Chlorotriethylsilane → HCID 86722367, compound

Temperature

0 °C

A solution of (3R,4aR,12bS)-9-(4-fluorophenyl)-3-hydroxy-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazole-12b-carbonitrile; compound with (3S,4aS,12bR)-9-(4-fluorophenyl)-3-hydroxy-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazole-12b-carbonitrile (32, R1=4-Fluorophenyl, R3=Trifluoromethyl) (3.0 g, 6.77 mmol) in THF (60 mL) was cooled to about 0° C. under nitrogen. LiHMDS (1M solution in hexane, 8.12 mL, 8.12 mmol) was added dropwise, maintaining the reaction temperature below about 3° C. and the anion was stirred for an additional 10 min at 0° C. Triethylchlorosilane (1.72 mL, 10.2 mmol) was added and the reaction was stirred at about 0° C. for 6 h. The reaction was quenched by addition of sat. aq. NH4Cl (50 mL), and extracted with EtOAc (100 mL). The organic layer was dried over Na2SO4 and filtered. The filterate was treated with silica gel (10 g) and concentrated to dryness. The residue was purified on silica gel (120 g) using a gradient of 5-20% EtOAc in heptane. Product fractions were combined and concentrated to about 50 mL volume. Product was filtered off, rinsed with heptane (10 mL) and dried under reduced pressure to yield (3S,4aS,12bR)-9-(4-fluorophenyl)-3-((triethylsilyl)oxy)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazole-12b-carbonitrile; compound with (3R,4aR,12bS)-9-(4-fluorophenyl)-3-((triethylsilyl)oxy)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazole-12b-carbonitrile (39, R1=4-Fluorophenyl, R3=Trifluoromethyl) as a white solid (2.88 g, 76%); LC/MS, method 4, Rt=2.47 min, MS m/z 558 (M+H)+, 1H NMR (400 MHz, DMSO) δ 8.32 (d, J=0.8 Hz, 1H), 8.09 (s, 1H), 7.83-7.77 (m, 2H), 7.67 (s, 1H), 7.45-7.38 (m, 2H), 3.37-3.25 (m, 1H), 2.12-3.00 (m, 1H), 2.62-2.52 (m, 2H), 2.47-2.38 (m, 1H), 2.27-2.16 (m, 1H), 2.07-1.92 (m, 3H), 1.86-1.54 (m, 3H), 1.38-1.24 (m, 1H), 0.99-0.92 (m, 9H), 0.72-0.62 (m, 6H).

1. temperaturemaintaining the reaction temperature below about 3° C.
2. stirringthe reaction was stirred at about 0° C. for 6 h
3. customThe reaction was quenched by addition of sat. aq. NH4Cl (50 mL)
4. extractionextracted with EtOAc (100 mL)
5. dry with materialThe organic layer was dried over Na2SO4
6. filtrationfiltered
7. additionThe filterate was treated with silica gel (10 g)
8. concentrationconcentrated to dryness
9. customThe residue was purified on silica gel (120 g)
10. concentrationconcentrated to about 50 mL volume
11. filtrationProduct was filtered off
12. washrinsed with heptane (10 mL)
13. customdried under reduced pressure

ORD record

ord-8f28cc4eb6ce495eab450ab56ba9991a

Source dataset

uspto-grants-2015_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09193744B2