Synthesis
General procedure for the synthesis of 2-amino-3-methyl-5-iodopyridine from 2-amino-3-methyl-5-bromopyridine: 5-bromo-3-methylpyridin-2-amine (2 g, 10.6 mmol), sodium iodide (3.2 g, 21.4 mmol), and copper iodide (0.190 g, 1.06 mmol) were added to dioxane (10 mL), the solution was degassed and tetramethylethane-1,2-diamine (0.803 mL, 1.06 mmol) was added. The mixture was heated at 110 °C overnight. After completion of the reaction, it was cooled to room temperature, water was added and the crude product was extracted with ethyl acetate. The residue was purified by column chromatography to afford 5-iodo-3-methylpyridin-2-amine as a beige solid (2.3 g, 93% yield). Similar to the procedure described in Example 40, 6-fluoro-7-(methylamino)-2,3-dihydrobenzo[e][1,3]oxazin-4-one (0.100 g, 0.51 mmol) was reacted with 5- iodo-3-methylpyridin-2-amine (0.119 g, 0.53 mmol) to give, after reversed-phase HPLC purification, the pure 3- (6-amino pyridin-3-yl) -6-fluoro-7-(methylamino)-2,3-dihydrobenzo[e][1,3]oxazin-4-one (0.020 g, 13% yield). ES-MS (M + H)+ = 303. Following the method of sulfonylurea formation described in Example 5, 3-(6-amino-5-methylpyridin-3-yl)-6-fluoro-7-(methylamino)-2,3-dihydrobenzo[e] [1,3]oxazin-4-one (0.010 g, 0.034 mmol) was coupled with ethyl (5-chlorothiophene-2-sulfonyl)-carbamate (0.048 g, 0.166 mmol) to afford 1-(5-chlorothiophene-2-ylsulfonyl)-3-(5-(6-fluoro-7-(methylamino)-4-oxo-2H-benzo[e][1,3]oxazine -3(4H)-yl)-3-methylpyridin-2-yl)urea (0.016 g, 85% yield).RP-HPLC retention time: 2.7 min; ES-MS (M + H)+ = 526.0; 1H-NMR (DMSO-d6) δ (ppm): 2.2 (s, 3H), 2.8 (s, 3H), 5.6 (s, 2H), 6.2 ( d, 1H), 6.8 (bs, 1H), 7.2 (s, 1H), 7.4 (d, 1H), 7.6 (s, 1H), 7.8 (d, 1H), 8.2 (d, 1H), 9.6 (bs, 1H).
