72.9% |
Stage #1: methyl 5-bromo-2-(trifluoromethyl)isonicotinate; 3,4-difluoro-2-methylaniline With tris-(dibenzylideneacetone)dipalladium(0); Cs2CO3; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In 1,4-dioxane at 100℃; Inert atmosphere;
Stage #2: With sodium hydroxide In 1,4-dioxane at 65℃; for 29220h; Inert atmosphere;
Stage #3: With hydrogenchloride In lithium hydroxide monohydrate Cooling; |
5-((3,4-Difluoro-2-methylphenyl)amino)-2-(trifluoromethyl)isonicotinic acid, hydrochloride
To a mixture of methyl 5-bromo-2-(trifluoromethyl)isonicotinate (14 g, 49.3 mmol) and 3,4-difluoro-2-methylaniline (8.47 g, 59.1 mmol) in 1,4-dioxane (224 mL) was added cesium carbonate (32.1 g, 99 mmol), then Pd2(dba)3 (2.257 g, 2.465 mmol) and 2,2'- bis(diphenylphosphaneyl)-1,1'-binaphthalene (3.07 g, 4.93 mmol). The mixture was stirred at 100 °C under nitrogen overnight. The reaction was cooled and then filtered through celite. The crude solution was heated at 65°C with 5N sodium hydroxide (49.3 mL, 246 mmol) for 40m. The solution was cooled, and 75mL of 6N HCl was added and allowed to stir to give a yellow suspension. This was filtered to give solid, a second crop was also collected and the solids combined and slurried with 100mL diethyl ether, sonicated and filtered to give a lemon yellow solid, which was dried for 18h under vacuum to provide 5-((3,4-difluoro-2- methylphenyl)amino)-2-(trifluoromethyl)isonicotinic acid, hydrochloride as a yellow solid (13.25g, 35.9 mmol, 72.9% yield). MS (m/z) 331.1 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 9.47 (s, 1 H) 8.06 - 8.16 (m, 1 H) 7.97 - 8.06 (m, 1 H) 7.30 - 7.41 (m, 1 H) 7.18 - 7.31 (m, 1 H) 3.37 (br s, 3 H) 2.17 (s, 3 H). |
72.9% |
Stage #1: methyl 5-bromo-2-(trifluoromethyl)isonicotinate; 3,4-difluoro-2-methylaniline With tris-(dibenzylideneacetone)dipalladium(0); Cs2CO3; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In 1,4-dioxane at 100℃; Inert atmosphere;
Stage #2: With sodium hydroxide In 1,4-dioxane at 65℃; for 29220h; Inert atmosphere;
Stage #3: With hydrogenchloride In lithium hydroxide monohydrate Cooling; |
5-((3,4-Difluoro-2-methylphenyl)amino)-2-(trifluoromethyl)isonicotinic acid, hydrochloride
To a mixture of methyl 5-bromo-2-(trifluoromethyl)isonicotinate (14 g, 49.3 mmol) and 3,4-difluoro-2-methylaniline (8.47 g, 59.1 mmol) in 1,4-dioxane (224 mL) was added cesium carbonate (32.1 g, 99 mmol), then Pd2(dba)3 (2.257 g, 2.465 mmol) and 2,2'- bis(diphenylphosphaneyl)-1,1'-binaphthalene (3.07 g, 4.93 mmol). The mixture was stirred at 100 °C under nitrogen overnight. The reaction was cooled and then filtered through celite. The crude solution was heated at 65°C with 5N sodium hydroxide (49.3 mL, 246 mmol) for 40m. The solution was cooled, and 75mL of 6N HCl was added and allowed to stir to give a yellow suspension. This was filtered to give solid, a second crop was also collected and the solids combined and slurried with 100mL diethyl ether, sonicated and filtered to give a lemon yellow solid, which was dried for 18h under vacuum to provide 5-((3,4-difluoro-2- methylphenyl)amino)-2-(trifluoromethyl)isonicotinic acid, hydrochloride as a yellow solid (13.25g, 35.9 mmol, 72.9% yield). MS (m/z) 331.1 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 9.47 (s, 1 H) 8.06 - 8.16 (m, 1 H) 7.97 - 8.06 (m, 1 H) 7.30 - 7.41 (m, 1 H) 7.18 - 7.31 (m, 1 H) 3.37 (br s, 3 H) 2.17 (s, 3 H). |