Azobisisobutyronitrile → HCID 86722388, compound

HRID 718790Notes

Reaction equation

HRID 718790 reaction equation
[CH2:1]([C@:3]12[CH2:27][CH2:26][C@@:25]([C:29]([F:32])([F:31])[F:30])([OH:28])[CH2:24][C@H:4]1[CH2:5][CH2:6][CH2:7][C:8]1[C:9]2=[CH:10][C:11]2[CH:12]=[N:13][N:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:15]=2[CH:16]=1)[CH3:2].C1C(=O)N(Br)C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[CH2:1]([C@:3]12[CH2:27][CH2:26][C@@:25]([C:29]([F:32])([F:31])[F:30])([OH:28])[CH2:24][C@H:4]1[CH2:5][CH:6]=[CH:7][C:8]1[C:9]2=[CH:10][C:11]2[CH:12]=[N:13][N:14]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[C:15]=2[CH:16]=1)[CH3:2]

Participants

6

Reactant 3

HCID 6547AzobisisobutyronitrileHCID 67184N-bromobutanimideHCID 74221111HCID 74221111, compound

Product 1

HCID 86722388HCID 86722388, compoundYield 16%

Reagents, catalysts & solvents 2

HCID 5943Carbon TetrachlorideSolventHCID 6344DichloromethaneSolvent

Procedure

(3R,4aR,12bS)-12b-Ethyl-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3-ol (15, R1=4-Fluorophenyl, R2=Ethyl, R3=Trifluoromethyl) (0.030 g, 0.067 mmol), NBS (0.013 g, 0.074 mmol), and AIBN (0.0011 g, 0.0067 mmol) were dissolved in CCl4 (1 mL) and then mixed at reflux for about 2 h. The reaction was diluted with DCM (10 mL) and then washed with water (2×3 mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified on silica gel (4 g) using a gradient of 0-30% EtOAc in heptane. Product fractions were combined and concentrated under reduced pressure to dryness. The residue was purified on silica gel (12 g) using a gradient of 0-20% EtOAc in heptane. Product fractions were combined and concentrated under reduced pressure to dryness. The residue was further purified by reverse phase HPLC (Atlantis Prep T3 OBD (Waters), 5 μm particle size 19×100 mm) using a gradient of 10-95% MeCN in aq. NH4OAc (50 mM). The fractions containing product were combined and concentrated under reduced pressure to remove the organic volatiles. The resulting mixture was frozen then lyophilized to give (3R,4aR,12bS)-12b-ethyl-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,2,3,4,4a,5,9,12b-octahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3-ol (47, R1=4-Fluorophenyl, R2=Ethyl, R3=Trifluoromethyl) (0.0050 g, 16% yield); LC/MS, method 2, Rt=3.00 min.; MS m/z: 445 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.33 (s, 1H), 7.87 (s, 1H), 7.85-7.79 (m, 2H), 7.72 (s, 1H), 7.44-7.37 (m, 2H), 6.58 (dd, J=12.4, 2.5 Hz, 1H), 5.84-5.76 (m, 1H), 5.59 (s, 1H), 2.84-2.73 (m, 1H), 2.64-2.56 (m, 1H), 2.23-2.08 (m, 2H), 2.06-1.96 (m, 1H), 1.78-1.38 (m, 6H), 0.65 (t, J=7.3 Hz, 3H).

Workup

  1. additionmixed
  2. temperatureat reflux for about 2 h
  3. washwashed with water (2×3 mL)
  4. dry with materialThe organic layer was dried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure
  7. customThe residue was purified on silica gel (4 g)
  8. concentrationconcentrated under reduced pressure to dryness
  9. customThe residue was purified on silica gel (12 g)
  10. concentrationconcentrated under reduced pressure to dryness
  11. customThe residue was further purified by reverse phase HPLC (Atlantis Prep T3 OBD (Waters), 5 μm particle size 19×100 mm)
  12. additionThe fractions containing product
  13. concentrationconcentrated under reduced pressure
  14. customto remove the organic volatiles
  15. temperatureThe resulting mixture was frozen

Sources & evidence

ORD record
ord-759eef5c2cb6495480e5722da94199ce
Source dataset
uspto-grants-2015_11
Patent number
US09193744B2

Reaction notes

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