tert-butyl 4-hydroxy-4-(3-hydroxypropyl)piperidine-1-carboxylate

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: Palladium on carbon (5%, 800 mg) was added to a solution of 1,1-dimethylethyl 4-hydroxy-4-(3-hydroxypropynyl)-1-piperidinecarboxylate (from step (ii) above; 8.37 g, 32.8 mmol) in ethanol (400 ml), acetic acid (40 ml) and water (5 ml) and the mixture was shaken under an atmosphere of hydrogen (40 psi) for 20 hours. The mixture was filtered through Hyflo™ and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (50:50 increasing to 0:100), to give the title compound (4.84 g, 57%). The mixture was filtered through Hyflo™ the solvent was evaporated under reduced pressure The residue was purified by flash column chromatography on silica gel eluting with isohexane/EtOAc (50:50 increasing to 0:100)

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

実験手順: Palladium on carbon (5%, 800 mg) was added to a solution of 1,1-dimethylethyl 4-hydroxy-4-(3-hydroxypropynyl)-1-piperidinecarboxylate (from step (ii) above; 8.37 g, 32.8 mmol) in ethanol (400 ml), acetic acid (40 ml) and water (5 ml) and the mixture was shaken under an atmosphere of hydrogen (40 psi) for 20 hours. The mixture was filtered through Hyflo™ and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (50:50 increasing to 0:100), to give the title compound (4.84 g, 57%). The mixture was filtered through Hyflo™ the solvent was evaporated under reduced pressure The residue was purified by flash column chromatography on silica gel eluting with isohexane/EtOAc (50:50 increasing to 0:100)

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

実験手順: A mixture of 1-tert-butoxycarbonyl-4-(3-hydroxypropyl)piperidin-4-ol and 4M HCl-dioxane solution was stirred at ambient temperature for 3.5 hours to yield 4-(3-hydroxypropyl)piperidin-4-ol hydrochloride.

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

実験手順: A mixture of BH3 in THF (21 mL, 21.0 mmol) was added slowly to a mixture of tert-butyl 4-allyl-4-hydroxypiperidine-1-carboxylate (500 mg, 2.07 mmol) and THF (5 L) at 0° C. under nitrogen, and then stirred for 30 min. The resulting mixture was allowed to warm to room temperature and stirred overnight. The mixture was cooled to 0° C. and 3N sodium hydroxide (1 mL) was added followed by the addition of 30% hydrogen peroxide (1 mL). The resulting mixture was allowed to warm to room temperature and stirred for 2.5 hours. The mixture was then treated with water (10 mL) and extracted with EA (3×20 mL). The combined organic extracts were dried over Na2SO4 and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel with (30% EtOAc/PE) to give tert-butyl 4-hydroxy-4-(3-hydroxypropyl) piperidine-1-carboxylate 13B (629 mg) as a colorless oil. 1H NMR (CHLOROFORM-d) δ: 3.65 (t, J=5.7 Hz, 4H), 3.36 (br. s., 2H), 3.16 (br. s., 2H), 1.63-1.71 (m, 2H), 1.53-1.62 (m, 4H), 1.41-1.48 (m, 9H). stirred overnight The mixture was cooled to 0° C. to warm to room temperature stirred for 2.5 hours extracted with EA (3×20 mL) The combined organic extracts were dried over Na2SO4 the solvent was removed in vacuo The residue was purified by column chromatography on silica gel with (30% EtOAc/PE)

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: A solution of diethyl diazenedicarboxylate (3.35 mL, 21.3 mmol) in tetrahydrofuran (50 mL) was added over 15 minutes to a stirred, cooled (0° C.) solution of 1,1-dimethylethyl 4-hydroxy-4-(3-hydroxypropyl)-1-piperidinecarboxylate (Description 73, 4.6 g, 17.8 mmol) and triphenylphosphine (5.58 g, 21.3 mmol) in tetrahydrofuran (150 mL) and the mixture was stirred at 0° C. for 1 hour, then at room temperature for 24 hours. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (75:25 increasing to 50:50), to give the title compound (3.18 g, 70%). m/z (ES+) 242 (M+1). at room temperature for 24 hours The solvent was evaporated under reduced pressure the residue was purified by flash column chromatography on silica gel eluting with isohexane/EtOAc (75:25 increasing to 50:50)

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

実験手順: A solution of diethyl diazenedicarboxylate (3.35 mL, 21.3 mmol) in tetrahydrofuran (50 mL) was added over 15 minutes to a stirred, cooled (0° C.) solution of 1,1-dimethylethyl 4-hydroxy-4-(3-hydroxypropyl)-1-piperidinecarboxylate (Description 73, 4.6 g, 17.8 mmol) and triphenylphosphine (5.58 g, 21.3 mmol) in tetrahydrofuran (150 mL) and the mixture was stirred at 0° C. for 1 hour, then at room temperature for 24 hours. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (75:25 increasing to 50:50), to give the title compound (3.18 g, 70%). m/z (ES+) 242 (M+1). at room temperature for 24 hours The solvent was evaporated under reduced pressure the residue was purified by flash column chromatography on silica gel eluting with isohexane/EtOAc (75:25 increasing to 50:50)

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

実験手順: A mixture of BH3 in THF (21 mL, 21.0 mmol) was added slowly to a mixture of tert-butyl 4-allyl-4-hydroxypiperidine-1-carboxylate (500 mg, 2.07 mmol) and THF (5 mL) at 0° C. under nitrogen, and then stirred for 30 min. The resulting mixture was allowed to warm to room temperature and stirred overnight. The mixture was cooled to 0° C. and 3N sodium hydroxide (1 mL) was added followed by the addition of 30% hydrogen peroxide (1 mL). The resulting mixture was allowed to warm to room temperature and stirred for 2.5 hours. The mixture was then treated with water (10 mL) and extracted with EA (3×20 mL). The combined organic extracts were dried over Na2SO4 and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel with (30% EtOAc/PE) to give tert-butyl 4-hydroxy-4-(3-hydroxypropyl)piperidine-1-carboxylate 13B (6:29 mg) as a colorless oil. 1H NMR (CHLOROFORM-d) δ: 3.65 (t, J=5.7 Hz, 4H), 3.36 (br. s., 2H), 3.16 (br. s., 2H), 1.63-1.71 (m, 2H), 1.53-1.62 (m, 4H), 1.41-1.48 (m, 9H). stirred overnight The mixture was cooled to 0° C. to warm to room temperature stirred for 2.5 hours extracted with EA (3×20 mL) The combined organic extracts were dried over Na2SO4 the solvent was removed in vacuo The residue was purified by column chromatography on silica gel with (30% EtOAc/PE)

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

実験手順: Palladium on carbon (5%, 800 mg) was added to a solution of 1,1-dimethylethyl 4-hydroxy-4-(3-hydroxypropynyl)-1-piperidinecarboxylate (from step (ii) above; 8.37 g, 32.8 mmol) in ethanol (400 ml), acetic acid (40 ml) and water (5 ml) and the mixture was shaken under an atmosphere of hydrogen (40 psi) for 20 hours. The mixture was filtered through Hyflo™ and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (50:50 increasing to 0:100), to give the title compound (4.84 g, 57%). The mixture was filtered through Hyflo™ the solvent was evaporated under reduced pressure The residue was purified by flash column chromatography on silica gel eluting with isohexane/EtOAc (50:50 increasing to 0:100)

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

実験手順: A mixture of 1-tert-butoxycarbonyl-4-(3-hydroxypropyl)piperidin-4-ol and 4M HCl-dioxane solution was stirred at ambient temperature for 3.5 hours to yield 4-(3-hydroxypropyl)piperidin-4-ol hydrochloride.

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

実験手順: A mixture of BH3 in THF (21 mL, 21.0 mmol) was added slowly to a mixture of tert-butyl 4-allyl-4-hydroxypiperidine-1-carboxylate (500 mg, 2.07 mmol) and THF (5 L) at 0° C. under nitrogen, and then stirred for 30 min. The resulting mixture was allowed to warm to room temperature and stirred overnight. The mixture was cooled to 0° C. and 3N sodium hydroxide (1 mL) was added followed by the addition of 30% hydrogen peroxide (1 mL). The resulting mixture was allowed to warm to room temperature and stirred for 2.5 hours. The mixture was then treated with water (10 mL) and extracted with EA (3×20 mL). The combined organic extracts were dried over Na2SO4 and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel with (30% EtOAc/PE) to give tert-butyl 4-hydroxy-4-(3-hydroxypropyl) piperidine-1-carboxylate 13B (629 mg) as a colorless oil. 1H NMR (CHLOROFORM-d) δ: 3.65 (t, J=5.7 Hz, 4H), 3.36 (br. s., 2H), 3.16 (br. s., 2H), 1.63-1.71 (m, 2H), 1.53-1.62 (m, 4H), 1.41-1.48 (m, 9H). stirred overnight The mixture was cooled to 0° C. to warm to room temperature stirred for 2.5 hours extracted with EA (3×20 mL) The combined organic extracts were dried over Na2SO4 the solvent was removed in vacuo The residue was purified by column chromatography on silica gel with (30% EtOAc/PE)