反应详情

To a solution of [4-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenyl]carbamic acid tert-butyl ester (2.6 g, 6.98 mmol) in dry DMF (75 ml) was added NaH (0.35 g, 8.38 mmol 60% in mineral oil) and the resulting mixture was stirred for 1 hr. Methyl iodide (521 μl, 8.38 mmol) was added and the stirring was continued for an additional 1 hr. The reaction mixture was quenched with water (50 ml) followed by extraction with diethyl ether (2×50 ml). The combined organic phases were washed with saturated aqueous ammonium chloride, dried (Na2SO4), filtered and evaporated in vacuo. The residue was dissolved in DCM (40 ml) and TFA (25 ml) was added. The resulting mixture was stirred for 18 hrs. at room temperature and evaporated in vacuo. To the residue was added water (10 ml) and the pH was adjusted to 9 by addition of 1 N sodium hydroxide. The aqueous phase was extracted with diethyl ether (2×25 ml) and the combined organic phases were dried (Na2SO4), filtered and evaporated in vacuo affording 2.5 g crude product which was purified by column chromatography (silica gel) using a mixture of EtOAc-Heptane (1:1) as eluent. Pure fractions were collected and evaporated to dryness affording a slowly crystallizing oil which was washed with diethyl ether (10 ml), filtered off and dried in vacuo at 50° C. afforded 0.9 g (45%) of the title compound as a solid.

1. waitthe stirring was continued for an additional 1 hr
2. customThe reaction mixture was quenched with water (50 ml)
3. extractionfollowed by extraction with diethyl ether (2×50 ml)
4. washThe combined organic phases were washed with saturated aqueous ammonium chloride
5. dry with materialdried (Na2SO4)
6. filtrationfiltered
7. customevaporated in vacuo
8. dissolutionThe residue was dissolved in DCM (40 ml)
9. additionTFA (25 ml) was added
10. stirringThe resulting mixture was stirred for 18 hrs
11. customat room temperature and evaporated in vacuo
12. additionTo the residue was added water (10 ml)
13. additionthe pH was adjusted to 9 by addition of 1 N sodium hydroxide
14. extractionThe aqueous phase was extracted with diethyl ether (2×25 ml)
15. dry with materialthe combined organic phases were dried (Na2SO4)
16. filtrationfiltered
17. customevaporated in vacuo
18. customaffording 2.5 g crude product which
19. customwas purified by column chromatography (silica gel)
20. additiona mixture of EtOAc-Heptane (1:1) as eluent
21. customPure fractions were collected
22. customevaporated to dryness
23. customaffording
24. customa slowly crystallizing oil which
25. washwas washed with diethyl ether (10 ml)
26. filtrationfiltered off
27. customdried in vacuo at 50° C.