Dimethyl Sulfoxide → rac-(2'R,4aR,12bR)-12b-ethyl-9-(4-fluorophenyl)-2,4,4a,5,6,7,9,12b-octahydro-1H-spiro[benzo[6,7]cyclohepta[1,2-f]indazole-3,2'-oxirane]

Temperature

65 °C

A flask with stir bar and nitrogen line was charged with sodium hydride (60% in oil 0.106 g, 2.66 mmol) and DMSO (7 mL). The mixture was warmed in an oil bath heated to about 65° C. for about 45 min. The mixture was cooled to rt, diluted with THF (7 mL) then cooled to about 0° C. Trimethylsulfoxonium iodide (0.585 g, 2.66 mmol) was added and the mixture was stirred for about 15 min. (4aR,12bR)-12b-Ethyl-9-(4-fluoro-phenyl)-1,2,4a,5,6,7,9,12b-octahydro-4H-9,10-diaza-benzo[3,4]cyclohepta[1,2-f]inden-3-one; compound with (4aS,12bS)-12b-ethyl-9-(4-fluoro-phenyl)-1,2,4a,5,6,7,9,12b-octahydro-4H-9,10-diaza-benzo[3,4]cyclohepta[1,2-f]inden-3-one (9, R1=4-Fluorophenyl, R2=Ethyl) (0.500 g, 1.328 mmol) suspended in THF (9 mL) was added to the reaction mixture. After about 15 min the ice bath was removed and the mixture was allowed to warm to rt for about 6 h. The mixture was concentrated under reduced pressure and the residue was partitioned between EtOAc (100 mL) and water (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (25 mL). The combined organic layers were washed with water (2×50 mL) and brine (30 mL). The organic solution was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified on silica gel (25 g) using a gradient of 0-20% EtOAc in DCM. Product fractions were combined and concentrated under reduced pressure to yield rac-(2′R,4aS,12bS)-12b-ethyl-9-(4-fluorophenyl)-2,4,4a,5,6,7,9,12b-octahydro-1H-spiro[benzo[6,7]cyclohepta[1,2-f]indazole-3,2′-oxirane] (14, R1=4-Fluorophenyl, R2=Ethyl) (0.462 g, 1.183 mmol, 89% yield); LC/MS, method 3, Rt=3.14 min, MS m/z 391 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.27 (d, J=0.8 Hz, 1H), 7.93 (s, 1H), 7.85-7.78 (m, 2H), 7.56 (s, 1H), 7.45-7.37 (m, 2H), 3.26-3.19 (m, 1H), 2.97-2.92 (m, 1H), 2.67 (d, J=4.7 Hz, 1H), 2.62 (d, J=4.7 Hz, 1H), 2.36-2.32 (m, 1H), 2.23-2.14 (m, 1H), 2.12-1.91 (m, 4H), 1.91-1.68 (m, 3H), 1.62-1.54 (m, 1H), 1.32-1.28 (m, 1H), 1.26-1.16 (m, 1H), 1.07-0.94 (m, 1H), 0.40 (t, J=7.3 Hz, 3H).

1. temperatureThe mixture was warmed in an oil bath
2. temperatureThe mixture was cooled to rt
3. temperaturethen cooled to about 0° C
4. additionwas added to the reaction mixture
5. customAfter about 15 min the ice bath was removed
6. temperatureto warm to rt for about 6 h
7. concentrationThe mixture was concentrated under reduced pressure
8. customthe residue was partitioned between EtOAc (100 mL) and water (50 mL)
9. customThe layers were separated
10. extractionthe aqueous layer was extracted with EtOAc (25 mL)
11. washThe combined organic layers were washed with water (2×50 mL) and brine (30 mL)
12. dry with materialThe organic solution was dried over MgSO4
13. filtrationfiltered
14. concentrationconcentrated under reduced pressure
15. customThe residue was purified on silica gel (25 g)
16. concentrationconcentrated under reduced pressure

ORD record

ord-e7b5cf57db944d53baea1bc5b72df6f4

Source dataset

uspto-grants-2015_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09193744B2