Acetaldehyde → HCID 86722324, compound

Temperature

-70 °C

A three necked round bottom flask with septum, nitrogen line, thermometer and stir bar was charged with the 1-(4-fluorophenyl)-5,7,8,9-tetrahydrocyclohepta[f]indazol-6(1H)-one (6, R1=4-Fluorophenyl) (3.75 g, 12.74 mmol) and THF (50 mL). The solution was cooled to about −70° C. then LiHMDS (12.74 mL, 12.74 mmol) was added keeping the internal temp below about −60° C. The mixture was warmed to about 0° C. over about 5 min then cooled to about −70° C. Acetaldehyde (0.786 g, 17.84 mmol) was added in one portion. The mixture was stirred for about 2 h at about −78° C. then the cold bath was removed and the mixture was allowed to warm to about 10° C. Brine (25 mL), water (25 mL) and EtOAc (100 mL) were added and the layers were separated. The aqueous layer was extracted with EtOAc (50 mL) then the organic solutions were combined, extracted with brine (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified on silica gel (120 g) using a gradient of 0-50% EtOAc in heptane. Product fractions were combined and concentrated under reduced pressure to yield (E)-5-ethylidene-1-(4-fluorophenyl)-5,7,8,9-tetrahydrocyclohepta[f]indazol-6(1H)-one (3.23 g, 79%); LC/MS, method 3, Rt=2.68 min, MS m/z 321 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.36 (d, J=0.8 Hz, 1H), 7.87-7.80 (m, 2H), 7.75 (s, 1H), 7.70 (s, 1H), 7.50-7.40 (m, 2H), 7.12 (q, J=7.4 Hz, 1H), 2.82 (t, J=7.0 Hz, 2H), 2.28 (t, J=7.1 Hz, 2H), 2.01-1.91 (m, 2H), 1.87 (d, J=7.4 Hz, 3H).

1. customthe internal temp below about −60° C
2. temperatureThe mixture was warmed to about 0° C. over about 5 min
3. temperaturethen cooled to about −70° C
4. stirringThe mixture was stirred for about 2 h at about −78° C.
5. customthe cold bath was removed
6. temperatureto warm to about 10° C
7. additionBrine (25 mL), water (25 mL) and EtOAc (100 mL) were added
8. customthe layers were separated
9. extractionThe aqueous layer was extracted with EtOAc (50 mL)
10. extractionextracted with brine (50 mL)
11. dry with materialdried over MgSO4
12. filtrationfiltered
13. concentrationconcentrated under reduced pressure
14. customThe residue was purified on silica gel (120 g)
15. concentrationconcentrated under reduced pressure

ORD record

ord-9271c78f470d416fbb8d062790b394da

Source dataset

uspto-grants-2015_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09193744B2