3-溴-2,2-二甲基丙酸甲酯

反应条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 3-Bromo-2,2-dimethyl-propionic acid methyl ester (0.75 g) was added to a mixture of 4-bromo-1H-pyridin-2-one (0.55 g) and potassium carbonate (0.75 g) in N,N-dimethylformamide (10 mL) at room temperature. The mixture was heated to 60° C. and stirred at this temperature overnight. After stirring at 80° C. for another 8 h, the mixture was cooled to room temperature and water was added. The resultant mixture was extracted with ethyl acetate and the combined organic extracts were washed with brine and dried (MgSO4). The solvent was evaporated and the residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate 4:1) to afford the title compound; 3-(4-bromo-pyridin-2-yloxy)-2,2-dimethyl-propionic acid methyl ester (0.35 g) was also obtained from this reaction. Yield: 0.29 g (32% of theory); Mass spectrum (ESI+): m/z=288/300 (Br) [M+H]+. After stirring at 80° C. for another 8 h the mixture was cooled to room temperature The resultant mixture was extracted with ethyl acetate the combined organic extracts were washed with brine dried (MgSO4) The solvent was evaporated the residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate 4:1)

反应条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 3-Bromo-2,2-dimethyl-propionic acid methyl ester (0.75 g) was added to a mixture of 4-bromo-1H-pyridin-2-one (0.55 g) and potassium carbonate (0.75 g) in N,N-dimethylformamide (10 mL) at room temperature. The mixture was heated to 60° C. and stirred at this temperature overnight. After stirring at 80° C. for another 8 h, the mixture was cooled to room temperature and water was added. The resultant mixture was extracted with ethyl acetate and the combined organic extracts were washed with brine and dried (MgSO4). The solvent was evaporated and the residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate 4:1) to afford the title compound; 3-(4-bromo-pyridin-2-yloxy)-2,2-dimethyl-propionic acid methyl ester (0.35 g) was also obtained from this reaction. Yield: 0.29 g (32% of theory); Mass spectrum (ESI+): m/z=288/300 (Br) [M+H]+. After stirring at 80° C. for another 8 h the mixture was cooled to room temperature The resultant mixture was extracted with ethyl acetate the combined organic extracts were washed with brine dried (MgSO4) The solvent was evaporated the residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate 4:1)

反应条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 3-Bromo-2,2-dimethyl-propionic acid methyl ester (0.75 g) was added to a mixture of 4-bromo-1H-pyridin-2-one (0.55 g) and potassium carbonate (0.75 g) in N,N-dimethylformamide (10 mL) at room temperature. The mixture was heated to 60° C. and stirred at this temperature overnight. After stirring at 80° C. for another 8 h, the mixture was cooled to room temperature and water was added. The resultant mixture was extracted with ethyl acetate and the combined organic extracts were washed with brine and dried (MgSO4). The solvent was evaporated and the residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate 4:1) to afford the title compound; 3-(4-bromo-pyridin-2-yloxy)-2,2-dimethyl-propionic acid methyl ester (0.35 g) was also obtained from this reaction. Yield: 0.29 g (32% of theory); Mass spectrum (ESI+): m/z=288/300 (Br) [M+H]+. After stirring at 80° C. for another 8 h the mixture was cooled to room temperature The resultant mixture was extracted with ethyl acetate the combined organic extracts were washed with brine dried (MgSO4) The solvent was evaporated the residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate 4:1)

反应条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 3-Bromo-2,2-dimethyl-propionic acid methyl ester (0.75 g) was added to a mixture of 4-bromo-1H-pyridin-2-one (0.55 g) and potassium carbonate (0.75 g) in N,N-dimethylformamide (10 mL) at room temperature. The mixture was heated to 60° C. and stirred at this temperature overnight. After stirring at 80° C. for another 8 h, the mixture was cooled to room temperature and water was added. The resultant mixture was extracted with ethyl acetate and the combined organic extracts were washed with brine and dried (MgSO4). The solvent was evaporated and the residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate 4:1) to afford the title compound; 3-(4-bromo-pyridin-2-yloxy)-2,2-dimethyl-propionic acid methyl ester (0.35 g) was also obtained from this reaction. Yield: 0.29 g (32% of theory); Mass spectrum (ESI+): m/z=288/300 (Br) [M+H]+. After stirring at 80° C. for another 8 h the mixture was cooled to room temperature The resultant mixture was extracted with ethyl acetate the combined organic extracts were washed with brine dried (MgSO4) The solvent was evaporated the residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate 4:1)

反应条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 3-Bromo-2,2-dimethyl-propionic acid methyl ester (0.75 g) was added to a mixture of 4-bromo-1H-pyridin-2-one (0.55 g) and potassium carbonate (0.75 g) in N,N-dimethylformamide (10 mL) at room temperature. The mixture was heated to 60° C. and stirred at this temperature overnight. After stirring at 80° C. for another 8 h, the mixture was cooled to room temperature and water was added. The resultant mixture was extracted with ethyl acetate and the combined organic extracts were washed with brine and dried (MgSO4). The solvent was evaporated and the residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate 4:1) to afford the title compound; 3-(4-bromo-pyridin-2-yloxy)-2,2-dimethyl-propionic acid methyl ester (0.35 g) was also obtained from this reaction. Yield: 0.29 g (32% of theory); Mass spectrum (ESI+): m/z=288/300 (Br) [M+H]+. After stirring at 80° C. for another 8 h the mixture was cooled to room temperature The resultant mixture was extracted with ethyl acetate the combined organic extracts were washed with brine dried (MgSO4) The solvent was evaporated the residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate 4:1)

反应条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 3-Bromo-2,2-dimethyl-propionic acid methyl ester (0.75 g) was added to a mixture of 4-bromo-1H-pyridin-2-one (0.55 g) and potassium carbonate (0.75 g) in N,N-dimethylformamide (10 mL) at room temperature. The mixture was heated to 60° C. and stirred at this temperature overnight. After stirring at 80° C. for another 8 h, the mixture was cooled to room temperature and water was added. The resultant mixture was extracted with ethyl acetate and the combined organic extracts were washed with brine and dried (MgSO4). The solvent was evaporated and the residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate 4:1) to afford the title compound; 3-(4-bromo-pyridin-2-yloxy)-2,2-dimethyl-propionic acid methyl ester (0.35 g) was also obtained from this reaction. Yield: 0.29 g (32% of theory); Mass spectrum (ESI+): m/z=288/300 (Br) [M+H]+. After stirring at 80° C. for another 8 h the mixture was cooled to room temperature The resultant mixture was extracted with ethyl acetate the combined organic extracts were washed with brine dried (MgSO4) The solvent was evaporated the residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate 4:1)

反应条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 3-Bromo-2,2-dimethyl-propionic acid methyl ester (0.75 g) was added to a mixture of 4-bromo-1H-pyridin-2-one (0.55 g) and potassium carbonate (0.75 g) in N,N-dimethylformamide (10 mL) at room temperature. The mixture was heated to 60° C. and stirred at this temperature overnight. After stirring at 80° C. for another 8 h, the mixture was cooled to room temperature and water was added. The resultant mixture was extracted with ethyl acetate and the combined organic extracts were washed with brine and dried (MgSO4). The solvent was evaporated and the residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate 4:1) to afford the title compound; 3-(4-bromo-pyridin-2-yloxy)-2,2-dimethyl-propionic acid methyl ester (0.35 g) was also obtained from this reaction. Yield: 0.29 g (32% of theory); Mass spectrum (ESI+): m/z=288/300 (Br) [M+H]+. After stirring at 80° C. for another 8 h the mixture was cooled to room temperature The resultant mixture was extracted with ethyl acetate the combined organic extracts were washed with brine dried (MgSO4) The solvent was evaporated the residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate 4:1)

反应条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a suspension of (±)-2-(2,2,2-trifluoro-1-hydroxy-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)benzo[d]oxazole-5-carbonitrile (Example 128-A) (50 mg, 0.100 mmol) in DMF (0.3 ml), NaH (oil dispersion, 60%) (11.96 mg, 0.299 mmol) was added at rt under nitrogen. After stirring for 15 min., 3-bromo-2,2-dimethylpropionic acid methyl ester (0.043 ml, 0.299 mmol; CAS#30452-00-7) was added at the same temperature. The mixture was warmed up to 90° C. After stirring for 2 h, the mixture was cooled to rt and diluted with EtOAc and 1M NaHSO4aq. The organic layer was separated, dried over Na2SO4, filtered, and concentrated. To a solution of the resulting residue in THF (0.5 ml), potassium trimethylsilanolate (38.5 mg, 0.300 mmol) was added at rt under nitrogen. After stirring for 19 h, additional THF (0.5 ml) and potassium trimethylsilanolate were added. The mixture was heated at 50° C. for 1 h, and then the mixture was cooled to rt. The mixture was diluted with EtOAc, 1M HCl aq. and brine. The layers were separated and the aqueous layer extracted twice with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The crude was purified by RP-HPLC (HC-A) to give the title compound as a 0.25-TFA salt. was added at rt under nitrogen After stirring for 2 h the mixture was cooled to rt The organic layer was separated dried over Na2SO4 filtered concentrated After stirring for 19 h The mixture was heated at 50° C. for 1 h the mixture was cooled to rt The layers were separated the aqueous layer extracted twice with EtOAc The combined organic layer was washed with brine dried over Na2SO4 filtered concentrated The crude was purified by RP-HPLC (HC-A)

反应条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 3-Bromo-2,2-dimethyl-propionic acid methyl ester (0.75 g) was added to a mixture of 4-bromo-1H-pyridin-2-one (0.55 g) and potassium carbonate (0.75 g) in N,N-dimethylformamide (10 mL) at room temperature. The mixture was heated to 60° C. and stirred at this temperature overnight. After stirring at 80° C. for another 8 h, the mixture was cooled to room temperature and water was added. The resultant mixture was extracted with ethyl acetate and the combined organic extracts were washed with brine and dried (MgSO4). The solvent was evaporated and the residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate 4:1) to afford the title compound; 3-(4-bromo-pyridin-2-yloxy)-2,2-dimethyl-propionic acid methyl ester (0.35 g) was also obtained from this reaction. Yield: 0.29 g (32% of theory); Mass spectrum (ESI+): m/z=288/300 (Br) [M+H]+. After stirring at 80° C. for another 8 h the mixture was cooled to room temperature The resultant mixture was extracted with ethyl acetate the combined organic extracts were washed with brine dried (MgSO4) The solvent was evaporated the residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate 4:1)

反应条件: temp:95.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: (±)-Cis-3-(4-{4-[acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-2,2-dimethyl-propionic acid methyl ester was prepared from (±)-cis-N-(4-chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-propionamide. (±)-Cis-N-(4-chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-propionamide (400 mg, 0.92 mmol) was dissolved in DMF (25 mL) at room temperature. Potassium carbonate (1 g, 7.1 mmol) was added, followed by 3-bromo-2,2-dimethyl-propionic acid methyl ester (400 mg, 0.92 mmol), the reaction was heated to 95° C. and stirred over night. The reaction mixture was cooled to room temperature, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (95/5 dichloromethane/ethyl acetate-70/30 dichloromethane/ethyl acetate) to afford the pure ester (40 mg, 8%). The reaction mixture was cooled to room temperature filtered concentrated in vacuo The crude product was purified by silica gel chromatography (95/5 dichloromethane/ethyl acetate-70/30 dichloromethane/ethyl acetate)

反应条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 3-Bromo-2,2-dimethyl-propionic acid methyl ester (0.75 g) was added to a mixture of 4-bromo-1H-pyridin-2-one (0.55 g) and potassium carbonate (0.75 g) in N,N-dimethylformamide (10 mL) at room temperature. The mixture was heated to 60° C. and stirred at this temperature overnight. After stirring at 80° C. for another 8 h, the mixture was cooled to room temperature and water was added. The resultant mixture was extracted with ethyl acetate and the combined organic extracts were washed with brine and dried (MgSO4). The solvent was evaporated and the residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate 4:1) to afford the title compound; 3-(4-bromo-pyridin-2-yloxy)-2,2-dimethyl-propionic acid methyl ester (0.35 g) was also obtained from this reaction. Yield: 0.29 g (32% of theory); Mass spectrum (ESI+): m/z=288/300 (Br) [M+H]+. After stirring at 80° C. for another 8 h the mixture was cooled to room temperature The resultant mixture was extracted with ethyl acetate the combined organic extracts were washed with brine dried (MgSO4) The solvent was evaporated the residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate 4:1)

反应条件: temp:95.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: (±)-Cis-3-(4-{4-[acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-2,2-dimethyl-propionic acid methyl ester was prepared from (±)-cis-N-(4-chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-propionamide. (±)-Cis-N-(4-chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-propionamide (400 mg, 0.92 mmol) was dissolved in DMF (25 mL) at room temperature. Potassium carbonate (1 g, 7.1 mmol) was added, followed by 3-bromo-2,2-dimethyl-propionic acid methyl ester (400 mg, 0.92 mmol), the reaction was heated to 95° C. and stirred over night. The reaction mixture was cooled to room temperature, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (95/5 dichloromethane/ethyl acetate—70/30 dichloromethane/ethyl acetate) to afford the pure ester (40 mg, 8%). The reaction mixture was cooled to room temperature filtered concentrated in vacuo The crude product was purified by silica gel chromatography (95/5 dichloromethane/ethyl acetate—70/30 dichloromethane/ethyl acetate)