反应详情

温度

130 °C

A mixture of 4-(3-aminopropyl)-1-methylpiperazine (0.1 mmol), Et3N (0.1 mmol) and 4-(7-fluoro-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.1 mmol), prepared as described in Example 65b, in DMF (1 mL) was stirred at 130° C. for 3 h. It was then diluted with water and extracted with EtOAc. The combined extracts were washed with water, brine, dried (anhydrous MgSO4), filtered and concentrated in vacuo. The crude product was then treated with 3M HCl/MeOH (2 mL) and stirred at rt for 2 h, then concentrated in vacuo. The crude residue was dissolved in a mixture of DCM:MeOH (1:1; 2 mL) and neutralized with excess Et3N and treated with (4-isopropoxy-phenyl)-carbamic acid 4-nitrophenyl ester (0.11 mmol), which was prepared as described in Example 1a, at rt for 1 h. It was then concentrated in vacuo and the crude product was dissolved in DCM and washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude product was then purified by Preparative TLC (silica gel; DCM:MeOH, 9:1) to obtain 3.2 mg (6% overall yield over the three steps) of the title compound. 1H-NMR (300 MHz, CDCl3): 8.97 (s, 1H), 7.88 (d, 1H), 7.28-7.22 (m, 3H), 6.97-6.81 (m, 4H), 6.33 (s, 1H), 4.53-4.43 (m, 1H), 4.30-4.20 (d, 2H), 3.66-3.32 (m, 2H), 3.11 (t, 2H), 2.85-2.55 (m, 8H), 2.43 (s, 4H), 2.20-1.85 (m, 8H), 1.31 (d, 6H). LC/MS (ESI): 546.2 (MH)+.

1. customprepared
2. extractionextracted with EtOAc
3. washThe combined extracts were washed with water, brine
4. dry with materialdried (anhydrous MgSO4)
5. filtrationfiltered
6. concentrationconcentrated in vacuo
7. additionThe crude product was then treated with 3M HCl/MeOH (2 mL)
8. stirringstirred at rt for 2 h
9. concentrationconcentrated in vacuo
10. dissolutionThe crude residue was dissolved in a mixture of DCM:MeOH (1:1; 2 mL)
11. customwas prepared
12. waitas described in Example 1a, at rt for 1 h
13. concentrationIt was then concentrated in vacuo
14. dissolutionthe crude product was dissolved in DCM
15. washwashed with water, brine
16. dry with materialdried over anhydrous MgSO4
17. filtrationfiltered
18. concentrationconcentrated in vacuo
19. customThe crude product was then purified by Preparative TLC (silica gel; DCM:MeOH, 9:1)
20. customto obtain 3.2 mg (6%