(2R)-1-甲基吡咯烷-2-甲醛

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: N-[4-[(3-Chloro-4-fluoro-phenyl)amino]-7-ethoxy-quinazolin-6-yl]-2-diethoxyphosphoryl-acetamide 7b (300 mg, 0.59 mmol) was dissolved in 10 mL of tetrahydrofuran. The mixture was cooled to −78° C. in a dry ice bath. Under argon, a solution of lithium bis(trimethylsilyl)amide (1 M) in toluene (1.2 mL, 1.18 mmol) was added dropwise. After the mixture was stirred for 30 minutes, (2R)-1-methylpyrrolidine-2-carbaldehyde 5c (133 mg, 1.18 mmol) was added, and the mixture was stirred for another 1 hour, then warm up to room temperature and stirred for 12 hours. The reaction mixture was concentrated, added with 10 mL of water, extracted with dichloromethane (25 mL×3). The combined organic extracts were washed with saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with elution system A to obtain the title compound (E)-N-[4-[(3-chloro-4-fluoro-phenyl)amino]-7-ethoxy-quinazolin-6-yl]-3-[(2R)-1-methylpyrrolidin-2-yl]prop-2-enamide 9 (130 mg, yield 47.3%) as a yellow solid. the mixture was stirred for another 1 hour warm up to room temperature stirred for 12 hours The reaction mixture was concentrated added with 10 mL of water extracted with dichloromethane (25 mL×3) The combined organic extracts were washed with saturated brine (30 mL×2) dried over anhydrous sodium sulfate filtered concentrated under reduced pressure the resulting residue was purified by silica gel column chromatography with elution system

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: N-[4-[(3-Chloro-4-fluoro-phenyl)amino]-7-(2-methoxyethoxy)quinazolin-6-yl]-2-diethoxyphosphoryl-acetamide 8d (200 mg, 0.37 mmol) was dissolved in 10 mL of tetrahydrofuran. The mixture was cooled to −78° C. in a dry ice bath. Under argon, a solution of lithium bis(trimethylsilyl)amide (1 M) in toluene (740 μL, 0.74 mmol) was added dropwise. After stirring for 30 minutes, (2R)-1-methylpyrrolidine-2-carbaldehyde 5c (84 mg, 0.74 mmol) was added to the reaction solution. The reaction mixture was stirred for another 1 hour, then warmed up to room temperature and stirred for 12 hours. The reaction mixture was concentrated, added with 10 mL of water, extracted with dichloromethane (25 mL×3). The combined organic extracts were washed with saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with elution system A to obtain the title compound (E)-N-[4-[(3-chloro-4-fluoro-phenyl)amino]-7-(2-methoxyethoxy)quinazolin-6-yl]-3-[(2R)-1-methylpyrrolidin-2-yl]prop-2-enamide 8 (100 mg, yield 54.2%) as a yellow solid. The reaction mixture was stirred for another 1 hour warmed up to room temperature stirred for 12 hours The reaction mixture was concentrated added with 10 mL of water extracted with dichloromethane (25 mL×3) The combined organic extracts were washed with saturated brine (30 mL×2) dried over anhydrous sodium sulfate filtered concentrated under reduced pressure the resulting residue was purified by silica gel column chromatography with elution system

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

实验步骤: N-[4-[[3-Chloro-4-(2-pyridylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolyl]-2-diethoxyphosphoryl-acetamide 1d (250 mg, 0.40 mmol) was dissolved in 10 mL of dry tetrahydrofuran in a dry ice bath, followed by dropwise addition of a solution of lithium bis(trimethylsilyl)amide (1 M) in toluene (440 μL, 0.44 mmol). The reaction mixture was stirred for 30 minutes, added dropwise with a solution of (2R)-1-methylpyrrolidine-2-carbaldehyde 5c (90 mg, 0.80 mmol) in 5 mL of tetrahydrofuran, and stirred for 30 minutes, then warmed up to room temperature and stirred for 12 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with elution system A to obtain the title compound (E)-N-[4-[[3-chloro-4-(2-pyridylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolyl]-3-[(2R)-1-methylpyrrolidin-2-yl]prop-2-enamide 5 (46 mg, yield 19.7%) as a yellow solid. stirred for 30 minutes stirred for 12 hours The reaction mixture was concentrated under reduced pressure the resulting residue was purified by silica gel column chromatography with elution system

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

实验步骤: The title compound was prepared following the procedure described in Intermediate 138 using 1-BOC-aziridine-2-carboxylic acid.

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: N-[4-[(3-Chloro-4-fluoro-phenyl)amino]-7-ethoxy-quinazolin-6-yl]-2-diethoxyphosphoryl-acetamide 7b (300 mg, 0.59 mmol) was dissolved in 10 mL of tetrahydrofuran. The mixture was cooled to −78° C. in a dry ice bath. Under argon, a solution of lithium bis(trimethylsilyl)amide (1 M) in toluene (1.2 mL, 1.18 mmol) was added dropwise. After the mixture was stirred for 30 minutes, (2R)-1-methylpyrrolidine-2-carbaldehyde 5c (133 mg, 1.18 mmol) was added, and the mixture was stirred for another 1 hour, then warm up to room temperature and stirred for 12 hours. The reaction mixture was concentrated, added with 10 mL of water, extracted with dichloromethane (25 mL×3). The combined organic extracts were washed with saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with elution system A to obtain the title compound (E)-N-[4-[(3-chloro-4-fluoro-phenyl)amino]-7-ethoxy-quinazolin-6-yl]-3-[(2R)-1-methylpyrrodin-2-yl]prop-2-enamide 9 (130 mg, yield 47.3%) as a yellow solid. the mixture was stirred for another 1 hour warm up to room temperature stirred for 12 hours The reaction mixture was concentrated added with 10 mL of water extracted with dichloromethane (25 mL×3) The combined organic extracts were washed with saturated brine (30 mL×2) dried over anhydrous sodium sulfate filtered concentrated under reduced pressure the resulting residue was purified by silica gel column chromatography with elution system

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: N-[4-[(3-Chloro-4-fluoro-phenyl)amino]-7-(2-methoxyethoxy)quinazolin-6-yl]-2-diethoxyphosphoryl-acetamide 8d (200 mg, 0.37 mmol) was dissolved in 10 mL of tetrahydrofuran. The mixture was cooled to −78° C. in a dry ice bath. Under argon, a solution of lithium bis(trimethylsilyl)amide (1 M) in toluene (740 μL, 0.74 mmol) was added dropwise. After stirring for 30 minutes, (2R)-1-methylpyrrolidine-2-carbaldehyde 5c (84 mg, 0.74 mmol) was added to the reaction solution. The reaction mixture was stirred for another 1 hour, then warmed up to room temperature and stirred for 12 hours. The reaction mixture was concentrated, added with 10 mL of water, extracted with dichloromethane (25 mL×3). The combined organic extracts were washed with saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with elution system A to obtain the title compound (E)-N-[4-[(3-chloro-4-fluoro-phenyl)amino]-7-(2-methoxyethoxy)quinazolin-6-yl]-3-[(2R)-1-methylpyrrolidin-2-yl]prop-2-enamide 8 (100 mg, yield 54.2%) as a yellow solid. The reaction mixture was stirred for another 1 hour warmed up to room temperature stirred for 12 hours The reaction mixture was concentrated added with 10 mL of water extracted with dichloromethane (25 mL×3) The combined organic extracts were washed with saturated brine (30 mL×2) dried over anhydrous sodium sulfate filtered concentrated under reduced pressure the resulting residue was purified by silica gel column chromatography with elution system

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

实验步骤: N-[4-[[3-Chloro-4-(2-pyridylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolyl]-2-diethoxyphosphoryl-acetamide 1d (250 mg, 0.40 mmol) was dissolved in 10 mL of dry tetrahydrofuran in a dry ice bath, followed by dropwise addition of a solution of lithium bis(trimethylsilyl)amide (1 M) in toluene (440 μL, 0.44 mmol). The reaction mixture was stirred for 30 minutes, added dropwise with a solution of (2R)-1-methylpyrrolidine-2-carbaldehyde 5c (90 mg, 0.80 mmol) in 5 mL of tetrahydrofuran, and stirred for 30 minutes, then warmed up to room temperature and stirred for 12 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with elution system A to obtain the title compound (E)-N-[4-[[3-chloro-4-(2-pyridylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolyl]-3-[(2R)-1-methylpyrrolidin-2-yl]prop-2-enamide 5 (46 mg, yield 19.7%) as a yellow solid. stirred for 30 minutes stirred for 12 hours The reaction mixture was concentrated under reduced pressure the resulting residue was purified by silica gel column chromatography with elution system