ethyl 4-hydroxy-4-methylpiperidine-1-carboxylate

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

実験手順: At 0° C. under N2 atmosphere, to a solution of ethyl 4-hydroxy-4-methylpiperidine-1-carboxylate (283) (2.4 g, 12.8 mmol) in bromobenzene (20.1 g, 128 mmol) was added trifluoromethanesulfonic acid (19.2 g, 128 mmol). The resulting mixture was stirred at RT for 3 hours before being poured onto ice. The mixture was basified with 1N NaOH and extracted with DCM (20 mL×3). The combined organic layers were washed with brine, dried, concentrated in vacuo and subjected to silica flash column using 0 to 20% EtOAc in PE to give ethyl 4-(4-bromophenyl)-4-methylpiperidine-1-carboxylate (284) (3.4 g, 81%) as a light yellow oil. before being poured onto ice extracted with DCM (20 mL×3) The combined organic layers were washed with brine dried concentrated in vacuo

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

実験手順: At −30° C. and under N2 atmosphere, to a solution of ethyl 4-oxopiperidine-1-carboxylate (282) (6.0 g, 35.1 mmol) in anhydrous Et2O (100 mL) was added MeMgBr (3.0 M, 14 mL, 42.1 mmol). The resulting mixture was stirred at 0° C. for 2 hours before being quenched with aqueous NH4Cl solution. The mixture was extracted with DCM (30 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo and subjected to silica flash column chromatography using 0 to 50% EtOAc in PE (petroleum ether) to isolate ethyl 4-hydroxy-4-methylpiperidine-1-carboxylate (283) (4 g, 61%) as an oil. before being quenched with aqueous NH4Cl solution The mixture was extracted with DCM (30 mL×3) The combined organic layers were washed with brine dried over Na2SO4 concentrated in vacuo

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

実験手順: At −30° C. and under N2 atmosphere, to a solution of ethyl 4-oxopiperidine-1-carboxylate (282) (6.0 g, 35.1 mmol) in anhydrous Et2O (100 mL) was added MeMgBr (3.0 M, 14 mL, 42.1 mmol). The resulting mixture was stirred at 0° C. for 2 hours before being quenched with aqueous NH4Cl solution. The mixture was extracted with DCM (30 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo and subjected to silica flash column chromatography using 0 to 50% EtOAc in PE (petroleum ether) to isolate ethyl 4-hydroxy-4-methylpiperidine-1-carboxylate (283) (4 g, 61%) as an oil. before being quenched with aqueous NH4Cl solution The mixture was extracted with DCM (30 mL×3) The combined organic layers were washed with brine 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: A mixture of ethyl 4-hydroxy-4-methylpiperidine-1-carboxylate (2.81 g, 15.01 mmol), bromobenzene (23.56 g, 150 mmol), and trifluoromethanesulfonic acid (22.52 g, 150 mmol) was stirred at room temperature for 3 h. The reaction mixture was poured into ice, basified with 1N NaOH, extracted with methylene chloride twice. The combined organic phases were washed with water and concentrated. The residue was purified by MPLC (ISCO, hexane/ethyl acetate, 80 g silica gel column) to give 4.28 g of product as a slightly yellow oil. LCMS: (M+H)+=326.01, 328.01. The reaction mixture was poured into ice extracted with methylene chloride twice The combined organic phases were washed with water concentrated The residue was purified by MPLC (ISCO, hexane/ethyl acetate, 80 g silica gel column)

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

実験手順: At 0° C. under N2 atmosphere, to a solution of ethyl 4-hydroxy-4-methylpiperidine-1-carboxylate (283) (2.4 g, 12.8 mmol) in bromobenzene (20.1 g, 128 mmol) was added trifluoromethanesulfonic acid (19.2 g, 128 mmol). The resulting mixture was stirred at RT for 3 hours before being poured onto ice. The mixture was basified with 1N NaOH and extracted with DCM (20 mL×3). The combined organic layers were washed with brine, dried, concentrated in vacuo and subjected to silica flash column using 0 to 20% EtOAc in PE to give ethyl 4-(4-bromophenyl)-4-methylpiperidine-1-carboxylate (284) (3.4 g, 81%) as a light yellow oil. before being poured onto ice extracted with DCM (20 mL×3) The combined organic layers were washed with brine dried concentrated in vacuo

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

実験手順: At −30° C. and under N2 atmosphere, to a solution of ethyl 4-oxopiperidine-1-carboxylate (282) (6.0 g, 35.1 mmol) in anhydrous Et2O (100 mL) was added MeMgBr (3.0 M, 14 mL, 42.1 mmol). The resulting mixture was stirred at 0° C. for 2 hours before being quenched with aqueous NH4Cl solution. The mixture was extracted with DCM (30 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo and subjected to silica flash column chromatography using 0 to 50% EtOAc in PE (petroleum ether) to isolate ethyl 4-hydroxy-4-methylpiperidine-1-carboxylate (283) (4 g, 61%) as an oil. before being quenched with aqueous NH4Cl solution The mixture was extracted with DCM (30 mL×3) The combined organic layers were washed with brine dried over Na2SO4 concentrated in vacuo