Reaction Steps
To a solution of N-(4-fluoro-3-methoxybenzyl)-6-((hydroxyimino)methyl)-2-methylpyrimidine-4-carboxamide (4.0 g, 12.57 mmol, Preparation #9) and 1-cyclopropyl-5-vinylpyridin-2(1H)-one (2.026, 12.57 mmol, Preparation #F.1.33) in DCM (60 mL) was added 9% aqueous sodium hypochlorite solution (60 mL, 12.57 mmol, Avra labs) drop wise at 10-15° C. for about 30 min. The reaction mixture was allowed to stir for another 15-30 min, reaction mixture was diluted with water (100 mL) and the product extracted with DCM (100 mL). The combined organic layers were dried over sodiumsulphate and evaporated to dryness. The resulting crude material contained two products, and these were separated by silica gel column chromatography eluting with 2% methanol in DCM. Relevant fractions containing product were combined and evaporated under reduced pressure to obtain the first eluting compound as 6-(5-(5-chloro-1-cyclopropyl-6-oxo-1,6-dihydropyridin-3-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide, 1H NMR (400 MHz, DMSO): δ 9.518-9.486 (m, 1H), 8.177 (s, 1H), 7.889-7.883 (d, J=2.4 Hz, 1H), 7.753-7.747 (d, J=2.4 Hz, 1H), 7.186-7.120 (m, 2H), 6.907-6.871 (m, 1H), 5.757-5.672 (m, 1H), 4.492-4.476 (d, J=6.4, Hz, 2H), 3.820 (s, 3H), 3.784-3.740 (m, 1H), 3.502-3.371 (m, 2H), 2.762 (s, 3H), 1.091-0.902 (m, 4H); MS m/z: 512.2 (M+H)+. and the second eluting compound as 6-(5-(5-chloro-1-cyclopropyl-6-oxo-1,6-dihydropyridin-3-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide 0.28 g (4.67%) as a brown color solid. 1HNMR (400 MHz, DMSO): δ 9.515-9.485 (m, 1H), 8.179 (s, 1H), 7.680-7.675 (d, J=2 Hz, 1H), 7.489-7.459 (dd, J=9.6 Hz, 1H), 7.180-7.119 (m, 2H), 6.900-6.874 (m, 1H), 6.448-6.390 (dd, J=13.6 Hz, 1H), 5.757-5.661 (m, 1H), 4.489-4.474 (d, J=6 Hz, 2H), 3.817 (s, 3H), 3.805-3.732 (m, 1H), 3.472-3.342 (m, 2H), 2.759 (s, 3H), 1.073-0.863 (m, 4H); MS m/z: 478.2 (M+H)+.
