts were extremely cloudy; they were dried (Na2SO4), filtered and concentrated. The residue was dissolved/suspended in chloroform (70 mL) and the observed particulates were removed via filtration through a glass frit. The solution was concentrated to give 15 g of brown oil. This material was used without purification in the subsequent step. was concentrated The residue was dissolved in water (100 mL) then basified to pH 11 via addition of solid potassium carbonate The resulting solution was extracted with dichloromethane (2×150 mL) they were dried (Na2SO4) filtered concentrated the observed particulates were removed via filtration through a glass frit The solution was concentrated

反応条件: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (5S)-(−)-2,2,3-Trimethyl-5-benzyl-4-imidazolidinone dichloroacetic acid (90 mg, 0.259 mmol), N-fluorobenzenesulfonimide (484 mg, 1.53 mmol), 2-propanol (0.4 ml) and tetrahydrofuran (dehydrated) (3.6 ml) were mixed at room temperature. The reaction mixture was cooled to −10° C., and pentanal (0.175 ml, 1.67 mmol) was then added, followed by stirring for three hours and 20 minutes while naturally warming from −10° C. to room temperature. Benzyl N-(piperidin-4-yl)carbamate obtained in Example 1b (304 mg, 1.3 mmol) and sodium triacetoxyborohydride (600 mg, 2.83 mmol) were added to the reaction mixture, which was stirred at room temperature for 15 hours and 40 minutes. Water and an aqueous sodium bicarbonate solution were added to the reaction mixture, the insoluble matter was removed by filtration, and the resulting filtrate was extracted with ethyl acetate twice. The organic layer was washed with brine and dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (silica gel, elution solvent: ethyl acetate/heptane) to give a chiral form mixture of the title compound (44 mg, yield 10.5%). while naturally warming from −10° C. to room temperature was stirred at room temperature for 15 hours and 40 minutes the insoluble matter was removed by filtration the resulting filtrate was extracted with ethyl acetate twice The organic layer was washed with brine dried over anhydrous sodium sulfate the solvent was distilled off The residue was purified by silica gel column chromatography (silica gel, elution solvent: ethyl acetate/heptane) to give

反応条件: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (5S)-(−)-2,2,3-Trimethyl-5-benzyl-4-imidazolidinone dichloroacetic acid (90 mg, 0.259 mmol), N-fluorobenzenesulfonimide (484 mg, 1.53 mmol), 2-propanol (0.4 ml) and tetrahydrofuran (dehydrated) (3.6 ml) were mixed at room temperature. The reaction mixture was cooled to −10° C., and pentanal (0.175 ml, 1.67 mmol) was then added, followed by stirring for three hours and 20 minutes while naturally warming from −10° C. to room temperature. Benzyl N-(piperidin-4-yl)carbamate obtained in Example 1b (304 mg, 1.3 mmol) and sodium triacetoxyborohydride (600 mg, 2.83 mmol) were added to the reaction mixture, which was stirred at room temperature for 15 hours and 40 minutes. Water and an aqueous sodium bicarbonate solution were added to the reaction mixture, the insoluble matter was removed by filtration, and the resulting filtrate was extracted with ethyl acetate twice. The organic layer was washed with brine and dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (silica gel, elution solvent: ethyl acetate/heptane) to give a chiral form mixture of the title compound (44 mg, yield 10.5%). while naturally warming from −10° C. to room temperature was stirred at room temperature for 15 hours and 40 minutes the insoluble matter was removed by filtration the resulting filtrate was extracted with ethyl acetate twice The organic layer was washed with brine dried over anhydrous sodium sulfate the solvent was distilled off The residue was purified by silica gel column chromatography (silica gel, elution solvent: ethyl acetate/heptane) to give

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

実験手順: A mixture of tert-butyl 4-{[(benzyloxy)carbonyl]amino}piperidine-1-carboxylate obtained in Example 1a (13.1 g, 39.2 mmol), a 5 N aqueous hydrochloric acid solution (40 ml, 200 mmol) and methanol (40 ml) was stirred at mom temperature for 23 hours. A 5 N aqueous sodium hydroxide solution (40 ml) was added to the reaction mixture under ice-cooling. Water and the solvent were distilled off from the reaction mixture while the mixture was azeotropically distilled with ethanol. Ethanol was added to the residue, the insoluble matter was removed by filtration, and the filtrate was concentrated to give the title compound (9.10 g, yield 99.1%). cooling Water and the solvent were distilled off from the reaction mixture while the mixture was azeotropically distilled with ethanol Ethanol was added to the residue the insoluble matter was removed by filtration the filtrate was concentrated

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Methyl 3-bromobenzoate (230 mg, 1.07 mmol), palladium acetate (12 mg, 0.054 mmol), BINAP (133 mg, 0.214 mmol) and cesium carbonate (767 mg, 2.35 mmol) were added to a solution of benzyl piperidin-4-yl-carbamate obtained in Example (192b) (248 mg, 0.817 mmol) in 1,4-dioxane (10 mL) and N,N-dimethylformamide (2.5 mL), and the mixture was stirred at 100° C. for 20 hours. The reaction solution was cooled, diluted with ethyl acetate, and washed with brine. The organic layer was dried over magnesium sulfate, and then the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=3/1) to obtain 80 mg of the title compound as a colorless oily substance (20%). The reaction solution was cooled washed with brine The organic layer was dried over magnesium sulfate the solvent was evaporated under reduced pressure The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=3/1)

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

実験手順: A 4 N hydrochloric acid/1,4-dioxane solution (20 mL) was added to tert-butyl 4-benzyloxycarbonylaminopiperidine-1-carboxylate obtained in Example (192a) (1.5 g, 4.49 mmol). The mixture was stirred at room temperature for one hour, and the solvent was evaporated under reduced pressure. The resulting residue was dissolved in methanol. Amberlite IRA-400(Cl) ion exchange resin (20 g) was added, and the mixture was stirred at room temperature for one hour. Amberlite was filtered off, and then the solution was concentrated under reduced pressure to obtain 910 mg of the title compound as a colorless oily substance. the solvent was evaporated under reduced pressure The resulting residue was dissolved in methanol Amberlite IRA-400(Cl) ion exchange resin (20 g) was added the mixture was stirred at room temperature for one hour Amberlite was filtered off the solution was concentrated under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Methyl 3-bromobenzoate (230 mg, 1.07 mmol), palladium acetate (12 mg, 0.054 mmol), BINAP (133 mg, 0.214 mmol) and cesium carbonate (767 mg, 2.35 mmol) were added to a solution of benzyl piperidin-4-yl-carbamate obtained in Example (192b) (248 mg, 0.817 mmol) in 1,4-dioxane (10 mL) and N,N-dimethylformamide (2.5 mL), and the mixture was stirred at 100° C. for 20 hours. The reaction solution was cooled, diluted with ethyl acetate, and washed with brine. The organic layer was dried over magnesium sulfate, and then the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=3/1) to obtain 80 mg of the title compound as a colorless oily substance (20%). The reaction solution was cooled washed with brine The organic layer was dried over magnesium sulfate the solvent was evaporated under reduced pressure The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=3/1)