1-(3,4-dichlorophenyl)-2-(propan-2-ylamino)ethanol

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

実験手順: To a 0° C. solution of 0.048 g (0.16 mmol) triphosgene in 1 mL CH2Cl2 was slowly added a solution of 0.1 g 0.48 mmol) N-(4-amino-benzyl)-2,2-dimethyl-propionamide and 0.07 mL (0.5 mmol) triethylamine in 8 mL CH2Cl2 over 20 min. The reaction mixture was allowed to warm to room temperature for 15 min., then recooled to 0° C. whereupon a solution of 0.2 g (0.9 mmol) 2-methylamino-1-(3,4-dichlorophenyl)ethanol (prepared as in scheme 1, step 2) and 0.1 mL (0.5 mmol) triethylamine in 2 mL CH2Cl2 was added. The reaction mixture was allowed to warn to room temperature and stir 1 hour, then diluted with 100 mL EtOAc, washed with 100 mL each of, saturated aqueous NaHCO3, 10% aqueous KHSO4, and brine, then dried over Na2SO4, filtered and concentrated. Purification by flash chromatography (2.5×12 cm silica gel, linear gradient 3-5% MeOH/CH2Cl2) afforded 0.14 g N-(4-{3-[2-(3,4-Dichloro-phenyl)-2-hydroxy-ethyl]-3-methyl-ureido}-benzyl)-2,2-dimethyl-propionamide. 1H NMR(300 mHz, CD3OD) δ 7.61 (d, 1H, J=1.83 Hz); 7.49 (d, 1H, J=8.24 Hz); 7.35 (dd, 1H, J=1.83 and 8.24 Hz); 7.26 (d, 2H, J=8.54 Hz); 7.17 (d, 2H, J=8.55 Hz); 4.93 (m, 1H); 4,31 (s, 2H); 3.54 (m, 2H); 2.96 (s, 3H); 1.20 (s, 9H). was added to warn to room temperature washed with 100 mL each of, saturated aqueous NaHCO3, 10% aqueous KHSO4, and brine dried over Na2SO4 filtered concentrated Purification by flash chromatography (2.5×12 cm silica gel, linear gradient 3-5% MeOH/CH2Cl2)

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

実験手順: To a solution of 0.89 g (3 mmol) triphosgene in 10 ml CH2Cl2 was added a solution of 2.0 g (8 mmol) 4-aminobenzylamine, tertbutylcarbamate and 1.69 ml (9.7 mmol) diisopropylethylamine in 25 ml CH2Cl2 dropwise over 1 hour. After the addition was complete, a solution of 1.79 g (8 mmol) 2-isopropylamino-1-(3,4-dichlorophenyl)-ethanol and 1.69 ml (9.7 mmol) diisopropylethylamine in 25 ml CH2Cl2 was added over 5 min. The reaction mixture was stirred for 10 min. diluted with 200 ml EtOAc, washed with 200 ml each of saturated aqueous NaHCO3, water, and brine, then dried over Na2SO4 , filtered and concentrated. Purification by flash chromatography (50% EtOAc/hexanes) provided 4 g (4-{3-[2-(3,4-Dichloro-phenyl)-2-hydroxy-ethyl]-3-isopropyl-ureido}-benzyl)-carbamic acid tert-butyl ester. 1H NMR (300 mHz, CDCl3) 8.85 (br s, 1H); 7.45 (m, 2H); 7.3-7.0 (m, 5H); 5.82 (s, 1H); 5.12 (br s, 1H); 4.7 (d, 1H, J=8 Hz); 4.4-4.15 (m, 3H); 3.42 (dd, 1H, J=16 and 8 Hz); 3.1 (d, 1H, J=16 Hz); 1.4 (s, 9H); 1.9 (d, 3H, J=7 Hz); 1.07 (d, 3H, J=7 Hz). After the addition washed with 200 ml each of saturated aqueous NaHCO3, water, and brine dried over Na2SO4 filtered concentrated Purification by flash chromatography (50% EtOAc/hexanes)

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

実験手順: A mixture of 3.9 g (14 mmol) 2-bromo-1-(3,4-dichlorophenyl)ethanol and 10 ml isopropylamine was sealed and heated to 80° C. for 16 h, then cooled to room temperature, diluted with 500 mL EtOAc, washed with 400 mL saturated aqueous NaHCO3, and 500 mL brine, then dried over Na2SO4, filtered and concentrated. Purification by flash chromatography (5×8 cm silica gel, elute with 250 mL 3%MeOH/CH2Cl2, 100 mL 50% EtOH/CH2Cl2, then 200 mL EtOH) afforded 2.7 g 2-isopropylamino-1-(3,4-dichlorophenyl)ethanol. 1H NMR(400 mHz, CDCl3) 7.48 (d, 1H, J=1.92 Hz); 7.40 (d, 1H, J=8.22 Hz); 7.20 (dd, 1H, J=8.23and 1.92 Hz); 4.59 (dd, 1H, J=8.96 and 3.75 Hz); 2.94 (dd, 1H, J=12.2 and 3.66 Hz); 2.83 (sept, 1H, J=6.31 Hz); 2.57 (dd, 1H, J=12.3 and 8.87 Hz); 1.09 (d, 3H, J=6.31 Hz); 1.08 (d, 3H, J=6.22 Hz). was sealed cooled to room temperature washed with 400 mL saturated aqueous NaHCO3, and 500 mL brine dried over Na2SO4 filtered concentrated Purification by flash chromatography (5×8 cm silica gel elute with 250 mL 3%MeOH/CH2Cl2, 100 mL 50% EtOH/CH2Cl2

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

実験手順: To a 0° C. solution of 0.048 g (0.16 mmol) triphosgene in 1 mL CH2Cl2 was slowly added a solution of 0.1 g 0.48 mmol) N-(4-amino-benzyl)-2,2-dimethyl-propionamide and 0.07 mL (0.5 mmol) triethylamine in 8 mL CH2Cl2 over 20 min. The reaction mixture was allowed to warm to room temperature for 15 min., then recooled to 0° C. whereupon a solution of 0.2 g (0.9 mmol) 2-methylamino-1-(3,4-dichlorophenyl)ethanol (prepared as in scheme 1, step 2) and 0.1 mL (0.5 mmol) triethylamine in 2 mL CH2Cl2 was added. The reaction mixture was allowed to warn to room temperature and stir 1 hour, then diluted with 100 mL EtOAc, washed with 100 mL each of, saturated aqueous NaHCO3, 10% aqueous KHSO4, and brine, then dried over Na2SO4, filtered and concentrated. Purification by flash chromatography (2.5×12 cm silica gel, linear gradient 3-5% MeOH/CH2Cl2) afforded 0.14 g N-(4-{3-[2-(3,4-Dichloro-phenyl)-2-hydroxy-ethyl]-3-methyl-ureido}-benzyl)-2,2-dimethyl-propionamide. 1H NMR(300 mHz, CD3OD) δ 7.61 (d, 1H, J=1.83 Hz); 7.49 (d, 1H, J=8.24 Hz); 7.35 (dd, 1H, J=1.83 and 8.24 Hz); 7.26 (d, 2H, J=8.54 Hz); 7.17 (d, 2H, J=8.55 Hz); 4.93 (m, 1H); 4,31 (s, 2H); 3.54 (m, 2H); 2.96 (s, 3H); 1.20 (s, 9H). was added to warn to room temperature washed with 100 mL each of, saturated aqueous NaHCO3, 10% aqueous KHSO4, and brine dried over Na2SO4 filtered concentrated Purification by flash chromatography (2.5×12 cm silica gel, linear gradient 3-5% MeOH/CH2Cl2)

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

実験手順: To a solution of 0.89 g (3 mmol) triphosgene in 10 ml CH2Cl2 was added a solution of 2.0 g (8 mmol) 4-aminobenzylamine, tertbutylcarbamate and 1.69 ml (9.7 mmol) diisopropylethylamine in 25 ml CH2Cl2 dropwise over 1 hour. After the addition was complete, a solution of 1.79 g (8 mmol) 2-isopropylamino-1-(3,4-dichlorophenyl)-ethanol and 1.69 ml (9.7 mmol) diisopropylethylamine in 25 ml CH2Cl2 was added over 5 min. The reaction mixture was stirred for 10 min. diluted with 200 ml EtOAc, washed with 200 ml each of saturated aqueous NaHCO3, water, and brine, then dried over Na2SO4 , filtered and concentrated. Purification by flash chromatography (50% EtOAc/hexanes) provided 4 g (4-{3-[2-(3,4-Dichloro-phenyl)-2-hydroxy-ethyl]-3-isopropyl-ureido}-benzyl)-carbamic acid tert-butyl ester. 1H NMR (300 mHz, CDCl3) 8.85 (br s, 1H); 7.45 (m, 2H); 7.3-7.0 (m, 5H); 5.82 (s, 1H); 5.12 (br s, 1H); 4.7 (d, 1H, J=8 Hz); 4.4-4.15 (m, 3H); 3.42 (dd, 1H, J=16 and 8 Hz); 3.1 (d, 1H, J=16 Hz); 1.4 (s, 9H); 1.9 (d, 3H, J=7 Hz); 1.07 (d, 3H, J=7 Hz). After the addition washed with 200 ml each of saturated aqueous NaHCO3, water, and brine dried over Na2SO4 filtered concentrated Purification by flash chromatography (50% EtOAc/hexanes)

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

実験手順: A mixture of 3.9 g (14 mmol) 2-bromo-1-(3,4-dichlorophenyl)ethanol and 10 ml isopropylamine was sealed and heated to 80° C. for 16 h, then cooled to room temperature, diluted with 500 mL EtOAc, washed with 400 mL saturated aqueous NaHCO3, and 500 mL brine, then dried over Na2SO4, filtered and concentrated. Purification by flash chromatography (5×8 cm silica gel, elute with 250 mL 3%MeOH/CH2Cl2, 100 mL 50% EtOH/CH2Cl2, then 200 mL EtOH) afforded 2.7 g 2-isopropylamino-1-(3,4-dichlorophenyl)ethanol. 1H NMR(400 mHz, CDCl3) 7.48 (d, 1H, J=1.92 Hz); 7.40 (d, 1H, J=8.22 Hz); 7.20 (dd, 1H, J=8.23and 1.92 Hz); 4.59 (dd, 1H, J=8.96 and 3.75 Hz); 2.94 (dd, 1H, J=12.2 and 3.66 Hz); 2.83 (sept, 1H, J=6.31 Hz); 2.57 (dd, 1H, J=12.3 and 8.87 Hz); 1.09 (d, 3H, J=6.31 Hz); 1.08 (d, 3H, J=6.22 Hz). was sealed cooled to room temperature washed with 400 mL saturated aqueous NaHCO3, and 500 mL brine dried over Na2SO4 filtered concentrated Purification by flash chromatography (5×8 cm silica gel elute with 250 mL 3%MeOH/CH2Cl2, 100 mL 50% EtOH/CH2Cl2