methyl 2-amino-4-chloro-5-iodobenzoate

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

実験手順: To a mixture of iodine (68 g, 0.27 mol) and silver sulfate (84 g, 0.27 mol) in absolute EtOH (2.5 L) was added methyl 2-amino-4-chlorobenzoate (50 g, 0.27 mol). The reaction mixture was allowed to stir at rt for 45 min. The reaction mixture was then filtered through a pad of Celite® and the filtrate was concentrated. The residue was dissolved in EtOAc (2 L) and washed with saturated aqueous NaHCO3 (3×400 mL), water (3×400 mL), and brine. The organic solution was dried over Na2SO4, filtered, and concentrated to give methyl 2-amino-4-chloro-5-iodobenzoate (85 g, 99%). The reaction mixture was then filtered through a pad of Celite® the filtrate was concentrated The residue was dissolved in EtOAc (2 L) washed with saturated aqueous NaHCO3 (3×400 mL), water (3×400 mL), and brine The organic solution was dried over Na2SO4 filtered concentrated

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

実験手順: Methyl 2-amino-4-chloro-5-iodobenzoate (Intermediate 2) (1 g, 3.21 mmol) and ethyl 2-(o-tolyloxy)acetate (Aldrich, 0.655 g, 3.37 mmol) were dissolved in THF (10 mL) and KHMDS 1M/THF (9.63 mL, 9.63 mmol) was added in one portion at room temperature under N2. The reaction mixture was stirred at room temperature for 1 h before quenched with MeOH and concentrated under reduced pressure. The residue was dissolved in 1N NaOH then extracted with Et2O. The aqueous extracts were acidified with 1N HCl and the resulting precipitate was collected by filtration then washed successively with water and diethyl ether to give 7-chloro-4-hydroxy-6-iodo-3-(o-tolyloxy)quinolin-2(1H)-one (1.03 g, 2.409 mmol, 75% yield) as white solid. LCMS: (M+H)+=428; Rt=2.46 min. before quenched with MeOH concentrated under reduced pressure The residue was dissolved in 1N NaOH then extracted with Et2O the resulting precipitate was collected by filtration then washed successively with water and diethyl ether

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

実験手順: To a solution of 2-(phenylsulfonyl) acetic acid (Lancaster Synthesis Ltd., 0.771 mg, 3.85 mmol) in dichloromethane (50 mL) was added oxalyl chloride (4.17 mL, 4.17 mmol) and few drops of DMF. The reaction mixture was stirred 2 hours at room temperature. To a solution of methyl 2-amino-4-chloro-5-iodobenzoate (Intermediate 2) (1 g, 3.21 mmol) and triethylamine (1.074 mL, 7.70 mmol) in dichloromethane (50 mL) at RT was added dropwise the acid chloride prepared above. The reaction mixture was stirred at room temperature overnight then quenched with aqueous solution of NaHCO3. The organic layer was and washed with saturated NaHCO3, water and brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound methyl 4-chloro-5-iodo-2-(2-(phenylsulfonyl)acetamido)benzoate (1.1 g, 2.228 mmol, 69.4% yield) as pale yellow powder. LCMS: (M+H)+=494; Rt=3.58 min. prepared above The reaction mixture was stirred at room temperature overnight then quenched with aqueous solution of NaHCO3 washed with saturated NaHCO3, water and brine The organic layer was dried over anhydrous Na2SO4 filtered concentrated in vacuo

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

実験手順: To a solution of methyl 2-amino-4-chloro-5-iodobenzoate (Intermediate 2) (8 g, 25.7 mmol) and pyridine (2.18 mL, 27 mmol) in dichloromethane (200 mL) was added ethyl 3-chloro-3-oxopropanoate (Aldrich, 3.45 mL, 27 mmol) and the reaction mixture was stirred overnight at room temperature. The reaction mixture was evaporated to dryness, diluted with ethyl acetate, washed successively with water and brine. The organic layer was then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated in pentane, filtered and dried to give the title compound methyl 4-chloro-2-{[3-(ethyloxy)-3-oxopropanoyl]amino}-5-iodobenzoate (8.24 g, 19.36 mmol, 75% yield) as beige solid. LCMS: (M+H)+=426; Rt=3.78 min. The reaction mixture was evaporated to dryness diluted with ethyl acetate washed successively with water and brine The organic layer was then dried over anhydrous sodium sulfate filtered concentrated in vacuo The residue was triturated in pentane filtered dried

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

実験手順: A suspension of methyl 2-amino-4-chloro-5-iodobenzoate (Intermediate 2) (8.2 g, 26.3 mmol), (4-bromophenyl)boronic acid (5.29 g, 26.3 mmol), tetrakis(triphenylphosphine) palladium (0.304 g, 0.263 mmol) and sodium carbonate (79 mL, 1M in water, 79 mmol) in 1,4-dioxane (300 mL) was stirred 3 days at 80° C. After cooling, the mixture was filtered through celite, the filtrate was then diluted with water and extracted twice with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated in diisopropylether, filtered and washed with acetonitrile then diisopropylether to give the title compound methyl 4-amino-4′-bromo-6-chloro-3-biphenylcarboxylate (2.5 g, 7.34 mmol, 27.9% yield) as an off-white powder. LCMS: (M+H)+=340-342; Rt=4.09 min. After cooling the mixture was filtered through celite the filtrate was then diluted with water extracted twice with dichloromethane The organic layer was dried over anhydrous sodium sulfate filtered concentrated in vacuo The residue was triturated in diisopropylether filtered washed with acetonitrile

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

実験手順: To a solution of methyl 2-amino-4-chlorobenzoate (Aldrich, 111 g, 600 mmol) and silver sulfate (187 g, 600 mmol) in ethanol (1000 mL) was added dropwise in 8 hours a solution of iodine (152 g, 600 mmol) in ethanol (2000 mL). The reaction mixture was stirred overnight then filtered through a celite plug. The filtrate was concentrated under reduced pressure and the residue was triturated in n-heptane. The resulting solid was filtered, washed with diisopropyl ether to give the title compound methyl 2-amino-4-chloro-5-iodobenzoate (103.76 g, 334 mmol, 55.6% yield) as a white powder. LCMS: (M+H)+=312; Rt=3.46 min. then filtered through a celite plug The filtrate was concentrated under reduced pressure the residue was triturated in n-heptane The resulting solid was filtered washed with diisopropyl ether

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

実験手順: To a mixture of iodine (68 g, 0.27 mol) and silver sulfate (84 g, 0.27 mol) in absolute EtOH (2.5 L) was added methyl 2-amino-4-chlorobenzoate (50 g, 0.27 mol). The reaction mixture was allowed to stir at rt for 45 min. The reaction mixture was then filtered through a pad of Celite® and the filtrate was concentrated. The residue was dissolved in EtOAc (2 L) and washed with saturated aqueous NaHCO3 (3×400 mL), water (3×400 mL), and brine. The organic solution was dried over Na2SO4, filtered, and concentrated to give methyl 2-amino-4-chloro-5-iodobenzoate (85 g, 99%). The reaction mixture was then filtered through a pad of Celite® the filtrate was concentrated The residue was dissolved in EtOAc (2 L) washed with saturated aqueous NaHCO3 (3×400 mL), water (3×400 mL), and brine The organic solution was dried over Na2SO4 filtered concentrated

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

実験手順: Prepared essentially as described in EXAMPLE 1, Step A from 5.0 g 2-amino-4-chloro-5-iodobenzoic acid methyl ester and 2.8 g (5-chlorothiophen-2-yl)acetyl chloride (also prepared essentially as described in EXAMPLE 1) to give the title compound (5.0 g). Prepared essentially also prepared essentially

反応条件: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 2-amino-4-chloro-5-iodobenzoic acid methyl ester (2.26 g in 25 mL dichloroethane) was added (3,5-dimethylphenyl) acetyl chloride (1.2 g in 15 mL dichloroethane) and the mixture heated to 75° C. on an oil bath. After 3 hours, the reaction was cooled and the solvent removed in vacuo. The title compound was isolated by crystallization from methanol (2.7 g). the reaction was cooled the solvent removed in vacuo

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

実験手順: To a suspension of 2-acetylamino-4-chlorobenzoic acid methyl ester (2.0 g in 80 mL of dry chloroform) and 2.5 g silver trifluoromethanesulfonate was added iodine (2.87 g in 40 mL chloroform) and the mixture stirred at room temperature. After 5 hours, the mixture was filtered over diatomaceous earth and the filtrate concentrated in vacuo. Purification of the resulting oil by flash chromatography on silica gel (hexane:ethyl acetate, 95:5; then 90:10) gave the title compound (2.26 g). the mixture was filtered over diatomaceous earth the filtrate concentrated in vacuo Purification of the resulting oil by flash chromatography on silica gel (hexane

反応条件: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 2-amino-4-chloro-5-iodo-benzoic acid methyl ester (2.26 g in 25 mL dichloroethane) was added (3,5-dimethylphenyl) acetyl chloride (1.2 g in 15 mL dichloroethane) and the mixture heated to 75° C. on an oil bath. After 3 hours, the reaction was cooled and the solvent removed in vacuo. The title compound was isolated by crystallization from methanol (2.7 g). the reaction was cooled the solvent removed in vacuo

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

実験手順: To a suspension of 2-acetylamino-4-chlorobenzoic acid methyl ester (2.0 g in 80 mL of dry chloroform) and 2.5 g silver trifluoroacetate was added iodine (2.87 g in 40 mL chloroform) and the mixture stirred at room temperature. After 5 hours, the mixture was filtered over diatomaceous earth and the filtrate concentrated in vacuo. Purification of the resulting oil by flash chromatography on silica gel (hexane:ethyl acetate, 95:5; then 90:10) gave the title compound (2.26 g). the mixture was filtered over diatomaceous earth the filtrate concentrated in vacuo Purification of the resulting oil by flash chromatography on silica gel (hexane