反应详情

温度

0 °C

LiHMDS (Aldrich) (2.44 mL, 2.44 mmol) was added dropwise at 0° C. to a stirred solution of 4-(2-fluoro-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.507 g, 0.815 mmol) and tert-butyl 5-aminopyridin-2-ylcarbamate (0.204 g, 0.976 mmol) in THF (2 mL). The dark red mixture was stirred at 0° C. for 2 h. More LiHMDS (1.6 mL, 1.6 mmol) was added dropwise at 0° C. and stirring was continued for another 30 min. The reaction was quenched by adding 0.3 mL of sat'd NH4Cl. The reaction mixture was partitioned between water (40 mL) and EtOAc (40 mL). The aqueous phase was extracted with EtOAc (2×30 mL). The combined organic layers were washed with saturated aqueous sodium chloride (40 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (100 g, eluent: iPrOH (w/10% NH4OH) in CHCl3 0%-10%) to give tert-butyl 5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-2-ylamino)pyridin-2-ylcarbamate (0.306 g, 46% yield). 1H NMR (400 MHz, CDCl3) δ 11.76 (s, 1H); 8.71 (d, J=2.54 Hz, 1H); 8.42 (d, J=2.35 Hz, 1H); 8.23 (d, J=2.35 Hz, 1H); 7.94 (dd, J=9.00, 2.54 Hz, 1H); 7.83 (d, J=9.00 Hz, 1H); 7.15-7.25 (m, 5H); 6.86 (dd, J=11.15, 8.61 Hz, 4H); 4.83 (d, J=10.17 Hz, 4H); 3.76-3.85 (m, 6H); 3.50 (s, 2H); 3.18 (br. s., 4H); 2.71 (s, 3H); 2.59 (s, 3H); 2.55 (t, J=4.50 Hz, 4H); 1.53 (s, 9H).

1. stirringstirring
2. waitwas continued for another 30 min
3. customThe reaction was quenched
4. additionby adding 0.3 mL of sat'd NH4Cl
5. customThe reaction mixture was partitioned between water (40 mL) and EtOAc (40 mL)
6. extractionThe aqueous phase was extracted with EtOAc (2×30 mL)
7. washThe combined organic layers were washed with saturated aqueous sodium chloride (40 mL)
8. dry with materialdried over sodium sulfate
9. filtrationfiltered
10. concentrationconcentrated in vacuo
11. customThe crude product was purified by silica gel chromatography (100 g, eluent: iPrOH (w/10% NH4OH) in CHCl3 0%-10%)