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 wt % in oil, 0.212 g, 5.31 mmol) and DMSO (9 mL) then the mixture was warmed in an oil bath heated to about 65° C. for about 1 h. The mixture was cooled to rt, diluted with THF (18 mL) then cooled to about 0° C. Trimethylsulfonium iodide (1.084 g, 5.31 mmol) was added then the mixture was stirred for about 15 min. rac-(4aR,12bR)-12b-Ethyl-9-(4-fluorophenyl)-1,4,4a,5,6,7,9,12b-octahydrobenzo[6,7]cyclohepta[1,2-f]indazole-3 (2H)-one (9, R1=4-Fluorophenyl, R2=Ethyl) (0.800 g, 2.125 mmol) was added in one portion then the mixture was stirred and allowed to warm to rt. After stirring overnight the mixture was concentrated under reduced pressure to remove THF. The mixture was partitioned between water (50 mL) and EtOAc (50 mL). The aqueous layer was extracted with EtOAc (25 mL). The combined organics were washed with water (2×25 mL) then brine (25 mL), dried over MgSO4, then filtered. The filtrate was concentrated under reduced pressure then the material was purified on silica gel (40 g) using 0-10% EtOAc in DCM. Product fractions containing the epoxide isomer with the higher Rf (TLC, 95:5 DCM/EtOAc, vis by UV) were collected and concentrated under reduced pressure to yield 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] (154, R1=4-Fluorophenyl, R2=Ethyl) (0.308 g, 37.1%); LC/MS, method 3, Rt=2.94 min, MS m/z 391 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.26 (d, J=0.8 Hz, 1H), 7.89 (s, 1H), 7.84-7.77 (m, 2H), 7.56 (s, 1H), 7.45-7.36 (m, 2H), 3.26-3.18 (m, 1H), 2.97-2.92 (m, 1H), 2.61-2.54 (m, 2H), 2.24-2.15 (m, 1H), 2.03-1.71 (m, 8H), 1.62-1.58 (m, 1H), 1.39-1.21 (m, 2H), 1.06-1.01 (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 in one portion
5. stirringthe mixture was stirred
6. temperatureto warm to rt
7. stirringAfter stirring overnight the mixture
8. concentrationwas concentrated under reduced pressure
9. customto remove THF
10. customThe mixture was partitioned between water (50 mL) and EtOAc (50 mL)
11. extractionThe aqueous layer was extracted with EtOAc (25 mL)
12. washThe combined organics were washed with water (2×25 mL)
13. dry with materialbrine (25 mL), dried over MgSO4
14. filtrationfiltered
15. concentrationThe filtrate was concentrated under reduced pressure
16. customthe material was purified on silica gel (40 g)
17. additionProduct fractions containing the epoxide isomer with the higher Rf (TLC, 95:5 DCM/EtOAc, vis by UV)
18. customwere collected
19. concentrationconcentrated under reduced pressure

ORD record

ord-0a7562ab97a54eacb60e1f37303cbfa8

Source dataset

uspto-grants-2015_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09193744B2