Methyl vinyl ketone → Rac-9-(4-fluorophenyl)-3-oxo-1,2,3,5,6,7,9,12b-octahydrobenzo[6,7]cyclohepta[1,2-f]indazole-12b-carbonitrile

HRID 718772Notes

Reaction equation

HRID 718772 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]4[C:21]([C:22]#[N:23])=[C:20](O)[CH2:19][CH2:18][CH2:17][C:14]=4[CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:25][C:26](=[O:29])[CH:27]=[CH2:28]>CCO.CC1C=CC(S(O)(=O)=O)=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[CH:15]=[C:14]4[CH2:17][CH2:18][CH2:19][C:20]5[C:21]([C:22]#[N:23])([CH2:28][CH2:27][C:26](=[O:29])[CH:25]=5)[C:13]4=[CH:12][C:11]=3[CH:10]=[N:9]2)=[CH:6][CH:7]=1

Participants

5

Reactant 2

HCID 6570Methyl vinyl ketoneHCID 867223551-(4-Fluorophenyl)-6-hydroxy-1,7,8,9-tetrahydrocyclohepta[f]indazole-5-carbonitrile

Product 1

HCID 86722360Rac-9-(4-fluorophenyl)-3-oxo-1,2,3,5,6,7,9,12b-octahydrobenzo[6,7]cyclohepta[1,2-f]indazole-12b-carbonitrileYield 80.2%

Reagents, catalysts & solvents 2

HCID 6101p-Toluenesulfonic acidCatalystHCID 702EthanolSolvent

Procedure

A solution of 1-(4-fluorophenyl)-6-hydroxy-1,7,8,9-tetrahydrocyclohepta[f]indazole-5-carbonitrile (29, R1=4-Fluorophenyl) (30.0 g, 94 mmol) in EtOH (640 mL) was treated with TEA (3.93 mL, 28.2 mmol) and but-3-en-2-one (15.5 mL, 188 mmol) and the mixture was stirred mechanically at rt for about 18 h. The volume of the reaction was reduced to about 300 mL under reduced pressure and the intermediate was filtered off and washed with heptane (50 mL). The solid intermediate is taken up in toluene (1500 mL), treated with pTSA (0.894 g, 4.70 mmol) and heated at reflux with a Dean-Stark trap for about 5 h, then stirred at about 90° C. for about 16 h. The reaction was cooled to rt, washed with sat. aq. NaHCO3 (300 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield rac-9-(4-fluorophenyl)-3-oxo-1,2,3,5,6,7,9,12b-octahydrobenzo[6,7]cyclohepta[1,2-f]indazole-12b-carbonitrile (30, R1=4-Fluorophenyl) (28.0 g, 72%) as a tan foam. LC/MS, method 3, Rt=2.42 min, 1H NMR (400 MHz, DMSO) δ 8.45 (d, J=0.9 Hz, 1H), 8.20 (s, 1H), 7.84-7.78 (m, 2H), 7.69 (s, 1H), 7.48-7.39 (m, 2H), 6.18 (s, 1H), 3.01-2.59 (m, 6H), 2.46-2.37 (m, 1H), 2.24-2.12 (m, 1H), 2.02-1.87 (m, 2H).

Workup

  1. filtrationthe intermediate was filtered off
  2. washwashed with heptane (50 mL)
  3. temperatureheated
  4. temperatureat reflux with a Dean-Stark trap for about 5 h
  5. stirringstirred at about 90° C. for about 16 h
  6. temperatureThe reaction was cooled to rt
  7. washwashed with sat. aq. NaHCO3 (300 mL)
  8. dry with materialdried over Na2SO4
  9. filtrationfiltered
  10. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-fe1bd7fc699540c692835dd86f79dd70
Source dataset
uspto-grants-2015_11
Patent number
US09193744B2

Reaction notes

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