ethyl 1-methylpiperidine-4-carboxylate

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:0.00; pressure:0.00; stir:

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:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 12.5 cm3 of a 4 N aqueous sodium hydroxide solution are added, at 20° C., to 7.60 g of ethyl 1-methyl-4-piperidinecarboxylate in solution in 35 cm3 of ethanol. After stirring for 20 hours, the reaction mixture is concentrated to a reduced volume and then neutralized with 12.5 cm3 of a 4 N aqueous hydrochloric acid solution and finally concentrated to dryness under reduced pressure (2.7 kPa). The residue is stirred in 60 cm3 of anhydrous ethanol, and then filtered. The filtrate is concentrated to dryness under reduced pressure (2.7 Kpa) at 20° C., to give 6.3 g of 1-methyl-4-piperidinecarboxylic acid in the form of a white solid. the reaction mixture is concentrated to a reduced volume finally concentrated to dryness under reduced pressure (2.7 kPa) The residue is stirred in 60 cm3 of anhydrous ethanol filtered The filtrate is concentrated to dryness under reduced pressure (2.7 Kpa) at 20° C.

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Piperidine-4-carboxylic acid ethyl ester (78 g) was dissolved in MeOH (1.2 L) at RT then formaldehyde (37%, 90 ml) and acetic acid (42 ml) were added and stirred for 2 h. The mixture was cooled to 0° C., NaCNBH3 (70 g) was added, and the mix was stirred for 20 min at 0° C., then overnight at RT. The mixture was cooled to 0° C. then quenched with 6N NaOH. The mixture was concentrated in vacuo to an aqueous layer, which was extracted with EtOAc (4×), brine-washed, dried over Na2SO4, and concentrated in vacuo to provide 1-methylpiperidine-4-carboxylic acid ethyl ester. the mix was stirred for 20 min at 0° C. overnight at RT The mixture was cooled to 0° C. then quenched with 6N NaOH The mixture was concentrated in vacuo to an aqueous layer, which was extracted with EtOAc (4×), brine- washed dried over Na2SO4 concentrated in vacuo

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

実験手順: Butyllithium in hexane (192 ml) was added dropwise at -70° C. under nitrogen to a solution of N-(1-methylethyl)-2-propanamine (43.4 ml) in tetrahydrofuran (400 ml) and the mixture was stirred for 30 minutes. A solution of intermediate (1) (0.236 mol) in tetrahydrofuran (50 ml) was added dropwise and the mixture was stirrred at -70° C. for 1 hour. Ethyl 1-methyl-4-piperidinecarboxylate (0.284 mol) in tetrahydrofuran (50 ml) was added and after the addition was completed, the mixture was stirred at -70° C. for 1 hour. The mixture was brought slowly to room temperature. The mixture was poured into water and extracted with 1,1'-oxybisethane/dichloromethane. The organic layer was dried (MgSO4) and evaporated. The residue (64.3 g) was purified by column chromatography over silica gel (eluent: CH2Cl2 /CH3OH/NH4OH 96/4/0.1 to 90/10/0.1) (35-70 μm). The pure fractions were collected and evaporated, yielding 29.55 g (41% ) of (1-methyl-4-piperidinyl)[2-[2-(3-thienyl)ethyl]-2H-1,2,4-triazol-3-yl]methanone (interm. 3); the mixture was stirrred at -70° C. for 1 hour after the addition the mixture was stirred at -70° C. for 1 hour was brought slowly to room temperature extracted with 1,1'-oxybisethane/dichloromethane The organic layer was dried (MgSO4) evaporated The residue (64.3 g) was purified by column chromatography over silica gel (eluent: CH2Cl2 /CH3OH/NH4OH 96/4/0.1 to 90/10/0.1) (35-70 μm) The pure fractions were collected evaporated

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

実験手順: To an ice-cooled solution of 1-methyl-piperidine-4-carboxylic acid ethyl ester (0.855 g, 5 mmol) in THF (30 ml) was added dropwise a 1M solution of LiAlH4 in THF (20 ml, 20 mmol). The reaction mixture was then stirred for 18 h whilst warming to ambient temperature, and then quenched by careful addition of water (0.75 ml), 10% aqueous NaOH (0.75 ml) then water (3×0.75 ml) and stirred at ambient temperature for 2 h. The resultant mixture was reduced in vacuo, shaken with ethyl acetate and filtered to remove inorganic residues. The filtrate was reduced in vacuo to give (1-methyl-piperidin-4-yl)-methanol as a colourless oil (0.468 g, 73%). (LC/MS: Rt 0.33, [M+H]+ 130.20). quenched by careful addition of water (0.75 ml), 10% aqueous NaOH (0.75 ml) water (3×0.75 ml) and stirred at ambient temperature for 2 h shaken with ethyl acetate filtered to remove inorganic residues

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

実験手順: To an ice-cooled solution of 1-methyl-piperidine-4-carboxylic acid ethyl ester (0.855 g, 5 mmol) in THF (30 ml) was added dropwise a 1M solution of LiAlH4 in THF (20 ml, 20 mmol). The reaction mixture was then stirred for 18 h whilst warming to ambient temperature, and then quenched by careful addition of water (0.75 ml), 10% aqueous NaOH (0.75 ml) then water (3×0.75 ml) and stirred at ambient temperature for 2 h. The resultant mixture was reduced in vacuo, shaken with ethyl acetate and filtered to remove inorganic residues. The filtrate was reduced in vacuo to give (1-methyl-piperidin-4-yl)-methanol as a colourless oil (0.468 g, 73%). (LC/MS: Rt 0.33, [M+H]+ 130.20). quenched by careful addition of water (0.75 ml), 10% aqueous NaOH (0.75 ml) water (3×0.75 ml) and stirred at ambient temperature for 2 h shaken with ethyl acetate filtered to remove inorganic residues

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

実験手順: Thionyl chloride (0.80 ml, 11 mmol) was added dropwise to a suspension of the HCl salt of 1-methyl-piperidine-4-carboxylic acid (1.80 g, 10 mmol) in ethanol (25 ml). The reaction mixture was stirred at ambient temperature overnight, then reduced in vacuo and dried by azeotrope with toluene (×3) to give 1-methyl-piperidine-4-carboxylic acid ethyl ester as a colourless solid (1.7 g, 100%). (LC/MS: Rt 0.41, [M+H]+ 172.08). dried by azeotrope with toluene (×3)