2-(4-fluorophenyl)acetamide

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

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

実験手順: To a solution/suspension of 4-fluorophenylacetamide (77 mg, 0.50 mmol, see generally, J. Med. Chem. 2003, 46, 4333–4341, the disclosure of which is herein incorporated by referene) in dichloroethane (2 mL) was added oxalyl chloride (0.175 mL, 2.00 mmol). The reaction was heated at 80° C. for 24 h and then 70° C. for two days. By this time, most of the solids had dissolved and the reaction was yellow. LC/MS analysis found a peak with a molecular weight of 211 corresponding to methyl 2-(4-fluorophenyl)acetylcarbamate, resulting from quenching of the isocyanate with methanol. The reaction was concentrated in vacuo to give a yellow slurry. The slurry was redissolved in dichloroethane (2 mL) and again concentrated in vacuo. The resulting residue was redissolved again in dichloroethane (2 mL) to give a 0.25 M solution of 2-(4-fluorophenyl)acetyl isocyanate in dichloroethane, which was used directly in subsequent reactions. By this time, most of the solids had dissolved resulting from quenching of the isocyanate with methanol The reaction was concentrated in vacuo to give a yellow slurry again concentrated in vacuo The resulting residue was redissolved again in dichloroethane (2 mL)

反応条件: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-(4-Fluorophenyl)acetamide (125 mg) was dissolved in 1,2-dichloroethane (9 ml) under a nitrogen atmosphere, and then oxalyl chloride (0.10 ml) was added thereto, followed by stirring at 110° C. overnight. The reaction mixture was concentrated under a reduced pressure to give a residue, which was then dissolved in N,N-dimethylformamide (1 ml) under a nitrogen atmosphere. A solution of 3-[6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl]-1,1-dimethylurea (90 mg) in N,N-dimethylformamide (2 ml) was then added thereto, followed by stirring for 30 min. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate, water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:3). Fractions containing the target compound were concentrated to give a residue, to which diethyl ether (2 ml)-hexane (1 ml) was added to suspend. The solid was filtered off and dried under aeration to provide the titled compound (72.4 mg, 49.8%) as a pale yellow solid. The reaction mixture was concentrated under a reduced pressure to give a residue, which by stirring for 30 min The reaction mixture was partitioned between ethyl acetate and water The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate, water and brine in this order dried over anhydrous sodium sulfate The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:3) Fractions containing the target compound were concentrated to give a residue The solid was filtered off dried under aeration

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

実験手順: 4-Fluorophenylacetic acid (1 g, 6.49 mmol) was dissolved in acetonitrile (40 ml) and cooled to 0° C. in an ice bath. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.492 g, 7.79 mmol) was added, followed by 1-hydroxybenzotriazole (1.19 g, 7.79 mmol). The mixture was stirred at 0° C. for 2.5 hours, and then concentrated ammonium hydroxide (0.865 ml, 13.0 mmol) was added slowly. The mixture then stirred at RT for an additional 2 hours. After this time the solids were filtered off, and the filtrate was diluted with ethyl acetate (50 mL). The solution was washed with saturated aqueous NaHCO3 (2×50 mL) and brine (50 mL), dried (MgSO4) and concentrated in vacuo to yield 2-(4-fluorophenyl)acetamide (0.87 g, 88% yield) as a white solid which was used as is in the next reaction. 1H NMR (400 MHz, DMSO-d6): δ 7.45 (broad s, 1H), 7.26 (m, 2H), 7.09 (m, 2H), 6.87 (broad s, 1H), 3.34 (s, H). The mixture then stirred at RT for an additional 2 hours After this time the solids were filtered off the filtrate was diluted with ethyl acetate (50 mL) The solution was washed with saturated aqueous NaHCO3 (2×50 mL) and brine (50 mL) dried (MgSO4) concentrated in vacuo

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

実験手順: 4-Fluorophenylacetic acid (1 g, 6.49 mmol) was dissolved in acetonitrile (40 ml) and cooled to 0° C. in an ice bath. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.492 g, 7.79 mmol) was added, followed by 1-hydroxybenzotriazole (1.19 g, 7.79 mmol). The mixture was stirred at 0° C. for 2.5 hours, and then concentrated ammonium hydroxide (0.865 ml, 13.0 mmol) was added slowly. The mixture then stirred at RT for an additional 2 hours. After this time the solids were filtered off, and the filtrate was diluted with ethyl acetate (50 mL). The solution was washed with saturated aqueous NaHCO3 (2×50 mL) and brine (50 mL), dried (MgSO4) and concentrated in vacuo to yield 2-(4-fluorophenyl)acetamide (0.87 g, 88% yield) as a white solid which was used as is in the next reaction. 1H NMR (400 MHz, DMSO-d6): δ 7.45 (broad s, 1H), 7.26 (m, 2H), 7.09 (m, 2H), 6.87 (broad s, 1H), 3.34 (s, H). The mixture then stirred at RT for an additional 2 hours After this time the solids were filtered off the filtrate was diluted with ethyl acetate (50 mL) The solution was washed with saturated aqueous NaHCO3 (2×50 mL) and brine (50 mL) dried (MgSO4) concentrated in vacuo

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

実験手順: To a solution/suspension of 4-fluorophenylacetamide (77 mg, 0.50 mmol, see generally, J. Med. Chem. 2003, 46, 4333–4341, the disclosure of which is herein incorporated by referene) in dichloroethane (2 mL) was added oxalyl chloride (0.175 mL, 2.00 mmol). The reaction was heated at 80° C. for 24 h and then 70° C. for two days. By this time, most of the solids had dissolved and the reaction was yellow. LC/MS analysis found a peak with a molecular weight of 211 corresponding to methyl 2-(4-fluorophenyl)acetylcarbamate, resulting from quenching of the isocyanate with methanol. The reaction was concentrated in vacuo to give a yellow slurry. The slurry was redissolved in dichloroethane (2 mL) and again concentrated in vacuo. The resulting residue was redissolved again in dichloroethane (2 mL) to give a 0.25 M solution of 2-(4-fluorophenyl)acetyl isocyanate in dichloroethane, which was used directly in subsequent reactions. By this time, most of the solids had dissolved resulting from quenching of the isocyanate with methanol The reaction was concentrated in vacuo to give a yellow slurry again concentrated in vacuo The resulting residue was redissolved again in dichloroethane (2 mL)

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

実験手順: To a solution/suspension of 4-fluorophenylacetamide (77 mg, 0.50 mmol, see generally, J. Med. Chem. 2003, 46, 4333–4341, the disclosure of which is herein incorporated by referene) in dichloroethane (2 mL) was added oxalyl chloride (0.175 mL, 2.00 mmol). The reaction was heated at 80° C. for 24 h and then 70° C. for two days. By this time, most of the solids had dissolved and the reaction was yellow. LC/MS analysis found a peak with a molecular weight of 211 corresponding to methyl 2-(4-fluorophenyl)acetylcarbamate, resulting from quenching of the isocyanate with methanol. The reaction was concentrated in vacuo to give a yellow slurry. The slurry was redissolved in dichloroethane (2 mL) and again concentrated in vacuo. The resulting residue was redissolved again in dichloroethane (2 mL) to give a 0.25 M solution of 2-(4-fluorophenyl)acetyl isocyanate in dichloroethane, which was used directly in subsequent reactions. By this time, most of the solids had dissolved resulting from quenching of the isocyanate with methanol The reaction was concentrated in vacuo to give a yellow slurry again concentrated in vacuo The resulting residue was redissolved again in dichloroethane (2 mL)

反応条件: temp:0.00; pressure:0.00; stir:

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

実験手順: 4-Fluorophenylacetic acid (1 g, 6.49 mmol) was dissolved in acetonitrile (40 ml) and cooled to 0° C. in an ice bath. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.492 g, 7.79 mmol) was added, followed by 1-hydroxybenzotriazole (1.19 g, 7.79 mmol). The mixture was stirred at 0° C. for 2.5 hours, and then concentrated ammonium hydroxide (0.865 ml, 13.0 mmol) was added slowly. The mixture then stirred at RT for an additional 2 hours. After this time the solids were filtered off, and the filtrate was diluted with ethyl acetate (50 mL). The solution was washed with saturated aqueous NaHCO3 (2×50 mL) and brine (50 mL), dried (MgSO4) and concentrated in vacuo to yield 2-(4-fluorophenyl)acetamide (0.87 g, 88% yield) as a white solid which was used as is in the next reaction. 1H NMR (400 MHz, DMSO-d6): δ 7.45 (broad s, 1H), 7.26 (m, 2H), 7.09 (m, 2H), 6.87 (broad s, 1H), 3.34 (s, H). The mixture then stirred at RT for an additional 2 hours After this time the solids were filtered off the filtrate was diluted with ethyl acetate (50 mL) The solution was washed with saturated aqueous NaHCO3 (2×50 mL) and brine (50 mL) dried (MgSO4) concentrated in vacuo

反応条件: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-(4-Fluorophenyl)acetamide (125 mg) was dissolved in 1,2-dichloroethane (9 ml) under a nitrogen atmosphere, and then oxalyl chloride (0.10 ml) was added thereto, followed by stirring at 110° C. overnight. The reaction mixture was concentrated under a reduced pressure to give a residue, which was then dissolved in N,N-dimethylformamide (1 ml) under a nitrogen atmosphere. A solution of 3-[6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl]-1,1-dimethylurea (90 mg) in N,N-dimethylformamide (2 ml) was then added thereto, followed by stirring for 30 min. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate, water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:3). Fractions containing the target compound were concentrated to give a residue, to which diethyl ether (2 ml)-hexane (1 ml) was added to suspend. The solid was filtered off and dried under aeration to provide the titled compound (72.4 mg, 49.8%) as a pale yellow solid. The reaction mixture was concentrated under a reduced pressure to give a residue, which by stirring for 30 min The reaction mixture was partitioned between ethyl acetate and water The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate, water and brine in this order dried over anhydrous sodium sulfate The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:3) Fractions containing the target compound were concentrated to give a residue The solid was filtered off dried under aeration

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

実験手順: 4-Fluorophenylacetic acid (1 g, 6.49 mmol) was dissolved in acetonitrile (40 ml) and cooled to 0° C. in an ice bath. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.492 g, 7.79 mmol) was added, followed by 1-hydroxybenzotriazole (1.19 g, 7.79 mmol). The mixture was stirred at 0° C. for 2.5 hours, and then concentrated ammonium hydroxide (0.865 ml, 13.0 mmol) was added slowly. The mixture then stirred at RT for an additional 2 hours. After this time the solids were filtered off, and the filtrate was diluted with ethyl acetate (50 mL). The solution was washed with saturated aqueous NaHCO3 (2×50 mL) and brine (50 mL), dried (MgSO4) and concentrated in vacuo to yield 2-(4-fluorophenyl)acetamide (0.87 g, 88% yield) as a white solid which was used as is in the next reaction. 1H NMR (400 MHz, DMSO-d6): δ 7.45 (broad s, 1H), 7.26 (m, 2H), 7.09 (m, 2H), 6.87 (broad s, 1H), 3.34 (s, H). The mixture then stirred at RT for an additional 2 hours After this time the solids were filtered off the filtrate was diluted with ethyl acetate (50 mL) The solution was washed with saturated aqueous NaHCO3 (2×50 mL) and brine (50 mL) dried (MgSO4) concentrated in vacuo