tert-butyl N-[(2S)-1-hydroxybutan-2-yl]carbamate

反応条件: temp:-60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Under an atmosphere of argon, oxalyl chloride (7.01 g, 4.75 ml, 55.3 mmol, Eq: 1.00) was combined with CH2Cl2 (100 ml) to give a colorless solution. The reaction was cooled to −60° C. Then dimethyl sulfoxide (10.8 g, 9.8 ml, 138 mmol, Eq: 2.5) diluted in CH2Cl2 (20 ml) was added dropwise at −60° C. The reaction was stirred for 10 min at −60° C. Then (S)-tert-butyl-1-hydroxybutan-2-ylcarbamate (11.62 g, 55.3 mmol, Eq: 1.00) dissolved in 20 ml CH2Cl2 was added dropwise at −70° C. The reaction was allowed to warm to −40° C. for 10 min and then cooled to −70° C. again. A solution of triethylamine (15.7 g, 21.6 ml, 155 mmol, Eq: 2.8) in 20 ml CH2Cl2 was added dropwise. The reaction mixture was allowed to warm to room temperature over 2 hours. The reaction mixture was poured into 100 ml satd. sodium dihydrogenphosphate solution and extracted with ethyl acetate (2×150 mL). The organic layer was back-extracted with brine (1×50 mL). The organic layers were dried over Na2SO4 and concentrated in vacuo. The title compound was obtained as a light yellow oil (11.12 g, quant., MS (m/e)=188.2 [M+H+]). to give a colorless solution was added dropwise at −60° C was added dropwise at −70° C to warm to −40° C. for 10 min cooled to −70° C. again to warm to room temperature over 2 hours The reaction mixture was poured into 100 ml sodium dihydrogenphosphate solution and extracted with ethyl acetate (2×150 mL) The organic layer was back-extracted with brine (1×50 mL) The organic layers were dried over Na2SO4 concentrated in vacuo

反応条件: temp:-60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Under an atmosphere of argon, oxalyl chloride (7.01 g, 4.75 ml, 55.3 mmol, Eq: 1.00) was combined with CH2Cl2 (100 ml) to give a colorless solution. The reaction was cooled to −60° C. Then dimethyl sulfoxide (10.8 g, 9.8 ml, 138 mmol, Eq: 2.5) diluted in CH2Cl2 (20 ml) was added dropwise at −60° C. The reaction was stirred for 10 min at −60° C. Then (S)-tert-butyl-1-hydroxybutan-2-ylcarbamate (11.62 g, 55.3 mmol, Eq: 1.00) dissolved in 20 ml CH2Cl2 was added dropwise at −70° C. The reaction was allowed to warm to −40° C. for 10 min and then cooled to −70° C. again. A solution of triethylamine (15.7 g, 21.6 ml, 155 mmol, Eq: 2.8) in 20 ml CH2Cl2 was added dropwise. The reaction mixture was allowed to warm to room temperature over 2 hours. The reaction mixture was poured into 100 ml satd. sodium dihydrogenphosphate solution and extracted with ethyl acetate (2×150 mL). The organic layer was back-extracted with brine (1×50 mL). The organic layers were dried over Na2SO4 and concentrated in vacuo. The title compound was obtained as a light yellow oil (11.12 g, quant., MS (m/e)=188.2 [M+H+]). to give a colorless solution was added dropwise at −60° C was added dropwise at −70° C to warm to −40° C. for 10 min cooled to −70° C. again to warm to room temperature over 2 hours The reaction mixture was poured into 100 ml sodium dihydrogenphosphate solution and extracted with ethyl acetate (2×150 mL) The organic layer was back-extracted with brine (1×50 mL) The organic layers were 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: 2-Chloro-4-(1H-pyrazol-3-yl)benzonitrile (1.06 g, 4.40 mmol), N-Boc-(S)-(−)-2-amino-1-butanol (1.0 g, 5.28 mmol) and triphenylphosphine (1.73 g, 6.61 mmol) were dissolved in 15 ml of dry THF under nitrogen atmosphere. DIAD (1.73 ml; 8.81 mmol) was added slowly by syringe to cooled (0° C.) reaction mixture. After being stirred overnight at RT, the reaction mixture was evaporated to dryness. The evaporation residue was dissolved in 20 ml of 10% HCl (g)/EtOH-solution and stirred at RT overnight to induce Boc-deprotection. Solvents were evaporated and the evaporation residue was taken up in water and brine. Thus obtained solution was washed twice with DCM, made alkaline (pH˜12) by adding 2 M NaOH-solution, and extracted twice with DCM. The latter organic extracts were combined, dried over Na2SO4, filtered and evaporated to give 568 mg (47%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ0.87-0.94 (m, 3H), 1.10-1.45 (m, 2H), 2.97-3.05 (m. 1H), 4.01 (dd, 1H), 4.13 (dd, 1H), 4.68-4.86 (m, 1H), 6.97 (d, 1H), 7.86 (d, 1H), 7.95 (dd, 1H), 7.97 (dd, 1H), 8.10-8.12 (m, 1H). MS [M+1]: m/z [274.8+1]. to cooled (0° C.) reaction mixture the reaction mixture was evaporated to dryness The evaporation residue was dissolved in 20 ml of 10% HCl (g)/EtOH-solution stirred at RT overnight Solvents were evaporated Thus obtained solution was washed twice with DCM by adding 2 M NaOH-solution extracted twice with DCM dried over Na2SO4 filtered evaporated

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

実験手順: 2-Chloro-4-(1H-pyrazol-3-yl)benzonitrile (1.06 g, 4.40 mmol), N-Boc-(S)-(−)-2-amino-1-butanol (1.0 g, 5.28 mmol) and triphenylphosphine (1.73 g, 6.61 mmol) were dissolved in 15 ml of dry THF under nitrogen atmosphere. DIAD (1.73 ml; 8.81 mmol) was added slowly by syringe to cooled (0° C.) reaction mixture. After being stirred overnight at RT, the reaction mixture was evaporated to dryness. The evaporation residue was dissolved in 20 ml of 10% HCl (g)/EtOH-solution and stirred at RT overnight to induce Boc-deprotection. Solvents were evaporated and the evaporation residue was taken up in water and brine. Thus obtained solution was washed twice with DCM, made alkaline (pH˜12) by adding 2 M NaOH-solution, and extracted twice with DCM. The latter organic extracts were combined, dried over Na2SO4, filtered and evaporated to give 568 mg (47%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ0.87-0.94 (m, 3H), 1.10-1.45 (m, 2H), 2.97-3.05 (m. 1H), 4.01 (dd, 1H), 4.13 (dd, 1H), 4.68-4.86 (m, 1H), 6.97 (d, 1H), 7.86 (d, 1H), 7.95 (dd, 1H), 7.97 (dd, 1H), 8.10-8.12 (m, 1H). MS [M+1]: m/z [274.8+1]. to cooled (0° C.) reaction mixture the reaction mixture was evaporated to dryness The evaporation residue was dissolved in 20 ml of 10% HCl (g)/EtOH-solution stirred at RT overnight Solvents were evaporated Thus obtained solution was washed twice with DCM by adding 2 M NaOH-solution extracted twice with DCM dried over Na2SO4 filtered evaporated

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

実験手順: To an ice cold solution of (S)-tert-butyl(1-hydroxybutan-2-yl)carbamate (9.5 g, 50 mmol) and triethylamine (10.5 mL, 75 mmol) in ether (200 mL) was added methanesulfonyl chloride (4.0 mL, 50 mmol). After 1 h, water was added, and the resulting mixture was extracted with DCM, dried (Na2SO4), filtered, and concentrated to give an oil (13.4 g, 100%) which was used directly without further purification. the resulting mixture was extracted with DCM dried (Na2SO4) filtered concentrated

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

実験手順: To an ice cold solution of (S)-tert-butyl(1-hydroxybutan-2-yl)carbamate (9.5 g, 50 mmol) and triethylamine (10.5 mL, 75 mmol) in ether (200 mL) was added methanesulfonyl chloride (4.0 mL, 50 mmol). After 1 h, water was added, and the resulting mixture was extracted with DCM, dried (Na2SO4), filtered, and concentrated to give an oil (13.4 g, 100%) which was used directly without further purification. the resulting mixture was extracted with DCM dried (Na2SO4) filtered concentrated

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

実験手順: To a solution of (S)-tert-butyl 1-hydroxybutan-2-ylcarbamate (1 eq, from the previous step) in THF (0.23 M) at 0° C. was added portionwise 60% wt NaH (2 eq). The reaction was stirred at 0° C. for 30 minutes, and then a solution of tert-butyl 2-bromoacetate (1 eq) in THF (0.12 M) was added dropwise. The reaction was warmed to room temperature and stirred for 1 hour. The reaction was quenched slowly with saturated aqueous NH4C1 solution and diluted with ether. The organic layer was washed with water, brine, dried over anhydrous MgSO4, and concentrated en vaccuo. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using a gradient of 0-40% ethyl acetate in hexanes to give the product as an oil. The reaction was warmed to room temperature stirred for 1 hour The reaction was quenched slowly with saturated aqueous NH4C1 solution diluted with ether The organic layer was washed with water, brine dried over anhydrous MgSO4 concentrated en vaccuo The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO)

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

実験手順: To a solution of (S)-2-aminobutan-1-ol (1 eq) in THF (0.26 M) at 0° C. was added di-tert-butyl carbonate (1 eq) and triethylamine (1 eq). The reaction was stirred at room temperature for 3 hours. The reaction mixture was concentrated en vaccuo; and the residue was diluted in ethyl acetate. The organic solution was washed with water (2×), brine, dried over anhydrous MgSO4, and concentrated en vaccuo. The material was carried onto the next step without further purification. The reaction mixture was concentrated en vaccuo and the residue was diluted in ethyl acetate The organic solution was washed with water (2×), brine dried over anhydrous MgSO4 concentrated en vaccuo The material was carried onto the next step without further purification

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

実験手順: To a solution of (S)-tert-butyl 1-hydroxybutan-2-ylcarbamate (1 eq, from the previous step) in THF (0.23 M) at 0° C. was added portionwise 60% wt NaH (2 eq). The reaction was stirred at 0° C. for 30 minutes, and then a solution of tert-butyl 2-bromoacetate (1 eq) in THF (0.12 M) was added dropwise. The reaction was warmed to room temperature and stirred for 1 hour. The reaction was quenched slowly with saturated aqueous NH4Cl solution and diluted with ether. The organic layer was washed with water, brine, dried over anhydrous MgSO4, and concentrated en vaccuo. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using a gradient of 0-40% ethyl acetate in hexanes to give the product as an oil. The reaction was warmed to room temperature stirred for 1 hour The reaction was quenched slowly with saturated aqueous NH4Cl solution diluted with ether The organic layer was washed with water, brine dried over anhydrous MgSO4 concentrated en vaccuo The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO)

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

実験手順: To a solution of (S)-tert-butyl 1-hydroxybutan-2-ylcarbamate (1 eq, from the previous step) in THF (0.23 M) at 0° C. was added portionwise 60% wt NaH (2 eq). The reaction was stirred at 0° C. for 30 minutes, and then a solution of tert-butyl 2-bromoacetate (1 eq) in THF (0.12 M) was added dropwise. The reaction was warmed to room temperature and stirred for 1 hour. The reaction was quenched slowly with saturated aqueous NH4Cl solution and diluted with ether. The organic layer was washed with water, brine, dried over anhydrous MgSO4, and concentrated en vaccuo. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using a gradient of 0-40% ethyl acetate in hexanes to give the product as an oil. The reaction was warmed to room temperature stirred for 1 hour The reaction was quenched slowly with saturated aqueous NH4Cl solution diluted with ether The organic layer was washed with water, brine dried over anhydrous MgSO4 concentrated en vaccuo The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO)

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

実験手順: To a solution of (S)-2-aminobutan-1-ol (1 eq) in THF (0.26 M) at 0° C. was added di-tert-butyl carbonate (1 eq) and triethylamine (1 eq). The reaction was stirred at room temperature for 3 hours. The reaction mixture was concentrated en vaccuo; and the residue was diluted in ethyl acetate. The organic solution was washed with water (2×), brine, dried over anhydrous MgSO4, and concentrated en vaccuo. The material was carried onto the next step without further purification. The reaction mixture was concentrated en vaccuo and the residue was diluted in ethyl acetate The organic solution was washed with water (2×), brine dried over anhydrous MgSO4 concentrated en vaccuo The material was carried onto the next step without further purification

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

実験手順: To a solution of (S)-2-aminobutan-1-ol (1 eq) in THF (0.26 M) at 0° C. was added di-tert-butyl carbonate (1 eq) and triethylamine (1 eq). The reaction was stirred at room temperature for 3 hours. The reaction mixture was concentrated en vaccuo; and the residue was diluted in ethyl acetate. The organic solution was washed with water (2×), brine, dried over anhydrous MgSO4, and concentrated en vaccuo. The material was carried onto the next step without further purification. The reaction mixture was concentrated en vaccuo and the residue was diluted in ethyl acetate The organic solution was washed with water (2×), brine dried over anhydrous MgSO4 concentrated en vaccuo The material was carried onto the next step without further purification