反应详情

4-[4-(6-Fluoro-pyrido[3,4-d]pyrimidin-4-ylamino)-2-methyl-phenoxyl-piperidine-1-carboxylic acid tert-butyl ester: A solution of 6-Fluoro-3H-pyrido[3,4-d]pyrimidin-4-one (2.0 g, 12.11 mmol), SOCl2 (14.4 g, 121.1 mmol), and DMF (0.4 mL) in DCE (40 mL) was heated to reflux for 4 h. The reaction was then concentrated and the resulting dark residue was dissolved in t-BuOH/DCE 1:1 (40 mL), NEt3 (2.45 g, 24.22 mmol) and 4-(4-Amino-2-methyl-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (3.7 g, 12.11 mmol) were added, the resulting solution was heated to reflux for 2 h. The reaction was concentrated, the residue was dissolved in EtOAc and washed 2× water then the organic layer was dried over Na2SO4. Purification by flash column chromatography (CH2Cl2/MeOH 98:2) gave the title compound as a yellow solid (3.08 g, 56%). LRMS: 454.2; 398.2; 354.2 (MH+); 1H NMR (DMSO-d6, 400 MHz): δ 9.88 (s, 1H), δ 8.84 (s, 1H), δ 8.56 (s, 1H), δ 8.17 (s, 1H), δ 7.53-7.55 (m, 2H), δ 7.00-7.02 (m, 1H), δ 4.50-4.55 (m, 1H), δ 3.21-3.26 (m, 2H), δ 2.16 (s, 3H), δ 1.83-1.89 (m, 2H), δ 1.51-1.59 (m, 1H), δ 1.37 (s, 9H).

1. temperatureto reflux for 4 h
2. concentrationThe reaction was then concentrated
3. dissolutionthe resulting dark residue was dissolved in t-BuOH/DCE 1:1 (40 mL)
4. temperaturethe resulting solution was heated
5. temperatureto reflux for 2 h
6. concentrationThe reaction was concentrated
7. dissolutionthe residue was dissolved in EtOAc
8. washwashed 2× water
9. dry with materialthe organic layer was dried over Na2SO4
10. customPurification by flash column chromatography (CH2Cl2/MeOH 98:2)