反应详情

Combine (R)-5-chloro-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (5.00 g, 14.5 mmol) and 2-fluoro-4-iodoaniline (3.45 g, 14.5 mmol) in THF (25 mL). Cool in an ice-bath. Add lithium hexamethyldisilazide (1.0 M in THF, 36.4 mL, 36.4 mmol) maintaining the temperature below about 10° C. After 10 minutes, warm to ambient temperature. After 30 minutes, heat to 55° C. After 20 hour, cool to ambient temperature, add dimethylacteamide (35 mL) and evaporate in vacuo to remove most of the THF. Cool the remaining mixture in an ice-bath then add water (17.5 mL) to form a solid. Add water (20 mL), then collect the solid by filtration, rinse with water (3×15 mL), heptane (15 mL), and dry in vacuo to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ10.14 (s, 1H), 8.60 (s, 1H), 7.68 (d, 1H, J=10.4, 2.0 Hz), 7.52 (d, 1H, J=8.8 Hz), 6.96 (td, 1H, J=8.8, 6.0 Hz), 4.41 (m, 1H), 4.25 (dd, 1H, J=13.6, 3.6 Hz), 4.06 (dd, 1H, J=8.8, 6.4 Hz), 3.98 (dd, 1H, J=13.6, 7.6 Hz), 3.78 (dd, 1H, J=9.2, 5.6 Hz), 3.58 (s, 3H), 1.37 (s, 3H), 1.23 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ161.1 (d, J=4.4 Hz), 155.7 (d, J=8.8 Hz), 155.4, 153.3, 151.1 (d, J=109 Hz), 135.6, 133.6 (d, J=7.3 Hz), 133.1 (d, J=3.7 Hz), 127.9 (d, J=13.2 Hz), 125.2 (d, J=6.5 Hz), 123.9 (d, J=21.9 Hz), 109.1, 95.1 (d, J=4.4 Hz), 87.1 (d, J=7.3 Hz), 72.2, 66.1, 48.9, 28.8, 26.6, 25.0; 19F NMR (376 MHz, DMSO-d6) δ-124.5, −149.3; MS (M+H)+m/z calcd 545.0. found 545.0.

1. temperatureCool in an ice-bath
2. waitAfter 30 minutes
3. temperatureheat to 55° C
4. waitAfter 20 hour
5. temperaturecool to ambient temperature
6. customevaporate in vacuo
7. customto remove most of the THF
8. temperatureCool the remaining mixture in an ice-bath
9. customadd water (17.5 mL) to form a solid
10. customAdd water (20 mL), then collect the solid
11. filtrationby filtration
12. washrinse with water (3×15 mL), heptane (15 mL)
13. customdry in vacuo