8-azaspiro[4.5]decane

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: To a solution of 8-azaspiro[4.5]decane (which has been described in WO 9800404 A1 6.2 g, 44.5 mmol) in dichloromethane (130 ml), which was cooled to 0° C., triethylamine (7.5 ml, 53.4 mmol) was added then a solution of tert-butyl dicarbonate (10.68 g, 48.9 mmol) in dichloromethane (50 ml) was added in 20 minutes. The clear solution was maintained under stirring at room temperature for 18 hours, then dichloromethane (50 ml) was added and the organic solution was washed with water (2×20 ml), HCl 0.1N (20 ml) then water (2×20 ml). The organic solvent was anhydrified (Na2SO4) and evaporated to give a crude that was purified on silica gel column (Hexane/AcOEt 95/5) to give 6 g of the title compound (light yellow solid). The clear solution was maintained the organic solution was washed with water (2×20 ml), HCl 0.1N (20 ml) evaporated to give a crude that was purified on silica gel column (Hexane/AcOEt 95/5)

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

実験手順: To a solution of 8-azaspiro[4.5]decane (which has been described in WO 9800404 A1 6.2 g, 44.5 mmol) in dichloromethane (130 ml), which was cooled to 0° C., triethylamine (7.5 ml, 53.4 mmol) was added then a solution of tert-butyl dicarbonate (10.68 g, 48.9 mmol) in dichloromethane (50 ml) was added in 20 minutes. The clear solution was maintained under stirring at room temperature for 18 hours, then dichloromethane (50 ml) was added and the organic solution was washed with water (2×20 ml), HCl 0.1N (20 ml) then water (2×20 ml). The organic solvent was anhydrified (Na2SO4) and evaporated to give a crude that was purified on silica gel column (Hexane/AcOEt 95/5) to give 6 g of the title compound (light yellow solid). The clear solution was maintained the organic solution was washed with water (2×20 ml), HCl 0.1N (20 ml) evaporated to give a crude that was purified on silica gel column (Hexane/AcOEt 95/5)

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: Was prepared from (3,3-pentamethylenglutarimide by lithium aluminium hydride reduction in tetrahydrofurane under standard conditions. Flash chromatography (silica, eluent dichloromethane/methanol/triethylamine 10:2:0.1) afforded the title compound as light yellow oil (>95% yield). MS 154(M+H+).

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

実験手順: Methyl (S)-4,4-difluoro-2-isocyanato-5-phenylpentanoate (425 mg, 1.58 mmol) were dissolved in 25 ml of dichloromethane. 8-Azaspiro[4.5]decane (220 mg, 1.58 mmol, 1 eq.) and DIPEA (269 μl, 204 mg, 1.58 mmol, 1 eq.) were added to this solution which was stirred at RT overnight. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC (gradient: acetonitrile/water and addition of 0.05% TFA). The product-containing fractions were combined and freed from the solvent under reduced pressure. The solvent was removed under reduced pressure the residue was purified by preparative HPLC (gradient: acetonitrile/water and addition of 0.05% TFA)

反応条件: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1.57 ml of phosgene (20% solution in toluene, 2.96 mmol) were initially charged in 5 ml of dichloroethane and cooled to −20° C., then a mixture of 8-azaspiro-[4,5]decane (750 mg, 2.96 mmol) and triethylamine (1.28 ml, 9.2 mmol, 3.1 eq.) was added slowly. After 30 min, the mixture was allowed to come to RT; after 1 h, according to LC-MS, a little starting material was still present but also three new peaks. Subsequently, the mixture was added to 2 N aqueous HCl, the aqueous phase was extracted with dichloromethane, and the organic phase was washed with saturated NaHCO3 solution and dried over sodium sulfate; subsequently, the mixture was concentrated by rotary evaporation under reduced pressure. Crude yield: 592 mg was added slowly to come to RT after 1 h the aqueous phase was extracted with dichloromethane the organic phase was washed with saturated NaHCO3 solution dried over sodium sulfate subsequently, the mixture was concentrated by rotary evaporation under reduced pressure

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

実験手順: Was prepared from (3,3-pentamethylenglutarimide by lithium aluminium hydride reduction in tetrahydrofurane under standard conditions. Flash chromatography (silica, eluent dichloromethane/methanol/triethylamine 10:2:0.1) afforded the title compound as light yellow oil (>95% yield). MS 154(M+H+).

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

実験手順: Methyl (S)-4,4-difluoro-2-isocyanato-5-phenylpentanoate (425 mg, 1.58 mmol) were dissolved in 25 ml of dichloromethane. 8-Azaspiro[4.5]decane (220 mg, 1.58 mmol, 1 eq.) and DIPEA (269 μl, 204 mg, 1.58 mmol, 1 eq.) were added to this solution which was stirred at RT overnight. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC (gradient: acetonitrile/water and addition of 0.05% TFA). The product-containing fractions were combined and freed from the solvent under reduced pressure. The solvent was removed under reduced pressure the residue was purified by preparative HPLC (gradient: acetonitrile/water and addition of 0.05% TFA)

反応条件: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1.57 ml of phosgene (20% solution in toluene, 2.96 mmol) were initially charged in 5 ml of dichloroethane and cooled to −20° C., then a mixture of 8-azaspiro-[4,5]decane (750 mg, 2.96 mmol) and triethylamine (1.28 ml, 9.2 mmol, 3.1 eq.) was added slowly. After 30 min, the mixture was allowed to come to RT; after 1 h, according to LC-MS, a little starting material was still present but also three new peaks. Subsequently, the mixture was added to 2 N aqueous HCl, the aqueous phase was extracted with dichloromethane, and the organic phase was washed with saturated NaHCO3 solution and dried over sodium sulfate; subsequently, the mixture was concentrated by rotary evaporation under reduced pressure. Crude yield: 592 mg was added slowly to come to RT after 1 h the aqueous phase was extracted with dichloromethane the organic phase was washed with saturated NaHCO3 solution dried over sodium sulfate subsequently, the mixture was concentrated by rotary evaporation under reduced pressure