4-amino-3-chloro-N-methylbenzamide

反応条件: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of (S)-6-(2-chloro-4-((tetrahydrofuran-3-yl)oxy)-7-((2-(trimethylsilyl)ethoxy)-methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylbenzo[d]oxazole (1 equiv), 4-amino-3-chloro-N-methylbenzamide (1.2 equiv), tris(dibenzylideneacetone)dipalladium(0) (0.1 equiv), xantphos (0.2 equiv) in 1,4-dioxane (0.1 M) was added cesium carbonate (1.4 equiv). The reaction was heated, under microwave irradiation, in a microwave reactor at 150° C. for 2 h. The reaction mixture was quenched with saturated aqueous sodium chloride and then washed with ethyl acetate. The organic phase was combined and washed with saturated aqueous sodium chloride. The organic layer was dried (anhydrous magnesium sulfate), filtered, and concentrated. The crude was purified by silica gel column chromatography (20-80% ethyl acetate (with 10% 1N ammonia in methanol) in hexane). Concentration of the desired fractions under reduced pressure afforded the title compound (64.7% yield) as yellow solid; MS (ESI) m/z 649.6 [M+1]+. The reaction mixture was quenched with saturated aqueous sodium chloride washed with ethyl acetate washed with saturated aqueous sodium chloride The organic layer was dried (anhydrous magnesium sulfate) filtered concentrated The crude was purified by silica gel column chromatography (20-80% ethyl acetate (with 10% 1N ammonia in methanol) in hexane)

反応条件: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of (S)-6-(2-chloro-4-((tetrahydrofuran-3-yl)oxy)-7-((2-(trimethylsilyl)ethoxy)-methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylbenzo[d]oxazole (1 equiv), 4-amino-3-chloro-N-methylbenzamide (1.2 equiv), tris(dibenzylideneacetone)dipalladium(0) (0.1 equiv), xantphos (0.2 equiv) in 1,4-dioxane (0.1 M) was added cesium carbonate (1.4 equiv). The reaction was heated, under microwave irradiation, in a microwave reactor at 150° C. for 2 h. The reaction mixture was quenched with saturated aqueous sodium chloride and then washed with ethyl acetate. The organic phase was combined and washed with saturated aqueous sodium chloride. The organic layer was dried (anhydrous magnesium sulfate), filtered, and concentrated. The crude was purified by silica gel column chromatography (20-80% ethyl acetate (with 10% 1N ammonia in methanol) in hexane). Concentration of the desired fractions under reduced pressure afforded the title compound (64.7% yield) as yellow solid; MS (ESI) m/z 649.6 [M+1]+. The reaction mixture was quenched with saturated aqueous sodium chloride washed with ethyl acetate washed with saturated aqueous sodium chloride The organic layer was dried (anhydrous magnesium sulfate) filtered concentrated The crude was purified by silica gel column chromatography (20-80% ethyl acetate (with 10% 1N ammonia in methanol) in hexane)

反応条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The solution of 4-amino-3-chlorobenzoic acid (1 equiv), EDCI (1.2 equiv), methylamine hydrochloride (1.2 equiv) in DMF (1.5 M) was added sodium bicarbonate (1 equiv). The reaction was stirred at 25° C. for 15 h. The reaction mixture was quenched with saturated aqueous sodium chloride and then extracted with ethyl acetate. The organic phase was combined and washed with saturated aqueous sodium chloride. The organic layer was dried (anhydrous magnesium sulfate), filtered, and concentrated. The crude product was purified by silica gel column chromatography (0-90% ethyl acetate (with 10% 1N ammonia in methanol) in hexane). Concentration of the desired fractions afforded the title compound (89% yield) as colorless oil; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.67 (d, J=4.29 Hz, 3 H) 5.81 (s, 2 H) 6.72 (d, J=8.59 Hz, 1 H) 7.49 (dd, J=8.39, 2.15 Hz, 1 H) 7.67 (d, J=1.95 Hz, 1 H) 8.08 (d, J=4.29 Hz, 1 H); MS (ESI) m/z 185.0 [M+1]+. The reaction mixture was quenched with saturated aqueous sodium chloride extracted with ethyl acetate washed with saturated aqueous sodium chloride The organic layer was dried (anhydrous magnesium sulfate) filtered concentrated The crude product was purified by silica gel column chromatography (0-90% ethyl acetate (with 10% 1N ammonia in methanol) in hexane)

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a degassed mixture of 6-(2-chloro-4-(cyclopentyloxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylbenzo[d]oxazole (1 equiv), 4-amino-3-chloro-N-methylbenzamide (1 equiv) and cesium carbonate (3 equiv) in 1,4-dioxane (0.1 M) was added palladium acetate (0.2 equiv) and 2,2′-bis-diphenylphosphanyl-[1,1′]binaphthalenyl (0.2 equiv). The reaction was stirred at 100° C. for 4 h. The reaction mixture was cooled to room temperature, and concentrated. The residue was purified by silica gel chromatography (0-5% MeOH in DCM) to afford the title compound (65% yield). MS (ESI) m/z 648.2 [M+1]+. The reaction mixture was cooled to room temperature concentrated The residue was purified by silica gel chromatography (0-5% MeOH in DCM)

反応条件: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of (S)-6-(2-chloro-4-((tetrahydrofuran-3-yl)oxy)-7-((2-(trimethylsilyl)ethoxy)-methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylbenzo[d]oxazole (1 equiv), 4-amino-3-chloro-N-methylbenzamide (1.2 equiv), tris(dibenzylideneacetone)dipalladium(0) (0.1 equiv), xantphos (0.2 equiv) in 1,4-dioxane (0.1 M) was added cesium carbonate (1.4 equiv). The reaction was heated, under microwave irradiation, in a microwave reactor at 150° C. for 2 h. The reaction mixture was quenched with saturated aqueous sodium chloride and then washed with ethyl acetate. The organic phase was combined and washed with saturated aqueous sodium chloride. The organic layer was dried (anhydrous magnesium sulfate), filtered, and concentrated. The crude was purified by silica gel column chromatography (20-80% ethyl acetate (with 10% 1N ammonia in MeOH) in hexane). Concentration of the desired fractions under reduced pressure afforded the title compound (64.7% yield) as yellow solid; MS (ESI) m/z 649.6 [M+1]+. The reaction mixture was quenched with saturated aqueous sodium chloride washed with ethyl acetate washed with saturated aqueous sodium chloride The organic layer was dried (anhydrous magnesium sulfate) filtered concentrated The crude was purified by silica gel column chromatography (20-80% ethyl acetate (with 10% 1N ammonia in MeOH) in hexane)

反応条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The solution of 4-amino-3-chlorobenzoic acid (1 equiv), EDCI (1.2 equiv), methylamine hydrochloride (1.2 equiv) in DMF (1.5 M) was added sodium bicarbonate (1 equiv). The reaction was stirred at 25° C. for 15 h. The reaction mixture was quenched with saturated aqueous sodium chloride and then extracted with ethyl acetate. The organic phase was combined and washed with saturated aqueous sodium chloride. The organic layer was dried (anhydrous magnesium sulfate), filtered, and concentrated. The crude product was purified by silica gel column chromatography (0-90% ethyl acetate (with 10% 1N ammonia in MeOH) in hexane). Concentration of the desired fractions afforded the title compound (89% yield) as colorless oil; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.67 (d, J=4.29 Hz, 3H) 5.81 (s, 2H) 6.72 (d, J=8.59 Hz, 1H) 7.49 (dd, J=8.39, 2.15 Hz, 1H) 7.67 (d, J=1.95 Hz, 1H) 8.08 (d, J=4.29 Hz, 1H); MS (ESI) m/z 185.0 [M+1]+. The reaction mixture was quenched with saturated aqueous sodium chloride extracted with ethyl acetate washed with saturated aqueous sodium chloride The organic layer was dried (anhydrous magnesium sulfate) filtered concentrated The crude product was purified by silica gel column chromatography (0-90% ethyl acetate (with 10% 1N ammonia in MeOH) in hexane)

反応条件: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of (S)-6-(2-chloro-4-((tetrahydrofuran-3-yl)oxy)-7-((2-(trimethylsilyl)ethoxy)-methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylbenzo[d]oxazole (1 equiv), 4-amino-3-chloro-N-methylbenzamide (1.2 equiv), tris(dibenzylideneacetone)dipalladium(0) (0.1 equiv), xantphos (0.2 equiv) in 1,4-dioxane (0.1 M) was added cesium carbonate (1.4 equiv). The reaction was heated, under microwave irradiation, in a microwave reactor at 150° C. for 2 h. The reaction mixture was quenched with saturated aqueous sodium chloride and then washed with ethyl acetate. The organic phase was combined and washed with saturated aqueous sodium chloride. The organic layer was dried (anhydrous magnesium sulfate), filtered, and concentrated. The crude was purified by silica gel column chromatography (20-80% ethyl acetate (with 10% 1N ammonia in methanol) in hexane). Concentration of the desired fractions under reduced pressure afforded the title compound (64.7% yield) as yellow solid; MS (ESI) m/z 649.6 [M+1]+. The reaction mixture was quenched with saturated aqueous sodium chloride washed with ethyl acetate washed with saturated aqueous sodium chloride The organic layer was dried (anhydrous magnesium sulfate) filtered concentrated The crude was purified by silica gel column chromatography (20-80% ethyl acetate (with 10% 1N ammonia in methanol) in hexane)

反応条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The solution of 4-amino-3-chlorobenzoic acid (1 equiv), EDCI (1.2 equiv), methylamine hydrochloride (1.2 equiv) in DMF (1.5 M) was added sodium bicarbonate (1 equiv). The reaction was stirred at 25° C. for 15 h. The reaction mixture was quenched with saturated aqueous sodium chloride and then extracted with ethyl acetate. The organic phase was combined and washed with saturated aqueous sodium chloride. The organic layer was dried (anhydrous magnesium sulfate), filtered, and concentrated. The crude product was purified by silica gel column chromatography (0-90% ethyl acetate (with 10% 1N ammonia in methanol) in hexane). Concentration of the desired fractions afforded the title compound (89% yield) as colorless oil; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.67 (d, J=4.29 Hz, 3 H) 5.81 (s, 2 H) 6.72 (d, J=8.59 Hz, 1 H) 7.49 (dd, J=8.39, 2.15 Hz, 1 H) 7.67 (d, J=1.95 Hz, 1 H) 8.08 (d, J=4.29 Hz, 1 H); MS (ESI) m/z 185.0 [M+1]+. The reaction mixture was quenched with saturated aqueous sodium chloride extracted with ethyl acetate washed with saturated aqueous sodium chloride The organic layer was dried (anhydrous magnesium sulfate) filtered concentrated The crude product was purified by silica gel column chromatography (0-90% ethyl acetate (with 10% 1N ammonia in methanol) in hexane)