反应详情

A solution of rac-(7 aR,11 aS)-11a-ethyl-2-methyl-7,7a,8,10,11,11a-hexahydro-6H-spiro[dibenzo[b,d]oxepine-9,2′-[1,3]dioxolan]-3-amine (88, R2=Ethyl) (6.40 g, 20.2 mmol) in chloroform (202 mL) was treated with potassium acetate (3.96 g, 40.3 mmol) and acetic anhydride (5.71 mL, 60.5 mmol) and the mixture was stirred at rt for about 10 min. 18-crown-6 (0.266 g, 1.01 mmol) and isoamyl nitrite (6.79 mL, 50.4 mmol) were each added sequentially in one portion and the reaction mixture was heated at reflux for about 68 h. The reaction was allowed to cool to rt and then the mixture was partitioned between DCM (100 mL) and a mixture of sat. aq. NaHCO3 and water (100 mL each). After separating the layers, the organic phase was washed with brine (250 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The sample was purified on silica gel (330 g, eluted with 0% to 50% EtOAc in Heptane). Collection and concentration of the appropriate fractions gave rac-1-((4aR,12bS)-12b-ethyl-1,4,4a,5,6,12b-hexahydrospiro[benzo[4,5]oxepino[3,2-f]indazole-3,2′-[1,3]dioxolan]-9(2H)-yl)ethanone (89, R2=Ethyl) (3.02 g, 40.4%). LC/MS, method 3, 2.51 min, MS m/z 371 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.04-7.98 (m, 2H), 7.54 (s, 1H), 4.36-4.24 (m, 1H), 4.00-3.84 (m, 4H), 3.77-3.66 (m, 1H), 2.76 (s, 3H), 2.48-2.38 (m, 1H), 2.35-2.20 (m, 2H), 2.02-1.92 (m, 1H), 1.88-1.79 (m, 1H), 1.75-1.46 (m, 5H), 1.39-1.30 (m, 1H), (t, J=7.4 Hz, 3H).

1. additioneach added sequentially in one portion
2. temperaturethe reaction mixture was heated
3. temperatureat reflux for about 68 h
4. temperatureto cool to rt
5. customthe mixture was partitioned between DCM (100 mL)
6. additiona mixture of sat. aq. NaHCO3 and water (100 mL each)
7. customAfter separating the layers
8. washthe organic phase was washed with brine (250 mL)
9. dry with materialdried over Na2SO4
10. filtrationfiltered
11. concentrationconcentrated under reduced pressure
12. customThe sample was purified on silica gel (330 g, eluted with 0% to 50% EtOAc in Heptane)
13. customCollection and concentration of the appropriate fractions