Cerium(III) chloride → HCID 131734189, compound

Temperature

50 °C

THF (2 mL) was added to cerium(III) chloride (0.130 g, 0.527 mmol). The suspension was warmed to about 50° C. for about 30 min then cooled to about −78° C. A solution of methylmagnesium bromide (3.0 M solution in Et2O, 0.165 mL, 0.495 mmol) and THF (2 mL) was added dropwise and the reaction mixture was stirred for about 15 min. A solution of rac-(4aS,12bR,E)-2-benzylidene-12b-ethyl-9-(4-fluorophenyl)-1,4,4a,5,6,7,9,12b-octahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3 (2H)-one (53, R1=4-Fluorophenyl, R2=Ethyl) (0.100 g, 0.215 mmol) and THF (2 mL) was added dropwise via syringe and the reaction was stirred at about −78° C. for about 1 h. Methylmagnesium bromide (3.0 M solution in Et2O, 0.16 mL, 0.48 mmol) was added. After about 1 h, methylmagnesium bromide (3.0 M solution in Et2O, 0.1 mL, 0.3 mmol) was added. After about 1 h, the reaction was quenched with MeOH (1 mL) maintaining an internal temperature of less than about −60° C. Sat. aq. NH4Cl (2 mL), water (2 mL), and EtOAc (20 mL) were added and the mixture was allowed to warm to rt. EtOAc (50 mL) and water (20 mL) were added. The layers were separated and the aqueous layer was extracted with EtOAc (20 mL). The combined organics were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel (25 g) using a gradient of 0-10% EtOAc in heptane. The product fractions were combined and concentrated under reduced pressure to give rac-(3R,4aS,12bR,E)-2-benzylidene-12b-ethyl-9-(4-fluorophenyl)-3-methyl-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3-ol (54, R1=4-Fluorophenyl, R2=Ethyl, R3=Methyl) (0.057 g. 55% yield); LC/MS, method 3, Rt=3.16 min.; MS m/z: 481 (M+H)+. 1H NMR (400 MHz, DMSO) δ 7.76-7.70 (m, 2H), 7.64 (s, 1H), 7.62-7.55 (m, 2H), 7.46 (s, 1H), 7.43-7.35 (m, 5H), 6.86 (s, 1H), 6.80 (s, 1H), 4.57 (s, 1H), 3.63-3.53 (m, 1H), 3.06-2.86 (m, 2H), 2.36-1.99 (m, 4H), 1.81-1.61 (m, 2H), 1.61-1.42 (m, 3H), 1.39 (s, 3H), 1.30-1.22 (m, 1H), 0.51 (t, J=7.3 Hz, 3H).

1. temperaturethen cooled to about −78° C
2. stirringthe reaction was stirred at about −78° C. for about 1 h
3. waitAfter about 1 h
4. waitAfter about 1 h
5. customthe reaction was quenched with MeOH (1 mL)
6. temperaturemaintaining an internal temperature of less than about −60° C
7. additionSat. aq. NH4Cl (2 mL), water (2 mL), and EtOAc (20 mL) were added
8. temperatureto warm to rt
9. additionEtOAc (50 mL) and water (20 mL) were added
10. customThe layers were separated
11. extractionthe aqueous layer was extracted with EtOAc (20 mL)
12. dry with materialThe combined organics were 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-bc5373790d1143efa397aaf5dc6bd00e

Source dataset

uspto-grants-2015_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09193744B2