ethyl 4-piperidin-1-ylbutanoate

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: To a solution of ethyl 3-bromobutanoate (6.0 mL, 42 mmol) in N,N-dimethylformamide (20 mL) at 0° C. was added piperidine (8.0 mL, 80 mmol) and the mixture was warmed to room temperature then stirred 16 h. The reaction mixture was diluted with ethyl acetate (200 mL) and washed with a solution of brine and 2.0M aqueous sodium hydroxide (4:1 v/v). The organic phase was then dried over anhydrous sodium sulfate, filtered and concentrated to give ethyl 4-piperidin-1-ylbutanoate (6.8 g, 81% yield) as brown oil. MS (EI) for C11H21NO2: 200 (MH+). washed with a solution of brine and 2.0M aqueous sodium hydroxide (4:1 v/v) The organic phase was then dried over anhydrous sodium sulfate filtered concentrated

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

実験手順: To a solution of ethyl 3-bromobutanoate (6.0 mL, 42 mmol) in N,N-dimethylformamide (20 mL) at 0° C. was added piperidine (8.0 mL, 80 mmol) and the mixture was warmed to room temperature then stirred 16 h. The reaction mixture was diluted with ethyl acetate (200 mL) and washed with a solution of brine and 2.0M aqueous sodium hydroxide (4:1 v/v). The organic phase was then dried over anhydrous sodium sulfate, filtered and concentrated to give ethyl 4-piperidin-1-ylbutanoate (6.8 g, 81% yield) as brown oil. MS (EI) for C11H21NO2: 200 (MH+). washed with a solution of brine and 2.0M aqueous sodium hydroxide (4:1 v/v) The organic phase was then dried over anhydrous sodium sulfate filtered concentrated

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

実験手順: 4-Piperidinobutyric acid hydrochloride may be obtained by working according to the method described in Example 4 for the preparation of 1-methyl-3-piperidinecarboxylic acid hydrochloride, but starting with ethyl 4-piperidinobutyrate (19.9 g) and 6N aqueous hydrochloric acid solution (66.5 cc), and by heating for 24 hours under reflux. 4-Piperidinobutyric acid hydrochloride (16.3 g), m.p. 190° C., is thereby obtained. by heating for 24 hours under reflux

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

実験手順: To a solution of ethyl 4-chlorobutyrate (0.5 g, 3.32 mmol) in DMF (2 mL), piperidine (0.98 mL, 9.96 mmol), triethylamine (1.4 mL, 9.96 mmol) and a catalytic amount of KI were added and the resulting solution was refluxed overnight. After cooling at room temperature the solution was diluted with a saturated solution of NaHCO3 (10 mL) and extracts with Et2O (3×10 mL). The collected organic extracts were dried over Na2SO4, filtered and evaporated under vacuum to give the ethyl 4-piperidin-1-ylbutanoate as an oily residue (0.6 g, 3 mmol) pure enough for the next step. To a solution of the ester in dioxane (5 mL), few drops of 37% HCl were added and the solution was refluxed overnight. After cooling at room temperature the solvent was evaporated under vacuum and the residue was dried overnight in oven at 60° C. in vacuo. The crude 4-piperidin-1-ylbutanoic acid was dissolved in CH3OH (4 mL) and NaHCO3 (0.5 g, 6 mmol) was added. After stirring for 2 h, the precipitate was filtered off and the mother liquors concentrated to afford the intermediate sodium 4-piperidin-1-ylbutanoate (0.55 g, 2.84 mmol) as a colourless oil. 1H-NMR (DMSO-d6) δ 3.35 (m, 2H), 2.80 (m, 2H), 2.70 (m, 2H), 2.15 (t, 2H, J=3 Hz), 1.95 (m, 2H), 1.75 (m, 6H). the solution was refluxed overnight was evaporated under vacuum the residue was dried overnight in oven at 60° C. in vacuo The crude 4-piperidin-1-ylbutanoic acid was dissolved in CH3OH (4 mL) the precipitate was filtered off the mother liquors concentrated

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

実験手順: To a solution of ethyl 4-chlorobutyrate (0.5 g, 3.32 mmol) in DMF (2 mL), piperidine (0.98 mL, 9.96 mmol), triethylamine (1.4 mL, 9.96 mmol) and a catalytic amount of KI were added and the resulting solution was refluxed overnight. After cooling at room temperature the solution was diluted with a saturated solution of NaHCO3 (10 mL) and extracts with Et2O (3×10 mL). The collected organic extracts were dried over Na2SO4, filtered and evaporated under vacuum to give the ethyl 4-piperidin-1-ylbutanoate as an oily residue (0.6 g, 3 mmol) pure enough for the next step. To a solution of the ester in dioxane (5 mL), few drops of 37% HCl were added and the solution was refluxed overnight. After cooling at room temperature the solvent was evaporated under vacuum and the residue was dried overnight in oven at 60° C. in vacuo. The crude 4-piperidin-1-ylbutanoic acid was dissolved in CH3OH (4 mL) and NaHCO3 (0.5 g, 6 mmol) was added. After stirring for 2 h, the precipitate was filtered off and the mother liquors concentrated to afford the intermediate sodium 4-piperidin-1-ylbutanoate (0.55 g, 2.84 mmol) as a colourless oil. 1H-NMR (DMSO-d6) δ 3.35 (m, 2H), 2.80 (m, 2H), 2.70 (m, 2H), 2.15 (t, 2H, J=3 Hz), 1.95 (m, 2H), 1.75 (m, 6H). the solution was refluxed overnight was evaporated under vacuum the residue was dried overnight in oven at 60° C. in vacuo The crude 4-piperidin-1-ylbutanoic acid was dissolved in CH3OH (4 mL) the precipitate was filtered off the mother liquors concentrated

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

実験手順: To a solution of ethyl 4-chlorobutyrate (0.5 g, 3.32 mmol) in DMF (2 mL), piperidine (0.98 mL, 9.96 mmol), triethylamine (1.4 mL, 9.96 mmol) and a catalytic amount of KI were added and the resulting solution was refluxed overnight. After cooling at room temperature the solution was diluted with a saturated solution of NaHCO3 (10 mL) and extracts with Et2O (3×10 mL). The collected organic extracts were dried over Na2SO4, filtered and evaporated under vacuum to give the ethyl 4-piperidin-1-ylbutanoate as an oily residue (0.6 g, 3 mmol) pure enough for the next step. To a solution of the ester in dioxane (5 mL), few drops of 37% HCl were added and the solution was refluxed overnight. After cooling at room temperature the solvent was evaporated under vacuum and the residue was dried overnight in oven at 60° C. in vacuo. The crude 4-piperidin-1-ylbutanoic acid was dissolved in CH3OH (4 mL) and NaHCO3 (0.5 g, 6 mmol) was added. After stirring for 2 h, the precipitate was filtered off and the mother liquors concentrated to afford the intermediate sodium 4-piperidin-1-ylbutanoate (0.55 g, 2.84 mmol) as a colourless oil. 1H-NMR (DMSO-d6) δ 3.35 (m, 2H), 2.80 (m, 2H), 2.70 (m, 2H), 2.15 (t, 2H, J=3 Hz), 1.95 (m, 2H), 1.75 (m, 6H). the resulting solution was refluxed overnight The collected organic extracts were dried over Na2SO4 filtered evaporated under vacuum

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

実験手順: To a solution of ethyl 3-bromobutanoate (6.0 mL, 42 mmol) in N,N-dimethylformamide (20 mL) at 0° C. was added piperidine (8.0 mL, 80 mmol) and the mixture was warmed to room temperature then stirred 16 h. The reaction mixture was diluted with ethyl acetate (200 mL) and washed with a solution of brine and 2.0M aqueous sodium hydroxide (4:1 v/v). The organic phase was then dried over anhydrous sodium sulfate, filtered and concentrated to give ethyl 4-piperidin-1-ylbutanoate (6.8 g, 81% yield) as brown oil. MS (EI) for C11H21NO2: 200 (MH+). washed with a solution of brine and 2.0M aqueous sodium hydroxide (4:1 v/v) The organic phase was then dried over anhydrous sodium sulfate filtered concentrated

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: To a suspension of crude 4-piperidin-1-yl-butyric acid ethyl ester from the previous step (about 25 mmol) in 15 mL of water, NaOH (1.4 g, 25 mmol) was added and the mixture was heated at reflux for 16 hours. The reaction was then allowed to cool down to room temperature, the solution was acidified at 0° C. with HCl 6N and concentrated under reduced pressure. The residue was treated with EtOH and the sodium chloride which precipitated was filtered off. Evaporation of the solvent under reduced pressure afforded 2.8 g of the title compound as a white solid in 58% overall yield of steps a) and b) the mixture was heated at reflux for 16 hours concentrated under reduced pressure The residue was treated with EtOH the sodium chloride which precipitated was filtered off Evaporation of the solvent under reduced pressure

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

実験手順: 4-Piperidinobutyric acid hydrochloride may be obtained by working according to the method described in Example 4 for the preparation of 1-methyl-3-piperidinecarboxylic acid hydrochloride, but starting with ethyl 4-piperidinobutyrate (19.9 g) and 6N aqueous hydrochloric acid solution (66.5 cc), and by heating for 24 hours under reflux. 4-Piperidinobutyric acid hydrochloride (16.3 g), m.p. 190° C., is thereby obtained. by heating for 24 hours under reflux

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

実験手順: To a solution of ethyl 4-chlorobutyrate (0.5 g, 3.32 mmol) in DMF (2 mL), piperidine (0.98 mL, 9.96 mmol), triethylamine (1.4 mL, 9.96 mmol) and a catalytic amount of KI were added and the resulting solution was refluxed overnight. After cooling at room temperature the solution was diluted with a saturated solution of NaHCO3 (10 mL) and extracts with Et2O (3×10 mL). The collected organic extracts were dried over Na2SO4, filtered and evaporated under vacuum to give the ethyl 4-piperidin-1-ylbutanoate as an oily residue (0.6 g, 3 mmol) pure enough for the next step. To a solution of the ester in dioxane (5 mL), few drops of 37% HCl were added and the solution was refluxed overnight. After cooling at room temperature the solvent was evaporated under vacuum and the residue was dried overnight in oven at 60° C. in vacuo. The crude 4-piperidin-1-ylbutanoic acid was dissolved in CH3OH (4 mL) and NaHCO3 (0.5 g, 6 mmol) was added. After stirring for 2 h, the precipitate was filtered off and the mother liquors concentrated to afford the intermediate sodium 4-piperidin-1-ylbutanoate (0.55 g, 2.84 mmol) as a colourless oil. 1H-NMR (DMSO-d6) δ 3.35 (m, 2H), 2.80 (m, 2H), 2.70 (m, 2H), 2.15 (t, 2H, J=3 Hz), 1.95 (m, 2H), 1.75 (m, 6H). the solution was refluxed overnight was evaporated under vacuum the residue was dried overnight in oven at 60° C. in vacuo The crude 4-piperidin-1-ylbutanoic acid was dissolved in CH3OH (4 mL) the precipitate was filtered off the mother liquors concentrated