反应详情

To a solution of 4-[7-(-hydroxy-ethoxy)-quinazolin-4-yl]-piperidine-1-carboxylic acid tert-butyl ester (0.5 mmol), prepared as described in Example 169a, in anhydrous DCM, was added Et3N (1 mmol) and methanesulfonyl chloride (1 mmol) and the mixture was stirred at rt for 2 h. It was then washed with water (3×), dried over anhydrous MgSO4, filtered and concentrated in vacuo to obtain crude 4-[7-(3-methanesulfonyloxy-ethoxy)-quinazolin-4-yl]-piperidine-1-carboxylic acid tert-butyl ester. This (0.1 mmol) was dissolved in anhydrous DMSO together with 1-methyl-piperazin-2-one (0.2 mmol) and the mixture was stirred at 100° C. for 2 h and then diluted with water and extracted with DCM. The DCM extract was washed with water (3×), dried over anhydrous MgSO4, filtered and concentrated in vacuo. To this was added 3M HCl/MeOH (1 mL) and the mixture was stirred at rt for 2 h and then concentrated in vacuo and the residue was dissolved in a 1:1 mixture of DCM:MeOH, neutralized with excess Et3N and treated with (4-pyrrolidin-1-yl-phenyl)-carbamic acid 4-nitrophenyl ester hydrochloride (0.11 mmol), as prepared by the method outlined in Example 74a. The mixture was stirred at rt overnight and then concentrated in vacuo and partitioned between water and DCM. DCM layer was drawn off, washed with water thrice, then dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by Preparative TLC (silica gel; DCM:MeOH, 95:5) followed by a further purification by Preparative HPLC to obtain 5.6 mg (6%) of the title compound. 1H-NMR (300 MHz, CD3OD): 9.10 (s, 1H), 8.44 (d, 1H), 7.59-7.31 (m, 6H), 4.62 (t, 2H), 4.37 (m, 2H), 4.04-3.93 (m, 4H), 3.78-3.54 (m, 8H), 3.21 (m, 2H), 3.03 (s, 3H), 2.30-2.18 (m, 5H), 2.11-1.91 (m, 4H). LC/MS (ESI): 558.3 (MH)+.

1. washIt was then washed with water (3×)
2. dry with materialdried over anhydrous MgSO4
3. filtrationfiltered
4. concentrationconcentrated in vacuo
5. customto obtain crude 4-[7-(3-methanesulfonyloxy-ethoxy)-quinazolin-4-yl]-piperidine-1-carboxylic acid tert-butyl ester
6. stirringthe mixture was stirred at 100° C. for 2 h
7. extractionextracted with DCM
8. extractionThe DCM extract
9. washwas washed with water (3×)
10. dry with materialdried over anhydrous MgSO4
11. filtrationfiltered
12. concentrationconcentrated in vacuo
13. additionTo this was added 3M HCl/MeOH (1 mL)
14. stirringthe mixture was stirred at rt for 2 h
15. concentrationconcentrated in vacuo
16. dissolutionthe residue was dissolved in a 1:1 mixture of DCM
17. customas prepared by the method
18. stirringThe mixture was stirred at rt overnight
19. concentrationconcentrated in vacuo
20. custompartitioned between water and DCM
21. washwashed with water thrice
22. dry with materialdried over anhydrous MgSO4
23. filtrationfiltered
24. concentrationconcentrated in vacuo
25. customThe residue was purified by Preparative TLC (silica gel; DCM:MeOH, 95:5)
26. customfollowed by a further purification by Preparative HPLC