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Stage #1: 2-(2,4-difluorophenyl)-6-(2,6-difluorophenylamino)nicotinic acid; bis(trichloromethyl) carbonate With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at -35 - 20℃;
Stage #2: With ammonia In tetrahydrofuran at -30℃; |
Preparation of2-(2,4-difluorophenyl)-6-(l-(2,6-difluorophenyl)ureido)nicotinamide (10) [0188] Triphosgene (38.87 g, 0.1276 mol, 0.9 eq) and compound 9(51.14 g, 0.1412 mo, 1 eq.) were charged to a reactor. Anhydrous THF (486 rnL, 9.5 vol) was then added and the clear solution was cooled to - 30 +/- 5 0C. Diisopropylethylamine (73.79 mL, 0.424 mol, 3.0 eq) in THF (103 rnL, 2.5 vol) was charged to the reactor keeping the temperature below -20 0C. After addition, the reaction mixture was warmed to 20 +/- 3 0C. The mixture was stirred for 2 hours and was then filtered through celite, and the cake was rinsed with THF (767 mL, 15 vol). The filtrate was cooled to - 30 0C and anhydrous NH3 (3 equiv.) added. The resulting white slurry was purged with N2 and warmed up to 20 +/- 3 0C for 1 hour. The reaction mixture was then cooled to 0 +/- 5 0C for 30 minutes. The mixture was again filtered and the reactor was rinsed with THF (255 mL, 5 vol). The cake was rinsed with H2O (255 mL, 5.0 vol) followed by IN H2SO4 (10 vol). The solid was then transferred to a vacuum oven and dried at 35 +/- 3 0C to give the title compound, 10, as a white solid. (1H NMR, 500 MHz; DMSO-d6) δ 7.97 (d, IH), 7.85 (s, IH), 7.56 (quin, IH), 7.45 (q, IH), 7.40 (s, 2H), 7.28 (t, 3H), 7.15 (td, IH), 7.06 (d, IH). |
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Stage #1: 2-(2,4-difluorophenyl)-6-(2,6-difluorophenylamino)nicotinic acid; bis(trichloromethyl) carbonate With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at -35 - 23℃;
Stage #2: With ammonia In tetrahydrofuran at -30 - 23℃; for 1h; |
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Preparation of2-(2,4"difluorophenyl)-6-(l-(2,6- difluorophenl)ureido)nicoHnamide (10)9 10[00124] Triphosgene (38.87 g, 0.1276 mol, 0.9 eq) and Compound 9 (51.14 g, 0.1412 mo, 1 eq.) were charged to a reactor. Anhydrous THF (486 mL, 9.5 vol) was then added and the clear solution was cooled to - 30 +/- 5 0C, Diisopropylethylamine (73.79 mL, 0.424 mol, 3.0 eq) in THF (103 mL, 2.5 vol) was charged to the reactor keeping the temperature below - 200C. After addition, the reaction mixture was warmed to 20 +/- 3 0C. The mixture was stirred for 2 hours and was then filtered through celite, and the cake was rinsed with THF (767 mL, 15 vol). The filtrate was cooled to - 300C and anhydrous NH3 (3 equiv.) added. The resulting white slurry was purged with N2 and warmed up to 20 +/- 3 0C for 1 hour. The reaction mixture was then cooled to 0 +/- 5 0C for 30 minutes. The mixture was again filtered and the reactor was rinsed with THF (255 mL, 5 vol). The cake was rinsed with H2O (255 mL, 5.0 vol) followed by IN H2SO4 (10 vol). The solid was then transferred to a vacuum oven and dried at 35 +/- 3 0C to give the title Compound, 10, as a white solid. (1H NMR, 500 MHz; DMSO-d6) δ 7.97 (d, IH), 7.85 (s, IH), 7.56 (quin, IH), 7.45 (q, IH), 7.40 (s, 2H), 7.28 (t, 3H), 7.15 (td, IH), 7.06 (d, IH). |