Benzyl Bromide → (4r,7s)-1-Benzyl-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one

HRID 1438009Notes

Reaction equation

HRID 1438009 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@H:15]3[C:19]([CH3:21])([CH3:20])[C@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.C(O)C>[CH2:23]([N:10]1[C:11]2[C@:12]3([CH3:22])[C:19]([CH3:21])([CH3:20])[C@@H:15]([CH2:14][CH2:13]3)[C:16]=2[C:17](=[O:18])[N:9]1[C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1

Participants

6

Reactant 2

HCID 7498Benzyl BromideHCID 57941350(4r,7s)-2-(2,4-Difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one2×

Product 1

HCID 16116871(4r,7s)-1-Benzyl-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-oneYield 80%

Reagents, catalysts & solvents 3

HCID 67553Tetrabutylammonium IodideCatalystHCID 702EthanolSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
50 °C

Procedure

A solution of (4R,7S)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 42; 213 mg, 0.7 mmol), tetrabutylammonium iodide (271 mg, 0.7 mmol) and benzyl bromide (0.45 mL, 3.7 mmol) in dimethylformamide (1.4 mL) was heated at 100° C. in a sealed tube for 24 h and then left at room temperature for a further 24 h. The solvent was evaporated and ethyl acetate was added. The solution was washed with 10% aqueous sodium thiosulfate and brine, dried (sodium sulfate), filtered, evaporated, and purified using an Analogix Intelliflash 280 system (Analogix, Inc. Burlington, Wis.) with a RS-12G silica gel column, eluting with 10-100% ethyl acetate/hexanes, to give a light brown foam. This was dissolved in ethanol and the solution was treated with activated carbon (15 mg) and heated at 50° C. for 1 h. The mixture was filtered through Celite and the Celite was washed with ethanol. The combined filtrates were evaporated and the resulting foam was dried under high vacuum to give (4R,7S)-1-benzyl-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (220 mg, 80%) as an off-white solid. ES(+)-MS (M+H) 395.

Workup

  1. customThe solvent was evaporated
  2. additionethyl acetate was added
  3. washThe solution was washed with 10% aqueous sodium thiosulfate and brine
  4. dry with materialdried (sodium sulfate)
  5. filtrationfiltered
  6. customevaporated
  7. custompurified
  8. washeluting with 10-100% ethyl acetate/hexanes
  9. customto give a light brown foam
  10. additionthe solution was treated with activated carbon (15 mg)
  11. filtrationThe mixture was filtered through Celite
  12. washthe Celite was washed with ethanol
  13. customThe combined filtrates were evaporated
  14. customthe resulting foam was dried under high vacuum

Sources & evidence

ORD record
ord-485ef22d2858448ea0ef678cf9e5f14a
Source dataset
uspto-grants-2009_11
Patent number
US07622492B2

Reaction notes

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