反应详情

A 25 mL round-bottom flask equipped with air cooled reflux condenser was charged with rac-(4aR,12bS)-12b-ethyl-1,2,4,4a,5,6,9,12b-octahydro spiro[benzo[4,5]oxepino[3,2-f]indazole-3,2′-[1,3]dioxolane] (90, R2=Ethyl) (1.00 g, 3.05 mmol), 4-iodo-2-methylpyridine (prepared as described in US 20070287708; 1.19 g, 4.57 mmol), CuI (0.058 g, 0.30 mmol), K3PO4 (1.29 g, 6.09 mmol) and (+/−)-trans-cyclohexane-1,2-diamine (0.070 g, 0.61 mmol) in dioxane (7.5 mL). The reaction mixture was heated at reflux in a heating block for about 18 h. The reaction mixture was filtered through a pad of Celite® using washes of EtOAc (2×20 mL). The filtrate was concentrated under reduced pressure and the residue was purified on silica gel (40 g, eluted with 0% to 100% EtOAc in DCM). Collection and concentration of the appropriate fractions gave rac-(4aR,12bS)-12b-ethyl-9-(2-methylpyridin-4-yl)-1,2,4,4a,5,6,9,12b-octahydrospiro[benzo[4,5]oxepino[3,2-f]indazole-3,2′-[1,3]dioxolane] (91, R1=2-methylpyridin-4-yl, R2=Ethyl) (1.11 g, 87%). LC/MS, method 3, Rt=2.47 min, MS m/z 420 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.57 (d, J=5.9 Hz, 1H), 8.19 (s, 1H), 7.86-7.70 (m, 2H), 7.65 (s, 1H), 7.53 (s, 1H), 4.39-4.30 (m, 1H), 4.01-3.85 (m, 4H), 3.82-3.70 (m, 1H), 2.87-2.68 (m, 4H), 2.50-2.40 (m, 1H), 2.32-2.21 (m, 2H), 2.03-1.32 (m, 7H), (t, J=7.4 Hz, 3H).

1. customA 25 mL round-bottom flask equipped with air
2. temperaturecooled
3. temperaturereflux condenser
4. temperatureThe reaction mixture was heated
5. temperatureat reflux in a heating block for about 18 h
6. filtrationThe reaction mixture was filtered through a pad of Celite®
7. concentrationThe filtrate was concentrated under reduced pressure
8. customthe residue was purified on silica gel (40 g, eluted with 0% to 100% EtOAc in DCM)
9. customCollection and concentration of the appropriate fractions