Tetrahydrofuran → HCID 86722460, compound

HRID 718846Notes

Reaction equation

HRID 718846 reaction equation
[Li]CCCC.Br[C:7]1[C:15]2[N:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[N:13]=[CH:12][C:11]=2[CH:10]=[C:9]2[C:23]3([CH2:37][CH3:38])[CH2:31][CH2:30][C:29]([C:33]([F:36])([F:35])[F:34])([OH:32])[CH2:28][CH:24]3[CH2:25][CH2:26][O:27][C:8]=12.C1COCC1>CO>[CH2:37]([C@:23]12[CH2:31][CH2:30][C@:29]([C:33]([F:35])([F:36])[F:34])([OH:32])[CH2:28][C@@H:24]1[CH2:25][CH2:26][O:27][C:8]1[C:9]2=[CH:10][C:11]2[CH:12]=[N:13][N:14]([C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[C:15]=2[CH:7]=1)[CH3:38].[CH2:37]([C@@:23]12[CH2:31][CH2:30][C@@:29]([C:33]([F:35])([F:36])[F:34])([OH:32])[CH2:28][C@H:24]1[CH2:25][CH2:26][O:27][C:8]1[C:9]2=[CH:10][C:11]2[CH:12]=[N:13][N:14]([C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[C:15]=2[CH:7]=1)[CH3:38]

Participants

5

Reactant 3

HCID 8028TetrahydrofuranHCID 86722461HCID 86722461, compound2×HCID 178418339Butyllithium2×

Product 1

HCID 86722460HCID 86722460, compound

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

n-BuLi (1.6 M solution in hexanes, 0.900 mL, 1.440 mmol) was added dropwise to a solution of 3R,4aR,12bR)-8-bromo-12b-ethyl-9-(4-fluorophenyl)-3-(trifluoromethyl)-2,3,4,4a,5,6,9,12b-octahydro-1H-benzo[4,5]oxepino[3,2-f]indazol-3-ol; compound with 3S,4aS,12bS)-8-bromo-12b-ethyl-9-(4-fluorophenyl)-3-(trifluoromethyl)-2,3,4,4a,5,6,9,12b-octahydro-1H-benzo[4,5]oxepino[3,2-f]indazol-3-ol (108, R1=4-Fluorophenyl, R2=Ethyl, R3=Trifluoromethyl) (0.364 g, 0.690 mmol) and THF (10.0 mL) under a nitrogen atmosphere at about −78° C. After about 45 min, n-BuLi (1.6 M solution in hexanes, 0.100 mL, 0.160 mmol) was added dropwise over about 2 min. After about 30 min, MeOH (0.4 mL) was added dropwise. The cold bath was removed. Sat. aq. NH4Cl (20 mL), water (5 mL) and EtOAc (20 mL) were added. The layers were separated and the organics were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified on silica gel (40 g) using a gradient of 0-2% EtOAc in DCM. The fractions containing the product were combined and concentrated under reduced pressure to afford (3R,4aR,12bR)-12b-ethyl-9-(4-fluorophenyl)-3-(trifluoromethyl)-2,3,4,4a,5,6,9,12b-octahydro-1H-benzo[4,5]oxepino[3,2-f]indazol-3-ol; compound with (3S,4aS,12bS)-12b-ethyl-9-(4-fluorophenyl)-3-(trifluoromethyl)-2,3,4,4a,5,6,9,12b-octahydro-1H-benzo[4,5]oxepino[3,2-f]indazol-3-ol (109, R1=4-Fluorophenyl, R2=Ethyl, R3=Trifluoromethyl) (0.273 g, 88% yield) of an ivory solid. LC/MS, method 2, Rt=2.77 min, MS m/z 449 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.27 (d, J=1.0 Hz, 1H), 7.82-7.74 (m, 3H), 7.44-7.36 (m, 2H), 7.31 (d, J=0.9 Hz, 1H), 5.91 (s, 1H), 4.45-4.34 (m, 1H), 3.60-3.47 (m, 1H), 2.40-2.25 (m, 1H), 2.23-1.49 (m, 10H), 0.38 (t, J=7.4 Hz, 3H).

Workup

  1. customat about −78° C
  2. waitAfter about 30 min
  3. customThe cold bath was removed
  4. additionSat. aq. NH4Cl (20 mL), water (5 mL) and EtOAc (20 mL) were added
  5. customThe layers were separated
  6. dry with materialthe organics were dried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated under reduced pressure
  9. customThe residue was purified on silica gel (40 g)
  10. additionThe fractions containing the product
  11. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-f24c6abcd9234dbd9e2ecb9b66934ce0
Source dataset
uspto-grants-2015_11
Patent number
US09193744B2

Reaction notes

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