4-chloro-2-fluoro-6-iodoaniline

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

実験手順: To a mixture of 3-ethynylpyridine (1.13 g, 11 mmol) and 2-fluoro-4-chloro-6-iodoaniline (2.71 g, 10 mmol) in triethylamine (100 mL) is added PdCl2(PPh3)2 (175 mg, 0.25 mmol) and CuI (95 mg, 0.50 mmol) and the mixture is refluxed for 1 h. The solvent is removed in vacuo and the residue is purified by silica gel flash chromatography (dichloromethane-methanol, 1:0 to 24:1) to give 4-chloro-2-fluoro-6-pyridin-3-ylethynyl-phenylamine. MS (ESI) m/z 247 (M+H)+. the mixture is refluxed for 1 h The solvent is removed in vacuo the residue is purified by silica gel flash chromatography (dichloromethane-methanol, 1:0 to 24:1)

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

実験手順: To a mixture of 3-ethynylpyridine (1.13 g, 11 mmol) and 2-fluoro-4-chloro-6-iodoaniline (2.71 g, 10 mmol) in triethylamine (100 mL) is added PdCl2(PPh3)2 (175 mg, 0.25 mmol) and CuI (95 mg, 0.50 mmol) and the mixture is refluxed for 1 h. The solvent is removed in vacuo and the residue is purified by silica gel flash chromatography (dichloromethane-methanol, 1:0 to 24:1) to give 4-chloro-2-fluoro-6-pyridin-3-ylethynyl-phenylamine. MS (ESI) m/z 247 (M+H)+. the mixture is refluxed for 1 h The solvent is removed in vacuo the residue is purified by silica gel flash chromatography (dichloromethane-methanol, 1:0 to 24:1)

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

実験手順: A mixture of 4-chloro-2-fluoro-6-iodoaniline (0.100 g; 0.368 mmol), 5-(2,5-difluorobenzyl)-N-(4-(triethylsilyl)but-3-ynyl)isoxazole-3-carboxamide (0.150 g; 0.347 mmol), Bis(diphenylphosphino)ferrocene]palladium(II) chloride (0.015 g; 0.018 mmol), lithium chloride (0.016 mg; 0.368 mmol), sodium carbonate (0.078 g; 0.737 mmol) in DMF (5 mL) was stirred at 100° C. overnight. The solution was reputed between ethyl acetate and brine, washed with sodium thiosulphate, dried and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica (eluent 2 to 60% ethyl acetate in heptane) to yield 0.05 g (25%) of N-(2-(5-chloro-7-fluoro-2-(triethylsilyl)-1H-indol-3-yl)ethyl)-5-(2,5-difluorobenzyl)isoxazole-3-carboxamide as a yellow oil. washed with sodium thiosulphate dried concentrated under reduced pressure The crude mixture was purified by flash chromatography on silica (eluent 2 to 60% ethyl acetate in heptane)

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

実験手順: A mixture of 4-chloro-2-fluoro-6-iodoaniline (0.100 g; 0.368 mmol), 5-(2,5-difluorobenzyl)-N-(4-(triethylsilyl)but-3-ynyl)isoxazole-3-carboxamide (0.150 g; 0.347 mmol), Bis(diphenylphosphino)ferrocene]palladium(II) chloride (0.015 g; 0.018 mmol), lithium chloride (0.016 mg; 0.368 mmol), sodium carbonate (0.078 g; 0.737 mmol) in DMF (5 mL) was stirred at 100° C. overnight. The solution was reputed between ethyl acetate and brine, washed with sodium thiosulphate, dried and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica (eluent 2 to 60% ethyl acetate in heptane) to yield 0.05 g (25%) of N-(2-(5-chloro-7-fluoro-2-(triethylsilyl)-1H-indol-3-yl)ethyl)-5-(2,5-difluorobenzyl)isoxazole-3-carboxamide as a yellow oil. washed with sodium thiosulphate dried concentrated under reduced pressure The crude mixture was purified by flash chromatography on silica (eluent 2 to 60% ethyl acetate in heptane)

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

実験手順: A mixture of 4-chloro-2-fluoro-6-iodoaniline (0.100 g; 0.368 mmol), 5-(2,5-difluorobenzyl)-N-(4-(triethylsilyl)but-3-ynyl)isoxazole-3-carboxamide (0.150 g; 0.347 mmol), Bis(diphenylphosphino)ferrocene]palladium(II) chloride (0.015 g; 0.018 mmol), lithium chloride (0.016 mg; 0.368 mmol), sodium carbonate (0.078 g; 0.737 mmol) in DMF (5 mL) was stirred at 100° C. overnight. The solution was reparted between ethyl acetate and brine, washed with sodium thiosulphate, dried and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica (eluent 2 to 60% ethyl acetate in heptane) to yield 0.05 g (25%) of N-(2-(5-chloro-7-fluoro-2-(triethylsilyl)-1H-indol-3-yl)ethyl)-5-(2,5-difluorobenzyl)isoxazole-3-carboxamide as a yellow oil. washed with sodium thiosulphate dried concentrated under reduced pressure The crude mixture was purified by flash chromatography on silica (eluent 2 to 60% ethyl acetate in heptane)

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

実験手順: 4-Chloro-2-fluoro-6-iodoaniline (0.100 g; 0.368 mmol), 4-(3-fluorobenzyl)-N-(4-(triethylsilyl)but-3-ynyl)benzamide (0.145 g; 0.368 mmol), bis(diphenylphosphino)ferrocene]palladium(II) chloride (0.015 g; 0.018 mmol), lithium chloride (0.016 mg; 0.368 mmol) and sodium carbonate (0.078 g; 0.737 mmol) were suspended in DMF (5 mL) and the mixture was stirred at 100° C. for 18 hours. The solution was concentrated under reduced pressure and diluted in ethyl acetate. The organic layer was successively washed with brine, sodium thiosulfate, dried and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (eluent 2 to 60% ethyl acetate in heptane) to afford 0.102 g (51%) of the title compound as a yellow oil. The solution was concentrated under reduced pressure diluted in ethyl acetate The organic layer was successively washed with brine, sodium thiosulfate dried concentrated under reduced pressure The crude residue was purified by flash chromatography on silica gel (eluent 2 to 60% ethyl acetate in heptane)

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

実験手順: To a mixture of 3-ethynylpyridine (1.13 g, 11 mmol) and 2-fluoro-4-chloro-6-iodoaniline (2.71 g, 10 mmol) in triethylamine (100 mL) is added PdCl2(PPh3)2 (175 mg, 0.25 mmol) and CuI (95 mg, 0.50 mmol) and the mixture is refluxed for 1 h. The solvent is removed in vacuo and the residue is purified by silica gel flash chromatography (dichloromethane-methanol, 1:0 to 24:1) to give 4-chloro-2-fluoro-6-pyridin-3-ylethynyl-phenylamine. MS (ESI) m/z 247 (M+H)+. the mixture is refluxed for 1 h The solvent is removed in vacuo the residue is purified by silica gel flash chromatography (dichloromethane-methanol, 1:0 to 24:1)

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

実験手順: To a mixture of 3-ethynylpyridine (1.13 g, 11 mmol) and 2-fluoro-4-chloro-6-iodoaniline (2.71 g, 10 mmol) in triethylamine (100 mL) is added PdCl2(PPh3)2 (175 mg, 0.25 mmol) and CuI (95 mg, 0.50 mmol) and the mixture is refluxed for 1 h. The solvent is removed in vacuo and the residue is purified by silica gel flash chromatography (dichloromethane-methanol, 1:0 to 24:1) to give 4-chloro-2-fluoro-6-pyridin-3-ylethynyl-phenylamine. MS (ESI) m/z 247 (M+H)+. the mixture is refluxed for 1 h The solvent is removed in vacuo the residue is purified by silica gel flash chromatography (dichloromethane-methanol, 1:0 to 24:1)

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 4-chloro-2-fluoro-6-iodoaniline (0.5 g, 1.8 mmol), vinylmethylsulfone (0.2 g, 1.8 mmol), Cs2CO3 (1.17 g, 3.6 mmol) and DMF (15 mL) was heated with stirring at 50° C. overnight. The resulting mixture was poured into water and then extracted with EA (50 mL×3). The combined organic phases were dried over Na2SO4 and then concentrated. The residue was purified by column chromatography (EtOAc:PE=1:40) to give 4-chloro-2-fluoro-6-iodo-N-[2-(methylsulfonyl)ethyl]aniline (0.42 g, yield: 61%). was heated extracted with EA (50 mL×3) The combined organic phases were dried over Na2SO4 concentrated The residue was purified by column chromatography (EtOAc:PE=1:40)

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

実験手順: To a solution of 4-chloro-2-fluoroaniline (1.15 g, 7.9 mmol) in 125 mL of ethanol added silver sulphate (1.7 g, 8.3 mmol), then followed by addition of I2 (2.1 g, 8.3 mmol) in portions. After the addition was completed, the mixture was stirred at RT for 2 hours. The mixture was filtered through celite and the filtration was evaporated to give dark oil which was dissolved in 125 mL of DCM. The solution was washed with 2 M sodium hydroxide (40 mL×2), saturated Na2S2O3 (40 mL×2) and water (40 mL×2). The resulting solution was dried over MgSO4 and then evaporated to give the crude 4-chloro-2-fluoro-6-iodoaniline as dark oil (2.1 g, yield: 98%). After the addition The mixture was filtered through celite the filtration was evaporated to give dark oil which The solution was washed with 2 M sodium hydroxide (40 mL×2), saturated Na2S2O3 (40 mL×2) and water (40 mL×2) The resulting solution was dried over MgSO4 evaporated

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

実験手順: The title compound was prepared in analogy to example 10 step A from 4-chloro-2-fluoro-6-iodoaniline (500 mg, 1.84 mmol) and 1-chloro-2-ethynyl-benzene (302 mg, 2.21 mmol). Brown solid (1.05 g, 68%). Rf 0.3 (1:9 Ethyl acetate:heptane) as a bright blue spot under UV light.

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

実験手順: The general procedure was used to convert 4-Chloro-2-fluoro-6-iodo-phenylamine and phenylacetylene to the title product. Purification by flash chromatography gave the analytically pure product as a white solid, 92% yield. 1H NMR (300 MHz, DMSO) δ 12.13 (s, 1H), 7.98-7.95 (d, J=7.72, 2H), 7.51-7.46 (t, J=7.53, 2H), 7.44 (s, 1H), 7.40-7.35 (t, J=7.72, 1H), 7.11-7.07 (d, J=10.92, 1H), 6.96 (s, 1H). 13C NMR (75 MHz, DMSO) δ 150.98, 147.70, 141.53, 133.51, 132.04, 129.73, 129.04, 126.54, 124.59, 124.10, 116.44, 108.27, 100.39. Anal. Calcd. for C14H9ClFN: C, 68.44; H, 3.69; Cl, 14.43; F, 7.73; N, 5.70. Found C, 68.26; H, 3.76; Cl, 14.70; F, 7.5; N, 5.72. m.p.: 153-155° C.