反应详情

To a solution of (S)-3-fluoro-N6-(1′-(4-fluorophenyl)ethyl)-N2-(5-methyl-1H-pyrazol-3-yl)-5-nitropyridine-2,6-diamine (Method 47, 0.6 g, 1.6 mmol) in a mixture of MeOH-THF (1:1, 40 ml) under nitrogen was added zinc dust (0.52 g, 8.0 mmol). A saturated aqueous solution of NH4Cl (4.0 ml) was then added slowly from an addition funnel over 20 minutes. Upon completion of the addition, the reaction was allowed to stir for an additional 30 minutes, at which point a saturated aqueous solution of NH4OAc (5.0 ml) was added, and the reaction was stirred for 30 minutes. EtOAc (15 ml) was then added, and the reaction was stirred vigorously. The remaining solids were then filtered through celite, and the organic fraction was separated from the remaining filtrate, dried over Na2SO4, filtered and concentrated to give to give crude (S)-5-fluoro-N2-(1′-(4-fluorophenyl)ethyl)-N6-(5-methyl-1H-pyrazol-3-yl)pyridine-2,3,6-triamine (0.50 g, 90%) which was used without further purification. The above amine was immediately placed in EtOH (30 ml) and formamidine acetate (0.36 g, 3.4 mmol) was added. The reaction was flushed with nitrogen and heated to 95° C. for 12 hours. The reaction was cooled to room temperature, and a saturated aqueous NaHCO3 solution (5 ml) was added, along with EtOAc (15 ml). The resulting mixture was stirred vigorously for 10 minutes. The layers were then allowed to separate, and the organic fraction was isolated, washed with brine (15 ml), dried over Na2SO4, filtered and concentrated. The resulting dark residue was purified by column chromatography (hexanes-EtOAc=1:30) to give the title compound (0.30 g, 48%). 1H NMR (400 MHz, CD3OD) δ 8.29 (s, 1H), 7.57 (d, J=11.1 Hz, 1H), 7.46-7.42 (m, 2H), 7.04-7.00 (m, 2H), 6.29 (s, 1H), 5.15-5.10 (m, 1H), 2.37 (s, 3H), 1.58 (d, J=7.0 Hz, 3H). MS: Calcd.: 354. Found: [M+H]+ 355.

1. additionUpon completion of the addition
2. additionwas added
3. stirringthe reaction was stirred vigorously
4. filtrationThe remaining solids were then filtered through celite
5. customthe organic fraction was separated from the remaining filtrate
6. dry with materialdried over Na2SO4
7. filtrationfiltered
8. concentrationconcentrated
9. customto give