p-Toluenesulfonic acid → (4aR,12bS)-12b-ethyl-9-(2-methylpyridin-4-yl)-4,4a,5,6,9,12b-hexahydro-1H-benzo[4,5]oxepino[3,2-f]indazol-3(2H)-one

HRID 718833Notes

Reaction equation

HRID 718833 reaction equation
[CH2:1]([C:3]12[CH2:31][CH2:30][C:25]3(OCC[O:26]3)[CH2:24][CH:4]1[CH2:5][CH2:6][O: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][N:20]=[C:19]([CH3:23])[CH:18]=3)[C:15]=2[CH:16]=1)[CH3:2].CC1C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH2:1]([C@:3]12[CH2:31][CH2:30][C:25](=[O:26])[CH2:24][C@H:4]1[CH2:5][CH2:6][O: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][N:20]=[C:19]([CH3:23])[CH:18]=3)[C:15]=2[CH:16]=1)[CH3:2]

Participants

4

Reactant 2

HCID 6101p-Toluenesulfonic acidHCID 86722438rac-(4aR,12bS)-12b-ethyl-9-(2-methylpyridin-4-yl)-1,2,4,4a,5,6,9,12b-octahydrospiro[benzo[4,5]oxepino[3,2-f]indazole-3,2'-[1,3]dioxolane]

Product 1

HCID 86722440(4aR,12bS)-12b-ethyl-9-(2-methylpyridin-4-yl)-4,4a,5,6,9,12b-hexahydro-1H-benzo[4,5]oxepino[3,2-f]indazol-3(2H)-oneYield 101%

Reagents, catalysts & solvents 1

HCID 180AcetoneSolvent2×

Procedure

A 100 mL round-bottom flask equipped with air cooled reflux condenser and nitrogen inlet adapter was charged with rac-(4aR,12bS)-12b-ethyl-9-(2-methylpyridin-4-yl)-1,2,4,4a,5,6,9,12b-octahydrospiro[benzo[4,5]oxepino[3,2-f]indazole-3,2′-[1,3]dioxolane] (91, R1=2-methylpyridin-4-yl, R2=Ethyl) (1.11 g, 2.65 mmol) and pTSA (0.654 g, 3.44 mmol) in acetone (26.5 mL) and the reaction mixture was heated at about reflux in a heating block for about 16 h, after which additional acetone (26.5 mL) was added and heating continued for 1 h. The reaction mixture was allowed to cool and then was quenched by careful addition of sat. aq. NaHCO3 (25 mL). The mixture was concentrated under reduced pressure and the remainder was partitioned against EtOAc (50 mL). After separating the layers, the aqueous phase was extracted with EtOAc (2×25 mL). The combined organic phases were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give (4aR,12bS)-12b-ethyl-9-(2-methylpyridin-4-yl)-4,4a,5,6,9,12b-hexahydro-1H-benzo[4,5]oxepino[3,2-f]indazol-3(2H)-one (92, R1=2-methylpyridin-4-yl, R2=Ethyl) (1.00 g, 2.66 mmol, 101% yield), which was used without further purification. LC/MS, method 3, Rt=2.13 min, MS m/z 376 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.60 (d, J=5.9 Hz, 1H), 8.25 (s, 1H), 7.95-7.75 (m, 2H), 7.72 (s, 1H), 7.61 (s, 1H), 4.45-4.36 (m, 1H), 3.88-3.71 (m, 1H), 2.93-2.54 (m, 6H), 2.51-2.29 (m, 3H), 2.23-2.06 (m, 1H), 1.96-1.83 (m, 1H), 1.72-1.42 (m, 2H), 0.68 (s, 1H), (t, J=7.5 Hz, 3H).

Workup

  1. customA 100 mL round-bottom flask equipped with air
  2. temperaturecooled
  3. temperaturereflux condenser and nitrogen inlet adapter
  4. temperaturethe reaction mixture was heated at
  5. temperatureabout reflux in a heating block for about 16 h
  6. temperatureheating
  7. temperatureto cool
  8. customwas quenched by careful addition of sat. aq. NaHCO3 (25 mL)
  9. concentrationThe mixture was concentrated under reduced pressure
  10. customthe remainder was partitioned against EtOAc (50 mL)
  11. customAfter separating the layers
  12. extractionthe aqueous phase was extracted with EtOAc (2×25 mL)
  13. washThe combined organic phases were washed with brine (100 mL)
  14. dry with materialdried over Na2SO4
  15. filtrationfiltered
  16. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-4f0d6d9be14e488da9feab2360c63491
Source dataset
uspto-grants-2015_11
Patent number
US09193744B2

Reaction notes

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