反应详情

To a mixture of 4-tert-butoxycarbonylamino-benzoic acid (50 g, 0.21 mol) and HOBT (31.33 g, 0.231 mol) in dry THF (0.5 L) was added EDAC (44.44 g, 0.231 mol). The resulting mixture was stirred for 10 min followed by addition of a mixture of DIPEA (40.4 ml, 0.231 mol) and 1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane (39.4 ml, 0.231 mol). The reaction mixture was stirred for an additional 16 hrs. and evaporated to dryness. To the residue was added water (600 ml) and the resulting mixture was extracted with EtOAc (3×500 ml). The combined organic phases were dried (Na2SO4), filtered and evaporated in vacuo. The resulting residue was purified by column chromatography (silica gel) using a mixture of EtOAc-Heptane (1:2) as eluent. Pure fractions were collected and evaporated to dryness. To the solid residue was added diethyl ether (100 ml) and the precipitate was filtered off, washed with diethyl ether and dried in vacuo at 50° C. affording 60.5 g (77%) of [4-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenyl]carbamic acid tert-butyl ester as a solid.

1. stirringThe reaction mixture was stirred for an additional 16 hrs
2. customand evaporated to dryness
3. additionTo the residue was added water (600 ml)
4. extractionthe resulting mixture was extracted with EtOAc (3×500 ml)
5. dry with materialThe combined organic phases were dried (Na2SO4)
6. filtrationfiltered
7. customevaporated in vacuo
8. customThe resulting residue was purified by column chromatography (silica gel)
9. additiona mixture of EtOAc-Heptane (1:2) as eluent
10. customPure fractions were collected
11. customevaporated to dryness
12. additionTo the solid residue was added diethyl ether (100 ml)
13. filtrationthe precipitate was filtered off
14. washwashed with diethyl ether
15. customdried in vacuo at 50° C.