Sodium hydride → rac-(2'R,4aS,12bR)-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'-oxirane]

HRID 718834Notes

Reaction equation

HRID 718834 reaction equation
[H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH2:9]([C@:11]12[CH2:35][CH2:34][C:33](=[O:36])[CH2:32][C@H:12]1[CH2:13][CH2:14][O:15][C:16]1[C:17]2=[CH:18][C:19]2[CH:20]=[N:21][N:22]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([CH3:31])[CH:26]=3)[C:23]=2[CH:24]=1)[CH3:10]>CS(C)=O.C1COCC1>[CH2:9]([C:11]12[CH2:35][CH2:34][C:33]3([CH2:4][O:36]3)[CH2:32][CH:12]1[CH2:13][CH2:14][O:15][C:16]1[C:17]2=[CH:18][C:19]2[CH:20]=[N:21][N:22]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([CH3:31])[CH:26]=3)[C:23]=2[CH:24]=1)[CH3:10]

Participants

6

Reactant 3

HCID 24758Sodium hydrideHCID 74498Sulfoxonium, trimethyl-, iodide (1:1)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)-one

Product 1

HCID 86722441rac-(2'R,4aS,12bR)-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'-oxirane]Yield 82.1%

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
60 °C

Procedure

A 100 mL round-bottom flask equipped with rubber septum and nitrogen inlet needle was charged with sodium hydride (60 wt % in oil, 0.212 g, 5.29 mmol) in DMSO (13 mL) and then the mixture was heated at about 60° C. in a heating block for about 30 min. The mixture was allowed to cool to rt, at which point trimethylsulfoxonium iodide (1.16 g, 5.29 mmol) was added in one portion and the reaction mixture was stirred for about 15 min. A solution of rac-(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) (0.993 g, 2.64 mmol) in THF (13 mL) was added in one portion. After about 30 min the reaction was concentrated under reduced pressure and the residue was partitioned between EtOAc (50 mL) and water (50 mL). The layers were separated and the aqueous phase was extracted with EtOAc (2×10 mL). The combined organic phases were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was purified on silica gel (40 g, EtOAc). Collection and concentration of the appropriate fractions gave rac-(2′R,4aS,12bR)-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′-oxirane] (93, R1=2-methylpyridin-4-yl, R2=Ethyl) (0.844 g, 82%). LC/MS, method 3, Rt=2.40 min, MS m/z 390 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.61-8.55 (m, 1H), 8.23 (s, 1H), 7.91-7.76 (m, 2H), 7.69 (s, 1H), 7.56 (s, 1H), 4.43-4.31 (m, 1H), 3.84-3.71 (m, 1H), 2.98-2.70 (m, 3H), 2.71-2.56 (m 2H), 2.56-2.16 (m, 4H), 2.07-1.93 (m, 1H), 1.93-1.77 (m, 1H), 1.73-1.33 (m, 4H), 0.97-0.83 (m, 1H), 0.74-0.56 (t, J=7.5 Hz, 3H).

Workup

  1. customA 100 mL round-bottom flask equipped with rubber septum and nitrogen inlet needle
  2. additionwas added in one portion
  3. concentrationAfter about 30 min the reaction was concentrated under reduced pressure
  4. customthe residue was partitioned between EtOAc (50 mL) and water (50 mL)
  5. customThe layers were separated
  6. extractionthe aqueous phase was extracted with EtOAc (2×10 mL)
  7. washThe combined organic phases were washed with brine (50 mL)
  8. dry with materialdried over Na2SO4
  9. filtrationfiltered
  10. concentrationconcentrated under reduced pressure
  11. customThe material was purified on silica gel (40 g, EtOAc)
  12. customCollection and concentration of the appropriate fractions

Sources & evidence

ORD record
ord-0d92038e1aa5420ba3f762c567f73669
Source dataset
uspto-grants-2015_11
Patent number
US09193744B2

Reaction notes

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