反应详情

温度

80 °C

A mixture of (tetrahydro-pyran-4-yl)-methanol (0.2 mmol), KOtBu (0.2 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 DMSO (1 mL), was stirred at 80° C. for 1 h. It was then diluted with water and extracted with DCM. The combined extracts were washed with water, brine, dried with 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 and then concentrated in vacuo. The crude deprotected intermediate was dissolved in a mixture of DCM:MeOH (1:1; 2 mL) and neutralized with excess Et3N and treated with (4-pyrrolidin-1-yl-phenyl)-carbamic acid 4-nitrophenyl ester hydrochloride (0.11 mmol), prepared by the method as outlined in Example 74a, at rt overnight. It was then concentrated in vacuo and the crude product was dissolved in DCM and washed with water thrice, then washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude product was then purified by Preparative TLC (silica gel; DCM:MeOH, 9.5:0.5) followed by a further purification by Preparative HPLC to obtain 1.5 mg (3%) of the title compound. 1H-NMR (300 MHz, CDCl3+CD3OD): 9.05 (s, 1H), 8.09 (m, 1H), 7.52-7.23 (m, 6H), 4.30 (m, 2H), 4.03-3.94 (m, 4H), 3.75-3.50 (m, 8H), 3.48-3.38 (m, 2H), 2.30-2.18 (m, 4H), 2.17-2.00 (m, 2H), 1.97-1.85 (m, 2H), 1.75 (m, 2H), 1.55-1.41 (m, 2H). LC/MS (ESI): 516.2 (MH)+.

1. customprepared
2. extractionextracted with DCM
3. washThe combined extracts were washed with water, brine
4. dry with materialdried with 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. dissolutionwas dissolved in a mixture of DCM:MeOH (1:1; 2 mL)
11. customprepared by the method
12. waitas outlined in Example 74a, at rt overnight
13. concentrationIt was then concentrated in vacuo
14. dissolutionthe crude product was dissolved in DCM
15. washwashed with water thrice
16. washwashed with brine
17. dry with materialdried over anhydrous MgSO4
18. filtrationfiltered
19. concentrationconcentrated in vacuo
20. customThe crude product was then purified by Preparative TLC (silica gel; DCM:MeOH, 9.5:0.5)
21. customfollowed by a further purification by Preparative HPLC