反应详情

温度

0 °C

A solution of 6-amino-4-(tert-butylamino)nicotinonitrile (intermediate 197, 402 mg, 1.794 mmol) in anhydrous DMF (3 ml) was added drop wise to a mixture of di(1H-1,2,4-triazol-1-yl)methanone (327 mg, 1.794 mmol) and DMF (3 ml) cooled at 0° C. After stirring for 45 minutes at 0° C. the reaction mixture was allowed to warm to room temperature and a solution 1-((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)-4-methylpiperazin-2-one (intermediate 81, 300 mg, 0.897 mmol) in DMF (3 ml) was added. The reaction mixture was stirred for approximately 7 h at room temperature, quenched by the addition of MeOH and concentrated. The residue was diluted with EtOAc and water, filtered to remove insoluble byproducts. Phases were separated and the aqueous layer was washed with EtOAc. The organic layers were combined, washed with brine, dried using Na2SO4, filtered and evaporated. The crude product was purified using silica gel column chromatography eluting with a gradient of MeOH (0-3%) in DCM. Fractions containing the product were combined and evaporated to yield the title compound as a yellow solid. (UPLC-MS 3) tR 0.93 min, ESI-MS 551.4 [M+H]+. 1H NMR (600 MHz, CDCl3) δ 13.68 (s, 1H), 8.17 (s, 1H), 7.88 (s, 1H), 7.47 (s, 1H), 5.42 (s, 1H), 4.89 (s, 1H), 4.85 (s, 2H), 4.05-4.00 (m, 2H), 3.48 (s, 6H), 3.30 (br s, 2H), 3.25 (br s, 2H), 2.82 (t, 2H), 2.66 (br s, 2H), 2.39 (br s, 3H), 2.00-1.93 (m, 2H), 1.50 (s, 9H).

1. temperatureto warm to room temperature
2. stirringThe reaction mixture was stirred for approximately 7 h at room temperature
3. customquenched by the addition of MeOH
4. concentrationconcentrated
5. additionThe residue was diluted with EtOAc and water
6. filtrationfiltered
7. customto remove insoluble byproducts
8. customPhases were separated
9. washthe aqueous layer was washed with EtOAc
10. washwashed with brine
11. customdried
12. filtrationfiltered
13. customevaporated
14. customThe crude product was purified
15. washeluting with a gradient of MeOH (0-3%) in DCM
16. additionFractions containing the product
17. customevaporated