(5-氨基-2-氟苯基)-氨基甲酸叔丁酯

反应条件: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a mixture of tert-butyl (2-fluoro-5-aminophenyl)carbamate (2.02 g, 8.93 mmol), K2CO3 (2.47 g, 17.86 mmoll) and NaI (4.02 g, 26.79 mmol) in DMF (60 mL) was added 2,2′-dichlorodiethyl ether (1.28 g, 8.93 mmol) slowly at 150° C. under N2. The reaction was heated at 150° C. overnight, then cooled to rt, poured into water (200 mL) and extracted with CH2Cl2 (200 mL×2). The combined organic phases were washed with water (200 mL×2) and brine (200 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=4:1) to give the title compound as a yellow solid (0.93 g, 35%). cooled to rt extracted with CH2Cl2 (200 mL×2) The combined organic phases were washed with water (200 mL×2) and brine (200 mL) dried over anhydrous Na2SO4 concentrated in vacuo The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=4:1)

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

实验步骤: To a solution of tert-butyl (2-fluoro-5-nitrophenyl)carbamate (3.54 g, 13.8 mmol) in MeOH (100 mL) was added catalyst 10% Pd/C (0.15 g). The reaction was stirred at rt under H2 overnight, and filtered. The filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=4:1) to give the title compound as a yellowish solid (2.02 g, 65%). filtered The filtrate was concentrated in vacuo The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=4:1)

反应条件: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a mixture of tert-butyl (2-fluoro-5-aminophenyl)carbamate (2.02 g, 8.93 mmol), K2CO3 (2.47 g, 17.86 mmoll) and NaI (4.02 g, 26.79 mmol) in DMF (60 mL) was added 2,2′-dichlorodiethyl ether (1.28 g, 8.93 mmol) slowly at 150° C. under N2. The reaction was heated at 150° C. overnight, then cooled to rt, poured into water (200 mL) and extracted with CH2Cl2 (200 mL×2). The combined organic phases were washed with water (200 mL×2) and brine (200 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=4:1) to give the title compound as a yellow solid (0.93 g, 35%). cooled to rt extracted with CH2Cl2 (200 mL×2) The combined organic phases were washed with water (200 mL×2) and brine (200 mL) dried over anhydrous Na2SO4 concentrated in vacuo The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=4:1)

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

实验步骤: To a solution of tert-butyl (2-fluoro-5-nitrophenyl)carbamate (3.54 g, 13.8 mmol) in MeOH (100 mL) was added catalyst 10% Pd/C (0.15 g). The reaction was stirred at rt under H2 overnight, and filtered. The filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=4:1) to give the title compound as a yellowish solid (2.02 g, 65%). filtered The filtrate was concentrated in vacuo The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=4:1)

反应条件: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a mixture of tert-butyl (2-fluoro-5-aminophenyl)carbamate (2.02 g, 8.93 mmol), K2CO3 (2.47 g, 17.86 mmoll) and NaI (4.02 g, 26.79 mmol) in DMF (60 mL) was added 2,2′-dichlorodiethyl ether (1.28 g, 8.93 mmol) slowly at 150° C. under N2. The reaction was heated at 150° C. overnight, then cooled to rt, poured into water (200 mL) and extracted with CH2Cl2 (200 mL×2). The combined organic phases were washed with water (200 mL×2) and brine (200 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=4:1) to give the title compound as a yellow solid (0.93 g, 35%). cooled to rt extracted with CH2Cl2 (200 mL×2) The combined organic phases were washed with water (200 mL×2) and brine (200 mL) dried over anhydrous Na2SO4 concentrated in vacuo The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=4:1)

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

实验步骤: To a solution of tert-butyl (2-fluoro-5-nitrophenyl)carbamate (3.54 g, 13.8 mmol) in MeOH (100 mL) was added catalyst 10% Pd/C (0.15 g). The reaction was stirred at rt under H2 overnight, and filtered. The filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=4:1) to give the title compound as a yellowish solid (2.02 g, 65%). filtered The filtrate was concentrated in vacuo The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=4:1)

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

实验步骤: To a solution of tert-butyl(5-amino-2-fluorophenyl)carbamate (795 mg, 3.51 mmol) produced in Example D17(i) in N,N-dimethylformamide (15 mL) was added 1-chloropyrrolidine-2,5-dione (493 mg, 3.69 mmol), and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (50 mL), and the mixture was extracted with ethyl acetate (50 mL, 15 mL). The combined organic layer was washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0→90/10), and the fractions containing the object product were concentrated under reduced pressure to give the title compound (727 mg, 79%) as a yellow solid. the mixture was extracted with ethyl acetate (50 mL, 15 mL) The combined organic layer was washed with saturated brine (10 mL) dried over anhydrous sodium sulfate The insoluble material was filtered off the filtrate was concentrated under reduced pressure The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0→90/10) the fractions containing the object product were concentrated under reduced pressure

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

实验步骤: To a solution of tert-butyl(5-amino-2-fluorophenyl)carbamate (10.0 g, 44.2 mmol) in tetrahydrofuran (60 mL) was added a mixture of formic acid (8.34 mL, 221 mmol) and acetic anhydride (5.01 mL, 53.0 mmol), and the mixture was stirred at room temperature for 16 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (100 mL), and the mixture was extracted with ethyl acetate (100 mL, 30 mL). The combined organic layer was washed with saturated brine (10 mL), filtered through a silica gel pad, and the filtrate was concentrated under reduced pressure to give tert-butyl [2-fluoro-5-(formylamino)phenyl]carbamate as a brown oil. The obtained compound was used for the next reaction without further purification. the mixture was extracted with ethyl acetate (100 mL, 30 mL) The combined organic layer was washed with saturated brine (10 mL) filtered through a silica gel pad the filtrate was concentrated under reduced pressure

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

实验步骤: To a solution of the above-mentioned crude product of a mixture of tert-butyl(2-fluoro-5-nitrophenyl)carbamate and di-tert-butyl(2-fluoro-5-nitrophenyl)imidodicarbonate in ethanol (600 mL)/tetrahydrofuran (60 mL) was added 10% palladium-carbon (12.0 g), and the mixture was stirred at room temperature under a hydrogen atmosphere (1 atm) for 24 hr. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. To a solution of the obtained residue in methanol (200 mL)/tetrahydrofuran (50 mL) was added potassium carbonate (25.4 g, 184 mmol), and the mixture was stirred at 60° C. for 4 hr. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. To the obtained residue was added water (200 mL), and the mixture was extracted with ethyl acetate (300 mL, 100 mL). The combined organic layer was washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate and hexane to give the title compound (26.4 g, 63%) as pale-brown crystals. The insoluble material was filtered off the filtrate was concentrated under reduced pressure the mixture was stirred at 60° C. for 4 hr The insoluble material was filtered off the filtrate was concentrated under reduced pressure To the obtained residue was added water (200 mL) the mixture was extracted with ethyl acetate (300 mL, 100 mL) The combined organic layer was washed with saturated brine (100 mL) dried over anhydrous sodium sulfate The insoluble material was filtered off the filtrate was concentrated under reduced pressure The obtained residue was recrystallized from ethyl acetate and hexane