反应详情

Lithium bis(trimethylsilyl)amide (1.0 M solution in THF) (1.42 mL, 1.42 mmol) was added to a solution of 6-(2-fluoro-5-((1R)-1-(4-(methylsulfonyl)-1-piperazinyl)ethyl)-3-pyridinyl)-N,N-bis(4-methoxybenzyl)-2-methyl-4-pyrimidinamine (0.300 g, 0.47 mmol) and 5-fluoro-6-methoxypyridin-3-amine (Anichem, Inc. North Brunswick, N.J.) (0.101 g, 0.71 mmol) in THF (1.5 mL) at −10° C. More lithium bis(trimethylsilyl)amide (1.0 M solution in THF) (1.42 mL, 1.42 mmol) and 5-fluoro-6-methoxypyridin-3-amine (0.101 g, 0.71 mmol) were added and the reaction mixture was stirred for another hour. Saturated NH4Cl (aq.) was added and the mixture was extracted with EtOAc (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude material was adsorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 100% EtOAc in hexane, to provide 6-(2-((5-fluoro-6-methoxy-3-pyridinyl)amino)-5-((1R)-1-(4-(methylsulfonyl)-1-piperazinyl)ethyl)-3-pyridinyl)-N,N-bis(4-methoxybenzyl)-2-methyl-4-pyrimidinamine (0.200 g, 0.264 mmol, 55.9% yield) as a brown foam. m/z (ESI, +ve) 757.2 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 11.92 (br. s., 1H) 8.24 (dd, J=12.52, 2.15 Hz, 1H) 8.13 (d, J=1.57 Hz, 1H) 8.03 (d, J=2.15 Hz, 1H) 7.50 (br. s., 1H) 7.19 (d, J=6.46 Hz, 4H) 6.87 (d, J=8.61 Hz, 5H) 6.52 (br. s., 1H) 4.79 (br. s., 4H) 4.01 (s, 3H) 3.79 (s, 6H) 3.44 (br. s., 1H) 3.17 (br. s., 4H) 2.75 (s, 3H) 2.66 (s, 3H) 2.40-2.59 (m, 4H) 1.34 (br. s., 3H)

1. extractionthe mixture was extracted with EtOAc (3×)
2. dry with materialThe combined organic layers were dried over anhydrous Na2SO4
3. filtrationfiltered
4. concentrationconcentrated
5. custompurified by chromatography through a Redi-Sep pre-packed silica gel column (40 g)
6. washeluting with a gradient of 0% to 100% EtOAc in hexane