1-benzyl-3,3-difluoropiperidine-4,4-diol

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

実験手順: Ethyl 1-benzyl-5,5-difluoro-4-oxopiperidine-3-carboxylate (6.00 g, 20.2 mmol; prepared as described in WO 2005/040120, p. 30) was dissolved in 3N HCl (60 mL) and heated to reflux for 16 hours. The reaction was cooled, adjusted to pH 8 with solid NaHCO3, then extracted three times with ethyl acetate. The combined organics were washed with saturated NaCl, dried over Na2SO4 and concentrated in vacuo to a white solid (5.1 g). MS APCI (+) m/z 244.0 (M+1) detected. heated to reflux for 16 hours The reaction was cooled extracted three times with ethyl acetate The combined organics were washed with saturated NaCl dried over Na2SO4 concentrated in vacuo to a white solid (5.1 g)

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

実験手順: In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of 1-benzyl-3,3-difluoropiperidine-4,4-diol (WO2008/121687 and WO2005/040120) (2.88 g, 11.85 mmol) in dry MeOH (58 mL) was added NaBH4 (672 mg, 17.76 mmol) portionwise at 0° C. The reaction mixture was stirred at 0° C. for 15 min. Aq. 0.1M NaHCO3 (5 mL) was then added and the mixture further stirred for 5 min, dried (MgSO4), filtered and concentrated under reduced pressure. The crude residue was purified by FC (hept-EA, 2:1→1:1) and the title compound obtained as a beige oil. LC-MS-conditions 08: tR=0.42 min; [M+H]+=228.32. the mixture further stirred for 5 min dried (MgSO4) filtered concentrated under reduced pressure The crude residue was purified by FC (hept-EA, 2:1→1:1)

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

実験手順: In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of 1-benzyl-3,3-difluoropiperidine-4,4-diol (WO2008/121687 and WO2005/040120) (2.88 g, 11.85 mmol) in dry MeOH (58 mL) was added NaBH4 (672 mg, 17.76 mmol) portionwise at 0° C. The reaction mixture was stirred at 0° C. for 15 min. Aq. 0.1M NaHCO3 (5 mL) was then added and the mixture further stirred for 5 min, dried (MgSO4), filtered and concentrated under reduced pressure. The crude residue was purified by FC (hept-EA, 2:1→1:1) and the title compound obtained as a beige oil. LC-MS-conditions 08: tR=0.42 min; [M+H]+=228.32. the mixture further stirred for 5 min dried (MgSO4) filtered concentrated under reduced pressure The crude residue was purified by FC (hept-EA, 2:1→1:1)

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

実験手順: A solution of ethyl 1-benzyl-5,5-difluoro-4-oxopiperidine-3-carboxylate (4.272 g, 14.4 mmol) dissolved in 3 N HCl (175 mL) was heated at reflux for 14 hours. The reaction mixture was cooled to room temperature, then solid NaHCO3 was added until pH 8 and extracted three times with ethyl acetate, the combined organic layers were dried over Na2SO4 and the solvents were evaporated. The title compound was obtained as white solid (3.5 g, 100%). was heated at reflux for 14 hours extracted three times with ethyl acetate the combined organic layers were dried over Na2SO4 the solvents were evaporated

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

実験手順: A solution of ethyl 1-benzyl-5,5-difluoro-4-oxopiperidine-3-carboxylate (4.272 g, 14.4 mmol) dissolved in 3 N HCl (175 mL) was heated at reflux for 14 hours. The reaction mixture was cooled to room temperature, then solid NaHCO3 was added until pH 8 and extracted three times with ethyl acetate, the combined organic layers were dried over Na2SO4 and the solvents were evaporated. The title compound was obtained as white solid (3.5 g, 100%). was heated at reflux for 14 hours extracted three times with ethyl acetate the combined organic layers were dried over Na2SO4 the solvents were evaporated

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

実験手順: In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of 1-benzyl-3,3-difluoropiperidine-4,4-diol (WO2008/121687 and WO2005/040120) (2.88 g, 11.85 mmol) in dry MeOH (58 mL) was added NaBH4 (672 mg, 17.76 mmol) portionwise at 0° C. The reaction mixture was stirred at 0° C. for 15 min. Aq. 0.1M NaHCO3 (5 mL) was then added and the mixture further stirred for 5 min, dried (MgSO4), filtered and concentrated under reduced pressure. The crude residue was purified by FC (hept/EA, 2:1→1:1) and the title compound obtained as a beige oil. LC-MS-conditions 08: tR=0.42 min; [M+H]+=228.32. the mixture further stirred for 5 min dried (MgSO4) filtered concentrated under reduced pressure The crude residue was purified by FC (hept/EA, 2:1→1:1)

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

実験手順: In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of 1-benzyl-3,3-difluoropiperidine-4,4-diol (WO2008/121687 and WO2005/040120) (2.88 g, 11.85 mmol) in dry MeOH (58 mL) was added NaBH4 (672 mg, 17.76 mmol) portionwise at 0° C. The reaction mixture was stirred at 0° C. for 15 min. Aq. 0.1M NaHCO3 (5 mL) was then added and the mixture further stirred for 5 min, dried (MgSO4), filtered and concentrated under reduced pressure. The crude residue was purified by FC (hept/EA, 2:1→1:1) and the title compound obtained as a beige oil. LC-MS-conditions 08: tR=0.42 min; [M+H]+=228.32. the mixture further stirred for 5 min dried (MgSO4) filtered concentrated under reduced pressure The crude residue was purified by FC (hept/EA, 2:1→1:1)

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

実験手順: In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of 1-benzyl-3,3-difluoropiperidine-4,4-diol (WO2008/121687 and WO2005/040120) (2.88 g, 11.85 mmol) in dry MeOH (58 mL) was added NaBH4 (672 mg, 17.76 mmol) portionwise at 0° C. The reaction mixture was stirred at 0° C. for 15 min. Aq. 0.1M NaHCO3 (5 mL) was then added and the mixture further stirred for 5 min, dried (MgSO4), filtered and concentrated under reduced pressure. The crude residue was purified by FC (hept/EA, 2:1→1:1) and the title compound obtained as a beige oil. LC-MS-conditions 08: tR=0.42 min; [M+H]+=228.32. the mixture further stirred for 5 min dried (MgSO4) filtered concentrated under reduced pressure The crude residue was purified by FC (hept/EA, 2:1→1:1)

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of ethyl 1-benzyl-5,5-difluoro-4-hydroxy-1,2,5,6-tetrahydropyridine-3-carboxylate (5.0 g) and conc. hydrochloric acid (40 mL) in 1,4-dioxane (15 mL) was stirred at 80° C. for 3 hr. The reaction mixture was concentrated under reduced pressure, and diluted with ethyl acetate, and the mixture was adjusted to pH-9 with saturated aqueous sodium carbonate solution. The aqueous layer was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with dichloromethane to give the title compound (1.40 g). The reaction mixture was concentrated under reduced pressure diluted with ethyl acetate The aqueous layer was extracted with ethyl acetate the organic layer was dried over anhydrous sodium sulfate concentrated under reduced pressure The residue was washed with dichloromethane

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of ethyl 1-benzyl-5,5-difluoro-4-hydroxy-1,2,5,6-tetrahydropyridine-3-carboxylate (5.0 g) and conc. hydrochloric acid (40 mL) in 1,4-dioxane (15 mL) was stirred at 80° C. for 3 hr. The reaction mixture was concentrated under reduced pressure, and diluted with ethyl acetate, and the mixture was adjusted to pH-9 with saturated aqueous sodium carbonate solution. The aqueous layer was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with dichloromethane to give the title compound (1.40 g). The reaction mixture was concentrated under reduced pressure diluted with ethyl acetate The aqueous layer was extracted with ethyl acetate the organic layer was dried over anhydrous sodium sulfate concentrated under reduced pressure The residue was washed with dichloromethane

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

実験手順: Ethyl 1-benzyl-5,5-difluoro-4-oxopiperidine-3-carboxylate (6.00 g, 20.2 mmol; prepared as described in WO 2005/040120, p. 30) was dissolved in 3N HCl (60 mL) and heated to reflux for 16 hours. The reaction was cooled, adjusted to pH 8 with solid NaHCO3, then extracted three times with ethyl acetate. The combined organics were washed with saturated NaCl, dried over Na2SO4 and concentrated in vacuo to a white solid (5.1 g). MS APCI (+) m/z 244.0 (M+1) detected. heated to reflux for 16 hours The reaction was cooled extracted three times with ethyl acetate The combined organics were washed with saturated NaCl dried over Na2SO4 concentrated in vacuo to a white solid (5.1 g)

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

実験手順: Ethyl 1-benzyl-5,5-difluoro-4-oxopiperidine-3-carboxylate (6.00 g, 20.2 mmol; prepared as described in WO 2005/040120, p. 30) was dissolved in 3N HCl (60 mL) and heated to reflux for 16 hours. The reaction was cooled, adjusted to pH 8 with solid NaHCO3, then extracted three times with ethyl acetate. The combined organics were washed with saturated NaCl, dried over Na2SO4 and concentrated in vacuo to a white solid (5.1 g). MS APCI (+) m/z 244.0 (M+1) detected. heated to reflux for 16 hours The reaction was cooled extracted three times with ethyl acetate The combined organics were washed with saturated NaCl dried over Na2SO4 concentrated in vacuo to a white solid (5.1 g)